Abstract
Background
The optimal duration of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) in acute coronary syndrome (ACS) remains debated. While DAPT with aspirin and a P2Y12 inhibitor prevents ischemic events, it increases bleeding risk. This meta-analysis evaluates whether early aspirin discontinuation with P2Y12 inhibitor monotherapy offers comparable efficacy and improved safety versus standard long-term DAPT.
Methods
This review, conducted according to PRISMA guidelines, searched PubMed, Cochrane Central and Clinicaltrials.gov up to September 2025 for RCTs comparing short-term DAPT (≤3 months) followed by P2Y12 inhibitor monotherapy with standard-duration DAPT (≥6-12 months). Outcomes included NACE, MACE, all-cause and cardiovascular mortality, myocardial infarction, stroke, stent thrombosis, and BARC 3 or 5 bleeding. Random-effects models were applied to estimate pooled risk ratios and 95% CIs.
Results
Ten RCTs involving 35,277 patients were included. Compared with standard DAPT, short-term DAPT followed by P2Y12 inhibitor monotherapy significantly reduced NACE (RR = 0.80, 95% CI 0.71-0.90; p = 0.0002; I2 = 38%), and BARC type 3 or 5 bleeding (RR = 0.48, 95% CI 0.40-0.58; p < 0.001; I2 = 0%), without significant differences in MACE (RR: 1.01 [0.86, 1.19]; p = 0.87; I2 = 41%) or all-cause mortality (RR: 0.96 [0.80, 1.16]; p = 0.69; I2 = 4%).
Conclusion
Early transition to P2Y12 inhibitor monotherapy after 1–3 months of DAPT in ACS patients undergoing PCI significantly reduces bleeding without increasing ischemic events. Ticagrelor- or prasugrel-based monotherapy represents a safe and effective alternative to conventional 12-month DAPT.
Keywords: P2Y12 inhibitor, dual antiplatelet therapy, acute coronary syndrome, percutaneous coronary intervention, meta-analysis
Introduction
Acute coronary syndrome (ACS) requires timely intervention to reduce mortality and major adverse cardiovascular events (MACE). 1 Dual antiplatelet therapy (DAPT)—aspirin plus a P2Y12 inhibitor—is a key management strategy and significantly reduces thrombotic events following percutaneous coronary intervention (PCI).2,3 However, prolonged DAPT increases the risk of bleeding, highlighting the need for alternative strategies. 4
To reduce bleeding risk, early aspirin discontinuation with P2Y12 inhibitor monotherapy has been investigated. Recent trials and meta-analyses have shown that short-term DAPT (1-3 months) followed by P2Y12 monotherapy offers comparable ischemic protection to the standard 12-month DAPT regimen, while significantly reducing major bleeding rates.5,6 These benefits appear consistent across patient subgroups.7,8
Despite encouraging results from recent trials, significant heterogeneity in study designs, definitions, and patient risk profiles has led to uncertainty about the generalizability of P2Y12 inhibitor monotherapy compared to standard DAPT. Therefore, an updated and comprehensive synthesis of current evidence is critically needed to clarify whether P2Y12 inhibitor monotherapy is an effective and safe alternative to standard DAPT across different clinical scenarios.
Recent meta-analyses have assessed P2Y12 inhibitor monotherapy after short-duration DAPT in patients with ACS. Galli et al 9 found that P2Y12 inhibitor monotherapy reduces bleeding without increasing ischemic events, with outcomes varying by agent. Laudani et al 10 compared aspirin and P2Y12 inhibitor monotherapy using both pairwise and network meta-analyses. However, a gap in data still exists when considering outcomes specifically after PCI and using standard duration DAPT as a comparator to measure change in ischemic events. This study aims to bridge that gap
Methods
This systematic review and meta-analysis adhered to the PRISMA guidelines (PROSPERO ID: CRD420251162976).11,12 As the analyses used publicly available data, Institutional Review Board approval was not required.
Objectives and Eligibility Criteria
This meta-analysis aimed to directly compare the efficacy and safety of P2Y12 inhibitor monotherapy to DAPT in patients undergoing PCI. Included trials were primary or secondary analyses of RCTs involving adults who underwent PCI with drug-eluting stents, compared short-term DAPT (≤3 months) followed by P2Y12 inhibitor monotherapy to standard-duration DAPT (≥6-12 months), and reported clinical outcomes such as MACE, NACE, all-cause mortality, cardiovascular death, myocardial infarction (MI), stroke, stent thrombosis, and BARC type 3 or 5 bleeding.
Data Sources and Search
We searched PubMed, Cochrane Central and Clinicaltrials.gov from database inception to September 2025, with no language restrictions. Supplementary Table S1 details search strategies. Additional references were identified through a manual review and snowball sampling.
Search results were imported into Rayyan.AI. 13 Duplicates were removed, and the remaining records were screened by two reviewers (M.I. and F.A.K.) using titles and abstracts, followed by full-text reviews. Disagreements were resolved with the assistance of a third reviewer (S.A.W.) until a consensus was reached.
Data Extraction and Quality Assessment
We extracted trial details, baseline data, treatments, and outcomes using a pre-designed Excel sheet. Outcomes included MACE, NACE, all-cause mortality, CV death, MI, stroke, stent thrombosis, and BARC 3 or 5 bleeding. If not directly reported, outcomes were calculated from raw data.
The risk of bias was assessed using the Cochrane Risk of Bias 2.0 tool. Two reviewers (A.Z. and M.I.) independently performed the extraction and bias assessment; disagreements were resolved through discussion with a third reviewer (S.A.W.). Certainty of evidence was assessed by M.I. using GRADEpro GDT software. 14 The GRADE domains evaluated for each outcome were: (1) risk of bias, (2) inconsistency, (3) indirectness, (4) imprecision, and (5) publication bias.
Statistical Analysis
Dichotomous outcomes were analyzed using risk ratios (RRs), and continuous outcomes were reported as weighted mean differences (WMDs) where applicable. Individual patient-level time-to event data were unavailable across the included trials. Therefore, all outcomes were analyzed using cumulative event counts at the longest reported follow-up. Kaplan-Meier analyses and hazard ratios were not pooled, in line with PRISMA and Cochrane guidance for aggregate-data meta-analysis. For studies reporting continuous data as medians with interquartile ranges, values were converted to means and standard deviations (SDs) via the Box–Cox transformation. 15 Heterogeneity was assessed with Higgins’ I2 statistic: I2 ≤ 50% (low), 50% < I2 ≤ 75% (substantial), and I2 > 75% (considerable). The chi-square (χ2) test was applied, with p ≤ 0.10 indicating significant heterogeneity.
A random-effects model was used to account for heterogeneity; otherwise, a fixed-effects Mantel–Haenszel model was applied. Subgroup analyses were performed based on study-level characteristics: P2Y12 inhibitor type (clopidogrel, ticagrelor, prasugrel), and the timing of aspirin withdrawal (early vs delayed).
Publication bias was assessed with funnel plots for the primary outcomes. Complete leave-one-out sensitivity analyses were performed for outcomes demonstrating heterogeneity (I2 > 0). All statistical analyses were conducted using Review Manager (RevMan, Version 5.4, The Cochrane Collaboration, Copenhagen, Denmark). A p-value <0.05 was considered significant.
Results
The PRISMA flow chart (Supplementary Figure S1) summarizes the search and trial selection. Out of 292 initial records, ten RCTS ultimately met the inclusion criteria.5,16–24 These trials compared short-duration DAPT with standard 12-month DAPT following PCI using contemporary drug-eluting stents (DES). Ticagrelor was the primary P2Y12 inhibitor in seven of the ten studies. Clopidogrel was predominant in two trials, and prasugrel in one. Regarding study quality, the risk of bias assessment indicated an overall low to moderate risk across the included studies. Notably, the GLOBAL LEADERS trial 23 demonstrated a high risk of bias due to selection of the reported results (Supplementary Figure S2). Turning to participant demographics, a total of 35,277 participants were included (n = 17,596 in the P2Y12i arm and n = 17,679 in the DAPT arm), with a mean age ranging from 59.7 to 66.8 years across the studies. The baseline characteristics of patients from each trial included in the study are presented in Table 1.
Table 1.
Participant Baseline Characteristics.
| Study (year) | GLOBAL LEADERS (2019) | SMART-CHOICE (2019) | TWILIGHT-ACS (2020) | TICO (2020) | STOPDAPT-2 ACS (2021) | T-PASS (2023) | ULTIMATE-DAPT (2024) | SHARE (2024) | NEO-MINDSET (2025) | TARGET-FIRST (2025) |
|---|---|---|---|---|---|---|---|---|---|---|
| Trial design | Superiority | Non-inferiority | Superiority | Non-inferiority | Non-inferiority | Non-inferiority | Non-inferiority | Non-inferiority | Non-inferiority | Non-inferiority |
| Blinding | Open label | Open label | Double blind | Open label | Open label | Open label | Double blind | Open label | Open label | Open label |
| Randomization time | In hospital | Within 3 months after index procedure | 3 months | In hospital | In hospital | After index procedure | 1 month | Within 3 months after index procedure | <1 month (within 4 days of hospitalization) | 1 month |
| Short DAPT duration | 1 month | 3 months | 3 months | 3 months | 1–2 months (39 days) | <1 month (16 days) | 1 month | 3 months | DAPT discontinued immediately after randomization | 1 month |
| P2Y12 inhibitor used in the monotherapy arm | TICA | CLO | TICA | TICA | CLO | TICA | TICA | TICA | PRA | TICA |
| Standard DAPT definition | 12-month DAPT (TIC) | 12-month DAPT (CLO) | 15-month DAPT (TIC) | 12-month DAPT (TIC) | 12-month DAPT (CLO) | 12-month DAPT (TIC) | 12-month DAPT (TIC) | 12-month DAPT (TIC/ CLO) | 12-month DAPT (TIC/ PRA) | 12-month DAPT (PRA/ TIC/ CLO) |
| Number of participants, n | 7487 | 2993 | 4614 | 3056 | 4136 | 2850 | 3400 | 1387 | 3410 | 1942 |
| Patients in P2Y12 Inhibitor monotherapy arm, n | 3750 | 1495 | 2273 | 1527 | 2058 | 1426 | 1700 | 694 | 1712 | 961 |
| Patients in DAPT arm, n | 3737 | 1498 | 2341 | 1529 | 2078 | 1424 | 1700 | 693 | 1698 | 981 |
| Age, years (P2Y12i / DAPT) | - | 64.5 (64.6/64.4) | 64.2 (64.2/64.2) | 61 (61/61) | 66.8 (67.0/66.6) | 61 (61/61) | - | 63 (62.8/63.2) | 59.7 (59.5/59.8) | 61.0 (61/61) |
| Female, % (P2Y12i / DAPT) | 1724 (23.2/22.9) | 795 (27.3/25.8) | 1161 (25.5/24.8) | 628 (21.2/19.9) | 856 (20.8/20.6) | 476 (16.3/17.1) | 879 (25.7/26.1) | 332 (22.5/25.4) | 999 (29.3/29.3) | 420 (23.2/20.1) |
| Body mass index (P2Y12i / DAPT)ª | - | 24.6 (24.5/24.7) | 28.4 (28.4/28.4) | 24.9 (24.9/24.9) | 24.2 (24.1/24.2) | 25.1 (25.1/25.0) | - | 25.1 (25.1/25.0) | 27.6 (27.6/27.5) | 27.1 (26.7/27.4) |
| Diabetes mellitus, % (P2Y12i / DAPT) | 1604 (21.6/21.3) | 1122 (38.2/36.8) | 1614 (35.6/34.3) | 835 (27.4/27.3) | 1229 (29.5/29.9) | 830 (29.6/28.7) | 1075 (31.8/31.5) | 470 (32.8/35.1) | 936 (26.8/28.1) | 281 (14.0/14.9) |
| Diabetes with insulin treatment, % (P2Y12i / DAPT) | 451 (5.6/6.5) | - | 458 (9.7/10.1) | - | 125 (2.5/3.6) | 72 (2.8/2.2) | 280 (8.0/8.5) | - | - | 69 (3.7/3.4) d |
| Hypertension, % (P2Y12i / DAPT) | 5083 (68.6/67.9) | 1840 (61.6/61.3) | 3111 (67.5/67.4) | 1541 (49.8/51.1) | 2810 (67.8/68.1) | 1348 (46.9/47.7) | 2121 (62.2/62.5) | 812 (56.7/60.5) | 2183 (63.8/64.2) | 751 (38.2/39.1) |
| Current smoking, % (P2Y12i / DAPT) | 2543 (34.3/33.6) | 791 (28.4/24.5) | 1150 (23.3/26.6) | 1142 (36.3/38.4) | 1420 (34.9/33.8) | 1094 (39.1/37.7) | 968 (28.6/28.4) | 404 (31.0/27.3) | 1185 (36.1/36.0) d | 812 (41.9/41.8) d |
| Prior MI, % (P2Y12i / DAPT)b | 1380 (18.3/18.6) | 127 (4.1/4.3) | 1167 (25.4/25.2) | 113 (4.2/3.2) | 244 (6.6/5.3) | 52 (1.9/1.8) | 299 (8.4/9.2) | 76 (5.2/5.8) | 333 (10.0/9.5) | NR e |
| Prior PCI, % (P2Y12i / DAPT)b | 1726 (22.8/23.4) | - | 1583 (34.2/34.4) | 262 (8.8/8.3) | 427 (10.9/9.7) | 184 (6.5/6.5) | 345 (10.1/10.2) | 176 (10.7/14.7) | 284 (8.3/8.4) | NR e |
| Prior CABG, % (P2Y12i / DAPT) | 275 (3.5/3.9) | - | 400 (8.8/8.5) | 18 (0.5/0.7) | 27 (0.4/0.9) | 6 (0.3/0.1) | 6 (0.1/0.2) | 19 (1.9/0.9) | 56 (1.8/1.5) | NR e |
| Prior stroke, % (P2Y12i / DAPT) | 175 (2.2/2.5) | 201 (6.6/6.8) | - | 126 (3.9/4.3) | 193 (4.8/4.6) | 92 (3.0/3.4) | 301 (9.1/8.7) | 61 (3.9/4.9) | - | 35 (1.6/2.0) |
| Chronic kidney disease, % (P2Y12i / DAPT)c | 967 (13.4/12.5) | 97 (2.9/3.5) | 662 (14.6/15.1) | 620 (19.1/21.5) | 138 (3.3/3.4) | 222 (8.3/7.3) | 248 (7.0/7.6) | 40 (3.3/2.5) | - | 36 (1.6/2.1) |
| Peripheral arterial disease, % (P2Y12i / DAPT) | 387 (5.1/5.3) | - | 262 (5.7/5.6) | - | 82 (1.9/2.0) | - | 155 (4.5/4.7) | - | - | 59 (3.5/2.5) |
| Dyslipidemia, % (P2Y12i / DAPT)d | 4389 (60.8/62.0) | 1352 (45.1/45.5) | - | 1846 (60.5/60.3) | 2764 (66.7/66.9) | 2106 (73.5/74.3) | 2335 (69.3/68.1) | 592 (40.7/44.8) | 916 (27.1/26.6) | 540 (28.2/27.4) |
| Clinical presentation | ||||||||||
| Unstable angina, % (P2Y12i / DAPT) | 2022 (26.8/27.2) | 958 (31.2/32.8) | - | 926 (28.9/31.7) | 986 (23.3/24.4) | 708 (24.3/25.4) | 1376 (39.3/41.7) | - | 252 (7.4/7.4) | - |
| STEMI, % (P2Y12i / DAPT) | 2092 (28.3/27.6) | 314 (11.0/10.0) | - | 1103 (35.8/36.4) | 2324 (74.7/72.8) | 1150 (40.2/40.6) | 948 (28.7/27.1) | - | 2119 (61.8/62.5) | - |
| NSTEMI, % (P2Y12i / DAPT) | 3373 (44.9/45.2) | 469 (16.0/15.4) | - | 1027 (35.3/31.9) | 826 (25.3/27.2) | 992 (35.6/34.1) | 1076 (32.1/31.2) | - | 1039 (30.8/30.2) | - |
P2Y12i = P2Y12 Inhibitor; DAPT= dual antiplatelet therapy; TICA, ticagrelor; CLO, clopidogrel; PRA, prasugrel; MI, myocardial infarction; PCI, percutaneous coronary intervention; CABG, coronary artery bypass grafting; STEMI, ST-segment elevation myocardial infarction; NSTEMI, non-ST-segment elevation myocardial infarction. ªCalculated as weight in kilograms divided by height in meters squared. bSMART-CHOICE trial reported only ‘prior revascularization’ without distinguishing between PCI and CABG. cChronic kidney disease was defined as an estimated glomerular filtration rate of less than 60 mL/min/1.73m2 of body surface area, but defined as less than 30 mL/min/1.73m2 or maintenance dialysis therapy in STOPDAPT-2 ACS; those not receiving dialysis in STOP-DAPT-2 ACS were 47 (P2Y12i arm) and 42 (DAPT arm). dReported as hypercholesterolemia in GLOBAL LEADERS and TARGET-FIRST trial and as hyperlipidemia in STOPDAPT-2 ACS trial. eTARGET-FIRST trial reported prior MI and prior PCI as a combined variable (57/959 [5.9%] vs 67/975 [6.9%]); separate values and prior CABG were not reported. Percentages standardized to one decimal place for consistency. Only covariates consistently reported across most studies included.
Net Adverse Clinical Events
Ten studies reported NACE. A meta-analysis revealed that P2Y12 inhibitor monotherapy significantly reduced the risk of NACE compared with standard DAPT (RR: 0.80 [0.71, 0.90]; p = 0.0002; I2 = 38%; Figure 1). Subgroup analysis did not show any effect modification by duration of aspirin withdrawal (p-interaction: 0.88; Supplementary Figure S3) or by the type of P2Y12 inhibitor used (p-interaction: 0.35; Supplementary Figure S4) (Table 2). Sensitivity analysis by removing STOPDAPT-2 ACS reduced the heterogeneity (RR: 0.78 [0.70, 0.88]; p < 0.001; I2 = 27%; Supplementary Figure S5).
Figure 1.
Net adverse clinical events.
Table 2.
Subgroup Analyses of Treatment Effects Comparing P2Y12 Inhibitor Monotherapy Versus Standard DAPT by Type of P2Y12 Inhibitor and the Timing of Aspirin Withdrawal.
| Subgroup A | Subgroup B | Subgroup C | Outcome | Chi-Square | p for Interaction |
|---|---|---|---|---|---|
| Ticagrelor | Clopidogrel | Prasugrel | NACE | 2.08 | 0.35 |
| BARC 3 or 5 bleeding | 1.36 | 0.51 | |||
| MACE | 9.44 | 0.009 | |||
| All-cause mortality | 6.8 | 0.03 | |||
| Stent thrombosis | 4.92 | 0.09 | |||
| Myocardial infarction | 2.59 | 0.27 | |||
| Stroke | 1.73 | 0.42 | |||
| Cardiovascular death | 3.36 | 0.19 | |||
| Early Aspirin Withdrawal | Delayed Aspirin Withdrawal | - | NACE | 0.02 | 0.88 |
| BARC 3 or 5 bleeding | 0.81 | 0.37 | |||
| MACE | 0.01 | 0.94 | |||
| All-cause mortality | 0.08 | 0.77 | |||
| Stent thrombosis | 0.69 | 0.41 | |||
| Myocardial infarction | 0.33 | 0.56 | |||
| Stroke | 1.4 | 0.24 | |||
| Cardiovascular death | 1.97 | 0.16 |
BARC Type 3 or 5 Bleeding
BARC type 3 or 5 bleeding was reported by ten studies. A meta-analysis revealed that P2Y12 inhibitor monotherapy significantly reduced the risk of BARC type 3 or 5 bleeding compared with standard DAPT (RR: 0.48 [0.40, 0.58]; p < 0.001; I2 = 0%; Figure 2). Subgroup analysis did not show effect modification by duration of aspirin withdrawal (p-interaction: 0.37; Supplementary Figure S6) or by the type of P2Y12 inhibitor used (p-interaction: 0.51; Supplementary Figure S7) (Table 2).
Figure 2.
BARC type 3 or 5 bleeding.
Major Adverse Cardiovascular Events
Ten studies reported MACE. A meta-analysis showed that P2Y12 inhibitor monotherapy was not associated with a significant difference in risk of MACE compared with standard DAPT (RR: 1.01 [0.86, 1.19]; p = 0.87; I2 = 41%; Figure 3). Subgroup analysis did not show effect modification by duration of aspirin withdrawal (p-interaction: 0.94; Supplementary Figure S8) When stratified by the type of P2Y12 inhibitor used, all three — ticagrelor (RR: 0.90 [0.78, 1.04]; p = 0.15, I2 = 0), clopidogrel (RR: 1.40 [1.02, 1.92]; p = 0.04, I2 = 14%), and prasugrel (RR: 1.27 [0.98, 1.65]; p = 0.08) showed variable effects on MACE, with a greater reduction observed in the ticagrelor subgroup (p-interaction = 0.009; Supplementary Figure S9) (Table 2). Sensitivity analysis by removing STOPDAPT-2 ACS reduced heterogeneity considerably (RR: 0.98 [0.85, 1.12]; p = 0.74; I2 = 16%; Supplementary Figure S10).
Figure 3.
Major adverse cardiovascular evets.
All-Cause Mortality
All-cause mortality was reported by ten studies. A meta-analysis showed that P2Y12 inhibitor monotherapy was not associated with a significant difference in all-cause mortality compared with standard DAPT (RR: 0.96 [0.80, 1.16]; p = 0.69; I2 = 4%; Figure 4). Subgroup analysis did not show effect modification by duration of aspirin withdrawal (p-interaction: 0.77; Supplementary Figure S11) (Table 2). When stratified by the type of P2Y12 inhibitor used, all three — ticagrelor (RR: 0.78 [0.62, 1.00]; p = 0.05, I2 = 0), clopidogrel (RR: 1.33 [0.87, 2.04]; p = 0.19, I2 = 0), and prasugrel (RR: 1.23 [0.85, 1.77]; p = 0.27) showed variable effects on all-cause mortality, with a greater reduction observed in the ticagrelor subgroup (p-interaction = 0.03; Supplementary Figure S12) (Table 2). Sensitivity analysis by removing STOPDAPT-2 ACS reduced heterogeneity to zero (RR: 0.92 [0.76, 1.11]; p = 0.38; I2 = 0%; Supplementary Figure S13).
Figure 4.
All-cause mortality.
Stent Thrombosis
Stent thrombosis was reported by ten studies. A meta-analysis showed that P2Y12 inhibitor monotherapy was not associated with a significant difference in the risk of stent thrombosis compared with standard DAPT (RR: 1.24 [0.84, 1.82]; p = 0.28; I2 = 0%; Figure 5). Subgroup analysis did not show effect modification by duration of aspirin withdrawal (p-interaction: 0.41; Supplementary Figure S14) or by the type of P2Y12 inhibitor used (p-interaction: 0.09; Supplementary Figure S15) (Table 2).
Figure 5.
Stent thrombosis.
Myocardial Infarction
MI was reported by ten studies. A meta-analysis showed that P2Y12 inhibitor monotherapy was not associated with a significant difference in the risk of MI compared with standard DAPT (RR: 1.06 [0.86, 1.32]; p = 0.59; I2 = 22%; Figure 6). Subgroup analysis did not show effect modification by duration of aspirin withdrawal (p-interaction: 0.56; Supplementary Figure S16) or by the type of P2Y12 inhibitor used (p-interaction: 0.27; Supplementary Figure S17) (Table 2). Sensitivity analysis by removing STOPDAPT-2 ACS reduced heterogeneity to zero (RR: 1.00 [0.84, 1.20]; p = 0.99; I2 = 0%; Supplementary Figure S18).
Figure 6.
Myocardial infarction.
Stroke
Stroke was reported by ten studies. A meta-analysis showed that P2Y12 inhibitor monotherapy was not associated with a significant difference in the risk of stroke compared with standard DAPT (RR: 1.17 [0.89, 1.52]; p = 0.25; I2 = 0%; Figure 7). Subgroup analysis did not show effect modification by duration of aspirin withdrawal (p-interaction: 0.24; Supplementary Figure S19) or by the type of P2Y12 inhibitor used (p-interaction: 0.42; Supplementary Figure S20) (Table 2).
Figure 7.
Stroke.
Cardiovascular Death
Cardiovascular death was reported by nine studies. A meta-analysis showed that P2Y12 inhibitor monotherapy was not associated with a significant difference in the risk of cardiovascular death compared with standard DAPT (RR: 0.93 [0.72, 1.20]; p = 0.59; I2 = 0%; Figure 8). Subgroup analysis did not show effect modification by duration of aspirin withdrawal (p-interaction: 0.16; Supplementary Figure S21) or by the type of P2Y12 inhibitor used (p-interaction: 0.19; Supplementary Figure S22) (Table 2).
Figure 8.
Cardiovascular death.
Grade Certainty of the Evidence
The certainty of evidence for comparing P2Y12 monotherapy with P2Y12 plus aspirin in acute coronary syndrome was predominantly high. Findings were consistent across key outcomes. High-certainty evidence supported significant reductions in BARC type 3 or 5 bleeding, favoring P2Y12 monotherapy. Similarly, NACE, MACE, and MI were supported by high-certainty evidence. This indicates robust benefit with P2Y12 alone. Moderate-certainty evidence suggested P2Y12 monotherapy likely results in little or no difference in all-cause mortality, stroke, and stent thrombosis. In contrast, evidence for cardiovascular death was of low certainty, reflecting some imprecision and variability across studies. Overall, these findings suggest that P2Y12 monotherapy maintains similar efficacy to dual antiplatelet therapy while significantly reducing the risk of bleeding (Table 3).
Table 3.
GRADE Certainty Assessment and Summary of Findings Table.
| [ p2y12i] compared to [p2y12i + aspirin] for [Acute coronary syndrome] | ||||||
|---|---|---|---|---|---|---|
|
Patient or population: [Acute coronary syndrome] Setting: Intervention: [ p2y12i] Comparison: [p2y12i + aspirin] | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect (95% CI) |
№ of participants (studies) |
Certainty of the evidence (GRADE) |
Comments | |
| Risk with [p2y12i + aspirin] | Risk with [ p2y12i] | |||||
| ALL CAUSE MORTALITY | 13 per 1000 |
12 per 1000 (10 to 15) |
RR 0.96 (0.80 to 1.16) |
37692 (10 RCTs) |
⊕⊕⊕◯ Moderatea,b |
[ p2y12i] likely results in little to no difference in ALL CAUSE MORTALITY. |
| BARC TYPE 3 OR 5 | 18 per 1000 |
8 per 1000 (7 to 10) |
RR 0.48 (0.40 to 0.58) |
37597 (10 RCTs) |
⊕⊕⊕⊕ Highc |
[ p2y12i] results in a reduction in BARC TYPE 3 OR 5. |
| CV Death | 8 per 1000 |
8 per 1000 (6 to 10) |
RR 0.93 (0.72 to 1.20) |
30251 (9 RCTs) |
⊕⊕◯◯ Lowd |
The evidence suggests that [ p2y12i] results in little to no difference in CV Death. |
| STROKE | 5 per 1000 |
6 per 1000 (5 to 8) |
RR 1.17 (0.89 to 1.52) |
37631 (10 RCTs) |
⊕⊕⊕◯ Moderatee |
[ p2y12i] probably results in little to no difference in STROKE. |
| MACE | 30 per 1000 |
31 per 1000 (26 to 36) |
RR 1.01 (0.86 to 1.19) |
37553 (10 RCTs) |
⊕⊕⊕⊕ Highf |
[ p2y12i] results in little to no difference in MACE. |
| MI | 14 per 1000 |
14 per 1000 (12 to 18) |
RR 1.06 (0.86 to 1.32) |
37571 (10 RCTs) |
⊕⊕⊕⊕ Highg |
[ p2y12i] results in little to no difference in MI. |
| NACE | 59 per 1000 |
48 per 1000 (42 to 53) |
RR 0.80 (0.71 to 0.90) |
37415 (10 RCTs) |
⊕⊕⊕⊕ High |
[ p2y12i] results in large reduction in NACE. |
| STENT THROMBOSIS | 3 per 1000 |
3 per 1000 (2 to 5) |
RR 1.24 (0.84 to 1.82) |
37609 (10 RCTs) |
⊕⊕⊕◯ Moderateh |
[ p2y12i] probably results in little to no difference in STENT THROMBOSIS. |
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio
|
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. |
Explanations
a. Forest plot shows wide confidence intervals and likely variability across studies; overlapping but differing effect estimates suggest moderate heterogeneity.
b. The total events are low (all-cause mortality rare in this comparison), and confidence intervals cross the line of no effect — downgraded for imprecision.
c. Confidence intervals likely include both benefit and harm (borderline or wide CI), reducing precision.
d. "Serious imprecision due to the confidence interval (RR 0.93; 95% CI: 0.72 to 1.20) crossing the line of no effect (1.0), and including both a potential appreciable benefit and harm. Although the number of events (239 total) is relatively adequate, the result is not statistically significant, and the confidence interval includes both potential benefit and harm, lowering certainty in the effect estimate."
e. Serious imprecision due to the 95% confidence interval (RR 1.17, 95% CI 0.92 to 1.50) crossing the line of no effect and including both potential benefit and harm. Although event count (n=224) is reasonable, statistical significance is not reached
f. The pooled estimate shows a wide 95% CI that crosses the line of no effect, and the event rate is low (mortality rare) → downgraded for imprecision.
g. 95% CI of the pooled RR crosses the line of no effect and includes both potential benefit and harm; event rates are modest.
h. Few events and wide confidence intervals; the estimate is imprecise.
Discussion
The main findings of this meta-analysis were that P2Y12 inhibitor monotherapy after 1 to 3 months of DAPT significantly reduced the risk of NACE compared with continued DAPT. There was no significant difference in MACE. No significant differences were seen in all-cause mortality, stent thrombosis, MI, stroke, or cardiovascular death. For the secondary outcomes, P2Y12 monotherapy led to a substantial reduction in bleeding events (BARC type 3 or 5).
Standard practice currently endorses DAPT, consisting of aspirin combined with a P2Y12 receptor inhibitor after implantation of a DES. Patients with stable coronary artery disease (CAD) receive this for at least 6 months. Those with ACS continue for 12 months. 25 In the context of primary PCI for ST-segment elevation myocardial infarction (STEMI), guidelines recommend the early administration of a P2Y12 receptor antagonist, such as clopidogrel, with a 600 mg loading dose. This is followed by a maintenance dose of 75 mg daily for one year in patients receiving a stent. 26
The evolution of PCI technology and pharmacotherapy has prompted reconsideration of DAPT durations. Advances, such as new-generation DES featuring thinner struts and more biocompatible polymers, have reduced the risk of stent thrombosis and other adverse events. Additionally, potent P2Y12 inhibitors (ticagrelor, prasugrel) are now available. Increasing recognition of the prognostic impact of bleeding complications also shapes decision-making. As balancing ischemic protection and bleeding risk becomes crucial,27,28 interest is growing in antithrombotic strategies that shorten DAPT and transition to P2Y12 inhibitor monotherapy. 29 These approaches aim to maintain efficacy while improving safety in contemporary PCI practice.
Although previous meta-analyses have concluded that P2Y12 inhibitor monotherapy is effective in reducing bleeding in ACS, they have been limited by either lacking a comparison against a standard DAPT or in specifically evaluating outcomes after PCI. 9 To the bespet of our knowledge, this is the most updated meta-analysis since that of M.Galli et al to specifically evaluate NACE as the primary composite endpoint by comparing P2Y12 inhibitor monotherapy and extended dual antiplatelet therapy after PCI in ACS patients. This directly addresses the clinical balance between ischemic protection and bleeding risk in DAPT de-escalation. M. Galli et al reported that P2Y12 inhibitor monotherapy after short DAPT reduced bleeding without increasing ischemic events in ACS patients. Ticagrelor monotherapy showed superior outcomes compared with clopidogrel, providing conclusive evidence for improved net clinical benefit versus prolonged DAPT. In contrast, a previous meta-analysis examined aspirin monotherapy versus P2Y12 inhibitor monotherapy after short DAPT for PCI in ACS, focusing on a different therapeutic question. 10
Our meta-analysis incorporated three recently published RCTs—SHARE, NEOMINDSET, and TARGET FIRST,17–19 thereby expanding the current evidence base. By including these trials, our study more comprehensively evaluates the strategy of withdrawing aspirin and continuing P2Y12 inhibitor monotherapy versus maintaining prolonged DAPT. The addition of these recent RCTs and a larger cumulative sample size strengthens the robustness and precision of the pooled estimates, providing more conclusive evidence supporting the potential net clinical benefit of P2Y12 inhibitor monotherapy compared with extended DAPT.
The greater net benefit of P2Y12 inhibitor monotherapy compared to extended DAPT is biologically plausible. Aspirin inhibits cyclooxygenase-1 and reduces prostaglandin synthesis, impairing gastric mucosal protection and cerebral vessel autoregulation. In turn, aspirin may cause gastrointestinal and intracranial bleeding.30,31 By contrast, P2Y12 receptor inhibitors act selectively on the ADP-mediated platelet activation pathway, thereby avoiding toxicities associated with prostaglandin-mediated effects. Potent P2Y12 agents such as ticagrelor and prasugrel provide more rapid, potent, and consistent platelet inhibition compared to clopidogrel. Clopidogrel's efficacy is limited by interindividual variability and CYP2C19-dependent metabolism. 32 These pharmacologic differences help explain why trials using ticagrelor or prasugrel showed reductions in bleeding without an increase in ischemic events, whereas strategies relying on clopidogrel suggested a possible excess ischemic risk when aspirin was withdrawn early. A meta-analysis of recent trials found that early discontinuation of aspirin and continuation of P2Y12 inhibitor monotherapy did not raise the risk of major adverse cardiovascular events and reduced the risk of bleeding compared to standard 12-month DAPT. 33
As stated earlier, most trials that supported the benefit used potent P2Y12 inhibitors (ticagrelor/prasugrel) and withdrew aspirin after 1–3 months of DAPT. In contrast, the discordant trials led to moderate heterogeneity for some ischemic endpoints. STOPDAPT-2 ACS used clopidogrel monotherapy after only 1–2 months of DAPT in ACS patients—a less potent regimen in this high-risk group. 24 This likely led to a numerically higher incidence of ischemic events. It contributed to moderate heterogeneity in NACE and MACE. Heterogeneity was reduced after excluding STOPDAPT-2 ACS. NEO-MINDSET tested immediate aspirin discontinuation after PCI with potent P2Y12 inhibitors, leading to an early excess of ischemic events, including stent thrombosis, and further increased variability in MACE and mortality outcomes. 20 Excluding NEO-MINDSET with STOPDAPT-2 ACS eliminated heterogeneity for MACE and all-cause mortality, making the results consistent across the remaining trials.
These patterns suggest heterogeneity primarily stemmed from multiple factors. First, the groups compared the potency of P2Y12 inhibitors—clopidogrel (less potent) and ticagrelor/prasugrel (more potent) with DAPT courses. Second, studies differed in the timing of aspirin withdrawal: some were immediate, others after 1–3 months. Third, trial design and population characteristics varied, including ACS severity, blinding, and endpoint adjudication. When studies with divergent designs or less potent P2Y12 agents were excluded, the pooled estimates became homogeneous and specifically supported the safety of short-course DAPT compared to longer DAPT, when followed by potent P2Y12 monotherapy.
Overall, the evidence shows that the safety and efficacy of P2Y12 inhibitor monotherapy depend critically on both the P2Y12 agent and the timing of aspirin withdrawal. Ticagrelor- or prasugrel-based regimens, with aspirin stopped after 1–3 months, provide the most consistent balance of reduced bleeding and preserved ischemic protection.
The totality of evidence supports consideration of updates to clinical guidelines, prompting guideline-making bodies to incorporate agent- and timing-specific de-escalation pathways rather than one-size-fits-all DAPT durations. From a research perspective, new randomized trials are warranted for underrepresented groups, such as elderly patients, those requiring chronic anticoagulation, individuals at high bleeding risk, or complex PCI populations. Additionally, conducting head-to-head comparisons of monotherapy agents (ticagrelor vs prasugrel vs clopidogrel) in prespecified subgroups remains important. Longer-term follow-up will help track late ischemic events. Whenever practice changes, robust monitoring for rare ischemic complications, comprehensive education for patients and clinicians, and thoughtful consideration of drug availability and cost across healthcare settings are essential.
Limitations
Despite the strengths of this meta-analysis, several limitations should be noted. First, this meta-analysis used trial-level aggregate data; time-to-event analysis and Kaplan-Meier curves could not be evaluated, limiting assessment of event timing and early-versus-late hazard differences. Second, trial designs differed, including the type of P2Y12 inhibitor, the timing of aspirin withdrawal, and the duration of monotherapy; these differences could affect the pooled effect estimates. Third, studies enrolled patients from diverse populations, from high-risk ACS to stable coronary artery disease, which may limit generalizability. Fourth, some trials had limited follow-up, making the long-term safety and efficacy of P2Y12 monotherapy beyond 23 months unclear. Fifth, the effect sizes for some outcomes were derived from a small number of studies and may not have reached statistical significance due to limited sample sizes. There was an imbalance in the number of studies and patients treated with ticagrelor compared with clopidogrel, with ticagrelor serving as the primary P2Y₁₂ inhibitor in seven of the ten studies, clopidogrel in two, and prasugrel in one. This predominance of ticagrelor may have introduced bias in estimating the overall treatment effect. In addition, this analysis was at the trial level, and an individual-patient meta-analysis may be informative, particularly for evaluating potential heterogeneity across subgroups. Finally, because most trials evaluated potent P2Y12 inhibitors, such as ticagrelor or prasugrel, the results may not be applicable in settings where only clopidogrel is available.
Conclusion
This meta-analysis shows that early transition to P2Y12 inhibitor monotherapy after a short DAPT course in ACS patients undergoing PCI effectively reduces bleeding events and does not increase ischemic risk. The findings support a shift to individualized antiplatelet strategies, especially with ticagrelor- or prasugrel-based monotherapy after 1–3 months of DAPT. This is a safe and efficacious alternative to conventional 12-month DAPT. More large-scale, long-term studies are needed to clarify optimal timing, agent selection, and use across different patient populations.
Supplemental Material
Supplemental material, sj-docx-1-cat-10.1177_10760296261422490 for Potent P2Y12 Inhibitor Monotherapy Versus Dual Antiplatelet Therapy After Percutaneous Coronary Intervention for Acute Coronary Syndromes: A Systematic Review and Meta-Analysis by Muhammad Ibrahim, Shahtaj Tariq, Muhammad Khalid Afridi, Aroosa Zafar, Fawaz Ahmed Khamisani and Hasibullah Aminpoor, S. M. Washaqul Arfin, Gregg C. Fonarow, Stephen J. Greene, Muzammil H. Musani, Saad Ahmed Waqas in Clinical and Applied Thrombosis/Hemostasis
Acknowledgements
The authors sincerely thank Muhammad Faizur Rahman for his valuable support in addressing the reviewers’ comments and assisting with the revision of the manuscript.
Abbreviations
- DAPT
dual antiplatelet therapy
- ACS
acute coronary syndrome
- PCI
percutaneous coronary intervention
- NACE
net adverse clinical events
- MACE
major adverse cardiovascular events
- MI
myocardial infarction
- DES
drug-eluting stent
- RCT
randomized control trials
Footnotes
ORCID iDs: Aroosa Zafar https://orcid.org/0009-0002-2050-6351
Hasibullah Aminpoor https://orcid.org/0000-0003-1817-7800
Ethics Approval: Not applicable. This study is a systematic review and meta-analysis of previously published data, and therefore did not require approval by an Institutional Review Board or Ethics Committee.
Human Ethics and Consent to Participate Declarations: not applicable.
Author Contributions: Conceptualization: Muhammad Ibrahim
Data curation: S M Washaqul Arfin
Formal analysis: Muhammad Ibrahim
Investigation: Fawaz Ahmed Khamisani, Hasibullah Aminpoor
Methodology: Muhammad Khalid Afridi
Project administration: Saad Ahmed Waqas, Muzammil H. Musani
Supervision: Muhammad Ibrahim
Validation: Gregg C. Fonarow, Stephen J. Greene
Visualization: Aroosa Zafar
Writing – original draft: Shahtaj Tariq, Muhammad Ibrahim
Writing – review and editing: Muhammad Ibrahim, Saad Ahmed Waqas
Funding: The authors received no financial support for the research, authorship, and/or publication of this article.
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Glossary: ACS (Acute Coronary Syndrome): A spectrum of conditions caused by reduced blood flow to the heart, including unstable angina and myocardial infarction.
PCI (Percutaneous Coronary Intervention): A non-surgical procedure to open narrowed coronary arteries, often with stent placement.
DAPT (Dual Antiplatelet Therapy): Combination of aspirin and a P2Y12 inhibitor used after PCI to prevent thrombotic events.
P2Y12 Inhibitors: Antiplatelet agents (eg, clopidogrel, ticagrelor, prasugrel) that block the P2Y12 receptor on platelets to prevent aggregation.
NACE (Net Adverse Clinical Events): Composite endpoint combining ischemic and bleeding outcomes to assess overall treatment benefit.
MACE (Major Adverse Cardiovascular Events): Includes cardiovascular death, myocardial infarction, or stroke.
BARC (Bleeding Academic Research Consortium) Classification: A standardized scale to grade bleeding severity in cardiovascular trials.
I2 Statistic: Quantifies heterogeneity in meta-analyses, indicating how much variability in results is due to differences between studies.
RR (Risk Ratio): Compares the probability of an event occurring between treatment and control groups.
GRADE (Grading of Recommendations, Assessment, Development and Evaluations): Framework used to assess certainty of evidence in systematic reviews.
Supplemental Material: Supplemental material for this article is available online.
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Associated Data
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Supplementary Materials
Supplemental material, sj-docx-1-cat-10.1177_10760296261422490 for Potent P2Y12 Inhibitor Monotherapy Versus Dual Antiplatelet Therapy After Percutaneous Coronary Intervention for Acute Coronary Syndromes: A Systematic Review and Meta-Analysis by Muhammad Ibrahim, Shahtaj Tariq, Muhammad Khalid Afridi, Aroosa Zafar, Fawaz Ahmed Khamisani and Hasibullah Aminpoor, S. M. Washaqul Arfin, Gregg C. Fonarow, Stephen J. Greene, Muzammil H. Musani, Saad Ahmed Waqas in Clinical and Applied Thrombosis/Hemostasis