TRA 2P-TIMI 50 - TIMI Study Group

Thrombin Receptor Antagonist in
Secondary Prevention of Atherothrombosis
NCT00526474; Trial funded by Merck
David A. Morrow, MD, MPH
On behalf of the TRA 2°P-TIMI 50
Steering Committee and Investigators
ACC 2012, Chicago, March 24, 2012
Protease-activated receptor (PAR)-1
Thrombin
Vorapaxar
C C
• 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)
C C
X
Signal
Shape Change
Activation
Aggregation
Adapted from Vu TH et al.
Cell 1991;64:1057–66.
TRA (Vorapaxar) Program
TRA Program
(38,500 pts)
NSTEACS
2º Prevention
12,944
~26,500 pts
Vorapaxar
Placebo
Median F/U 1.4 years
• CV Death, MI, Stroke, Hosp for
ischemia, Urgent Coronary Revasc.
HR 0.92 (0.85, 1.01), p=0.072
• CV Death, MI, Stroke
HR 0.89 (0.81, 0.98), p=0.018
Tricoci et al. N Engl J Med 2012;366:20-33
Vorapaxar
Placebo
Median F/U 2.5 years
Primary Objectives
Primary Objective
To test the hypothesis that vorapaxar will  atherothrombotic events in stable pts w/ atherosclerosis
treated for ≥1 yr in addition to standard therapy.
Parallel Scientific Objectives
To test the hypotheses that …
1. antagonism of PAR-1 is a valuable novel target
2. adding a new antiplatelet agent to ASA is
effective for long-term 2° prevention in stable pts
Trial Organization
TIMI Study Group
Eugene Braunwald (Chair)
BM Scirica, MP Bonaca
Polly Fish
David A. Morrow (PI)
Stephen D. Wiviott (CEC)
Sabina A. Murphy (Statistics)
Worldwide Monitoring Teams
Covance – Jennifer Mead
ICON – Jeroen Kleijne
WCT – Lucy Bennett
Merck Monitoring
Sponsor: Merck
John Strony
Ann Killian
Gail Berman/Leslie Lipka
Xuan Liu, Weili He
Data Safety Monitoring Board
Robert Frye (Chair)
J. Donald Easton
P. Gabriel Steg
Kent R. Bailey
Judith Hochman
Freek Verheught
Steering Committee
Argentina
S Ameriso/ E Paolasso
Australia
P Aylward/G Hankey
Austria
M Pichler
Belgium
F van de Werf
Brazil
J Nicolau
Canada
P Teal/P Theroux
Chile
R Corbolan
Colombia
D Isaza
Czech Republic
J Spinar
Denmark
P Grande
Finland
M Nieminen
France
JP Bassand
Germany
C Diehm/H Diener
Hungary
R Kiss
Israel
H Hod
Italy
D De Ferrari/P Merlini
Japan
S Goto/Y Shinohara
Netherlands
T Oude Ophius
New Zealand
H White
Norway
D Nilsen/L Thomassen
Poland
M Tendera
Portugal
J Morais
South Africa
A Dalby
Spain
A Betriu
Sweden
M Dellborg
Switzerland
H Bounameaux
United Kingdom
K Fox/R Wilcox
United States
M Alberts/M Creager
P Gurbel/J P Mohr
D Moliterno/J Olin
K M Welch
Trial Design
Prior MI, CVA, or PAD
Standard care
including oral antiplt rx
Key Inclusion:
1) Type 1 MI: 2 wks - 12 mo
2) Ischemic CVA: 2 wk - 12 mo
3) PAD: claudication + abnl
ABI or prior revasc
RANDOMIZE 1:1 DOUBLE BLIND
Vorapaxar
2.5 mg/d
Stratified by:
1) Qualifying athero
2) Use of thienopyridine
Follow up Visits
Day 30, Mo 4, Mo 8, Mo 12
Q6 months
Final Visit
Placebo
Minimum of
1 year of follow-up
Event Driven Design
Endpoints
Efficacy: hierarchical testing
1. Cardiovascular (CV) death, MI, or stroke
2. 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)
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
Enrollment
Enrolled 9/2007-11/2009: 32 countries, 1032 sites, 26449 patients
32 (0.1%) lost to F/U
2.0% withdrew consent for F/U
Baseline Characteristics
Placebo
(N = 13224)
Vorapaxar
(N = 13225)
61 (53, 69)
11
24
61 (53, 69)
11
24
MI
(n = 17779, %)
PAD
(n = 3787, %)
Stroke (n = 4883, %)
67
14
19
67
14
18
Any CAD (%)
Any prior stroke (%)
Diabetes (%)
Current smoker (%)
eGFR <60 ml/min/1.73 m2
78
22
25
21
15
78
22
25
21
16
Age (yrs, median)
≥ 75 yrs (%)
Female (%)
Qualifying Atherosclerosis
Background Therapy
Placebo
(N = 13224)
Vorapaxar
(N = 13225)
Antiplatelet Therapy, %
Qualifying MI
Aspirin
Thienopyridine
98
78
98
78
PAD
Aspirin
Thienopyridine
88
37
88
37
Aspirin
Thienopyridine
Dipyridamole
81
24
19
Stroke
(28% DAPT)
(8% DAPT)
81
24
20
Other Medications at Enrollment
Lipid-lowering agent (%)
ACEI or ARB (%)
Beta-blocker (qualifying MI)
92
75
84
91
74
84
Primary Efficacy Evaluation
CV Death, MI, or Stroke
12%
N = 26449
Median f/u
2.5 years
Event Rate (%)
10%
Placebo
Vorapaxar
10.5%
9.3%
8%
6%
4%
Hazard Ratio 0.87;
95% CI 0.80 to 0.94
p < 0.001
2%
0%
0
60
120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080
Days since randomization
Additional Major Efficacy Outcomes
CV death, MI, Stroke, or Urgent
Coronary Revascularization
CV death or MI
14%
9%
Placebo
12.4%
12%
Placebo
8.2%
8%
7%
8%
Vorapaxar
11.2%
6%
Event Rate (%)
Event Rate (%)
10%
6%
5%
Vorapaxar
7.3%
4%
3%
4%
Hazard Ratio 0.88;
95% CI 0.82 to 0.95
p = 0.001
2%
0%
Hazard Ratio 0.86;
95% CI 0.78 to 0.94
p = 0.002
2%
1%
0%
0
180
360
540
720
Days since randomization
900
1080
0
180
360
540
720
Days since randomization
900
1080
Selected Efficacy Outcomes
Overall Population
Placebo
(N = 13224)
Vorapaxar
(N = 13225)
HR
p-value
10.5
9.3
0.87
<0.001
CV death
3.0
2.7
0.89
0.15
MI
6.1
5.2
0.83
0.001
Any Stroke
2.8
2.8
0.97
0.73
2.6
2.2
0.85
0.059
Urgent coronary
revascularization
2.6
2.5
0.88
0.11
CVD, MI, Stroke,
UCR, vascular hosp.
14.7
13.1
0.87
<0.001
All-cause mortality
5.3
5.0
0.95
0.41
3-yr KM rate (%)
CV death, MI, stroke
Ischemic stroke
UCR = recurrent ischemia leading to urgent coronary revascularization
Efficacy Outcomes
No History of Stroke (N= 20,699)
Placebo
(N = 10344)
Vorapaxar
(N = 10335)
HR
p-value
9.6
8.3
0.84
<0.001
CV death
2.8
2.5
0.87
0.13
MI
6.4
5.5
0.84
0.004
Any Stroke
1.7
1.5
0.82
0.11
1.5
1.1
0.72
0.013
CVD, MI, Stroke, urg
coronary revasc.
11.8
10.6
0.86
<0.001
CV death or MI
8.4
7.4
0.85
0.002
CVD, MI, Stroke,
UCR, vascular hosp.
14.0
12.3
0.86
<0.001
3-yr KM rate (%)
CV death, MI, stroke
Ischemic stroke
UCR = recurrent ischemia leading to urgent coronary revascularization
CV Death, MI, or Stroke in
Major Subgroups
Subgroup
Overall
Age
<75
>=75
Body weight
>=60kg
<60kg
Qualifying Athero
MI
PAD
Stroke
History of Stroke
No
Yes
Thienopyridine at Rando
Yes
No
CV Death, MI, or
Stroke
total no.
26449
Interaction
p-value
Hazard Ratio (95% CI)
0.87 (0.80, 0.94)
0.54
23429
3020
0.86 (0.78, 0.94)
0.91 (0.75, 1.10)
0.033
24546
1852
0.85 (0.78, 0.92)
1.22 (0.88, 1.69)
0.058
17779
3787
4883
0.80 (0.72, 0.89)
0.94 (0.78, 1.14)
1.03 (0.85, 1.25)
0.22
20699
5746
0.84 (0.76, 0.93)
0.95 (0.80, 1.11)
0.76
16442
10007
0.88 (0.79, 0.98)
0.85 (0.74, 0.98)
0.5
No interaction by sex, or region.
1
Vorapaxar Better
2
Vorapaxar Worse
5
Bleeding Endpoints
Overall Population
Placebo
(N = 13166)
Vorapaxar
(N = 13186)
HR
p-value
GUSTO Moderate or
Severe
2.5
4.2
1.66
<0.001
TIMI Clinically
Significant
11.1
15.8
1.46
<0.001
TIMI Non-CABG
Major
1.8
2.8
1.46
<0.001
Intracranial
0.5
1.0
1.94
<0.001
Fatal
0.2
0.3
1.46
0.19
3-yr KM rate (%)
No significant heterogeneity in GUSTO Mod/Sev
bleeding across any of major subgroups
Major Bleeding Endpoints
8
7
3-yr KM rate (%)
Prior Stroke
n = 5746
Placebo
Vorapaxar
No Hx of Stroke
n = 20699
6
5
4.1
4
3
2.5
2.4
2.1
1.8
2
0.9
1
0.3 0.5
0.4 0.6
0.2 0.3
0
TIMI NonCABG Major
ICH
Fatal
TIMI NonCABG Major
ICH
Fatal
ARD 2.0%
HR 1.87
P<0.001
ARD 1.5%
HR 2.55
P<0.001
ARD 0.2%
HR 1.48
P=0.46
ARD 0.7%
HR 1.35
P=0.005
ARD 0.2%
HR 1.55
P=0.049
ARD 0.1%
HR 1.44
P=0.30
GUSTO Moderate or Severe
Bleeding in Major Subgroups
10
9
8
7
6
5
4
3
2
1
0
Placebo
3-yr KM rate (%)
Age
8.4
Weight
Qual Athero
7.7
7.4
5.5
3.7
3.7
2.4
2.2
2.9%
1.69
P-interact
1.5%
1.65
0.87
4.2
4.0
Age ≥75 y Age <75 y Wt <60kg Wt ≥60kg
ARD
HR
Vorapaxar
4.0%
1.95
1.6%
1.64
0.50
4.5
3.4
2.4
2.1
Stroke
PAD
MI
1.8%
1.93
2.9%
1.62
1.3%
1.61
0.69
Net Clinical Outcome
HR VORA
All pts
(Including
Stroke)
No Hx
Stroke
CV death, MI, stroke, UCR,
GUSTO mod/sev bleed
Death, MI, stroke,
GUSTO severe bleed
CV death, MI, stroke, UCR,
GUSTO mod/sev bleed
Death, MI, stroke,
n = 20,699 GUSTO severe bleed
PLAC RRR (%)
13.4
14.0
4
11.9
12.8 8
12.8
13.4
10.8
11.8 11
P =0.20
P =0.020
6
P =0.16
P =0.010
CV death, MI, stroke, UCR,
No Hx
P =0.004
GUSTO mod/sev bleed
Stroke/TIA
Wgt ≥60kg Death, MI, stroke,
GUSTO severe bleed
P <0.001
n = 18,966
0.7
0.8
0.9
1
Vorapaxar Better
12.0
13.4
12
10.0
11.7 16
1.25
Vorapaxar Worse
Summary
When added to standard of care, including
aspirin & thienopyridine, in stable pts w/ hx
atherothrombosis, 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
Conclusions
1. 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
For Every 1000 Pts
Treated with Vorapaxar
15
No History of Stroke/TIA; Wgt ≥60 kg (n = 18,966)
10
Events / 1000 Pts
10
5
0
0
-5
-6
-10
-25
-5
-11
-15
-20
2
-19
CVD, MI
or Stroke
MI
CV Death
P<0.001 P<0.001 P=0.033
*excluding ICH
Stroke
P<0.001
Fatal
Bleed
P=NS
ICH
P=0.15
*GUSTO
Mod/Sev
P<0.001