Study casts doubt on Ticagrelor's superiority over Clopidogrel in real-world scenario.

Ticagrelor had established itself as the go-to P2Y12 inhibitor for the treatment of acute coronary syndromes (ACS) based on the results of the PLATO trial, which showed that it reduced ischemic events without increasing major bleeding compared with clopidogrel. But the results in a real-world scenario (in contrast to the stringently selected population in trials) may yield different results. According to a study published in JAHA and conducted in a real-world ACS population, Ticagrelor doesn't lessen risks of MI or death and may increase bleeding relative to clopidogrel.

Major bleeding after acute coronary syndrome predicts a poor outcome but is challenging to define. The choice of antiplatelet influences bleeding risk. Following the PLATO trial, ticagrelor has replaced clopidogrel as first‐line therapy for many centers across the world. It should be noted that the median age in the study was 62 years, with only 15% of patients being older than 75, <30% being women and <5% suffering with chronic renal disease. Age, female sex, and renal dysfunction are all factors associated with bleeding that are markedly more prevalent in populations with ACS in clinical practice.

Despite these differences between clinical practice and randomized clinical trials, the major bleeding event rate in PLATO was unusually high for any study of antiplatelets in ACS. For these reasons, it is conceivable that the net clinical benefit of ticagrelor compared with clopidogrel seen in PLATO may be less marked in real world populations.

To explore PLATO's real-world applicability, the investigators examined data on 5,116 patients (median age 68 years; 34% women) treated between 2011 and 2015, a span during which ticagrelor displaced clopidogrel as the P2Y12 inhibitor of choice. Overall, nearly half of patients were medically treated, with 39% undergoing PCI and 13% CABG.

In the overall cohort, there were no differences between the ticagrelor and clopidogrel groups in BARC type 3 to 5 bleeding or PLATO major bleeding. After excluding patients who underwent CABG, though, ticagrelor was associated with significantly higher rates of both BARC type 3 to 5 bleeding and PLATO major bleeding.

There were no signs that ticagrelor resulted in lower rates of adverse clinical outcomes, including MI, stroke, and all-cause mortality. The unadjusted rate of confirmed type 1 or 2 MI was 3.8% in the ticagrelor group and 3.7% in the clopidogrel group (adjusted HR 1.20; 95% CI 0.87-1.64). The lack of a significant difference was consistent in revascularized and medically treated patients, although there was a nonsignificant trend suggesting a greater risk in the ticagrelor group.

"Everything in terms of the trends for bleeding favors ticagrelor, yet the results still bear out that especially in the medically treated population, ticagrelor was associated with significantly more bleeding and there was no hint of a reduction in MI," Senior author Aleem Khand said.

Michael Savage, MD (Thomas Jefferson University Hospital, Philadelphia), however, provided a more-cautious interpretation of the data, pointing out that the study was retrospective and included a patient population smaller than the PLATO population.

Khand stressed, however, that "we're not saying that there is no place for the potent antiplatelets. I think there is. . . . But to give everyone this is probably unwise, and I think you'll see a shift in practice [away from a strategy of] universal potent antiplatelets for all to one that is a bit more nuanced to the bleeding-thrombotic balance."

Although there are many limitations to these results but a strong take-home message is that the risk-benefit ratio in patients in medically treated acute coronary syndrome does not favor potent antiplatelets and should influence treatment decisions.

Source: Mullen L, Meah MN, Elamin A, et al. Risk of major bleeding with potent antiplatelet agents after an acute coronary event: a comparison of ticagrelor and clopidogrel in 5116 consecutive patients in clinical practice. J Am Heart Assoc. 2021;10:e019467.