Risks of Stroke and Mortality in Atrial Fibrillation Patients Treated With Rivaroxaban and Warfarin

Mark Alberts, MD; Yen-Wen Chen, PhD; Jennifer H. Lin, PhD; Emily Kogan, MS; Kathryn Twyman, PhD; Dejan Milentijevic, PhD


Stroke. 2020;51(2):549-555. 

In This Article

Abstract and Introduction


Background and Purpose: Oral anticoagulation therapy is standard of care for patients with nonvalvular atrial fibrillation to prevent stroke. This study compared rivaroxaban and warfarin for stroke and all-cause mortality risk reduction in a real-world setting.

Methods: This retrospective cohort study (2011–2017) included de-identified patients from the Optum Clinformatics Database who started treatment with rivaroxaban or warfarin within 30 days following initial diagnosis of nonvalvular atrial fibrillation. Before nonvalvular atrial fibrillation diagnosis, patients had 6 months of continuous health plan enrollment and CHA2DS2-VASc score ≥2. Stroke severity was determined by the National Institutes of Health Stroke Scale, imputed based on machine learning algorithms. Stroke and all-cause mortality risks were compared by treatment using Cox proportional hazard regression, with inverse probability of treatment weighting to balance cohorts for baseline risk factors. Stratified analysis by treatment duration was also performed.

Results: During a mean follow-up of 27 months, 175 (1.33/100 patient-years [PY]) rivaroxaban-treated and 536 (1.66/100 PY) warfarin-treated patients developed stroke. The inverse probability of treatment weighting model showed that rivaroxaban reduced stroke risk by 19% (hazard ratio [HR], 0.81 [95% CI, 0.73–0.91]). Analysis by stroke severity revealed risk reductions by rivaroxaban of 48% for severe stroke (National Institutes of Health Stroke Scale score, 16–42; HR, 0.52 [95% CI, 0.33–0.82]) and 19% for minor stroke (National Institutes of Health Stroke Scale score, 1 to <5; HR, 0.81 [95% CI, 0.68–0.96]), but no difference for moderate stroke (National Institutes of Health Stroke Scale score, 5 to <16; HR, 0.93 [95% CI, 0.78–1.10]). A total of 41 (0.31/100 PY) rivaroxaban-treated and 147 (0.44/100 PY) warfarin-treated patients died poststroke, 12 (0.09/100 PY) and 67 (0.20/100 PY) of whom died within 30 days, representing mortality risk reductions by rivaroxaban of 24% (HR, 0.76 [95% CI, 0.61–0.95]) poststroke and 59% (HR, 0.41 [95% CI, 0.28–0.60]) within 30 days.

Conclusions: After the initial diagnosis of atrial fibrillation, patients treated with rivaroxaban versus warfarin had significant risk reduction for stroke, especially severe stroke, and all-cause mortality after a stroke. Findings from this observational study may help inform anticoagulant choice for stroke prevention in patients with nonvalvular atrial fibrillation.


Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting an estimated 3 to 6 million people in the United States.[1,2] The prevalence of AF is expected to rise with the aging population and reach 12 million by 2030.[1] AF is associated with a 4- to 5-fold increased risk of ischemic stroke, and the proportion of strokes attributable to AF increases with advancing age, ranging from ≈10% overall to 24% in those aged 80 to 89 years.[1,3,4] The burden of stroke is substantial because it is a leading cause of functional impairment.[4] Effective prevention remains the best approach to limit stroke burden. Oral anticoagulation therapy with direct-acting oral anticoagulants (DOACs) is the current standard of care for stroke prevention in patients with nonvalvular AF (NVAF).[5]

Patients with AF experience particularly high stroke-related disease burden. They are 3 to 4 times more likely to suffer severe strokes and have greater initial functional impairment compared with patients with normal sinus rhythm.[6,7] For patients with AF, risks of 1-year disability and 1-year mortality after stroke are twice those of non-AF–related strokes; hospital stays are longer and acute and long-term costs are higher.[6,7]

Rivaroxaban, a factor Xa inhibitor used in clinical practice since its approval in November 2011,[8] has increasing use in patients with existing and newly diagnosed AF.[9] Results from clinical and observational studies support the efficacy and safety of rivaroxaban in this population, including better effectiveness than warfarin for preventing stroke or systemic embolism.[9,10] In the noninferiority clinical trial, ROCKET-AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation), secondary end points of all-cause mortality and stroke severity were favorably impacted by rivaroxaban versus warfarin.[11] It is important to note, however, that treatment with warfarin in the clinical trial setting is well controlled, with medication reminders, coagulation testing, and associated dose adjustments. This contrasts with the real-world setting, in which studies show that international normalized ratio (INR) monitoring is not routinely performed in warfarin-treated patients and approximately two-thirds of patients have poor INR (<2) control.[12–14] Warfarin's narrow therapeutic range, broad dose-response variability, and food and drug interactions pose challenges to anticoagulation maintenance.[15] Patients with NVAF and INR <2 have an increased risk of death or developing such cardiovascular-related events as acute coronary syndrome, ischemic stroke, transient ischemic attack, and systemic embolism compared with those with INR of 2 to 3.[13,14] The need for constant INR monitoring and the potential consequences of poor anticoagulation maintenance in warfarin-treated patients pose a substantial burden.

Since the introduction of DOACs in 2010, few studies on the effectiveness of anticoagulation therapy have included stroke severity as an outcome measure. However, it is important to understand how anticoagulants protect patients not just from stroke but also from more severe strokes that lead to poor functional outcomes. Stroke severity, as assessed using the National Institutes of Health Stroke Scale (NIHSS), is a strong predictor of outcome. In the clinical trial setting, a score of 16 or higher (moderately severe to severe stroke) was found to predict a high probability of death or severe disability.[16]

Using integrated claims and electronic health record data, we found mortality risk to be significantly higher (≥100-fold) among patients with more severe stroke compared with patients without stroke.[17] Although the absence altogether of anticoagulant therapy has been associated with higher NIHSS scores, few studies compare the effectiveness of specific anticoagulation therapies on the reduction in stroke risk by severity.

Because NIHSS scores are absent from administrative claims databases, machine learning models have been used to predict risks of stroke and stroke outcomes.[18–20] We have previously developed and validated an imputed NIHSS score methodology using machine learning algorithms and predictive modeling that was based on features identified in claims and electronic health record databases.[21,22]

For comparison to clinical trial findings, specifically the ROCKET-AF trial in which stroke severity was an outcome measure, the objective of this study was to understand, in a real-world setting, the effects of rivaroxaban and warfarin on stroke outcomes, overall and by stroke severity, using imputed NIHSS scores.