Conference Coverage

Platelet Activity, Clinical Benefit Disconnected Post ACS

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TRILOGY ACS Results in More Questions Than Answers

The results of this substudy were very clear: Treatment with prasugrel substantially reduced ADP-induced platelet aggregation. About 10% of patients treated with prasugrel had high platelet reactivity, compared with about 50% of the clopidogrel-treated patients. But most important, the investigators showed no independent relationship between platelet activity, as measured by the device they used, and outcomes. There was a relation in an unadjusted analysis, but when corrected for baseline differences, there was no significant effect.

The neutral outcome between prasugrel and clopidogrel seen in TRILOGY ACS contrasts with the consistent benefit seen with ticagrelor over clopidogrel in PLATO (Study of Platelet Inhibition and Patient Outcomes).

The TRILOGY ACS substudy results leave us with more questions than answers: Why was there no association between platelet reactivity and outcomes in TRILOGY ACS? Would this lack of association also apply to other P2Y12 inhibitors, such as ticagrelor, or to other types of platelet inhibitors? How might the preventive effects seen with ticagrelor and vorapaxar be explained? And how should these unique results influence future use of platelet function measurement in either trials or in practice, and how should future trials address intensified platelet inhibition as a way to improve long-term outcomes in acute coronary syndrome patients?

Lars Wallentin, M.D., is a professor of medicine and director of the Clinical Research Center at Uppsala University in Sweden. He served as lead investigator for the PLATO trial, the pivotal trial of ticagrelor. He has received research funding and other financial benefit from AstraZeneca, the company that markets ticagrelor (Brilinta), and that he has served as a consultant to and has received research funding from several other drug companies. Dr. Wallentin made these comments as the designated discussant for the TRILOGY ACS substudy.



LOS ANGELES – Treatment proven to cut platelet reactivity in medically managed patients following an acute coronary syndrome event failed to improve clinical outcomes in a trial substudy with more than 2,500 patients, prompting experts to rethink their approach to managing patients with acute coronary disease who do not receive a coronary stent.

The "lack of a significant, independent association between platelet reactivity and ischemic outcomes may explain the comparable clinical outcomes" in the overall results of the TRILOGY ACS (Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes) trial, Dr. Paul A. Gurbel said at the annual scientific sessions of the American Heart Association.

Dr. Paul A. Gurbel

"The value of platelet function testing will depend on the risk of the patient," said Dr. Gurbel, director of the Center for Thrombosis Research at Sinai Hospital in Baltimore. He drew a distinction between the patients enrolled in TRILOGY ACS, which by design restricted enrolled acute coronary syndrome patients to only those targeted for exclusively medical management, and ACS patients who need to receive one or more coronary stents.

"In low-risk patients [those who don’t need a stent], it’s hard to do any change of treatment that improves outcomes, but we don’t have data on personalizing antiplatelet treatment for higher-risk patients," who require stenting, he said. "We know that in higher-risk patients, administering a more potent antiplatelet agent does have clinical benefit.

"I think the key is all about risk. The TRILOGY results clearly show that events occurred even at very low levels of platelet reactivity. That tells you something is driving these ischemic events beyond the interaction of ADP with a P2Y12 receptor," the action blocked by the two thienopyridines compared in TRILOGY ACS, prasugrel (Effient) and clopidogrel [Plavix], Dr. Gurbel said in an interview. "This pathway is very important, but it doesn’t seem to play a major role unless the patient has a stent."

Dr. Gurbel suggested that in the nonstented, medically managed ACS patients in TRILOGY ACS, other factors that might drive ischemic events could include endothelial dysfunction and nonthrombotic mediated ischemic events. "With patients who have stents, it’s a purer pathophysiology, where we know that the P2Y12 receptor plays an important role.

To Dr. Gurbel, the new findings he reported from the TRILOGY ACS substudy suggest that a similar comparison of platelet reactivity following prasugrel or clopidogrel treatment should be done in ACS patients who have undergone percutaneous coronary intervention and received a stent.

Mitchel L. Zoler/IMNG Medical Media

Dr. Lars Wallentin

Dr. Lars Wallentin had a different take on the findings. He suggested that the way to optimize treatment in medically managed ACS patients is to "try something different," such as ticagrelor (Brilinta), the investigational agent vorapaxar, or an anticoagulant. The substudy results "show you can’t reduce risk by increasing the dose of a thienopyridine," said Dr. Wallentin, professor of medicine and director of the Clinical Research Center at Uppsala University in Sweden.

The TRILOGY ACS platelet-function substudy piggybacked on a clinical-event comparison of prasugrel and clopidogrel in 9,326 ACS patients managed medically. Primary results from the overall trial, first reported last August, showed no difference in clinical end points between patients who received these two thienopyridines.

The prespecified substudy, which included 1,286 patients treated with prasugrel and 1,278 who received clopidogrel, involved serial measurements of platelet reactivity in these patients using VerifyNow devices, at baseline, after 2 hours, and at 1, 3, 6, 12, 18, 24, and 30 months into the study. These measurements showed that prasugrel treatment resulted in robust, statistically significant incremental reductions in platelet activity, compared with clopidogrel, within 1 month after the onset of treatment and continuing through the study’s 2.5 years.

In univariate analyses, reduced platelet reactivity significantly linked with reduced numbers of clinical events through 30 months. However, after adjustment for a long list of potential confounders at baseline, the degree of platelet reactivity failed to show any statistically significant relation to the incidence of clinical events, Dr. Gurbel reported.

Concurrent with his talk at the meeting, the findings appeared in an article published online (JAMA 2012;308:1785-94).

The TRILOGY ACS study was sponsored by Eli Lilly and Daiichi Sankyo, which market prasugrel. Dr. Gurbel said that he has been a consultant to and has received research grants from Eli Lilly and from several other drug companies. Dr. Wallentin served as lead investigator for PLATO, the pivotal trial of ticagrelor. He has received research funding and other financial benefit from AstraZeneca, the company that markets ticagrelor, and that he has served as a consultant to and has received research funding from several other drug companies.

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