Venous Thromboembolism Risk in Stroke Patients Receiving Extended-Duration Enoxaparin Prophylaxis: Sub-Analysis of the EXCLAIM Study

Abstract Background: Venous thromboembolism (VTE) is a common complication after acute ischemic stroke. Short-term (10 ± 4 days) prophylaxis reduces the risk of VTE in ischemic stroke patients (Lancet2007; 369:1347–1355), but the efficacy and safety of extended VTE prophylaxis in patients with stroke remains unknown. The EXCLAIM study demonstrated that extended-duration enoxaparin prophylaxis (28 ±4 days) reduced the risk for VTE compared with placebo (2.5% vs 4.0%, respectively: absolute difference − 1.5%, 95.8% confidence interval −2.5 to −0.5%; p= 0.002), in acutely ill medical patients with recent reduced mobility who had already received a short-term 10 ± 4 days prophylaxis regimen (J Thromb Haemost2007;5:Supp.1:O-S-001). In this analysis of the EXCLAIM study, we evaluated the benefit-to-risk ratio of extended-duration enoxaparin in a population of ischemic stroke patients at high risk for VTE. Methods: Acutely ill medical patients enrolled in EXCLAIM were aged ≥40 years and had recently reduced mobility (≤3 days). Of the 7500 patients enrolled, 7415 received enoxaparin 40mg subcutaneous (SC) once-daily for 10 ± 4 days. Of these, 6085 patients were randomized to receive double-blind therapy (enoxaparin 40mg SC once-daily or placebo) for a further 28 ± 4 days. The primary efficacy endpoint, VTE, defined as the composite of symptomatic or asymptomatic deep-vein thrombosis, symptomatic pulmonary embolism (PE), or fatal PE, was assessed at completion of the randomized treatment. The primary safety endpoint, major bleeding, was assessed through 48 hours after the last dose of randomized treatment. Secondary endpoints included symptomatic VTE and major and total (major plus minor) bleeding. Results: Of the 5,963 randomized patients who received at least 1 dose of study treatment, 389 (6.5%) had acute ischemic stroke. Of these, 198 received extended-duration enoxaparin prophylaxis and 191 received placebo. Key demographic variables were comparable in both groups. The VTE rate in the placebo group was higher in ischemic stroke patients, compared with those without (8.0% vs 3.7%). The incidence of VTE was significantly reduced in patients receiving extended-duration enoxaparin prophylaxis vs placebo (p<0.05). Major bleeding was increased in patients receiving extended-duration enoxaparin prophylaxis vs patients receiving placebo, however this difference was not statistically significant (Table). Conclusion: Our findings support that acute ischemic stroke patients are at increased risk for VTE, compared with the general medical population. Acutely ill patients with ischemic stroke receiving extended-duration enoxaparin experienced a significantly reduced risk of VTE and a non-statistically significant increase in major bleeding compared with patients receiving placebo, after all patients completed a short-term 10 ± 4 days enoxaparin regimen. These findings warrant further studies of extended-duration VTE prophylaxis in patients with acute ischemic stroke. Table. Efficacy and safety outcomes in stroke patients receiving extended-duration enoxaparin prophylaxis vs placebo. Stroke patients, n=389 Parameter Extended-duration enoxaparin, n (%) Placebo, n (%) Relative risk (95.8% CI) P-value †Efficacy endpoints were assessed in all randomized patients who received at least 1 dose of study drug and had an evaluable ultrasound. ‡Safety endpoints were assessed in all randomized patients who received at least 1 dose of study drug. Efficacy † N=166 N=150 VTE 4 (2.4) 12 (8.0) 0.30 (0.10–0.91) 0.0236 Symptomatic VTE 0 (0.0) 2 (1.3) 0.1356 Safety ‡ N=198 N=191 Major bleeding 3 (1.5) 0 (0.0) 0.0881 Major and minor bleeding 12 (6.1) 5 (2.6) 2.32 (0.83–6.45) 0.0972

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