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

Leon et al. NEJM 1998

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”

Bhatt et al. JAMA 2010; 304:1350-7.

CV Death, MI, Stroke

%

21.1 17.2 12.2 9.1

4 8 12 16 20 24

Prior Ischemic Event <=1 Yr Prior Ischemic Event >1 y Stable Atherosclerotic disease Risk Factor only

REACH Registry (4-yr outcomes) 64,977 patients ≥ 45 years old

Patients with Prior MI Remain at High Risk for Ischemic Events

Probability of Primary Events PAD with and without Diabetes Probability of Primary Events Time (year) post-randomization

Gutierrez et al. ACC 2016

Risk after ACS with Diabetes, Polyvascular Disease

• r Both

CURE: benefit of DAPT with aspirin and clopidogrel after ACS

Proportion Event-Free .90 .92 .94 .96 .98 1.00

Week

1 2 3 4 RRR: 21% 95% CI, 0.67–0.92 P=.003 Clopidogrel Placebo

CV Death, MI, or Stroke First 30 Days

• No. at Risk

5981 5481 4742 4004 3180 2418 5954 5390 4639 3929 3159 2388 Clopidogrel 6259 6145 6070 6026 5990 Placebo 6303 6159 6048 5993 5965

• No. at Risk

Proportion Event-Free RRR: 18% 95% CI, 0.70–0.95 P=.009 Clopidogrel Placebo

CV Death, MI, or Stroke >30 Days–1 Year

Month

1 4 6 8 10 12 .90 .92 .94 .96 .98 1.00

Yusuf S, et al. Circulation. 2003;107:966-972.

12,562 Patients with NSTEACS (mostly conservatively managed)

8,688 8,763

10 20 30 8 6 4 2 CV Death, MI, or Stroke (%) Clopidogrel Ticagrelor 4.77 5.43

HR 0.88 (95% CI 0.77–1.00), p=0.045

• No. at risk

Clopidogrel Ticagrelor 9,291 9,333 8,875 8,942 8,763 8,827

Days after randomisation 31 90 150 210 270 330 8 6 4 2 Clopidogrel Ticagrelor 5.28 6.60

8,688 8,673 8,286 8,397 6,379 6,480

Days after randomisation*

HR 0.80 (95% CI 0.70–0.91), p<0.001

8,437 8,543 6,945 7,028 4,751 4,822

CV Death, MI, or Stroke (%)

Potent P2Y12 Inhibitor After ACS Reduces Risk Early and Late & Reduces Mortality

*Excludes patients with any primary event during the first 30 days

18,624 Patients w/in 24 hrs of onset of ACS (64% underwent PCI) Death from any cause 4.5% vs 5.9% HR 0.78 (0.69 – 0.89), p<0.001

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 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) EXCELLENT 1443 12 vs 6 2.0 (0.37-11.11) 0.17 (0.02-1.39) 0.54 (0.21-1.35) OPTIMIZE 3120 12 vs 3 1.41 (0.63-3.13) 0.95 (0.42-2.04) 0.85 (0.57-1.29) ARCTIC- Interruption 1259 Continued DAPT vs. ASA 6.94 (0.85-56.61) 0 vs 3 events* 1.04 (0.41-26.2) ITALIC 1850 12 vs 6 3 vs. 0 events* 0 vs. 3 events* 0.67 (0.19-2.38) ISAR-SAFE 4005 12 vs 6 1.25 (0.34-4.76) 0.80 (0.21-3.03) 9 events 1.08 (0.51-2.27) 27 events

8

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 2104. Schultz-Schupke, et al. EHJ Jan 25, 2015.

Mauri et al. NEJM 2014

~ 46% with history of MI

Death, MI or stroke

DAPT: Withdrawal of Thienopyridine 12

Months after Coronary Stenting

Moderate/Severe Bleeding 2.5% vs.1.6% All Cause Mortality 2.0% vs 1.5%

CHARISMA: Prior MI

a post-hoc exploratory subgroup

10 8 6 4 2

6 12 18 24 30

HR=0.774 (95% CI [0.613–0.978]) P=0.031 N=3,846 CV Death, MI, or Stroke (%) Months Since Randomization 8.3% 6.6% Placebo + ASA Clopidogrel + ASA

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

23% risk reduction if prior MI

10

DAPT: Prior MI and Efficacy for MACE

Yeh et al. JACC 2015

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

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

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

• r chronic non-end stage renal dysfunction

Event-driven trial

PEP: CVD/MI/Stroke Secondary: CV Death, Mortality Exploratory: Coronary death Safety: TIMI Major, ICH, Fatal

Ticagrelor 60 mg bid

Trial Design

Bonaca MP et al. NEJM 2015;372:1791-800

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21,162 patients randomized at 1161 sites in 31 countries between 10/2010 – 5/2013

Poland: 1399 Sweden: 507 Canada: 1306 United States 2601 U.K.: 647 Netherlands: 1560 Belgium: 431 Germany: 924 France: 333 Spain: 535 Czech Rep: 870 Italy: 392 South Africa: 473 Australia: 327 Japan: 903 Hungary: 831 Bulgaria: 447 China: 383 S Korea: 506 Philippines: 250 Colombia: 528 Chile: 322 Argentina: 499 Brazil: 864 Peru: 245 Romania: 404 Slovakia: 475 Russia: 1061 Ukraine: 623 Turkey: 180

13

Norway: 336

Global Enrollment

America First! Netherlands Second…

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• No. Patients – 1560 No. Sites - 41

Average patients per site = 38 Patient Retention 99.94%

NLI: DR. TON OUDE OPHUIS

NETHERLANDS But Actually…

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Months from Randomization

Ticagrelor 60 mg HR 0.84 (95% CI 0.74 – 0.95) P=0.004 CV Death, MI, or Stroke (%)

3 6 9 12 15 18 21 24 27 30 33 36

Ticagrelor 90 mg HR 0.85 (95% CI 0.75 – 0.96) P=0.008

Placebo (9.0%) Ticagrelor 90 (7.8%) Ticagrelor 60 (7.8%)

Primary Endpoint

6 5 4 3 10 9 8 7 2 1

N = 21,162 Median follow-up 33 months

Bonaca MP et al. NEJM 2015;372:1791-800

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0% 1% 2% 3% 4% 731 821 911 1001 0% 1% 2% 3% 4% 366 456 546 636 726 0% 1% 2% 3% 4% 90 180 270 360 3.3% 3.0% 2.8% 3.0% 2.6% HR 0.82 (95% CI 0.67 – 0.99) HR 0.90 (95% CI 0.74 – 1.11) HR 0.79 (95% CI 0.62 – 1.00)

Median 1.7 yrs From Index MI (1.2 – 2.3) Median 2.7 yrs From Index MI (2.2 – 3.3) Median 3.7 yrs From Index MI (3.2 – 4.3) First year in Trial Second year in Trial Third year in Trial

Placebo

2.7%

Ticagrelor 60 mg Twice Daily

Efficacy over time

Bonaca MP et al. JACC in Press

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Components of Primary Endpoint

0.85 (0.75-0.96) 0.008 0.84 (0.74-0.95) 0.004 0.84 (0.76-0.94) 0.001

CV Death, MI, or Stroke

(1558 events) HR (95% CI) P value

1 0.8 0.6 0.4 1.25 1.67

Ticagrelor better Placebo better

Endpoint

Ticagrelor 60 mg Ticagrelor 90 mg Pooled

CV Death

(566 events) 0.87 (0.71-1.06) 0.15 0.83 (0.68-1.01) 0.07 0.85 (0.71-1.00) 0.06

Myocardial Infarction

(898 events) 0.81 (0.69-0.95) 0.01 0.84 (0.72-0.98) 0.03 0.83 (0.72-0.95) 0.005

Stroke

(313 events) 0.82 (0.63-1.07) 0.14 0.75 (0.57-0.98) 0.03 0.78 (0.62-0.98) 0.03

Bonaca MP et al. NEJM 2015;372:1791-800

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Bleeding

2,6 1,3 0,6 0,6 0,1 2,3 1,2 0,7 0,6 0,3 1,1 0,4 0,6 0,5 0,3 1 2 3 4 5 TIMI Major TIMI Minor Fatal bleeding or ICH ICH Fatal Bleeding 3-Year KM Event Rate (%)

Ticagrelor 90 mg Ticagrelor 60 mg Placebo P<0.001 P<0.001 P=NS P=NS P=NS Ticag 60: HR 2.32 (1.68-3.21) Ticag 90: HR 2.69 (1.96-3.70)

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• 18
• 5
• 8
• 4

9

• 20
• 15
• 10
• 5

5 10 15 CV Death, MI, or Stroke CV Death MI Stroke Intracranial Hemorrhage or Fatal Bleeding Major bleed Total # of Events Prevented over 3 Years per 1000 Patients Initiated on Treatment

Ticagrelor 60

Events Prevented and Caused for 1000 Patients Initiated on Ticagrelor 60 mg Twice Daily and Followed for 3 Years

Bonaca MP et al. JACC in Press

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MACE in Patients with & without Prior PCI/Stent

Prior PCI/Stent N = 16,891

CVD / MI / Stroke

Ticagrelor Better Placebo Better 1.0 3 Year KM Rates Ticagrelor Placebo P-value 0.016 0.042 0.0092 0.14 0.0495 0.044 0.86 (0.75 – 0.99) 0.84 (0.73 – 0.97) 0.85 (0.75 – 0.96) 6.8 7.1 7.0 7.8 HR (95% CI) 0.80 (0.64 – 1.00) 0.85 (0.68 – 1.06) 0.82 (0.68 – 0.99) 11.7 10.5 11.1 13.2 Ticagrelor 60 mg Ticagrelor 90 mg Pooled

CVD / MI / Stroke

No Prior PCI/Stent N = 4,271

All p-interaction NS

Any MI

Ticagrelor Better Placebo Better 1.0 3 Year KM Rate (%) Ticagrelor Placebo P–value 0.0055 0.81 (0.69 – 0.95) 0.84 (0.72 – 0.98) 0.83 (0.72 – 0.95) 4.53 4.40 4.47 5.25 HR (95% CI) Ticagrelor 60 mg Ticagrelor 90 mg Pooled

Benefit of Ticagrelor By Size of MI

1.25 2.00 0.75 0.50

MI with Tn ≥ 25 x ULN MI with Tn ≥ 50 x ULN MI with Tn ≥ 100 x ULN MI with Tn ≥ 200 x ULN

0.0052 0.77 (0.60 – 0.98) 0.71 (0.55 – 0.92) 0.74 (0.60 – 0.91) 1.68 1.74 1.71 2.18 0.0044 0.71 (0.53 – 0.94) 0.70 (0.53 – 0.93) 0.71 (0.55 – 0.90) 1.34 1.29 1.31 1.75 0.0096 0.76 (0.55 – 1.04) 0.64 (0.45 – 0.89) 0.70 (0.53 – 0.92) 0.93 1.05 0.99 1.30 0.022 0.71 (0.47 – 1.07) 0.62 (0.40 – 0.95) 0.66 (0.47 – 0.94) 0.52 0.61 0.56 0.83

ULN = upper limit of normal

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~40% Reduction in Very Large MI

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0.0% 0.5% 1.0% 1.5% 2.0% 90 180 270 360 450 540 630 720 810 900 990 1080

Effect of Ticagrelor on STEMI

Ticagrelor 60 mg HR 0.62 (95% CI 0.45 – 0.86) P=0.00016 Ticagrelor 90 mg HR 0.57 (95% CI 0.41 – 0.79) P=0.0008

Placebo Ticagrelor 90 Ticagrelor 60

Days from Randomization

STEMI (%) ~40% Reduction in New STEMI during Follow up

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0,0% 0,5% 1,0% 1,5% 2,0% 2,5% 180 360 540 720 900 1080 Any Stroke at 3 Years (%)

1.94%

Days from Randomization

1.47% Placebo Ticagrelor 60 mg BID

Any Stroke HR 0.75 (0.57 – 0.98) P=0.034

Effect of Ticagrelor on Stroke

22 19 28 18 14 15 8 5 6 5 6 3 15 7

20 40 60 80 100 120

Placebo Ticagrelor 60 mg

Rankin 0 Rankin 1 Rankin 2 Rankin 3 Rankin 4 Rankin 5 Rankin 6

Number (N)

99 72

Asymptomatic No Significant Disability Slight Disability Moderate Disability Moderately Severe Disability Severe Disability Dead

HR 0.57 (0.33 – 0.99) P=0.045

Modified Rankin Score at 30 Days

43% Reduction in Moderate-Severely Disabling or Fatal Stroke

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0,0% 0,2% 0,4% 0,6% 0,8% 1,0% 1,2% 1,4% 180 360 540 720 900 1080

Thrombotic Complications (%) Days from Randomization

Placebo

N=105

Ticagrelor 60 mg HR 0.68 (0.47 – 0.99) P=0.041

Ticagrelor 60 mg

N=47

N=14,112 patients Median FUP of 33 months

Venous Thromboembolism Reduced with Ticagrelor

Cavellari I, Bonaca MP et al. Circulation 2017

Outcomes with Continued DAPT after MI

6,4 2,3 3,5 1,4 0,6 7,5 2,6 4,4 1,7 1,4 1 2 3 4 5 6 7 8 9 10

MACE CV Death MI Stroke Stent Thrombosis (Def/Prob)

Event Rate (%) Extended DAPT Aspirin Alone RR 0.78 P = 0.001 RR 0.85 P = 0.03 RR 0.70 P = 0.003 RR 0.81 P = 0.02 RR 0.50 P = 0.02

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

~15% Reduction in Cardiovascular Mortality

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

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CVD/MI/Stroke (%) Days from Randomization

9.9% 8.0% 7.4%

Placebo Ticagrelor 60 mg BID Ticagrelor 90 mg BID HR 0.75 (95% CI 0.61 – 0.92) P=0.0064 HR 0.70 (95% CI 0.57 – 0.87) P=0.0009

Greater Benefit in Patients Continuing

• n P2Y12 Inhibition

NNT=40 NNT=53

0% 2% 4% 6% 8% 10% 12% 90 180 270 360 450 540 630 720 810 900 990 1080

Bonaca et al. EHJ 2015

~13 Events Prevented per 1000 vs 9 Bleeds ~20 Events Prevented per 1000

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Efficacy of ticagrelor by eGFR

HR 95% CI 0.81 (0.68 – 0.96) ARR = 2.70% NNT 37 HR 95% CI 0.88 (0.77 – 1.00) ARR = 0.63%

Primary Endpoint: CV death, MI, stroke

Months since randomization 12 24 36

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% 7.43% 6.80%

3-yr KM %

2 6 12 10 8 16 14 4

Magnani G et al. and Bonaca MP EHJ 2015

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Coronary Events in Multivessel Disease

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

Bansilal S, et al. ACC 2016

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MACE with Ticagrelor in Diabetics

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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• 16
• 6

2 23

• 20
• 15
• 10
• 5

5 10 15 20 25

GDF-15 < 1200 GDF-15 >= 1200

Events Prevented or Caused for 1000 Initiated on Ticagrelor 60 for 3 Years

Events prevented or caused for 1000 Patients Initiated on Treatment for 3 Years GDF-15 Concentration at Baseline No excess in ICH or Fatal Bleeding CV Death, MI, Stroke CV Death, MI, Stroke Major Bleeds Major Bleeds Bonaca et al. ESC 2017

PEGASUS-TIMI 54 and COMPASS – Trial Comparison

*Doses pooled

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 - 16-17% 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

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 (0.76 – 0.94) 0.001 0.76 (0.66 – 0.86) <0.001 CV Death 0.83 (0.68 – 1.01) 0.07 0.78 (0.64 – 0.96) 0.02 MI 0.84 (0.72 – 0.98) 0.03 0.86 (0.70 – 1.05) 0.14 Stroke 0.75 (0.57 – 0.98) 0.03 0.58 (0.44 – 0.76) <0.001 VTE 0.68 (0.47 – 0.99) 0.041 0.61 (0.37 – 1.00) 0.05 MALE (PAD)* 0.65 (0.44 – 0.95) 0.026 0.54 (0.35 – 0.84) 0.005 Mortality 0.89 (0.76 – 1.04) 0.14 0.82 (0.71 – 0.96) 0.01 Bleeding leading to transfusion 1.52 (0.99 – 2.33) 0.058 1.97 (1.37 – 2.83) <0.001 GUSTO Severe vs. Major Bleeding 1.83 (1.22 – 2.74) 0.004 1.70 (1.40 – 2.05) <0.001 Fatal Bleeding or ICH 1.22 (0.74 – 2.01) 0.43 1.23 (0.76 – 2.01) 0.40 NET Outcome (CVD/MI/Stroke/ICH/F atal bleeding) 0.86 (0.77 – 0.97) 0.016 0.80 (0.70 – 0.91) <0.001

*Doses pooled

0% 2% 4% 6% 8% 10% 12% 14% 16% 18% 366 456 546 636 726 816 906 996 1086 0% 2% 4% 6% 8% 10% 12% 14% 16% 18% 90 180 270 360

First Year Years 2 + 3

Drug discontinuation for AE by Treatment

KM Rate Days from Randomization

Ticagarelor 90 mg twice daily Ticagrelor 60 mg twice daily Placebo

16% 13% 6% 6.0% 4.5% 6.5%

P-value for each dose vs. placebo < 0.01 P<0.01 for each dose

• vs. placebo

Treatment Arm Annualized Rate Ticagrelor 90 3.3% Ticagrelor 60 3.0% Placebo 2.3%

50 100 150 200 250 300 350 400 450 500 90 180 270 360 450 540 630 720 810 900 990

Discontinuation over time for Dyspnea by Randomization Group

Number of Patients Discontinued for Dyspnea Days From Randomization

Ticagrelor 90 mg twice daily Ticagrelor 60 mg twice daily Placebo 8 11 53 P<0.01 for each dose vs. placebo Median Days to Discontinuation

Efficacy of Ticagrelor – On Treatment*

CVD / MI / Stroke

Ticagrelor Better Placebo Better 1.0 Ticagrelor Placebo 3 Year KM Rate (%) P-value <0.001

*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

CV Death Coronary Heart Disease Death

<0.001 <0.001 0.031 0.076 0.019 0.052 0.087 0.029 0.79 (0.68 – 0.91) 0.78 (0.68 – 0.90) 0.78 (0.70 – 0.88) 6.8 6.6 6.7 8.4 HR (95% CI) 0.78 (0.60 – 1.03) 0.74 (0.57 – 0.97) 0.76 (0.61 – 0.96) 1.8 1.9 1.9 2.4 0.75 (0.54 – 1.04) 0.72 (0.52 – 1.00) 0.74 (0.56 – 0.97) 1.2 1.3 1.3 1.6 Ticagrelor 60 mg Ticagrelor 90 mg Pooled

Myocardial Infarction Stroke

0.0236 0.0080 0.0036 0.048 0.094 0.029 0.78 (0.65 – 0.94) 0.81 (0.68 – 0.97) 0.80 (0.68 – 0.93) 4.1 3.8 4.0 4.9 0.77 (0.56 – 1.05) 0.73 (0.53 – 1.00) 0.75 (0.58 – 0.97) 1.4 1.4 1.4 1.8

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Patients ≤ 2 Yrs from MI or 1 Yr from ADP Receptor Blocker Treatment

5391 5246 5138 4914 4380 3177 1485 5388 5280 5187 4999 4436 3253 1507 T60 EU Placebo EU

Number at risk:

7.85% 9.56%

180 360 540 720 900 1080

Days after randomization

0% 2% 4% 6% 8% 10%

T60 EU Placebo EU

Primary endpoint(%)

Outcome Ticagrelor 60 (N=5388) Placebo (N=5391) Hazard ratio (95% CI) P value n 3-yr n 3-yr PEP 373 7.9 463 9.6 0.80 (0.70, 0.91) 0.001 CV death 119 2.6 167 3.6 0.71 (0.56, 0.90) 0.0041 MI 230 4.8 274 5.6 0.83 (0.70, 0.99) 0.041 Stroke 71 1.5 95 2.0 0.74 (0.55, 1.01) 0.058 All-cause mortality 206 4.4 256 5.4 0.80 (0.67, 0.96) 0.018 TIMI major bleeding 94 2.5 43 1.1 2.36 (1.65, 3.39) <0.0001 Fatal or intracranial bleeding 27 0.8 25 0.7 1.17 (0.68, 2.01) 0.58

Dellborg et al. ESC 2017

PAD+CAD Higher Risk Than PAD or CAD Alone

Franzone et al. JAHA 2016

8,4% 6,0% 4,6% 19,3% 22,3% 11,7% 0% 5% 10% 15% 20% 25% PEGASUS-TIMI 54 PRODIGY DAPT No PAD PAD

Secemsky et al. AHA 2016 Bonaca et al. JACC 2016

CVD / MI / Stroke

60% increased risk of MACE after adjusting for risk factors

Longer DAPT in PAD With CAD/ACS

Franzone et al. JAMA Cardiology 2016

27% 16% 7% ARR PAD with prior ACS HR 0.46 (0.25 – 0.87) P=0.016 P-interaction 0.011 9% 7%

All Cause Mortality 21.1% vs 10.2% HR 0.45 (0.23 – 0.88) P=0.02

TIMI Major Bleeding 1.8% vs 3.5% HR 0.50 (0.09 – 2.74) P=0.43 GUSTO Mod/Severe 2.6% vs 2.6% HR 1.02 (0.21 – 5.04) P=0.51

Large reduction in MACE Lower mortality Modest bleeding excess

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CVD / MI / Stroke

Ticagrelor Better Placebo Better 1.0 Absolute Risk Difference at 3 Years

P=0.045

CV Death Mortality

P=0.014 P=0.0074

0.69 (0.47 – 0.99) HR (95% CI) 0.47 (0.25 – 0.86) 0.52 (0.32 – 0.84) 10 0.1

TIMI Major Bleeding

– 5.2 – 5.4 – 5.7

P=0.82

1.18 (0.29 – 4.70) 0.02

0% 5% 10% 15% 20% 25% CV Death, MI, or Stroke (%)

Days from Randomization P-interaction NS

Ticagrelor 60 mg BID Placebo

ASA+Ticagrelor in PAD with Prior MI

Bonaca MP et al. JACC 2016

PAD No PAD 19.3% 14.1%

ARR 5.2% NNT 20

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Major Adverse Limb Events with Ticagrelor

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 Bonaca MP et al. JACC 2016

Vorapaxar and Limb Vascular Efficacy

Hospitalization for Acute Limb Ischemia

Pre-specified, adjudicated 2.3% 3.9% Hazard Ratio 0.58 95% CI 0.39 to 0.86 p = 0.006

Placebo Vorapaxar N = 3767

Days from randomization Peripheral Revascularization Prespecified, Investigator 18.4% 22.2% Hazard Ratio 0.84; 95% CI 0.73 to 0.97 p = 0.017

Bonaca et al. Circulation 2012

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

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

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

14,6 9,9 12,6 7,9

5 10 15 KM Rate (%) at 3 Years

HR 0.85 (0.79-0.92) P<0.0001 HR 0.80 (0.73-0.88) P<0.0001

CVD, MI, stroke UA, cor revasc CVD, MI, stroke

Sabatine MS et al. NEJM 2017;376:1713-22

Evolocumab (median 30 mg/dl, IQR 19-46 mg/dl) Placebo 59% reduction P<0.00001 Absolute  56 mg/dl

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

Peripheral Artery Disease and Risk in Placebo Patients

Days from Randomization

CVD / MI / Stroke

adjusted age, sex, race, BMI, diabetes, hypertension, smoking, eGFR, CHF, prior MI, CABG/PCI, and history of stroke or TIA.

0% 2% 4% 6% 8% 10% 12% 14% 16% 180 360 540 720 900

Days from Randomization

0% 2% 4% 6% 8% 10% 12% 14% 16% 180 360 540 720 900

P=0.0028

7.6% 10.3% 14.9%

P=0.0001

CVD / MI / Stroke 7.6% 13.0%

Adjusted HR 1.81

(1.53 – 2.14) P<0.001

PAD N=1784 MI or Stroke and no PAD N=11996 MI or Stroke and no PAD N=11996 PAD with MI/Stroke N=1036 PAD no MI/Stroke N=748

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

MI or Stroke and no PAD N=23,922 PAD N=3,642 Age, median (IQR) 63 (56, 69) 64 (58, 69) Female sex (%) 24 28 History Hypertension (%) 79 85 Current Smoker (%) 27 36 History of Diabetes (%) 36 43 History of Stroke (%) 20 15 History of Myocardial Infarction (%) 86 50 Statin, High/Moderate (%) 69 / 30 69 / 31 Antiplatelet therapy (%) 93 89 Anticoagulant therapy (%) 8 11 ACE-I or ARB use at baseline (%) 78 76

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

Baseline Characteristics

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

CV Death, MI or Stroke Placebo Evolocumab 13.0%

7.6%

9.5%

6.2%

PAD 3.5% ARR NNT2.5y 29 No PAD 1.4% ARR NNT2.5y 72

PAD

N=3,642

27% RRR

HR 0.73 (0.59 – 0.91) P=0.0040

p-interaction = 0.41 No PAD N=23,922 HR 0.81 95% CI (0.73 – 0.90) P<0.001

Days from Randomization

CV Death, MI or Stroke in Patients with and without Peripheral Artery Disease

0% 2% 4% 6% 8% 10% 12% 14% 90 180 270 360 450 540 630 720 810 900

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

0% 2% 4% 6% 8% 10% 12% 90 180 270 360 450 540 630 720 810 900 CV Death, MI or Stroke Days from Randomization Placebo Evolocumab 10.3% 5.5% PAD 4.8% ARR NNT2.5y 21

PAD (no MI/stroke, N=1505) 43% RRR

HR 0.57 (0.38 – 0.88) P=0.0095

CV Death, MI or Stroke in Patients with PAD and no MI or Stroke

Outcome HR 95% CI MACE 0.57 (0.38–0.88) CV Death 0.78 (0.39–1.57) MI 0.66 (0.38–1.14) Stroke 0.30 (0.11–0.82) Mortality 0.86 (0.51- 1.45)

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

Major Adverse Limb Events Placebo 0.45% 0,0% 0,1% 0,2% 0,3% 0,4% 0,5% 90 180 270 360 450 540 630 720 810 900

Days from Randomization

Major Adverse Limb Events

Placebo Evolocumab 0.45% 0.27%

All Patients

N=27,564

42% RRR

HR 0.58 (0.38 – 0.88) P=0.0093 0,0% 0,1% 0,2% 0,3% 0,4% 0,5% 90 180 270 360 450 540 630 720 810 900

Days from Randomization

Outcome HR 95% CI MALE 0.58 (0.38–0.88) ALI or major amputation 0.52 (0.31–0.89) ALI 0.55 (0.31–0.97) Major amputation 0.57 (0.17–1.95) Urgent revascularization 0.69 (0.38–1.26)

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

0,0% 0,5% 1,0% 1,5% 2,0% 2,5% 3,0% 90 180 270 360 450 540 630 720 810 900 Major Adverse Limb Events Placebo Evolocumab 2.6% 1.3%

Major Adverse Limb Events in Patients with PAD and no MI or Stroke

Days from Randomization

1.3% ARR PAD (no MI/stroke, N=1505) 57% RRR

HR 0.43 (0.19 – 0.99) P=0.042

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

0% 2% 4% 6% 8% 10% 12% 14% 90 180 270 360 450 540 630 720 810 900 Placebo Evolocumab 12.8% 6.5% PAD 6.3% ARR NNT2.5y 16 Days from Randomization

MACE or MALE In Patients with PAD and no MI or Stroke

MACE or MALE

PAD (no MI/stroke, N=1505) 48% RRR

HR 0.52 (0.35 – 0.76) P=0.0006

The DAPT Score

53 0% 5% 10% 15% 20% 25% 30%

• 2 -1 0 1 2 3 4 5 6 7 8 9 10

Percentage of Patients DAPT Score Variable Points Patient Characteristic Age ≥ 75

• 2

65 - <75

• 1

< 65 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 Distribution of DAPT Scores among all randomized subjects in the DAPT Study

Yeh et al. JAMA 2016

54

Continued Thienopyridine vs. Placebo, by DAPT Score, Excluding PES

Risk Difference (Continued Thienopyridine – Placebo), 12-30M

P values are for comparison of risk differences across DAPT Score category (interaction).

Myocardial Infarction

• r Stent Thrombosis

GUSTO Moderate

• r Severe Bleed

Net Adverse Events P=0.06 P=0.07 P=0.17 Mortality P=0.003

• 0,52%

1,44% 1,03% 0,79%

• 1,90%

0,38%

• 1,67%
• 0,01%
• 4,0%
• 3,0%
• 2,0%
• 1,0%

0,0% 1,0% 2,0% 3,0% 4,0%

DAPT Score < 2 DAPT Score ≥ 2

Yeh et al. JAMA 2016

Variable HR (95% CI) p-value Points CHF 2.03 (1.68, 2.46) <0.001 1 Prior Stroke 1.83 (1.39, 2.40) <0.001 1 Hypertension 1.61 (1.34, 1.93) <0.001 1 Diabetes mellitus 1.49 (1.27, 1.75) <0.001 1 Current Smoking 1.47 (1.23, 1.75) <0.001 1 Prior CABG 1.44 (1.20, 1.73) <0.001 1 Age≥75 1.40 (1.11, 1.75) 0.004 1 Peripheral arterial disease 1.36 (1.13, 1.64) 0.001 1 Renal dysfunction (eGFR< 60) 1.36 (1.12, 1.65) 0.002 1 Maximum Possible # Risk Indicators 9

Multivariable Model

Risk of CV death, MI or ischemic stroke in placebo-treated cohort (N=8598)

Bohula et al. Circulation in Press

Efficacy & Safety By Risk Group

# Risk Indicators 1-2 ≥3 3217 (19) 9967 (61) 3214 (20) 3,6% 8,1% 17,7% 3,5% 6,0% 14,5% 0,1% 1,0% 2,0% 0,7% 1,1% 1,9% 0% 2% 4% 6% 8% 10% 12% 14% 16% 18% 20% CV death / MI / ischemic stroke at 3 Yrs (%) Placebo (CV death, MI, or Ischemic Stroke) Vorapaxar (CV death, MI, or Ischemic Stroke) Placebo (GUSTO Severe Bleeding) Vorapxar (GUSTO Severe Bleeding) ARR 2.1% (1.0, 3.4) NNT 48 ARR 3.2% (0.4, 6.3) NNT 31 CVD/MI/iCVA: p-trend<0.001 p-interaction = 0.35 GUSTO Severe: p-trend<0.01 p-interaction = 0.13

Prior MI without a history of stroke or TIA

Bohula et al. AHA 2015 CHF, prior stroke, HTN, DM, age, smoking, CABG, PAD, renal dysfunction

PARIS Risk Score

Baber et al. JACC 2016

PRECISE-DAPT – Bleeding Risk in ACS

http://precisedaptscore.com/webcalculator.php

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

Which Post-MI Have Greatest Benefit?

Baber et al. JACC 2016

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 ▲Ischemic Risk Hypertension ▲Ischemic Risk Prior PCI ▲Ischemic Risk ▲Ischemic Risk Stent Diameter ▲Ischemic Risk Paclitaxel Stent ▲Ischemic Risk

Yeh et al. JAMA 2016 Bohula et al. Circ 2016 Slide by Marc Bonaca

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 P2Y12
• 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