Standard-Dose DOAC Better for Kidney-Impaired Patients

Standard-dose direct oral anticoagulants (DOACs) safely bested both lower doses and warfarin among patients with kidney dysfunction in subgroup analysis across pivotal clinical trials in atrial fibrillation (AF).

The benefit for prevention of stroke or systemic embolism actually increased as creatinine clearance (CrCl) fell among patients with CrCl less than 87 mL/min (4.8% decrease in HR per 10-mL/min, P_interaction=0.01).

Mortality risk was lower as well with regular-dose DOACs than warfarin among those with CrCl less than 77 mL/min, with a trend for greater benefit the lower the kidney function (P_interaction=0.08), Christopher Granger, MD, of the Duke Clinical Research Institute in Durham, North Carolina, and colleagues reported in Circulation.

Compared with low-dose DOACs, standard doses had a nonsignificant trend for less stroke and systemic embolism (HR difference 2.8 percentage points, P_interaction=0.21) and significantly lower mortality (5.8 percentage points, P=0.001).

Bleeding risk didn't differ for standard-dose DOACs compared with warfarin down to a CrCl of at least 25 mL/min in the trials, or for standard-dose versus low-dose DOACs.

"Taken together, these results support the use of DOACs over warfarin down to a CrCl of at least 25 mL/min and emphasize the importance of prescribing guideline-supported doses of DOACs in the prevention of [stroke and systemic embolism]," the researchers wrote.

Too often, patients with kidney dysfunction who do not meet criteria for DOAC dose reduction are underdosed in an attempt to reduce the risk of bleeding or other complications from anticoagulation, despite being a group at higher risk of complications from atrial fibrillation, Granger's group noted.

"These results also suggest that it is inappropriate, and even dangerous, to reduce DOAC dose with kidney dysfunction unless the patient meets prespecified criteria for dose reduction; doing so may result in a higher incidence of stroke and death without providing any safety benefit in terms of bleeding or ICH [intracerebral hemorrhage]," the authors added.

That's in harmony with a prior, smaller secondary analysis of the ARISTOTLE trial of patients who received warfarin or standard-dose apixaban (Eliquis) and had one versus no criteria (weight, age, or kidney function) for dose reduction, which was triggered once two criteria were met.

"Taken together with our findings, these results strongly suggest that there is no role for dose reduction in patients who do not meet criteria," Granger and colleagues emphasized.

While all DOACs are cleared renally to some extent, the proportion ranges from 27% for apixaban to 80% with dabigatran (Pradaxa). Recommended CrCl thresholds for use in stroke prevention in AF follows suit:

• For dabigatran, CrCl >30 mL/min (reduced dose for CrCl 15–30 mL/min)
• For edoxaban (Savaysa) and rivaroxaban (Xarelto), CrCl >50 mL/min (dose reduction for CrCl 15–50 mL/min)
• For apixaban, CrCl >25 mL/min (dose adjustment when meeting two or more criteria for older age, lower weight, or poor kidney function)

Granger and colleagues' analysis encompassed data from the COMBINE AF, a database with individual patient data from the RE-LY, ROCKET AF, ARISTOTLE, and ENGAGE AF-TIMI 48 trials. Those trials allowed patients with CrCl as low as 25 to 30 mL/min.

The network meta-analysis included 71,683 patients (mean age 70.6 years, 37% female) with a median follow-up of 23.1 months and a mean CrCl of 75.5 mL/min. Among them, 24,396 patients had a CrCl under 60 mL/min and 28,891 had a CrCl of 60-89 mL/min. Participants were classified according to the drug and dose randomly assigned, not the dose delivered due to due to individual clinical characteristics like age or weight. CrCl was analyzed as a continuous variable rather than categorically.

Limitations included reliance solely on baseline CrCl, without accounting for changes over time, and the relatively few events at the lowest values (<25 mL/min) of CrCl.

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