P2Y₁₂ inhibitor monotherapy after short DAPT in acute coronary syndrome: a systematic review and meta-analysis

Abstract

Background

P2Y₁₂ inhibitor monotherapy after a short course of dual antiplatelet therapy (DAPT) may balance ischaemic and bleeding risks in patients with acute coronary syndrome (ACS). However, it remains uncertain how different P2Y₁₂ inhibitors used as monotherapy affect outcomes.

Methods and results

Randomized controlled trials comparing P2Y₁₂ inhibitor monotherapy after a short course of DAPT (≤3 months) vs. 12-month DAPT in ACS were included. The primary endpoint was major adverse cardiovascular events (MACE). All analyses included an interaction term for the P2Y₁₂ inhibitor used as monotherapy. Trial sequential analyses were run to explore whether the effect estimate of each outcome may be affected by further studies. Seven trials encompassing 27 284 ACS patients were included. Compared with 12-month DAPT, P2Y₁₂ inhibitor monotherapy after a short course of DAPT was associated with no difference in MACE [odds ratio (OR) 0.92, 95% confidence interval (CI) 0.76–1.12] and a significant reduction in net adverse clinical events (NACE) (OR 0.75; 95% CI 0.60–0.94), any bleeding (OR 0.54, 95% CI 0.43–0.66), and major bleeding (OR 0.47, 95% CI 0.37–0.60). Significant interactions for subgroup difference between ticagrelor and clopidogrel monotherapy were found for MACE (P_int = 0.016), all-cause death (P_int = 0.042), NACE (P_int = 0.018), and myocardial infarction (P_int = 0.028). Trial sequential analysis showed conclusive evidence of improved NACE with ticagrelor, but not with clopidogrel monotherapy, compared with standard DAPT.

Conclusions

In patients with ACS, P2Y₁₂ inhibitor monotherapy after short DAPT halves bleeding without increasing ischaemic events compared with standard DAPT. Ticagrelor, but not clopidogrel monotherapy, reduced MACE, NACE, and mortality compared with standard DAPT, supporting its use after aspirin discontinuation.

Graphical Abstract

Forest plots of the main outcomes for the comparison of P2Y₁₂ inhibitor monotherapy after a short course of DAPT vs. standard DAPT and subgroup analysis according to the P2Y₁₂ inhibitor used after aspirin discontinuation. The figure illustrates the treatment effect estimate for pre-specified endpoints comparing P2Y₁₂ inhibitor monotherapy after a short course of DAPT and standard DAPT along with results in the specific subgroup of P2Y₁₂ inhibitor administered. For each endpoint, results of the pooled analysis of short DAPT are presented on top and highlighted by a light blue box, while results of the specific subgroups are shown subsequently. Each treatment estimate and respective 95% CI are illustrated by one circle and line, respectively, along with text highlighting the specific OR and 95% CI, trial sequential analysis result, and P_int. Abbreviations: CI, confidence interval; Clopi, clopidogrel; DAPT, dual antiplatelet therapy; GRADE, Grading of Recommendation Assessment, Development, and Evaluations; MACE, major adverse cardiovascular events; NACE, net adverse clinical events; OR, odds ratio; P_int, P for interaction; Pra, prasugrel; Tica, ticagrelor.

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Introduction

In patients with acute coronary syndrome (ACS), dual antiplatelet therapy (DAPT) for 12 months combining aspirin and a potent P2Y₁₂ inhibitor (i.e. ticagrelor, prasugrel) is the standard of care for the treatment and prevention of ischaemic events.¹ However, the benefits of DAPT are offset by an increase in bleeding, a complication closely associated with mortality.² After an ACS or percutaneous coronary intervention (PCI), the risk of ischaemic events is initially high (i.e. 1–3 months) and gradually decreases thereafter, while the risk of bleeding tends to remain stable over time.³ To deal with these dynamic fluctuations in bleeding and ischaemic risks, DAPT de-escalation strategies have been proposed to improve safety without compromising efficacy.⁴

Short DAPT by discontinuing the P2Y₁₂ inhibitor 3–6 months after ACS and maintaining aspirin monotherapy has been one of the first DAPT de-escalation strategies to be implemented.^3,4 However, due to a numerical increase in ischaemic events compared with standard 12-month DAPT, particularly in patients with ACS,^5,6 this strategy has been selectively recommended for high bleeding risk (HBR) patients.¹ A strategy of P2Y₁₂ inhibitor monotherapy while discontinuing aspirin after a short course of DAPT has also been explored, showing overall more promising results.^7–10 However, it remains debated whether the specific P2Y₁₂ inhibitor used as monotherapy may differentially affect safety and efficacy outcomes. Clopidogrel, but not ticagrelor or prasugrel, is associated with broad interindividual variability in pharmacological response, resulting in high platelet reactivity (HPR), a marker of thrombotic risk, in nearly 30% of patients, raising concerns about the efficacy of a strategy of P2Y₁₂ inhibitor monotherapy with clopidogrel, particularly in high-risk patients such as those with ACS.¹¹ We therefore sought to perform an updated systematic review and meta-analysis of randomized controlled trials (RCTs) that compared P2Y₁₂ inhibitor monotherapy after a short course of DAPT (≤3 months) vs. standard 12-month DAPT, stratified by the P2Y₁₂ inhibitor used in the monotherapy arm, in patients with ACS.

Methods

The study protocol adhered to the 2020 recommendations of Preferred Reporting Items for Systematic Reviews and Meta-Analyses for pairwise meta-analyses of RCTs (Supplementary  material online, Table S1) and Cochrane Collaboration.^12,13 The study protocol is registered in PROSPERO (CRD42023494797). As the present research was a meta-analysis of published studies, the requirement for ethics committee approval was waived.

Eligibility criteria

Studies were considered for the inclusion in the meta-analysis if they satisfied the following criteria: (i) inclusion of patients presenting with ACS undergoing PCI with drug-eluting stent (DES) implantation; (ii) random allocation to P2Y₁₂ inhibitor monotherapy after initial DAPT or standard 12-month DAPT; and (iii) reporting at least one of the pre-specified endpoints of interest. Studies focusing on patients with an indication to oral anticoagulation therapy or using antiplatelet agents other than oral P2Y₁₂ inhibitors were excluded. No language restrictions were imposed.

Search, data extraction, and qualitative assessment

The detailed search strategy for each database is reported in Supplementary  material online, Table S2. Information sources included MEDLINE through PubMed, Cochrane, and Web of Science databases from January 2009 to June 2024. Websites of leading cardiology societies, news outlets, and reference lists of each eligible study were also inspected. Two investigators (G.O. and M.S.) independently screened the studies and disagreements were resolved by consensus. Data pertaining to the outcomes of interest, as well as the primary clinical and procedural characteristics, were extracted at the study level and entered into dedicated electronic spreadsheets. Key trial-level data, encompassing design features, follow-up duration, and endpoint definition, were extensively summarized. Before running the statistical analyses, the reviewers collegially assessed the quality of each trial by using the Cochrane's Risk of Bias (RoB) 2 tool.¹⁴ Posterior qualitative assessment of the meta-analysis results was also performed through Grading of Recommendations, Assessment, Development, and Evaluations (GRADE).¹⁵ Publication bias was assessed by visual assessment of contour-enhanced funnel plots and Egger's regression test and results were corrected through trim and fill method for those endpoints suspected of publication bias.¹⁶

Endpoints

The pre-specified primary endpoint was trial defined major adverse cardiovascular events (MACE). Secondary endpoints included net benefit endpoints [i.e. all-cause death and trial-defined net adverse clinical events (NACE)], individual ischaemic endpoints [i.e. cardiovascular death, myocardial infarction (MI), stroke, and stent thrombosis], and bleeding endpoints (i.e. any bleeding and trial-defined major bleeding). In cases where a study reported multiple definitions of MACE or major bleeding, our approach was to prioritize those definitions more aligned with the Academic Research Consortium recommendations.^17,18

Statistical analysis

To account for biological variability and the absence of significant difference on follow-up times between studies included, pairwise meta-analysis through frequentist random-effects restricted maximum likelihood model was performed to compute odds ratios (ORs) and 95% confidence intervals (CIs) for each outcome of interest. To explore possible differences in outcomes between ticagrelor and clopidogrel monotherapy compared with DAPT, all analyses included a pre-specified interaction analysis by means of Z- and Q-test for subgroups depending on the P2Y₁₂ inhibitor administered in the monotherapy arm.¹⁹ Absolute risk reduction and number needed to treat to benefit (NNTB) or harm (NNTH) were calculated based on the absolute risk differences.

Statistical heterogeneity was assessed through τ², I², and prediction intervals. Further exploration of individual trial heterogeneity against individual trial impact was performed for those endpoints with significant heterogeneity, in order to detect possible outliers influencing effect-size estimation.²⁰

Sensitivity analyses were conducted by repeating the analyses within trials selectively including East Asian patients, trials using very short (≤1 month) DAPT and trials using short (3 months) DAPT in the experimental arm. Finally, trial sequential analysis to evaluate whether the results could be deemed conclusive or not was performed for each outcome and in each subgroup for all pre-specified endpoints.²¹ All analyses were performed using R 4.3.1.

Results

Study selection and baseline characteristics

The selection process is summarized in Figure 1. After screening, seven RCTs with a total of 27 284 patients were selected, appraised for quality, and included in the meta-analysis.^22–28 Of these, five trials used a strategy of ticagrelor monotherapy against ticagrelor-based DAPT^22–26 and two trials clopidogrel monotherapy against clopidogrel-based DAPT.^27,28 Four trials explored the effects of P2Y₁₂ inhibitor monotherapy after 1-month DAPT and three trials after 3-month DAPT course. Mean DAPT duration in the P2Y₁₂ inhibitor monotherapy arm was 51 days.

Table 1 summarizes the key characteristics of included trials. Demographic and procedural characteristics were similar between treatment arms (P2Y₁₂ inhibitor monotherapy vs. 12-month DAPT) (Supplementary material online, Tables S3–S4). In the study population, weighted mean age was 63.5 years, women represented the 22.5% and diabetes mellitus the 27.7% of patients. Available endpoints across included trials are displayed in Supplementary material online, Table S5, while endpoint definitions across included trials are displayed in Supplementary material online, Table S6.

Supplementary material online, Figures S1 and S2 display the overall and individual risk of bias of included trials, respectively. One study reported a high risk of bias due to unbalanced deviations from intended interventions,²⁷ while some concerns arose in two studies due to the lack of stratification for ACS presentation.^22,23 Although Egger's regression test suggested the absence of publication bias, the visual inspection of the funnel plots revealed slight asymmetry for NACE, any bleeding, and major bleeding (Supplementary material online, Figure S3).

Primary endpoint

The pooled analysis showed no difference in MACE between P2Y₁₂ inhibitor monotherapy after short DAPT versus 12-month DAPT (OR 0.92; 95% CI 0.76–1.12; P = 0.424; NNTB = 475) with moderate heterogeneity (τ² = 0.027; I² = 37%; prediction interval = 0.57–1.51) (Figure 2). The quality of evidence was deemed low (Supplementary material online, Table S7). Of note, the pre-specified subgroup analysis by the P2Y₁₂ inhibitor used in the monotherapy arm showed a significant interaction (P_int = 0.016), with a reduction in MACE in trials of ticagrelor monotherapy (OR 0.84; 95% CI 0.71–0.98; P = 0.028; NNTB = 206) but not in trials of clopidogrel monotherapy (OR 1.32; 95% CI 0.94–1.84; P = 0.105; NNTH = 140), and low heterogeneity in both subgroups (Figure 3). Quality of evidence was deemed moderate for ticagrelor monotherapy and very low for clopidogrel monotherapy (Supplementary material online, Table S7).

Secondary endpoints

Net benefit and mortality

P2Y₁₂ inhibitor monotherapy after short DAPT significantly reduced NACE (OR 0.75; 95% CI 0.60–0.94; P = 0.011; NNTB = 72) and was associated with a non-significant reduction in all-cause death compared to 12-month DAPT (Figure 2), with high heterogeneity for NACE (τ² = 0.025; I² = 68%; prediction interval = 0.22–2.71) and low heterogeneity for all-cause death (τ² = 0.019; I² = 23%; prediction interval = 0.46–1.57). There was a significant interaction for subgroup difference according to the P2Y₁₂ inhibitor used for both all-cause death (P_int = 0.042) and NACE (P_int = 0.018). Ticagrelor (OR 0.70; 95% CI 0.58–0.84; P < 0.001; NNTB = 53), but not clopidogrel monotherapy (OR 1.16; 95% CI 0.79–1.63; P = 0.487; NNTH = 272) reduced NACE. Similarly, ticagrelor (OR 0.77; 95% CI 0.61–0.98; P = 0.035; NNTB = 334), but not clopidogrel monotherapy (OR 1.49; 95% CI 0.80–2.69; P = 0.179; NNTH = 224) reduced all-cause death. Within the specific subgroups, heterogeneity was moderate for NACE in the ticagrelor (τ² = 0.016; I² = 46%; prediction interval = 0.35–1.34) but not clopidogrel (τ² = 0.000; I² = 0%) subgroup, and low for all-cause death in both ticagrelor (τ² = 0.000; I² = 0%; prediction interval = 0.53–1.14) and clopidogrel monotherapy (τ² = 0.000; I² = 0%) (Figure 3). The quality of evidence supporting results on all-cause death and NACE was deemed moderate in the pooled analysis and in both monotherapy subgroups (Supplementary material online, Table S7).

Individual ischaemic endpoints

Compared with 12-month DAPT, P2Y₁₂ inhibitor monotherapy after short DAPT was not associated with an increased risk of ischaemic events (Figure 2). Heterogeneity was high for MI (τ² = 0.119; I² = 51%; prediction interval = 0.33–3.05) and low for all other ischaemic endpoints. There was a significant interaction for subgroup difference in MI according to the P2Y₁₂ inhibitor used (P_int = 0.028). Ticagrelor monotherapy was associated with a non-significant reduction in MI, while clopidogrel monotherapy with an increased risk of MI (OR 1.87; 95% CI 1.05–3.32; P = 0.034; NNTH = 136) with low heterogeneity in both subgroups (τ² = 0.035; I² = 24% for ticagrelor and τ² = 0.000; I² = 0% for clopidogrel monotherapy) (Figure 3).

Overall, the quality of evidence for ischaemic endpoints was high for cardiovascular death and low for MI, while other ischaemic endpoints relied on moderate quality of evidence (Supplementary  material online, Table S7). Within P2Y₁₂ inhibitor monotherapy subgroups, the quality of evidence for ticagrelor monotherapy was high for cardiovascular death and moderate for other endpoints, while for clopidogrel monotherapy was moderate for all ischaemic endpoints.

Bleeding endpoints

P2Y₁₂ inhibitor monotherapy after short DAPT was associated with a significant reduction in any bleeding (OR 0.54; 95% CI 0.43–0.66; P < 0.001; NNTB = 46) and major bleeding (OR 0.47; 95% CI 0.37–0.60; P < 0.001; NNTB = 83), with high heterogeneity for any bleeding (τ² = 0.040; I² = 59%; prediction interval = 0.30–0.96) and low heterogeneity for major bleeding (τ² = 0.029; I² = 19%; prediction interval = 0.25–0.85) (Figure 2), without significant interaction for subgroup differences by the P2Y₁₂ inhibitor used, compared with 12-month DAPT (Figure 3). Any bleeding (OR 0.54; 95% CI 0.43–0.69; P < 0.001; NNTB = 39) and major bleeding (OR 0.47; 95% CI 0.36–0.62; P < 0.001; NNTB = 77) were both reduced by ticagrelor monotherapy, with high heterogeneity for any bleeding (τ² = 0.049; I² = 71%; prediction interval = 0.24–1.22) and moderate heterogeneity for major bleeding (τ² = 0.031; I² = 32%; prediction interval = 0.22–1.02); clopidogrel monotherapy was associated with a reduction in any bleeding (OR 0.49; 95% CI 0.30–0.78; P = 0.003; NNTB = 91) and major bleeding (OR 0.41; 95% CI 0.20–0.83; P = 0.013; NNTB = 131) with low heterogeneity (τ² = 0.000; I² = 0%) for both endpoints (Figure 3).

Overall, the quality of evidence for bleeding endpoints was deemed low for any bleeding and moderate for major bleeding. However, the quality of evidence for ticagrelor monotherapy was deemed moderate for both any bleeding and major bleeding, while deemed low for any bleeding and moderate for major bleeding for clopidogrel monotherapy (Supplementary material online, Table S7). Forest plots with single trial effect estimate, weight, and interaction analysis for each endpoint are shown in the appendix (Supplementary material online, Figures S4–S12).

Trial sequential analyses

Trial sequential analysis showed that there is conclusive evidence supporting the better safety of P2Y₁₂ inhibitor monotherapy after short DAPT compared with 12-month DAPT. However, while the evidence on bleeding events is conclusive for benefit, the evidence on MACE is conclusive for lack of benefit, and further evidence is needed to derive final conclusions for other ischaemic endpoints (Figures 2 and 4). Conversely, no conclusive evidence was detected for the analysis focused on clopidogrel monotherapy vs. 12-month DAPT (Supplementary material online, Figure S13).

On the other hand, trial sequential analysis focusing on ticagrelor monotherapy showed conclusive evidence supporting reduced NACE and any bleeding compared with 12-month DAPT, while other endpoints still need further evidence to derive definite conclusions (Supplementary material online, Figure S14).

Sensitivity analyses

Sensitivity analyses were generally consistent with the main analysis, with some fluctuation in MACE and NACE in both the overall analysis of short DAPT compared with standard DAPT and the subgroups focusing on ticagrelor and clopidogrel monotherapy (Supplementary material online, Table S8). Of note, most of the evidence for clopidogrel monotherapy derived from trials exploring the effect of 1-month DAPT duration (Supplementary material online, Table S8). Influence analysis revealed that STOPDAPT-2 ACS introduced heterogeneity for MACE, NACE, and MI, while T-PASS trial introduced heterogeneity for NACE and GLOBAL LEADERS introduced heterogeneity within MI and bleeding endpoints in the overall analysis of P2Y₁₂ inhibitor monotherapy after a short course of DAPT (Supplementary material online, Figures S15–S19). GLOBAL LEADERS was also the main driver of heterogeneity for NACE and bleeding endpoints within the ticagrelor subgroup (Supplementary material online, Figures S20–S22). Repetition of the analysis after their exclusion was consistent with the main analysis, with negligible heterogeneity (Supplementary material online, Figures S23–S30). Leave-one-out analysis showed no other major influence of one trial over another in the overall analysis of P2Y₁₂ inhibitor monotherapy after a short course of DAPT (Supplementary material online, Figure S31) nor in the ticagrelor (Supplementary material online, Figure S32) or clopidogrel (Supplementary material online, Figure S33) monotherapy subgroups, although most of the estimates for clopidogrel monotherapy relied on a single trial. Trim and fill correction for comparisons of P2Y₁₂ inhibitor monotherapy after a short course of DAPT and standard DAPT yielded results consistent with the main analysis for any bleeding (OR 0.61; 95% CI 0.50–0.75; P < 0.001), and major bleeding (OR 0.57; 95% CI 0.43–0.74; P < 0.001), but the reduction in NACE was no longer significant (OR 0.80; 95% CI 0.63–1.00; P = 0.059).

Discussion

The main findings of this study can be summarized as follows: (i) P2Y₁₂ inhibitor monotherapy after short DAPT reduces bleeding without affecting ischaemic events in ACS patients; (ii) the use of different P2Y₁₂ inhibitors (i.e. clopidogrel or ticagrelor) as monotherapy significantly affects outcomes, with ticagrelor being associated with better outcomes than clopidogrel; (iii) clopidogrel monotherapy reduces any bleeding and major bleeding but increases MI without any benefit in NACE compared with 12-month DAPT; and (iv) trial sequential analysis suggests that ticagrelor monotherapy, but not clopidogrel monotherapy, may improve MACE and mortality and is associated with conclusive evidence of improved NACE compared with 12-month DAPT.

DAPT after ACS has been traditionally implemented to prevent recurrent ischaemic events such as spontaneous MI or stent thrombosis, and reduce the incidence of other adverse events associated with systemic atherosclerotic disease progression.³ The availability of new-generation DES associated with very low rates of stent thrombosis (<1% at 1 year),²⁹ together with the new pharmacological regimens associated with reduced ischaemic events, has questioned the need for the current standard of 12-month DAPT.³ The increasing awareness that bleeding carries important prognostic implications,² together with the fluctuations over time of bleeding and ischaemic risks, with ischaemic risk prevailing over bleeding risk in the early months after ACS/PCI, has recently fueled the enthusiasm towards the implementation of DAPT de-escalation strategies, such as short DAPT, in ACS.^3,4

Because aspirin has been the backbone of antiplatelet therapy for over 40 years, the first short DAPT strategy to be adopted consisted in discontinuing the P2Y₁₂ inhibitor and maintaining aspirin monotherapy.³ However, the numerical increase in ischaemic events with aspirin monotherapy after 3/6-month DAPT compared to standard 12-month DAPT in ACS patients has limited its application to HBR patients.^1,5,6 The understanding that the P2Y₁₂ receptor pathway plays a central role in platelet activation, aggregation, and amplification processes, together with the encouraging results from clinical settings in which a strategy of P2Y₁₂ inhibitor monotherapy was first adopted—such as patients with aspirin intolerance/hypersensitivity or those with concomitant indication for oral anticoagulant—has sparked the interest in P2Y₁₂ inhibitor monotherapy after a short course of DAPT.^8,30 While the GLOBAL LEADERS trial and subsequent more recent RCTs showed that P2Y₁₂ inhibitor monotherapy could be a viable alternative to standard 12-month DAPT,^{22–25,27,31} some limitations hindering the adoption of such strategy as the new standard of care for patients with ACS remain.^1,8,32 Indeed, many RCTs included patients with both chronic and acute coronary syndromes, with results varying significantly when the same strategy was selectively applied to patients with ACS.^28,33 Furthermore, many of these trials focused on East Asian patients, preventing the generalizability of their findings to the general population, as East Asians typically present a high bleeding and low ischaemic risk compared with other ethnicities.^34,35 Most importantly, the appraisal of the safety and efficacy of a P2Y₁₂ inhibitor monotherapy strategy has been hindered by the fact that both clopidogrel and potent P2Y₁₂ inhibitors (prasugrel and ticagrelor) are included under the generic definition of ‘P2Y₁₂ inhibitors’ despite having very different pharmacodynamic profiles that result in different clinical effects.³⁶ Indeed, clopidogrel, but not ticagrelor or prasugrel, is associated with a large variability in interindividual pharmacological response, resulting in HPR and subsequent increased ischaemic risk in nearly 30% of patients.^11,37

On this background, our analysis is the first to simultaneously address these confounding factors in the appraisal of the safety and efficacy of a P2Y₁₂ inhibitor monotherapy regimen compared with standard 12-month DAPT in the specific setting of ACS.^7,38–40 Indeed, the exclusive inclusion of ACS patients differentiates the present study from another meta-analysis that included patients undergoing PCI irrespective of clinical presentation, which nevertheless had similar results to our study.⁴¹ To this end, the present findings are more directly applicable to clinical practice, where ticagrelor is routinely used in the setting of ACS and rarely considered after elective PCI. In addition, we first included the recent data from the T-PASS and ULTIMATE DAPT trial, which was not considered in previous studies and extends the evidence for ticagrelor monotherapy even after less than 1 month of DAPT.^41,42 Moreover, our study originally provides a trial sequential analysis to explore whether the effect estimate of each outcomes is large enough to be unaffected by further studies. Finally, we provided a detailed assessment of the quality of evidence for each effect estimate using GRADE.

We found that the use of different P2Y₁₂ inhibitors (i.e. clopidogrel or ticagrelor) as monotherapy significantly affects outcomes in the high-risk setting of ACS patients. In fact, while both ticagrelor and clopidogrel monotherapy significantly reduce bleeding to a similar extent, ticagrelor, but not clopidogrel, is associated with reduced ischaemic and mortality outcomes compared with standard DAPT duration. Our findings are consistent and were mainly driven by the data from STOPDAPT-2 ACS trial, in which clopidogrel monotherapy after 1–2 months of DAPT was associated with an increased risk of cardiovascular events compared with standard DAPT after ACS,²⁸ and are in line with previous network meta-analyses suggesting a significant mortality benefit with ticagrelor monotherapy but not with other P2Y₁₂ inhibitors.^43,44 These differences were particularly evident when DAPT was stopped between 1 and 3 months, while the increased ischaemic harm in clopidogrel monotherapy was mitigated when DAPT was discontinued after 3 months, suggesting that clopidogrel monotherapy may still hold potential for clinical benefit when DAPT is planned for a longer period of time. However, trial sequential analysis highlighted that the evidence for ticagrelor, but not clopidogrel monotherapy, is sufficient to claim final conclusion over NACE reduction compared with standard 12-month DAPT, while the evidence on clopidogrel is still scarce and of lower quality. Overall, these findings have important clinical implications, supporting the hypothesis that different pharmacological properties of P2Y₁₂ inhibitors translate into different risk/benefit balance and, according to the current evidence, ticagrelor should be preferred over clopidogrel, unless contraindicated, when discontinuing aspirin after a short course of DAPT in ACS patients.

Limitations

The results of this meta-analysis must be interpreted in light of some limitations. First, the lack of patient-level data did not allow to deeply explore the influence of other covariates on the overall treatment estimate. However, the performance of multiple sensitivity analyses showing consistent results with the main analysis supports the validity of the results. Second, the evidence supporting the current analysis relied on both randomized trials and ACS data extracted from trials with larger population, with original trials slightly differing in terms of timing of aspirin discontinuation and timing of randomization, potentially introducing an unquantifiable risk of bias. Such risk may also have been increased by imbalances in the percentages of ST-segment elevation myocardial infarction patients originally included in each group, being higher in clopidogrel monotherapy trials rather than ticagrelor monotherapy trials. However, the leave-one-out analysis and specific sub-analyses revealed no major influence of any trial or sub-analysis over others. Third, there was an imbalance in the number of studies and subsequent included patients treated with ticagrelor compared with clopidogrel monotherapy, resulting in the inclusion of 5877 patients receiving clopidogrel and 21 407 patients receiving ticagrelor. Such imbalance may have represented a source of bias in the treatment effect estimate, although multiple sensitivity analyses performed helped to at least partially mitigate these concerns. Fourth, some endpoints were associated with high between-trial heterogeneity. Although influence analyses and repetition of the main analysis without the most influential trials yielded consistent results, other sources of heterogeneity not identifiable at the trial-level data might exist. This heterogeneity is further suggested by minor asymmetries in funnel plots. While trim and fill corrections provided consistent outcomes, the limited number of trials included precluded a thorough investigation into the impact of publication bias. Fifth, with the exception of SMART-CHOICE that included a small percentage of patients undergoing monotherapy with prasugrel, this potent P2Y₁₂ inhibitor was not used in included studies, preventing from drawing any conclusions on the safety and efficacy of prasugrel monotherapy vs. standard 12-month DAPT. Finally, since no direct comparison of ticagrelor and clopidogrel monotherapy has been performed, the highlighted differences between these two strategies should be interpreted with caution, relying only on interaction analysis.

Conclusions

In patients presenting with ACS undergoing PCI, a strategy of P2Y₁₂ inhibitor monotherapy after a short course of DAPT reduces bleeding without any trade-off in efficacy compared with standard 12-month DAPT. Although there was no significant interaction for subgroup differences according to the P2Y₁₂ inhibitor used on bleeding, ticagrelor was associated with more favourable ischaemic benefit, while clopidogrel rose some concerns for potential harm, resulting in significant interaction for net benefit. Overall, these observations suggest that ticagrelor monotherapy should be preferred when discontinuing aspirin after a short course of DAPT in patients with ACS.

Acknowledgement

This study is registered in PROSPERO (CRD42023494797).

Funding

The study was not funded.

Conflict of interest: E.P.N. reports research grants from Abbott and Amgen, and lecture fees/honoraria from Amgen, AstraZeneca, Bayer, Pfizer, and Sanofi–Regeneron, outside the submitted work. R.M. reports the following outside of the submitted work: institutional research payments from Abbott, Abiomed, Alleviant Medical, AM-Pharma, Amgen, Arena, AstraZeneca, Atricure, Bayer, Biosensors, Biotronik, Boston Scientific, Bristol Myers Squibb, CardiaWave, CeloNova, Chiesi, Concept Medical, CSL Behring, Cytosorbents, Daiichi Sankyo, Element Science, Faraday, Humacyte, Idorsia Pharmaceuticals, Janssen, Medtronic, Novartis, OrbusNeich, PhaseBio, Philips, Pi-Cardia, RenalPro, Shockwave, Vivasure, and Zoll; personal fees from Ciné-Med Research and WebMD; equity <1% in Applied Therapeutics, Elixir Medical, Stel, and ControlRad (spouse); Scientific Advisory Board for American Medical Association, American College of Cardiology (Board of Trustees Member), Society for Cardiovascular Angiography and Interventions (Women in Innovations Committee Member), and JAMA Associate Editor; and Faculty Cardiovascular Research Foundation (no fee). M.V. reports personal fees from AstraZeneca, grants and personal fees from Terumo, personal fees from Alvimedica/CID, personal fees from Abbott Vascular, personal fees from Daiichi Sankyo, personal fees from Bayer, personal fees from CoreFLOW, personal fees from Idorsia Pharmaceuticals Ltd, personal fees from Departement Klinische Forschung, Universität Basel, personal fees from Bristol Myers Squibb SA/Janssen, personal fees from Medscape, personal fees from Biotronik, personal fees from Novartis, and personal fees from Vesalio, outside the submitted work. D.C. reports receiving personal honoraria from Novo Nordisk, Sanofi, Terumo; and payment to the institution from Meditronic, outside the present work. D.J.A. declares that he has received consulting fees or honoraria from Abbott, Amgen, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, CSL Behring, Daiichi Sankyo, Eli Lilly, Faraday, Haemonetics, Janssen, Merck, Novartis, Novo Nordisk, PhaseBio, PLx Pharma, Pfizer, Sanofi, and Vectura, outside the present work; D.J.A. also declares that his institution has received research grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi Sankyo, Eisai, Eli Lilly, Faraday, Gilead, Janssen, Matsutani Chemical Industry Co., Merck, Novartis, Osprey Medical, Renal Guard Solutions, and Scott R. MacKenzie Foundation. All other authors have no conflicts of interest to disclose.

Data availability

All data are available upon reasonable request to the corresponding author.

References

Author notes