NEO-MINDSET: Early withdrawal of aspirin after percutaneous coronary intervention for acute coronary syndrome
Reported from ESC Congress 2025
Daniele Giacoppo reports and provides his perspective on the main results of the ambitious NEOMINDSET trial, presented by Pedro Lemos from the Hospital Israelita Albert Einstein, São Paulo, Brazil, during a Late Breaking Trials session at the ESC Congress 2025 in Madrid, and simultaneously published in the New England Journal of Medicine.
Why this study? – The rationale
Current clinical guidelines recommend that patients with an acute coronary syndrome (ACS), irrespective of whether they undergo myocardial revascularization, should receive 12 months of dual antiplatelet therapy (DAPT), with acetylsalicylic acid and a P2Y12 inhibitor, preferably prasugrel or ticagrelor, unless individual conditions indicate an increased risk of bleeding or, conversely, an individual risk of ischemic events that outweighs the risk of bleeding, thereby requiring personalized DAPT durations.1
Over the past 15 years, at least 20 randomized clinical trials, including variable proportions or only patients with ACS requiring percutaneous coronary intervention (PCI), have almost consistently shown that reduced DAPT durations are not associated with increased rates of ischaemic events.2 Of note, in some of these trials, major bleeding was significantly reduced in patients assigned to short DAPT durations compared with standard DAPT.2 The assessment of DAPT in randomized trials has progressively involved shorter durations, with the most recent investigations comparing only 1-to-3 months of DAPT, generally followed by P2Y12 inhibitor monotherapy, with standard 12-month DAPT.3
Against this background and in light of the substantial advance in stent technology and procedural optimization, it has been hypothesized that in patients admitted for ACS who were successfully revascularized by PCI without significant residual coronary artery disease, discontinuing aspirin at discharge and continuing potent P2Y12 inhibitor monotherapy may be as safe and effective as standard prolonged DAPT. Preliminary evidence from small, low-ischemic risk cohorts of patients with chronic coronary syndrome has indicated that this minimalistic approach may be a valid option, offering potentially maximal bleeding reduction without increased ischemic harm.4
The NEO-MINDSET trial was designed to address the question of whether initiating monotherapy with a potent P2Y12 inhibitor before discharge in patients who underwent successful PCI for ACS is noninferior to standard 12-month DAPT with a potent P2Y12 inhibitor.5
How was it executed? – The methodology
NEO-MINDSET was an investigator-initiated, open-label, assessor-blinded, randomized trial conducted at 50 Brazilian sites. Patients undergoing physician-defined successful PCI with implantation of at least one drug-eluting stent for the treatment of ACS were randomly assigned within the first 4 days of hospitalization to either potent P2Y12 inhibitor monotherapy or standard DAPT with a potent P2Y12 inhibitor. All patients included in the trial received guideline-recommended DAPT from the index PCI and randomization. Patients assigned to P2Y12 monotherapy stopped treatment with aspirin and continued P2Y12 inhibitor monotherapy with prasugrel or ticagrelor, or switched from clopidogrel to a potent P2Y12 inhibitor depending on prior therapy. Patients assigned to DAPT continued treatment with aspirin and a P2Y12 inhibitor. If a potent P2Y12 inhibitor was not already in use in the context of DAPT, clopidogrel was switched to prasugrel or ticagrelor. Both P2Y12 inhibitor monotherapy and DAPT regimens were maintained for 12 months.
The two ranked primary outcomes were a composite of all-cause death, myocardial infarction, stroke, or urgent target-vessel revascularization and a composite of major or clinically relevant nonmajor bleeding defined by the Bleeding Academic Research Consortium (BARC) classification (BARC events type 2, 3, or 5).
Regarding the composite outcome of ischaemic events, a sample size of 3,400 patients was estimated to provide 80% power to demonstrate noninferiority of potent P2Y12 inhibitor monotherapy to DAPT at a one-sided α of 0.025, assuming a 12-month rate of 7.0% in the DAPT group and 9.5% in the potent P2Y12 inhibitor monotherapy group (margin of noninferiority of 2.5%). If noninferiority was established, superiority testing for the co-primary composite bleeding endpoint was prespecified using fixed-sequence hierarchical testing to preserve α. The sample size of 3400 patients was estimated to provide 88% power to demonstrate superiority at a two-sided alpha level of 0.025, assuming a 12-month rate of 8.0% in the DAPT group and 5.0% in the potent P2Y12 inhibitor group.
What is the main result?
A total of 3,413 patients underwent 1:1 randomization from October 2020 through October 2023. After exclusion of randomization errors and informed consent withdrawals, 1,712 patients were assigned to potent P2Y12 inhibitor monotherapy and 1,698 to DAPT. The mean age was 59.6 years, 29% were female, 68.5% were white, 27.4% had diabetes, 9.8% had a prior myocardial infarction, and 19.8% were at high bleeding risk according to the BARC risk score. ST-segment elevation myocardial infarction (STEMI) was the main variant (62.1%) of ACS, followed by non-ST-segment myocardial infarction (NSTEMI) (30.5%), and unstable angina (7.4%). Multivessel coronary artery disease was observed in 43.9% and the left anterior descending was the most frequently involved vessel (59.1%). Median time from admission to PCI was 1.0 day and median time from admission to randomization was 2.0 days. A mean of 1.6 stents per patient were implanted for a mean total stent length of 39.1 mm per patient. Intravascular imaging was used in only 1.5%. The predominant type of P2Y12 inhibitor given before randomization was clopidogrel (84.6%). After randomization, prasugrel was administered in 69.3%. Staged PCI was performed in 9.2%.
At 12 months, the primary composite endpoint of all-cause death, myocardial infarction, stroke, or urgent target vessel revascularization occurred in 119 patients (7.0%) in the potent P2Y12 monotherapy group and in 93 patients (5.5%) in the DAPT group (hazard ratio [HR] 1.28, 95% confidence interval [CI] 0.98 to 1.68), leading to an absolute risk difference (ARD) of 1.47% (95% CI from -0.16% to 3.10%). This difference did not meet the criterion for noninferiority as the upper limit of the 95% CI exceeded the noninferiority margin of 2.5% (Pnoninferiority=0.11). Although missing the primary noninferiority in the context of a fixed-sequence hierarchical design precluded formal superiority testing for the co-primary composite endpoint of major or clinically nonmajor bleeding, the difference between the two treatment groups without adjustment for multiplicity resulted in a significant reduction in BARC 2, 3, or 5 events associated with potent P2Y12 inhibitor monotherapy compared with DAPT (2.0% vs 4.9%; ARD of -2.97%, 95% CI -4.20% to -1.73%; HR 0.40, 95% CI 0.26 to 0.59).
The assessment of individual secondary endpoints, including all-cause death, cardiovascular death, myocardial infarction, stroke, definite or probable stent thrombosis, and urgent target vessel revascularization, did not reveal significant differences between treatment groups, except for invasive coronary interventions which occurred more frequently in patients assigned to P2Y12 monotherapy than in those assigned to DAPT (2.6% vs 1.6%; HR 1.65, 95% CI 1.01 to 2.69). Both BARC 2 (2.7% vs 4.6%; HR 0.58, 95% CI 0.40 to 0.84) and 3 (0.7% vs 2.0%; HR 0.33, 95% CI 0.17 to 0.65) were significantly lower in patients assigned to potent P2Y12 inhibitor monotherapy compared with those assigned to DAPT. A net composite endpoint of adverse clinical events combining both ischemic and bleeding outcomes did not reveal significant differences between treatment groups. The results were consistent across major clinical subgroups.
Critical reading and its relevance for clinical practice
The pivotal NEO-MINDSET investigated the effects of immediate postprocedural aspirin withdrawal in patients on DAPT who underwent PCI with drug-eluting stents for ACS.5 The main result was that potent P2Y12 inhibitor monotherapy failed to demonstrate noninferiority to DAPT, with early separation of the Kaplan-Meier curves driven by an excess of events shortly after PCI and potent P2Y12 inhibitor monotherapy initiation.5
Although the authors emphasized that no statistically significant differences in ischaemic endpoints were observed, it should be acknowledged that the trial was underpowered to assess superiority for individual outcomes, event rates were lower than expected, and there was a consistent numerical increase of events across all individual ischaemic endpoints in patients assigned to potent P2Y12 inhibitor monotherapy. In more detail, P2Y12 monotherapy compared with DAPT was associated at 1 year with ARDs of +0.5% for cardiovascular death, +0.6% for myocardial infarction, +0.3% for stroke, +0.6% for urgent target vessel revascularization, and +0.5% in definite or probable stent thrombosis.5 The combination of first events occurring in different patients produced larger between-group differences in the primary composite endpoint of ischemic events.
Previously, the STOPDAPT-3 trial tested early aspirin withdrawal following PCI compared with DAPT in 6002 Japanese patients.6 Despite some important differences between the study design of NEO-MINDSET and that of STOPDAPT-3, it should be recognized that in the STOPDAPT-3 trial P2Y12 monotherapy failed to attest superiority over DAPT for the primary endpoint of 30-day major bleeding. In the same trial, although the co-primary composite endpoint of ischemic events was not significantly different between treatment groups, patients assigned to P2Y12 inhibitor monotherapy showed higher rates of unplanned coronary revascularization and definite or probable stent thrombosis at 30 days compared with those assigned to DAPT.
In contrast, randomized trials comparing 1 month of DAPT followed by P2Y12 inhibitor monotherapy, such as GLOBAL-LEADERS, STOPDAPT-2, T-PASS, and TARGET-FIRST, have generally not shown signals of harm associated with reduced DAPT. These conclusions, coupled with the consistent direction of treatment effects across ischemic endpoints in NEO-MINDSET and the signals of harm associated with early aspirin withdrawal in the STOPDAPT-3 trial, may indicate that immediate postprocedural P2Y12 inhibitor monotherapy is less safe than at least 1 month of DAPT. In addition, while reductions in major bleeding despite numerically increased ischaemic events may be appealing in patients at high bleeding risk, this trade-off appears less favourable in patients without high bleeding risk. In this regard, only one-fifth of patients in the NEO-MINDSET trial were classified as high bleeding risk. Ongoing trials, such as LEGACY (NCT05125276), will likely shed light on unaddressed questions.11
References
- Byrne RA, Rossello X, Coughlan JJ, et al. ESC Guidelines for the management of acute coronary syndromes. Eur Heart J 2023;44:3720-3826.
- Valgimigli M, Landi A, Angiolillo DJ, et al. Demystifying the Contemporary Role of 12-Month Dual Antiplatelet Therapy After Acute Coronary Syndrome. Circulation 2024;150:317-335.
- Giacoppo D, Matsuda Y, Fovino LN, et al. Short dual antiplatelet therapy followed by P2Y12 inhibitor monotherapy vs. prolonged dual antiplatelet therapy after percutaneous coronary intervention with second-generation drug-eluting stents: a systematic review and meta-analysis of randomized clinical trials. Eur Heart J 2021;42:308-319.
- Kogame N, Guimarães PO, Modolo R, et al. Aspirin-Free Prasugrel Monotherapy Following Coronary Artery Stenting in Patients With Stable CAD: The ASET Pilot Study. JACC Cardiovasc Interv 2020;13:2251-2262.
- Guimarães PO, Franken M, Tavares CAM, et al. Early Withdrawal of Aspirin after PCI in Acute Coronary Syndromes. N Engl J Med 2025, 31st August (Ahead of Print).
- Watanabe H, Natsuaki M, Morimoto T, et al. Aspirin vs. clopidogrel monotherapy after percutaneous coronary intervention: 1-year follow-up of the STOPDAPT-3 trial. Eur Heart J 2024;45:5042-5054.
- Vranckx P, Valgimigli M, Jüni P, et al. Ticagrelor plus aspirin for 1 month, followed by ticagrelor monotherapy for 23 months vs aspirin plus clopidogrel or ticagrelor for 12 months, followed by aspirin monotherapy for 12 months after implantation of a drug-eluting stent: a multicentre, open-label, randomised superiority trial. Lancet 2018;392:940-949.
- Watanabe H, Domei T, Morimoto T, et al. Effect of 1-Month Dual Antiplatelet Therapy Followed by Clopidogrel vs 12-Month Dual Antiplatelet Therapy on Cardiovascular and Bleeding Events in Patients Receiving PCI: The STOPDAPT-2 Randomized Clinical Trial. JAMA 2019;321:2414-2427.
- Hong SJ, Lee SJ, Suh Y, et al. Stopping Aspirin Within 1 Month After Stenting for Ticagrelor Monotherapy in Acute Coronary Syndrome: The T-PASS Randomized Noninferiority Trial. Circulation 2024;149:562-573.
- Tarantini G, Honton B, Paradies V, et al. Early Discontinuation of Aspirin after PCI in Low-Risk Acute Myocardial Infarction. N Engl J Med 2025, 31st August (Ahead of Print).
- van der Sangen NMR, Küçük T, Sivanesan S, et al. Less bleeding by omitting aspirin in non-ST-segment elevation acute coronary syndrome patients: Rationale and design of the LEGACY study. Am Heart J 2023;265:114-120.
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