CASSIOPEA

Clinical study Assessing SSR126517E Injections Once-weekly in Pulmonary Embolism therapeutic Approach (2010)

Condition

Treatment of acute pulmonary embolism (PE)

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Objective

To assess the non-inferiority of idrabiotaparinux to warfarin in patients with acute symptomatic PE

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Trial design

Randomized, double-blind, double-dummy, non-inferiority phase III study
Active treatment: enoxaparin 1.0 mg/kg s.c. twice daily for 5–10 days followed by subcutaneous idrabiotaparinux 3.0 mg once weekly and placebo tablets (n=1599)
Control treatment: enoxaparin 1.0 mg/kg s.c. twice daily for 5–10 days followed by adjusted-dose warfarin (target INR 2.0–3.0) plus weekly placebo injections (n=1603)
Both regimens lasted 3 months or 6 months dependent on clinical presentation. 79% of the patients continued study therapy for 6 months (n=1269 in the enoxaparin-idrabiotaparinux group and n=1267 in the enoxaparin-warfarin group)

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Endpoints

Primary efficacy endpoint: symptomatic recurrent VTE, defined as either recurrent PE or DVT within 99 days of randomization
Secondary efficacy endpoint: symptomatic recurrent VTE within 190 days in patients assigned to receive treatment for 6 months
Primary safety endpoint: clinically relevant bleeding (major or non-major) and death from all causes

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Trial participants

3202 patients aged 18–96 years with objectively confirmed, symptomatic, acute PE

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Results

Efficacy outcome: At day 99, 2.1% (34 of 1599) patients randomly allocated to receive enoxaparin-idrabiotaparinux and 2.7% (43 of 1603) patients given enoxaparin-warfarin had recurrent venous thromboembolic events (p=0.0001 for non-inferiority). Incidence of recurrent VTE also did not differ significantly between treatment groups at day 190 for patients assigned to receive 6 months’ treatment: 2.3% with enoxaparin-idrabiotaparinux vs. 2.8% with enoxaparin-warfarin (p=0.0001 for non-inferiority). However, the protective effect of idrabiotaparinux remained present for additional 6 months after treatment cessation, whereas there was an almost immediate and constant increase over time of recurrent VTE after cessation of warfarin. During follow-up after planned end of study drug intake (i.e., 99 days or 190 days), there were only 9 recurrences in patients originally assigned to receive idrabiotaparinux and 47 in those assigned to receive warfarin in one year
Safety outcome: By day 99, more patients had clinically relevant bleeding in the enoxaparin-warfarin group (4,5%) than in the enoxaparin-idrabiotaparinux group (6.6%) (p=0.0098 for superiority). However, this difference did not persist to 190 days in patients assigned to receive 6 months’ treatment (6.6% vs. 8,1%; p=0.17 for superiority)

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Summary

Efficacy: In patients with symptomatic acute pulmonary embolism treated with enoxaparin for 5–10 days, once weekly subcutaneous idrabiotaparinux was as effective as adjusted daily doses of warfarin for long-term treatment and prevention of VTE. The indirect factor Xa inhibitor showed a protective effect up to 12 months
Safety: Idrabiotaparinux was associated with less frequent bleeding than was treatment with warfarin

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Reference

Büller HR, Gallus AS, Pillion G, Prins MH, Raskob GE, for the CASSIOPEA Investigators. Enoxaparin followed by once-weekly idrabiotaparinux versus enoxaparin plus warfarin for patients with acute symptomatic pulmonary embolism: a randomised, double-blind, double-dummy, non-inferiority trial. Lancet 2012;379:123-129

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Corresponding author

Prof. Harry R. Büller, Department of Vascular Medicine, Academic Medical Centre, Meibergdreef 9, 1105 AZ Amsterdam, Netherlands, e-mail: h.r.buller@amc.uva.nl

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