Apixaban for AF in End-Stage Renal Disease: Fewer Strokes, Major Bleeds vs Warfarin

July 31, 2018

Treatment with apixaban (Eliquis, Bristol-Myers Squibb/Pfizer), regardless of dosage, was associated with significantly less major bleeding compared with warfarin in a particularly high-risk population with nonvalvular atrial fibrillation (AF), those with end-stage renal disease (ESRD), in an analysis based on Medicare data.

The risk for thromboembolic events or death was also significantly reduced for apixaban at the standard 5-mg, twice-daily dosage, but not at the lower 2.5-mg, twice-daily dosage.

Patients with ESRD had typically been excluded from the large trials of anticoagulation in AF that established direct oral anticoagulants (DOACs) in clinical practice. Among those agents, apixaban is generally favored when renal function is poor because it is less reliant on the kidneys for clearance, explained Konstantinos C. Siontis, MD, Mayo Clinic, Rochester, Minnesota, to the theheart.org | Medscape Cardiology. That's based largely on pharmacokinetic data rather than trial results, he cautioned.

Despite residual confounding in the current observational analysis, "I think this is the best data we have so far" in patients with AF and ESRD, said Siontis, who is lead author on the report, published July 24 in Circulation.

"Until we have randomized, controlled trial data, I think it's somewhat reassuring to know that apixaban is not a culprit for more bleeding in these patients, and it might seem like a reasonable agent to use in this population," he said.

The lack of difference between the 5-mg and 2.5-mg twice-daily dosages in terms of major bleeding "I think speaks to the overall high bleeding risk in these patients, that the addition of apixaban may not impact to a very significant degree no matter what dose we use."

This is speculation, Siontis acknowledged, as is the possibility — because the risk for major bleeding is similar at the two dosages — that the 5-mg twice-daily dosage with its superior thromboembolic protection can be preferred in patients with ESRD.

The group retrospectively looked at Medicare data from 2010 to 2015 for 25,523 patients, 45.7% of whom were women, who had been diagnosed with nonvalvular AF within a year before receiving a prescription for apixaban (2351 patients) or warfarin (23,172 patients). Those prescribed other DOACs were few and so were excluded from the study.

After patients were matched by prognostic score, one apixaban patient for every three taking warfarin (2351 and 7053 patients, respectively), no significant hazard ratio (HR) reduction was seen for patients receiving the DOAC vs warfarin for the endpoint of stroke or systemic embolism. But the  risk for major bleeding decreased significantly:

  • Stroke or systemic embolism: HR, 0.88 (95% confidence interval [CI], 0.69 - 1.12; P = .29);

  • Major bleeding: HR, 0.72 (95% CI, 0.59 - 0.87; P < .001).

There was no significant risk difference for intracranial hemorrhage, although apixaban showed a trend toward a reduced mortality benefit (HR, 0.85; 95% CI, 0.71 - 1.01; P = .06).

A secondary analysis with multivariate adjustment on the entire cohort produced similar results, the group reports: no significant risk reduction for the composite and individual clinical endpoints, except for major bleeding: HR, 0.68 (95% CI, 0.57 - 0.81), although the P value for interaction was nonsignificant at .67.

In prespecified sensitivity analyses, HRs for stroke or systemic embolism (P = .04), death (P = .003), and major bleeding (P = .02) were significantly reduced for patients prescribed the standard 5-mg twice-daily apixaban dosage compared with those prescribed warfarin.

And, for the higher vs lower apixaban dosage, both stroke or systemic embolism (P = .04) and death (P = .01) were significantly reduced but major bleeding (P = .93) was not.

Table. Outcomes HRs Comparing Standard (5 mg) and Reduced (2.5 mg) Twice-Daily Apixaban Dosages and Warfarin

Endpoints HR (95% Confidence Interval)
5.0 mg vs Warfarin 5.0 mg vs 2.5 mg 2.5 mg vs Warfarin
Stroke or systemic embolism 0.64 (0.42 - 0.97) 0.61 (0.37 - 0.98) 1.11 (0.82 - 1.50)
Death 0.63 (0.46 - 0.85) 0.64 (0.45 - 0.92) 1.07 (0.87 - 1.33)
Major bleeding 0.71 (0.53 - 0.95) 0.98 (0.68 - 1.42) 0.71 (0.56 - 0.91)


Also in the prognosis-matched analysis, HRs were not significantly reduced with 2.5-mg twice-daily apixaban vs warfarin for stroke or systemic embolism (P =.49) or for death (P = .52). But there was a reduced HR for major bleeding (P = .007).

Forthcoming data from a randomized trial could potentially inform guidelines on how to anticoagulate patients with AF and severe renal disease. The ongoing Renal Hemodialysis Patients Allocated Apixaban Versus Warfarin in Atrial Fibrillation (RENAL-AF) trial is expected to enroll more than 700 patients with AF who are undergoing dialysis.

The trial is randomly assigning patients to apixaban at 5 mg twice daily (or 2.5 mg twice daily in selected cases) or warfarin. The primary endpoint is major or clinically relevant nonmajor bleeding over 15 months.

But RENAL-AF does not have a placebo control group. Siontis pointed out that many patients in the current analysis so poorly tolerated oral anticoagulation that they went off apixaban or warfarin during the study period.

Indeed, "About two thirds of patients in each group were no longer taking the anticoagulant 12 months after the initial prescription," he and his colleagues write.

"It's a little controversial whether patients on dialysis with AFib should be anticoagulated at all," Siontis said. "It's something to keep in mind, even though we find that apixaban is potentially safer and equally effective or better than warfarin in these patients, the question still remains, Is apixaban better than nothing?"

Siontis and colleagues report no relevant disclosures.

Circulation. Published online June 28, 2018. Abstract

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