PREVAIL: Enoxaparin Bests Heparin for VTE Prophylaxis Poststroke

Susan Jeffrey

April 20, 2007

April 20, 2007 — Results of a randomized trial show a significant reduction in venous thromboembolism (VTE) events in stroke patients receiving the low-molecular-weight heparin enoxaparin ( Lovenox, Sanofi-Aventis) vs unfractionated heparin (UFH), without a significant increase in clinically important bleeding.

These results, from the Prevention of VTE After Acute Ischemic Stroke with LMWH Enoxaparin (PREVAIL) study, presented previously at the American Society of Hematology 48th Annual Meeting and Exposition and more recently at the American Stroke Association International Stroke Conference 2007, are now published in the April 21 issue of the Lancet.

David G. Sherman, MD, from the University of Texas Health Science Center, in San Antonio, was principal investigator of the trial, which included patients from 15 countries.

"Enoxaparin is preferable to unfractionated heparin for venous thromboembolism prophylaxis in this high-risk medically ill population, in view of its better clinical benefits-to-risk ratio and convenience of once-daily administration," the authors conclude.

Best Treatment Uncertain

Patients with acute ischemic stroke are at increased risk for VTE events, including deep venous thrombosis (DVT) and pulmonary embolism (PE). Without prophylaxis, up to 75% of patients with hemiplegia after a stroke will develop DVT and 20% will develop PE, which is fatal in 1% to 2% of patients, the researchers write.

Prophylaxis with either low-molecular-weight heparin or unfractionated heparin is currently recommended in these patients. However, they write, "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."

PREVAIL was an open-label trial comparing the efficacy and safety of enoxaparin vs unfractionated heparin in preventing VTE events in patients with acute ischemic stroke confirmed by computed tomography (CT) who had sufficient paralysis that they were unable to walk unassisted.

A total of 1762 patients were enrolled within 48 hours of stroke symptom onset and randomized to receive either 40 mg daily of enoxaparin given subcutaneously or 5000 IU of heparin twice daily for 10 days plus or minus 4 days — depending on when the patient was able to be ambulated. They were followed for a period of 90 days. Patients were also stratified by stroke severity according to National Institutes of Health Stroke Scale (NIHSS) scores as severe (14 or higher) and less severe (less than 14).

The primary efficacy end point was a composite of symptomatic or asymptomatic DVT and symptomatic or fatal PE during the treatment period. Safety end points included symptomatic intracranial bleeding, major extracranial bleeding, and all-cause mortality. To be included in the primary efficacy analysis, all patients must have undergone a venogram or other imaging; of the 1762 patients enrolled, 1335 were considered in the primary efficacy end point, 666 in the enoxaparin group and 669 in the unfractionated heparin group.

Results showed a 43% reduction in the primary end point (risk ratio, 0.57; 95% CI, 0.44 – 0.76;  P = .0001, adjusted for NIHSS score) with enoxaparin vs unfractionated heparin.

PREVAIL: Primary Composite End Point and VTE Events

End Point
Enoxaparin, n (%)
Unfractionated Heparin, n (%)
P
Composite end point
68 (10)
121 (18)
.0001
Symptomatic VTE
2 (<1)
7 (1)
.096
All DVT
67 (10)
118 (18)
< .001
PE
2 (< 1)
7 (1)
.059

The reduction in the primary end point remained significant in those with both more and less severe strokes.

PREVAIL: Primary End-Point Results In Patients With More and Less Severe Strokes
NIHSS score
Enoxaparin (%)
UFH (%)
P
> 14
16
30
.0036
< 14
8
14
.0044

In terms of safety, the occurrence of any bleeding was similar between groups, and the composite of symptomatic intracranial hemorrhage (ICH) and major extracranial hemorrhage was "closely similar," the authors note. There was no difference in symptomatic ICH, but major extracranial bleeding was higher with enoxaparin. Most of these were gastrointestinal bleeding events, they add, and did not increase mortality.

PREVAIL: Bleeding End Points with Enoxaparin vs Unfractionated Heparin
End Point
Enoxaparin, n (%)
UFH, n (%)
P
Any bleeding
69 (8)
71 (8)
.83
Symptomatic ICH and extracranial hemorrhage
11 (1)
6 (1)
.23
Symptomatic ICH
4 (1)
6 (1)
.55
Major extracranial hemorrhage
7 (1)
0 (0)
.015


In the past, treating physicians have had to make a choice at the beside, typically between heparin and a low-molecular-weight heparin — enoxaparin being the most commonly used low-molecular-weight heparin in the United States, Dr. Sherman told Medscape when these results were first presented.

"Now, with the PREVAIL study, we have evidence from a single large study that shows, in a very powerful way, that enoxaparin is more effective in preventing clots than is unfractionated heparin. My suspicion is that many treating physicians, if not most or all, will select enoxaparin as their drug of choice for prevention of DVT and pulmonary embolus, as opposed to unfractionated heparin."


The PREVAIL study was funded by Sanofi-Aventis, maker of enoxaparin. Dr. Sherman is on the Sanofi-Aventis speakers' bureau and consulted with Sanofi-Aventis on stroke-related research and educational activities.

Lancet. 2007;369:1347-1355.

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