Current issues of ACP Journal Club are published in Annals of Internal Medicine


Therapeutics

Review: Low-molecular-weight heparin reduces death but not recurrent VTE events, bleeding, or thrombocytopenia in VTE

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ACP J Club. 2000 July-Aug;133:7. doi:10.7326/ACPJC-2000-133-1-007

Related Content in this Issue
• Companion Abstract and Commentary: Low-molecular-weight heparin reduced recurrent VTE in patients with pulmonary embolism and proximal DVT


Source Citation

Dolovich LR, Ginsberg JS, Douketis JD, Holbrook AM, Cheah G. A meta-analysis comparing low-molecular-weight heparins with unfractionated heparin in the treatment of venous thromboembolism. Examining some unanswered questions regarding location of treatment, product type, and dosing frequency. Arch Intern Med. 2000 Jan 24;160:181-8. [PubMed ID: 10647756]


Abstract

Questions

In adults with venous thromboembolism (VTE), is low-molecular-weight heparin (LMWH) more effective than unfractionated heparin (UH)? Does the setting (outpatient or inpatient) and regimen influence effectiveness?

Data sources

Studies were identified by searching MEDLINE (1986 to 1996), HEALTH (1975 to 1996), and the Cochrane Library and reviewing the reference lists of review articles, files of local thromboembolism experts, and abstracts from recent meetings.

Study selection

2 reviewers independently selected studies that were randomized controlled trials; involved adults with confirmed VTE; compared intravenous UH with subcutaneous LMWH; and evaluated the outcomes of recurrent VTE, bleeding, death, or thrombocytopenia. Exclusion criteria were publication language other than English or French, inability to extract data, no patient follow-up beyond initial administration of heparin therapy, or comparison of subcutaneous UH with LMWH. Disagreement was resolved by consensus.

Data extraction

Data were extracted on setting; LMWH regimen; duration of treatment and follow-up; and event rates for recurrent VTE, major bleeding, and total mortality. 2 reviewers independently assessed the quality of study methods; discrepancies were resolved by review of the original study.

Main results

13 studies involving 4447 patients (mean age range 57 to 67 y, 44% to 61% men) met the inclusion criteria. 883 of these patients had pulmonary embolism (PE). Treatment duration ranged from 5 to 10 days, and follow-up ranged from 2 to 20 months. Fewer patients who received LMWH died than did those who received UH (10 studies, P = 0.03) (Table). Groups did not differ for rates of recurrent VTE, PE, bleeding, or thrombocytopenia. A trend existed toward fewer patients with major bleeding in the LWMH group than in the UH group (relative risk reduction 37%, 95% CI -5% to 63%). 3 studies examined outpatient therapy; inpatient LWMH therapy was associated with a 60% (CI 24% to 70%) relative risk reduction in major bleeding, whereas outpatient LWMH therapy led to a nonsignificant relative risk increase of 18% (CI -44% to 149%). Subgroup analysis of once-daily and twice-daily LWMH showed no differences between LWMH and UH or between the 2 schedules. Differences among the 5 LMWH products were not tested in meta-analyses because the number of studies for each product was too small.

Conclusions

In adults with venous thromboembolism (VTE), low-molecular weight heparin (LMWH) reduced death and led to rates of bleeding, recurrent VTE, and thrombocytopenia similar to those of intravenous unfractionated heparin (UH). For inpatients, LMWH produced fewer major bleeding events than did UH, whereas bleeding rates were similar for both treatments in outpatients.

Source of funding: No external funding.

For correspondence: Dr. L.R. Dolovich, Centre for Evaluation of Medicines and Department of Pharmacy, St. Joseph’s Hospital, 50 Charlton Avenue East, Hamilton, Ontario L8N 4A6, Canada. FAX 905-521-6136.


Table. Low-molecular-weight heparin (LMWH) vs intravenous unfractionated heparin (UH) in recurrent venous thromboembolism*

Outcome at 3 to 6 mo Number of studies Weighted event rates RRR (95% CI) NNT (CI)
LMWH UH
Death 10 5.0% 6.5% 24% (2 to 41) 64 (38 to 768)

*Abbreviations defined in Glossary; NNT, CI, and weighted event rates calculated from data in article.


Commentary

The rising cost of health care has drawn substantial attention from all areas of our society. New technology is believed to be a major source of the cost increase. Therefore, it is noteworthy when a new technology simultaneously improves or maintains the quality of care while reducing the associated cost. The management of VTE by using 1 of several different types of LMWH may be an example of this type of improvement. Although LMWHs are substantially more expensive than UH, they are reported to be cost-effective when used in the ambulatory care setting (1, 2). Consequently, in the current era of managed care, considerable enthusiasm exists for the ambulatory management of VTE. Given the 2 recent reports from Hull and Dolovich and their colleagues, how enthusiastic should we remain?

These 2 studies explore several important issues related to the use of LMWHs for patients with acute VTE. First, Hull and colleagues present results from a subgroup analysis of a larger randomized controlled trial. Their analysis supports the greater efficacy of subcutaneous tinzaparin therapy in reducing recurrent VTE over that of standard UH (3) for hospitalized patients with proximal DVT and an associated PE. In the analysis, they adjusted for a baseline age imbalance; otherwise, groups were comparable. Because most of the patients with proximal DVT had asymptomatic PE (> 85% without PE symptoms), some would presumably be candidates for outpatient management (4). This study affirms and strengthens observations from 2 tinzaparin trials included in the systematic review and meta-analysis by Dolovich and colleagues. A future meta-analysis with inclusion of the subgroups analyzed in the study by Hull and colleagues will need to be done to determine whether a class-specific reduction in recurrent VTE or total mortality, or both, occur.

Second, the systematic review by Dolovich and colleagues has shown that 5 different LMWHs are at least equivalent to UH in preventing recurrent VTE. For each LMWH included, the point estimate of total mortality reduction favors LMWH but is not significant until the data are pooled across LMWH class. The LMWHs are not directly compared to determine relative efficacy or safety. The reason for a mortality reduction without a similar reduction in recurrent VTE remains unclear.

Third, the study by Hull and colleagues supports the observation by Dolovich and colleagues that once-daily dosing is equivalent to twice-daily dosing for reducing recurrent VTE and total mortality. This characteristic of treatment will probably improve patient compliance in the outpatient setting.

Finally, the systematic review reported by Dolovich and colleagues should generate some caution with respect to the implementation of an outpatient VTE program. Although not statistically significant, the risk for major bleeding seemed to be higher in studies done in the “ambulatory” setting. In each of the 3 outpatient trials, < 50% of the included patients were managed entirely in the outpatient setting. In these studies, insufficient data existed to determine whether the risk for major bleeding differed between those primarily treated as out-patients and those initially treated in the hospital. Furthermore, when this approach is used outside a trial setting, bleeding complications will probably be higher than those currently reported. Close monitoring and careful patient selection that mirror the trial setting must be incorporated into an outpatient VTE treatment program.

Brian P. Schmitt, MD
Northwestern University Medical School
Chicago, Illinois, USA


References

1. O’Brien B, Levine M, Willan A, et al. Economic evaluation of outpatient treatment with low-molecular-weight heparin for proximal vein thrombosis. Arch Intern Med. 1999;159:2298-304.

2. Rodger M, Bredeson C, Wells PS, et al. Cost-effectiveness of low-molecular-weight heparin and unfractionated heparin in treatment of deep vein thrombosis. CMAJ. 1998;159:931-8.

3. Hull RD, Raskob GE, Rosenbloom D, et al. Optimal therapeutic level of heparin therapy in patients with venous thrombosis. Arch Intern Med. 1992;152:1589-95.

4. The Columbus Investigators. Low-molecular-weight heparin in the treatment of patients with venous thromboembolism. N Engl J Med. 1997;337:657-62.