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


Low-molecular-weight heparin reduced recurrent VTE in patients with pulmonary embolism and proximal DVT


ACP J Club. 2000 July-Aug;133:6. doi:10.7326/ACPJC-2000-133-1-006

Related Content in this Issue
• Companion Abstract and Commentary: Review: Low-molecular-weight heparin reduces death but not recurrent VTE events, bleeding, or thrombocytopenia in VTE

Source Citation

Hull RD, Raskob GE, Brant RF, et al., for the American-Canadian Thrombosis Study Group. Low-molecular-weight heparin vs heparin in the treatment of patients with pulmonary embolism. Arch Intern Med. 2000 Jan 24;160:229-36. [PubMed ID: 10647762]



In adults with documented pulmonary embolism and proximal deep venous thrombosis (DVT), is low-molecular-weight heparin (LMWH) given subcutaneously without anticoagulant monitoring more effective than unfractionated heparin in preventing recurrent proximal DVT?


Subgroup analysis of a randomized {allocation concealed*}†, blinded (patients and outcome assessors),* controlled trial with 3-month follow-up.


15 centers in the United States and Canada.


200 patients who were ≥ 18 years of age (65% ≥ 60 y of age, 56% women) and had proximal DVT on venography and high-probability findings on perfusion lung scanning. Exclusion criteria were active bleeding or contraindications to anticoagulants; allergy to heparin, bisulfites, or fish; pregnancy; ≥ 2 previously documented episodes of DVT or pulmonary embolism (PE); history of protein C deficiency or heparin-associated thrombocytopenia; severe malignant hypertension; severe hepatic or renal failure; treatment with warfarin sodium, LMWH, or heparinoids in the previous 7 days or with subcutaneous heparin in the previous 12 hours; or current use of intravenous unfractionated heparin (UH). Follow-up was 100%.


After stratification according to study center, history of venous thromboembolism (VTE), and presence of risk factors for bleeding, patients were allocated to subcutaneous LMWH (tinzaparin sodium), 175 international factor Xa inhibitory units/kg of body weight per day (n = 97), or to UH (n = 103). UH was given according to a protocol nomogram, with an initial bolus dose of 5000 U.S. Pharmacopeia units and continuous infusion at 40320 U/d for patients without risk factors for bleeding and 29 760 U/d for patients with risk factors for bleeding, for 5 to 6 days. All patients received warfarin sodium, 10 mg initially with adjustment to maintain an international normalized ratio of 2.0 to 3.0 for 3 months.

Main outcome measures

Recurrent VTE, bleeding, and death.

Main results

At 3 months, fewer patients in the LWMH group than in the UH group had recurrent VTE (P = 0.009); the groups had similar rates of bleeding and death (Table).


In adults with documented pulmonary embolism and proximal deep venous thrombosis, low-molecular-weight heparin reduced the incidence of recurrent venous thromboembolism and led to similar rates of bleeding and death as did intravenous unfractionated heparin.

*See Glossary.

†Information provided by author.

Sources of funding: In part, Heart and Stroke Foundation and Novo Nordisk.

For correspondence: Dr. R.D. Hull, Thrombosis Research Unit, 601 South Tower, Foothills Hospital, 1403-29 Street N.W., Calgary, Alberta T2N 2T9, Canada. FAX 403-270-7891.

Table. Low-molecular-weight heparin (LMWH) vs intravenous unfractionated heparin (UH) in adults with venous thromboembolism‡

Outcomes at 3 mo LWMH UH RRR (95% CI) NNT (CI)
Recurrent venous thromboembolism 0% 6.8% 100% (43 to 100) 15 (8 to 36)
Major bleeding 1.0% 1.9% 47% (-300 to 930) Not significant
Minor bleeding 1.0% 2.9% 65% (-143 to 95) Not significant
Death 6.2% 8.7% 29% (-84 to 73) Not significant

‡Abbreviations defined in Glossary; RRR, NNT, and CI calculated from data in article.


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


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.