Oral rivaroxaban for the treatment of symptomatic venous thromboembolism (a pooled analysis of the EINSTEIN DVT

Oral Rivaroxaban for the Treatment of Symptomatic Venous Thromboembolism: A Pooled Analysis of the EINSTEIN DVT and EINSTEIN PE Studies Anthonie WA Lensing on behalf of the EINSTEIN Investigators Bayer symposium - Da Nang, 13 October Venous thromboembolism  1-2 new cases per 1000 per year  If no or inadequate anticoagulant treatment is given  recurrent thrombotic complications in 20-30%  Heparin/vitamin K antagonist (VKA)  VKA has a slow onset of action; heparin is needed for the first week of treatment  VKA has an unpredictable anticoagulant effect, requiring – frequent INRs and dose adjustments  Heparin/VKA recurrent VTE rate: ~ 3% at 6 mo Rivaroxaban Specific, direct factor Xa inhibitor High oral bioavailability Rapid onset of action Half-life: 7–11 hours Only 1/3 renally cleared Small change in exposure with varying bodyweight Wide therapeutic window Absorption limited if > 50 mg Rivaroxaban Can Rivaroxaban be given in a fixed dose without the requirement for monitoring and replace heparin and VKA treatment in DVT/PE patients? EINSTEIN DVT and EINSTEIN PE studies Randomized, open-label, event-driven, non-inferiority studies of identical design with a priori specified combined analyses  Primary efficacy outcome: recurrent VTE  Safety outcome: major bleeding 1. N Engl J Med 2010;363:2499 2. N Engl J Med 2012;366:1287–97 15 mg bid DVT without PE 1 N=3449 N=8282 Rivaroxaban Day 1 Day 21 Enoxaparin bid for at least 5 days + VKA, INR 2.0–3.0 PE with or without DVT 2 N=4833 Predefined treatment period of 3, 6, or 12 months 20 mg od 30-day post-study treatment period Rivaroxaban R EINSTEIN DVT/PE: primary efficacy outcome Number of patients at risk Rivaroxaban 4150 4018 3969 3924 3604 3579 3283 1237 1163 1148 1102 1034 938 Enoxaparin/VKA 4131 3932 3876 3826 3523 3504 3236 1215 1149 1109 1071 1019 939 0.5 3.0 2.5 2.0 1.5 1.0 0.0 Rivaroxaban N=4150 Enoxaparin/VKA N=4131 0 30 60 90 120 150 180 210 240 270 300 330 360 Time to event (days) Cumulative event rate (%) Rivaroxaban n/N (%) Enoxaparin/VKA n/N (%) HR (95% CI) 86/4150 (2.1) 95/4131 (2.3) 0.89 (0.66–1.19) EINSTEIN DVT/PE: major bleeding Number of patients at risk Rivaroxaban 4130 3921 3862 3611 3479 3433 2074 1135 1095 1025 969 947 499 Enoxaparin/VKA 4116 3868 3784 3525 3394 3348 1835 1109 1065 990 950 916 409 0.5 3.0 2.5 2.0 1.5 1.0 0.0 Rivaroxaban N=4130 Enoxaparin/VKA N=4116 0 30 60 90 120 150 180 210 240 270 300 330 360 Time to event (days) Cumulative event rate (%) Rivaroxaban n/N (%) Enoxaparin/VKA n/N (%) HR (95% CI) p-value 40/4130 (1.0) 72/4116 (1.7) 0.54 (0.37–0.79) p=0.002 Outcome Rivaroxaban (N=4130) Enoxaparin/VKA (N=4116) HR (95% CI) p-value n % n % Major bleeding* 40 1.0 72 1.7 0.54 (0.37–0.79) 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 and/or transfusions ≥2 units 27 0.7 37 0.9 Gastrointestinal 15 0.4 26 0.6 EINSTEIN DVT/PE: types of major bleeding *Some patients had >1 event Einstein DVT/PE: Clinical presentation of major bleeding Major bleeding Rivaroxaban n=45 VKA n=79 Category 1 Controllable 18 (40.0%) 17 (21.5%) Category 2 Requires measures to control, not serious 19 (42.2%) 34 (43.0%) Category 3 Serious bleeding 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 - Major bleeding and use of prohemostatic measures Rivaroxaban n=45 Enox/VKA n=79 Vitamin K 1 30 FFP 4 11 Prothrombin complex 2 9 rFVIIa 1 0 [...]... LMWH/VKA is often prescribed in practice In EINSTEIN DVT/ PE patients with cancer were not excluded Classification of DVT/ PE patients with cancer Patients with cancer were classified as:  Active cancer at baseline (diagnosis or treatment < 6 months or recurrent or metastatic cancer)  Active cancer during the study (a new diagnosis of cancer)  A history of cancer (all other) EINSTEIN DVT/ PE: Analysis. .. diagnosed during the study EINSTEIN DVT/ PE in cancer: Major bleeding and kidney function 14 13.0 Major bleeding (%) 12 Rivaroxaban 10 Enoxaparin/VKA ptrend=0.01 ptrend=0.92 8 6 5.0 4 2.4 2.7 2.2 2 2.1 0 >80 50−80 Creatinine clearance (ml/min) 80 50−80 Creatinine clearance (ml/min) 25% of. .. History of cancer (n=469) Active cancer at baseline (n=462) Active cancer during study (n=193) EINSTEIN DVT/ PE: Outcomes No known cancer Rivaroxaban Enoxaparin/VKA HR (95% CI) Recurrent VTE, n (%) 65/3563 (1.8) 70/3594 (1.9) 0.93 (0.66–1.30) Major bleeding, n (%) 31/3546 (0.9) 53/3582 (1.5) 0.58 (0.37–0.91) Mortality, n (%) 33/3563 (0.9) 42/3594(1.2) 0.77 (0.49–1.22) EINSTEIN DVT/ PE: Outcomes History of. .. common femoral/ iliac vein EINSTEIN PE: Repeat CT scan at 3 weeks in 264 patients Rivaroxaban N=135 Enoxaparin/VKA 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 Venous thromboembolism and cancer Long-term LMWH is recommended LMWH is often not used based on medical, economic and quality of life... Non-inferiority versus enoxaparin/VKA for efficacy – Including cancer patients  Approximately 50% risk reduction for major bleeding – Including cancer patients  Consistent efficacy and safety results irrespective of age, body weight, gender, renal function, severity of DVT/ PE, and treatment of first/recurrent VTE  Single-drug approach: no LMWH needed .. .EINSTEIN DVT/ PE: outcomes in fragile patients* Outcome Rivaroxaban Enoxaparin/VKA HR (95% CI) n/N % n/N % Non-fragile 65/3359 1.9 65/3349 1.9 0.98 (0.70–1.38) Fragile 21/791 2.7 30/782 3.8 0.68 (0.39–1.18) Non-fragile 30/3342 0.9 37/3337 1.1 0.80 (0.49–1.29) Fragile 10/788 1.3 35/779 4.5 0.27 (0.13–0.54) Recurrent VTE Major bleeding *Age >75 years, CrCl