Definitions for the strength of evidence (high, moderate, low, or insufficient evidence to determine net benefits or risks) and strength of recommendations (strong, weak) are defined at the end of the "Major Recommendations" field.
Recommendation 1: The American College of Physicians (ACP) recommends assessment of the risk for thromboembolism and bleeding in medical (including stroke) patients prior to initiation of prophylaxis of venous thromboembolism (VTE) (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. 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 VTE 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 pulmonary embolisms (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 deep venous thrombosis (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 confidence intervals (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. 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, 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 low-molecular-weight heparin (LMWH) and unfractionated heparin (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). 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 VTE (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 stand-alone intervention in medical patients to reliably estimate benefits and harms.
See the Figure in the original guideline document for a summary of the recommendations and clinical considerations.
ACP does not support the application of performance measures in medical (including stroke) patients that promotes universal VTE 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 trade-off 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 physicians 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.
|The American College of Physicians' Guideline Grading System*
|Quality of Evidence
||Strength of Recommendation
||Benefits Clearly Outweigh Risks and Burden or Risks and Burden Clearly Outweigh Benefits
||Benefits Finely Balanced with Risks and Burden
|Insufficient evidence to determine net benefits or risks
*Adopted from the classification developed by the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) workgroup.