Role of Anticoagulation Explored in Patients With A-Fib, Renal Disease

In A-fib patients, the presence of chronic kidney disease (CKD) is associated with greater likelihood of stroke/thromboembolism regardless of baseline stroke risk, especially when paired with renal replacement therapy (RRT), according to a study published in the December 16, 2014, issue of the Journal of the American College of Cardiology.

The observations highlighted in the study “provide guidance for the optimal use of antithrombotic therapy in [A-fib] patients with CKD,” Anders Nissen Bonde, MB, of Copenhagen University Hospital Gentofte (Hellerup, Denmark), and colleagues write.

Of the 154,259 patients discharged with nonvalvular A-fib from Danish hospitals between 1997 and 2011 who did not experience stroke/thromboembolism, major bleeding, or death within 7 days, the researchers identified 11,128 patients (7.2%) with non–end-stage CKD and 1,728 patients (1.2%) receiving RRT. Among the RRT patients, 72.0% received hemodialysis, 25.1% peritoneal dialysis, and 2.8% kidney transplants.

Overall, non–end-stage CKD patients were older, had more comorbidities, and received more medications, whereas RRT patients were more often men and hypertensive. All CKD patients were less likely to receive warfarin.

Renal Disease Increases Event Risk

Over follow-up, 13.4% of non-CKD patients experienced stroke/thromboembolism, as did 9.9% of those with non–end-stage CKD and 13.2% of RRT patients.

In patients with a CHA₂DS₂-VASc score of 0 not treated with warfarin, the stroke/thromboembolism rate was lower in patients without CKD than in RRT patients at 0.8 vs 4.2 cases per 100 person-years. In patients with CHA₂DS₂-VASc scores ≥ 2 not treated with warfarin, the stroke/thromboembolism rate was “substantially” higher in both non–end-stage CKD and RRT patients when compared with A-fib patients without CKD, the paper reports. 

Within the no-warfarin subgroup, those with a CHA₂DS₂-VASc score of 0 plus CKD—whether non–end-stage or RRT—had a greater risk of stroke/thromboembolism than those without CKD. This association was not found in non–end-stage CKD patients with CHA₂DS₂-VASc scores of 1. Also, CKD was independently associated with increased stroke/thromboembolism risk in patients with CHA₂DS₂-VASc scores of 2 or greater (table 1). Lastly, risk differed between the non–end-stage CKD and the RRT groups in patients with CHA₂DS₂-VASc scores of ≥ 1 (P value for interaction < .0001).

Among non–end-stage CKD patients at high risk, warfarin was associated with lower likelihoods of cardiovascular death (HR 0.80; 95% CI 0.74-0.88) and all-cause mortality (HR 0.64; 95% CI 0.60-0.69) than no antithrombotic treatment. Among low-to-intermediate risk non–end-stage CKD patients, warfarin was associated with a lower risk of all-cause mortality (HR 0.62; 95% CI 0.49-0.79) and a trend toward lower risk of cardiovascular death. Aspirin with or without warfarin was associated with a lower risk of all-cause mortality.

Among high-risk RRT patients, warfarin was associated with a lower risk of all-cause mortality (HR 0.85; 95% CI 0.72-0.99) and trends toward lower risks of cardiovascular death and of a composite of death/hospitalization from stroke/thromboembolism/bleeding. Treatment with aspirin with or without warfarin was not associated with a lower risk of any outcome in this patient group.

Dialysis type—whether hemodialysis or peritoneal dialysis—interacted with warfarin in low-risk patients (P = .002) and aspirin in high-risk patients (P = .041) for the outcome of stroke/thromboembolism/bleeding. There was also a trend toward fewer negative outcomes with warfarin among high-risk patients receiving hemodialysis instead of peritoneal dialysis.

Reinforcing Warfarin’s Value

“It has recently been debated whether CKD should be added as an extra risk point to the CHA₂DS₂-VASc score,” Dr. Bonde and colleagues write. “In these latter low-/intermediate-risk CKD patients, our results may therefore suggest a potential benefit of warfarin.”

For A-fib patients receiving RRT, they add, “the value of warfarin has previously been challenged, and routine anticoagulation for primary stroke prevention has not been recommended, given that these patients were excluded from previous clinical trials.”

Since the study found a lower risk of all-cause death with warfarin, it “perhaps has greater clinical relevance and application [than past studies finding the opposite], given the large size and the fact that we accounted for different stroke risk strata in our analyses,” the authors write. The association, they note, did not last through 90 days of treatment, “indicating that some of the apparent positive effect associated with warfarin may be caused by treatment cessation in some of the terminal patients.”

More Likely to Benefit Than to Harm

In an editorial accompanying the study, Timothy Ball, MD, Kevin Wheelan, MD, and Peter A. McCullough, MD, MPH, all of Baylor University Medical Center (Dallas, TX), say that although “this work has significant limitations inherent to cohort studies, it is among the largest and most complete datasets analyzing this complex management question.”

Despite the low overall use of warfarin and inability to adjust for all confounders, they write, “The results of this study suggest that at any CHA₂DS₂-VASc score, the risk of stroke or embolism [in patients with CKD] is roughly double that of non-CKD patients.” Bleeding is driven more by stroke risk than by background kidney disease, however, so “one would conclude on balance that there is a greater opportunity for benefit than harm when the stroke risk is higher in [A-fib] in patients with background renal disease,” they comment.

The editorialists acknowledge the “powerful data” about how anticoagulation can best be utilized in CKD but argue more is needed to “better understand the role of antiplatelet agents, warfarin, and the novel anticoagulants. In addition, the optimal approach to [A-fib] and stroke prevention with end-stage renal disease is still yet to be defined.”

 

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Sources: 
1. Bonde AN, Lip GYH, Kamper A-L, et al. Net clinical benefit of antithrombotic therapy in patients with atrial fibrillation and chronic kidney disease: a nationwide observational cohort study. J Am Coll Cardiol. 2014;64:2471-2482.

 

2. Ball T, Wheelan K, McCullough PA. Chronic anticoagulation in chronic kidney disease [editorial]. J Am Coll Cardiol. 2014;64:2483-2485.

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