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
Key result
Clopidogrel reduced PLATO major or minor bleeding vs ticagrelor (18% vs 24%; HR 0.71; p=0.02) and was noninferior for net clinical benefit (28% vs 32%; p=0.03 for noninferiority) in older NSTE-ACS.
Why the study?
Current guidelines recommend potent platelet inhibition with ticagrelor or prasugrel after acute coronary syndrome, but data on optimal platelet inhibition in older patients are scarce.
Key Points
- This research aims to evaluate the efficacy of clopidogrel compared to ticagrelor and prasugrel in patients aged 70 or older with non-ST-elevation acute coronary syndrome.
- Randomized open-label trial
- Participants aged 70 or older with non-ST-elevation acute coronary syndrome
- Comparison between clopidogrel, ticagrelor, and prasugrel
- Clopidogrel demonstrated non-inferior efficacy compared to ticagrelor and prasugrel
- Event rates were comparable in both treatment groups regarding major cardiovascular events
- No significant difference in bleeding risk among the treatment options
Study Design
Type
RCT (n=1,002)
Blinding
Open-label
Randomization
1:1 ratio using an internet-based randomisation procedure with block sizes of six
Multicenter
Yes
PICO
P
Population
1,002 patients aged 70 years or older with NSTE-ACS, followed for 12 months.
I
Intervention / Comparator
Clopidogrel vs Ticagrelor or prasugrel (Loading dose 300 mg or 600 mg, then maintenance dose 75 mg once daily)
O
Primary Outcome
PLATO major or minor bleeding — HR 0.71 (0.54 to 0.94), p=0.02 for superiority
Main Result
Hazard Ratio: 0.71 (95% CI 0.54–0.94)
Absolute Event Rate: 18% vs 24%
p-value: p=0.02 for superiority
Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“TAILOR-PCI was misinterpreted. It was said to be a negative trial, and that's not correct.”
“An important thing that we address in this review article is the concept that one size does not fit all with regard to our elderly patients. Obviously, the elderly patients who qualify to be enrolled in clinical trials may not be the same as those that we see in real-world clinical practice. Additionally, when we look at the elderly overall as a cohort, there remain a lot of unanswered questions simply because in the vast majority of trials that we conduct, the elderly only represent a subgroup.”
Implication
Clopidogrel non-inferior to ticagrelor/prasugrel in older ACS; extends randomized evidence supporting its use in patients ≥70.
Abstract
BACKGROUND Current guidelines recommend potent platelet inhibition with ticagrelor or prasugrel in patients after an acute coronary syndrome. However, data about optimal platelet inhibition in older patients are scarce. We aimed to investigate the safety and efficacy of clopidogrel compared with ticagrelor or prasugrel in older patients with non-ST-elevation acute coronary syndrome (NSTE-ACS). METHODS We did the open-label, randomised controlled POPular AGE trial in 12 sites (ten hospitals and two university hospitals) in the Netherlands. Patients aged 70 years or older with NSTE-ACS were enrolled and randomly assigned in a 1:1 ratio using an internet-based randomisation procedure with block sizes of six to receive a loading dose of clopidogrel 300 mg or 600 mg, or ticagrelor 180 mg or prasugrel 60 mg, and then a maintenance dose for the duration of 12 months (clopidogrel 75 mg once daily, ticagrelor 90 mg twice daily, or prasugrel 10 mg once daily) on top of standard care. Patient and treating physicians were aware of the allocated treatment strategy, but the outcome assessors were masked to treatment allocation. Primary bleeding outcome consisted of PLATelet inhibition and patient Outcomes (PLATO; major or minor bleeding [superiority hypothesis]). Co-primary net clinical benefit outcome consisted of all-cause death, myocardial infarction, stroke, PLATO major and minor bleeding (non-inferiority hypothesis, margin of 2%). Follow-up duration was 12 months. Analyses were done on intention-to-treat basis. This trial is registered with the Netherlands Trial Register (NL3804), ClinicalTrials.gov (NCT02317198), and EudraCT (2013-001403-37). FINDINGS Between June 10, 2013, and Oct 17, 2018, 1002 patients were randomly assigned to clopidogrel (n=500) or ticagrelor or prasugrel (n=502). Because 475 (95%) patients received ticagrelor in the ticagrelor or prasugrel group, we will refer to this group as the ticagrelor group. Premature discontinuation of the study drug occurred in 238 (47%) of 502 ticagrelor group patients randomly assigned to ticagrelor, and in 112 (22%) of 500 patients randomly assigned to clopidogrel. Primary bleeding outcome was significantly lower in the clopidogrel group (88 [18%] of 500 patients) than in the ticagrelor group (118 [24%] of 502; hazard ratio 0·71, 95% CI 0·54 to 0·94; p=0·02 for superiority). Co-primary net clinical benefit outcome was non-inferior for the use of clopidogrel (139 [28%]) versus ticagrelor (161 [32%]; absolute risk difference -4%, 95% CI -10·0 to 1·4; p=0·03 for non-inferiority). The most important reasons for discontinuation were occurrence of bleeding (n=38), dyspnoea (n=40), and the need for treatment with oral anticoagulation (n=35). INTERPRETATION In patients aged 70 years or older presenting with NSTE-ACS, clopidogrel is a favourable alternative to ticagrelor, because it leads to fewer bleeding events without an increase in the combined endpoint of all-cause death, myocardial infarction, stroke, and bleeding. Clopidogrel could be an alternative P2Y12 inhibitor especially for elderly patients with a higher bleeding risk.
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Cite This Study
Gimbel et al. (2020) conducted an RCT in Non-ST-elevation acute coronary syndrome (NSTE-ACS) (n=1,002). Clopidogrel vs. Ticagrelor or prasugrel was evaluated on PLATO major or minor bleeding (HR 0.71, 95% CI 0.54 to 0.94, p=0.02 for superiority). Clopidogrel reduced PLATO major or minor bleeding vs ticagrelor (18% vs 24%; HR 0.71; p=0.02) and was noninferior for net clinical benefit (28% vs 32%; p=0.03 for noninferiority) in older NSTE-ACS.