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This paper, written by Amir Qaseem, MD, PhD, MHA; Roger Chou, MD; Linda L. Humphrey, MD, MPH; Melissa Starkey, PhD; and Paul Shekelle, MD, PhD, was developed for the Clinical Guidelines Committee of the American College of Physicians: Paul Shekelle, MD, PhD (Chair); Roger Chou, MD; Paul Dallas, MD; Thomas D. Denberg, MD, PhD; Nick Fitterman, MD; Mary Ann Forciea, MD; Robert H. Hopkins Jr., MD; Linda L. Humphrey, MD, MPH; Tanveer P. Mir, MD; Holger J. Schünemann, MD, PhD; Donna E. Sweet, MD; and David S. Weinberg, MD, MSc. Approved by the ACP Board of Regents on 30 July 2011.
From the American College of Physicians, Philadelphia, Pennsylvania; Oregon Health & Science University, Portland, Oregon; and West Los Angeles Veterans Affairs Medical Center, Los Angeles, California.
Note: Clinical practice guidelines are "guides" only and may not apply to all patients and all clinical situations. Thus, they are not intended to override clinicians' judgment. All ACP clinical practice guidelines are considered automatically withdrawn or invalid 5 years after publication, or once an update has been issued.
Disclaimer: The authors of this article are responsible for its contents, including any clinical or treatment recommendations. No statement in this article should be construed as an official position of the U.S Department of Veterans Affairs.
Acknowledgment: The authors thank the ACP Performance Measurement Committee for its review of and comments on the manuscript.
Financial Support: Financial support for the development of this guideline comes exclusively from the ACP operating budget.
Potential Conflicts of Interest: Any financial and nonfinancial conflicts of interest of the group members were declared, discussed, and resolved. Dr. Humphrey: Consultancy: U.S. Preventive Services Task Force. Royalties: UpToDate. Dr. Shekelle: Consultancy: ECRI Institute; Employment: Department of Veterans Affairs; Grants/grants pending (money to institution): Agency for Healthcare Research and Quality, Department of Veterans Affairs, Centers for Medicare & Medicaid Services; Royalties: UpToDate. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M11-1931.
Requests for Single Reprints: Amir Qaseem, MD, PhD, MHA, American College of Physicians, 190 N. Independence Mall West, Philadelphia, PA 19106; e-mail, firstname.lastname@example.com.
Current Author Addresses: Drs. Qaseem and Starkey: 190 N. Independence Mall West, Philadelphia, PA 19106.
Dr. Chou: 3181 SW Sam Jackson Park Road, Mail Code: BICC, Portland, OR 97239.
Dr. Humphrey: 3710 SW US Veterans Hospital Road, Portland, OR 97201.
Dr. Shekelle: 11301 Wilshire Boulevard, Los Angeles, CA 90073.
Author Contributions: Conception and design: A. Qaseem.
Analysis and interpretation of the data: A. Qaseem, R. Chou, L.L. Humphrey, P. Shekelle.
Drafting of the article: A. Qaseem, R. Chou, M. Starkey.
Critical revision of the article for important intellectual content: A. Qaseem, R. Chou, L.L. Humphrey, P. Shekelle.
Final approval of the article: A. Qaseem, R. Chou, L.L. Humphrey, M. Starkey, P. Shekelle.
Statistical expertise: A. Qaseem.
Administrative, technical, or logistic support: A. Qaseem, M. Starkey.
Collection and assembly of data: A. Qaseem, M. Starkey.
Description: The American College of Physicians (ACP) developed this guideline to present the evidence and provide clinical recommendations on prophylaxis of venous thromboembolism for hospitalized nonsurgical patients (medical patients and patients with acute stroke).
Methods: This guideline is based on published literature on the topic from 1950 through April 2011 that was identified by using MEDLINE, the Cochrane Library, and reference lists of pertinent randomized trials and systematic reviews to identify additional reports. Searches were limited to randomized trials and English-language publications. The primary outcome for this guideline was total mortality up to 120 days after randomization. Secondary outcomes included symptomatic deep venous thrombosis; all pulmonary embolisms; fatal pulmonary embolism; all bleeding events; major bleeding events; and, for mechanical prophylaxis, effects on skin. This guideline grades the evidence and recommendations by using the ACP's clinical practice guidelines grading system.
Recommendation 1: ACP recommends assessment of the risk for thromboembolism and bleeding in medical (including stroke) patients prior to initiation of prophylaxis of venous thromboembolism (Grade: strong recommendation, moderate-quality evidence).
Recommendation 2: ACP recommends pharmacologic prophylaxis with heparin or a related drug for venous thromboembolism in medical (including stroke) patients unless the assessed risk for bleeding outweighs the likely benefits (Grade: strong recommendation, moderate-quality evidence).
Recommendation 3: ACP recommends against the use of mechanical prophylaxis with graduated compression stockings for prevention of venous thromboembolism (Grade: strong recommendation, moderate-quality evidence).
Policy Implication: ACP does not support the application of performance measures in medical (including stroke) patients that promotes universal venous thromboembolism prophylaxis regardless of risk.
Venous thromboembolism (VTE), comprising pulmonary embolism (PE) and deep venous thrombosis (DVT), is a common clinical problem and is associated with substantial morbidity and mortality (1). Most hospitalized medical patients have at least 1 risk factor for VTE, and this risk persists for several weeks after discharge (1). Twenty-six percent of patients with undiagnosed and untreated PE will have a subsequent fatal embolic event, whereas another 26% will have a nonfatal recurrent embolic event (2). Studies show that between 5% and 10% of all in-hospital deaths are a direct result of PE (3–5). The incidence of PE in the United States is estimated to be 1 case per 1000 persons per year, and PE accounts for 200 000 to 300 000 hospitalizations per year (6–7).
The purpose of this guideline is to present clinical recommendations on prophylaxis of VTE in adult hospitalized medical patients and patients with acute stroke, based on the available evidence on the benefits and harms of prophylaxis of VTE in these patient populations. The target audience for this guideline is all clinicians, and the target patient population is all hospitalized nonsurgical patients who are at risk for VTE.
The guideline is based on a systematic evidence review that addressed the following questions:
Key question 1: What are the benefits and harms of subcutaneous low-dose heparin products for VTE prophylaxis in hospitalized medical patients?
Key question 2: What is the comparative effectiveness of different low-dose heparin products (low-molecular-weight heparin [LMWH], unfractionated heparin [UFH]) for VTE prophylaxis?
Key question 3: What is the effectiveness and comparative effectiveness of mechanical devices for VTE prophylaxis?
Key question 4: Do results vary by general medical patient populations: general medical inpatients and patients with acute stroke?
The systematic evidence review was conducted by the Minnesota Evidence-based Practice Center (8). The literature search included studies identified by using MEDLINE and the Cochrane Library for clinical trials of VTE prophylaxis. The authors reviewed titles and abstracts of identified references and used reference lists of pertinent randomized trials and systematic reviews to identify additional reports. The studies selected included English-language, randomized trials published between 1950 and April 2011. Included trials evaluated treatments that are commonly recommended and used to prevent VTE, including subcutaneous low-dose (<20 000 U/d) UFH or similar prophylactic doses of LMWH or related agents (such as fondaparinux) and graduated compression stockings or other mechanical measures (such as intermittent pneumatic compression). The primary outcome of interest was total mortality up to 120 days after randomization. Secondary outcomes included symptomatic DVT; all PEs; fatal PE; all bleeding events; and major bleeding events (variably defined by trials, but typically defined as a decrease in hemoglobin level >20 g/L, transfusion of ≥2 units of blood, or life-threatening bleeding at a critical site); and, for mechanical prophylaxis, effects on skin. Details regarding the review methods can be found in the accompanying evidence review (8). To guide our recommendations, we prioritized outcomes on the basis of clinical importance, starting with total mortality. In the absence of statistically significant effects on total mortality, we then weighted effects on all PEs versus effects on major bleeding events, followed by symptomatic DVT, all bleeding (including minor bleeding) events, and effects on skin.
This guideline rates the evidence and recommendations by using the guideline grading system of the American College of Physicians (ACP), which is based on the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) system (Table). Details of the ACP guideline development process can be found in the methods article (9).
Ten trials (10–19) (n = 20 717) evaluated medical patients without stroke. The results showed that compared with no heparin prophylaxis, heparin prophylaxis was not associated with a statistically significant reduced risk for mortality (risk ratio [RR], 0.94 [95% CI, 0.84 to 1.04]; I2 = 0%; absolute reduction, 4 events per 1000 persons treated [CI, −11 to 3 events]) (moderate-quality evidence). However, heparin prophylaxis was associated with a reduced risk for PE (RR, 0.69 [CI, 0.52 to 0.90]; I2 = 0%; absolute reduction, 4 events per 1000 persons treated [CI, −6 to −1 event]) (moderate-quality evidence) but an increased risk for all bleeding events (RR, 1.34 [CI, 1.08 to 1.66]; absolute increase, 9 events per 1000 persons treated [CI, 2 to 18 events]) (moderate-quality evidence). Although the risk for major bleeding events increased, the difference did not reach statistical significance (RR, 1.49 [CI, 0.91 to 2.43]; I2 = 16%; absolute increase, 1 event per 1000 persons treated [CI, 0 to 4 events]) (low-quality evidence). Also, heparin prophylaxis resulted in an absolute reduction of 2 fewer symptomatic DVTs per 1000 patients treated (CI, −6 to 4 events), although the difference was not statistically significant (RR, 0.78 [CI, 0.45 to 1.35]) (low-quality evidence).
Evidence from 8 trials (20–27) (n = 15 405) of patients with acute stroke showed that compared with no heparin prophylaxis, heparin prophylaxis was not associated with a statistically significant reduction in risk for mortality (RR, 0.91 [CI, 0.70 to 1.18]; I2 = 32%; absolute reduction, 9 events per 1000 persons treated [CI, −29 to 18 events]) (low-quality evidence), PE (RR, 0.72 [CI, 0.50 to 1.04]; I2 = 20%; absolute reduction, 3 events per 1000 persons treated [CI, −5 to 0 events]) (low-quality evidence), or symptomatic DVT (RR, 0.14 [CI, 0.00 to 7.09]; absolute reduction, 9 events per 1000 persons treated [CI, −10 to 57 events]) (low-quality evidence). Heparin prophylaxis was associated with an increased risk for major bleeding events (RR, 1.66 [CI, 1.20 to 2.28]; I2 = 0%; absolute increase, 6 events per 1000 persons treated [CI, 2 to 12 events]) (moderate-quality evidence). The pooled trials were heterogeneous in their patient samples and treatment. The strongest evidence on the benefits and harms of VTE prophylaxis came from a single large randomized, controlled trial of patients with acute ischemic stroke (n = 14 578 [excluding patients randomly assigned to high-dose heparin]) (21). It found no statistically significant difference between low-dose heparin and no heparin in 14-day all-cause mortality (8.7% vs. 9.3%; RR, 0.94 [CI, 0.84 to 1.05]), fatal PE (0.51% vs. 0.40%; odds ratio [OR], 1.30 [CI, 0.77 to 2.18]), or all (fatal and nonfatal) PEs (0.68% vs. 0.83%; OR, 0.82 [CI, 0.55 to 1.21]). The study showed a statistically significant increase in 14-day hemorrhagic stroke or serious extracranial hemorrhage (1.3% vs. 0.80%; OR, 1.73 [CI, 1.22 to 2.46]) and a statistically significant decrease in 14-day recurrent ischemic stroke (2.6% vs. 4.0%; RR, 0.65 [CI, 0.54 to 0.80]).
For mortality, PE, and major bleeding events, pooled estimates for medical patients without stroke and patients with acute stroke were very similar. Although the point estimate for the effects on DVT risk was substantially stronger in patients with stroke than in medical patients without stroke, it was too imprecise to draw conclusions about differential risks. Combining evidence from the 2 populations (18 trials; 36 122 participants) showed that heparin was associated with a borderline statistically significant reduction in risk for mortality compared with no heparin prophylaxis (RR, 0.93 [CI, 0.86 to 1.00]; I2 = 2%; absolute reduction, 6 events per 1000 persons treated [CI, −11 to 0 events]), a statistically significant reduction in risk for PE (RR, 0.70 [CI, 0.56 to 0.87]; I2 = 0%; absolute reduction, 3 events per 1000 persons treated [CI, 5 to −1 events]), and no statistically significant decrease in symptomatic DVT (RR, 0.75 [CI, 0.43 to 1.30]; absolute reduction, 2 events per 1000 persons treated [CI, −6 to 3 events]). These trials also showed a statistically significant increased risk for all bleeding events (RR, 1.28 [CI, 1.05 to 1.56]; absolute increase, 9 events per 1000 persons treated [CI, 2 to 18 events]) and major bleeding events (RR, 1.61 [CI, 1.23 to 2.10]; I2 = 0%; absolute increase, 4 events per 1000 persons treated [CI, 1 to 7 events]).
Nine trials (28–36) (n = 11 650) that compared LMWH with UFH in medical patients showed no statistically significant difference in mortality (RR, 0.91 [CI, 0.73 to 1.13]; I2 = 25%; absolute reduction, 9 events per 1000 persons treated [CI, −28 to 13 events]) (moderate-quality evidence), PE (RR, 0.70 [CI, 0.44 to 1.11]; I2 = 0%; absolute reduction, 2 events per 1000 persons treated ([CI, −4 to 1 event]) (low-quality evidence), or major bleeding events (RR, 0.89 [CI, 0.70 to 1.15]; I2 = 0%; absolute reduction, 3 events per 1000 persons treated [CI, −7 to 3 events]) (low-quality evidence).
Five trials (37–41) (n = 2785) that compared LMWH with UFH in patients with acute stroke did not show statistically significant differences for mortality (RR, 1.00 [CI, 0.81 to 1.22]; I2 = 1%; absolute reduction, 0 events per 1000 persons treated [CI, −23 to 26 events]) (moderate-quality evidence), symptomatic DVT (RR, 0.34 [CI, 0.11 to 1.00]; absolute reduction, 7 events per 1000 persons treated [CI, −9 to 0 events]) (low-quality evidence), PE (RR, 0.57 [CI, 0.25 to 1.34]; I2 = 18%; absolute reduction, 4 events per 1000 persons treated [CI, −8 to −3 events]) (low-quality evidence), or major bleeding events (RR, 1.49 [CI, 0.73 to 3.06]; I2 = 0%; absolute reduction, 4 events per 1000 persons treated [CI, −2 to 19 events]) (low-quality evidence).
Evidence from all trials (n = 14 435) comparing LMWH with UFH did not show a statistically significant difference between LMWH and UFH for mortality (RR, 0.94 [CI, 0.82 to 1.08]; I2 = 16%) or major bleeding events (RR, 0.95 [CI, 0.75 to 1.20]; I2 = 0%), although a nonsignificant difference favored LMWH for PE (OR, 0.67 [CI, 0.45 to 1.00]; P = 0.053; I2 = 0%).
Evidence on clinical outcomes from randomized, controlled trials evaluating mechanical devices versus no mechanical devices is sparse. Three trials included in the systematic review compared mechanical devices with no mechanical devices, but 1 large trial (n = 2518) included 232 of the 247 deaths reported. It included patients with acute stroke and compared thigh-length graduated compression stockings with no stockings (42). The results showed no statistically significant difference in risk for mortality (RR, 1.11 [CI, 0.87 to 1.42]) (low-quality evidence), symptomatic DVT, or PE. However, risk for lower-extremity skin damage statistically significantly increased among patients treated with compression stockings (RR, 4.02 [CI, 2.34 to 6.91]; absolute increase, 39 events per 1000 patients treated [CI, 17 to 77 events]) (moderate-quality evidence). The 2 other studies showed no differences in rates of PE or mortality (43–44).
Four studies met inclusion criteria but could not be meaningfully combined with the studies described because they evaluated different clinical comparisons or interventions. One randomized, controlled trial (n = 300) that evaluated LMWH prescribed for different durations in medical patients (45) reported 2 deaths in patients who received LMWH only while immobilized (mean, 5.1 days) compared with no deaths in patients who received LMWH while immobilized and for 10 additional days (mean, 14.5 days) (RR, 0.00). A randomized trial (n = 90) of patients who were enrolled at least 7 days after stroke compared LMWH with intermittent pneumatic compression (46). Most patients received heparin prophylaxis before randomization. The study reported 2 symptomatic DVTs and 1 minor bleeding event in the LMWH group compared with no events in the compression group. Another study (n = 151) that included patients with acute cerebral hemorrhage compared compression stockings with or without pneumatic compression and found no statistically significant difference in risk for all-cause mortality through 3 months (22% vs. 31%; RR, 0.69 [CI, 0.4 to 1.20]) (47). One symptomatic DVT occurred in each group (RR, 1.04 [CI, 0.07 to 16]) (47). Another study found that proximal DVT occurred more in patients with stroke who wore below-knee stockings than in those who wore thigh-length stockings (48). One study (n = 6085) of hospitalized, immobile medical patients who had completed an initial 10-day course of open-label enoxaparin prophylaxis compared an additional 28 days of enoxaparin (40 mg) with placebo (49). After 90 days, the treatment group had a statistically significant reduction in risk for symptomatic VTE (from 28 [1.1%] to 8 [0.3%] events) and an increase in all bleeding events (from 116 [3.9%] to 186 [6.3%] events) and major bleeding events (from 10 [0.3%] to 25 [0.8%] events), with no difference in mortality risk (hazard ratio, 1.04).
Randomized trials of heparin versus no heparin therapy for medical patients did not show a statistically significant reduction in the risk for mortality or symptomatic DVT and showed an increased risk for bleeding events. However, PE was significantly reduced in medical patients. For patients with acute stroke, heparin increased the risk for major bleeding, with no effect on mortality, symptomatic DVT, or PE. Studies comparing LMWH with UFH did not show any differences in clinical outcomes. Mechanical prophylaxis was not associated with any improvement in clinical outcomes in patients with acute stroke and resulted in an increased risk for lower-extremity skin damage, although evidence on the effects of mechanical prophylaxis was sparse.
The decision to initiate VTE prophylaxis in medical (including stroke) patients should be based on an individualized assessment of the risk for thromboembolism and bleeding, as well as an assessment of the potential harms against modest or even no benefit. Trials that evaluated the benefits and harms of heparin prophylaxis generally enrolled patients who were considered to be at higher risk for VTE. Risk factors for thromboembolism include presence of inherited conditions—such as factor V Leiden mutation, prothrombin gene mutation, protein S or C deficiency, and antithrombin deficiency—or acquired risk factors—such as surgery, cancer, immobilization, trauma, presence of a central venous catheter, pregnancy, drugs (for example, oral contraceptives, hormone replacement therapy, or tamoxifen), congestive heart failure, chronic renal disease, the antiphospholipid antibody syndrome, obesity, smoking, older age, and history of thromboembolism. Some evidence suggests that heparin is less beneficial in younger patients than in patients older than 75 years (5, 49–50). Many risk assessment tools are available for estimating thromboembolism risk, but the current evidence is insufficient to recommend a validated tool. Although such instruments may be useful, decisions about heparin prophylaxis may also be based on general evidence regarding the risk factors for VTE and bleeding.
Heparin and related drugs are associated with an increased risk for bleeding. Risk factors for bleeding with anticoagulant therapy include older age; female sex; diabetes; hypertension; presence of cancer; acute or chronic alcoholism; liver disease; severe chronic kidney disease; peptic ulcer disease; anemia; poor treatment adherence; prior stroke or intracerebral hemorrhage; presence of bleeding lesions; bleeding disorder; and concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, antiplatelet agents, antibiotics, statins, fibrates, and steroids.
In hospitalized medical patients, prophylaxis with heparin is associated with a statistically significant reduction in PEs (absolute decrease, 4 events per 1000 persons treated) and increase in all bleeding events (absolute increase, 9 events per 1000 persons treated), a non–statistically significant increase in major bleeding events (absolute increase, 1 event per 1000 persons treated), and no effect on mortality or symptomatic DVT. In most patients, the clinical benefit of reduction of PEs outweighs the harm of increased risk for bleeding events.
In patients with acute stroke, the pooled results from the evidence review showed no statistically significant benefit from heparin prophylaxis on mortality, PE, or symptomatic DVT. The pooled results also showed a statistically significant increase in risk for major bleeding events (absolute increase, 6 events per 1000 persons treated) that outweighed the potential reduction in PEs (absolute decrease, 3 events per 1000 persons treated). However, the pooled results showed wide CIs that also encompassed potential substantial net benefits. Seven of 8 studies that evaluated the effect of heparin on mortality were small (sample size range, 32 to 305 participants) and were published before 1996. Some did not describe use of CT to exclude intracranial hemorrhage before randomization. The strongest evidence in patients with stroke comes from the International Stroke Trial, a large study that randomly assigned 14 578 patients with suspected acute ischemic stroke to receive low-dose (5000 IU twice daily) heparin or no heparin (21). It found no statistically significant differences between low-dose heparin and no heparin in 14-day all-cause mortality, fatal PE, or all (fatal and nonfatal) PEs. Although the risk for hemorrhagic stroke or serious extracranial hemorrhage statistically significantly increased (absolute increase, 5 events per 1000 persons treated), this was offset by a statistically significant and larger decrease in risk for recurrent ischemic stroke (absolute decrease, 14 events per 1000 persons treated). Results of the International Stroke Trial and pooled estimates from patients with stroke were generally consistent with findings from pooled analyses of medical patients without stroke; thus, evidence was insufficient to conclude that risks and benefits of VTE prophylaxis differ between medical patients with stroke and those without stroke. Evidence on the risks and benefits in patients with stroke is relatively weaker than that in medical patients without stroke, although prevention of recurrent ischemic stroke may be an additional benefit in this population.
The optimal duration of heparin prophylaxis is uncertain. Almost all trials evaluated heparin therapy for patients during hospitalization. A recent study evaluated extended (posthospitalization) heparin therapy for high-risk (immobile) patients (49), but more research is needed to understand the effects of extended therapy on the balance of benefits and harms.
Clinical benefits and harms do not statistically significantly differ between LMWH and UFH. Fondaparinux has not been directly compared with heparin. All prophylactic heparins reviewed for this guideline are administered as subcutaneous injections. The dosage varies from 2 or 3 times daily for UFH to once daily for LMWH or fondaparinux. The average wholesale drug costs are about $10 per day for UFH, $35 per day for LMWH (generic enoxaparin is available), and $60 per day for fondaparinux. In 4 trials that compared UFH with LMWH and assessed heparin-induced thrombocytopenia, 7 cases of heparin-induced thrombocytopenia occurred out of about 1900 in patients receiving UFH and 1 case occurred out of about 1900 patients receiving LMWH (P = 0.07) (29, 31, 33, 37). Hence, the choice of agent for prophylaxis of VTE should be based on ease of use, adverse effect profile, and cost of medication.
Mechanical prophylaxis with graduated compression stockings was not effective in preventing VTE or reducing mortality and resulted in clinically important lower-extremity skin damage. Clinicians who initiate VTE prophylaxis should select heparin (or related drugs) rather than graduated compression stockings for patients in whom heparin can be used. In patients at high risk for bleeding events or in whom heparin is contraindicated for other reasons, intermittent pneumatic compression may be a reasonable option, because evidence suggests that it is beneficial in surgical patients. However, intermittent pneumatic compression has not been sufficiently evaluated as a standalone intervention in medical patients to reliably estimate benefits and harms.
See the Figure for a summary of the recommendations and clinical considerations.
ACP = American College of Physicians; DVT = deep venous thrombosis; PE = pulmonary embolism; VTE = venous thromboembolism.
ACP does not support the application of performance measures in medical (including stroke) patients that promotes universal venous thromboembolism prophylaxis regardless of risk.
In the United States, many organizations have developed performance measures intended to increase the appropriate use of VTE prophylaxis in hospitalized patients. However, in some clinical settings, performance measures have been based on rates of VTE prophylaxis in all patients, regardless of their underlying risk. The evidence reviewed for the clinical recommendations in this guideline does not support routine prophylaxis of VTE in all medical patients and emphasizes the tradeoff in harms and benefits. Clinicians caring for these patients must assess the risks and benefits before deciding whether to initiate prophylaxis. In some cases, not prescribing VTE prophylaxis may be justified because the estimated tradeoff between potential risks and benefits is small or unclear. Because no standard, accepted formula for risk assessment exists to identify which medical patients are likely to benefit from VTE prophylaxis, the decision is best left to physician judgment, and performance measures targeting all patients are inappropriate. Until we can better identify patients who truly benefit, performance measures that encourage VTE prophylaxis for all medical patients may encourage physicians to use prophylaxis in low-risk patients for whom the risks may exceed the benefit.
Video News Release - ACP's Preventing VTE Guideline
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The background review and ACP Venous Thromboembolism Prophylaxis guidelines by Lederle, Qaseem, and colleagues(1, 2) concluded that heparin prophylaxis for medical patients does not reduce mortality and does increase major bleeding. Additionally, heparin prophylaxis hurts patients with repeated needle sticks and subcutaneous hematomas, takes valuable clinician time, and costs money. Heparin significantly reduces the risks of asymptomatic PE and DVT but not symptomatic VTE. The ACP recommends that physicians prescribe heparin if the risk for VTE is greater than the risk for bleeding. However, there is no validated process of determining if the risk of VTE is greater than the risk for bleeding.
With three coauthors, my review of the literature of anticoagulant prophylaxis against hospital acquired VTE showed that anticoagulants increase the risk of death in medical patients.(3) Our review included an important study not referenced in the ACP review because it was not an RCT. Goldhaber and colleagues reviewed charts to find the incidence of developing DVT, PE, and fatal PE (FPE) during hospitalization and within 30 days after hospital discharge in about 80,000 medical, surgical, neurological, obstetrical, and pediatric patients admitted over a two year period in Boston's Brigham and Women's Hospital.(4) Out of 384 patients with hospital-acquired VTE (about 1 per 200 admissions), less than 25% came from general surgical or orthopedic surgical services and the rest came from medical or oncology services. Only 318 hospital acquired VTE patients (82.8%) were potential candidates for prophylaxis (i.e., they had two or more VTE risk factors). Of prophylaxis candidates, 170 (53%) had received anticoagulants. Out of 13 patients with FPE (all on medical or oncology wards and no stroke patients), 12 had received anticoagulant prophylaxis. Estimating that 32% of the hospitalized patients were at risk for VTE and that 50% of all patients at increased risk for VTE received anticoagulants,(3) anticoagulation prophylaxis was associated with a 12- fold increase in FPE (OR: 12.0; 95% CI, 1.6-92). Notably, the rate of FPE estimated in anticoagulated and unanticoagulated high VTE risk patients in the Goldhaber patient chart study was an order of magnitude less than the rate in the largely industry funded RCTs included in the ACP review (heparin: 12/12 300 (0.10%) versus 46/13 839 (0.33%); no heparin: 1/12 300 (0.008%) versus 66/18 462 (0.36%)).(1, 3)
To reduce deaths and vascular complications of heparin and other anticoagulants, the ACP guidelines should declare prophylactic anticoagulation of medical inpatients contraindicated.
1. Lederle FA, Zylla D, MacDonald R, Wilt TJ. Venous Thromboembolism Prophylaxis in Hospitalized Medical Patients and Those With Stroke: A Background Review for an American College of Physicians Clinical Practice Guideline 10.1059/0003-4819-155-9-201111010-00008. Annals of Internal Medicine. 2011;155(9):602-615.
2. Qaseem A, Chou R, Humphrey LL, Starkey M, Shekelle P. Venous Thromboembolism Prophylaxis in Hospitalized Patients: A Clinical Practice Guideline From the American College of Physicians 10.1059/0003-4819-155-9- 201111010-00011. Annals of Internal Medicine. 2011;155(9):625-632.
3. Cundiff D, Agutter P, Malone P, Pezzullo J. Diet as prophylaxis and treatment for venous thromboembolism? Theoretical Biology and Medical Modelling. 2010(1):http://www.tbiomed.com/content/7/1/31/comments.
4. Goldhaber S, Dunn K, MacDougall R. New onset of venous thromboembolism among hospitalized patients at Brigham and Women's Hospital is caused more often by prophylaxis failure than by withholding treatment. Chest. 2000;118:1680-4.
None declared
The recent review supporting the ACP guideline for hospitalized medical and stroke patients (1) showed that heparin, both LMW and unfractionated, fails to reduce mortality from VTE and DVT-related morbidity in patients overall, but increases the likelihood of major bleeding. Our recent article (2) yielded the same inferences but surprisingly was not cited in (1). The authors of (1) recommend that, for most patients, heparin prophylaxis should be used only when the VTE risk exceeds the bleeding risk, but it is not clear how these risks are to be computed and compared. In (2) we suggested that certain diets (Mediterranean, vegetarian or vegan) could be prophylactic against VTE, citing independent support for this proposal; it would entail no bleeding risk, though a large trial would be required to validate it (2). The necessary trial for medical and post-stroke patients need not have a heparin prophylaxis control arm since this ACP review (1) demonstrated that heparin does not benefit patients.
The new ACP VTE prophylaxis guideline recommends against mechanical prophylaxis with graduated compression stockings because of limited benefit and deleterious effects on the skin, though the authors admit their evidence is sparse and of moderate quality (1). One argument for early mobilization and mechanical prophylaxis is that these measures were infrequently utilized before the 1980s; since then they have become widely practiced, and the incidence of hospital-acquired VTE has decreased around four-fold (2). Our understanding of the etiology of DVT and VTE (3) indicates that the most effective form of mechanical prophylaxis would be intermittent pneumatic compression with pulses at 30-60 minute intervals. This would suffice to empty the valve pockets during non-pulsatile venous flow at frequent enough intervals to preclude the suffocating hypoxemia that initiates thrombogenesis. The experiments that confirmed our account of DVT etiology (4) imply that this approach to prophylaxis would be valuable, but further animal experiments followed by clinical trials are needed to test the implication. In view of the continuing high incidence of DVT/VTE in hospitals, such studies should receive priority. The authors of (1) have made clear the paucity of evidence in this area.
Yours faithfully,
Paul S. Agutter: Theoretical Medicine and Biology Group, Glossop, Derbyshire, UK; email@example.com P. Colm Malone: firstname.lastname@example.com
1. Qaseem A, Chou R, Humphrey LL, Starkey M, Shekelle P. Venous thromboembolism prophylaxis in hospitalized patients: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2011;155:625-32. [PMID: 22041951]
2. Cundiff DK, Agutter PS, Malone PC, Pezzullo J. Diet as prophylaxis and treatment for venous thromboembolism? Theor Biol Med Model 2010;7:31. [PMID: 20701748] http://www.tbiomed.com/content/7/1/31/comments.
3. Malone PC, Agutter PS. The Aetiology of Deep Venous Thrombosis. Dordrecht: Springer; 2008.
4. Hamer JD, Malone PC. Experimental deep vein thrombosis by a non- invasive method. Ann R Coll Surg Engl. 1984;66:416-9. [PMID: 6508162]
There appears to be a disconnect in the evidence based guidelines from the American College of Physicians. It is pleasing to see the background review for the VTE guidelines by Lederle et al has been copublished by the editors, but this appears to have been ignored (at least in part) by the clinical guideline committee of the American College of Physicians when making their clinical practice guidelines. Specifically, recommendation 2 states that pharmacologic prophylaxis with heparin is recommended for VTE prophylaxis in medical patients unless the assessed risk for bleeding outweighs the likely benefits and grades this as a strong recommendation with moderate-quality evidence. The discussion then states that "the clinical benefit of reduction of PEs outweighs the harm of increased risk for bleeding events." Yet, Lederle et al caution about the validity of the PE data as "the funnel plot and Egger analyses suggested that the decrease in PE incidence may have been exaggerated by publication bias."
Given this caution, the lack of mortality benefit, and the increased risk of bleeding, why has the position been taken that VTE prophylaxis with heparin adds anything to the clinical management of the standard "higher risk" medical patient which is the population included in the background meta-analysis by Lederle? Where is the moderate-quality evidence to make such a strong recommendation? Is their any scenario that is readily identifiable when the risk of VTE is greater than the risk for bleeding? Surely, the normative approach based on the evidence is to only consider prophylaxis in specific circumstances (yet what they are is yet to be determined), rather than as the routine. Primum non nocere!
Here at Los Angeles Dept. of Coroner it seems that we have ten to twenty such deaths per month. Most often the use of "blood thinners" is not listed on the death certificate and the type of trauma has not been made clear. A good reseach project would be to collect all the many cases of deaths by blunt head trauma/and or subdural hematomas from the death certificate statistics and then clarify how many are due to minor head trauma while on anticoagulants. I think the results would be shocking and turn "weighing the benefits and risks" of administering such therapies into a whole new ball game. Just about everytime I fill out the worksheets for the mortuary external examinations to be done by our deputy coroners I see several such cases. I do this several times per month and other doctors cover this duty the other twenty seven days of the month. It seems epidemic. It is truely alarming to me. Even just interviewing coroner/medical examiners of the major cities should produce a very ugly hypothesis of a very real problem ignored far too long.
We thank Drs. Agutter, Cundiff, and Mills for their comments regarding the American College of Physicians' recent clinical guideline on venous thromboembolism (VTE) prophylaxis in hospitalized patients (1).
In response to Dr. Mills, the pooled results from medical patients showed that prophylaxis with heparin is associated with a statistically significant reduction in PEs (absolute decrease, 4 events per 1000 persons treated) but a non-statistically significant increase in major bleeding events (absolute increase, 1 event per 1000 persons treated), and no effect on mortality or symptomatic DVT. Hence, there is more benefit from potential reduction in PE events relative to the risk of bleeding events. As far as the rating of our evidence goes, according to the GRADE system, publication bias is just one of the factors in addition to others such as the number of trials, quality, consistency between trials, and precision of estimates that should be considered when rating the quality of evidence and grading the strength of recommendations. Funnel plots can be helpful in understanding the risk of publication bias, but results must be interpreted cautiously, because the small sample effects evaluated in funnel plots can be due to factors other than publication bias (such as differences in study quality, populations, or outcomes) (2, 3). Other approaches for examining the likelihood of publication bias have similar limitations (4). In addition, the possibility of publication bias by itself does not necessarily invalidate estimates of treatment effects. In this case, many unpublished small trials of heparin prophylaxis showing no reduced risk of PE would have to exist in order to lower the absolute decrease in events from 4 events per 1000 persons treated to 1 or fewer events per 1000 persons treated, and result in no net benefit relative to the risk of major bleeding. This is unlikely. Therefore we stand by our original recommendation and grading of evidence.
As far as Drs. Cundiff's and Agutter's comments are concerned, our literature review only included evidence from randomized controlled trials because they are less susceptible to bias than observational studies when designed and carried out correctly. Both Drs. Agutter and Cundiff refer to a review focusing on diet and VTE. Their review included no studies that actually evaluated the association between a prophylactic intervention and clinical outcomes. Rather it discussed possible mechanisms for benefit and epidemiological studies and proposed a possible dietary intervention for future research (5). Hence this paper was not included in the review for our guideline.
Authors: Amir Qaseem, MD, PhD, MHA American College of Physicians, 190 N. Independence Mall West, Philadelphia, PA 19106
Roger Chou, MD Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Mail Code: BICC, Portland, OR 97239.
Linda Humphrey, MD Oregon Health and Science University, 3710 SW US Veterans Hospital Road, Portland, OR 97201
Paul Shekelle, MD, PhD Greater Los Angeles VA Health Center/RAND, 1776 Main Street, Santa Monica, CA 90401
1. Qaseem A, Chou R, Humphrey LL, Starkey M, Shekelle P. Venous Thromboembolism Prophylaxis in Hospitalized Patients: A Clinical Practice Guideline From the American College of Physicians. Annals of Internal Medicine. 2011;155(9):625-32. 2. Lau J, Ioannidis JP, Terrin N, Schmid CH, Olkin I. The case of the misleading funnel plot. BMJ. 2006;333(7568):597-600. 3. Terrin N, Schmid CH, Lau J. In an empirical evaluation of the funnel plot, researchers could not visually identify publication bias. J Clin Epidemiol. 2005;58(9):894-901. 4. Guyatt GH, Oxman AD, Montori V, Vist G, Kunz R, Brozek J, et al. GRADE guidelines: 5. Rating the quality of evidence--publication bias. J Clin Epidemiol. 2011;64(12):1277-82. 5. Cundiff DK, Agutter PS, Malone PC, Pezzullo JC. Diet as prophylaxis and treatment for venous thromboembolism? Theor Biol Med Model. 2010;7:31.
Preventing Venous Thromboembolism in Hospitalized Patients: Recommendations From the American College of Physicians
The full reports are titled "Venous Thromboembolism Prophylaxis in Hospitalized Patients: A Clinical Practice Guideline From the American College of Physicians" and "Venous Thromboembolism Prophylaxis in Hospitalized Medical Patients and Those With Stroke: A Background Review for an American College of Physicians Clinical Practice Guideline." They are in the 1 November 2011 issue of Annals of Internal Medicine (volume 155, pages 625-632 and pages 602-615). The first report was written by A. Qaseem, R. Chou, L.L. Humphrey, M. Starkey, and P. Shekelle, for the Clinical Guidelines Committee of the American College of Physicians; the second report was written by F.A. Lederle, D. Zylla, R. MacDonald, and T.J. Wilt.
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Top Definition
Someone in the corporate world who slacks off most of the time, and whose level of productivity is seen as his/her "typical". However, once this person actually starts doing productive work, it's extremely good and effective.
Harvey Keitel was a slackoff superstar in Pulp Fiction.
โดย man-tow-notch 14 มกราคม 2009
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Can you define these popular missing words?

subset: commoncrawl


text:
Weight Loss Tea Reviews
Drinking tea goes back thousands of years. A popular part of weight loss diets today incorporate tea into their everyday meal plans. Green teas are noted to help promote weight loss. It boosts your metabolism and can effectively help the body burn more calories. Some of the teas we've reviewed do not have sufficient information to make them a good choice for dieters. Keep looking through our long list of teas to find the right weight loss tea for your specific dietary needs.
There are many health benefits related to tea – whether black, white, green, oolong, etc. Tea is a great antioxidant, can decrease your risks of cancers, coronary heart disease, strengthen the immune system, and also help in weight loss (and more on Wikipedia). Other teas may not help in weight loss, but can help in detoxifying the body, which is a plus. There are teas that have many healing qualities and some that give rapid weight loss and guarantees success. There are teas that also give an energy boost without the crash caffeine will give. Some have strong flavors, while others are mild.
As with all diet products, carefully choose your weight loss tea. It may be the one key to helping you lose weight and keeping it off.


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Suggest Salem Parks Comm. considers a sprayground
To the editor:
There was recently an article regarding the Parks Commission suggestions for usage of shale lease money that has been set aside for council members to use for projects to benefit constituents.
I agree with Vice Chairman Terry Hoopes who said a parks project would benefit everyone, but question whether a dog park is needed for Salem and if it would truly benefit many.
We were recently in DC and took advantage of one of several spraygrounds they have in parks. (I won't try to describe them, but you can go online to see several that various cities have.)
A sprayground would benefit parents/grandparents of young children by providing a free cooling water/play experience for the kids.
I believe anything we can do to add a benefit to young families in Salem would be a plus for the community. If we can provide something unique for little kids, that would surely be a positive step to help get/keep families with little ones in town.
Should keep informed on college loan rate hike
To the editor:
If it seems like you have heard this story before you have. Last year the proposed student loan interest rate hike issue was being addressed in Washington. A year later that issue is being revisited.
College students taking out new loans for the fall term will see interest rates twice what they were in the spring - unless Congress fulfills its pledge to restore lower rates when it returns after the July 4 holiday.
Subsidized Stafford loans, which account for roughly a quarter of all direct federal borrowing, went from 3.4 percent interest to 6.8 percent interest on July 1.
Efforts to keep interest rates from doubling on new Stafford loans fell apart last week. But if an agreement remains elusive, students could find themselves saddled with higher interest rates this year than last.
The only silver lining is that you really can't take out student loans more than 10 days before the term starts. But that is little consolation for students looking at unexpected costs waiting for them on graduation day if Congress doesn't take action before it breaks again for the month of August.
In April, the Democrats solution was setting interest rates at the cost of the 10 year treasury note, plus a 0.93 percent margin, with no cap on the maximum interest rate that students could pay. Also called for locked-in interest rates for the life of the loan, meaning that the interest rate that you pay today on the loan would be the same as the interest rate that you pay in 10 years.
In mid-May, Republican Congressman John Kline proposed the Smarter Solutions for Students Act, which was very similar to the previous suggestion. Kline's bill would set the subsidized rate at the cost of the 10 year treasury note, plus a 2.5 percent margin, and would be capped at 8.5 percent. The bill was recently approved in the House of Representatives by a vote of 221-198, but was rejected by the Senate along with the Democratic solution above.
No matter which solution you support, if you have a student in or about to enter college and if they will be borrowing for there education you will want to keep informed on this matter.
Thanks for those helping with Salem Super Cruise
To the editor:
I would like to publicly thank those individuals, organizations, and departments who once again contributed to the success of the Salem Super Cruise; and there were many.
As the planning committees for the Cruise are established six months prior to the event, these individuals spend many hours working to make certain that deadlines are met and results are achieved. That is how this has worked successfully with the following: Ron Waite, advertising; Mick Orosz, concessions; Sam and Judy Sicilia, and Tom and Patty Hall, parking and the Show & Shine. And so it was with Dominic and Mark Righetti with the addition of the Auto Cross and Steve Rouse for developing our new website (salemsupercruise.com).
For preparing and maintaining our city's appearance, a big thank you to the following: the Salem Beautification Committee, the street department, traffic and safety department, and the city electrician. The Salem Police Department, fire department, Columbiana County Sheriff's Department, State Highway Patrol, Salem Police Auxiliary, and the Salem-Perry Township Crime Watch, all worked very hard to make this a safe event for the many thousands of visitors to Salem. Also, thank you to Salem Community Hospital for providing bottled water for the cruise attendees.
A special thank you to our Administrative Assistant Debbie Bricker, Auditor Betty Brothers, and Phyllis McKinley, who spent countless hours covering many bases to ensure the overall success of the cruise weekend. These ladies, along with Mayor Berlin and his wife Chris, Council President Mickey Weaver and husband Dennis, and my wife Cindy, made up the early morning clean-up crew.
Thank you once again to Salem Tire for organizing the appearance of the Goodyear Blimp, Expert Tire for bringing in "Big Foot," and Stadium GM for hosting Dale Earnhardt Jr.'s race car.
Larry Shields of the Salem News provided excellent coverage of many of the events throughout the weekend, as well as coverage of the Cruise since January.
Last but not least, I want to thank the citizens and businesses of Salem and surrounding areas for their participation and cooperation, as well as all of the "car cruisers" that made this year's event one of the most successful weekends yet. We look forward to seeing everyone again at next year's cruise - to be held June 19-22, 2014.
Service and safety director
Appreciates participants in July 4th pet, vehicle parades
To the editor:
At this time I would like to acknowledge all of the participants in the pet parade and vehicle parade on the Fourth of July.
There was a lot of work put into the parades by the kids, moms and dads and grandmas and grandpas. I was very impressed an delighted at the turnout of everyone from the contestants as well as the spectators.
I need to thank Herron Distributors and Attorney Goll for their donations, as well as the Salem Area Chamber of Commerce for funding the award medals.
Each year I need three judges for the event. Bob Merry, Elizabeth Thatcher and B.J. Abrams, have always been there for me. Last of all but not at all least, I thank the Salem News for the fantastic coverage leading up to the event. They always come through starting with the pre-picture by Mary Ann Greier. I thank J.D. for coming out on the holiday to take many photos, I'm sure he had family to be with and celebrate. Again, thanks to all for a great day.


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Asase Yaa African-American Dance TheatreThe members of Asase Yaa have traveled to around the world, bridging the gap between African and African-American culture. They've worked with VH1 Hip Hop Honors Awards, Stars of New York Dance, and the premiere of the HBO "Sing your Song" documentary with Harry Belafonte. Presented by Kente Arts Alliance.02/01/2014Time: 8:00 pmNew Hazlett Theater, 6 Allegheny Square East, Pittsburgh, PAwebsite | map
Compagnie KafigThis innovative hip-hop ensemble has become an international phenomenon. Inspired by an encounter with eleven young dancers from the shantytowns of Brazil, director and choreographer Mourad Merzouki created Correria and Agwa—two heart-stopping works that showcase a sensational combination of athletic samba, hip-hop and capoeira dance styles. The all-male company from Brazil exhibits theatrical intelligence and is gifted with irresistible personality and astonishing dancing. Bursting with fun, humor and vitality, this show is set to an energetic soundtrack of samba and bossa nova music.02/01/2014Time: 8:00 pmByham Theater, 101 6th St., Pittsburgh, PAwebsite | map
Gershwin ValentineA pianist praised for her "vivid and beautiful playing," (New York Times) Joyce Yang performs Gershwin's Concerto in F with the Westmoreland Symphony and music director Daniel Meyer. Vaughan Williams' Symphony No. 5 completes the evening. 02/01/2014Time: 7:30 pmPalace Theater, 21 W. Otterman St., Greensburg, PAwebsite | map
"PSO Musicians Care" Fund Benefit ConcertThe musicians of the Pittsburgh Symphony Orchestra present a concert to fund public school music programs. Donations will aid in the repair and purchase of musical instruments, transporting students to Heinz Hall for the PSO's education concerts, and music career scholarships. Music Director Manfred Honeck conducts the program of Bach, Haydn, Strauss, Beethoven, and Tchaikovsky.02/01/2014Time: 8:00 pmLocation: Upper St. Clair High School, 1825 McLaughlin Run Rd., Pittsburgh, PAwebsite
Peter Serkin, pianoPeter Serkin's program includes Sweelinck's Capriccio, Nielen's Theme and Variations, Op. 40; Wuorinen's Scherzo, Reger's Three Pieces from "Aus Menem Tagebuch," Crawford's Study in Mixed Accents, Stravinsky's Four Etudes, Op. 7; and Beethoven's "Les Adieux" Sonata in E-flat major, Op. 81a.02/03/2014Time: 7:30 pmCarnegie Music Hall, 4400 Forbes Ave., Pittsburgh, PAwebsite | map
Claude Bolling's Suite for Flute & Jazz Piano TrioIncidental Chamber Players perform Claude Bolling's Suite for Flute and Jazz Trio followed by performances by students from Pittsburgh School of Creative Performing and Creative Arts. Free admission. Donations to support CAPA are encouraged.02/04/2014Time: 6:30 pmLocation: Biddle's Escape, 401 Biddle Ave, Pittsburgh, PAwebsite
Art.Write.Now.Tour 2013 –14This nationwide traveling exhibition showcases more than 130 pieces of original art and literary work created by teen winners of the 2013 Scholastic Art & Writing Awards. These awards, judged by panels of professionals, have a legacy dating back to 1923, when Pittsburgh native M.R. Robinson founded Scholastic Inc. Past winners include Andy Warhol, Sylvia Plath, Truman Capote, Richard Avedon, Lena Dunham, Robert Redford, Joyce Carol Oates, Stephen King, Zac Posen, and many more.02/05/2014 - 03/02/2014Andy Warhol Museum, 117 Sandusky St., Pittsburgh, PAwebsite | map
University of Pittsburgh Symphony Orchestra: Britten & BeethovenTenor Robert Frankenberry joins the University of Pittsburgh Symphony Orchestra for Britten's Nocturne, then takes the conductor's podium for Beethoven's Triple Concerto. Director Roger Zahab will pick up his violin to perform the Beethoven with cellist Paula Tuttle and pianist Donna Amato.02/05/2014Time: 8:00 pmLocation: Bellefield Hall, 315 S. Bellefield Av., Pittsburgh, PAwebsite
(Another) Evening of One-ActsOn the heels of 2013's successful Evening of One-Acts, Stage Right is presenting (Another) Evening of One-Acts -- all written or premiered in Pittsburgh. The show includes the world premiere of Savesies, by Phillip Beard, the hilarious story of two South Side neighbors arguing (in genuine Pittsburghese) over the last parking space on their street, as they prepare for a Fourth of July cookout.02/06/2014 - 02/15/201402/06 - 8:00 pm02/07 - 8:00 pm02/08 - 8:00 pm02/13 - 8:00 pm02/14 - 8:00 pm02/15 - 8:00 pmLocation: Boyd Community Center, 1220 Powers Run Rd, Pittsburgh, PAwebsite
The Planets with NASA FilmManfred Honeck leads a celebration of Pittsburgh composers. Five composers contributed movements to a world premiere suite inspired by the classical "elements" earth, water, air, fire, and metal. NASA video footage accompanies The Planets. From bellicose Mars to mystical Neptune, Holst's iconic musical portrayal of the planets and their astrological significance delights audiences with its richly-colored orchestration and memorable melodies.02/07/2014 - 02/09/201402/07 - 8:00 pm02/08 - 8:00 pm02/09 - 2:30 pmHeinz Hall, 600 Penn Ave., Pittsburgh, PAwebsite | map
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Britney Spears once believed in a fairy-tale ending for herself and Jason Trawick. But by mid-December, she was no longer wearing her engagement ring, and she knew it just wasn't going to happen, a source close to her family tells PEOPLE.
"Britney spent Christmas in L.A. with [sons] Preston and Jayden. Jason was around for parts of the holiday, but it was very obvious that they were not really together anymore," the source says.
"They were not affectionate and instead just seemed to keep things going for the boys' sake. Britney looked a bit gloomy and tense over the holidays."
Trawick, 41, moved out after the holidays, and the couple officially announced their split last Friday.
Having dated her former agent since 2009, and been engaged for a year, Spears, 31, had been talking a lot about her wedding last summer. "But lately she acted like she knew it would not happen," the source says. "She hasn't talked about her wedding plans in a couple of months."
That was quite a change from the early months of her engagement, when Spears was very focused on wedding planning. "She would spend hours online looking at dresses and dreaming," says the source.
Another source says the pair's problems were significant enough that they had never set a wedding date.
"Britney wanted to rush in, but there were things that needed to improve before they got to that place," this source says.
"They love each other, but like any relationship, and especially this one, there were some major challenges and hurdles and constant work that needed to be done. At the end of the day, it just wasn't working, and things were't going to change, so it was time to let go."
Reporting by PERNILLA CEDENHEIM and JENNIFER GARCIA
Britney Spears Dreamed of a Wedding, But the Ring Was Off Before the Holidays
Kevin Mazur/Wireimage


text:
Noun 1. A person who seems addicted to behaving like an asshole. 2. An alcoholic who exhibits extreme asshole behavior.
3. Someone addicted to asses.
3. Someone addicted to asses.
"John, even at my mother's funeral, you still acted like a jerk. I swear you are an assaholic. I want a divorce!"
viết bởi funkstank 29 Tháng sáu, 2009
Trending Now
Can you define these popular missing words?
Top Definition
Describes an individual that is addicted to being or becoming an Asshole.
Don't mind him, he is just an assaholic.
viết bởi FionaX 23 Tháng mười, 2006
A term used to describe anyone who has an insatiable need for the ass. one who likes to lick,fondle,caress,stroke,eat,bite,sniff,or wipe other peoples asses and cannot stop, usually this leads to crack addiction
"Teresa is a major assaholic"
viết bởi Grey (Clitmaster) 21 Tháng chín, 2004
a person who loves ass
i love ass! i think im an assaholic
viết bởi joey 29 Tháng tư, 2003
When someone has had too much to drink and they act like a total asshole.
You drank way too much last night, fell over the table, broke several glasses and were a complete assaholic!
viết bởi Chadds Ford Group 16 Tháng tư, 2009
In addition to the other definitions, it's a characterization of an obnoxious remark or action; i.e., something an asshole would say. Basically, it's the adjective form of "asshole".
Guy: "Yeah, I'd fuck her if she wasn't so ugly."
Girl: "Wow, that was a pretty assaholic remark."
Girl: "Wow, that was a pretty assaholic remark."
viết bởi hnath 19 Tháng một, 2006
When a man loves ass so much that he becomes very irritable until he gets his first slice of the day.
That darn Bobby is so mean in the morning until he gets laid, he must be an assaholic.
viết bởi lou-man 03 Tháng mười, 2003


text:
Dolce Salon & Spa
Boasting three locations with a combined 132 styling stations and 64 spa rooms, Dolce Salon & Spa caters to most every need. The salon offers full hair and nail care, facials, massages, body treatments, waxing, makeup applications, facial peels, bridal services and spa parties. But it's the charm and amazing creature comforts that keep clients coming back. Every spa is done in chic feminine decor, with chandeliers in the treatment rooms, lemonade and coffee served at arrival, and, of course, friendly service.
Touch of Tranquility Massage, Gilbert
Camelback Inn, Scottsdale
Elements Therapeutic Massage, Valley-wide
Massage Envy, Valley-wide
Aji Spa & Salon at Sheraton Wild Horse Pass, Chandler
Mood Swings Salon, Tempe
Southwest Institute of Healing Arts, Tempe
Fuchsia Spa, Mesa
A customer gets a facial at Dolce Salon & Spa.


text:
SALEM - Individual talent, no matter how superb, does not automatically make a successful basketball team. In order to achieve anything meaningful, a team not only needs it's stars to blend their games with the rest of the group, it also needs players outside the spotlight to happily accept their given roles.
Fortunately for the Salem Quakers, that is precisely what has happened this season. The result has been a 19-6 record and a shot at their first district title against Cardinal Mooney on Saturday night.
The Quakers boast 10 seniors on their roster, an unusual number for a basketball team, which only has five starting spots to go around.
"The guys who don't play a lot have kept a great attitude," Salem coach Rich Hart said. "They could have left once they realized they would not start, but everybody on our bench brings intensity each day to practice. They genuinely care about the team and they bust their tails trying to make everyone better."
"This year has really been nice," senior forward Zak Wukotich. "We've stayed together for four years, and it's been nice to win together."
The senior class entered this year with the Quakers coming off of three straight losing seasons. But Hart could tell that something special was brewing during the end of 2012, when the Quakers nearly upset Poland in the sectional final.
"Even though we went 9-12 last year, we had 10 or 11 games that could have gone our way," Hart said. "With the way we fought Poland in the tournament I thought we could be pretty good this year."
Hart proved to be correct, as the team has more than doubled its win total. Anyone who follows the Quakers knows all about guard Ryan Bush and forwards Anthony Shivers and Max Wolfgang. Together the trio accounts for the vast majority of Salem's scoring and rebounding. However, the Quakers would not be on the verge of a district championship without the contributions of Wukotich and senior point guard Brendan Webb, both of whom embody the selflessness on the team's roster.
Webb does not put up gaudy scoring numbers, but his ball-handling and passing skills are invaluable to the Salem offense.
"Everybody on this team knows their role," Webb said. "Ryan (Bush), and Tony (Shivers) handle the scoring, Max (Wolfgang) handles the rebounding, and my job is to facilitate. That's what I try to stick to."
Wukotich does not start but is a versatile defender of the bench, capable of guarding both post men and wings, a skill that should prove useful against Cardinal Mooney's athletic lineup.
"I'm always ready to come off the bench and supply defense," Wukotich said. "Whenever Tony (Shivers) or Max (Wolfgang) get into foul trouble I'm ready to come into the game and play hard."
"Role players are vital to any team," Hart said. "We are lucky to have so many guys that embrace their jobs without complaining."
For the Quakers to accomplish their goal of the district title its going to take one more game of the same effort.
"We've been looking forward to this all year, so we'll be ready to get after it." Webb said "What's great about this team is the chemistry we have with each other We've played together forever and everyone is happy to see each other do well."


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#80 - Flarius
Reply 0(11/09/2012) [-]
All I can say is, a confident girl would show off her naked body because she isn't scared of showing it to the world. "OMG OMG A NAKED GIRL, SLUUUUUUUUUUUUUUUUT." The fact we wear clothes is mostly to keep us warmm, and because we'd get fined up the ass for not wearing clothes in public. Pretty sure, way way back with the first humans, they were naked all the time.
#85 to #80 - jakefenris
Reply +3(11/09/2012) [-]
I would agree with you, though there is a big difference between dressing confidently and dressing like a whore. To my knowledge most human culture groups wore clothing to cover up the genitals, but it is really only in North America that a woman's breasts are seen as sexual and covered up.
#118 to #85 - DisgruntledTomato
Reply 0(11/09/2012) [-]
Yes because you see that in Asia countries, Oceania, Europe, South America, Most of Africa.
#119 to #118 - jakefenris
Reply 0(11/09/2012) [-]
Historically yes you do, Aboriginal cultures in most areas of the world did not cover their upper bodies.
#120 to #119 - DisgruntledTomato
Reply 0(11/09/2012) [-]
Historically perhaps, but you were referring to North America in the present.
#123 to #120 - jakefenris
Reply +1(11/09/2012) [-]
"I would agree with you, though there is a big difference between dressing confidently and dressing like a whore. To my knowledge most human culture groups have historically worn clothing to cover up the genitals, on average current era America sees a topless woman as a bigger deal than most countries, even going so far as to shun women who breast feed in public." edited.
#122 to #120 - jakefenris
Reply 0(11/09/2012) [-]
You are correct, I should have reviewed my comment and fixed it for present-tense.
#100 to #85 - XSpitfireX
Reply +2(11/09/2012) [-]
Implying that in Europe women walk round with tits on show
#101 to #100 - jakefenris
Reply -3(11/09/2012) [-]
To my knowledge it's more common and acceptable.
#109 to #101 - archosaurusrev
Reply +1(11/09/2012) [-]
You're narrow minded as hell, you know that?
Do you even know anything about any European countries apart from Germany, Italy and Greece?
If a woman walked around with her breasts showing here in Finland, she would be fined off her ass.
Do you even know anything about any European countries apart from Germany, Italy and Greece?
If a woman walked around with her breasts showing here in Finland, she would be fined off her ass.
#112 to #109 - jakefenris
Reply 0(11/09/2012) [-]
How am I narrow minded for thinking it should be acceptable and lawful for a woman to have the right to walk around topless without hate?
#113 to #112 - archosaurusrev
Reply -1(11/09/2012) [-]
No, you didn't say that, you said "To my knowledge it's more common and acceptable.", referring to Europe as a whole.
#116 to #113 - jakefenris
Reply 0(11/09/2012) [-]
And how is saying that narrow minded? "To my knowledge" means I could be wrong and am looking for conformation.
#117 to #116 - archosaurusrev
Reply -1(11/09/2012) [-]
You expressed your false knowledge without researching the subject, and acted based on assumptions.
#121 to #117 - jakefenris
Reply 0(11/09/2012) [-]
I expressed the information I had available and don't consider it big enough a deal to bother looking up. I was going to post a list of countries and their nude beach numbers but I didn't think people cared. I did indeed make assumptions based mostly on second hand knowledge. Clearly you missed where I stated it was my understanding, and that I could be wrong. I am more than happy to be corrected, but you can do so without attacking me.
#104 to #101 - XSpitfireX
Reply +2(11/09/2012) [-]
Nope, I've never seen it, at least not in the UK
#105 to #104 - jakefenris
Reply -1(11/09/2012) [-]
From my understanding it's more common in the Mediterranean region, in Spain and France, though I could be wrong.
#106 to #105 - XSpitfireX
Reply 0(11/09/2012) [-]
Yeah I would have thought so too
#88 to #85 - Flarius
Reply 0(11/09/2012) [-]
There is only a difference though because our society makes it that way. Like a short skirt is skanky because it shows off a lot of the girls legs, yet a longer knee high skirt is much more acceptable, but I agree. I'm thinking though if we were hairy like monkeys way way back when we first became a species, no loin cloth would be needed. I'm glad women cover up, otherwise us men, as a sex, would be ****** from us getting hit my cars and what not from looking at naked girls.
#95 to #88 - jakefenris
Reply +2(11/09/2012) [-]
A short skirt isn't whorish unless it isn't covering a person's underwear. If someone is wearing pants that might as well be a thong, that's whorish. You should read up on some of the stories about first times at nude beaches, when it becomes the norm nudity isn't a big deal or a distraction.


text:
Ben Flajnik has seen the pictures of his ex-fiancée with another Bachelor franchise alum and has to wonder: Who is that woman?
"I'm glad there is a new guy," he says, referring to Courtney Robertson's new relationship with Bachelorette hunk Arie Luyendyk. "I see certain things in the media and I wonder, did I ever really know her? I try to avoid it all together."
He continues, "I look at these staged photos of the two of them and I'm like: Why is she doing this? The girl that I loved never wanted to be famous and I look at these set-ups and I think I got out at the right time."
Flajnik admits his split with the controversial Robertson was tough, but throwing himself into his winery, Envolve Winery, helped take his mind off the failed relationship.
"It was really the perfect time for the breakup because harvest is the busiest time of the year for me and it was a distraction," he said Tuesday night at wine pairing party at Las Vegas's Bratalian with Carla Pellegrino, a contestant on the upcoming Top Chef Season 10.
Though he has no interest is being a Bachelor again, Flajnik says he hasn't given up on love.
"I do miss the constant interaction and companionship," he said. "I'm open to dating for sure."
Ben Flajnik Bristles at Ex Courtney Robertson with Arie Luyendyk


text:
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Wall Street Decline Takes Its Toll...
As Immunotherapy Revolutionizes the Cancer Treatment...
LC-MS Gains Favor Due To the...
Expanding Use of NGS Has Largely...
The world's population is getting older and is requiring more effective, often biological-based treatments for endemic diseases such as diabetes and rheumatoid arthritis. "In emerging markets, governments are looking to vaccinate or treat diseases in larger numbers of their population. Many of the big pharmas don't have blockbusters in their pipeline anymore; now it's all about producing smaller quantities of a greater variety of targeted vaccines, biologicals, and biosimilars," explained Scott Ripley, marketing leader EMEA, GE Healthcare Life Sciences.
These trends will drive the demand for greater access to biologicals and vaccines, which will put the emphasis on being flexible and cost-effective to ensure biomanufacturing facilities are working at full capacity.
To drive down manufacturing costs, pharmas need to operate flexible facilities to maximize facility utilization while minimizing the risks associated with multiproduct manufacturing at various stages of clinical development and licensed production.
"In today's market, facility utilization is key. If you're not sweating your asset and only making one or two batches of a biological per year, then the cost of goods of that product is going to be very high," Ripley said. "For many CMOs, for example, every day they don't use their bioprocessing facilities costs them up to $2 million per day in lost revenues."
Using traditional stainless steel bioreactors and fixed chromatography and filter systems, it can take anywhere from two to seven years to design and build a plant for specific large-scale production of a monoclonal or vaccine. This is a major gamble because if the product fails at Phase III, manufacturers can be left with a plant they find difficult to reconfigure.
One solution to this capacity and flexibility conundrum is to implement single-use biomanufacturing technology that can be swapped around to adapt to different production campaigns. Single-use bioreactors, for example, are established technology that can increase operational efficiency by reducing change over time. With single-use bioreactors there is no need for cleaning in place and cleaning validation steps, or steam sterilization and cool-down time before a bioreactor can be used.
"Cleaning and sterilizing are not value-added steps in biomanufacturing, so it's desirable that they are kept to a minimum or removed to improve efficiency," explained Neil Ross, marketing manager—bioprocess EMEA, GE Healthcare Life Sciences. "The proof is in the application, and there are many examples of biologicals in clinical-stage manufacture being produced quicker than if a traditional stainless steel route was implemented."
Single-use technology has developed rapidly in the past five years, and it is now possible to implement an end-to-end process from cell to biological using an entirely disposable set-up.
GE Healthcare's ReadytoProcess™ platform now offers around 250 different types of configurations that scientists could put together for their manufacturing.
"ReadyToProcess is a bit like Lego—you take what you need to get your process up and running and put it all together," said Jonathan Royce, bioprocess marketing program manager.
"Our complete ReadyToProcess factory in a box is made possible by the use of ReadyMate™ disposable aseptic connectors," Ross added. "These don't come as either male or female connectors, which is unique, and they come in a range of sizes for scalable operation. They can be operated at pressures up to 5 bar and the pressure drop can be as low as 0.2 bar at flow rates as high as 6,000 L/hr."
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text: The entire city seems to be for rent in summer. Apartments come in all shapes from four walls and a bed for 200uah to fully furnished multi-bedroom cottages that may cost up to $500 a night. Prices drop drastically in the low season – you can get a nice apartment in the town centre for as little as 60uah in winter. The biggest concentration of holiday houses and apartment dealers carrying signs like Жилье, Квартиры or Сдается can be found at the beginning of vul Drazhinskogo above Massandra Beach.


text:
Sources: The Washington Post, ABC News, The New York Times
quote: When he took office the economy was in a nosedive and nothing could have stopped it. Did he make it worse? Yes, but he inherited a sinking ship.
quote: You just don't want to see the true evil that took place. That our President purposefully and intentionally manipulated the events taking place to gain political power and ram through an agenda. Fixing the economy, like any normal President would have attempted, was NOT his primary concern.
quote: You cant blame Obama for this mess
quote: At best you can say he made it worse
quote: What depression? Its already on its way back up.
quote: In the depression we had 25% unemployment and masses of people standing in line for a free bowl of govt. soup.
quote: I DONT think he is doing a good job, its just not his fault.
quote: You are no better than Michael Moore or Nancy Pelosi
quote: Calm down man, its not as bad as all that.
quote: People like you are the problem in this country
quote: Seriously... Consider this - In Jan 2009 when Obama took office the economy was in a freefall and America was looking like a joke to the international community...
quote: Do you seriously think the economy works that fast that Obama affected it???
quote: There is no flip flopping. I think what Obama did will make matters worse, but he didnt cause it
quote: Freegin economics 101


text:
Event Calendar
Throughout the year, Ojai hosts a steady stream of cultural events, culinary delights, concerts, and festivals. Check out what's happening in Ojai California, as well as at Ojai Valley Inn & Spa.
Camp Ojai | Superhero Saturday
When: 05/04/2013, 05/11/2013, 05/18/2013, 05/25/2013
Saturday | Superheroes
Calling all superheroes; we need your specialized powers to stop the Ojai Super Villain! You will be assigned your special super powers for the day, make super accessories, and create our own super slime.


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In the state of Wisconsin, wrongful death claims can result in a variety of damages. Some of them include:
- Loss of support
- Loss of services
- Lost prospect of inheritance
- Medical expenses
- Funeral expenses
- For monetary damages, $350,000 may be awarded for the loss of society and companionship to the spouse, children, parents or minor siblings of a deceased adult. In the case of a loss of a child, $500,000 may be awarded.
Source: https://docs.legis.wisconsin.gov/statutes/statutes/895/I/04
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How Do Volumizing Shampoos Work?
Volumizing shampoos often work by targeting the roots of the hair. These formulas are very beneficial for women with fine hair that tends to lie flat against the scalp. To lift the roots, the formulas usually stiffen and reinforce the base of the hair strands, and their effects can be amplified by drying your hair with your head turned upside down or lifting the hair away from the scalp with a round brush when you blow dry.
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To find the best volumizing shampoo for your needs, take into consideration your specific concerns and the possible reasons for your lack of body or thickness. Then, browse the volumizing shampoo collection here at drugstore.com, where you're sure to find a great solution for your limp or thin tresses.
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text:
on November 12, 2012 - 10:27 AM
Two adults and two children fled an early-morning fire today on Old Lakeshore Road on the Cattaraugus Indian Reservation, Erie County sheriff's officials reported.
The resident, Franklin C. White III, told fire officials that he, his girlfriend and two young children fled the blaze that engulfed his residence at 11387 Old Lakeshore Road at about 2:30 a.m.
White also told authorities that he had had a fire going near the house and thought he had put it out before he went inside. But the fire apparently rekindled, leaving the residence fully engulfed when firefighters responded to the home.


text:
Entertainment Photos
Photos: Cinco de Mayo Celebration with Ballet Folklorico Ollimpaxqui in McKinney
Photo: Andy Jacobsohn/Staff Photographer
Performer Luis Enrique Chavez Ruiz changes costumes between performances during a presentation by Ballet Folklorico Ollimpaxqui to celebrate Cinco de Mayo at Press Elementary in McKinney, Texas on May 1, 2014. Ollimpaxqui, performed by native Mexicans, means "joyful movement."
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Premium Sticky Yoga Mat (5mm)
Our Premium Sticky Yoga Mat provides the same non-stick surface as our normal mats but with an extra thick cushion for comfort and stability. Perfect for any yoga practice.
- Non-slip surface
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- Made exclusively by Gaiam
- 6P and latex free
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Measurements: 68"L x 24"W x 5mm.
Materials: PVC. Latex Free. 6P Free: Free of DEHP, DBP, BBP, DINP, DIDP, and DNOP phthalates.
Care Instructions: Yoga mats release a very strong but harmless odor when first opened. Please unroll and air out your mat 2-3 days before use. Spot clean with our Yoga Mat Wash or damp cloth with cold water and mild detergent. Dry flat. The mat may fade and become brittle and unusable if exposed to the sun for extended periods of time. We recommend storing your mat in a mat bag when not in use. Learn more about How to Remove That New Yoga Mat Smell.


text:
Gunshot victim identified; no other details released
July 22, 2013
LISBON — A man found shot to death at a Steubenville Pike home Friday morning has been identified by the county sheriff's department, but no additional details about the incident are being released......
ooops, another repeat offender back on the streets now dead and the obvious drug connection. Oh will it ever ever end!
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Monday, January 14, 2013
Students in Pren Woods history classes at Alston Middle School recently performed puppet shows to review the topics they studied during second quarter. Student groups were assigned random topics and created their projects around them. This group did a puppet show on the reasons Rome fell and the importance of the Byzantine Empire. Shown from left are Ryleigh Altman, Kaylee Watson, Jordan Campeau, Matthew Franchi, and Dylan Kubat.
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