Cochrane for Clinicians

Putting Evidence into Practice

Low-Molecular-Weight Heparin for Initial Treatment of Venous Thromboembolism

DAN BREWER, M.D., Department of Family Medicine, University of Tennessee, Knoxville, Tennessee

The Cochrane Abstract below 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.

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.

Clinical Scenario

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.

Clinical Question

Should venous thromboembolism initially be treated with unfractionated heparin or a low-molecular-weight heparin (LMWH)?

Evidence-Based Answer

LMWH is safer and more effective than unfractionated heparin for initial treatment of venous thromboembolism.

Practice Pointers

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."

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.

The Author

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: dbrewer2@utk.edu). Reprints are not available from the author.

REFERENCES

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.

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Cochrane Briefs

Antibiotics for Acute Laryngitis in Adults

Clinical Question

Are antibiotics effective for the treatment of acute laryngitis in adults?

Evidence-Based Answer

Two small trials of antibiotic treatment in acute laryngitis do not support routine use of antibiotics in these patients. Most patients will feel better in five to seven days, and it is unlikely that they will experience a clinically important benefit from antibiotics.

Practice Pointers

Laryngitis is characterized by hoarseness accompanied by varying degrees of sore throat, congestion, and other symptoms of upper respiratory tract infection. Although it usually is a viral infection, bacteria such as Haemophilus influenzae, Chlamydia pneumoniae, Moraxella catarrhalis, and Streptococcus pneumoniae have been isolated from the respiratory tract of symptomatic patients. Whether the bacteria are the cause of infection and whether treatment with antibiotics improves symptoms is not clear. Nevertheless, many physicians routinely prescribe antibiotics for adults with laryngitis. Reveiz and colleagues reviewed the literature to assess the effectiveness of different antibiotics for the treatment of acute laryngitis in adults, and to report any associated adverse effects.

Despite an extensive review, only two relevant clinical trials were identified. They were conducted by the same group of Swedish researchers and were published in 1985 and 1993. In the first trial, penicillin V (800 mg) or placebo was given twice daily for five days to 100 adults with laryngitis. Symptoms reported by the patients and a blinded assessment of voice quality were recorded for up to six months. There was no significant difference found between antibiotic and placebo groups for any of the measured outcomes.

The second study compared erythromycin with placebo. The authors found a small benefit in voice after one week (number needed to treat = five) and an improvement in reported cough symptoms at two weeks in the treatment group. Adverse events were not reported.

The poor quality of the literature for such a common condition is similar to that for bronchitis and other upper respiratory tract infections. Even patients with purulent secretions usually have viral infections and do not benefit from antibiotics.1

MARK H. EBELL, M.D., M.S.

Reveiz L, et al. Antibiotics for acute laryngitis in adults. Cochrane Database Syst Rev 2005;(1):CD004783.

REFERENCE

1. Snow V, Mottur-Pilson C, Gonzales R. Principles of appropriate antibiotic use for treatment of nonspecific upper respiratory tract infections in adults. Ann Intern Med 2001;134:487-9.

Follow-up After Surgically Treated Breast Cancer

Clinical Question

What follow-up should women have after surgical treatment of breast cancer?

Evidence-Based Answer

The best available evidence supports clinical breast examinations every three to six months for five years and annual mammography for asymptomatic breast cancer survivors. More intensive follow-up and subspecialist visits do not improve survival.

Practice Pointers

Rojas and colleagues identified four studies that compared different approaches to follow-up in 3,055 women who were surgically treated for Stage I, II, or III breast cancer. Two studies (2,563 women) compared a minimal follow-up strategy (i.e., clinical breast examination every three to six months and annual mammography) with more intensive follow-up that included laboratory and imaging tests such as chest radiograph and bone scan in addition to regular examinations. After five to 10 years, the studies found no difference in overall mortality (relative risk [RR], 0.98; 95 percent confidence interval [CI], 0.84 to 1.15) or quality of life between groups. One study found a benefit in disease-free survival in the intensive follow-up group (bone scan and chest radiograph every six months), though the other did not. The pooled RR for disease-free survival for both studies was 0.84 (P = .05; 95 percent CI, 0.71 to 1.00).

One study with 296 women compared hospital-based subspecialist follow-up with follow-up by the patient's family physician. There was no significant difference in the likelihood of recurrence (7 percent with family physicians versus 11 percent with subspecialists) and patients reported more satisfaction with care from their family physician. A limitation of these studies is their age, but recent evidence-based guidelines are consistent with their findings. The Institute for Clinical Systems Improvement1 and the National Comprehensive Cancer Network2 also recommend clinical breast examinations every four to six months for five years, then annually, with annual mammograms for asymptomatic breast cancer survivors. They do not recommend routine laboratory or imaging studies for asymptomatic women who are not expected to have a recurrence.

MARK H. EBELL, M.D., M.S.

Rojas MP, et al. Follow-up strategies for women treated for early breast cancer. Cochrane Database Syst Rev 2000;(4):CD001768.

REFERENCES

1. Institute for Clinical Systems Improvement. Breast cancer treatment. Bloomington, Min.: Institute for Clinical Systems Improvement, 2004.

2. National Comprehensive Cancer Network. Accessed online April 22, 2005, at: http://www.nccn.org/default.asp.

The series coordinator for AFP is Clarissa Kripke, M.D., Department of Family and Community Medicine, University of California, San Francisco.

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