This Journal Club Presentation was prepared during my Ambulatory Care Rotation at Jackson Memorial Hospital in Miami, Florida.

1. Journal Club Presentation
Thrombin-Receptor Antagonist Vorapaxar in
Acute Coronary Syndromes
N Engl J Med 2012;366(1):20-33
Authors: Tricoci P, Huang Z, Held C, et. al.
J o y A. Aw o n i yi , P h a r m D . C a n d i d a t e
Florida A&M University
March 23, 2012
Ambulatory Care II Rotation
Jackson Memorial Hospital
Preceptors:
D r. J a y B l a k e , P h a r m D . a n d D r. K e l v i n Tr o c a r d , P h a r m D .

2. Background
Acute Coronary Syndromes
1
 AHA defines Acute Coronary Syndromes as “Any
constellation of clinical symptoms that are compatible
with acute myocardial ischemia”
 Myocardial Infarction
 ST-Segment Elevation and Depression
 Non ST Elevation Myocardial Infarction (NSTEMI)
 Unstable Angina
 Characterized by an imbalance between oxygen supply
and demand
 This article focused on treatment of patients with acute
coronary syndromes without ST-segment elevation

3. Background
ACS Treatments
2
Treatment Goals Categories of Treatment
 Provide immediate relief  Anti-ischemic Agents
of ischemia  Decrease myocardial oxygen
consumption and/or induce
vasodilation
 Prevent serious adverse  Anticoagulation Agents
outcomes  Inhibit thrombin generation or
activity, decreasing thrombus-
 Death related events
 Myocardial (Re)infarction  Antiplatelet Agents
 Prevents acute plaque rupture
and artherothrombotic events
 Coronary Revascularization
 Relieves angina and ongoing
myocardial ischemia

4. Background
Vorapaxar
3
 Competitive Protease- Effects of PAR-1 Receptor
Activated Receptor-1 (PAR- Activation
1) antagonist
Thrombin
Increase in
activates PAR-
 Action results in potent cytosolic Ca2+
1 Receptor
inhibition of rapid thrombin-
induced platelet
aggregation
Increase in
Inhibition of
platelet
cAMP
 Previous studies suggested response to
formation
agonists
that its use was associated
fewer MIs without
significantly increasing the
risk of bleeding Platelet
Aggregation

5. Study Objectives
4
 To determine whether the addition of vorapaxar to
standard therapy would be superior to placebo in
reducing recurrent ischemic cardiovascular events
 To determine vorapaxar’s safety profile in patients with
cute coronary syndromes without ST-segment elevation
TRACER
Thrombin Receptor Antagonist for Clinical Event Reduction
in Acute Coronary Syndromes

6. Methods
5
Study Design Research and Analysis
 Analysis performed
 Multi-national independently at the Duke
Clinical Research Institute
 Randomized  Study design and data
collection performed by
several international
academic research
 Double-blind organizations
 Study Funded by Merck
 Placebo-Controlled Pharmaceuticals

7. Methods
6
Inclusion Criteria
 Acute symptoms of  One of the following:
coronary ischemia within  Cardiac Troponin or CK-
24 hours before hospital MB higher than ULN
presentation
 New ST segment
depression of greater than
 One of the following: 0.1mV
 Age at least 55 years  Transient ST-segment
 Previous MI, PCI, or CABG elevation more than
 Diabetes Mellitus 0.1mV in at least 2 leads
 Peripheral Arterial Disease

8. Methods
7
Exclusion Criteria
 Concurrent or anticipated treatment  Females whom were breast-feeding,
with Warfarin, oral factor Xa pregnant or intended on becoming
inhibitors or oral direct thrombin
inhibitors pregnant
 Concurrent or anticipated treatment  Severe Valvular heart disease
with potent CYP3A4 enzyme
inducers or inhibitors
 Known history of thrombocytopenia
 Evidence of abnormal bleeding occurring within 30 days before
within 30 days of enrollment enrollment
 History of intracranial hemorrhage
 Known active hepatobiliary disease
 Known current substance abuse

9. Methods
8
Study Population
 12,944 patients enrolled
 6471 assigned to placebo
 30 did not receive treatment
 6573 assigned to vorapaxar
 27 did not receive treatment
 761 declined to continue participation during follow-up
 512 assessed at the end of the study
 15 lost to follow-up
 818 sites
 37 Countries

10. Methods
9
Study Procedure
 Patients randomized in 1:1 ratio and assigned to receive vorapaxar
or placebo
 Stratification based on intention to use glycoprotein IIb/IIIa inhibitor and intention
to use a parenteral direct thrombin inhibitor
 Loading dose given immediately after randomization and 1 hour
before any cardiac revascularization procedure
 Maintenance dose continued for a planned minimum of 1 year
 Follow up assessments performed during hospitalization, at 1, 4, 8,
and 12 months, and then at the end of the study

11. Study Outcomes
10
• Composite of death from
Primary cardiovascular causes, MI,
stroke, recurrent ischemia with
Endpoint re-hospitalization, or urgent
coronary revascularization
• Composite of death from
Secondary Cardiovascular causes, MI, or
stroke
Endpoint • Other exploratory efficacy
endpoints
• Composite of moderate or
Safety severe bleeding according to
GUSTO classification and
Endpoints significant bleeding according to
TIMI classification

12. Statistical Analysis
11
 1900 primary endpoint events Analysis Method
would provide a Power greater
than 95% to detect a 15% hazard Efficacy Time to first
reduction occurrence of any of
the composite
 1457 secondary endpoint events endpoints
would provide a Power of 90% to Hazard Cox-proportional
detect a 15% hazard reduction
Ratios Hazards model
 Significance level of 0.049 for the 95% Cox proportional
analysis of all key efficacy Confidence Hazards model
endpoints Intervals
Safety Cox-proportional
 Superiority cannot be declared Analyses Hazards Model
for secondary endpoint if not
achieved for primary endpoint. Event rates 2-year Kaplan Meier
Estimates

13. Results
12
Timeline of Study Events
December 18, June 4, 2010 June 25, 2010 January 8, January 13,
2007 • Ending of • Planned formal 2011 2011
• Beginning of Recruitment interim analysis • Unplanned • All sites notified
Recruitment Period Continuation of Safety Review to tell all patients
Period the study • Recommendation to stop taking
to stop the trial study drug

14. Results
Study Drug and Concomitant Therapies
13
Median time
Median time to Median time
study drug
randomization after exposure to study Rate of Study Drug
administered prior
hospitalization – drug – discontinuation
to PCI – hours
hours (IQ range) days (IQ range)
(IQ Range)
21.2 379.0 3.5
Vorapaxar 28.2%
(12.2 – 40.6) (231.1 – 585.0) (1.8 – 20.6)
21.1 393.0 3.5
Placebo 26.8%
(12.2 – 41.1) (236.0 – 588.0) (1.8 – 20.8)
21.2 386.0 3.5
All patients 27.5%
(12.2 – 40.8) (233.0 – 586.0) (1.8 – 20.7)

15. Results
Primary Efficacy Endpoint
14
25.0%  Events
 Death from cardiovascular causes
19.9%
20.0% 18.5%  Myocardial infarction
17.0%
15.9%  Stroke
15.0%  Recurrent ischemia with
rehospitalization
10.0%  Urgent coronary revascularization
5.0%  Hazard Ratio
 0.92
0.0%  95% CI: 0.85-1.01
Percentage of Event Rate at 2
Patients with Years  P = 0.07
Event
Placebo Vorapaxar

16. Results
Primary Efficacy Endpoint
15

17. Results
Key Secondary Endpoint
16
18.0% 16.4%  Events
16.0% 14.7%
14.1%  Death from cardiovascular
14.0% 12.7%
12.0%
causes
10.0%  Myocardial infarction
8.0%  Stroke
6.0%
4.0%
2.0%  Hazard Ratio
0.0%  0.88
Percentage of Event Rate at 2
Patients with Years  95% CI: 0.81-0.98
Event
Placebo Vorapaxar  P = 0.02

18. Results
Key Secondary Endpoint
17

19. Results
18
The main effect observed was the reduction in the rate of MI with Vorapaxar
Vorapaxar 208 621 96 203 79
Placebo 207 698 103 189 69
0 500 1000 1500
Rate at 2 years
Death from Cardiovascular Causes Vorapaxar 11.1% vs
Myocardial Infarction Placebo 12.5%
Stroke
• HR: 0.88
Urgent Coronary Reascularization • 95% CI, 0.79-0.98
Recurrent Ischemia with rehospitalization • P=0.02

20. Results
Safety Endpoints
19
GUSTO
Global Use of Strategies to Open
Occluded Arteries
 Mild Bleeding:
 Bleeding without blood transfusion
or hemodynamic compromise
 Moderate Bleeding
 Bleeding requiring transfusion of
whole blood or packed red blood
cells without hemodynamic
compromise
 Severe Bleeding “Vorapaxar increased the rate of
 Bleeding that was fatal, intracranial moderate or severe bleeding as
or that caused hemodynamic
compromise requiring intervention compared to placebo”

21. Results
Safety Endpoints
20
TIMI
Thrombolysis in Myocardial Infarction
 Bleeding Requiring medical
attention:
 Clinically overt bleeding that requires
unplanned medical treatment
 Minor Bleeding
 Any clinically overt sign of
hemorrhage associated with a fall in
HgB of 3-5mg/dL
 Major Bleeding
“The rate of clinically significant TIMI
 Any intracranial or overt signs of
hemorrhage associated with a drop bleeding was increased among
in HgB of 5 or greater g/dL patients treated with vorapaxar”

22. Conclusion
21
“In patients with ACS without ST-segment
elevation, the addition of vorapaxar to standard
therapy did not significantly reduce the primary
composite end-point, but significantly increased the
risk of major bleeding, including intracranial
hemorrhage.”

23. Journal Critique
22
STRENGTHS
 Appropriate study design  The use of both TIMI and
 Multicenter, Randomized GUSTO Classification
 Each classification identifies
 Appropriate sample size at risk patients that the other
does not
 Number needed for a >95%
 GUSTO is driven by clinical
Power was exceeded
data
 Not many lost to follow-up
 TIMI is driven by laboratory
data (Hgb and Hct values)
 Well distributed baseline
characteristics

24. Journal Critique
23
WEAKNESSES
 Inability to establish  Many patients at high risk
superiority with secondary for bleeding at baseline
endpoints  47.7% of patients in placebo
group, 47.8% of patients in
vorapaxar group had TIMI
 Study Population Risk score between 5 and 7
 85% White, 2.5%
Black, 8.3% Asian, 4% other
 0.4-0.5% of patients did not
receive randomized
treatment

25. Study Applications
24
 Vorapaxar is not likely to receive approval as it posses an
unacceptable risk to patients without any established benefit.
 The future of Vorapaxar
 TIMI 50 Trial is another Phase III trial to examine the use of this drug
 Study was completed in December 2011, no results have been posted
 The trial was discontinued in patients who experienced a stroke, but will be
continued in patients with previous MI or peripheral disease
 Another drug with a similar mechanism of action, Atopaxar, is
currently in Phase-II Stage of development
 So far no sign in an increase of clinically significant bleeding
 Studies are being conducted in Japan

26. QUESTIONS???
25

27. References
26
 Anderson JL, Adams CD, Antman EM, et al. 2011 ACCF/AHA focused update incorporated into the ACC/AHA
2007 Guidelines for the Management of Patients with Unstable Angina/Non-ST-Elevation Myocardial
Infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force
on Practice Guidelines. Circulation 2011;123:e426-e579.
 Antman EM, Cohen M, Bernink PJ, McCabe, CH, et al. The TIMI Risk Score for Unstable Angina/Non-ST
Elevation MI: A Method for Prognostication and Therapeutic Decision Making. JAMA 2000;284(7):835-842.
 Bassand JP, Hamm CQ, Ardissino D, et al. Guidelines for the diagnosis and treatment of non-ST-segment
elevation acute coronary syndromes. Eur Heart J 2007;28:1598-1660.
 Brass LF. Thrombin and Platelet Activation. Chest, 2003 Sept;124(3):18S-25S.
 Rao SV, O’Grady K, Pieper KS, Granger CB, et al. A Comparison of the Clinical Impact of Bleeding Measured
by Two Different Classifications Among Patients with Acute Coronary Syndromes. J Am Coll
Cardio, 2006;47:809-816.
 ClinicalTrials.gov. “Trial to Assess the Effects of SCH 530348 in Preventing Heart attack and Stroke in
Patients with Atherosclerosis (TRA 2P – TIMI 50) (Study P04737AM3)”. Available at:
http://www.clinicaltrials.gov/ct2/show/NCT00526474?term=vorapaxar&rank=5. Accessed on 19 Mar 2012.
Last Updated 13 Feb 2012.
 Tricoci P, Huang Z, Held C, et al. Thrombin-Receptor Antagonist Vorapaxar n Acute Coronary Syndromes. N
Engl J Med 2012;336(1):20-33.

28. THANK YOU!!
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