Highlights
– Early aspirin withdrawal (within 4 days) after successful PCI for ACS reduced major or clinically relevant nonmajor bleeding versus 12‑month dual antiplatelet therapy (DAPT).
– The trial did not demonstrate noninferiority for a composite ischemic endpoint (death, MI, stroke, or urgent target‑vessel revascularization) at 12 months; the upper bound of the 95% CI exceeded the pre-specified noninferiority margin.
– Stent thrombosis was numerically higher in the P2Y12 monotherapy group (12 vs 4 events), raising safety concerns despite fewer bleeding events.
Background and clinical context
Dual antiplatelet therapy (DAPT) with aspirin plus a P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor) for 12 months has been the standard of care after percutaneous coronary intervention (PCI) in patients with acute coronary syndromes (ACS), balancing prevention of ischemic events against the risk of bleeding. Over the last decade, several randomized trials have explored strategies to shorten aspirin exposure or to adopt P2Y12 inhibitor monotherapy after a period of DAPT, with the aim of reducing bleeding while preserving ischemic protection. Most previous studies tested P2Y12 monotherapy after a short course (usually ≥1–3 months) of DAPT; whether immediate or very early aspirin withdrawal (within days of PCI) is safe in ACS has been uncertain.
Study design — NEO-MINDSET trial (brief)
NEO-MINDSET was a multicenter, open-label, randomized trial performed in Brazil (ClinicalTrials.gov number NCT04360720) that enrolled patients hospitalized for ACS who had undergone successful PCI. Within the first 4 days of hospitalization, eligible patients were randomized 1:1 to one of two antiplatelet strategies:
- P2Y12 inhibitor monotherapy (ticagrelor or prasugrel) with aspirin stopped early, or
- Conventional DAPT (aspirin plus the same potent P2Y12 inhibitor) continued for 12 months.
Two hierarchical primary outcomes were prespecified and assessed at 12 months: (1) a composite ischemic outcome (death from any cause, myocardial infarction [MI], stroke, or urgent target‑vessel revascularization), tested for noninferiority with a noninferiority margin of 2.5 percentage points in absolute risk; and (2) major or clinically relevant nonmajor bleeding, tested for superiority.
Population and interventions
3410 patients were randomized and included in the intention-to-treat analysis: 1712 assigned to early aspirin withdrawal with potent P2Y12 inhibitor monotherapy and 1698 assigned to continued DAPT. The choice of potent P2Y12 inhibitor (ticagrelor or prasugrel) was permitted per investigator discretion. All patients had undergone successful PCI for ACS.
Key results
At 12 months the main outcomes were:
- Composite ischemic outcome (death, MI, stroke, or urgent target‑vessel revascularization): occurred in 119 patients (Kaplan–Meier estimate 7.0%) in the monotherapy group versus 93 patients (5.5%) in the DAPT group. The absolute risk difference was 1.47 percentage points (95% confidence interval [CI], -0.16 to 3.10). The noninferiority analysis yielded P = 0.11, so prespecified noninferiority was not demonstrated (the upper bound of the 95% CI exceeded the pre-specified margin of +2.5 percentage points).
- Major or clinically relevant nonmajor bleeding: occurred in 33 patients (Kaplan–Meier estimate 2.0%) in the monotherapy group and 82 patients (Kaplan–Meier estimate 4.9%) in the DAPT group. Absolute risk difference was -2.97 percentage points (95% CI, -4.20 to -1.73), a statistically and clinically meaningful reduction in bleeding with P2Y12 monotherapy.
- Stent thrombosis: 12 events in the monotherapy group versus 4 events in the DAPT group (numerically higher with early aspirin withdrawal).
Interpretation of the efficacy (ischemia) result
The point estimate showed a 1.47% absolute increase in the composite ischemic endpoint with early aspirin withdrawal, but the confidence interval ranged from a small reduction to an absolute increase of 3.10%. Because the trial used a noninferiority margin of 2.5 percentage points, the upper bound of the CI exceeded the margin, and noninferiority was not established (P = 0.11). Clinically, this means the study could not rule out a clinically relevant increase in ischemic risk with immediate aspirin withdrawal in an ACS population.
Interpretation of the safety (bleeding) result
P2Y12 inhibitor monotherapy led to a substantial reduction in major or clinically relevant nonmajor bleeding (absolute reduction ~3.0%), corresponding to a number needed to treat (NNT) of about 34 to prevent one such bleeding event over 12 months. This is consistent with the expected benefit of removing aspirin, which contributes to bleeding risk.
Stent thrombosis signal
Although overall stent thrombosis events were few, there were three times as many events in the monotherapy arm (12 vs 4). The absolute numbers are small and the trial was not powered for this endpoint; nevertheless, stent thrombosis is a serious and potentially fatal complication, and this numerical imbalance warrants careful consideration when applying the trial findings.
Context with prior evidence
Previous randomized trials have examined P2Y12 monotherapy strategies, often after a short course of DAPT. For example, the TWILIGHT trial (NEJM 2019) randomized high‑risk patients to ticagrelor monotherapy versus ticagrelor plus aspirin after an initial 3 months of DAPT and found reduced bleeding with no increase in ischemic events. Those trials differ from NEO‑MINDSET in two important ways: (1) many enrolled heterogeneous populations with a mix of stable coronary disease and ACS, and (2) P2Y12 monotherapy was initiated after a short but not immediate period of DAPT (typically 1–3 months), allowing early healing of the stented lesion. NEO‑MINDSET tested an earlier switch strategy—within days of PCI in ACS—which may carry different risks because the early post‑PCI and post‑ACS period is when thrombotic risk is highest.
Mechanistic considerations
Aspirin irreversibly inhibits platelet cyclooxygenase-1, suppressing thromboxane A2–mediated platelet activation, while potent P2Y12 inhibitors block ADP-mediated platelet activation. The two mechanisms are complementary, and in the prothrombotic milieu of ACS (vulnerable plaque, inflammatory activation, endothelial disruption), dual inhibition may provide additive protection against stent thrombosis and recurrent ischemia, particularly in the early weeks after stent deployment. Removing aspirin very early relies on potent P2Y12 blockade alone to suppress platelet reactivity — effective for many patients but perhaps insufficient for some high‑risk lesions or procedural situations.
Strengths and limitations of the trial
Strengths:
- Large randomized multicenter design with pragmatic enrollment across Brazilian centers.
- Use of potent contemporary P2Y12 inhibitors (ticagrelor or prasugrel) and clinically meaningful endpoints adjudicated through 12 months.
Limitations:
- The trial was open-label, which could affect management decisions and ascertainment of some endpoints, although major outcomes are less susceptible to bias.
- NEO‑MINDSET enrolled patients in Brazil; geographic and practice differences may affect generalizability to other populations.
- Heterogeneity in choice of P2Y12 inhibitor (ticagrelor vs prasugrel) and procedural variables may influence outcomes; subgroup data will be important to interpret (e.g., ACS subtype, stent type, lesion complexity).
- Not powered for stent thrombosis; the observed numerical imbalance, while concerning, must be interpreted cautiously.
- Noninferiority was not met; the trial cannot exclude a clinically meaningful increase in ischemic events with immediate aspirin withdrawal.
Clinical implications — how should clinicians interpret and apply NEO-MINDSET?
NEO‑MINDSET provides high-quality evidence that in patients with ACS undergoing PCI, early aspirin withdrawal within 4 days and continuation of potent P2Y12 inhibitor monotherapy substantially reduces bleeding risk, but this strategy did not demonstrate noninferiority for ischemic events at 12 months and was associated with a numerical excess of stent thrombosis. Practical implications:
- For the routine ACS population, these data do not support broad adoption of immediate aspirin withdrawal after PCI in place of 12 months of DAPT.
- For selected patients at very high bleeding risk or with strong contraindications to prolonged aspirin (for example, prior life‑threatening bleeding), early aspirin withdrawal may be considered after individualized assessment of ischemic risk and procedural factors. Shared decision-making and careful follow-up are essential.
- If clinicians consider aspirin withdrawal, ensure adherence to potent P2Y12 inhibitor therapy and inspect procedural details (stent expansion, lesion complexity, intravascular imaging where available) that may influence thrombotic risk.
Unanswered questions and future research
Key areas that require further data include:
- Identification of subgroups who may safely receive early aspirin withdrawal (e.g., low‑risk ACS, optimal stent deployment, intravascular imaging guidance).
- Mechanistic and platelet-function studies to determine which patients maintain sufficient antiplatelet effect with P2Y12 inhibitor monotherapy.
- Larger pooled analyses or meta-analyses combining trials with early aspirin withdrawal to better estimate rare but serious adverse events such as stent thrombosis.
- Longer-term follow-up to ensure late ischemic risks are not underestimated and to gauge net clinical benefit over time.
Conclusion
NEO‑MINDSET demonstrates that early aspirin withdrawal after successful PCI for ACS and continuation of potent P2Y12 inhibitor monotherapy substantially reduces bleeding but failed to show noninferiority for ischemic outcomes at 12 months, with a numerical excess of stent thrombosis. The trial highlights an important trade‑off: bleeding reduction versus potential incremental ischemic risk. For now, the standard approach of DAPT for 12 months after ACS remains the default; early aspirin withdrawal should be reserved for carefully selected patients with high bleeding risk or contraindications to aspirin, and clinicians should proceed cautiously until further confirmatory evidence and subgroup analyses are available.
Funding and trial registration
The NEO-MINDSET trial was funded by the Brazilian Ministry of Health. ClinicalTrials.gov number: NCT04360720. Full citation: Guimarães PO, Franken M, Tavares CAM, et al.; NEO-MINDSET Trial Investigators. Early Withdrawal of Aspirin after PCI in Acute Coronary Syndromes. N Engl J Med. 2025 Nov 27;393(21):2095-2106. doi: 10.1056/NEJMoa2507980. Epub 2025 Aug 31. PMID: 40888723.
Selected references
1. Guimarães PO, Franken M, Tavares CAM, et al.; NEO-MINDSET Trial Investigators. Early Withdrawal of Aspirin after PCI in Acute Coronary Syndromes. N Engl J Med. 2025 Nov 27;393(21):2095-2106. doi: 10.1056/NEJMoa2507980.
2. TWILIGHT Investigators. Ticagrelor with or without Aspirin in High-Risk Patients after PCI. N Engl J Med. 2019;381:2032-2042. (Ticagrelor monotherapy after 3 months DAPT reduced bleeding without increasing ischemic events in high‑risk patients.)
Author note
This summary is intended for clinicians and policy-makers to interpret the NEO‑MINDSET findings in the context of current practice. It highlights the need for individualized decision-making and further research before adopting very early aspirin withdrawal after PCI for ACS as routine practice.
