Comparison of efficacy and safety profiles of rivaroxaban and aspirin versus clopidogrel and aspirin in the prevention of atherosclerotic events in Chinese dyslipidemic patients with coronary artery disease

Purpose: To compare the efficacy and safety profiles of rivaroxaban (R) + aspirin (A) and clopidogrel (C) + aspirin (A) in the prevention of atherosclerotic events in Chinese dyslipidemic patients with coronary artery disease (CAD). Methods: Coronary artery disease patients were given either R (10 mg daily) + A (100 mg daily) or C (75 mg daily) plus A (100 mg daily), with 105 subjects in each group. Each patient was followed up for 30 months. The following clinical outcomes (as aspects of primary endpoints) were assessed: percentge of patients with incidence of atherosclerotic events, and deaths due to any cause/cardiovascular causes. Hazard ratios and safety were also determined. Results: A total of 210 enrolled patients completed the study. Compared to C + A group, patients treated with R + A had slightly lower incidence of atherosclerotic events (33.2 vs 32.6 %, p > 0.05) and lower death rate due to any cause/cardiovascular causes (3.1 vs 2 %, p > 0.05). Patients treated with R + A had significantly greater incidence of bleeding (p < 0.05). Conclusion: The R + A treatment is more effective than C + A treatment in the prevention of atherosclerotic events, although this was not statistically significant different. The incidence of bleeding are significantly higher in R + A group than in C + A group.


INTRODUCTION
Atherosclerotic diseases have a tendency to provoke arterial thrombosis which is a long-term consequence of severe atherosclerosis [1][2][3][4][5][6]. Reduction of cholesterol level is essential for the prevention of arterial thrombosis [3][4][5][6][7][8][9]. The role of platelets in pathogenesis of atherothrombosis has been well documented. Low-dose aspirin is often used for heart disease patients. The use of low-dose aspirin in combination with clopidogrel as dual antiplatelet therapy is the most recommended treatment for CAD patients with heart diseases and myocardial infarction (MI), with and without ST-segment elevation. Moreover, it has been reported that dual antiplatelet is effective among CAD patients undergoing angioplasty with stenting [5][6][7][8][9].
Several studies have shown significantly greater protection against CVS events in CAD patients on dual antiplatelet therapy than in patients who took only aspirin (A) or clopidogrel (C) [5][6][7][8].
There are some reports on the efficacy of rivaroxaban (R) in controlling atherothrombosis and preventing atherosclerotic events in non-Chinese patients with CAD [9][10][11][12][13]. The present study was designed to determine and compare the effectiveness and safety profiles of rivaroxaban + aspirin and clopidogrel + aspirin in the prevention of atherosclerotic events in Chinese dyslipidaemic patients with CAD.

Patients and ethics
Chinese patients with history of stable atherosclerotic vascular diseases were enrolled. Written informed consent was obtained from each enrolled patient. The study received approval from the institutional ethics committee of Ningbo Women and Children's Hospital, vide, approval no. NWCH/20223D/MAR-20/ICE-328. The procedures used in the study were in line with the ethical principles laid down in the Helsinki Declaration and its later amendments [14]. Patients with a history of severe renal impairment, liver disease, lung disease, severe CAD and thyroid disease were excluded. Moreover, patients with any other pathology likely to affect the study outcomes, and patients who received concomitant and contra-indicated medications, as well as patients undergoing any other form of surgery, were excluded.

Treatments and procedures
Subjects who met the eligibility criteria were enrolled and were given either rivaroxaban (R) (10 mg daily via the oral route) in combination with aspirin (100 mg daily via the oral route), or clopidogrel (C) (75 mg daily via the oral route) in combination with aspirin (A) (100 mg daily via the oral route). There were 105 patients in each group. Each enrolled patient was carefully monitored and followed up for 30 months.

Assessment of efficacy and safety profiles
Baseline characteristics of each patient were assessed. The following clinical outcomes (as aspects of primary endpoints) were assessed: incidence of atherosclerotic events, percentage of patients who died due to any cause, percentage of death from cardiovascular causes, percentage of patients with MI, percentage of patients with ischemic stroke, percentage of patients with stroke, and percentage of patients hospitalized due to heart attack. The following safety endpoints (as parts of secondary endpoints) were assessed: incidence of severe bleeding, incidence of fatal bleeding, incidence of intracranial hemorrhage, and incidence of moderate bleeding.

Statistical analysis
No formal sample size calculation was performed in this study, since it was designed as a pilot study. Appropriate method was used to analyze data based on type and distribution (normal and non-normal). The data were analyzed using Graph Pad (version 9.4.1) software. Significant difference was assumed at p ˂ 0.05.

RESULTS
A total of 210 patients (105 patients in each group) were enrolled, and all patients completed the study. The demography and baseline characteristics of patients in both treatment groups were comparable, as shown in Table 1.
A summary of primary outcomes is presented in Table 2. Patients treated with R + A had slightly lower incidence of atherosclerotic events than those treated with C + A. Although death due to any cause or due to cardiovascular causes was slightly higher in patients treated with C + A than in those treated with R + A, there were no statistically significant differences between the two groups. There was a slightly higher number of patients with non-fatal MI in the group treated with C + A than in patients who received R + A, although the difference was not statistically significant. Similarly, there was a slightly higher population of patients with non-fatal ischemic stroke in the group treated with C + A than in the group that received R + A. However, the difference was also not statistically significant. Moreover, although the number of patients hospitalized due to heart attack was slightly higher in the group treated with C + A than in the group given R + A, the difference was not significant.
A summary of safety endpoints is shown in Table 3. Patients treated with R + A had significantly greater incidence of severe bleeding than patients treated with C + A.  Values of p based on categorical variables were calculated using Chi-square test Incidence of fatal bleeding was slightly higher in patients treated with R + A than in patients treated with C + A. The number of patients with non-fatal intracranial hemorrhage was slightly higher in the group treated with R + A than in the group given R + A. In contrast, the number of patients with moderate bleeding was significantly higher in the group treated with R + A than in those treated with C + A (p ˂ 0.05). These results are presented in Table 3.
For patients aged more than 75 years, subgroup analysis showed slightly higher incidence of MI/stroke/death in patients treated with R + A than in patients treated with C + A (Table 4).
With respect to female gender, sub-group analysis showed slightly lower incidence of MI/stroke/death in patients treated with R+A than in patients treated with C + A. Moreover, sub-group analysis of patients with type 2 diabetes showed non-significant difference in incidence of MI/stroke/death between patients treated with R+A and patients treated with C + A, although the former had slightly lower incidence. Similarly, sub-group analysis revealed slightly lower incidence of MI/stroke/death in patients treated with R + A than in those treated with C + A.  Sub-group analysis for obese and overweight patients showed slightly lower incidence of MI/stroke/death in patients treated with R + A than in patients treated with C + A, but the differences were not statistically significant. For hypertension and hypercholesterolemia, subgroup analysis showed that the incidence of MI/stroke/death was slightly higher in patients treated with R + A than in patients treated with C + A. In patients with history of bypass surgery, angioplasty, infarction and stroke, subgroup analysis revealed slightly lower incidence of MI/stroke/death in patients treated with R + A than in those treated with C + A. Bleeding was the most common adverse event in both treatment groups. The incidence of bleeding was significantly higher in patients treated with R + A than in patients treated with C + A. These results are shown in Table 5.

DISCUSSION
In China, there are no studies on comparison of safety and efficacy profiles of R + A and C + A in the prevention of atherosclerotic events in Chinese dyslipidaemic patients with CAD thereby making this the first of such study. The findings are consistent with those reported in previous studies in which R + A produced lower CVS-related death than aspirin monotherapy [10][11][12][13]. However, the risk of bleeding associated with R + A was higher than that in aspirin monotherapy. In the published studies, the risk of bleeding associated with R + A was 50 % higher than the corresponding risk associated with aspirin monotherapy [9][10][11][12][13].
In the present study, the risk of severe bleeding in R + A was 13 %, which was significantly higher than 3 % risk in C + A group. In a previous study, R + A produced 25 % lower clinically beneficial outcomes than aspirin monotherapy (4.7 vs. 5.9 %). In an earlier published study, R + A did not significantly differ from aspirin monotherapy in terms of clinical outcomes. However, the incidence of bleeding was higher with rivaroxaban alone. In contrast to findings in an earlier study, the present study has demonstrated that patients treated with R + A and those who received C + A did not differ significantly. Furthermore, subgroup analysis showed slightly lower incidence of MI/stroke/death in R + A group than in R + A group.
Overall, the results of the present study suggest that R + A is as effective as C + A in preventing atherosclerotic events in Chinese dyslipidaemia patience. Incidents of atherosclerotic events were slightly lower in patients treated with R + A than in those treated with C + A. Overall, both study drugs were statistically similar with respect to primary endpoints. In numerical terms, R + A was more effective than C + A in prevention of atherosclerotic events. The possible reason for the non-significant differences in clinical outcomes between the two groups may be due to the low sample size used in the study. However, there was higher incidence of bleeding in R + A than in C + A.

Limitations of the study
The results of this study may not be generalized to the Chinese population due to the low sample size used. Thus, a study with a large sample size is required to validate the results reported here.

CONCLUSION
This study has demonstrated that R + A is slightly more effective than C + A in preventing atherosclerotic events in Chinese dyslipidemic patients with CAD. However, there is higher incidence of bleeding in patients treated with R + A than in those given C + A. Therefore, the use of R + A may be a better alternative for Chinese CAD patients for whom C + A combined treatment is not suitable.