Post-hoc analysis from the phase 3 NAVIGATE ESUS trial (NCT02313909) provided evidence that rivaroxaban (Xarelto; Janssen), an anticoagulant, was superior to aspirin at reducing the risk of recurrent stroke or systemic embolism in patients with left ventricular (LV) dysfunction.
Led by Alexander E. Merkler, MD, MS, assistant professor of neurology, Weill Cornell Medicine, the study included 7213 participants who had neuroimaging-confirmed embolic strokes of undetermined source (ESUS) between 7 days and 6 months before screening. Of those, 7107 (98.5%) had a documented assessment of LV function at study entry (December 2014) and were included in the exploratory analysis.
Investigators randomly assigned patients to either 15 mg of rivaroxaban or 100 mg of aspirin once daily for the prevention of recurrent stroke. Among the 7107 participants, 502 (7%) had LV dysfunction reported. Over a median follow-up of 10.4 months, the primary outcome of recurrent stroke or systemic embolism occurred in 321 participants (4.9%) per year). When comparing the 2 treatments, event rates were 2.4% per year (95% CI, 1.1-5.4) in those assigned to rivaroxaban versus 6.5% (95% CI, 4.0-11) in those on aspirin.
In those without LV dysfunction (n = 6605), event rates were similar between treatment arms, with event rates of 5.3% per year (95% CI, 4.5-6.2) for those on rivaroxaban and 4.5% per year on aspirin (95% CI, 3.8-5.3). After adjusting for the main effects of assigned treatment and LV dysfunction, the observed heterogeneity of treatment effect was statistically significant (P = .03 for interaction).
Those with LV dysfunction treated with rivaroxaban also showed significantly lower risk of the primary outcome (HR, 0.36 [95% CI, 0.14-0.93]), whereas those without LV dysfunction had similar risk (HR, 1.16 [95% CI, 0.93-1.46]).
Secondary outcomes, which included recurrent stroke, systemic embolism, myocardial infarction, or cardiovascular mortality, occurred in 390 of 7107 participants (overall, 5.5%), 201 (6.1% per year) of which were in the rivaroxaban group and 189 (5.7% per year) assigned to aspirin. For the 502 participants with LV dysfunction, rates were 4.9% per year (95% CI, 2.8-8.6) in those assigned to rivaroxaban compared to 9.5% per year (95% CI, 6.3-14) in the aspirin group.
The study authors concluded that a "dedicated secondary stroke prevention trial in patients with LV dysfunction should be considered to evaluate the efficacy and safety of anticoagulation to prevent cardiac embolism and subsequent stroke."
Annualized primary event rates for those without LV dysfunction assigned to rivaroxaban (6.2% per year [95% CI, 5.4-7.1]) were comparable to those on aspirin (5.4% per year [95% CI, 4.7-6.3]). The P value for interaction for treatment effect was 0.5 after adjusting for the main effects of assigned treatment and LV dysfunction status.
As for safety, a major bleeding event occurred in 83 participants of the total cohort; however, nearly 95% (n = 78) of events occurred in those without evidence of LV dysfunction, (rivaroxaban: n = 55; aspirin: n = 23) with the remaining 5 occurring in participants with evidence of LV dysfunction (rivaroxaban: n = 5; aspirin: n = 0).
All baseline characteristics between those with LV dysfunction were similar, except for the fact that those randomized to rivaroxaban were less likely to have diabetes (23% vs 35%). A Cox proportional hazard model that adjusted for the main effects of diabetes also continued to show the heterogeneity of treatment effect with LV dysfunction (P = .04 for interaction). Furthermore, after this adjustment, rivaroxaban remained associated with a lower risk of the primary outcome (HR, 0.35 [95% CI, 0.14-0.9]).
Previous research by Hart et al and Diener et al concluded that anticoagulation is not superior to antiplatelet therapy among all patients with ESUS,2,3 however, the etiologies of ESUS in these trials were heterogenous, and the risk of recurrent stroke among patients without sources of cardiac embolism may not necessarily be reduced by anticoagulation, according to Merkler and colleagues.