Reduces bleeding risk compared to stronger P2Y12 inhibitors

It appears a “less is more” approach may be the best way to treat elderly patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS).

Dutch researchers found that it may be more appropriate to treat older patients (70 years or older) with the P2Y12 inhibitor clopidogrel rather than the more potent P2Y12 inhibitors ticagrelor and prasugrel because it reduces the risk of bleeding without increasing thrombotic events.

The study, by Marieke Gimbel, MD, Department of Cardiology, St Antonius Hospital, Nieuwegein, Netherlands, and colleagues was published in the Lancet.

According to Gimbel and colleagues, current guidelines recommend the use of potent P2Y12 inhibitors ticagrelor or prasugrel with aspirin, as opposed to the less potent clopidogrel, for patients with ACS, unless there is an excessive risk of bleeding. Those recommendations are based on the TRITON-TIMI 38 and PLATO trials, both of which showed that prasugrel and ticagrelor were superior to clopidogrel in reducing cardiovascular death, myocardial infarction, and stroke.

However, the authors pointed out, the data are unclear concerning optimal platelet inhibition in older patients who higher risks of bleeding and thrombotic events. Therefore, in the open-label, randomized controlled POPular AGE trial, their objective was to investigate clopidogrel versus ticagrelor or prasugrel in patients aged 70 years or older with a NSTE-ACS.

POPular AGE was conducted at 12 sites (10 hospitals and 2 university hospitals) in the Netherlands. Between June 10, 2013, and Oct. 17, 2018, 1002 patients were randomly assigned to received either clopidogrel (500) or ticagrelor or prasugrel (502).

Patients assigned to clopidogrel received a loading dose of either 300 mg or 600 mg followed by a maintenance dose of 75 mg once daily for 12 months on top of standard care. Patients assigned to ticagrelor received a loading dose of 180 mg and then a maintenance dose of 90 mg twice daily, while those assigned to prasugrel received a loading dose of 60 mg followed by a maintenance dose of 10 mg once daily, on top of standard care.

Gimbel and colleagues noted that prasugrel is not recommended in patients 75 years or older and was not prescribed to patients who had a stroke or transient ischemic attack. Therefore, if those patients were randomly assigned to receive ticagrelor or prasugrel, they could only receive ticagrelor. Consequently, 475 of the 502 patients assigned to the ticagrelor or prasugrel group ended up receiving ticagrelor, so the researchers referred to this group as the ticagrelor group.

The trial had two primary outcomes. The first was any major or minor bleeding requiring medical intervention, while the second was a combined endpoint of all-cause death, myocardial infarction, stroke, and major or minor bleeding.

Of the 502 patients in the ticagrelor group, 47% prematurely discontinued the study drug, compared to 22% of the 500 patients in the clopidogrel group. The most important reasons for discontinuation or switching of ticagrelor were dyspnea, concomitant use of nonvitamin K oral anticoagulants, and bleeding, while the most important reasons for discontinuation or switching of clopidogrel were revision of diagnosis, bleeding, and undergoing coronary artery bypass grafting.

The primary bleeding outcome was significantly lower in the clopidogrel group (18%) than in the ticagrelor group (24%), hazard ratio 0.71, 95% CI 0.54 to 0.94. In addition, there were 5 fatal bleedings in the ticagrelor group, while there were none in the clopidogrel group.

The composite clinical benefit outcome occurred in 28% of patients in the clopidogrel group compared to 32% in the ticagrelor group (absolute risk difference −4%, 95% CI −10.0 to 1.4).

“These results need confirmation from future trials to change guidelines regarding antiplatelet therapy in older patients,” wrote Gimbel and colleagues. “In the meantime, for older patients especially at an increased risk of bleeding, clopidogrel can be used as first choice therapy.”

In a commentary accompanying the study, Peter R. Sinnaeve, MD, PhD, University Hospitals Leuven, Leuven, Belgium, and Sofie A. Gevaert, MD, PhD, Ghent University Hospital, Ghent, Belgium, wrote that while the authors of POPular AGE should be congratulated for bringing such an important study to a successful conclusion, it does not end the discussion about what dual antiplatelet therapy is optimal for aging patients, “because there are several other options that still need to be considered and, ideally, explored in clinical trials on older patients.”

For example, given the safety of current drug-eluding stents, they suggested that dual antiplatelet treatment of short duration of any P2Y12 inhibitor might be appropriate in any frail or elderly patient. Or, another option could be guided therapy or the planned de-escalation to clopidogrel after a short period or treatment with ticagrelor or prasugrel.

  1. The P2Y12 inhibitor clopidogrel may be a better option for treating older patients with non-ST-elevation acute coronary syndrome than the more potent P2Y12 inhibitors ticagrelor and prasugrel.

  2. Clopidogrel reduces the risk of bleeding without increasing thrombotic events in those patients.

Michael Bassett, Contributing Writer, BreakingMED™

Gimbel reports grants from the Netherlands Organization for Health Research and Development, a Dutch government institution called ZonMw, during the conduct of the study.

Sinnaeve reports grants, institutional fees, and non-financial support from AstraZeneca and Daiichi Sankyo.

Gevaert reports consultancy and speaker’s fees from AstraZeneca, outside the area of work commented on here.

Cat ID: 102

Topic ID: 74,102,282,494,730,102,308,192,255,925