title: Efficacy and tolerability of initial therapy with single-pill combination telmisartan/hydrochlorothiazide 80/25 mg in patients with grade 2 or 3 hypertension: a multinational, randomized, double-blind, active-controlled trial. Rationale and design of the Kanyini guidelines adherence with the polypill (Kanyini-GAP) study: a randomised controlled trial of a polypill-based strategy amongst Indigenous and non Indigenous people at high cardiovascular risk An International Randomised Placebo-Controlled Trial of a Four-Component Combination Pill (“Polypill”) in People with Raised Cardiovascular Risk Comparison of Risk Factor Reduction and Tolerability of a Full-Dose Polypill (With Potassium) Versus Low-Dose Polypill (Polycap) in Individuals at High Risk of Cardiovascular Diseases: The Second Indian Polycap Study (TIPS-2) Investigators Effects of a fixed-dose combination strategy on adherence and risk factors in patients with or at high risk of CVD: the UMPIRE randomized clinical trial. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial Impact of Combination Therapy with Amlodipine and Atorvastatin on Plasma Adiponectin Levels in Hypertensive Patients with Coronary Artery Disease: Combination Therapy and Adiponectin The fixed-dose combination drug for secondary cardiovascular prevention project: improving equitable access and adherence to secondary cardiovascular prevention with a fixed-dose combination drug. Study design and objectives. A Polypill for primary prevention of cardiovascular disease: A feasibility study of the World Health Organization Randomized Polypill Crossover Trial in People Aged 50 and Over The Anglo-Scandinavian Cardiac Outcomes Trial: blood pressure-lowering limb: effects in patients with type II diabetes Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial Implementation of a simple age-based strategy in the prevention of cardiovascular disease: the Polypill approach. Use of secondary prevention drugs for cardiovascular disease in the community in high-income, middle-income, and low-income countries (the PURE Study): a prospective epidemiological survey The use of a single-pill calcium channel blocker/statin combination in the management of hypertension and dyslipidemia: a randomized, placebo-controlled, multicenter study. A pilot double-blind randomised placebo-controlled trial of the effects of fixed-dose combination therapy ('polypill') on cardiovascular risk factors. International open-label studies to assess the efficacy and safety of single-pill amlodipine/atorvastatin in attaining blood pressure and lipid targets recommended by country-specific guidelines: the JEWEL programme Antihypertensive efficacy of hydrochlorothiazide vs chlorthalidone combined with azilsartan medoxomil. Proactive multiple cardiovascular risk factor management compared with usual care in patients with hypertension and additional risk factors: the CRUCIAL trial Effects of body size and hypertension treatments on cardiovascular event rates: subanalysis of the ACCOMPLISH randomised controlled trial Characteristics and lipid distribution of a large, high-risk, hypertensive population: the lipid-lowering component of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Simultaneous treatment to attain blood pressure and lipid goals and reduced CV risk burden using amlodipine/atorvastatin single-pill therapy in treated hypertensive participants in a randomized controlled trial Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Single-pill combination of telmisartan/amlodipine in patients with severe hypertension: results from the TEAMSTA severe HTN study. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial A randomized, placebo-controlled trial to evaluate the efficacy, safety, and pharmacodynamic interaction of coadministered amlodipine and atorvastatin in 1660 patients with concomitant hypertension and dyslipidemia: the respond trial. Laboratory-based versus non-laboratory-based method for assessment of cardiovascular disease risk: the NHANES I Follow-up Study cohort Preservation of Bioavailability of Ingredients and Lack of Drug-Drug Interactions in a Novel Five-Ingredient Polypill (Polycap™) Long-term follow-up for mortality and cancer in a randomized placebo-controlled trial of vitamin D(3) and/or calcium (RECORD trial). IMProving Adherence using Combination Therapy (IMPACT): design and protocol of a randomised controlled trial in primary care. Single-pill therapy in the treatment of concomitant hypertension and dyslipidemia (the amlodipine/atorvastatin gemini study). Serum cholesterol, blood pressure, cigarette smoking, and death from coronary heart disease. Overall findings and differences by age for 316,099 white men. Multiple Risk Factor Intervention Trial Research Group. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. Efficacy and safety of coadministered amlodipine and atorvastatin in patients with hypertension and dyslipidemia: results of the AVALON trial. Single-pill amlodipine/atorvastatin helps patients of diverse ethnicity attain recommended goals for blood pressure and lipids (the Gemini-AALA study) Improved attainment of blood pressure and cholesterol goals using single-pill amlodipine/atorvastatin in African Americans: the CAPABLE trial. Effects of homocysteine-lowering with folic acid plus vitamin B12 vs placebo on mortality and major morbidity in myocardial infarction survivors: a randomized trial. Effects of a polypill (Polycap) on risk factors in middle-aged individuals without cardiovascular disease (TIPS): a phase II, double-blind, randomised trial. Variation of some inflammatory markers in hypertensive patients after 1 year of olmesartan/amlodipine single-pill combination compared with olmesartan or amlodipine monotherapies. Long-Term Tolerability and Efficacy of Single-Pill Combinations of Telmisartan 40-80 mg Plus Amlodipine 5 or 10 mg in Patients Whose Blood Pressure Was Not Initially Controlled by Amlodipine 5-10 mg: Open-Label, Long-Term Follow-Ups of the TEAMSTA-5 and TEAMSTA-10 Studies.
abstract: BACKGROUND Patients with grade 2 or 3 hypertension may require high-dose combination therapy to achieve blood pressure ( BP ) targets in a timely manner . OBJECTIVES This study compared the effectiveness and tolerability of a single-pill combination ( SPC ) of telmisartan/hydrochlorothiazide 80/25 mg ( T80/H25 ) with T80 monotherapy . METHODS In a Phase IV , multinational , r and omized , double-blind , double-dummy , active-controlled , parallel-group trial , 894 patients with mean seated trough cuff systolic BP [ SBP ] ≥160 mm Hg and diastolic BP [ DBP ] ≥100 mm Hg were r and omly assigned in a 2:1 ratio to receive T40/H12.5 SPC or telmisartan 40 mg monotherapy for 1 week before the dose was uptitrated to T80/H25 SPC or T80 , respectively , administered for 6 weeks . The primary efficacy measure was the change from baseline in mean seated cuff trough SBP . Adverse events ( AEs ) were recorded . RESULTS A total of 888 patients received treatment ( 294 and 594 patients in the T80/H25 and T80 groups , respectively ) ( mean age , 57.0 years ; age ≥65 years , 25.7 % ; male , 53.8 % ; white , 68.0 % ) ; 61 patients prematurely  discontinued . Mean baseline SBP/DBP values were 172.3/104.3 mm Hg ( T80/H25 ) and 173.3/104.5 mm Hg ( T80 ) . After 7 weeks , SBP was changed by -37.0 and -28.5 mm Hg in the T80/H25 and T80 groups ( P < 0.0001 ) ; DBP was changed by -18.6 and -15.4 mm Hg respectively ( P < 0.0001 ) . These differences were significant after 2 weeks at the higher dosage ( P < 0.0001 ) . BP target ( SBP/DBP < 140/<90 mm Hg ) was achieved in 55.5 % and 34.7 % of patients in the T80/H25 and T80 groups ( P < 0.0001 ) . T80/H25 SPC and T80 had a similar frequency of overall AEs ( 16.0 % vs 17.0 % ) . The prevalences of treatment-related AEs with T80/H25 SPC and T80 were low ( 4.6 % and 2.8 % ) , as were the rates of AEs that led to discontinuation ( 1.0 % and 2.8 % ) . CONCLUSIONS In these patients with grade 2 or 3 hypertension , initial therapy with T80/H25 was associated with a significantly greater reduction in mean seated cuff trough SBP compared with T80 alone , as well as with improved hypertension goal attainment rates . Both treatments appeared to be well tolerated Background The Kanyini Guidelines Adherence with the Polypill ( Kanyini-GAP ) Study aims to examine whether a polypill-based strategy ( using a single capsule containing aspirin , a statin and two blood pressure-lowering agents ) amongst Indigenous and non-Indigenous people at high risk of experiencing a cardiovascular event will improve adherence to guideline -indicated therapies , and lower blood pressure and cholesterol levels . Methods / Design The study is an open , r and omised , controlled , multi-centre trial involving 1000 participants at high risk of cardiovascular events recruited from mainstream general practice s and Aboriginal Medical Services , followed for an average of 18 months . The participants will be r and omised to one of two  versions  of  the polypill  , the version chosen by the treating health professional according to clinical features of the patient , or to usual care . The primary study outcomes will be changes , from baseline measures , in serum cholesterol and systolic blood pressure and self-reported current use of aspirin , a statin and at least two blood pressure lowering agents . Secondary study outcomes include cardiovascular events , renal outcomes , self-reported barriers to indicated therapy , prescription of indicated therapy , occurrence of serious adverse events and changes in quality -of-life . The trial will be supplemented by formal economic and process evaluations . Discussion The Kanyini-GAP trial will provide new evidence as to whether or not a polypill-based strategy improves adherence to effective cardiovascular medications amongst individuals in whom these treatments are indicated . Trial Registration This trial is registered with the Australian New Zeal and Clinical Trial Registry ACTRN126080005833347 Background There has been widespread interest in the potential of combination cardiovascular medications containing aspirin and agents to lower blood pressure and cholesterol ( ‘ polypills ’ ) to reduce cardiovascular disease . However , no reliable placebo-controlled data are available on both efficacy and tolerability . Methods We conducted a r and omised , double-blind placebo-controlled trial of a polypill ( containing aspirin 75 mg , lisinopril 10 mg , hydrochlorothiazide 12.5 mg and simvastatin 20 mg ) in 378 individuals without an indication for any component of the polypill , but who had an estimated 5-year cardiovascular disease risk over 7.5 % . The primary outcomes were systolic blood pressure ( SBP ) , LDL-cholesterol and tolerability ( proportion discontinued r and omised therapy ) at 12 weeks follow-up . Findings At baseline , mean BP was 134/81 mmHg and mean LDL-cholesterol was 3.7 mmol/L. Over 12 weeks , polypill treatment reduced SBP by 9.9 ( 95 % CI : 7.7 to 12.1 ) mmHg and LDL-cholesterol by 0.8 ( 95 % CI 0.6 to 0.9 ) mmol/L. The discontinuation rates in the polypill group compared to placebo were 23 % vs 18 % ( RR 1.33 , 95 % CI 0.89 to 2.00 , p = 0.2 ) . There was an excess of side effects known to the component medicines ( 58 % vs 42 % , p = 0.001 ) , which was mostly apparent within a few weeks , and usually did not warrant cessation of trial treatment . Conclusions This polypill achieved sizeable reductions in SBP and LDL-cholesterol but caused side effects in about 1 in 6 people . The halving in predicted cardiovascular risk is moderately lower than previous estimates and the side effect rate is moderately higher . Nonetheless , substantial net benefits would be expected among patients at high risk . Trial Registration Australian New Zeal and Clinical Trials Registry Background — A daily single capsule ( polycap ) of 3 blood pressure ( BP ) lowering drugs ( hydrochlorthiazide , 12.5 mg ; atenolol , 50 mg ; ramipril , 5 mg ) at low doses , simvastatin ( 20 mg ) , and aspirin ( 100 mg ) has been demonstrated to be well tolerated and to reduce BP and low-density lipoprotein cholesterol . We examined the incremental effects of 2 ( full dose ) plus K+ supplementation versus single polycap ( low dose ) on risk factors and tolerability . Methods and Results — After a run-in period , 518 individuals with previous vascular disease or diabetes mellitus from 27 centers in India were r and omly assigned to a single-dose polycap or to 2 capsules of the polycap plus K+ supplementation for 8 weeks . The effects on BP , heart rate ( HR ) , serum lipids , serum and urinary K+ , and tolerability were assessed using an intention-to-treat analysis . The full-dose polycap ( plus K+ supplementation )  reduced BP by a further 2.8 mm Hg systolic and 1.7 mm Hg diastolic , compared with that observed with the low-dose polycap ( P=0.003 ; P=0.001 ) , but there were no differences in HR ( 0.1 bpm ) . The differences in total and low-density lipoprotein cholesterol between the full-dose and low-dose polycap was 7.2 mg/dL ( P=0.014 ) and 6.6 mg/dL ( P=0.006 ) , respectively , but there were no differences in high-density lipoprotein cholesterol or triglycerides . The rates of discontinuation of the study drug after r and omization were similar in the 2 groups ( 6.9 % low dose versus 7.8 % full dose ) . Conclusions — The full-dose polycap ( plus K+ supplementation ) reduces BP and low-density lipoprotein cholesterol to a greater extent compared with the low dose , with similar tolerability . Therefore , the full-dose polycap should potentially lead to larger benefits . Clinical Trial Registration — URL : http://www.ctri.nic.in . Unique identifier : CTRI/2010/091/000054 IMPORTANCE Most patients with cardiovascular disease ( CVD ) do not take recommended medications long-term . The use of fixed-dose combinations ( FDCs ) improves adherence in several clinical areas . Previous trials of cardiovascular FDCs have assessed short-term effects compared with placebo or no treatment . OBJECTIVE To assess whether FDC delivery of aspirin , statin , and 2 blood pressure-lowering agents vs usual care improves long-term adherence to indicated therapy and 2 major CVD risk factors , systolic blood pressure ( SBP ) and low-density lipoprotein cholesterol ( LDL-C ) . DESIGN , SETTING , AND PARTICIPANTS The UMPIRE trial , a r and omized , open-label , blinded-end-point trial among 2004 participants with established CVD or at risk of CVD enrolled July 2010-July 2011 in India and Europe . The trial follow-up concluded in July 2012 . INTERVENTIONS Participants were r and omly assigned ( 1:1 ) to an FDC-based strategy  ( n=1002 ) containing either ( 1 ) 75 mg aspirin , 40 mg simvastatin , 10 mg lisinopril , and 50 mg atenolol or ( 2 ) 75 mg aspirin , 40 mg simvastatin , 10 mg lisinopril , and 12.5 mg hydrochlorothiazide or to usual care ( n=1002 ) . MAIN OUTCOMES AND MEASURES Adherence to medication ( defined as self-reported use of antiplatelet , statin , and ≥2 BP-lowering medications ) and changes in SBP and LDL-C from baseline . RESULTS At baseline , mean BP was 137/78 mm Hg , LDL-C was 91.5 mg/dL , and 1233 ( 61.5 % ) of 2004 participants reported use of antiplatelet , statin , and 2 or more BP-lowering medications . Median follow-up was 15 months ( interquartile range , 12 - 18 months ) . The FDC group had improved adherence vs usual care ( 86 % vs 65 % ; relative risk [ RR ] of being adherent , 1.33 ; 95 % CI , 1.26 - 1.41 ; P < .001 ) with concurrent reductions in SBP ( -2.6 mm Hg ; 95 % CI , -4.0 to -1.1 mm Hg ; P < .001 ) and LDL-C ( -4.2 mg/dL ; 95 % CI , -6.6 to -1.9 mg/dL ; P < .001 ) at the end of the study . Although there was consistency of effects across predefined subgroups , evidence existed of larger benefits in patients with lower adherence at baseline . In this subgroup of 727 participants ( 36 % ) , adherence at the end of study was 77 % vs 23 % ( RR , 3.35 ; 95 % CI , 2.74 - 4.09 ; P < .001 for interaction ) , SBP was reduced by 4.9 mm Hg ( 95 % CI 7.3 - 2.6 mm Hg ; P = .01 for interaction ) , and LDL-C was reduced by 6.7 mg/dL ( 95 % CI , 10.5 - 2.8 mg/dL ; P = .11 for interaction ) . There were no significant differences in serious adverse events or cardiovascular events ( 50 [ 5 % ] in the FDC group and 35 [ 3.5 % ] in the usual care group ; RR , 1.45 ; 95 % CI , 0.94 - 2.24 ; P=.09 ) between the groups . CONCLUSIONS AND RELEVANCE Among patients with or at high risk of CVD , use of an FDC strategy for blood pressure , cholesterol , and platelet control vs usual care result ed in significantly improved medication adherence at 15 months and statistically significant but small improvements in SBP and LDL-C. TRIAL REGISTRATION clinical trials.gov Identifier : NCT01057537 BACKGROUND The lowering of cholesterol concentrations in individuals at high risk of cardiovascular disease improves outcome . No study , however , has assessed benefits of cholesterol lowering in the primary prevention of coronary heart disease ( CHD ) in hypertensive patients who are not conventionally deemed dyslipidaemic . METHODS Of 19342 hypertensive patients ( aged 40 - 79 years with at least three other cardiovascular risk factors ) r and omised to one of two antihypertensive regimens in the Anglo-Sc and inavian Cardiac Outcomes Trial , 10305 with non-fasting total cholesterol concentrations 6.5 mmol/L or less were r and omly assigned additional atorvastatin 10 mg or placebo .  These patients formed the lipid-lowering arm of the study . We planned follow-up for an average of 5 years , the primary endpoint being non-fatal myocardial infa rct ion and fatal CHD . Data were analysed by intention to treat . FINDINGS Treatment was stopped after a median follow-up of 3.3 years . By that time , 100 primary events had occurred in the atorvastatin group compared with 154 events in the placebo group ( hazard ratio 0.64 [ 95 % CI 0.50 - 0.83 ] , p=0.0005 ) . This benefit emerged in the first year of follow-up . There was no significant heterogeneity among prespecified subgroups . Fatal and non-fatal stroke ( 89 atorvastatin vs 121 placebo , 0.73 [ 0.56 - 0.96 ] , p=0.024 ) , total cardiovascular events ( 389 vs 486 , 0.79 [ 0.69 - 0.90 ] , p=0.0005 ) , and total coronary events ( 178 vs 247 , 0.71 [ 0.59 - 0.86 ] , p=0.0005 ) were also significantly lowered . There were 185 deaths in the atorvastatin group and 212 in the placebo group ( 0.87 [ 0.71 - 1.06 ] , p=0.16 ) . Atorvastatin lowered total serum cholesterol by about 1.3 mmol/L compared with placebo at 12 months , and by 1.1 mmol/L after 3 years of follow-up . INTERPRETATION The reductions in major cardiovascular events with atorvastatin are large , given the short follow-up time . These findings may have implication s for future lipid-lowering guidelines Abstract Background : In many countries , combination therapy with amlodipine and atorvastatin is indicated for the treatment of patients with hypertension and hypercholesterolemia . The aim of this study was to investigate the impact of this combination therapy on plasma adiponectin levels . Hypothesis : Combination therapy with amlodipine and atorvastatin would increase plasma adiponectin levels . Methods : A total of 25 patients with coronary artery disease and concomitant hypertension and hypercholesterolemia were evaluated . The combination of amlodipine and atorvastatin in 8 different dosage strengths were flexibly titrated over a period of 14 weeks . Lipid profile and plasma adiponectin were measured . Brachial flow-mediated dilation ( FMD ) was determined by vascular ultrasound . Results : As compared with baseline , combination therapy with amlodipine and atorvastatin significantly reduced systolic and diastolic blood pressure , total cholesterol , and low-density lipoprotein cholesterol ( all P < 0.05 ) . Furthermore , there were significant increases in adiponectin levels ( mean [ 95 % confidence interval ( CI ) ] , 12.1 [ 10.7 - 13.7 ] vs 8.1 [ 6.5 - 10.0 ] μg/mL ; P < 0.001 ) and brachial FMD ( 4.4 ± 0.6 % vs 5.6 ± 0.5 % ; P = 0.046 ) over 14 weeks of treatment . The change in adiponectin levels correlated significantly with the changes in diastolic blood pressure ( r = −0.49 ; P = 0.014 ) and FMD ( r = 0.55 ; P = 0.007 ) . Conclusion : The results of this study indicate that along with its antihypertensive and cholesterol-lowering effects , combination therapy with amlodipine and atorvastatin appears to increase plasma adiponectin levels and improve endothelial function In spite of advances in prevention and treatment , the burden of cardiovascular diseases is increasing . A fixed-dose combination ( FDC ) pill , or " polypill , " composed of evidence -based drugs has been proposed as a means of improving cardiovascular prevention by reducing cost and increasing patient adherence to treatment . The aim of the FOCUS project , funded by the 7th Framework Programme of the European Commission , is to characterize the factors that underlie inadequate secondary prevention and to test a new FDC . To achieve these goals , a 9-member consortium has been constituted , including institutions from Argentina , France , Italy , Spain , and Switzerl and . FOCUS Phase-1 will examine factors potentially related to lack of adequate secondary prevention in 4,000 post-myocardial infa rct ion ( MI ) patients and analyze the relationship between these factors and patient treatment adherence . Primary end points will be ( 1 ) the percentage of patients receiving aspirin , angiotensin-converting enzyme inhibitors , and statins and ( 2 ) adherence to treatment measured by the Morisky-Green test . FOCUS Phase-2 is a r and omized trial that will compare adherence to treatment in 1,340 post-myocardial infa rct ion patients either receiving an FDC comprising aspirin ( 100 mg ) , ramipril ( 2.5 , 5 , or 10 mg ) , and simvastatin ( 40 mg ) or receiving the same 3 drugs separately Background The feasibility of conducting a large-scale Polypill clinical trial in developing countries remains unclear . More information is needed regarding the efficacy in reducing the risk factors of cardiovascular disease ( CVD ) , side effects , improvement in adherence and physician/patient " acceptability " of the Polypill . Methods We conducted an open-label , parallel-group , r and omized clinical trial involving three sites in Sri Lanka that enrolled a total of 216 patients without established CVD . The trial compared a Polypill ( 75 mg aspirin , 20 mg simvastatin , 10 mg lisinopril and 12.5 mg hydrochlorothiazide ) to St and ard Practice . After r and omization , patients were followed monthly for three months . Pre-specified primary outcomes included reduction in systolic blood pressure , total cholesterol and estimated 10-year CVD risk . We also evaluated the recruitment process and acceptability of the Polypill by both physicians and patients . Results Patients were recruited in a six-month period as planned . Two hundred three patients ( 94.0 % ) completed the treatment program and returned for their three-month follow-up visits . No safety concerns were reported . These findings suggest a high rate of patient acceptability , a finding that is bolstered by the majority of patients completing the trial ( 90 % ) indicating that they would take the Polypill " for life " if proven to be effective in reducing CVD risk . Approximately 86 % of the physicians surveyed agreed with and supported use of the Polypill for primary prevention and 93 % for secondary prevention of CVD . Both the Polypill and St and ard Practice result ed in marked reductions in systolic blood pressure , total cholesterol and 10-year risk of CVD . However , the differences between the treatment groups were not statistically significant . Conclusions We successfully completed a Polypill feasibility trial in Sri Lanka . We were able to document high acceptability of the Polypill to patients and physicians . We were unable to estimate the risk factor reductions on the Polypill because the control group received similar treatment with individual drugs . The Polypill was however simpler and achieved comparable risk factor reductions , highlighting its potential usefulness in the prevention of CVD.Trial registration number Clinical trials.gov : Background A Polypill is proposed for the primary prevention of cardiovascular disease in people judged to be at risk on account of their age alone . Its efficacy in reducing cholesterol and blood pressure is uncertain . Methods We conducted a r and omized double-blind placebo-controlled crossover trial of a Polypill among individuals aged 50 + without a history of cardiovascular disease and compared the reductions with those predicted from published estimates of the effects of the individual drugs . Participants took the Polypill ( amlodipine 2.5 mg , losartan 25 mg , hydrochlorothiazide 12.5 mg and simvastatin 40 mg ) each evening for 12 weeks and a placebo each evening for 12 weeks in r and om sequence . The mean within-person differences in blood pressure and low density lipoprotein ( LDL ) cholesterol at the end of each 12 week period were determined . Results 84 out of 86 participants completed both treatment periods . The mean systolic blood pressure was reduced by 17.9 mmHg ( 95 % CI , 15.7–20.1 ) on the Polypill , diastolic blood pressure by 9.8 mmHg ( 8.1–11.5 ) , and LDL cholesterol by 1.4 mmol/L ( 1.2–1.6 ) , reductions of 12 % , 11 % , and 39 % respectively . The results were almost identical to those predicted ; 18.4 mmHg , 9.7 mmHg , and 1.4 mmol/L respectively . Conclusion The Polypill result ed in the predicted reductions in blood pressure and LDL cholesterol . Long term reductions of this magnitude would have a substantial effect in preventing heart attacks and strokes . Trial Registration Controlled-Trials.com IS RCT Objective To compare the effects of two antihypertensive treatment strategies for the prevention of coronary heart disease and other cardiovascular events in the large sub population ( n = 5137 ) with diabetes mellitus in the blood pressure-lowering arm of the Anglo-Sc and inavian Cardiac Outcomes Trial . Methods Patients had either untreated hypertension or treated hypertension . For those with type II diabetes mellitus , inclusion criteria required at least two additional risk factors . Patients were r and omized to amlodipine with addition of perindopril as required ( amlodipine-based ) or atenolol with addition of thiazide as required ( atenolol-based ) . Therapy was titrated to achieve a target blood pressure of less than 130/80 mmHg . Results The trial was terminated early due to significant benefits on mortality and stroke associated with the amlodipine-based regimen . In patients with diabetes mellitus , the amlodipine-based treatment reduced the incidence of the composite endpoint – total cardiovascular events and procedures – compared with the atenolol-based regimen ( hazard ratio 0.86 , confidence interval 0.76–0.98 , P = 0.026 ) . Fatal and nonfatal strokes were reduced by 25 % ( P = 0.017 ) , peripheral arterial disease by 48 % ( P = 0.004 ) and noncoronary revascularization procedures by 57 % ( P < 0.001 ) . For the other endpoints included in the composite , the endpoint differences were less clear including coronary heart disease deaths and nonfatal myocardial infa rct ions ( the primary endpoint ) , which were reduced nonsignificantly by 8 % ( hazard ratio 0.92 , confidence interval 0.74–1.15 ) . Conclusion In the large diabetic subgroup in the blood pressure-lowering arm of the Anglo-Sc and inavian Cardiac Outcomes Trial , the benefits of amlodipine-based treatment , compared with atenolol-based treatment , on the incidence of total cardiovascular events and procedures was significant ( 14 % reduction ) and similar to that observed in the total trial population ( 16 % reduction ) BACKGROUND The Valsartan Antihypertensive Long-term Use Evaluation ( VALUE ) trial was design ed to test the hypothesis that for the same blood-pressure control , valsartan would reduce cardiac morbidity and mortality more than amlodipine in hypertensive patients at high cardiovascular risk . METHODS 15?245 patients , aged 50 years or older with treated or untreated hypertension and high risk of cardiac events participated in a r and omised , double-blind , parallel-group comparison of therapy based on valsartan or amlodipine . Duration of treatment was event-driven and the trial lasted until at least 1450 patients had reached a primary endpoint , defined as a composite of cardiac mortality and morbidity .  Patients from 31 countries were followed up for a mean of 4.2 years . FINDINGS Blood pressure was reduced by both treatments , but the effects of the amlodipine-based regimen were more pronounced , especially in the early period ( blood pressure 4.0/2.1 mm Hg lower in amlodipine than valsartan group after 1 month ; 1.5/1.3 mm Hg after 1 year ; p<0.001 between groups ) . The primary composite endpoint occurred in 810 patients in the valsartan group ( 10.6 % , 25.5 per 1000 patient-years ) and 789 in the amlodipine group ( 10.4 % , 24.7 per 1000 patient-years ; hazard ratio 1.04 , 95 % CI 0.94 - 1.15 , p=0.49 ) . INTERPRETATION The main outcome of cardiac disease did not differ between the treatment groups . Unequal reductions in blood pressure might account for differences between the groups in cause-specific outcomes . The findings emphasise the importance of prompt blood-pressure control in hypertensive patients at high cardiovascular risk BACKGROUND A combination of medications that simultaneously reduce several cardiovascular risk factors in people above a specified age , without selection based on risk factor measurement , has been proposed as a simple strategy for reducing the risk of cardiovascular disease and shown to be effective in r and omized trials ( the Polypill approach ) . AIMS To assess acceptance of the Polypill approach and adherence to preventive treatment among individuals taking part in a cardiovascular disease prevention service . METHODS Daily treatment with simvastatin ( 40 mg ) , amlodipine ( 2.5 mg ) , bendroflumethiazide ( 1.25 mg ) , lisinopril ( 5 mg ) [ or c and esartan ( 4 mg ) if cough was reported ] and folic acid ( 0.8 mg ) was offered , as separate components , to people ≥ 55 years with no history of cardiovascular , renal or liver disease . An audit of adverse effects , adherence and requests for blood pressure and cholesterol measurement was determined by telephone consultation . RESULTS Between 2006 and 2010 , 269 participants started treatment with the Polypill components . Follow-up ranged from 3 to 48 months ( mean 20 ) . A total of 222 participants ( 83 % ) adhered to treatment , including 30 ( 11 % ) who switched from the angiotensin-converting enzyme inhibitor ( lisinopril ) to the angiotensin receptor blocker ( c and esartan ) because of cough . Ten participants ( 4 % ) continued to take treatment but stopped taking one or more drugs because of other symptoms , and 37 ( 14 % ) stopped all treatment , eight because of adverse effects and 29 for non-medical reasons . No one requested a blood pressure or cholesterol measurement . CONCLUSION This is the first demonstration of the application of the Polypill approach in practice . The method was accepted and the Polypill components were well tolerated , with good adherence and no dem and for information about risk factors BACKGROUND Although most cardiovascular disease occurs in low-income and middle-income countries , little is known about the use of effective secondary prevention medications in these communities . We aim ed to assess use of proven effective secondary preventive drugs ( antiplatelet drugs , β blockers , angiotensin-converting-enzyme [ ACE ] inhibitors or angiotensin-receptor blockers [ ARBs ] , and statins ) in individuals with a history of coronary heart disease or stroke . METHODS In the Prospect i ve Urban Rural Epidemiological ( PURE ) study , we recruited individuals aged 35 - 70 years from rural and urban communities in countries at various stages of economic development . We assessed rates of previous cardiovascular disease ( coronary heart disease or stroke ) and use of proven effective  secondary preventive drugs  and blood-pressure-lowering drugs with st and ardised question naires , which were completed by telephone interviews , household visits , or on patient 's presentation to clinics . We report estimates of drug use at national , community , and individual levels . FINDINGS We enrolled 153,996 adults from 628 urban and rural communities in countries with incomes classified as high ( three countries ) , upper-middle ( seven ) , lower-middle ( three ) , or low ( four ) between January , 2003 , and December , 2009 . 5650 participants had a self-reported coronary heart disease event ( median 5·0 years previously [ IQR 2·0 - 10·0 ] ) and 2292 had stroke ( 4·0 years previously [ 2·0 - 8·0 ] ) . Overall , few individuals with cardiovascular disease took antiplatelet drugs  ( 25·3 % ) , β blockers ( 17·4 % ) , ACE inhibitors or ARBs ( 19·5 % ) , or statins ( 14·6 % ) . Use was highest in high-income countries ( antiplatelet drugs 62·0 % , β blockers 40·0 % , ACE inhibitors or ARBs 49·8 % , and statins 66·5 % ) , lowest in low-income countries ( 8·8 % , 9·7 % , 5·2 % , and 3·3 % , respectively ) , and decreased in line with reduction of country economic status ( p(trend)<0·0001 for every drug type ) . Fewest patients received no drugs in high-income countries ( 11·2 % ) , compared with 45·1 % in upper middle-income countries , 69·3 % in lower middle-income countries , and 80·2 % in low-income countries . Drug use was higher in urban than rural areas ( antiplatelet drugs 28·7 % urban vs 21·3 % rural , β blockers 23·5%vs 15·6 % , ACE inhibitors or ARBs 22·8%vs 15·5 % , and statins 19·9%vs 11·6 % ; all p<0·0001 ) , with greatest variation in poorest countries ( p(interaction)<0·0001 for urban vs rural differences by country economic status ) . Country-level factors ( eg , economic status ) affected rates of drug use more than did individual-level factors ( eg , age , sex , education , smoking status , body-mass index , and hypertension and diabetes statuses ) . INTERPRETATION Because use of secondary prevention medications is low worldwide-especially in low-income countries and rural areas - systematic approaches are needed to improve the long-term use of basic , inexpensive , and effective drugs . FUNDING Full funding sources listed at end of paper ( see Acknowledgments ) Poor control of hypertension or dyslipidemia may at least in part be due to these risk factors being treated in isolation . The Caduet in Untreated Subjects Population ( CUSP ) trial was an 8-week , r and omized , double-blind , placebo-controlled trial evaluating the efficacy/safety of the combination of a calcium channel blocker ( amlodipine besylate ) and a statin ( atorvastatin calcium ) in a single-pill form ( 5/20 mg ) plus therapeutic lifestyle changes ( TLC ) compared with placebo plus TLC in patients with comorbid hypertension and dyslipidemia without evidence of cardiovascular disease . At week 4 , additional antihypertensive/lipid-lowering medication was permitted . The primary end point was the proportion of patients in whom the dual goal of blood pressure ( < 140/90 mm Hg ) and low-density lipoprotein cholesterol control ( < 100 mg/dL ) was met at week 4 . This dual goal attainment was significantly greater with amlodipine/atorvastatin plus TLC compared with placebo plus TLC at week 4 ( 47.6 % vs 1.7 % ; P<.001 ) , with further improvements at week 8 . Most adverse events were mild to moderate . Therapy with single-pill amlodipine/atorvastatin plus TLC in these patients significantly increased dual blood pressure/low-density lipoprotein cholesterol goal attainment compared with placebo plus TLC AIM Our objective was to investigate the effects and tolerability of fixed-dose combination therapy on blood pressure and LDL in adults without elevated blood pressure or lipid levels . METHODS This was a double-blind r and omised placebo-controlled trial in residents of Kalaleh , Golestan , Iran . Following an 8-week placebo run-in period , 475 participants , aged 50 to 79 years , without cardiovascular disease , hypertension or hyperlipidaemia were r and omised to fixed-dose combination therapy with aspirin 81 mg , enalapril 2.5 mg , atorvastatin 20 mg and hydrochlorothiazide 12.5 mg ( polypill ) or placebo for a period of 12 months . The primary outcomes were changes in LDL-cholesterol , systolic and diastolic blood pressure and adverse reactions . Analysis was by intention-to-treat basis . RESULTS At baseline , there were differences in systolic blood pressure ( 6 mmHg ) . Taking account of baseline differences , at 12 months , polypill was associated with statistically significant reductions in blood pressure ( 4.5/1.6 mmHg ) and LDL-cholesterol ( 0.46 mmol/l ) . The study drug was well tolerated , but result ed in the modest reductions in blood pressure and lipid levels . CONCLUSION The effects of the polypill on blood pressure and lipid levels were less than anticipated , raising questions about the reliability of the reported compliance . There is a case for a fully powered trial of a polypill for the prevention of cardiovascular disease Background Single-pill amlodipine/atorvastatin targets the two most common modifiable cardiovascular risk factors , hypertension and dyslipidaemia . We evaluated the clinical utility of this single pill to help patients across Europe and Canada achieve country-specific targets for blood pressure ( BP ) and low-density lipoprotein cholesterol ( LDL-C ) . Design Two 16-week , open-label studies conducted in 122 study centres across the United Kingdom and Canada ( JEWEL 1 ) and 113 centres across 11 European countries ( JEWEL 2 ) . Methods Patients with uncontrolled BP and controlled/uncontrolled LDL-C qualifying for treatment according to local governing guidelines were administered single-pill amlodipine/atorvastatin with appropriate lifestyle modification . Eight dosages of amlodipine/atorvastatin ( 5/10–10/80 mg ) were titrated to achieve country-specific BP and LDL-C targets . The primary outcome was the percentage of patients reaching country-specific BP and LDL-C targets in 16 weeks . Results Among 2245 patients enrolled in the studies ( JEWEL 1 , n = 1138 ; JEWEL 2 , n = 1107 ) , 62.9 % in JEWEL 1 and 50.6 % in JEWEL 2 achieved both country-specific BP and LDL-C goals . BP was reduced by 20.4/10.7 and 21.8/12.6 mmHg in JEWEL 1 and JEWEL 2 , respectively , and reductions in LDL-C were 0.90 mmol/l ( 34.8 mg/dl ) and 1.09 mmol/l ( 42.2 mg/dl ) , respectively . The most common adverse events were peripheral oedema ( 11.0 % ) , joint swelling ( 2.9 % ) and headache ( 2.9 % ) , of which , only oedema was linked to study treatment . Conclusion Single-pill amlodipine/atorvastatin is an effective and well-tolerated treatment , which in a real-world setting helped more than half of the patients achieve both BP and LDL-C targets as recommended by local guidelines . Although fewer patients met their goals in JEWEL 2 than JEWEL 1 , reductions in BP and LDL-C were slightly greater in JEWEL 2 , suggesting that the observed differences are likely because of more stringent targets in Europe than in the UK/Canada BACKGROUND Chlorthalidone has proven efficacy to reduce cardiovascular morbidity and mortality , yet it is infrequently used in practice . This study provides a direct comparison of chlorthalidone with hydrochlorothiazide , each combined with the angiotensin receptor blocker azilsartan medoxomil , on blood pressure reduction and control rates . METHODS This is a r and omized , double-blind , titrate-to-target blood pressure trial comparing the single-pill combination of azilsartan medoxomil and chlorthalidone versus co-administration of azilsartan medoxomil and hydrochlorothiazide in participants with stage 2 primary hypertension . After 2 weeks of treatment with azilsartan medoxomil 40 mg alone , all participants also received 12.5 mg of diuretic for 4 weeks ( up to week 6 ) and were titrated to 25 mg for another 4 weeks ( up to week 10 ) if they failed to achieve target blood pressure . The primary end point was change in clinic systolic blood pressure . Target blood pressure was defined as clinic blood pressure < 140/90 mm Hg for participants without diabetes or chronic kidney disease or < 130/80 mm Hg for participants with diabetes or chronic kidney disease . RESULTS The mean age of the 609 participants was 56.4 years , and the mean baseline clinic blood pressure was 164.6/95.4 mm Hg . The primary end point analysis at week 6 demonstrated a greater reduction of clinic systolic blood pressure for the chlorthalidone ( -35.1 mm Hg ) versus hydrochlorothiazide combination ( -29.5 mm Hg ) ( mean difference , -5.6 mm Hg ; 95 % confidence interval , -8.3 to -2.9 ; P < .001 ) . The mean difference in 24-hour ambulatory systolic blood pressure at week 6 was -5.8 mm Hg ( 95 % confidence interval , -8.4 to -3.2 ; P < .001 ) , favoring the azilsartan medoxomil/chlorthalidone group . The percentage of participants achieving target clinic blood pressure at week 6 was greater for the chlorthalidone versus hydrochlorothiazide combination ( 64.1 % vs 45.9 % , P < .001 ) . Drug discontinuations due to adverse events were not statistically significantly different between groups ( 9.3 % vs 7.3 % , P = .38 ) , and hypokalemia was uncommon in both groups . CONCLUSIONS Chlorthalidone combined with azilsartan medoxomil provides better blood pressure reduction and a higher likelihood of achieving blood pressure control than hydrochlorothiazide combined with azilsartan medoxomil . This benefit occurred without a difference in safety measurements Abstract Objective : To investigate whether a proactive multifactorial risk factor intervention strategy using single-pill amlodipine/atorvastatin ( 5/10 , 10/10 mg ) in addition to other antihypertensive and lipid-lowering therapy , as required , result ed in greater reduction in calculated Framingham 10-year coronary heart disease ( CHD ) risk compared with usual care ( UC ) after 52-weeks treatment . Research design and methods : Prospect i ve , multinational , open-label , cluster r and omized trial , with the investigator as the unit of r and omization . Eligible hypertensive patients were 35–79 years of age , with ≥3 additional cardiovascular risk factors , but no history of CHD and baseline total cholesterol ( TC ) ≤6.5 mmol/l . Clinical trial registration : Trial registration : Clinical Trials.gov identifier : NCT00407537 . Main outcome measure : The primary endpoint was calculated Framingham 10-year CHD risk at 52 weeks . Results : Of the 140 r and omized sites , 136 sites contributed 1461 patients . Mean baseline age and low-density lipoprotein cholesterol ( LDL-C ) were comparable between treatment arms . Mean baseline BP ( 150.3/89.7 vs. 144.3/86.5 mmHg ) and Framingham CHD risk ( 20.0 vs. 18.1 % ) were higher in the proactive intervention versus the UC arm ( p < 0.002 for both ) . At week 52 , mean CHD risk was 12.5 % in the proactive intervention arm and 16.3 % in the UC arm ( p < 0.001 ) . The difference , observed at weeks 16 and 52 , was primarily driven by significant differences in systolic BP and in TC between the two arms . Overall , adverse events ( AEs ) were reported in 48.8 % and 44.0 % of patients in the proactive intervention and the UC arm , respectively . Although there were differences in the incidence of AEs between the treatment arms , the AE profile in the proactive intervention arm was consistent with previous safety experience for this medication . Conclusions : A proactive multifactorial risk factor intervention strategy that simultaneously treated both BP and cholesterol regardless of individual risk factors per se , is more effective in reducing calculated Framingham 10-year CHD risk than UC in patients with hypertension and additional risk factors BACKGROUND In previous clinical trials in high-risk hypertensive patients , paradoxically higher cardiovascular event rates have been reported in patients of normal weight compared with obese individuals . As a prespecified analysis of the Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension ( ACCOMPLISH ) trial , we aim ed to investigate whether the type of hypertension treatment affects patients ' cardiovascular outcomes according to their body size . METHODS On the basis of body-mass index ( BMI ) , we divided the full ACCOMPLISH cohort into obese ( BMI ≥30 , n=5709 ) , overweight ( ≥25 to < 30 , n=4157 ) , or normal weight ( < 25 , n=1616 ) categories . The ACCOMPLISH cohort had already been r and omised to treatment with single-pill combinations of either benazepril and hydrochlorothiazide or benazepril and amlodipine . We compared event rates ( adjusted for age , sex , diabetes , previous cardiovascular events , stroke , or chronic kidney disease ) for the primary endpoint of cardiovascular death or non-fatal myocardial infa rct ion or stroke . The analysis was by intention to treat . This trial is registered with Clinical Trials.gov , number NCT00170950 . FINDINGS In patients allocated benazepril and hydrochlorothiazide , the primary endpoint ( per 1000 patient-years ) was 30·7 in normal weight , 21·9 in overweight , and 18·2 in obese patients ( overall p=0·0034 ) . However , in those allocated benazepril and amlodipine , the primary endpoint did not differ between the three BMI groups ( 18·2 , 16·9 , and 16·5 , respectively ; overall p=0·9721 ) . In obese individuals , primary event rates were similar with both benazepril and hydrochlorothiazide and benazepril and amlodipine , but rates were significantly lower with benazepril and amlodipine in overweight patients ( hazard ratio 0·76 , 95 % CI 0·59 - 0·94 ; p=0·0369 ) and those of normal weight ( 0·57 , 0·39 - 0·84 ; p=0·0037 ) . INTERPRETATION Hypertension in normal weight and obese patients might be mediated by different mechanisms . Thiazide-based treatment gives less cardiovascular protection in normal weight than obese patients , but amlodipine-based therapy is equally effective across BMI subgroups and thus offers superior cardiovascular protection in non-obese hypertension . FUNDING Novartis Pharmaceuticals The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial ( ALLHAT ) consisted of 42,418 participants r and omized to one of four antihypertensive treatment groups : chlorthalidone , amlodipine , lisinopril , or doxazosin .  A subset of these participants with fasting low-density lipoprotein cholesterol levels 100 - 189 mg/dL were r and omized into a lipid-lowering component : 5170 to receive pravastatin ( 40 mg daily ) and 5185 to receive usual care . This report describes the characteristics and lipid distribution of these participants . There were no important differences between the r and omized treatment groups . Women had higher total cholesterol , low-density lipoprotein cholesterol , and high-density lipoprotein cholesterol than men . There was a similar finding for black participants compared with whites , except blacks had lower triglycerides . Diabetics had lower high-density lipoprotein cholesterol and higher triglycerides than nondiabetics , and patients with body mass index < 25 kg/m(2 ) had higher high-density lipoprotein cholesterol but lower low-density lipoprotein cholesterol and triglycerides than patients with higher body mass index . The success of the r and omization of this large , diverse population and the differences in the lipid distributions among its subgroups will allow further underst and ing of optimal lipid-lowering treatment TOGETHER investigated whether targeting multiple cardiovascular ( CV ) risk factors using single-pill amlodipine/atorvastatin ( AML/ATO ) and therapeutic lifestyle changes ( TLC ) results in greater blood pressure (BP)/lipid control and additional reduction in estimated cardiovascular disease ( CVD ) risk compared with blood pressure intervention only using amlodipine ( AML ) + TLC . TOGETHER was a 6-week , r and omized , double-blind , double-dummy trial using hypertensive participants with additional CV risk factors without CVD/diabetes . Participants were r and omized to either AML/ATO ( 5 to 10/20 mg ) + TLC or AML ( 5 to 10 mg ) + TLC . The primary end point was the difference in proportion of participants attaining both BP ( < 140/90 mm Hg ) and low-density lipoprotein cholesterol ( LDL-C ) ( < 100 mg/dL ) goals at week 6 . At week 6 , 67.8 % of participants receiving AML/ATO + TLC attained the combined BP/LDL-C goal versus 9.6 % with AML + TLC ( RD [ A – B ] : 58.2 ; 95 % CI [ 48.1 to 68.4 ] P < 0.001 ; OR : 19.0 ; 95 % CI 9.1 to 39.6 ; P < 0.001 ) . Significant reductions from baseline in LDL-C , total cholesterol and triglycerides and estimated 10-year Framingham risk were also observed . Treatment with AML/ATO was well tolerated . In conclusion , a multifactorial CV management approach is more effective in achieving combined BP/LDL-C targets as well as CV risk reduction compared with BP intervention only in this patient population CONTEXT Antihypertensive therapy is well established to reduce hypertension-related morbidity and mortality , but the optimal first-step therapy is unknown . OBJECTIVE To determine whether treatment with a calcium channel blocker or an angiotensin-converting enzyme inhibitor lowers the incidence of coronary heart disease ( CHD ) or other cardiovascular disease ( CVD ) events vs treatment with a diuretic . DESIGN The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial ( ALLHAT ) , a r and omized , double-blind , active-controlled clinical trial conducted from February 1994 through March 2002 . SETTING AND PARTICIPANTS A total of 33 357 participants aged 55 years or older with hypertension and at least 1 other CHD risk factor from 623 North American centers . INTERVENTIONS Participants were r and omly assigned to receive chlorthalidone , 12.5 to 25 mg/d ( n = 15 255 ) ; amlodipine , 2.5 to 10 mg/d ( n = 9048 ) ; or lisinopril , 10 to 40 mg/d ( n = 9054 ) for planned follow-up of approximately 4 to 8 years . MAIN OUTCOME MEASURES The primary outcome was combined fatal CHD or nonfatal myocardial infa rct ion , analyzed by intent-to-treat . Secondary outcomes were all-cause mortality , stroke , combined CHD ( primary outcome , coronary revascularization , or angina with hospitalization ) , and combined CVD ( combined CHD , stroke , treated angina without hospitalization , heart failure [ HF ] , and peripheral arterial disease ) . RESULTS Mean follow-up was 4.9 years . The primary outcome occurred in 2956 participants , with no difference between treatments . Compared with chlorthalidone ( 6-year rate , 11.5 % ) , the relative risks ( RRs ) were 0.98 ( 95 % CI , 0.90 - 1.07 ) for amlodipine ( 6-year rate , 11.3 % ) and 0.99 ( 95 % CI , 0.91 - 1.08 ) for lisinopril ( 6-year rate , 11.4 % ) . Likewise , all-cause mortality did not differ between groups . Five-year systolic blood pressures were significantly higher in the amlodipine ( 0.8 mm Hg , P = .03 ) and lisinopril ( 2 mm Hg , P<.001 ) groups compared with chlorthalidone , and 5-year diastolic blood pressure was significantly lower with amlodipine ( 0.8 mm Hg , P<.001 ) . For amlodipine vs chlorthalidone , secondary outcomes were similar except for a higher 6-year rate of HF with amlodipine ( 10.2 % vs 7.7 % ; RR , 1.38 ; 95 % CI , 1.25 - 1.52 ) . For lisinopril vs chlorthalidone , lisinopril had higher 6-year rates of combined CVD ( 33.3 % vs 30.9 % ; RR , 1.10 ; 95 % CI , 1.05 - 1.16 ) ; stroke ( 6.3 % vs 5.6 % ; RR , 1.15 ; 95 % CI , 1.02 - 1.30 ) ; and HF ( 8.7 % vs 7.7 % ; RR , 1.19 ; 95 % CI , 1.07 - 1.31 ) . CONCLUSION Thiazide-type diuretics are superior in preventing 1 or more major forms of CVD and are less expensive . They should be preferred for first-step antihypertensive therapy This 8-week , r and omized , double-blind , controlled study compared efficacy and tolerability of telmisartan/amlodipine ( T/A ) single-pill combination ( SPC ) vs the respective monotherapies in 858 patients with severe hypertension ( systolic/diastolic blood pressure [ SBP/DBP ] ≥180/95 mm Hg ) . At 8 weeks , T/A provided significantly greater reductions from baseline in seated trough cuff SBP/DBP ( -47.5 mm Hg/-18.7 mm Hg ) vs T ( P<.0001 ) or A ( P=.0002 ) monotherapy ; superior reductions were also evident at 1 , 2 , 4 , and 6 weeks . Blood pressure ( BP ) goal and response rates were consistently higher with T/A vs T or A. T/A was well tolerated , with less frequent treatment-related adverse events vs A ( 12.6 % vs 16.4 % ) and a numerically lower incidence of peripheral edema and treatment discontinuation . In conclusion , treatment of patients with substantially elevated BP  with T/A SPCs result ed in high and significantly greater BP reductions and higher BP goal and response rates than the respective monotherapies . T/A SPCs were well tolerated BACKGROUND Type 2 diabetes is associated with a substantially increased risk of cardiovascular disease , but the role of lipid-lowering therapy with statins for the primary prevention of cardiovascular disease in diabetes is inadequately defined . We aim ed to assess the effectiveness of atorvastatin 10 mg daily for primary prevention of major cardiovascular events in patients with type 2 diabetes without high concentrations of LDL-cholesterol . METHODS 2838 patients aged 40 - 75 years in 132 centres in the UK and Irel and were r and omised to placebo  ( n=1410 ) or atorvastatin 10 mg daily ( n=1428 ) . Study entrants had no documented previous history of cardiovascular disease , an LDL-cholesterol concentration of 4.14 mmol/L or lower , a fasting triglyceride amount of 6.78 mmol/L or less , and at least one of the following : retinopathy , albuminuria , current smoking , or hypertension . The primary endpoint was time to first occurrence of the following : acute coronary heart disease events , coronary revascularisation , or stroke . Analysis was by intention to treat . FINDINGS The trial was terminated 2 years earlier than expected because the prespecified early stopping rule for efficacy had been met . Median duration of follow-up was 3.9 years ( IQR 3.0 - 4.7 ) . 127 patients allocated placebo ( 2.46 per 100 person-years at risk ) and 83 allocated atorvastatin ( 1.54 per 100 person-years at risk ) had at least one major cardiovascular event ( rate reduction 37 % [ 95 % CI -52 to -17 ] , p=0.001 ) . Treatment would be expected to prevent at least 37 major vascular events per 1000 such people treated for 4 years . Assessed separately , acute coronary heart disease events were reduced by 36 % ( -55 to -9 ) , coronary revascularisations by 31 % ( -59 to 16 ) , and rate of stroke by 48 % ( -69 to -11 ) . Atorvastatin reduced the death rate by 27 % ( -48 to 1 , p=0.059 ) . No excess of adverse events was noted in the atorvastatin group . INTERPRETATION Atorvastatin 10 mg daily is safe and efficacious in reducing the risk of first cardiovascular disease events , including stroke , in patients with type 2 diabetes without high LDL-cholesterol . No justification is available for having a particular threshold level of LDL-cholesterol as the sole arbiter of which patients with type 2 diabetes should receive statins . The debate about whether all people with this disorder warrant statin treatment should now focus on whether any patients are at sufficiently low risk for this treatment to be withheld Guidelines stress the importance of the simultaneous management of multiple cardiovascular risk factors . This can in part be achieved by coadministration of lipid-lowering and antihypertensive treatments . Potential pharmacodynamic interaction between drugs should be investigated as part of developing single-pill combinations . The Respond trial assessed whether combining amlodipine to treat hypertension and atorvastatin to treat dyslipidemia affected the action of either monotherapy . A total of 1660 hypertensive patients with dyslipidemia received 1 of 15 combinations of amlodipine ( placebo , 5 , or 10 mg ) and atorvastatin ( placebo , 10 , 20 , 40 , or 80 mg ) in a 3 x 5 factorial r and omized , placebo-controlled design . At 8 weeks , combination-treated patients experienced dose-related and statistically significant reductions in systolic blood pressure , low-density lipoprotein cholesterol , and Framingham risk score . Overall , coadministered atorvastatin and amlodipine was well tolerated and without adverse pharmacodynamic interaction ; combination treatment did not affect the low-density lipoprotein cholesterol-lowering efficacy and safety of atorvastatin , or the systolic blood pressure-lowering efficacy and safety of amlodipine BACKGROUND Around 80 % of all cardiovascular deaths occur in developing countries . Assessment of those patients at high risk is an important strategy for prevention . Since developing countries have limited re sources for prevention strategies that require laboratory testing , we assessed if a risk prediction method that did not require any laboratory tests could be as accurate as one requiring laboratory information . METHODS The National Health and Nutrition Examination Survey ( NHANES ) was a prospect i ve cohort study of 14 407 US participants aged between 25 - 74 years at the time they were first examined ( between 1971 and 1975 ) . Our follow-up study population included participants with complete information on these surveys who did not report a history of cardiovascular disease ( myocardial infa rct ion , heart failure , stroke , angina ) or cancer , yielding an analysis data set N=6186 . We compared how well either method could predict first-time fatal and non-fatal cardiovascular disease events in this cohort . For the laboratory-based model , which required blood testing , we used st and ard risk factors to assess risk of cardiovascular disease : age , systolic blood pressure , smoking status , total cholesterol , reported diabetes status , and current treatment for hypertension . For the non-laboratory-based model , we substituted body-mass index for cholesterol . FINDINGS In the cohort of 6186 , there were 1529 first-time cardiovascular events and 578 ( 38 % ) deaths due to cardiovascular disease over 21 years . In women , the laboratory-based model was useful for predicting events , with a c statistic of 0.829 . The c statistic of the non-laboratory-based model was 0.831 . In men , the results were similar ( 0.784 for the laboratory-based model and 0.783 for the non-laboratory-based model ) . Results were similar between the laboratory-based and non-laboratory-based models in both men and women when restricted to fatal events only . INTERPRETATION A method that uses non-laboratory-based risk factors predicted cardiovascular events as accurately as one that relied on laboratory-based values . This approach could simplify risk assessment in situations where laboratory testing is inconvenient or unavailable Background The Polycap ™ ( polypill ; aspirin [ acetylsalicylic acid ] , ramipril , simvastatin , atenolol , and hydrochlorothiazide ) was found to be safe and effective for reducing multiple  cardiovascular risk factors in The Indian Polycap ™ Study ( TIPS ) . Objective We evaluated the bioavailability of each ingredient of the Polycap ™ and determined any drug-drug interactions relative to single component reference preparations . Methods The bioavailability of the ingredients of the Polycap ™ ( T ; test ) when formulated as a single capsule was compared with that of identical capsules with each of its ingredients administered separately ( R ; reference ) in a five-arm , r and omized , single-dose , two-period , two-treatment , two-sequence , crossover trial with at least a 2-week washout period in a total of 195 healthy volunteers . Plasma concentrations of each drug and , where applicable , its active metabolite were measured using vali date d liquid chromatographyt and em mass spectrometry and ultra-performance liquid chromatography . Mean pharmacokinetic parameters and their st and ard deviations were computed for each analyte . Results Comparative bioavailability was computed and no drug-drug interactions and no difference in comparative bioavailability were concluded for each ingredient based on point estimates of the T/R ratio of the geometric means falling within 80–125 % for peak plasma concentration ( Cmax ) , area under the plasma concentration-time curve from time zero to the last measurable concentration ( AUCt ) , and AUC from time zero to infinity ( AUC∞ ) . The T/R ratio for Cmax , AUCt and AUC∞ was within 80–125 % for atenolol , hydrochlorothiazide , ramipril , ramiprilat and dose-normalized salicylic acid . However , for simvastatin , the T/R point estimates for Cmax , AUCt and AUC∞ for Ln-transformed data were significantly lower ( ∼3–4 % ) than the lower bound of 80 % . For its active metabolite , simvastatin acid , these estimates were significantly higher ( ∼25–35 % ) than the higher bound of 125 % . Thus , the increased bioavailability of active simvastatin acid appeared to compensate for the loss of bioavailability of simvastatin . Conclusion The Polycap ™ was found to be effective and safe in the previously published TIPS trial . The present study in healthy volunteers establishes that Polycap ™ is safe ( no serious adverse events ) and well tolerated , and that there is no indication of pharmacokinetic drug-drug interactions for any of the ingredients , with their bioavailabilities being well preserved CONTEXT Vitamin D or calcium supplementation may have effects on  vascular disease and cancer .  OBJECTIVE Our objective was to investigate whether vitamin D or calcium supplementation affects mortality , vascular disease , and cancer in older people . DESIGN AND SETTING The study included long-term follow-up of participants in a two by two factorial , r and omized controlled trial from 21 orthopedic centers in the United Kingdom . PARTICIPANTS Participants were 5292 people ( 85 % women ) aged at least 70 yr with previous low-trauma fracture . INTERVENTIONS Participants were r and omly allocated to daily vitamin D(3 ) ( 800 IU ) , calcium ( 1000 mg ) , both , or placebo for 24 - 62 months , with a follow-up of 3 yr after intervention . MAIN OUTCOME MEASURES All-cause mortality , vascular disease mortality , cancer mortality , and cancer incidence were evaluated . RESULTS In intention-to-treat analyses , mortality [ hazard ratio ( HR ) = 0.93 ; 95 % confidence interval ( CI ) = 0.85 - 1.02 ] , vascular disease mortality ( HR = 0.91 ; 95 % CI = 0.79 - 1.05 ) , cancer mortality ( HR = 0.85 ; 95 % CI = 0.68 - 1.06 ) , and cancer incidence ( HR = 1.07 ; 95 % CI = 0.92 - 1.25 ) did not differ significantly between participants allocated vitamin D and those not . All-cause mortality ( HR = 1.03 ; 95 % CI = 0.94 - 1.13 ) , vascular disease mortality ( HR = 1.07 ; 95 % CI = 0.92 - 1.24 ) , cancer mortality ( HR = 1.13 ; 95 % CI = 0.91 - 1.40 ) , and cancer incidence ( HR = 1.06 ; 95 % CI = 0.91 - 1.23 ) also did not differ significantly between participants allocated calcium and those not . In a post hoc statistical analysis adjusting for compliance , thus with fewer participants , trends for reduced mortality with vitamin D and increased mortality with calcium were accentuated , although all results remain nonsignificant . CONCLUSIONS Daily vitamin D or calcium supplementation did not affect mortality , vascular disease , cancer mortality , or cancer incidence BACKGROUND Cardiovascular disease ( CVD ) is the leading cause of death , and principal reason for the large difference in life expectancy between indigenous Māori and the non-indigenous population in New Zeal and . CVD guidelines recommend that people who are at high risk or who have had previous CVD should be offered aspirin , blood pressure lowering and lipid lowering therapies . However , prescribing and adherence rates are low and CVD events remain high . AIM To assess whether a medication strategy using a fixed dose combination pill ( ' polypill ' ) could improve prescribing and adherence to recommended medications , lower blood pressure and improve lipids compared with current care over 12 months . METHODS IMProving Adherence using Combination Therapy ( IMPACT ) is an open-label r and omised controlled trial comparing a once-daily polypill containing four preventive medications with usual care .  Six hundred participants who have had previous CVD events or are at high risk of CVD will be enrolled , including 300 Māori . Participants are identified , enrolled and prescribed either the polypill or current medications at their usual primary health care practice , with medications ( including the polypill ) dispensed through local community pharmacies . The polypill contains 75 mg aspirin , 40 mg simvastatin , 10 mg lisinopril and either 12.5 mg hydrochlorothiazide or 50 mg atenolol . Primary outcomes are adherence to guidelines -recommended medications and changes in systolic blood pressure and low density lipoprotein at 12 months . Secondary outcomes include other lipids , medication dispensing , barriers to adherence , CVD and other serious adverse events , quality of life and prescriber acceptability . The trial is registered with the Australian New Zeal and Clinical Trial Registry ( ACTRN12606000067572 ) The Gemini Study was a 14-week , open-label , non-comparative , office-based , multicenter trial to evaluate single-pill therapy in the treatment of concomitant hypertension and dyslipidemia . In addition to recommending lifestyle modifications , eight dosage strengths of amlodipine/atorvastatin single pill ( 5/10 , 5/20 , 5/40 , 5/80 , 10/10 , 10/20 , 10/40 , and 10/80 mg ) were electively titrated to improve  blood pressure and lipid control . A total of 1220 patients with uncontrolled hypertension at baseline received study medication . At baseline ,  mean blood pressure was 146.6/87.9 mm Hg and mean low-density lipoprotein cholesterol concentration was 152.9 mg/dL. At study end , 57.7 % of patients had achieved both their blood pressure and low-density lipoprotein cholesterol goals ( 51.9 % of patients with uncontrolled low-density lipoprotein cholesterol at baseline ) . The mean dose of study medication at end point was amlodipine component 7.1 mg and atorvastatin component 26.2 mg . Fifty-eight patients ( 4.8 % ) discontinued therapy due to adverse events . Single-pill therapy is effective in reducing both blood pressure and lipid levels and in helping patients achieve goals for both hypertension and dyslipidemia To assess the combined influence of blood pressure ( BP ) , serum cholesterol level , and cigarette smoking on death from coronary heart disease ( CHD ) and to describe how these associations vary with age , data on those factors and on mortality for 316,099 men screened for the Multiple Risk Factor Intervention Trial ( MRFIT ) were examined . Vital status of participants has been determined after an average follow-up of 12 years ; 6327 deaths from CHD have been identified . Strong grade d relationships between serum cholesterol levels above 4.65 mmol/L ( 180 mg/dL ) , systolic BP above 110 mm Hg , and diastolic BP above 70 mm Hg and mortality due to CHD were evident . Smokers with serum cholesterol and systolic BP levels in the highest quintiles had CHD death rates that were approximately 20 times greater than nonsmoking men with systolic BP and cholesterol levels in the lowest quintile . Systolic and diastolic BP , serum cholesterol level , and cigarettes per day were significant predictors of death due to CHD in all age groups . Systolic BP was a stronger predictor than diastolic BP . These results , together with the findings of clinical trials , offer strong support for intensified preventive efforts in all age groups BACKGROUND Cardiovascular morbidity is a major burden in patients with type 2 diabetes . In the Steno-2 Study , we compared the effect of a targeted , intensified , multifactorial intervention with that of conventional treatment on modifiable risk factors for cardiovascular disease in patients with type 2 diabetes and microalbuminuria . METHODS The primary end point of this open , parallel trial was a composite of death from cardiovascular causes , nonfatal myocardial infa rct ion , nonfatal stroke , revascularization , and amputation .  Eighty patients were r and omly assigned to receive conventional treatment in accordance with national guidelines and 80 to receive intensive treatment , with a stepwise implementation of behavior modification and pharmacologic therapy that targeted hyperglycemia , hypertension , dyslipidemia , and microalbuminuria , along with secondary prevention of cardiovascular disease with aspirin . RESULTS The mean age of the patients was 55.1 years , and the mean follow-up was 7.8 years . The decline in glycosylated hemoglobin values , systolic and diastolic blood pressure , serum cholesterol and triglyceride levels measured after an overnight fast , and urinary albumin excretion rate were all significantly greater in the intensive-therapy group than in the conventional-therapy group . Patients receiving intensive therapy also had a significantly lower risk of cardiovascular disease ( hazard ratio , 0.47 ; 95 percent confidence interval , 0.24 to 0.73 ) , nephropathy ( hazard ratio , 0.39 ; 95 percent confidence interval , 0.17 to 0.87 ) , retinopathy ( hazard ratio , 0.42 ; 95 percent confidence interval , 0.21 to 0.86 ) , and autonomic neuropathy ( hazard ratio , 0.37 ; 95 percent confidence interval , 0.18 to 0.79 ) . CONCLUSIONS A target-driven , long-term , intensified intervention aim ed at multiple risk factors in patients with type 2 diabetes and microalbuminuria reduces the risk of cardiovascular and microvascular events by about 50 percent The AVALON study was a r and omized , multicenter trial to assess the efficacy and safety of coadministered amlodipine and atorvastatin in patients with hypertension and dyslipidemia . Phase one was an 8-week , double-blind , double-dummy , placebo-controlled period whereby patients received amlodipine 5 mg , atorvastatin 10 mg , amlodipine 5 mg and atorvastatin 10 mg , or placebo . Thereafter , all patients received single-blind amlodipine 5 mg and atorvastatin 10 mg for 8-weeks , followed by 12 weeks of open-label treatment where doses could be titrated to improve low-density lipoprotein cholesterol and blood pressure control .  A total of 847 patients entered the double-blind phase . At Week 8 , 45 % of the patients receiving amlodipine 5 mg and atorvastatin 10 mg reached both their blood pressure and low-density lipoprotein cholesterol goals , compared with 8.3 % with amlodipine ( p < 0.001 ) , 28.6 % with atorvastatin ( p < 0.001 ) , and 3.5 % with placebo . At 28 weeks , 67.1 % of patients coadministered amlodipine and atorvastatin ( mean doses , 7.6 mg and 28.4 mg , respectively ) achieved both targets . Framingham estimated 10-year risk of coronary heart disease declined from baseline levels of 15.1 % to 6.9 % at Week 28 . Following coadministered treatment , the adverse events reported were similar to either agent alone . Concomitant administration of amlodipine and atorvastatin is an effective and well tolerated treatment for coexisting hypertension and dyslipidemia The Gemini-AALA ( Australia , Asia , Latin America , Africa/Middle East ) study evaluated the efficacy and safety of single-pill amlodipine/atorvastatin ( Caduet ) for the treatment of patients of diverse ethnicity with concomitant hypertension and dyslipidaemia . This was a 14-week , open-label study including patients from 27 countries across the Middle East , Asia-Pacific , Africa and Latin America . Eight dosage strengths of single-pill amlodipine/atorvastatin ( 5/10 , 10/10 , 5/20 , 10/20 , 5/40 , 10/40 , 5/80 and 10/80 mg ) were titrated to improve blood pressure and lipid control . Blood pressure and lipid goals were determined according to the Seventh Report of the Joint National Committee on Prevention , Detection , Evaluation , and Treatment of High Blood Pressure ( JNC 7 ) and National Cholesterol Education Program Expert Panel on Detection , Evaluation , and Treatment of High Blood Cholesterol in Adults ( NCEP ATP III ) guidelines , respectively ( blood pressure , < 140/90 or < 130/80 mm Hg ; low-density lipoprotein cholesterol ( LDL-C ) , < 4.1 to < 2.6 mmol l−1 ( < 160 to < 100 mgdl−1 ) ) . Overall , 1649 patients received study medication . Most patients ( 91.4 % ) had ⩾1 cardiovascular risk factor ( as defined by NCEP ATP III guidelines ) in addition to hypertension/dyslipidaemia , and 61.7 % had coronary heart disease/risk equivalent . At baseline , mean blood pressure was 146.6/88.3 mm Hg and LDL-C was 3.4 mmol l−1 ( 130.2 mgdl−1 ) . At week 14 , 55.2 % of patients reached both blood pressure and lipid goals , 61.3 % reached blood pressure goal and 87.1 % reached lipid goal ( 34.0 % were at lipid goal at baseline ) . Mean blood pressure reduction was 20.2/11.4 mm Hg . For patients who were lipid-lowering drug naive at baseline , mean reduction in LDL-C was 41.0 % . Treatment-related adverse events led to the discontinuation of 3.6 % of patients . Single-pill amlodipine/atorvastatin therapy was well tolerated and effective for the reduction of blood pressure and lipids to recommended goals in patients from diverse ethnic background OBJECTIVE To investigate the efficacy and safety of single-pill amlodipine/atorvastatin therapy for the simultaneous treatment of hypertension ( HTN ) and dyslipidemia in African Americans . PATIENTS AND METHODS Conducted between July 19 , 2004 , and August 9 , 2005 , the Clinical Utility of Caduet in Simultaneously Achieving Blood Pressure and Lipid End Points trial was a 20-week , open-label , noncomparative , multicenter trial of the efficacy and safety of single-pill amlodipine/atorvastatin in controlling elevated blood pressure ( BP ) and low-density lipoprotein cholesterol ( LDL-C ) in African Americans with concomitant HTN and dyslipidemia and either no additional risk factors , 1 or more cardiovascular risk factors , or coronary heart disease or a risk equivalent . Eight dosage strengths of single-pill amlodipine/atorvastatin were flexibly titrated . The primary efficacy assessment of the main trial was the percentage of patients who attained the LDL-C treatment goals of both the Seventh Report of the Joint National Committee on the Prevention , Detection , Evaluation , and Treatment of High Blood Pressure and the National Cholesterol Education Program Adult Treatment Panel III . RESULTS Of the 1170 African American patients screened , 501 were enrolled in the study and 499 received drug therapy . At end point , 236 ( 48.3 % ) of 489 patients reached both their BP and LDLC goals ( vs 4 [ 0.8 % ] of 484 at baseline ) ; 280 ( 56.8 % ) of 493 reached BP goals ( vs 7 [ 1.4 % ] of 494 at baseline ) ; and 361 ( 73.7 % ) of 490 reached LDL-C goals ( vs 138 [ 28.5 % ] of 484 at baseline ) . Among the 499 patients receiving drug therapy , common treatment-related adverse events were peripheral edema ( 17 patients [ 3.4 % ] ) , headache ( 11 [ 2.2 % ] ) , myalgia ( 11 [ 2.2 % ] ) , and constipation ( 10 [ 2.0 % ] ) . CONCLUSION Single-pill amlodipine/atorvastatin therapy was well tolerated and effectively targeted HTN and dyslipidemia in this population of African Americans who were at risk of cardiovascular disease CONTEXT Blood homocysteine levels are positively associated with cardiovascular disease , but it is uncertain whether the association is causal . OBJECTIVE To assess the effects of reducing homocysteine levels with folic acid and vitamin B(12 ) on vascular and nonvascular outcomes . DESIGN , SETTING , AND PATIENTS Double-blind r and omized controlled trial of 12,064 survivors of myocardial infa rct ion in secondary care hospitals in the United Kingdom between 1998 and 2008 . INTERVENTIONS 2 mg folic acid plus 1 mg vitamin B(12 ) daily vs matching placebo . MAIN OUTCOME MEASURES First major vascular event , defined as major coronary event ( coronary death , myocardial infa rct ion , or coronary revascularization ) , fatal or nonfatal stroke , or noncoronary revascularization . RESULTS Allocation to the study vitamins reduced homocysteine by a mean of 3.8 micromol/L ( 28 % ) . During 6.7 years of follow-up , major vascular events occurred in 1537 of 6033 participants ( 25.5 % ) allocated folic acid plus vitamin B(12 ) vs 1493 of 6031 participants ( 24.8 % ) allocated placebo ( risk ratio [ RR ] , 1.04 ; 95 % confidence interval [ CI ] , 0.97 - 1.12 ; P = .28 ) . There were no apparent effects on major coronary events ( vitamins , 1229 [ 20.4 % ] , vs placebo , 1185 [ 19.6 % ] ; RR , 1.05 ; 95 % CI , 0.97 - 1.13 ) , stroke ( vitamins , 269 [ 4.5 % ] , vs placebo , 265 [ 4.4 % ] ; RR , 1.02 ; 95 % CI , 0.86 - 1.21 ) , or noncoronary revascularizations ( vitamins , 178 [ 3.0 % ] , vs placebo , 152 [ 2.5 % ] ; RR , 1.18 ; 95 % CI , 0.95 - 1.46 ) . Nor were there significant differences in the numbers of deaths attributed to vascular causes ( vitamins , 578 [ 9.6 % ] , vs placebo , 559 [ 9.3 % ] ) or nonvascular causes ( vitamins , 405 [ 6.7 % ] , vs placebo , 392 [ 6.5 % ] ) or in the incidence of any cancer ( vitamins , 678 [ 11.2 % ] , vs placebo , 639 [ 10.6 % ] ) . CONCLUSION Substantial long-term reductions in blood homocysteine levels with folic acid and vitamin B(12 ) supplementation did not have beneficial effects on vascular outcomes but were also not associated with adverse effects on cancer incidence . TRIAL REGISTRATION is rct n.org Identifier : IS RCT N74348595 BACKGROUND The combination of three blood-pressure-lowering drugs at low doses , with a statin , aspirin , and folic acid ( the polypill ) , could reduce cardiovascular events by more than 80 % in healthy individuals . We examined the effect of the Polycap on blood pressure , lipids , heart rate , and urinary thromboxane B2 , and assessed its tolerability . METHODS In a double-blind trial in 50 centres in India , 2053 individuals without cardiovascular disease , aged 45 - 80 years , and with one risk factor were r and omly assigned , by a central secure website , to the Polycap ( n=412 ) consisting of low doses of thiazide ( 12.5 mg ) , atenolol ( 50 mg ) , ramipril ( 5 mg ) , simvastatin ( 20 mg ) , and aspirin ( 100 mg ) per day , or to eight other groups , each with about 200 individuals , of aspirin alone , simvastatin alone , hydrochlorthiazide alone , three combinations of the two blood-pressure-lowering drugs , three blood-pressure-lowering drugs alone , or three blood-pressure-lowering drugs plus aspirin . The primary outcomes were LDL for the effect of lipids , blood pressure for antihypertensive drugs , heart rate for the effects of atenolol , urinary 11-dehydrothromboxane B2 for the antiplatelet effects of  aspirin , and rates of discontinuation of drugs for safety . Analysis was by intention to treat . This study is registered with Clinical Trials.gov , number NCT00443794 . FINDINGS Compared with groups not receiving blood-pressure-lowering drugs , the Polycap reduced systolic blood pressure by 7.4 mm Hg ( 95 % CI 6.1 - 8.1 ) and diastolic blood pressure by 5.6 mm Hg ( 4.7 - 6.4 ) , which was similar when three blood-pressure-lowering drugs were used , with or without aspirin . Reductions in blood pressure increased with the number of drugs used ( 2.2/1.3 mm Hg with one drug , 4.7/3.6 mm Hg with two drugs , and 6.3/4.5 mm Hg with three drugs ) . Polycap reduced LDL cholesterol by 0.70 mmol/L ( 95 % CI 0.62 - 0.78 ) , which was less than that with simvastatin alone ( 0.83 mmol/L , 0.72 - 0.93 ; p=0.04 ) ; both reductions were greater than for groups without simvastatin ( p<0.0001 ) . The reductions in heart rate with Polycap and other groups using atenolol were similar ( 7.0 beats per min ) , and both were significantly greater than that in groups without atenolol ( p<0.0001 ) . The reductions in 11-dehydrothromboxane B2 were similar with the Polycap ( 283.1 ng/mmol creatinine , 95 % CI 229.1 - 337.0 ) compared with the three blood-pressure-lowering drugs plus aspirin ( 350.0 ng/mmol creatinine , 294.6 - 404.0 ) , and aspirin alone ( 348.8 ng/mmol creatinine , 277.6 - 419.9 ) compared with groups without aspirin . Tolerability of the Polycap was similar to that of other treatments , with no evidence of increasing intolerability with increasing number of active components in one pill . INTERPRETATION This Polycap formulation could be conveniently used to reduce multiple risk factors and cardiovascular risk The purpose of this study was to evaluate a fixed olmesartan/amlodipine combination on blood pressure control , lipid profile , insulin sensitivity , and some inflammatory markers compared with single-drug monotherapy . A total of 276 hypertensive patients were r and omly assigned to olmesartan 20 mg , amlodipine 10 mg , or a single pill containing olmesartan/amlodipine combination 20/5 mg for 12 months . We evaluated the following at baseline and after 6 and 12 months : body weight , body mass index , systolic ( SBP ) and diastolic blood pressures ( DBP ) , fasting plasma glucose ( FPG ) , fasting plasma insulin ( FPI ) , lipid profile , tumor necrosis factor-α ( TNF-α ) , retinol binding protein-4 ( RBP-4 ) , and interleukins 6 and 7 ( IL-6 and IL-7 ) . At baseline , and after 6 and 12 months , patients underwent an  euglycemic , hyperinsulinemic clamp . The olmesartan/amlodipine combination provided a greater decrease of SBP and DPB compared with amlodipine and olmesartan monotherapies . The olmesartan/amlodipine combination  decreased FPG after 12 months compared with amlodipine monotherapy . The combination decreased FPI and homeostasis model assessment index and increased M value both compared with baseline and with olmesartan and amlodipine monotherapies . Olmesartan/amlodipine  decreased IL-7 , but not IL-6 , compared with single drug components . The olmesartan/amlodipine combination is effective and safe in reducing blood pressure and has some additive effects not shown by single drugs , such as an improvement of IL-7 BACKGROUND Two 8-week , r and omized , double-blind , controlled studies previously evaluated the efficacy and tolerability of single-pill combinations of telmisartan 40 - 80 mg/amlodipine 5 - 10 mg ( T40 - 80/A5 - 10 ) in patients with hypertension not at diastolic blood pressure ( DBP ) goal ( DBP < 90 mm Hg ) after 6 weeks of amlodipine 5 mg monotherapy ( A5 ) ( TEAMSTA-5 ) or amlodipine 10 mg monotherapy ( A10 ) ( TEAMSTA-10 ) . The long-term ( ≥6 months ) tolerability and efficacy of single-pill combinations of T40-T80/A5-A10 have now been evaluated in 2 open-label studies in patients who had successfully completed either TEAMSTA-5 or TEAMSTA-10 ( TEAMSTA-5 and TEAMSTA-10 Follow-Ups ) . METHODS In the TEAMSTA-5 Follow-Up , 976 patients whose blood pressure was not initially controlled by taking A5 received T40/A5 for 4 or 8 weeks , with consecutive uptitration to T80/A5 if DBP was ≥90 mm Hg . In TEAMSTA-10 Follow-Up , 838 patients not initially achieving blood pressure control using A10 received T40/A10 for 4 weeks before r and omization to T40/A10 or T80/A10 ; after 4 weeks , patients r and omized to T40/A10 with DBP ≥90 mm Hg were uptitrated to T80/A10 . In both studies , add-on antihypertensive medication was allowed if DBP was not at goal . RESULTS Treatment compliance in both follow-up studies was ≥98.4 % . Single-pill combinations of T40-T80/A5-A10 result ed in additional clinical ly relevant blood pressure reductions and 67 % to 93 % of patients achieved DBP goal ( < 90 mm Hg ) ; only 1 % to 19 % of patients received additional medication for hypertension , of whom 29 % to 76 % achieved DBP goal . Long-term treatment with T40-T80/A5-A10 was well tolerated , with comparable adverse event profiles for all telmisartan/amlodipine combinations . The most common drug-related adverse events were peripheral edema ( 1.9%-3.9 % ) and dizziness ( 1.5 % in the T80/A5 group only ) ; these were consistent with the known tolerability profiles of telmisartan/amlodipine combinations . Overall treatment discontinuation rates due to adverse events were low ( 0.7%-1.5 % ) . CONCLUSIONS In patients not achieving DBP goal with either A5 or A10 monotherapy , the vast majority achieved DBP goal with single-pill combinations of T40-T80/A5-A10 . Long-term treatment was well tolerated with high compliance , promoting treatment adherence regardless of telmisartan/amlodipine dose . Clinical Trials.gov identifiers : NCT00614380 ( TEAMSTA-5 Follow-up ) and NCT00624052 ( TEAMSTA-10 Follow-up )
target: Reductions in blood pressure and lipid parameters are generally lower than those previously projected , though substantial heterogeneity of results exists .
  Fixed-dose combination therapy is associated with modest increases in adverse events compared with placebo , single drug active component , or usual care but may be associated with improved adherence to a multidrug regimen .
background: BACKGROUND Cardiovascular disease ( CVD ) is the leading cause of death and disability worldwide , yet CVD risk factor control and secondary prevention rates remain low .
  A fixed-dose combination of blood pressure and cholesterol lowering and antiplatelet treatments into a single pill , or polypill , has been proposed as one strategy to reduce the global burden of CVD by up to 80 % given its potential for better adherence and lower costs .
  OBJECTIVES To determine the effectiveness of fixed-dose combination therapy on reducing fatal and non-fatal CVD events and on improving blood pressure and lipid CVD risk factors for both primary and secondary prevention of CVD .
  We also aim ed to determine discontinuation rates , adverse events , health-related quality of life , and costs of fixed-dose combination therapy .