Safety and Efficacy of Ticagrelor versus Clopidogrel in East Asian Patients with Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention Treated with Dual Antiplatelet Therapy: A Meta-Analysis of Randomized Controlled Trials

Introduction: The treatment strategy for dual antiplatelet therapy (DAPT) with ticagrelor has been controversial in East Asian patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). Our meta-analysis aimed to demonstrate whether intensified antithrombotic regimens with ticagrelor plus aspirin have more beneficial effects and fewer adverse events compared to those of clopidogrel plus aspirin in East Asian patients with ACS undergoing PCI. Methods: We searched PubMed, Embase, Web of Science, ScienceDirect, Clinical Trials, Cochrane Library, and Chinese Clinical Trial Registry for randomized controlled trials (RCTs) comparing the efficacy of DAPT with ticagrelor or clopidogrel plus aspirin for secondary prevention of ACS in East Asian patients undergoing PCI. Risk ratios (RRs) and 95% confidence intervals (CIs) were used as the metrics of choice for assessing treatment effects. The primary endpoint was bleeding events, and the secondary endpoints were major adverse cardiovascular and cerebrovascular events (MACCEs, including cardiovascular death, nonfatal myocardial infarction [MI], and stroke), all-cause death, and definite/probable/possible stent thrombosis. The I2 index was used to assess heterogeneity. Results: Six RCTs involving a total of 2,725 patients met the inclusion criteria. The incidence of all bleeding events with ticagrelor was higher than that with clopidogrel (RR, 1.65; 95% CI, 1.31–2.07), but the incidence of MACCE was not significantly different between the two groups (RR, 1.08; 95% CI, 0.54–2.16). All-cause death (RR, 1.10; 95% CI, 0.67–1.79), cardiovascular death (RR, 1.42; 95% CI, 0.68–2.98), nonfatal MI (RR, 0.92; 95% CI, 0.48–1.78), stroke (RR, 1.00; 95% CI, 0.40–2.50), and stent thrombosis (RR, 0.76; 95% CI, 0.19–2.98) were not statistically different between the two groups. Conclusion: Ticagrelor increased the risk of bleeding and did not increase treatment efficacy compared to that of clopidogrel in the East Asian population who have ACS treated with PCI.


Introduction
Acute coronary syndrome (ACS), which encompasses ST-elevation myocardial infarction (STEMI), non-STelevation myocardial infarction (NSTEMI), and unstable angina (UA), remains the main cause of mortality and disability worldwide despite recent pharmacological and technological innovations [1]. Percutaneous coronary intervention (PCI) of the culprit vessels remains the standard of care for patients with ACS [2].
Dual antiplatelet therapy (DAPT), which reduces the prevalence rates of adverse cardiovascular events in patients with ACS [3], has been recommended by most guidelines worldwide for post-PCI patients [4,5]. According to the current guidelines outlined in the Platelet Inhibition and Patient Outcomes (PLATO) study [6], patients with ACS should undergo DAPT with ticagrelor plus aspirin. Ticagrelor, a P2Y 12 inhibitor, exerts faster and more significant platelet inhibition with less patientto-patient variation than that of clopidogrel [1,5], which is widely used for the secondary prevention of ACS. Ticagrelor improves cardiovascular outcomes in ACS and has replaced clopidogrel as first-line therapy worldwide. However, some researchers reported that East Asian patients have a reduced anti-ischemic benefit and increased bleeding risk during antithrombotic therapy compared with those of Caucasian patients [7]. Since ticagrelor has been approved in current clinical practice, the unique risk-benefit trade-off of ticagrelor in East Asian individuals has been the focus of researchers lately.
Although ticagrelor therapy might be consistent among various races according to previous research studies [8,9], the differences in the levels of hemostatic factors and plasma endothelial activated markers might be contributing factors to the ethnic disparity observed in antithrombotic therapy [10][11][12][13]. In patients treated with DAPT, East Asian individuals showed higher bleeding rates than those of individuals from Southeast Asia/India [14].
Studies focusing on the application of DAPT with ticagrelor plus aspirin in specific patient populations with ACS after PCI are needed given the widespread routine use of PCI and ticagrelor. Our meta-analysis aimed to demonstrate whether intensified antithrombotic regimens with ticagrelor plus aspirin have more beneficial effects and fewer adverse events compared to those of clopidogrel plus aspirin in East Asian patients with ACS undergoing PCI.

Data Source and Search Strategy
We searched PubMed, Embase, Web of Science, Science-Direct, Cochrane Library, Clinical Trial Registries, and ChiCTR Registries using the snowballing mode (i.e., references from identified articles) to retrieve as many articles as possible up to January 31, 2022. We performed a systematic literature review using the following keywords: acute coronary syndrome, ACS, ST-segment elevation myocardial infarction, STEMI, non-STsegment elevation myocardial infarction, NSTEMI, unstable angina, UA, myocardial infarction, MI, in-stent restenosis, angioplasty, percutaneous coronary intervention, PCI, percutaneous coronary revascularization, PCR, coronary stent, post-stent, ticagrelor, AZD6140, Brilinta, and Brilique. Three investigators (Q. W., C. W., and X. Q.) independently reviewed the studies. Conflicts were resolved through consensus or discussion with the senior author (J. L.). The search strategy, study selection, data extraction, and data analyses were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [15]. There were no restrictions on language. The search strategies for the databases are listed in online supplementary Table 1 (for all online suppl. material, see https://doi.org/10.1159/000530602). This research was registered with PROSPERO (International Prospective Register of Systematic Reviews, CRD42021246338).

Data Extraction and Quality Assessment
Two investigators (L. Z. and X. H.) independently extracted and tabulated the data. Discrepancies were resolved by the senior author (J. L.). Data on the patient's age, sex, body mass index (BMI), hypertension, dyslipidemia, diabetes mellitus (DM), chronic kidney disease (CKD), smoking status, prior myocardial infarction (MI), prior PCI, blinding method, follow-up interval, dose, duration time, radial access, stent type, major adverse cardiovascular and cerebrovascular events (MACCEs), and bleeding outcomes were collected. Duplicate records of patients in different articles were excluded, and only the study data that best met the inclusion criteria were included in the main and subgroup studies. The quality of each study was assessed using the Cochrane Collaboration Assessment Tool.

Inclusion/Exclusion Criteria and Study Selection
The inclusion criteria were as follows: (1) randomized controlled trial (RCT); (2) ticagrelor management, including a loading dose of 180 mg and maintenance dose of 90 mg b.i.d.; (3) patients with ACS, including UA, STEMI, NSTEMI, and MI; (4) undergoing PCI; and (5) conforming to the current medication guidelines for DAPT. The exclusion criteria were as follows: (1) duplicate records; (2) reviews, meta-analyses, non-randomized trials, expert consensus, letters, meeting abstracts, and study designs; (3) sample size of less than 25 patients per group; (4) only abstracts; and (5) trials without posted results or published data.

Objectives and Definitions
The primary objective of this analysis was to compare the outcomes of DAPT with ticagrelor or clopidogrel in East Asian patients with ACS undergoing PCI. DAPT with standard doses of ticagrelor and aspirin was evaluated. A loading dose of 180 mg and maintenance dose of 90 mg b.i.d. were considered the standard doses of ticagrelor. Aspirin was administered according to the local guidelines for usage. When data regarding the loading dose were not specifically described, it was assumed that a standard dose had not been administered. East Asian population includes individuals from South Korea, North Korea, Japan, Mongolia, and China. We attempted to determine which countries the patients originated from, and if the information was not available, we used the countries where the RCTs were registered or the location of the trial center.

Outcomes
The primary endpoint was bleeding events, and the secondary endpoints were MACCE, all-cause mortality, cardiovascular mortality, nonfatal MI, definite/probable/possible stent thrombosis (ST), and stroke. MACCE was defined as a composite of cardiovascular death, nonfatal MI, or stroke. Definite/probable/possible ST was defined based on the Academic Research Consortium definition. Major bleeding event was defined based on the thrombolysis in myocardial infarction (TIMI) definition or PLATO definition. The definitions of the main outcomes of all the included studies are listed in online supplementary Table 2.

Statistical Analysis
The risk of bias analysis was performed using the Cochrane Review Manager version 5.4. Heterogeneity was measured using the I 2 method and was considered significant if I 2 >25%. A fixed-(I 2 ≤25%) or random-effect model (I 2 >25%) was used to minimize the influence on effect size in smaller randomized clinical trials. Forest plots were used to illustrate the risk ratio (RR) and corresponding 95% confidence intervals (CIs). Sensitivity analyses were conducted for all endpoints. p < 0.05 (two sided) was considered statistically significant for all tests. All analyses were performed using R Studio (version 1.2.1335) meta-packages.

Study Characteristics
We included six studies with 2,725 patients [16][17][18][19][20][21]. Figure 1 shows the search strategy of our meta-analysis. The main features of the included trials are presented in Table 1 [16] included 352 patients with single de novo coronary stenosis and randomly assigned these patients to either the clopidogrel plus aspirin or ticagrelor plus aspirin group after drug-eluting stent implantation for 1year follow-up in China. Park et al. (TICAKOREA) [18] included 800 Korean patients who were randomly assigned to receive ticagrelor or clopidogrel, and both groups received aspirin. The primary safety outcome was clinically significant bleeding after 12 months. Wang et al. [20] included 298 patients who were randomized to either the ticagrelor or clopidogrel groups. The primary endpoint was ST-segment resolution 90 min after PCI, and the secondary endpoints included myocardial blush grade, corrected TIMI frame count after the procedure, left ventricular ejection fraction, and MACCE at the 6-month follow-up time point. Gu et al. [17] enrolled 74 patients and randomly assigned them to the ticagrelor or high-dose clopidogrel group for a 3-month follow-up. Tang et al. [21] enrolled 400 patients in China; all patients received aspirin and were randomized to receive clopidogrel or ticagrelor.

Patients
The baseline patients' characteristics are summarized in Table 2. We collected data on the age, sex, BMI, and rate of hypertension, DM, dyslipidemia, current smoking, prior MI, previous stroke, prior PCI, and prior CKD, and follow-up time of the included trials.

Discussion
This meta-analysis found that the incidence of all bleeding events associated with ticagrelor was higher than that of clopidogrel in East Asian patients undergoing PCI for ACS. However, the incidence of MACCE was not significantly different between the ticagrelor and clopidogrel groups. Thus, clopidogrel may be a more suitable antiplatelet medication for the East Asian population.
In the present study, we included studies that used DAPT with aspirin plus a P2Y 12 inhibitor, and studies that did not explicitly use aspirin were excluded. The current guidelines for DAPT are based on studies in non-East Asian populations [22]. DAPT with aspirin plus a potent P2Y 12 inhibitor (prasugrel or ticagrelor) is also recommended in the Korean guidelines [23][24][25]. Clopidogrel should only be permitted when prasugrel or ticagrelor is not available or contraindicated in patients with NSTEMI. Patients with STEMI who undergo primary PCI should receive aspirin plus a P2Y 12 inhibitor as soon as they are diagnosed with STEMI. In line with the recommendations for patients with NSTEMI, DAPT with aspirin and a potent P2Y 12 inhibitor (prasugrel or ticagrelor) is the mainstay of treatment. Similarly, prasugrel and clopidogrel are the two main recommended thienopyridine antiplatelet drugs in Japan [26]. Ticagrelor is approved for patients in Japan when other P2Y 12 inhibitors are unsuitable. Furthermore, a study done in China showed that, in a special population with a high risk of bleeding, ticagrelor with a dose <90 mg prescribed twice daily may have a better benefit-to-risk ratio, and there is a need for further evidence to support these findings [27].
Our study aimed to discuss the optimized application of antithrombotic treatment in East Asian patients with ACS after PCI. Since the recommendation of DAPT for 12 months for patients with ACS by the 2016 American College of Cardiology/American Heart Association (ACC/AHA) guidelines [3], new RCTs have studied different regimens and durations of antiplatelet therapy, and their treatment recommendations vary according to the risk of bleeding. A shorter duration of DAPT may be reasonable for individuals with a high risk of bleeding. Moreover, the characteristics of patients with high bleeding risk included those aged ≥65 years, having BMI <18.5 kg/m 2 , DM, prior bleeding, or taking oral anticoagulants [3].  We limited our study to East Asian patients diagnosed with ACS who underwent PCI and were treated with ticagrelor or clopidogrel plus aspirin. We narrowed the search strategy due to the inconsistencies in applying current guidelines and expert consensus [28]. Furthermore, the purpose of our targeted and relevant research was to apply the antithrombotic treatment to East Asian patients undergoing PCI for ACS. We included six RCTs that were conducted in China, Japan, and South Korea. No RCTs from North Korea or Mongolia met the inclusion criteria, despite our best research efforts. This study provided evidence for precise antithrombotic therapy after PCI in East Asian patients with ACS.
Owing to differences in region, ethnicity, and metabolic pattern, the dose and duration of ticagrelor in the East Asian population are likely to be different from those in other regions. Therefore, many ongoing studies have focused on individualized DAPT, shorter duration of DAPT, and de-escalation of a P2Y 12 inhibitor [29]. Numasawa Y et al. [11] aimed to select the optimal, tailored antithrombotic regimen for patients with ACS undergoing PCI. In addition, the health economics and outcome benefits of the treatment regimen must be considered. Wu B et al. [30] found that ticagrelor treatment for ACS for 12 months is not a cost-effective option for preventing thrombotic events in East Asia.
We searched for systematic reviews and meta-analyses on ticagrelor in recent years as comprehensively as possible, and our findings were inconsistent with those of several previous studies. Wu H et al. [31] demonstrated that DAPT with ticagrelor in European and American populations is more beneficial and safer than that of clopidogrel. The Asian population displays the same benefit, but the risk of bleeding significantly increases. Gan et al. [32] indicated that the new P2Y 12 inhibitors decrease mortality in patients undergoing PCI compared with that of clopidogrel.
However, the results of some studies were consistent with our findings. Wu B et al. [30] indicated that ticagrelor and clopidogrel display similar efficacy in East Asian patients with ACS, but the administration of ticagrelor had an increased risk of major bleeding. Furthermore, Misumida et al. [33] demonstrated that ticagrelor is associated with a higher risk of major bleeding than that of clopidogrel in East Asian patients with ACS. Our study did not include several large-scale randomized trials because these studies did not meet the inclusion criteria. The Asian subgroup analysis of the PLATO trial [9,34] included patients who were treated with multiple therapies, including coronary artery bypass grafting. The GLOBAL LEADERS trial enrolled patients with stable coronary artery disease (CAD) [35]. Moreover, the TWILIGHT-ACS trial included data from different regional groups, which could not be extracted separately [36]. The PEGASUS-TIMI 54 trial compared ticagrelor (60 or 90 mg twice a day) with placebo in highrisk patients with prior MI after DAPT for 12 months [37]. The SMART-CHOICE trial compared three regimens which included clopidogrel, prasugrel, and ticagrelor. As a matter of rigor, we did not include these studies [38].
Notably, some clinical trials have not been completed, such as the TROUPER trial (NCT03357874) and TC4 trial (NCT04057300). These large-scale, multicenter, controlled, randomized trials could provide further evidence on the efficacy of ticagrelor and clopidogrel. In the past decade, the prevalence of cardiovascular disease and subsequent healthcare costs have increased worldwide, leading to a careful assessment of the cost-effectiveness of changes in antiplatelet therapy strategies. As research continues in this field, pioneering clinical trials need to establish optimized strategies and constraints for ticagrelor in a specific population.
There were several limitations in our meta-analyses. First, the risks of major bleeding defined by PLATO and by TIMI were inconsistent, possibly because the sample sizes of some trials included in our study were relatively small, excluded several large-scale RCTs and real-world trials. We retrieved as many clinical trials as possible, but the evidence grades of some trials were deemed incomplete according to our inclusion criteria. Our study aimed to evaluate the efficacy and safety of ticagrelor; therefore, the results of some trials focusing on multiple P2Y 12 inhibitors were not included. We focused on ACS but not CAD. The results of some trials included patients with stable CAD, which were not included in our study. There were differences in the follow-up period across the included studies due to the limitation of data, and the statistical analysis of outcome endpoints in special populations, such as groups with CKD, DM, and multivessel CAD, was not conducted in this study.
Second, due to the lack of data, the impact of concomitant usage of anticoagulants was unable to be explored in this meta-analysis, which needs further investigation in subsequent studies. Additionally, the follow-up period of Gu et al. [17] was shorter than that of the other trials. Lastly, no observational studies were conducted.

Conclusion
Ticagrelor increased the risk of bleeding and did not increase treatment efficacy compared to that of clopidogrel in the East Asian population who have ACS treated with PCI.

Statement of Ethics
An ethics statement is not applicable because this study is based exclusively on published literature.

Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Funding Sources
This research was funded by the China National Key R&D Project (No. SQ2022YFC2500062), project title: coronary heart disease (CHD) individualized precision diagnosis system building and optimization strategy research for coronary heart disease.

Author Contributions
Xiaozeng Wang and Jingyuan Li conceived and designed the study. Qian Wang, Chunliu Wu, and Xiaoyu Qu independently assessed studies for possible inclusion and collected the data. Lei Zhang, Xiaofeng He, and Jingyuan Li extracted data from research. Miaohan Qiu and Sicong Ma analyzed the data. Jingyuan Li drafted the manuscript. All authors revised and approved the final version of the manuscript.

Data Availability Statement
All data generated or analyzed during this study are included in this article and its online supplementary materials. Further inquiries can be directed to the corresponding author.