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

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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

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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

• f 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.

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Bhatt DL. N Engl J Med 2007;357:2078-81.

Role of Platelet Activation and Aggregation

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Bhatt DL, Grosser T, Dong J, et al. JACC 2017.

Enteric Coated Aspirin

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ADP Receptors

Receptor subtype Molecular structure Intrinsic ion channel GPCR Gq GPCR Gi Secondary messenger system ­[Na+/Ca2+]i ­PLC/IP3 ­[Ca2+]i ¯AC ¯[cAMP] Functional response Shape change aggregation Shape change transient aggregation Sustained aggregation secretion

G protein G protein

P2Y1 Clopidogrel P2Y12 Active metabolite AR–C69931MX

Bhatt DL et al. Nat Rev Drug Discov. 2003;2:15-28.

P2X1

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Mehta SR, Yusuf S, Peters RJG, et al. Lancet. 2001;358:527-533.

.00 .05 .10 .15 0 10 100 300 400 200

Cumulative Hazard Rate Clopidogrel + Aspirin (n=1313)

31%

Relative Risk Reduction

Placebo + Aspirin (n=1345)

Median time to PCI

Days of Follow-up 12.6% 8.8%

P=.002

PCI-CURE Study: CV Death or MI From Randomization

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CREDO: Long-Term (1 Year) Benefits of Clopidogrel in PCI Patients

MI, stroke, or death – ITT population

* Plus ASA and other standard therapies. Steinhubl S, Berger P, Tift Mann III J et al. JAMA. 2002;Vol 288,No 19:2411-2420.

Combined endpoint

• ccurrence (%)

Months from randomization 27% RRR

P=0.02 Placebo* Clopidogrel* 5 10 15 8.5% 11.5% 3 6 9 12

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Bhatt DL, Cryer BL, Contant CF, et al. N Engl J Med 2010;363:1909-17.

COGENT Trial – Effect of PPI

• n Composite GI Events

HR=0.34, 95% CI=0.18-0.63

Time (Days) Probability of Freedom from Primary Gastrointestinal Endpoint 50 100 150 180 200 0.00 0.90 1.00

Placebo Omeprazole P<0.001 by the log-rank test

• No. at Risk

Placebo 1885 1455 951 523 260 231 Omeprazole 1876 1500 987 553 250 215

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Bhatt DL. N Engl J Med 2009;361:940-2.

Mechanism of Action of Prasugrel

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TRITON TIMI-38: Net Clinical Benefit Bleeding Risk Subgroups

OVERALL

>= 60 kg < 60 kg < 75 >=75 No Yes 0.5 1 2 Prior Stroke / TIA Age Wgt Risk (%) + 54

• 16
• 1
• 16

+3

• 14
• 13

Prasugrel Better Clopidogrel Better

HR Pint = 0.006 Pint = 0.18 Pint = 0.36

Post hoc analysis

Wiviott SD et al. NEJM. 2007;357:2001-15.

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Bhatt DL. N Engl J Med 2007;357:2078-81.

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Mechanism of Action of Ticagrelor

Bhatt DL. Nature Reviews Cardiology. 2009;6:737-38.

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PLATO: CV Death, MI, or Stroke

• No. at risk

Clopidogrel Ticagrelor 9,291 9,333 8,521 8,628 8,362 8,460 8,124 Days after randomisation 6,743 6,743 5,096 5,161 4,047 4,147 60 120 180 240 300 360 12 11 10 9 8 7 6 5 4 3 2 1 13 Cumulative incidence (%) 9.8 11.7 8,219 HR 0.84 (95% CI 0.77–0.92), p=0.0003 Clopidogrel Ticagrelor

Wallentin L, et al. N Engl J Med. 2009.

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• No. at risk

Clopidogrel Ticagrelor 9,291 9,333 8,560 8,678 8,405 8,520 8,177

Days after randomisation

6,703 6,796 5,136 5,210 4,109 4,191

60 120 180 240 300 360 6 5 4 3 2 1 7

Cumulative incidence (%) Clopidogrel Ticagrelor 5.8 6.9

8,279

HR 0.84 (95% CI 0.75–0.95), p=0.005 60 120 180 240 300 360 6 4 3 2 1

Clopidogrel Ticagrelor 4.0 5.1

HR 0.79 (95% CI 0.69–0.91), p=0.001 7 5

9,291 9,333 8,865 8,294 8,780 8,822 8,589

Days after randomisation

7079 7119 5,441 5,482 4,364 4,419 8,626

Myocardial infarction Cardiovascular death

Cumulative incidence (%)

PLATO: Secondary Endpoints

Wallentin L, et al. N Engl J Med. 2009.

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Major Bleeding: Non-CABG vs CABG

p=0.026 p=0.025 NS NS 9

K-M estimated rate (% per year)

Non-CABG PLATO major bleeding 8 7 6 5 4 3 2 1 Non-CABG TIMI major bleeding CABG PLATO major bleeding CABG TIMI major bleeding

4.5 3.8 2.8 2.2 7.4 7.9 5.3 5.8

Ticagrelor Clopidogrel Wallentin L, et al. N Engl J Med. 2009.

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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

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.

P<0.001 across all timepoints, Bonferroni adjusted

LTA= light transmittance aggregometry; ADP is the agonist

1. Immediate and sustained ticagrelor reversal with bolus + prolonged infusion of 18 g PB2452. 2. Significant reversal was

• bserved 5 minutes after

initiation of PB2452 infusion. 3. Duration of reversal was infusion-time dependent, lasting 20-24 hours with a 16- hour infusion. Bhatt DL, Pollack CV, Weitz JI, et al. N Engl J Med. 2019.

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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)

Primary Efficacy Results (MI/Stroke/CV Death) by Pre-Specified Entry Category

0.6 0.8 1.4 1.2

Clopidogrel + ASA Better Placebo + ASA Better

1.6 0.4

* 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.

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Primary Endpoint (MI/Stroke/CV Death) in Patients With Previous MI, IS, or PAD*

“CAPRIE-like Cohort”

*Post hoc analysis.

Bhatt DL et al. J Am Coll Cardiol. 2007;49:1982-1988.

Cardiovascular Death/MI/Stroke (aspirin background therapy)

Placebo Clopidogrel HR (95% CI) P value Prior MI 8.3% 6.6% 0.774 (0.613, 0.978) 0.031 Prior IS 10.7% 8.4% 0.780 (0.624, 0.976) 0.029 Prior PAD 8.7% 7.6% 0.869 (0.671, 1.125) 0.085 Entire Cohort 8.8% 7.3% 0.829 (0.719, 0.956) 0.010 0.5 1 2 Placebo Clopidogrel P value Prior MI 8.3% 6.6% 0.774 (0.613, 0.978) 0.031 Prior IS 10.7% 8.4% 0.780 (0.624, 0.976) 0.029 Prior PAD 8.7% 7.6% 0.869 (0.671, 1.125) 0.085 Entire Cohort 8.8% 7.3% 0.829 (0.719, 0.956) 0.010 0.5 1 2

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PEGASUS – TIMI 54

Stable pts with history of MI 1-3 yrs prior + ³1 additional atherothrombosis risk factor*

N ~ 21,000

Ticagrelor 90 mg bid Placebo

RANDOMIZE DOUBLE BLIND

Follow-up Visits Q4 mos for 1st yr, then Q6 mos

Planned treatment with ASA 75 – 150 mg & Standard background care

Primary Efficacy Endpoint: CV Death, MI, or Stroke Primary Safety Endpoint: TIMI Major Bleeding

* Age >65 yrs, diabetes, 2nd prior MI, multivessel CAD,

• r chronic non-end stage renal dysfunction

Min 12 mos and median 26 mos follow-up Event-driven trial

Ticagrelor 60 mg bid

Bonaca MP, Bhatt DL, Braunwald E, et al. Am Heart J. 2014;167:437-44.

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PEGASUS – TIMI 54

Bonaca MP, Bhatt DL, Cohen M, et al. NEJM. 2015.

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12/7/19 11 PEGASUS TIMI 54 – Components of Primary Endpoint

Bonaca MP, Bhatt DL, Cohen M, et al. NEJM. 2015.

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PEGASUS – TIMI 54

Bonaca MP, Bhatt DL, Cohen M, et al. NEJM. 2015.

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An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School

Primary Endpoint - MACE

Days from Randomization CV Death, MI, Stroke (%)

11.6% 10.1% 7.8% 6.7%

Benefit in Diabetic vs. Non-Diabetic Patients: Interaction P=0.99

Ticagrelor in Non-Diabetic Patients HR 0.84 (95% CI 0.74 – 0.96) ARR 1.1%; P=0.01 Ticagrelor in Diabetic Patients HR 0.84 (95% CI 0.72 – 0.99) ARR 1.5%; P=0.03

Ticagrelor (doses pooled) Placebo

Bhatt DL, Bonaca MP, Bansilal S, et al. Steg PG. JACC. 2016.

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An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School

Coronary Death

Days from Randomization Coronary Death (%)

Benefit in Diabetic vs. Non-Diabetic Patients: Interaction P=0.21

3.4% 2.3% 1.5% 1.4%

Ticagrelor in Non-Diabetic Patients HR 0.88 (95% CI 0.65 – 1.19) ARR 0.1%; P=0.39 Ticagrelor in Diabetic Patients HR 0.66 (95% CI 0.48 – 0.91) ARR 1.1%; P=0.01

Ticagrelor (doses pooled) Placebo

Bhatt DL, Bonaca MP, Bansilal S, et al. Steg PG. JACC. 2016.

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An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School

CV Death, MI, or Stroke (%)

Days from Randomization

0% 5% 10% 15% 20% 25% 90 180 270 360 450 540 630 720 810 900 990 1080

19.3% 15.2% 8.4% 7.4%

PAD HR 0.75

95% (CI 0.55 – 1.01)

ARR 4.1% NNT 25

No PAD HR 0.86

95% (CI 0.77 – 0.96) P-interaction 0.41

Ticagrelor (pooled doses) Placebo ARR 1.0% NNT 100

MACE with Ticagrelor by PAD at Baseline

Bonaca MP, Bhatt DL, Storey RF, et al. JACC. 2016.

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An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School

Ischemic Events and Bleeding with Ticagrelor in Patients with PAD

CVD / MI / Stroke

Ticagrelor Better Placebo Better 1.0 Absolute Risk Difference at 3 Years P-value 0.045

CV Death Myocardial Infarction Stroke Mortality

0.24 0.014 0.46 0.59 0.30 0.097 0.25 0.0074 0.53 0.81 (0.57 – 1.15) 0.69 (0.47 – 0.99) HR (95% CI) 0.83 (0.50 – 1.38) 0.47 (0.25 – 0.86) 0.76 (0.45 – 1.28) 0.87 (0.53 – 1.44) 0.63 (0.29 – 1.38) 0.49 (0.21 – 1.14) 0.88 (0.58 – 1.32) 0.52 (0.32 – 0.84) Ticagrelor 60 mg Ticagrelor 90 mg 10 0.1

TIMI Major Bleeding

– 5.2 – 3.0 – 5.4 – 1.7 – 1.0 – 2.0 – 1.1 – 0.9 – 5.7 – 2.3 0.82 0.57 1.46 (0.39 – 5.43) 1.18 (0.29 – 4.70) 0.02 0.22

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An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School

Acute Limb Ischemia or Peripheral Revascularization for Ischemia (%)

Days from Randomization

0.0% 0.2% 0.4% 0.6% 0.8% 1.0%

180 360 540 720 900 1080

0.71% 0.46%

HR 0.65 95% CI (0.44 – 0.95) P=0.026

Number at Risk Placebo Ticagrelor

7067 14095 6988 13929 6912 13789 6701 13425 6077 12186 4518 9154 2123 4296

Major Adverse Limb Events with Ticagrelor

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An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School

Events at 3 Years (KM %) Ticagrelor doses pooled N=14,095 Placebo N=7,067

0.71% 0.13% 0.70% 0.46% 0.09% 0.44%

0.00% 0.20% 0.40% 0.60% 0.80% 1.00%

ALI or Peripheral Revascularization for Ischemia Acute Limb Ischemia Peripheral Revascularization for Ischemia

HR 0.63 95% CI (0.43 – 0.93) HR 0.56 95% CI (0.23 – 1.37) HR 0.65 95% CI (0.44 – 0.95) P=0.026

Major Adverse Limb Events with Ticagrelor

Bonaca MP, Bhatt DL, Storey RF, et al. JACC. 2016.

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doi: 10.1093/eurheartj/ehv443

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CHARISMA 125 1903 162 1943 PRODIGY 63 732 69 733 ARCTIC-Int’n 3 156 4 167 DAPT 59 1805 108 1771 DES-LATE 56 1512 66 1551 PEGASUS 980 14095 578 7067

TOTAL 1286 20203 987 13232 6.4% 7.5%

Primary Endpoint – CV Death, MI, or Stroke

P = 0.001

0.77 (0.61 - 0.98) 0.91 (0.65 - 1.28) 0.79 (0.18 - 3.51) 0.52 (0.38 - 0.72) 0.85 (0.60 - 1.21) 0.84 (0.76 - 0.94) Study Events Total Events Total

Extended Aspirin Risk Ratio DAPT Alone (95% CI)

0.2 0.5 1 2

Extended DAPT Better Aspirin Alone Better

0.78 (0.67 - 0.90)

Udell JA, et al. Eur Heart J 2015 at eurheartj.oxfordjournals.org.

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CHARISMA 53 1903 65 1943 PRODIGY 31 732 31 733 ARCTIC-Int’n 0 156 1 167 DAPT 11 1805 16 1771 DES-LATE 21 1512 21 1551 PEGASUS 356 14095 210 7067

TOTAL 472 20203 344 13232 2.3% 2.6% P = 0.03

0.82 (0.57 - 1.18) 1.00 (0.61 - 1.64) 0.36 (0.01 - 8.69) 0.67 (0.31 - 1.44) 1.00 (0.55 - 1.83) 0.85 (0.71 - 1.00) Study Events Total Events Total

Extended Aspirin Risk Ratio DAPT Alone (95% CI)

0.2 0.5 1 2

Extended DAPT Better Aspirin Alone Better

0.85 (0.74 - 0.98)

Cardiovascular Death

Udell JA, et al. Eur Heart J 2015 at eurheartj.oxfordjournals.org.

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CHARISMA 45 1903 39 1943 PRODIGY 9 732 6 733 ARCTIC-Int’n 2 156 0 167 DAPT 34 1805 14 1771 DES-LATE 39 1512 31 1551 PEGASUS 242 13946 54 6996

TOTAL 371 20054 144 13161 1.9% 1.1% P = 0.004

1.17 (0.76 - 1.79) 1.50 (0.53 - 4.20) 5.35 (0.26 - 110.6) 2.38 (1.27 - 4.43) 1.27 (0.79 - 2.03) 2.50 (1.86 - 3.36) Study Events Total Events Total

Extended Aspirin Risk Ratio DAPT Alone (95% CI)

0.5 1 2 5

Extended DAPT Better Aspirin Alone Better

1.73 (1.19 - 2.50)

Major Bleeding

Udell JA, et al. Eur Heart J 2015 at eurheartj.oxfordjournals.org.

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TICAGRELOR IN STABLE CAD AND T2D TREATED WITH ASA

THEMIS: Ticagrelor Added to Aspirin in Patients with Stable Coronary Disease and Diabetes

Presented by Deepak L. Bhatt, MD, MPH

Philippe Gabriel Steg,* Deepak L Bhatt,* Tabassome Simon, Kim M. Fox, Shamir R. Mehta, Robert A. Harrington, Claes Held, Marielle Andersson, Anders Himmelmann, Wilhelm Ridderstråle, Maria Leonsson-Zachrisson, Yuyin Liu, Grzegorz Opolski, Dmitry Zateyshchikov, Junbo Ge, José Carlos Nicolau, Ramón Corbalán, Jan Hein Cornel, Petr Widimský, Lawrence A. Leiter

• n behalf of the THEMIS Steering Committee and Investigators

*co-Chairs and co-Principal Investigators of THEMIS European Society of Cardiology 2019

ClinicalTrials.gov registration: NCT01991795

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Primary Composite Endpoint

Cardiovascular death/MI/stroke

Cumulative %

6 12 18 24 30 36 42 48 54 14 13 12 11 10 9 8 7 6 5 4 3 2 1

9416 9414 9237 9246 9074 9076 8909 8909 8692 8692 5974 5934 3664 3682 1684 1685 170 174

Months from Randomization

9619 9601

N at Risk

Ticagrelor Placebo

6.9%

KM estimates at 36 months

7.6% Placebo Ticagrelor HR 0.90 (95% CI 0.81–0.99) P=0.038

CI=confidence interval; HR=hazard ratio; KM=Kaplan-Meier; MI=myocardial infarction; N=number of patients

Steg PG, Bhatt DL, et al. NEJM 2019 DOI: 10.1056/NEJMoa1908077.

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Bleeding Outcomes

Ticagrelor (N=9562) Placebo (N=9531) Patients with events (%) Event rate/ 100 patient years) Patients with events (%) Event rate/ 100 patient years) Hazard Ratio (95% CI) p- value TIMI major bleeding 206 (2.2%) 0.89 100 (1.0%) 0.38 2.32 (1.82–2.94)<0.001 TIMI major or minor bleeding 285 (3.0%) 1.23 129 (1.4%) 0.49 2.49 (2.02–3.07)<0.001 TIMI major, minor, or requiring medical attention 1072 (11.2%) 4.61 485 (5.1%) 1.85 2.51 (2.26–2.80)<0.001 PLATO major bleeding 310 (3.2%) 1.33 145 (1.5%) 0.55 2.41 (1.98–2.93)<0.001 BARC bleeding 5 (fatal bleeding) 17 (0.2%) 0.07 10 (0.1%) 0.04 1.90 (0.87–4.15) 0.11 5 or 4 17 (0.2%) 0.07 11 (0.1%) 0.04 1.73 (0.81–3.69) 0.16 5, 4 or 3 341 (3.6%) 1.47 163 (1.7%) 0.62 2.36 (1.96–2.84)<0.001 Intracranial hemorrhage 70 (0.7%) 0.30 46 (0.5%) 0.18 1.71 (1.18–2.48) 0.005 Spontaneous 28 (0.3%) 0.12 27 (0.3%) 0.10 1.17 (0.69–1.98) 0.57 Procedural 1 (0.0%) 0.00 3 (0.0%) 0.01 Traumatic 41 (0.4%) 0.18 16 (0.2%) 0.06 2.87 (1.61–5.12)<0.001

Includes events with onset from randomization up to 7 days after last dose. BARC bleeding was defined according to a score of 3 to 5 as follows: type 3, bleeding with a decrease in the hemoglobin of more than 3 g per deciliter, any transfusion, cardiac tamponade, or intracranial or ocular involvement; type 4, CABG-related bleeding; and type 5, fatal bleeding. Traumatic ICH: 27 (66%) on ticagrelor and 6 (38%) on placebo reported as subdural bleeding by investigators.

BARC=Bleeding Academic Research Consortium, CABG=coronary artery bypass grafting; CI=confidence interval; N=number of patients; PLATO=PLATelet

inhibition and patient outcomes; TIMI=Thrombolysis in Myocardial Infarction

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Permanent Treatment Discontinuation

Number at risk Ticagrelor 9562 7904 7316 6831 6414 6029 4105 2483 1172 173 Placebo 9531 8660 8179 7772 7367 6974 4786 2959 1362 218

Cumulative %

40 35 30 25 20 15 10 5

HR 1.50 (95% CI 1.42–1.58) P<0.0001

KM estimates at 36 months

33.8% 24.1% Months from Randomization Placebo Ticagrelor

Discontinuation due to dyspnea 6.9% on ticagrelor vs. 0.8% on placebo (HR 9.27 [7.30-11.77] p <0.001); due to bleeding 4.9% vs 1.3% (HR 4.04 [3.32-4.92] p<0.001). CI=confidence interval; HR=hazard ratio; KM=Kaplan-Meier

9.7%

6 12 18 24 30 36 42 48 54

9.7% Excess in Discontinuation ~2/3 due to dyspnea ~1/3 due to bleeding Steg PG, Bhatt DL, et al. NEJM 2019 DOI: 10.1056/NEJMoa1908077.

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Primary Composite Endpoint

Cardiovascular death/MI/stroke – on treatment*

Cumulative %

14 13 12 11 10 9 8 7 6 5 4 3 2 1

7891 8639 7291 8136 6799 7702 6343 7373 5962 6875 4040 4712 2431 2904 1137 1333 168 213

Months from Randomization

9562 9531 Number at Risk Ticagrelor Placebo KM estimates at 36 months

6.4% 5.2% Placebo Ticagrelor HR 0.81 (95% CI 0.71–0.92) P=0.001

*Prespecified analysis with patients censored 3 days after the last dose; CI=confidence interval; HR=hazard ratio; KM=Kaplan-Meier; MI=myocardial infarction; N=number of patients 6 12 18 24 30 36 42 48 54

Steg PG, Bhatt DL, et al. NEJM 2019 DOI: 10.1056/NEJMoa1908077.

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TICAGRELOR IN STABLE CAD AND T2D TREATED WITH ASA

THEMIS-PCI: Ticagrelor Added to Aspirin in Patients with Diabetes and Stable Coronary Artery Disease with a History of Prior Percutaneous Coronary Intervention

Presented by Ph. Gabriel Steg, MD

Deepak L. Bhatt,* Philippe Gabriel Steg,* Shamir R. Mehta, Lawrence A. Leiter, Tabassome Simon, Kim Fox, Claes Held, Marielle Andersson, Anders Himmelmann, Wilhelm Ridderstråle, Jersey Chen, Yang Song, Rafael Diaz, Shinya Goto, Stefan K James, Kausik K. Ray, Alexander Parkhomenko, Mikhail N. Kosiborod, Darren K. McGuire, Robert A. Harrington,

• n behalf of the THEMIS Steering Committee and Investigators

*co-Chairs and co-Principal Investigators of THEMIS

European Society of Cardiology 2019

ClinicalTrials.gov registration: NCT01991795

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Cumulative %

6 12 18 24 30 54 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Placebo Ticagrelor 36 42 48 Number at risk Ticagrelor 4061 3980 3890 3823 3744 3638 2482 1536 700 68 Placebo4005 3930 3859 3798 3740 3630 2458 1551 690 71

Months from Randomization

History of PCI No History of PCI

Primary Efficacy Endpoint

CV death/MI/stroke (ITT)

Interaction p=0.16

CI=Confidence Interval; CV=cardiovascular; HR=hazard ratio; KM=Kaplan-Meier; ITT=intention to treat; MI=myocardial infarction; PCI=percutaneous coronary intervention

Number at risk Ticagrelor5558 5436 5347 5251 5165 5054 3492 2128 984 102 Placebo5596 5484 5387 5278 5169 5062 3476 2131 995 103

Cumulative %

6 12 18 24 30 54 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Ticagrelor 36 42 48

HR 0.85 (95% CI 0.74, 0.97) p=0.013 Months from Randomization

Placebo

KM at 36 months

6.5% HR 0.85 (95% CI 0.74, 0.97) P=0.013

KM at 36 months

7.5% 7.4% HR 0.98 (95% CI 0.84, 1.14) P=0.76

Ticagrelor Ticagrelor Placebo Placebo

6.5% 7.4% 7.7% 7.5%

Bhatt DL, Steg PG, et al. Lancet 2019 http://dx.doi.org/10.1016/ S0140-6736(19)31887-2.

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Efficacy Endpoints

ITT Population

Hazard ratios, p-values calculated for ticagrelor vs placebo from a Cox proportional hazards model with treatment as the only explanatory variable. * Includes deaths based on publicly available vital status data in patients who withdrew consent. ALI=acute limb ischemia; CI=confidence interval; CV=cardiovascular; ITT=intention to treat; MI=myocardial infarction; N=number of patients; PCI=percutaneous coronary intervention; STEMI=ST segment elevation MI

Ticagrelor (N=9619) Placebo (N=9601) Subgroup N Patients with events (%) N Patients with events (%) Hazard Ratio (95% CI) P- value P-inter- action CV death/MI/stroke (Primary) History of PCI 5558 404 (7.3%) 5596 480 (8.6%) 0.85 (0.74–0.97) 0.013 0.16 No history of PCI 4061 332 (8.2%) 4005 338 (8.4%) 0.98 (0.84–1.14) 0.76

All-cause death/MI/stroke History of PCI 5558 494 (8.9%) 5596 603 (10.8%) 0.82 (0.73–0.93) 0.0014 0.021 No history of PCI 4061 425 (10.5%) 4005 415 (10.4%) 1.02 (0.89–1.17) 0.80 All-cause death/MI/stroke/ ALI/ major amputation, vascular etiology History of PCI 5558 500 (9.0%) 5596 616 (11.0%) 0.82 (0.72–0.92) 0.0007 0.023 No history of PCI 4061 427 (10.5%) 4005 423 (10.6%) 1.00 (0.88–1.15) 0.97 Bhatt DL, Steg PG, et al. Lancet 2019 http://dx.doi.org/10.1016/ S0140-6736(19)31887-2.

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Efficacy Endpoints

ITT Population

Hazard ratios, p-values calculated for ticagrelor vs placebo from a Cox proportional hazards model with treatment as the only explanatory variable. * Includes deaths based on publicly available vital status data in patients who withdrew consent. ALI=acute limb ischemia; CI=confidence interval; CV=cardiovascular; ITT=intention to treat; MI=myocardial infarction; N=number of patients; PCI=percutaneous coronary intervention; STEMI=ST segment elevation MI

Ticagrelor (N=9619) Placebo (N=9601) Subgroup N Patients with events (%) N Patients with events (%) Hazard Ratio (95% CI) P- value P-inter- action CV death/MI/stroke (Primary) History of PCI 5558 404 (7.3%) 5596 480 (8.6%) 0.85 (0.74–0.97) 0.013 0.16 No history of PCI 4061 332 (8.2%) 4005 338 (8.4%) 0.98 (0.84–1.14) 0.76

All-cause death/MI/stroke History of PCI 5558 494 (8.9%) 5596 603 (10.8%) 0.82 (0.73–0.93) 0.0014 0.021 No history of PCI 4061 425 (10.5%) 4005 415 (10.4%) 1.02 (0.89–1.17) 0.80 All-cause death/MI/stroke/ ALI/ major amputation, vascular etiology History of PCI 5558 500 (9.0%) 5596 616 (11.0%) 0.82 (0.72–0.92) 0.0007 0.023 No history of PCI 4061 427 (10.5%) 4005 423 (10.6%) 1.00 (0.88–1.15) 0.97 CV death History of PCI 5558 174 (3.1%) 5596 183 (3.3%) 0.96 (0.78–1.18) 0.68 0.41 No history of PCI 4061 190 (4.7%) 4005 174 (4.3%) 1.08 (0.88–1.33) 0.44 All-cause death* History of PCI 5558 282 (5.1%) 5596 323 (5.8%) 0.88 (0.75–1.03) 0.11 0.059 No history of PCI 4061 297 (7.3%) 4005 269 (6.7%) 1.09 (0.93–1.29) 0.29 MI History of PCI 5558 171 (3.1%) 5596 216 (3.9%) 0.80 (0.65–0.97) 0.027 0.42 No history of PCI 4061 103 (2.5%) 4005 112 (2.8%) 0.91 (0.70–1.19) 0.51 STEMI History of PCI 5558 16 (0.3%) 5596 51 (0.9%) 0.32 (0.18–0.55) <0.0001 0.85 No history of PCI 4061 6 (0.1%) 4005 21 (0.5%) 0.28 (0.11–0.70) 0.007 Stroke History of PCI 5558 96 (1.7%) 5596 131 (2.3%) 0.74 (0.57–0.96) 0.024 0.26 No history of PCI 4061 84 (2.1%) 4005 90 (2.2%) 0.93 (0.69–1.25) 0.62 ALI /major amputation of vascular etiology History of PCI 5558 7 (0.1%) 5596 15 (0.3%) 0.47 (0.19–1.15) 0.099 0.88 No history of PCI 4061 6 (0.1%) 4005 14 (0.3%) 0.43 (0.16–1.11) 0.080 Bhatt DL, Steg PG, et al. Lancet 2019 http://dx.doi.org/10.1016/ S0140-6736(19)31887-2.

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Ticagrelor Placebo Subgroup N Patients with events (%) N Patients with events (%) Hazard Ratio (95% CI) P-value P- interaction TIMI major bleeding History of PCI 5536 111 (2.0%) 5564 62 (1.1%) 2.03 (1.48–2.76) <0.0001 0.20 No history of PCI 4026 95 (2.4%) 3967 38 (1.0%) 2.79 (1.91–4.06) <0.0001 BARC type 2, 3, 4

• r 5

History of PCI 5536 632 (11.4%) 5564 313 (5.6%) 2.32 (2.02–2.65) <0.0001 0.041 No history of PCI 4026 453 (11.3%) 3967 176 (4.4%) 2.89 (2.43–3.44) <0.0001 Fatal bleeding (BARC type 5) History of PCI 5536 6 (0.1%) 5564 6 (0.1%) 1.13 (0.36–3.50) 0.83 0.22 No history of PCI 4026 11 (0.3%) 3967 4 (0.1%) 3.04 (0.97–9.55) 0.057 Intracranial hemorrhage History of PCI 5536 33 (0.6%) 5564 31 (0.6%) 1.21 (0.74–1.97) 0.45 0.036 No history of PCI 4026 37 (0.9%) 3967 15 (0.4%) 2.74 (1.51–5.00) 0.00098

Hazard ratios and p-values are calculated for ticagrelor vs placebo from a Cox proportional hazards model with treatment as the only explanatory variable. BARC=Bleeding Academic Research Consortium; CI=confidence interval; PCI=percutaneous coronary intervention; TIMI=thrombolysis in myocardial infarction

Bleeding Endpoints

Safety Population

Bhatt DL, Steg PG, et al. Lancet 2019 http://dx.doi.org/10.1016/ S0140-6736(19)31887-2.

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Cumulative %

6 12 18 24 30 54 16 14 12 10 8 6 4 2 Placebo Ticagrelor 36 42 48

Number at risk Ticagrelor 5558 5433 5339 5240 5153 5037 3484 2124 981 100 Placebo 5596 5480 5390 5274 5166 5060 3470 2128 993 102

HR 0.85 (95% CI 0.75, 0.95) p=0.0052 Months from Randomization Cumulative %

6 12 18 24 30 54 16 14 12 10 8 6 4 2 Ticagrelor Placebo 36 42 48

Number at risk Ticagrelor 4061 3978 3881 3813 3728 3620 2471 1527 696 68 Placebo 4005 3932 3859 3799 3737 3628 2455 1549 690 70

Months from Randomization HR 1.06 (95% CI 0.93, 1.21) p=0.3852

Net Clinical Benefit

All-cause death, MI, stroke, fatal bleed, or ICH (ITT)*

History of PCI No history of PCI

Interaction p=0.012

KM at 36 months KM at 36 months

*Prespecified definition of net clinical benefit. CI=confidence interval; HR=hazard ratio; ICH=intracranial hemorrhage; ITT=intention to treat; MI=myocardial infarction; PCI=percutaneous coronary intervention

HR 0.85 (95% CI 0.75, 0.95) p=0.005 HR 1.06 (95% CI 0.93, 1.21) p=0.39

Placebo Placebo Ticagrelor Ticagrelor

8.2% 9.7% 9.1% 9.9%

Bhatt DL, Steg PG, et al. Lancet 2019 http://dx.doi.org/10.1016/ S0140-6736(19)31887-2.

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Ticagrelor (N=9562) Placebo (N=9531) Subgroup N Patients with events (%) N Patients with events (%) Hazard Ratio (95% CI) p-value p- interaction CV death/ MI/stroke History of PCI 5536 225 (4.1%) 5564 347 (6.2%) 0.73 (0.62–0.87) 0.0003 0.036 No history of PCI 4026 200 (5.0%) 3967 233 (5.9%) 0.96 (0.80–1.16) 0.70 All-cause death/ MI/ stroke History of PCI 5536 242 (4.4%) 5564 378 (6.8%) 0.73 (0.62–0.85) <.0001 0.01 No history of PCI 4026 222 (5.5%) 3967 250 (6.3%) 1.00 (0.83–1.20) 0.99 All-cause death/ MI/ stroke/ ALI/ major amputation of vascular etiology History of PCI 5536 244 (4.4%) 5564 387 (7.0%) 0.71 (0.61–0.84) <.0001 0.011 No history of PCI 4026 224 (5.6%) 3967 258 (6.5%) 0.98 (0.82–1.17) 0.78 CV death History of PCI 5536 60 (1.1%) 5564 85 (1.5%) 0.81 (0.58–1.12) 0.20 0.15 No history of PCI 4026 86 (2.1%) 3967 87 (2.2%) 1.11 (0.83–1.50) 0.48 All-cause death* History of PCI 5536 77 (1.4%) 5564 118 (2.1%) 0.74 (0.56–0.99) 0.044 0.021 No history of PCI 4026 110 (2.7%) 3967 105 (2.6%) 1.18 (0.90–1.54) 0.22 MI History of PCI 5536 109 (2.0%) 5564 177 (3.2%) 0.70 (0.55–0.88) 0.003 0.21 No history of PCI 4026 69 (1.7%) 3967 86 (2.2%) 0.90 (0.66–1.24) 0.51 STEMI History of PCI 5536 9 (0.2%) 5564 39 (0.7%) 0.26 (0.13–0.54) 0.0003 0.76 No history of PCI 4026 3 (0.1%) 3967 16 (0.4%) 0.21 (0.06–0.73) 0.014 Stroke History of PCI 5536 65 (1.2%) 5564 99 (1.8%) 0.74 (0.54–1.02) 0.062 0.38 No history of PCI 4026 62 (1.5%) 3967 76 (1.9%) 0.91 (0.65–1.28) 0.59 ALI/major amputation of vascular etiology History of PCI 5536 3 (0.1%) 5564 9 (0.2%) 0.38 (0.10–1.39) 0.14 0.65 No history of PCI 4026 5 (0.1%) 3967 10 (0.3%) 0.55 (0.19–1.61) 0.27

Primary and Secondary Efficacy Endpoints

On treatment

Hazard ratios and P-values calculated for ticagrelor vs placebo from a Cox proportional hazards model with treatment as the only explanatory variable. Includes events with onset date at or after randomization day up to 7 days after the last dose; only patients who took at least 1 dose of study drug are included. The number of first events for the components are the actual number of first events for each component and do not add up to the number of events in the composite endpoint. Includes deaths based on publicly available vital status data in patients who have withdrawn consent. ALI= acute limb ischemia; CI=confidence interval; CV=cardiovascular; MI=myocardial infarction; PCI=percutaneous coronary intervention; STEMI=ST-segment elevation MI

Bhatt DL, Steg PG, et al. Lancet 2019 http://dx.doi.org/10.1016/ S0140-6736(19)31887-2.

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Benefit of Ticagrelor vs Placebo

as a Function of Time between PCI and randomization

Dotted lines signify 95% confidence interval; HR=hazard ratio; PCI=percutaneous coronary intervention

HR=1

0.50 0.75 1.00 1.25 0 1 2 3 4 5 6 7 8 9 10

Hazard Ratio Years from most recent PCI to randomization

Bhatt DL, Steg PG, et al. Lancet 2019 http://dx.doi.org/10.1016/ S0140-6736(19)31887-2.

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Study Design

Enrollment Period

3 Months

Randomization Period

12 Months

Observation Period

3 Months

High-Risk PCI Patients

(N=9006)

N = 7119

Standard of Care Standard of Care 15 M 18 M 0 M 3 M

Not Randomized (N=1887)

4 M 9 M Ticagrelor + Placebo Ticagrelor + Aspirin Ticagrelor + Aspirin (Open label)

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3555 3474 3424 3366 3321 Ticagrelor + Placebo 3564 3454 3357 3277 3213 Ticagrelor + Aspirin

• No. at risk

2 4 6 8 10 3 6 9 12 Months since randomization

Ticagrelor + Aspirin Ticagrelor + Placebo

Cumulative incidence (%)

7.1% 4.0%

Placebo vs Aspirin HR (95%CI): 0.56 (0.45 to 0.68) P <0.001

Primary Endpoint: BARC 2, 3 or 5 Bleeding

ITT Cohort

ARD = -3.08% (-4.15% to -2.01%) NNT = 33

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2 4 6 8 10 Cumulative incidence (%)

Ticagrelor + Aspirin Ticagrelor + Placebo

3 6 9 12 Months since randomization

BARC 3 or 5 Bleeding

ITT Cohort

3555 3504 3475 3440 3423 Ticagrelor + Placebo 3564 3516 3470 3426 3390 Ticagrelor + Aspirin

• No. at risk

1.0%

Placebo vs Aspirin HR (95%CI): 0.49 (0.33 to 0.74) P = 0.0006

2.0%

ARD = -0.99% (-1.55% to -0.43%) NNT = 100

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Key Secondary Endpoint: Death, MI or Stroke

PP Cohort

3524 3457 3412 3365 3330 Ticagrelor + Placebo 3515 3466 3415 3361 3320 Ticagrelor + Aspirin

• No. at risk

3 6 9 12 Months since randomization

Ticagrelor + ASA Ticagrelor + Placebo

Cumulative incidence (%)

3.9% 3.9%

Placebo vs Aspirin HR (95%CI): 0.99 (0.78 to 1.25) Pnon-inferiority <0.001

ARD = -0.06% (-0.97% to 0.84%)

2 4 6 8 10

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Antiplatelet and Anticoagulant Pathways

Bhatt, D. L. (2018) Advances in atherosclerosis, atrial fibrillation, and valvular disease.

• Nat. Rev. Cardiol. doi:10.1038/nrcardio.2017.212

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www.phri.ca

COMPASS trial in patients with CAD or PAD: Primary outcome

Eikelboom JW, et al. N Engl J Med 2017; 377: 1319-30.

51

www.phri.ca

Benefits of COMPASS regimen according to number

• f enrichment criteria

Darmon A, et al. J Am Coll Cardiol 2019; 73: 3281-91

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Pr Primary Efficacy Endpoint CV V death, MI or stroke (ITT) T)

Prior PCI

Interaction p=0.85

No Prior PCI

HR 0.74 (95% CI 0.61-0.88) HR 0.76 (95% CI 0.61-0.94)

PCI

53

Sa Safety E Endpoi

• int

Ma Major Bl

• r Bleeding*

*The primary safety outcome was modified International Society of Thrombosis and Hemostasis (ISTH) major bleeding, defined as: i) fatal bleeding and/or ii) symptomatic bleeding in a critical area

• r organ or bleeding into the surgical site requiring re-operation and/or iii) bleeding leading to hospitalization (including presentation to an acute care facility without an overnight stay).

Symptomatic bleeding into a critical organ or area included intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with compartment syndrome.

Follow-up Time Cumulative Incidence Risk 0.0 0.02 0.04 0.06 0.08 0.10 0.12 0.14 1y 2y 3y DPI ASA Alone

# at Risk 1 2 3

DPI ASA Alone

4963 4346 2216 406 4899 4319 2298 427

Major Bleed, Previous PCI Follow-up Time Cumulative Incidence Risk 0.0 0.02 0.04 0.06 0.08 0.10 0.12 0.14 1y 2y 3y DPI ASA Alone

# at Risk 1 2 3

DPI ASA Alone

3342 2839 1412 221 3356 2859 1392 226

Major Bleed, No PCI

Prior PCI No Prior PCI

Interaction p=0.68

HR 1.72 (95% CI 1.34-2.21) HR 1.58 (95% CI 1.15-2.17)

PCI

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Se Secon

• ndary E

Efficacy cy E Endpoi

• int

Al All-Cause Death (ITT) T)

Prior PCI No Prior PCI

HR 0.73 (95% CI 0.58-0.92) HR 0.80 (95% CI 0.64-1.00)

Interaction p=0.59

PCI

55

Ben Benefit t of DP DPI I vs As Aspirin

as a function of time from the most recent percutaneous coronary intervention

CV Death, MI, Stroke All-cause mortality

The p-value of interaction between treatment group and time since percutaneous coronary intervention was 0.66 The p-value of interaction between treatment group and time since percutaneous coronary intervention was greater than 0.99

PCI

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57

VKA

(INR 2–3)

Apixaban 5 mg BID

Apixaban 2.5 mg BID in selected patients

Primary outcome: ISTH major / CRNM bleeding Secondary outcome(s): death / hospitalization, death / ischemic events

Randomize n=4600 patients

INCLUSION

• Atrial fibrillation (prior, persistent, >6 hr)

–Physician decision for OAC

• Acute coronary syndrome or PCI

–Planned P2Y12 inhibitor for ≥6 months EXCLUSION

• Contraindication to DAPT
• Other reason for VKA

(prosthetic valve, moderate / severe mitral stenosis)

Trial Design

Aspirin for all on the day of ACS or PCI Aspirin versus placebo after randomization

Open Label

Aspirin Placebo

Double Blind

Aspirin Placebo

Double Blind

Lopes RD, et al. Am Heart J. 2018;200:17-23.

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VKA + Aspirin (18.7%) Apixaban + Aspirin (13.8%) Apixaban + Placebo (7.3%) VKA + Placebo (10.9%)

Major / CRNM Bleeding

Apixaban + Placebo

• vs. VKA + Aspirin:

11.4% absolute risk reduction (NNT=9) 59

VKA + Placebo (27.3%) Apixaban + Placebo (22.0%) Apixaban + Aspirin (24.9%) VKA + Aspirin (27.5%)

Death / Hospitalization

Apixaban + Placebo

• vs. VKA + Aspirin:

5.5% absolute risk reduction (NNT=18) 60

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Rivaroxaban Monotherapy versus Combination Therapy in Patients with Atrial Fibrillation and Stable Coronary Artery Disease

Satoshi Yasuda, Koichi Kaikita, Masaharu Akao, Junya Ako, Tetsuya Matoba, Masato Nakamura, Katsumi Miyauchi, Nobuhisa Hagiwara, Kazuo Kimura, Atsushi Hirayama, Kunihiko Matsui, Hisao Ogawa,

• n behalf of the AFIRE (Atrial Fibrillation and Ischemic events with Rivaroxaban in

patiEnts with stable coronary artery disease) Investigators Atrial Fibrillation and Ischemic events with Rivaroxaban in patiEnts with stable coronary artery disease

61

A multicenter, prospective, randomized, open-label, parallel-group trial 1)

1) Yasuda S, et al. Int J Cardiol. 2018. 2) Tanigawa T, et al. Drug Metab Pharmacokinet. 2013.

Atrial Fibrillation and Ischemic events with Rivaroxaban in patiEnts with stable coronary artery disease: AFIRE Study

R A N D O M I Z E Rivaroxaban Monotherapy Combination Therapy

u Rivaroxaban 10 or 15 mg/day 2)* u Rivaroxaban 10 or 15 mg/day u Single antiplatelet Aspirin 81 or 100 mg/day, Clopidogrel 50 or 75 mg/day, Prasugrel 2.5 or 3.75 mg/day

2200 patients with AF (CHADS2≥1) and stable CAD Key inclusion criteria

u Underwent PCI or CABG more than 1 year earlier u Angiographically confirmed CAD (with stenosis of ≥50%) not requiring revascularization

Key exclusion criteria

u A history of stent thrombosis u Coexisting active tumor u Poorly controlled hypertension *The level of rivaroxaban in blood samples obtained from Japanese patients who were taking rivaroxaban at the 15-mg dose was similar to the level in white patients who were taking the 20-mg dose.

UMIN Clinical Trials Registry number, UMIN000016612. ClinicalTrials.gov number, NCT02642419.

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Kaplan-Meier Estimates of First Occurrence of Primary Safety Events

2.76% per patient-year 1.62% per patient-year

HR, 0.59 (0.39 to 0.89) P=0.01 (sup.) Combination therapy Monotherapy

63

Kaplan-Meier Estimates of First Occurrence of Primary Efficacy Events

5.75% per patient-year 4.14% per patient-year

HR, 0.72 (0.55 to 0.95) P<0.001 (noninf.) Combination therapy Monotherapy

*In the assessment for superiority for the primary efficacy end point (that was not prespecified), the P value was 0.02.

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• In ACS + PCI, at least 12 months of DAPT if no bleeding
• If post-MI, diabetes, complex stenting/disease, consider longer
• If Afib + PCI, aspirin in house, but then NOAC + clopidogrel
• If very high risk due to ACS, complex stenting, consider ticagrelor
• After 1 year, in general drop the antiplatelet if stable
• If high bleeding risk post PCI, can abbreviate DAPT at 3 months
• At that point ticagrelor or clopidogrel monotherapy are options
• In patients not on DAPT but at high ischemic/low bleeding risk:
• Consider COMPASS regimen of low-dose aspirin and low-dose riva

Conclusions

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www.brighamandwomens.org/heart

Deepak L. Bhatt, MD, MPH Executive Director, Interventional Cardiovascular Programs, BWH Heart & Vascular Center; Professor of Medicine, Harvard Medical School Email: DLBhattMD@post.harvard.edu Twitter: @DLBhattMD

Thank You!

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