Prasugrel monotherapy from the start of primary PCI does not meet noninferiority — aspirin stays

Design

multicentre, open-label, randomised noninferiority trial in Japan (PREMIUM)

Population

2,216 patients with STEMI undergoing primary PCI, randomised before the procedure

Primary outcome

composite of death from any cause, stroke or myocardial infarction at 12 months

Effect

11.0% with prasugrel monotherapy vs 8.5% with dual antiplatelet therapy (HR 1.34; 95% CI 1.02-1.75), noninferiority not met; major bleeding 5.6% vs 8.4% (HR 0.66; 95% CI 0.47-0.91)

An open-label randomised trial across Japanese centres assigned 2,216 patients with STEMI, before primary PCI, either to low-dose prasugrel alone or to prasugrel plus aspirin for 12 months. The primary composite of death from any cause, stroke or myocardial infarction at 12 months occurred in 11.0% of the monotherapy group and 8.5% of the dual therapy group. Noninferiority was not established.

The result matters because the direction of travel in antiplatelet research has been towards shorter and lighter regimens, and several trials have supported dropping aspirin after an initial period. This trial asked the more aggressive question — omit it from the outset, at the moment of highest thrombotic risk — and the answer was no.

The bleeding signal is real and should not be dismissed: major bleeding was less frequent on monotherapy, 5.6% versus 8.4%. But the trade being offered here is bleeding reduction against an ischaemic point estimate that favours dual therapy, in a composite that includes death. That is not a trade most clinicians will take at the time of primary PCI.

Where aspirin-free strategies still have an evidence base is later — de-escalation after a defined period of dual therapy, in patients selected for bleeding risk. Nothing here undermines that. What it removes is the option of starting without aspirin.

• Give aspirin with the P2Y12 inhibitor at primary PCI; do not start with a single agent on bleeding grounds
• Reserve aspirin-free strategies for planned de-escalation after an initial dual-therapy period
• Document bleeding risk at admission so the later de-escalation decision is made on recorded grounds, not recollection
• Note that this trial used prasugrel; it does not test ticagrelor or clopidogrel monotherapy from the outset
• Review the discharge prescription against what the patient can actually sustain for 12 months

The statistics, in plain English

Noninferiority was prespecified as the upper bound of the 95% confidence interval for the hazard ratio staying below 1.50. The observed hazard ratio was 1.34 with an interval of 1.02 to 1.75, so the upper bound crossed the margin and the test failed. Note what the lower bound of 1.02 also implies: the interval sits almost entirely above 1.0, so this is not merely a failure to prove equivalence — the data lean towards monotherapy being worse for the ischaemic composite. The bleeding result, HR 0.66 with an interval of 0.47 to 0.91, is a genuine reduction, but it was a secondary outcome that by the trial's own hierarchy was only to be tested for superiority if noninferiority had first been established.

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