Stroke and Bleeding in Atrial Fibrillation with Chronic Kidney Disease

The prevalence of both atrial fibrillation and chronic kidney disease increases with age. The prevalence of atrial fibrillation is 2.3% among persons 40 years of age or older and 5.9% among those 65 years of age or older, and the prevalence of end-stage renal disease increases from approximately 3.5% among persons 45 to 64 years of age to nearly 6% among those 75 years of age or older. Many patients have both disorders, and the number of such patients is increasing.

Atrial fibrillation greatly increases the risk of stroke (by a factor of 5) and chronic kidney disease increases the risk of stroke among patients without atrial fibrillation. Among women, both chronic kidney disease and atrial fibrillation have been associated with an increase in the risk of myocardial infarction.

Warfarin has traditionally been used to reduce the risk of stroke or systemic thromboembolism in patients with atrial fibrillation. However, some studies have suggested that the use of warfarin may actually increase the risk of ischemic stroke among patients undergoing dialysis. As well, the risk of bleeding associated with warfarin treatment is increased among patients with atrial fibrillation who also have chronic kidney disease.

The objective of this cohort study [N Engl J Med 2012;367:625-35] was to determine the risk of stroke or systemic thromboembolism and bleeding associated with chronic kidney disease among patients with atrial fibrillation and to determine whether the effect of warfarin and aspirin differed between patients with and without chronic kidney disease.

The Danish investigators used national registries to identify all patients discharged from the hospital with a diagnosis of nonvalvular atrial fibrillation between 1997 and 2008. To investigate the risk associated with the severity of non-end-stage chronic kidney disease, patients were stratified in a time-dependent manner according to the treatment dose of loop diuretics.

The authors studied the influence of the underlying renal disease in non-end-stage chronic kidney disease by comparing the following diagnostic groups: autosomal dominant polycystic kidney disease, chronic glomerulonephritis, diabetic nephropathy, chronic tubulointerstitial nephropathy, hypertensive nephropathy, and other causes. The risk of stroke or systemic thromboembolism associated with non-end-stage chronic kidney disease or disease requiring renal-replacement therapy was estimated by means of time-dependent Cox proportional-hazards models, with adjustment for changes in renal status or antithrombotic treatment during follow-up.

Of the 132,372 patients included in the analysis, 3587 (2.7%) had non-end-stage chronic kidney disease, and 901 (0.7%) required renal-replacement therapy. Among the patients who had no renal disease initially, non-end-stage chronic kidney disease developed in 4538 patients (3.5%) after a median of 893 days (interquartile range, 313 to 1715), and renal-replacement therapy was required in 477 patients (0.4%) after a median of 217 days (interquartile range, 33 to 681).

Of the 1378 patients requiring renal-replacement therapy during the study period, 1074 (77.9%) were receiving hemodialysis, 212 (15.4%) were receiving peritoneal dialysis, and 92 (6.7%) underwent kidney transplantation. Compared with patients who did not have renal disease, the risk of stroke or systemic thromboembolism was increased among patients with non-end-stage chronic kidney disease (hazard ratio [HR], 1.49; 95% confidence interval [CI], 1.38-1.59; P<.001) and among those requiring renal replacement therapy (HR, 1.83; 95% CI, 1.57-2.14; P<.001).

In an analysis that compared all patients who had any renal disease with those who had no renal disease, warfarin decreased the risk of stroke or systemic thromboembolism (HR, 0.76; 95% CI, 0.64-0.91; P=.003), as did warfarin plus aspirin (HR, 0.74; 95% CI, 0.56 to 0.98; P=.04).

Aspirin was associated with an increased risk of stroke or systemic thromboembolism overall and among patients who had any renal disease, compared with those who had no renal disease (HR, 1.17; 95% CI, 1.01-1.35; P=.04). The risk of bleeding was also increased among patients who had non-end-stage chronic kidney disease or required renal replacement therapy, and was further increased with warfarin, aspirin, or both.