Anticoagulant also failed to protect against ischemic stroke or improve mortality

The use of warfarin in patients with end-stage-renal disease (ESRD) and atrial fibrillation (AF) did not prevent ischemic stroke nor did it favorably affect mortality, a systemic review and meta-analysis of the observational literature has shown.

Moreover, the use of warfarin to prevent strokes in the same patient population actually increased the risk of hemorrhagic stroke even though somewhat paradoxically, it did not increase the risk of any other major bleeding event, the same analysis indicated.

“[P]atients with end-stage renal disease (ESRD) are at higher risk of ischemic stroke and bleeding events [and they] also have a higher incidence of AF compared with the general population,” Mandeep Randhawa, MD, Michigan State University, Kalamazoo, Michigan and colleagues observed in JAMA Network Open.

“Available data show that warfarin use is not associated with any benefit in the prevention of ischemic stroke—[i]nstead, it is associated with a significant increase in the risk of hemorrhagic stroke , no significant difference in the risk of major bleeding, and no association with overall mortality,” investigators concluded.

For the review and meta-analysis, 15 studies consisting of 47,480 patients with ESRD and AF were analyzed.

Some 22% of the entire cohort had been prescribed warfarin, as investigators observed.

The mean follow-up was 2.6 years.

In studies of ischemic stroke, 23% of 43,231 patients were receiving warfarin and among them, 7.7% had an ischemic stroke compared with 7.1% of patients who were not receiving warfarin, for a Hazard Ratio (HR) of 0.96 (95% CI, 0.82-1.13)—”indicating no benefit of using warfarin for patients with ESRD and AF in preventing ischemic strokes,” as the authors emphasized.

Among 32,342 patients in studies of hemorrhagic stroke, 22.1% were receiving warfarin

In this cohort of patients, the incidence of hemorrhagic stroke at 2.4% was 54% higher for patients who took warfarin compared to 1.9% for those who did not, at a HR of 1.46 (95% CI, 1.05-2.04), investigators noted.

A total of 27,251 patients were involved in studies assessing major bleeding events, among whom 21.1% were taking warfarin.

In this group, 16.1% of patients on the anticoagulant had a major bleeding event compared with 15% of patients not on anticoagulation, for a HR of 1.20 (95% CI, 0.99-1.47)—indicating there was no association of warfarin use with major bleeding events, as Randhawa and colleagues pointed out.

Lastly, among 29,623 patients involved in mortality studies—20.6% of whom were taking warfarin—the death rate was 43.4% for patients receiving anticoagulation compared to 52.5% of those who were not, for a HR of 0.95 (95% CI, 0.83-1.09).

“[Again, t]his suggests that overall mortality does not seem to be associated with anticoagulation for these patients,” researchers observed.

Inconsistent Guidelines

As the authors point out, the fact that there have been no randomized trials evaluating the role of anticoagulation in patients with ESRD and AF has led to certain inconsistencies in guidelines governing the use of anticoagulation in this patient population.

For example, both the American Heart Association and the American College of Cardiology recommend the use of anticoagulation in patients with ESRD and AF while the European Cardiovascular Society underscores the fact that there is no evidence upon which to base such a recommendation.

The Kidney Disease: Improving Global Outcomes guidelines actually recommends against the use of warfarin in ESRD patients with AF.

Instead of standard anticoagulation, the authors suggested that left atrial appendage occlusion (LAAO) devices such as the WATCHMAN device might be a “promising alternative” for patients with ESRD and AF.

Results from the Percutaneous Left Atrial Appendage Closure for Stroke Prophylaxis in Patients with Atrial Fibrillation (PROTECT AF) found that the WATCHMAN device was noninferior to systemic anticoagulation with warfarin, reducing mortality and stroke in patients with AF although not ESRD.

The authors cautioned that the evidence available regarding the use of warfarin for ischemic stroke prevention in ESRD patients with AF is “observational” and “conflicting” with no data from randomized clinical trials available to date.

Thus, limitations of the study include the design which is retrospective and observational in nature.

Commenting on the findings, Emille Belley-Cote, MD, PhD, and John Eikelboom, MBBS, both from McMaster University in Hamilton, Ontario, pointed out that randomized trials of patients with AF but not ESRD have repeatedly demonstrated that warfarin is highly effective, reducing stroke risk by about two-thirds and mortality by about one-fourth compared to patients who do not receive anticoagulation.

On the other hand, “[w]e believe that the signal of net harm in the updated meta-analysis by Randhawa et al should dampen enthusiasm for the use of warfarin among patients with AF and ESRD,” they wrote.

The editorialists also pointed to the high rates of major bleeding at approximately 15% uncovered in the same analysis.

“Even in the absence of warfarin therapy, [major bleeding rates] were double those of ischemic stroke and mortality rates of 40% to 50% during a mean of 2.6 years of follow-up,” Belley-Cote and Eikelboom pointed out.

“These data underscore the need for new approaches to reduce the burden of morbidity and mortality among patients with AF and ESRD,” they suggested.

One increasingly popular approach favored in the United States is to use apixaban for stroke prevention in patients with ESRD and AF.

However, evidence supporting this strategy is apparently of poor quality, as the editorialists noted.

A second approach may well be to use a LAAO device, as the authors themselves suggested.

While these devices have not been randomly evaluated in patients with ESRD and AF, “they appear to be noninferior to anticoagulation in patients with AF without ESRD who have a contraindication to long-term anticoagulation,” Belley-Cote and Eikelboom stated, adding that while the decision to withhold anticoagulation or to use a LAOO device in patients with ESRD and AF must be based on clinical judgment, physicians also need to remember the time-honored adage: “primum non nocere,” they cautioned.

  1. Warfarin did not prevent ischemic stroke in end-stage renal disease patients with atrial fibrillation.

  2. The risk of hemorrhagic stroke was significantly higher in end-stage renal disease patients with atrial fibrillation receiving warfarin compared to those patients who did not receive anticoagulation.

Pam Harrison, Contributing Writer, BreakingMED™

Randhawa had no conflicts of interest to declare although several of his co-investigators did which are listed in the publication.

Belley-Cote reported receiving no grants or honoraria from industry.

Eikelboom reports receiving honoraria and grant support from AstraZeneca, Bayer, Boehringer ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi-Sakyo, Eli Lilly, GlaxoSmithKline, Janssen, Sanofi-Aventis and Servier.

Cat ID: 127

Topic ID: 81,127,730,913,914,127,192

References

Randhawa MS, et al “Association between use of warfarin for atrial fibrillation and outcomes among patients with end-stage renal disease: A systematic review and meta-analysis.” JAMA Network Open 2020; 3(4): e202175

Belley-Cote EP, Eikelboom JW “Anticoagulation for stroke prevention in patients with atrial fibrillation and end-stage renal disease—First, do no harm” JAMA Network Open 2020; 3(4):e202237