Warfarin use associates with increased risk for stroke in hemodialysis patients with atrial fibrillation

Abstract

Use of warfarin, clopidogrel, or aspirin associates with mortality among patients with ESRD, but the risk-benefit ratio may depend on underlying comorbidities. Here, we investigated the association between these medications and new stroke, mortality, and hospitalization in a retrospective cohort analysis of 1671 incident hemodialysis patients with preexisting atrial fibrillation. We followed patient outcomes from the time of initiation of dialysis for an average of 1.6 yr. Compared with nonuse, warfarin use associated with a significantly increased risk for new stroke (hazard ratio 1.93; 95% confidence interval 1.29 to 2.90); clopidogrel or aspirin use did not associate with increased risk for new stroke. Analysis using international normalized ratio (INR) suggested a dose-response relationship between the degree of anticoagulation and new stroke in patients on warfarin (P = 0.02 for trend). Warfarin users who received no INR monitoring in the first 90 d of dialysis had the highest risk for stroke compared with nonusers (hazard ratio 2.79; 95% confidence interval 1.65 to 4.70). Warfarin use did not associate with statistically significant increases in all-cause mortality or hospitalization. In conclusion, warfarin use among patients with both ESRD and atrial fibrillation associates with an increased risk for stroke. The risk is greatest in warfarin users who do not receive in-facility INR monitoring.

Figure 1.

Crude stroke curves by drug exposure. (A) Under an intention-to-treat assumption, increased incidence of new stroke was associated with patients who were on warfarin. (B) Similar results were noted when patients were censored when they changed their warfarin, clopidogrel, or aspirin prescription after study enrollment.

Figure 2.

Stratified analysis. Patients at higher risk for future stroke (higher CHADS² score) had better risk-benefit profiles (warfarin*CHADS² = 0.84; P = 0.31 for interaction) with warfarin use when compared with nonusers. With the exception of diabetes, there were no statistical differences in the prevalence of warfarin use, INR level, or INR monitoring with increasing risk for stroke (CHADS² score) and by five well-established risk factors for future stroke in atrial fibrillation. The crude ischemic stroke rate in warfarin users was 5.8 strokes per 100 patient-years (95% CI 4.6 to 7.4) versus 2.3 strokes per 100 patient-years in nonusers (95% CI 1.5 to 3.6). The crude hemorrhagic stroke rate in warfarin users was 1.2 strokes per 100 patient-years (95% CI 0.7 to 2.1) versus 0.5 strokes per 100 patient-years in nonusers (95% CI 0.2 to 1.4). ^†Statistically significant difference (P = 0.03) in prevalence of warfarin use in diabetic versus nondiabetic incident dialysis patients with atrial fibrillation. §As expected, patients with a higher propensity for warfarin prescription had a higher prevalence of warfarin use. ^¥After matching, the caliper width of the propensity score between the two groups was found to be ±0.6 SD. *Values reported only for patients who had a stroke outcome. CHF, congestive heart failure; HTN, hypertension.

Figure 3.

HRs for stroke with warfarin use (versus nonuse) by strata of INR level. The graph demonstrates a dose-response relationship between warfarin and new stroke. Patients with higher levels of anticoagulation, as quantified by the INR level, have an increased risk for new stroke (P = 0.04 for trend) with warfarin use (versus nonuse). Patients who were on warfarin and had no INR monitoring had the highest risk for new stroke. The stroke risk, as quantified by the CHADS² score, among the five categories of INR were statistically (P = 0.11) and clinically no different.