More Strokes, Bleeding in AF Patients With Renal Disease

Pauline Anderson

August 15, 2012

August 15, 2012 — Chronic kidney disease (CKD) raises the risk for both stroke and bleeding in patients with atrial fibrillation (AF), a new study confirms. The research also shows that warfarin reduces the risk for stroke but increases the bleeding risk in this patient population, and aspirin increases bleeding without reducing the risk for stroke.

It is clear that aspirin should not be used in AF patients with renal disease, but additional study is needed to further weigh the risks versus benefits of using warfarin, lead author Jonas Bjerring Olesen, MD, research fellow from the Department of Cardiology, Copenhagen University Hospital, in Hellerup, Denmark, told Medscape Medical News.

Dr. Jonas Bjerring Olesen

These patients, who are at increased risk for both stroke and bleeding, represent "a very fragile patient group" that needs "very close monitoring," Dr. Olesen added.

The study is published in the August 16 issue of the New England Journal of Medicine.

Renal Disease

Patients with AF are treated with antithrombotic therapy to reduce the risk for stroke and systemic thromboembolism, the researchers point out, but some studies have suggested that warfarin might actually increase stroke risk for those AF patients on dialysis, and that bleeding risk associated with warfarin treatment is elevated in those with CKD.

"Despite the size of this patient group, large randomized trials of antithrombotic therapy in patients with atrial fibrillation have typically excluded those who also have moderate to severe chronic kidney disease, and the treatment of these patients has been based on data obtained from smaller observational studies," they write.

This new Danish cohort study included 132,372 patients discharged from the hospital with a diagnosis of nonvalvular AF from 1997 to 2008. Researchers linked several national registries to gather information on renal status and pharmacologic treatments, and estimated the risks for stroke, systemic thromboembolism, and bleeding, including gastrointestinal, intracranial, urinary tract, and airway bleeding.

At baseline, 96.6% of the study population had no renal disease, 2.7% had non–end-stage CKD, and 0.7% required renal replacement therapy. Of those who had no renal disease initially, 3.5% developed non–end-stage CKD after a median of 893 days, and renal replacement therapy was required in 0.4%.

Study outcomes included hospitalization or death from stroke or systemic thromboembolism, bleeding, myocardial infarction (MI), and death from any cause.

Results showed that compared with patients without renal disease, the risk for stroke or systemic thromboembolism was increased among both patients with non–end-stage CKD and those requiring renal replacement therapy.

Table. Risk for Stroke and Systemic Thromboembolism With CKD vs No CKD

Group Hazard Ratio 95% Confidence Interval P Value
Non–end-stage CKD 1.49 1.38 - 1.59 < .001
CKD requiring RR therapy 1.83 1.57 - 2.14 < .001

CKD, chronic kidney disease; RR, renal replacement.

The risk for MI and death from any cause was also increased among patients with AF and CKD compared with those who had no renal disease.

Treatment Effects

An analysis of treatment effects showed that warfarin decreased the risk for stroke or systemic thromboembolism in the overall study population and among patients with any renal disease compared with those with no renal disease.

Aspirin, however, was associated with increased risk for stroke or systemic thromboembolism overall, and among patients who had any renal disease compared with those with no renal disease.

Although warfarin therapy was associated with a significant reduction in the risk for stroke or thromboembolism, the risk of bleeding among the patient population taking this therapy was significantly increased. Bleeding risk in these patients was also increased for aspirin and for warfarin plus aspirin.

Table. Efficacy and Bleeding Risk by Treatment in CKD vs No CKD

Comparison Hazard Ratio 95% Confidence Interval P Value
Stroke or systemic thromboembolism 0.76 0.64 - 0.91 .003
Bleeding 1.33 1.16 - 1.53 < .001
Stroke or systemic thromboembolism 1.17 1.01 - 1.35 .04
Bleeding 1.17 1.02 - 1.34 .03
Warfarin Plus Aspirin
Bleeding 1.61 1.32 - 1.96 < .001

CKD, chronic kidney disease.

"Thus, the net clinical effect of warfarin treatment requires careful assessment in patients with chronic kidney disease, and the data do not provide clear guidance regarding indications for anticoagulant therapy in patients with both atrial fibrillation and chronic kidney disease," noted the authors.

Currently, renal disease is viewed as a bleeding risk factor but not a stroke risk factor, said Dr. Olesen. He noted that renal disease is included in the HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile International Normalized Ratio [INR], Elderly, Drugs/Alcohol) score, which is a tool that is used to assess bleeding risk in AF patients, but is not included in scores typically used to estimate stroke risk in these patients, for example, the CHAD2 score.

"Perhaps we should start including renal disease or chronic kidney disease as a risk factor for stroke in these patients," said Dr. Olesen.

The number of patients with both AF and renal disease is increasing because of the aging population and improved survival rates in both diseases, said Dr. Olesen. A clinical trial is needed to determine whether the positive effects of warfarin on stroke outweigh the risk of bleeding in these patients, he added.

Risks vs Benefits

Asked to comment on the study, Brian Silver, MD, director of the Stroke Center, and associate professor of neurology at Alpert Medical School, Brown University, in Providence, Rhode Island, said that it is clear from the article that aspirin is not beneficial in AF patients with kidney disease, but that warfarin might be used with caution.

"It sounds like aspirin doesn't confer an advantage in these folks because aspirin doesn't seem to reduce thromboembolic risk but does raise bleeding risk, so you're getting net harm with no benefit," said Dr. Silver.

The issue of using anticoagulant medication in this population is less clear, he said.

"The risk of bleeding was raised by about a third, and the risk of thromboembolic disease — primary stroke — was reduced by about a quarter, so if you just use purely numerical comparisons, you would say that the risks outweigh the benefits, so we shouldn't use warfarin in these cases," he said. "However, with someone having a bleeding complication, which is certainly serious, the long-term disability related to that may not be the same as having, say, a major stroke."

Dr. Silver pointed out that it is unclear from the study how serious the stroke and bleeding events were. However, Dr. Olesen notes that supplementary data showed that 40% of strokes and systemic thromboembolisms were fatal, but only 14% of bleeding events were fatal. "Although we haven't examined this specific topic in this population, there's a clear indication that the strokes are more severe than the bleeding events," he said.

After reading the article, Dr. Silver said he will likely use warfarin in AF patients with renal disease but will be mindful of the fact that they face an elevated bleeding risk. "It means that I and others will have to be extra vigilant about controlling their INR."

Dr. Silver agreed that the role of warfarin and of newer similar agents should be evaluated in a clinical trial that includes patients with CKD.

This study was supported by the Lundbeck Foundation. Dr. Olesen has disclosed that he received travel support from AstraZeneca and Boehringer Ingelheim on behalf of his institution. For complete disclosure details, see the journal Web site. Dr. Silver has disclosed no relevant financial relationships.

N Engl J Med. 2012;367:625-635.


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