Cochrane for Clinicians
Putting Evidence into Practice
Low-Molecular-Weight Heparin for Initial Treatment of Venous Thromboembolism
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Am Fam Physician. 2005 Jul 1;72(01):75-76.
This clinical content conforms to AAFP criteria for evidence-based continuing medical education (EB CME). EB CME is clinical content presented with practice recommendations supported by evidence that has been reviewed systematically by an AAFP-approved source. The practice recommendations in this activity are available online at http://www.cochrane.org/cochrane/revabstr/AB001100.htm.
A 72-year-old woman presents with swelling and pain in her calf that has lasted two days. Evaluation reveals that she has an acute thromboembolism of the deep femoral vein.
Should venous thromboembolism initially be treated with unfractionated heparin or a low-molecular-weight heparin (LMWH)?
LMWH is safer and more effective than unfractionated heparin for initial treatment of venous thromboembolism.
The standard treatment of acute venous thromboembolism has been unfractionated heparin administered intravenously for five to 10 days until adequate anticoagulation can be achieved with oral agents. However, the more predictable anticoagulant effect of LMWHs, a number of which have been approved in the past decade, allows standard doses to be given without laboratory monitoring in appropriate patients. Additionally, by effecting a steady state of adequate anticoagulation more quickly and consistently, LMWH may reduce hemorrhage caused by excessive anticoagulation and increase treatment efficacy.
Van Dongen and associates1 analyzed studies comparing the effects of unfractionated heparin and LMWH in patients with venous thromboembolism and evaluated differences between the treatments in symptomatic recurrence of venous thromboembolism, change in thrombus size, rate of hemorrhage, and overall mortality. Eight different preparations of LMWH or heparinoid were used in the trials (i.e., nadroparin, tinzaparin, enoxaparin, dalteparin, CY 222, certoparin, ardeparin, and reviparin). The results showed LMWH to be superior in efficacy to unfractionated heparin, with fewer thrombotic complications (number needed to treat [NNT] to prevent one complication = 37) and more frequent reduction in thrombus size (NNT = 13). Furthermore, LMWH was found to be safer, being associated with fewer instances of major hemorrhage (NNT = 125) and fewer deaths (NNT = 67).
Of the 22 trials included in the review, six involved patients with malignant disease (a common risk factor for venous thromboembolism). These six trials showed a reduction in mortality with LMWH, whereas no statistically significant reduction in mortality was found in the 16 trials involving patients without cancer.
Thirteen of the 22 trials excluded patients with pulmonary embolus, while two trials included patients with pulmonary embolus exclusively. Five trials included patients with isolated symptomatic distal venous thromboembolism as well as those with proximal venous thromboembolism. Although the reviewers of this article1 felt that no firm recommendation could be made about initial treatment of pulmonary embolism, a recent meta-analysis2 concluded that LMWH “appears to be as effective and safe as dose-adjusted intravenous unfractionated heparin for the initial treatment of nonmassive pulmonary embolism.”
Background. Low-molecular-weight heparins (LMWHs) have been shown to be effective and safe in preventing venous thromboembolism, and also may be effective for the initial treatment of this condition.
Objectives. To determine the effect of LMWH compared with unfractionated heparin for the initial treatment of venous thromboembolism.
Search Strategy. The authors1 identified trials from the Cochrane Peripheral Vascular Diseases Group’s Specialised Register, CENTRAL, and LILACS. They also contacted colleagues and pharmaceutical companies for additional information.
Selection Criteria. The authors selected randomized controlled trials comparing fixed-dose subcutaneous LMWH with adjusted-dose intravenous or subcutaneous unfractionated heparin in persons with venous thromboembolism.
Data Collection and Analysis. At least two reviewers assessed trials for inclusion and quality, and extracted data independently.
Primary Results. Twenty-two studies (n = 8,867) were included in the analysis. Thrombotic complications occurred in 151 of 4,181 (3.6 percent) participants treated with LMWH, compared with 211 of 3,941 (5.4 percent) participants treated with unfractionated heparin (odds ratio [OR], 0.68; 95 percent confidence interval [CI], 0.55 to 0.84; 18 trials). Thrombus size was reduced in 53 percent of participants treated with LMWH and in 45 percent of those treated with unfractionated heparin (OR, 0.69; 95 percent CI, 0.59 to 0.81; 12 trials). Major hemorrhages occurred in 41 of 3,500 (1.2 percent) participants treated with LMWH, compared with 73 of 3,624 (2.0 percent) participants treated with unfractionated heparin (OR, 0.57; 95 percent CI, 0.39 to 0.83; 19 trials). In 18 trials, 187 of 4,193 (4.5 percent) participants treated with LMWH died, compared with 233 of 3,861 (6.0 percent) participants treated with unfractionated heparin (OR, 0.76; 95 percent CI, 0.62 to 0.92).
Nine studies (n = 4,451) examined proximal thrombosis; 2,192 participants were treated with LMWH and 2,259 with unfractionated heparin. Subgroup analysis showed statistically significant reductions favoring LMWH in thrombotic complications and major hemorrhage. By the end of follow-up, 80 (3.6 percent) participants treated with LMWH had thrombotic complications, compared with 143 (6.3 percent) treated with unfractionated heparin (OR, 0.57; 95 percent CI, 0.44 to 0.75). Major hemorrhage occurred in 18 (1.0 percent) participants treated with LMWH, compared with 37 (2.1 percent) treated with unfractionated heparin (OR, 0.50; 95 percent CI, 0.29 to 0.85). Nine studies (n = 4,157) showed a statistically significant reduction favoring LMWH with respect to mortality. By the end of follow-up, 3.3 percent (70 of 2,094) of participants treated with LMWH had died, compared with 5.3 percent (110 of 2,063) of participants treated with unfractionated heparin (OR, 0.62; 95 percent CI, 0.46 to 0.84).
Reviewers’ Conclusions. LMWH is more effective than unfractionated heparin for the initial treatment of venous thromboembolism. LMWH significantly reduces the occurrence of major hemorrhage during initial treatment and overall mortality at follow-up.
These summaries have been derived from Cochrane reviews published in the Cochrane Database of Systematic Reviews in the Cochrane Library. Their content has, as far as possible, been checked with the authors of the originalreviews, but the summaries should not be regarded as an official product of the Cochrane Collaboration; minorediting changes have been made to the text (http://www.cochrane.org).
Another advantage of LMWH is the less intense nursing care and laboratory monitoring that it requires, allowing patients to be more ambulatory. Outpatient therapy also has been studied.3 Treatment of venous thromboembolism with LMWH has been shown to be cost-effective, despite the higher price of LMWH.4 One question that remains unanswered, though, is what differences, if any, may be found in the efficacy and safety of the various LMWH preparations.
DAN BREWER, M.D., is associate professor in the Department of Family Medicine at the University of Tennessee, Knoxville.
Address correspondence to Dan Brewer, M.D., Department of Family Medicine, University of Tennessee, 1924 Alcoa Highway, Knoxville, TN 37920 (e-mail: firstname.lastname@example.org). Reprints are not available from the author.
1. van Dongen CJ, van den Belt AG, Prins MH, Lensing AW. Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for venous thromboembolism. Cochrane Database Syst Rev. 2004;(4):CD001100
2. Quinlan DJ, McQuillan A, Eikelboom JW. Low-molecular-weight heparin compared with intravenous unfractionated heparin for treatment of pulmonary embolism: a meta-analysis of randomized, controlled trials. Ann Intern Med. 2004;140:175–83.
3. Koopman MM, Prandoni P, Piovella F, Ockelford PA, Brandjes DP, van der Meer J, et al. Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. The Tasman Study Group. N Engl J Med. 1996;334:682–7.
4. van den Belt AG, Bossuyt PM, Prins MH, Gallus AS, Buller HR. Replacing inpatient care by outpatient care in the treatment of deep venous thrombosis—an economic evaluation. TASMAN Study Group. Thromb Haemost. 1998;79:259–63.
The Cochrane Abstract is a summary of a review from the Cochrane Library. It is accompanied by an interpretation that will help clinicians put evidence into practice. Dan Brewer, M.D., presents a clinical scenario and question based on the Cochrane Abstract, followed by an evidence-based answer and a full critique of the review.
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