Rapaport Lecture: Antiplatelet Therapy after PCI Making Sense of - PDF document

12/7/19 Rapaport Lecture: Antiplatelet Therapy after PCI – Making Sense of the Evidence Deepak L. Bhatt, MD, MPH Executive Director of Interventional Cardiovascular Programs, Brigham and Women’s Hospital Heart and Vascular Center Professor of Medicine, Harvard Medical School 1 Disclosures Dr. Deepak L. Bhatt discloses the following relationships - Advisory Board: Cardax, Cereno Scientific, Elsevier Practice Update Cardiology, Medscape Cardiology, PhaseBio, Regado Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care, TobeSoft; Chair: American Heart Association Quality Oversight Committee; Data Monitoring Committees: Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo), Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Vice-Chair, ACC Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), Medtelligence/ReachMD (CME steering committees), Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer) , Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Research Funding : Abbott, Afimmune, Amarin, Amgen, AstraZeneca , Bayer , Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Idorsia, Ironwood, Ischemix, Lilly, Medtronic, PhaseBio , Pfizer, PLx Pharma, Regeneron, Roche, Sanofi Aventis, Synaptic, The Medicines Company; Royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); Site Co-Investigator: Biotronik, Boston Scientific, St. Jude Medical (now Abbott), Svelte; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Fractyl, Merck, Novo Nordisk, Takeda. This presentation discusses off label and investigational uses of drugs. THEMIS and THEMIS-PCI were funded by AstraZeneca. COMPASS was funded by Bayer. 2 1

12/7/19 Role of Platelet Activation and Aggregation Bhatt DL. N Engl J Med 2007;357:2078-81. 3 Enteric Coated Aspirin Bhatt DL, Grosser T, Dong J, et al. JACC 2017. 4 2

12/7/19 ADP Receptors AR–C69931MX Clopidogrel Receptor subtype P2Y 1 P2Y 12 Active P2X 1 metabolite G protein G protein Molecular Intrinsic GPCR GPCR structure ion channel G q G i Secondary ­ [Na + /Ca 2+ ] i ­ PLC/IP 3 ¯ AC messenger system ­ [Ca 2+ ] i ¯ [cAMP] Functional Shape change Shape change Sustained response aggregation transient aggregation aggregation secretion Bhatt DL et al. Nat Rev Drug Discov . 2003;2:15-28. 5 PCI-CURE Study: CV Death or MI From Randomization Placebo + Aspirin .15 12.6% Median 31% (n=1345) time to PCI Cumulative Hazard Rate Relative Risk Reduction .10 8.8% Clopidogrel + Aspirin .05 (n=1313) P =.002 .00 0 10 100 200 300 400 Days of Follow-up Mehta SR, Yusuf S, Peters RJG, et al. Lancet . 2001;358:527-533. 6 3

12/7/19 CREDO: Long-Term (1 Year) Benefits of Clopidogrel in PCI Patients MI, stroke, or death – ITT population 15 Placebo* Clopidogrel* Combined endpoint 11.5% 27% RRR occurrence (%) 10 P =0.02 8.5% 5 0 0 3 6 9 12 Months from randomization * Plus ASA and other standard therapies. Steinhubl S, Berger P, Tift Mann III J et al. JAMA . 2002;Vol 288,No 19:2411-2420. 7 COGENT Trial – Effect of PPI on Composite GI Events Primary Gastrointestinal Endpoint Omeprazole 1.00 Probability of Freedom from Placebo 0.90 HR=0.34, 95% CI=0.18-0.63 P<0.001 by the log-rank test 0.00 0 50 100 150 180 200 Time (Days) No. at Risk Placebo 1885 1455 951 523 260 231 Omeprazole 1876 1500 987 553 250 215 Bhatt DL, Cryer BL, Contant CF, et al. N Engl J Med 2010;363:1909-17. 8 4

12/7/19 Mechanism of Action of Prasugrel Bhatt DL. N Engl J Med 2009;361:940-2. 9 TRITON TIMI-38: Net Clinical Benefit Bleeding Risk Subgroups Post hoc analysis Risk (%) Yes + 54 Prior Stroke / TIA -16 No P int = 0.006 -1 >=75 Age -16 P int = 0.18 < 75 +3 < 60 kg Wgt P int = 0.36 >= 60 kg -14 -13 OVERALL 0.5 1 2 Prasugrel Better Clopidogrel Better HR Wiviott SD et al. NEJM . 2007;357:2001-15. 10 5

12/7/19 Bhatt DL. N Engl J Med 2007;357:2078-81. 11 Mechanism of Action of Ticagrelor Bhatt DL. Nature Reviews Cardiology . 2009;6:737-38. 12 6

12/7/19 PLATO: CV Death, MI, or Stroke 13 12 Clopidogrel 11.7 11 Cumulative incidence (%) 10 9.8 9 Ticagrelor 8 7 6 5 4 3 2 1 HR 0.84 (95% CI 0.77–0.92), p=0.0003 0 0 60 120 180 240 300 360 Days after randomisation No. at risk 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 Wallentin L, et al. N Engl J Med. 2009. 13 PLATO: Secondary Endpoints Myocardial infarction Cardiovascular death 7 7 6.9 Clopidogrel 6 6 5.8 Cumulative incidence (%) Cumulative incidence (%) Clopidogrel 5.1 5 5 Ticagrelor 4 4.0 4 Ticagrelor 3 3 2 2 1 1 HR 0.84 (95% CI 0.75–0.95), p=0.005 HR 0.79 (95% CI 0.69–0.91), p=0.001 0 0 0 60 120 180 240 300 360 0 60 120 180 240 300 360 Days after randomisation Days after randomisation No. at risk 9,333 8,294 8,822 8,626 7119 5,482 4,419 Ticagrelor 9,333 8,678 8,520 8,279 6,796 5,210 4,191 9,291 8,865 8,780 8,589 7079 5,441 4,364 Clopidogrel 9,291 8,560 8,405 8,177 6,703 5,136 4,109 Wallentin L, et al. N Engl J Med. 2009. 14 7

12/7/19 Major Bleeding: Non-CABG vs CABG 9 Ticagrelor NS Clopidogrel 7.9 8 K-M estimated rate (% per year) 7.4 7 NS 5.8 6 5.3 p=0.026 5 4.5 3.8 4 p=0.025 2.8 3 2.2 2 1 0 Non-CABG Non-CABG CABG CABG PLATO major TIMI major PLATO major TIMI major bleeding bleeding bleeding bleeding Wallentin L, et al. N Engl J Med. 2009. 15 Onset and Duration of Ticagrelor Reversal - LTA Volunteers in Cohorts 7-10 were given fixed 18-g doses of PB2452 for 8, 12, and 16 hours in Cohorts 7, 8, and 9/10, respectively 1. Immediate and sustained ticagrelor reversal with bolus + P<0.001 across all timepoints, Bonferroni adjusted prolonged infusion of 18 g PB2452. 2. Significant reversal was observed 5 minutes after initiation of PB2452 infusion. 3. Duration of reversal was infusion-time dependent, lasting 20-24 hours with a 16- hour infusion . P values by timepoint for each cohort Cohort 5min 0.25h 0.5h 1h 2h 3h 6h 8h 10h 12h 16h 20h 7 0.040 0.040 0.131 0.037 0.040 0.019 0.019 0.019 0.152 0.019 0.019 0.224 8 0.019 0.019 0.019 0.019 0.019 0.019 0.019 0.019 0.152 0.019 0.019 0.019 10 0.043 0.020 0.020 0.020 0.020 0.020 0.020 0.020 N/A 0.020 0.020 0.020 Due to the small sample size for cohort 9 (n=3), statistical testing was not performed. For Cohorts 9 and 10, no 10-hour timepoint was collected. P-values for time point 24 hours or above are not significant. LTA= light transmittance aggregometry; ADP is the agonist Bhatt DL, Pollack CV, Weitz JI, et al. N Engl J Med . 2019. 16 8

12/7/19 Primary Efficacy Results (MI/Stroke/CV Death) by Pre-Specified Entry Category Population RR (95% CI) p value Qualifying CAD, CVD or PAD * 0.88 (0.77, 0.998) 0.046 (n=12,153) Multiple Risk Factors * 1.20 (0.91, 1.59) 0.20 (n=3,284) Overall Population † 0.93 (0.83, 1.05) 0.22 (n=15,603) 1.2 1.4 1.6 0.4 0.6 0.8 Clopidogrel + ASA Placebo + ASA Better Better * A statistical test for interaction showed marginally significant heterogeneity (p=0.045) in treatment response for these pre- specified subgroups of patients † 166 patients did not meet any of the main inclusion criteria Bhatt DL, Fox KA, Hacke W, et al. NEJM 2006. 17 Primary Endpoint (MI/Stroke/CV Death) in Patients With Previous MI, IS, or PAD* “CAPRIE-like Cohort” Cardiovascular Death/MI/Stroke (aspirin background therapy) Placebo Placebo Clopidogrel Clopidogrel HR (95% CI) P value P value Prior MI Prior MI 8.3% 8.3% 6.6% 6.6% 0.774 (0.613, 0.978) 0.774 (0.613, 0.978) 0.031 0.031 Prior IS Prior IS 10.7% 10.7% 8.4% 8.4% 0.780 (0.624, 0.976) 0.780 (0.624, 0.976) 0.029 0.029 Prior PAD Prior PAD 8.7% 8.7% 7.6% 7.6% 0.869 (0.671, 1.125) 0.869 (0.671, 1.125) 0.085 0.085 Entire Cohort Entire Cohort 8.8% 8.8% 7.3% 7.3% 0.829 (0.719, 0.956) 0.829 (0.719, 0.956) 0.010 0.010 0.5 0.5 1 1 2 2 *Post hoc analysis. Bhatt DL et al. J Am Coll Cardiol. 2007;49:1982-1988. 18 9