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Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombosis
On behalf of the TRA 2°P-TIMI 50 Steering Committee and Investigators
NCT00526474; Trial funded by Merck
** CONFIDENTIAL FINAL DRAFT **EMBARGOED UNTIL SAT 3/24 10AM
Protease-activated receptor (PAR)-1
Thrombin
Signal
CC CC CC CC
Vorapaxar
• Vorapaxar is an oral, potent, and selective antagonist of PAR-1
• Metabolism by CYP3A4 enzymes• No meaningful renal clearance• Long half-life (T1/2 > 100 hrs)
Shape ChangeActivation
Aggregation
X
** CONFIDENTIAL FINAL DRAFT / EMBARGOED **
TRA Program(38,500 pts)
TRA (Vorapaxar) Program
NSTEACS12,944
2º Prevention~26,500 pts
Vorapaxar Placebo Vorapaxar Placebo
Median F/U 1.4 years
3
Median F/U 2.5 years
• CV Death, MI, Stroke, Hosp for ischemia, Urgent Coronary Revasc. HR 0.92 (0.85, 1.01), p=0.072
• CV Death, MI, StrokeHR 0.89 (0.81, 0.98), p=0.018
** CONFIDENTIAL FINAL DRAFT / EMBARGOED **
Primary Objectives
Primary ObjectiveTo test the hypothesis that vorapaxar will ↓ athero-thrombotic events in stable pts w/ atherosclerosis treated for ≥1 yr in addition to standard therapy.
Parallel Scientific ObjectivesTo test the hypotheses that …1. antagonism of PAR1 is a valuable novel target2. adding a new antiplatelet agent to ASA is
effective for long-term 2° prevention in stable pts
** CONFIDENTIAL FINAL DRAFT / EMBARGOED **
Trial OrganizationTIMI Study GroupEugene Braunwald (Chair) David A. Morrow (PI)BM Scirica, MP Bonaca Stephen D. Wiviott (CEC)Polly Fish Sabina A. Murphy (Statistics)
Worldwide Monitoring TeamsCovance – Jennifer Mead WCT – Lucy BennettICON – Jeroen Kleijne Merck Monitoring
Sponsor: Merck John Strony Gail Berman/Leslie Lipka Ann Killian Xuan Liu, Weili He
Data Safety Monitoring BoardRobert Frye (Chair) Kent R. BaileyJ. Donald Easton Judith HochmanP. Gabriel Steg Freek Verheught
** CONFIDENTIAL FINAL DRAFT / EMBARGOED **
ArgentinaS Ameriso/ E PaolassoAustraliaP Aylward/G HankeyAustria M PichlerBelgiumF van de Werf BrazilJ NicolauCanada P Teal/P TherouxChileR CorbolanColombiaD IsazaCzech Republic J Spinar
National Lead InvestigatorsDenmarkP GrandeFinlandM NieminenFrance JP BassandGermany C Diehm/H DienerHungary R KissIsrael H HodItaly D De Ferrari/P MerliniJapanS GotoNetherlands T Oude Ophius
New ZealandH WhiteNorwayD Nilsen/L ThomassenPoland M TenderaPortugalJ MoraisSouth Africa A DalbySpain A BetriuSwedenM DellborgSwitzerlandH BounameauxUnited Kingdom R Wilcox
** CONFIDENTIAL FINAL DRAFT / EMBARGOED **
Prior MI, CVA, or PAD
Vorapaxar2.5 mg/d
PlaceboRANDOMIZE 1:1 DOUBLE BLIND
Follow up VisitsDay 30, Mo 4, Mo 8, Mo 12
Q6 months
Standard care including oral antiplt rx
Final Visit Event Driven Design
Minimum of1 year of follow-up
Key Inclusion:1) MI: 2 wks - 12 mo 2) Ischemic CVA: 2 wk-12 mo3) PAD: claudication + abnl
ABI or prior revasc
Trial Design
Stratified by:1) Qualifying athero2) Use of thienopyridine
** CONFIDENTIAL FINAL DRAFT / EMBARGOED **
EndpointsEfficacy: hierarchical testing1. Cardiovascular (CV) death, MI, or stroke2. CV death, MI, stroke, or urgent coronary
revascularization 3. CV death or MI
Bleeding endpoints of primary interest:• GUSTO moderate or severe bleeding• TIMI Clinically Significant Bleeding:
TIMI major, TIMI minor, or bleeding requiring medical attention (medical/surgical rx, lab eval)
** CONFIDENTIAL FINAL DRAFT / EMBARGOED **
DSMB Action
January, 2011, the DSMB announced that based on its ongoing review of safety:– ↑ ICH with vorapaxar in pts w/ a prior stroke D/C all pts with a prior stroke
– Trial should continue in pts without a hx of stroke
Analyses• 1st line analysis in all patients, including stroke • 2nd line analysis (new): pts w/out prior stroke• Special interest in patients who qualified w/ MI
** CONFIDENTIAL FINAL DRAFT / EMBARGOED **
EnrollmentEnrolled 9/2007-11/2009: 32 countries, 1032 sites, 26449 patients
32 (0.1%) lost to F/U2.0% withdrew consent for F/U
** CONFIDENTIAL FINAL DRAFT / EMBARGOED **
Baseline Characteristics
Age (yrs, median)≥ 75 yrs (%)
Female (%)
MI (n = 17779, %)PAD (n = 3787, %)Stroke (n = 4883, %)
Qualifying Atherosclerosis
Placebo(N = 13224)
61 (53, 69)1124
671419
Vorapaxar(N = 13225)
61 (53, 69)1124
671418
Any CAD (%)Any prior stroke (%)Diabetes (%)Current smoker (%)eGFR <60 ml/min/1.73 m2
7822252115
7822252116
** CONFIDENTIAL FINAL DRAFT / EMBARGOED **
Background TherapyPlacebo
(N = 13224)Vorapaxar(N = 13225)
Lipid-lowering agent (%)ACEI or ARB (%)Beta-blocker (qualifying MI)
927584
917484
Qualifying MI AspirinThienopyridine
PAD AspirinThienopyridine
Stroke AspirinThienopyridineDipyridamole
Antiplatelet Therapy, %9878
8837
812419
9878
8837
812420
Other Medications at Enrollment
** CONFIDENTIAL FINAL DRAFT / EMBARGOED **
Primary Efficacy EvaluationCV Death, MI, or Stroke
0%
2%
4%
6%
8%
10%
12%
0 60 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080
Even
t Rat
e (%
)
Days since randomization
9.3%
10.5%
Hazard Ratio 0.87;95% CI 0.80 to 0.94p < 0.001
N = 26449Median f/u2.5 years
PlaceboVorapaxar
** CONFIDENTIAL FINAL DRAFT / EMBARGOED **
Additional Major Efficacy Outcomes
CV death, MI, Stroke, or Urgent Coronary Revascularization
0%
2%
4%
6%
8%
10%
12%
14%
0 180 360 540 720 900 1080
Even
t Rat
e (%
)
Days since randomization
Placebo
Vorapaxar11.2%
12.4%
Hazard Ratio 0.88;95% CI 0.82 to 0.95p = 0.001
CV death or MI
0%
1%
2%
3%
4%
5%
6%
7%
8%
9%
0 180 360 540 720 900 1080
Even
t Rat
e (%
)
Days since randomization
Placebo
Vorapaxar7.3%
8.2%
Hazard Ratio 0.86;95% CI 0.78 to 0.94p = 0.002
** CONFIDENTIAL FINAL DRAFT / EMBARGOED **
Selected Efficacy Outcomes
CV death, MI, stroke
CV death
MI
Any Stroke
Ischemic stroke
Urgent coronaryrevascularization
CVD, MI, Stroke, UCR, vascular hosp.
All-cause mortality
Placebo(N = 13224)
10.5
3.0
6.1
2.8
2.6
2.6
14.7
5.3
Vorapaxar(N = 13225)
9.3
2.7
5.2
2.8
2.2
2.5
13.1
5.0
HR p-value
0.87
0.89
0.83
0.97
<0.001
0.15
0.001
0.73
0.85
0.88
0.87
0.95
0.059
0.11
<0.001
0.41
3-yr KM rate (%)
UCR = recurrent ischemia leading to urgent coronary revascularization
** CONFIDENTIAL FINAL DRAFT / EMBARGOED **
Efficacy Outcomes No History of Stroke (N= 20,699)
CV death, MI, stroke
CV death
MI
Any Stroke
Ischemic stroke
CVD, MI, Stroke, urgcoronary revasc.
CV death or MI
CVD, MI, Stroke, UCR, vascular hosp.
Placebo(N = 10344)
9.6
2.8
6.4
1.7
1.5
11.8
8.4
14.0
Vorapaxar(N = 10335)
8.3
2.5
5.5
1.5
1.1
10.6
7.4
12.3
HR p-value
0.84
0.87
0.84
0.82
<0.001
0.13
0.004
0.11
0.72
0.86
0.85
0.86
0.013
<0.001
0.002
<0.001
3-yr KM rate (%)
UCR = recurrent ischemia leading to urgent coronary revascularization
** CONFIDENTIAL FINAL DRAFT / EMBARGOED **
CV Death, MI, or Stroke in Major Subgroups
0.5 1 2 5
No 0.85 (0.74, 0.98)Yes 0.88 (0.79, 0.98)
Thienopyridine at Rando 0.76
Stroke 1.03 (0.85, 1.25)PAD 0.94 (0.78, 1.14)MI 0.80 (0.72, 0.89)
Qualifying Athero 0.058<60kg 1.22 (0.88, 1.69)>=60kg 0.85 (0.78, 0.92)
Body weight 0.033>=75 0.91 (0.75, 1.10)<75 0.86 (0.78, 0.94)
Age 0.54Overall 0.87 (0.80, 0.94)
Vorapaxar Better Vorapaxar Worse
Hazard Ratio (95% CI)Subgroup total no.
Yes 0.95 (0.80, 1.11)No 0.84 (0.76, 0.93)
History of Stroke 0.22
26449
234293020
CV Death, MI, or Stroke
185224546
48833787
17779
574620699
1000716442
Interaction p-value
No interaction by sex, or region.
** CONFIDENTIAL FINAL DRAFT / EMBARGOED **
Bleeding EndpointsOverall Population
GUSTO Moderate or Severe
TIMI Clinically Significant
TIMI Non-CABGMajor
Intracranial
Fatal
Placebo(N = 13166)
2.5
11.1
1.8
0.5
0.2
Vorapaxar(N = 13186)
4.2
15.8
2.8
1.0
0.3
HR p-value
1.66
1.46
1.46
1.94
1.46
<0.001
<0.001
<0.001
<0.001
0.19
3-yr KM rate (%)
No significant heterogeneity in GUSTO Mod/Sevbleeding across any of major subgroups
** CONFIDENTIAL FINAL DRAFT / EMBARGOED **
Major Bleeding Endpointsby History of Stroke
2.1
0.90.3
1.8
0.4 0.2
4.1
2.4
0.5
2.5
0.6 0.30
1
2
3
4
5
6
7
8
TIMI Non-CABG Major
ICH Fatal TIMI Non-CABG Major
ICH Fatal
PlaceboVorapaxar
ARD 2.0%HR 1.87P<0.001
ARD 1.5%HR 2.55P<0.001
ARD 0.2%HR 1.48P=0.46
ARD 0.2%HR 1.55P=0.049
ARD 0.1%HR 1.44P=0.30
3-yr KM rate (%)
ARD 0.7%HR 1.35P=0.005
Prior Stroken = 5746
No Hx of Stroken = 20699
** CONFIDENTIAL FINAL DRAFT / EMBARGOED **
GUSTO Moderate or Severe Bleeding in Major Subgroups
5.5
2.2
3.7
2.4 2.4
4.5
2.1
8.4
3.7
7.7
4.0 4.2
7.4
3.4
0123456789
10Placebo Vorapaxar
ARDHR
2.9%1.69
3-yr KM rate (%)
Age ≥75 y Age <75 y Wt <60kg Wt ≥60kg Stroke PAD MI
Age Weight Qual Athero
1.5%1.65
4.0%1.95
1.6%1.64
1.8%1.93
2.9%1.62
1.3%1.61
P-interact 0.87 0.50 0.69
** CONFIDENTIAL FINAL DRAFT / EMBARGOED **
Net Clinical Outcome
1 1.250.90.8Vorapaxar Better Vorapaxar Worse
HR VORA PLAC RRR (%)
0.7
Death, MI, stroke, GUSTO severe bleed
11.9 12.8 8P =0.020
CV death, MI, stroke, UCR,GUSTO mod/sev bleed
13.4 14.0 4P =0.20
All pts
Death, MI, stroke, GUSTO severe bleed
10.0 11.7 16P <0.001
CV death, MI, stroke, UCR,GUSTO mod/sev bleed
12.0 13.4 12P =0.004No Hx
Stroke/TIAWgt ≥60kg
n = 18,966
** CONFIDENTIAL FINAL DRAFT / EMBARGOED **
Death, MI, stroke, GUSTO severe bleed
10.8 11.8 11P =0.010
CV death, MI, stroke, UCR,GUSTO mod/sev bleed
12.8 13.4 6P =0.16No Hx
Stroken = 20,699
SummaryWhen added to standard of care, including aspirin & thienopyridine, in stable pts w/ hxatherothrombosis, vorapaxar significantly …• ↓ CV death, MI, or stroke• ↑ mod & severe bleeding, including ICH
In addition, our findings indicate … • significant ↓ in thrombosis adding to standard
rx, including ASA, for long-term rx in pts with prior MI
• unacceptable ICH risk in pts with prior stroke• uncertain benefit in pts with PAD
** CONFIDENTIAL FINAL DRAFT / EMBARGOED **
Conclusions1. PAR-1 antagonism is an effective
approach to reducing recurrent atherothrombosis
2. More intensive antiplatelet therapy for long-term 2° prevention reduces recurrent thrombosis in patients with prior MI
3. Patient selection is necessary to balance the antithrombotic benefit vs. risk of bleeding
** CONFIDENTIAL FINAL DRAFT / EMBARGOED **
For Every 1000 Pts Treated with Vorapaxar
-19
-11
-6 -5
02
10
-25
-20
-15
-10
-5
0
5
10
15
Even
ts /
1000
Pts
No History of Stroke/TIA; Wgt ≥60 kg (n = 18,966)
CVD, MIor StrokeP<0.001
MIP<0.001
CV DeathP=0.033
StrokeP<0.001
Fatal BleedP=NS
ICHP=0.15
*GUSTO Mod/SevP<0.001
*excluding ICH
** CONFIDENTIAL FINAL DRAFT / EMBARGOED **