Journal 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.

Stella Pangalila
406171035
 Background
• AHA mendefinisikan Acute Coronary Syndrome sebagai istilah
yang mencakup spektrum kondisi klinis yang ditandai dengan
iskemia miokard secara akut.
– Myocardial Infarction
• Peningkatan / penurunan ST segmen
– Non ST Elevation Myocardial Infarction (NSTEMI)
• Unstable angina
• Ditandai dengan ketidakseimbangan antara ketersediaan
oksigen dengan kebutuhannya
• Pada artikel ini memfokuskan pengobatan pada pasien
dengan Sindrom koroner akut tanpa elevasi ST segmen.
 Background
ACS Treatments

Treatmen Goals Categories of Treatment

• Segera berikan pertolongan
pada Iskemia
• Mencegah terjadinya hasil
yang buruk
– Meninggal
– (Re)infarction Miocard
• Anti-ischemic Agents
– Menurunkan konsumsi oksigen
miokard dan / memicu
vasodilatasi
• Anticoagulation Agents
– Menghambat pembentukan
trombin atau aktifitas,
menurunkan trombus
• Antiplatelet Agents
– Mencegah ruptur plak dan
artherothrombotic events
• Coronary revasculariztion
– Mengurangi angina dan iskemi
yang sedang berlangsung
 Background
Vorapaxar

• Competitive Protease- Effects of PAR-1 Receptor

Activated Receptor-1 Activation
(PAR-1) antagonist
Thrombin Increase in cystolic
• Action results in potent activates PAR-1 Ca2+
inhibition of rapid Receptor
thrombin-induced
Increase in platelet
platelets aggregation response to Inhibition of
cAMP formation
• Previous studies agonists
suggested that its use was
associated fewer Mis
Platelets Aggregation
without significantly
increasing the risk of
bleeding
 Study Objectives
• 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
acute coronary syndrome without elevasi ST segmen
 Methods
Study design Research and Analysis
• Multi-national • Analysis performed
• Randomized independently at the Duke
• Double-blind Clinical Research Institute
• Placebo-Controlled • Study design and data
collecting performed by
several international
academic research
organizations
• Study Funded by Merch
Pharmaceuticals
 Methods
Kriteria Inklusi
• Acute symptoms of
coronary ischemia within 24
hours before hospital
presentation
• One of the following :
– Age at least 55 years
– Previous MI, PCI, or CABG
– Diabetes Melitus
– Peripheral Arterial Diasease
• One of the following :
– Cardiac troponin or CKMB
higher than ULN
– New ST segment depression
of greater than 0,1 mV
– Transient ST segment
elevation more than 0,1mV in
at least 2 leads.
 Methods
Kriteria Eksklusi
• Concurrent or anticipated
treatment with Warfarin, oral
factor Xa inhibitors or oral
direct thrombin inhibitors
• Concurrent or anticipated
treatment with potent CYP3A4
enzyme inducers or inhibitors
• Evidence of abnormal bleeding
within 30 days of enrollment
• History of intracranial
hemorrhage
• Known current substace abuse
• Females whim were breast-
feeding, pregnant or intended
on becoming pregnant
• Severe valvular heart disease
• Known history of
thromocytopenia occuring
within 30 days before
enrollment
• Known active hepatobilliary
disease
 Methods
• 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 study
• 15 lost to follow-up
– 818 sites
– 37 countries
 Study Analysis
• 1900 primary endpoint events
would provide a power greater Analysis Method
than 95% to detect a 15% Efficacy Time to first occurrence of any
hazard reduction of the composite endpoints
• 1457 secondary endpoint events Hazard Cox-propotional Hazards model
would provide a power of 90%
to detect a 15% hazard Ratios
reduction 95% Cox propotional Hazards model
• Significance level of 0.049 for Confidence
the analysis of all key efficacy Intervals
endpoints
Safety Cox propotional Hazards model
• Superiority cannot be declared Analyses
for secondary endpoint if not
achieved for primary endpoint. Event rates 2-years Kaplan Meier Estimtes
 Results
• Timeline to Study events
January
June 25, January 8,
June 4, 13, 2011
December 2010 2011
18, 2007 2010 • All sites
• Planned • Unplann
notified
• Beginning • Ending formal ed safety
to tell all
of of interim rewie
patients
recruitme recruitm analysis • Recome to stop
nt period ent continuati ndation taking
period on of the to stop study
study the trial drugs
 Results
Safety Endpoints

• GUSTO (Global Use of Strategies to Open Occluded

Arteries
• Mild bleeding :
– Bleeding without blood transfusion of hemodynamic
compromise
• Moderate Bleeding
– Bleeding requiring transfusion of whole blood or packed
red blood cells without hemodynamic compromise
• Severe Bleeding
– Bleeding that was fatal, intracranial or that caused
hemodynamics compromise requiring intervention
“Vorapaxar increased the rate of moderate or
severe bleeding as compared to placebo”.
 Results
Safety Endpoints

• TIMI (Thrombolysis in myocardial infarction)

• Bleeding requiring medical attention:
– Clinically overt bleeding that requires unplanned
medical treatment
• Minor bleeding
– Any clinically overt sign of hemorrage associated
with a fall in HgB of 3-5mg/dl
• Major bleeding
– Any intracranial or overt signs of hemorrhage
associated with a drop in HgB of 5 or greater g/dl
“The rate of clinically significant TIMI bleeding was
increased among patients treared with vorapaxar”
 Conclusion
• 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