Sunday, January 26, 2014

Warfarin for Atrial Fibrillation in Dialysis Patients: Where’s the data?

ESRD patients have an increased incidence of atrial fibrillation (AF) and a higher risk of stroke compared to patients with normal renal function. However they also have an increased bleeding tendency due in part to uremia and the associated platelet dysfunction. Anticoagulation with warfarin for AF is widespread in the general population, where the sense of risk and benefit are better understood. Like many other conditions, ESRD patients are routinely excluded from clinical trials in AF and therefore we lack hard data on how to manage our ESRD patients with AF. We must rely on observational data, which is often contradictory. Firstly, increased INR variability has been demonstrated in dialysis patients treated with warfarin and they spend much time outside of target INR range. Some registry data supports warfarin use with a suggestion of improved survival in dialysis patients with AF while other studies demonstrate an increased risk of stroke with warfarin [here, here, here]. Overall, the majority of studies do not support a protective effect for warfarin in ESRD patients with AF.

A current study from Canada in Circulation weighs in on the issue. The authors conducted a retrospective cohort study of patients > 65 years admitted with a diagnosis of AF from 1998 to 2007. There were 1,626 dialysis patients (46% received warfarin) and >200,000 non-dialysis patients. In a multivariate analysis, warfarin use in the dialysis patients was associated with similar risk of non-hemorrhagic stroke but a significantly higher risk of bleeding (defined as intra-cerebral, intra-ocular, GI, unspecified hemorrhage & hematuria; HR 1.44). The non-dialysis patients did see a lower incidence of ischemic stroke with warfarin use.

Our ESRD patients comprise a unique cohort with labile, often high blood pressure, repetitive AV access puncture, proven variability in INR and usually anticoagulation use during dialysis. They are certainly high risk for bleeding. Moreover, warfarin use is associated with accelerated vascular calcification in CKD patients and calciphylaxis, an admittedly uncommon but devastating condition. Unfortunately we suffer from a lack of alternatives to warfarin. Accumulation of low-molecular weight heparin in ESRD precludes its use and there is no experience with newer agents such as direct thrombin and Factor Xa inhibitors.
Many authors, including those at UpToDate, recommend warfarin use with AF and an eGFR<15mls/min. They are equivocal when CHADS2=0, but this is rare in a dialysis patient. Remember CHADS2 includes congestive heart failure, hypertension, age ≥75, diabetes and previous stroke/TIA. Despite older age being part of the CHADS2 score suggesting treatment efficacy, age >75 has been associated with a particularly high risk of bleeding in dialysis patients treated with warfarin. Also, CKD is part of the HAS-BLEED score which predicts high risk of hemorrhagic complications to warfarin when the score is ≥3. Many dialysis patients would fall into this category based on hypertension, older age and concomitant meds (85% in the current study in Circulation). I often feel uncomfortable using warfarin in ESRD and certainly feel it should be an individualized patient choice. With the current evidence (or lack of it) to guide us and the significant potential for harm, withholding warfarin for many of our older dialysis patients would not seem unreasonable.


Veeraish Chauhan said...

Thanks Paul! A very pertinent issue that always has me flummoxed! I covered something on similar lines earlier here:

Paul Phelan said...

Thanks Veeraish. I should have linked to your previous post!

Henry said...

How do you feel about coumadin's risk for calciphyllaxis being a further argument against the use in the chronic dialysis patient?

Paul Phelan said...

Henry, yes coumadins association with calciphylaxis seems robust and is an obvious concern given the severity of the condition. As calciphylaxis is quite uncommon, I wouldn't withhold warfarin based on this association alone but it is another concern when anticogulating dialysis patients, especially given a lack of any strongly proven benefit.