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Phase III studies of direct oral anticoagulants for treatment and prevention of VTE Dabigatran, apixaban, edoxaban and rivaroxaban Phase III VTE acute treatment studies Trial name Design Initial treatment with heparin/ fondaparinux Treatment duration (months) Long-term treatment regimen Active comparator EINSTEIN DVT Open label No 3, or 12 od Enoxaparin/VKA EINSTEIN PE Open label No 3, or 12 od Enoxaparin/VKA RE-COVER Double blind Yes bid UFH/LMWH/warfarin RE-COVER II Double blind Yes bid UFH/LMWH/warfarin Double blind No bid Enoxaparin/warfarin Double blind Yes 3–12 od UFH/LMWH/warfarin Rivaroxaban Dabigatran Apixaban AMPLIFY Edoxaban Hokusai-VTE All studies had identical outcomes definitions and used the same independent adjudication committee Treatment of acute VTE: RE-COVER and RE-COVER II – study design Predefined treatment period of months Symptomatic VTE RE-COVER Dabigatran 150 mg bid N=2564 R Symptomatic VTE RE-COVER II UFH/LMWH VKA target INR 2.5 (range 2.0–3.0) N=2568 Day • “Unselected” patient population • Dabigatran: thrombin inhibitor Day Treatment of acute VTE: AMPLIFY – study design Treatment period of months Apixaban 10 mg bid for days, then mg bid for months Symptomatic mainly unprovoked DVT or PE R N=5395 Standard therapy Enoxaparin mg/kg bid warfarin (INR 2.0–3.0) • Low bleeding risk population • Apixaban: Xa inhibitor Agnelli G et al, N Engl J Med 2013 Treatment of acute VTE: Hokusai-VTE – study design Maximum treatment period of 12 months Edoxaban LMWH/UFH (at least days) followed by edoxaban 60 mg* od Symptomatic DVT and/or PE R N=8292 Standard care LMWH/UFH (at least days) and warfarin (INR 2.0–3.0) • “Unselected” patient population • Edoxaban: Xa inhibitor *30 mg od in patients with CrCl 30–50 ml/min, body weight ≤60 kg or receiving potent P-glycoprotein inhibitors The Hokusai-VTE Investigators, N Engl J Med 2013 Treatment of acute VTE: EINSTEIN DVT/PE – study design Randomized, open-label, event-driven, non-inferiority studies of identical design with a priori specified combined analyses Predefined treatment period of 3, 6, or 12 months Day Day 21 Rivaroxaban Rivaroxaban 15 mg bid 20 mg od N=8282 R PE with or without DVT N=4833 Enoxaparin bid for at least days + VKA, INR 2.0–3.0 “Unselected” patient population  Rivaroxaban: Xa inhibitor  N Engl J Med 2010;363:2499 N Engl J Med 2012;366:1287–97 30-day post-study treatment period DVT without PE1 N=3449 Treatment of acute VTE: RE-COVER & – efficacy and safety outcomes Heparin/dabigatran Events N=2553 n (%) Heparin/warfarin N=2554 Pooled HR (95% CI) n (%) Recurrent VTE 1.09 (0.76-1.57) 60 (2.4) 55 (2.2) 37 (1.4) 51 2.0 p[...]... bleeding Rivaroxaban n=45 VKA n=79 Category 1 Controllable 18 (40.0%) 17 (21.5%) Category 2 Not serious but 19 (42.2%) requires measures to control 34 (43.0%) Category 3 Serious 7 (15.6%) 26 (32.9%) Category 4 Fatal 1 (2.2%) 2 (2.5%) Category 3+4 rivaroxaban vs VKA: odds ratio 0.39, 95% CI: 0.16-0.96; p=0.04) Einstein DVT/PE: Prohemostatic measures Rivaroxaban n=45 Enox/VKA n=79 Vitamin K 1 30 FFP 4 11 Prothrombin... Enoxaparin/VKA HR (95% CI) n/N % n/N % Fragile 21/791 2.7 30/782 3.8 0.68 (0.39–1.18) Non-fragile 65/3359 1.9 65/3349 1.9 0.98 (0.70–1.38) Fragile 10/788 1.3 35/779 4.5 0.27 (0.13–0.54) Non-fragile 30/3342 0.9 37/3337 1.1 0.80 (0.49–1.29) Recurrent VTE Major bleeding *Age >75 years, CrCl 1 event Rivaroxaban (N=4130) Enoxaparin/VKA (N=4116) n % n % 40 1.0 72 1.7 HR (95% CI) p-value 0.54 (0.37–0.79) p=0.002 EINSTEIN DVT/PE: types of major bleeding Outcome Rivaroxaban (N=4130) Enoxaparin/VKA (N=4116) n % n % Major bleeding* 40 1.0 72 1.7 Fatal 3