Correct DOAC Dose Up in the Air for Many Afib Patients With Renal Dysfunction

Direct oral anticoagulant (DOAC) users with chronic kidney disease (CKD) are subject to disparate dosing adjustment formulas that may differ on what the right dose is for thromboembolic risk reduction, observational data suggest.

In the Prevention of Thromboembolic Events-European Registry in Atrial Fibrillation (PREFER in AF) and PREFER in AF Prolongation registries, atrial fibrillation (Afib) patients who met Cockcroft-Gault criteria for a dabigatran (Pradaxa), edoxaban (Savaysa), or rivaroxaban (Xarelto) dose reduction ended up reclassified to a higher DOAC dose in 19% and 16% of cases according to the Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formulas, respectively.

Meanwhile, those eligible for a Cockcroft-Gault DOAC dose increase would have been directed to reduced dosing in 24% and 23% of cases under MDRD and CKD-EPI criteria, according to Raffaele De Caterina, MD, PhD, of Pisa University Hospital in Italy, and colleagues.

Their study of 1,288 Afib patients in Europe is published online in Circulation: Cardiovascular Quality and Outcomes.

Ultimately, Afib patients with Cockcroft-Gault-determined renal dysfunction who were reclassified as having an estimated glomerular filtration rate (eGFR) >50 mL/minute by the CKD-EPI formula tended to have a higher 1-year thromboembolic risk (4.1% vs 0.8%; OR 5.5, 95% CI 1.5-20.8). A trend of more bleeding events among people with discordant renal function results was observed as well.

MDRD and CKD-EPI tended to suggest lower estimated glomerular filtration rates (eGFRs) than the Cockcroft-Gault equation did in people with mild renal dysfunction, but higher eGFRs in those with moderate-to-severe or severe renal dysfunction. Discrepancies between Cockcroft-Gault and MDRD or CKD-EPI were especially large in patients with a body weight ≤60 kg and a BMI ≥30.

“These data support the need for a reassessment of the best method to determine a renal indication for dose reduction of DOACs,” the study authors wrote.

The Cockcroft-Gault formula has been used in DOAC trials and is recommended by guidelines for the estimation of creatinine clearance, a proxy for renal function, in Afib patients taking DOACs for stroke prevention.

“In clinical practice, however, most laboratories use either the MDRD or the CKD-EPI formula. These methods do not require weight as an input and have been shown to be more accurate compared with the CG [Cockcroft-Gault] formula, particularly in subgroups at the extremes of the age and weight spectrums,” De Caterina’s group explained.

“Physicians should be aware that using the widely adopted MDRD and CKD-EPI formulae inevitably leads to a dosing of DOACs … that has not been prospectively evaluated. As shown in our hypothesis-generating analysis, this practice might have an impact on hard clinical outcomes,” the authors concluded.

It may be time to consider something besides the Cockcroft-Gault to guide renal dosing adjustments for DOACs, commented Brittany Smith, PharmD, of University of Kentucky HealthCare Gill Heart and Vascular Institute in Lexington, and Robert DiDomenico, PharmD, of the University of Illinois at Chicago College of Pharmacy, in an accompanying editorial.

They said that eGFR, calculated by MDRD and CKD-EPI, has been shown to guide treatment decisions, optimize dosing, and predict adverse outcomes in other settings.

“As with DOACs, academic scientists, the pharmaceutical industry, and the FDA should evaluate whether these formulas optimize dosing of renally cleared drugs and incorporate them into renal dosing recommendations if studies validate GFR-based renal dosing adjustments similar to what [De Caterina’s team described]. Then we will be able to turn the page from CG formula,” wrote Smith and DiDomenico.

Until then, they said, renal assessment at baseline and regularly throughout the course of DOAC therapy remains important. The concept of the virtual anticoagulation clinic may prove its worth during the COVID-19 pandemic in particular, the editorialists added.

Study participants had been enrolled in PREFER in AF and PREFER in AF Prolongation in 2012-2016.

Limiting the sample size of the study was the fact that out of more than 9,000 Afib patients in the two registries, just 1,288 had sufficient creatinine values — given established CKD — and were included in the analysis.

The actual DOAC dosing for each patient was also not recorded in the registries, De Caterina and colleagues acknowledged, adding that notably, DOAC dose adjustments are not based on creatinine clearance in the case of apixaban (Eliquis).