Vorapaxar for Secondary Prevention in Patients with Prior Myocardial Infarction

Benjamin M. Scirica, MD, MPHOn behalf of the TRA 2°P-TIMI 50 Steering Committee and Investigators

NCT00526474; Trial funded by Merck

Clinical Trial UpdateEuropean Society of Cardiology

Munich, August 26, 2012

Background

• The benefit of adding other antiplatelet drugs to aspirin for long-term 2°prevention in stable patients with prior MI is uncertain

• Vorapaxar inhibits platelet activation by antagonizing thrombin-mediated activation of the protease activated receptor (PAR)-1

Prior MI, CVA, or PADN=26,449

Vorapaxar2.5 mg/d

Placebo

RANDOMIZE 1:1 DOUBLE BLIND

Follow up VisitsDay 30, Mo 4, Mo 8, Mo 12

Q6 months

Standard care including oral antiplt rx

Final Visit

Primary Efficacy Analysis:1. CVD/MI/Stroke2. CVD/MI/Stroke/Urgent

Coronary RevascPrincipal Safety EP:• GUSTO Mod/Sev bleeding

Median F/U 30 Months

Prior MI Inclusion:Type 1 MI >2 wks and <12 months before randomization

Trial Design

Stratified by:1) Qualifying Disease State2) Use of thienopyridine

Morrow et al. N Engl J Med 2012ClinicalTrials.gov NCT00526474

Background – 1° Efficacy EvaluationOverall Population

CV Death, MI, or Stroke

9.3%

10.5%

Hazard Ratio 0.87p < 0.001

N = 26449Mean f/u: 2.5 years Placebo

Vorapaxar

GUSTO Mod/Sev at 3 yrs4.2 v. 2.5%, HR 1.66, p<0.001

Morrow et al. N Engl J Med 2012ClinicalTrials.gov NCT00526474c

Statistical MethodsPrior MI Cohort

Prior MI Cohort• Prospectively defined subgroup of 1° interest• 17,779 patients (67% of total trial population)Low-bleeding Risk Cohort• Based on prior studies1, we applied previously

established criteria to identify patients with a low risk of bleeding who have potential for improved net clinical outcomes with potent antiplatelet Rx:• No hx of stroke/TIA• Weight ≥60 kg• Age <75 yr-14,909 patients (84% of prior MI cohort)

1 Wiviott SD, et al. NEJM 2007

Baseline CharacteristicsPrior MI Cohort

Prior MI CohortN=17,779

DemographicsAge, median (IQR) 59 (51-66)Age >=75 years (%) 8Female (%) 21

Clinical CharacteristicsDiabetes mellitus (%) 22Hypertension (%) 63Hyperlipidemia (%) 85Current smoker (%) 20Prior coronary revasc (%) 86Any cerebrovascular event (%) 5

Baseline Medical TherapyAspirin (%) 98Thienopyridine (%) 78Lipid-lowering therapy (%) 96

No differences between treatment groups

Primary Efficacy EvaluationPrior MI Cohort

CV Death, MI, or Stroke

8.1%

9.7%

Hazard Ratio 0.80;95% CI 0.72 - 0.89p < 0.001

Placebo

Vorapaxar

N = 17,779Mean f/u: 2.5 years

Vora Plac HR P-valueCV Death 2.0 2.4 0.84 0.12MI 5.7 7.0 0.79 <0.001Stroke 1.3 1.6 0.77 0.06

Efficacy by Time from Qual MIPrior MI Cohort

Time from qualifying MI to Randomizations

7.1%

8.8%

HR 0.82p = 0.011

< 3 months 3 to 6 months >6 monthsHR 0.79

p = 0.023HR 0.78

p = 0.026

7.5%

9.4%8.9%

10.4%

N = 7801 N = 5151 N = 4703

Efficacy Early and LatePrior MI Cohort

Days 0 to 360

3.2%

4.0%

HR 0.79p = 0.003

Day 360 to 1080

5.5%

6.5%HR 0.82

p = 0.004

Efficacy in Key Subgroups Prior MI Cohort

Bleeding EndpointsPrior MI Cohort

2,1

10,4

1,60,4 0,1

3,4

15,1

2,20,6 0,2

0

2

4

6

8

10

12

14

16

GUSTO Mod/Sev

TIMI Clinically Significant*

TIMI Non-CABG Major

ICH Fatal

PlaceboVorapaxar

HR 1.61p < 0.001

HR 1.49p < 0.001

HR 1.29p = 0.033

HR 1.54p = 0.076

HR 1.56p = 0.30

3-yr KM rates (%)

* TIMI Major/Minor/Requiring medical attention

3-yr KM rate (%) Voran=8880

Placn=8849 HR

p-value

All-cause death, MI, stroke, GUSTO Severe bleeding

10.1 11.4 0.86 0.003

CV Death, MI, Stroke,UCR, GUSTO Mod/Severe bleeding

12.5 13.4 0.91 0.038

Net Clinical Outcome

GU

STO

Mod

erat

e / S

ever

e B

leed

ing

(%)

Bleeding in Select SubgroupsPrior MI Cohort

1,9

4,6

2,13,1

2,1

3,4

1,8

3,93,0

7,1

3,2

6,0

3,2

8,0

2,7

6,9

0

2

4

6

8

Placebo Vorapaxar

Age Weight Prior Stroke/TIA

Any High Risk Feature

<75 yr >75 yr >60 kg <60 kg No Yes No Yes

3-yr

Kap

lan-

Mei

er ra

tes

(%)

GUSTO Mod/Severe

Bleeding

Efficacy EvaluationLow Bleeding Risk Cohort (N= 14,909)

CV Death

6.8%

8.6%

Placebo

Vorapaxar

HR 0.75p < 0.0001

CV Death, MI, or Stroke

1.5%

2.0%

HR 0.73p = 0.02

SummaryWhen added to standard of care including aspirin ± thienopyridine in stable pts w/ hxprior MI, vorapaxar significantly:• ↓ CV death, MI, or stroke• ↑ mod & severe bleeding• Improved net clinical outcome

The benefit of vorapaxar was consistent:• Regardless of the timing of MI• Both early (<1 yr) and late (>1 yr from rando.)• With or without thienopyridine use

Conclusions

In appropriately selected patients, our findings demonstrate the benefit of prolonged antiplatelet therapy through inhibition of PAR-1, when added to ASA + thienopyridine for long-term 2° prevention in patients with prior MI

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