P2Y12 Inhibitor Selection and Ischemic Outcomes in Patients with Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention: A Real-World Registry Analysis

Abstract

This study evaluated whether ticagrelor use is associated with improved ischemic outcomes compared with clopidogrel in Korean patients with acute coronary syndrome undergoing percutaneous coronary intervention. We analyzed patient-level data from 1,199 patients (614 clopidogrel, 585 ticagrelor) enrolled in two prospective registries. Stabilized inverse probability of treatment weighting (IPTW) was applied to balance baseline characteristics between the two groups. The primary endpoint was major adverse cardiovascular events (MACE), defined as a composite of all-cause death, myocardial infarction, stroke, or any revascularization. After IPTW adjustment, the weighted incidence of MACE was 8.1% in the clopidogrel group and 5.0% in the ticagrelor group, but this difference did not reach statistical significance (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.33-1.14; p=0.120). Target vessel failure also showed no significant differences between the groups (HR, 0.54; p=0.177). All-cause death was nominally lower in the ticagrelor group (3.4% vs. 1.1%; HR, 0.33; p=0.025); however, this was not accompanied by a reduction in other ischemic endpoints. Subgroup analyses revealed no significant treatment-by-subgroup interactions across various ischemic- or bleeding-risk features. In conclusion, ticagrelor did not demonstrate a statistically significant reduction in ischemic events compared with clopidogrel in this real-world Korean registry. These findings support the importance of individualized P2Y12 inhibitor selection based on patient-specific risk profiles.

INTRODUCTION

Dual antiplatelet therapy with aspirin and a P2Y12 inhibitor remains a cornerstone of secondary prevention after percutaneous coronary intervention (PCI) in patients with acute coronary syndrome (ACS).1 Among oral P2Y12 inhibitors, ticagrelor provides more rapid, potent, and consistent platelet inhibition than clopidogrel because it directly and reversibly inhibits the P2Y12 receptor without requiring hepatic bioactivation. In the Platelet Inhibition and Patient Outcomes (PLATO) trial, ticagrelor significantly reduced the composite of cardiovascular death, myocardial infarction (MI), or stroke compared with clopidogrel in patients with ACS, without a significant increase in overall major bleeding as defined in the trial.2 These findings established ticagrelor as a major, potent P2Y12 inhibitor for ACS management.

However, subsequent randomized and observational studies in East Asian patients have not consistently reproduced the ischemic superiority observed in PLATO. In the Study to Assess Safety and Efficacy of Ticagrelor [AZD6140] Versus Clopidogrel in Asian/Japanese Patients With Non-ST or ST Elevation Acute Coronary Syndromes (PHILO) trial, which enrolled Japanese, Korean, and Taiwanese patients with ACS, ticagrelor did not show a clear ischemic advantage over clopidogrel and was associated with numerically more bleeding events.3 In the Ticagrelor Versus Clopidogrel in Asian/Korean Patients with ACS Intended for Invasive Management (TICA KOREA) randomized trial, ticagrelor significantly increased clinically significant bleeding as compared with clopidogrel in Korean patients with ACS intended for invasive management, without a significant reduction in ischemic events.4 Similarly, data from the Korea Acute Myocardial Infarction Registry-National Institutes of Health (KAMIR-NIH) suggested that ticagrelor did not reduce ischemic events compared with clopidogrel but was associated with increased bleeding complications in Korean patients with acute myocardial infarction.5

In routine clinical practice, the choice of a P2Y12 inhibitor is influenced by multiple factors, including ACS presentation, comorbidities, renal function, bleeding risk, lesion complexity, physician preference, and evolving practice patterns. Therefore, additional real-world data are needed to evaluate whether ticagrelor use is associated with improved ischemic outcomes compared with clopidogrel in Korean ACS patients undergoing PCI. In the present study, we analyzed patient-level data from two consecutive Jeonbuk stent registries conducted during different time periods. We compared ischemic clinical outcomes between patients discharged on clopidogrel and those discharged on ticagrelor after PCI for ACS. We further examined whether the association between P2Y12 inhibitor type and major adverse cardiovascular events differed according to high ischemic-risk and high bleeding-risk features.

MATERIALS AND METHODS

1. Study population

This study was a patient-level analysis of two prospective stent registries conducted at three tertiary cardiovascular centers in Jeonbuk Province, Republic of Korea. The Jeonbuk SYNERGY stent registry (KCT0003392) was conducted between 2016 and 2019 and enrolled all-comer patients with coronary artery disease who underwent successful implantation of the SYNERGY everolimus-eluting stent.6 The Jeonbuk Orsiro stent registry (KCT0005008) was conducted between 2019 and 2022 and similarly enrolled all-comer patients with coronary artery disease who underwent successful PCI with the Orsiro sirolimus-eluting stent. In the Orsiro registry, enrollment of patients with diabetes mellitus or prediabetes was encouraged; however, enrollment was not restricted according to glycemic status.

The present analysis was restricted to patients with ACS, defined as unstable angina, non-ST-segment elevation MI (NSTEMI), or ST-segment elevation MI (STEMI). Among 1,586 patients enrolled in the two registries, 289 patients with chronic coronary syndrome (stable angina) were excluded. Of the remaining 1,297 patients with ACS, 8 patients without a recorded discharge antiplatelet regimen and 90 patients discharged on prasugrel were excluded. Finally, 1,199 patients discharged on either clopidogrel or ticagrelor were included in the current analysis: 614 patients in the clopidogrel group and 585 patients in the ticagrelor group (Fig. 1).

FIG. 1. Flow chart of the study population.

Clinical follow-up was scheduled at 12±2 months after the index PCI, and all clinical outcomes were administratively censored at 400 days; accordingly, the present analysis evaluates 400-day, rather than exactly 1-year, outcomes. The median follow-up duration was 400 days (interquartile range, 373-400 days). The discharge P2Y12 inhibitor was used as the primary exposure variable, and patients were classified according to whether they were discharged on clopidogrel or ticagrelor. Clinical outcomes were assessed through follow-up visits, review of medical records, and registry outcome data. The study protocol was approved by the Institutional Review Board of Wonkwang University Hospital (WKUH 201604-HR-036 and WKUH 2019-01-027-002), and informed consent was obtained from all participants at the time of enrollment in the respective registries.

2. Endpoints and definitions

The primary endpoint was major adverse cardiovascular events (MACE), defined as a composite of all-cause death, MI, stroke, or any revascularization including target vessel revascularization (TVR), and non-TVR. The secondary endpoint was target vessel failure (TVF), defined as a composite of cardiac death, target-vessel MI, or TVR. Individual clinical outcomes included all-cause death, cardiac death, MI, target-vessel MI, stroke, TVR, non-TVR, stent thrombosis, and any revascularization.7

Anemia was defined according to the World Health Organization definition as hemoglobin <13 g/dL in men and <12 g/dL in women.8 Chronic kidney disease was defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m² calculated using the 2021 Chronic Kidney Disease Epidemiology Collaboration creatinine equation.9 Complex PCI was defined as the presence of at least one of the following procedural features: treatment of ≥3 lesions, implantation of ≥3 stents, total stent length >60 mm, bifurcation PCI with two stents implanted, or PCI for a chronic total occlusion.10 High ischemic-risk features were selected based on prior studies and guideline-based procedural risk criteria and included diabetes mellitus, left ventricular ejection fraction <40%, anemia, STEMI presentation, multivessel disease, and complex PCI. High bleeding-risk features were selected based on available components of the Academic Research Consortium for High Bleeding Risk criteria and included age ≥75 years, estimated glomerular filtration rate <60 mL/min/1.73 m², estimated glomerular filtration rate <30 mL/min/1.73 m², hemoglobin <11 g/dL, and previous stroke.11,12

3. Statistical analysis

Continuous variables are presented as mean±standard deviation, and categorical variables are presented as number and percentage. Baseline characteristics were compared between patients discharged on clopidogrel and those discharged on ticagrelor. To reduce treatment selection bias, propensity scores for receiving ticagrelor were estimated using a multivariable logistic regression model including baseline clinical, laboratory, angiographic, procedural, discharge medication, and registry-source variables. Stabilized inverse probability of treatment weighting (IPTW) was then applied. Covariate balance before and after IPTW was assessed using absolute standardized mean differences (SMDs), and an absolute SMD <0.10 was considered to indicate adequate balance.

Clinical outcomes were compared before and after IPTW. Before IPTW, crude event rates were calculated as the number and percentage of events in each treatment group, and unadjusted hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. After IPTW, weighted event rates were calculated, and treatment effects were estimated using IPTW-weighted Cox proportional hazards models with robust variance estimation. HRs were reported for ticagrelor compared with clopidogrel. Weighted cumulative incidence curves for MACE and TVF were generated from IPTW-weighted Kaplan–Meier estimates and displayed as 1 minus the survival probability. As a sensitivity analysis, multivariable Cox proportional hazards regression models were constructed for MACE and TVF in the original cohort. The models included discharge P2Y12 inhibitor type, age, diabetes mellitus, eGFR <60 mL/min/1.73 m², STEMI presentation, multivessel disease, and complex PCI. Adjusted HRs with 95% CIs were reported for each covariate.

Prespecified subgroup analyses were performed for MACE to evaluate whether the association between discharge P2Y12 inhibitor type and ischemic outcomes differed according to clinically relevant ischemic- and bleeding-risk features. Within each subgroup, HRs for ticagrelor versus clopidogrel were estimated using Cox proportional hazards models. Treatment-by-subgroup interactions were assessed by including treatment group, subgroup variable, and the corresponding interaction term in Cox models. Because the two registries were conducted during different calendar periods, registry-era analyses were performed to explore whether P2Y12 inhibitor selection and clinical outcomes differed according to registry source. The distribution of discharge P2Y12 inhibitor type was compared between the SYNERGY and Orsiro registries. Clinical outcomes were then assessed within each registry according to discharge P2Y12 inhibitor type. Treatmentby-registry interaction was evaluated using Cox proportional hazards models including treatment group, registry source, and their interaction term. All clinical outcomes were administratively censored at 400 days. A two-sided p-value <0.05 was considered statistically significant. All statistical analyses were performed using R version 4.5.2 (R Foundation for Statistical Computing, Vienna, Austria).

RESULTS

A total of 1,199 patients with ACS who were discharged on either clopidogrel or ticagrelor were included in the final analysis. Of these, 614 patients were discharged on clopidogrel and 585 patients were discharged on ticagrelor. The distribution of discharge P2Y12 inhibitor differed between the two registry cohorts (Table 1). In the SYNERGY registry, 388 of 576 patients (67.4%) were discharged on clopidogrel and 188 patients (32.6%) were discharged on ticagrelor. In contrast, in the Orsiro registry, 226 of 623 patients (36.3%) were discharged on clopidogrel and 397 patients (63.7%) were discharged on ticagrelor. Among patients discharged on clopidogrel, treatment persistence was high at both 3 and 6 months. In the overall population, 583 of 587 patients (99.3%) with available 3-month medication data and 558 of 567 patients (98.4%) with available 6-month medication data remained on clopidogrel. Among patients discharged on ticagrelor, 513 of 560 patients (91.6%) with available 3-month data and 465 of 553 patients (84.1%) with available 6-month data remained on ticagrelor. Switching from ticagrelor to clopidogrel occurred in 42 patients (7.5%) at 3 months and 82 patients (14.8%) at 6 months. At 12 months, persistence diverged markedly by discharge regimen: 528 of 531 patients (99.4%) discharged on clopidogrel remained on clopidogrel, whereas only 123 of 425 patients (28.9%) discharged on ticagrelor remained on ticagrelor. This reduction predominantly reflected reimbursement-driven de-escalation and routine discontinuation at completion of 12-month dual antiplatelet therapy rather than early treatment change, as switching within the first 6 months was uncommon (14.8%).

TABLE 1. Temporal shift in P2Y12 inhibitor selection.

Values are presented as number (%). Baseline percentages were calculated among patients in each registry cohort according to discharge. Percentages at 3, 6, and 12 months were calculated among patients initially discharged on the corresponding P2Y12 inhibitor who had available follow-up medication data at that time point. Patients with no active P2Y12 inhibitor recorded were excluded from the denominator; at 12 months these exclusions include planned discontinuation of the P2Y12 inhibitor at completion of dual antiplatelet therapy.

Baseline characteristics before and after IPTW are shown in Table 2. Before weighting, several baseline characteristics differed between the two groups. Patients discharged on clopidogrel were older than those discharged on ticagrelor (67.2±11.6 vs. 62.9±9.7 years; SMD=0.404), and the ticagrelor group had a higher proportion of male patients (84.6% vs. 67.1%; SMD=0.418), current smokers (40.2% vs. 23.3%; SMD=0.369), and STEMI presentation (39.7% vs. 18.2%; SMD=0.486). After stabilized IPTW, most baseline clinical, laboratory, angiographic, and procedural variables were well balanced between the two groups, with absolute SMD values <0.10 (Fig. 2). However, residual imbalance remained for discharge aspirin use (SMD=0.280) and registry source (SMD=0.124). The lower rate of discharge aspirin use in the ticagrelor group was driven almost entirely by the later-era Orsiro registry (2019-2022), in which aspirin was prescribed in 64.5% of ticagrelor-treated patients versus 100% in the earlier SYNERGY cohort, reflecting the increasing adoption of early aspirin discontinuation and ticagrelor monotherapy during that period.

TABLE 2. Baseline characteristics before and after inverse probability of treatment weighting.

Values are presented as mean±standard deviation, number (%), weighted mean±standard deviation, or weighted % as appropriate. Standardized mean differences (SMD) were calculated to assess covariate balance, with an absolute value <0.10 indicating adequate balance. Weighted estimates were derived using inverse probability of treatment weighting (IPTW). NSTEMI: non-ST-segment elevation myocardial infarction, STEMI: ST-segment elevation myocardial infarction, eGFR: estimated glomerular filtration rate, LDL: low density lipoprotein, ACEI: angiotensin converting enzyme inhibitor, ARB: angiotensin receptor blocker.

FIG. 2. Covariate balance before and after inverse probability of treatment weighting (IPTW). IPTW substantially improved covariate balance, with most variables achieving an absolute standardized mean difference <0.10 after weighting. Abbreviations are as defined in Table 1.

During follow-up, MACE occurred in 74 of 1,199 patients (6.2%), and TVF occurred in 31 patients (2.6%). Before IPTW, MACE occurred in 45 patients (7.3%) in the clopidogrel group and 29 patients (5.0%) in the ticagrelor group (unadjusted HR, 0.67; 95% CI, 0.42-1.07; p=0.096). TVF occurred in 18 patients (2.9%) in the clopidogrel group and 13 patients (2.2%) in the ticagrelor group (unadjusted HR, 0.75; 95% CI, 0.37-1.54; p=0.439). After IPTW, the weighted incidence of MACE was 8.1% in the clopidogrel group and 5.0% in the ticagrelor group. However, the difference did not reach statistical significance in the IPTW-weighted Cox model (HR, 0.61; 95% CI, 0.33-1.14; p=0.120). The weighted incidence of TVF was 3.6% in the clopidogrel group and 2.0% in the ticagrelor group, without a statistically significant difference between groups (HR, 0.54; 95% CI, 0.22-1.33; p=0.177). Weighted cumulative incidence curves for MACE and TVF are shown in Fig. 3. Among individual outcomes, all-cause death was lower in the ticagrelor group after IPTW (3.4% vs. 1.1%; HR, 0.33; 95% CI, 0.12-0.87; p=0.025). However, cardiac death, MI, target-vessel MI, stroke, TVR, non-TVR, stent thrombosis, and any revascularization did not differ significantly between the two groups after IPTW (Table 3).

FIG. 3. Weighted cumulative incidence curves for ischemic clinical outcomes after inverse probability of treatment weighting (IPTW). Weighted cumulative incidence curves are shown for (A) major adverse cardiovascular events and (B) target vessel failure according to P2Y12 inhibitor type in the ACS population.

TABLE 3. Clinical outcomes before and after inverse probability of treatment weighting.

Values are presented as number (%), or weighted % as appropriate. Target vessel failure (TVF) was defined as a composite of cardiac death, target-vessel myocardial infarction (MI), or target vessel revascularization (TVR). Major adverse cardiovascular events (MACE) was defined as a composite of all-cause death, MI, stroke, or any revascularization. IPTW: inverse probability of treatment weighting, HR: hazard ratio, CI: confidence interval.

In multivariable Cox regression analysis, ticagrelor use was not significantly associated with lower risks of MACE (adjusted HR, 0.85; 95% CI, 0.52-1.40; p=0.530) or TVF (adjusted HR, 0.97; 95% CI, 0.44-2.17; p=0.950) compared with clopidogrel (Table 4). Age was independently associated with both MACE (HR per 1 year, 1.03; 95% CI, 1.01-1.05; p=0.005) and TVF (HR per 1 year, 1.05; 95% CI, 1.02-1.09; p=0.001). eGFR <60 mL/min/1.73 m² and multivessel disease were significantly associated with MACE ([HR, 2.16; 95% CI, 1.32-3.55; p=0.002] and [HR, 2.42; 95% CI, 1.41-4.14; p=0.001]).

TABLE 4. Predictors of major adverse cardiovascular events (MACE) and target vessel failure (TVF).

Complex percutaneous coronary intervention (PCI) was defined as the presence of at least one of the following procedural features: treatment of ≥3 lesions, implantation of ≥3 stents, total stent length >60 mm, bifurcation PCI with two stents implanted, or PCI for a chronic total occlusion. HR: hazard ratio, CI: confidence interval, eGFR: estimated glomerular filtration rate, STEMI: ST-segment elevation myocardial infarction.

Subgroup analyses for MACE are shown in Fig. 4. The association between ticagrelor use and MACE was generally consistent across both high ischemic-risk and high bleeding-risk subgroups. No significant treatment-by-subgroup interaction was observed for any ischemic-risk features and bleeding-risk features.

FIG. 4. Subgroup analyses for major adverse cardiovascular events (MACE) according to ischemic- and bleeding-risk features. Forest plots show the association between ticagrelor use and MACE compared with clopidogrel across prespecified subgroups. (A) Subgroup analysis according to high ischemic-risk features, including diabetes mellitus, left ventricular ejection fraction (LVEF) <40%, anemia, ST-segment elevation myocardial infarction (STEMI), multivessel disease, and complex percutaneous coronary intervention (PCI). (B) Subgroup analysis according to high bleeding-risk features, including age ≥75 years, estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m², eGFR <30 mL/min/1.73 m², hemoglobin <11 g/dL, and previous stroke. Hazard ratios (HR) and 95% confidence interval (CI) are for ticagrelor versus clopidogrel. p-values for interaction were calculated using Cox proportional hazards models including treatment group, subgroup, and treatment-by-subgroup interaction terms.

Registry-era analyses are shown in Table 5. In the SYNERGY registry, MACE occurred in 22 of 388 patients (5.7%) in the clopidogrel group and 6 of 188 patients (3.2%) in the ticagrelor group (HR, 0.56; 95% CI, 0.23-1.38; p=0.206). In the Orsiro registry, MACE occurred in 23 of 226 patients (10.2%) in the clopidogrel group and 23 of 397 patients (5.8%) in the ticagrelor group (HR, 0.56; 95% CI, 0.32-1.00; p=0.051). There was no significant treatment-by-registry interaction for MACE (p for interaction=0.986).

TABLE 5. Registry-era analysis of P2Y12 inhibitor selection and clinical outcomes.

HR: hazard ratio, CI: confidence interval, MACE: major adverse cardiovascular events, TVF: target vessel failure.

In a sensitivity analysis restricted to patients discharged on aspirin, propensity scores and stabilized IPTW were recalculated within the aspirin-treated subset (Table 6). The results were consistent with those in the main analysis; ticagrelor was not significantly associated with lower risks of MACE (IPTW-adjusted HR, 0.82; 95% CI, 0.41-1.63; p=0.562) or TVF (IPTW-adjusted HR, 0.60; 95% CI, 0.21-1.75; p=0.350) as compared with clopidogrel.

TABLE 6. Sensitivity analysis restricted to patients receiving aspirin.

Values are presented as number (%), or weighted % as appropriate. Target vessel failure (TVF) was defined as a composite of cardiac death, target-vessel myocardial infarction (MI), or target vessel revascularization (TVR). Major adverse cardiovascular events (MACE) was defined as a composite of all-cause death, MI, stroke, or any revascularization. IPTW: inverse probability of treatment weighting, HR: hazard ratio, CI: confidence interval.

DISCUSSION

The main finding of our study is that, in a real-world Korean ACS PCI registry, ticagrelor was not associated with a significant reduction in ischemic events compared with clopidogrel. After IPTW adjustment, patients discharged on ticagrelor had numerically lower rates of MACE and TVF, but neither difference reached statistical significance, and ticagrelor use was not independently associated with MACE or TVF in multivariable Cox analysis. These associations were consistent across the ischemic- and bleeding-risk subgroups examined. All-cause death was nominally lower in the ticagrelor group after IPTW; however, this was based on only 23 events, was not accompanied by any reduction in myocardial infarction or in the composite MACE and TVF endpoints, and was not adjusted for multiple comparisons. Given the wide confidence interval and its discordance with randomized data in East Asian patients, this isolated mortality signal most likely reflects chance or residual confounding rather than a true survival benefit.

Ticagrelor provides more rapid, potent, and consistent P2Y12 inhibition than clopidogrel, and in the PLATO trial it reduced the composite of cardiovascular death, myocardial infarction, or stroke in patients with ACS.2,13 This benefit, however, has not been consistently reproduced in East Asians. In the PHILO study and the TICA KOREA trial, ticagrelor increased clinically significant bleeding without reducing ischemic events,3,4 and KAMIR-NIH analyses similarly found no clear ischemic advantage of potent P2Y12 inhibitors over clopidogrel in Korean AMI patients, with more in-hospital major bleeding and no reduction in 3-year MACE or NACE.14,15 These data suggest that the risk–benefit balance of potent P2Y12 inhibition differs between Western and East Asian populations.

Our findings are broadly consistent with the “East Asian paradox,” which posits that East Asian patients have a lower ischemic risk but a higher vulnerability to bleeding during antithrombotic therapy compared to Western populations.16,17 In this context, escalating to a more potent P2Y12 inhibitor may not translate into a measurable reduction in ischemic events, particularly when contemporary PCI techniques, second-generation drug-eluting stents, and intensive secondary prevention have already minimized absolute event rates. The relatively low overall incidence of MACE and TVF in our study and the modest absolute differences between treatment groups further support this interpretation.

The decision to use potent P2Y12 inhibition should be individualized by integrating both ischemic and bleeding risks. Current European recommendations emphasize balancing ischemic risk features, such as diabetes, multivessel disease, complex PCI, and recurrent ischemic events, against bleeding-risk features when determining antiplatelet intensity and duration.11 In East Asian patients, this individualized approach may be particularly important because ischemic and bleeding risks frequently overlap, and Western-derived risk scores may not fully capture the risk profile of Asian patients. Korean registry-based efforts, including KAMIR-derived risk stratification tools, have also highlighted the need for population-specific prediction models to guide antiplatelet decisions.18 Importantly, our results should not be read as evidence of equivalence: the point estimates for MACE and TVF favored ticagrelor, and an adequately powered cohort might have detected a difference. Because the study was observational and not powered for superiority, equivalence, or non-inferiority, the appropriate interpretation is that ticagrelor did not show a significant ischemic benefit over clopidogrel—not that the two agents are equivalent.

Because the two registries were conducted in sequential calendar periods (2016-2019 and 2019-2022) and ticagrelor use rose substantially over time (32.6% in the SYNERGY registry vs 63.7% in the Orsiro registry), temporal changes in clinical practice could have confounded the comparison. Several considerations mitigate this concern. First, both registries used contemporary drug-eluting stents (thin-strut everolimus-eluting SYNERGY and ultrathin-strut sirolimus-eluting Orsiro) with comparable efficacy and safety, making a differential stent effect on the between-drug comparison unlikely. Second, the registry source was included in the propensity score model, and in the registry-stratified analysis, the direction and magnitude of the ticagrelor-versus-clopidogrel association were virtually identical across eras (HR, 0.56 in both registries), with no significant treatment-by-registry interaction (p=0.986), arguing against era as a major effect modifier. Third, because ticagrelor was preferentially used in the later period—when adjunctive secondary-prevention therapy and interventional techniques were generally more contemporary—any residual temporal confounding would be expected to favor the ticagrelor group; the absence of a significant ischemic benefit despite this potential favorable bias reinforces the robustness of our null primary finding, whereas the same era advantage may partly explain the isolated lower all-cause mortality observed with ticagrelor. Nevertheless, unmeasured temporal confounding inherent to pooling two sequential registries cannot be fully excluded.

This study has several limitations. First, as an observational registry analysis, treatment allocation was not randomized, and residual imbalance—such as the difference in discharge aspirin use—may have introduced selection bias. This difference likely reflected a temporal shift in antiplatelet practice rather than a random imbalance; following the Ticagrelor With Aspirin or Alone in High-Risk Patients after Coronary Intervention (TWILIGHT) trial in 2019 and the Ticagrelor Monotherapy After 3 Months in the Patients Treated With New Generation Sirolimus-Eluting Stent for Acute Coronary Syndrome (TICO) trial in 2020, which showed that omitting aspirin while continuing ticagrelor monotherapy reduced bleeding without increasing ischemic events, operators increasingly withheld aspirin when prescribing a potent P2Y12 inhibitor, so that aspirin-free regimens were largely confined to ticagrelor-treated patients in the later-era Orsiro registry.19,20 Reassuringly, a sensitivity analysis restricted to aspirin-treated patients yielded results consistent with the main analysis. Second, because the Orsiro registry preferentially enrolled patients with diabetes mellitus or prediabetes, the pooled study population was enriched for dysglycemia and may not be fully representative of the general Korean ACS population; although IPTW balanced diabetes and other measured covariates between the treatment groups, this enrichment could limit the generalizability of our findings. Third, the absence of systematically collected bleeding outcomes precluded a formal assessment of the net clinical benefit, which is a central consideration for potent P2Y12 inhibitor use in East Asian patients. Our research question and conclusions are confined to ischemic outcomes, and because we found no ischemic advantage for ticagrelor, this null finding is not reversed by the absence of bleeding data. Moreover, all-cause mortality—which incorporates fatal bleeding—was captured and was not higher in the ticagrelor group, and no significant interaction was observed across high-bleeding-risk subgroups. Nevertheless, non-fatal bleeding was not recorded; we therefore make no claim regarding net clinical benefit, and adequately powered studies incorporating bleeding endpoints are needed to define the optimal antiplatelet strategy in this population. Fourth, because patients were enrolled at discharge, those who died or were transferred during the index hospitalization were excluded, potentially introducing survivor bias. Finally, medication switching during follow-up, particularly de-escalation from ticagrelor to clopidogrel, might have attenuated the observed differences between groups. Because these were stent registries rather than dedicated antiplatelet-therapy studies, the exact duration of P2Y12 inhibitor exposure and the precise timing of any switch were not systematically recorded; antiplatelet use was ascertained only at discharge and at the 3-, 6-, and 12-month follow-up visits, and patients were classified according to the discharge regimen. A formal as-treated or time-varying exposure analysis was therefore not feasible, and the primary comparison should be interpreted as an intention-to-treat analysis based on the discharge P2Y12 inhibitor.

In conclusion, ticagrelor did not demonstrate a statistically significant reduction in ischemic events compared with clopidogrel in this real-world Korean ACS PCI registry. These findings support the need for individualized P2Y12 inhibitor selection in Korean ACS patients, balancing both ischemic and bleeding risks. Further adequately powered studies incorporating bleeding outcomes are warranted to define the optimal personalized antiplatelet strategy in this population.