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2022;7:407–417.)[10]
10. Not every shortened strategy produces superiority: GLOBAL LEADERS tested one month of DAPT followed by 23 months of ticagrelor monotherapy but did not significantly reduce two-year death or new Q-wave myocardial infarction compared with conventional therapy—3.8% versus 4.4% (). It nevertheless helped establish the feasibility of aspirin withdrawal after an initial protected period. (Vranckx P, Valgimigli M, Jüni P, et al. Lancet. 2018;392:940–949.)[11][12][13]
The central message is not that aspirin must be administered indefinitely, nor that an aspirin-free strategy is intrinsically unsafe. Rather, timing appears to determine whether aspirin withdrawal is beneficial or hazardous:
• At primary PCI or day zero: PREMIUM and STOPDAPT-3 raise ischemic concerns.
• After one month without adverse events: ULTIMATE-DAPT supports ticagrelor monotherapy.
• After three event-free months: TWILIGHT and TICO provide the most consistent bleeding benefit without apparent ischemic penalty.
• With clopidogrel in ACS: STOPDAPT-2 ACS advises caution.
Thus, aspirin may function as a temporary “bridge” across the intensely thrombogenic early phase of STEMI rather than as an obligatory lifelong partner. The emerging strategy is not “no aspirin,” but aspirin first, then timely and individualized withdrawal—earlier in patients dominated by bleeding risk and later in those with large thrombus burden, complex PCI, residual disease, diabetes, renal dysfunction, or recurrent ischemia.
The collective evidence suggests that P2Y12-inhibitor monotherapy can reduce bleeding after PCI, but the timing of aspirin withdrawal is crucial. PREMIUM indicates that removing aspirin immediately during primary PCI for STEMI may be a step too early.
Ten-point summary
1. PREMIUM addressed the earliest withdrawal strategy: In 2,280 STEMI patients undergoing contemporary primary PCI, prasugrel monotherapy initiated without aspirin was compared with 12-month aspirin plus prasugrel therapy. This was the first adequately powered randomized trial specifically evaluating aspirin omission from the time of primary PCI. (Nakazawa G, et al. New England Journal of Medicine. 2026; doi:10.1056/NEJMoa2606997.)[1]
2. Immediate aspirin omission failed noninferiority: At 12 months, the composite of all-cause death, myocardial infarction, or stroke occurred in 11.0% with prasugrel monotherapy versus 8.5% with DAPT (HR 1.34; 95% CI 1.02–1.75). Thus, the upper confidence limit could not exclude clinically meaningful ischemic harm. (Nakazawa G, et al. New England Journal of Medicine. 2026; doi:10.1056/NEJMoa2606997.)[2][1]
3. Bleeding improved, but at a potential ischemic cost: BARC type 3 or 5 bleeding occurred in 5.6% with prasugrel monotherapy versus 8.4% with DAPT (HR 0.66; 95% CI 0.47–0.91). However, because the primary noninferiority endpoint was not met, the bleeding reduction cannot establish overall clinical superiority. (Nakazawa G, et al. New England Journal of Medicine. 2026; doi:10.1056/NEJMoa2606997.)[2]
4. STOPDAPT-3 provided an earlier warning: Among ACS or high-bleeding-risk patients undergoing PCI, immediate low-dose prasugrel monotherapy did not significantly reduce 30-day major bleeding compared with aspirin plus prasugrel—4.47% versus 4.71%. Although cardiovascular noninferiority was demonstrated, subacute stent thrombosis was higher without aspirin: 0.58% versus 0.17% (HR 3.40). (Natsuaki M, Watanabe H, Morimoto T, et al. Circulation. 2024;149:585–600.)[3][4][5]
5. STOP-IMH offered reassuring but underpowered evidence: In this pilot trial of 200 STEMI patients, immediate ticagrelor monotherapy produced similar 13-month MACCE to ticagrelor plus aspirin—4.1% versus 4.0%. Clinically relevant non-access-site bleeding was lower, 2.0% versus 9.9%, but the study was far too small to establish ischemic safety. (Yosofi B, Woelders ECI, Peeters DAM, et al. EuroIntervention. 2026; doi:10.4244/EIJ-D-26-00421.)[6]
6. One month of DAPT appears substantially safer than zero DAPT: In ULTIMATE-DAPT, 3,400 event-free ACS patients stopped aspirin one month after PCI. Ticagrelor monotherapy reduced BARC 2, 3, or 5 bleeding from 4.6% to 2.1% while maintaining similar MACCE rates—3.6% versus 3.7%. (Ge Z, Kan J, Gao X, et al. Lancet. 2024;403:1866–1878.)[7]
7. Three-month withdrawal has the strongest supporting evidence: TWILIGHT randomized 7,119 high-risk, event-free PCI patients after three months of DAPT. Ticagrelor monotherapy reduced BARC 2, 3, or 5 bleeding from 7.1% to 4.0%, while death, myocardial infarction, or stroke remained 3.9% in both groups. Importantly, patients presenting with STEMI were excluded, limiting direct extrapolation to primary PCI. (Mehran R, Baber U, Sharma SK, et al. New England Journal of Medicine. 2019;381:2032–2042.)[8]
8. TICO extended the evidence to ACS and STEMI: Among 3,056 ACS patients, including 36% with STEMI, ticagrelor monotherapy after three months of DAPT reduced net adverse clinical events from 5.9% to 3.9% and major bleeding from 3.0% to 1.7%, without a significant increase in ischemic events. (Kim BK, Hong SJ, Cho YH, et al. JAMA. 2020;323:2407–2416.)[9]
9. The choice of P2Y12 inhibitor matters: In STOPDAPT-2 ACS, clopidogrel monotherapy after one to two months of DAPT failed noninferiority versus 12-month DAPT—primary events were 3.2% versus 2.8%. Bleeding decreased, but myocardial infarction increased from 0.9% to 1.6%, suggesting that clopidogrel may not provide adequate early protection in unselected ACS patients. (Watanabe H, Morimoto T, Natsuaki M, et al. JAMA Cardiology.
