TRITON-TIMI: Regardless of stent timing and type, prasugrel bests clopidogrel
CHICAGO—Prasugrel had earlier been shown to block platelet activity in patients with acute coronary syndromes (ACS) more effectively than clopidogrel, and to cut by more than half the risk of thrombosis. Now a new analysis of data from the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel (TRITON-TIMI 38) reveals that the investigational drug maintains its edge over clopidogrel regardless of the type of stent, the amount of time since the stenting procedure, or the way stent thrombosis is defined.

Stephen D. Wiviott, MD, from Brigham and Women’s Hospital presented the study in a late-breaking clinical trials session at the American College of Cardiology (ACC) Scientific Sessions on Sunday.

For the main TRITON-TIMI 38 study, researchers recruited over 13,000 patients with ACS who needed stenting from 707 medical centers in 30 countries. Patients were randomly assigned to antiplatelet therapy consisting of either a 300-mg loading dose of clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) before the procedure, followed by a maintenance dose of 75 mg daily for one year, or to a loading dose of 60 mg of prasugrel (Effient, Eli Lilly/Daiichi Sankyo) followed by 10 mg daily for one year.

Of the 12,844 patients who ultimately were treated with at least one coronary stent, 6,461 patients received only bare-metal stents (BMS), and 5,743 patients received only drug-eluting stents (DES). Overall, prasugrel better reduced both early stent thrombosis when compared with clopidogrel (0.64 percent vs. 1.56 percent, p<0.001) and late stent thrombosis (0.49 percent vs. 0.82 percent, p=0.035).

The comparison of prasugrel versus clopidogrel by stent thrombosis definition and stent type is shown in the table.

Stent Thrombosis: Prasugrel vs Clopidogrel
Stent Definition Clop Pras HR* P-Value
Any Definite 2% 0.9% 0.42 <0.0001
Any Def/Probable 2.3% 1.1% 0.48 <0.0001
Any Def/Prob/Poss 2.7% 1.5% 0.56 <0.0001
BMS Def/Probable 2.4% 1.3% 0.52 0.0009
DES Def/Probable 2.3% 0.8% 0.36 <0.0001
PES* Def/Probable 2.3% 0.8% 0.33 0.002
SES* Def/Probable 2.1% 0.7% 0.33 0.004
*PES = paclitaxel-eluting stent, SES = sirolimus-eluting stent, HR = hazard ratio

“Our data indicate that an agent with more rapid, consistent and greater inhibition of platelet aggregation [prasugrel] results in a greater reduction of stent thrombosis regardless of stent type, both early and late, and across a broad array of patient and procedural characteristics,” Wiviott said.

Researchers also found a significant reduction in cardiovascular death, non-fatal MI or non-fatal stroke in patients who received prasugrel (9.9 percent) compared with those who received clopidogrel (12.1 percent). This was, however, accompanied by an increase in TIMI major bleeding in the prasugrel arm: 1.8 percent to 2.4 percent.

In his comment, George D. Dangas, MD, from Columbia University Medical Center in New York, praised the trial for being the first substudy involving the tolerance of alternative antiplatelet therapy on early and late stent thrombosis of the largely off-label use of DES and BMS.

He also liked that all subsets—DES, BMS, PES, and SES—were well represented and that the long-term follow up (450 days) allowed for good evaluation of late thrombosis.

“What did we learn from the drug aspect of the investigation? That an agent is able to produce fast achievement of enhanced inhibition of platelet activation, reaching a level of 70 to 80 percent compared to a 30 to 35 percent range, lowers both early and late stent thrombosis in all subgroups reported here today,” he said.

Whether this effect is independent of other clinical, angiographic and procedural variables of stent thrombosis needs to be further evaluated with multivariant analysis, he added.

Prasugrel warrants a careful risk-benefit analysis since it increases bleeding, Dangas said, and wondered if it would be possible to distinguish ahead of time patients at risk for stent thrombosis versus those at risk for bleeding and treat each one accordingly.

Regarding stents, the study showed that both DES and BMS have a very safe profile with respect to early and late stent thrombosis. Both types of stents had strikingly similar rates, he said.

He concluded that it’s difficult to improve stent outcomes solely by stent technology and operator training and called for large scale and long term investigation of combination pharmacological strategies.