Outcomes After Warfarin Initiation in a Cohort of Hemodialysis Patients With Newly Diagnosed Atrial Fibrillation

Abstract

Background: Although warfarin is indicated to prevent ischemic strokes in most patients with atrial fibrillation (AF), evidence supporting its use in hemodialysis patients is limited. Our aim was to examine outcomes after warfarin therapy initiation, relative to no warfarin use, following incident AF in a large cohort of hemodialysis patients who had comprehensive prescription drug coverage through Medicare Part D.

Study design: Retrospective observational cohort study.

Setting & participants: Patients in the US Renal Data System undergoing maintenance hemodialysis who had AF newly diagnosed in 2007 to 2011, with Medicare Part D coverage, who had no recorded history of warfarin use.

Predictor: Warfarin therapy initiation, identified by a filled prescription within 30 days of the AF event.

Outcomes: Death, ischemic stroke, hemorrhagic stroke, severe gastrointestinal bleeding, and composite outcomes.

Measurements: HRs estimated by applying Cox regression to an inverse probability of treatment and censoring-weighted cohort.

Results: Of 12,284 patients with newly diagnosed AF, 1,838 (15%) initiated warfarin therapy within 30 days; however, ∼70% discontinued its use within 1 year. In intention-to-treat analyses, warfarin use was marginally associated with a reduced risk of ischemic stroke (HR, 0.68; 95% CI, 0.47-0.99), but not with the other outcomes. In as-treated analyses, warfarin use was associated with reduced mortality (HR, 0.84; 95% CI, 0.73-0.97).

Limitations: Short observation period, limited number of nonfatal events, limited generalizability of results to more affluent patients.

Conclusions: In hemodialysis patients with incident AF, warfarin use was marginally associated with reduced risk of ischemic stroke, and there was a signal toward reduced mortality in as-treated analyses. These results support clinical equipoise regarding the use of warfarin in hemodialysis patients and underscore the need for randomized trials to fill this evidence gap.

Keywords: Dialysis; atrial fibrillation (AF); bleeding; cardiac arrhythmia; drug safety; end-stage renal disease (ESRD); hemodialysis; hemorrhagic stroke; ischemic stroke; mortality; oral anticoagulation; prevention; warfarin.

Figure 1

Study population selection from the US Renal Data System. We identified a cohort of adult patients on hemodialysis who were newly diagnosed with atrial fibrillation (AF) in 2007-2011 and who participated in a low-income subsidy program of Medicare Part D. Index date – the 30^th day after discharge from the first hospitalization with an AF diagnosis or the 30^th day after a first outpatient AF diagnosis. ESRD – end-stage renal disease.

Figure 2

Timeline of enrollment criteria, ascertainment of exposure, covariates, and outcomes for patients on maintenance hemodialysis newly diagnosed with atrial fibrillation as inpatients (Panel A) or outpatients (Panel B) between 7/1/2007 and 12/1/2011. AF – atrial fibrillation. Patients were required to have continuous Medicare A and B coverage for at least one year prior to either the AF admission or the 1^st outpatient AF diagnosis until 30 days after discharge or the 1^st outpatient diagnosis. They also were required to have continuous enrollment in a low-income subsidy program of Medicare Part D for at least 6 months prior to admission/1^st outpatient diagnosis until 30 days after discharge/1^st outpatient diagnosis. Patients with any AF in at least the year prior to admission/1^st outpatient diagnosis were excluded, as were patients with any warfarin prescription in the 6 months prior to admission/1^st outpatient diagnosis. Patients were considered users if they filled a prescription for warfarin in the 30 days after discharge/1^st outpatient diagnosis. Outcomes were ascertained starting 30 days after discharge/1^st outpatient diagnosis (index date) until 12/31/2011.

Figure 3

Hazard ratios for all study outcomes for both the primary analyses [based on the full inverse probability of treatment and censoring-weighted (IPTW) cohort] and the sensitivity analyses [based on the propensity score (PS) matched cohort]. Panel A: Stroke and bleeding outcomes. Panel B: Mortality and composite outcome. AT60 – as treated analysis where patients were censored 60 days after their drug supply ran out, AT30 – as treated analysis where patients were censored 30 days after their drug supply ran out, ITT – intention to treat.

Figure 3

Hazard ratios for all study outcomes for both the primary analyses [based on the full inverse probability of treatment and censoring-weighted (IPTW) cohort] and the sensitivity analyses [based on the propensity score (PS) matched cohort]. Panel A: Stroke and bleeding outcomes. Panel B: Mortality and composite outcome. AT60 – as treated analysis where patients were censored 60 days after their drug supply ran out, AT30 – as treated analysis where patients were censored 30 days after their drug supply ran out, ITT – intention to treat.

Figure 4

Time to warfarin cessation for users and time to warfarin use for nonusers, in years. Warfarin users, those who filled a first prescription within 30 days of the index atrial fibrillation event, were considered to have discontinued warfarin use if they had not refilled their prescription within 60 days after their most recent supply expired. For example, if someone received a 30-day supply of warfarin, they had 90 days from their previous filled prescription to refill it.