A Pooled Analysis of the EINSTEIN DVT and EINSTEIN PE Studies - PowerPoint PPT Presentation

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 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 2 VKA, INR 2.0 – 3.0 N=4833  Primary efficacy outcome: recurrent VTE  Safety outcome: major bleeding N Engl J Med 2010;363:2499 2. N Engl J Med 2012;366:1287 – 97 1.

EINSTEIN DVT/PE: primary efficacy outcome Rivaroxaban Enoxaparin/VKA HR (95% CI) n/N (%) n/N (%) 3.0 Enoxaparin/VKA 0.89 (0.66 – 1.19) 86/4150 95/4131 Cumulative event rate (%) N=4131 (2.1) (2.3) 2.5 2.0 Rivaroxaban N=4150 1.5 1.0 0.5 0.0 0 30 60 90 120 150 180 210 240 270 300 330 360 Time to event (days) 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

EINSTEIN DVT/PE: major bleeding Rivaroxaban Enoxaparin/VKA HR (95% CI) n/N (%) n/N (%) p -value 3.0 Cumulative event rate (%) 0.54 (0.37 – 0.79) 40/4130 72/4116 (1.0) (1.7) p =0.002 2.5 2.0 Enoxaparin/VKA N=4116 1.5 1.0 Rivaroxaban N=4130 0.5 0.0 0 30 60 90 120 150 180 210 240 270 300 330 360 Time to event (days) 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

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 Major bleeding Rivaroxaban n=45 VKA n=79 Category 1 18 (40.0%) 17 (21.5%) Controllable Category 2 Requires 19 (42.2%) 34 (43.0%) measures to control, not serious Category 3 7 (15.6%) 26 (32.9%) Serious bleeding 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 - Major bleeding and use of prohemostatic measures Rivaroxaban Enox/VKA n=45 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 0.98 (0.70 – 1.38) 65/3359 1.9 65/3349 1.9 Non-fragile 0.68 (0.39 – 1.18) Fragile 21/791 2.7 30/782 3.8 Major bleeding 0.80 (0.49 – 1.29) Non-fragile 30/3342 0.9 37/3337 1.1 0.27 (0.13 – 0.54) Fragile 10/788 1.3 35/779 4.5 *Age >75 years, CrCl <50 ml/min, or body weight ≤50 kg

EINSTEIN DVT/PE: Major bleeding and kidney function 14 12 Rivaroxaban p trend =0.92 Major bleeding (%) Enoxaparin/VKA p trend =0.01 10 8 6 4.0 4 3.0 1.4 2 1.0 0.9 0.8 0 50−80 >80 <50 Creatinine clearance (ml/min)

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 vasculature 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

Venous thromboembolism and cancer  Long-term LMWH is recommended  LMWH is often not used based on medical, economic and quality of life considerations  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 populations 8281 patients randomized No known History of Active cancer Active cancer cancer cancer at baseline during study (n=7157) (n=469) (n=462) (n=193)

EINSTEIN DVT/PE: Outcomes No known cancer Rivaroxaban Enoxaparin/VKA HR (95% CI) 0.93 (0.66 – 1.30) Recurrent VTE, n (%) 65/3563 (1.8) 70/3594 (1.9) 0.58 (0.37 – 0.91) Major bleeding, n (%) 31/3546 (0.9) 53/3582 (1.5) 0.77 (0.49 – 1.22) Mortality, n (%) 33/3563 (0.9) 42/3594(1.2)

EINSTEIN DVT/PE: Outcomes History of cancer Rivaroxaban Enoxaparin/VKA HR (95% CI) 0.98 (0.28 – 3.43) Recurrent VTE, n (%) 5/233 (2.1) 5/236 (2.1) 0.23 (0.03 – 2.06) Major bleeding, n (%) 1/231 (0.4) 4/236 (1.7) 1.12 (0.30 – 4.22) Mortality, n (%) 5/233 (2.1) 4/236 (1.7)

EINSTEIN DVT/PE: Outcomes 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

EINSTEIN DVT/PE in cancer: Major bleeding and kidney function 14 13.0 12 Rivaroxaban p trend =0.92 Major bleeding (%) Enoxaparin/VKA p trend =0.01 10 8 6 5.0 4 2.7 2.4 2.2 2.1 2 0 50−80 >80 <50 Creatinine clearance (ml/min)

EINSTEIN DVT/PE: conclusions  In patients with acute symptomatic DVT and/or PE, rivaroxaban showed:  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