Ticagrelor's benefits appear to carry over time, according to an analysis that found ticagrelor treatment resulted in not only fewer primary outcome events (MI, cardiovascular death, stroke) but also fewer subsequent events compared with clopidogrel. But an accompanying editorial questioned the use of composite endpoints to track subsequent events, and suggested a protocol to define and report recurrent endpoints more specifically. 

The study and editorial appeared in the Feb. 12 issue of Circulation.

Noting that the custom in randomized clinical trials is to censor patients after they reach any primary endpoint, but continue to follow them if they survive, Payal Kohli, MD, of Brigham and Women’s Hospital in Boston, and colleagues suggested that information on the ultimate outcomes of these censored patients would be useful for clinicians. They used data from the PLATO (PLATelet inhibitions and patient Outcomes) trial to assess the effect of ticagrelor on recurrent cardiovascular events, compared with clopidogrel.

PLATO randomized 18,624 patients to receive either ticagrelor (Brilinta, AstraZeneca) or clopidogrel (Plavix, Bristol-Myers Squibb) within 24 hours of an acute coronary syndrome (ACS). During the trial, 1,888 patients experienced a primary endpoint, 318 of whom experienced more than one occurrence of a composite of the primary endpoints of cardiovascular death (CVD), MI and stroke. The patients who experienced multiple events were older, more likely to have diabetes mellitus, previous MI or coronary artery bypass graft and impaired renal function, and less likely to be male.

In the PLATO trial, patients randomized to receive ticagrelor experienced reduced incidence of primary endpoints (hazard ratio [HR] of 0.84) compared to patients who received clopidrogel. Researchers in the current study found that ticagrelor also reduced the risk for time to second occurrence (HR 0.8) of the composite endpoint or all cause death.

Ticagrelor patients had a reduced hazard (HR 0.88) for time to any artherothrombotic event (CVD/MI/stroke/severe recurrent ischemia/recurrent ischemia/transient ischemic attack/other arterial thrombotic events), and a lower number of recurrent events at 740, vs. 834 for the patients receiving clopidogrel.

The rates of major bleeding were similar between patients in the ticagrelor group and patients in the clopidrogel group. However, ticagrelor increased the rate of minor bleeding; there were 234 minor bleeding events among the ticagrelor group compared to 188 in the clopidrogel group. There were no differences in the patients who terminated treatment due to bleeding.

Ticagrelor treatment, “resulted in a greater prevention of not only first, but also subsequent, occurrences of cardiovascular events,” Kohli et al concluded.

In an accompanying editorial, Paul W. Armstrong, MD, and Cynthia M. Westerhout, PhD, urged caution when making clinical decisions about continuing ticagrelor therapy for individual patients. They noted that 83 percent “of the overall treatment effect of ticagrelor on the primary composite endpoint was expressed on the first event. In contrast, there was only a modest and non-significant additional advantage of ticagrelor on the recurrence of the three components of the composite.”

They suggested that composite endpoints do not allow a clinician to assess the real risk of continuing treatment to individual patients. “[W]e can surmise that a large MI with heart failure versus a small periprocedural MI or a disabling non-fatal hemorrhagic stroke versus a transient left arm weakness would have dramatically different consequences on patient care,” they wrote.

Acknowledging that the work of Kohli et al “provided welcome attention to the potential power of counting more than one event per patient in a clinical trial,” the editorialists proposed that future clinical trials in cardiovascular medicine:

• Record all patient events and report per-patient and overall rates;
• Prespecify event definitions to allow easier inter-trial comparisons; and
• Establish consensus on clinical significance of endpoints to determine a weighted score for each patient.