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This report is based on research conducted by the Oregon Evidence-based Practice Center (EPC) under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (Contract No. 290-02-0024). The findings and conclusions in this document are those of the authors, who are responsible for its contents; the findings and conclusions do not necessarily represent the views of AHRQ. Therefore, no statement in this article should be construed as an official position of the Agency for Healthcare Research and Quality or of the U.S. Department of Health and Human Services. This report is intended as a reference and not as a substitute for clinical judgment. Anyone who makes decisions concerning the provision of clinical care should consider this report in the same way as any medical reference and in conjunction with all other pertinent information. This report may be used, in whole or in part, as the basis for development of clinical practice guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied. Comparative Effectiveness Review Number 4 Comparative Effectiveness and Safety of Analgesics for Osteoarthritis Comparative Effectiveness Review Number 4 Comparative Effectiveness and Safety of Analgesics for Osteoarthritis Prepared for: Agency for Healthcare Research and Quality U.S. Department of Health and Human Services 540 Gaither Road Rockville, MD 20850 www.ahrq.gov Contract No. 290-02-0024 Prepared by: Oregon Evidence-based Practice Center Investigators Roger Chou, M.D. Mark Helfand, M.D. Kim Peterson, M.S. Tracy Dana, M.L.S. Carol Roberts, B.S. AHRQ Publication No. 06-EHC009-EF September 2006 This document is in the public domain and may be used and reprinted without permission except those copyrighted materials noted for which further reproduction is prohibited without the specific permission of copyright holders. None of the investigators has any affiliations or financial involvement that conflicts with the material presented in this report. Suggested citation: Chou R, Helfand M, Peterson K, Dana T, Roberts C. Comparative Effectiveness and Safety of Analgesics for Osteoarthritis. Comparative Effectiveness Review No. 4. (Prepared by the Oregon Evidence-based Practice Center under Contract No. 290-02-0024.) Rockville, MD: Agency for Healthcare Research and Quality. September 2006. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm. ii Preface The Agency for Healthcare Research and Quality (AHRQ) conducts the Effective Health Care Program as part of its mission to organize knowledge and make it available to inform decisions about health care. As part of the Medicare Prescription Drug, Improvement, and Modernization Act of 2003, Congress directed AHRQ to conduct and support research on the comparative outcomes, clinical effectiveness, and appropriateness of pharmaceuticals, devices, and health care services to meet the needs of Medicare, Medicaid, and the State Children's Health Insurance Program (SCHIP). AHRQ has an established network of Evidence-based Practice Centers (EPCs) that produce Evidence Reports/Technology Assessments to assist public- and private-sector organizations in their efforts to improve the quality of health care. The EPCs now lend their expertise to the Effective Health Care Program by conducting Comparative Effectiveness Reviews of medications, devices, and other relevant interventions, including strategies for how these items and services can best be organized, managed, and delivered. Systematic reviews are the building blocks underlying evidence-based practice; they focus attention on the strength and limits of evidence from research studies about the effectiveness and safety of a clinical intervention. In the context of developing recommendations for practice, systematic reviews are useful because they define the strengths and limits of the evidence, clarifying whether assertions about the value of the intervention are based on strong evidence from clinical studies. For more information about systematic reviews, see www.effectivehealthcare.ahrq.gov/reference/purpose.cfm. AHRQ expects that Comparative Effectiveness Reviews will be helpful to health plans, providers, purchasers, government programs, and the health care system as a whole. In addition, AHRQ is committed to presenting information in different formats so that consumers who make decisions about their own and their family's health can benefit from the evidence. Transparency and stakeholder input are essential to the Effective Health Care Program. Please visit the Web site (www.effectivehealthcare.ahrq.gov) to see draft research questions and reports or to join an e-mail list to learn about new program products and opportunities for input. Comparative Effectiveness Reviews will be updated regularly. iii Acknowledgments We would like to acknowledge with appreciation the members of the Technical Expert Panel for their advice and consultation. In addition, we would also like to acknowledge Eric Johnson, Ph.D., for reviewing this manuscript. Technical Expert Panel Vibeke Strand, M.D. Adjunct Clinical Professor Division of Immunology, Stanford University Portola Valley, CA Expertise: Rheumatology Kenneth Saag, M.D., M.Sc. UAB Center for Education and Research on Therapeutics (CERTs) of Musculoskeletal Disorders Birmingham, AL Expertise: Rheumatology Leslie J. Crofford, M.D. UK Hospital, University of Kentucky Lexington, KY Expertise: Rheumatology Michel Boucher, B.Pharm., M.Sc. Canadian Coordinating Office for Health Technology Assessment Ottawa, Ontario Expertise: Pharmacology Lara Maxwell Coordinator, Cochrane Musculoskeletal Group Institute of Population Health University of Ottawa Ottawa, Ontario Expertise: Rheumatology AHRQ Contacts Beth A. Collins Sharp, Ph.D., R.N. Carmen Kelly, Pharm.D., R.Ph. Director Task Order Officer Evidence-based Practice Center Program Evidence-based Practice Center Program Center for Outcomes and Evidence Center for Outcomes and Evidence Agency for Healthcare Research and Quality Agency for Healthcare Research and Quality Rockville, MD Rockville, MD iv Contents Executive Summary ................................................................................................................... 1 Chapter 1. Introduction ............................................................................................................17 Scope and Key Questions .............................................................................................................19 Chapter 2. Methods ....................................................................................................................23 Topic Development.......................................................................................................................23 Search Strategy .............................................................................................................................23 Study Selection .............................................................................................................................23 Data Extraction .............................................................................................................................24 Quality Assessment.......................................................................................................................24 Assessing Research Quality.............................................................................................24 Assessing Research Applicability....................................................................................24 Rating a Body of Evidence ..............................................................................................25 Data Synthesis...............................................................................................................................25 Effectiveness Versus Efficacy .........................................................................................25 Data Presentation .............................................................................................................25 Chapter 3. Results .....................................................................................................................27 Overview.......................................................................................................................................27 Key Question 1a. What are the Comparative Benefits and Harms of Treating Osteoarthritis with Oral Medications or Supplements? ...................................................27 Benefits: Effectiveness and Efficacy ...............................................................................27 Safety: Serious Gastrointestinal and Cardiovascular Events ...........................................30 Other Adverse Events Associated with Selective and Non-Selective NSAIDs ..............61 Key Question 1b. How Do these Benefits and Harms Change with Dosage and Duration of Treatment, and What is the Evidence that Alternative Dosage Strategies, such as Intermittent Dosing and Drug Holidays, Affect the Benefits and Harms of Oral Medication Use? .................................................................73 Key Question 2. Do the Comparative Benefits and Harms of Oral Treatments for Osteoarthritis Vary for Certain Demographic and Clinical Subgroups? .........................75 Demographic Subgroups Include Age, Sex, and Race ....................................................75 Co-Existing Diseases Include History of Previous Bleeding Ulcer due to NSAIDs; Hypertension, Edema, Ischemic Heart Disease, and Heart Failure .................76 Concomitant Anticoagulant or Aspirin Use.....................................................................77 Key Question 3. What Are the Comparative Effects of Co-Prescribing of H2-Antagonists, Misoprostol, or Proton Pump Inhibitors (PPIs) on the Gastrointestinal Harms Associated with NSAID Use?....................................................80 Key Question 4. What Are the Comparative Benefits and Harms of Treating Osteoarthritis with Oral Medications as Compared with Topical Preparations?....................................................................................................................81 Topical NSAIDs – Efficacy .............................................................................................81 Topical NSAIDs – Safety ................................................................................................84 Topical Salicylates (Including Capsaicin) .......................................................................85 v Chapter 4. Summary and Discussion.............................................................................................87 Discussion .....................................................................................................................................92 Chapter 5. Future Research ...........................................................................................................97 Addendum .....................................................................................................................................99 References ......................................................................................................................................101 Tables Table 1. One year risk of GI bleeding due to NSAID ...................................................................18 Table 2. Comparison of rofecoxib and celecoxib in flare-ups of chronic osteoarthritis of the knee........................................................................................................................29 Table 3. Head to head efficacy comparisons at 6 weeks (mean change from baseline)................30 Table 4. Re-analysis of the CLASS and VIGOR Trials ................................................................35 Table 5. CV events in trials of rofecoxib versus non-selective NSAIDs: meta-analyses...................................................................................................................39 Table 6. CV events in trials of rofecoxib versus placebo: meta-analyses ....................................41 Table 7. CV events in trials of celecoxib: meta-analysis of 15 trials in patients with arthritis .............................................................................................................................42 Table 8. CV events in trials of celecoxib: meta-analysis of 41 trials ...........................................42 Table 9. MI's in trials of celecoxib: meta-analysis of 31 trials in patients with arthritis .............................................................................................................................43 Table 10. MI's in trials of celecoxib: meta-analysis of trials of at least 6 weeks duration with published or publicly available data ........................................................................44 Table 11. CV events in trials of celecoxib: meta-analysis of 41 trials of at least 4 weeks duration ............................................................................................................................44 Table 12. Serious GI events in observational studies ......................................................................46 Table 13. Cardiovascular events in observational studies ...............................................................48 Table 14. Baseline rates of MI, upper GI bleed, and congestive heart failure (CHF) and risk associated with selective and non-selective NSAIDs in an Ontario cohort of elderly persons..................................................................................................51 Table 15. Effects of selective or non-selective NSAIDs on number of serious adverse events ...............................................................................................................................51 Table 16. Myocardial infarction in trials of valdecoxib for chronic pain: meta-analysis of 19 trials ........................................................................................................................52 Table 17. Cardiovascular events in trials of valdecoxib versus placebo: meta-analysis of 14 trials .......................................................................................................................53 Table 18. Relative Risk (95% CI) of UGIB for NSAIDs vs. non-use .............................................57 Table 19. Rate Ratios (95% CI): COX 2 inhibitor relative to NSAID ............................................58 Table 20. Risk of myocardial infarction associated with naproxen in recent observational studies not included in the Juni meta-analysis ..........................................59 Table 21. Risk of myocardial infarction associated with non-selective, non-naproxen NSAIDs............................................................................................................................60 vi Table 22. Toxicity Index Scores from ARAMIS database studies..................................................66 Table 23. Tolerability profile of COX-2's vs. NSAIDs in meta-analysis and systematic reviews ...........................................................................................................67 Table 24. Pain relief in systematic reviews of acetaminophen versus NSAID ...............................68 Table 25. Adverse events in systematic reviews of acetaminophen versus NSAID .......................69 Table 26. Incidence of hypertension in the Nurses' Health Study and Physicians' Health Study according to use of acetaminophen or NSAIDs.........................................71 Table 27. Response rates in the Glucosamine/chondroitin Arthritis Intervention Trial (GAIT) .............................................................................................................................73 Table 28. Celecoxib in patients with bleeding ulcer history............................................................76 Table 29. Placebo-controlled trials of gastroprotective agents........................................................80 Table 30. Head-to-head trials of gastroprotective agents ................................................................81 Table 31. Head-to-head trials of topical versus oral NSAID for osteoarthritis ...............................82 Table 32. Clinical success rates in recent placebo-controlled trials of topical NSAIDs .................83 Table 33. Adverse events from a trial comparing topical to oral diclofenac...................................85 Table 34. Summary of findings with strength of evidence..............................................................87 Figures Figure 1. Clinical success in trials comparing a topical versus an oral NSAID ...............................83 Figure 2. Withdrawal due to adverse events in trials comparing a topical to an oral NSAID .............................................................................................................................84 Appendixes Appendix A. Pharmacokinetics, Indications and Dosing of Included Drugs ...................................118 Appendix B. Cycloxygenase Selectivity of NSAIDs .......................................................................123 Appendix C. Comparable NSAID Dose Levels ...............................................................................124 Appendix D. Exact Search Strings....................................................................................................125 Appendix E. Quality Assessment Methods ......................................................................................130 Appendix F. Evidence Tables ...........................................................................................................133 vii Executive Summary Background Osteoarthritis is a chronic condition involving degeneration of cartilage within the joints. It is the most common form of arthritis and is associated with pain, substantial disability, and reduced quality of life. About 6 percent of U.S. adults aged 30 years or older have symptomatic osteoarthritis of the knee, and 3 percent have symptomatic osteoarthritis of the hip. Osteoarthritis increases with age: the incidence and prevalence increase two- to tenfold from age 30 to 65 and continue to increase after age 65. The total costs for arthritis, including osteoarthritis, may be greater than 2 percent of the gross domestic product, with more than half of these costs related to work loss. Common oral medications for osteoarthritis include nonsteroidal antiinflammatory drugs (NSAIDs) and acetaminophen. Patients with osteoarthritis also use over-the-counter supplements not regulated by the U.S. Food and Drug Administration (FDA) as pharmaceuticals, including glucosamine and chondroitin, as well as topical agents. Opioid medications are also used for selected patients with refractory, chronic pain but are not recommended for first-line treatment of osteoarthritis and therefore not included in this review. Each class of medication or supplement is associated with a unique balance of risks and benefits. In addition, efficacy and safety may vary for individual drugs within a class. Nonpharmacologic interventions (such as physical therapy, weight reduction, and exercise) also help improve pain and functional status in patients with osteoarthritis. A challenge in treating osteoarthritis is deciding which medications will provide the greatest symptom relief with the fewest serious adverse effects. NSAIDs decrease pain, inflammation, and fever by blocking cyclo-oxygenase (COX) enzymes. Understanding of the pharmacology of NSAIDs continues to evolve, but it is now thought that most NSAIDs block three different COX isoenzymes, known as COX-1, COX-2, and COX-3. COX-1 protects the lining of the stomach from acid. COX-2 is found in joint and muscle, and mediates effects on pain and inflammation. By blocking COX-2, NSAIDs reduce pain compared to placebo in patients with arthritis, low back pain, minor injuries, and soft tissue rheumatism. However, NSAIDs that also block the COX-1 enzyme (also called "nonselective NSAIDs") can cause gastrointestinal bleeding. In the United States, there are an estimated 16,500 annual deaths due to NSAID-induced gastrointestinal complications, a higher death rate than that for cervical cancer or malignant melanoma. Theoretically, NSAIDs that block only the COX-2 enzyme (also called "coxibs," "COX-2 selective NSAIDs," or "selective NSAIDs") should be safer with regard to gastrointestinal bleeding, but they also appear to be associated with increased rates of serious cardiovascular and other adverse effects. Less is known about COX-3, which is found in the cerebral cortex and cardiac tissue and appears to be involved in centrally mediated pain. For this report, we defined the terms "selective NSAIDs" or "COX-2 selective NSAIDs" as drugs in the "coxib" class (celecoxib, rofecoxib, valdecoxib, etoricoxib, lumiracoxib). We defined "partially selective NSAIDs" as other drugs shown to have partial in vitro COX-2 selectivity (etodolac, nabumetone, meloxicam). Aspirin differs from other NSAIDs because it irreversibly inhibits platelet aggregation, and the salicylic acid derivatives (aspirin and salsalate) 1 were considered a separate subgroup. We defined "nonaspirin, nonselective NSAIDs" or simply "nonselective NSAIDs" as "all other NSAIDs." This report summarizes the available evidence comparing the benefits and harms of analgesics in the treatment of osteoarthritis. Oral agents include: • Aspirin • Ketorolac • Aacetaminophen • Lumiracoxib1 • Celecoxib • Meclofenamate sodium • Choline magnesium trisalicylate • Mefenamic acid • Chondroitin • Meloxicam • Diclofenac • Nabumetone • Diflunisal • Naproxen • Etodolac • Oxaprozin • Etoricoxib1 • Piroxicam • Fenoprofen • Rofecoxib1 • Flurbiprofen • Salsalate • Glucosamine • Sulindac • Ibuprofen • Tenoxicam1 • Indomethacin • Tiaprofenic acid1 • Ketoprofen • Tolmetin • Ketoprofen ER • Valdecoxib1 1 These drugs are currently not approved by the FDA for use in the United States (etoricoxib, lumiracoxib, tenoxicam, tiaprofenic acid) or have been withdrawn from the market (rofecoxib and valdecoxib). Questions addressed in this report are: 1. What are the comparative benefits and harms of treating osteoarthritis with oral medications or supplements? How do these benefits and harms change with dosage and duration of treatment, and what is the evidence that alternative dosage strategies, such as intermittent dosing and drug holidays, affect the benefits and harms of oral medication use? (Note: The only benefits considered under this question are improvements in osteoarthritis symptoms from long-term use. Evidence of harms associated with NSAID use include long-term studies of these drugs for treating osteoarthritis or rheumatoid arthritis and for cancer prevention. 2. Do the comparative benefits and harms of oral treatments for osteoarthritis vary for certain demographic and clinical subgroups of patients? ● Demographic subgroups include age, sex, and race. ● Coexisting diseases include hypertension, edema, ischemic heart disease, heart failure; peptic ulcer disease; history of previous bleeding due to NSAIDs. 2 ● Concomitant medication use includes anticoagulants. 3. What are the comparative effects of coprescribing of H2-antagonists, misoprostol, or proton pump inhibitors (PPIs) on the gastrointestinal harms associated with NSAID use? 4. What are the comparative benefits and harms of treating osteoarthritis with oral medications as compared with topical preparations? Topical preparations include: capsaicin, diclofenac, ibuprofen, ketoprofen, and salicylate. A summary of the findings is shown in Table A. Conclusions Oral NSAIDs Benefits: improvements in osteoarthritis symptoms • Nonselective NSAID vs. another nonselective NSAID Many trials found no clear differences between various nonaspirin, nonselective NSAIDs or partially selective NSAIDs (meloxicam, nabumetone, etodolac) in efficacy for pain relief or improvement in function. In one short-term trial, salsalate and aspirin did not differ significantly in efficacy for pain relief or symptom improvement. No studies evaluated the comparative efficacy of salsalate or aspirin vs. a nonaspirin NSAID. • COX-2 selective (NSAID) vs. nonselective NSAID COX-2 selective NSAIDs and nonselective NSAIDs did not clearly differ in efficacy for pain relief, based on many good-quality, published trials. • COX-2 selective NSAID vs. different COX-2 selective NSAID Celecoxib and rofecoxib did not differ significantly in efficacy for pain relief at commonly used and comparable doses, based on consistent evidence from six good-quality trials. No studies compared efficacy of COX-2s other than celecoxib and rofecoxib. Harms: gastrointestinal (GI) and cardiovascular (CV) • Rofecoxib vs. nonselective NSAID 3 In the only large, long-term trial (VIGOR), rofecoxib 50 mg daily caused fewer serious ulcer complications than naproxen 1,000 mg daily in patients with rheumatoid arthritis but also significantly increased the risk of myocardial infarction. The overall rate of serious adverse events was higher with rofecoxib than with naproxen. • There were about 16 fewer symptomatic ulcers, including 5.2 fewer serious GI complications, for every 1,000 patients treated with rofecoxib vs. naproxen after a median of 9 months of treatment. • There were 3.0 additional myocardial infarctions for every 1,000 patients treated with rofecoxib compared to naproxen in VIGOR. Rofecoxib was associated with an increased risk of myocardial infarction relative to placebo in the most comprehensive systematic review of randomized controlled trials (RCTs). • About 3.5 additional myocardial infarctions occurred for every 1,000 patients treated for 1 year with rofecoxib compared to placebo in the systematic review. Rofecoxib was withdrawn from the market in September 2004, primarily because of CV risks. • Celecoxib vs. nonselective NSAID or placebo It is not clear whether celecoxib has fewer potential harms than nonselective NSAIDs when used longer than 3-6 months. In the only large, published trial (CLASS), celecoxib at 800 mg daily did not decrease predefined serious ulcer complications overall compared with diclofenac and ibuprofen; the risk of serious GI events was lower than with ibuprofen, but not diclofenac, at 6 months in patients who did not use aspirin; and there was no reduction in serious GI events at the end of followup. The overall rate of serious adverse events with celecoxib was similar to the rate with ibuprofen and diclofenac. In fair-quality meta-analyses of arthritis trials, most of which evaluated short- term use, celecoxib caused fewer ulcer complications than nonselective NSAIDs and did not increase the risk of myocardial infarction. Celecoxib 400 mg twice daily was associated with an increased risk of serious CV events (CV death or myocardial infarction) relative to placebo in a long-term trial of polyp prevention. Celecoxib was associated with an increased risk of myocardial infarction relative to placebo in the most comprehensive systematic review of RCTs. Most of the 4 CV events with celecoxib were reported in two large polyp-prevention trials evaluating 200 mg or 400 mg twice daily, or 800 mg once daily. • About 3.5 additional myocardial infarctions occurred for every 1,000 patients treated for 1 year with celecoxib compared to placebo. • Valdecoxib vs. nonselective NSAID or placebo Valdecoxib was associated with a lower risk of upper GI complications compared with diclofenac, ibuprofen, or naproxen in two fair-quality meta-analyses of published and unpublished trials. There have been too few events reported in RCTs of patients with chronic conditions to accurately assess CV risk associated with valdecoxib. Two short-term trials in a high-risk post-coronary-artery-surgery setting found that valdecoxib was associated with a two- to threefold higher risk of CV events compared with placebo. Valdecoxib was withdrawn from the market due to life-threatening skin reactions and increased CV risk. • Etoricoxib vs. nonselective NSAID Etoricoxib was associated with fewer GI adverse events (perforations, symptomatic ulcers, and bleeds) than nonselective NSAIDs in a fair-quality meta-analysis of 10 trials. In primarily short-term trials, systematic reviews of RCTs suggest that etoricoxib has a similar CV safety profile compared to other NSAIDs, with the possible exception of naproxen. Definitive conclusions are not possible because of small numbers of CV events. • Lumiracoxib vs. nonselective NSAID Results from one large trial (TARGET) found fewer adverse GI events with lumiracoxib than with naproxen and ibuprofen. There was no statistically significant difference in rates of serious CV events between lumiracoxib relative to naproxen or ibuprofen in TARGET. Too few events have been reported in RCTs to accurately assess CV risk associated with lumiracoxib. • Partially selective NSAID vs. nonselective NSAID 5 Meloxicam: There were no significant differences in risks of serious GI events in several meta-analyses of up to 28 primarily short-term clinical trials, and no difference in CV risk in three observational studies. Nabumetone or etodolac: There was insufficient evidence to make reliable judgments about relative GI safety and no evidence on CV safety. • Nonselective NSAID vs. nonselective NSAID or any COX-2 selective NSAID No clear difference in GI safety was found among nonselective NSAIDs at commonly used doses. The CV safety of naproxen was moderately superior to that of any COX-2 selective NSAID in a large systematic review of RCTs. • There were 3.3 additional myocardial infarctions for every 1,000 patients treated with any COX-2 inhibitor instead of naproxen for 1 year. The CV safety of nonselective NSAIDs other than naproxen (data primarily on ibuprofen and diclofenac) was similar to that of COX-2 selective NSAIDs in a large systematic review. In indirect analyses, naproxen was the only nonselective NSAID associated with neutral CV risk relative to placebo. • Aspirin Aspirin is associated with a lower risk of thromboembolic events and a higher risk of GI bleeds compared to placebo or nonuse when given in long-term prophylactic doses. There is insufficient evidence to assess the balance of GI and CV safety of higher dose aspirin as used for pain relief compared with nonaspirin NSAIDs. • Salsalate Salsalate was associated with a lower risk of adverse events than other selective and nonselective NSAIDs using broad composite endpoints in older, poor-quality observational studies. In a more recent observational study, salsalate had a similar rate of complications compared with other NSAIDS. Almost no data are available on CV safety. Harms: mortality Individual trials were not large enough to detect differences in mortality between the 6 included drugs. One meta-analysis of celecoxib found no difference between celecoxib and nonselective NSAIDs, but there were few events. In one fair-quality cohort study, nabumetone was associated with a lower risk of all- cause mortality compared with diclofenac and naproxen, but this finding has not been replicated. Harms: hypertension, congestive heart failure (CHF), edema, and impaired renal function All NSAIDs and COX-2 inhibitors can cause or aggravate these conditions. There is good evidence from short-term trials that, on average, nonselective NSAIDs raise mean blood pressure by about 5.0 mm Hg (95-percent confidence interval [CI] 1.2 to 8.7). However, similar average blood pressure changes may not necessarily correspond with similar likelihoods of an event requiring withdrawal, medication change, or other clinical consequences. Evidence from good-quality observational studies suggests that rofecoxib is associated with greater risks of hypertension, CHF, and edema than celecoxib. Indirect evidence from various meta-analyses of either rofecoxib or celecoxib vs. nonselective NSAIDs are consistent with these findings. Direct randomized trial evidence, however, is limited in quantity and difficult to interpret because of possible non-equivalent dosing of drugs. Evidence regarding the comparative risk of renal dysfunction for celecoxib and rofecoxib is sparse. There was weak evidence that aspirin and sulindac have less hypertensive effect than other nonselective NSAIDs. There were no clear differences among other selective or nonselective NSAIDs for these adverse events. Harms: hepatotoxicity Clinically significant hepatotoxicity was rare. Among currently marketed NSAIDs, only diclofenac was associated with a significantly higher rate of liver-related discontinuations compared with placebo (1 additional case for every 53 patients treated with diclofenac). Tolerability Relative to nonselective NSAIDs, COX-2 selective and partially selective NSAIDs were better or similarly tolerated and aspirin was less well tolerated. There were no clear differences in tolerability among COX-2 selective or 7 nonselective NSAIDs. Uncertainty remains regarding the comparative tolerability of salsalate and nonselective NSAIDs. Available evidence is somewhat sparse and mixed, with two of three short-term trials suggesting salsalate is less well tolerated than nonselective NSAIDs and older, flawed observational studies suggesting that salsalate is less toxic than nonselective NSAIDs. Other oral agents: benefits and harms • Acetaminophen Acetaminophen was modestly inferior to NSAIDs for pain and function in four systematic reviews. • Pain severity ratings averaged less than 10 points higher for acetaminophen compared to NSAIDs on 100-point visual analog scales. Compared with NSAIDs, acetaminophen had fewer GI side effects (clinical trials data) and serious GI complications (observational studies). Acetaminophen may be associated with modest increases in blood pressure and renal dysfunction (observational studies). One good-quality, prospective observational study found an increased risk of CV events with heavy use of acetaminophen that was similar to the risk associated with heavy use of NSAIDs. Acetaminophen at therapeutic doses does not appear to be associated with an increased risk of hepatotoxicity compared to nonuse in patients without underlying liver disease. • Glucosamine and chondroitin In one large, good-quality trial the combination of pharmaceutical-grade glucosamine hydrochloride plus chondroitin (not currently available in the United States) was not superior to placebo among all patients studied. Neither glucosamine nor chondroitin alone was superior to placebo. In an analysis of a small subgroup of patients with at least moderate baseline pain, there was a modest benefit for pain relief from the combination, but this did not appear to be a preplanned analysis. Systematic reviews of older trials found glucosamine modestly superior to oral NSAIDs and placebo in most trials, but there was some inconsistency between trials, most trials had some flaws, and results may not be directly applicable to the United States because the positive trials primarily evaluated pharmaceutical-grade glucosamine available in Europe. 8 Only 2 of 20 placebo-controlled trials assessed effects of glucosamine on radiologic disease progression. One fair- and one good-quality trial found pharmaceutical-grade glucosamine superior to placebo for progression of knee joint space narrowing over 3 years. Glucosamine and chondroitin were generally well tolerated and no serious adverse events were reported in clinical trials. Effect of dosage and duration of treatment on the benefits and harms of oral medication use • We found no studies evaluating the GI or CV safety of alternative dosing strategies (such as alternate day dosing, once daily versus twice daily dosing, or periodic drug holidays). • The risk of GI bleeding increases with higher doses of nonselective NSAIDs. • The most comprehensive systematic review of RCTs found no clear association between duration of exposure and CV risk of COX-2 inhibitors. However, estimates of CV risk with shorter duration of exposure are imprecise due to low numbers of events. • The most comprehensive systematic review of RCTs found higher doses of celecoxib associated with increased CV risk, but could not determine the effects of dose on CV risk associated with rofecoxib due to low numbers of events at lower doses. Most trials of nonselective NSAIDs involved high doses. Differences in demographic and clinical subgroups • GI and CV complication rates are higher among older patients and those with predisposing comorbid conditions, but there is no evidence that the relative safety of different NSAIDs varies according to baseline risk. o Compared to nonuse of NSAIDs, one additional death per 1 year of use occurred for every 13 patients treated with rofecoxib, 14 with celecoxib, 45 with ibuprofen, and 24 with diclofenac in one large, population-based observational study of high- risk patients with acute myocardial infarction. • There is no evidence that the comparative safety or efficacy of specific selective or nonselective NSAIDs varies depending on age, gender, or racial group, although data are sparse. • Among patients who had a recent episode of upper GI bleeding, there is good evidence that rates of recurrent ulcer bleeding are high (around 5 percent after 6 months) in patients prescribed celecoxib or a nonselective NSAID plus a PPI. 9 Concomitant anticoagulant use • Concomitant use of anticoagulants (e.g., warfarin) and any nonselective NSAID increases the risk of GI bleeding three- to sixfold compared to anticoagulants alone. • Reliable conclusions about the safety of selective NSAIDs used with anticoagulants are not possible due to flaws in existing observational studies, although there are case reports of serious bleeding events, primarily in the elderly. Concomitant aspirin use • In the CLASS studies, there was no difference in rates of ulcer complications between celecoxib and nonselective NSAIDs in the subgroup of patients who took aspirin. • Concomitant low-dose aspirin use increased the rate of endoscopic ulcers by about 6 percent in both patients on celecoxib and those on nonselective NSAIDs in one meta- analysis. • Rofecoxib plus low-dose aspirin or ibuprofen alone were associated with similar risks of endoscopic ulcers (16-17 percent), which were significantly higher than those for placebo (6 percent) or aspirin alone (7 percent). • The most comprehensive systematic review of RCTs found that compared to nonuse of aspirin, concomitant aspirin use did not ameliorate the increased risk of vascular events associated with COX-2 selective NSAIDs. Effects of coprescribing H2-antagonists, misoprostol, or PPIs • Consistent evidence from good-quality systematic reviews and numerous clinical trials found coprescribing of PPIs to be associated with the lowest rates of endoscopically detected duodenal ulcers relative to gastroprotective agents. • Coprescribing of misoprostol is associated with similar rates of endoscopically detected gastric ulcers as coprescribing of PPIs. • While misoprostol offers the advantage of being the only gastroprotective agent to reduce rates of perforation, obstruction, or bleeding, there is a high rate of withdrawals due to adverse GI symptoms. • The risk of endoscopic duodenal ulcers for standard-dose H2 blockers was lower than placebo, similar to misoprostol, and higher than omeprazole. Standard dosages of H2 blockers were associated with no reduction of risk for gastric ulcers relative to placebo. • Double (full) dose H2 blockers were associated with a lower risk of endoscopic gastric and duodenal ulcers relative to placebo. It is unknown how full-dose H2 blockers compare to other antiulcer medications because head-to-head trials are lacking. 10 Comparison of oral medications with topical preparations • Topical NSAIDs: efficacy Studies of topical NSAIDs typically evaluated proprietary formulations not approved by the FDA. Topical NSAIDs were similar to oral NSAIDs for pain relief in trials primarily of patients with osteoarthritis of the knee, with topical diclofenac (often with dimethyl sulphoxide [DMSO], a drug not approved for use in humans in the United States) best studied. Topical ibuprofen was superior to placebo in several trials. • Topical NSAIDs: safety Consistent evidence from good-quality trials, systematic reviews, and observational studies found topical NSAIDs to be associated with increased local adverse events compared with oral NSAIDs. Total adverse events and withdrawal due to adverse events were similar. Data from one good-quality trial found topical NSAIDs superior to oral NSAIDs for GI events, including severe events, and changes in hemoglobin. • Topical salicylates and capsaicin Topical salicylates were no better than placebo in higher quality placebo- controlled trials. Compared to placebo, one additional patient achieved pain relief for every eight that used topical capsaicin in a good-quality meta-analysis, but capsaicin was associated with increased local adverse events and withdrawals due to adverse events. Balance of evidence and harms Each of the analgesics evaluated in this report was associated with a unique set of benefits and risks. Each was also associated with gaps in the evidence necessary to determine the true balance of benefits vs. harms. The role of selective and nonselective oral NSAIDs and alternative agents will continue to evolve as additional information emerges. At this time, although the amount and quality of evidence vary, no currently available analgesic reviewed in this report was identified as offering a clear overall advantage compared with the others. This is not surprising, given the complex tradeoffs between the many benefits (pain relief, improved function, 11 improved tolerability, and others) and harms (CV, renal, GI, and others) involved. Individuals are likely to differ in how they prioritize the importance of the various benefits and harms of treatment. Adequate pain relief at the expense of an increase in CV risk, for example, could be an acceptable tradeoff for some patients. Others may consider even a marginal increase in CV risk unacceptable. Factors that should be considered when weighing the potential effects of an analgesic include age (older age being associated with increased risks for bleeding and CV events), comorbid conditions, and concomitant medication use (such as aspirin and anticoagulation medications). As in other medical decisions, choosing the optimal analgesic for an individual with osteoarthritis should always involve careful consideration and thorough discussion of the relevant tradeoffs. Remaining Issues • The CV safety of nonselective NSAIDs has not been well studied in large, long-term clinical trials. Naproxen, in particular, may be associated with fewer CV risks than other NSAIDs and should be investigated in long-term, appropriately powered trials. • Large observational studies assessing the safety of NSAIDs have been helpful for assessing comparative benefits and harms but have generally had a narrow focus on single adverse events. Observational studies that take a broader view of all serious adverse events would be substantially more helpful for assessing the overall tradeoffs between benefits and harms. • The CV risks and GI benefits associated with different COX-2 selective NSAIDs may vary. Large, long-term trials with active and placebo-controlled arms would be needed to assess the safety and benefits of any new COX-2 selective analgesic. • Meta-analyses of the risks associated with selective COX-2 inhibitors need to continue to assess the effects of dose and duration as more data become available; current estimates of risks at lower doses and with shorter duration of exposure are less precise than estimates at higher doses and longer duration of exposure because of small numbers of events. • Large, long-term trials of the GI and CV safety associated with full-dose aspirin, salsalate, or acetaminophen compared with nonaspirin NSAIDs or placebo are lacking. Recent observational data suggesting an increased CV risk with heavy use of acetaminophen highlight the need for long-term, appropriately powered clinical trials. • Given the large number of patients who meet criteria for aspirin prophylaxis for CV events, more trials evaluating the dose-related effects of aspirin 50-1500 mg on GI benefits and CV safety are needed. • The effects of alternative dosing strategies such as intermittent dosing or drug holidays have not been assessed. Studies evaluating the benefits and risks associated with such strategies compared with conventional dosing could help clarify the effects of these alternative dosing strategies. In addition, although there is speculation that once daily versus twice daily dosing 12 of certain COX-2 inhibitors could reduce CV risk, this hypothesis has not yet been tested in a clinical trial. • Most trials showing therapeutic benefits from glucosamine were conducted using pharmaceutical-grade glucosamine not available in the United States and may not be applicable to currently available over-the-counter preparations. Large trials comparing currently available over-the-counter preparations of glucosamine and chondroitin with oral NSAIDs are needed, as these are likely to remain available even if the FDA approves pharmaceutical-grade formulations. • No topical NSAIDs are FDA approved in the United States, yet compounding of NSAIDs is widely available. Although recent trials of topical NSAIDs are promising, most have been conducted using a proprietary formulation of diclofenac with DMSO, which is not approved in the United States for use in humans. Cohort studies using large observational databases may be required to adequately assess CV risk. As this report was going to press, two relevant meta-analyses on risks associated with NSAIDs were published. We were unable to fully incorporate these studies into this report, but found their results generally consistent with our conclusions: A fair-quality meta-analysis of arrhythmia and renal event (peripheral edema, hypertension, or renal dysfunction) risk from 114 randomized trials of COX-2 selective NSAIDs found rofecoxib associated with increased risks of arrhythmia (primarily ventricular fibrillation, cardiac arrest, or sudden cardiac death) and renal dysfunction (peripheral edema, hypertension, or renal dysfunction) relative to control treatments (placebo, other NSAIDs, or mixed/other) . The increased risk was equivalent to approximately 1.1 additional arrhythmia events per 1,000 patients treated with rofecoxib. Celecoxib was associated with lower risks of renal dysfunction and hypertension than control treatments, although there was no difference for the pre-specified, primary composite renal outcome of peripheral edema, hypertension, renal dysfunction or arrhythmia. There was no clear association between other COX-2 inhibitors (valdecoxib/parecoxib, etoricoxib, or lumiracoxib) and either arrhythmia or renal events (no arrhythmia events reported with lumiracoxib). A good-quality meta-analysis of cardiovascular risk (primarily myocardial infarction) from 23 observational studies was largely consistent with our qualitative assessment of the observational literature. It found rofecoxib associated with a dose-dependent, increased risk of cardiovascular events that was detectable during the first month of treatment. Of the other NSAIDs, diclofenac was associated with the highest risk, followed by indomethacin and meloxicam. Celecoxib, naproxen, piroxicam, and ibuprofen were not associated with increased risks. Assessments of increased risk were modest (relative risks all <2.0), and all of the main analyses were associated with substantial between-study heterogeneity. 13 Table A. Summary of Findings on Comparative Effectiveness and Safety of Analgesics for Osteoarthritis, with Strength of Evidence Treatment Benefits: symptom relief Harms: gastrointestinal, cardiovascular, and other Special considerations in subgroups COX-2 selective Good evidence COX-2-selective GI: Fair to good evidence of fewer serious GI events with COX-2 Good evidence that risk of GI bleeding NSAIDs NSAIDs are comparable in efficacy selective NSAIDs compared to nonselective NSAIDs, at least in the and CV events increases with age. (pain relief) to nonselective NSAIDs. first 6 months of treatment. Good evidence that risk of GI bleeding is Good evidence COX-2 selective CV: Comparative data on CV risks of COX-2 selective vs. greater in patients with prior bleeding NSAIDs are comparable in efficacy to nonselective and partially selective NSAIDs are sparse, with a few episodes. each other. exceptions (see below). Fair evidence that COX-2 selective NSAIDs Fair evidence that risks of CV and renal are associated with increased risks of serious CV events (primarily events are higher in patients with cardiac myocardial infarction) compared to placebo. CV risks may increase and renal comorbidities. with greater dosages and durations of treatment, but estimates of risks at lower doses and with shorter durations of treatment are imprecise due to small numbers of events. o Rofecoxib was withdrawn from the market in September 2004, primarily because of CV risks. o Cautions about CV risk apply primarily to rofecoxib and celecoxib, as CV safety data are less precise (due to small numbers of events) for valdecoxib, etoricoxib, and lumiracoxib. Other o Valdecoxib was withdrawn from the market due to life- threatening skin reactions and increased CV risk. o Fair evidence suggests that rofecoxib is associated with greater risk of hypertension, CHF, edema, and cardiorenal events than celecoxib. NSAIDs : Good evidence nonselective and GI : Good evidence that all nonselective NSAIDs are associated with Good evidence that risk of GI bleeding nonselective partially selective NSAIDs are comparable, dose-dependent increases in risk of serious GI events and CV events increases with age. (including naproxen), comparable in efficacy to each other. compared to nonuse. Good evidence that coprescription of Good evidence that risk of GI bleeding is partially selective misoprostol or PPIs can attenuate this risk, but misoprostol is less well greater in patients with prior bleeding tolerated. episodes. o No clear evidence (fair for meloxicam and poor for etodolac and Fair evidence that risks of CV and renal nabumetone) that partially selective NSAIDs are associated with events are higher in patients with cardiac decreased risk relative to nonselective NSAIDs. and renal comorbidities. CV : Data on CV risks of nonselective and partially selective NSAIDs Fair evidence that using NSAIDs are sparse, with a few exceptions: concomitantly with anticoagulants o Fair evidence that high doses of ibuprofen and diclofenac carry increases GI bleeding risk three- to similar risks of serious CV events compared to COX-2 selective sixfold. NSAIDs. o Fair evidence that naproxen is associated with a lower risk of CV events than COX-2 selective NSAIDs and no excess risk compared to placebo. Other: Fair evidence that diclofenac is associated with higher rates of aminotransferase elevations than other NSAIDs. 14 Treatment Benefits: symptom relief Harms: gastrointestinal, cardiovascular, and other Special considerations in subgroups Aspirin/ No evidence comparing efficacy of Good evidence that aspirin 50-1500 mg (for thrombotic event Good evidence that concomitant use of salsalate aspirin or salsalate to COX-2s or prophylaxis) is associated with greater risks of serious GI events aspirin attenuates or eliminates the GI NSAIDs. compared to placebo or when added to warfarin. benefits of COX-2 selective NSAIDs. Good evidence that low-dose aspirin is effective for preventing CV Fair evidence that concomitant use of events. low-dose aspirin does not eliminate CV Insufficient evidence to assess GI and CV risks associated with higher risks when added to NSAIDs . doses of aspirin for pain control or with salsalate. Acetaminophen Good evidence that acetaminophen is Good evidence of lower risk of GI complications with acetaminophen None modestly inferior in efficacy compared compared to NSAIDs. to NSAIDs. Fair evidence of increased risk of blood pressure and renal dysfunction with acetaminophen compared to nonuse. Poor evidence (a single observational study) that heavy use of acetaminophen carries a similar CV risk compared to heavy use of NSAIDs. Glucosamine Fair evidence (some inconsistency Good evidence that glucosamine and chondroitin are well tolerated and None (pharmaceutical between clinical trials) that do not appear to be associated with serious adverse events. grade)/ pharmaceutical-grade glucosamine chondroitin and chondroitin are not more effective than placebo in unselected patients, including one recent, large, good- quality trial finding no beneficial effects from glucosamine or chondroitin alone or in combination. In an analysis of a small subgroup of patients with at least moderate baseline pain in the latter trial, there appeared to be a modest benefit for pain relief from the combination, but this did not appear to be a preplanned analysis. Fair evidence of no clear difference in efficacy between pharmaceutical- grade glucosamine or chondroitin and NSAIDs. No studies compared glucosamine or chondroitin to acetaminophen. 15 Treatment Benefits: symptom relief Harms: gastrointestinal, cardiovascular, and other Special considerations in subgroups Topical NSAIDs Good evidence they are comparable to Good evidence that topical NSAIDs are associated with increased None oral NSAIDs for pain relief in trials local adverse events compared with oral NSAIDs. primarily of patients with knee Good evidence that topical and oral NSAIDs are comparable in rates osteoarthritis. of total adverse events and withdrawals due to adverse events. o Most trials of topical NSAIDs Good evidence that topical NSAIDs are associated with fewer GI evaluate proprietary formulations not events, including severe events, and changes in hemoglobin compared available in the United States. to oral NSAIDs. Topical salicylates Fair evidence that capsaicin, but not Good evidence that topical capsaicin is associated with increased local None and capsaicin topical salicylates are superior for pain adverse events and withdrawals due to adverse events compared to relief compared to placebo. placebo. Abbreviations: CHF = congestive heart failure; COX = cyclo-oxygenase; CV = cardiovascular; GI = gastrointestinal; NSAID=nonsteroidal antiinflammatory drug; PPI=proton pump inhibitor. 16 Chapter 1. Introduction Osteoarthritis, the most common form of arthritis, is associated with substantial disability and reduced quality of life.2 Among U.S. adults aged 30 or older, approximately 6% have symptomatic osteoarthritis of the knee, and 3% have symptomatic osteoarthritis of the hip.3 Osteoarthritis increases with age, with the incidence and prevalence increasing 2- to 10-fold from age 30 to 65, and continues to increase after age 65.4 Osteoarthritis accounts for more disability in walking, stair climbing, and other tasks requiring use of the lower extremities than any other disease, particularly in the elderly.5 The total costs for arthritis, including osteoarthritis, may be greater than 2% of the gross domestic product,3 with more than half of these costs related to work loss.5 In addition to non-pharmacologic interventions (such as physical therapy, weight reduction, and exercise), numerous medications and over-the-counter supplements are available to treat pain and potentially improve functional status in patients with osteoarthritis. Each class of medication or supplement is associated with a unique balance of risks and benefits. In addition, efficacy and safety may also vary for individual drugs within a class. Oral medications commonly used to treat osteoarthritis include nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen (Appendix A). Many are available at lower over-the-counter and higher prescription doses. Commonly used supplements sold over-the-counter and not regulated as pharmaceuticals by the FDA include glucosamine and chondroitin. Topical agents frequently used by patients with osteoarthritis are rubefacients (including capsaicin), NSAIDs, and other miscellaneous preparations.6 Opioid medications are also used for patients with chronic pain, especially if it is refractory to other therapies, but are not recommended for first-line treatment for osteoarthritis or other conditions because of risks of addiction, tolerance, diversion, and other adverse events.7, 8 NSAIDs exert analgesic, anti-inflammatory, and anti-pyretic effects by blocking cyclo- oxygenases (COX), enzymes that are needed to produce prostaglandins. Understanding of the pharmacology of NSAIDs continues to evolve, but it is now thought that most NSAIDs block three different COX isoenzymes, known as COX-1, COX-2, and COX-3. COX-2, found in joint and muscle, contributes to pain and inflammation. Because they block COX-2, non-steroidal anti-inflammatory drugs reduce pain compared to placebo in patients with arthritis,9 low back pain,10 minor injuries, and soft tissue rheumatism. Less is known about COX-3, which has been found in the cerebral cortex and cardiac tissue and appears to have effects on centrally-mediated pain.1 NSAIDs are also associated with important adverse effects. NSAIDs cause gastrointestinal (GI) bleeding because they also block the COX-1 enzyme, which protects the lining of the stomach from acid. In the 1990s in the United States, nonaspirin NSAIDs are estimated cause 32,000 hospitalizations and 3,200 deaths annually from GI bleeding.11 A risk analysis12 based on a retrospective case-control survey of emergency admissions for upper GI disease in two United Kingdom general hospitals provided useful estimates of the frequency of serious GI complications from NSAIDs.13 In people taking NSAIDs, the 1-year risk of serious GI bleeding ranges from 1 in 2,100 in adults under age 45 to 1 in 110 for adults over age 75, and the risk of death ranges from 1 in 12,353 to 1 in 647 (Table 1). In addition to age, prednisone use, disability level, and previous NSAID-induced GI symptoms are risk factors for GI bleeding. 17 Table 1. One year risk of GI bleeding due to NSAID Age range (years) Chance of GI bleed due to NSAID Chance of dying from GI bleed due to NSAID Risk in any one year is 1 in: 16-45 2100 12,353 45-64 646 3800 65-74 570 3353 > 75 110 647 Data are from Blower,13 recalculated in Moore12 and in Bandolier14 NSAIDs differ in their selectivity for COX-2—how much they affect COX-2 relative to COX-1. Theoretically, an NSAID that blocks COX-2 but not COX-1 might reduce pain and inflammation in joints but leave the stomach lining alone. Appendix B15 summarizes the NSAIDs and their selectivity based on assay studies (done in the laboratory instead of in living patients). The table gives an idea of how widely NSAIDs vary in their selectivity, but should be interpreted with caution. Different assay methods give different results, and assay method may not reliably predict what will happen when the drug is given to patients. Clinical studies, rather than these assay studies, are the best way to determine whether patients actually benefit from using more selective NSAIDs. In addition to their propensity to cause GI bleeding, NSAIDs are also associated with adverse effects on blood pressure, renal function, and fluid retention. Mechanisms may involve attenuation of prostaglandin-mediated vasodilation, promotion of sodium and water retention, increased vascular resistance, and increased renal endothelin-1 synthesis.16-18 An association between selective COX-2 inhibitors and increased rates of myocardial infarction was first observed in the large, pivotal Vioxx Gastrointestinal Outcomes Research (VIGOR) trial comparing high-dose rofecoxib (50 mg) to naproxen 1000 mg.19 Reasons for the increase in thromboembolic cardiovascular event risk are complex and not completely understood, but may be related in part to suppression of endothelial-derived prostaglandin I2 formation by selective COX-2 inhibition, in the setting of unaffected platelet production of pro- thrombotic COX-1 mediated thromboxane A2.20 Blood pressure elevations associated with COX-2 inhibitors may also play a role in increasing cardiovascular risk.21 On September 30, 2004, rofecoxib was withdrawn from the market after a long-term polyp prevention trial found an increased risk of myocardial infarction compared with placebo.22 On December 9, 2004, the US Food and Drug Administration issued a black-box warning for valdecoxib for life-threatening skin reactions and increased cardiovascular risk. This drug was subsequently also withdrawn voluntarily by the manufacturer.23 Aspirin, or acetylsalicylic acid, has long been known to have analgesic, anti-pyretic, and anti- inflammatory effects.24 It is thought to be the most consumed medicinal drug in the world. Like the non-aspirin NSAIDs, aspirin's effects are due to blockade of cyclo-oxygenases. However, an important distinction between aspirin and non-aspirin NSAIDs is that aspirin also induces irreversible functional defects in platelets (although non-aspirin NSAIDs also have effects on platelet aggregation, they are short-lived). Because of these antiplatelet effects, low-dose aspirin is also used prophylactically to reduce the risk of thrombotic events.25 However, even at doses of 325 mg daily or lower, the potential cardiovascular benefits must be balanced against dose- dependent risk of aspirin-induced adverse GI events. Salsalate, a nonacetylated salicylate, is a prodrug of salicylic acid, the active metabolite of aspirin. However, salsalate is considered a relatively weak inhibitor of cyclo-oxygenases.26 Acetaminophen (also known as paracetamol) is an anti-pyretic and analgesic medication that 18 is not thought to have significant anti-inflammatory properties. Although its mechanism of inducing analgesia is still not completely understood, it is thought to work in part by indirectly decreasing production of prostaglandins through inhibitory effects involving COX-2.16, 27 Acetaminophen is frequently recommended as a first line agent for osteoarthritis and other pain conditions because of its perceived favorable safety profile—particularly with regard to ulcer risk.28 Chondroitin sulfate and glucosamine sulfate are natural compounds found in cartilage. Both are marketed to patients who have osteoarthritis. The precise mechanisms of action are unknown, but may involve promoting maintenance and repair of cartilage. Glucosamine, for example, has been shown to increase proteoglycan synthesis.29 In the European Union countries, glucosamine is available as a prescription drug manufactured by the Rotta Pharmaceutical Company. In the U.S., by contrast, glucosamine and chondroitin are considered dietary supplements and are not regulated as pharmaceuticals. Adequate standardization of glucosamine and chondroitin preparations is a significant concern. It has been shown that the actual content often varies substantially from what is stated on the label.30 Such inconsistencies may have implications on estimates of efficacy and safety for different commercial preparations. Topical administration of NSAIDs could theoretically result in local analgesic and anti- inflammatory effects by direct absorption through the skin, with reduced systemic adverse events compared with oral administration.31 Experimental studies indicate that topical administration is associated with substantially higher concentrations of NSAIDs in soft tissue (particularly meniscus and cartilage) and lower peak plasma concentrations compared with oral administration.6 For a topical NSAID to be effective, it has to reach the inflamed tissue in sufficient concentrations to produce analgesic and anti-inflammatory activity. The solubility of specific NSAIDs varies considerably, and is also affected by the carrier or formulation used.31 Superior in vivo permeability characteristics, however, may not predict clinical effectiveness. In contrast to topical NSAIDs, whose mechanism of action involves inhibition of cyclo- oxygenase, topical rubefacients are thought to relieve pain through counter irritation.6, 32 Although the mechanism of action of topical preparations containing salicylate esters is unclear, they are now usually classified as rubefacients rather than topical NSAIDs because they may not work via inhibition of cyclo-oxygenase.6, 33 Capsaicin, which is also often classified as a rubefacient, is derived from the hot chili pepper (Capsicum species). It is applied topically and thought to work by stimulating the release of substance P and other neuropeptides from sensory nerve endings.34 Although this release can initially lead to burning and pain, analgesia occurs after repeated and continued application, as substance P becomes depleted. Although a wide variety of other rubefacients are available, only topical salicylates and capsaicin were included in this review. The purpose of this report was to assess the comparative efficacy and safety of non-opioid oral medications (selective and non-selective non-aspirin NSAIDs, aspirin, salsalate, and acetaminophen), over-the-counter supplements (chondroitin and glucosamine), and topical agents (NSAIDs and rubefacients, including capsaicin) for osteoarthritis. Scope and Key Questions 1. What are the comparative benefits and harms of treating osteoarthritis 19 with oral medications or supplements? How do these benefits and harms change with dosage and duration of treatment, and what is the evidence that alternative dosage strategies, such as intermittent dosing and drug holidays, affect the benefits and harms of oral medication use? (Note: This question addresses the therapeutic benefits of long-term use for the condition osteoarthritis. However, the question does address all harms associated with NSAID use, including use for other labeled indications such as the treatment of rheumatoid arthritis.) Oral NSAIDs include: • aspirin • meclofenamate sodium • celecoxib • mefenamic acid • choline magnesium • meloxicam trisalicylate • diclofenac • nabumetone • diflunisal • naproxen • etodolac • oxaprozin • etoricoxib* • piroxicam • fenoprofen • rofecoxib* • flurbiprofen • salsalate • ibuprofen • sulindac • indomethacin • tenoxicam* • ketoprofen • tiaprofenic acid* • ketoprofen ER • tolmetin • ketorolac • valdecoxib* • lumiracoxib* * These drugs are currently not approved (etoricoxib, lumiracoxib, tenoxicam, tiaprofenic acid) for use in the United States by the FDA or have been withdrawn from the market (rofecoxib and valdecoxib) Other oral agents include acetaminophen, chondroitin, and glucosamine. See Appendix A for a detailed listing of pharmacokinetics, indications, and recommended dosing information for all included drugs. Appendix C shows low, medium and high doses for the more commonly used NSAIDs. For this report, we defined the terms "selective NSAID" or "COX-2 selective NSAID" as drugs in the "coxib" class (e.g. celecoxib, rofecoxib, and valdecoxib). We grouped etodolac, nabumetone, and meloxicam into a separate category that we referred to as "partially selective NSAIDs," to explore how in vitro differences in COX-2 selectivity might translate into clinical differences in safety. The salicylic acid derivatives aspirin and salsalate were also considered a separate subgroup. We defined "non-aspirin, non-selective NSAIDs" or simply "non-selective NSAIDs" as all other NSAIDs. We included evidence on the efficacy and safety of the COX-2 inhibitor rofecoxib, even though it is no longer available in the U.S., because it was the first drug to be associated with cardiovascular risks and therefore provides important historical context and illustrates important issues to consider when evaluating the risks and benefits of selective and non-selective NSAIDs. For other COX-2 inhibitors not approved by the FDA for use in the U.S. 20 (lumiracoxib and etoricoxib) or withdrawn from the market (valdecoxib), we focused only on evidence regarding long-term, serious GI and CV adverse events, which is likely to be the most important factor driving future decisions regarding their use. "Benefits" include relief of pain and osteoarthritic symptoms and improved functional status. The main outcome measures for this review were pain, functional status, and discontinuations due to lack of efficacy. Frequently used outcome measures include visual and categorical pain scales:35 Visual analogue scale (VAS): Using VAS, patients indicate their level of pain, function, or other outcome by marking a scale labeled with numbers (such as 0 to 100) or descriptions (such as "none" to "worst pain I've ever had"). An advantage of VAS is that they provide a continuous range of values for relative severity. A disadvantage is that the meaning of a pain score for any individual patient depends on the patient's subjective experience of pain. This poses a challenge in objectively comparing different patients' scores, or even different scores from the same patient. Categorical pain scales consist of several pain category options from which a patient must choose (e.g., no pain, mild, moderate, or severe). A disadvantage of categorical scales is that patients must chose among categories that may not accurately describe their pain. A variety of disease-specific and non-specific scales are used to assess these outcomes in patients with osteoarthritis. Commonly used categorical pain scales include: • The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), a 24- item, disease-specific questionnaire used to assess the functional status of patients with osteoarthritis of the knee and hip. A lower score indicates better function.36 • The Medical Outcomes Short Form-36 (SF-36) health survey, a commonly used general instrument for measuring health-related quality of life across different diseases.37 • Patient Global Assessment of Disease Status and Investigator Global Assessment of Disease Status. The patient or investigator answers questions about the overall response to treatment, functional status, and pain response, using a VAS or categorical scale. • American College of Rheumatology (ACR) criteria measure disease activity and response to treatment. ACR 20, ACR 50, or ACR 70 reflect either an improvement to the 20%, 50%, or 70% level in the parameters outlined. Another method for measuring outcomes is classifying patients dichotomously as "responders" or "non-responders." Responders are often defined as patients with at least a 50% improvement in pain or function. The Outcomes Measures in Arthritis Clinical Trials- Osteoarthritis Research Society International (OMERACT-OARSI) criteria, for example, were developed through a consensus process and classifies patients as responders if they meet specific pre-defined criteria (>=50% improvement in pain or function that was >=20 mm on a 100 mm VAS, or a >=20% improvement in at least two of pain, function, or patient global assessment that was >=10 mm on a 100 mm VAS).38 "Harms" include tolerability (not having to stop the drug due to adverse effects); cardiovascular, hepato-, renal, and gastrointestinal toxicity; and increased risk for hospitalizations, drug interactions, and death. For gastrointestinal toxicity, we focused on serious complications associated with NSAIDs including perforation, bleeding ulcer, and gastric 21 outlet obstruction, though we also evaluated other gastrointestinal side effects (such as nausea, dyspepsia, and gastrointestinal tolerability. We only considered rates of endoscopic ulcers when data on clinical ulcer complications were incomplete or not available. 2. Are there clinically important differences in the harms and benefits of oral treatments for osteoarthritis for certain demographic and clinical subgroups? • Demographic subgroups include age, sex, and race. • Co-existing diseases include hypertension, edema, ischemic heart disease, heart failure, PUD, and history of previous bleeding due to NSAIDS. • Concomitant medication use includes anticoagulants and aspirin. 3. What is the evidence that the gastrointestinal harms of NSAID use are reduced by co-prescribing of H2-antagonists, misoprostol, or proton pump inhibitors? 4. What are the benefits and safety of treating osteoarthritis with oral medications as compared with topical preparations? Topical preparations include: • Capsaicin • Diclofenac • Ibuprofen • Ketoprofen • other NSAIDs • salicylates 22 Chapter 2. Methods Topic Development The topic for this report was nominated in a public process. The key questions were developed by investigators from the Oregon EPC with input from a Technical Expert Panel (TEP) formed for this project. Contacted via teleconference, the TEP served in an advisory capacity for this report, helping to refine key questions, identify important issues, and define parameters for the review of evidence. Search Strategy A comprehensive search of the scientific literature was conducted to identify relevant studies addressing the key questions. Results from previously conducted meta-analyses and systematic reviews on these topics were sought and used where appropriate and updated when necessary. To identify systematic reviews, in addition to MEDLINE, we searched the Cochrane Database of Systematic Reviews and the websites of the Canadian Coordinating Office for Health Technology Assessment (CCOHTA), Bandolier, and the NHA Health Technology Assessment Programme. To identify articles relevant to each key question, we searched the Cochrane Database of Systematic Reviews (through 3rd Quarter 2005) the Cochrane Central Register of Controlled Trials (through 3rd Quarter 2005) and Ovid ®MEDLINE (1966- July, 2005.) We used relatively broad searches, combining terms for drug names with terms for relevant research designs, limiting to those studies that focused on osteoarthritis and rheumatoid arthritis (see Appendix D for the complete search strategy). Other sources include reference lists of review articles and unpublished materials from the US Food and Drug Administration (FDA). Pharmaceutical manufacturers were invited to submit scientific information packets, including citations if applicable. All 2,665 citations from these sources were imported into an electronic database (EndNote® 9.0) and considered for inclusion. Study Selection Systematic reviews and controlled trials pertinent to the key questions were included. We retrieved any blinded or open, parallel or crossover randomized controlled trial that compared one included drug to another, another active comparator, or placebo. We also included cohort and case-control studies with at least 1,000 cases or participants that evaluated serious gastrointestinal and cardiovascular endpoints that were inadequately addressed by randomized controlled trials. 23 Data Extraction The following data were extracted from included trials: study design, setting, population characteristics (including sex, age, ethnicity, diagnosis), eligibility and exclusion criteria, interventions (dose and duration), method of outcome ascertainment if available, and results for each outcome, focusing on efficacy and safety. We recorded intention-to-treat results if available. Quality Assessment Assessing Research Quality We assessed the internal validity (quality) of systematic reviews and randomized trials based on the predefined criteria listed in Appendix E. These criteria are based on those developed by the US Preventive Services Task Force and the National Health Service Centre for Reviews and Dissemination (UK).39 We rated the internal validity of each trial based on the methods used for randomization, allocation concealment, and blinding; the similarity of compared groups at baseline; maintenance of comparable groups; adequate reporting of dropouts, attrition, crossover, adherence, and contamination; loss to followup; and the use of intention-to-treat analysis. Trials that had a fatal flaw in one or more categories were rated poor quality; trials that met all criteria were rated good quality; the remainder were rated fair quality. As the "fair quality" category is broad, studies with this rating vary in their strengths and weaknesses: the results of some fair- quality studies are likely to be valid, while others are only probably valid. A "poor quality" trial is not valid—the results are at least as likely to reflect flaws in the study design as the true difference between the compared drugs. Included systematic reviews were also rated for quality based on pre-defined criteria (see Appendix E) assessing whether they had a clear statement of the questions(s), reported inclusion criteria, used an adequate search strategy, assessed validity, reported adequate detail of included studies, and used appropriate methods to synthesize the evidence. We included systematic reviews and meta-analyses that included unpublished data inaccessible to the public, but because the results of such analyses are not verifiable, we considered this a methodological shortcoming. For assessing the internal validity of observational studies, we evaluated whether they used nonbiased selection methods; whether rates of loss to follow-up were acceptable; whether pre- defined outcomes were specified; whether they used appropriate methods for ascertaining exposures, potential confounders, and outcomes; and whether they performed appropriate statistical analyses of potential confounders. Although many tools exist for quality assessment of nonrandomized trials, there is no consensus on optimal quality rating methods.40 We therefore did not use a formal scoring system to rate the quality of the observational studies included in this review, but noted methodological deficiencies in any of the above areas when present. Assessing Research Applicability The applicability of trials and other studies was assessed based on whether the publication 24 adequately described the study population, how similar patients were to the target population in whom the intervention will be applied, whether differences in outcomes were clinically (as well as statistically) significant, and whether the treatment received by the control group was reasonably representative of standard practice. We also recorded the funding source and role of the sponsor. Rating a Body of Evidence Overall quality ratings for an individual study were based on ratings of the internal and external validity of the trial. A particular randomized trial might receive two different ratings: one for efficacy and another for adverse events. The overall strength of evidence for a particular key question reflects the quality, consistency, and power of the set of studies relevant to the question. We assessed the overall strength of evidence for a body of literature about a particular key question, by examining the type, number and quality of studies; the strength of association; the consistency of results within and between study designs; and the possibility for publication bias. Consistent results from good-quality studies across a broad range of populations suggest a high degree of certainty that the results of the studies were true (that is, the entire body of evidence would be considered "good-quality.") For a body of fair-quality studies, however, consistent results may indicate that similar biases are operating in all the studies. Unvalidated assessment techniques or heterogeneous reporting methods for important outcomes may weaken the overall body of evidence for that particular outcome or make it difficult to accurately estimate the true magnitude of benefit or harm. Data Synthesis Effectiveness Versus Efficacy Throughout this report, we highlight effectiveness studies conducted in primary care or office-based settings that use less stringent eligibility criteria, assess health outcomes of most importance to patients, and have longer follow-up periods than most efficacy studies. The results of effectiveness studies are more applicable to the "average" patient than results from highly selected populations in efficacy studies. Examples of "effectiveness" outcomes include quality of life, global measures of successful treatment, and the ability to work or function in social activities. These outcomes are more important to patients, family, and care providers than surrogate or intermediate measures such as scores based on psychometric scales. Further discussion of these issues is available at http://effectivehealthcare.ahrq.gov/reference/purpose.cfm. Data Presentation We constructed evidence tables showing study characteristics, quality ratings, and results for all included studies. We also performed two quantitative analyses for this review. An important limitation of observational studies of NSAIDs is that none simultaneously assessed the risk for 25 serious cardiac and GI events. We therefore re-analyzed data from a set of observational studies that reported rates of three different serious adverse events in the same population. We assumed that the adverse events occurred independently and that the logarithm of the rate ratios was distributed normally. After estimating the effect (number of events prevented or caused) for each of the three adverse events, we estimated the net effects on all three serious adverse events using Monte Carlo simulation. We also pooled clinical success rates and withdrawal due to adverse events from head-to- head trials of topical versus oral NSAIDs using a random effects model (Dersimonian-Laird method, using RevMan® statistical software). We performed standard chi-square tests for heterogeneity. Because only four trials were available for pooling, we did not attempt meta- regression analyses to evaluate potential sources of heterogeneity. 26 Chapter 3. Results Overview Searches identified 2,789 publications: 1,522 from the Cochrane Central Register of Controlled Trials, 68 from the Cochrane Database of Systematic Reviews, 1015 from MEDLINE and 184 from the combination of other sources listed above. There were also 59 studies not previously reviewed for inclusion that were suggested through peer review or public comment or published after the searches were conducted. Following application of inclusion criteria, 351 publications were included in this review. Key Question 1a. What are the comparative benefits and harms of treating osteoarthritis with oral medications or supplements? Benefits: Effectiveness and Efficacy Effectiveness Studies No controlled clinical trials of COX-2 inhibitors and/or NSAIDs met all major criteria for an effectiveness study (conducted in mainly primary care or office-based settings, used broad enrollment criteria, and evaluated longer-term, "real-life" outcomes). Efficacy Non-selective NSAIDs vs. other NSAIDs. Several good-quality systematic reviews by the Cochrane Collaboration evaluated trials that compared non-aspirin NSAIDs for OA of the hip (trials published through 1994),41 for OA of the back (through 1998),10 and for OA of the knee (through 1997).42 These reviews found no clear differences among non-aspirin and primarily non-selective NSAIDs in efficacy. There were also no differences between diclofenac and sustained-release etodolac in patients with OA of the knee43 or between piroxicam and standard formulation etodolac in patients with OA of the knee or hip44 in two trials published subsequent to the Cochrane reviews. Nabumetone was similar in efficacy to the non-selective NSAIDs diclofenac SR45 and etodolac46 in two 4-week trials, as reported in the Cochrane review of OA of the knee.42 No studies of meloxicam, salsalate, or aspirin were included in any Cochrane reviews. We identified nine double-blinded trials of meloxicam 7.5 mg, 15 mg, and 25 mg versus other NSAIDs and found no clear or consistent differences in efficacy. 47-55 In two of the trials, however, patients taking non-selective NSAIDs were significantly less likely to withdraw due to 27 lack of efficacy than patients taking meloxicam. 49, 54 In the only head-to-head trial of salsalate (3 g) in patients with OA, efficacy was similar to that of 3.6 g soluble aspirin after two weeks of treatment.56 Celecoxib vs. non-selective NSAIDS. Celecoxib and non-selective NSAIDs were associated with similar decreases in symptom severity and improvements in functional capacity (PGA, WOMAC) after 6- to 24-weeks in five published trials of patients with primarily OA. 57-60 A good-quality systematic review funded by the makers of celecoxib reached similar conclusions based on data from published and unpublished trials of at least 12 weeks' duration in patients with either OA or RA.61 Using an alternative endpoint, a more recent systematic review (published in 2005) with access to all unpublished manufacturer-held clinical trial reports reached slightly different conclusions about the relative efficacy of celecoxib and NSAIDs.62 Moore et al meta-analyzed data from 31 primarily short-term (≤ 12 weeks) trials and concluded that celecoxib at dose of 200-400 mg was associated with slightly higher rates of withdrawals due to lack of efficacy compared to non-selective NSAIDs (RR 1.1; 95% CI 1.02, 1.23). CLASS remains the pivotal, long-term study (6 to 13 months) of celecoxib in patients with rheumatoid and osteoarthritis. It randomized a total of 7,968 patients to celecoxib or the non-selective NSAIDs ibuprofen or diclofenac. A higher proportion of non-selective NSAID patients withdrew due to lack of efficacy (14.8% vs. 12.6%, p=0.005). However, CLASS focused on assessment of adverse events rather than efficacy, and other efficacy results were reported. SUCCESS-1, a shorter (12- week), double-blind, randomized trial of 13,274 patients with osteoarthritis, found no clinically meaningful differences between celecoxib 100 mg or 200 mg twice daily and the non-selective NSAIDs diclofenac or naproxen.63 Rofecoxib vs. non-selective NSAIDs. We were unable to determine whether all manufacturer-sponsored trials of rofecoxib versus NSAIDs have been published.19, 64-76 All but one of the trials included osteoarthritis patients, and all but two70, 72 were supported by the manufacturer of rofecoxib. All but two of the OA trials73, 76 have been previously analyzed in a good-quality Cochrane review.77 Conclusions of the Cochrane review are consistent with our findings that there were no consistent differences between rofecoxib and non-selective NSAIDs in efficacy for OA. In addition, a pivotal, good-quality trial (VIGOR) and a good-quality Cochrane review found rofecoxib equivalent to naproxen in efficacy for rheumatoid arthritis.19, 78 Valdecoxib vs. non-selective NSAIDs. In clinical trials submitted to the FDA, valdecoxib was as effective as ibuprofen (800 mg 3 times/day), diclofenac (75 mg twice daily), and naproxen (500 mg twice daily) in treating osteoarthritis symptoms. Published trials found no difference in efficacy between valdecoxib and naproxen79-81 or ibuprofen or diclofenac.82 A fifth trial found no difference in efficacy between valdecoxib 20-40 mg and slow-release diclofenac 75 mg in treating rheumatoid arthritis.83 Comparisons between selective COX-2 inhibitors. We found six published randomized, multicenter, fair-to-good quality trials that directly compared COX-2 inhibitors for osteoarthritis of the knee.84-89 Pharmaceutical manufacturers were reported as funding sources in all but one study.88 This small (N=30), short-term (7 days), fair-quality trial found that rofecoxib 25 mg and celecoxib 200 mg had similar effects on patients' pain intensity, 3-hour pain relief, global 28 assessment of efficacy and rescue medication use.88 Two trials of higher-risk osteoarthritic patients with hypertension (both funded by the maker of celecoxib) found no differences in efficacy between rofecoxib 25 mg and celecoxib 200 mg daily, but reported a higher rate of adverse events with rofecoxib.84, 85 The remaining three trials appeared to enroll patients with similar demographics and baseline levels of pain and were more homogeneous in design (see table below).86, 87, 89 All compared rofecoxib 25 mg qd and celecoxib 200 mg qd in patients with flare-ups of chronic osteoarthritis of the knee and were 6 weeks in duration. One trial, funded by the manufacturer of celecoxib, found no difference in efficacy between rofecoxib and celecoxib, but a higher rate of adverse events with rofecoxib.86 Another (VACT, or Vioxx Acetaminophen Celecoxib Trial)87 trial, funded by the manufacturer of rofecoxib, found rofecoxib more effective than celecoxib, with no differences in rates of adverse effects. The most recent study, funded by the maker of celecoxib,89 found no difference in either efficacy or adverse effects between celecoxib and rofecoxib. Table 2. Comparison of rofecoxib and celecoxib in flare-ups of chronic osteoarthritis of the knee 86 Characteristic McKenna Geba87 Gibofsky89 Rofecoxib 25mg (n) 59 95 190 Celecoxib 200mg (n) 60 97 189 Aspirin 325 qd permitted Yes No Yes Mean age 62 62.6 62.9 Mean osteoarthritis duration 10.5 years 10 years 9 years Percent white 80% 85% NR Baseline pain on walking (score) 72 72 68 Discontinued trial by 6 wks: Rofecoxib 25mg 16% 19% 15% Celecoxib 200mg 22% 17% 16% All three trials were probably adequately randomized and blinded, and didn't have statistically significant differences in baseline characteristics. Gibofsky and colleagues hypothesized that neither McKenna nor Geba were powered sufficiently to measure differences between celecoxib and rofecoxib. Gibofsky viewed the McKenna study as being powered only to compare active treatments with placebo and the Geba study as powered to compare rofecoxib with acetaminophen. Therefore, Gibofsky, and colleagues set out to conduct a study powered to compare celecoxib and rofecoxib, with a sample size based on results of the McKenna study. Efficacy results are summarized in Table 3 below. Mean changes in WOMAC VAS score for Walking Pain were similar for celecoxib 200 mg and rofecoxib 25 mg across trials. In the Geba trial, rofecoxib was associated with significantly greater mean reductions than celecoxib on VAS scores for WOMAC Rest Pain and Night Pain and a similar mean reduction in Morning Stiffness. WOMAC Composite Score results from Geba and Gibofsky were conflicting. In the Gibofsky trial, there were no differences, but in the Geba trial, there were significant differences favoring rofecoxib for mean changes in the WOMAC pain (7 points) and stiffness (8 points) subscales. However, an analysis of data from randomized trials estimated that the minimal perceptible improvement for each WOMAC scale was a difference of 11 mm.90 29 Table 3. Head to head efficacy comparisons at 6 weeks (mean change from baseline) WOMAC VAS Scores WOMAC Composite Subscales Walking Rest Morning Night Arthritis pain pain stiffness pain pain Pain Stiffness Function Total Geba87 Rofecoxib -42 -31.1* -36.2 -32.7** nr -35.4* -35* -29.7 -26 Celecoxib -36.2 -23.4 -29.1 -22.6 nr -28.6 -27.9 -24.9 -26 86 McKenna Rofecoxib -38 nr nr nr -40 nr nr nr nr Celecoxib -38 nr nr nr -39 nr nr nr nr 89 Gibofsky Rofecoxib -29.2 nr nr nr nr -42.6 -34.7 -35.5 -20.1 Celecoxib -31.5 nr nr nr nr -42.0 -36.7 -37.9 -22.1 *p≤0.05; **p<0.001; nr=not reported Safety: Serious Gastrointestinal and Cardiovascular Events Rofecoxib and Celecoxib: GI and CV Safety in CLASS and VIGOR GI Safety Two pivotal studies were large enough to evaluate serious complications of peptic ulcer disease (bleeding, perforations, obstruction) as a primary endpoint in average-risk patients (those without a recent UGI bleed). The VIGOR trial19 evaluated rofecoxib versus naproxen and the CLASS trials60 evaluated celecoxib versus ibuprofen and diclofenac. VIGOR (Vioxx Gastrointestinal Outcomes Research) Trial. VIGOR, a randomized, double- blind trial, compared twice the highest recommended dose of rofecoxib (50 mg daily) to naproxen 500 mg twice a day in 8,076 patients with rheumatoid arthritis. VIGOR found a statistically significant reduction in complicated upper GI events (defined as perforation, obstruction, or severe upper gastrointestinal bleeding. During a median follow-up of 9 months, the rates of confirmed upper gastrointestinal events were 3.0% vs. 1.4% (NNT to prevent one event 62), and the rates of complicated, confirmed upper gastrointestinal events were 0.9% vs. 0.4% (NNT 192). VIGOR met all but one of the criteria for a good-quality study. The one weakness was the varying duration of exposure among study participants. The duration of VIGOR was designed to be both time and event driven, so that the trial would terminate after a minimum of 120 patients experienced clinical upper GI events (or 40 patients experienced complicated upper GI events) and for at least 6 months after randomization of the last patient enrolled. Because patients were enrolled over a 6-month period, patients in VIGOR were followed for varying lengths of time. The longest time a patient could have remained in the study was 13 months, but half of the patients were followed for 9 months or less, and only about 1,000 patients (13%) were followed for longer than 10 months. By 13 months, about 29% of the subjects had discontinued the study drugs. Similar proportions discontinued naproxen or rofecoxib because of an adverse event (naproxen—16.1%, rofecoxib—16.4%). In 2003, the VIGOR investigators published a post hoc analysis of lower GI events, defined 30 as bleeding with a 2 g/dL drop in hemoglobin or hospitalization, or hospitalization for perforation, ulceration, diverticulitis, or obstruction.91 There were 11 events in the rofecoxib group and 24 events in the naproxen group (0.41 versus 0.89 per 100 patient-years; RR 0.46, 95% CI 0.22 to 0.93). The absolute risk difference (per 100 patient-years) was –0.48 (95% CI – 0.91 to –0.05), with a NNT of 208. When the investigators combined the analysis of lower GI events with previously reported results on upper GI complications (0.6 with rofecoxib versus 1.4 with naproxen per 100 patient-years92), the rates of all serious GI events were 0.96 for rofecoxib and 2.26 per 100 patient-years for naproxen (relative risk 0.43, 95% CI 0.27 to 0.67, NNT 77). CLASS (Celecoxib Long-term Arthritis Safety Study.) CLASS was designed as two trials with separate patient recruitment and randomization procedures: one compared celecoxib 400 mg twice a day with ibuprofen 800 mg three times a day, and the other compared celecoxib 400 mg twice a day with diclofenac 75 mg twice a day.60 Because the FDA was concerned that selective COX-2 inhibitors could interfere with the benefits of COX-2 in ulcer healing and lead to a long term increase in GI complications without warning symptoms, the pre-specified primary outcome was "ulcer-related complications."93 Another pre-specified outcome was ulcer related complications plus symptomatic ulcers. The planned maximum duration of the trials were 15 and 12 months, respectively, or until at least 20 ulcer-related complications occurred in each trial, or 45 in both trials combined.94 The protocols stated that celecoxib would be claimed to be different from traditional NSAIDs only if there were statistically significant differences between celecoxib and each of the comparators, as well as between celecoxib versus the comparator groups combined. The CLASS trials were stopped early after the predefined threshold of ulcer complications occurred. However, the analysis and reporting of the results as presented in the main publication in JAMA were in part incomplete and differed in some ways from the protocols. The JAMA article reported truncated 6-month results even though the median duration of follow-up was 9 months (range 6 to 13 months), and combined the ibuprofen and diclofenac results without reporting the results of the two trials separately.60 Subsequently, additional details of the study have been made public on the FDA web site94 and have been extensively analyzed. The findings of the FDA analysis suggest that the published results of CLASS are, in part, misleading because they appear to selectively report results at the point in time at which celecoxib was most effective.95-97 There were 3,987 subjects randomized to celecoxib and 3,981 subjects randomized to non- selective NSAIDs in the CLASS trials. For the combined outcome of ulcer complications or symptomatic ulcers, the JAMA article reported that patients on celecoxib experienced fewer GI complications compared with patients in the combined NSAID groups (32/3987 versus 51/3981, annualized incidence rates 2.08% vs. 3.54%, p=0.02),60 while the rate of complicated ulcers alone was not significantly different (13/3987 vs. 22/3981, annualized incidence rates 0.76% vs. 1.45%, p=0.09). However, by 12 months, according to FDA documents (see Table 14, FDA Medical Officer Review)94 there was no longer a trend favoring celecoxib for the primary outcome of complicated ulcers. There were 17/3987 events in the celecoxib group (0.43%) versus 21/3981 (0.53%) in the NSAID groups combined.94 This difference was not statistically significant (relative risk 1.10, 95% CI 0.47 to 2.5897, 98, also see Figure 4, Scheiman review99). For the individual comparisons between celecoxib and ibuprofen or diclofenac, which were not reported in the JAMA article, there was no difference in the rate of ulcer complications at either 6 months or at the end of follow-up.97 For the outcome of ulcer complications or symptomatic ulcers, celecoxib was superior to ibuprofen, but not to diclofenac at either 6 months or at the end 31 of follow-up.97 Authors of CLASS have not completely explained the reasons for selective reporting of results, though they contend that combining the two trials and reporting ulcer complications plus symptomatic ulcers as a primary outcome were permitted by the protocols.100, 101 However, reporting only combined results appears to obscure differences between the results for the two comparator drugs.96 The investigators' main argument for reporting truncated data is that results after 6 months were not interpretable because of high and differential rates of drop-outs due to symptomatic ulcers, which could have biased results against celecoxib because of depletion of high-risk patients in the non-selective NSAID arms.100, 101 On closer inspection, however, this rationale appears flawed, as neither symptomatic ulcers nor gastrointestinal symptoms predicted ulcer complications.96 Furthermore, simply truncating data is not considered an acceptable method for resolving issues related to high drop-out rates. Twenty per cent of the patients in the CLASS trial took aspirin in addition to their study. drug. When patients taking aspirin were excluded from the analysis, there were fewer confirmed serious ulcer complications in the celecoxib group than in the ibuprofen group (p=0.03).94, 97 However, serious ulcer complications for celecoxib and diclofenac were equivalent even when patients taking aspirin were excluded from the analysis. Changes in hemoglobin or hematocrit were not a primary outcome of CLASS and were not reported in the main JAMA publication. However, rates of significant hemoglobin (>2 g/dL) and/or hematocrit drops (>=0.10), a surrogate marker for GI blood loss, are available from the FDA Medical Officer Review.94 Over the entire study period, patients randomized to celecoxib were significantly less likely to experience declines in these laboratory parameters (87/3701 or 2.4%) relative to patients randomized to either diclofenac (82/1849 or 4.4%) or ibuprofen (102/1802, 5.7%). Celecoxib was also superior when patients were stratified according to aspirin use (4.1% vs. 6.9% and 7.5%) or non-use (1.9% vs. 3.7% and 5.2%). However, the significance of these findings is unclear as they were not associated with differences in clinically relevant outcomes (such as rates of MI, angina, or congestive heart failure). In summary, the CLASS trials did not demonstrate a statistically significant advantage over either diclofenac or ibuprofen for the primary endpoint of complicated ulcers for all patients enrolled over the full duration of follow-up. Celecoxib appeared superior to ibuprofen, but not diclofenac, in a subgroup of subjects not taking aspirin. In its decision regarding labeling for celecoxib, the FDA agreed with its Advisory Committee recommendations that CLASS did not demonstrate a safety advantage in upper gastrointestinal safety for celecoxib compared with either ibuprofen or diclofenac.102 Comparison between VIGOR and CLASS. There are several possible reasons why rofecoxib (VIGOR), but not celecoxib (CLASS), significantly reduced ulcer complications. First, patient populations and study designs differed. VIGOR included patients aged 50 or older with rheumatoid arthritis, while CLASS had a broader age range of patients with either osteoarthritis or rheumatoid arthritis. VIGOR also prohibited the use of aspirin while CLASS did not. However, the rate of ulcers in the patients taking a control drug was almost three times as high in VIGOR as in CLASS, although rates of ulcer complications were similar. In addition, VIGOR compared rofecoxib to naproxen and CLASS compared celecoxib to diclofenac and ibuprofen. This could have affected the results if the non-selective comparator NSAIDs are associated with differential risk of ulcers. Finally, it is possible that rofecoxib, which has greater COX-2 selectivity, is truly more gastroprotective than celecoxib. 32 CV Safety CV risk in VIGOR. Findings from the VIGOR trial raised concerns that the putative GI safety benefits of COX-2 selective NSAIDs relative to non-selective NSAIDs may have come at the expense of increased cardiovascular events. The main publication of VIGOR19 reported that "the incidence of myocardial infarction was lower among patients in the naproxen group than among those in the rofecoxib group (0.1 percent vs. 0.4 percent; relative risk, 0.2; 95 percent confidence interval, 0.1 to 0.7); the overall mortality rate and the rate of death from cardiovascular causes were similar in the two groups." This corresponds to one additional heart attack for every 333 patients treated with rofecoxib instead of with naproxen. A re-analysis of VIGOR with three additional myocardial infarctions not included in the results originally submitted for journal publication estimated a relative risk for myocardial infarction of 5.00 (95% CI 1.68 to 20.13) for rofecoxib compared with naproxen among all patients, and 3.00 (95% CI 0.91 to 12.78) among patients in whom aspirin was not indicated.103 For patients who had indications for aspirin, 8 MIs occurred during 105 person-years of exposure to rofecoxib, compared with no MIs during 102 person-years of exposure to naproxen. Blinded adjudication of the VIGOR trial data classified 45/4047 (one in every 90) rofecoxib patients and 19/4029 (one in 212) naproxen patients as having serious thrombotic events (heart attack, stroke, unstable angina, transient ischemic attack, resuscitated cardiac arrest, and sudden death).104 This corresponds to one additional serious thrombotic event for every 156 patients taking rofecoxib. CV risk in CLASS. The original publication of the CLASS trials, using 6-month data, reported that celecoxib had no effect on the rate of myocardial infarction or for any cardiovascular event (stroke, myocardial infarction, or angina) compared with diclofenac and ibuprofen.60 The number of myocardial infarctions was 10/3987 (0.3%) with celecoxib versus 11/3981 (0.3%) with the non-selective NSAIDS). The full CLASS data on thrombotic events were analyzed in more detail by White and colleagues,105 who also found no differences in the rates of any significant cardiovascular event for the overall sample or for the subgroup who did not use aspirin. For the overall sample, myocardial infarctions occurred in 19/3987 (0.5%) of patients on celecoxib and 13 (0.3%) on diclofenac or ibuprofen. In fact, more detail about the design of the CLASS trials is necessary to judge the validity and generalizability of these results. In particular, reporting of longer-term data is important because 6 months of exposure to celecoxib may not be enough time to assess cardiovascular risk. At 8 months in the VIGOR trial there was no significant difference between rofecoxib and naproxen in the cumulative incidence of events. From 8 to 12 months, differences in the incidence of myocardial infarction between rofecoxib and naproxen became apparent (Figure 1 of Mukherjee106). This observation could be due to increased power due to a larger number of events with longer follow-up, or in part to a duration-dependent increase in risk. Based on the pattern observed in VIGOR, if celecoxib is associated with an increased risk of cardiovascular events, it may not be seen until 10 or 12 months of followup. In the VIGOR trial, 2,140 subjects, about one-fourth of the original sample, were available for 10 months of followup, and 1,045 were available for 12 months. In the CLASS trials, 2,770 subjects, about one-third of the original sample, had at least 9 months of follow-up, and 1,126 had at least 12 months of follow-up, suggesting that an analysis should have been able to detect an increased risk of cardiovascular events similar to that observed in VIGOR, if it was present (see Table 4, FDA Medical Officer Review94). White and colleagues argue that their meta-analysis shows that celecoxib is safer than rofecoxib.105 To support their argument, they note that the annualized rate of all cardiovascular 33 thromboembolic events in the naproxen group in the VIGOR trial and the non-aspirin celecoxib users in the CLASS trial were similar. However, this comparison of rates across the VIGOR and CLASS studies is imprecise. After 8 months, about 0.4% of naproxen patients had experienced an event in VIGOR, compared to about 0.8% of non-aspirin celecoxib users in CLASS. It is not clear whether or not this is a statistically significant difference. By contrast, Mukherjee and colleagues suggested that the selective NSAIDs as a class might be associated with an increased risk of myocardial infarction because the 0.8% rate of myocardial infarction on celecoxib in the CLASS trials and the 0.74% rate on rofecoxib in VIGOR are both higher than the 0.52% rate observed in a meta-analysis 107 of patients receiving placebo in studies of aspirin prophylaxis.106 In our opinion, all of these conclusions are unsubstantiated because they involve cross-trial and historical comparisons. The importance of analyzing longer-term data and assessing dose effects are underscored by the results of the long-term Adenoma Prevention with Celecoxib (APC) trial in a different population—that of patients receiving celecoxib for colorectal polyp prevention.108 This trial, which randomized patients to celecoxib versus placebo, was terminated after 33 months because of a higher rate of cardiovascular events (death from cardiovascular causes, myocardial infarction, stroke, or heart failure) in the celecoxib arms. According to Figure 1 in the main publication of this trial,108 the difference in rates of events became most apparent only after twelve to eighteen months. There was also a non-significant increase in risk with higher compared to lower doses of celecoxib. Compared with placebo, the relative risk of cardiovascular events in patients randomized to celecoxib 400 mg twice daily was 3.4 (95% CI 1.4 to 8.3) compared to 2.5 (95% CI 1.0 to 6.3) in patients randomized to 200 mg twice daily.108 Much of the increased risk was due to differences in rates of fatal or nonfatal myocardial infarctions, which occurred in 22/1356 (1.6%) of celecoxib users and 3/679 (0.4%) of patients on placebo.109 On the other hand, data from PreSAP,110 another polyp prevention trial, and preliminary data from ADAPT,111 an Alzheimer's prevention trial, found no significant increase in cardiovascular events with celecoxib 400 mg once daily (PreSAP, RR 1.3, 95% CI 0.6 to 2.6109) or 200 mg twice daily (ADAPT) compared to placebo. However, the lack of an association could be due to insufficient power to detect a difference because of the small number of myocardial infarctions associated with celecoxib in these trials (2 in ADAPT112 and 9 in PreSAP109). Alternatively, the smaller relative risk in PreSAP relative to APC could be related to a higher placebo event rate in PreSAP (7.2 versus 3.4 per 1000 patient-years).109 SUCCESS-I, a recently published, large (N=13,274) trial of osteoarthritis patients, also reported no significant difference in rates of cardiovascular thromboembolic events with celecoxib 100 mg or 200 mg twice daily versus diclofenac or naproxen (10 events or 0.55/100 patient-years in the combined celecoxib arms versus 1 event or 0.11/100 patient-years in the non-selective NSAID arms, p=0.11), but may have been too short in duration (12 weeks) and have recorded too few events to detect a difference.63 Overall rate of serious adverse events in CLASS and VIGOR. One Canadian analysis used FDA materials to analyze the rates of serious adverse events, defined as death, hospitalization, or "any life-threatening event, or event leading to severe disability" in the CLASS and VIGOR trials.113 This measure combines the rates of serious upper GI complications (in which coxibs are expected to have an advantage over NSAIDs) with other serious adverse events. The numbers of all serious adverse events were drawn directly from FDA materials, pages 7 and 8 (rofecoxib114) and 57 (celecoxib94). 34 In the Canadian re-analysis, shown in Table 4, the rates were calculated using the number of patients as the denominator. These simple rates are compared with the number of serious upper GI events, which constitute only about 10% of all serious adverse events (the two rightmost columns in the table). Using all serious adverse events as the criterion for "harm," the number- needed-to-harm one person was 82 for celecoxib vs. diclofenac, 129 for celecoxib vs. ibuprofen, 100 for celecoxib vs. diclofenac and ibuprofen, and 65 for rofecoxib vs. naproxen. The Canadian authors also pooled the results for celecoxib and rofecoxib, assigning more weight to VIGOR, which had a longer duration than CLASS. In the pooled analysis, the number needed to harm was 78 for the selective COX-2 inhibitors versus non-selective NSAIDs and was statistically significant. Table 4. Re-analysis of the CLASS and VIGOR Trials113 ALL SERIOUS ADVERSE EVENTS SERIOUS UPPER GI EVENTS Trial Treatment Control Treatment Control CLASS60 270/3987 (6.8%) 230/3981(5.8%) 20/3987 (0.5%) 24/3981 (0.6%) (Celecoxib 400 mg) VIGOR 19 378/4047 (9.3%)* 315/4029 (7.8%) 16/4047 (0.4%)* 37/4029 (0.9%) (Rofecoxib 50 mg) *statistically significant vs. control group. For the VIGOR trial, the FDA calculated rates of serious adverse events in exactly the same manner as the Canadian investigators.114 The FDA analysis shows that the rates of each serious adverse event (except GI adverse events) were higher for rofecoxib than for naproxen. For the CLASS trials, the FDA used patient-years as the denominator instead of a simple proportion to calculate rates of serious adverse events.94 This approach was used because the two trials that make up CLASS had different durations. In the FDA analysis, the rates of all serious adverse events combined were 11.6 per 100 patient-years for celecoxib; 10.3 per 100 patient-years for diclofenac, and 10.6 per 100 patient-years for ibuprofen, a difference that was not statistically significant. In summary, the FDA data clearly show that these two coxibs, in doses higher than those commonly used in practice, do not reduce the overall rate of serious adverse events, and may have increased them. It should be noted, however, that not all serious adverse events are equal in importance to patients and physicians. A reduction in the rate of one kind of adverse event might be considered more important than an increase in another one. Rofecoxib and Celecoxib: Further Analyses of CV Toxicity and GI Safety The GI and CV risk profiles of celecoxib and rofecoxib relative to one another and to NSAIDs, placebo, or no treatment have also been assessed in numerous meta-analyses of randomized trials and observational studies. We were unable obtain final results of one systematic review evaluating the GI safety associated with selective and non-selective NSAIDs in time to include it in this report.115 However, analyses of GI safety with celecoxib and rofecoxib in this systeamtic review were based on results from CLASS,60 VIGOR,19 the then- unpublished SUCCESS-1 trial of celecoxib,116 and two previously published meta-analyses117, 118 (all included in this report). 35 Systematic Reviews and Meta-analyses of GI Safety Rofecoxib. VIGOR remains the only individual trial large enough to adequately assess rates of upper GI complications with rofecoxib and non-selective NSAIDs in patients with arthritis. However, the manufacturer of rofecoxib also sponsored a prospective meta-analysis of GI safety from eight smaller phase 2b/3 osteoarthritis trials (N=5425).118 It found the 12-month combined incidence of perforations, symptomatic ulcers, and upper GI bleeding significantly lower with rofecoxib compared to non-selective NSAIDs (1.3% vs. 1.8%, P=0.046; rate per 100 patient- years 1.33 vs. 2.60, RR 0.51, 95% CI 0.26 to 1.00). The rate of ulcer complications alone, however, was not reported. A Food and Drug administration review has been critical of several aspects of this meta-analysis.119 It notes that it is not clear how assiduously investigators of the trials adhered to the pre-specified protocols (for example, by not delivering the prespecified type of primary source material mandated in the original protocol), and that most (50 of 62) cases were unblinded before the adjudication process occurred. In addition, the FDA review suggests that simple pooling and comparisons of the rofecoxib and the non-selective NSAIDs outcomes may be misleading because study duration varied, different patient withdrawal criteria were applied, different diagnostic surveillance methods (including endoscopic surveillance in two trials) were employed, doses of rofecoxib varied, and different comparator NSAIDs were used. Rates of complicated ulcers at 12 weeks, for example, were substantially higher in patients on ibuprofen (1.12%) compared with diclofenac (0.19%). Further, combining symptomatic ulcers and ulcer complications may be less informative because the morbidity associated with ulcer complications is substantially higher than the morbidity associated with symptomatic ulcers. Data reported on the FDA web site (page 78) indicate that only six complicated ulcers in 3,357 patients on rofecoxib and five in 1,564 patients on non-selective NSAIDs (cumulative incidence at 12 months 0.45% vs. 0.55%) occurred; the difference was not statistically significant (relative risk using Cox proportional hazards model 0.51, 95% CI 0.16 to 1.69).119 An updated meta-analysis of 20 trials sponsored by the manufacturer of rofecoxib (excluding VIGOR) reported 0.21 vs. 0.45 confirmed complicated PUBs per 100 patient-years of exposure (p=0.03) among 10,026 subjects randomized to rofecoxib and 7,046 to non-selective NSAIDs. However, this meta-analysis was rated fair-quality because it did not evaluate the effects of study quality, duration of therapy, or dose (about 30% of patients received 12.5 mg of rofecoxib, about 50% received 25 mg, and about 10% received 50 mg).120 With regard to duration of exposure, the results as presented in this study are somewhat misleading, as the rate of PUBs are reported as occurring over 24.8 months (last point in time at which there were >200 patients left in each treatment group), even though the median duration of exposure was only 3 months. Only one- quarter of the patients receiving rofecoxib had over 6 months of exposure. The only randomized controlled trial evidence clearly demonstrating a lower risk of complicated ulcers with long-term use of rofecoxib compared with non-selective NSAIDs therefore comes from VIGOR, which evaluated a higher-than-conventional dose of 50 mg of rofecoxib. Although the most recent meta-analysis120 reporting rates of complicated ulcers is consistent with VIGOR, its results appear primarily applicable to patients with shorter-term (<6 months) exposure to rofecoxib. Celecoxib. One manufacturer-funded, fair-quality meta-analysis examined the endpoint of "UGI ulcer complications" in 14 RCTs of celecoxib (not including CLASS) versus placebo or non-selective NSAIDs (usually naproxen).121 The trials ranged in duration from 2 to 24 weeks, with most lasting 6 or 12 weeks. The strength of this meta-analysis was that the endpoint—upper 36 GI bleeding with endoscopic findings of an ulcer or large erosion, perforation, or gastric outlet obstruction—was similar to those used in the VIGOR and CLASS trials. A Safety Committee adjudicated potential ulcer complications in a blinded manner. These endpoints were ascertained through a monitoring program that appears to have been superimposed on all of the trials; it is not clear how assiduously investigators complied with this program. Not all of the included trials have been published, and their quality was not assessed as part of the meta-analysis. In addition, like the meta-analysis of rofecoxib trials described above, results of the trials were simply pooled despite differences in dose of celecoxib, duration of therapy, or which comparator NSAID was used. In the 14 trials, there were 2 UGI ulcer complications among 6,376 patients in the celecoxib group (3 per 10,000), 9 among 2,768 in the NSAIDs group (33 per 10,000) and none in the placebo group (0/1,864). This corresponded to annual rates of two per 1,000 per year for celecoxib and about 17 per 1,000 per year for NSAIDs (p=0.002). There are several possible reasons why the results of the meta-analysis differed from those of CLASS, which did not clearly show a decreased risk of UGI ulcer complications for celecoxib compared to diclofenac and ibuprofen. First, the incidence of serious ulcer complications in CLASS was much higher than in the trials included in the meta-analysis. In the CLASS trials, the annualized rate of serious ulcer complications was 7.6 per 1,000 per year for celecoxib and 14.5 per 1,000 per year for the two NSAIDs combined.60 The nearly four-fold higher rate of ulcer complications in the CLASS trials compared to the other celecoxib trials could be due in part to enrollment of a higher-risk population, the use of concomitant medications, the dose of celecoxib evaluated, or other factors. In CLASS, for example, 21% of patients randomized to celecoxib were on aspirin and 30.6% on corticosteroids. By contrast, only 12.4% of patients in the meta-analysis were taking aspirin, and 13.5% were on corticosteroids.121 In addition, antiulcer medications (except for occasional antacids) were prohibited in CLASS, but used in 16.5% of celecoxib patients in the meta-analysis. Another potential explanatory factor is that the high dose of celecoxib used in CLASS—400 mg twice daily—was evaluated in only about 10% of the patients in the meta-analysis. It is possible that using higher doses of celecoxib could attenuate GI safety benefits because of incomplete COX-2 selectivity. Finally, different comparator NSAIDs could be associated with different risks of GI complications. In the meta- analysis, six trials (N=6151) compared celecoxib to naproxen versus only three trials (N=2439) that compared celecoxib to diclofenac or ibuprofen (the drugs evaluated in CLASS). Pooling data from trials evaluating different comparator NSAIDs could obscure differential effects on GI safety if they were present. Moore, McQuay and others conducted a separate meta-analysis of celecoxib trials for osteoarthritis or rheumatoid arthritis, with funding from Pfizer and the Oxford Pain Relief Trust.62 The authors obtained a declaration from Pfizer that they had received information on all completed clinical trials of celecoxib and would be permitted to publish the results no matter what their findings showed. However, much of the data on which this meta-analysis was based remains inaccessible to the public. The unpublished data used in this meta-analysis add value in that they may help provide the most comprehensive and precise estimates of adverse events. However, although the meta-analysis methods appeared appropriate, it is impossible to verify whether the meta-analysis assessed validity appropriately, abstracted outcomes correctly, or otherwise confirm the reproducibility of the meta-analysis. Moore and colleagues reviewed over 180,000 pages of company documents, which included detailed information on study methods. All 31 included trials were rated 5 out of 5 on the Jadad quality scale, and 16 out of 16 on an eight-item validity scale. Only two of the 31 trials were 37 longer than 12 weeks in duration. The meta-analysis found celecoxib associated with a lower risk of hemoglobin fall of 20 g/L or more (a marker for a significant GI bleed) (RR 0.72, 95% CI 0.56 to 0.92) and hematocrit fall of 5% or more (RR 0.78, 95% CI 0.69 to 0.89) compared with non-selective NSAIDs.62 Although the risk of complicated ulcers was not evaluated as a separate outcome, celecoxib was also associated with a lower risk of clinical ulcers and bleeds than non- selective NSAIDs in 18 trials (RR 0.61, 95% CI 0.46 to 0.81). When the analysis was limited to trials evaluating doses of 200 or 400 mg daily of celecoxib (in other words, excluding the results of CLASS), the benefit was more pronounced (RR 0.35, 95% CI 0.22 to 0.56). The largest (N=13,274) randomized controlled trial (SUCCESS-1) of celecoxib (included in the Moore meta-analysis) assessed ulcer complications through 12 weeks.63 It found that in patients with osteoarthritis, celecoxib was associated with a lower incidence of ulcer complications than naproxen or diclofenac (0.1% versus 0.8%, OR 7.02, 95% CI 1.46 to 33.8; p=0.008). Post hoc analysis indicated that non-aspirin users in the non-selective NSAID groups had a significantly higher risk of ulcer complications when compared to non-aspirin users in the celecoxib group (OR=12.05, 95% CI 1.45-100.09.) Among aspirin users, there was no statistically significant difference in the rates of ulcer complications for both NSAIDs and celecoxib. 63 Systematic Reviews and Meta-analyses of CV Toxicity Rofecoxib. VIGOR and other randomized trials of rofecoxib have been extensively re- examined to further explore its cardiovascular risk profile. Many questions have been raised in response to the disparate findings of these analyses and a myriad of possible explanatory factors have been proposed. Rofecoxib versus non-selective NSAIDs. In October 2001, a fair-quality meta-analysis published in Circulation122 by Konstam and colleagues reported pooled results from 23 rofecoxib Phase IIb through V trials sponsored by Merck. The investigators stratified results by patient group (rheumatoid arthritis, osteoarthritis, or Alzheimer's disease) and by control group (placebo, naproxen, or non-naproxen NSAID). The risk of cardiovascular events was 1.69 times higher for rofecoxib than for naproxen (95% CI 1.07 to 2.69), but was not elevated in trials comparing rofecoxib to non-naproxen NSAIDs (RR 0.79, 95% CI 0.40 to 1.55) (Table 5). The authors hypothesized that rofecoxib might have been an "innocent bystander" in the VIGOR trial. In other words, rather than rofecoxib increasing the rate of cardiovascular events, naproxen might have reduced it. A problem with the Konstam analysis122 is that the non-naproxen and naproxen studies are not directly comparable. VIGOR, the only long-term COX-2 trial to demonstrate a significant reduction in serious GI events, used rofecoxib 50 mg, prohibited aspirin, and followed patients for 9 months. By contrast, some of the non-naproxen-controlled studies were 12 weeks or shorter in duration, permitted aspirin, or used lower doses of rofecoxib. The data presented in the meta- analysis are also inadequate to judge the quality of the included studies and how concomitant aspirin use, duration of treatment, or dose might have affected rates of cardiovascular events, as adjustment using individual patient risk factors was not performed. A subsequent meta-analysis by Reicen and colleagues, also rated fair-quality, provided a more detailed analysis of eight phase IIb/III trials of osteoarthritis patients previously included in the Konstam analysis.123 Although the Konstam meta-analysis cites a planned duration of follow- up of 86 weeks for these trials, the Reicen meta-analysis reports that the mean duration of 38 treatment was actually 3½ months. Like the Konstam study, insufficient information was provided to judge the quality of the studies analyzed or the effects of concomitant aspirin. The incidence of thrombotic cardiovascular adverse events was lower in the rofecoxib treatment group (1.93/100 patient-years) compared with the non-naproxen NSAID (ibuprofen, diclofenac, or nabumetone) groups (2.27/100 patient-years) (Table 5). The conclusion of the Reicen analysis—that there were no significant differences between rofecoxib and non-naproxen NSAIDs—may be valid for this set of studies. However, the results do not address the more specific question of whether rofecoxib is safe at the dosage proven to reduce serious GI events associated with long-term use. The analysis combined data from all rofecoxib doses (12.5, 25, and 50 mg/day); only 545 of the patients received the 50 mg/day dose. Although 50 mg/day is higher than doses used conventionally, the issue of dose may be important because only the 50 mg dose has been shown to reduce serious GI adverse events compared to non-selective NSAIDs in a long-term trial.19 It is possible that lower doses of rofecoxib do not increase cardiovascular events compared with non-naproxen NSAIDs. However, even though lower, conventional doses of rofecoxib would be expected to be associated with lower long-term rates of GI ulcer complications compared to higher doses, this has not been proven in clinical trials. Using a different methodology from the studies by Konstam and Reicen, a good-quality meta-analysis funded by the Swiss National Science Foundation came to different conclusions (Table 5).124 Juni and colleagues included 18 randomized controlled trials of rofecoxib in patients with chronic musculoskeletal disorders (N=25,273), using published data on myocardial infarction as well as unpublished data available from the FDA. They found that the risk of myocardial infarction was higher in patients in the rofecoxib arms of trials compared with patients in the combined comparator arms (naproxen, non-naproxen NSAIDs, or placebo) (RR 2.24, 95% CI 1.24 to 4.02). The risk did not vary according to dose of rofecoxib or duration of therapy (shorter versus longer than 6 months). Trials with an external endpoint committee had a substantially higher risk for myocardial infarction (RR 3.88, 95% CI 1.88 to 8.02) than those without an external endpoint committee (RR 0.79, 95% CI 0.29 to 2.13). VIGOR contributed 8,076 of the 21, 432 included in the meta-analysis. However, even when the results of VIGOR were excluded, the increased risk of myocardial infarction in trials with an external endpoint committee persisted (RR 2.5, 95% CI 1.1 to 6.0).125 Table 5. CV events in trials of rofecoxib versus non-selective NSAIDs: meta-analyses Study Outcome Comparison Relative risk (95% CI) Konstam, 2001122 Cardiovascular events Rofecoxib versus non-naproxen NSAIDs 0.79 (0.40-1.55) Rofecoxib versus naproxen 1.69 (1.07-2.69) Reicin, 2002123 Cardiovascular events Rofecoxib versus non-selective NSAIDs 1.44 (0.65-3.17) Juni, 2004124 Myocardial infarction Rofecoxib versus any comparator 2.24 (1.24-4.02) Subgroup analyses: Rofecoxib versus non-naproxen NSAIDs 1.55 (0.55-4.36) Rofecoxib versus naproxen 2.93 (1.36-6.33) Unlike the previous meta-analyses by Reicen and Konstam, the Juni meta-analysis analyzed aggregated study-level data, evaluated the effects of variables related to methodologic quality (allocation concealment and use of an external endpoint committee), and assessed the outcome of myocardial infarction (rather than composite cardiovascular endpoints, which could have diluted the effects on myocardial infarction rates). A major point of contention, however, centers on 39 whether the Juni meta-analysis inappropriately combined results from different control interventions. Although Reicen and others have criticized this method of analysis because different control interventions may be associated with different risks for myocardial infarction,126 Juni and colleagues' methods appear defensible based on their meta-regression analyses for potential sources of heterogeneity. They found that the only significant source of variation between study results was related to the use of an independent, external endpoint committee, and not to the type of control intervention. For studies with an external endpoint committee, the relative risks for myocardial infarction for rofecoxib compared with placebo, non-naproxen NSAIDs, or naproxen were 2.31, 2.98, and 3.72, respectively, with overlapping confidence intervals (p=0.41 for interaction).125 The Reicen and Konstam meta-analyses did not assess the effects of this potential source of bias. Other criticisms of Juni have centered on its exclusion of two Alzheimer's trials (discussed below) and on some of its statistical methods (such as adding 0.5 to both arms of a trial when no events occurred in one of the arms). However, Juni and colleagues appeared to follow pre-specified inclusion criteria (trials of patients with musculoskeletal disease), and the statistical methods for dealing with empty cells meet current standards for conducting meta-analysis.127 A post-hoc re-analysis of the Juni study sponsored by the manufacturer of rofecoxib and criticizing its methods and conclusions is available on-line, but has not been published in the peer-reviewed literature.128 A fourth, fair-quality meta-analysis evaluated the cardiovascular risks of selective versus non-selective NSAIDs.129 However, it only reported results for all COX-2 inhibitors pooled together. It is discussed in the section on cardiovascular risks associated with non-selective NSAIDs. Rofecoxib versus placebo. The manufacturer-funded meta-analyses by Konstam and Reicin found no significant differences in cardiovascular risk between rofecoxib and placebo.122, 123 In the Konstam analysis, the relative risk of cardiovascular events (cardiovascular, hemorrhagic, or unknown death; nonfatal yocardial infarction; and nonfatal stroke) was 0.85 (95% CI 0.51 to 1.38).122 A total of 33 cardiovascular events were reported in the rofecoxib arms. In the Reicin analysis, the incidence of thrombotic cardiovascular AEs was 2.71/100 patient-years in the rofecoxib group and 2.57/100 patient-years in the placebo group (7 events reported in the rofecoxib arms).123 There were too few events to evaluate the risk of myocardial infarction alone: 3 in the rofecoxib arms in one meta-analysis123 and 19 fatal and nonfatal myocardial infarctions or resuscitated cardiac arrests in the other.122 In the Juni meta-analysis, the relative risk for myocardial infarction with rofecoxib relative to placebo was 1.04 (95% CI 0.34 to 3.12) when all trials were pooled, but 2.31 (95% CI 0.49 to 10.82) in trials with an external endpoint committee.125 In two subsequent trials of cognitively impaired adults, rates of thrombotic vascular events were similar for rofecoxib 25 mg and placebo.130, 131 Four thrombotic vascular events (myocardial infarction not reported separately) occurred in 321 patients randomized to rofecoxib (1.2%) compared to 11 of 327 (3.4%) randomized to placebo in one 12-month trial of 692 patients (mean age=75.5 years) with mild to moderate Alzheimer's dementia.130 In the second trial, 38 of 723 patients with mild cognitive impairment randomized to rofecoxib (5.2%) and 36 of 728 randomized to placebo (4.9%) had a confirmed serious thrombotic vascular event after 115-130 weeks (mean age=74.9 years); the number of confirmed nonfatal myocardial infarctions was 13 versus 10.131 However, more deaths occurred in the rofecoxib group in this trial (24 or 3.3% versus 15 or 2.1%). 40 On the other hand, in another long-term (the Adenomatous Polyp Prevention on Vioxx, or APPROVe) trial of a different population—that of patients receiving rofecoxib for prevention of colon polyps—rofecoxib 25 mg/day was associated with an increased risk of cardiac events (myocardial infarction, sudden death from cardiac causes, or unstable angina pectoris) relative to placebo (RR 2.80, 95% CI 1.44 to 5.45).132 Though the rate of events appeared to diverge only after 18 months in the initially published report,132 a subsequent analysis that included adverse events originally censored because they occurred more than 14 days after discontinuation of therapy suggests that the curves began to diverge by 4 to 6 months.133 The risk of cerebrovascular events and peripheral vascular events were not significantly higher on rofecoxib (RR 2.32, 95% CI 0.89 to 6.74 and 0.46, 95% CI 0.08 to 2.03, respectively). Reasons for the discordant findings between the APPROVe and the Alzheimer's trials are unclear but could be related to differential underlying risk in the populations studied, duration of exposure, or differential use of aspirin or other antiplatelet agents. The most recent and comprehensive meta-analysis included 37 placebo-controlled trials of rofecoxib.129 It includes data from the trials evaluated in the earlier meta-analyses122-124 as well as newer information from the long-term polyp prevention and cognitive impairment trials. Much of the data regarding cardiovascular event rates were obtained by requesting unpublished data from trial sponsors. The meta-analysis was rated fair quality because it did not adequately assess the quality of included trials. Rofecoxib was associated with greater risks relative to placebo for the outcomes "any vascular event" (1.5% or 98/6638 versus 1.1% or 72/6415, RR 1.38, 95% CI 1.01 to 1.87) and myocardial infarction (0.8% or 54/6638 versus 0.5% or 30/6415, RR 1.76, 95% CI 1.14 to 2.73), but not for the outcomes stroke or vascular death. This is equivalent to approximately one additional myocardial infarction per 289 patients exposed to rofecoxib for one year instead of placebo. About 85% of the vascular events occurred in patients on a 25 mg dose of rofecoxib. Approximately 40% (21 of 54) of the myocardial infarctions were from the APPROVe trial.132 Table 6. CV events in trials of rofecoxib versus placebo: meta-analyses Study Outcome Number of Relative risk for (95% CI) events Konstam, 2001122 Combined cardiovascular 33 0.84 (0.51-1.38) events Reicin, 2002123 Combined cardiovascular 7 1.42 (0.24-6.22) events Juni, 2004125 Myocardial infarction Not reported 1.04 (0.34-3.12); all trials 2.31 (0.49 -10.82); only trials with external endpoint committee Kearney, 2006129 Myocardial infarction 54 1.76 (1.14-2.73) Celecoxib. Five meta-analyses (three funded by the manufacturer of celecoxib62, 134, 135) have analyzed the cardiovascular risks associated with celecoxib in primarily unpublished trials.62, 129, 134-136 The first, a fair-quality study by White and others, included 13 new drug application studies and two large post-marketing trials (CLASS and SUCCESS) of 18,942 patients randomized to celecoxib with osteoarthritis or rheumatoid arthritis.134 Only two of the 15 trials were longer than 12 weeks in duration. The meta-analysis did not provide enough information about the design of the included studies to judge their quality. A total of 25 cardiovascular events (0.8%) and 6 myocardial infarctions (0.2%) occurred in patients randomized to celecoxib. 41 There were no differences in risk of cardiovascular events (cardiovascular, hemorrhagic and unknown deaths; nonfatal MI, or nonfatal stroke), fatal myocardial infarction, or nonfatal myocardial infarction between patients randomized to celecoxib versus those randomized to placebo, all NSAIDs, or naproxen (Table 7). There were also no differences in the subgroup of patients who were aspirin non-users. The authors did not perform an analysis of risk associated with different doses of celecoxib. Table 7. CV events in trials of celecoxib: meta-analysis of 15 trials in patients with arthritis 134 Comparison Relative risk for cardiovascular, hemorrhagic and unknown deaths; nonfatal MI; or nonfatal stroke (95% CI) All patients Celecoxib versus placebo 0.85 (0.23 to 3.15) Celecoxib versus all NSAIDs 1.06 (0.70 to 1.61) Celecoxib versus naproxen 0.85 (0.29 to 2.46) Aspirin nonusers Celecoxib versus placebo 0.60 (0.11 to 3.29) Celecoxib versus all NSAIDs 0.86 (0.48 to 1.56) Celecoxib versus naproxen 0.82 (0.18 to 3.70) A second, more comprehensive meta-analysis was presented to the FDA's Arthritis Advisory Committee in February 2005.135 It included 41 trials of celecoxib (N=24,933) for chronic conditions; 33 of the trials were in patients with osteoarthritis or rheumatoid arthritis. Only four of the 41 trials were longer than 12 weeks in duration. The investigators used full follow-up data from the CLASS trials (2,320 patient-years for 3,987 patients). In addition to the composite outcome of any cardiovascular thromboembolic event, the analysis also reported separate analyses for myocardial infarction, stroke, and peripheral vascular events. Over 80% of the cardiovascular events occurred in three large trials: CLASS (N=7,968), SUCCESS (N=13,194), and CAESAR (N=916) (the latter trial remains unpublished). The methods and limitations of this study were similar to the White meta-analysis. There were no significant differences between celecoxib and comparators for myocardial infarction, though event rates were low: only nine myocardial infarctions occurred among 7,462 celecoxib-exposed patients (0.12%) in the placebo-controlled trials. There were also no significant differences for any other cardiovascular thromboembolic event. Table 8. CV events in trials of celecoxib: meta-analysis of 41 trials135 Comparison Relative risk for myocardial infarction (95% CI) All patients Celecoxib >=200 mg/day versus placebo 1.58 (0.92-2.72) Celecoxib >=200 mg/day versus non-selective NSAIDs 1.65 (0.38-7.21) Aspirin nonusers Celecoxib >=200 mg/day versus placebo 1.40 (0.61-3.21) Celecoxib >=200 mg/day versus non-selective NSAIDs 1.64 (0.17-15.33) Another meta-analysis of manufacturer-held reports of 31 trials by Moore and colleagues found that celecoxib was not associated with a significantly increased risk for myocardial infarction compared with non-selective NSAIDs, any active comparator (including rofecoxib or 42 paracetamol), any comparator (including placebo), or any non-coxib comparator using a fixed- effect model in patients with rheumatoid or osteoarthritis, though trends towards increased risk were present (Table 9).62 The overall proportion of patients randomized to celecoxib with myocardial infarction was less than 0.3% (fewer than 60 cases in the largest comparison). There were too few myocardial infarctions in the celecoxib arms of trials comparing celecoxib to placebo (10 events), paracetamol (0 events), or rofecoxib (1 event) to analyze differences in risk. In the two largest trials included in the meta-analysis (CLASS and SUCCESS-I), myocardial infarctions occurred in 0.23% (29 of 12,787) of patients randomized to celecoxib 200 to 800 mg and in 0.18% (15 of 8,375) randomized to a non-selective NSAID (RR 1.7, 95% CI 0.88 to 3.2). Although this study appears to adhere to high standards for conducting meta-analysis, its results are not verifiable because it analyzed publicly inaccessible data. In addition, myocardial infarctions in the included trials were as reported by investigators, and not subject to adjudication. The duration of exposure to celecoxib in the trials varied, with a mean of about 7 months. The authors of the meta-analysis were unable to perform an analysis on effects of duration of exposure, because the trial reports generally did not provide sufficient information on median duration of use. Table 9. MI's in trials of celecoxib: meta-analysis of 31 trials in patients with arthritis62 Comparison Relative risk for myocardial infarction Celecoxib 200 or 400 mg/day versus NSAID 1.9 (0.87 to 4.1) Celecoxib any dose versus NSAID 1.6 (0.93 to 2.6) Celecoxib any dose versus any active comparator 1.4 (0.87 to 2.3) Celecoxib any dose versus any comparator 1.4 (0.88 to 2.2) Celecoxib any dose versus non-coxib comparator 1.4 (0.88 to 2.2) A fourth meta-analysis of CV risk associated with celecoxib (not funded by the manufacturer) was less comprehensive because it did not have access to all of the trial data.136 It limited its analysis to trials that were at least 6 weeks duration and reported cardiovacular events in published articles or publicaly available material on the FDA or manufacturer website, and also differed from the Moore analysis by including trials of patients receiving celecoxib for colon polyp prevention and Alzheimer's disease. It found that the risk of myocardial infarction was increased in 3 trials (APC, ADAPT, PreSAP; none of arthritis patients) comparing celecoxib to placebo (OR 2.26, 95% CI 1.0 to 5.1) and in 5 trials (APC, CLASS, ADAPT, PreSAP, VACT; the latter 2 of arthritis patients) comparing celecoxib to placebo, diclofenac, ibuprofen, or paracetamol (OR 1.88, 95% CI 1.15 to 3.08) (Table 10). No heterogeneity was present. There was no association between celecoxib use and either cerebrovascular events, cardiovascular death, or composite cardiovascular events. Although this study was rated good quality, lack of comprehensiveness is a concern because it excluded 42 celecoxib trials either because they were shorter than 6 weeks or because publicly available information on cardiovascular events was not available. In addition, nearly two-thirds (18 of 29) of the myocardial infarctions in the placebo- controlled trials (the primary analysis) came from the APC (polyp prevention) trial. On the other hand, the meta-analysis also did not include the recently published, large (N=13,274), 12-week SUCCESS-I Study, which reported results consistent with its findings (10 myocardial infarctions or 0.55/100 patient-years in the combined celecoxib arms versus 1 myocardial infarction or 0.11/100 patient-years in the combined non-selective NSAID arms).63 43 Table 10. MI's in trials of celecoxib: meta-analysis of trials of at least 6 weeks duration with published or 136 publicly available data Comparison Relative risk for myocardial infarction Celecoxib any dose versus placebo (3 trials) 2.3 (1.0 to 5.1) Celecoxib any dose versus placebo, diclofenac, 1.9 (1.2 to 3.1) ibuprofen, or paracetamol The fifth meta-analysis (also not funded by the manufacturer) analyzed data from 41 published and unpublished trials of celecoxib (8,976 patient-years of exposure).129 Nine of the trials were longer than 12 weeks in duration. Characteristics of this study, which also evaluated cardiovascular risks associated with other selective and non-selective NSAIDs, are discussed in the rofecoxib section above. Data on celecoxib risk primarily came from patients with osteoarthritis or rheumatoid arthritis (33 trials), but studies of low back or temporamandibular joint pain, ankylosing spondilitis, Alzheimer's disease, and colon polyp prevention were also included. Myocardial infarction rates were higher with celecoxib relative to placebo (0.5% or 44/8976 person-years versus 0.2% or 9/4953, RR 2.13, 95% CI 1.20 to 3.80), and for combined vascular events (0.9% vs. 0.6%, RR 1.51, 95% CI 1.02 to 2.24), but there were no significant differences in risk of stroke alone or vascular death (Table 11). This is equivalent to approximately one additional myocardial infarction for every 325 patients treated with celecoxib instead of placebo for one year. The 99% confidence interval (reported in the article because of multiple subgroup analyses) remained significant for myocardial infarction, but not for combined vascular events. Two large polyp prevention trials accounted for about 60% (27 of 44) of the myocardial infarctions in patients randomized to celecoxib.109 A trend towards increased risk of vascular events (p=0.03) with higher doses of celecoxib was present, but nearly all of the events at the highest (800 mg daily) dose occurred in the polyp prevention trials. Analyses on the effects of duration and independent event adjudication were not stratified by specific COX-2 inhibitor, nor were estimates of cardiovascular risk with specific COX-2 inhibitors relative to naproxen or non-naproxen NSAIDs (see section on CV risk of non-selective NSAIDs). Table 11. CV events in trials of celecoxib: meta-analysis of 41 trials of at least 4 weeks duration129 Comparison Outcome Relative risk (95% CI) Celecoxib any dose versus placebo Any vascular event 1.5 (1.0 to 2.2) Celecoxib any dose versus placebo Myocardial infarction 2.1 (1.2 to 3.8) Celecoxib any dose versus placebo Stroke 1.1 (0.6 to 2.2) Celecoxib any dose versus placebo Vascular death 1.3 (0.6 to 2.8) The estimates of risk for myocardial infarction with celecoxib relative to placebo in the non- manufacturer-funded meta-analyses129, 136 are higher than in the manufacturer-funded meta- analyses.134, 135 The major reason for the difference in estimates appears to be the inclusion of two recent, long-term trials of colon polyp prevention (APC and PreSAP) in the former.108, 110 A large number of myocardial infarctions occurred in these trials (27, compared to a total of nine in the most comprehensive manufacturer-funded meta-analysis135), and estimates of risk from both trials were higher than previous pooled estimates without these trials (RR 1.58, 95% CI 0.92 to 2.72).135 In one meta-analysis,129, 136 the rate of nonfatal myocardial infarction was 1.3% (18/1356) with celecoxib (200 or 400 mg twice daily) versus 0.4% (3/679) with placebo (RR 44 2.67, 95% CI 0.5 to 8.41) in the APC trial108 and 1.0% (9/933) versus 0.5% (3/628) for a relative risk of 1.84 (95% CI 0.54 to 6.28) in PreSAP (400 mg once daily).110 A subsequent analysis of the APC trial and PreSAP using slightly different data (due to the identification of additional events after study closure) reported a pooled relative risk of 1.9 (95% CI 1.1 to 3.1, no heterogeneity) for the composite outcome of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or heart failure.109 Rates of fatal or nonfatal myocardial infarction in were 1.6% (22/1356) versus 0.4% (3/679) in the APC trial and 9/933 (1.0%) vs. 4/628 (0.6%) in PreSAP. In summary, celecoxib appears associated with an increased risk of myocardial infarctions or thromboembolic cardiovascular events relative to placebo. Much of the evidence for increased cardiovascular risk comes from two large, long-term polyp prevention studies comparing celecoxib 200 or 400 mg twice daily, or 400 mg once daily to placebo. Although trends toward increased myocardial infarction risk with celecoxib relative to placebo as well as relative to other NSAIDs are also present in meta-analyses of primarily short-term trials of arthritis patients, small numbers of events limit the precision of estimates from those trials. Observational Studies of GI and CV Safety Overview. Numerous long-term observational studies have evaluated the GI and CV risks associated with selective and non-selective NSAIDs. The studies primarily relied on claims data or other administrative databases or on electronic medical record data collected in practice networks to identify cases, and prescription claims to determine exposure. A strength of these studies is that they evaluated much larger populations than could be enrolled into clinical trials.137 In addition, they reflect how coxibs and other NSAIDs are actually used in practice better than many clinical trials, which are usually short term, require rigid dosing regimens, limit the use of other drugs, and implement strategies to monitor and enhance compliance. Population- and practice-based studies may also better represent patients who would be excluded from randomized trials because of comorbidities, age, or other factors. On the other hand, the most important weakness of observational studies is that patients are allocated treatment in a non-randomized matter. This can lead to biased estimates of effects even when appropriate statistical adjustment on a variety of confounding variables is performed.40 In addition, data sources typically cannot reliably assess over-the-counter aspirin, NSAIDs, or acid- suppressing medication use,137 and information on prescription fills may not always accurately correspond to the actual degree of exposure to the drugs. Rofecoxib. Five observational studies reported rates of serious GI events for rofecoxib relative to celecoxib, NSAIDs, and non-use.138-142(Table 12). In direct comparisons, rofecoxib was associated with a similar risk of upper GI complications compared to meloxicam,140 but a greater risk of upper GI hemorrhage than celecoxib, non-selective NSAIDs, and diclofenac plus misoprostol.139, 142 In a nested case-control study, the risk of upper GI bleeding was modestly higher for rofecoxib compared to celecoxib, NSAIDs, or non-use (RR in the range of 1 to 2.)138 Another case-control study that reported higher relative risks of serious GI events with rofecoxib should be interpreted with caution because exposure information was ascertained using unblinded patient interviewing, which is more susceptible to recall bias than blinded coding of exposures status from prescription or general practice databases.141 Analyses of the effects of exposure duration, dosage, and study duration on risk of serious GI events were generally not reported. In fact, COX-2 dosages were only reported in one study 45 which reported that the proportion of patients on celecoxib receiving >200 mg/day was 19%, and the proportion of patients on rofecoxib on >25 mg/day was 8%.139 Table 12. Serious GI events in observational studies Author, Year Study design Mean Duration Sample size age (yrs) (days) Outcome Main findings Hippisley-Cox NR; ≥ 25 Unclear Complicated GI event ↑ risk relative to non-use: 138 2005 No for celecoxib (RR 1.25; 95% CI 0.91, 1.72) Case-control Yes for rofecoxib (RR 1.79; 95% CI 1.42, Cases: 9407 2.26); overall selective (RR 1.72; 95% CI 1.29, 2.29) and non-selective NSAIDs (1.67; 95% CI 1.43, 1.94); ibuprofen (RR 1.58; 95% CI 1.37, 1.83); diclofenac (RR 2.07; 95% CI 1.82, 2.35); naproxen (RR 1.97; 95% CI 1.48, 2.61) Mamdani 2002139 75.7 141 Upper GI hemorrhage ↑ risk relative to celecoxib: Cohort Yes for rofecoxib (RR 1.9; 95% CI 1.2, 2.8), n=143,969 non-selective NSAIDs (RR 1.9; 95% CI 1.0, 3.5) and diclofenac+ misoprostol (RR 3.2; 95% CI 1.6, 6.5) Layton 2003140 60.4-62.5 270 Upper GI Similar risk for rofecoxib and meloxicam (RR Cohort complications 0.91; 95% CI 0.59, 1.42) n=34,355 (perforations/bleeding) Laporte 2004141 NR; ≥ 18 NR Upper GI bleeding ↑ risk vs. non-use for rofecoxib (RR 7.2; 95% Case-control CI 2.3, 23.0), diclofenac (RR 3.7; 95% CI 2.6, Cases=2,813 5.4), ibuprofen (RR 3.1; 95% CI 2.0, 4.9), indomethacin (RR 10.0; 95 % CI 4.4, 22.6), ketoprofen (RR 10.0; 95% CI 3.9, 25.8), ketorolac(RR 24.7; 95% CI 8.0, 77.0), meloxicam (RR 5.7; 95% CI 2.2, 15.0), naproxen (RR 10.0; 95 % CI 5.7, 17.6), nimesulide (RR 3.2; 95% CI 1.9, 5.6), piroxicam (RR 15.5; 95% CI 10.0, 24.2) Kasliwal 2006142 62.5 Median Upper GI Rofecoxib versus celecoxib aRR (95% CI): Cohort Rofecoxib=111 complications 1.60 (0.95, 2.70) n=32,726 Celecoxib=90 (perforations/bleeding) p<0.0001 Fourteen observational studies evaluated the risk of cardiovascular events associated with rofecoxib (Table 13).142-155 Interpretation of the studies is complicated by the use of different study designs, adjustment for different confounders, and evaluation of different populations and outcomes. Six of these studies appeared to rely exclusively on administrative and pharmaceutical databases to determine outcomes, exposures, and comorbidities.143, 147, 149-152 The other studies supplemented administrative or claims data with chart review;145, 153 clinical or practice-based databases,146, 148, 155 or telephone interviews.144 An interim analysis of one study relied on a combination of a medication surveillance database, physician questionnaires, hospital admission data, spontaneous reports, and national morbidity and mortality databases.154 Several studies indicate that using claims data is quite accurate (positive predictive value >90%) for identifying myocardial infarction.156, 157 A weakness of relying exclusively on administrative databases, however, is that they frequently have incomplete information about potentially important confounders such as income level, obesity, smoking status, and level of 46 education.157 All three of the observational studies that collected information about body mass index, for example, supplemented administrative databases with other sources.144-146 Unmeasured confounders could result in less accurate estimates of cardiovascular risk, though one analysis suggests that the effects would be only modest.158 On the other hand, studies can also 'overcontrol' if they attempt to adjust for cardiovascular risk factors identified after the initiation of treatment, when the risk factors are actually intermediate effects of the drugs themselves that predispose to subsequent cardiovascular events.159 Rofecoxib was associated with an increased risk of CV events relative to non-selective NSAIDs in three of five studies40, 144, 152, 153 and an increased risk relative to celecoxib in three of five studies.142, 144, 145, 154, 160 In studies that compared rofecoxib, celecoxib, or NSAID use to non-use, none of the drugs were consistently associated with increased risk of CV events.143, 146, 147, 149, 151, 155 CV event risk estimates from two observational studies of rofecoxib relative to naproxen (Solomon 2004145: OR 1.17, 95% CI 0.90, 1.52; Kimmel 2005144: OR 3.30, 95% CI 1.37, 8.40) were lower than the estimated relative risk for myocardial infarction of 5.00 (95% CI 1.68 to 20.13) for rofecoxib compared with naproxen in VIGOR.103 It is likely that the inconsistencies in effect magnitudes were due in large part to population differences and study methodology. For example, risk estimates from the Solomon 2004 study145 may only be generalizable to a population that is of a more advanced age than that of VIGOR (81.6 vs. 58 years) and of a possibly lower income level, as it focused on low-income Medicare beneficiaries. Participants in the Kimmel 2005 study,144 on the other hand, were similar in mean age to those in VIGOR (53.1 vs. 58 years), but different methods of data ascertainment may have affected risk estimates. This study, which found the highest risk of MI associated with rofecoxib compared with celecoxib (OR 2.72), differed from the others in that it collected information about exposures and covariates using structured telephone interviews rather than by using administrative or large practice databases.144 The use of structured telephone interviews could have enhanced the ability of the investigators to measure relevant confounders and drug exposures. On the other hand, participation bias (only 50% of those approached participated) and recall bias could have skewed the results, though it is not clear that such biases should favor either rofecoxib or celecoxib. Results of studies that found similar risk of CV events with rofecoxib and meloxicam152 or celecoxib142, 154 may also be less reliable. These studies adjusted for far fewer demographic and prognostic factors than other studies that adjusted for multiple demographic factors and comorbidities. Another factor that varied between studies was how exposure status was defined. In one of the studies that reported no association between rofecoxib use and cardiovascular thrombotic events, use of selective COX-2 inhibitors was defined as prescriptions within 6 months of the index date.150 By contrast, other studies defined current use as occurring on or near the index date, which strengthens confidence in inferences about the link between rofecoxib and the observed MIs. 47 Table 13. Cardiovascular events in observational studies Author, Year Mean Rate of aspirin Exposure Main findings Data source age use (% pts) (days) Sample size Levesque 2005143 NR; ≥ 66 22.50% 844.8 Acute MI, fatal or nonfatal Cohort ↑ risk relative to NSAID non-use: n=59724 Yes for rofecoxib, regardless of dose (Overall RR 1.24; 95% CI 1.05, 1.46) No for celecoxib (Overall RR 0.99; 95% CI 0.85, 1.16), naproxen (RR 1.17; 95% CI 0.75, 1.84) or meloxicam (95% CI 1.06; 95% CI 0.49, 2.30) Kimmel 2005144 NR; aged 33.60% NR Nonfatal MI Case-control 40 to 75 ↑ risk for rofecoxib when directly compared with Cases: 1718 celecoxib (OR 2.72; 95% CI 1.24 to 5.95) or naproxen (OR 3.39; 95% CI 1.37, 8.40) ↑ risk for rofecoxib* relative to ibuprofen or diclofenac (OR 2.04; 95% CI 1.16, 3.60) or naproxen (OR 3.30; 95% CI 1.37, 8.40) Risk for celecoxib* similar to ibuprofen or diclofenac (OR 0.77; 95% CI 0.4, 1.48) or naproxen (OR 0.81; 95% CI 0.37, 1.77) *Regardless of aspirin use Solomon 2004145 NR; > 80 NR 1-30 days Acute MI Case-control 31-90 days ↑ risk for rofecoxib relative to celecoxib (OR 1.24; Cases=10,895 > 90 days 95% CI 1.05, 1.46) Risk for rofecoxib similar to naproxen (aOR 1.17; 95% CI 0.9, 1.52) or ibuprofen (aOR 1.21; 95% CI 0.92, 1.58) or other NSAIDs (aOR 1.17; 95% CI 0.99, 1.38) Risk for celecoxib similar to naproxen (aOR 0.95; 95% CI 0.74, 1.21) or ibuprofen (aOR 0.98; 95% CI 0.76, 1.26) or other NSAIDs (aOR 0.95, 95% CI 0.82, 1.10) Hippisley-Cox NR; aged NR NR First ever MI 146 2005 25-100 ↑ risk relative to nonuse: Case-control Yes for rofecoxib (aOR 1.32; 95% CI 1.09, 1.61), Cases: 9218 other selective NSAIDs (aOR 1.27; 95% CI 1.00, 1.61), ibuprofen (aOR 1.24; 95% CI 1.11, 1.39), diclofenac (aOR 1.55; 95% CI 1.39, 1.72), naproxen (aOR 1.27; 95% CI 1.01, 1.60) and other non- selective NSAIDs (aOR 1.21; 95% CI 1.02, 1.44) No for celecoxib (aOR 1.21; 95% CI 0.96, 1.54) Mamdani 2003147 NR; ≥ 66 14.70% 165.6 Incidence of hospitalization for acute MI: risk Cohort relative to non-use n=166,964 Similar risk for rofecoxib (aRR 1.0; 95% CI 0.8, 1.4), celecoxib (aRR 0.9; 95% CI 0.7, 1.4), naproxen (aRR 1.0; 95% CI 0.6, 1.7), or non-naproxen non-selective NSAIDs (aRR 1.2; 95% CI 0.9, 1.4) Graham 2005160 NR: 18-84 Telephone Mean=113 Acute MI requiring admission or sudden cardiac Case-control interview days before death: risk relative to celecoxib Cases=8,143 subgroup event ↑ risk for rofecoxib for all dosages (aOR 1.59; 95% CI (n=817): 23% 1.10, 2.32) or for dosages > 25 mg (aOR 3.58; 95% CI 1.27, 10.11), but dosages ≤ 25 mg had risk similar to celecoxib (aOR 1.47; 95% CI 0.99, 2.17) ↑ risk for ibuprofen (aOR 1.26; 95% CI 1.00, 1.60), naproxen (aOR 1.36; 95% CI 1.06, 1.75), or other NSAIDs (aOR 1.35; 95% CI 1.06, 1.72) 48 Author, Year Mean Rate of aspirin Exposure Main findings Data source age use (% pts) (days) Sample size Johnsen 2005149 69.6 6.9% high dose NR Acute MI: risk relative to nonusers Case-control ↑ risk current (aRR 1.80; 95% CI 1.47, 2.21)and new Cases=10,280 users (aRR 2.52; 95% CI 1.45, 3.13) of rofecoxib ↑ risk for new users of celecoxib (aRR 2.13; 95% CI 1.45, 3.13) and similar risk for current and non-users of celecoxib (aRR 1.25; 95% CI 0.97, 1.62) Similar risk for new (aRR 1.65; 95% CI 0.57, 4.83) or current users of naproxen (aRR 1.50; 95% CI 0.99, 2.29) relative to nonuse ↑ risk for new (aRR 2.65; 95% CI 2.00, 3.50) or current users of other nonaspirin NSAIDs (aRR 1.68; 95% CI 1.52, 1.85) naproxen (aRR 2.13; 95% CI 1.45, 3.13) and similar risk for current and non-users of celecoxib (aRR 1.25; 95% CI 0.97, 1.62) Shaya 2005150 NR; 70% NR ≥ 60 prior to Cardiovascular thrombotic events: relative to Cohort were aged event non-naproxen NSAIDs n=6,250 50 years Similar for rofecoxib (aOR 0.99; 95% CI 0.76, 1.30) 50% black or or celecoxib (aOR 1.19; 95% CI 0.93, 1.51) younger Ray 2002161 61.5 NR NR Serious CHD (hospital admission for AMI or Cohort death from CHD): relative to non-use n=378,776 Similar risks for rofecoxib at dosages ≤ 25 mg (aIRR 1.03; 95% CI 0.78, 1.35) or > 25 mg (aIRR 1.70; 95% CI 0.98, 2.95), celecoxib (aIRR 0.96; 95% CI 0.76, 1.21), ibuprofen (aIRR 0.91; 95% CI 0.78, 1.06), or naproxen (aIRR 0.93; 95% CI 0.82, 1.06 relative to nonuse Layton 2003152 NR NR 270 Thromboembolic events: Rofecoxib vs Cohort meloxicam n=34,355 (A) cardiovascular: similar risk (RR 1.38; 95% CI 0.71, 2.67) ;(B) cerebrovascular: increased risk with rofecoxib (RR 1.68; 95% CI 1.15, 2.46) (C) peripheral venous thrombotic: lower risk for rofecoxib (RR 0.29; 95% CI 0.11, 0.78) Velentgas NR (40-64 NR 5.1 months Combined endpoint of acute coronary syndrome 153 2005 years) and myocardial infarction: risk relative to Cohort ibuprofen or diclofenac (adjusted rate ratios) n=424,584 Increased risk for current use of rofecoxib (1.35; 95% CI 1.09, 1.68) and but not for recent use (1.15; 95% CI 0.88, 1.50) No increased risk for current (1.03; 95% CI 0.83, 1.27) or recent use of celecoxib (0.91; 95% CI 0.70, 1.17) No increased risk for current (1.14 95% CI 0.93, 1.39) or recent use of naproxen (0.86; 95% CI 0.70, 1.04) Harrison- NR NR NR Thrombotic cardiovascular events Woolrych 2005154 Celecoxib and rofecoxib were associated with similar Cohort risks (aHR 0.94; 95% CI 0.51, 1.70) Interim analysis of 11,149 of 58,849 who completed follow- up by 11/30/04 49 Author, Year Mean Rate of aspirin Exposure Main findings Data source age use (% pts) (days) Sample size Andersohn 68.7 NR Mean=542 aRR (95% CI) for diagnosis of AMI, death from 155 2006 days AMI, or sudden death from coronary heart Case-control disease (CHD) relative to nonuse: Cases=3,643 Increased risk for celecoxib 1.56 (1.23, 1.98), rofecoxib 1.33 (1.06, 1.67), etoricoxib 2.02 (1.08, 3.80) and diclofenac 1.36 (1.17, 1.58) No increased risk for valdecoxib 4.26 (0.60, 30.27), ibuprofen 1.00 (0.83, 1.21) or naproxen 1.16 (0.86, 1.58) Kasliwal 2006142 62.5 Rofecoxib=35.3% Median aRR (95% CI) for rofecoxib versus celecoxib Cohort Celecoxib=21.9% Rofecoxib=111 (adjusted for age, age2, sex, and concomitant use of n=32,726 P<0.0001 Celecoxib=90 the combination of aspirin and/or p<0.0001 antiplatelet/anticoagulant agents (a) Cardiovascular TE: 1.04 (0.50, 2.17) (b) Cerebrovascular TE: 1.43 (0.86, 2.38) (c) Peripheral venous (DVT/PE): 0.36 (0.01, 1.34) aOR=adjusted odds ratio; aRR=adjusted relative risk; aIRR=adjusted incidence rate ratios; aHR=adjusted hazard ratio; CI=confidence interval Celecoxib. As summarized above, celecoxib was consistently associated with lower risks of serious GI139 and CV events144, 145, 160 than rofecoxib in several observational studies. Observational studies also demonstrated that, compared with non-selective NSAIDs, celecoxib was consistently GI protective139, 162 or neutral138 and was never associated with higher risks of CV events.144, 145, 150, 160. Specifically, with regard to GI safety, celecoxib was associated with significantly lower risks of GI hemorrhage when directly compared to non-selective NSAIDs (relative risk 0.23, 95% CI 0.12, 0.43)139 and of perforation or bleeding compared to meloxicam (RR 0.56; 95% CI 0.32, 0.96).162 Risk of complicated GI events was significantly lower for NSAID nonuse relative to numerous NSAIDs (i.e., selective NSAIDs, ibuprofen, diclofenac, naproxen, non-selective) but was similar relative to celecoxib.138 With regard to CV safety, celecoxib was associated with similar risks (estimate range 0.77 to 1.19) of serious CV events compared to ibuprofen, diclofenac, naproxen, and "other NSAIDs"144, 145, 150 and, in one study, was associated with significantly lower risks of acute MI requiring admission or sudden cardiac death than ibuprofen, naproxen, or other NSAIDs.160 Relative to non-use, some observational studies have shown an increased risk of MI associated with celecoxib149, 155, whereas others have not.143, 146, 147 In the two studies that found an association, the increased MI risk was either time-dependent149 or dose-dependent.155 Additional analysis of observational studies. An important limitation of the observational studies is that they did not simultaneously assess the risk for serious cardiac and GI events. We re-analyzed data from three studies that reported rates of acute myocardial infarction,147 hospital admissions for congestive heart failure,163 and upper gastrointestinal bleeding139 in a large cohort of elderly patients in Ontario, Canada, to estimate the net effects of selective and non-selective NSAIDs on serious cardiovascular and GI events in this population. Although the three studies evaluated the cohort at slightly different points in time, study methods and populations characteristics appeared essentially identical. 50 We calculated the effects of selective and non-selective NSAIDs on numbers of acute myocardial infarction, upper GI bleed, and hospitalization for heart failure using baseline rates of events in patients not exposed to NSAIDs and estimates of risk as reported in the studies (Table 14). We then estimated the net effects on all three serious adverse events using Monte Carlo simulation (see Methods section for additional details). Table 14. Baseline rates of MI, upper GI bleed, and congestive heart failure (CHF) and risk associated with selective and non-selective NSAIDs in an Ontario cohort of elderly persons Adverse Study, year Baseline Risk with Risk with Risk with non- Risk with event rates (per celecoxib rofecoxib selective naproxen 1000 NSAIDs person- years) Myocardial Mamdani, 8.2 0.9 (0.7 to 1.0 (0.8 to 1.4) 1.5 (1.2 to 1.8) 1.0 (0.6 to 147 infarction 2003 1.2) 1.7) Upper GI Mamdani, 2.2 1.0 (0.7 to 1.9 (1.3 to 2.8) 4.0 (2.3 to 6.9) 4.0 (2.3 to 139 bleed 2002 1.6) 6.9) Heart failure Mamdani, 9.1 1.0 (0.8 to 1.8 (1.5 to 2.2) 1.4 (1.0 to 1.9) 1.4 (1.0 to admission 2004163 1.3) 1.9) Our results (see Table 15) suggest that in this population, under real-world conditions, use of celecoxib was neutral with regard to these adverse events when compared with non-use. On the other hand, use of rofecoxib, non-selective NSAIDs, and naproxen were all associated with more serious adverse events than they prevented (Table 15). Rofecoxib and naproxen essentially appeared equivalent when considering all three adverse events together, though rofecoxib was associated with more heart failure admissions and fewer GI bleeds. Our estimates are consistent with analyses of serious adverse events in VIGOR (discussed earlier), which found that rates were essentially equivalent for rofecoxib and non-selective NSAIDs.113, 114 However, the result are discordant from analyses of serious adverse events in CLASS, which found that celecoxib offered no advantage over non-selective NSAIDs.94, 113 Differences in populations (the Ontario cohort only enrolled patients over 65 years old who filled multiple prescriptions), indications for starting celecoxib, dosing of celecoxib, or co-medication use might account for this discrepancy. In addition, because these studies only included patients who filled multiple prescriptions for NSAIDs, the analyses could underestimate early adverse events. Table 15. Effects of selective or non-selective NSAIDs on number of serious adverse events Estimated effect on Estimated effect on Estimated effect on Net effect on MI's (number per GI bleed (number heart failure number of MI's, GI 1000 person-years) per 1000 person- admissions bleeds, and heart years) (number per 1000 failure admissions person-years) (number per 1000 person-years) Celecoxib -0.82 (-2.46 to 1.64) 0 (-0.66 to 1.32) 0 (-1.82 to 2.73) -0.70 (-3.58 to 2.71) Rofecoxib 0 (-1.64 to 3.28) +1.98 (0.66 to 3.96) +7.28 (4.55 to 10.92) +9.42 (5.47 to 13.99) Non-selective +4.1 (1.64 to 6.56) +6.6 (2.86 to 12.98) +3.64 (0 to 8.19) +14.68 (8.59 to NSAIDs 22.72) Naproxen 0 (-3.28 to 5.74) +6.6 (2.86 to 12.98) +3.64 (0 to 8.19) +10.77 (3.92 to 19.89) 51 GI and CV Safety of Valdecoxib The risk of clinically significant upper GI events (bleeding, perforation, and gastric outlet obstruction) with valdecoxib was evaluated in a fair-quality, manufacturer-funded meta-analysis of eight randomized controlled trials of 12 to 26 weeks duration.117 This study prospectively defined ulcer complications and used independent adjudication to determine adverse events. However, it is not described how assiduously the trials adhered to the adjudication process. Four of the trials were not published, and there was insufficient information about study design to determine the quality of the trials. The meta-analysis found valdecoxib associated with a significantly lower rate of significant upper GI events compared with non-selective NSAIDs (0.68% vs. 1.96%, all patients; 0.29% vs. 2.08%, non-aspirin users; p<0.05). Another meta- analysis of five trials by the same authors found valdecoxib associated with a lower risk of 'moderate-to-severe' upper GI symptoms compared with non-specific NSAIDs (HR 0.59, 95% CI 0.47 to 0.74) and similar risk relative to placebo.164 Adverse events were self-reported by patients in these trials, and the quality of the trials was not assessed by the meta-analysts. Two of the included trials were published only in abstract form. We found no published trials evaluating the risk of cardiovascular events associated with valdecoxib in patients with arthritis. Valdecoxib was not associated with an increased risk of cardiovascular events relative to placebo or other NSAIDs in any of three fair-quality meta- analyses of primarily unpublished data. The ability to detect increased cardiovascular risk in all of these meta-anslyses is limited by small numbers of events. A meta-analysis funded by Pfizer and presented to the FDA in February 2005 analyzed primarily unpublished data from 19 trials of patients with chronic pain (methods described above in the section on celecoxib).135 Thirteen studies were of patients with osteoarthritis or rheumatoid arthritis. Three were longer than 12 weeks in duration. There was no association between valdecoxib use and either cardiovascular thromboembolic events or myocardial infarction (Table 16). However, only 5 of 4,438 patients (0.2%) randomized to valdecoxib in the placebo-controlled trials and 6 of 4,591 (0.1%) in the active-controlled trials had a cardiovascular event. An earlier meta-analysis of 10 trials (also funded by Pfizer, and using similar methods) also found no difference in risk for myocardial infarction between valdecoxib and either placebo or other NSAIDs.134 Table 16. Myocardial infarction in trials of valdecoxib for chronic pain: meta-analysis of 19 trials135 Comparison Relative risk for myocardial infarction Valdecoxib >=10 mg/day versus placebo 1.80 (0.47-6.97) Valdecoxib >=10 mg/day versus non-selective NSAID 0.32 (0.12-0.87) The most recent meta-analysis (not funded by the manufacturer) included 14 placebo- controlled trials (Table 17).129 There were no significant differences between valdecoxib and placebo for the outcomes any vascular event (RR 1.47, 95% CI 0.44 to 4.95), myocardial infarction (RR 1.65, 95% CI 0.28 to 9.87), stroke (RR 0.85, 95% CI 0.07 to 10.6) or vascular death (RR 2.72, 95% CI 0.49 to 15.2). A total of 14 vascular events (1.9%) and 8 myocardial infarctions (1.1%) occurred among the 748 patients in the valdecoxib arms. 52 129 Table 17. Cardiovascular events in trials of valdecoxib versus placebo: meta-analysis of 14 trials Comparison Outcome Relative risk Valdecoxib versus placebo Any vascular event 1.47 (0.44-4.95) Valdecoxib versus placebo Myocardial infarction 1.65 (0.28-9.87) Valdecoxib versus placebo Stroke 0.85 (0.07-10.6) Valdecoxib versus placebo Vascular death 2.72 (0.49-15.2) None of the meta-analyses included two short-term (<2 month) trials in the high-risk setting of post-coronary artery bypass surgery.165, 166 In these trials, parecoxib (an intravenous coxib rapidly converted to valdecoxib) followed by valdecoxib (40 mg bid165 or 20 mg bid166) was associated with a two- to three-fold higher short-term risk of cardiovascular events compared with placebo (pooled relative risk 3.08, 95% CI 1.20 to 7.87).167 FDA information. A warning was added to the valdecoxib product label in November, 2002. It was prompted by reports of cases of serious anaphylactic reactions and serious dermatologic adverse events in postmarketing surveillance.168 A study of two large European data sources and the US FDA spontaneous adverse events reporting system prior to the introduction of COX-2 inhibitors found other NSAIDs—in particular piroxicam and tenoxicam—also associated with Stevens-Johnson syndrome and toxic epidermal necrolysis.169 However, the rates of these events were extremely low, on the order of one per 100,000 or less during an initial 8-week course of therapy. GI and CV Safety of Etoricoxib A fair quality meta-analysis of ten RCTs, which included long-term (>1 year) data from 7 trials of OA, RA, or ankylosing spondylitis patients, found etoricoxib at doses ranging from 5 to 120 mg/day (mean dose 87 mg/day) associated with a lower risk of confirmed PUBs (upper GI perforations, symptomatic gastroduodenal ulcers, and upper GI bleeding) compared to diclofenac 150 mg/day, naproxen 1000 mg/day or ibuprofen 2400 mg/day (1.24% vs. 2.48%, RR 0.48, 95% CI 0.32, 0.73).170 This meta-analysis was rated fair quality because it did not provide adequate detail of the included trials and did not evaluate the effects of dose, duration, or other potential sources of heterogeneity. In addition, it included results of noncomparative extension phases in its analyses, resulting in unequal durations of follow-up for the etoricoxib group (median 12.4 months) compared to the non-selective NSAID groups (median 6.3 months). There were too few events in patients on concomitant aspirin (8 overall) to evaluate its effects on GI safety. An earlier meta-analysis that used similar methods to analyze rates of perforations, symptomatic ulcers, and bleeds reported similar results.171 There is only limited evidence regarding the CV risk associated with long-term use of etoricoxib. One 52-week trial reported that no patients randomized to naproxen and five (2%) randomized to etoricoxib (four receiving 90 mg/day; one 120 mg/day) experienced a serious cardiovascular adverse event.172 Three meta-analyses have evaluated cardiovascular risks associated with etoricoxib. The largest and most recent meta-analysis (by Kearney and colleagues) included 17 placebo- controlled trials of patients (1,167 person-years of exposure) mainly with osteoarthritis or rheumatoid arthritis.129 Most of the trials had short (less than 12 weeks) placebo-controlled periods. There was no difference between etoricoxib and placebo for risk of any vascular event (RR 1.78, 95% CI 0.43 to 7.40), myocardial infarction (RR 4.48, 95% CI 0.20 to 99.4), stroke 53 (RR 1.17, 95% CI 0.21 to 6.51), or vascular death (RR 4.48, 95% CI 0.36 to 56.3). The number of cardiovascular events was very low, with only two myocardial infarctions over 753 person- years of exposure to etoricoxib (0.3%). A less-comprehensive systematic review of five short- term trials (all included in the Kearney meta-analysis) also found no significant increased risk of thromboembolic event (pulmonary embolism, deep vein thrombosis, myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack) with etoricoxib (dose range 30 to 90 mg) versus placebo (OR 1.49, 95% CI 0.42-5.31).173 A third meta-analysis (available only as an abstract) of 12 trials of unspecified durations found that the cardiovascular safety of etoricoxib compared favorably to placebo and non-selective NSAIDs (RR 1.11, 95% CI 0.32, 3.81 and RR 0.83, 95% CI 0.26, 2.64, respectively) though there was a trend towards increased risk compared to naproxen (RR 1.70, 95% CI 0.91,3.18).174 GI and CV Safety of Lumiracoxib One large (N=18,325), long-term (52 weeks) study of osteoarthritis patients (The Therapeutic Arthritis Research and Gastrointestinal Event Trial, or TARGET) compared the safety of a supratherapeutic dose of lumiracoxib (400 mg/day) to naproxen (1000 mg/day) or ibuprofen (2400 mg/day) over 52 weeks.175-177 In patients not taking aspirin, lumiracoxib was associated with a lower risk of bleeding, perforation, or obstruction compared to naproxen or ibuprofen (HR 0.21, 95% CI 0.12, 0.37, 1-year incidence of ulcer complications 0.25% vs. 1.09%).175 There was no difference in ulcer complication risk among aspirin users (HR 0.79, 95% CI 0.40, 1.55). The rate of myocardial infarction was low, ranging from 0.16% to 0.38%, and there were no statistically significant differences between interventions (HR 1.77 for lumiracoxib versus naproxen, 95% CI 0.82, 3.84 and HR 0.66 for lumiracoxib versus ibuprofen, 95% CI 0.21, 2.09).177 A recent fair-quality meta-analysis of 12 primarily short-term trials found no significant increase in risk of vascular events (RR 1.13, 95% CI 0.43 to 2.93), myocardial infarction (RR 1.07, 95% CI 0.20 to 5.63), stroke (RR 0.63, 95% CI 0.13 to 3.11), or vascular death (RR 2.55, 95% CI 0.54 to 12.0) with lumiracoxib relative to placebo.129 The number of events, however, was low, with only five myocardial infarctions among 1375 patients in the lumiracoxib arms (0.4%). GI and CV Safety: Comparison of NSAIDs Partially selective NSAIDs. Evidence that meloxicam, nabumetone, and etodolac prevent ulcer complications is weaker than that for coxibs. Meloxicam is the most widely studied of the three drugs and was generally associated with no advantage in GI protection relative to other partially-selective and non-selective NSAIDs or non-use.143, 178-185 Evidence for nabumetone and etodolac is sparse and insufficient to make reliable judgments about comparative GI and CV safety. Meloxicam. Risks of serious ulcer complications (perforation, bleeding, or obstruction) and/or MI were reported in one clinical trial of meloxicam179 and three observational studies.143, 180, 182 In the single, poor-quality (non-randomized and non-blinded) trial, meloxicam was not associated with significant differences in rates of GI hemorrhage at 6 months relative to other NSAIDs (RR 0.32; 95% CI 0.06, 1.63) in 4,526 rheumatoid arthritis patients seen by family or internal medicine physicians in Germany between August 1996 and July 1997.179 However, 54 differences in baseline disease severity could have favored the control group, and it is unclear whether the analyses adjusted for such baseline differences. Estimates of GI and CV risk have also been reported in two recent (2004) cohort studies that followed participants for 14 months180 and 2.4 years.143 GI complication-related hospitalizations were similar for meloxicam (0), nabumetone (1, 4.5%), salsalate (1, 5.9%), naproxen (5, 7.9%), and ibuprofen (0) among a cohort of long-term care residents in Indiana (mean age=81.2 years).180 In a cohort of 59,724 elderly individuals in Quebec, meloxicam (adjusted rate ratio 1.06; 95% CI 0.49, 2.30) and naproxen (1.17; 95% CI 0.75, 1.84) were associated with similar increases in risk of MI relative to non- use.143 Meloxicam (RR 1.5; 95% CI 0.1, 17.1), naproxen (RR 1.0; 95% CI 0.3, 3.3), and piroxicam (RR 0.7; 95% CI 0.2, 2.3) were also associated with similar nonsignificant risks of MI relative to diclofenac in a nested case-control study using data from the UK GPRD.182 Estimates of GI risk as measured by a composite score that included GI tolerability, PUBs, hospitalization or GI-related death outcomes were reported in a good-quality meta-analysis.183 Compared to non-use, the composite GI risk for meloxicam (RR 1.24; 95% CI 0.98, 1.56) was comparable with that of non-selective NSAIDs. Relative risks of GI hospitalizations or GI- related deaths alone were not reported. Composite GI outcome data from cohort studies were also analyzed in this study and suggested higher risk estimates (combined NSAID RR 2.2, 95% CI 1.7, 2.9) than the trials, but the results were not stratified by individual NSAIDs. Three meta-analyses focussing only on short-term trials reported PUBs (perforation, symptomatic ulcer, or bleeding) associated with meloxicam. The first meta-analysis included 10 trials (seven double-blinded).181 Most of the patients were followed for only 4 weeks, and the dose of meloxicam was 7.5 mg in 4 trials and 15 mg in 6 trials. The meta-analysis did not report absolute event rates, but found that the risk of PUBs was reduced in the meloxicam patients (OR 0.52, 95% CI 0.28-0.96) relative to non-selective NSAIDs. A twelve-week double-blind trial of meloxicam 7.5, 15 or 22.5 mg and diclofenac 75 mg bid in RA patients (n=894) published after this meta-analysis found similar PUB rates (1.1%, 0.5%, 0.6%, and 0%, respectively) in all arms.178 In a more recent meta-analysis funded by the manufacturer of meloxicam and using manufacturer-held documents from 28 trials, there was a dose-response relationship between meloxicam and PUBs as ascertained by a blinded, external adjudication committee.186 Meloxicam at 7.5 mg was associated with lower PUB rates during the first 60 days compared to diclofenac, piroxicam, or naproxen, but the 15 mg dose was only associated with lower PUB rates than piroxicam. In a third meta-analysis (not yet published) of three short-term (4- to 6- week) trials, there was no difference in the risk of complicated ulcers (perforations, obstructions and bleeds) associated with meloxicam relative to the non-selective NSAIDs piroxicam (two trials47, 52) and diclofenac(one trial49), with a relative risk of 0.50 ( 95% CI 0.23, 1.12).115 Nabumetone. For nabumetone, a fair-quality meta-analysis of six short-term (3 to 6 months) studies (five published and one abstract) found one PUB event among 4,098 patients taking nabumetone versus 17 events among 1,874 non-selective NSAID patients; this result was highly statistically significant.187 The absolute PUB rates were about 2 versus 6 per 1,000 patient-years. For comparison, in a similar meta-analysis of rofecoxib studies, the PUB rates per 1,000 patients per year were 13 for rofecoxib and 26 for NSAIDs;118 it is not clear why the rates of PUBs were so much lower in the nabumetone trials. There was also a significant reduction in treatment- related hospitalizations in the nabumetone group (6.4 per 1,000 patients per year vs. 20.3 per 1,000 patients per year). The results of this meta-analysis are not directly comparable to other trials and meta-analyses that reported complicated ulcers as a separate outcome because 55 symptomatic ulcers were also included. In addition, the methods used to ascertain the endpoints in the trials were not described in enough detail to determine whether they were accurate and applied consistently. Finally, the similarity of the subjects in the efficacy trials to a broader group of NSAID users could not be determined. Etodolac. We found no trials reporting rates of serious GI complications in patients taking etodolac. In two observational studies, etodolac was not associated with a lower rate of PUBs compared to non-use184 or naproxen.188 In another observational study using data from the UK General Practice Database, the adjusted relative risks of PUB compared with non-use ranged from 2.2 (95% CI 0.4, 11.3) for etodolac to 6.2 (95% CI 3.7, 10.1) for piroxicam and overlapped across all NSAIDs studied.189 When compared to naproxen using historical data from Dallas Veterans Affairs Medical Center records, etodolac had a GI protective effect for all users (RR 0.24, 95% CI 0.09, 0.63) and for NSAID-naïve users (RR 0.18, 95% CI 0.05, 0.61) only when low-dose aspirin was not taken concomitantly.188 Non-selective NSAIDs - GI safety. Randomized controlled trials115 and observational studies11, 190, 191 consistently report that non-selective, non-aspirin NSAIDs are associated with increased risks of serious GI events relative to non-use. There is no clear, consistent evidence that any one non-selective, non-aspirin NSAID is any less risky than another. Preliminary results (not yet published) from a meta-analysis of randomized controlled trials found that selective COX-2 inhibitors as a class (defined by the investigators as celecoxib, rofecoxib, valdecoxib, lumiracoxib, and meloxicam) were associated with lower risks of complicated ulcers (perforation, obstruction, or bleed) when compared with naproxen (0.34; 95% CI 0.24, 0.48), ibuprofen (0.46; 95% CI 0.30, 0.70), and diclofenac (0.31; 95% CI 0.06, 1.61).115 There were no clear differences among the three non-selective NSAIDs. The validity of these findings, however, cannot be assessed until the full report is published. However, they are consistent with results from a previous meta-analysis in which increased risks of GI complications (major plus minor) were similar for different NSAIDs relative to non-use: indomethacin (RR 2.25; 95% CI 1.01, 5.07), naproxen (RR 1.83; 95% CI 1.25, 2.68), diclofenac (RR 1.73; 95% CI 1.21, 2.46), piroxicam (RR 1.66; 95% CI 1.14, 2.44), tenoxicam (RR 1.43; 95% CI 0.40, 5.14), meloxicam (RR 1.24; 95% CI 0.98, 1.56) and ibuprofen (RR 1.19; 95% CI 0.93, 1.54).183 In an earlier, collaborative meta-analysis of cohort and case-control studies published between 1985 and 1994, use of all non-selective NSAIDs were associated with significantly increased risks of peptic ulcer complication hospitalizations relative to non-use.190 Ibuprofen, at doses used in general practice, was associated with the lowest risk of peptic ulcer complication- related hospitalizations.190 In a subsequent meta-analysis of cohort and case-control studies published between 1990 and 1999, however, risk of serious GI event-related hospitalizations and specialist visits was dose-dependent, and was no lower for ibuprofen compared to any other non- aspirin, non-selective NSAID when results were stratified by low to medium (RR 2.1, 95% CI 1.6, 2.7) or high dose (RR 5.5, 95% CI 3.0, 10.0) (Table 18).184, 191 A more recent review of observational studies published through 2002 also found GI bleeding risk increased for all non- selective NSAIDs, and risk appeared related more to dose than to the specific drug evaluated.11 56 Table 18. Relative Risk (95% CI) of UGIB* for NSAIDs vs. non-use Hernandez-Diaz Garcia-Rodriquez 191 2000 2001184 Dose Overall NSAID Overall Low-Medium High Diclofenac 3.3 (2.8, 3.9) 3.1 (2.0, 4.7) 3.6 (2.3, 5.6) 4.6 (3.6, 5.8) Ibuprofen 1.9 (1.6, 2.2) 2.1 (1.6, 2.7) 5.5 (3.0, 10.0) 2.5 (1.9, 3.4) Indomethacin 4.6 (3.8, 5.5) 3.0 (2.2, 4.2) 6.5 (4.8, 8.6) 5.2 (3.2, 8.3) Ketoprofen 4.6 (3.3, 6.4) NR NR 3.3 (1.9, 5.9) Naproxen 4.0 (3.5, 4.6) 3.5 (2.8, 4.3) 5.1 (3.8, 6.9) 4.0 (2.8, 5.8) Piroxicam 6.3 (5.5, 7.2) 5.6 (4.7, 6.7) 6.2 (4.4, 8.7) 6.2 (3.7, 10.1) Sulindac 3.6 (2.8, 4.7) NR NR NR *Upper GI tract bleeding/perforation Non-selective NSAIDs were also associated with an increased risk of serious GI events in more recent observational studies. Ibuprofen (Odds Ratio 1.42, 95% CI 1.27, 1.59), diclofenac (OR 1.96; 95% CI 1.78, 2.15) and naproxen (OR 2.12, 95% CI 1.73, 2.15) were all associated with increased risks of GI hemorrhage, perforation, surgery or undefined uncomplicated events relative to non-use in a case-control study of the UK General Practice Research Database.138 Odds ratios for upper GI events resulting in hospitalization associated with NSAIDs relative to non-use ranged from 3.1 (95% CI 2.0, 4.9) for ibuprofen to 24.7 (95% CI 8.0, 77.0) for ketorolac based on data from 10 hospitals in Spain using a case-control design.141 Non-selective NSAIDs – CV Safety Randomized controlled trials. Evidence regarding the comparative risk of serious CV events for non-selective NSAIDs is more limited than the evidence for selective COX-2 inhibitors. In particular, long-term clinical trials are lacking. A recent, fair-quality meta-analysis by Kearney and colleagues of 91 trials (mostly ranging from 4 to 13 weeks in duration) evaluated risks with any non-selective NSAID (33,260 person-years of exposure) compared to any COX-2 inhibitor (23,325 person-years of exposure).129 Most of the trials evaluated naproxen (42 trials), ibuprofen (24 trials), and diclofenac (26 trials); only 7 evaluated other non-selective NSAIDs. Generalizability to usual practice could be limited because the majority of the trials evaluated higher than standard doses of NSAIDs. Much of the data regarding cardiovascular event rates were obtained by requesting unpublished data from trial sponsors. Other characteristics of this meta-analysis are discussed in more detail in the section on cardiovascular risks associated with rofecoxib. Table 19 shows estimates of risk for different cardiovascular outcomes with COX-2 inhibitors relative to non-selective NSAIDs. Risk of myocardial infarction was similar with COX-2 inhibitors and non-naproxen NSAIDs, but about two-fold greater for COX-2 inhibitors compared to naproxen (0.6% or 99/16360 vs. 0.3% or 30/10,978, RR 2.04, 95% CI 1.41 to 2.96). This is equivalent to about one additional myocardial infarction for every 301 patients treated for one year with a COX-2 inhibitor instead of naproxen. COX-2 inhibitor use was also associated with a lower risk of stroke relative to non-naproxen NSAIDs (RR 0.62, 95% CI 0.41 to 0.95). In subgroup analyses of specific non-selective NSAIDs (ibuprofen, diclofenac, other non-selective NSAIDs), the difference in stroke risk was only observed with diclofenac, which was usually evaluated at high doses (RR 0.48, 95% CI 0.27 to 0.83). There was insufficient data to analyze the effects of lower doses on estimates of risk. 57 129 Table 19. Rate Ratios (95% CI)*: COX 2 inhibitor relative to non-selective NSAID Myocardial Vascular NSAID group Vascular events Infarction Stroke Death Any non-selective 1.16 (0.97 to 1.38) 1.53 (1.19 to 1.97), 0.83 (0.62 to 1.12) 0.97 (0.69 to 1.35) NSAID p=0.0009 Any non-naproxen, 0.88 (0.69 to 1.12) 1.20 (0.85 to 1.68) 0.62 (0.41 to 0.95), 0.67 (0.43 to 1.06) non-selective NSAID p=0.03 Naproxen 1.57 (1.21 to 2.03) 2.04 (1.41 to 2.96), 1.10 (0.73 to 1.65) 1.47 (0.90 to 2.40) p=0.0002 *Rate ratios below 1 favor COX 2 inhibitors and rate ratios above 1 favor NSAIDs Kearney and colleagues found insufficient data to directly estimate risks of non-selective NSAIDs from placebo-controlled trials. Indirect analyses (based on trials of non-selective NSAIDs versus COX-2 inhibitors and trials of COX-2 inhibitors versus placebo) suggest an increased risk of vascular events with ibuprofen (RR 1.51, 95% CI 0.96 to 2.37) and diclofenac (RR 1.63, 95% CI 1.12 to 2.37) relative to placebo, but not with naproxen (RR 0.92, 95% CI 0.67 to 1.26). However, indirect analyses should be interpreted with caution because they can give discrepant results compared to head-to-head comparisons.192 In December 2004, the Alzheimer's Disease Anti-Inflammatory Prevention Trial (ADAPT) was suspended in part because of an "apparent increase in cardiovascular and cerebrovascular events among the participants taking naproxen when compared with those on placebo."111 However, further details from the ADAPT trial have not yet become available. Observational studies—naproxen. The risk of MI and other cardiovascular events associated with various non-selective NSAIDs has been evaluated in numerous observational studies. Naproxen has been the most extensively studied non-selective NSAID because of interest generated after the results of the VIGOR trial were published. In order to assess the proposed hypothesis that naproxen is protective against myocardial infarction (rather than rofecoxib causing additional myocardial infarctions), authors of a meta-analysis of randomized controlled trials of rofecoxib also analyzed 11 observational studies of naproxen (four based on the General Practice Research Database).124 Compared with non-naproxen NSAIDs, naproxen was associated with a small cardioprotective effect (OR 0.86, 95% CI 0.75 to 0.99). The modest cardioprotective effect would not completely explain the 80% reduction in risk with naproxen compared with rofecoxib observed in the VIGOR trial. In addition, meta-regression analyses indicated that the funding source largely explained between-study heterogeneity. Specifically, Merck-funded studies of naproxen reported larger cardioprotective effects. An FDA review of four observational studies of naproxen reporting a cardioprotective effect illustrate some difficulties in interpreting the results.148 In a study by Rahme and colleagues, current exposure to naproxen was associated with a lower risk of acute MI compared with exposure to other NSAIDs (OR 0.79, 95% CI 0.63 to 0.99).193 However, when the FDA reviewer re-analyzed the data to compare current exposure to naproxen to non-use of NSAIDs, naproxen was associated with a higher risk (OR 1.28, 95% CI 1.10 to 1.49).148 Although the FDA re-analysis was not adjusted for confounders, examination of adjusted and unadjusted results in the paper suggests that the effects of adjusting would be minor. A study by Kimmel and colleagues found naproxen associated with a lower risk of MI compared with non-use (OR 0.48, 95% CI 0.28 to 0.82), but the results were susceptible to participation bias (about 50% of cases and controls participated) and recall bias (exposure determined by telephone interviews rather than by using pharmaceutical databases or other sources).194 The third study, by Watson 58 and colleagues, reported a lower risk of thromboembolic cardiovascular events with current use of naproxen versus non-use (OR 0.61, 95% CI 0.39 to 0.94), but did not adequately control for baseline cardiovascular risk (it used an unvalidated composite measure of risk).195 Further, when the endpoint of MI alone rather than the composite endpoint of thromboembolic cardiovascular events (which included subdural hematoma, subarachnoid hemorrhage, ischemic stroke, sudden death, or MI) was evaluated, the reduction in risk was not significant (OR 0.57, 95% CI 0.31 to 1.06). Finally, a study by Solomon and colleagues reported a lower risk of MI with use of naproxen within 6 months of an acute MI (OR 0.84, 95% CI 0.72 to 0.98).196 However, the risk was reduced to a similar degree when the naproxen prescription had run out between 61 and 180 days earlier. Unless naproxen exerts a long-term cardioprotective effect (which is thought to be highly unlikely), these findings are suggestive of underlying selection bias—in other words, persons receiving naproxen were at lower risk for cardiovascular events, and adjustment for known confounders did not eliminate this bias. In four other recent observational studies (not included in the Juni systematic review) evaluating cardiovascular risk, naproxen was not associated with a cardioprotective effect relative to non-use (Table 20).143, 146, 149, 155, 160 However, naproxen was also not clearly associated with an increased risk of myocardial infarction. None of these studies received pharmaceutical industry funding. The FDA review also included two other unpublished studies (Ingenix and MediCal studies) that found no cardioprotective benefit associated with naproxen.148 Table 20. Risk of myocardial infarction associated with naproxen in recent observational studies not included in the Juni meta-analysis Study Estimate of risk (current use versus no or remote use) Hippisley-Cox, 2005146 1.27 (1.01 to 1.60) Levesque, 2005143 1.17 (0.75 to 1.84) Johnsen, 2005149 1.50 (0.99 to 2.29) Andersohn 2006155 1.16 (0.86 to 1.58) Overall, the general conclusion from observational studies of a modest decrease in cardiovascular risk associated with naproxen relative to other NSAIDs appears consistent with a systematic review of RCTs.129 On the other hand, protective cardiovascular effects of naproxen relative to non-use observed in some observational studies usually appear to be explainable by issues related to study design or analysis. More recent, high-quality observational studies are mostly consistent with a neutral cardiovascular effect of naproxen relative to non-use. Observational studies—non-naproxen NSAIDs. Results from observational studies regarding the cardiovascular risk associated with non-naproxen, non-selective NSAIDs are mixed. Non-selective NSAIDs as a class and individual NSAIDs have not been consistently associated with increased risks. Results from recent observational studies from the COX-2 era are summarized in Table 21. 59 Table 21. Risk of myocardial infarction associated with non-selective, non-naproxen NSAIDs Study Drug Estimate of risk (current use versus no or remote use) Hippisley-Cox, 2005146 Ibuprofen 1.24 (1.11 to 1.39) Diclofenac 1.55 (1.39 to 1.72) Other non-selective, non-naproxen 1.21 (1.02 to 1.44) NSAIDs 160 Graham, 2005 Non-selective, non-naproxen 1.13 (1.01 to 1.27) NSAIDs Levesque, 2005143 Non-selective, non-naproxen 1.00 (0.73 to 1.37) NSAIDs Johnsen, 2005149 Non-selective, non-naproxen 1.50 (0.99 to 2.29) NSAIDs Garcia Rodriguez, 2004185 Ibuprofen 1.06 (0.87 to 1.29) Diclofenac 1.18 (0.99 to 1.40) Ketoprofen 1.08 (0.59 to 1.96) Piroxicam 1.25 (0.69 to 2.25) Indomethacin 0.86 (0.56 to 1.32) Other non-selective, non-naproxen 0.89 (0.63 to 1.25) NSAIDs Mamdani, 2003147 Non-selective, non-naproxen 1.2 (0.9 to 1.4) NSAIDs Ray, 2002151 Ibuprofen 0.91 (0.78 to 1.06) Solomon, 2002196 Ibuprofen 1.02 (0.88 to 1.18) Watson, 2002195 Ibuprofen 0.74 (0.35 to 1.55) Diclofenac 1.68 (1.14 to 2.49) Andersohn, 2006155 Ibuprofen 1.00 (0.83, 1.21) Diclofenac 1.36 (1.17, 1.58) Schlienger 2002197 Ibuprofen 1.17 (0.87, 1.58) Diclofenac 1.38 (1.08, 1.77) Piroxicam 1.65 (0.78, 3.49) Ketoprofen 1.39 (0.77, 2.51) Indomethacin 1.03 (0.58, 1.85) Flurbiprofen 2.26 (0.93, 5.46) In April 2005, after reviewing the available observational data, the FDA issued a Public Health Advisory stating, "Long-term controlled clinical trials have not been conducted with most of these (non-selective) NSAIDs. However, the available data suggest that use of these drugs may increase CV risk. It is very difficult to draw conclusions about the relative CV risk among the COX-2 selective and non-selective NSAIDs with the data available. All sponsors of non- selective NSAIDs will be asked to conduct and submit to FDA a comprehensive review and analysis of available controlled clinical trial databases pertaining to their NSAID product(s) to which they have access to further evaluate the potential for increased CV risk."198 The FDA also required labeling changes to both prescription and non-prescription non-selective NSAIDs warning about potential cardiovascular risks. Aspirin. Aspirin is known to be protective against occlusive vascular events because of its irreversible antiplatelet effects. In a collaborative meta-analysis of 65 randomized controlled trials of aspirin for prophylaxis against thrombotic events, any dose of aspirin reduced the risk of vascular events by an average of 23% (standard error 2).199 The cardioprotective effects of aspirin appeared lower (13%) in three trials evaluating doses of lower than 75 mg/day, but in trials that directly compared higher and lower doses, there were no significant differences. Again, the populations evaluated in these trials probably varied substantially from trials of 60 patients with arthritis. In fact, randomized controlled trials assessing the risk of upper GI bleeding with aspirin have mainly been conducted in populations receiving aspirin as prophylaxis for thrombotic events. It is for this reason that the populations evaluated in these trials may differ on risk factors for bleeding compared to patients who take aspirin for arthritis, as well as being at higher cardiovascular risk. Randomized controlled trials200 and observational studies generally reported that aspirin increases risk of serious GI events relative to placebo or non-use,138, 190, 200, 201 but at a rate similar to that of other non-selective NSAIDs.138, 189, 190 In these studies, the dose of aspirin varied widely and was generally lower (50 mg to 1500 mg daily) than the doses considered effective for analgesia and anti-inflammatory effects, and patients typically received aspirin for prolonged periods. In a good-quality meta-analysis of 24 randomized trials with nearly 66,000 participants, the risk of gastrointestinal hemorrhage was 2.47% with aspirin compared with 1.42% with placebo (OR 1.68, 95% CI 1.51 to 1.88), based on an average of 28 months therapy.200 There was no relation between gastrointestinal hemorrhage and dose in this study. Further, modified release formulations did not attenuate the risk for bleeding. In a more recent, fair-quality meta-analysis of 31 randomized trials with over 190,000 subjects, the risk of major bleeding was 1.56% with doses <100 mg, 1.54% with 100-200 mg, and 2.29% with >200.202 Although the difference between doses >200 and <100 was statistically significant, the absolute differences are small. Systematic reviews of cohort and case-control studies published between 1985 and 2001 reported similar findings,189, 190, 201 except that the most recent review found a dose-response relationship between aspirin and risk of bleeding.189 However, aspirin was associated with upper GI bleeding even at low doses. Findings from a recent UK practice-based case-control study (9,407 cases) found that compared with non-use, aspirin was associated with an increased risk of complicated or uncomplicated adverse GI events (odds ratio 1.60, 95% CI 1.49, 1.72) similar to that of naproxen, diclofenac, and ibuprofen.138 These findings are consistent with a systematic review of observational studies that only assessed peptic ulcer-related hospitalizations.190 Salsalate. Serious GI event rates (bleeding, perforation, obstruction) associated with salsalate were only reported in one cohort of long-term care residents in Indiana. The number of cases of GI-related hospitalizations associated with salsalate (1, 5.9%) after 14 months was similar to that of other selective and non-selective NSAIDs (cited in partially selective NSAID section above).180 Other Adverse Events Associated with Selective and Non-Selective NSAIDs Mortality. Large clinical trials have not shown differences in mortality rates between different NSAIDs. In VIGOR, for example, mortality was 0.5% with rofecoxib versus 0.4% with naproxen,19 and in CLASS mortality rates were 0.47%, 0.37%, and 0.45% for celecoxib, diclofenac, and ibuprofen, respectively.94 A meta-analysis that included unpublished company clinical trial data (including CLASS) found no significant difference in rates of death in patients randomized to celecoxib compared with non-selective NSAIDs, though there were few events (0.03% or 6/18,325 in the celecoxib arms versus 0.11% or 14/12,685 in the NSAID arms).62 In one retrospective cohort study of Saskatchewan health-services databases that followed patients from 6 months following prescription until death, nabumetone was associated with significantly lower rates of all-cause mortality compared with diclofenac (adjusted odds ratio 1.96; 95% CI 61 1.25, 3.07) and naproxen (adjusted odds ratio 2.95, 95% CI 1.88, 4.62).203 However, we found no other studies replicating this finding. Hypertension, CHF, edema, and renal function. All non-selective NSAIDs appear to be associated with increases in blood pressure. However, evidence regarding differential effects of specific NSAIDs is somewhat conflicting. Two meta-analyses of placebo-controlled trials have compared the effects of different non-selective NSAIDs on blood pressure increases.204, 205 One meta-analysis found that non-selective NSAIDs raised mean blood pressure by an average of about 5.0 mm Hg (95% CI, 95% CI 1.2 to 8.7).204 Piroxicam produced the most marked elevation in blood pressure.204 By contrast, the other meta-analysis found that piroxicam and ibuprofen had negligible effects on blood pressure, and that indomethacin and naproxen were associated with the largest increases.205 In both meta-analyses, aspirin and sulindac were associated with minimal hypertensive affect. In an analysis of head-to-head trials, there were no significant differences between indomethacin and sulindac (10 trials), indomethacin and salicylate (one trial), diclofenac and sulindac (one trial), ibuprofen and sulindac (one trial), and naproxen and sulindac (three trials).204 The reliability of the meta-analyses is compromised by a high likelihood of publication bias; more than half of published NSAID trials did not report hypertension rates as an outcome.205 Several studies have reported hypertension outcomes for selective COX-2 inhibitors compared to non-selective NSAIDs. One fair-quality meta-analysis found COX-2 inhibitors as a class (celecoxib, rofecoxib, and etoricoxib) not associated with an increased risk of developing hypertension compared to non-selective NSAIDs (RR 1.25, 95% CI 0.87 to 1.78). Pooling evidence on blood pressure effects from various selective and non-selective NSAIDs may be misleading, however, because of potential differences between COX-2 inhibitors, dissimarilities in dosing and comparator drugs, and a high likelihood of publication bias affecting conclusions. Evidence regarding risks of hypertension with rofecoxib is somewhat mixed. A good-quality Cochrane review found that rates of edema and hypertension were not reported in most trials.77 For rofecoxib versus nabumetone, there was no difference in the rate of hypertension in two trials (pooled RR 1.46, 95% CI 0.53 to 4.12). A meta-analysis of nine phase IIb/III osteoarthritis trials sponsored by the manufacturer of rofecoxib found that rofecoxib 12.5 mg and 25 mg daily were associated with higher rates of lower extremity edema, congestive heart failure, and hypertension than placebo.206 Edema and hypertension rates were similar between the rofecoxib (1.2 per 100 patient-months) and ibuprofen (1.3 per 100 patient-months) groups but somewhat higher than in the diclofenac group (0.3 per 100 patient months). Discontinuations due to these adverse events were rare: of 2,829 randomized to rofecoxib, seven discontinued due to edema, two due to hypertension, and one due to CHF. However, five of the nine trials were shorter than 6 weeks in duration, so these rates may not be representative of results in long-term users. A more recent fair-quality meta-analysis of arthritis trials found rofecoxib associated with a higher risk of developing hypertension compared to either placebo (RR 2.63, 95% CI 1.42 to 4.65) or non-selective NSAIDs (RR 1.78, 95% CI 1.17 to 2.69).21 Results of large, longer-term trials appear to be consistent with an increased risk of hypertension with rofecoxib compared to either placebo or non-selective NSAIDs. In VIGOR (N=8,076) rofecoxib 50 mg daily was associated with a higher risk of developing hypertension compared to naproxen (RR 1.69, 95% CI 1.42-1.99) and a higher risk of discontinuation due to hypertension-related adverse events (RR 4.67, 95% CI 1.93 to 11.28).114 In addition, 19 patients developed CHF-related adverse events during 4,047 patient-years of exposure, compared with 62 nine patients during 4,029 patient-years of exposure to naproxen (RR 2.11, 95% CI 0.96 to 4.67). In the long-term APPROVe polyp prevention trial, hypertension (RR 2.02, 95% CI 1.71 to 2.38), edema (RR 1.57, 95% CI 1.17 to 2.10), and heart failure or pulmonary edema (RR 4.61, 95% CI 1.50 to 18.83) were all increased with rofecoxib 25 mg qD compared with placebo.132 In contrast to rofecoxib, several meta-analyses of celecoxib suggest no increased risk of hypertension or heart failure compared to non-selective NSAIDs. In fact, a recent fair-quality meta-analysis found celecoxib (dose not specified) not associated with an increased risk of hypertension compared to either placebo (RR 0.81, 95% CI 0.13 to 5.21) or non-selective NSAIDs (RR 0.82, 95% CI 0.68 to 1.00).21 On the other hand, a Pfizer-funded meta-analysis submitted to the FDA found that, for celecoxib (any dose), the risk of developing hypertension was higher than placebo (1.1% vs. 0.7%, p=0.023) but lower than the non-selective NSAIDs (1.5% vs. 2.0%, p=0.002).135 Heart failure was more frequent in patients taking celecoxib than those taking placebo (13 of 8,405 versus one of 4,057, p=0.046), though not compared with non- selective NSAIDs (0.1% vs. 0.2%, p=0.056). A third meta-analysis, funded in part by the manufacturer, reported similar findings for risk of hypertension (celecoxib vs. non-selective NSAID RR 1.1, 95% CI 0.90 to 1.3) and heart failure (celecoxib vs. non-selective NSAID RR 0.70, 95% CI 0.43 to 1.1).62 Most of the trials included in the meta-analyses were short-term and only one meta-analysis62 evaluated the quality of the trials. However, results from large trials of celecoxib are consistent with the meta-analyses. In CLASS (N=8,059), celecoxib was associated with a similar rate of hypertension (new-onset and aggravated pre-existing) compared with diclofenac (2.7% vs. 2.6%), but a significantly lower rate than ibuprofen (2.7% vs. 4.2%).105 CHF rates were similar in patients randomized to celecoxib versus either ibuprofen or diclofenac (0.3% vs. 0.3%). In the shorter-term SUCCESS-I trial (N=13,274), rates of hypertension were similar with celecoxib 100 or 200 mg bid compared to either diclofenac or naproxen (RR 0.86, 95% CI 0.62 to 1.20).21 The APC polyp prevention trial found celecoxib associated with significant systolic blood pressure elevations compared to placebo at 1 and 3 years at either 200 mg twice daily (2.0 mm Hg at 1 year and 2.6 mm Hg at 3 years) and 400 mg twice daily (2.9 mm Hg at 1 year and 5.2 mm Hg at 3 years).109 By contrast, the PreSAP polyp prevention trial found no difference in systolic blood pressure elevations between celecoxib 400 mg once daily and placebo.109 The APC polyp prevention trial found no difference in rates of heart failure between patients randomized to celecoxib versus those randomized to placebo, though event rates were low (five cases of heart failure among 1,356 subjects).108 Direct evidence on comparative blood pressure effects of celecoxib compared to rofecoxib is more limited. A good-quality Cochrane review found no difference in rates of clinically significant increases in blood pressure or edema with rofecoxib versus celecoxib in three head- to-head trials of average-risk populations with osteoarthritis.77 Another meta-analysis that used unpublished clinical trial reports also found no difference in risk of hypertension or aggravated hypertension in patients on celecoxib versus rofecoxib (RR 0.75, 95% CI 0.52 to 1.1).62 On the other hand, in contrast to the Cochrane review, this meta-analysis found a lower rate of edema with celecoxib versus rofecoxib (5 trials, RR 0.72, 95% CI 0.62 to 0.83). A third meta-analysis found rofecoxib associated with a greater risk of developing a clinically important elevation in systolic blood pressure (RR 1.50, 95% CI 1.00 to 2.26), though the difference was not statistically significant.21 Three other short-term head-to-head trials of celecoxib and rofecoxib in higher-risk populations (hypertensive, osteoarthritic patients) funded by the manufacturer of celecoxib should be interpreted cautiously because they evaluated doses (rofecoxib 25 mg daily and 63 celecoxib 200 mg daily) that may not provide equivalent pain relief.84, 85, 207 Two 6-week trials of elderly (>65 years) patients with osteoarthritis and on antihypertensive therapy (SUCCESS VI and SUCCESS VII) found that rates of increased systolic blood pressure (>20 mm Hg increase and absolute value >140 mm Hg) were higher in patients randomized to rofecoxib (n=399) compared to celecoxib (n=411): 14.9% vs. 6.9% (p<0.01) in one trial85 and 17% vs. 11% (p=0.032) in the other.84 However, in one of these trials (SUCCESS VI),84 there was an important baseline difference in the proportion of patients who took an ACE inhibitor for hypertension (40% for celecoxib-treated patients versus 29% for rofecoxib-treated patients, p=0.002). This could suggest inadequate randomization, as successful randomization is unlikely to have resulted in such a marked baseline difference. In the third trial (CRESCENT), which enrolled patients with controlled hypertension, diabetes, and osteoarthritis, the proportion that developed ambulatory hypertension (systolic blood pressure >135) was higher with rofecoxib than with celecoxib (30% vs. 16%, p=0.05).207 In the CRESCENT and SUCCESS-VI trials, edema was more common in patients assigned to rofecoxib compared with those assigned to celecoxib (7.7% vs. 4.7%, p<0.05207 and 9.5% vs. 4.9%, p=0.01484). Three patients on rofecoxib and two on celecoxib developed heart failure in CRESCENT compared with four versus none in SUCCESS-VI; these differences were not significant. Discontinuations due to these adverse events did not differ. With regards to renal toxicity, there is little evidence to suggest that selective NSAIDs as a class are safer than non-selective NSAIDs. A systematic review of five small (sample size range 15 to 67), short-term (28 days or less) trials found that selective NSAIDs had similar effects on glomerular filtration rate and creatinine clearance in three trials, and were modestly superior in two.208 The clinical effects of the modest differences observed in the latter two trials are unclear. Another meta-analysis found that celecoxib at 200 to 400 mg was not associated with a greater risk of increase in creatinine greater than 1.3 times the upper limit of normal compared to non- selective NSAIDs (RR 0.78, 95% CI 0.46 to 1.3).62 There is also no clear evidence suggesting that celecoxib is associated with improved renal safety compared with rofecoxib. In the CLASS trial, there was one fewer episode of edema, hypertension, or increased creatinine for every 62 patients treated with celecoxib instead of ibuprofen 800 mg tid or diclofenac 75 bid.60 The effects of celecoxib on renal function were also reviewed in a meta-analysis of primarily unpublished data (not including CLASS) that found the overall incidence of renal adverse events similar to that of non-selective NSAIDs.209 In VIGOR, the incidence of adverse events related to renal function (outcome not specifically defined) was similar for the rofecoxib and naproxen groups (1.2% versus 0.9%), with 0.2% discontinuing treatment in each arm because of these events.19 A meta-analysis of manufacturer's data found rofecoxib associated with an overall incidence of elevations in serum creatinine similar to non-selective NSAIDs.206 Discontinuations due to elevated serum creatinine were rare, and there were no cases of acute renal failure (not defined) associated with rofecoxib. The risks of hypertension and heart failure with rofecoxib and celecoxib have also been evaluated in several good-quality observational studies. A large case-control study found that rofecoxib users were at significantly increased risk for new-onset hypertension compared with patients taking celecoxib (OR 1.6, 95% CI 1.2 to 2.1).210 A retrospective cohort study found rofecoxib associated with an increased risk of admission for heart failure compared with NSAID–non-users (RR 1.8, 95% CI 1.5 to 2.2), though celecoxib was not (RR 1.0, 95% CI 0.8 to 1.3).163 Rofecoxib (HR 1.27, 95% CI 1.09 to 1.49) and non-selective NSAIDs (HR 1.26, 95% CI 1.00 to 1.57) were also associated with higher risks of death or recurrent CHF compared with 64 celecoxib in another study of high-risk patients following a heart-failure admission.211 In two observational studies, use of non-selective NSAIDs was associated with heart-failure admissions (RR 1.4, 95% CI 1.0 to 1.9)163 and newly diagnosed heart failure (adjusted RR 1.6, 95% CI 1.2 to 2.1)212 when compared with non-use. Hepatotoxicity. We identified one systematic review that evaluated rates of aminotransferase elevations, liver-related discontinuations, and other serious hepatic adverse events, including hospitalizations and deaths, in randomized controlled trials of rofecoxib, celecoxib, valdecoxib, meloxicam, diclofenac, naproxen, and ibuprofen in adults with osteoarthris or rheumatoid arthritis.213 It identified 67 published articles and 65 studies accessible from the FDA archives. Diclofenac (3.55%, 95% CI 3.12% to 4.03%) and rofecoxib (1.80%, 95% CI 1.52% to 2.13%) had higher rates of aminotransferase elevations >3 times the upper limit of normal compared with placebo (0.29%; 95% CI 0.17% to 0.51%) and the other NSAIDs (all < or = 0.43%). However, only diclofenac was associated with a higher rate of liver-related discontinuations than placebo (2.17%, 95% CI 1.78% to 2.64%). Serious complications related to liver toxicity were extremely rare: only one liver-related hospitalization (among 37,671 patients) and death (among 51,942 patients) occurred in a patient on naproxen in the VIGOR trial. There was also a statistically significant difference in elevated (three times above the upper limit of normal) transaminase levels between lumiracoxib (which is chemically related to diclofenac) and naproxen or ibuprofen (HR 3.97, 95% CI 2.96, 5.32) in the large TARGET (N=18,325) trial, though these elevations were reversible upon drug discontinuation.175 A recent systematic review of seven population-based epidemiological studies of hepatotoxicity with NSAIDs found a similarly low risk of serious hepatic toxicity.214 In those studies, the excess risk of liver injury associated with current NSAIDs ranged from 4.8 to 8.6/100,000 person-years of exposure compared with past use. There were zero deaths from liver injury associated with NSAIDs in over 396,392 patient-years of exposure. A recent cohort study from Italy found that nimesulide, an NSAID not available in the U.S., was associated with a higher incidence of serious liver injury compared with other NSAIDs.215 None of the other NSAIDs, including celecoxib, were associated with an increased risk of serious liver injury. An earlier review of five population-based studies found sulindac associated with a 5-10 fold higher incidence of hepatic injury compared with other NSAIDs.216 Diclofenac was associated with higher rates of aminotransferase elevations compared with users of other NSAIDs, but not with a higher incidence of serious liver disease. Tolerability: Comparison of NSAIDS Partially selective NSAIDs. Evidence is mixed regarding the relative tolerability of meloxicam (7.5 mg or 15 mg) compared to non-selective NSAIDs. The meta-analysis of meloxicam studies mentioned earlier found lower rates of any gastrointestinal event (OR 0.64; 95% CI 0.59, 0.69) and withdrawals due to GI events (OR 0.59; 95% CI 0.52, 0.67) compared with NSAIDs, but as mentioned before it included some inadequately blinded studies, which are less reliable for assessing withdrawals and attributing the cause of adverse events.181 The double- blind trial of meloxicam 7.5, 15, and 22.5 mg and diclofenac 75 mg bid mentioned earlier217 found no significant differences in rates of withdrawals due to adverse events or in incidence of overall and gastrointestinal tolerability. In the nabumetone meta-analysis, the incidence of GI adverse events was significantly lower on nabumetone compared to non-selective NSAIDs (25.3% vs. 28.2%, p=.007), corresponding to 65 about one fewer event for every 34 patients treated with nabumetone.187 Numerous randomized controlled trials reported microscopic bleeding or endoscopic outcomes with etodoloca. However, we identified no randomized trials or systematic reviews assessing the clinical tolerability of etodolac relative to non-selective NSAIDs. Non-selective NSAIDs. One Cochrane review evaluated the tolerability of different NSAIDs.41 The only relatively consistent finding was that indomethacin was associated with higher rates of toxicity than other NSAIDs, but it was not clear if these differences were statistically significant. Aspirin and salsalate. Five randomized trials have evaluated the efficacy or safety of aspirin or salsalate compared with non-aspirin NSAIDs in patients with arthritis.56, 218-221 All were short- term in duration (≤ 12 weeks) and involved a total of 471 patients; of the subjects enrolled, only four had osteoarthritis of the hip/knee for every 100 patients with rheumatoid arthritis. Aspirin was associated with higher incidence of overall adverse events than salsalate (70% vs. 40%, p<0.05)56 and diclofenac (61% vs. 46%; p<0.05);218 these led to higher rates of withdrawals due to adverse events for aspirin compared with diclofenac (23% vs. 6%; p<0.05). Salsalate was associated with a higher incidence of overall adverse events compared to other non-selective NSAIDs in two220, 221 of three trials, but the actual rates were not reported. The overall safety profile of salsalate has also been evaluated in the rheumatoid arthritis population using the Arthritis, Rheumatism, and Aging Medical Information System (ARAMIS) databases. These studies reported summary measures of drug toxicity based on tabulations of mean frequencies of overall adverse events per patient years, weighted by severity, and adjusted for differences in demographic factors. Numerically larger index scores indicate greater levels of toxicity. The summary index score takes into account symptoms from all body systems, laboratory abnormalities, and all-cause hospitalizations.201, 222-224 Symptoms were assessed every 6 months using patient self-report in response to open-ended questions. Hospitalization and death data were ascertained from discharge summaries and death certificates. Descriptions of study methods varied, but in general the ARAMIS studies were somewhat vague with regard to patient selection and ascertainment methods; adverse events were not clearly defined or prespecified; exposure duration and length of follow-up were unclear; and adjustments were made only for demographic factors such as age and gender. Because the results of these studies are more subject to recall bias and had other methodological shortcomings, the findings that aspirin, salsalate, and ibuprofen were the least toxic among the NSAIDs studied (Table 22 below) are less convincing than results of more recent observational studies (discussed earlier). Table 22. Toxicity Index Scores from ARAMIS database studies Study Aspirin Ibuprofen Salsalate Others (range) Fries 1991222 1.19 1.94 1.28 2.17 (Naproxen) to 3.99 (Indomethacin) Fries 1993224 1.33 1.89 NR 1.90 (Naproxen) to 2.86 (Tolmetin) Fries 1996223 1.77 2.68 2.00 1.63 (Sulindac) to 3.09 (Ketoprofen) 201 Singh 1997 2.25 1.95 1.79 3.29 (Naproxen) to 5.14 (Meclofenamate) COX-2 vs. NSAID. Two manufacturer-funded meta-analyses61, 62 and one good-quality Cochrane review225 found celecoxib consistently associated with more favorable overall and GI tolerability profiles relative to some, but not all, non-selective NSAIDs in short-term RCTs of 66 patients with OA/RA (Table 23). Evidence of relative tolerability is less consistent for rofecoxib compared to partially-selective or non-selective NSAIDs in short-term RCTs of patients with OA/RA as reported in one manufacturer-funded meta-analysis,226 two good-quality Cochrane reviews;77, 78 and one other RCT that was not included in the systematic reviews.76 Effect size differences between the COX-2 manufacturer-funded analyses and the Cochrane reviews may have been due, in large part, to differences in methods of study selection and statistical analyses. The Cochrane Reviews primarily relied upon electronic database searches for identification of published RCTs evaluating narrow patient populations, and results from each trial were generally presented separately.77, 78, 225 Manufacturer-funded meta-analyses relied soley62, 226 or in part61 on internal records to identify studies and presented only pooled estimates of broader populations including OA and RA patients. Table 23. Tolerability profile of COX-2's vs. NSAIDs in meta-analysis and systematic reviews Review AE incidence Withdrawals Overall GI-related Any AE GI-related Celecoxib vs. NSAIDs for OA/RA Manufacturer-funded meta-analyses Deeks 200261 - - RR 0.86 (0.72, 1.04) RR 0.54 (0.42, 0.71) Moore 200562 0.96 (0.94, 0.98) 0.84 (0.81, 0.87) RR 0.86 (0.81, 0.91) RR 0.75 (0.7, 0.8) Celecoxib vs. individual NSAIDs for RA Garner 2005a225 (Cochrane Collaboration Systematic Review) Celecoxib vs. Naproxen - - No differences No differences (RR Range: 1.02- (RR Range: 0.26-0.61) 1.36) Celecoxib vs. Diclofenac 0.75 (0.62, 0.90) 0.95 (0.85, 1.04 0.54 (0.36, 0.79) 0.36 (0.21, 0.60) Rofecoxib vs. NSAIDs for OA Watson 2000226 (Manufacturer-funded meta-analysis) 6-month - 0.86 (0.78, 0.95) - 0.68 (0.50, 0.92) 12-month - 0.88 (0.80, 0.97) - 0.70 (0.52, 0.94) Garner 2005c77 (Cochrane Collaboration Systematic Review) Rofecoxib vs. Diclofenac No differences - 12.5 mg: 0.71 (0.52, - (RR range: 0.98- 0.97) 1.01) 25 mg: 0.70 (0.51, 0.95) Rofecoxib vs. Ibuprofen NS (RR range: - ↓ risk in 2 of 3 RCTs No differences in 3 of 4 0.98-1.04) RCTs Rofecoxib vs. Naproxen No differences 0.55 (0.42, 0.73) No differences ↓ risk in 2 of 3 RCTs Rofecoxib vs. Nabumetone NR NR No differences No differences Rofecoxib vs. Naproxen in RA Garner 2005b78 (Cochrane Collaboration Systematic Review) - - 1.02 (0.92, 1.12) 0.74 (0.64, 0.85) A manufacturer-funded meta-analysis found that tolerability of valdecoxib relative to NSAIDs appeared to be time-dependent.227 Significant increases in overall adverse event incidence (RR 1.1; 95% CI 1.04, 1.2) and incidence of GI adverse events (RR 1.4; 95% CI 1.2, 1.6) for valdecoxib relative to NSAIDs did not lead to increased risk of discontinuation in RCTs 67 of 6-12 weeks' duration. By 12-26 weeks, however, valdecoxib was associated with significantly lower rates of overall adverse events (RR 0.9; 95% CI 0.85, 0.93) and GI-related adverse events (RR 0.7; 95% CI 0.7, 0.8) relative to non-selective NSAIDs, as well as lower rates of discontinuation due to any adverse event (RR 0.9; 95% CI 0.85, 0.93) and due to GI- related adverse events (RR 1.4; 95% CI 1.2, 1.6). Comparison between COX-2 inhibitors. Incidence of and withdrawals due to overall or GI- related adverse events were similar for celecoxib and rofecoxib across a manufacturer-funded meta-analysis62 and a good-quality Cochrane review.77 The manufacturer-funded meta-analysis reported that rofecoxib and celecoxib were associated with similar risks of any adverse event (RR 0.97; 95% CI 0.84, 1.1), any GI-related adverse event (RR 0.87, 95% CI 0.74, 1.03), and GI-adverse event discontinuation (RR 0.7; 95% CI 0.5, 1.2) using data from five 6- to 12-week RCTs of patients with either OA or RA.62 The Cochrane review of rofecoxib for osteoarthritis77 found no differences for either the total number of withdrawals (RR 0.93, 95% CI 0.76 to 1.14) or the number of withdrawals due to adverse events (RR 1.03, 95% CI 0.77 to 1.39) in five trials that compared celecoxib to rofecoxib. Acetaminophen. We identified four systematic reviews that evaluated the efficacy and safety of acetaminophen compared with NSAIDs (selective or non-selective) for osteoarthritis.228-231 The studies generally met all criteria for good-quality systematic reviews, except that three229-231 did not provide sufficient detail about trials that were excluded. The overall conclusion from the reviews was that NSAIDs are modestly superior to acetaminophen for general or rest pain (Table 24). For pain on motion and overall assessment of clinical response, NSAIDs also appeared modestly superior, though the differences were not always statistically significant.229, 230. Only two reviews assessed functional disability; neither found clear differences.229, 230 Table 24. Pain relief in systematic reviews of acetaminophen versus NSAID Systematic Date of last Number of Main results for outcome of general or rest pain review search head-to-head trials included Towheed, Through 8/02 5 (1 trial NSAIDs superior for rest pain (SMD 0.32, 95% CI 0.08 229 2005 evaluated a to 0.56) and HAQ pain (SMD 0.27, 95% CI 0.05 to 0.48) coxib) Zhang, 2004231 Through 7/03 8 (3 trials NSAIDS superior using WOMAC scale (pooled ES 0.3, evaluated 95% CI 0.17 to 0.44) and clinical response rate (RR coxibs) 1.24, 95% CI 1.08 to 1.41) Lee, 2004228 Through 2/03 6 (1 trial NSAIDs superior for rest pain (weighted mean difference evaluated a –6.33, 95% CI –9.24 to –3.41) coxib) Wegman, Through 12/01 3 (no trials NSAIDs superior for general/rest pain (standardized 230 2004 evaluated mean difference 0.33, 95% CI 0.15 to 0.51) coxibs) The risk of adverse events with acetaminophen versus NSAIDs was assessed in three systematic reviews (Table 25).228, 229, 231 In two reviews, there were no differences in withdrawal due to any adverse event.229, 231 However, acetaminophen was associated with fewer gastrointestinal side effects compared with non-selective NSAIDs (though not compared with coxibs)229, 231 and fewer withdrawals due to gastrointestinal adverse events.229 68 Table 25. Adverse events in systematic reviews of acetaminophen versus NSAID Systematic review Withdrawal due to GI adverse events adverse events Towheed, 2005229 No difference (8% Withdrawal due to GI adverse event vs. 9%) Naproxen or ibuprofen vs. acetaminophen: RR 2.15 (95% CI 1.05 to 4.42) Any GI adverse event Non-selective NSAID vs. acetaminophen: RR 2.24 (95% CI 1.23 to 4.08) Coxib vs. acetaminophen: RR 0.96 (95% CI 0.57 to 1.61) Zhang, 2004231 Not reported GI discomfort Non-selective NSAID vs. acetaminophen: RR 1.39 (95% CI 1.07 to 1.80) Coxib vs. acetaminophen: RR 0.65 (95% CI 0.17 to 2.52) Lee, 2004228 NSAID vs. Not reported acetaminophen: OR 1.45, 95% CI 0.93 to 2.27) Results of recent, good-quality randomized trials (not included in any of the systematic reviews) were consistent with the systematic reviews. One two-week trial (N=222) found ibuprofen 1,200 mg/day more effective than paracetamol 3,000 mg/day for pain relief (p<0.005) and functional disability using WOMAC scores (-20.8 versus –13.4, p<0.001).232 Two cross- over trials of identical design (N=524 and 556) found celecoxib modestly superior to acetaminophen for WOMAC scores (difference in WOMAC score improvements ranged from 2.8 to 5.0 points on a 100-point scale), visual analogue pain scales (mean difference in scores ranged from 3.5 to 7.7 mm on a 100 mm scale), and patient preferences (53% and 50% favored celecoxib, versus 24% and 32% favored acetaminophen).233 In all three trials, tolerability and safety were equivalent. Clinical trials of acetaminophen have not been large enough to assess serious but less common complications such as PUB, myocardial infarction, acute renal failure, or hypertension. However, observational studies provide some additional information about the safety of acetaminophen relative to NSAIDs. A good-quality nested case-control study of 1,197 cases and 10,000 controls from a population-based cohort of 458,840 persons in the General Practice Research Database found current acetaminophen use associated with a lower risk for symptomatic peptic ulcer (adjusted RR 1.9, 95% CI 1.5 to 2.3) than NSAID use (adjusted RR 4.0, 95% CI 3.2 to 5.1) when each was compared with non-use.234 There was no clear relationship between higher acetaminophen dose and increased risk for symptomatic ulcers. An earlier analysis on the same database also found current acetaminophen use associated with a lower risk for upper gastrointestinal bleeds or perforations (adjusted RR 1.3, 95% CI 1.1 to 1.5) than current NSAID use (adjusted OR 3.9, 95% CI 3.4 to 4.6), each compared with non-use.184 A retrospective cohort study of elderly patients found that patients using lower doses of acetaminophen (<2,600 mg/day) had lower rates of GI events (defined as GI-related hospitalizations, ulcers, and dyspepsia) compared with users of NSAIDs (RR 0.73, 95% CI 0.67 to 0.80 for 1,951 to 2,600 mg/day), but the risks were similar at higher doses (RR 0.93 to 0.98).235 Although GI hospitalization rates were not reported separately, the authors noted that dyspepsia was responsible for most of the increase in GI events in the high-dose acetaminophen groups. A meta-analysis on individual patient data from three earlier retrospective case-control studies (2472 cases) was consistent with the above studies.236 It found acetaminophen associated 69 with a minimal increase in the risk for serious upper gastrointestinal bleeding (OR 1.2, 95% CI 1.1 to 1.5). By contrast, non-selective NSAIDs were associated with higher risks, though estimates of risk varied considerably for different NSAIDs (OR 1.7 for ibuprofen to 34.9 for ketoprofen). No randomized trial has evaluated the association between acetaminophen use and myocardial infarction or other thromboembolic cardiovascular events. However, a recent analysis from the large, prospective Nurses' Health Study found heavy use of acetaminophen (more than 22 days/month) associated with an increased risk of cardiovascular events (RR 1.35, 95% CI 1.14 to 1.59) similar to that with heavy use of NSAIDs (RR 1.44, 95% CI 1.27 to 1.65).237 Dose- and frequency-dependent effects were both significant. The association between renal failure and acetaminophen use has been evaluated in several case-control studies. Interpretation of these studies, however, is difficult because many had important flaws (such as failure to identify patients early enough in the course of their disease to insure that the disease had not led to a change in the use of analgesics, failure to specify diagnostic criteria, failure to adjust for the use of other analgesics, incompleteness of data on exposure, and use of proxy respondents) in the collection or analysis of data.238 The largest (926 cases) case-control study was designed to try to avoid many of these flaws.239 It found regular use of acetaminophen associated with an increased risk for chronic renal failure (Cr >3.8 for men and >3.2 for women) compared with non-use (OR 2.5, 95% CI 1.7 to 3.6). Use of NSAIDs was not associated with an increased risk (OR 1.0). A prospective cohort study of 1,697 women in the Nurses' Health Study found increased lifetime acetaminophen exposure associated with a higher risk of decline in glomerular filtration rate of 30% or greater (p<0.001), though NSAIDs were not (p=0.88).240 The absolute risk of renal function decline, however, was modest, even in women reporting high amounts of lifetime acetaminophen use. Compared with women consuming less than 100 g of cumulative acetaminophen, the odds of a decline in GFR of at least 30 mL/min per 1.73 m2 for women consuming more than 3,000 g was 2.04 (95% CI, 1.28 to 3.24). By contrast, analyses of men in the Physicians' Health Study found no association between acetaminophen or NSAIDs and change in kidney function.241, 242 The risk of heart failure associated with acetaminophen has not been well studied. In a single study using the General Practice Research Database, current use of acetaminophen was associated with a higher risk of newly diagnosed heart failure compared with non-use (RR 1.33, 95% CI 1.06 to 1.67), though the risk was lower compared with current use of NSAIDs (RR 1.59, 95% CI 1.23 to 2.05).212 The risk of hypertension has been evaluated using data from the Nurses' Health Studies243-245 and the Physicians' Health Study.246 In the Nurses' Health Studies, acetaminophen and NSAIDs were associated with similar increases in risk of incident hypertension (Table 26). In the Physicians' Health Study, on the other hand, there was no association between NSAID or acetaminophen use and hypertension. 70 Table 26. Incidence of hypertension in the Nurses' Health Study and Physicians' Health Study according to use of acetaminophen or NSAIDs Study Acetaminophen use versus non-use: NSAID use versus non-use: odds odds ratio ratio Nurses' Health Study I 1.93 (1.30 to 2.88) 1.78 (1.21 to 2.61) (women 51 to 77 years 243 old) Nurses' Health Study II 1.99 (1.39 to 2.85) 1.60 (1.10 to 2.32) (women 34 to 53 years old)243 Physicians' Health 1.08 (95% CI 0.87 to 1.34) 1.05 (95% CI 0.89 to 1.24) 246 Study Although overdoses with acetaminophen can lead to potentially life-threatening hepatotoxicity, it is not clear if hepatotoxicity is associated with therapeutic doses in patients without underlying liver disease.16 We identified no studies comparing the incidence of hepatotoxicity with therapeutic doses of acetaminophen and NSAIDs. We also identified no studies comparing the incidence of myocardial infarctions in persons using acetaminophen compared with NSAIDs. Glucosamine and Chondroitin Data regarding the comparative efficacy of glucosamine versus NSAIDs in patients with osteoarthritis are mixed. The most promising results have been observed in trials sponsored by Rotta Research Laboratories (based in Europe), which manufactures pharmaceutical grade glucosamine not available in the U.S. Because the content and purity of over-the-counter glucosamine preparations vary substantially, the results of the Rotta trials may not be directly applicable in the U.S.247 A recently updated (searches through November 2004), good-quality Cochrane review included four short-term (4 to 8 weeks) head-to-head trials of glucosamine versus an oral NSAID (ibuprofen or piroxicam).248 Two of the trials were rated 5 out of 5 on the Jadad scale, and the other two were rated 3 or 4 out of 5. Rotta Research Laboratories sponsored three of the trials; the fourth249 was also conducted in Europe, but funding information was not reported. One of the trials has only been published as an abstract,250 and analyses were based on data from an unpublished manuscript. Two of the four trials found glucosamine superior to oral NSAIDs for efficacy,249, 250 and two found no difference.251, 252 In pooled analyses, glucosamine was superior to an oral NSAID for improving pain (three trials, standardized mean difference –0.40, 95% CI – 0.60 to –0.19), but not for improving function using the Lequesne Index (two trials, SMD –0.36, 95% CI –1.07 to 0.35). Glucosamine was also associated with fewer adverse events (RR 0.29, 95% CI 0.19 to 0.44) and withdrawals due to toxicity (RR 0.06, 95% CI 0.01 to 0.25). Two small (N=40 and N=45), 12-week Canadian trials, neither funded by Rotta Research Laboratories, have also recently been published. Neither found differences between glucosamine and ibuprofen for general osteoarthritis pain253 or for tempomandibular joint osteoarthritis.254 Only limited details of the study design were reported for the first trial, though the second met all criteria for a good-quality study. Evidence regarding the efficacy of glucosamine compared with placebo has also been mixed. The Cochrane review found glucosamine no better than placebo when the analysis was restricted to the eight trials with adequate allocation concealment.248 By contrast, when all placebo- 71 controlled trials were included in the analysis, glucosamine was superior for both pain and function using the Lequesne index. The benefits of glucosamine also varied substantially depending on the preparation being studied. Specifically, glucosamine performed better in the seven trials evaluating the Rotta preparation (a prescription formulation available in Europe) (SMD –1.31, 95% CI –1.99 to –0.64) compared with the eight trials using non-Rotta preparations (SMD –0.15, 95% CI –0.35 to 0.05). In fact, all of the five trials that found no benefit from glucosamine evaluated a non-Rotta brand of glucosamine and also had limited or no affiliation with a manufacturer of glucosamine. Older systematic reviews found glucosamine superior to placebo, but did not include several newer and higher quality trials that demonstrated no effect, and also noted important methodological flaws that could have exaggerated estimates of effect.255, 256 The Cochrane review248 and one other recent, good-quality systematic review257 included two trials (one fair-quality and one good-quality) that found glucosamine (Rotta brand) superior to placebo for reducing progression of knee joint space narrowing over 3 years (SMD 0.24, 95% CI 0.04 to 0.43248 and RR 0.46, 95% CI 0.28 to 0.73257). Other trials were too short in duration (mean 9 weeks) to assess joint space narrowing as an outcome. In all of the systematic reviews, rates of adverse events were no different between glucosamine and placebo. We identified no trials comparing chondroitin sulfate to oral NSAIDs. Three systematic reviews evaluated the efficacy and safety of chondroitin compared with placebo. The most recent, fair-quality systematic review found indistinguishable efficacy for glucosamine and chondroitin and combined the results of the trials.256 When all trials were pooled, active treatment was associated with an increased likelihood of being a responder (RR 1.59, 95% CI 1.39 to 1.83) compared with placebo. The results of the chondroitin trials were not reported separately. The chondroitin trials also received lower quality ratings than the glucosamine trials, but the effects of quality scores on the findings were not evaluated. Assessment of the effects of quality on assessments of estimates of benefit are important because an earlier, good-quality systematic review found pooled effect sizes for pain relief substantially lower for chondroitin trials with quality scores below the median (effect size 1.7, 95% CI 0.7 to 2.7) compared with trials with quality scores above the median (ES 0.8, 95% CI 0.6 to 1.0).255 Smaller chondroitin trials also reported higher effects. The third systematic review was also rated fair quality because it did not evaluate the effects of study quality on results.258 It found chondroitin superior to placebo for pain and function, but longer and larger studies were needed. All three systematic reviews found chondroitin tolerated as well as placebo, with only mild adverse events. Results of a large (N=1,583), NIH-funded, randomized trial (Glucosamine/chondroitin Arthritis Intervention Trial) comparing placebo, celecoxib, glucosamine, chondroitin, and glucosamine plus chondroitin were recently published (Table 27).259 Using pharmaceutical grade glucosamine hydrochloride (rather than the over-the-counter glucosamine sulfate commonly available in U.S. as supplements not regulated as pharmaceuticals by the FDA) and chondroitin under an investigational new drug application, the study randomized patients stratified according to baseline pain severity. It found no differences between glucosamine, chondroitin, or the combination relative to placebo among all patients for achieving a clinical response (>20% improvement in WOMAC Pain score after 24 weeks), though the combination was superior to placebo for achieving a clinical response in an analysis of a small (20% of enrollees) subgroup of patients with moderate to severe (WOMAC 301 to 400 mm) baseline pain (79% vs. 54.3%, p=0.002). There were no statistically significant differences between celecoxib and any of the other active treatment arms (glucosamine alone, chondroitin alone, or glucosamine plus chondroitin) or placebo and either glucosamine or chondroitin alone. The 72 authors postulated that lack of effect in the mild baseline pain group could have been due in part to floor effects. High placebo response rates were also observed. All of the interventions were well tolerated. Table 27. Response rates in the Glucosamine/chondroitin Arthritis Intervention Trial (GAIT) 260 Intervention All patients Moderate-severe Mild baseline pain baseline pain (WOMAC (WOMAC pain score 125- pain score 301-400 mm) 300) Placebo 60.1% 54.3% 61.7% Celecoxib 70.1% (p=0.008 vs. 69.4% (p=0.06 vs.placebo) 70.3% (p=0.04 vs. placebo) placebo) Glucosamine 64.0% (p=0.30 vs. 65.7% (p=0.17 vs. 63.6% (p=0.67 vs. placebo) placebo) placebo) Chondroitin 65.4% (p=0.17 vs. 61.4% (p=0.39 vs. 66.5% (p=0.27 vs. placebo) placebo) placebo) Glucosamine + chondroitin 66.6% (p=0.09 vs. 79.2% (p=0.002 vs. 62.9% (p=0.80 vs. placebo) placebo) placebo) Key Question 1b. How do these benefits and harms change with dosage and duration of treatment, and what is the evidence that alternative dosage strategies, such as intermittent dosing and drug holidays, affect the benefits and harms of oral medication use? Duration of exposure and dose may have an influence on the benefits and harms associated with selective and non-selective NSAIDs, though data are limited and somewhat inconsistent. For rofecoxib, the VIGOR trial found that an increased risk of cardiovascular events appeared to became apparent only after 8 months of treatment.106 Similarly, initial reports of the APPROVe trial appeared to show a duration-dependent effect, as the cardiovascular event rate curves for rofecoxib and placebo diveraged only after about 18 months.132 However, a re-analysis that included originally censored events (occurring 14 days or more after discontinuation of study drug) suggests that the curves began to diverge after only 4 to 6 months, with no evidence of deviation from the proportional hazard over time.133 The lack of an association with shorter duration of exposure in VIGOR could have been due in part to lack of power to detect differences due to small numbers of events. Supporting this hypothesis are two recent meta- analyses that found that risk of cardiovascular events with rofecoxib124 or COX-2 inhibitors in general129 did not vary according to duration of treatment. One of the meta-analyses also found that cardiovascular risk of rofecoxib did not vary according to dose.124 However, the presence or absence of dose-dependent cardiovascular effects are difficult to analyze because 85% (84/98) of the events in patients allocated to rofecoxib in placebo-controlled trials occurred at a dose of 25 mg/day.129 Observational data also suggests that increased cardiovascular risk with rofecoxib may occur at lower doses145 and with shorter-term exposure.152, 261 Odds of acute MI were greater overall for rofecoxib relative to celecoxib in a case-control study of low-income Medicare beneficiaries 73 (mean age 79 years) exposed to treatment for ≤ 90 days.145 The risk estimate for those taking rofecoxib > 25 mg (OR 1.70; 95% CI 1.07, 2.71) was greater than for those taking ≤ 25 mg (OR 1.21; 95% CI 1.01, 1.44), however.145 Risk of CV events was similar for rofecoxib and meloxicam, regardless of duration, in a cohort study in which data was ascertained from an England National Health Services database using a Prescription Event Monitoring system.262 In a case-control study of elderly patients in Quebec, the risk of acute myocardial infarction was highest following the first prescription of rofecoxib (adjusted RR 1.64, 95% CI 1.20 to 2.23 compared to non-use) and returned to baseline by the 8th prescription.261 Some studies also suggest that duration of exposure and dose could influence the cardiovascular safety of celecoxib. Celecoxib was not associated with excess cardiovascular risk when compared with diclofenac or ibuprofen in the CLASS trials60 or in meta-analyses105, 135 of mostly short-term trials of patients with arthritis. The long-term (33 months) APC polyp prevention trial was the first trial to clearly show an increased risk of cardiovascular events relative to placebo with celecoxib.108 However, even though it's possible that the lack of an association in CLASS and earlier meta-analyses could be due in part to less risk with shorter duration of exposure, an alternative explanation is lack of power due to small numbers of events. Regarding dose-dependent effects, one recent meta-analysis129 of 41 placebo-controlled trials found higher doses associated with greater cardiovascular risks relative to placebo (p=0.03), though most of the events at the highest dose (800 mg/day) came from two long-term polyp prevention trials.108, 263 Analysis of the CLASS data also suggests that celecoxib was more effective at reducing GI events at 6 months compared with longer duration of exposure.60 In fact, effects on pre-defined, serious GI complications were no longer present after 12 months, though interpretation of final results is problematic because of high withdrawal rates.97 By contrast, in VIGOR, the GI benefit of rofecoxib compared to naproxen was seen early and sustained over the duration of the trial (median 9 months).19 One good-quality systematic review of eight trials found that higher doses of non-selective and partially selective NSAIDs were generally associated with greater efficacy for some measures of pain relief when directly compared to lower doses.264 Higher doses were also associated with greater withdrawals due to adverse events in two of four trials. In observational studies, the risk for GI bleeding with non-selective NSAIDs also appears to increase with higher doses.11, 191, 236 By contrast, the risk of bleeding associated with acetaminophen was not associated with dose in one meta-analysis of three case-control studies,236 though there was a modest dose response in another case-control study of elderly patients.235 At low over-the- counter doses, the risk of GI hospitalizations associated with aspirin, acetaminophen, and ibuprofen were similar to background rates in patients with rheumatoid arthritis or osteoarthritis in the ARAMIS database.265 A systematic review of observational studies found that use of aspirin and non-aspirin NSAIDs at over-the-counter doses is associated with an increased risk of GI bleeding, though the risk is lower than observed at prescription doses (approximately twofold greater risk at over-the-counter doses and sixfold or higher increases at heavy prescription levels.11 One recent analysis of the Nurses' Health Study found that the risk of cardiovascular events was dose-related for both NSAIDs and acetaminophen.237 We found no studies evaluating the effects of alternative drug strategies such as intermittent dosing or drug holidays on risks and benefits of oral medication use. Although one difference between the APC trial (which found an increased risk of CV events with celecoxib) and the PreSAP trial (which reported no association) was twice-daily (APC) versus once-daily (PreSAP) 74 dosing, no study has directly compared such dosing strategies.109 Furthermore, other studies of twice-daily dosing with celecoxib (such as CLASS60 and ADAPT111) reported no increase in CV risk. Key Question 2. Do the comparative benefits and harms of oral treatments for osteoarthritis vary for certain demographic and clinical subgroups? Demographic Subgroups Include Age, Sex, and Race In general, the risk of cardiovascular, cardiorenal, and gastrointestinal adverse events associated with NSAIDs increase with age.13 In one UK population, for example, the risk of adverse gastrointestinal outcomes in patients taking selective or non-selective NSAIDs was 1.36 per 1,000 patient-years for all patients 25 years or older, but 4.03 per 1,000 patient-years in patients aged 65 or more.138 Similarly, the risk of myocardial infarction was 1.71 per 100 person-years for all patients 25 years or older, but 4.57 per 100 person-years for those 65 or older.146 We found no trial designed to assess whether the relative harms and benefits associated with different NSAIDs for osteoarthritis varies according to age. However, even if the relative benefits and harms associated with different drugs are consistent across age groups, the absolute effects would increase with age because of greater baseline CV and GI risk. Studies that evaluated the efficacy and safety of selective and non-selective NSAIDs in average-risk elderly patients have generally reported similar findings compared with studies in populations with younger adults. An individual patient data meta-analysis of three celecoxib trials, for example, found effects of celecoxib 200 mg/day or 400 mg/day and naproxen 1,000 mg/day similar in elderly patients when evaluating WOMAC and SF-36 scores.266 For the SF- 36, there were no statistically significant differences: naproxen scored better than celecoxib 200 mg on four of 10 components of the SF-36, while celecoxib 200 mg scored better on six, including general health. Celecoxib 200 mg was significantly better than placebo on nine of the 10 components, while naproxen was significantly better than placebo on seven. The study also confirmed that the overall incidence of GI adverse events was lower with celecoxib; the difference was about one event in 20 patients for celecoxib 200 mg and one in 10 for celecoxib 400 mg. Similarly, a meta-analysis of three rofecoxib trials reported similarly consistent efficacy for rofecoxib 12.5 mg or 25 mg daily compared to placebo among various subgroups defined by age, gender, race, location of osteoarthritis, baseline symptoms, and baseline functional status.267 Another meta-analysis found that trials of NSAIDs in patients over the age of 60 reported similar risks for GI complications compared to trials of patients under the age of 60.183 Data suggesting differential effects of oral medications for osteoarthritis according to gender, ethnicity, or race are scant. In most of the published trials, a majority of subjects were women. As noted in the discussion of acetaminophen, results from the Nurses' Health Studies suggest that acetaminophen is associated with modest reductions in renal function in women,243 but results from the Physicians' Health Study have found no association between acetaminophen use and renal dysfunction in men.246 The effects of different NSAIDs in specific ethnic minorities have only been evaluated in small studies. In a randomized crossover study of 25 black and 75 Hispanic patients on ACE inhibitors, peak increases in blood pressure were similar in patients on diclofenac compared with celecoxib.268 An observational study of 120 Native American patients seen in an Indian Health Service clinic in Phoenix who were switched to rofecoxib found that mean systolic blood pressure increased by 2.9 mm Hg overall (p=0.015) and by 4.8 mm Hg (p=0.009) in hypertensive patients.269 We did not find any other publications focusing on the differential efficacy or safety of coxibs in African-Americans, Hispanics, or other ethnic minorities. Co-Existing Diseases Include History of Previous Bleeding Ulcer Due to NSAIDs; Hypertension, Edema, Ischemic Heart Disease, and Heart Failure. Rates of recurrent ulcer bleeding were similar for celecoxib 200 mg and the combinations of extended-release diclofenac 75 mg BID plus omeprazole 20 mg QD270 or naproxen 250 mg TID plus lansoprazole 30 mg QD271 in two fair-quality, 24-week, parallel trials involving a total of 529 patients who presented with a bleeding ulcer (Table 28). There were also no differences between celecoxib and either combination therapy in other adverse events including GI, renal, and cardiovascular symptoms or in rates of withdrawals due to adverse events. One exception was that celecoxib 200 mg QD was associated with a higher rate of dyspepsia than naproxen 250 mg TID plus lansoprazole 30 mg QD.271 The high rates of recurrent bleeding in both the celecoxib-treated patients and in the combination therapy groups—over 10 times as high as the rate in the CLASS trial— suggest that NSAIDs and coxibs should be used with caution, if at all, in patients who have a recent history of a bleeding ulcer. Table 28. Celecoxib in patients with bleeding ulcer history Recurrent ulcer Study bleeding at 6 months Other adverse Withdrawals due to Sample Size Treatments (difference; 95% CI) events adverse events Chan 2002270 Celecoxib 200 mg BID 4.9% vs. 6.3% No differences 13.3% vs. 11.9%, n=287 Diclofenac 75 mg BID plus (–1.5%, CI –6.8, 3.8%; NS* omeprazole 20 mg QD NS) Lai 2005271 ** Celecoxib 200 mg QD 3.7% vs. 6.3% (-2.6; No differences for 10% vs. 7.4%, NS n=242 Naproxen 250 mg TID plus CI –9.1, 3.7; NS) all but dyspepsia: lansoprazole 30 mg QD 15% vs. 5.7%, p=0.02 *Includes withdrawals due to lack of efficacy **Open trial We found no randomized controlled trial evaluating the risk of bleeding with rofecoxib compared with celecoxib in high-risk patients. A Danish population-based case-control study of high-risk patients with previous gastrointestinal diseases found that rofecoxib (OR 2.1, 95% CI 1.2 to 3.5) and non-selective NSAIDs (OR 3.3, 95% CI 2.4 to 4.4), but not celecoxib (OR 1.3, 95% CI 0.7 to 2.8),272 were associated with higher risks of upper gastrointestinal bleeding. We found no randomized trials designed to assess whether the relative harms and benefits associated with different oral treatments for osteoarthritis vary according to underlying cardiovascular or renal risk. One recent analysis of three large polyp prevention trials of celecoxib or rofecoxib 109, 132 and one observational study of rofecoxib273 found consistent risks for cardiovascular events among users at low and high baseline cardiovascular risk. However, 76 even if the relative risk of cardiovascular harms is consistent across risk groups, the absolute effects with any specific drug would be greater in patients at higher baseline risk. This is strikingly illustrated by a recent, good-quality population-based study of a very high risk group of 58,000 Danish patients with previous myocardial infarction that found hazard ratios for death of 2.80 (95% CI 2.41 to 3.25) for rofecoxib, 2.57 (95% CI 2.15 to 3.08) for celecoxib, 1.50 (95% CI 1.36 to 1.67) for ibuprofen, 2.40 (95% CI 2.09 to 2.80) for diclofenac, and 1.29 (95% CI 1.16 to 1.43) for other NSAIDs compared to non-use of NSAIDs.274 Because of high rates of death in this population (95 per 1000 person-years in those not using NSAIDs), the estimated number of patients needed to treat with an NSAID for one year to cause one additional death was very low, at 13 (95% CI 10-20) for rofecoxib, 14 (95% CI 10-24) for celecoxib, 45 (95% CI 29-102) for ibuprofen, and 24 (95% CI 16-45) for diclofenac. Only a few trials have evaluated the effects of different medications on cardiovascular and cardiorenal events specifically in high-risk patients. Three randomized trials sponsored by the manufacturer of celecoxib found higher rates of hypertension or blood pressure increases in patients randomized to rofecoxib compared with patients randomized to celecoxib, but no differences in discontinuations due to adverse events or for episodes of heart failure.84, 85, 207 As noted earlier, the results of these trials must be interpreted cautiously because they evaluated possibly non-equivalent doses of rofecoxib and celecoxib, and because one of the trials84 had important baseline differences suggesting inadequate randomization. A meta-analysis funded by the manufacturer of rofecoxib found that in a high-risk subgroup of patients in whom aspirin was indicated (history of cardiovascular disease), rofecoxib was not associated with an increased risk of myocardial infarction compared with either placebo or non- selective NSAIDs.123 However, the duration of the included trials may have been too short (median 3½ months) to detect an increased risk, few events were observed, and only a minority of patients received the high dose of rofecoxib evaluated in the VIGOR trial. We found no trials evaluating comparative risks of different oral medications in patients with known congestive heart failure. A recent, good-quality population based retrospective cohort study, however, found that the risk of death and recurrent congestive heart failure was higher in patients prescribed NSAIDs (HR 1.26, 95% CI 1.00 to 1.57) or rofecoxib (HR 1.27, 95% CI 1.09 to 1.49), each compared with those prescribed celecoxib.211 We also found no trials comparing the risks and benefits of different oral medications in patients with known renal failure. Concomitant Anticoagulant or Aspirin Use Concomitant anticoagulants. Concomitant use of anticoagulants and non-selective NSAIDs increases the risk of GI bleeding three- to six-fold compared to anticoagulants alone.275, 276 Several observational studies have evaluated whether COX-2 selective agents are associated with a lower risk for bleeding compared with non-selective agents in patients on anticoagulation. A good-quality nested case-control study of elderly (>66 years old) patients on warfarin in Ontario, Canada, evaluated the association between hospitalization for upper gastrointestinal bleeding (361 cases) and use of selective or non-selective NSAIDs.277 It found that after adjustment for potential confounders (antiplatelet agents, hypoglycemic agents, glucocorticoids, gastroprotective agents, history of previous bleed, and comorbidities), recent use of non-selective NSAIDs (OR 1.9, 95% CI 1.4 to 3.7), celecoxib (1.7, 95% CI 1.2 to 3.6), and rofecoxib (2.4, 95% CI 1.7 to 3.6) were all associated with increased and overlapping risks for upper gastrointestinal bleeding, compared with non-use. Because this study relied on pharmaceutical 77 databases to identify exposures prior to hospitalization, it could not assess the confounding effects of over-the-counter use of aspirin, other NSAIDs, or acid suppressive medications. It also was unable to control for variations in INR level and the risk for bleeding. A smaller, fair-quality nested case-control study of patients in the Netherlands evaluated the risk of bleeding in anticoagulated patients receiving partially selective (meloxicam or nabumetone) COX-2 inhibitors or non-selective NSAIDs.278 No case (N=154) received either celecoxib or rofecoxib. This study also differed from the Ontario study in that it included all cases of minor visible bleeding, hematoma, or black tarry stools. It used a questionnaire to assess exposure status and comorbidities. Patients were interviewed over the phone if answers were incomplete or unclear. The response rates were significantly higher in the cases (approximately 70%) compared with controls (approximately 31%). The study found that non- selective NSAIDs were associated with an increased risk of bleeding compared with partially selective NSAIDs after adjustment for duration of use and INR level (OR 3.07, 95% CI 1.18 to 8.03). An open, crossover trial compared celecoxib 200 mg and rofecoxib 25 mg in 18 patients with OA, RA, or chronic pain who were stable (three consecutive INRs within 15% of each other) on warfarin therapy.279 The trial was designed to measure mean change in INR and safety parameters. Similar rates of edema, heart failure and other adverse events were found for celecoxib and rofecoxib. The INR increased by 5% to 15% between weeks one and three for both coxibs. Four minor bleeds were reported; none were associated with a significant decrease in hemoglobin concentration. Postmarketing case reports of serious bleeding events, some fatal, have also been reported with concomitant anticoagulation and both rofecoxib and celecoxib. Most of these events occurred in elderly patients.135, 280 We found no studies evaluating risks and benefits of concomitant anticoagulants and aspirin in patients with arthritis. Combination therapy has been studied in patients with indications for thromboembolic prophylaxis. However, the results of those studies are not directly applicable to patients with arthritis because of important differences in the populations (particularly with regard to cardiovascular risk), and because aspirin was used in lower, prophylactic doses (rather than anti-inflammatory and analgesic doses). One fair-quality meta-analysis (did not evaluate quality of included trials) found major bleeding risk increased with warfarin plus aspirin versus warfarin alone (at the same intensity) in patients with mechanical heart valves (3 trials, RR 1.58, 95% CI 1.02 to 2.44).281 In patients with recent myocardial infarction or atrial fibrillation (one trial each), the increase in risk was not statistically significant (RR 3.07, 95% CI 0.33 to 28.38 and RR 2.13, 95% CI 0.20 to 23.03, respectively). In patients with mechanical heart valves, the increase in bleeding risk was offset by a reduction in thromboembolic events (RR 0.33, 95% CI 0.19 to 0.58), and there was no difference in all-cause mortality (RR 0.78, 95% CI 0.29 to 1.83). Other evidence on the risks and benefits of combination therapy has focused on comparing warfarin plus aspirin to aspirin alone. A recent good-quality meta-analysis of 10 trials, for example, found that the combination of warfarin plus aspirin increased the risk of major bleeding compared with aspirin alone following myocardial infarction or the acute coronary syndrome (RR 2.5, 95% CI 1.7 to 3.7).282 However, the increase in bleeding risk was offset by lower risks for myocardial infarction, ischemic stroke, and revascularization. Mortality did not differ. No study evaluated risk of bleeding in anticoagulated patients on acetaminophen compared with those on NSAIDs. A small, randomized controlled trial found acetaminophen associated with greater increases in INR levels compared with placebo.283 Several observational studies 78 have also found an association between excess anticoagulation and use of acetaminophen.284, 285 However, changes in INR are not the only important factor for predicting increased risk of bleeding. NSAIDs, for example, also affect platelet function and disrupt the gastric mucosal lining. Studies evaluating actual bleeding complications are necessary to better assess the comparative risks from acetaminophen and other NSAIDs. No studies evaluated risk of bleeding in anticoagulated patients on glucosamine, chondroitin, or topical agents. Concomitant aspirin. Beneficial effects of COX-2 selective inhibition on GI complication rates may be attenuated or eliminated by the concomitant use of aspirin. In the 20 per cent of patients in the CLASS trial who took aspirin in addition to their study drug, there was no difference in ulcer complications or ulcer complications plus symptomatic ulcers in patients randomized to celecoxib versus those randomized to diclofenac, ibuprofen, or the two NSAID comparators combined.96 Similarly, a meta-analysis of randomized controlled trials found that beneficial effects of celecoxib on risk of endoscopically detected ulcers were reduced in patients on prophylactic aspirin (RR 0.49, 95% CI 0.28 to 0.86) compared with those not on aspirin (RR 0.27, 95% CI 0.16 to 0.48).61 This analysis excluded the results of the CLASS trials because they did not evaluate endoscopic ulcers as an outcome and because of high, differential withdrawal rates. A re-analysis that included the full CLASS trials results found no benefit (rather than a reduced benefit) from celecoxib in patients on aspirin (RR 0.96, 95% CI 0.63 to 1.46),286 but the appropriateness of combining data from trials reporting endoscopic ulcers with data from the CLASS trials on withdrawal rates, symptomatic ulcers, and ulcer complications, is disputed.287 Another meta-analysis found that use of aspirin increased the rate of endoscopic ulcers by about 6% in patients randomized to celecoxib (4.2% without aspirin and 9.9% with aspirin) and in those randomized to a non-selective NSAID (17.6% and 23.8%).62 In the TARGET trial, no reduction in ulcer complications with lumiracoxib compared to non-selective NSAIDs was observed in the subgroup of patients on aspirin (HR 0.79, 95% CI 0.40, 1.55).175 There is less evidence on the effects of aspirin on the GI risk associated with rofecoxib. A recent trial that randomized osteoarthritis patients to placebo, enteric-coated aspirin (81 mg/day), rofecoxib 25 mg/day + aspirin 81 mg/day, or ibuprofen 2,400 mg/day found similar rates of endoscopic ulcers in the rofecoxib + aspirin arm (16.1%) and the ibuprofen alone arm (17.1%); both rates were significantly higher than the placebo (5.8%) and aspirin alone (7.3%) arms.288 A meta-analysis of aspirin users in two trials comparing celecoxib 200 mg daily and rofecoxib 25 mg daily found celecoxib associated with a lower rate of withdrawals due to GI adverse events than rofecoxib (0.7% vs. 3.9%, p<0.05), as well as with GI symptoms.289 However, there were no reported serious GI events. Interpretation of these results is limited by nonequivalent dosing of the COX-2 inhibitors, pooling of data across trials, and post-hoc subgroup analyses of the aspirin-users data. Concomitant aspirin use has not been shown to eliminate or reduce excess cardiovascular risks associated with COX-2 inhibitors. In large polyp prevention trials of rofecoxib132 and celecoxib,109 use or non-use of low-dose aspirin did not affect the observed increased risk of thrombotic events.132 A recent meta-analysis of 84 placebo-controlled trials that permitted aspirin (including the polyp prevention trials) found a very similar risk of vascular events among those using aspirin (RR 1.57, 95% CI 0.90 to 2.72) and aspirin non-users (RR 1.51, 95% CI 1.14 to 2.01), though the absolute rate of events was higher in aspirin users (1.9%/year versus 1.1%/year).129 Consistent with these findings, two large observational studies using the UK 79 GPRD185 and QRESEARCH146 databases found no significant interaction between concurrent NSAID and aspirin use and the risk of myocardial infarction. One observational study found that in patients with known cardiovascular disease, there was a higher rate of overall mortality (adjusted hazard ratio 1.93, 95% CI 1.30 to 2.87) and cardiovascular death among users of ibuprofen plus aspirin compared with users of aspirin alone, suggesting that ibuprofen (or other NSAIDs) could interfere with the cardioprotective effects of aspirin.290 However, this study only evaluated small numbers of patients on NSAIDs, and did not adjust for important comorbidities. Key Question 3. What are the comparative effects of co- prescribing of H2-antagonists, misoprostol, or proton pump inhibitors (PPIs) on the gastrointestinal harms associated with NSAID use? Misoprostol, standard- and double-dose H2 blockers and PPIs were all effective in reducing the risk of NSAID-associated endoscopic gastric and duodenal ulcers relative to placebo in three good-quality systematic reviews (Table 29)291-293 of numerous randomized controlled trials of OA/RA patients.9, 69, 291, 294-321 H2 blockers,320-330 misoprostol (RR 0.36, 95% CI 0.20 to 0.67), and PPIs (RR 0.09, 95% CI 0.02 to 0.47) also reduced NSAID-associated symptomatic ulcers, but not serious cardiovascular or renal illness or death.293 Misoprostol has been studied most extensively and is the only agent proven to decrease risk of ulcer complications (MUCOSA).317 In a large, good-quality trial, misoprostol was associated with a rate of definite ulcer complications of 25/4404 (0.6%) compared to 44/4439 (0.9%) with placebo (p=0.049).317 However, misoprostol is also the only agent to be associated with a significant risk of treatment withdrawal due to nausea (RR=1.30, 95% CI 1.08 to 1.55), diarrhea (RR=2.40, 95% CI: 2.05 to 2.81), and abdominal pain (RR=1.36, 95% CI 1.20 to 1.55. Table 29. Placebo-controlled trials of gastroprotective agents291-293 Prevention of # PCT studies endoscopic ulcers Prevention of clinical GI Treatment Duration Gastric Duodenal events* Misoprostol 1-1.5 months: 1-1.5 months: 1-1.5 months: RR=0.28; Silverstein 1995 (MUCOSA): 8 RR=0.17, 95% CI: 95% CI 0.09-0.31 OR 0.598; 95% CI 0.364 to 0.09 to 0.31 0.982 ≥ 3 months: 11 3 months: RR=0.47, 95% 3 months: CI 0.33 to 0.69 RR=0.26; 95% CI 0.17 to 0.39 H2 blockers Standard Standard dose: Standard dose at 1 and None doses (150 insignificant effect 3 months: RR=0.24, mg): 7 Double dose: 95% CI: 0.10 to 0.57 and Double doses RR=0.44, 95% CI: RR=0.36, 95% CI: 0.18 (300 mg): 3 0.026 to 0.74 to 0.74 1-3 months Double dose: 0.26, 95% CI 0.11 to 0.65 PPIs 4 RR=0.40, 95% CI RR 0.19, 95% CI 0.09 to None Duration NR 0.32 to 0.51 0.37 *Upper GI hemorrhage, perforation, pyloric obstruction, death) 80 Table 30 reflects the results from five trials306, 309, 314, 319, 321 that directly compare one gastroprotective agent with another, as reported in the Canadian Coordinating Office for Health Technology Assessment review.292 Both misoprostol and omeprazole were superior to ranitidine for the prevention of gastric ulcers. Omeprazole and lansoprazole also appeared superior to misoprostol and ranitidine for the prevention of duodenal ulcers. Table 30. Head-to-head trials of gastroprotective agents292 Reductions in ulcer risk Comparison Gastric Duodenal Misoprostol vs. ranitidine* RR=0.12 No differences (2 trials; n=600) 95% CI 0.03 to 0.89 Omeprazole 20 mg vs. ranitidine RR=0.32 RR=0.11 150 mg (1 trial, n=425) 95% CI 0.17 to 0.62 95% CI 0.01 to 0.89 PPI** vs. misoprostol*** No differences RR=0.29 95% CI 0.15 to 0.56 *standard dose **omeprazole or lansoprazole ***secondary prophylaxis trials A good-quality meta-analysis of 26 trials found co-administration of a PPI with a non- selective NSAID associated with a greater reduction in dyspepsia, epigrastric pain and nausea than a selective COX-2 inhibitor alone, when each was compared to a non-selective NSAID alone (relative risk reduction 66% and absolute risk reduction 9% for the PPI + non-selective NSAID versus RRR 12% and ARR 3.7% with COX-2 inhibitor).331 Key Question 4. What are the comparative benefits and harms of treating osteoarthritis with oral medications as compared with topical preparations? Topical NSAIDs - Efficacy Four trials directly compared topical and oral NSAIDs for osteoarthritis. Two recent good- quality systematic reviews332, 333 included three334-336 of these trials (an older systematic review was excluded because its results appear outdated.337). One systematic review (by Lin et al332) only included osteoarthritis trials, while the other systematic review (by Mason et al333) included osteoarthritis and other chronic pain conditions. The systematic reviews also used different methods for abstracting and pooling efficacy data. Specifically, the primary outcome in Mason et al was a dichotomous outcome: the proportion of patients with clinical success (defined as approximately a 50% reduction in pain) at the end of the trial. By contrast, the primary outcome used by Lin et al was continuous: the difference in standardized effect sizes for the outcomes of pain, function, or stiffness measured at the end of each week of treatment. Two335, 336 of the trials received 5 out of 5 points on the Jadad quality scale; the third334 received a score of 3.333 Mason et al found topical and oral NSAIDs equivalent for clinical success after 3 to 4 weeks 81 (pooled relative risk 1.1; 95% CI 0.9 to 1.3).333 Although Lin et al found topical NSAIDs inferior to oral NSAIDs for pain and function after one week of treatment, this finding was based on data from only one RCT (effect size –0.38 for pain, 95% CI –0.66 to –0.10 and ES –0.32 for function, 95% CI –0.60 to –0.04).332 There were no significant differences between topical and oral NSAIDs after 2 (one RCT), 3 (two RCTs) or 4 (one RCT) weeks. Effect sizes could not be calculated for one of the three RCTs.334 The largest and longest trial (by Tugwell et al) comparing topical and oral NSAIDs was published in 2004—too late to be included in the systematic reviews.338 This good-quality study found the proportion of responders (as defined by Outcomes Measures in Arthritis Clinical Trials and the Osteoarthritis Research Society VI recommendations) at 12 weeks similar in patients randomized to topical or oral diclofenac (66% vs. 70%, p=0.37). There were also no clinically relevant differences for the outcomes of mean change in pain scores, physical function, or patient global assessment. The topical diclofenac evaluated in this trial was a proprietary formulation with DMSO (a drug not approved for topical use in humans by the FDA) not available in the U.S. We pooled rates of clinical response from the four trials (including Tugwell et al) comparing topical and oral NSAIDs, using intention-to-treat (missing values=failure) results and methods similar to the Mason meta-analysis. We found no differences between topical and oral NSAIDs (OR=0.95, 95% CI 0.70-1.30). It should be noted that the Sandelin study, which reported the lowest efficacy for topical versus oral NSAIDs, evaluated topical eltenac, a drug that is no longer being investigated for use in humans.335 Table 31. Head-to-head trials of topical versus oral NSAID for osteoarthritis Author, year Condition Comparison Duration of Definition of clinical Number enrolled study success Dickson, 1991 334 OA of knee Piroxicam 0.5% 4 weeks Patient global 235 Ibuprofen 400 mg po assessment 'good' or tid 'excellent' Sandelin, 1997 335 OA of knee Eltenac 1% gel 4 weeks Physician global 208 Diclofenac 50 mg bid assessment 'good' Zacher, 2001 336 OA of fingers Diclofenac 1% gel 3 weeks >=40% improvement 321 Ibuprofen 400 mg po in pain on 100 mm tid VAS Tugwell, 2004338 OA of knee Diclofenac 1.5% in 12 weeks OMERACT VI 622 carrier with 45.5% criteria38 for clinical DMSO responder Diclofenac 50 mg po tid 82 Figure 1. Clinical success in trials comparing a topical versus an oral NSAID Review: NSAIDs Comparison: 01 Topical vs. oral NSAID Outcome: 01 Clinical success Study Topical NSAID Oral NSAID OR (random) Weight OR (random) or sub-category n/N n/N 95% CI % 95% CI Year Dickson 68/117 65/118 22.68 1.13 [0.68, 1.90] 1991 Sandelin 22/126 23/82 16.05 0.54 [0.28, 1.06] 1997 Zacher 66/165 53/156 26.35 1.30 [0.82, 2.04] 2001 Tugwell 201/303 210/303 34.92 0.87 [0.62, 1.23] 2004 Total (95% CI) 711 659 100.00 0.95 [0.70, 1.30] Total events: 357 (Topical NSAID), 351 (Oral NSAID) Test for heterogeneity: Chi² = 5.18, df = 3 (P = 0.16), I² = 42.1% Test for overall effect: Z = 0.31 (P = 0.76) 0.1 0.2 0.5 1 2 5 10 Favours oral Favours topical Only three small (sample sizes 40, 85, and 129), short-term (2- to 4-week) trials directly compared different topical NSAIDs for chronic pain conditions. They found no differences between topical diclofenac and indomethacin,339 topical flurbiprofen and piketoprofen,340 or topical ketoprofen and diclofenac.341 The two systematic reviews came to somewhat different conclusions regarding the efficacy of topical NSAIDs compared with placebo. Lin et al found that topical NSAIDs were effective only during the first 2 weeks of treatment.332 However, their conclusions at 3 and 4 weeks were entirely based on three trials that evaluated eltenac gel (no longer produced or studied for human use) or a topical salicylate (no longer classified as a topical NSAID). Mason et al, on the other hand, found NSAIDs superior to placebo (relative risk for improvement in symptoms 1.9, 95% CI 1.7 to 2.2) from 14 placebo-controlled trials of varying duration, with a number needed to treat for one case of clinical success (approximate 50% reduction in pain) of 4.6 (95% CI 3.8 to 5.9).333 Results were not sensitive to quality ratings, trial sample size, outcome measured, or condition (knee osteoarthritis versus other musculoskeletal conditions). Four placebo-controlled trials of topical NSAIDs for osteoarthritis342-345 have been published since the systematic reviews were conducted. Three of these trials lasted longer than 4 weeks, and all found topical NSAIDs effective. The results of these trials are summarized in Table 32 for the dichotomous outcome "clinical success. " The longest trial of topical versus oral NSAIDs—a 2-year study of topical versus oral ibuprofen funded by the UK Health Technology Assessment Program—will not be completed until 2007.346 Table 32. Clinical success rates in recent placebo-controlled trials of topical NSAIDs Study Duration Definition of 'clinical Treatment group Proportion of subjects success' classified as 'clinical success' at end of study period Bookman, 2004343 4 weeks >50% reduction in pain Diclofenac 44/84 (52.4%) Vehicle-control 26/79 (32.9%) Placebo 28/84 (33.3%) Roth, 2004344 12 weeks >50% reduction in pain Diclofenac 79/163 (48.5%) Vehicle-control 55/159 (34.6%) Baer, 2005342 6 weeks >50% reduction in pain Diclofenac 46/105 (43.8%) Vehicle-control 27/107 (25.2%) Trnavsky, 2004345 7 days Reduction of >18 mm Ibuprofen 21/25 (84.0%) in VAS or >23% from Placebo 10/25 (40.0%) baseline for pain 83 Placebo-controlled trials also suggest that topical NSAIDs differ with regard to efficacy. Topical diclofenac, which has been evaluated in the most (eight) trials, was consistently superior to placebo or associated with a trend towards superiority.333, 342-344 Several of these trials evaluated a proprietary compound (not available in the U.S.) of topical diclofenac in a carrier containing DMSO (Pennsaid®).347 Ibuprofen was superior to placebo for chronic pain conditions in three RCTs.333, 345 By contrast, evidence regarding the efficacy of other topical NSAIDs for chronic conditions is much more scant (see Mason,333 Additional Files 4 and 5). Four trials found topical piroxicam no better than placebo, homeopathic gel, or glyceryl trinitrate 1% cream. One RCT found topical ketoprofen no better than placebo. Topical felbinac, flufenamate, and indomethacin have only been evaluated in one or two small trials each. Evidence on topical flurbiprofen was mixed: one trial found topical flurbiprofen superior to placebo, but another found no differences. Topical NSAIDs – Safety Topical NSAIDs were associated with increased local adverse events (skin reactions such as rash, itch, and burning) compared with oral NSAIDs in two recent systematic reviews.332, 333 However, there were no differences for total adverse events, systemic adverse events, withdrawal due to adverse events, gastrointestinal events, or central nervous system events. For the outcome of withdrawal due to adverse events, we found no differences when we pooled the three trials included in the earlier reviews and a fourth,338 more recent trial. Figure 2. Withdrawal due to adverse events in trials comparing a topical to an oral NSAID Review: NSAIDs Comparison: 01 Topical vs. oral NSAID Outcome: 02 Withdrawal due to adverse events Study Topical NSAID Oral NSAID OR (random) Weight OR (random) or sub-category n/N n/N 95% CI % 95% CI Year Dickson 9/117 7/118 23.77 1.32 [0.48, 3.67] 1991 Sandelin 4/126 1/82 7.97 2.66 [0.29, 24.19] 1997 Zacher 5/165 16/156 23.60 0.27 [0.10, 0.77] 2001 Tugwell 64/311 79/311 44.66 0.76 [0.52, 1.11] 2004 Total (95% CI) 719 667 100.00 0.75 [0.38, 1.48] Total events: 82 (Topical NSAID), 103 (Oral NSAID) Test for heterogeneity: Chi² = 6.14, df = 3 (P = 0.11), I² = 51.1% Test for overall effect: Z = 0.82 (P = 0.41) 0.1 0.2 0.5 1 2 5 10 Favours topical Favours oral Among the head-to-head trials, Tugwell et al provides the most information about adverse events because it has the largest sample size, the longest duration of follow-up, and used pre- specified definitions for adverse events and adverse-event severity.338 Topical diclofenac was associated with more local skin reactions but with fewer systemic and laboratory adverse events (Table 33). 84 Table 33. Adverse events from a trial comparing topical to oral diclofenac338 Adverse event Topical diclofenac in Oral diclofenac P value for DMSO carrier (n=311) (n=311) difference Withdrawal due to adverse event 21% 25% 0.15 Increase in mean blood pressure >= 5 mm Hg 24% 28% 0.30 Dry skin 27% 1% <0.0001 Rash 12% 2% <0.0001 Pruritus 6% 0.6% <0.0001 Gastrointestinal events (abdominal pain, 35% 48% 0.0006 constipation, diarrhea, dyspepsia, flatulence, melena, nausea, vomiting) Severe gastrointestinal event (defined as 2.6% 10.2% 0.0003 producing significant impairment of functioning and definite hazard to patient's health) Melena 1% 2% 0.36 Asthma 3% 0.6% 0.02 Dizziness 0.6% 4% 0.002 Dyspnea 0% 2% 0.01 Hemoglobin went from normal to abnormal 2% 10% <0.0001 Alanine transaminase increase to >3 times the 1.1% 4.7% 0.01 upper limit or normal Creatinine clearance went from normal to 4% 10% 0.01 abnormal No RCT was adequately designed to assess risks for serious but uncommon adverse events such as myocardial infarction, renal failure, or gastrointestinal bleeding. We identified one case- control study (1,103 cases) that evaluated the risk of hospital admission for upper gastrointestinal bleeding and perforation in patients taking topical NSAIDs.348 After adjusting for the confounding effects of exposure to oral NSAIDs and ulcer healing drugs, there was no association between exposure to topical NSAIDs within 45 days of an upper GI bleed (OR 1.45, 95% CI 0.84 to 2.50 with community controls and OR 1.06, 95% CI 0.60 to 1.88 with hospital controls). By contrast, oral NSAIDs were associated with increased risk (OR 2.59, 95% CI 2.12 to 3.16 for community controls and 2.00, 95% CI 1.60 to 2.50 for hospital controls). In a nested case-control study of the General Practice Research Database, topical NSAID use was not associated with symptomatic peptic ulcer (RR=1.0 versus non-use, 95% CI 0.6 to 1.7), though oral NSAID use was associated with increased risk (RR=4.0, 95% CI 3.2 to 5.1).234 We identified one case-control study of similar design that found exposure to topical NSAIDs not associated with acute renal failure (adjusted OR 1.33, 95% CI 0.79 to 2.24 using community controls and 1.04, 95% CI 0.60 to 1.83 using hospital controls).349 Recent exposure to oral NSAIDs, on the other hand, was associated with increased risk of renal failure using either community (adjusted OR 2.20, 95% CI 1.49 to 3.25) or hospital (adjusted OR 1.84, 95% CI 1.15 to 2.93) controls. We identified no studies comparing the risk of cardiovascular events in persons on topical versus oral NSAIDs. Topical Salicylates (Including Capsaicin) We identified no trials comparing topical salicylates to oral or topical NSAIDs. One recent good-quality systematic review found topical salicylates superior to placebo for pain relief when data from six trials were pooled (relative benefit 1.5, 95% CI 1.3 to 1.9; NNT 5.3, 95% CI 3.6 to 85 10.2).32 However, the three higher quality trials found no significant benefit (relative benefit 1.3, 95% CI 0.98 to 1.6). Local adverse events were rare, but the quality of adverse-event reporting was poor. We identified no trials comparing topical capsaicin to oral or topical NSAIDs. One recent good-quality systematic review found that for chronic musculoskeletal pain, capsaicin was superior to placebo for achieving clinical success (defined as approximately a 50% reduction in pain), with a relative benefit of 1.5 (three trials, 95% CI 1.1 to 2.0) and number needed to treat of 8.1 (4.6 to 34).350 About 54% of patients had local adverse events with capsaicin, compared with 15% with placebo (relative risk 3.6, 95% CI 2.6 to 5.0). Withdrawals due to adverse events were also significantly more likely with capsaicin (13% vs. 3%, relative risk 4.0, 95% CI 2.3 to 6.8). An older systematic review was excluded because it appears outdated.351 86 Chapter 4. Summary and Discussion The table below summarizes the strength of evidence and results for each key question. Publication bias is an issue for all of these questions, because we do not know the complete details or results of unpublished trials submitted to the FDA or trials that have been conducted but not published or submitted to the FDA Table 34. Summary of findings with strength of evidence Key Question Level of Evidence Conclusion 1a. What are the comparative benefits and harms of treating osteoarthritis with oral medications or supplements? Efficacy: Non-selective NSAID Non-selective NSAID vs. non- No difference in efficacy between various non- vs. non-selective NSAID selective NSAID: good. aspirin, non-selective NSAIDs or partially Consistent evidence from selective NSAIDs (meloxicam, nabumetone, several good-quality systematic etodolac). No difference between salsalate reviews and published trials. and aspirin in one short-term trial. There were Salsalate vs. aspirin. Poor. One no trials or eligible observational studies of short-term trial. salsalate or aspirin vs. non-aspirin NSAIDs. Salsalate or aspirin vs. non- aspirin NSAIDs. Poor. Efficacy: COX-2 selective vs. Good. Consistent evidence No difference. non-selective NSAID from many published trials Efficacy: COX-2 selective vs. Good. Consistent evidence No clinically significant differences at COX-2 selective from six published trials. comparable doses. GI and CV safety: Rofecoxib Good. One large published trial, In a pivotal, long-term trial (VIGOR) of patients multiple meta-analyses and with rheumatoid arthritis, rofecoxib 50 mg systematic reviews of published daily reduced symptomatic ulcers and serious and unpublished trials, multiple ulcer complications compared with naproxen. observational studies. After an average of 9 months, rofecoxib use was associated with 1 fewer symptomatic ulcer for every 62 patients treated; one fewer serious GI complication for every 191; and one additional MI for every 333 patients. The overall rate of serious adverse events, however, was higher with rofecoxib than naproxen. Higher-quality systematic reviews and observational studies are generally consistent with these findings (about 3.5 additional myocardial infarctions for every 1000 patients treated for one year). One long- term placebo-controlled polyp prevention trial also found an increased risk of MI. GI and CV safety: Celecoxib Fair: Multiple meta-analyses and In the only published large, long-term study systematic reviews of mostly (CLASS), celecoxib was no better than short-term published and diclofenac or ibuprofen for complicated or unpublished trials, multiple symptomatic ulcers at the end of follow-up. In observational studies. subgroup analyses of patients not on aspirin, celecoxib was superior to ibuprofen but not to diclofenac for ulcer complications. There was no increase in the rate of cardiovascular events for celecoxib in CLASS. The overall rate of serious adverse events was similar 87 Key Question Level of Evidence Conclusion with celecoxib compared to ibuprofen and diclofenac. Systematic reviews and other meta-analyses of primarily short-term, unpublished data and lower doses found celecoxib superior to non-selective NSAIDs for ulcer complications. Observational studies are generally consistent with the short-term trials. However, recent meta-analyses found an increased risk of myocardial infarction with celecoxib compared with placebo (about 3.5 myocardial infarction for every 1000 patients treated for one year), with much of the evidence for increased risk coming from two large polyp prevention trials. GI and CV safety: Valdecoxib Fair: Fair quality meta-analyses Compared to non-selective NSAIDs, of published and unpublished valdecoxib was associated with one fewer trials upper GI complication with valdecoxib for every 78 patients treated for 3 to 6 months. There was no association between valdecoxib and myocardial infarction in primarily short- term chronic pain trials. However, two short- term trials in a high-risk post-coronary artery surgery setting found that valdecoxib was associated with an acute two- to three-fold higher risk of cardiovascular events compared with placebo. GI and CV safety: Etoricoxib Fair: Several fair quality meta- GI safety: Etoricoxib was associated with analyses of published and fewer perforations, symptomatic ulcers, and unpublished trials bleeds than diclofenac, ibuprofen, and naproxen (rate/100 patient-years 1.00 vs. 2.47). CV safety: Based on limited data from short- term trials, etoricoxib has a cardiovascular safety profile similar to non-selective NSAIDs, with the possible exception of naproxen. GI and CV safety: Lumiracoxib Fair: One large, long-term trial GI safety: In patients not taking low-dose aspirin, lumiracoxib was associated with a lower risk of ulcer complications compared to naproxen and ibuprofen (1-year incidence 0.25% vs. 1.09%, p<0.0001). CV safety: There were no differences in the risk of serious CV events (rates ranged from 0.11% to 0.38% after 1 year). GI and CV safety: Partially GI safety: Fair for meloxicam GI safety: Meloxicam and non-selective selective NSAIDs (short-term RCTs, meta- NSAIDs were generally associated with analyses, observational similar risks of serious GI events; evidence studies); poor for nabumetone was insufficient to make reliable judgments and etodolac about GI safety of nabumetone and etodolac CV safety: Poor for all; two CV safety: Very sparse evidence that observational studies for meloxicam and non-selective NSAIDs were meloxicam associated with similar risks of serious CV events; no evidence for nabumetone and etodolac GI and CV safety: Non- Good for GI safety. Consistent No clear difference in GI safety between non- selective NSAIDs evidence from many published selective NSAIDs at commonly used doses. trials, systematic reviews, and Naproxen was associated with a modest observational studies cardiovascular protective effect compared to other NSAIDs in a good-quality systematic 88 Key Question Level of Evidence Conclusion Fair for CV safety. No large, review of observational studies, but long-term controlled trials. methodological issues could have affected the Almost all evidence from results. observational studies Comparative CV safety of other non-aspirin NSAIDs is not clear. A large systematic review of RCTs addressing this issue has not yet been published. GI and CV safety: Aspirin Fair. Many trials and systematic Aspirin is associated with a lower risk of reviews, but almost exclusively thromboembolic events and a higher risk of GI in patients receiving aspirin at bleeds when given in prophylactic doses. doses used for cardiovascular There is insufficient evidence to assess safety prophylaxis. of aspirin in doses used for pain control compared with non-aspirin NSAIDs. GI and CV safety: Salsalate Poor. Flawed observational Salsalate was associated with a lower risk of data adverse events using broad composite endpoints in older, poor-quality observational studies. In a more recent observational study, salsalate had a similar rate of complications compared with other NSAIDs. Almost no data is available on CV safety. Mortality Fair. Individual trials not large No difference between celecoxib and non- enough to detect differences in selective NSAIDs, but few deaths occurred. mortality. One meta-analysis of In one cohort study, nabumetone was celecoxib using unpublished associated with lower all-cause mortality information, and one fair-quality compared with diclofenac and naproxen, but observational study of non- this finding has not been replicated. selective NSAIDs. HTN, CHF, edema, and Fair. Multiple systematic All NSAIDs are associated with deleterious impaired renal function reviews, clinical trials, and effects on blood pressure, edema, and renal observational studies, but function. Indirect evidence and observational analyses limited by inconsistent data suggests that rofecoxib is associated reporting of results and probable with a greater risk of hypertension, CHF, and publication bias edema compared to celecoxib. Rofecoxib was also associated with more cardiorenal events than celecoxib in three head-to-head trials of high-risk patients, but possible nonequivalent dosing limits interpretation of these results. No clear differences between celecoxib, partially selective, and non- selective NSAIDs. Hepatotoxicity Good. Systematic reviews of Clinically significant hepatotoxicity was rare. multiple trials and observational Several NSAIDs associated with high rates of studies hepatotoxicity have been removed from the market. Among currently marketed NSAIDs, diclofenac was associated with a higher rate of liver-related discontinuations compared with placebo (2.17%). Tolerability Good for coxibs and non- Relative to non-selective NSAIDs, coxibs and selective NSAIDs (consistent partially selective NSAIDs were at least as results from multiple systematic well tolerated and aspirin was less tolerated; reviews); fair for partially salsalate was less well tolerated than non- selective NSAIDs, aspirin, and selective NSAIDs in 2 of 3 trials, but less toxic salsalate (few meta-analyses in flawed observational studies; no clear and short-term trials) differences among coxibs or among non- selective NSAIDs Acetaminophen Good overall. Consistent results Acetaminophen is modestly inferior to NSAIDs from multiple systematic reviews for reducing pain and improving function. for efficacy and GI adverse Acetaminophen is superior to NSAIDs for GI events. side effects (clinical trials data) and GI Poor for cardiovascular safety complications (observational studies). 89 Key Question Level of Evidence Conclusion (no evidence on myocardial Acetaminophen may be associated with infarctions) and fair for renal modest increases in blood pressure and renal safety (observational studies) dysfunction (observational studies). Acetaminophen does not appear to be associated with an increased risk of hepatotoxicity at therapeutic doses in patients without underlying liver disease. Glucosamine and chondroitin Fair. Inconsistent evidence from A recent large, good-quality NIH-funded trial clinical trials. The most found that pharmaceutical grade glucosamine promising results have been hydrochloride and chondroitin sulfate alone or obtained in trials funded by a in combination were not superior to placebo European manufacturer of among all patients studied. In a small pharmaceutical grade subgroup of patients with at least moderate glucosamine not approved in the baseline pain, there appeared to be a modest U.S. benefit for pain relief from the combination, but this did not appear to be a preplanned analysis. In older trials, many with some flaws, glucosamine was superior to oral NSAIDs and placebo in trials evaluating pharmaceutical grade glucosamine and funded by its manufacturer. Other trials found no difference between glucosamine and placebo or glucosamine and oral NSAIDs. Chondroitin was superior to placebo in older, flawed trials. Data on the effects of glucosamine on slowing progression of disease are limited to two trials showing beneficial effects on progression of knee joint narrowing. Glucosamine and chondroitin were consistently well tolerated, with no serious adverse events reported in the trials. 1b. How do these benefits and Good for safety (consistent Risk of GI bleeding increases with higher harms change with dosage evidence from multiple clinical doses of non-selective NSAIDs. Effects of and duration of treatment, and trials and observational studies), dose and duration are somewhat inconsistent. what is the evidence that no evidence for alternative Celecoxib was most effective for GI safety at 6 alternative dosage strategies, dosage strategies. months and not after longer follow-up in the such as intermittent dosing CLASS trials. A trend towards a dose- and drug holidays, affect the dependent CV risk of celecoxib was observed benefits and harms of oral in a long-term prevention trial. CV risk of medication use? rofecoxib became most apparent after 8 months in VIGOR and after 18 months in the APPROVe prevention trial, but interpretation of earlier risk is imprecise because of small numbers of events. Most, but not all, observational studies suggest a dose- dependent effect of rofecoxib on MI risk. 2. Do the comparative benefits and harms of oral treatments for osteoarthritis vary for certain demographic and clinical subgroups? Demographic subgroups Good (age, sex) Most studies included a majority of women. including age, sex, and race The risks of GI and CV events increase in Poor (race) older patients. The data that selective COX-2 inhibitors are safe and efficacious in different racial groups have been presented to the FDA. In the peer-reviewed literature, there is no evidence that the comparative efficacy of different selective and non-selective NSAIDs varies according to age, gender, or race. 90 Key Question Level of Evidence Conclusion Pre-existing disease including Previous bleeding: Good Risk of bleeding is higher in patients with prior history of previous bleeding due Hypertension, edema: Fair bleeding or PUD. Two trials found high rates to NSAIDs or peptic ulcer Ischemic Heart Disease: Poor of recurrent ulcer bleeding in patients disease; hypertension, edema, (no comparative studies) randomized either to celecoxib or a non- ischemic heart disease, and Heart failure: Fair selective NSAID + PPI. Risk of CV and renal heart failure events is higher in patients with cardiac and renal co-morbidities. In a single observational study that examined mortality, rofecoxib and non-selective NSAIDs were associated with higher rates of death and recurrent heart failure than celecoxib. Concomitant anticoagulant use Fair overall: Primarily Concomitant use of anticoagulants and non- observational studies selective NSAIDs increase the risk of GI bleeding three- to six-fold. Reliable conclusions about the safety of selective NSAIDs in the setting of anticoagulation could not be drawn from flawed observational studies, though there are case reports of serious bleeding events (primarily in the elderly). Warfarin plus aspirin (prophylactic doses) increased the risk of bleeding compared with warfarin alone in patients with indications for antithrombotic prophylaxis. Acetaminophen can increase INR levels, but effects on bleeding rates have not been studied. Concomitant aspirin use Good for GI safety: Consistent Concomitant use of aspirin appears to evidence from clinical trials and attenuate or eliminate the GI benefits of observational studies selective NSAIDs. Concomitant low-dose aspirin increased the rate of endoscopic Fair for CV safety: Subgroup ulcers by about 6% in patients on celecoxib analyses from few trials, few and those on non-selective NSAIDs in one observational studies meta-analysis. In one trial, rofecoxib plus low- dose aspirin and ibuprofen were associated with a similar risk of endoscopic ulcers (16- 17%); both were significantly higher than placebo (6%) or aspirin alone (7%). Evidence regarding the effects of concomitant aspirin use on CV risk associated with selective or non-selective NSAIDs is limited, though three polyp prevention trials of rofecoxib or celecoxib found that concomitant aspirin use did not attenuate the observed increased risk of CV events. 3. What are the comparative Good: Consistent evidence Co-prescribing of misoprostol or PPIs with effects of co-prescribing of from good-quality systematic NSAIDs offers some advantages over full- H2-antagonists, misoprostol, reviews and numerous clinical dose H2-antagonists. PPIs are associated or proton pump inhibitors trials with the lowest rates of endoscopically (PPIs) on the gastrointestinal detected duodenal ulcers. Misoprostol and harms associated with NSAID PPIs are associated with similar rates of use? endoscopically detected gastric ulcers as PPIs. While misoprostol offers the advantage of being the only gastroprotective agent to reduce rates of clinical GI events, it is also associated with an increased risk of GI-related adverse event withdrawals. Full-dose H2 blockers were associated with lower ulcer risk than placebo, but head-to-head trials against PPIs and misoprostol are lacking. Endoscopic duodenal ulcer risk for standard dose H2 91 Key Question Level of Evidence Conclusion blockers was lower than placebo, similar to misoprostol, and higher than omeprazole; standard dosages of H2 blockers and placebo were associated with similar gastric ulcer risk 4. What are the comparative benefits and harms of treating osteoarthritis with oral medications as compared with topical preparations? Topical NSAIDs: efficacy Good: Consistent evidence for Topical NSAIDs are similar to oral NSAIDs for selected topical NSAIDs from efficacy. Topical diclofenac is the best clinical trials studied, though many trials evaluated a formulation using a DMSO carrier that is not available in the U.S. Topical ibuprofen was superior to placebo in several trials. Topical NSAIDs: safety Good: Consistent evidence Topical NSAIDs are associated with increased from trials and systematic local adverse events compared with oral reviews and observational NSAIDs. Total adverse events and studies withdrawal due to adverse events are similar. Topical NSAIDs are superior for GI events, including severe events, and changes in hemoglobin (data from one good-quality trial). Topical salicylates: (including Fair: Only placebo-controlled Topical salicylates were no better than capsaicin) trials, many of which were placebo in higher-quality trials. Topical flawed capsaicin was superior to placebo (NNT 8.1), but associated with increased local adverse events and withdrawals due to adverse events. Discussion This report provides a comprehensive summary of the comparative efficacy and safety of oral nonsteroidal anti-inflammatory drugs (NSAIDs) (selective, non-selective, aspirin, and salsalate), acetaminophen, certain over-the-counter supplements (chondroitin and glucosamine), and topical agents (NSAIDs and rubefacients, including capsaicin) that are commonly used for pain control and improvement of functional status in patients with osteoarthritis. At this time, no drug or supplement is known to modify the course of disease, though initial long-term trials of pharmaceutical grade glucosamine suggest an effect on radiologic evidence for disease progression. Evidence regarding the benefits of oral NSAIDs from primarily short-term randomized controlled trials is abundant and demonstrates no clear, consistent differences for relieving pain or other osteoarthritis-related symptoms, or for superior tolerability. On the other hand, much of the uncertainty and confusion regarding NSAIDs centers on their comparative safety. The trade-offs between reduced GI risk and increased CV harms was first clearly observed in VIGOR. In this trial, rofecoxib 50 mg daily significantly reduced symptomatic ulcers (NNT=62) and serious ulcer complications (NNT=191) compared with naproxen in patients with rheumatoid arthritis.19 However, the GI-protective effects were accompanied by a more than four-fold increase in myocardial infarctions, or one additional myocardial infarction for every 333 patients treated with rofecoxib. When considering all "serious" adverse events, moreover, 92 rofecoxib was not associated with any clear benefit compared with naproxen.114 Rofecoxib became the focus of intense scrutiny following publication of VIGOR. Subsequently, multiple observational studies138-141, 143-152 and systematic reviews124, 129 of RCTs have reported findings largely consistent with an increased risk of cardiovascular events with exposure to rofecoxib. Rofecoxib was voluntarily withdrawn from the market in 2004, after a long-term placebo-controlled polyp prevention trial reported increased cardiovascular risk.132 Valdecoxib was likewise voluntarily withdrawn from the market in 2005. Withdrawal was recommended by FDA based on their conclusion that valdecoxib associated with no clear GI benefit,117 an increased risk of serious skin reactions,168 and potential increased risk of CV events.165, 166 As a result, celecoxib is the only selective NSAID currently available in the U.S. The same concerns about the overall safety of rofecoxib have been directed at celecoxib. The evidence regarding the relative GI and CV safety of celecoxib, however, is less clear. In CLASS, the largest published study of GI complications, celecoxib was not significantly different than diclofenac or ibuprofen for either ulcer complications or myocardial infarctions by the end of follow-up.94 Like the VIGOR trial, re-analysis of all serious adverse events in CLASS found no significant advantage for celecoxib.94 On the other hand, systematic reviews and other meta-analyses of primarily short-term and frequently unpublished data found that celecoxib (primarily at lower doses than were used in CLASS) was associated with lower rates of ulcer complications than non-selective NSAIDs.62, 121 These findings, in combination with earlier systematic reviews of primarily short-term trials that found no increased cardiovascular risk with celecoxib, suggested a possible advantage of celecoxib over non-selective NSAIDs.62, 134, 135 More recent meta-analyses (including data from long-term polyp prevention trials) reporting an increased risk of myocardial infarctions with celecoxib (particularly at high doses) relative to placebo, however, raise additional questions about its appropriate use.129, 136 Well-designed, long-term observational studies could provide 'real-world' information not available from most RCTs, which are usually designed as short-term efficacy trials that evaluate selected populations and employ rigid dosing regimens (often at high doses) under carefully controlled conditions. Observational studies are generally consistent with the RCTs in that celecoxib is consistently GI protective139, 162 or neutral138 and not associated with higher risks of CV events relative to non-selective NSAIDs.144, 145, 150, 160 Additionally, celecoxib is associated with lower risks of serious GI events than rofecoxib.139, 142 Evidence from observational studies is less clear with regard to how celecoxib compares to rofecoxib in terms of CV risk due to differences in outcome reporting and in the number and type of factors adjusted for in outcome analyses. An important drawback of the observational studies, however, is that they largely focus on individual adverse events in isolation. More informative analyses of the overall trade-off between risks and benefits would consider net harms from all serious adverse events. Our re- analysis of results from three studies139, 147, 163 reporting myocardial infarctions, heart failure hospitalizations, and gastrointestinal bleeding in an elderly Canadian population receiving multiple prescriptions suggests that in everyday use, celecoxib may confer net advantages in terms of the number of these events compared with rofecoxib and non-selective NSAIDs. However, additional studies on original data are needed to confirm this finding in other settings. The cardiovascular effects of naproxen and other non-selective NSAIDs have been the subject of considerable debate since the publication of the VIGOR trial. At this time, among NSAIDs with sufficient evidence to assess cardiovascular risk, naproxen appears to offer the most favorable cardiovascular safety profile. In a recent, comprehensive systematic review, 93 naproxen (even at high doses) was moderately superior to COX-2 inhibitors for cardiovascular safety.129 In addition, naproxen was the only NSAID (selective or non-selective) associated with a neutral cardiovascular effect relative to placebo, though these analyses were primarily based on indirect comparisons. The cardiovascular risks of non-naproxen, non-selective NSAIDs were similar to the selective COX-2 inhibitors, though most of the evidence was limited to high-dose ibuprofen and diclofenac. At this time, there is insufficient evidence to reliably judge the relative cardiovascular safety of other non-selective NSAIDs or the partially selective drugs nabumetone, diclofenac, and meloxicam. For GI safety, no clear advantage for any particular partially selective or non-selective NSAIDs has been demonstrated. Topical NSAIDs may offer the advantages of local analgesic and anti-inflammatory effects without the systemic side effects of oral administration. They would probably be most useful in patients with a limited number of affected joints. Although topical NSAIDs appear comparable to oral NSAIDs for pain relief in several trials, the most convincing evidence comes from a recent trial that evaluated a proprietary formulation of diclofenac with DMSO that has not been FDA-approved.338 Topical NSAIDs appear safer than oral NSAIDs for GI safety, but data on comparative cardiovascular risks are not available. The relative benefits of topical rubefacients compared with topical or oral NSAIDs has not been adequately studied, and other than for capsaicin (which is sometimes classified separately from the rubefacients), there is insufficient evidence to prove that topical rubefacients are superior to placebo for osteoarthritis. Acetaminophen is often considered an attractive alternative to NSAIDs because of its perceived safety profile. It was associated with GI-protective effects relative to non-selective NSAIDs,229, 231 though at the expense of modestly inferior efficacy.234 More evidence is needed to compare the effects of acetaminophen and NSAIDs on other important adverse events such as cardiovascular safety, renal dysfunction, blood pressure, and heart failure. However, one recent observational study found that heavy use of acetaminophen is associated with increased cardiovascular risks similar to that seen with NSAIDs.237 Aspirin is another alternative that has the advantage of a cardiovascular protective effect. However, nearly all of the evidence on cardiovascular and GI safety of aspirin is from trials using lower, preventative doses rather than higher anti-inflammatory and analgesic doses. Glucosamine and chondroitin are widely available as over-the-counter supplements. The highly variable content of currently available products, however, remains a significant issue in the U.S. Further, nearly all of the trials demonstrating benefits of glucosamine have been conducted using pharmaceutical grade preparations not currently available in the U.S.248 Compared with the evidence for glucosamine, the evidence for chondroitin appears less promising. While these agents appear to be safe in the short term, high-quality, long-term safety data are sparse. A recent large, NIH-sponsored trial helps clarify the role of these supplements in management of osteoarthritis.259 It found that the combination of pharmaceutical grade glucosamine and chondroitin was modestly superior to placebo only in an analysis of a small subgroup of patients with at least moderate severity of baseline disease. Neither glucosamine nor chondroitin alone was superior to placebo overall or in the subgroup of patients with greater baseline severity. Data on effects of glucosamine on osteoarthritis progression are limited to two trials showing a beneficial effect on knee joint space narrowing over three years using a pharmaceutical grade preparation. Strategies to reduce the risk of GI complications in patients taking NSAIDs include co- prescription of misoprostol, standard- or double-dose H2 blockers, or PPIs. All of these strategies are effective in reducing the risk of NSAID-associated endoscopic gastric and 94 duodenal ulcers relative to use of non-selective NSAIDs alone. Misoprostol (RR 0.36, 95% CI 0.20 to 0.67) and PPIs (RR 0.09, 95% CI 0.02 to 0.47) also reduced NSAID-associated symptomatic ulcers.293 Further, misoprostol is the only agent proven to decrease risk of clinical GI events, but is associated with an increased risk of withdrawals due to nausea, diarrhea, and/or abdominal pain.317 In high-risk patients (those with a recent bleed), non-selective NSAIDs and the combination of a non-selective NSAID plus a PPI were both associated with similar, high rates of recurrent bleeding.270, 271 In summary, each of the analgesics evaluated in this report was associated with a unique set of risks and benefits. The role of selective and non-selective oral NSAIDs and alternative agents will continue to evolve as additional information emerges. At this time, although the amount and quality of evidence varies, no currently available analgesic reviewed in this report offers a clear overall advantage compared with the others, which is not surprising given the complex trade-offs between the many benefits (pain relief, improved function, improved tolerability, and others) and harms (cardiovascular, renal, GI, and others) involved. In addition, individuals are likely to differ in how they prioritize the importance of the various benefits and harms of treatment. Adequate pain relief at the expense of a small increase in CV risk, for example, could be an acceptable trade-off for many patients. Others may consider even a marginal increase in CV risk unacceptable. Factors that should be considered when weighing the potential effects of an analgesic include age (older age being associated with increased risks for bleeding and cardiovascular events), co-morbid conditions, and concomitant medication use (such as aspirin and anticoagulation). As in other medical decisions, choosing the optimal analgesic for an individual with osteoarthritis should always involve careful consideration and thorough discussion of the relevant trade-offs. 95 96 Chapter 5. Future Research • Nearly all of the clinical trials reviewed in this report were "efficacy" trials conducted in ideal settings and selected populations. "Pragmatic" trials that allow flexible dosing or medication switches and other clinical trials of effectiveness would be very valuable for learning the outcomes of different analgesic interventions in real-world settings. • The cardiovascular safety of non-selective NSAIDs has not been adequately assessed in large, long-term clinical trials. Naproxen in particular may have a different cardiovascular safety profile than other NSAIDs and should be investigated in long-term, appropriately powered trials. The cardiovascular risks associated with the partially selective NSAIDs meloxicam, nabumetone, and diclofenac also have not been well studied. • Large observational studies assessing the safety of NSAIDs have been helpful for assessing comparative benefits and harms, but have generally had a narrow focus on single adverse events. Observational studies that take a broader view of all serious adverse events would be substantially more helpful for assessing the overall trade-offs between benefits and harms. • The cardiovascular risks and GI benefits associated with different COX-2 selective NSAIDs may vary. Large, long-term trials with active and placebo-controlled arms would be needed to assess the safety and benefits of any new COX-2 selective analgesic. • Meta-analyses of the risks associated with selective COX-2 inhibitors need to better assess for the effects of dose and duration, as most of the cardiovascular risks have only occurred with prolonged use and at higher doses. • Large, long-term trials of the GI and cardiovascular safety associated with full-dose aspirin, salsalate, or acetaminophen compared with non-aspirin NSAIDs or placebo are lacking. • Given the large number of patients who meet criteria for aspirin prophylaxis for cardiovascular events, more trials evaluating the effects of low-dose aspirin on GI and CV risks are needed. • Trials and observational studies evaluating comparative safety or efficacy should be sufficiently inclusive to evaluate whether effects differ by race or gender. • Genetic testing could theoretically help predict patients who are at higher risk of cardiovascular complications from selective COX-2 inhibitors because of differences in the COX-2 gene promoter or other genes. This is a promising area of future research. 97 • The effects of alternative dosing strategies such as intermittent dosing or drug holidays have not been assessed. Studies evaluating the benefits and risks associated with such strategies compared with conventional dosing could help clarify the effects of these alternative dosing strategies. In addition, although there is speculation that once daily versus twice daily dosing of certain COX-2 inhibitors could affect CV risk, this hypothesis has not yet been tested in a clinical trial. • Most trials showing therapeutic benefits from glucosamine were conducted using pharmaceutical grade glucosamine not available in the U.S. and may not be applicable to currently available over-the-counter preparations. Large trials comparing currently available over-the-counter preparations to oral NSAIDs are needed, as these are likely to remain available even if the FDA approves a pharmaceutical grade glucosamine. Additional long-term trials are also required to further evaluate effects of glucosamine on progression of joint space narrowing. • No topical NSAIDs are FDA-approved in the U.S., yet compounding of NSAIDs is widely available. Although recent trials of topical NSAIDs are promising, most have been conducted using a proprietary formulation of diclofenac with DMSO. A UK trial of topical versus oral ibuprofen is currently in progress and will help clarify the benefits and safety of topical versus oral NSAIDs. However, cohort studies using large observational databases may be required to adequately assess cardiovascular risk. 98 Addendum As this report was going to press, two relevant meta-analyses on risks associated with NSAIDs were published. We were unable to fully incorporate these studies into our report, but their results generally appear consistent with our conclusions. One meta-analysis evaluated risk of renal events (peripheral edema, hypertension, or renal dysfunction) and arrhythmias from 114 randomized trials of COX-2 selective NSAIDs [Zhang J, Ding EL, Song Y. Adverse effects of cyclooxygenase 2 inhibitors on renal and arrhythmia events. Meta-analysis of randomized trials. JAMA. 2006;296:(doi:10.1001/jama.296.13.jrv6001)]. It was rated fair-quality because it did not assess the quality of included studies. It found rofecoxib associated with increased risks of arrhythmia relative to control (placebo, other NSAID, or mixed/other) treatments (RR 2.90, 95% CI 1.07 to 7.88), though the number and rate of events was low (13/10126 or 0.1% in the rofecoxib arms, with 10 of the events ventricular fibrillation, cardiac arrest, or sudden cardiac death). The increase in risk was equivalent to about 1.1 additional arrhythmia events per 1000 patients treated with rofecoxib. Rofecoxib was also associated with an increased risk of peripheral edema (RR 1.43, 95% CI 1.23 to 1.66), hypertension (RR 1.55, 95% CI 1.29 to 1.85) and renal dysfunction (RR 2.31, 95% CI 1.05 to 5.07). For composite renal events (peripheral edema, hypertension, or renal dysfunction), risks were significantly higher with increased dose and increased duration of rofecoxib. Celecoxib was associated with lower risks of renal dysfunction (RR 0.61, 95% CI 0.40 to 0.94) and hypertension (RR 0.83, 95% CI 0.71 to 0.97) than control treatments, though there was no difference for composite renal events (RR 0.97, 95% CI 0.84 to 1.12) or arrhythmia (RR 0.84, 95% CI 0.45 to 1.57). There was no clear association between other COX-2 inhibitors (valdecoxib/parecoxib, etoricoxib, or lumiracoxib) and arrhythmia or renal events, though there was a trend towards increased renal events with valdecoxib/parecoxib (RR 1.24, 95% CI 1.00 to 1.55), and no arrhythmia events were reported in six trials of lumiracoxib. Several factors complicate interpretation of estimates of arrhythmia risk from this meta- analysis. First, the rate of arrhythmias varied widely between control arms for different COX-2 selective inhibitors. For example, the rate of arrhythmias was fourteen-fold higher in the control arms of the celecoxib trials compared to the control arms of the rofecoxib trials (18/6568 or 0.3% vs. 2/10,126 or 0.01%). In addition, the proportion of specific arrhythmia events varied widely between drugs. For valdecoxib, over half (69/129 or 53%) of the arrhythmia events were atrial fibrillation, compared to 14% (3/22) for celecoxib and 8% (1/13) for rofecoxib. Finally, even though funnel plots and statistical tests did not suggest the presence of publication bias, only a minority of trials reported usable data on arrhythmia events. For example, only 10 of 37 included trials of celecoxib (accounting for about one-third of trial participants) had data that could be used in the analysis of arrhythmia events. The second meta-analysis evaluated cardiovascular risk (primarily myocardial infarction) associated with NSAIDs from 23 observational studies (mostly of older populations) [McGettigan P, Henry D. Cardiovascular risk and inhibition of cyclooxygenase. A systematic review of the observational studies of selective and nonselective inhibitors of cyclooxygenase 2. JAMA. 2006;296:(doi:10.1001/jama.292.13.jrv60011)]. Its results are largely consistent with our 99 qualitative assessment of cardiovascular risk from the observational literature. This meta- analysis appears to meet criteria for a good-quality systematic review, but its interpretation is complicated by the presence of substantial (p<=0.001), unexplained between-study heterogeneity for the main pooled analyses. It found rofecoxib associated with an increased risk of cardiovascular events at both lower (25 mg/day or less, RR 1.33, 95% CI 1.00 to 1.79) and higher (>25 mg/day, RR 2.19, 95% CI 1.64 to 2.91) doses, with the increased risk observable during the first month of treatment. Of the other NSAIDs, diclofenac (RR 1.40, 95% CI 1.16 to 1.70) was associated with the greatest cardiovascular risk, followed by indomethacin (RR 1.30, 95% CI 1.07 to 1.60) and meloxicam (RR 1.25, 95% CI 1.00 to 1.55). Celecoxib (RR 1.06, 95% CI 0.91 to 1.23), naproxen (RR 0.97, 95% CI 0.87 to 1.07), piroxicam (RR 1.06, 95% CI 0.70 to 1.59), and ibuprofen (RR 1.07, 95% CI 0.97 to 1.18) were not associated with increased risks. 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