Rationale and design of the optimal antithrombotic treatment for acute coronary syndrome patients with concomitant atrial fibrillation and implanted with new‐generation drug‐eluting stent: OPtimal management of anTIthroMbotic Agents (OPTIMA)‐4 trial

Abstract Background About 5%–15% of acute coronary syndrome (ACS) patients undergoing stent implantation have concomitant atrial fibrillation and need both antiplatelet and anticoagulant therapies. The optimal antithrombotic regimen remains uncertain in this scenario. Hypothesis A multicenter randomized controlled trial (OPtimal management of anTIthroMbotic Agents [OPTIMA]‐4) is designed to test the hypothesis that, for ACS patients with concomitant nonvalvular atrial fibrillation (NVAF) and having low‐to‐moderate risk of bleeding, clopidogrel is comparable in efficacy but superior in safety compared to ticagrelor while being used in combination with dabigatran after new‐generation drug‐eluting stent (DES) implantation. Methods ACS patients who have low‐to‐moderate risk of bleeding (e.g., HAS‐BLED score ≤ 2) and require anticoagulation therapy (CHA2DS2‐VASc score ≥ 2) will be recruited after implantation of new‐generation DES. A total of 1472 eligible patients will be randomly assigned to receive a 12‐month dual antithrombotic treatment of either clopidogrel 75 mg daily or ticagrelor 90 mg twice daily in combination with dabigatran 110 mg twice daily. Participants will be followed up for 12 months after randomization. The primary efficacy endpoint is a composite of cardiovascular death, myocardial infarction, unplanned revascularization, ischemic stroke, and systemic thromboembolism. The primary safety endpoint is set as major bleeding or clinically relevant nonmajor bleeding defined by the International Society of Thrombosis and Hemostasis. The enrollment and follow‐up have been launched. Results The first enrollment occurred on March 12, 2018. The recruitment is anticipated to be completed before December 31, 2024. Conclusions The OPTIMA‐4 trial offers an opportunity to assess the optimal dual antithrombotic regimen in ACS patients with concomitant NVAF after the implantation of new‐generation DES.


| INTRODUCTION
Dual antiplatelet therapy (DAPT) with aspirin and adenosine diphosphate (ADP) antagonist has been recommended for patients after drug-eluting stent (DES) implantation to prevent stent thrombosis (recommendation level: IA), 1 and oral anticoagulants (OAC) is recommended for atrial fibrillation (AF) patients with CHA 2 DS 2 -VASc score ≥ 2 to prevent ischemic stroke. 2 Thus, for patients undergoing percutaneous coronary intervention (PCI) with concomitant AF, triple antithrombotic therapy (TATT) including both DAPT and OAC would be indicated. 3 However, previous studies have reported that TATT based on warfarin or new oral anticoagulants (NOAC) significantly increased the bleeding incidence compared with dual antithrombotic therapy (DATT). 4,5 The new-generation DES with better biocompatibility or biodegradable polymers or non-polymer has been widely used in clinical practice. Compared with the first-generation DES, the new-generation DES is associated with faster endothelialization and lower incidence of stent thrombosis and is therefore less dependent on DAPT. 6 In the era of new-generation DES, current guidelines have recommended a shortened concomitant nonvalvular atrial fibrillation (NVAF) and having low-tomoderate risk of bleeding, clopidogrel is comparable in efficacy but superior in safety compared to ticagrelor while being used in combination with dabigatran after new-generation DES implantation.

| Study design
A multicenter, open-label, randomized, controlled clinical trial (OPTIMA-4) is designed. The study design is shown in Figure 1. The study complies with the Declaration of Helsinki as amended in Seoul, Korea (64th, 2013), and is to be performed in accordance with the International Conference on Harmonization "Good Clinical Practices." Before participating in this study, patients should be informed about the objectives, rights, duties, possible risks, and benefits of the study in lay language, and written informed consent should be signed as required. Written informed consent for publication of their clinical details and/or clinical images should be obtained from the patient/parent/guardian/relative of the patient. Patients can be identified only by a unique identification code and randomization number to maintain their confidentiality. The investigators will report the progress of this study to the ethics committee annually until the study is completed. The study has been registered at Clinicaltrials.gov (identifier: NCT 03234114).

| Participant selection
The main inclusion criteria are ACS patients with concomitant nonvalvular AF, who underwent new-generation DES implantation with CHA 2 DS 2 -VASc score ≥ 2 and in an acceptable risk of bleeding (e.g., HAS-BLED score ≤ 3). The detailed inclusion and exclusion criteria are listed in Table 1. A total of 1472 patients will be required and recruited at 66 medical centers in China (see Supporting Information: Appendix 2).

| Randomization
Within 120 h of the new-generation DES implantation, eligible patients will be randomized in a 1:1 ratio to receive either clopidogrel 75 mg daily or ticagrelor 90 mg twice daily in combination with dabigatran 110 mg twice daily for 12 months. The randomization will be done by the investigators through a central 24 h computerized randomization system of REDCap, 12 using a random permuted block design with block sizes of four. The system can be accessed using personalized login data. Treatment allocation will be revealed for the patients and attending physicians.

| PCI procedure
PCI procedures will be performed by well-experienced interventional cardiologists performing over 500 cases of PCI per year, and radial access should be chosen as a priority. Successful PCI is defined as thrombolysis in myocardial infarction flow grade 3 in the target vessel with less than 10% residual stenosis. New-generation DES (with better biocompatibility or biodegradable polymers or non-polymer demonstrated in Supporting Information: Appendix 3) is required to be implanted in OPTIMA-4 trial.

| Combined medications
The low-molecular-weight heparin (LWMH) (100 IU/kg, injected subcutaneously every 12 h) is recommended for up to 7 days during the perioperative period. Dabigatran is required to be prescribed after randomization and discontinuation of the LWMH. A bolus of unfractionated heparin (UFH) (100 IU/kg) should be injected intravenously during the PCI procedure. The activated clotting time (ACT) should be monitored every 1 h and an extra UFH should be administered if the ACT is low than 300 s. The platelet glycoprotein IIb/IIIa receptor inhibitors, e.g., Tirofiban, are not recommended unless a heavy thrombus burden is shown in coronary angiography. Other antithrombotic agents, e.g., prasugrel or rivaroxaban, are not allowed to be administered during the study period. Proton pump inhibitors could be administered for patients with high risk of gastrointestinal bleeding. Other medications (e.g., statins, β-blockers, angiotensin-converting enzyme inhibitors, etc.) could be administered at the discretion of the attending physicians.

| Pharmacodynamic, pharmacokinetic, and pharmacogenomic studies
The pharmacodynamic, pharmacokinetic, and pharmacogenomic studies of the antithrombotic agents will be performed in qualified centers for consented participants. The pharmacodynamic study of the antiplatelet drugs will be performed by light transmission aggregometry (LTA). In detail, 2 mL venous blood will be separately collected into two 3.2% sodium citrate vacutainer tubes (Becton, Dickinson and Company) at 7:30 a.m. on the day of discharge. Then blood samples will be subjected to an LTA test within 2 h, as previously described. 13 Samples will be centrifuged at 200g for 8 min to obtain platelet-rich plasma (PRP). Platelet-poor plasma (PPP) will be prepared by centrifuging the remaining blood at 2465g for 10 min.
Platelet counts will be adjusted by adding PPP to the PRP to achieve a count of 250 × 10 9 /L. Both the ADP (final concentration 5 μmol/L) induced platelet aggregation (PL ADP ) and the arachidonic acid (AA) (final concentration 1 mmol/L) induced platelet aggregation (PL AA ) will be detected using the Chronolog Model 700 aggregometer (Chrono-log Corporation). The pharmacokinetic study of dabigatran will be performed as follows. Venous blood (2 mL) will be collected into a 3.2% sodium citrate vacutainer tube (Becton, Dickinson and Company) at 0.5 h before the dosing after at least six doses. Samples will be centrifuged at 2500g for 15 min at 25°C within 1 h. After centrifugation, the upper plasma will be stored below −80°C, and the concentration of dabigatran will be detected by high-performance liquid chromatography-tandem mass spectrometry in the pharmaceutical department of Fujian Medical University Union Hospital. 14 The pharmacogenomic studies of the antithrombotic agents will be performed as follows. Two milliliters of blood will be drawn into a BD Vacutainer tube (Becton, Dickinson and Company) containing 3.6 mg K2-ethylenediaminetetraacetic acid and stored below −80°C. The following single-nucleotide polymorphisms (SNPs) will be detected: (1) clopidogrel-related SNPs: CYP2C19 (rs12248560, rs28399504, rs41291556, rs4244285, rs4986893, rs5633701, rs72552267, rs72558186) 15

| Study visits and follow-up
All subjects will be followed up at 1 month (±7 days), 6 months (±7 days), and 12 months (±7 days) in the outpatient clinic, and at 2 weeks (±7 days), 2 months (±7 days), and 3 months (±7 days) by telephone. The patients' primary and secondary endpoints, (severe) adverse events, medications, and the results of the tests mentioned above will be carefully recorded during the follow-up.

| Sample size determination and statistical analysis
The OPTIMA-4 trial aims to simultaneously test the following two hypotheses of dabigatran-based DATT in eligible patients: (1) clopidogrel is superior to ticagrelor regarding major bleeding and CRNMB events and (2) clopidogrel is noninferior to ticagrelor regarding the composite efficacy endpoint. According to the RE-DUAL PCI trial, the anticipated incidence of annual efficacy endpoint is 18.9% in the arm of ticagrelor. 9 We set a noninferiority margin ratio of 1.38 and α of .025 (one-sided), 655 patients in each group are required to achieve a statistical power of 80%. 9  To control the type I error at one-side 0.025 level, a hierarchical procedure for multiple testing will be used. The paradigm of the hierarchical procedure in OPTIMA-4 trial is detailed below: Step 1: Superiority of dabigatran combined with clopidogrel to dabigatran combined with ticagrelor concerning major bleeding and CRNMB is met at the one-sided 0.025 level of significance.
Step 2: Noninferiority of dabigatran combined with clopidogrel to dabigatran combined with ticagrelor for the efficacy endpoint is met at the one-sided 0.025 level of significance.
If step 1 fails to meet statistical significance, step 2 will not be performed.
The primary endpoints will be treated as time-to-event endpoints, and the Kaplan-Meier method will be employed to estimate the cumulative incidences of endpoints by treatment group. The primary endpoints between the two groups will be compared using the Cox proportional hazards model with treatment as a fixed effect and adjusted for other covariates separately. The estimated hazard ratio (HR) and two-sided 95% confidential interval (CI) or one-sided 97.5% CI for the noninferiority test will be provided. For the noninferiority test in the composite efficacy endpoint, the noninferiority margin is 1.38 on the HR scale. The upper boundary of CI for the HR (one-sided 97.5%) will be compared to this margin. All the above analyses will also be conducted in predefined subgroups. The secondary time-to-event endpoints will be analyzed using the methods mentioned above. All statistical analyses will be performed using SAS version 9.4 (SAS Institute Inc.).
The analysis sets are as follows: (1)

| Study administration and management
The local Institutional Review Board or Ethics Committee at each participating co-center must approve the study, and all patients must provide written informed consent before enrollment. This trial will add new evidence on the optimal antithrombotic strategy for the above mentioned patients.
TATT was proposed for ACS patients with concomitant AF after PCI to prevent major adverse cardiovascular events (MACEs) over a decade ago. 25 Nowadays, the ischemic risk for these patients has been reduced due to the improvement of new-generation DES and the introduction of advanced antithrombotic agents, 11,26,27 while the bleeding risk becomes prevailing for these patients under TATT. 28  The hierarchical statistical procedure is first based on the hypotheses that the clopidogrel group is superior to the ticagrelor group regarding the safety endpoint, and then noninferior to the latter regarding the efficacy endpoint. This design mainly concerns the major bleeding and CRNMB under DATT, which may result in unexpected discontinuation of antithrombotic agents and consequent increase of the ischemic risk.
The main inclusion and exclusion criteria are set on the basis of the following considerations. First, as only new-generation DES is required to be implanted in this trial, and the high thrombotic risk scenario such as left main coronary artery DES implantation will be excluded, it would be acceptable to initiate DATT within 5 days after PCI, instead of after 1-week 1-month TATT. Second, because all enrolled patients will receive dabigatran-based DATT, they need to meet the criteria of CHA 2 DS 2 -VASc score ≥ 2 which indicates high risk of thromboembolism and requirement of anticoagulant. Third, patients with acceptable risk of bleeding (e.g., HAS-BLED score ≤ 3) will be recruited, whereas those with high risk of bleeding will be excluded, considering the fact that 12-month DATT has been recommended by current guidelines for the latter. 7 Besides, previous studies enrolled patients with the average HAS-BLED score ≤ 3 and showed the superiority of 12-month NOAC-based DATT. 5,[8][9][10] Finally, valvular AF patients will not be enrolled owing to little evidence that NOAC is beneficial for these patients. 30

AUTHOR CONTRIBUTIONS
Chunjian Li and Xiaoxuan Gong designed the study. Xiaoxuan Gong, Rui Hua, and Jianling Bai contributed equally to writing the manuscript and share the first authorship. Jianling Bai made the statistical analysis plan and Jinhua Zhang provided the pharmacokinetics detection of the antithrombotic agents. Other authors were major contributors to patients' enrollment and management from cocenters. All authors have read and approved the final manuscript.