The morbidity of stroke has been reported as 2.6% for adult population and 15.1% for elderly aged 65 years and above [1]. The elderly patients aged 75 years or above with atrial fibrillation (AF) have relatively higher risk of stroke and death [2, 3]. The risk of stroke in these patients was not different between Japan and UK [3]. As the morbidity rate continues to increase, medical expenses for treatment of stroke are also expected to increase [1]. The risk factors for stroke in patients with AF include those used to calculate the CHA₂DS₂-VASc score proposed in the European Society of Cardiology Guidelines in 2010 [4]. Among these risk factors, stroke/transient ischemic attack (TIA)/thromboembolism and elderly age (> 75 years) are associated with the highest risk [4]. History of stroke is a particularly strong risk factor for stroke, 2.5 times higher susceptibility to stroke development in affected patients [5]. In the previous study for secondary prevention of stroke, recurrent stroke continued to account for 25–30% of all stroke [6].

Rivaroxaban, one of the non-vitamin K antagonist oral anticoagulants (NOACs), was approved in Japan in April 2012 [7]. The efficacy and safety of rivaroxaban were demonstrated in the ROCKET AF Trial [8], and the safety of Japan-specific rivaroxaban dosages [15 mg/day in patients with creatinine clearance (CrCl) ≥ 50 ml/min; 10 mg/day in patients with CrCl 30–49 ml/min] was shown in the J-ROCKET AF Trial [9]. In the J-ROCKET AF Trial, evidence for the safety and efficacy in Japanese patients was not sufficiently accumulated because of the lack of data for patients with CHADS₂ scores of 0 or 1 [9]. However, the recent findings of our EXPAND Study reported in 2017 and 2018 showed the efficacy and safety of rivaroxaban in routine clinical practice including patients with such scores [10, 11]. The present report describes a sub-analysis of our EXPAND Study, addressing the primary and secondary prevention of stroke and systemic embolism (SE) with rivaroxaban in patients with non-valvular atrial fibrillation (NVAF). The primary and secondary prevention groups were defined as patients with and without history of stroke or TIA, respectively. We expect that our sub-analysis will provide the demographic characteristics by primary and secondary prevention groups and ensure the safety and efficacy of rivaroxaban of Japan-specific dosages in routine clinical practice.

This was a sub-analysis report by the preventive group for stroke or SE in the EXPAND Study to observe the efficacy and safety of Japan-specific dosages of rivaroxaban in Japanese patients with NVAF in a real-world clinical setting. This report provides the first evidence on the efficacy and safety of Japan-specific dosage of rivaroxaban in Japanese patients in a real-world clinical setting according to primary and secondary prevention.

Similar to the previous reports of the sub-analyses for the phase III trials of rivaroxaban (ROCKET and J-ROCKET AF Trial conducted globally and in Japan, respectively) [12, 13], the EXPAND Study showed that the incidence of stroke or SE was higher in the secondary prevention group compared with the primary prevention group. In the EXPAND Study, cardiovascular death and all-cause death were significantly higher in the secondary prevention group compared with the primary prevention group. There were no differences in the incidences of cardiovascular events, including acute MI, unstable angina pectoris, percutaneous coronary intervention/coronary artery bypass graft, or the incidence of ISTH major bleeding events. The incidence of intracranial hemorrhage was higher in the secondary prevention group compared with the primary prevention group among the sites of ISTH major bleeding events. Thus, as compared with the previous sub-analysis reports [12, 13], the EXPAND Study showed similar outcomes except for the low incidence rate of all ISTH major bleeding events.

The demographic characteristics of the patients enrolled in the EXPAND Study and the J-RHYTHM Registry were similar, demonstrating the real-world practice [10, 11, 14, 15]. The mean CHADS₂ score was 1.6 and 1.4 points for the primary prevention group, and 3.7 and 3.4 points for the secondary prevention group in the EXPAND Study and J-RHYTHM Registry, respectively. Regarding the incidences of events, both the EXPAND Study and the J-RHYTHM Registry showed higher incidence of thromboembolism (ischemic stroke/TIA/SE) in the secondary prevention group [14]. Meanwhile, for ISTH major bleeding events, only the J-RHYTHM Registry showed a different incidence between primary and secondary prevention groups (primary 1.7% vs. secondary 3.0%, P = 0.003). This higher incidence of bleeding was likely to arise through the higher combined usage of warfarin and antiplatelet agents in the secondary prevention group compared with the primary prevention group in the J-RHYTHM Registry (primary 16.1% vs. secondary 32.4%, P < 0.001). The EXPAND Study also showed higher combined use of antiplatelet agents in the secondary prevention group (12.2 vs. 22.0%, P < 0.001). Moreover, the HAS-BLED score in the EXPAND Study was higher in the secondary prevention group than in the primary prevention group (1.2 vs. 2.3 points, P < 0.001) (Table 1). However, the incidence rates of ISTH major and no-major bleeding were comparable between the primary and secondary prevention groups (ISTH major bleeding; 1.2 vs 1.5%/year, P = 0.132) (non-major bleeding; 4.9 vs. 4.9%/year, P = 0.963) (Table 2). However, no difference was noted in the incidence of major bleeding events between the primary and secondary prevention groups (1.2 vs. 1.5%/year, P = 0.132). The patients who treated with concomitant use of warfarin and aspirin had higher risk of bleeding compared with those who treated with warfarin alone [16]. Other reports have also described increased incidences of bleeding events with combined use of anticoagulant and antiplatelet drugs [17‐19]. Further studies on the risk of developing bleeding events under combined use of rivaroxaban and antiplatelet drugs in comparison with combination of warfarin and antiplatelet drugs should be conducted.

In the sub-analysis for the phase III trials of rivaroxaban (ROCKET and J-ROCKET AF Trials), no significant differences were noted for efficacy (stroke/SE) or safety (ISTH major bleeding) between the primary and secondary prevention groups treated with rivaroxaban and warfarin [12, 13]. However, in both warfarin and rivaroxaban groups, the secondary prevention group had higher incidences of stroke and SE compared with the primary prevention group, while the primary prevention group had a higher incidence of major bleeding events compared with the secondary prevention group [12, 13] (Table 4). In those trials, the primary prevention group had more risk factors of bleeding as components of the HAS-BLED score [20] than the secondary prevention group (Table 5). It is possible that the primary prevention group had higher risk of bleeding compared with the secondary prevention group in general.

In the EXPAND Study, the incidences of stroke and SE were similar to those in the studies mentioned above. However, regarding the incidence of major and non-major bleeding events, no significant difference was noted between the primary and secondary prevention groups in this study (Table 2). The possible reasons are that the ROCKET and J-ROCKET AF Trials did not include patients with CHADS₂ scores of 0 and 1 [8, 9], while the EXPAND Study did include those with such scores [10, 11], and that the ROCKET and J-ROCKET AF Trial potentially had more patients with risk of bleeding in the primary prevention group than the EXPAND Study (Table 4). In addition to that, the differences in CHADS₂ and HAS-BLED scores were approximately two and one scores between the 2 groups of those scores in the EXPAND Study, respectively. Consequently, the patient background of each prevention group in this study did not differ significantly except for the history of stroke. As shown in Table 4, the incidence rate of stroke or SE in the secondary prevention group of the EXPAND Study was higher than that of the J-ROCKET AF Trial (2.2 and 1.7%/year, respectively), even though mean CHADS₂ score in the EXPAND Study was lower than that in the J-ROCKET AF Trial (1.6 and 2.9 points, respectively). By contrast, the incidence rate of ISTH major bleeding in both the primary and secondary prevention groups of the EXPAND Study were much lower (1.2 and 1.5%/year, respectively) than those of the J-ROCKET AF Trial (4.0 and 2.4/year, respectively), despite mean CHADS₂ scores of the secondary prevention group were comparable between the EXPAND Study and J-ROCKET AF Trial (3.7 and 3.5 points, respectively). We consider that off-label dose reduction was attributable to these results. Furthermore, it could be another reason for the higher incidence rate of stroke or SE in the secondary prevention group of the EXPAND Study that patients with acute stage of stroke within 2 weeks after the onset, who were at high risk of recurrence, were included in the EXPAND Study but not in the J-ROCKET AF Trial. We plan to clarify these issues in the ongoing exploratory analyses of our study.

In the EXPAND Study, the incidence of intracranial hemorrhage was higher in the secondary prevention group than in the primary prevention group (primary 0.4%/year vs. secondary 0.8%/year, P =0.002), but gastrointestinal bleeding rate was not different between the 2 groups (primary 0.5%/year vs. secondary 0.4%/year, P =0.42). These results suggest that history of stroke is a risk factor of intracranial hemorrhage, but not a risk factor of gastrointestinal bleeding. The incidence of intracranial hemorrhage was higher in the secondary prevention group and the warfarin-treated group compared with the primary prevention group in the J-ROCKET AF Trial [9] as well. Further studies are needed to evaluate background factors with potential impacts on bleeding events and sites in the primary and secondary prevention groups.

The results of this sub-analysis allowed us to verify the low incidence of primary efficacy and safety endpoints in patients on Japan-specific dosages of rivaroxaban for not only primary but also secondary prevention of stroke and SE in Japanese patients with NVAF in a real-world clinical setting. In addition, as reported previously, the incidences of stroke and SE were higher in the secondary prevention group than in the primary prevention group. For bleeding events, further studies are needed to evaluate the difference in bleeding sites as our results were not consistent with those in the previous reports.