Phase III studies of direct oral anticoagulants for treatment and - PowerPoint PPT Presentation

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 Treatment Long-term Active with heparin/ duration treatment comparator fondaparinux (months) regimen Rivaroxaban EINSTEIN DVT Open label No 3, 6 or 12 od Enoxaparin/VKA EINSTEIN PE Open label No 3, 6 or 12 od Enoxaparin/VKA Dabigatran RE-COVER Double blind Yes 6 bid UFH/LMWH/warfarin RE-COVER II Double blind Yes 6 bid UFH/LMWH/warfarin Apixaban AMPLIFY Double blind No 6 bid Enoxaparin/warfarin Edoxaban 3 – 12 Hokusai-VTE Double blind Yes od UFH/LMWH/warfarin 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 6 months Dabigatran 150 mg bid Symptomatic VTE N=2564 RE-COVER R UFH/LMWH VKA target INR 2.5 (range 2.0 – 3.0) Symptomatic N=2568 VTE RE-COVER II Day 1 Day 6 • “Unselected” patient population • Dabigatran: thrombin inhibitor

Treatment of acute VTE: AMPLIFY – study design Treatment period of 6 months Apixaban 10 mg bid for 7 days, then 5 mg bid for 6 months Symptomatic mainly R unprovoked DVT or PE N=5395 Standard therapy Enoxaparin 1 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 5 days) followed by edoxaban 60 mg* od Symptomatic R DVT and/or PE N=8292 Standard care LMWH/UFH (at least 5 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 1 Day 21 DVT without 30-day post-study PE 1 treatment period Rivaroxaban Rivaroxaban N=3449 N=8282 15 mg bid 20 mg od R Enoxaparin bid for at least 5 days + PE with or without DVT VKA, INR 2.0 – 3.0 N=4833  “Unselected” patient population  Rivaroxaban: Xa inhibitor N Engl J Med 2010;363:2499 2. N Engl J Med 2012;366:1287 – 97 1.

Treatment of acute VTE: RE-COVER 1 & 2 – efficacy and safety outcomes Heparin/dabigatran Heparin/warfarin Pooled HR Events N=2553 N=2554 (95% CI) n (%) n (%) Recurrent VTE 1.09 (0.76-1.57) 60 (2.4) 55 (2.2) p <0.001 (non-inferiority) Major Bleeding 37 (1.4) 51 2.0 0.73 (0.48-1.11) Schulman S et al , N Engl J Med 2009

Treatment of acute VTE: AMPLIFY – efficacy and safety outcomes Apixaban Standard therapy HR N=2691 N=2704 Events (95% CI) n (%) n (%) 0.84 (0.60 – 1.18) Recurrent VTE 59 (2.3) 71 (2.7) p <0.001 (non-inferiority) 0.31 (0.17 – 0.55) Major bleeding 15 (0.6) 49 (1.8) p <0.001 Agnelli et al , 2013

Treatment of acute VTE: Hokusai-VTE – efficacy and safety outcomes Events Heparin/edoxaban Heparin/warfarin HR (N=4118) (N=4122) (95% CI) n (%) n (%) Recurrent VTE p <0.001 (non-inferiority) At end of study 0.89 (0.70 – 1.13) period* 130 (3.2) 146 (3.5) 0.82 (0.60 – 1.14) On treatment 66 (1.6) 80 (1.9) 0.84 (0.59 – 1.21) Major bleeding 56 (1.4) 66 (1.6) p =0.35 *12 months after the start of treatment regardless of treatment duration The Hokusai-VTE Investigators , N Engl J Med 2013

Treatment of acute VTE: EINSTEIN DVT/PE – efficacy and safety outcomes Rivaroxaban Standard therapy HR (N=4150) (N=4131) Events (95% CI) n (%) n (%) 0.89 (0.66 – 1.19) Recurrent VTE 86 (2.1) 95 (2.3) p <0.001 (non-inferiority) 0.54 (0.37 – 0.79) Major bleeding 405 (1.0) 72 (1.7) p <0.002 Agnelli et al , 2013

EINSTEIN DVT/PE: types of major bleeding Rivaroxaban Enoxaparin/VKA HR (95% CI) (N=4130) (N=4116) Outcome p-value n % n % 0.54 (0.37 – 0.79) Major bleeding* 40 1.0 72 1.7 p =0.002 Fatal Retroperitoneal Intracranial Gastrointestinal/thorax In a critical site Retroperitoneal Intracranial Pericardial Other Fall in hemoglobin ≥2 g/dl and/or transfusions ≥2 units Gastrointestinal *Some patients had >1 event

EINSTEIN DVT/PE: types of major bleeding Rivaroxaban Enoxaparin/VKA HR (95% CI) (N=4130) (N=4116) Outcome p-value n % n % 0.54 (0.37 – 0.79) Major bleeding* 40 1.0 72 1.7 p =0.002 Fatal 3 <0.1 8 0.2 Retroperitoneal 0 0 1 <0.1 Intracranial 2 <0.1 4 <0.1 Gastrointestinal/thorax 1 <0.1 3 <0.1 In a critical site 10 0.2 29 0.7 Retroperitoneal 1 <0.1 8 0.2 Intracranial 3 <0.1 10 0.2 Pericardial 0 0 2 <0.1 Other 6 0.1 7 0.2 Fall in hemoglobin ≥2 g/dl 27 0.7 37 0.9 and/or transfusions ≥2 units Gastrointestinal 15 0.4 26 0.6 *Some patients had >1 event

Einstein DVT/PE: Clinical presentation of major bleeding Rivaroxaban Major bleeding VKA n=79 n=45 Category 1 18 (40.0%) 17 (21.5%) Controllable Category 2 Not serious but 19 (42.2%) 34 (43.0%) requires measures to control Category 3 7 (15.6%) 26 (32.9%) Serious Category 4 1 (2.2%) 2 (2.5%) Fatal 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 2 9 complex rFVIIa 1 0

EINSTEIN DVT/PE: outcomes in fragile patients* Rivaroxaban Enoxaparin/VKA Outcome HR (95% CI) n/N % n/N % Recurrent VTE 0.68 (0.39 – 1.18) Fragile 21/791 2.7 30/782 3.8 0.98 (0.70 – 1.38) 65/3359 1.9 65/3349 1.9 Non-fragile Major bleeding 0.27 (0.13 – 0.54) 10/788 1.3 35/779 4.5 Fragile 0.80 (0.49 – 1.29) Non-fragile 30/3342 0.9 37/3337 1.1 *Age >75 years, CrCl <50 ml/min, or body weight ≤50 kg

EINSTEIN DVT/PE: Clot size and recurrent VTE Rivaroxaban Enoxaparin/VKA n/N % n/N % Limited 11/814 1.4 19/826 2.3 ≤25% of a single lobe, popliteal vein only Intermediate 47/1941 2.4 50/1942 2.6 Extensive 28/1218 2.3 25/1190 2.1 multiple lobes and >25% of entire pulmonary vasculature; involving common femoral/ iliac vein

EINSTEIN PE: Repeat CT scan at 3 weeks in 264 patients Rivaroxaban Enoxaparin/VKA N=135 N=129 Complete resolution 59 (44%) 57 (44%) Partial resolution 61 (45%) 58 (45%) No change 15 (11%) 12 (9%) Deteriorated 0 0 Van Es, et al. JTH, 11: 679 – 85

EINSTEIN DVT/PE: Outcomes in cancer patients Active cancer* Rivaroxaban Enoxaparin/VKA HR (95% CI) 0.67 (0.35 – 1.30) Recurrent VTE, n (%) 16/354 (4.5) 20/301 (6.6) 0.42 (0.18 – 0.99) Major bleeding, n (%) 8/353 (2.3) 15/298 (5.0) 0.93 (0.64 – 1.35) Mortality, n (%) 58/354 (16.4) 53/301 (17.6) *At baseline or diagnosed during the study

Overall summary: acute treatment studies • All DOACs non-inferior to standard therapy – important reductions in major bleeding with apixaban and rivaroxaban single drug treatment – No reduction in major bleeding for dabigatran and edoxaban dual drug treatment • Major bleeding is less severe with DOACs – less fatal bleeds – less critical organ bleeds (intracranial, retroperitoneal) – presentation and course of major bleeding less severe with DOACs • Results are consistent for subgroups