Elsevier

The Lancet

Volume 369, Issue 9570, 21–27 April 2007, Pages 1347-1355
The Lancet

Articles
The efficacy and safety of enoxaparin versus unfractionated heparin for the prevention of venous thromboembolism after acute ischaemic stroke (PREVAIL Study): an open-label randomised comparison

https://doi.org/10.1016/S0140-6736(07)60633-3Get rights and content

Summary

Background

Venous thromboembolism prophylaxis with low molecular weight heparin or unfractionated heparin is recommended in acute ischaemic stroke, but which regimen provides optimum treatment is uncertain. We aimed to compare the efficacy and safety of enoxaparin with that of unfractionated heparin for patients with stroke.

Methods

1762 patients with acute ischaemic stroke who were unable to walk unassisted were randomly assigned within 48 h of symptoms to receive either enoxaparin 40 mg subcutaneously once daily or unfractionated heparin 5000 U subcutaneously every 12 h for 10 days (range 6–14). Patients were stratified by National Institutes of Health Stroke Scale (NIHSS) score (severe stroke ≥14, less severe stroke <14). The primary efficacy endpoint was the composite of symptomatic or asymptomatic deep vein thrombosis, symptomatic pulmonary embolism, or fatal pulmonary embolism. Primary safety endpoints were symptomatic intracranial haemorrhage, major extracranial haemorrhage, and all-cause mortality. This study is registered with ClinicalTrials.gov, number NCT00077805.

Findings

In the efficacy population (ie, one or more dose received, presence of deep vein thrombosis or pulmonary embolism, or assessment for venous thromboembolism), enoxaparin (n=666) and unfractionated heparin (669) were given for 10·5 days (SD 3·2). Enoxaparin reduced the risk of venous thromboembolism by 43% compared with unfractionated heparin (68 [10%] vs 121 [18%]; relative risk 0·57, 95% CI 0·44–0·76, p=0·0001; difference −7·9%, −11·6 to −4·2); this reduction was consistent for patients with an NIHSS score of 14 or more (26 [16%] vs 52 [30%]; p=0·0036) or less than 14 (42 [8%] vs 69 [14%]; p=0·0044). 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 haemorrhage was small and closely similar between groups (enoxaparin 11 [1%] vs unfractionated heparin 6 [1%]; p=0·23). We noted no difference for symptomatic intracranial haemorrhage between groups (4 [1%] vs 6 [1%], respectively; p=0·55); the rate of major extracranial bleeding was higher with enoxaparin than with unfractionated heparin (7 [1%] vs 0; p=0·015).

Interpretation

Our results suggest that for patients with acute ischaemic 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.

Introduction

Stroke is a major health problem that is growing in importance.1 WHO estimates that 15 million people have a stroke every year, and this number is rising.2 Each year in the USA alone, 700 000 people have a first or recurrent stroke,3 88% of which are ischaemic. Stroke is also the third most common cause of death and the leading cause of disability in adults.4, 5

Venous thromboembolism is a common but preventable complication of acute ischaemic stroke, and is associated with increased mortality and long-term morbidity and substantial health-care costs for its management.6 The risk of venous thromboembolism for patients who have had an acute ischaemic stroke is close to that for patients undergoing major surgical procedures.6 Without venous thromboembolism prophylaxis, up to 75% of patients with hemiplegia after stroke develop deep vein thrombosis and 20% develop pulmonary embolism,7, 8 which is fatal in 1–2% of patients with acute ischaemic stroke and causes up to 25% of early deaths after strokes.9

The benefits of prophylaxis have been seen in patients with acute ischaemic stroke, and low molecular weight heparin and unfractionated heparin are therefore recommended in guidelines from expert consensus groups.10, 11, 12, 13, 14 For physicians to select the most appropriate prophylactic regimen, they need to decide which will achieve maximum reduction of venous thromboembolism risk while keeping the risk of bleeding to a minimum. Up to now, small-scale studies have suggested that low molecular weight heparin is better than or equivalent to unfractionated heparin for prevention of venous thromboembolism after acute ischaemic stroke,15, 16 but these studies were restricted in their ability to assess the benefit to risk ratio of the prophylactic treatments.

A meta-analysis showed that low molecular weight heparin and heparinoids reduce the risk of deep vein thrombosis and symptomatic pulmonary embolism by around two-thirds compared with placebo or no treatment, with a two-fold increase in the risk of extracranial bleeding.17 Meta-analyses of low-dose and high-dose low molecular weight and unfractionated heparin regimens have suggested that low-dose low molecular weight heparin could provide the best benefit to risk ratio in patients with acute ischaemic stroke by decreasing the risk of both deep vein thrombosis and pulmonary embolism without increasing the risk of intracranial or extracranial haemorrhage.18, 19 However, in one meta-analysis the investigators warn against drawing conclusions on the basis of haemorrhagic complications because of the low numbers of events.18 Nevertheless, prophylactic regimens used for patients with stroke are quite varied because many physicians remain uncertain about the best treatment, and data from studies with high numbers of patients are needed to resolve this issue.

We have therefore done a large scale, multinational, randomised study to compare the efficacy and safety of the low molecular weight heparin enoxaparin with that of unfractionated heparin for venous thromboembolism prophylaxis in patients with acute ischaemic stroke.

Section snippets

Patients

Patients were eligible for enrolment if they were 18 years or older with an acute ischaemic stroke confirmed by computed tomography (CT) or magnetic resonance imaging (MRI) and unable to walk unassisted because of motor impairment, with a score of 2 or more as indicated by National Institutes of Health Stroke Scale (NIHSS)20 for motor function of the leg. Onset of stroke symptoms had to have occurred within 48 h before randomisation. The panel shows exclusion criteria.

All patients provided

Results

In total, 1762 acute ischaemic stroke patients were randomly assigned between August, 2003, and April, 2006, at 200 centres in 15 countries (Australia, Austria, Brazil, Canada, Colombia, Czech Republic, India, Israel, Italy, South Korea, Mexico, Poland, South Africa, Turkey, and USA). Figure 1 shows the trial profile. Of the randomised patients, 13 (seven in enoxaparin group and six in unfractionated heparin group) did not receive study treatment and were not included in the safety or efficacy

Discussion

We have shown that enoxaparin 40 mg subcutaneously once daily is significantly more effective than unfractionated heparin 5000 U subcutaneously every 12 h for the prevention of venous thromboembolism in patients with acute ischaemic stroke, and noted a consistent reduction in the risk of proximal deep vein thrombosis. The risk of pulmonary embolism was lower in patients receiving enoxaparin than in those receiving unfractionated heparin, although this difference was not significant. The

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