October 25, 2012

MIAMI — Acute coronary syndrome (ACS) patients randomized to prasugrel (Effient, Lilly/Daiichi-Sanyo) following coronary angiography had significantly lower rates of major cardiovascular events compared with patients treated with clopidogrel. The results, from the TRILOGY-ACS trial, run counter to the results observed in the overall study. In TRILOGY-ACS, one of the few studies to focus on high-risk patients with ACS who are medically managed without revascularization, the newer antiplatelet agent prasugrel failed to show a reduction in the primary end point of major cardiovascular events compared with clopidogrel.

Presenting the results of the angiography cohort at TCT 2012, Dr Stephen Wiviott (Brigham and Women's Hospital, Boston, MA) told heartwire that the patients who underwent angiography prior to randomization to the antiplatelet drugs likely represent a true, higher-risk ACS patient population.

"I think angiography identifies a population of patients with ACS in whom we're sure they have active coronary disease driving their event," he said. "In order to get into the trial, if you had angiography, you had to demonstrate that you had significant coronary lesions. There are many people who come into the hospital who have ST-segment changes or positive troponin, and when we take them to the cath lab they don't have significant coronary lesions. I think the angiography creates a purer coronary-based population."

In doing so, the subgroup analysis of TRILOGY-ACS is then consistent with other ACS trials, such as TRITON-TIMI 38 and PLATO, he said.

Dr Roxana Mehran (Mount Sinai School of Medicine, New York), the moderator of the morning press conference where the results were presented, urged caution in interpreting the results, noting that the overall TRILOGY-ACS study was negative. She added that the significance of the interaction between angiography/no angiography and the primary outcome was not statistically significant.

"The overall trial was a negative trial, and whenever you look at a subgroup, even it's positive, as [Wiviott] pointed out very nicely, it's only hypothesis generating," said Mehran. "Furthermore, the p interaction term was not statistically significant, so although we're seeing the benefit, there is not a significant interaction, which is really important. All of that put aside, these are intriguing findings."

Reduction in the Primary End Point of 23%

In the double-blind, randomized TRILOGY-ACS trial, patients were eligible if they were selected for a final treatment strategy of medical management without revascularization within 10 days of their index ACS event. The 7243 ACS patients age <75 years taking aspirin were randomized to 30 months of treatment with prasugrel 10 mg daily or clopidogrel 75 mg daily (prasugrel 5 mg was used for those weighing <60 kg). The angiographic cohort included 3085 patients randomized to prasugrel or clopidogrel after angiography while 4158 patients were randomized to treatment without angiography.

Among patients who received angiography prior to randomization, treatment with prasugrel reduced the primary efficacy end point of cardiovascular death, MI, or stroke 23% compared with clopidogrel-treated patients. For those who did not undergo angiography, there was no difference in the primary end point between the two treatment arms.

TRILOGY-ACS: Angiographic Cohort Analysis Primary Endpoint and MI Risks

End point Prasugrel, n=1534 (%) Clopidogrel, n=1561 (%) Hazard ratio (95% CI)
Angiography cohort      
Cardiovascular death, MI, and stroke 10.7 14.9 0.77 (0.61–0.98)
MI 7.2 10.3 0.74 (0.55–1.00)
No angiography cohort      
Cardiovascular death, MI, and stroke 16.3 16.7 1.01 (0.84–1.20)
MI 9.2 10.6 1.00 (0.79–1.26)

Speaking with heartwire , Dr Michael Rinaldi (Sanger Heart and Vascular Institute, Charlotte, NC) agreed with the assessment of the TRILOGY-ACS researchers, noting that physicians in the study were likely worried about the patients who underwent angiography and as a result were able to stratify, to some extent, a group of patients at higher risk for adverse events. "For that group, focusing a more aggressive drug strategy with prasugrel likely gave them a better chance," said Rinaldi. "And there is a lot of clinical-trial evidence to suggest that this is true."

Such trials include the ACS studies leading to the approval of prasugrel and ticagrelor (Brilinta, AstraZeneca)--TRITON-TIMI 38 and PLATO, where there was a benefit of more aggressive antiplatelet therapy over clopidogrel. Other trials that included lower-risk patients, such as TRIGGER-PCI, failed to show a benefit of prasugrel over clopidogrel in stable coronary artery disease patients. "TRITON and PLATO were ACS patients, and these patients do seem to benefit from the more intensive antiplatelet therapy," said Rinaldi. For the nonangiography patients, who were likely assessed as lower risk by the participating physicians, there does not appear to be a benefit to treatment with prasugrel.

Overall, the major bleeding risks associated with prasugrel in TRILOGY-ACS were higher, although the difference did not reach statistical significance (2.7% vs 1.4%, respectively; p=0.07). When the researchers combined the end point of major and minor TIMI bleeding, there was a similar excess risk in both treatment arms.

Wiviott reports grant/research support from Eli Lilly, AstraZeneca, Merck, and Eisai; consulting fees/honoraria from Eli Lilly, Daiichi Sankyo, AstraZeneca, Bristol-Myers Squibb, Sanofi, and Eisai. Rinaldi reports no conflicts of interest.