Prasugrel more effective than clopidogrel but associated with increased bleeding

New antiplatelet drug more aggressive in treating patients with acute coronary syndromes.

Issue: December 2007

ORLANDO —The thienopyridine prasugrel was more effective than clopidogrel at lowering ischemic events but had one drawback: increased bleeding.

The results of the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel (TRITON-TIMI 38) suggested that prasugrel (Daiichi Sankyo) with aspirin administered to patients with acute coronary syndromes and scheduled for percutaneous coronary intervention had a more pronounced and more rapid inhibition of adenosine diphosphate and antiplatelet properties than higher doses of clopidogrel (Plavix, Sanofi Aventis) with aspirin.

“We can conclude that higher degrees of inhibition of platelet aggregation to support PCI are beneficial,” Elliot Antman, MD, a TRITON investigator and director of the cardiac unit at Brigham and Women’s Hospital, said at a press conference. “The higher inhibition of platelet aggregation achieved with prasugrel did in fact reduce events.”

Lower event rates

The TRITON-TIMI 38 trial researchers randomly assigned 13,608 patients into two arms of the double blind study. All patients had moderate- to high-risk ACS and were scheduled for PCI. Patients were separated into two tiers: those with unstable angina or non-STEMI (n=10,074), and those with STEMI (n=3,534). Follow-up was conducted at 30 days and 90 days and at three-month intervals for six to 15 months thereafter.

Patients on a prasugrel regimen of a 60-mg loading dose and 10-mg maintenance dose showed significant reductions in composite end points of cardiovascular death, MI and stroke (HR=0.81; 95% CI, 0.73-0.90), as well as lower rates of stent thrombosis (HR=0.48; 95% CI, 0.36-0.64), urgent target vessel revascularization (HR=0.66; 95% CI, 0.54-0.81) and MI (HR=0.76; 95% CI, 0.67-0.85) compared with patients on a 300-mg loading dose and 75-mg maintenance dose of clopidogrel. There was, however, a significant increase (32%) in major bleeding among the population. This study was simultaneously published in The New England Journal of Medicine.

“There was an early and sustained benefit in both the loading dose and the maintenance dose phases of the study. This benefit was applicable across the ACS spectrum,” said Antman. “There was also a significant increase in major bleeds. The net clinical benefit favored prasugrel overall in the trial. However, we probably should avoid prasugrel in patients with a prior transient ischemic attack or stroke.”

Post hoc analysis revealed patients older than 75 or who weighed <60 kg were at higher risk for bleeding with prasugrel than other patients. The researchers concluded that a modified maintenance dose in elderly and low body weight patients might help optimize the benefit-to-risk ratio in those patients.

“These were very positive results and were statistically significant,” Steve E. Nissen, MD, chairman, department of cardiovascular medicine, Cleveland Clinic, said in an interview. “There were some safety issues like increased bleeding with the drug, but in my view, the benefits significantly outweigh the hazards. The drug is potentially approvable and when given to the right patients would represent a real benefit.” – by Eric Raible

The results of TRITON-TIMI 38 are only applicable to highly-selected and carefully-monitored ACS patients who have already undergone coronary angiography and are considered suitable candidates for a PCI revascularization procedure. These results cannot be generalized to all ACS patients who are now more commonly being treated with aspirin and clopidogrel at the time of their initial presentation with ACS. A large randomized trial comparing prasugrel plus aspirin with clopidogrel plus aspirin is needed to address benefit-to-risk in these patients. TRITON-TIMI 38 clearly shows that one can reduce the incidence of a future MI with a more potent inhibitor of platelets but at a price of increased major bleeding risk. Further trials with prasugrel are needed to better define the right dose, which provides a balance between reducing adverse clinical outcomes and at the same time not increasing the risk of major and fatal bleeding.

—Udho Thadani, MD

For more information:

Wiviott S, Braunwald E, McCabe C, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357:2001-2015.
Antman E. Evaluation of prasugrel compared with clopidogrel in patients with acute coronary syndromes and planned percutaneous coronary intervention: The TRITON-TIMI 38 study. PS.01. Presented at: American Heart Association 30th Annual Scientific Sessions; Nov. 4-7, 2007; Orlando.