Abstract

Introduction The EXCLAIM study has shown that in acutely ill medical patients who have received a standard 10-day period of prophylaxis with enoxaparin, extended-duration prophylaxis with enoxaparin for 4 weeks reduces the relative risk of the primary composite endpoint of asymptomatic proximal deep-vein thrombosis (DVT), symptomatic DVT or pulmonary embolism (PE), and fatal PE by 44% compared with placebo (2.8% vs 4.9%; RR 0.56; 95% CI 0.39–0.80; p=0.0011). We assessed the consistency of these results using the composite efficacy endpoint recently proposed for venous thromboembolism (VTE) prophylaxis studies by the European Committee for Medicinal Products for Human Use (CHMP) which, in addition, takes all-cause mortality into account.

Methods Patients enrolled in the EXCLAIM study had a recent reduced mobility (≤3 days) due to a medical illness, were aged 40 years or older, and had anticipated level 1 (total bed rest or sedentary without bathroom privileges) or level 2 (level 1 with bathroom privileges) reduced mobility with further risk factors. Eligible patients received enoxaparin 40mg SC once-daily for 10±4 days. Patients were then double-blind randomized and received either enoxaparin 40mg SC once-daily or placebo for a further 28±4 days. Asymptomatic DVT were diagnosed by bilateral compression ultrasound after completion of the randomized treatment period. Suspected cases of symptomatic DVT or PE were confirmed by objective tests. Fatal PE were confirmed by autopsy where possible. Data were analyzed using the CHMP-recommended composite efficacy endpoint of proximal DVT, adjudicated PE and all-cause mortality.

Results Eligible patients enrolled at 370 sites in 20 countries received standard-duration prophylaxis with enoxaparin. Of these, 4114 patients were double-blind randomized and 4040 received extended-duration prophylaxis with enoxaparin (n=2013) and placebo (n=2027), respectively. Extended-duration enoxaparin reduced the relative risk of the CHMP composite endpoint by 26% compared with placebo (5.8% vs 7.9%; RR 0.74; 95% CI 0.58–0.95; p=0.018).

Conclusion The significant reduction in the incidence of the primary efficacy endpoint associated with the use of extended-duration enoxaparin compared with placebo, following standard duration enoxaparin, was consistent when applying both the pre-defined EXCLAIM and the CHMP-recommended composite endpoints, the latter of which included all-cause mortality in addition to proximal DVT and adjudicated PE.

Author notes

Disclosure:Consultancy: All authors were members of the EXCLAIM Steering Committee. S.S. consultancy for sanofi-aventis. R.D.H. consultancy for Bayer Pharmaceuticals Corporation, LEO Pharma Inc., Pfizer Inc., GlaxoSmithKline, Wyeth Pharmaceuticals, sanofi-aventis, Johnson & Johnson. V.F.T. consultancy for sanofi-aventis, Bayer. A.G.G.T. consultancy for sanofi-aventis. R.D.Y. consultancy for sanofi-aventis. Research Funding: The EXCLAIM study was sponsored by sanofi-aventis. R.D.H. grants and funding support from Bayer Pharmaceuticals Corporation, LEO Pharma Inc., sanofi-aventis U.S.; V.F.T. grant/research support from sanofi-aventis; R.D.Y. grant/research support from sanofi-aventis. Honoraria Information: M.M.S. Honoraria for consultancy and lectures from sanofi-aventis, Mitsubishi, Dade Behring and GlaxoSmithKline. Membership Information: V.F.T. Advisory boards: Scios, Bayer, Eisai; R.D.H. Advisory boards: Bayer Pharmaceuticals Corporation, Pfizer Inc., sanofi-aventis, Wyeth Pharmaceuticals, LEO Pharma, Inc.