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Journal Club: Thrombin-Receptor Antagonist Vorapaxar in Acute Coronary Syndromes
Journal Club PresentationThrombin-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 .
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
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
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
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
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
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
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
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
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
Study Outcomes 10 • Composite of death fromPrimary cardiovascular causes, MI, stroke, recurrent ischemia withEndpoint re-hospitalization, or urgent coronary revascularization • Composite of death fromSecondary Cardiovascular causes, MI, or stroke Endpoint • Other exploratory efficacy endpoints • Composite of moderate or Safety severe bleeding according to GUSTO classification andEndpoints significant bleeding according to TIMI classification
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
Results 12 Timeline of Study EventsDecember 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
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 3.5Vorapaxar 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 3.5All patients 27.5% (12.2 – 40.8) (233.0 – 586.0) (1.8 – 20.7)
Results Primary Efficacy Endpoint 1425.0% Events Death from cardiovascular causes 19.9%20.0% 18.5% Myocardial infarction 17.0% 15.9% Stroke15.0% Recurrent ischemia with rehospitalization10.0% Urgent coronary revascularization5.0% Hazard Ratio 0.920.0% 95% CI: 0.85-1.01 Percentage of Event Rate at 2 Patients with Years P = 0.07 Event Placebo Vorapaxar
Results 18The 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
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”
Results Safety Endpoints 20 TIMIThrombolysis 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”
Conclusion 21 “In patients with ACS without ST-segment elevation, the addition of vorapaxar to standard therapy did not significantly reduce the primarycomposite end-point, but significantly increased the risk of major bleeding, including intracranial hemorrhage.”
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
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
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
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.