Apixaban in Comparison With Warfarin in Patients With Atrial Fibrillation and Valvular Heart Disease

Abstract

Background— Apixaban is approved for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. However, the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial included a substantial number of patients with valvular heart disease and only excluded patients with clinically significant mitral stenosis or mechanical prosthetic heart valves. Methods and Results— We compared the effect of apixaban and warfarin on rates of stroke or systemic embolism, major bleeding, and death in patients with and without moderate or severe valvular heart disease using Cox proportional hazards modeling. Of the 18 201 patients enrolled in ARISTOTLE, 4808 (26.4%) had a history of moderate or severe valvular heart disease or previous valve surgery. Patients with valvular heart disease had higher rates of stroke or systemic embolism and bleeding than patients without valvular heart disease. There was no evidence of a differential effect of apixaban over warfarin in patients with and without valvular heart disease in reducing stroke and systemic embolism (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.51–0.97 and HR, 0.84; 95%, CI 0.67–1.04; interaction P =0.38), causing less major bleeding (HR, 0.79; 95% CI, 0.61–1.04 and HR, 0.65; 95% CI, 0.55–0.77; interaction P =0.23), and reducing mortality (HR, 1.01; 95% CI, 0.84–1.22 and HR, 0.84; 95% CI, 0.73–0.96; interaction P =0.10). Conclusions— More than a quarter of the patients in ARISTOTLE with nonvalvular atrial fibrillation had moderate or severe valvular heart disease. There was no evidence of a differential effect of apixaban over warfarin in reducing stroke or systemic embolism, causing less bleeding, and reducing death in patients with and without valvular heart disease. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00412984.

Safety and Efficacy of Novel Oral Anticoagulants Versus Warfarin in Medicare Beneficiaries With Atrial Fibrillation and Valvular Heart Disease

“…Previous post hoc analyses of patients with VHD included in the pivotal NOAC trials showed increased stroke and major bleeding risk among patients with VHD, similar to our study findings 8, 9, 10. The relative benefits of NOACs were comparable in patients with and without VHD, despite higher thromboembolic and bleeding risk in the VHD cohorts.…”

“…Some patients with VHD have been included in the NOAC trials. In the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial, 26% of patients had a history of moderate or severe VHD (most of them with mitral regurgitation) or previous valve surgery 8. Although these patients had higher rates of stroke and systemic embolism than those without, there was no evidence of differential effects of apixaban compared with warfarin on stroke, major bleeding, and all‐cause mortality between patients with and without VHD.…”

Prevalence, Characteristics, and Outcomes of Valvular Heart Disease in Patients With Atrial Fibrillation: Insights From the ORBIT‐AF (Outcomes Registry for Better Informed Treatment for Atrial Fibrillation)

“…VHD in the presence of AF greatly magnifies the risk of thromboembolism 1, 14, 15. Our study evaluated a large, contemporary, community‐based population and is notable for several findings: (1) the prevalence of significant VHD is substantial among patients with AF in community practice; (2) oral anticoagulation was high, with >90% use in patients with MS/MV and >80% use in patients with AR/AS, bioprosthetic valves, and surgical valve repair or balloon valvuloplasty; (3) individuals with significant VHD cluster more comorbidities that, in part, lend themselves to worse outcomes, including mortality, thromboembolism (stroke/non‐CNS embolism/TIA), and major bleeding; and (4) moderate or severe AS in the setting of AF is associated with greater mortality risk, and individuals with moderate or severe AR have a greater risk of major bleeding.…”

“…The ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events), ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in AF), and ENGAGE AF (Effective Anticoagulation With Factor Xa Next Generation in AF) investigators have published findings on patients with significant biological VHD treated with apixaban, rivaroxaban, and high‐dose edoxaban in their respective studies 1, 16, 17. In ARISTOTLE, 4808 patients (26.4%) had a history of moderate or severe VHD or prior valve surgery.…”

“…Historical data have shown, in small cohorts of individuals with mechanical valves (MVs) and rheumatic mitral stenosis (MS), worse outcomes in patients with these valve disorders in the setting of AF 1, 2, 3, 4, 5. Recent clinical trials of direct oral anticoagulants (DOACs) in patients with AF have varied in their definition of VHD and, consequently, inclusion and exclusion criteria for enrollment 6, 7, 8, 9.…”