Antithrombotic Therapy for Long-Term Secondary Prevention Considerations for Long-Term DAPT

Transcription

1 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

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

3 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

4 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 % Prior Ischemic Event <=1 Yr Prior Ischemic Event >1 y Stable Atherosclerotic disease Risk Factor only Bhatt et al. JAMA 2010; 304:

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

6 Proportion Event-Free Proportion Event-Free 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 First 30 Days >30 Days 1 Year Clopidogrel Clopidogrel.96 Placebo.94 RRR: 21%.92 95% CI, P= Week No. at Risk Clopidogrel Placebo Placebo RRR: 18% 95% CI, P=.009 Month No. at Risk Yusuf S, et al. Circulation. 2003;107:

7 CV Death, MI, or Stroke (%) CV Death, MI, or Stroke (%) 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 ( ), p< ,624 Patients w/in 24 hrs of onset of ACS (64% underwent PCI) Clopidogrel Ticagrelor Clopidogrel 5.28 Ticagrelor HR 0.88 (95% CI ), p= HR 0.80 (95% CI ), p<0.001 No. at risk Ticagrelor Days after randomisation 9,333 8,942 8,827 8, Days after randomisation * 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

8 Randomized trials of dual antiplatelet treatment duration after drug-eluting stents Trial Total DES Randomized Treatment Duration Bleeding HR (95% CI) Stent Thrombosis HR (95% CI) Myocardial Infarction HR (95% CI) REAL + ZEST LATE vs. ~ ( ) 1.23 ( ) 1.41 ( ) PRODIGY vs ( ) 0.87 ( ) 0.94 ( ) EXCELLENT vs ( ) 0.17 ( ) 0.54 ( ) OPTIMIZE vs ( ) 0.95 ( ) 0.85 ( ) ARCTIC- Interruption 1259 Continued DAPT vs. ASA 6.94 ( ) 0 vs 3 events* 1.04 ( ) ITALIC vs 6 3 vs. 0 events* 0 vs. 3 events* 0.67 ( ) 0.80 ( ) 1.08 ( ) ISAR-SAFE vs ( ) 9 events 27 events Park, et al. N Eng J Med 2010; 362:15. Valgimigli, et al. Circulation 2012;125:2015. Gwon, et al. Circulation 2012;125:505. Feres, et al. JAMA 2013; 310:510. Collet, et al. Lancet 2014;384:1577. Gillard, et al. J Am Coll Card Nov Schultz-Schupke, et al. EHJ Jan 25,

9 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

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

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

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

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

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

15 CV Death, MI, or Stroke (%) Primary Endpoint 10 9 N = 21,162 Median follow-up 33 months Placebo (9.0%) 8 7 Ticagrelor 90 (7.8%) Ticagrelor 60 (7.8%) Ticagrelor 90 mg HR 0.85 (95% CI ) P=0.008 Ticagrelor 60 mg HR 0.84 (95% CI ) P= Months from Randomization An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Bonaca MP et al. NEJM 2015;372:

16 Placebo 4% Ticagrelor 60 mg Twice Daily HR 0.82 (95% CI ) Efficacy over time First year in Trial Second year in Trial Third year in Trial 4% HR 0.90 (95% CI ) 4% HR 0.79 (95% CI ) 3% 3.3% 2.7% 3% 3.0% 2.8% 3% 3.0% 2.6% 2% 2% 2% 1% 1% 1% 0% Median 1.7 yrs From Index MI ( ) An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School 0% Median 2.7 yrs From Index MI ( ) 0% Median 3.7 yrs From Index MI ( ) Bonaca MP et al. JACC in Press

17 Components of Primary Endpoint Endpoint HR (95% CI) P value CV Death, MI, or Stroke (1558 events) 0.85 ( ) ( ) ( ) CV Death (566 events) 0.87 ( ) ( ) ( ) 0.06 Myocardial Infarction (898 events) 0.81 ( ) ( ) ( ) Stroke (313 events) 0.82 ( ) ( ) ( ) An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Ticagrelor better Placebo better Ticagrelor 90 mg Ticagrelor 60 mg Pooled Bonaca MP et al. NEJM 2015;372:

18 3-Year KM Event Rate (%) Bleeding 5 4 Ticag 90: HR 2.69 ( ) Ticag 60: HR 2.32 ( ) P<0.001 Ticagrelor 90 mg Ticagrelor 60 mg Placebo ,6 2,3 1,1 P< ,3 1,2 0,4 0,6 0,7 0,6 0,6 0,6 TIMI Major TIMI Minor Fatal bleeding or ICH P=NS P=NS P=NS ICH 0,5 0,1 0,3 0,3 Fatal Bleeding An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School

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

20 MACE in Patients with & without Prior PCI/Stent Prior PCI/Stent N = 16,891 3 Year KM Rates Ticagrelor Placebo 7.1 HR (95% CI) 0.86 ( ) P-value CVD / MI / Stroke ( ) ( ) No Prior PCI/Stent N = 4, ( ) CVD / MI / Stroke ( ) ( ) All p-interaction NS Ticagrelor Better 1.0 Placebo Better Ticagrelor 90 mg Ticagrelor 60 mg Pooled An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School

21 Benefit of Ticagrelor By Size of MI ULN = upper limit of normal 3 Year KM Rate (%) Ticagrelor Placebo HR (95% CI) P value Any MI ( ) 0.84 ( ) 0.83 ( ) MI with Tn 25 x ULN ( ) 0.71 ( ) 0.74 ( ) MI with Tn 50 x ULN ( ) 0.70 ( ) 0.71 ( ) MI with Tn 100 x ULN ( ) 0.64 ( ) 0.70 ( ) MI with Tn 200 x ULN Ticagrelor Better An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Placebo Better 0.71 ( ) 0.62 ( ) 0.66 ( ) ~40% Reduction in Very Large MI Ticagrelor 90 mg Ticagrelor 60 mg Pooled

22 STEMI (%) Effect of Ticagrelor on STEMI 2.0% 1.5% 1.0% Ticagrelor 90 mg HR 0.57 (95% CI ) P= Ticagrelor 60 mg HR 0.62 (95% CI ) P= ~40% Reduction in New STEMI during Follow up Placebo Ticagrelor 60 Ticagrelor % 0.0% An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Days from Randomization

23 Any Stroke at 3 Years (%) Effect of Ticagrelor on Stroke 2,5% 2,0% Placebo Ticagrelor 60 mg BID Any Stroke HR 0.75 ( ) P= % 1,5% 1.47% 1,0% 0,5% 0,0% An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Days from Randomization

24 Number (N) Modified Rankin Score at 30 Days Rankin 0 Rankin 1 Rankin 2 Rankin 3 Rankin 4 Rankin 5 Rankin 6 Asymptomatic No Significant Disability Slight Disability Moderate Disability Moderately Severe Disability Severe Disability Dead HR % Reduction in Moderate-Severely Disabling or Fatal Stroke ( ) P= Placebo Ticagrelor 60 mg

25 Thrombotic Complications (%) Venous Thromboembolism Reduced with Ticagrelor 1,4% 1,2% N=14,112 patients Median FUP of 33 months Placebo N=105 1,0% 0,8% Ticagrelor 60 mg HR 0.68 ( ) P=0.041 Ticagrelor 60 mg N=47 0,6% 0,4% 0,2% 0,0% Days from Randomization An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Cavellari I, Bonaca MP et al. Circulation 2017

26 Event Rate (%) Outcomes with Continued DAPT after MI RR 0.78 P = ,4 7,5 2,3 ~15% Reduction in Cardiovascular Mortality RR 0.85 P = ,6 RR 0.70 P = MACE CV Death MI Stroke Stent Thrombosis Udell JA, Bonaca MP et al. Eur Heart J 2015 at eurheartj.oxfordjournals.org. (Def/Prob) 3,5 4,4 RR 0.81 P = ,4 1,7 Extended DAPT Aspirin Alone RR 0.50 P = ,6 1,4

27 All Cause Mortality with Prolonged Intensive Antiplatelet Therapy after MI ~11% reduction in all cause mortality ~17% reduction in CV Mortality (about 60% of deaths) No excess in non-cv Mortality (about 40% of deaths) Bonaca MP and Sabatine MS. JAMA Cardiology 2016

28 CVD/MI/Stroke (%) Greater Benefit in Patients Continuing on P2Y 12 Inhibition 12% Ticagrelor 60 mg BID Placebo Ticagrelor 90 mg BID 10% HR 0.75 (95% CI ) P= HR 0.70 (95% CI ) P= % 8.0% 8% NNT=53 7.4% NNT=40 6% 4% 2% ~13 Events Prevented per 1000 vs 9 Bleeds ~20 Events Prevented per % An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Days from Randomization Bonaca et al. EHJ 2015

29 3-yr KM % Efficacy of ticagrelor by egfr 16 Primary Endpoint: CV death, MI, stroke egfr < 60 Placebo (N = 1,649) egfr < 60 Ticagrelor Pooled (N = 3,200) egfr 60 Placebo (N = 5,336) egfr 60 Ticagrelor Pooled (N = 10,713) 13.99% 11.29% HR 95% CI 0.81 ( ) ARR = 2.70% NNT % 6.80% HR 95% CI 0.88 ( ) ARR = 0.63% An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Months since randomization Magnani G et al. and Bonaca MP EHJ 2015

30 CV Death, MI, Stroke (%) Coronary Events in Multivessel Disease An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Days from Randomization Bansilal S, et al. ACC 2016

31 CV Death, MI, Stroke (%) MACE with Ticagrelor in Diabetics Ticagrelor (doses pooled) Placebo Ticagrelor in Diabetic Patients HR 0.84 (95% CI ) ARR 1.5%; P= % Benefit in Diabetic vs. Non-Diabetic Patients: Interaction P= % 7.8% 6.7% Ticagrelor in Non-Diabetic Patients HR 0.84 (95% CI ) ARR 1.1%; P=0.01 An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Days from Randomization Bhatt DL, Bonaca MP, Bansilal S, et al. Steg PG. JACC

32 Events prevented or caused for 1000 Patients Initiated on Treatment for 3 Years Events Prevented or Caused for 1000 Initiated on Ticagrelor 60 for 3 Years GDF-15 < 1200 GDF-15 >= 1200 Major Bleeds Major Bleeds CV Death, MI, Stroke CV Death, MI, Stroke No excess in ICH or Fatal Bleeding GDF-15 Concentration at Baseline An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Bonaca et al. ESC 2017

33 PEGASUS-TIMI 54 and COMPASS Trial Comparison Similarities Long-term secondary prevention Antithrombotic (safety concerns) Placebo controlled MACE primary outcome Differences Post-MI vs. enriched polyvascular (PAD, Carotid, CAD) PEGASUS-TIMI 54 PAD ~5% COMPASS PAD 27% Run-in phase to select patients who for adherence COMPASS % no difference between groups PEGASUS-TIMI 54-21% vs 28% vs 32% PPI factorial Mechanism of action Bleeding definitions Net benefit definitions Recent CABG included in COMPASS / excluded in PEGASUS-TIMI 54 *Doses pooled

34 PEGASUS-TIMI 54 and COMPASS - Outcome Comparison Outcome Ticagrelor 60 vs Placebo P-value Rivaroxaban 2.5 mg vs Placebo P-value CVD/MI/Stroke 0.84 ( ) ( ) <0.001 CV Death 0.83 ( ) ( ) 0.02 MI 0.84 ( ) ( ) 0.14 Stroke 0.75 ( ) ( ) <0.001 VTE 0.68 ( ) ( ) 0.05 MALE (PAD)* 0.65 ( ) ( ) Mortality 0.89 ( ) ( ) 0.01 Bleeding leading to transfusion GUSTO Severe vs. Major Bleeding 1.52 ( ) ( ) < ( ) ( ) <0.001 Fatal Bleeding or ICH 1.22 ( ) ( ) 0.40 NET Outcome (CVD/MI/Stroke/ICH/F atal bleeding) *Doses pooled 0.86 ( ) ( ) <0.001

35 KM Rate Drug discontinuation for AE by Treatment Ticagarelor 90 mg twice daily Ticagrelor 60 mg twice daily Placebo 18% 16% 14% 12% First Year Years P-value for each dose vs. placebo < % 13% 18% 16% 14% 12% Treatment Arm Annualized Rate Ticagrelor % Ticagrelor % Placebo 2.3% 10% 10% 8% 8% 6% 6% 6% 6.5% 6.0% 4% 4% 4.5% 2% 0% % 0% Days from Randomization P<0.01 for each dose vs. placebo

36 Number of Patients Discontinued for Dyspnea Discontinuation over time for Dyspnea by Randomization Group Placebo P<0.01 for each dose vs. placebo Ticagrelor 60 mg twice daily Ticagrelor 90 mg twice daily Median Days to Discontinuation Days From Randomization

37 Efficacy of Ticagrelor On Treatment* 3 Year KM Rate (%) Ticagrelor Placebo HR (95% CI) P-value ( ) <0.001 CVD / MI / Stroke ( ) < ( ) < ( ) CV Death ( ) ( ) ( ) Coronary Heart Disease Death ( ) ( ) ( ) Myocardial Infarction ( ) ( ) ( ) Stroke ( ) ( ) Ticagrelor Better 1.0 Placebo Better *N=20,942 patients who received at least one dose of study drug including events through 7 days from the last dose of study drug. Results consistent after propensity score adjustment Ticagrelor 90 mg Ticagrelor 60 mg Pooled

38 Primary endpoint(%) Patients 2 Yrs from MI or 1 Yr from ADP Receptor Blocker Treatment 10% 8% 9.56% 7.85% 6% 4% 2% 0% Number at risk: Placebo EU T60 EU Placebo EU T60 EU Days after randomization Outcome Ticagrelor 60 (N=5388) Placebo (N=5391) Hazard ratio (95% CI) P value n 3-yr n 3-yr PEP (0.70, 0.91) CV death (0.56, 0.90) MI (0.70, 0.99) Stroke (0.55, 1.01) All-cause mortality (0.67, 0.96) TIMI major bleeding (1.65, 3.39) < Fatal or intracranial bleeding (0.68, 2.01) 0.58 An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Dellborg et al. ESC 2017

39 CVD / MI / Stroke PAD+CAD Higher Risk Than PAD or CAD Alone 60% increased risk of MACE after adjusting for risk factors No PAD PAD 25% 22,3% 20% 19,3% 15% 11,7% 10% 5% 8,4% 6,0% 4,6% 0% PEGASUS-TIMI 54 PRODIGY DAPT Bonaca et al. JACC 2016 Franzone et al. JAHA 2016 Secemsky et al. AHA 2016

40 Longer DAPT in PAD With CAD/ACS PAD with prior ACS HR 0.46 ( ) P=0.016 P-interaction % 16% 9% 7% 7% ARR All Cause Mortality 21.1% vs 10.2% HR 0.45 ( ) P=0.02 TIMI Major Bleeding 1.8% vs 3.5% HR 0.50 ( ) P=0.43 GUSTO Mod/Severe 2.6% vs 2.6% HR 1.02 ( ) P=0.51 Large reduction in MACE Lower mortality Modest bleeding excess Franzone et al. JAMA Cardiology 2016

41 CV Death, MI, or Stroke (%) ASA+Ticagrelor in PAD with Prior MI 25% 20% 15% 10% 5% Placebo Ticagrelor 60 mg BID PAD 19.3% P-interaction NS 14.1% No PAD ARR 5.2% NNT 20 CVD / MI / Stroke CV Death Mortality TIMI Major Bleeding Absolute Risk Difference at 3 Years HR (95% CI) 0.69 ( ) P= ( ) P= ( ) P= ( ) P=0.82 0% 0.1 Ticagrelor Better 1.0 Placebo Better 10 Days from Randomization An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Bonaca MP et al. JACC 2016

42 Acute Limb Ischemia or Peripheral Revascularization for Ischemia (%) Major Adverse Limb Events with Ticagrelor 1.0% 0.8% HR % CI ( ) P= % 0.6% 0.4% 0.46% 0.2% Number at Risk Placebo Ticagrelor 0.0% An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Days from Randomization Bonaca MP et al. JACC 2016

43 Vorapaxar and Limb Vascular Efficacy Hospitalization for Acute Limb Ischemia Pre-specified, adjudicated 3.9% N = 3767 Peripheral Revascularization Prespecified, Investigator 22.2% Placebo 18.4% 2.3% Vorapaxar Hazard Ratio % CI 0.39 to 0.86 p = Hazard Ratio 0.84; 95% CI 0.73 to 0.97 p = Days from randomization Bonaca et al. Circulation 2012

44 More Intensive Antithrombotic Therapy Reduces MACE in PAD + CAD Not CAD Patients risk exceeds PAD or CAD alone PEGASUS-TIMI 54, PRODIGY, DAPT Concomitant CAD may an effect modifier and it remains unclear more potent strategies reduce MACE risk in PAD without CAD EUCLID ticagrelor monotherapy benefit if CAD COMPASS MACE benefit in PAD with/without CAD? More potent regimens reduce limb events (vorapaxar, ticagrelor, rivaroxaban) Robust benefit of more potent antithrombotic therapy with significantly reduced mortality in multiple trials

45 KM Rate (%) at 3 Years Summary of Effects of PCSK9i Evolocumab LDL-C by 59% to a median of 30 mg/dl CV outcomes in patients on statin Safe and well-tolerated Placebo 59% reduction P< Absolute 56 mg/dl HR 0.85 ( ) P< ,6 12,6 HR 0.80 ( ) P< ,9 7,9 Evolocumab (median 30 mg/dl, IQR mg/dl) 5 0 CVD, MI, stroke UA, cor revasc CVD, MI, stroke An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Sabatine MS et al. NEJM 2017;376:

46 CVD / MI / Stroke CVD / MI / Stroke 16% 14% 12% 10% 8% 6% Peripheral Artery Disease and Risk in Placebo Patients PAD with MI/Stroke N=1036 PAD N=1784 PAD no MI/Stroke N=748 MI or Stroke and no PAD N=11996 MI or Stroke and no PAD N=11996 Adjusted HR 1.81 ( ) P< % 7.6% 16% 14% 12% 10% 8% 6% 14.9% P= % P= % 4% 4% 2% 2% 0% Days from Randomization An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School 0% Days from Randomization adjusted age, sex, race, BMI, diabetes, hypertension, smoking, egfr, CHF, prior MI, CABG/PCI, and history of stroke or TIA.

47 Baseline Characteristics MI or Stroke and no PAD N=23,922 PAD N=3,642 Age, median (IQR) 63 (56, 69) 64 (58, 69) Female sex (%) History Hypertension (%) Current Smoker (%) History of Diabetes (%) History of Stroke (%) History of Myocardial Infarction (%) Statin, High/Moderate (%) 69 / / 31 Antiplatelet therapy (%) Anticoagulant therapy (%) 8 11 ACE-I or ARB use at baseline (%) All p-values < 0.05 except statin use/intensity (p=0.57) Statin dose at baseline missing in 10 (0.0%) without PAD and 3 (0.1%) with PAD An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School

48 CV Death, MI or Stroke CV Death, MI or Stroke in Patients with and without Peripheral Artery Disease 14% 12% 10% Placebo Evolocumab PAD N=3,642 27% RRR HR 0.73 ( ) P= % 9.5% PAD 3.5% ARR NNT 2.5y 29 8% 6% 7.6% 6.2% No PAD 1.4% ARR NNT 2.5y 72 4% No PAD N=23,922 2% HR % CI ( ) P< % p-interaction = An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Days from Randomization

49 CV Death, MI or Stroke CV Death, MI or Stroke in Patients with PAD and no MI or Stroke Placebo Evolocumab PAD (no MI/stroke, N=1505) 12% 10% 8% 43% RRR HR 0.57 ( ) P= % PAD 4.8% ARR NNT 2.5y 21 6% 5.5% 4% 2% 0% An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Days from Randomization Outcome HR 95% CI MACE 0.57 ( ) CV Death 0.78 ( ) MI 0.66 ( ) Stroke 0.30 ( ) Mortality 0.86 ( )

50 Major Adverse Limb Events Major Adverse Limb Events 0,5% 0,4% Placebo Evolocumab All Patients N=27,564 42% RRR HR 0.58 ( ) P= % 0,3% 0.27% 0,2% 0,1% 0,0% Outcome HR 95% CI MALE 0.58 ( ) ALI or major amputation 0.52 ( ) ALI 0.55 ( ) Major amputation 0.57 ( ) Urgent revascularization 0.69 ( ) An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Days from Randomization

51 Major Adverse Limb Events Major Adverse Limb Events in Patients with PAD and no MI or Stroke 3,0% Placebo Evolocumab PAD (no MI/stroke, N=1505) 57% RRR 2,5% 2,0% HR 0.43 ( ) P= % 1.3% ARR 1,5% 1,0% 1.3% 0,5% 0,0% An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Days from Randomization

52 MACE or MALE MACE or MALE In Patients with PAD and no MI or Stroke Placebo Evolocumab PAD (no MI/stroke, N=1505) 14% 48% RRR 12.8% 12% 10% HR 0.52 ( ) P= PAD 6.3% ARR NNT 2.5y 16 8% 6% 6.5% 4% 2% 0% An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Days from Randomization

53 Percentage of Patients The DAPT Score Variable Patient Characteristic Age <75-1 < 65 0 Diabetes Mellitus 1 Current Cigarette Smoker 1 Prior PCI or Prior MI 1 CHF or LVEF < 30% 2 Index Procedure Characteristic MI at Presentation 1 Vein Graft PCI 2 Stent Diameter < 3mm 1 Points Distribution of DAPT Scores among all randomized subjects in the DAPT Study 30% 25% 20% 15% 10% 5% 0% DAPT Score Yeh et al. JAMA 2016

54 Risk Difference (Continued Thienopyridine Placebo), 12-30M Continued Thienopyridine vs. Placebo, by DAPT Score, Excluding PES 4,0% Myocardial Infarction or Stent Thrombosis GUSTO Moderate or Severe Bleed Net Adverse Events Mortality 3,0% 2,0% 1,0% P=0.06 P=0.07 P=0.003 P=0.17 1,44% 1,03% 0,79% 0,38% 0,0% -0,01% -1,0% -0,52% DAPT Score < 2-2,0% -1,90% DAPT Score 2-1,67% -3,0% -4,0% P values are for comparison of risk differences across DAPT Score category (interaction). Yeh et al. JAMA 2016

55 Multivariable Model Risk of CV death, MI or ischemic stroke in placebo-treated cohort (N=8598) Variable HR (95% CI) p-value Points CHF 2.03 (1.68, 2.46) < Prior Stroke 1.83 (1.39, 2.40) < Hypertension 1.61 (1.34, 1.93) < Diabetes mellitus 1.49 (1.27, 1.75) < Current Smoking 1.47 (1.23, 1.75) < Prior CABG 1.44 (1.20, 1.73) < Age (1.11, 1.75) Peripheral arterial disease 1.36 (1.13, 1.64) Renal dysfunction (egfr< 60) 1.36 (1.12, 1.65) Maximum Possible # Risk Indicators 9 Bohula et al. Circulation in Press

56 CV death / MI / ischemic stroke at 3 Yrs (%) Efficacy & Safety By Risk Group Prior MI without a history of stroke or TIA 20% 18% 16% 14% Placebo (CV death, MI, or Ischemic Stroke) Vorapaxar (CV death, MI, or Ischemic Stroke) Placebo (GUSTO Severe Bleeding) Vorapxar (GUSTO Severe Bleeding) CVD/MI/iCVA: p-trend<0.001 p-interaction = 0.35 CHF, prior stroke, HTN, DM, age, smoking, CABG, PAD, renal dysfunction ARR 3.2% (0.4, 6.3) NNT 31 17,7% 14,5% 12% 10% 8% 6% GUSTO Severe: p-trend<0.01 p-interaction = 0.13 ARR 2.1% (1.0, 3.4) NNT 48 8,1% 6,0% 4% 3,6% 3,5% 2% 2,0% 1,0% 1,1% 0,7% 0,1% 0% # Risk Indicators Bohula et al. AHA (19) 9967 (61) 3214 (20) 1,9%

57 Baber et al. JACC 2016 PARIS Risk Score

58 PRECISE-DAPT Bleeding Risk in ACS Consideration for PEGASUS-TIMI 54 Population Hemoglobin at Baseline marker of occult bleeding? part of bleeding definition? Age Also associated with ischemic risk and greater benefit WBC Unclear mechanism Creatinine Clearance Also asociated with ischemic risk and greater benefit Prior Bleeding Excluded from trial

59 Which Post-MI Have Greatest Benefit? DAPT PARIS TIMI PEGASUS- TIMI 54 Diabetes Mellitus Ischemic Risk Ischemic Risk Ischemic Risk Ischemic Risk Prior MI/ACS Ischemic Risk Ischemic Risk Ischemic Risk Ischemic Risk Prior CABG / MVD Ischemic Risk Ischemic Risk Ischemic Risk Ischemic Risk Renal Dysfunction Ischemic Risk Ischemic Risk Ischemic Risk Current Smoking Ischemic Risk Ischemic Risk Ischemic Risk Ischemic Risk PAD Ischemic Risk Ischemic Risk CHF or low EF Ischemic Risk Ischemic Risk Ischemic Risk Age Bleeding Risk Bleeding Risk Ischemic Risk Ischemic Risk Prior stroke Hypertension Ischemic Risk Ischemic Risk Prior PCI Ischemic Risk Ischemic Risk Stent Diameter Paclitaxel Stent Ischemic Risk Ischemic Risk Slide by Marc Bonaca Yeh et al. JAMA 2016 Baber et al. JACC 2016 Bohula et al. Circ 2016

60 A Framework for Optimizing DAPT Duration Who Patients with prior MI at high risk: Diabetes mellitus Multiple prior MIs Renal dysfunction MVD / prior CABG PAD Recent MI/on P2Y 12 Not at high risk for bleeding Prior/risk of ICH Recent major Bleeding Bleeding diathesis On anticoagulation Low BMI / anemia < GDF-15 When Continue after started for MI and re-evaluate at each visit: Recent bleeding? Are they tolerating? Are they adherent? Contraindication s (e.g. new dx of AF requiring anticoagulation) Why To reduce long-term ischemic risk including: New spontaneous MI including STEMI Ischemic stroke including disabling events Limb ischemic events in PAD CV mortality as predominant cause of death Slide by Marc Bonaca