Comparing P2Y12 inhibitors in NSTE-ACS patients ≥70 years

Clopidogrel versus ticagrelor or prasugrel in patients aged 70 years or older with non-ST-elevation acute coronary syndrome (POPular AGE): the randomised, open-label, non-inferiority trial

Literature - Gimbel M, Qaderdan K, Willemsen L et al. - The Lancet 2020, 395: 1374–81, doi.org/10.1016/S0140-6736(20)30325-1

Introduction and methods

Results of TRITON-TIMI 38 [1] and PLATO [2] trials are the basis of current guidelines, recommending stronger P2Y12 inhibitors –ticagrelor and prasugrel- over clopidogrel in ACS patients who have no increased risk of bleeding. With increasing age, risk of bleeding and thrombotic complications increases, which makes it more difficult to chose optimal antithrombotic therapy [3,4]. In the TRITON-TIMI 38 trial, prasugrel did not result in a net clinical benefit in a subgroup of patients ≥75 years due to increased bleeding. More ticagrelor-associated bleeding was observed in the PLATO trial compared to clopidogrel-associated bleeding, especially in older patients [5]. These data suggest that treatment with stronger P2Y12 inhibitors in older patients is controversial.

Therefore, the POPular AGE trial investigated the optimal P2Y12 inhibitor in older patients with NSTE-ACS by evaluating safety and efficacy of clopidgrel compared with ticagrelor and prasugrel in patients ≥70 years. It was an open-label, randomized, clinical trial performed at 12 sites in the Netherlands. Eligible patients were randomized in a 1:1 ratio to receive clopidogrel, or ticagrelor or prasugrel on top of standard care. Between June 10, 2013 and Oct 17, 2018, 1002 patients were randomized. Median age was 77 years, 64% were male. Of patients randomized to ticagrelor or prasugrel, 95% were prescribed ticagrelor, and therefore referred to as ticagrelor group. The first co-primary outcome was PLATO major or minor bleeding (any bleeding requiring medical intervention). Secondary co-primary outcome was net clinical benefit, consisting of all-cause death, myocardial infarction, stroke and PLATO major and minor bleeding. Follow-up was 1 year.

Main results

PLATO major or minor bleeding occurred less often in the clopidogrel group than in the ticagrelor group (18% vs. 24%, HR 0.71, 95%CI:0.54-0.94, P=0.02 for superiority)
There was no difference in net clinical benefit outcome between those taking clopidgrel compared to the ticagrelor group (28% vs. 32%, absolute risk difference -4%, 95%CI: -10.0 to 1.4, P=0.03 for non-inferiority, and HR 0.82, 95%CI: 0.66-1.03, P=0.11).
Secondary outcomes of PLATO non-CAGB-related major bleeding and fatal bleeding were significantly lower in the clopidogrel group than in the ticagrelor group.
No significant differences were observed in thrombotic outcome, a composite of CV death, MI and stroke, or other secondary thrombotic outcomes, except for definite stent thrombosis, which occurred more frequently in those taking clopidogrel.
Discontinuation or switching of study drug occurred in 47% of patients in the ticagrelor group, compared to 22% in the clopidogrel group. Most important reasons for discontinuation or switching of ticagrelor were dyspnea, concomitant use of NOACs, and bleeding. For discontinuation or switching of clopidogrel, most important reasons were revision of diagnosis, bleeding and CABG.

Conclusion

Patients ≥70 years with NSTE-ACS who were randomized to clopidogrel had less bleeding without an increase in a composite of all-cause death, MI, stroke and bleeding, compared to those randomized to ticagrelor or prasugrel. These data suggest that clopidogrel could be considered in elderly patients with a higher bleeding risk.

References

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