The antiplatelet of choice for long-term, secondary prevention for patients with established coronary artery disease (CAD) may well be a P2Y12 inhibitor such as clopidogrel or ticagrelor rather than aspirin, suggests a patient-level meta-analysis of seven randomized trials.
The more than 24,000 patients in the meta-analysis, called PANTHER, had documented stable CAD, prior myocardial infarction (MI), or recent or remote surgical or percutaneous coronary revascularization.
About half of patients in each antiplatelet monotherapy trial received clopidogrel or ticagrelor, and the other half received aspirin. Follow-ups ranged from 6 months to 3 years.
Those taking a P2Y12 inhibitor showed a 12% reduction in risk (P = .012) for the primary efficacy outcome, a composite of cardiovascular (CV) death, MI, and stroke, over a median of about 1.35 years. The difference was driven primarily by a 23% reduction in risk for MI (P < .001); mortality seemed unaffected by antiplatelet treatment assignment.
Although the P2Y12 inhibitor and aspirin groups were similar with respect to risk of major bleeding, the P2Y12 inhibitor group showed significant reductions in risk for gastrointestinal (GI) bleeding, definite stent thrombosis, and hemorrhagic stroke; rates of hemorrhagic stroke were well under 1% in both groups.
The treatment effects were consistent across patient subgroups, including whether the aspirin comparison was with clopidogrel or ticagrelor.
“Taken together, our data challenge the central role of aspirin in secondary prevention and support a paradigm shift toward P2Y12 inhibitor monotherapy as long-term antiplatelet strategy in the sizeable population of patients with coronary atherosclerosis,” Felice Gragnano, MD, PhD, told theheart.org | Medscape Cardiology. “Given [their] superior efficacy and similar overall safety, P2Y12 inhibitors may be preferred [over] aspirin for the prevention of cardiovascular events in patients with CAD.”
Gragnano, of the University of Campania Luigi Vanvitelli, Caserta, Italy, who called PANTHER “the largest and most comprehensive synthesis of individual patient data from randomized trials comparing P2Y12 inhibitor monotherapy with aspirin monotherapy,” is lead author of the study, which was published online July 3 in the Journal of the American College of Cardiology.
Current guidelines recommend aspirin for antiplatelet monotherapy for patients with established CAD, Gragnano said, but “the primacy of aspirin in secondary prevention is based on historical trials conducted in the 1970s and 1980s and may not apply to contemporary practice.”
Moreover, later trials that compared P2Y12 inhibitors with aspirin for secondary prevention produced “inconsistent results,” possibly owing to their heterogeneous populations of patients with coronary, cerebrovascular, or peripheral vascular disease, he said. Study-level meta-analyses in this area “provide inconclusive evidence” because they haven’t evaluated treatment effects exclusively in patients with established CAD.
Most of the seven trials’ 24,325 participants had a history of MI, and some had peripheral artery disease (PAD); the rates were 56.2% and 9.1%, respectively. Coronary revascularization, either percutaneous or surgical, had been performed for about 70%. Most (61%) had presented with acute coronary syndromes, and the remainder had presented with chronic CAD.
About 76% of the combined cohorts were from Europe or North America; the rest were from Asia. The mean age of the patients was 64 years, and about 22% were women.
In all, 12,175 had been assigned to P2Y12 inhibitor monotherapy (62% received clopidogrelm and 38% received ticagrelor); 12,147 received aspirin at dosages ranging from 75 mg to 325 mg daily.
The hazard ratio (HR) for the primary efficacy outcome, P2Y12 inhibitors vs aspirin, was significantly reduced, at 0.88 (95% CI, 0.79 – 0.97; P = .012); the number needed to treat (NNT) to prevent one primary event over 2 years was 121, the report states.
The corresponding HR for MI was 0.77 (95% CI, 0.66 – 0.90; P < .001), for an NNT benefit of 136. For net adverse clinical events, the HR was 0.89 (95% CI, 0.81 – 0.98; P = .020), for an NNT benefit of 121.
Risk for major bleeding was not significantly different (HR, 0.87; 95% CI, 0.70 – 1.09; P = .23), nor were risks for stroke (HR, 0.84; 95% CI, 0.70 – 1.02; P = .076) or cardiovascular death (HR, 1.02; 95% CI, 0.86 – 1.20; P = .82).
Still, the P2Y12 inhibitor group showed significant risk reductions for the following:
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GI bleeding: HR, 0.75 (95% CI, 0.57 – 0.97; P = .027)
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Definite stent thrombosis: HR, 0.42 (95% CI, 0.19 – 0.97; P = .028)
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Hemorrhagic stroke: HR, 0.43 (95% CI, 0.23 – 0.83; P = .012)
The current findings are “hypothesis-generating but not definitive,” Dharam Kumbhani, MD, University of Texas Southwestern, Dallas, told theheart.org | Medscape Cardiology.
It remains unclear “whether aspirin or P2Y12 inhibitor monotherapy is better for long-term maintenance use among patients with established CAD. Aspirin has historically been the agent of choice for this indication,” said Kumbhani, who with James A. de Lemos, MD, of the same institution, wrote an editorial accompanying the PANTHER report.
“It certainly would be appropriate to consider P2Y12 monotherapy preferentially for patients with prior or currently at high risk for GI or intracranial bleeding, for instance,” Kumbhani said. For the remainder, aspirin and P2Y12 inhibitors are both “reasonable alternatives.”
In their editorial, Kumbhani and de Lemos call the PANTHER meta-analysis “a well-done study with potentially important clinical implications.” The findings “make biological sense: P2Y12 inhibitors are more potent antiplatelet agents than aspirin and have less effect on gastrointestinal mucosal integrity.”
But for now, they write, “both aspirin and P2Y12 inhibitors remain viable alternatives for prevention of atherothrombotic events among patients with established CAD.”
Gragnano had no disclosures; potential conflicts for the other authors are in the report. Kumbhani reports no relevant relationships; de Lemos has received honoraria for participation in data safety monitoring boards from Eli Lilly, Novo Nordisk, AstraZeneca, and Janssen.
J Am Coll Cardiol. Published online July 3, 2023. Abstract, Editorial
Batya Swift Yasgur, MA, LSW, is a freelance writer with a counseling practice in Teaneck, New Jersey. She is a regular contributor to numerous medical publications, including Medscape and WebMD, and is the author of several consumer-oriented health books as well as Behind the Burqa: Our Lives in Afghanistan and How We Escaped to Freedom (the memoir of two brave Afghan sisters who told her their story).
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