SLIDE 1 Oral Rivaroxaban for the Treatment of Symptomatic Venous Thromboembolism: A Pooled Analysis of the EINSTEIN DVT and EINSTEIN PE Studies
Anthonie WA Lensing
- n behalf of the EINSTEIN Investigators
Bayer symposium - Da Nang, 13 October
SLIDE 2
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
SLIDE 3
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
SLIDE 4
Rivaroxaban Can Rivaroxaban be given in a fixed dose without the requirement for monitoring and replace heparin and VKA treatment in DVT/PE patients?
SLIDE 5 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 PE1 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 DVT2 N=4833
Predefined treatment period of 3, 6, or 12 months 20 mg od
30-day post-study treatment period
Rivaroxaban
R
SLIDE 6 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 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)
SLIDE 7 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 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
SLIDE 8 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 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 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
SLIDE 9
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)
SLIDE 10
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
SLIDE 11 Outcome Rivaroxaban Enoxaparin/VKA HR (95% CI) n/N % n/N % Recurrent VTE 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) Major bleeding 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)
EINSTEIN DVT/PE:
- utcomes in fragile patients*
*Age >75 years, CrCl <50 ml/min, or body weight ≤50 kg
SLIDE 12
EINSTEIN DVT/PE: Major bleeding and kidney function
0.8 1.4 0.9 1.0 3.0 4.0 2 4 6 8 10 12 14 >80 50−80 <50 Major bleeding (%) Creatinine clearance (ml/min)
Rivaroxaban Enoxaparin/VKA ptrend=0.92 ptrend=0.01
SLIDE 13 Rivaroxaban Enoxaparin/VKA n/N % n/N % Limited
≤25% of vasculature of a single lobe, popliteal vein only
11/814 1.4 19/826 2.3 Intermediate 47/1941 2.4 50/1942 2.6 Extensive
multiple lobes and >25% of entire pulmonary vasculature; involving common femoral/ iliac vein
28/1218 2.3 25/1190 2.1
EINSTEIN DVT/PE: Clot size and recurrent VTE
SLIDE 14 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
Van Es, et al. JTH, 11: 679–85
SLIDE 15
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
SLIDE 16
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)
SLIDE 17
EINSTEIN DVT/PE: Analysis populations
Active cancer at baseline (n=462) Active cancer during study (n=193) History of cancer (n=469) No known cancer (n=7157) 8281 patients randomized
SLIDE 18
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)
SLIDE 19
EINSTEIN DVT/PE: Outcomes
History of cancer Rivaroxaban Enoxaparin/VKA HR (95% CI) Recurrent VTE, n (%) 5/233 (2.1) 5/236 (2.1) 0.98 (0.28–3.43) Major bleeding, n (%) 1/231 (0.4) 4/236 (1.7) 0.23 (0.03–2.06) Mortality, n (%) 5/233 (2.1) 4/236 (1.7) 1.12 (0.30–4.22)
SLIDE 20 EINSTEIN DVT/PE: Outcomes
Active cancer* Rivaroxaban Enoxaparin/VKA HR (95% CI) Recurrent VTE, n (%) 16/354 (4.5) 20/301 (6.6) 0.67 (0.35–1.30) Major bleeding, n (%) 8/353 (2.3) 15/298 (5.0) 0.42 (0.18–0.99) Mortality, n (%) 58/354 (16.4) 53/301 (17.6) 0.93 (0.64–1.35)
*At baseline or diagnosed during the study
SLIDE 21
EINSTEIN DVT/PE in cancer: Major bleeding and kidney function
2.4 2.2 2.1 2.7 5.0 13.0 2 4 6 8 10 12 14 >80 50−80 <50 Major bleeding (%) Creatinine clearance (ml/min)
Rivaroxaban Enoxaparin/VKA ptrend=0.92 ptrend=0.01
SLIDE 22
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
