Early discontinuation of acetylsalicylic acid after angioplasty in acute coronary syndromes: the NEO-MINDSET and TARGET-FIRST studies

Abstract

Dual antiplatelet therapy (DAPT) with acetylsalicylic acid (ASA) and a P2Y12 receptor inhibitor (P2Y12i) for 12 months represents the standard of care after acute coronary syndrome (ACS). However, balancing ischaemic protection against bleeding risk remains challenging, providing the rationale for the development of de-escalation strategies. European and U.S. guidelines allow shortening the duration of DAPT in patients at high bleeding risk, whilst still maintaining 12 months as the reference recommendation. Interest in abbreviated DAPT regimens has been driven by improvements in percutaneous coronary intervention devices and techniques, as well as by a better understanding of the temporal evolution of ischaemic and bleeding risks. Several trials have shown that short-duration DAPT followed by monotherapy—particularly with a P2Y12i—is not inferior in terms of ischaemic outcomes and significantly reduces bleeding events. In this context, the NEO-MINDSET trial failed to demonstrate the non-inferiority of immediate P2Y12i monotherapy compared with standard DAPT. In contrast, the TARGET-FIRST study confirmed the safety of ASA discontinuation after 30 days in selected patients, with a clear bleeding benefit. Overall, the available evidence indicates that immediate discontinuation of ASA in patients with acute coronary syndrome is not universally safe, whereas strategies based on at least 1 month of DAPT followed by monotherapy with a potent P2Y12i currently represent the most balanced approach for selected patients. More refined personalization of antiplatelet therapy, guided by an integrated assessment of ischaemic and bleeding risks, represents the future perspective in this field.

Introduction

In the early 2000s, antithrombotic management of acute coronary syndrome (ACS) relied almost exclusively on acetylsalicylic acid (ASA), with an as–yet-uncertain role for P2Y12 receptor inhibitors (P2Y12i). The progressive accumulation of evidence from clinical trials subsequently consolidated 12 months of dual antiplatelet therapy (DAPT) as the standard of care in patients with ACS undergoing percutaneous coronary intervention (PCI).

Advances in coronary stent technology and a better understanding of the distinct temporal patterns of ischaemic and bleeding risks after PCI have paved the way for strategies aimed at modulating both the intensity and duration of DAPT, including early discontinuation of either ASA or the P2Y12i.¹ Early studies primarily focused on shortening DAPT duration through discontinuation of the P2Y12i. In this context, the DAPT-STEMI trial (Randomized, Open-Label Trial of 6 Months Versus 12 Months DAPT After Drug-Eluting Stent in STEMI) demonstrated that 6 months of DAPT was non-inferior to the standard 12-month regimen in patients with ST-segment elevation myocardial infarction (STEMI) with respect to a composite endpoint of ischaemic and bleeding events.² Similar findings were reported in the SMART-DATE trial (Safety of 6-Month Duration of Dual Antiplatelet Therapy After Acute Coronary Syndromes), conducted in an Asian ACS population; however, analysis of individual endpoints revealed a significantly higher incidence of myocardial infarction in the 6-month DAPT group.³ An additional signal of caution emerged from the REDUCE trial (Randomized Evaluation of Short-Term Dual Antiplatelet Therapy in Patients With Acute Coronary Syndrome Treated With a New-Generation Stent), which compared 3 months of DAPT with the conventional strategy in patients with ACS and showed a higher incidence of mortality and in-stent thrombosis in the short-DAPT arm, despite achieving non-inferiority for the primary endpoint.⁴

Growing interest has therefore shifted towards ‘ASA-free’ strategies, based on early discontinuation of ASA with continuation of P2Y12i monotherapy. The TICO trial (Ticagrelor Monotherapy After 3 Months in the Patients Treated With New-Generation Sirolimus-Eluting Stent for Acute Coronary Syndrome) demonstrated non-inferiority of ticagrelor monotherapy after 3 months of DAPT with respect to a composite of ischaemic and bleeding events, although this difference was largely driven by a reduction in bleeding in the monotherapy group.⁵ These findings were not confirmed in the STOPDAPT-2 ACS trial (Short and Optimal Duration of Dual Antiplatelet Therapy-2 Study for Patients With ACS), in which a strategy of 1–2 months of DAPT followed by clopidogrel monotherapy was associated with an increased incidence of ischaemic events compared with 12 months of DAPT.⁶ Conversely, more recent studies—T-PASS (Ticagrelor Monotherapy in Patients Treated With New-Generation Drug-Eluting Stents for Acute Coronary Syndrome) and ULTIMATE-DAPT (Ticagrelor Alone Versus Ticagrelor Plus ASA From Month 1 to Month 12 After Percutaneous Coronary Intervention in Patients With Acute Coronary Syndromes)—have shown that discontinuation of ASA after the first month, with continuation of ticagrelor monotherapy, is non-inferior to 12 months of DAPT with ASA and ticagrelor and is associated with a significant reduction in clinically relevant bleeding.^7,8 Additional evidence was provided by the 4D-ACS trial, which reported both non-inferiority and superiority of 1 month of DAPT with prasugrel followed by prasugrel monotherapy at a 5-mg dose compared with conventional 12-month DAPT.⁹ In contrast, STOPDAPT-3 highlighted the limitations of immediate ‘ASA-free’ strategies, showing an increased incidence of unplanned revascularization and subacute stent thrombosis.¹⁰

Despite the growing body of evidence supporting early discontinuation of ASA after 1–3 months of DAPT, the generalizability of these findings remains limited. Many studies were conducted in Asian populations—characterized by ischaemic and bleeding risk profiles that may differ from those of Western populations—and frequently relied on composite endpoints combining ischaemic and bleeding events, complicating interpretation of the true balance between benefits and risks. Further uncertainty arises from the use of clopidogrel in some trials, a drug characterized by substantial interindividual variability that may compromise antithrombotic protection in patients with ACS.

In light of these methodological and clinical limitations, concerns persist regarding the efficacy and safety of short-DAPT strategies, particularly ultra-short regimens (≤1 month). In this context, the recent NEO-MINDSET and TARGET-FIRST trials provide additional evidence to inform clinical decision-making.

DAPT and short-DAPT recommendations

European guidelines recommend 12 months of DAPT with prasugrel or ticagrelor in patients with ACS (Class I, Level of Evidence B), reserving clopidogrel for patients with contraindications or intolerance to these agents (Class I, Level of Evidence C).¹¹ U.S. guidelines provide similar recommendations, with exceptions for patients at high bleeding risk.¹²

To mitigate bleeding risk, both European and American scientific societies endorse de-escalation strategies based on reducing the intensity of platelet inhibition through modification of the type, dose, or number of antiplatelet agents.¹³ European guidelines allow discontinuation of one of the two antiplatelet agents after 3–6 months in patients at low thrombotic risk (Class IIa, Level of Evidence A) or after 1 month in patients at high bleeding risk (Class IIb, Level of Evidence B).¹¹ U.S. guidelines permit shortening DAPT to 1 month in patients at high bleeding risk, with discontinuation of either ASA or the P2Y12i (Class IIb).¹² In addition, ticagrelor monotherapy after 1 month of DAPT is recommended as a strategy to reduce bleeding risk (Class I).¹²

Beyond shortening DAPT duration, both guidelines consider switching from ticagrelor or prasugrel to clopidogrel after 1 month to be an appropriate option in patients in whom bleeding risk predominates (Class IIb).^11,12

Limitations of DAPT and rationale for short-DAPT

The integration of abbreviated DAPT regimens stems from the intrinsic limitations of DAPT and the need to reduce bleeding risk without compromising ischaemic protection. After PCI, thrombotic risk is highest during the first month and progressively declines over the subsequent year, whereas bleeding risk—after a periprocedural peak—remains relatively stable.¹ Accordingly, because prolonged exposure to DAPT or to potent P2Y12i increases bleeding risk, modulation of antiplatelet therapy intensity after PCI or ACS may be appropriate in patients in whom bleeding risk predominates.¹³

De-escalation strategies can be broadly categorized into three approaches: dose reduction, switching, and discontinuation. Dose reduction involves the use of lower doses of ASA or P2Y12i; de-escalation by switching consists of replacing a potent P2Y12i—such as ticagrelor or prasugrel—with a less potent agent, such as clopidogrel; de-escalation by discontinuation entails early interruption of either ASA or the P2Y12i after a shortened period of DAPT, with continuation as monotherapy.¹³

‘ASA-free’ strategies based on continuation of P2Y12i monotherapy after short DAPT (1–3 months), as outlined above, have recently gained increasing attention (Figure 1). The pathophysiological rationale for ASA discontinuation is robust: P2Y12i monotherapy provides a level of platelet inhibition comparable to that achieved with DAPT, and in vitro studies suggest that the addition of ASA does not further reduce thrombogenicity in the presence of strong P2Y12 receptor inhibition.¹⁴ Consequently, discontinuation of ASA after the acute phase may improve the safety profile whilst preserving ischaemic protection.¹³ Consistently, a recent meta-analysis in patients with ACS suggests that, following abbreviated DAPT, P2Y12i monotherapy is superior to ASA monotherapy in terms of ischaemic protection.¹⁵

Figure 1.

Major clinical trials evaluating dual antiplatelet therapy de-escalation strategies through acetylsalicylic acid discontinuation after percutaneous coronary intervention. Each study is represented by a circle, the size of which is proportional to the sample size. The colour of the outer ring indicates the type of primary endpoint evaluated (orange: bleeding; yellow: major adverse cardiovascular events; light blue: net adverse clinical events), whereas the colour of the inner circle reflects the study outcome: green when the primary endpoint was met and red when it was not. The vertical position indicates the timing of acetylsalicylic acid discontinuation relative to the procedure (at percutaneous coronary intervention, before 1 month, at 1 month, between 1 and 2 months, or at 3 months), whilst the horizontal axis shows the year of publication of the results. * In ULTIMATE-DAPT, the primary superiority endpoint was clinically relevant bleeding (Bleeding Academic Research Consortium type 2, 3, or 5), and the primary non-inferiority endpoint was major adverse cardiac and cerebrovascular events, defined as the composite of cardiac death, myocardial infarction, ischaemic stroke, definite stent thrombosis, or clinically driven target-vessel revascularization.

The NEO-MINDSET and TARGET-FIRST studies

The NEO-MINDSET (Early Withdrawal of ASA after PCI in Acute Coronary Syndromes) and TARGET-FIRST (Early Discontinuation of ASA after PCI in Low-Risk Acute Myocardial Infarction) trials are positioned within the continuously evolving landscape that, over the past 15 years, has investigated shortened durations of DAPT after PCI.^16,17

NEO-MINDSET

NEO-MINDSET was a randomized, multicenter, open-label trial conducted across 50 centrer in Brazil, enrolling patients with ACS who had undergone successful PCI (Table 1). Within 4 days of hospital admission, patients were randomized to either potent P2Y12i monotherapy or standard DAPT for 12 months.¹⁶ The primary efficacy endpoint was a composite of death, myocardial infarction, stroke, or urgent revascularization, whilst the primary safety endpoint included Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding events.

Table 1.

Patient characteristics and clinical outcomes in the NEO-MINDSET and TARGET-FIRST studies.

	NEO-MINDSET		TARGET-FIRST
	Monotherapy	DAPT	Monotherapy	DAPT
Randomized patients (n)	1712	1698	961	981
Mean age (years)	59.5	59.8	61	61
Time to randomization (days)	2	2	37	37
Follow-up (months)	12	12	11	12
STEMI (%)	61.8	62.5	50.2	50.7
NSTEMI (%)	30.8	30.2	49.8	49.3
Unstable angina (%)	7.4	7.4	0	0
Multivessel coronary disease (%)	45.4	42.3	17.1	16.9
Primary efficacy endpoint (%)a HR, 95% CI	7.0 vs. 5.5 1.28 (0.98–1.68)		2.1 vs. 2.2 P = 0.02
All-cause death (%) HR, 95% CI	3.6 vs. 3.0 1.24 (0.85–1.79)		0.4 vs. 0.2 2.04 (0.37–11.14)
Myocardial infarction (%) HR, 95% CI	2.7 vs. 1.9 1.45 (0.92–2.30)		0.7 vs. 1.1 0.72 (0.27–1.88)
Urgent target-vessel revascularization (%) HR, 95% CI	1.3 vs. 0.7 1.83 (0.90–3.69)		NA
Stent thrombosis (%) HR, 95% CI	0.7 vs. 0.2 2.99 (0.97–9.28)		0,1 vs. 0
Stroke (%) HR, 95% CI	1.2 vs. 0.9 1.33 (0.68–2.60)		0.3 vs. 0.2 1.53 (0.26–9.18)
BARC 2/3/5 bleeding (%) HR, 95% CI	2.0 vs. 4.9 0.40 (0.26–0.59)		2.6 vs. 5.6 0.46 (0.29–0.75)

Abbreviations: BARC, Bleeding Academic Research Consortium; CI, confidence interval; DAPT, dual antiplatelet therapy; HR, hazard ratio; NSTEMI, non–ST-segment elevation myocardial infarction; PCI, percutaneous coronary intervention; STEMI, ST-segment elevation myocardial infarction.

^aIn NEO-MINDSET, the primary composite outcome included all-cause death, myocardial infarction, stroke, and urgent target-vessel revascularization. In TARGET-FIRST, the composite outcome included all-cause death, myocardial infarction, stent thrombosis, stroke, and major bleeding (BARC 3/5).

The planned sample size (n = 3400) provided 80% power to demonstrate non-inferiority of monotherapy, assuming an event rate of 7.0% with DAPT and 9.5% with monotherapy, with a non-inferiority margin of 2.5%. In the event of non-inferiority, a sequential superiority analysis for bleeding was prespecified.¹⁶

Between October 2020 and October 2023, 3413 patients were randomized, with a mean age of 59.6 years. High bleeding risk was present in 19.8% of patients; 62.1% presented with STEMI, 30.5% with non-ST-STEMI (NSTEMI), and 43.9% had multivessel coronary artery disease.¹⁶ At 12 months, the ischaemic endpoint occurred in 7.0% of patients receiving monotherapy and in 5.5% of those receiving DAPT [hazard ratio (HR), 1.28; 95% confidence interval (CI), 0.98–1.68], failing to meet the criterion for non-inferiority (absolute difference, 1.47%; 95% CI, −0.16 to 3.10; P = 0.11). BARC 2, 3, or 5 bleeding events were significantly lower in the monotherapy group (2.0% vs. 4.9%; HR, 0.40; 95% CI, 0.26–0.59). However, higher rates of stent thrombosis (0.7% vs. 0.2%) and invasive revascularization (2.6% vs. 1.6%) were observed in the monotherapy group. These findings were consistent across the explored subgroups.¹⁶

TARGET-FIRST

TARGET-FIRST was a prospective, multicenter, randomized, open-label trial conducted in 40 European centres (Table 1). The study enrolled patients aged ≥18 years with STEMI or NSTEMI who underwent PCI with complete revascularization. Patients at high bleeding risk and those at high ischaemic risk (including complex PCI, chronic total occlusion, extensive stenting >80 mm, left main disease, or severe calcification) were excluded.¹⁷

After an initial event-free period of at least 30 days of DAPT, patients were randomized to either continuation of DAPT for an additional 11 months or P2Y12i monotherapy. The primary endpoint was a composite of death, myocardial infarction, stent thrombosis, stroke, or BARC 3 or 5 bleeding; the key secondary endpoint was BARC 2, 3, or 5 bleeding. Sample size calculation was based on an expected incidence of 3.5% in the DAPT group and 2.5% in the monotherapy group, with a non-inferiority margin of 1.25%.¹⁷

Between March 2021 and March 2024, 2246 patients were enrolled and 1942 were randomized, with a mean age of 61 years. STEMI and NSTEMI were equally represented. Coronary artery disease was single-vessel in 83% of patients, and complete revascularization was achieved in 99.9%, with a median of one stent implanted, reflecting low anatomical complexity.¹⁷

At 11 months, the primary endpoint occurred in 2.1% of patients in the monotherapy group and in 2.2% of those in the DAPT group (absolute difference, −0.09%; 95% CI, −1.39 to 1.20), meeting the criterion for non-inferiority (P = 0.02). Individual endpoint components showed low and comparable incidence rates. BARC 2, 3, or 5 bleeding events were significantly reduced with monotherapy compared with DAPT (2.6% vs. 5.6%; HR, 0.46; 95% CI, 0.29–0.75).¹⁷

Critical considerations and future perspectives

The most recent evidence suggests that abbreviated DAPT regimens, particularly those based on early discontinuation of ASA, may be safe in many clinical settings without leading to a significant increase in ischaemic risk.¹³ However, the findings from the NEO-MINDSET and TARGET-FIRST trials indicate that the timing of ASA withdrawal, patient selection, and careful stratification of ischaemic and bleeding risks remain critical determinants for the appropriate choice of antithrombotic strategy.

NEO-MINDSET failed to demonstrate the non-inferiority of P2Y12i monotherapy compared with DAPT for the ischaemic endpoint. The early separation of risk curves was driven by an excess of events occurring in the immediate post-PCI phase, coinciding with the initiation of monotherapy. A prespecified analysis according to clinical presentation revealed divergent outcomes between NSTEMI and STEMI patients: in those with NSTEMI, ischaemic event rates were similar between treatment groups (5.1% vs. 6.0%; HR, 0.84; 95% CI, 0.39–2.02), whereas in patients with STEMI, early ASA discontinuation was associated with a significant increase in events at one year (8.2% vs. 5.2%; HR, 1.60; 95% CI, 1.14–2.24).¹⁸ This heterogeneity highlights how differences in ischaemic and bleeding risk profiles influence the efficacy and safety of short-DAPT strategies. Compared with NSTEMI patients, those with STEMI are generally younger, with a lower prevalence of renal dysfunction and fewer prior myocardial infarctions—characteristics that may modify the overall risk of adverse events.¹⁹

Furthermore, monotherapy was associated with a numerical increase across all individual ischaemic endpoints, including 12 cases of stent thrombosis, 10 of which occurred during the subacute phase (1–30 days). Similar findings had previously been reported in STOPDAPT-3 (Short and Optimal Duration of Dual Antiplatelet Therapy-3), which documented higher rates of unplanned revascularization and stent thrombosis in the monotherapy arm.¹⁰

In contrast, TARGET-FIRST is consistent with the results of T-PASS and ULTIMATE-DAPT, confirming that one month of DAPT followed by P2Y12i monotherapy is non-inferior to prolonged DAPT with respect to ischaemic events and significantly reduces BARC 2–5 bleeding.^7,8 The principal methodological strength of TARGET-FIRST lies in the selection of patients with acute myocardial infarction at low ischaemic and bleeding risk. Nevertheless, the very low incidence of ischaemic events warrants caution in interpreting these findings, as they derive from a highly selected patient population.

Overall, the convergence of evidence from NEO-MINDSET, STOPDAPT-3, and the aforementioned trials suggests that immediate discontinuation of ASA after PCI with transition to P2Y12i monotherapy is associated with a higher ischaemic risk compared with a strategy of at least one month of DAPT. This hypothesis is consistent with a recent meta-analysis showing that P2Y12i monotherapy after a DAPT duration of ≤3 months reduces bleeding by approximately 50% without increasing ischaemic events.²⁰ In the same meta-analysis, ticagrelor emerged as the agent with the most favourable ischaemic profile, whereas clopidogrel was associated with signals of potential harm. These findings align with the results of SMART-DATE and STOPDAPT-2 ACS, in which clopidogrel monotherapy after 1–2 months of DAPT was associated with an increased incidence of cardiovascular events compared with standard DAPT in patients with ACS.^3,6,20

Conclusions

Recent evidence increasingly indicates that immediate discontinuation of ASA at the time of PCI is associated with a non-negligible ischaemic risk, particularly in patients with ACS who do not exhibit features of high bleeding risk. In contrast, strategies incorporating at least one month of DAPT followed by monotherapy with a potent P2Y12i provide a more favourable risk–benefit profile in selected patients whose characteristics resemble those of participants enrolled in available clinical trials. Pending the results of ongoing studies (Table 2), the main challenge remains the accurate identification of patients who may be suitable for shorter DAPT durations, avoiding a one-size-fits-all approach and grounding therapeutic decisions in an integrated assessment of individual ischaemic and bleeding risks.

Table 2.

Ongoing randomized trials evaluating abbreviated DAPT strategies after PCI.

Trial name (ClinicalTrials.gov ID)	Sample size	Population	Intervention	Control	Primary endpoint
PREMIUM (NCT05709626)	2258	STEMI	Prasugrel monotherapy for 12 months	Prasugrel-based DAPT for 12 months	MACE at 1 year
STARS-DAPT (NCT05785897)	350	STEMI	Antiplatelet monotherapy with prasugrel or ticagrelor	DAPT for 12 months	MACCE at 1 year BARC 3 or 5 bleeding at 1 year
COMPARE STEMI-ONE (NCT05491200)	1656	STEMI	Short prasugrel-based DAPT (30–45 days) followed by prasugrel monotherapy	Prasugrel-based DAPT for 12 months	NACE at 11 months
SORT OUT XII DAPT Duration Trial (NCT06718179)	3150	ACS patients undergoing PCI	One-month DAPT followed by prasugrel monotherapy for 11 months	Prasugrel-based DAPT for 12 months	BARC 2–5 bleeding at 1 year MACCE at 1 year

Abbreviations: BARC, Bleeding Academic Research Consortium; DAPT, dual antiplatelet therapy; MACCE, major adverse cardiac and cerebrovascular events; MACE, major adverse cardiovascular events; NACE, net adverse cardiovascular events; PCI, percutaneous coronary intervention; ACS, acute coronary syndrome; STEMI, ST-segment elevation myocardial infarction.

Funding

We confirmed that no specific funding was received for the completion of this work.

Data availability

No new data were generated or analyzed in support of this research.

Disclaimer

This paper was originally published in the Italian language as ‘Sospensione precoce dell'acido acetilsalicilico dopo l'angioplastica nelle SCA: gli studi NEO- MINDSET e TARGET-FIRST’, in the Volume degli Atti del Congresso “Conoscere e Cuare il Cuore 2026”, published by Centro per la Lotta contro l'Infarto for distribution at the CCC Conference. This paper was translated by Dr. Mario Albertucci, representative of the CLI Foundation, and republished with permission.