Rivaroxaban superior to aspirin at reducing recurrent stroke in patients with embolic stroke of undetermined source and left ventricular dysfunction: (NAVIGATE ESUS Trial)

1. Rivaroxaban was superior to aspirin in reducing recurrent stroke or systemic embolism among patients with recent embolic stroke of undetermined source and left ventricular dysfunction.

2. Further research evaluating the efficacy and safety of long-term anticoagulation to prevent cardiac embolism and subsequent stroke in patients with left ventricular dysfunction should be considered.

Evidence Rating Level: 1 (Excellent)

Study Rundown: A subset of patients diagnosed with embolic ischemic stroke lack an identifiable cause/source of the embolus, referred to as embolic strokes of undetermined source (ESUS). In patients with ESUS and left ventricular (LV) dysfunction, the efficacy of anticoagulation vs aspirin at reducing recurrent stroke is unknown. This post hoc exploratory analysis used data from the NAVIGATE ESUS trial to determine whether anticoagulation was superior to aspirin in reducing the risk of cardiac embolism and subsequent stroke in patients with ESUS and evidence of LV dysfunction (defined as moderate to severe global impairment in LV contractility and/or a regional wall motion abnormality on echocardiography). The main endpoint was a reduction in risk of recurrent stroke or systemic embolism where secondary outcomes included recurrent stroke, systemic embolism, myocardial infarction, or cardiovascular mortality during a median follow-up of 10.4 months. A Cox proportional hazards model was used to assess for treatment interaction and to estimate the hazard ratios. Among 7,213 participants from the NAVIGATE ESUS trial, 502 (7.1%) had evidence of LV dysfunction, where those assigned to rivaroxaban vs aspirin had a lower risk of recurrent stroke or systemic embolism compared to participants without LV dysfunction. These results suggested that rivaroxaban, a factor Xa inhibitor, was superior to aspirin in reducing recurrent stroke or systemic embolism among patients with recent ESUS and evidence of LV dysfunction. Further research evaluating the efficacy and safety of long-term anticoagulation to prevent cardiac embolism and subsequent stroke in patients with LV dysfunction should be considered. A limitation of this study was the exploratory nature of the analysis in the setting of a negative overall trial, where the study findings should be considered hypothesis generating.

Click to read the study in JAMA Neurology

Relevant Reading: Rivaroxaban for stroke prevention after embolic stroke of undetermined source

In-Depth [randomized clinical trial]: This post hoc exploratory analysis of data from NAVIGATE ESUS, a phase 3 randomized clinical trial, included 7,213 participants, 7,107 (98.5%) of which had a documented assessment of LV function. Eligible patients were 50 years or older with neuroimaging-confirmed ESUS before screening from December 2014 to September 2017 across 459 stroke recruitment centers in 31 countries. Participants were randomized to receive either 15 mg of rivaroxaban or 100 mg of aspirin once daily. In total, LV dysfunction was present in 502 participants (7.1%; mean [SD] age, 67 [10] years; 130 [26%] women). Among these patients, annualized primary event rates were 2.4% (95%CI, 1.1-5.4) in those assigned to rivaroxaban vs 6.5% (95%CI, 4.0-11.0) in those assigned aspirin. In 6,605 participants without LV dysfunction, rates were similar between those assigned to rivaroxaban (5.3%; 95%CI, 4.5-6.2) vs aspirin (4.5%; 95%CI, 3.8-5.3). Furthermore, patients with LV dysfunction assigned to rivaroxaban had a lower risk of the primary outcome (HR, 0.36; 95%CI, 0.14-0.93) compared to those on aspirin, in contrast to participants without LV dysfunction (HR, 1.16; 95%CI, 0.93-1.46; P for treatment interaction = .03), with similar findings for secondary outcomes.

Image: PD

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