CHRISTOPHER B. GRANGER, MD Professor of Medicine Division of Cardiology, Department of Medicine; Director, Cardiac Care Unit Duke University Medical Center, Durham, NC Clinical and Economic Value of Rivaroxaban in Coronary Artery Disease
Disclosures Research contracts: AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Daiichi Sankyo, FDA, Janssen, Novartis, GSK, Medtronic Foundation, Pfizer, The Medicines Company, FDA, NIH Consulting/Honoraria: AstraZeneca, Bayer, BMS, Boston Scientific, GSK, Pfizer, Lilly, Daiichi Sankyo, Novartis, Boehringer Ingelheim, Medtronic, Medtronic Foundation, Rho For full listing see www.dcri.duke.edu/research/coi.jsp
Anticoagulation to prevent thrombotic coronary artery disease events: a paradigm shift?
Secondary Prevention with Warfarin and ASA vs ASA alone after ACS 10 trials; n = 5938 Rate ratio (95% CI) Death 0.96 (0.77 1.20) MI 0.56 (0.46 0.69) Ischemic stroke 0.46 (0.27 0.77) Major bleeding event 2.48 (1.67 3.68) Minor bleeding event 2.65 (2.14 3.29) 0.05 1.0 5.0 Warfarin + Rate ratio ASA better ASA better Rothberg MB et al. Ann Intern Med 2005;143;241-250
Warfarin and ASA vs ASA alone after ACS 10 trials; n = 5938 Rothberg MB et al. Ann Intern Med 2005;143;241-250
Do not add aspirin to oral anticoagulation without a clear indication
Bleeding According to Antiplatelet Rx W none ASA ASA + clopi D 150 D 110 Series of no, single, and dual antiplatelet therapy HRs adjusted for age, gender, warfarin experience, SBP, CAD, HF, hypertension, diabetes, TIA, CrCl and statin use. Circulation. published online December 27, 2012
ASPECT-2 and WARIS II Trials: OAC vs ASA vs Both ASPECT-2 WARIS II Death, MI, stroke Death, MI, stroke Advances in pharmacogenomics will ultimately permit patient-specific antithrombotic therapy for patients with acute coronary syndromes and other thrombotic disorders. Becker RC WARIS II editorial Lancet 2002; 360: 109 13 N Engl J Med 2002;347:969 974
DAPT Guidelines DAPT for at least one year following ACS DAPT for at least 6 months following DES for stable CAD Can shorten therapy based on high bleeding risk
Rivaroxaban in Coronary Disease Acute coronary syndromes»atlas trials Patients treated with stents»gemini Patients with AF and stents»pioneer (and RE-DUAL) Patients with AF and coronary disease»rocket Patients with stable vascular disease»compass
Estimated Cumulative Incidence (%) PRIMARY EFFICACY ENDPOINT: CV Death / MI / Stroke Placebo 2 Yr KM Estimate 10.7% 8.9% Rivaroxaban (both doses) HR 0.84 (0.74-0.96) mitt p = 0.008 ITT p = 0.002 ARR 1.8% NNT = 56 No. at Risk Placebo Rivaroxaban Months After Randomization 5113 4307 3470 2664 1831 1079 421 10229 8502 6753 5137 3554 2084 831 HR and 95% confidence interval estimates from Cox model stratified by thienopyridine use are provided per mitt approach; Stratified log-rank p-values are provided for both mitt and ITT approaches.
Estimated Cumulative incidence (%) 12% CV Death / MI / Stroke HR 0.85 mitt p=0.039 ITT p=0.011 EFFICACY ENDPOINTS: Very Low Dose 2.5 mg BID Patients Treated with ASA + Thienopyridine Cardiovascular Death Placebo HR 0.62 Placebo HR 0.64 10.4% 9.0% 5% 5% mitt p<0.001 ITT p<0.001 4.2% mitt p<0.001 ITT p<0.001 All Cause Death Placebo 4.5% 2.5% 2.7% Rivaroxaban 2.5 mg BID 12 0 12 24 12 Months Months Months 0 24 Rivaroxaban 2.5 mg BID NNT = 71 NNT = 59 Rivaroxaban 2.5 mg BID NNT = 56 0 24
Percent (%) TREATMENT-EMERGENT FATAL BLEEDS AND ICH 1.2 1 p=ns for Riva vs Placebo p=ns for Riva 5 vs Placebo p=ns for Riva 2.5 vs Placebo p=0.044 for Riva 2.5 vs 5 p=0.009 for Riva vs Placebo p= 0.005 Riva 5 vs Placebo P=0.037 for Riva 2.5 vs Placebo p=0.44 for Riva 2.5 vs 5 Placebo 2.5 mg Rivaroxaban 5.0 mg Rivaroxaban 0.8 0.7 0.6 0.4 0.2 0 0.4 0.2 0.2 0.1 n=9 n=6 n=15 0.4 n=5 n=14 n=18 p=ns for all comparisons 0.1 0.1 Fatal ICH Fatal ICH 0.2 n=4 n=5 n=8
Stent Thrombosis with NOAC Plus DAPT vs DAPT Alone Definite/prob 35% Definite/prob/poss 31% Gibson CM et al. J Am Coll Cardiol. 2013;62:286-290.
Stent Thrombosis with NOAC Plus DAPT vs DAPT Alone after ACS Reported stent thrombosis (%) Trial f/u (m) n NOAC Placebo RR 95% CI) NNT APPRAISE-2 8 7,392 0.9 1.3 0.73 (0.47-1.12) * 250 ATLAS-2 1 13 15,526 2.3 2.9 0.69 (0.51-0.93) ** 250 1 Both doses * p=0.15 ** p=0.02 Verheugt FWA. Eur Heart J 2013;34:1618-1620
For patients with ACS, after several days, on clopidogrel, randomized to rivaroxaban (2.5 bid) vs aspirin
Exploratory Individual Ischemic Endpoints Aspirin (N=1518) Rivaroxaban (N=1519) HR (95% CI) P Value CV death, MI, stroke, or definite stent thrombosis 72 (4.7%) 76 (5.0%) 1.06 (0.77 1.46) 0.73 MI 49 (3.2%) 56 (3.7%) 1.15 (0.78 1.68) 0.49 Stroke 12 (0.8%) 7 (0.5%) 0.58 (0.23 1.48) 0.25 All stent thrombosis 16 (1.1%) 17 (1.1%) 1.06 (0.54 2.11) 0.86
Stenting in patients with AF Prevent stent thrombosis Prevent stroke DAPT + OAC Causes lots of bleeding
Triple therapy perpectives North American Perspective 2016 ESC DAPT Guidelines Circ Cardiovasc Interv. 2016;9:e004395 Valgimigli M, et al. Eur Heart J 2017;0:1-48.
Dose of Rivaroxaban Varies in ACS & Atrial Fibrillation Patients ACS/ Stenting Stent + Afib Atrial Fibrillation DAPT + 2.5 mg BID Riva Riva 20 mg QD 4 Fold Difference in Riva Dose Between ACS and AF 1. Schmitt J et al Atrial fibrillation in acute myocardial infarction: a systematic review of the incidence, clinical features and prognostic implications. Eur Heart J 2009;30:1038 1045. Gibson et al. AHA 2016
TIMI Major, TIMI Minor, or Bleeding Requiring Medical Attention (%) Kaplan-Meier Estimates of First Occurrence of Clinically Significant Bleeding Events 26.7% VKA VKA + DAPT + DAPT Riva + DAPT p<0.000013 p<0.00018 18.0% 16.8% Riva + P2Y 12 v. VKA + DAPT HR=0.59 (95% CI: 0.47-0.76) p <0.000013 ARR=9.9 NNT=11 Riva + P2Y 12 HR = 0.63 (95% CI 0.50-0.80) HR ARR = 0.59 = (95% 8.7 Riva + CI DAPT 0.47-0.76) v. VKA + DAPT ARR NNT = 9.9 = 12HR=0.63 (95% CI: 0.50-0.80) NNT = 11 p <0.00018 ARR=8.7 NNT=12 Gibson et al. AHA 2016 No. at risk VKA Riva + DAPT P2Y 12 VKA Riva + DAPT VKA + DAPT 697 706 696 697 706 697 Days 593 636 628 555 600 606 521 579 585 461 543 426 509 510 383 329 409 593 636 555 600 521 579 461 543 426 509 409 329 593 555 521 461 426 329 Treatment-emergent period: period starting after the first study drug administration following randomization and ending 2 days after stop of study drug. Clinically significant bleeding is the composite of TIMI major, TIMI minor, and BRMA. Hazard ratios as compared to the VKA group are based on the (stratified, only for Overall, 2.5 mg BID/15 mg QD comparing VKA) Cox proportional hazards model. Log-Rank P-values as compared to VKA group are based on the (stratified, only for Overall, 2.5 mg BID/15 mg QD comparing VKA) two-sided log rank test.
Major Adverse Cardiac Events All Strata Kaplan-Meier Estimates Hazard Ratio (95% CI) Overall Riva + P2Y 12 (N=694) Riva + DAPT (N=704) VKA + DAPT (N=695) Riva + P2Y 12 vs. VKA + DAPT Riva + DAPT vs. VKA + DAPT Adverse CV Event 41 (6.5%) 36 (5.6%) 36 (6.0%) 1.08 (0.69-1.68) p=0.750 0.93 (0.59-1.48) p=0.765 CV Death 15 (2.4%) 14 (2.2%) 11 (1.9%) 1.29 (0.59-2.80) p=0.523 1.19 (0.54-2.62) p=0.664 MI 19 (3.0%) 17 (2.7%) 21 (3.5%) 0.86 (0.46-1.59) p=0.625 0.75 (0.40-1.42) p=0.374 Stroke 8 (1.3%) 10 (1.5%) 7 (1.2%) 1.07 (0.39-2.96) p=0.891 1.36 (0.52-3.58) p=0.530 Stent Thrombosis 5 (0.8%) 6 (0.9%) 4 (0.7%) 1.20 (0.32-4.45) p=0.790 1.44 (0.40-5.09) p=0.574 Adverse CV Events + Stent Thrombosis 41 (6.5%) 36 (5.6%) 36 (6.0%) 1.08 (0.69-1.68) P=0.750 0.93 (0.59-1.48) p=0.765 Gibson et al. AHA 2016 Treatment-emergent period: period starting after the first study drug administration following randomization and ending 2 days after stop of study drug. A subject could have more than component event. n = number of subjects with events, N = number of subjects at risk, % = KM estimate at the end of study. Hazard ratios as compared to VKA group are based on the (stratified, only for Overall, 2.5 mg BID/15 mg QD comparing VKA) Cox proportional hazards model. Log-Rank p-values as compared to VKA group are based on the (stratified, only for Overall 2.5 mg BID/15 mg QD comparing VKA) two-sided log rank test. CI = confidence interval, DAPT = dual antiplatelet therapy, HR = hazard ratio, VKA = vitamin K antagonist 6 Subjects were excluded from all efficacy analyses because of violations in Good Clinical Practice guidelines.
Probability of event (%) Primary Endpoint: Time to first ISTH major or clinically relevant non-major bleeding event 40 40 35 30 HR: 0.52 (95% CI: 0.42 0.63) Non-inferiority P<0.0001 P<0.0001 Warfarin triple therapy 35 30 HR: 0.72 (95% CI: 0.58 0.88) Non-inferiority P<0.0001 P=0.002 Warfarin triple therapy 25 25 20 20 Dabigatran 150 mg dual therapy 15 Dabigatran 110 mg dual therapy 15 10 10 5 5 0 0 90 180 270 360 450 540 630 720 0 0 90 180 270 360 450 540 630 720 Time to first event (days) Time to first event (days) Full analysis set presented. HRs and Wald CIs from Cox proportional-hazard model. For the dabigatran 110 mg vs warfarin comparison, the model is stratified by age, non-elderly vs elderly (<70 or 70 in Japan and <80 or 80 years old elsewhere). For the dabigatran 150 mg vs warfarin comparison, an unstratified model is used, elderly patients outside the USA are excluded. Noninferiority P value is one sided (alpha=0.025). Wald two-sided P value from (stratified) Cox proportional-hazard model (alpha=0.05)
Additional individual thromboembolic endpoints Dabi 110 mg dual therapy (n=981) n (%) Warfarin triple therapy (n=981) n (%) D110 DT vs warfarin TT Dabi 150 Warfarin D150 DT vs warfarin TT mg dual triple therapy therapy HR (95% CI) P value (n=763) (n=764) HR (95% CI) P value n (%) n (%) All-cause death 55 (5.6) 48 (4.9) 1.12 (0.76 1.65) 0.56 30 (3.9) 35 (4.6) 0.83 (0.51 1.34) 0.44 Stroke 17 (1.7) 13 (1.3) 1.30 (0.63 2.67) 0.48 9 (1.2) 8 (1.0) 1.09 (0.42 2.83) 0.85 Unplanned revascularization 76 (7.7) 69 (7.0) 1.09 (0.79 1.51) 0.61 51 (6.7) 52 (6.8) 0.96 (0.65 1.41) 0.83 MI 44 (4.5) 29 (3.0) 1.51 (0.94 2.41) 0.09 26 (3.4) 22 (2.9) 1.16 (0.66 2.04) 0.61 Stent thrombosis 15 (1.5) 8 (0.8) 1.86 (0.79 4.40) 0.15 7 (0.9) 7 (0.9) 0.99 (0.35 2.81) 0.98 Results presented are times to event. Stent thrombosis is time to definite stent thrombosis
Triple vs Dual Therapy in AF and PCI: Meta-analysis Piccini JP, Jones WS. N Engl J Med 2017;377:1580-1582
Eikelboom JW et al. N Engl J Med 2017; 377:1319-1330
Primary: CV death, stroke, MI Outcome R + A N=9,152 A N=9,126 Rivaroxaban + aspirin vs. aspirin N (%) N (%) HR (95% CI) p CV death, stroke, MI 379 (4.1%) 496 (5.4%) 0.76 (0.66-0.86) <0.0001 27
Components of primary outcome R + A N=9,152 Aspirin N=9,126 Riva + aspirin vs. aspirin N (%) N (%) HR (95% CI) p CV death 160 (1.7) 203 (2.2) 0.78 (0.64-0.96) 0.02 Stroke 83 (0.9) 142 (1.6) 0.58 (0.44-0.76) <0.0001 MI 178 (1.9) 205 (2.2) 0.86 (0.70-1.05) 0.14 Eikelboom JW et al. N Engl J Med 2017; 377:1319-1330 www.phri.ca October 4, 2017
Myocardial infarction Event R + A N=9,152 N (%) Aspirin N=9,126 N (%) HR (95% CI) Riva + aspirin vs. aspirin p MI or SCD 247 (2.7%) 289 (3.2%) 0.85 (0.72-1.00) 0.06 MI, SCD, or cardiac arrest 273 (3.0%) 333 (3.6%) 0.81 (0.69-0.95) 0.01 MI, SCD, resus. Cardiac arrest, or unstable angina 277 (3.0%) 331 (3.6%) 0.83 (0.71-0.97) 0.02 Eikelboom JW et al. N Engl J Med 2017; 377:1319-1330 www.phri.ca October 4, 2017
Rivaroxaban + aspirin vs aspirin Net benefit Outcome Riva + aspirin N=9,152 Aspirin N=9,126 Rivaroxaban + aspirin vs. aspirin N % N % HR 95% CI P Primary + severe bleeds 426 4.7 529 5.8 0.80 0.70-0.91 0.0005 Eikelboom JW et al. N Engl J Med 2017; 377:1319-1330 www.phri.ca October 4, 2017
COMPASS in context - Antithrombotics for 2 0 prevention CAPRIE Clopidogrel CHARISMA Clopidogrel + aspirin PEGASUS Ticagrelor 90 + aspirin PEGASUS Ticagrelor 60 + aspirin COMPASS Rivaroxaban + aspirin MACE 7% 7% 15% 16% 24% Death 2% 1% 0% 11% 18% Stroke - 21%* 18% 25% 42% MI - 6%* 19% 16% 14% M. Bleeds 27% -25%-62% -169% -132% -70% ICH 29% 4% -44% -33% -16% *Non-fatal. severe and moderate GUSTO, respectively www.phri.ca October 4, 2017
COMPASS in context Lipid lowering (1mmol/L) BP Lowering (10mm Hg) ACE (HOPE) COMPASS Rivaroxaban+ aspirin MACE 21% 20% 22% 24% Death 9% 13% 16% 18% Stroke 15% 27% 32% 42% MI 24% 17% 20% 14% MALE - - 11% 46% HOPE Investigators. N Engl J Med 2000;342:145-53. Ettehad D, et al. Lancet 2016;387:957-67. CTT Collaboration. Lancet 2015;385:1397-1405; Collins R, et al. Lancet 2016;388:2532-61. www.phri.ca October 4, 2017
Summary Oral anticoagulation provides substantial protection against thrombotic vascular events Oral anticoagulation, especially when combined with antiplatelet therapy, has substantial bleeding risk Some oral anticoagulation (rivaroxaban 2.5 bid) has been shown to be the sweet spot where the antithrombotic benefit is greater than the bleeding risk, supported by the 18% RRR in mortality in COMPASS (and mortality reduction in ATLAS-2) For patients like those in COMPASS, there are important overall benefits of rivaroxaban 2.5 bid with aspirin which are likely to be cost effective The cost effectiveness of this therapy in practice will depend on patient risks of thrombotic and bleeding events