The Myth of Class Effect Antithrombotics Christopher Cannon, MD Cardiovascular Division Brigham and Women s Hospital Associate Professor of Medicine Harvard Medical School Senior Investigator, TIMI Study Group
Presenter Disclosure Information Christopher Cannon The following relationships exist related to this presentation: Research Support: Accumetrics, AstraZeneca, GSK, Merck, Takeda - Advisory Boards (funds donated to charity) BMS-Sanofi partnership, Novartis, Alnylam - Honoraria for independent educational symposium Pfizer, AstraZeneca - Clinical Advisor and equity: Automedics Medical Systems
Class Effect Is it a Myth? Or Real? Definition: A generally similar effect across drugs in a class. Factors to consider between drugs: Dose/ potency Pleiotropic effects However, need to look at other trial factors Sample size/power / Beta error Patent population GP IIb/IIIa inhibitors P2Y12 inhibitors Oral anticoagulants
Glycoprotein (GP) IIb/IIIa Inhibition for Non-ST-Elevation ACS Trial N 30-Day Death or Nonfatal MI Risk Ratio and 95% CI Placebo GP IIb/IIIa Inhibitor PRISM 3,232 7.1% 5.8% PRISM-PLUS 12.0% 10.2% 1,915 PARAGON-A 11.7% 11.3% 2,282 PURSUIT* 15.7% 14.2% 9,461 PARAGON B 11.4% 10.6% 5,225 GUSTO-IV ACS 7,800 0.91 (0.85, 0.98) Pooled P=0.015 11.8% 31,402 0.5 GPI Better 1.0 Placebo Better 1.5 8.0% 8.7% 10.8% *High dose eptifibatide only. ACS=acute coronary syndrome; CI =confidence interval; GPI=glycoprotein IIb/IIIa inhibitor; GUSTO=Global Utilization of Strategies to Open Occluded Coronary Arteries; PARAGON=Platelet IIb/IIIa Antagonism for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network; PLUS=Patients Limited by Unstable Signs and Symptoms; PRISM=Platelet Receptor Inhibition in Ischemic Syndrome Management; PURSUIT=Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy. Boersma E, et al. Lancet. 2002;359(9302):189-198.
Benefits of GP IIb/IIIa by Troponin T (TnT) Status in Clinical Trials TnT-Positive TnT-Negative PARAGON-B PRISM CAPTURE Combined 0.125 0.5 1 2 0.125 0.5 1 2 GP IIb/IIIa Better GP IIb/IIIa Worse GP IIb/IIIa Better GP IIb/IIIa Worse CAPTURE= c7e3 Fab Antiplatelet Therapy In Unstable Refractory Angina; PARAGON=Platelet IIb/IIIa Antagonism for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network; PRISM=Platelet Receptor Inhibition in Ischemic Syndrome Management. Reprinted with permission from Newby LK, et al. Circulation. 2001;103(24):2891-2896.
GP IIb/IIIa Inhibition in PCI No Clopidogrel Pre-Loading, Unfractionated Heparin D = 5.5% 51% RR p <0.0001 D = 3.7% 35% RR p = 0.0034 AML
Primary Endpoint: 30-Day Death, MI, Urgent TVR But was tirofiban the right dose? 12% p=0.037 RR = 1.26 9% 6% 3% 0% Tirofiban Abciximab Topol EJ, et al. NEJM 2001; 344:1888 1894 % inhibition 100 90 80 70 60 50 40 30 20 10 0 Ab v. E P=0.0002 Ab v. T P=0.0002 E v. T P=0.003 abcixi mab eptifib atide tirofiban Simon DI, et al. Catheter CV Interv. 2001;52:425-432.
TENACITY 30-Day Clinical Outcome ntirofiban: 25 µg/kg bolus, 0.15 µg /kg/min x 12 hours nabciximab: 0.25 mg/kg bolus 0.125 µg/kg/min x 12hours 10% P=0.502 Abciximab (n=194) Tirofiban (n=189) 8% 6% 8.8 6.9 P=0.466 7.7 5.9 8.2 P=0.361 5.9 4% 2% 0 P=0.499 1.0 0 Composite Death MI Moliterno DM et al. Cardiovasc Cath Intervent 2009 Death/MI P=0.365 1.6 0.5 Urgent TVR Moliterno
30-Day: Death,MI, Urgent TVR IMPACT II Platelet Inhibition 50-60% 90-95% 10% 11.4% Placebo Eptifibatide 10.4% 9.9% 6.8% 5% p=0.ns p=0.0034 0% IMPACT II Inv. Lancet 1997;349:1422. ESPRIT Inv. Lancet. 2000;356:2037-44
Clopidogrel: Double vs Standard Dose CLOPIDOGREL in ACS with Planned Invasive Rx CV Death/MI/Stroke Standard Double HR 95% CI P Intn P PCI (2N=17,232) 4.5 3.9 0.85 0.74-0.99 0.036 0.016 No PCI (2N=7855) 4.2 4.9 1.17 0.95-1.44 0.14 Overall (2N=25,087) 4.4 4.2 0.95 0.84-1.07 0.370 Clopidogrel Standar d N=12579 Double N=12508 Hazard Ratio 95% CI P TIMI major* 0.95 1.04 1.09 0.85-1.40 0.50 CURRENT major 2.0 2.5 1.25 1.05-1.47 0.01 CURRENT severe 1.5 1.9 1.23 1.02-1.49 0.03
PRINCIPLE TIMI 44 Comparison with Higher Dose Clopidogrel N=201 IPA (%; 20 mm ADP) P<0.0001 for each IPA (%; 20 mm ADP) P<0.0001 Prasugrel 60 mg Clopidogrel 600 mg Hours Wiviott SD et al, Circulation. 2007;116:2923-2932. Copyright 2007 American Heart Association Clopidogrel 150 mg 14 Days 11 Prasugrel 10 mg
Endpoint (%) Prasugrel vs Clopiodogrel 15 10 CV Death / MI / Stroke Clopidogrel Prasugrel 12.1 9.9 138 events HR 0.81 (0.73-0.90) P=0.0004 NNT = 46 5 0 TIMI Major NonCABG Bleeds 0 30 60 90 180 270 360 450 Days Prasugrel Clopidogrel 2.4 1.8 35 events HR 1.32 (1.03-1.68) P=0.03 NNH = 167 Wiviott SD, Braunwald E, McCabe CH et al NEJM2007
Cumulative incidence (%) TICAGRELOR vs Clopidogrel in ACS 13 12 11 10 9 8 7 6 5 4 3 2 1 0 Clopidogrel Ticagrelor HR 0.84 (95% CI 0.77 0.92), p=0.0003 11.7 9.8 0 60 120 180 240 300 360 No. at risk Days after randomisation Ticagrelor 9,333 8,628 8,460 8,219 6,743 5,161 4,147 Clopidogrel 9,291 8,521 8,362 8,124 6,743 5,096 4,047 K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval Adapted from Wallentin L, et al. N Engl J Med. 2009;361:1045-1057.
Hierarchical testing major efficacy endpoints All patients* Ticagrelor (n=9,333) Clopidogrel (n=9,291) HR for (95% CI) p value Primary objective, n (%) CV death + MI + stroke 864 (9.8) 1,014 (11.7) 0.84 (0.77 0.92) <0.001 Secondary objectives, n (%) Total death + MI + stroke 901 (10.2) 1,065 (12.3) 0.84 (0.77 0.92) <0.001 CV death + MI + stroke + ischaemia + TIA + arterial thrombotic events 1,290 (14.6) 1,456 (16.7) 0.88 (0.81 0.95) <0.001 Myocardial infarction 504 (5.8) 593 (6.9) 0.84 (0.75 0.95) 0.005 CV death 353 (4.0) 442 (5.1) 0.79 (0.69 0.91) 0.001 Stroke 125 (1.5) 106 (1.3) 1.17 (0.91 1.52) 0.22 Total death 399 (4.5) 506 (5.9) 0.78 (0.69 0.89) <0.001 The percentages are K-M estimates of the rate of the endpoint at 12 months. Wallentin L, et al. N Engl J Med. 2009;361:1045-1057.
Proportion of population (%) STEMI Cohort endpoints at 30 days 10 N=3534 Clopidogrel Prasugrel p= 0.002 p= 0.004 p= 0.02 8 p= 0.01 6 4 2 p= 0.04 p= 0.13 p= 0.008 0 All Death MI UTVR Stent CV Death/ Thrombosis* MI CV Death/ MI/UTVR CV Death/ MI/Stroke Montalescot et al. Lancet 2009; 373: 723 31 (ESC 2008)
Proportion of population (%) STEMI Cohort endpoints at 15 months Clopidogrel Prasugrel 14 12 p= 0.007 p= 0.03 p= 0.02 10 p= 0.02 8 6 4 p= 0.11 p= 0.09 p= 0.02 2 0 All Death MI UTVR Stent CV Death/ Thrombosis* MI CV Death/ MI/UTVR CV Death/ MI/Stroke * ARC def/probable Montalescot et al. Lancet 2009; 373: 723 31 (ESC 2008)
PLATO intent for non-invasive management: Efficacy outcomes Event CV death, MI or stroke Ticagrelor,% (n=2601) Clopidogrel, % (n=2615) HR (95% CI) p value 12.0 14.3 0.045 MI 7.2 7.8 0.555 CV death 5.5 7.2 0.019 All-cause death 6.1 8.2 0.010 Non-CV death 0.6 1.0 0.252 Stroke 2.1 1.7 0.162 0.2 1.0 2.0 Ticagrelor better Clopidogrel better James S, et al. BMJ 2011;342:d3527. 17
Intensive Antiplatelet Therapy vs Standard Clopidogrel P< 0.05 (unless noted) Definite Stent Thrombosis Non-CABG Major Bleeding (Protocol Defined) NS NS # Total for TRITON, PLATO, CV for CURRENT Adapted from Wallentin L, N Engl J Med. 2009 Adapted from Wiviott SD, Lancet. 2008 Adapted from Mehta S, ESC 2009
108 0 Antiplatelet Therapy in ACS ASA ASA + Clopidogrel ASA + Prasugrel - 22% - 20% Reduction in Ischemic Events - 19% + 60% + 38% + 32% Placebo APTC CURE TRITON-TIMI 38 Single Dual Higher Antiplatelet Rx Antiplatelet Rx IPA Increase in Major Bleeds
New Anticoagulants ORAL AGENTS TF/VIIa Rivaroxaban Apixaban Edoxaban Darexaban (YM150) LY517717 Betrixaban TAK 442 X IXa VIIIa Va Xa II IX Dabigatran (Ximelagatran) IIa Fibrinogen Fibrin Adapted from Weitz & Bates, J Thromb Haemost 2007
Stroke or Systemic Embolism Dabigatran 110 vs. Warfarin Non-inferiority p-value <0.001 Superiority p-value 0.34 Dabigatran 150 vs. Warfarin <0.001 <0.001 Margin = 1.46 0.50 0.75 1.00 1.25 1.50 Dabigatran better HR (95% CI) Warfarin better
RE-LY Efficacy Dabigatran 110 mg Dabigatran 150 mg Stroke/SEE 0.91 (0.74-1.11) 0.66 (0.53-0.82) Ischemic Stroke 1.11 (0.89-1.40) 0.76 (0.60-0.98) Hemorrhagic Stroke 0.31 (0.17-0.56) 0.26 (0.14-0.49) Connolly, et al. N Engl J Med 2009;361:1139-51 0.1 0.3 0.5 1.0 2.0 Dabigatran Better Warfarin Better 22
RE-LY Safety Dabigatran 110 mg Dabigatran 150 mg Major Bleed 0.80 (0.69-0.93) 0.93 (0.81-1.07) ICH 0.31 (0.20-0.47) 0.40 (0.27-0.60) GI Bleed 1.10 (0.86-1.41) 1.50 (1.19-1.89) MI 1.29 (0.96-1.75) 1.27 (0.94-1.71) Connolly, et al. N Engl J Med 2009;361:1139-51 0.1 0.3 0.5 1.0 2.0 Dabigatran Better Warfarin Better 23
Cumulative event rate (%) 6 5 4 3 2 1 Primary Efficacy Outcome Stroke and non-cns Embolism Event Rate Rivaroxaban Warfarin 1.71 2.16 Warfarin Rivaroxaban 20 mg once daily HR (95% CI): 0.79 (0.66, 0.96) P-value Non-Inferiority: <0.001 0 0 120 240 360 480 600 720 840 960 No. at risk: Rivaroxaban 6958 6211 5786 5468 4406 3407 2472 1496 634 Warfarin 7004 6327 5911 5542 4461 3478 2539 1538 655 Event Rates are per 100 patient-years Based on Protocol Compliant on Treatment Population Days from Randomization
Primary Efficacy Outcome Stroke and non-cns Embolism On Treatment N= 14,143 Rivaroxaban Warfarin Event Event Rate Rate 1.70 2.15 HR (95% CI) 0.79 (0.65,0.95) P-value 0.015 ITT N= 14,171 2.12 2.42 0.88 (0.74,1.03) 0.117 Rivaroxaban better Warfarin better Event Rates are per 100 patient-years Based on Safety on Treatment or Intention-to-Treat thru Site Notification populations
Primary Safety Outcomes Major and non-major Clinically Relevant Rivaroxaban Event Rate Warfarin Event Rate HR (95% CI) P- value 14.91 14.52 1.03 (0.96, 1.11) 0.442 Major 3.60 3.45 1.04 (0.90, 1.20) 0.576 Non-major Clinically Relevant 11.80 11.37 1.04 (0.96, 1.13) 0.345 Event Rates are per 100 patient-years Based on Safety on Treatment Population
ARISTOTLE Atrial Fibrillation with At Least One Additional Risk Factor for Stroke Randomize Double blind (n = 18,183) Age 75 years Prior stroke, TIA or SE CHF or LVEF 40% Diabetes mellitus Hypertension Apixaban 5 mg oral twice daily + Warfarin placebo Apixaban placebo twice daily + Warfarin (target INR 2-3) Warfarin/warfarin placebo adjusted by INR/sham INR based on encrypted point-of-care testing device Primary outcome: stroke and systemic embolism Other outcomes: Death, MI, bleeding Stratified by warfarin-naïve status 448 events over anticipated 2 year median follow-up; >90% power to show non-inferiority (apixaban vs warfarin upper bound of 95% CI <1.38) 27
Granger CB et al. NEJM Online 2011 Atrial Fibrillation with At Least One Additional Risk Factor for Stroke
Overview of the New Anticoagulatnts for Atrial Fibrillation Comparison with Warfarin Stroke/Emb ICH Mortality Major bleed Dabi 150 bid Superior Superior HR 0.88 (.051) Equiv Dabi 110 bid Non-Inf Superior HR 0.91 (NS) Superior Riva 20 qd Non-Inf Superior HR 0.92 (NS) Equiv Apixiban 5 bid Superior Superior HR 0.89 (.047) Superior Adapted from Mega JL. NEJM 2011 online.
Class Effect Is it a Myth? Or Real? I would say mostly YES It is real The primary pharmacologic effect dominates But DOSE MATTERS! Pleiotropic effects could explain differences Some most apparent differences between drugs may relate more to trial and patient population differences than in the drug. We thus use the drugs at the doses tested in trials that show benefit.