Benefit and risk of adding rivaroxaban in patients with coronary artery disease: A systematic review and meta‐analysis

Abstract Background Although the European Medicines Agency and the US Food and Drug Administration have, respectively, approved rivaroxaban for the prevention of recurrent major adverse cardiovascular events in patients with myocardial infarction and stable coronary artery disease, its efficacy and safety is unclear. This meta‐analysis aimed to evaluate the benefit and risk of adding rivaroxaban in coronary artery disease (CAD) patients, focusing on treatment effects stratified by different baseline clinical presentations. Hypothesis There are differences in treatment effects of adding rivaroxaban among CAD patients with different baseline clinical presentations. Methods Medline, EMBASE, and Cochrane Databases were systematically searched from inception to 21 July 2020 for randomized controlled trials (RCTs) comparing rivaroxaban in CAD patients. The primary efficacy endpoint and safety endpoint were assessed by using Mantel–Haenszel pooled risk ratios (RRs) and 95% confidence intervals (CIs). Results Five RCTs that included 43 650 patients were identified. Patients receiving rivaroxaban had a significantly lower risk of the primary efficacy endpoint (RR, 0.86; 95% CI, 0.76–0.97, p = .01) accompanied by increased risk of the primary safety endpoint (RR, 1.83; 95% CI, 1.10–3.05, p = .02). Subgroup analyses showed that in males the risk–benefit appears to be more favorable while in patients ≥65 years, in females, in patients with diabetes, those with mild to moderate impaired renal function, and region of Asia/other seems unfavorable. Conclusion Rivaroxaban may provide an additional choice for secondary prevention in CAD patients. However, careful estimation of the risk of ischemic and bleeding events using patient characteristics are critical to achieving net benefit.


| INTRODUCTION
Antiplatelet agents are the cornerstone of secondary prevention in patients with coronary artery disease (CAD). Guidelines recommend lifelong use of single antiplatelet therapy in all patients with stable coronary artery disease (SCAD) and dual antiplatelet therapy (DAPT) in patients following acute coronary syndrome (ACS) for 12 months. 1 Despite the adherence to recommended antiplatelet therapy (APT), 12.2% of patients with SCAD and 18.3% of patients with ACS experience recurrent major adverse cardiovascular events (MACE). 2 There is evidence that anticoagulation is effective in reducing ischaemic events in ACS during the acute phase and that the combination with platelet inhibitors is more effective than either treatment alone. 3,4 Early meta-analyses revealed adding direct oral anticoagulants (DOAC) to APT in ACS after the acute phase could reduce the risk of ischemic events at the cost of a higher risk of bleeding. 5,6 However, with the results of the ATLAS ACS 2-TIMI 51 trial, 7

the European
Medicines Agency (EMA) approved rivaroxaban 2.5 mg twice daily for non-ST-elevation myocardial infarction and ST-segment elevation myocardial infarction (STEMI) patients after the acute phase. 8 Subsequently, the US Food and Drug Administration (FDA) approved rivaroxaban for the prevention of recurrent adverse cardiovascular events in patients with SCAD according to the results of the COM-PASS trial. 9 Nonetheless, recently meta-analyses demonstrated the addition of rivaroxaban to APT regimen was effective in patients with CAD, but the safety outcome was doubtful. [10][11][12] Interestingly, Chiarito et al 13 found the risk-benefit profile of DOAC appears unfavorable in patients with NSTE-ACS, whereas DOAC in addition to APT might represent an attractive option for patients with STEMI. Therefore, we conducted a meta-analysis to evaluate the benefit and risk of adding rivaroxaban in patients with CAD and focusing on treatment efficacy and safety stratified by different baseline clinical presentations.

| METHODS
We systematically searched Medline, EMBASE, and Cochrane Databases for all relevant articles adding rivaroxaban in patients with coronary heart disease through 21 July 2020. The literature was searched with the following keywords: Rivaroxaban, anticoagulant, coronary artery disease, coronary heart disease, acute coronary syndrome and random*. A comprehensive search of reference lists of all review articles and original studies retrieved by this method was performed to identify additional studies.

| Inclusion and exclusion criteria
Inclusion criteria were the following: (1) trials designed as RCT; (2) trials based on patients with CAD, including SCAD and ACS; (3) trials compared outcomes which were observed with the addition of rivaroxaban to APT; (4) trials reported the primary efficacy endpoint (ischemic events) and/or safety endpoint (bleeding events). Exclusion criteria were the following: (1) trials included patients need continued or planned treatment with rivaroxaban, such as atrial fibrillation and pulmonary embolism; (2) trials with sample size less than 500 or follow-up <6 months; (3) duplicate reports.

| Bias risk and study quality assessment
The methodological quality of eligible studies was assessed by the Cochrane collaboration's tool for assessing risk of bias including the following criteria: sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting, and other issues. The bias risk of each study was scored as low, unclear, or high in each section.

| Statistical analysis
Dichotomous data were expressed as RR with 95% confidence intervals (CIs). Heterogeneity of effect size across the studies was tested using Q statistics at the p < .10 level of significance. We also calculated the I 2 statistic with a quantitative measure of inconsistency across the studies. The data were pooled by random-effects model in case significant heterogeneity (Cochran test with p < .10 or I 2 > 50%) was found. Otherwise, the fixed-effects model was used. Sensitivity analyses with fixed-effect models were performed to assess consistency among effect estimates that were obtained with random-and fixed-effects models. Potential publication bias was visually inspected by funnel plot if more than 10 studies. We conducted subgroup ana-  Figure 1 shows a flow diagram for the selection process. A total of five RCTs 7,9,14-16 that included 43 650 patients were finally identified.  9 and CAD patients, 16 respectively. The methodological quality of the included studies was, in general, good as shown in Table 1.
The primary efficacy endpoint and safety endpoint were those adopted by the original studies. Our pooled analysis indicated that addition of rivaroxaban significantly reduced the incidence of the primary efficacy endpoint (RR, 0.86; 95% CI, 0.76-0.97, p = .01) ( Figure 2). However, addition of rivaroxaban was associated with significantly higher risk of the primary safety endpoint (RR, 1.83; 95% CI, 1.10-3.05, p = .02) ( Figure 3).
To explore the study heterogeneity, we further performed metaanalysis in subgroups based on several baseline clinical presentations (age, sex, history of MI, diabetes, renal function and region). Table 2 shows the risk of the primary efficacy endpoint in patients ≥65 years meta-analysis were as follows: (1) As published meta-analyses, adding rivaroxaban to standard APT after CAD is associated with a reduction in the risk of ischemic events at the cost of a higher risk of bleeding; (2) In males the risk-benefit profile of rivaroxaban in addition to standard APT appears to be more favorable. Males have a reduced bleeding risk than females might be that they are less challenged (no menstruation or childbirth); (3) In patients < 65 years, in females, in patients with diabetes, those with mild to moderate impaired renal function, and region of Asia/other are associated with increasing in the risk of bleeding and with a nonsignificant reduction in the risk of ischemic events. Earlier studies found a higher rate of cardiovascular adverse outcomes and lower quality of life in females compared with males, 20,21 which might be related to females more often present with atypical symptoms and signs. 22 Recent study demonstrated that females had higher rates of cardiovascular mortality and all-cause mortality than male 1 year after acute myocardial infarction, as well as significantly poorer health status, even after adjustment for potential confounders, including baseline health status. 23 Diabetes is a pro- The optimal antithrombotic therapy aims to prevent thrombosis while avoiding hemorrhage. The ATLAS ACS 2-TIMI 51 trial 7 and COMPASS trial 9 both indicated adding rivaroxaban to standard APT reduced the risk of MACE with higher risk of major bleeding, but without increasing the risk of fatal bleeding. In order to assess the net clinical benefit, the COMPASS trial 9 made a net benefit analysis incorporating both ischaemic and bleeding events and indicated a

| CONCLUSIONS
Rivaroxaban may provide an additional therapeutic choice for secondary prevention in patients with CAD. However, careful estimation the risk of cardiovascular ischemic and bleeding events using patient characteristics are critical to achieving net benefit.

CONFLICT OF INTEREST
The authors declare no potential conflict of interest.

DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article as no new data were created or analyzed in this study.