Renal Function in Patients With Atrial Fibrillation Receiving Anticoagulants: The Canaries in the Coal Mine

The past few years have witnessed unprecedented progress in the field of anticoagulation for atrial fibrillation (AF). Since 2010, 4 direct oral anticoagulants (DOACs) have been approved in nonvalvular AF based on pivotal trials. Patients with advanced chronic kidney disease (CKD) are arguably the highest-risk patients receiving anticoagulation from the standpoint of both stroke/systemic embolism and bleeding events. Although patients with estimated creatinine clearance (eCrCl) less than 30 mL/min/1.73m² (to convert to milliliters per second per meters squared, multiply by 0.0167) were excluded from trials, about 15% to 20% of enrollees had stage 3 CKD, providing clinicians representative data to derive meaningful conclusions to guide practice. Prespecified subgroup analysis and meta-analysis concur that the overall trial results (ie, noninferiority of the DOACs vs warfarin in the prevention of stroke/systemic embolism) are applicable to patients with stage 3 CKD, and several agents may actually have specific advantages.¹

Not enough attention has been focused on systemic approaches to recognize and anticipate the fresh set of challenges that will be posed in the era of the DOACs, particularly in this high-risk population. Published scenarios raise doubts about our maturity as a health care system to safely adapt to this new world of anticoagulation. Data from a large dialysis database showed that nearly 6% of patients with AF undergoing long-term hemodialysis initiated therapy with dabigatran or rivaroxaban from 2010 to 2014.² This is a troubling observation because these DOACs are not approved in dialysis patients owing to their exclusion from pivotal randomized clinical trials, and because use can be associated with heightened bleeding risk and erratic blood levels on dialysis. The DOACs were prescribed within 45 days of approval in the United States and steadily increased during the study period. Moreover, about 15% of dabigatran and 32% of rivaroxaban users were prescribed the full dose (without renal dose modification), whereas others received doses approved for patients with moderate CKD. Importantly, their use among hemodialysis patients was accompanied by serious consequences—higher associated risks of both major and fatal bleeding. A similar theme of enthusiastic prescription of dabigatran to dialysis patients was observed in data from the United States Renal Data System.³ In another example, hematologists in New Zealand carried out an audit of bleeding complications after introduction of dabigatran, reporting a higher occurrence of major bleeding episodes than would be anticipated from the representative randomized clinical trial.⁴ The authors concluded that errors by prescribers related to incorrect dosing/indication were major contributors in the context of clinical characteristics that affect accurate dosing (ie, higher age, impaired renal function).

In these examples, the lack of recognition of the significance of underlying renal impairment was a unifying denominator. The CKD population is most vulnerable to needing dose adjustments because of the high renal clearance of the DOACs, ranging from 25% (apixaban) to 80% (dabigatran). A post hoc observation of the Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial highlighted the temporal deterioration in eCrCl among all 3 study arms receiving long-term anticoagulation (high- and low-dose dabigatran and warfarin), albeit statistically significant in the warfarin arm.⁵ This observation may lend credence to the notion of warfarin-related nephropathy/glomerulopathy, but more importantly perhaps, indicates the need for temporal monitoring of renal function during anticoagulant therapy for AF, particularly in patients with CKD. Although most clinicians use estimated glomerular filtration rates to monitor renal function in practice, the doses of DOACs are approved based on eCrCl values (Cockroft-Gault equation). There is significant discordance in doses of some DOACs if estimated glomerular filtration rate is used to measure renal function instead of eCrCl; the discordance is higher for agents with greater renal clearance.⁶

These studies provide sobering forewarnings of the potential for clinical errors with use of DOACs among patients with CKD. As the coprevalence of AF and CKD steadily increases in an aging population, these examples will only become increasingly common. We need to couple our enthusiasm to adopt the DOACs with adequate systemwide measures to focus attention to prescriber education, achieving familiarity in their use and creating alerts to prevent errors. Although DOACs represent a huge advance in medical therapy, their use also involves a steep learning curve that could be unforgiving from a patient’s perspective. For clinicians who have long been accustomed to warfarin, without attendant need for significant dose adjustment in the face of kidney impairment and with the comfort of the availability of international normalized ratio (INR) levels to guide dosing changes, this is not a trivial change in perspective. Acute kidney injury is common among hospitalized patients, and it is now incumbent on inpatient health care professionals to actively recognize and ensure that dynamic dose adjustment of DOACs occurs consistently. Another important paradigm shift with the DOACs (relative to warfarin) is the rapid onset/offset of action, which poses challenges of exposure to a higher risk of thrombotic complications due to rapid offset or bleeding complications due to rapid onset if resumed too early after surgery/procedures. Moreover, the time window for holding doses of various DOACs prior to procedures is also contingent on renal clearance, which adds another dimension of complexity to clinical management.

The health care system is yet to factor in the “real-world” confusion among clinicians that is inevitable with need to rapidly amalgamate information pertaining to several DOACs and learn their respective caveats and doses in normal and impaired renal function and implications for onset/offset of action during routine medical occurrences/procedures. As the numbers of patients with AF receiving warfarin inevitably decline nationally, the already existing model of “anticoagulation clinics” could be tasked with being the gatekeepers of safety for patients receiving DOACs.⁷ The model of “warfarin clinics” has been widely implemented not just because patients receiving warfarin need INR monitoring, but because these clinics serve as a mechanism of monitoring high-risk patients receiving dangerous therapy by reinforcing compliance, influencing dietary habits, regulating use of medications that could influence INR levels, and providing a peer-support system, thus serving a safety-net function. An analogous anticoagulation model run by trained clinical pharmacists/nurses could serve the function of monitoring patients receiving DOACs in the new era, with a predetermined frequency of visits contingent on baseline renal function and renal clearance of the DOAC. Furthermore, it is clear that several inpatient concerns will need to be addressed expeditiously and may not be able to simply wait for an ambulatory visit. Hence, it would be imperative for such a model incorporating a team of experts to serve as a hovering “cloud” or resource for busy clinicians for inpatient concerns that arise in the management of DOACs, eg, drug interruptions for procedures/surgeries, dose modifications in the context of episodes of acute kidney injury, and anticipated interactions when new drugs are prescribed, while providing guidance regarding circumstances when it may be necessary to lean on laboratory measures to assess drug levels. In the era of widespread use of electronic health records, such a team could be tasked with “panel” management of patients receiving DOACs, possibly with electronic/virtual visits and alerts based on eCrCl and age.

It would be prudent for us to advocate for adoption of such a model of an “anticoagulation cloud” that would offer several foreseeable benefits: it would undoubtedly lead to eventual economic gains to the system by preventing incorrect dosing and attendant serious and often fatal complications, serve as huge clinician and patient satisfiers, and, most importantly, maintain the safety of the patient the foremost priority.

Corresponding Author: Gautam R. Shroff, MBBS, Division of Cardiology, Department of Internal Medicine, Hennepin County Medical Center, University of Minnesota Medical School, 701 Park Ave S, Minneapolis, MN 55415 (shrof010@umn.edu).

Published Online: June 15, 2016. doi:10.1001/jamacardio.2016.1258.

Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.