TOKYO and INDIANAPOLIS, Nov. 4 In the pivotalPhase III head-to-head TRITON TIMI-38 clinical trial, the investigationalantiplatelet agent prasugrel produced a highly significant 19 percentreduction in relative risk (p=0.0004) for the composite endpoint ofcardiovascular death, non-fatal heart attack or non-fatal stroke when comparedwith clopidogrel (Plavix(R)/Iscover(R)) in the treatment of patients acrossthe full spectrum of acute coronary syndrome undergoing percutaneous coronaryintervention.
A significant reduction in the risk for the composite endpoint favoringprasugrel (60 mg loading dose/10 mg maintenance dose) over clopidogrel (300 mgLD/75 mg MD) was observed as early as three days. The absolute difference inthis endpoint continued to increase over the course of the 15-month, 13,608-patient trial.
In the important subgroup of patients with diabetes, prasugrel reduced therelative risk of cardiovascular death, non-fatal myocardial infarction andnon-fatal stroke by 30 percent (p<0.001). In addition, in the key secondaryendpoint of stent thrombosis, prasugrel reduced the recurrence of stentthrombosis (a new clot that develops at the stent site) by 52 percent(p<0.0001).
TRITON also showed that treatment with prasugrel significantly reduced therelative risk of cardiovascular death, non-fatal heart attack and non-fatalstroke by 21 percent in patients with STEMI (ST-elevation myocardialinfarction, or high-risk heart attack) (p=0.02) and 18 percent in patientssuffering from UA (unstable angina, or chest pain)/NSTEMI (non-STEMI)(p=0.002). In addition, prasugrel-treated patients experienced a 34 percentdecline in urgent target vessel revascularization (a procedure to reopenblocked arteries) (p<0.001) and a 42 percent reduction in heart attack withsubsequent death from cardiovascular causes (p=0.02).
While the overall incidence of non-CABG (coronary artery bypass grafting)bleeding in TRITON was low in both the prasugrel and clopidogrel treatmentgroups, prasugrel-treated patients experienced a statistically significantincrease in non-CABG (coronary artery bypass grafting) major bleeding comparedto clopidogrel-treated patients (2.4 vs. 1.8 percent, or 146 vs. 111 patients,p=0.03), including higher rates of life-threatening bleeding (1.4 vs. 0.9percent, or 85 vs. 56 patients, p=0.01). Though infrequent, fatal bleeding wasstatistically more frequent among prasugrel-treated than clopidogrel-treatedpatients (0.4 percent vs. 0.1 percent, or 21 vs. five patients, p=0.002).However, death from cardiovascular causes occurred less frequently amongprasugrel-treated patients than clopidogrel-treated patients (2.1 percent vs.2.4 percent, or 133 vs. 150 patients, p=0.31), as did all-cause death (3.0percent vs. 3.2 percent, or 188 vs. 197 patients, p=0.64).
The study identified three distinct patient subpopulations with a higherrisk of major bleeding in both treatment arms - patients who were 75 years ofage or older, weighed less than 60 kg (132 lbs.), or had a prior history oftransient ischemic attack (TIA) or stroke. Researchers are evaluatingpharmacokinetic data from several prasugrel studies, including TRITON, todetermine whether a lower dose of prasugrel might be appropriate for somepatients. Among patients without any of these risk factors (80 percent of the13,608-patient TRITON study), there was no significant difference in majorbleeding between prasugrel- and clopidogrel-treated patients (2 percent vs.1.5 percent, p=0.17).
Based on an analysis using the combined endpoint of all-cause death, heartattack, stroke and major bleeding, the net clinical benefit for prasugrelcompared with clopidogrel was a significant 13 percent reduction in overallevents (12.2 vs. 13.9, p=0.004). In the subpopulations defined as being atgreater risk of bleeding, the net clinical benefit was not different betweenprasugrel- and clopidogrel-treated patients