key: cord-028907-m9psxg1f
authors: Li, Yi; Jing, Quanmin; wang, Bing; Wang, Xiaozeng; Li, Jing; Qiao, Shubing; Chen, Shaoliang; Angiolillo, Dominick J.; Han, Yaling
title: Extended antiplatelet therapy with clopidogrel alone versus clopidogrel plus aspirin after completion of 9- to 12-month dual antiplatelet therapy for ACS patients with both high bleeding and ischemic risk. Rationale and design of the OPT-BIRISK double blinded, placebo controlled randomized trial
date: 2020-07-09
journal: Am Heart J
DOI: 10.1016/j.ahj.2020.07.005
sha: 
doc_id: 28907
cord_uid: m9psxg1f

BACKGROUND: Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor is the cornerstone for prevention ischemic events in patients with acute coronary syndromes (ACS) and undergoing percutaneous coronary intervention (PCI). However, the optimal antiplatelet strategy for ACS patients with both high bleeding and high ischemic risks is unclear. STUDY DESIGN: The Optimal antiPlatelet Therapy for patients with high Bleeding and Ischemic RISK (OPT-BIRISK) trial is a multicenter, double blinded, placebo controlled, randomized study designed to test the superiority of extended antiplatelet therapy with clopidogrel monotherapy compared with aspirin and clopidogrel for reduction of bleeding events in ACS patients with both high bleeding and high ischemic risks (“bi-risk”). A total of 7700 patients who completed 9- to 12-month DAPT after new generation drug eluting stent implantation for the treatment of ACS will be randomized to receive clopidogrel monotherapy or aspirin plus clopidogrel for 9 months, followed by aspirin monotherapy for 3 months. The primary end point is Bleeding Academic Research Consortium type 2, 3 or 5 bleedings at 9 months after randomization. The key secondary endpoint is major adverse cardiac and cerebral events at 9 months after randomization, defined as a composite of all-cause death, myocardial infarction, stroke or coronary artery revascularization. CONCLUSION: OPT-BIRISK is the first large scale, randomized trial aimed to explore the optimal antiplatelet strategy for bi-risk ACS patients after PCI in current clinical practice. The results will add evidence regarding de-escalation antiplatelet therapy for patients at special risk.

J o u r n a l P r e -p r o o f 3 / 21 Background Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor is the cornerstone to prevent stent thrombosis and atherothrombotic events in patients with acute coronary syndromes (ACS) and/or undergoing percutaneous coronary intervention (PCI) [1] [2] [3] . Although DAPT reduces thrombotic events, this comes at the expense of increased bleeding, underscoring the importance of careful assessment of risks and benefits in the decision making process of choice and duration of antiplatelet therapy. A number of predictors have been associated with the risk of ischemic and bleeding complications, allowing for the development of scoring systems [4] [5] [6] [7] [8] . However, some predictors have been associated with high risk of both bleeding as well as ischemic events, as elderly, diabetes mellitus, renal dysfunction, anemia, and prior stroke [9] .

Defining the optimal antiplatelet treatment regimen for patients at high risk for both ischemic and bleeding complications, hereby called as "bi-risk", is a clinical challenge. Current practice guidelines recommend DAPT for at least 12 months after an episode of ACS event, followed by aspirin monotherapy indefinitely [1, 2] . For patients at high risk of ischemic events, DAPT beyond 1

year is reasonable, but it is based on the prerequisite that patients are not at high risk of bleeding. Several pivotal randomized trials have demonstrated that extended DAPT beyond 1

year resulted in significantly reduced major cardiac and cerebral ischemic events compared to aspirin alone, but was associated with higher bleeding risk, even among patients who did not previously experience ischemic or bleeding events during the first year or 1 to 3 years [10] [11] [12] .

Therefore, extended DAPT beyond 1 year might not be suitable for bi-risk patients due to their high bleeding risk.

J o u r n a l P r e -p r o o f

In recent years, a novel approach of dropping aspirin after a period of DAPT has emerged as a strategy aimed to reduce bleeding while preserving efficacy [13] . DAPT followed by chronic P2Y12

inhibitor monotherapy has now been tested in a number of randomized trials [14] [15] [16] [17] . Compared with aspirin monotherapy, P2Y12 inhibitor monotherapy has the potential to maintain antiischemic efficacy and prevent bleeding, especially gastrointestinal, which is mainly caused by aspirin and which accounts for most (up to 61.7% of post PCI bleedings) bleeding complications [18] . Therefore, extended antiplatelet therapy with P2Y12 inhibitor monotherapy is an attractive option for bi-risk patients. In order to test this hypothesis, we designed the Optimal antiPlatelet Therapy for high Bleeding and Ischemic RISK patients (OPT-BIRISK) trial, to determine if extended clopidogrel monotherapy will be superior to DAPT with clopidogrel and aspirin following completion of 9 to 12 months DAPT for ACS patients who received drug eluting stent (DES) implantation and possess both high bleeding and high ischemic characteristics.

OPT-BIRISK, formerly named East Asian Outcome (EA OUTCOME) trial, is a multicenter, prospective, double blinded, active-controlled randomized trial designed to examine the superiority of clopidogrel monotherapy for 9 months over DAPT with aspirin and clopidogrel on reducing bleeding in ACS patients with both high ischemic and bleeding risk who have completed 9 to 12 months of DAPT following PCI using new generation DES. The study design is shown in Figure 1 . This study was approved by the institutional ethics committee of the General J o u r n a l P r e -p r o o f 5 / 21

The study will enroll 7700 patients who completed 9 to 12month DAPT after new generation DES implantation for the treatment of ACS and are free from major adverse clinical events during the prior 6 months. Specific study inclusion and exclusion criteria are shown in Table1.

Bleeding and ischemic risks will be evaluated according to criteria listed in Table 2 , based upon the assessment at the time of index PCI. Each risk criterion of bleeding or ischemia were previously reported in literatures or was an individual component of established risk scores. Eligibility assessment will be performed between 9 to 12 months after index PCI. Patients eligible for enrollment and willing to participate in the study will be called back to clinic and an in-person interview performed. A written informed consent will be signed before screening.

Eligibility assessment using medical records free from consent was approved by ethic committee at General Hospital of Shenyang Northern Theater Command.

Patients eligible for randomization will be randomly assigned to receive either clopidogrel plus aspirin or clopidogrel plus placebo in a 1:1 ratio for 9 months, followed by open-label aspirin monotherapy for 3 months. Allocation to treatment will be acquired by an interactive web response system, incorporated within an electronic data capture system (Taimei Tech., Shanghai, China). After randomization, all patients will receive open-label, on-marketing packaged clopidogrel (Plavix, Sanofi Co Ltd., France) at a dose of 75 mg per day. Re-packaged aspirin (Bayer Aspirin, Bayer Pharmacy, Germany) at a dose of 100 mg per day or matching placebo (Boji Pharmacy, Guangzhou, China) will be given to patients allocated in the DAPT group and clopidogrel alone group, respectively. Study medications will not be discontinued unless Other cardiovascular medications will be at physicians' discretion.

Clinical follow up will be scheduled at 3, 6, 9 and 12 months via telephone or clinic visit after randomization. Throughout the study period, patients will be monitored for the occurrence of the following clinical events: death, myocardial infarction, stroke, any revascularization and any bleeding. Adverse events will be evaluated by the independent clinical event adjudication committee. Every event will be monitored until it is adequately resolved or explained.

The primary endpoint is clinically relevant bleeding at 9 months after randomization, which is defined as Bleeding Academic Research Consortium (BARC) Types 2, 3 or 5 bleeding. The definition of BARC bleeding Types were published elsewhere. In brief, BARC types 2, 3 and 5 bleeds are defined as clinically overt hemorrhage requiring medical attention (type 2), requiring transfusion, surgical correction or associated with a hemoglobin drop of at least 3 g/dl (type 3) or fatal events (type 5) [19] .

The key secondary endpoints are as follows: (1) major adverse cardiac and cerebral events (MACCE) at 9 months, defined as a composite of all-cause death, myocardial infarction, stroke or coronary artery revascularization; (2) each individual components of MACCE; (3) all bleeds, including BARC Type 1, 2, 3 or 5 bleedings; (4) definite/probable stent thrombosis. All deaths are considered cardiac-related unless non-cardiac causes were clearly identified. Myocardial infarction is defined according to the Third universal definition of myocardial infarction [20] .

Stroke is defined as an acute event of non-hemorrhagic cerebrovascular origin causing focal or global neurologic dysfunction lasting > 24 hours, which is confirmed by both clinical and radiographic means. Coronary artery revascularization is defined as any PCI or bypass surgery of Journal Pre-proof J o u r n a l P r e -p r o o f 7 / 21 lesion(s) in the main epicardial coronary artery or branches. Stent thrombosis is defined as the Academic Research Consortium definitions [21] .

We assume BARC Type 2, 3 or 5 bleedings to occur in 6.0% of patients during the 9-month study period in DAPT group [22] . In order to detect a 25% reduction in primary endpoint events, with two tailed alpha of 0.05 and power of 80%, 3470 patients for each group is needed to draw a conclusion that clopidogrel alone is superior to DAPT. Considering a loss of follow-up rate of 10%, the final sample size is 7700 patients, 3850 patients in each group.

For key secondary endpoint testing, we assume MACCE occurred in 8.0% of patients in the DAPT group, with a non-inferior margin of 1.6% (20% difference), one side alpha of 0.025, 7700 patients will provide 73% power to conclude that clopidogrel is non-inferior to DAPT in antiischemic efficacy.

All analyses will be performed according to the intention-to-treat principle based on the number of patients available for each analysis. The data will be presented as means ± SD; medians, with 25th and 75th percentiles; or counts or percentages. Baseline clinical and angiographic characteristics as well as procedural variables will be checked for statistically significant differences with Student t-test (continuous data) or contingency table analysis (categorical data).

Time to event variables will be estimated using Kaplan-Meier method and compared with log rank test. Last observation carry forward will be used in patient loss of follow-up but has clinical outcomes by at least one follow-up visit. Pre-specified analysis will consist of comparisons between the 2 study groups with regard to the primary and secondary endpoints. The analysis will also involve pre-specified subsets of interest: age, sex, diabetes mellitus, renal dysfunction, heart failure, anemia, prior systemic ischemic events, troponin positive ACS, complex PCI J o u r n a l P r e -p r o o f 8 / 21 (including PCI for left main disease, chronic total occlusion, small vessel disease, diffused lesion, bifurcation or severe calcification), complete revascularization, DES type, prior bleeding events, risk stratification by GRACE score, CRUSADE score and DAPT score.

No interim analysis will be performed for this study. An independent data safety monitoring board (DSMB) will monitor study data periodically during the trial and determine reporting and stopping rules in the DSMB charter.

Details of the study organization are shown in Appendix. This trial is a physician initiated study and is supported by research fund from Chinese National key R & D project (contract ID: 2016YFC1301303, 2016YFC1301300) and an investigator initiated grant from Sanofi (Paris, France). The sponsor is not involved in the study design, study processes, including site selection and management，data collection and analysis or decision to submit for publication. The authors are responsible for all the design and conduct of this study, all study analyses, the drafting and editing of the manuscript and its final contents.

OPT-BIRISK is the first large scale, placebo controlled randomized trial focused on an important patient cohort composed of ACS patients at high risk for both ischemic and bleeding complications. Defining the optimal antiplatelet therapy for such patients is challenging.

Although prior studies have been conducted on defining duration and choice of antiplatelet therapy in patients either at high bleeding or high ischemic risk, to date there have not been any study focusing on bi-risk patients. In this trial, we will test the hypothesis that, for bi-risk ACS patients, extended antiplatelet therapy beyond 9-12 months with sustained clopidogrel J o u r n a l P r e -p r o o f 9 / 21 monotherapy is superior to sustained DAPT in reducing bleeding events and is non-inferior to sustained DAPT on anti-ischemic efficacy. This trial will provide new insights and evidence on optimal antiplatelet therapy for a high risk patient cohort which is frequently encountered in real-world practice (about 60% according to our unpublished data).

The importance of aggressive antithrombotic therapies has been emphasized since the introduction of coronary stents over two decade ago, and was reinforced due to the fear of stent thrombosis after first generation DES implantation and concerns surrounding antiplatelet drug resistance [23] [24] [25] . However, over the most recent years improvements in stent design leading to better safety profiles and improved operator skills have led to a dramatic reduction in thrombotic complications leading to a change in perception on the duration and potency of antiplatelet agents needed [26] [27] [28] . Moreover, significantly improved compliance to guidelines recommended secondary prevention measures [29] , such as cholesterol lowering, antihypertensive and hypoglycemic treatment, resulted in significantly decrease on ischemic risks. In parallel there has been growing appreciation for the prognostic implications associated with bleeding, including increased risk of all-cause and cardiac mortalities [30] [31] [32] [33] . Even nuisance or minor bleeding can result in unexpected discontinuation of antiplatelet treatment and consequently increase ischemic risk [34, 35] . Accordingly, the primary endpoint of OPT-BIRISK is clinical relevant bleeding.

De-escalation of antiplatelet potency has emerged as strategy to reduce bleeding and a topic of ongoing investigation [24, 36] . This includes reduced antiplatelet agent dose, short DAPT duration, switching to a less potent agent and even early switching to mono-antiplatelet agent [37, 38] .

Traditionally, chronic aspirin monotherapy is the standard antiplatelet strategy recommended by current practice guidelines after discontinuation of DAPT. This approach has never been J o u r n a l P r e -p r o o f 10 / 21 challenged for about two decades due to its established anti-ischemic effectiveness and very low cost. However, aspirin alone or in adjunct to a P2Y12 inhibitor is the most important cause of antiplatelet related bleeding, especially gastrointestinal bleedings [39] . Therefore, it is reasonable to consider P2Y12 inhibitor monotherapy instead of aspirin based DAPT for patients who finished standard DAPT duration but still at high ischemic risk, in order to reduce bleeding risk without compromise in anti-ischemic effects. Recently published GLOBAL LEADERS/GLASSY, STOPDAPT 2, SMART-CHOICE and TWILIGHT are all trials intent to test the superiority of P2Y12 inhibitor monotherapy over DAPT in selected patients [14] [15] [16] [17] 40] . GLOBAL LEADERS failed to demonstrate the superiority of sustained ticagrelor monotherapy compared with standard DAPT, one major reason might be the unselected study populations in which more than half had stable coronary artery disease [14] . The open-label STOPDAPT 2 study focused on patients treated with CoCr EES, a device with low risk of stent thrombosis, and found 1-month DAPT followed by sustained clopidogrel monotherapy was superior to standard 12-month DAPT with significant improved net clinical benefits [15] . The open-label SMART-CHOICE study demonstrated that P2Y12 inhibitor monotherapy after mandatory 3-month DAPT was non-inferior to prolonged DAPT on ischemic risks and was better on reducing bleeding risks in a broad spectrum of PCI patients [16] . Different from the above studies, TWILIGHT and OPT-BIRISK are both double blinded trials focused on high risk patients, and the high risk criteria of these two trials partly overlap. TWILIGHT has demonstrated that among high risk patients who underwent PCI and DAPT, Dual antiplatelet therapy; # New generation DES refer to any DES with thin strut/Co-Cr alloy platform, or with biodegradable polymer/polymer free, or with more biocompatible drugs other than paclitaxel or sirolimus.

* Criteria of high bleeding and ischemic risk see Table 2 . 

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