Venous Thromboembolism Prophylaxis in Hospitalized Patients: A Clinical Practice Guideline From the American College of PhysiciansFREE
Publication: Annals of Internal Medicine
Volume 155, Number 9
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Abstract
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.
Methods
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).
Benefits and Harms of Heparin Prophylaxis Versus No Heparin Prophylaxis
Medical Patients
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]; I 2 = 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]; I 2 = 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]; I 2 = 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).
Acute Stroke
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]; I 2 = 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]; I 2 = 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]; I 2 = 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]).
All Patients Combined
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]; I 2 = 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]; I 2 = 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]; I 2 = 0%; absolute increase, 4 events per 1000 persons treated [CI, 1 to 7 events]).
Comparative Effectiveness of LMWH Versus UFH
Medical Patients
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]; I 2 = 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]; I 2 = 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]; I 2 = 0%; absolute reduction, 3 events per 1000 persons treated [CI, −7 to 3 events]) (low-quality evidence).
Acute Stroke
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]; I 2 = 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]; I 2 = 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]; I 2 = 0%; absolute reduction, 4 events per 1000 persons treated [CI, −2 to 19 events]) (low-quality evidence).
All Patients Combined
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]; I 2 = 16%) or major bleeding events (RR, 0.95 [CI, 0.75 to 1.20]; I 2 = 0%), although a nonsignificant difference favored LMWH for PE (OR, 0.67 [CI, 0.45 to 1.00]; P = 0.053; I 2 = 0%).
Comparative Effectiveness of Mechanical Devices Versus No Mechanical Devices
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).
Additional Evidence
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).
Summary
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.
Recommendations
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).
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.
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).
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.
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).
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.
Figure. Summary of the American College of Physicians' guideline on venous thromboembolism prophylaxis in hospitalized patients.
ACP = American College of Physicians; DVT = deep venous thrombosis; PE = pulmonary embolism; VTE = venous thromboembolism.
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.
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.
References
1.
Geerts WH, Pineo GF, Heit JA, Bergqvist D, Lassen MR, Colwell CW, et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126:338S-400S. [PMID: 15383478]
2.
Qaseem A, Snow V, Barry P, Hornbake ER, Rodnick JE, Tobolic T, et al; Joint American Academy of Family Physicians. American College of Physicians Panel on Deep Venous Thrombosis. Pulmonary Embolism. Current diagnosis of venous thromboembolism in primary care: a clinical practice guideline from the American Academy of Family Physicians and the American College of Physicians. Ann Intern Med. 2007;146:454-8. [PMID: 17371890]
3.
Lindblad B, Sternby NH, Bergqvist D. Incidence of venous thromboembolism verified by necropsy over 30 years. BMJ. 1991;302:709-11. [PMID: 2021744]
4.
Sandler DA, Martin JF. Autopsy proven pulmonary embolism in hospital patients: are we detecting enough deep vein thrombosis? J R Soc Med. 1989;82:203-5. [PMID: 2716016]
5.
Alikhan R, Peters F, Wilmott R, Cohen AT. Fatal pulmonary embolism in hospitalised patients: a necropsy review. J Clin Pathol. 2004;57:1254-7. [PMID: 15563663]
6.
Anderson FA Jr, Wheeler HB, Goldberg RJ, Hosmer DW, Patwardhan , Jovanovic B, et al. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study. Arch Intern Med. 1991;151:933-8. [PMID: 2025141]
7.
Silverstein MD, Heit JA, Mohr DN, Petterson TM, O'Fallon WM, Melton LJ 3rd. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med. 1998;158:585-93. [PMID: 9521222]
8.
Lederle FA, Zylla D, MacDonald R, Wilt T. Venous thromboembolism prophylaxis in hospitalized medical patients and those with stroke: background review for an American College of Physicians clinical practice guideline. Ann Intern Med. 2011;155:602-615.
9.
Qaseem A, Snow V, Owens DK, Shekelle P; Clinical Guidelines Committee of the American College of Physicians. The development of clinical practice guidelines and guidance statements of the American College of Physicians: summary of methods. Ann Intern Med. 2010;153:194-9. [PMID: 20679562]
10.
Weber C, Merminod T, Herrmann FR, Zulian GB. Prophylactic anti-coagulation in cancer palliative care: a prospective randomised study. Support Care Cancer. 2008;16:847-52. [PMID: 17940809]
11.
Belch JJ, Lowe GD, Ward AG, Forbes CD, Prentice CR. Prevention of deep vein thrombosis in medical patients by low-dose heparin. Scott Med J. 1981;26:115-7. [PMID: 7291971]
12.
Cohen AT, Davidson BL, Gallus AS, Lassen MR, Prins MH, Tomkowski W, et al; ARTEMIS Investigators. Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial. BMJ. 2006;332:325-9. [PMID: 16439370]
13.
Dahan R, Houlbert D, Caulin C, Cuzin E, Viltart C, Woler M, et al. Prevention of deep vein thrombosis in elderly medical in-patients by a low molecular weight heparin: a randomized double-blind trial. Haemostasis. 1986;16:159-64. [PMID: 3710294]
14.
Fraisse F, Holzapfel L, Couland JM, Simonneau G, Bedock B, Feissel M, et al. Nadroparin in the prevention of deep vein thrombosis in acute decompensated COPD. The Association of Non-University Affiliated Intensive Care Specialist Physicians of France. Am J Respir Crit Care Med. 2000;161:1109-14. [PMID: 10764298]
15.
Gärdlund B. Randomised, controlled trial of low-dose heparin for prevention of fatal pulmonary embolism in patients with infectious diseases. The Heparin Prophylaxis Study Group. Lancet. 1996;347:1357-61. [PMID: 8637340]
16.
Lederle FA, Sacks JM, Fiore L, Landefeld CS, Steinberg N, Peters RW, et al. The prophylaxis of medical patients for thromboembolism pilot study. Am J Med. 2006;119:54-9. [PMID: 16431185]
17.
Leizorovicz A, Cohen AT, Turpie AG, Olsson CG, Vaitkus PT, Goldhaber SZ; PREVENT Medical Thromboprophylaxis Study Group. Randomized, placebo-controlled trial of dalteparin for the prevention of venous thromboembolism in acutely ill medical patients. Circulation. 2004;110:874-9. [PMID: 15289368]
18.
Mahé I, Bergmann JF, d'Azémar P, Vaissie JJ, Caulin C. Lack of effect of a low-molecular-weight heparin (nadroparin) on mortality in bedridden medical in-patients: a prospective randomised double-blind study. Eur J Clin Pharmacol. 2005;61:347-51. [PMID: 15981008]
19.
Samama MM, Cohen AT, Darmon JY, Desjardins L, Eldor A, Janbon C, et al. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. Prophylaxis in Medical Patients with Enoxaparin Study Group. N Engl J Med. 1999;341:793-800. [PMID: 10477777]
20.
Dickmann U, Voth E, Schicha H, Henze T, Prange H, Emrich D. Heparin therapy, deep-vein thrombosis and pulmonary embolism after intracerebral hemorrhage. Klin Wochenschr. 1988;66:1182-3. [PMID: 3062268]
21.
The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. International Stroke Trial Collaborative Group. Lancet. 1997;349:1569-81. [PMID: 9174558]
22.
Kay R, Wong KS, Yu YL, Chan YW, Tsoi TH, Ahuja AT, et al. Low-molecular-weight heparin for the treatment of acute ischemic stroke. N Engl J Med. 1995;333:1588-93. [PMID: 7477193]
23.
McCarthy ST, Turner J. Low-dose subcutaneous heparin in the prevention of deep-vein thrombosis and pulmonary emboli following acute stroke. Age Ageing. 1986;15:84-8. [PMID: 3962762]
24.
McCarthy ST, Turner JJ, Robertson D, Hawkey CJ, Macey DJ. Low-dose heparin as a prophylaxis against deep-vein thrombosis after acute stroke. Lancet. 1977;2:800-1. [PMID: 71605]
25.
Prins MH, Gelsema R, Sing AK, van Heerde LR, den Ottolander GJ. Prophylaxis of deep venous thrombosis with a low-molecular-weight heparin (Kabi 2165/Fragmin) in stroke patients. Haemostasis. 1989;19:245-50. [PMID: 2550335]
26.
Sandset PM, Dahl T, Stiris M, Rostad B, Scheel B, Abildgaard U. A double-blind and randomized placebo-controlled trial of low molecular weight heparin once daily to prevent deep-vein thrombosis in acute ischemic stroke. Semin Thromb Hemost. 1990;16 Suppl 25-33. [PMID: 1962901]
27.
Turpie AG, Levine MN, Hirsh J, Carter CJ, Jay RM, Powers PJ, et al. Double-blind randomised trial of Org 10172 low-molecular-weight heparinoid in prevention of deep-vein thrombosis in thrombotic stroke. Lancet. 1987;1:523-6. [PMID: 2434815]
28.
Aquino JP, Gambier A, Ducros JJ. Prophylaxis of thromboembolic disorders in elderly patients with fraxiparine. In: Bounameaux H, Samama M, ten Cate JW, eds. Fraxiparine: Second International Symposium Recent Pharmacological and Clinical Data. Hoboken, NJ: J Wiley; 1991.
29.
Bergmann JF, Neuhart E. A multicenter randomized double-blind study of enoxaparin compared with unfractionated heparin in the prevention of venous thromboembolic disease in elderly in-patients bedridden for an acute medical illness. The Enoxaparin in Medicine Study Group. Thromb Haemost. 1996;76:529-34. [PMID: 8902991]
30.
Harenberg J, Kallenbach B, Martin U, Dempfle CE, Zimmermann R, Kübler W, et al. Randomized controlled study of heparin and low molecular weight heparin for prevention of deep-vein thrombosis in medical patients. Thromb Res. 1990;59:639-50. [PMID: 2173168]
31.
Harenberg J, Roebruck P, Heene DL. Subcutaneous low-molecular-weight heparin versus standard heparin and the prevention of thromboembolism in medical inpatients. The Heparin Study in Internal Medicine Group. Haemostasis. 1996;26:127-39. [PMID: 8738587]
32.
Kleber FX, Witt C, Vogel G, Koppenhagen K, Schomaker U, Flosbach CW; THE-PRINCE Study Group. Randomized comparison of enoxaparin with unfractionated heparin for the prevention of venous thromboembolism in medical patients with heart failure or severe respiratory disease. Am Heart J. 2003;145:614-21. [PMID: 12679756]
33.
Lechler E, Schramm W, Flosbach CW. The venous thrombotic risk in non-surgical patients: epidemiological data and efficacy/safety profile of a low-molecular-weight heparin (enoxaparin). The Prime Study Group. Haemostasis. 1996;26 Suppl 2 49-56. [PMID: 8707167]
34.
Cook D, Meade M, Guyatt G, Walter S, Heels-Ansdell D, Warkentin TE, et al; PROTECT Investigators for the Canadian Critical Care Trials Group and the Australian and New Zealand Intensive Care Society Clinical Trials Group. Dalteparin versus unfractionated heparin in critically ill patients. N Engl J Med. 2011;364:1305-14. [PMID: 21417952]
35.
Riess H, Haas S, Tebbe U, Gerlach HE, Abletshauser C, Sieder C, et al. A randomized, double-blind study of certoparin vs. unfractionated heparin to prevent venous thromboembolic events in acutely ill, non-surgical patients: CERTIFY Study. J Thromb Haemost. 2010;8:1209-15. [PMID: 20218984]
36.
Schellong SM, Haas S, Greinacher A, Schwanebeck U, Sieder C, Abletshauser C, et al. An open-label comparison of the efficacy and safety of certoparin versus unfractionated heparin for the prevention of thromboembolic complications in acutely ill medical patients: CERTAIN. Expert Opin Pharmacother. 2010;11:2953-61. [PMID: 20950224]
37.
Diener HC, Ringelstein EB, von Kummer R, Landgraf H, Koppenhagen K, Harenberg J, et al; PROTECT Trial Group. Prophylaxis of thrombotic and embolic events in acute ischemic stroke with the low-molecular-weight heparin certoparin: results of the PROTECT Trial. Stroke. 2006;37:139-44. [PMID: 16306456]
38.
Dumas R, Woitinas F, Kutnowski M, Nikolic I, Berberich R, Abedinpour F, et al. A multicentre, double-blind, randomized study to compare the safety and efficacy of once-daily ORG 10172 and twice-daily low-dose heparin in preventing deep-vein thrombosis in patients with acute ischaemic stroke. Age Ageing. 1994;23:512-6. [PMID: 9231947]
39.
Hillbom M, Erilä T, Sotaniemi K, Tatlisumak T, Sarna S, Kaste M. Enoxaparin vs heparin for prevention of deep-vein thrombosis in acute ischaemic stroke: a randomized, double-blind study. Acta Neurol Scand. 2002;106:84-92. [PMID: 12100367]
40.
Sherman DG, Albers GW, Bladin C, Fieschi C, Gabbai AA, Kase CS, et al; PREVAIL Investigators. The efficacy and safety of enoxaparin versus unfractionated heparin for the prevention of venous thromboembolism after acute ischaemic stroke (PREVAIL Study): an open-label randomised comparison. Lancet. 2007;369:1347-55. [PMID: 17448820]
41.
Turpie AG, Gent M, Côte R, Levine MN, Ginsberg JS, Powers PJ, et al. A low-molecular-weight heparinoid compared with unfractionated heparin in the prevention of deep vein thrombosis in patients with acute ischemic stroke. A randomized, double-blind study. Ann Intern Med. 1992;117:353-7. [PMID: 1503326]
42.
Dennis M, Sandercock PA, Reid J, Graham C, Murray G, Venables G, et al; CLOTS Trials Collaboration. Effectiveness of thigh-length graduated compression stockings to reduce the risk of deep vein thrombosis after stroke (CLOTS trial 1): a multicentre, randomised controlled trial. Lancet. 2009;373:1958-65. [PMID: 19477503]
43.
Muir KW, Watt A, Baxter G, Grosset DG, Lees KR. Randomized trial of graded compression stockings for prevention of deep-vein thrombosis after acute stroke. QJM. 2000;93:359-64. [PMID: 10873185]
44.
Prasad BK, Banerjee AK, Howard H. Incidence of deep vein thrombosis and the effect of pneumatic compression of the calf in elderly hemiplegics. Age Ageing. 1982;11:42-4. [PMID: 7072559]
45.
Luba M, Firek A, Kochanowski Z. [Two models of thromboprophylaxis in acutely ill medical inpatients]. Pol Arch Med Wewn. 2007;117:31-7. [PMID: 17722473]
46.
Green D, Akuthota V, Eiken M, Feinglass J, Fuller S, Hwang C, et al. Prevention of thromboembolism in stroke rehabilitation patients. Top Stroke Rehabil. 1998;5:68-74.
47.
Lacut K, Bressollette L, Le Gal G, Etienne E, De Tinteniac A, Renault A, et al; VICTORIAh (Venous Intermittent Compression and Thrombosis Occurrence Related to Intra-cerebral Acute hemorrhage) Investigators. Prevention of venous thrombosis in patients with acute intracerebral hemorrhage. Neurology. 2005;65:865-9. [PMID: 16186525]
48.
CLOTS (Clots in Legs Or sTockings after Stroke) Trial Collaboration. Thigh-length versus below-knee stockings for deep venous thrombosis prophylaxis after stroke: a randomized trial. Ann Intern Med. 2010;153:553-62. [PMID: 20855784]
49.
Hull RD, Schellong SM, Tapson VF, Monreal M, Samama MM, Nicol P, et al. EXCLAIM (Extended Prophylaxis for Venous ThromboEmbolism in Acutely Ill Medical Patients With Prolonged Immobilization) study. Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility: a randomized trial. Ann Intern Med. 2010;153:8-18. [PMID: 20621900]
50.
Kucher N, Leizorovicz A, Vaitkus PT, Cohen AT, Turpie AG, Olsson CG, et al. Efficacy and safety of fixed low-dose dalteparin in preventing venous thromboembolism among obese or elderly hospitalized patients: a subgroup analysis of the PREVENT trial. Arch Intern Med. 2005;165:341-5. [PMID: 15710801]
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Published In
Annals of Internal Medicine
Volume 155 • Number 9 • 1 November 2011
Pages: 625 - 632
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Published online: 1 November 2011
Published in issue: 1 November 2011
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© 2011 American College of Physicians.
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Venous Thromboembolism Prophylaxis in Hospitalized Patients: A Clinical Practice Guideline From the American College of Physicians. Ann Intern Med.2011;155:625-632. [Epub 1 November 2011]. doi:10.7326/0003-4819-155-9-201111010-00011
Venous Thromboembolism Prophylaxis in Hospitalized Patients: A Clinical Practice Guideline From the American College of Physicians. Ann Intern Med.2011;155:625-632. [Epub 1 November 2011]. doi:10.7326/0003-4819-155-9-201111010-00011
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Declare anticoagulants as VTE prophylaxis for medical patients ... CONTRAINDICATED
Editor,
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.
References
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.
Conflict of Interest:
None declared
ACP VTE guideline: a comment
Sirs,
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 protected] P. Colm Malone: [email protected]
References
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]
Conflict of Interest:
None declared
Show me the evidence - VTE prophylaxis
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!
Conflict of Interest:
None declared
Subdural Hematomas and Death In Older People With Minor Tauma, On Anticoagulants
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.
Conflict of Interest:
None declared
Author's Response
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
References
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.
Conflict of Interest:
None declared