Enoxaparin Outdoes Heparin for Post-Stroke Venous Thromboembolism

SAN ANTONIO, Tex., April 20 -- Enoxaparin (Lovenox), a low molecular-weight heparin, proved more effective than unfractionated heparin for preventing potentially fatal leg and lung clots after acute ischemic stroke, researchers reported.

In a head-to-head study of 1,762 stroke patients unable to walk unassisted, enoxaparin was 43% more effective at preventing venous thromboembolism than unfractionated heparin, David G. Sherman, M.D., of the University of Texas here, and colleagues reported in the Apil 21 issue of The Lancet.

The results of this study, Dr. Sherman concluded, suggest that for patients with acute ischemic stroke, enoxaparin is preferable to unfractionated heparin for venous thromboembolism prophylaxis in view of its better clinical benefits-to-risk ratio and convenience of once daily administration.

Venous thrombembolism with either low-molecular-weight heparin or unfractionated heparin is recommended for acute ischemic stroke, but because large studies are lacking, it has been uncertain which is the better regimen, Dr. Sherman said.

To compare the efficacy and safety of the drugs, the researchers undertook a large, 15-nation multinational randomized study (PREVAIL), sponsored by Sanofi-Aventis, maker of enoxaparin.

Within 48 hours of symptoms, 666 patients were given enoxaparin (40 mg subcutaneously) once daily for 10 days, while 669 got unfractionated heparin (5,000 U subcutaneously) every 12 hours, for 10 days (range for all, six to 14 days).

The patients were stratified by the National Institutes of Health Stroke Scale (NIHSS) (severe stroke ?14, less severe stroke < 14).

Enoxaparin reduced the risk of venous thromboembolism by 43% compared with unfractionated heparin (68 [10%] versus 121 [18%]; relative risk 0.57, 95% CI 0.44-0.76, P=0.0001; difference -7.9%, -11.6 to -4.2).

The greater reduction with enoxaparin was consistent for patients with an NIHSS score of 14 or more (26 [16%] versus 52 [30%]; P=0.0036) or less than 14 (42 [8%] versus 69 [14%]; P=0.0044).

Internal and external bleeding was rare in both groups, although rates for external bleeding were slightly higher in the patients taking enoxaparin. The findings were:

• The occurrence of any bleeding was similar with enoxaparin (69 [8%]) or unfractionated heparin (71 [8%]; P=0.83).
• The frequency of the composite of symptomatic intracranial and major extracranial hemorrhage was small and closely similar between groups (enoxaparin 11 [1%] versus unfractionated heparin 6 [1%]; P=0.23).
• There was no significant difference for symptomatic intracranial hemorrhage between groups (4 [1%] versus 6 [1%], respectively; P=0.55).
• However, the rate of major extracranial bleeding was slightly higher with enoxaparin than with unfractionated heparin (7 [1%] versus 0; P=0.015).

On the basis of these data, the researchers said, the number needed to treat to avoid one venous thromboembolism was 13, whereas the number needed to harm as a result of clinically important bleeding was 173.

The occurrence of venous thromboembolism was higher for patients with an NIHSS score of 14 or more, the researchers reported.

A post-hoc analysis of major subgroups-diabetes, obesity, previous stroke, age, for example--showed consistent reductions of venous thromboembolism risk for enoxaparin compared with unfractionated heparin. Importantly, the researchers said, delay in the start of treatment for up to 48 hours after stroke onset did not change the findings.

A potentially important difference between the PREVAIL study and many of the previous trials was the choice of the unfractionated heparin dosing regimen. In previous studies a three-times-daily schedule was used, whereas a twice-daily regimen was used in PREVAIL.

This twice-daily dosing decision was derived from a meta-analysis showing both twice- and thrice-daily regimens effective compared with placebo or no prophylaxis. Because this study did not compare the unfractionated heparin thrice-daily regimen, the risk reduction for that prophylactic regimen was difficult to discern.

A limitation of this study was its open-label design, allowing for possible bias in the declaration of potential endpoints. In PREVAIL, the primary efficacy endpoint of venous thromboembolism was composed largely of asymptomatic events that were assessed systematically.

Furthermore, researchers said, as in many similar studies, symptomatic deep vein thromboses and pulmonary emboli might have been under-reported, especially in these high-risk patients who probably had confounding diagnoses.