Adjunctive Vorapaxar Therapy in Patients With Prior Myocardial Infarction Treated With New Generation P2Y12 Receptor Inhibitors Prasugrel and Ticagrelor (VORA-PRATIC): A Prospective, Randomized, Pharmacodynamic Study
Phase: PHASE4
Conditions: Myocardial Infarction
Sponsor: University of Florida

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Adjunctive Vorapaxar Therapy in Patients with Prior Myocardial Infarction  
Treated with New Generation P2Y12 Receptor Inhibitors Prasugrel and Ticagrelor (VORA-
PRATIC): A Prospective, Randomized, Pharmacodynamic Study 
 
 
 
 
 
 
 
 
Dominick J. Angiolillo, MD, PhD 
University of Florida College of Medicine-Jacksonville 
655 West 8th Street 
Jacksonville, Florida, 32209 
Tel: +1-904-244-3933 
Fax: +1-904-244-3102 
E-mail: dominick.angiolillo@jax.ufl.edu    
 
 
 
 
 
 

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Summary  
Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor represents the standard 
of care for the long-term secondary prevention of atherothrombotic events in patients with 
myocardial infarction (MI). The novel P2Y12 receptor inhibitors prasugrel and ticagrelor are 
characterized by more prompt, potent, and predictable antiplatelet effects compared with 
clopidogrel and are associated with a greater reduction of ischemic events in acute coronary 
syndrome patients. However, rates of ischemic recurrences remain high, which may be in part due 
to the fact that other platelet signaling pathways, such as thrombin-induced platelet aggregation, 
continue to be activated. Vorapaxar is a novel, orally active, competitive and slowly reversible 
protease-activated receptor (PAR)-1 inhibitor, which exerts potent inhibition of thrombin-mediated 
platelet aggregation. It is approved for clinical use by the Food and Drug Administration for the 
reduction of thrombotic cardiovascular events in patients with a history of MI or with peripheral 
arterial disease. A large-scale clinical trial showed that the use of vorapaxar (2.5 mg once/daily) in 
addition to standard antiplatelet therapy (including aspirin and a P2Y12 receptor inhibitor) was 
effective in the secondary prevention of recurrent thrombotic events in patients with previous 
atherothrombosis, in particular in patients with prior MI, at the expense of an increase in major 
bleeding. However, to date clinical trial experience with vorapaxar has been almost exclusively with 
the P2Y12 receptor inhibitor clopidogrel and the effects of vorapaxar in combination with state-of-
the-art antiplatelet therapy in the post-MI setting, including prasugrel or ticagrelor, is largely 
unexplored. This may indeed represent a limitation for the uptake of vorapaxar in modern day 
clinical practice where these agents are being more broadly utilized. Further, the role of vorapaxar 
as part of a dual antithrombotic treatment regimen, in addition to a novel P2Y12 receptor inhibitor, 

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with withdrawal of aspirin, represents another important area of clinical interest as it has the 
potential to maximize ischemic protection while reducing the risk of bleeding. The proposed 
prospective, randomized, parallel-design, open label, study conducted in a real world clinical setting 
of post-MI patients will aim to assess the pharmacodynamic effects of vorapaxar in addition to 
antiplatelet therapy with a novel P2Y12 receptor inhibitor (prasugrel or ticagrelor) with and without 
aspirin. Pharmacodynamic assessments will be performed at multiple time points and with different 
assays exploring multiple pathways of platelet aggregation. Exploratory assessments on the safety 
of such approach will also be evaluated.

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Background and Significance 
Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor represents the 
standard of care for the long-term secondary prevention of atherothrombotic events in patients with 
myocardial infarction (MI) [1]. Clopidogrel is the most widely used P2Y12 receptor inhibitor and the 
use of DAPT with aspirin and clopidogrel has consistently demonstrated to reduce the risk of 
thrombotic recurrences in patients with acute coronary syndrome (ACS) [2]. However, clopidogrel 
is a prodrug characterized by high interindividual response variability [3]. The novel P2Y12 receptor 
inhibitors prasugrel and ticagrelor are characterized by more prompt, potent, and predictable 
antiplatelet effects compared with clopidogrel and are associated with a greater reduction of 
ischemic events in ACS patients, at the expense of an increase in major bleeding [4,5]. However, 
despite adequate cyclooxygenase-1 (COX-1) and ADP P2Y12-receptor blockade, rates of ischemic 
recurrences remain high, which may be in part due to the fact that other platelet signaling pathways, 
such as thrombin-induced platelet aggregation, continue to be activated and can thus contribute to 
thrombus formation [2,6,7]. In particular, the serine protease thrombin is one of the most potent 
platelet activators and the surface of activated platelets is the main source of circulating thrombin, 
especially following an ACS [6-8]. Vorapaxar is a novel, orally active, highly selective, competitive 
and slowly reversible protease-activated receptor (PAR)-1 inhibitor, which exerts potent inhibition 
of thrombin-mediated platelet activation and aggregation [9,10]. After oral administration vorapaxar 
is rapidly absorbed with high bioavailability (>90%) and is metabolized by cytochrome P450 (CYP) 
3A4. Pharmacokinetic studies have shown that vorapaxar has a dissociation half-life as long as 20 
hours which leads to consistent pharmacodynamic (PD) effects [9,10]. Importantly, there is an 

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interplay between purinergic and thrombin mediated platelet signaling pathways which may result 
in enhanced P2Y12 inhibition when vorapaxar is added to DAPT [11].  
Recently, vorapaxar (2.5 mg once daily) has been approved for clinical use by the US Food 
and Drug Administration (FDA) for the reduction of thrombotic cardiovascular events in patients 
with a history of MI or with peripheral arterial disease (PAD), and must be used in addition to 
standard-of-care antiplatelet therapy with aspirin and/or clopidogrel [12]. Vorapaxar has been also 
approved by the European Medicines Agency for the treatment of patients with previous MI [13]. 
These indications are largely attributed to the findings of the TRA 2P-TIMI 50 (Thrombin Receptor 
Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events - Thrombolysis in 
Myocardial Infarction 50) trial [14]. In particular, the trial showed that the use of vorapaxar (2.5 mg 
once/daily) in addition to standard antiplatelet therapy [including aspirin (94% of patients), a 
thienopyridine, or both (DAPT in 58% of patients; the thienopyridine was clopidogrel in 99.3% of 
patients)] was effective in the secondary prevention of recurrent thrombotic events (cardiovascular 
death, MI, or stroke) in patients with previous atherothrombosis, in particular in patients with prior 
MI, at the cost of increased bleeding [14,15]. However, the effects of vorapaxar in combination with 
state-of-the-art antiplatelet therapy in the post-MI setting, including prasugrel or ticagrelor, is 
largely unexplored.  
 
Study Rationale 
To date clinical trial experience with vorapaxar has been almost exclusively with the P2Y12 
receptor inhibitor clopidogrel and the effects of vorapaxar in combination with state-of-the-art 
antiplatelet therapy in the post-MI setting, including prasugrel or ticagrelor, is largely unexplored. 

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This may indeed represent a limitation for the uptake of vorapaxar in modern day clinical practice 
where these agents are being more broadly utilized [1,2]. This knowledge gap represents an 
important area for exploratory research as it represents how vorapaxar could potentially be used in 
daily clinical practice. Further, given the potent and comprehensive antiplatelet effects achieved 
with the novel P2Y12 receptor inhibitors, the role of aspirin when added to these agents have been 
questioned [16,17]. Prasugrel and ticagrelor are effective in inhibiting both ADP P2Y12-dependent 
and thromboxane A2-dependent pathways of platelet aggregation [16,17]. In particular, the platelet 
inhibition achieved by combining aspirin and a potent P2Y12-receptor blocker was shown to be no 
greater than that produced by the P2Y12-receptor blocker alone in healthy volunteers [16,17]. 
Therefore, the role of vorapaxar as part of a dual antithrombotic treatment regimen including 
prasugrel or ticagrelor and stopping aspirin, represents another important area of clinical interest as 
it has the potential to maximize ischemic protection while reducing the risk of bleeding. 
 
Study Aims 
 
To assess the pharmacodynamic effects of vorapaxar in addition to antiplatelet therapy with 
a novel P2Y12 receptor inhibitor (prasugrel or ticagrelor) with and without aspirin in a real-world 
setting of post-MI patients. Exploratory assessments on the safety will also be evaluated.  
 
Research Plan 
Study Population 
Inclusion criteria: 
1. Patients with a prior MI within the previous 12 months. 

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2. On DAPT with low-dose aspirin (81mg od) and either prasugrel (10mg od) or ticagrelor (90mg 
bid) as per standard-of-care. 
3. Free from bleeding and ischemic events after the index MI event. 
4. Age between 18 and 75 years old. 
Exclusion criteria: 
 
1. History of stroke, transient ischemic attack, or intracranial hemorrhage. 
2. Active pathological bleeding, history of bleeding events or increased risk of bleeding. 
3. Known severe hepatic impairment. 
4. Age >75 years. 
5. Body weight <60 Kg. 
6. Use of strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, posaconazole, clarithromycin, 
nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, boceprevir, telaprevir, telithromycin and 
conivaptan) or inducers (e.g., rifampin, carbamazepine, St. John’s Wort and phenytoin). 
7. On treatment with any oral anticoagulant (vitamin K antagonists, dabigatran, rivaroxaban, 
apixaban, edoxaban). 
8. On treatment with any antiplatelet agent other than aspirin, prasugrel and ticagrelor in the past 
14 days.  
9. Creatinine clearance <30 mL/minute. 
10. Platelet count <80x106/mL 
11. Hemoglobin <10g/dL 
12. Hemodynamic instability 

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13. Pregnant females [women of childbearing age must use reliable birth control (i.e. oral 
contraceptives) while participating in the study]. 
 
Research Design  
The proposed investigation will be a prospective, randomized, parallel-design, open label, 
PD study conducted in a real world clinical setting of post-MI patients. Patients will be required to 
be on DAPT for at least 2 weeks before randomization. Although vorapaxar is approved for use 
irrespective of the timing of the MI, the rationale for including patients after 2 weeks is that, given 
the negative results of the clinical trial with vorapaxar in the acute phase of ACS, it may be 
reasonable to wait until patients have been stabilized after their index MI [18]. The rationale for the 
exclusion of elderly patients (aged >75 years) and patients with a low body weight (<60 kg) is that 
prasugrel is generally not recommended in these patient populations [1,2]. 
The study will be performed at the University of Florida Health Science Center at UF Health 
Jacksonville - Division of Cardiology. Patients will be recruited in the Cardiology Clinics of our 
institution and will be screened by Cardiology Research staff, who will verify that all candidates 
meet inclusion and exclusion criteria. Results from blood tests performed within the last 90 days 
will be considered valid for screening purposes. If these are not available, a blood sample will be 
collected for the screening phase. Although the study has an open-label design, laboratory personnel 
performing PD testing will be blinded to treatment assignment. 
Patients on DAPT with aspirin and prasugrel/ticagrelor as part of their standard of care for at 
least 2 weeks and who are meeting study entry criteria will be randomly assigned in a 1:1:1 fashion 
to one of the following 3 treatment regimens: 1) DAPT (aspirin and prasugrel/ticagrelor) plus 

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vorapaxar 2.5mg od; 2) prasugrel/ticagrelor plus vorapaxar 2.5mg od; 3) continue DAPT with 
aspirin and prasugrel/ticagrelor. Randomized treatment will be administered for 30 ± 3 days; 
prasugrel and ticagrelor will be administered at their standard maintenance dose (10mg od and 
90mg bid, respectively). Randomization will be stratified according to type of P2Y12 inhibitor, in 
order to include at least 35% of patients on prasugrel. The rationale for predicting a higher number 
of randomized patients on ticagrelor derives from the more broad clinical indications of ticagrelor 
compared with prasugrel. Patient who entered the study before being on DAPT for 2 weeks will be 
required to complete 2 weeks of DAPT with aspirin and prasugrel/ticagrelor before randomization. 
Blood sampling for PD testing will be conducted at 3 time-points: a) baseline (while patients 
will be on standard DAPT prior to initiating randomized treatment); b) after 7-10 days of 
randomized study treatment; c) after 30 ± 3days of randomized study treatment. At each time point, 
blood will be collected before the morning dose of prasugrel/ticagrelor and vorapaxar, in order to 
measure trough levels of platelet inhibition. During study treatment in-hospital major adverse 
cardiac events (death, MI, stroke, and urgent revascularization procedures) and serious adverse 
events (bleeding and other adverse events) will be collected. Bleeding will be defined by the BARC 
(Bleeding Academic Research Consortium) definition [19]. 
After study completion, patients will resume antiplatelet treatment regimen at the discretion 
of the treating physician. A flow diagram of the study design is illustrated below. 

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Laboratory assessments 
Peripheral venous blood samples (20 mL) will be drawn through a short venous catheter 
inserted into a forearm vein and collected in citrate, EDTA, and serum tubes as appropriate for 
assessments. The first 2-4 mL of blood will be discarded to avoid spontaneous platelet activation. 
Blood sampling for PD will be performed at 3 time points as indicated above in the study design 
section. Various PD assays will be performed as described below. Given the potential interplay 
between PAR-1 and P2Y12 mediated signaling, assessments specific for both pathways will be 
conducted [11]: 

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1. Light transmittance aggregometry (LTA) 
2. Thrombelastograph Coagulation Analyzer TEG 6s Series system (CORA® system) 
3. Whole blood vasodilator-stimulated phosphoprotein (VASP) 
4. Serum thromboxane B2 
 
Description of laboratory assays 
1) Light transmittance aggregometry (LTA): Platelet aggregation will be performed using LTA 
according to standard protocols. Blood will be collected in citrated (3.8%) tubes. LTA will be 
assessed using platelet rich plasma (PRP) by the turbidimetric method in a 2-channel aggregometer 
(Chrono-Log 490 Model, Chrono-Log Corp., Havertown) as previously described [20,21]. Platelet 
agonists will include AA (1 mM), collagen (3µg/ml), ADP (5 and 20 µM), TRAP (15 μM), and a 
combination of 2 µg/ml collagen-related peptide + 5 µM ADP + 15 µM TRAP (CAT). The reagent 
cocktail CAT will allow to assess the overall platelet response to a combination of agonists that 
leads to activation of multiple platelet pathways. PRP will be obtained as a supernatant after 
centrifugation of citrated blood at 1000 rpm for 10 minutes. The isolated PRP will be kept at 37° C 
before use. Platelet poor plasma (PPP) will be obtained by a second centrifugation of the blood 
fraction at 2800 rpm for 10 minutes. Light transmission will be adjusted to 0% with the PRP and to 
100% for the PPP for each measurement. Curves will be recorded for 6 minutes and platelet 
aggregation will be determined as the maximal percent change (MPA) in light transmittance from 
baseline using PPP as a reference. 
2) TEG 6s Series system (CORA® system): the TEG 6s system (Haemonetics Corporation, 
Braintree, MA, USA) will be used according to manufacture instructions [22]. In brief, the CORA® 

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system is a new generation portable thrombelastography technology able to evaluate all phases of 
hemostasis, including time to clot formation, rate of clot formation, strength of clot and residual clot 
strength due to antiplatelet drugs, rate of clot lysis. Disposable assay cartridges contain all of the 
components necessary to allow the analyzer to prepare samples and perform hemostasis tests. The 
analyzer automatically draws the blood into the active area of the cartridge, meters the exact amount 
required for the test, and mixes it with the reagents spotted in the cartridge. The analyzer then 
monitors the harmonic motion of a pendant drop of blood in response to external vibration. As the 
sample transitions from a liquid state to a gel-like state during clotting, the modulus of elasticity and 
resonant frequency increase. The instrument measures these variations in resonant frequency during 
clotting and lysis. The results are displayed in a table and on a graphical tracing that reflects a 
hemostasis profile of clot formation. The resulting hemostasis profile is a measure of the time it 
takes for the first measurable clot to be formed, the kinetics of clot formation, the strength of the 
clot, and the breakdown of the clot, or fibrinolysis. In particular, the PlateletMapping Cartridge are 
used to assess platelet function in patients who have received platelet inhibiting drugs. The 
PlateletMapping assay consists of a set of agonists, ADP and arachidonic acid (AA) platelet 
agonists together with ActivatorF, which can measure the inhibition of platelet function. This assay 
specifically determines the MA (Maximum Amplitude, a measure of clot strength) and the 
reduction in MA due to antiplatelet therapy and reports it as a percentage of reduction in clot 
strength. The assay uses AA and ADP agonists to generate test results that reflect the inhibiting 
effects of antiplatelet agents such as TxA2 Inhibitors (e.g., aspirin) and ADP P2Y12 inhibitors (e.g., 
ticagrelor). Since thrombin (present in blood samples) is the primary and most potent activator of 
platelets, its activity must be inhibited with heparin so that the platelet activating effects of ADP and 

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AA can be measured. Since thrombin has been rendered inactive by heparin, activatorF is used to 
replace thrombin’s role in the conversion of fibrinogen to fibrin and Factor XIII to Factor XIIIa. 
Thus, with this cross-linked fibrin network as the foundation, additional clot strength due to 
platelet-fibrin bonding related to ADP and AA platelet receptor activation can be measured. The 
HKH reagent, a combination of kaolin and heparinase, generates test data for the uninhibited MA 
resulting from thrombin activation of the blood sample, while the heparinase neutralizes the effects 
of heparin. The HKH test provides measures of R (Reaction time; the amount of time between the 
start of the test and the beginning of coagulation), K (the speed of formation of the clot from R time 
to a specific clot strength), Angle (the speed of clot strengthening), LY30 (Percent lysis 30 minutes 
after MA is finalized) and MA parameters; The activatorF test provides the contribution of fibrin to 
the overall strength of the clot.  This test value is used in the calculation of aggregation/inhibition 
for MA ADP and MA AA. The AA and ADP test provide measures of MA, percent inhibition and 
percent aggregation. 
3) Whole blood vasodilator-stimulated phosphoprotein (VASP): VASP phosphorylation (VASP-P) 
is a marker of P2Y12 receptor reactivity. VASP will be assessed according to standard protocol 
using labeled monoclonal antibodies by flow cytometry with the Platelet VASP-FCM kit (Biocytex 
Inc., Marseille, France) as previously described [23]. PGE1 increases VASP-P levels by stimulation 
of adenylate cyclase. Binding of ADP to P2Y12 leads to Gi-coupled inhibition of adenylate cyclase. 
Therefore, the addition of ADP to PGE1-stimulated platelets reduces PGE1-induced VASP-P 
levels. If P2Y12 receptors are successfully inhibited by inhibitors, addition of ADP will not reduce 
the PGE1-stimulated VASP-P levels. The platelet reactivity ratio (PRI) will be calculated after 
measuring VASP-P levels after stimulation with PGE1 (MFI PGE1) and also PGE1 + ADP (MFI 

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PGE1 + ADP). The P2Y12 reactivity ratio = ([MFI PGE1] – [MFI PGE1 + ADP]/[MFI PGE1]) x 
100%. 
4) Serum thromboxane B2: The concentration of serum thromboxane B2 (TXB2) will be measured 
by using the TXB2 EIA kit (Cayman Chemical Company, Ann Arbor, MI) according to the 
instructions of the manufacturer, as previously described [24]. Briefly, samples will be diluted with 
EIA buffer to bring their concentrations within the range of the standard curve. No other 
purification will be performed on any of the samples. A standard curve will be established by serial 
dilution of TXB2 between 1000 pg/mL and 7.8 pg/mL using EIA buffer as the matrix. The 
concentration of TXB2 in the samples will be calculated from a logistic 4-parameter fit of the 
standard concentrations versus percentage bound/maximum bound. 
 
Study endpoints and sample size calculation 
The primary end point of our study is the comparison of CAT-induced MPA between DAPT 
and DAPT plus vorapaxar after 30 ± 3 days of treatment. We hypothesize that adjunctive vorapaxar 
will result into a significant reduction of platelet aggregation. Assuming a 10% absolute reduction 
in CAT-induced MPA with a common standard deviation of 13%, 37 patients per group will be 
needed to detect a significant difference between DAPT and DAPT plus vorapaxar with a 90% 
power and 2-sided alpha=0.05. Considering a possible 30-35% rate of invalid results due to 
hemolysis or drop-out and the three arms of treatment up to 146 patients will need to be 
randomized. Since there are no preliminary data in this particular setting, the sample size of our 
study was calculated based on previous data of vorapaxar in addition to DAPT with aspirin and 
clopidogrel [21]. This approach is in agreement with recommendations for pilot investigations [25]. 

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Our secondary outcome will be the comparison of CAT-induced MPA between vorapaxar in 
addition to a new generation P2Y12 receptor inhibitor (prasugrel or ticagrelor) and vorapaxar in 
addition to standard DAPT (aspirin and prasugrel/ticagrelor). We hypothesize that stopping aspirin 
will not lead to significant differences in CAT-induced MPA after 30 ± 3 days of treatment. 
Other objectives will include the comparisons among the 3 groups of all PD parameters 
measured by multiple assays at every time point, as well as intragroup comparisons of PD 
parameters in order to evaluate the variability over time of vorapaxar PD effects, as well as how PD 
measures will be affected by aspirin withdrawal.  
 
Statistical analysis plan  
Categorical variables will be expressed as frequencies and percentages. Continuous 
variables will be presented as mean ± SD or median [IQR]. Continuous variables will be analyzed 
for normal distribution with the Kolmogorov-Smirnov test. Comparisons between categorical 
variables will be performed using two-tailed Fisher’s exact test or the Pearson's chi-square test. 
Student´s t test, Mann-Whitney U-test and Wilcoxon test will be used to compare continuous 
variables when appropriate. An analysis of covariance (ANCOVA) method with a general linear 
model, using baseline variables significantly different between groups as covariates, will be used to 
evaluate the overall difference between groups and all between-groups comparisons, in line with 
other PD studies [23]. Analysis of variance (ANOVA) will be used to evaluate intragroup 
comparisons. A 2-tailed p value of < 0.05 is considered to indicate a statistically significant 
difference for all the analyses performed. Statistical analysis will be performed by our group using 
SPSS v22.0 software (SPSS Inc. Chicago, IL).  

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Publication Strategy/Additional Information  
Study subjects will be identified first (months 1-24): we expect to enroll approximately 5-6 
subjects monthly and complete enrollment in 24 months (total: 126 subjects enrolled). Months 25-
26 will be implied for statistical analysis and months 27-28 for manuscript preparation. We intend 
to present data at a major scientific meeting at completion of the study. 
We anticipate no major problems with the described protocol since the approach is a straight 
forward prospective study and is based on well-established methods. However, since there is limited 
experience with vorapaxar to define platelet function, variability may be higher than expected and 
we cannot currently perform a detailed sample size calculation. We anticipate adding this to the 
protocol after inclusion of the study population has been completed. If the sample size after one 
year is estimated to be too small, additional patients will be included. This approach is in agreement 
with recommendations for pilot investigations [25]. 
 
Possible Discomforts and Risk 
In clinical trials, the most common clinical side effects of vorapaxar were anemia (5%), 
depression (2.4%) and rash (2.2%) [14, 18]. The most important adverse effect associated with the 
use of vorapaxar is bleeding. The risk of TIMI clinically significant bleeding with vorapaxar is 
15.8% and 11.1% with placebo (HR 1.46; 95% CI, 1.36-1.57, p<0.001); the risk of TIMI non-
CABG-related major bleeding with vorapaxar is 2.8% and 1.8% with placebo (HR 1.46; 95% CI, 
1.22-1.75, p<0.001); the risk of intracranial bleeding (intracerebral, subdural or epidural) with 
vorapaxar is 1% vs 0.5% with placebo (HR 1.94; 95% CI 1.39-2.70; p <0.001) [14]. However, such 

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bleeding prevalence occurred in the setting of long-term (3 years) trial, while our study is limited to 
only approximately 30 days of vorapaxar therapy. We have also excluded from the study patients at 
increased risk of bleeding complications [12-14]. Moreover, the use of vorapaxar in this study is 
limited to the intended for use population at low risk of bleeding. All clinical events described 
above, if they were to occur, as well as death, myocardial infarction, stroke, and urgent 
revascularization procedure with PCI or coronary artery bypass grafting will be recorded. Bleeding 
data will be collected using BARC definitions [20]. Clinical events will be evaluated by a local 
committee, comprised of 2 faculty members (2 cardiologists), not directly involved in the research. 
In the event of a report of a serious adverse event (major bleeding – defined as life-threatening: 
fatal, symptomatic intracranial hemorrhage, leading to a drop in hemoglobin of at least 5 g/dL, 
significant hypotension requiring intravenous inotropes, requiring surgical intervention, or requiring 
transfusion of 4 or more units of blood; non–life-threatening: substantially disabling, intraocular 
bleeding leading to vision loss, or requiring at least 2 units of blood; thrombocytopenia <50,000 ) 
the local committee will meet and antiplatelet treatment management will be managed according to 
physician recommendation. 
 
Definition of Adverse Events 
An adverse event is any unintended or undesirable experience that occurs during the course 
of the clinical investigation whether or not it is considered to be therapy related.  This includes any 
newly occurring event or previous condition that has increased in severity or frequency since the 
initiation of study treatment.  Adverse events will be followed until resolution while the patient 

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remains on-study.  Once the patient is removed from study, events thought to be related to the study 
therapy will be followed until resolution or until the patient starts a new treatment regimen. 
Serious Adverse Events (SAE): An adverse event occurring while on study and considered 
related (reasonable possibility that the study treatment caused the adverse experience) to the study 
treatment that results in any of the following outcomes: 
- Death 
- A life-threatening adverse experience. 
- A persistent or significant disability, incapacity, or is a congenital anomaly, or birth  
defect. 
- Requires inpatient hospitalization, or prolongation of existing hospitalization. 
The definition of serious adverse event also includes ‘important medical event’.  Medical 
and scientific judgment should be exercised in deciding whether expedited reporting is appropriate 
in other situations, such as important medical events that may not be immediately life-threatening or 
result in death or hospitalization but may jeopardize the patient and/or may require medical or 
surgical intervention to prevent one of the other outcomes listed in the definition above.  These 
should also usually be considered serious.  Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not 
result in hospitalization; or development of drug dependency or drug abuse. 
 
Possible benefits 

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The present investigation is aimed to evaluate the PD effects of vorapaxar as an add-on 
therapy to standard antiplatelet treatment in patients with previous MI. This study is not designed to 
evaluate differences in clinical benefit. However, differences in antiplatelet profiles may potentially 
prompt further investigations of the clinical implication of this difference by means of a larger scale 
clinical study. 
Potential Financial Risks or Benefits 
 
None 
Conflict of Interest 
Dr. Angiolillo is a consultant for Merck, the maker of vorapaxar. 
 
 
 
 
 
 
 

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