Key Points

QuestionÌý What is the optimal antiplatelet regimen in patients with acute coronary syndromes (ACS) undergoing percutaneous coronary interventions (PCIs) who are at both high bleeding and ischemic risks (birisk)?

FindingsÌý In this double-blind, randomized clinical trial including 7758 PCI-treated birisk patients with ACS who completed 9 to 12 months of dual antiplatelet therapy (DAPT) after PCI, clopidogrel monotherapy for an additional 9 months resulted in a 25% reduction in the risk of Bleeding Academic Research Consortium types 2, 3, or 5 bleeding compared with clopidogrel plus aspirin.

MeaningÌý Among birisk patients with ACS who completed 9 to 12 months of DAPT after PCI, subsequent treatment with clopidogrel was superior to continuing DAPT with aspirin and clopidogrel in reducing clinically relevant bleeding.

ImportanceÌý Purinergic receptor P2Y12 (P2Y12) inhibitor monotherapy after a certain period of dual antiplatelet therapy (DAPT) may be an attractive option of maintenance antiplatelet treatment for patients undergoing percutaneous coronary intervention (PCI) who are at both high bleeding and ischemic risk (birisk).

ObjectiveÌý To determine if extended P2Y12 inhibitor monotherapy with clopidogrel is superior to ongoing DAPT with aspirin and clopidogrel after 9 to 12 months of DAPT after PCI in birisk patients with acute coronary syndromes (ACS).

Design, Setting, and ParticipantsÌý This was a multicenter, double-blind, placebo-controlled, randomized clinical trial including birisk patients with ACS who had completed 9 to 12 months of DAPT after drug-eluting stent implantation and were free from adverse events for at least 6 months at 101 China centers between February 2018 and December 2020. Study data were analyzed from April 2023 to May 2023.

InterventionsÌý Patients were randomized either to clopidogrel plus placebo or clopidogrel plus aspirin for an additional 9 months.

Main Outcomes and MeasuresÌý The primary end point was Bleeding Academic Research Consortium (BARC) types 2, 3, or 5 bleeding 9 months after randomization. The key secondary end point was major adverse cardiac and cerebral events (MACCE; the composite of all-cause death, myocardial infarction, stroke or clinically driven revascularization). The primary end point was tested for superiority, and the MACCE end point was tested for sequential noninferiority and superiority.

ResultsÌý A total of 7758 patients (mean [SD] age, 64.8 [9.0] years; 4575 male [59.0%]) were included in this study. The primary end point of BARC types 2, 3, or 5 bleeding occurred in 95 of 3873 patients (2.5%) assigned to clopidogrel plus placebo and 127 of 3885 patients (3.3%) assigned to clopidogrel plus aspirin (hazard ratio [HR], 0.75; 95% CI, 0.57-0.97; difference, −0.8%; 95% CI, −1.6% to −0.1%; P = .03). The incidence of MACCE was 2.6% (101 of 3873 patients) in the clopidogrel plus placebo group and 3.5% (136 of 3885 patients) in the clopidogrel plus aspirin group (HR, 0.74; 95% CI, 0.57-0.96; difference, −0.9%; 95% CI, −1.7% to −0.1%; P < .001 for noninferiority; P = .02 for superiority).

Conclusions and RelevanceÌý Among birisk patients with ACS who completed 9 to 12 months of DAPT after drug-eluting stent implantation and were free from adverse events for at least 6 months before randomization, an extended 9-month clopidogrel monotherapy regimen was superior to continuing DAPT with clopidogrel in reducing clinically relevant bleeding without increasing ischemic events.

Trial RegistrationÌý ClinicalTrials.gov Identifier:

Antiplatelet therapy is the cornerstone of treatment to reduce thrombotic events in patients with acute coronary syndromes (ACS) and in those undergoing percutaneous coronary intervention (PCI).^1-4 However, antiplatelet therapy also increases the risk of bleeding. Accordingly, assessing ischemic and bleeding risks in individual patients receiving antiplatelet therapy is crucial to balance the potential benefits and harm of treatment.⁵ Randomized clinical trials have demonstrated that adverse outcomes such as myocardial infarction (MI) and stent thrombosis are reduced with a prolonged (>1 year) course of dual antiplatelet therapy (DAPT) in patients at increased ischemic risk, such as those with ACS.^1-5 Conversely, patients at increased bleeding risk (eg, patients older than 75 years) warrant less intensive therapy.^1-5 In real-world practice, many patients are at increased risk for both ischemic and bleeding events; the optimal antithrombotic treatment regimen in such patients is unknown.⁶

In recent years, the use of purinergic receptor P2Y12 (P2Y12) inhibitor monotherapy after a brief (ie, 1-3 month) period of DAPT has emerged as an effective antiplatelet strategy to reduce bleeding in patients undergoing PCI, irrespective of PCI complexity.^7-9 However, increased ischemic event rates have been reported in patients with ACS after PCI who are treated with DAPT for only 1 to 2 months followed by clopidogrel monotherapy¹⁰ or with DAPT for only 6 months followed by aspirin monotherapy.¹¹ These observations underscore the importance of maintaining DAPT for guideline-recommended durations (eg, 12 months) in high ischemic-risk settings, particularly when using a P2Y12 inhibitor with modest platelet inhibitory effects such as clopidogrel.^1-4 Following this time frame, although a strategy of clopidogrel monotherapy is an attractive option, particularly for patients at both high ischemic and bleeding risk, this has never been tested.¹²

We, therefore, conducted the Optimal Antiplatelet Therapy for High Bleeding and Ischemic Risk Patients (OPT-BIRISK) trial to determine whether, in patients with ACS and both high bleeding- and ischemic-risk characteristics (birisk) who remained event-free after a standard course of DAPT after PCI, an extended course of clopidogrel monotherapy would be superior to ongoing DAPT treatment with aspirin and clopidogrel.

The OPT-BIRISK trial was an investigator-initiated, multicenter, double-blind, placebo-controlled, randomized clinical trial. The study rationale and design have been previously published (Supplement 1 and Supplement 2).¹³ The trial organization and participating centers are listed in the eAppendix in Supplement 3. The study protocol was approved by the ethics committee of the General Hospital of Northern Theater Command and was conducted in accordance with the Declaration of Helsinki. The study was approved by the ethics committee at each participating center and written informed consent was provided by all patients before randomization. This study followed the Consolidated Standards of Reporting Trials () reporting guidelines.

Patients who completed at least 9 months and no more than 12 months of DAPT (aspirin plus either clopidogrel or ticagrelor) after drug-eluting stent (DES) implantation for the treatment of ACS (unstable angina, non–ST-segment–elevation MI [NSTEMI] or ST-segment–elevation MI [STEMI]), who were free from major adverse clinical events during the prior 6 months, were eligible for enrollment. Study entry criteria and definitions of bleeding and ischemic risks at the time of index PCI are listed in the eAppendix in Supplement 3. In brief, patients with ACS were qualified as meeting criteria for both high ischemic and bleeding risk if 1 of the following 3 conditions were met: (1) any patient 75 years or older (ischemic risk criteria met by ACS; bleeding risk criteria met by advanced age), (2) patients aged 65 to 75 years who also met at least 1 additional criterion of ischemic or bleeding risk, or (3) patients 65 years or younger who met at least additional 1 criterion of ischemic risk and at least 1 additional criterion of bleeding risk. The standard DAPT course was allowed to range as short as 9 months and as long as 12 months before randomization because of the presence of criteria for both high bleeding as well as ischemic risk. Participant race and ethnicity data were not gathered as this study was conducted in domestic Chinese centers, where the vast majority of patients were East Asians.

Patients were randomly assigned in a 1:1 ratio using an interactive web response system with block size of 4, stratified by center. After randomization, patients were treated with repackaged aspirin, 100 mg per day (Bayer), or matching placebo (Boji Pharmacy) plus open-label clopidogrel, 75 mg per day (Sanofi Winthrop), in both groups for 9 months. Antiplatelet therapy was then used per physician discretion, although aspirin (100 mg per day) was recommended for at least 3 months after the randomization period to minimize the risk of a rebound in ischemic events. Follow-up was performed at 3, 6, 9, and 12 months after randomization.

The primary end point was the rate of clinically relevant bleeding 9 months after randomization (during the double-blind, placebo-controlled phase), defined as Bleeding Academic Research Consortium (BARC) types 2, 3, or 5 bleeding. The key secondary end point was the rate of major adverse cardiac and cerebral events (MACCE), defined as the composite of all-cause death, MI, stroke, or clinically driven revascularization, 9 months after randomization. Other end points included the 9-month postrandomization rates of the individual components of MACCE, any bleeding, and stent thrombosis. Bleeding was defined according to the BARC definition.¹⁴ Stent thrombosis was defined as definite or probable according to the ARC criteria.¹⁵ Detailed end point definitions and study processes appear in the eAppendix in Supplement 3. All end point events were adjudicated by an independent clinical events committee blinded to randomization assignment. An independent data safety monitoring board monitored study data periodically during the trial.

The trial was powered to demonstrate a reduction in clinically relevant (BARC types 2, 3, or 5) bleeding. Assuming a 6.0% incidence of the primary end point in the DAPT group during the randomization period and allowing for 10% loss to follow-up,¹⁶ 7700 total patients (3850 per group) would provide 80% power to detect a reduction in bleeding to 4.5% with 9 months of clopidogrel monotherapy compared with extended DAPT (a 25% relative reduction) tested with a log-rank test at a 2-sided α of .05. For the key secondary end point, we assumed MACCE would occur in 8.0% of patients in the DAPT group during the 9-month randomization period. With a noninferiority margin of 1.6% (20% relative difference), tested at a 1-sided α of .025, 7700 total patients would provide 73% power to conclude that clopidogrel monotherapy would be noninferior to DAPT in anti-ischemic efficacy during this period. If noninferiority was achieved, superiority would be tested.

All primary analyses were by intention to treat (ITT). Sensitivity analyses were performed in the per-protocol population, defined as patients assigned per ITT who did not have major protocol violations, did not use open-label aspirin during follow-up, and who completed 9-month follow-up after randomization or died. Categorical variables were compared using the χ² or Fisher exact test. Continuous data are presented as means with SD or medians with IQR and were compared using t tests if normally distributed or the Wilcoxon rank sum test if nonnormally distributed. Time to first event rates were estimated by the Kaplan-Meier method and were compared with the log-rank test. Hazard ratios (HRs) and 95% CIs were determined from a Cox model. Consistency of the treatment effect for the primary end point was examined by interaction testing in 14 prespecified subgroups. A 2-sided P value <.05 was considered significant for all superiority tests. All statistical analyses were performed with SAS, version 9.4 (SAS Institute). Study data were analyzed from April 2023 to May 2023.

A total of 7758 patients (mean [SD] age, 64.8 [9.0] years; 3183 female [41.0%]; 4575 male [59.0%]) who had presented with ACS, underwent PCI with newer-generation DES, completed 9 to 12 months of DAPT, and were free from adverse events for at least the prior 6 months were randomized at 101 Chinese centers between February 12, 2018, and December 4, 2020. A total of 3873 patients (49.9%) were randomly assigned to receive clopidogrel plus placebo, and 3885 patients (50.1%) were randomly assigned to receive clopidogrel plus aspirin (Figure 1). Demographic, clinical, and procedural characteristic were well matched between the 2 groups (Table 1 and Table 2). A total of 4072 patients (52.5%) had diabetes, 1418 (18.3%) had a history of MI, and 1171 (15.1%) had a history of ischemic stroke. A total of 4191 patients (54.0%) underwent index PCI for unstable angina, 1958 (25.2%) for NSTEMI, and 1609 (20.7%) for STEMI. The qualifying high ischemic- and bleeding-risk criteria are listed in eTable 1 in Supplement 3. Patients had a mean (SD) of 3.2 (1.6) high ischemic-risk criteria and a mean (SD) of 1.4 (0.9) high bleeding-risk criteria (eFigure 1 in Supplement 3). The median (IQR) time interval between the index PCI and randomization was 340 (307-358) days. Study medication adherence was high (eTable 2 in Supplement 3).

Complete clinical follow-up at 12 months after randomization was completed in 7558 of 7758 randomized patients (97.4%), and vital status was obtained in 7712 of 7758 patients (99.4%). The key outcomes are shown in Table 3, eTable 4 in Supplement 3, and Figure 2. The primary end point of BARC types 2, 3, or 5 bleeding at 9 months after randomization occurred in 95 of 3873 patients (2.5%) assigned to clopidogrel plus placebo and in 127 of 3885 patients (3.3%) assigned to clopidogrel plus aspirin (HR, 0.75; 95% CI, 0.57-0.97; difference, −0.8%; 95% CI, −1.6% to −0.1%; P = .03). The number needed to treat to prevent 1 BARC type 2, 3, or 5 bleed was 122. The treatment effect for the primary end point was consistent across prespecified subgroups except for patients with anemia (eFigure 2 in Supplement 3).

MACCE occurred in 101 of 3873 patients (2.6%) in the clopidogrel plus placebo group and in 136 of 3885 patients (3.5%) in the clopidogrel plus aspirin group (HR, 0.74; 95% CI, 0.57-0.96; difference, −0.9%; 95% CI, −1.7% to −0.1%; P for noninferiority <.001; P for superiority = .02). The number needed to treat to prevent 1 MACCE was 112. The incidences of all-cause death (13 of 3873 [0.3%] vs 18 of 3885 [0.5%]), MI (16 of 3873 [0.4%] vs 27 of 3885 [0.7%]), stroke (26 of 3873 [0.7%] vs 33 of 3885 [0.8%]), and clinically driven revascularization (53 of 3873 [1.4%] vs 71 of 3885 [1.8%]) were not significantly different between patients treated with clopidogrel plus placebo and clopidogrel plus aspirin respectively (Table 3). Three patients had stent thrombosis during the 9-month randomization period: 2 (0.05%) in the clopidogrel plus placebo group and 1 (0.03%) in the clopidogrel plus aspirin group. The effects of clopidogrel monotherapy on MACCE were consistent across prespecified subgroups (eFigure 3 in Supplement 3).

Safety and efficacy results in the per-protocol population (eTable 3 and eFigure 4 in Supplement 3) were consistent with those in the ITT population. The incidences of BARC types 2, 3, or 5 bleeding and MACCE were similar between groups during the 3-month open-label aspirin-only period after randomization, without evidence of rebound (eFigure 5 in Supplement 3). The risks of bleeding and ischemic events during the 9-month randomized period were also consistent between nonprespecified subgroups including the type of ACS, proton pump inhibitor use, and specific prerandomization P2Y12 inhibitor agent used (eTable 5 in Supplement 3). The incidence of net adverse clinical events (defined as a composite of BARC types 2, 3, 5 bleeding or MACCE) was also reduced with clopidogrel plus placebo compared with clopidogrel plus aspirin (191 of 3873 [4.9%] vs 256 of 3885 [6.6%]; HR, 0.74; 95% CI, 0.62-0.90; P = .002) (eFigure 6 in Supplement 3).

Patients with enriched ischemic or bleeding risk features have been studied in previous trials of optimal antiplatelet therapy after PCI.^17,18 However, OPT-BIRISK is the first, to our knowledge, dedicated large-scale, double-blind, placebo-controlled randomized clinical trial to examine the optimal long-term duration of DAPT in a common, difficult-to-treat patient cohort including birisk patients with ACS successfully treated with PCI who remain event free after an initial mandatory duration of DAPT. In this trial, among patients with ACS and high-risk criteria for both ischemic and bleeding treated with contemporary DES and who had completed 9 to 12 months of DAPT and were free from adverse events for at least 6 months, we evaluated the safety and efficacy of extending antiplatelet treatment for an additional 9 months with either clopidogrel monotherapy vs continuing DAPT with aspirin plus clopidogrel. The principal finding of the present trial is that clopidogrel monotherapy resulted in a 25% reduction in the risk of BARC types 2, 3, or 5 bleeding during the 9-month randomization period compared with ongoing DAPT. During this interval, clopidogrel monotherapy was also superior in reducing MACCE.

Aspirin monotherapy after a certain duration of DAPT after PCI has been the standard of care for decades. In recent years, DAPT followed by P2Y12 inhibitor monotherapy has emerged as a strategy to reduce bleeding after PCI,^7,8,19-21 although ischemic events have been reduced only with ticagrelor monotherapy. Conversely, in other studies, DAPT followed by clopidogrel or aspirin monotherapy was associated with an increase in ischemic events,^10,11 underscoring the importance of maintaining DAPT for guideline-recommended durations (eg, 12 months) in most high ischemic-risk patients unless ticagrelor monotherapy is used.

The present trial enrolled a unique difficult-to-treat patient population with criteria for not only increased ischemic risk but also increased bleeding risk who were maintained on standard DAPT by their treating physicians for at least 9 months and not more than 12 months before randomization without major adverse events. This time point was considered ideal to test our study hypothesis given the time-dependent risk of ischemia and bleeding after PCI in ACS,²² and the relatively high rate of DAPT discontinuation in patients with ACS at 9 to 12 months after PCI in older adult patients in China.²³ Moreover, although contemporary guidelines recommend potent P2Y12 inhibition with ticagrelor or prasugrel as the first-line choice for patients with ACS undergoing PCI,^1-4 clopidogrel remains the most commonly used P2Y12 inhibitor and represents the agent of choice for most East Asian patients, especially in those with features predisposing to bleeding.^24-27 In this regard, real-world studies have demonstrated that the benefits of ticagrelor compared with clopidogrel are principally observed in patients at low bleeding risk and are diminished in patients at high bleeding risk.²⁷

All patients are at an ongoing risk of major adverse cardiovascular events (2% to 3% per year) beyond the first year after stent implantation, a period when aspirin monotherapy is typically used.²⁸ Based on existing evidence,^16,29,30 current guidelines recommend considering extending DAPT beyond 1 year after PCI in patients at high ischemic risk to minimize the long-term rate of thrombotic events.^1-4 However, extended DAPT is associated with increased bleeding compared with aspirin alone^30,31 and is especially harmful in patients at high bleeding risk. Accordingly, guidelines do not recommend extending DAPT beyond 12 months in patients at increased bleeding risk, irrespective of ischemic risk.⁴ These observations underscore the need to better define alternative antiplatelet approaches for patients at both high ischemic and bleeding risk, representing the rationale for the present trial.

Emerging data suggest that long-term clopidogrel (or in some patients, more potent P2Y12 inhibitor therapy) is a superior monotherapy regimen to aspirin alone. In the Clopidogrel vs Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial clopidogrel monotherapy was marginally superior to aspirin in preventing thrombotic events in patients with established atherosclerotic vascular disease.³² The Harmonizing Optimal Strategy for Treatment of Coronary Artery Stenosis–Extended Antiplatelet Monotherapy (HOST-EXAM) trial compared clopidogrel vs aspirin for chronic antiplatelet monotherapy up to a median of 5.8 years in 5530 South Korean patients (72.1% ACS) who remained event free after a 6- to 18-month course of DAPT after PCI. Significant reductions in both thrombotic and bleeding events were noted in the clopidogrel monotherapy group.^33,34 However, the optimal antiplatelet regimen for extended treatment has not been defined in patients with ACS who are at increased bleeding risk as well as ongoing risk for recurrent ischemia. In the OPT-BIRISK trial, we therefore tested the safety and efficacy of extended clopidogrel monotherapy vs DAPT for 9 months after the successful completion of at least 9 months and not more than 12 months of DAPT in birisk patients with ACS who were treated with PCI. Our study demonstrated a significant reduction in clinically relevant bleeding with clopidogrel monotherapy, as well as a reduction in MACCE. These results extend the findings from previous studies that have shown that P2Y12 inhibitor monotherapy is associated with a lower risk of gastrointestinal mucosal injury compared with DAPT while providing effective platelet inhibition.^35-38 The outcomes from the present study, in concert with the findings from the HOST-EXAM trial and a prior meta-analysis,^33,39 suggest that chronic clopidogrel monotherapy should be a preferred treatment option after 9 to 12 months of DAPT in appropriate patients with ACS.

The incidence of the primary bleeding end point was lower than that estimated from the DAPT trial,¹⁶ which may be explained by ethnic differences between the studies and interval improvements in bleeding avoidance strategies. Nevertheless, the incidence of bleeding in the present study in the randomization period was similar to that observed between 1 to 2 years after PCI in other trials involving East Asian populations.^34,40 The treatment effect of withholding aspirin in reducing bleeding risk in this trial (25%) was smaller than that observed in previous trials (approximately 50%)^17,21 and was mainly derived from the reduction of BARC type 2 bleeding. This lower reduction may be explained by the study protocol requiring that patients had survived after 9 to 12 months of DAPT and were free from major ischemic and bleeding events for at least 6 months before randomization. Similarly, the observed MACCE rates were also less than anticipated, perhaps in part due to improvements in stent design and technique, making noninferiority for this key secondary end point easier to be achieved. Nevertheless, MACCE rates with clopidogrel monotherapy were significantly lower than with continued DAPT, demonstrating that this strategy may even provide benefit in reducing ischemic events. Neither MACCE nor other secondary end points were powered for superiority and their findings were not adjusted for multiplicity; these outcomes should thus be considered hypothesis generating. However, it is well-established that bleeding is correlated with ischemic events and is likely causative in some cases because of direct effects (hypotension, hypoxia), adverse consequences of blood transfusions or other invasive therapies to treat bleeding, and discontinuation of life-saving therapies as a response to bleeding or hypotension.^41-43 With this perspective and considering the large size of the present trial, the observed reduction in MACCE is plausible. Moreover, a borderline significant interaction for MACCE between study medications and different DAPT score stratifications was observed (eFigure 3 in Supplement 3), indicating that clopidogrel monotherapy may outperform DAPT in patients with a DAPT score less than 2 but not in those with a higher score. Further studies are warranted to determine patient cohorts who most benefit more from DAPT de-escalation.

Study limitations include the fact that the mean number of high-risk bleeding criteria was relatively low. If a higher bleeding risk population had been enrolled, the impact of clopidogrel monotherapy on bleeding compared with DAPT may have potentially been even more pronounced. As recommended in the guidelines,^1-4 bleeding and ischemic risk were assessed at the time of the index PCI; all patients were at high ischemic risk given their presentation with ACS, and all met additional risk criteria for increased ischemia or bleeding. However, enrolled patients were event free for at least 6 months after a 9- to 12-month course of DAPT, selecting for a relatively lower-risk subset of birisk patients. Nonetheless, these patients represent a large cohort commonly encountered in clinical practice in whom the question of continuing DAPT vs de-escalating to clopidogrel monotherapy at this time has not previously been addressed. Our trial results apply to this cohort. Methodologically, this is also the proper time to recruit and randomize this group. The OPT-BIRISK study was designed before publication of what are currently the most widely used high bleeding-risk criteria, the Predicting Bleeding Complications in Patients Undergoing Stent Implantation and Subsequent Dual Antiplatelet Therapy (PRECISE-DAPT) and Academic Research Consortium High Bleeding Risk (ARC-HBR) scores.^44,45 Not all patients enrolled in the present study met high bleeding-risk criteria according to these risk instruments. However, the birisk criteria we selected were chosen from elements from previously published risk scores for ischemia and bleeding (eTable 6 in Supplement 3), and performed well in discriminating birisk patients with ACS in a real-world registry.⁴⁶ Confirmatory studies are warranted to determine whether our findings apply to birisk populations defined by other ischemic and bleeding risk criteria. The present trial was conducted solely in a Chinese population. In this regard, the higher incidence of loss-of-function alleles adversely affecting clopidogrel metabolism and antiplatelet efficacy in East Asian patients may have increased ischemic event rates in the clopidogrel monotherapy arm.⁴⁷ The fact that MACCE rates were lower in this arm than when compared with ongoing DAPT thus supports use of this regimen in a population without these concerns. Finally, the ratio of unstable angina to NSTEMI was higher than in other studies from the US and elsewhere due to the infrequent use of high-sensitivity troponin tests in China. Also, prasugrel is not available in China; as such, the present results are applicable to P2Y12 inhibitor treatment with clopidogrel or ticagrelor only. Additional randomized clinical trials are warranted to examine whether clopidogrel monotherapy after a mandatory DAPT period in patients with ACS with high-risk bleeding characteristics is safe and effective in a Western population.

In conclusion, in the present large-scale, double-blind, placebo-controlled randomized clinical trial, among PCI-treated patients with ACS who are at high risk for both ischemic and bleeding events and who had completed 9 to 12 months of DAPT and were free from adverse events for at least 6 months, subsequent treatment with clopidogrel alone was superior to continuing DAPT with aspirin and clopidogrel in reducing clinically relevant bleeding and MACCE for an additional 9 months.

Accepted for Publication: February 2, 2024.

Published Online: April 17, 2024. doi:10.1001/jamacardio.2024.0534

Corresponding Author: Yaling Han, MD, State Key Laboratory of Frigid Zone Cardiovascular Disease, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang 110016, China (hanyaling@263.net).

Author Contributions: Dr Han had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Y. Li and J. Li contributed equally to this work.

Concept and design: Y. Li, Z. Wang, B. Liu, Jun Zhang, Li Li, Qu, Qiu, Chen, Zhou, Han.

Acquisition, analysis, or interpretation of data: Y. Li, J. Li, B. Wang, Jing, Y. Zeng, Hou, Z. Wang, A. Liu, Jinliang Zhang, Y. Zhang, P. Zhang, D. Jiang, B. Liu, Fan, Jun Zhang, Su, Yang, W. Jiang, Qu, H. Zeng, Lu Li, Qiu, Ru, Chen, Qiao, Stone, Angiolillo, Han.

Drafting of the manuscript: Y. Li, J. Li, Jing, Hou, Z. Wang, Jinliang Zhang, B. Liu, Fan, Jun Zhang, Li Li, Qu, Chen, Stone, Han.

Critical review of the manuscript for important intellectual content: B. Wang, Y. Zeng, Z. Wang, A. Liu, Y. Zhang, P. Zhang, D. Jiang, B. Liu, Jun Zhang, Su, Yang, W. Jiang, Qu, H. Zeng, Lu Li, Qiu, Ru, Chen, Zhou, Qiao, Stone, Angiolillo, Han.

Statistical analysis: Y. Li, J. Li, Jing, Hou, Z. Wang, A. Liu, Jinliang Zhang, Y. Zhang, B. Liu, Fan, Jun Zhang, Qiu, Chen, Zhou, Han.

Obtained funding: Zhou, Han.

Administrative, technical, or material support: B. Wang, Z. Wang, P. Zhang, Jun Zhang, Su, Qu, H. Zeng, Ru, Chen, Zhou, Han.

Supervision: B. Liu, Jun Zhang, Qu, Ru, Chen, Zhou, Stone, Angiolillo, Han.

Conflict of Interest Disclosures: Dr Stone reported receiving speaker fees from Medtronic, Pulnovo, Infraredx, Abiomed, Amgen, and Boehringer Ingelheim; consultant fees from Abbott, Daiichi Sankyo, Ablative Solutions, CorFlow, Cardiomech, Gore, Robocath, Miracor, Vectorious, Abiomed, Valfix, Apollo Therapeutics, TherOx, HeartFlow, Neovasc, Ancora, Elucid Bio, Occlutech, Impulse Dynamics, Adona Medical, Millennia Biopharma, Oxitope, Cardiac Success, and HighLife; research funding from Ancora, Cagent, Applied Therapeutics, and Biostar; equity or options from SpectraWave, Orchestra Biomed, Aria, Cardiac Success, Valfix, and Xenter; and research grants from Abbott, Abiomed, Bioventrix, Cardiovascular Systems Inc, Phillips, Biosense-Webster, Shockwave, Vascular Dynamics, Pulnovo, and V-wave outside the submitted work. Dr Angiolillo reported receiving consulting fees from Abbott, Amgen, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, CSL Behring, Daiichi Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, Novartis, PhaseBio, PLx Pharma, Pfizer, Sanofi, and Vectura and research grants from Amgen, AstraZeneca, Bayer, Biosensors, Celo-Nova, CSL Behring, Daiichi Sankyo, Eisai, Eli Lilly, Gilead, Idorsia, Janssen, Matsutani Chemical Industry Co., Merck, Novartis, and the Scott R. MacKenzie Foundation. No other disclosures were reported.

Funding/Support: This trial was funded by grants 2016YFC1301300, 2016YFC1301303, and 2022YFC2503500 from the National Key Research and Development Project and a research grant from Sanofi-Aventis Co. Ltd (Paris, France).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: The members of the OPT-BIRISK Investigators are listed in Supplement 4.

Data Sharing Statement: See Supplement 5.

Additional Contributions: We thank the investigator members of the OPT-BIRISK study group and Drs Xiaozeng Wang, MD (General Hospital of Northern Theater Command), Geng Wang, MD (General Hospital of Northern Theater Command), Kai Xu, MD (General Hospital of Northern Theater Command), Haiwei Liu, MD (General Hospital of Northern Theater Command), Yingyan Ma, MD (General Hospital of Northern Theater Command), Zhenyang Liang, MD (General Hospital of Northern Theater Command), Shaoyi Guan, MD (General Hospital of Northern Theater Command), Nan Ma, PhD (General Hospital of Northern Theater Command), Yuxin Dong, MBBS (CCRF [Beijing] Co Ltd), Peng Fan, MD (General Hospital of Northern Theater Command), Xinxin Yuan, MBBS (CCRF [Beijing] Co Ltd), Yu Zhao, MD (General Hospital of Northern Theater Command), Shanbao Chen, MD (General Hospital of Northern Theater Command), and Wenjing Dou, MD (General Hospital of Northern Theater Command), for coordination of the study.