Antithrombotic Therapy for Long-Term Secondary Prevention - PowerPoint PPT Presentation

Antithrombotic Therapy for Long-Term Secondary Prevention – Considerations for Long-Term DAPT Marc P. Bonaca, MD, MPH Vascular Section, Cardiovascular Division Investigator TIMI Study Group Brigham and Women’s Hospital Assistant Professor, Harvard Medical School WCN Congress 2017

Disclosures: PEGASUS-TIMI 54 funded by a research grant to Brigham & Women’s Hospital from AstraZeneca Consulting: Aralez, AstraZeneca, Merck, Bayer, Roche

Antithrombotic therapy after coronary stenting 1653 patients (1772 lesions) with successful stent implantation “Antithrombotic drugs are used after coronary -artery stenting to prevent stent thrombosis… After coronary stenting, aspirin and ticlopidine should be considered for the prevention of the serious complication of stent thrombosis” Leon et al. NEJM 1998

Patients with Prior MI Remain at High Risk for Ischemic Events REACH Registry (4- yr outcomes) 64,977 patients ≥ 45 years old CV Death, MI, Stroke 24 21.1 20 17.2 16 % 12.2 12 9.1 8 4 0 Prior Ischemic Prior Ischemic Stable Risk Factor only Event <=1 Yr Event >1 y Atherosclerotic disease Bhatt et al. JAMA 2010; 304:1350-7.

Risk after ACS with Diabetes, Polyvascular Disease or Both PAD with and without Diabetes Probability of Primary Events Probability of Primary Events Time (year) post-randomization Gutierrez et al. ACC 2016

CURE: benefit of DAPT with aspirin and clopidogrel after ACS 12,562 Patients with NSTEACS (mostly conservatively managed) CV Death, MI, or Stroke CV Death, MI, or Stroke > 30 Days – 1 Year First 30 Days 1.00 1.00 Proportion Event-Free Proportion Event-Free Clopidogrel Clopidogrel .98 .98 .96 .96 Placebo Placebo .94 .94 RRR: 21% RRR: 18% 95% CI, 0.67 – 0.92 .92 95% CI, 0.70 – 0.95 .92 P =.003 P =.009 .90 .90 0 1 2 3 4 1 4 6 8 10 12 Week Month No. at Risk No. at Risk Clopidogrel 6259 6145 6070 6026 5990 5981 5481 4742 4004 3180 2418 Placebo 6303 6159 6048 5993 5965 5954 5390 4639 3929 3159 2388 Yusuf S, et al. Circulation . 2003;107:966-972.

Potent P2Y 12 Inhibitor After ACS Reduces Risk Early and Late & Reduces Mortality Death from any cause 4.5% vs 5.9% HR 0.78 (0.69 – 0.89), p<0.001 18,624 Patients w/in 24 hrs of onset of ACS (64% underwent PCI) 8 8 CV Death, MI, or Stroke (%) CV Death, MI, or Stroke (%) 6.60 Clopidogrel 6 6 Clopidogrel 5.43 5.28 4.77 4 4 Ticagrelor Ticagrelor 2 2 HR 0.88 (95% CI 0.77 – 1.00), p=0.045 HR 0.80 (95% CI 0.70 – 0.91), p<0.001 0 0 31 90 150 270 330 0 10 20 30 210 Days after randomisation * Days after randomisation No. at risk Ticagrelor 9,333 8,942 8,827 8,763 8,673 8,543 8,397 7,028 6,480 4,822 Clopidogrel 9,291 8,875 8,763 8,688 8,688 8,437 8,286 6,945 6,379 4,751 *Excludes patients with any primary event during the first 30 days

Randomized trials of dual antiplatelet treatment duration after drug-eluting stents Stent Myocardial Total DES Treatment Bleeding Trial Thrombosis Infarction Randomized Duration HR (95% CI) HR (95% CI) HR (95% CI) REAL + ZEST LATE 2701 24 vs. ~12 2.96 (0.31-28.46) 1.23 (0.33-4.58) 1.41 (0.54-3.71) PRODIGY 1357 24 vs 6 2.17 (1.44-3.22) 0.87 (0.41-1.81) 0.94 (0.61-1.45) 1443 12 vs 6 2.0 (0.37-11.11) 0.17 (0.02-1.39) 0.54 (0.21-1.35) EXCELLENT OPTIMIZE 3120 12 vs 3 1.41 (0.63-3.13) 0.95 (0.42-2.04) 0.85 (0.57-1.29) Continued ARCTIC- 1259 DAPT vs. 6.94 (0.85-56.61) 0 vs 3 events* 1.04 (0.41-26.2) Interruption ASA ITALIC 12 vs 6 3 vs. 0 events* 0 vs. 3 events* 0.67 (0.19-2.38) 1850 0.80 (0.21-3.03) 1.08 (0.51-2.27) ISAR-SAFE 4005 12 vs 6 1.25 (0.34-4.76) 9 events 27 events Park, et al. N Eng J Med 2010; 362:15. Collet, et al. Lancet 2014;384:1577. Valgimigli, et al. Circulation 2012;125:2015. Gillard, et al. J Am Coll Card Nov 2104. Gwon, et al. Circulation 2012;125:505. Schultz-Schupke, et al. EHJ Jan 25, 2015. Feres, et al. JAMA 2013; 310:510. 8

DAPT : Withdrawal of Thienopyridine 12 Months after Coronary Stenting Death, MI or stroke ~ 46% with history of MI Moderate/Severe Bleeding 2.5% vs.1.6% All Cause Mortality 2.0% vs 1.5% Mauri et al. NEJM 2014

CHARISMA: Prior MI a post-hoc exploratory subgroup 23% risk reduction if prior MI 10 N=3,846 8.3% 8 Placebo + ASA CV Death, MI, or Stroke (%) Clopidogrel + ASA 6.6% 6 4 2 HR=0.774 (95% CI [0.613 – 0.978]) P=0.031 0 30 0 6 12 18 24 Months Since Randomization 10 Bhatt DL et al. J Am Coll Cardiol. 2007;49:1982-1988.

DAPT : Prior MI and Efficacy for MACE Patients without MI Patients with MI HR 0.83, p=NS HR 0.56, p<0.001 0.9% ARR at 18 Months ~3% ARR at 18 Months Mortality higher Mortality lower (NS) Yeh et al. JACC 2015

Trial Design Stable pts with history of MI 1-3 yrs prior +  1 additional atherothrombosis risk factor* * Age >65 yrs, diabetes, 2 nd prior MI, multivessel CAD, or chronic non-end stage renal dysfunction RANDOMIZE Planned treatment with ASA 75 – 150 mg & DOUBLE BLIND Standard background care Ticagrelor Ticagrelor Placebo 90 mg bid 60 mg bid Follow-up Visits Event-driven trial Q4 mos for 1 st yr, then Q6 mos PEP: CVD/MI/Stroke Secondary: CV Death, Mortality Exploratory: Coronary death Safety: TIMI Major, ICH, Fatal An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School Bonaca MP et al. NEJM 2015;372:1791-800

Global Enrollment 21,162 patients randomized at 1161 sites in 31 countries between 10/2010 – 5/2013 Czech Rep: 870 Poland: 1399 Sweden: 507 Norway: 336 Ukraine: 623 Russia: 1061 Netherlands: 1560 Canada: Romania: 404 1306 Netherlands Second … U.K.: 647 S Korea: 506 Slovakia: 475 Belgium: 431 United States Hungary: 831 Japan: 903 Germany: 924 2601 Bulgaria: 447 China: 383 France: 333 Turkey: 180 America First! Philippines: 250 Spain: 535 Colombia: 528 Italy: 392 Brazil: 864 Peru: 245 Chile: 322 Australia: 327 Argentina: 499 South Africa: 473 13 An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School

But Actually … NETHERLANDS NLI: DR. TON OUDE OPHUIS No. Patients – 1560 No. Sites - 41 Average patients per site = 38 Patient Retention 99.94% An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School

Primary Endpoint 10 N = 21,162 Placebo (9.0%) Median follow-up 33 months 9 Ticagrelor 90 (7.8%) 8 CV Death, MI, or Stroke (%) Ticagrelor 60 (7.8%) 7 6 5 Ticagrelor 90 mg 4 HR 0.85 (95% CI 0.75 – 0.96) P=0.008 3 Ticagrelor 60 mg 2 HR 0.84 (95% CI 0.74 – 0.95) P=0.004 1 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Months from Randomization An Academic Research Organization of Bonaca MP et al. NEJM 2015;372:1791-800 Brigham and Women’s Hospital and Harvard Medical School

Efficacy over time Ticagrelor 60 mg Twice Daily Placebo First year in Trial Second year in Trial Third year in Trial HR 0.79 HR 0.90 HR 0.82 (95% CI 0.62 – 1.00) (95% CI 0.74 – 1.11) 4% 4% 4% (95% CI 0.67 – 0.99) 3.3% 3.0% 3.0% 3% 3% 3% 2.7% 2.8% 2.6% 2% 2% 2% 1% 1% 1% 0% 0% 0% 731 821 911 1001 366 456 546 636 726 0 90 180 270 360 Median 1.7 yrs Median 2.7 yrs Median 3.7 yrs From Index MI From Index MI From Index MI (1.2 – 2.3) (2.2 – 3.3) (3.2 – 4.3) An Academic Research Organization of Bonaca MP et al. JACC in Press Brigham and Women’s Hospital and Harvard Medical School

Components of Primary Endpoint HR (95% CI) P value Endpoint 0.85 (0.75-0.96) 0.008 0.84 (0.74-0.95) 0.004 CV Death, MI, or Stroke (1558 events) 0.84 (0.76-0.94) 0.001 0.87 (0.71-1.06) 0.15 CV Death 0.83 (0.68-1.01) 0.07 (566 events) 0.85 (0.71-1.00) 0.06 0.81 (0.69-0.95) 0.01 Myocardial Infarction 0.84 (0.72-0.98) 0.03 (898 events) 0.83 (0.72-0.95) 0.005 0.82 (0.63-1.07) 0.14 0.75 (0.57-0.98) 0.03 Stroke (313 events) 0.78 (0.62-0.98) 0.03 Ticagrelor 90 mg 0.4 0.6 0.8 1 1.25 1.67 Ticagrelor 60 mg Ticagrelor better Placebo better Pooled An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School Bonaca MP et al. NEJM 2015;372:1791-800

Bleeding Ticag 90: HR 2.69 (1.96-3.70) 5 Ticagrelor 90 mg Ticag 60: HR 2.32 (1.68-3.21) Ticagrelor 60 mg 3-Year KM Event Rate (%) 4 P<0.001 Placebo 3 2,6 2,3 P<0.001 2 P=NS P=NS P=NS 1,3 1,2 1,1 1 0,7 0,6 0,6 0,6 0,6 0,5 0,4 0,3 0,3 0,1 0 TIMI Major TIMI Minor Fatal bleeding or ICH Fatal Bleeding ICH An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School

Events Prevented and Caused for 1000 Patients Initiated on Ticagrelor 60 mg Twice Daily and Followed for 3 Years Ticagrelor 60 15 Total # of Events Prevented over 3 Years per 1000 Patients Initiated on Treatment 9 10 5 0 0 -4 -5 -5 -8 -10 -15 -18 -20 CV Death, MI, or CV Death MI Stroke Intracranial Major bleed Stroke Hemorrhage or Fatal Bleeding An Academic Research Organization of Bonaca MP et al. JACC in Press Brigham and Women’s Hospital and Harvard Medical School