No Stroke Reduction but Increased Bleeding With OAC in Dialysis Patients

In patients with A-fib who are on chronic dialysis, oral anticoagulation with either warfarin or a direct oral anticoagulant (DOAC) does not reduce thromboembolic events, but—in general—increases major bleeding, according to a network meta-analysis.

Pooled observational data showed that neither apixaban (Eliquis; Bristol-Myers Squibb) nor warfarin lowered the risk of stroke/systemic thromboembolism compared with no anticoagulation, lead author Toshiki Kuno, MD, PhD (Icahn School of Medicine at Mount Sinai, Mount Sinai Beth Israel, New York, NY), and colleagues report.

Warfarin and two other DOACs—dabigatran (Pradaxa; Boehringer Ingelheim) and rivaroxaban (Xarelto; Bayer/Janssen)—had greater risks of major bleeding compared with either apixaban or no anticoagulation.

The study, published online ahead of the January 28, 2020, issue of the Journal of the American College of Cardiology, revealed few other differences between agents, with the exception of a lower risk of all-cause mortality with apixaban 5 mg twice daily versus warfarin, apixaban 2.5 mg twice daily, and no anticoagulation (HRs ranging from 0.61 to 0.65).

Speaking with TCTMD, Kuno said definitive conclusions cannot be drawn from the analysis, which was based entirely on observational data. “I think if you want to use anticoagulation, apixaban might be an option, but we cannot conclude it,” he said.

He stressed that it’s still not clear whether anticoagulation of any type is safe and beneficial in patients on dialysis, who have high risks of both thromboembolic events and major bleeding. Therefore, he added, “I think our study suggests that we need to do a randomized controlled trial of apixaban versus no anticoagulation.”

‘Navigating Through Darkness’

Patients on dialysis been excluded from the major trials that have established the benefits of oral anticoagulation—first with warfarin and then with the DOACs—for stroke prevention in the setting of A-fib. Thus, there is no standard of care when it comes to anticoagulating patients on dialysis, and comfort level among clinicians when it comes to using these agents in their patients with advanced kidney disease varies, according to Ron Wald, MDCM (St. Michael’s Hospital and the University of Toronto, Canada), who co-authored an editorial accompanying the study. Treating physicians are “navigating through darkness” when making anticoagulation decisions in their dialysis patients with A-fib, he told TCTMD.

Kuno and colleagues evaluated the evidence in this setting by performing a network meta-analysis incorporating data from 16 observational studies with a total of 71,877 patients who had A-fib and were on long-term dialysis. Only two of the studies involved the DOACs, and for dabigatran and rivaroxaban specifically, outcomes were restricted to major bleeding.

Compared with no anticoagulation, apixaban at either a 5-mg or 2.5-mg twice-daily dose and warfarin were not associated with a decreased risk of stroke/systemic thromboembolism, although there was significant heterogeneity in these analyses.

We simply don’t know what to do with these patients. Ron Wald

Warfarin carried greater major bleeding risks compared with apixaban 5 mg (HR 1.41; 95% CI 1.07-1.88), apixaban 2.5 mg (HR 1.40; 95% CI 1.07-1.82), and no anticoagulation (HR 1.31; 95% CI 1.15-1.50). Dabigatran and rivaroxaban were associated with more major bleeding compared with either dose of apixaban or no anticoagulation, with HRs ranging from 1.80 to 2.09. Dabigatran also came with more bleeding versus warfarin (HR 1.48; 95% CI 1.13-1.94).

 “Although these results should be interpreted cautiously because of high heterogeneity, warfarin, dabigatran, and rivaroxaban might not be preferred options because of their increased risk of bleeding in patients with atrial fibrillation on long-term dialysis,” Kuno et al write. “Further study is warranted to establish the benefit-to-risk ratio of oral anticoagulants in patients with atrial fibrillation on long-term dialysis.”

A Springboard for Future Research

Wald said that this network meta-analysis represents an important review of data that were available at the time the paper was written, but unfortunately, the strength of those data were not strong. “We simply don’t know what to do with these patients,” he said.

Due to the dearth of evidence regarding use of oral anticoagulation in patients with A-fib who are on dialysis, practice varies. Wald said, in general, that he feels comfortable using anticoagulation in the right patients, but that some of his colleagues are justifiably worried that the risks could outweigh the potential benefits.

This analysis does not really help sort out that uncertainty, Wald said, pointing to the inherent limitations of the included studies, none of which were randomized.

Asked about the signals of benefit with apixaban, including the lower risks of mortality and bleeding compared with other options, Wald noted that “apixaban is picking up steam in terms of its use and people’s comfort level with it, even in patients with advanced kidney disease, and that’s mainly because the FDA has approved it in patients at all levels of kidney function, rightly or wrongly.”

Beyond that, however, “we can’t comment on apixaban very much,” he said.

Like Kuno, Wald underscored that a more fundamental question than which anticoagulant to choose is whether the benefits outweigh the risks for any of them compared with no treatment. He pointed out that there are some trials exploring that question, including the SAFE-HD pilot trial from his group and the AVKDIAL trial in France.

This meta-analysis “should be a springboard for better research,” Wald said. “Readers who review the analysis should come away from it saying, ‘We really don’t know what we’re doing and we need better and bigger trials to answer this question.’ My hope is that the release of this meta-analysis will trigger clinicians to appreciate the poor evidence base in this area. By recognizing the fundamental equipoise that exists, clinicians should be inspired to enroll their patients, where feasible, in trials that are asking whether anticoagulation actually benefits patients on dialysis who have nonvalvular atrial fibrillation."