vorapaxar for secondary prevention in patients with prior
TRANSCRIPT
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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