Apixaban Effective, Safe in Atrial Fib Despite Declining Renal Function: ARISTOTLE

Patrice Wendling

July 15, 2016

UPPSALA, SWEDEN — A subanalysis of the ARISTOTLE trial provides reassurance for patients with atrial fibrillation (AF) and renal dysfunction but also raises questions about how direct oral anticoagulants (DOACs) should be monitored in AF[1].

Having previously demonstrated the superiority of apixaban (Eliquis, Pfizer/Bristol-Myers Squibb) over warfarin in 18,201 AF patients in the parent trial, the subanalysis aimed to assess the development of renal dysfunction and its association with efficacy and safety outcomes over 12 months of follow-up.

Using serial blood samples available in 16,869 patients, researchers found that 13.6% had worsening renal function, defined as a decline of more than 20% in estimated glomerular filtration rate (eGFR).

The rate of eGFR deterioration was variable but dropped more rapidly in older patients and those with low hematocrit, heart failure, vascular disease, or diabetes.

Patients with worsening renal function had consistently higher rates of stroke or systemic embolism (hazard ratio [HR] 1.53; 95% CI 1.17–2.01), major bleeding (HR 1.56; 95% CI 1.27–1.93), and all-cause mortality (HR 2.31; 95% CI 1.98–2.68). This was true irrespective of baseline renal function and using either the Cockcroft-Gault or Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations to estimate renal function.

However, when randomized to apixaban rather than warfarin, these patients had a lower relative risk of stroke or systemic embolism (HR 0.80; 95% CI 0.51–1.24; P=0.86) and major bleeding (HR 0.76; 95% CI 0.54–1.07; P=0.73). These benefits with apixaban over warfarin were also consistent without any significant interaction with worsening renal function over time when the Cockcroft-Gault, rather than the CKD-EPI, equation was used for GFR estimation (stroke/systemic embolism HR 0.83; 95% CI 0.52–1.32; interaction P=0.70; major bleeding HR 0.78; 95% CI 0.54–1.11; interaction P=0.62).

The beneficial effects of apixaban on these primary efficacy and safety outcomes were also consistent in patients with normal or stable poor renal function (<50 mL/min) over time, according to findings published online June 15, 2016 in JAMA Cardiology.

"At present, information [on renal function variability] is very limited, which increases the importance of the findings from this study on apixaban," lead author Dr Ziad Hijazi (Uppsala Clinical Research Center, Sweden) told heartwire from Medscape.

He added that the results are reassuring and "may guide clinicians in the treatment decision."

The risks related to worsening renal function in AF have previously been described only in smaller, registry-based cohorts and primarily confined to higher rates of mortality and composite CV events.

The importance of renal function and monitoring was emphasized by the Food and Drug Administration in a boxed warning for edoxaban (Savaysa, Daiichi-Sankyo) after the unexpected finding of higher stroke rates with the factor Xa inhibitor vs warfarin in AF patients with normal kidney function, defined by a creatinine clearance of 95 mL/min, he said.

Anticoagulation Cloud

In an accompanying editorial[2], Dr Gautam Shroff (University of Minnesota Medical School, Minneapolis), observes that a post hoc analysis of the RE-LY trial also identified temporal deterioration in estimated creatine clearance in all three arms (high- and low-dose dabigatran [Pradaxa, Boehringer Ingelheim] and warfarin).

He goes on to lay out a strong case for tasking today's warfarin clinics with being the "gatekeepers of safety" for patients receiving DOACs and for this model to incorporate 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."

Such concerns could include drug interruptions, dose modifications in the context of episodes of acute kidney injury, and new drug interactions. Guidance could also be offered on when it may be necessary to lean on laboratory measures to assess drug levels.

Shroff writes that CKD patients are the most vulnerable to needing dose adjustments because of the high renal clearance of the DOACs, ranging from 25% with apixaban to 80% with dabigatran.

There is significant discordance in doses of some DOACs if the eGFR rate is used to measure renal function instead of estimated creatine clearance (eCrCl), with the discordance higher for agents with greater renal clearance, he notes. DOAC doses are approved based on eCrCl values (Cockroft-Gault equation), although most clinicians use eGFR rates to monitor renal function in practice.

Shroff suggests that the widespread use of electronic medical records could also allow experts in the anticoagulation cloud to provide "panel management" of patients receiving DOACs, possibly via 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 important, maintain the safety of the patient, the foremost priority," he concludes.

Hijazi agreed that it is necessary to reevaluate these patients when clinically indicated and at least annually, as recommended in the current AF guidelines. He added, "The findings in the current study support a more individualized monitoring plan" and suggested that patients estimated to be at low risk of developing a substantial worsening of renal function could be monitored annually, while those at higher risk should be monitored "more closely—for example, every 3 to 6 months."

Hijazi reports receiving lecture fees from Boehringer Ingelheim; consulting fees from Bristol-Myers-Squibb and Pfizer; and institutional research grants from all three firms. Disclosures for the coauthors are listed in the article. Shroff reported no financial relationships.

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