Trial DesignEvaluation of prasugrel compared with clopidogrel in patients with acute coronary syndromes: design and rationale for the TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet InhibitioN with prasugrel Thrombolysis In Myocardial Infarction 38 (TRITON-TIMI 38)
Section snippets
Background
Dual antiplatelet therapy with aspirin and a thienopyridine is standard therapy for prevention of thrombotic complications of percutaneous coronary intervention (PCI).1, 2 Clopidogrel has largely replaced ticlopidine because of a better side-effect profile.3, 4 Studies have established the benefit of long-term clopidogrel for up to 1 year in subjects with an acute coronary syndrome (ACS), including those who undergo PCI.5, 6
Several important issues remain regarding this current standard. Most
Background on prasugrel
Prasugrel (CS-747, LY640315) is a thienopyridine that has been shown in preclinical studies to be more potent and rapid in onset than clopidogrel.15 Phase 1 studies in healthy human subjects showed greater inhibition of platelet aggregation (IPA) with a 60-mg dose of prasugrel than 300 mg of clopidogrel16 and repeat dosing with 10 mg of prasugrel compared with 75 mg of clopidogrel.17 There is also evidence that poor IPA response may be less frequent with an LD of 60 mg of prasugrel than 300 mg
Study objectives
The primary objective of TRITON-TIMI 38 is to test the hypothesis that prasugrel is superior to clopidogrel on a background of aspirin in the treatment of subjects with ACS who are to undergo PCI measured by the composite end point of cardiovascular (CV) death, nonfatal myocardial infarction (MI), or nonfatal stroke. Additional efficacy hypotheses include that prasugrel reduces the occurrence of (1) the primary composite at 30 or 90 days and (2) CV death, nonfatal MI, or urgent target vessel
Study design and population
TRITON-TIMI 38 is a randomized, double-blind, double-dummy, parallel-group, clinical trial with an active comparator (Figure 1). The study population includes subjects with moderate to high-risk ACS (Table I). Patients with unstable angina (UA) and non–ST-segment elevation MI (NSTEMI) and TIMI risk score21 of 3 or higher may be enrolled within 72 hours of symptom onset. Patients with ST-segment elevation MI (STEMI) may be enrolled either within 12 hours of the onset of symptoms (primary PCI) or
Treatment protocol and follow-up procedures
A loading dose of study medication is administered anytime after randomization until the completion of the PCI procedure (within 1 hour after the patient leaves the cardiac catheterization laboratory). Randomization may occur immediately after obtaining informed consent from patients with STEMI when primary PCI is planned. For patients with UA/NSTEMI or those enrolled post-STEMI, coronary angiography may reveal an anatomy that is not amenable to PCI, and therefore, randomization may occur only
Study closeout procedures
The analysis of the primary efficacy composite end point will include events occurring for each subject during the study period, defined as the day of randomization through the end of the study period (maximum 464 days, ie, 450+14 days), which is after randomization, as clarified hereinafter.
The completion date of the study will be determined by the executive committee as a specific date when the following are expected to be met: (1) 875 subjects with a primary end point in the UA/NSTEMI arm
Dosing regimens
The dosing regimen of prasugrel in TRITON-TIMI 38 is an LD of 60 mg and daily 10 mg of maintenance dose. These doses have been selected on the basis of nonclinical thrombosis models, nonclinical toxicology studies,22 dose escalation studies in healthy subjects,23 dose ranging versus clopidogrel in subjects with stable coronary artery disease,18 and the JUMBO-TIMI 26 study.20 These studies have demonstrated that prasugrel can achieve an increase in the inhibition of adenosine diphosphate–induced
Concomitant medications
All decisions regarding concomitant medications are left to the treating physician. It is recommended that long-term aspirin therapy be 75 to 162 mg. Patients may receive unfractionated heparin, low–molecular-weight heparin, any approved direct thrombin inhibitor, and/or GPIIb/IIIa receptor antagonist. Because of a lack of information regarding the safety of thienopyridines in combination with warfarin, blinded study drug is discontinued in patients requiring anticoagulation with warfarin, and
Study end points
The primary end point of the trial is the time of first occurrence of any element of the composite of CV death, nonfatal MI, or nonfatal stroke. Cardiovascular death is considered as any death with a demonstrable CV cause or any death that is not clearly attributable to a non-CV cause. Myocardial infarction must be distinct from the index event and is defined by symptoms suggestive of ischemia/infarction, electrocardiographic data, cardiac biomarker, or pathologic evidence of infarction
Determination of sample size
The study is designed to continue until 875 subjects with UA/NSTEMI reach one of the components of the primary end point. This provides 90% power to establish superiority relative to the primary composite end point of CV death, nonfatal MI, or nonfatal stroke in the UA/NSTEMI group. These calculations are based on the following assumptions: (1) 10.5% of subjects in the clopidogrel group will develop the primary end point within 1 year based on extrapolation from CURE and PCI CURE,5, 30, 31 (2)
Study organization
The TRITON-TIMI 38 trial is sponsored by Eli Lilly and Company (Indianapolis, IN) and Daiichi Sankyo Co. (Parsippany, NJ), and is coordinated by the TIMI Study Group. Quintiles Corporation serves as the contract research organization and provides data and site management services. The steering committee is responsible for the scientific content of the protocol, protocol implementation, results presentation, and written manuscripts. Trial operations are monitored and coordinated by the
Summary
TRITON-TIMI 38 is a phase 3, randomized, double-blind, double-dummy, parallel-group, clinical trial that assesses the efficacy and safety of prasugrel compared with that of clopidogrel in patients with an ACS undergoing PCI. This trial will provide important information regarding the safety and efficacy of prasugrel and whether this agent is superior to the current standard of care. Furthermore, this is the first large-scale clinical events trial that assesses whether a thienopyridine regimen
References (32)
- et al.
Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study
Lancet
(2001) - et al.
Durability of platelet inhibition by clopidogrel
Am J Cardiol
(2003) - et al.
Variability in platelet responsiveness to clopidogrel among 544 individuals
J Am Coll Cardiol
(2005) - et al.
The relation of dosing to clopidogrel responsiveness and the incidence of high post-treatment platelet aggregation in patients undergoing coronary stenting
J Am Coll Cardiol
(2005) - et al.
American College of Cardiology key data elements and definitions for measuring the clinical management and outcomes of patients with acute coronary syndromes. A report of the American College of Cardiology Task Force on Clinical Data Standards (Acute Coronary Syndromes Writing Committee)
J Am Coll Cardiol
(2001) - et al.
Expert consensus document on the use of antiplatelet agents. The task force on the use of antiplatelet agents in patients with atherosclerotic cardiovascular disease of the European society of cardiology
Eur Heart J
(2004) - et al.
ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines(ACC/AHA/SCAI writing committee to update the 2001 guidelines for percutaneous coronary intervention)
Circulation
(2006) - et al.
Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting: the clopidogrel aspirin stent international cooperative study (CLASSICS)
Circulation
(2000) - et al.
Bone marrow aplasia associated with ticlopidine therapy
Am J Hematol
(1993) - et al.
Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial
JAMA
(2002)
Optimal duration of pretreatment with clopidogrel prior to PCI: data from the Credo Trial
Circulation
Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity
Circulation
Prevalence of clopidogrel non-responders among patients with stable angina pectoris scheduled for elective coronary stent placement
Thromb Haemost
Clopidogrel resistance: a new chapter in a fast-moving story
Circulation
Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction
Circulation
Resistance to thienopyridines: clinical detection of coronary stent thrombosis by monitoring of vasodilator-stimulated phosphoprotein phosphorylation
Catheter Cardiovasc Interv
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2022, Pharmacology and TherapeuticsCitation Excerpt :NSTE-ACS patients with planned medical therapy or bypass surgery were not randomized and 99% of all randomized patients received PCI (Wiviott et al., 2006; Wiviott et al., 2007). The trial had a study period of up to 15 months to guarantee a median follow-up of at least 12 months representing the usual duration of dual anti-platelet therapy in ACS (Wiviott et al., 2006). In the overall trial population, which was treated by PCI in 99%, prasugrel compared to clopidogrel significantly reduced the primary endpoint of cardiovascular death, myocardial infarction and stroke by 19% (Fig. 1).
The TRITON-TIMI 38 trial is supported by Eli Lilly and Company, Indianapolis, IN, and Daiichi Sankyo Co., Parsippany, NJ.