'Well-Managed Warfarin' Good Enough in Atrial Fib: Analysis

Marlene Busko

April 22, 2016

SUNDSVALL, SWEDEN — Low rates of intracranial bleeding and other complications and low all-cause mortality were observed over 9 years of follow-up in a large registry study from Sweden looking at patients with atrial fibrillation who overall had well-managed anticoagulation with warfarin[1]. It also pointed to some risk factors for such complications, including renal failure and concomitant aspirin use.

"Well-managed warfarin therapy is associated with a low risk of complications and is still a valid alternative for prophylaxis of AF-associated stroke. Therapy should be closely monitored for patients with renal failure, concomitant aspirin use, and poor [international normalized ratio] INR control," Dr Fredrik Björck (Umeå University, Sundsvall, Sweden) and colleagues summarize in a report published April 20, 2016 in JAMA Cardiology.

Historically, observes an accompanying editorial[2], "among patients with AF, Sweden has some of the best INR control in the world," so these results may not be generalizable. Moreover, the study does not provide insight into which patients with well-managed warfarin therapy would have better outcomes with the novel oral anticoagulants (NOACs) than with warfarin.

"Features related to good INR control, such as adherence, lack of interruptions, and better healthcare, might also contribute to good outcomes with NOACs," according to editorialists Drs John H Alexander and Laine E Thomas (Duke Clinical Research Institute, Durham, NC).

In Sweden, Björck told heartwire from Medscape, "warfarin is still a valid option, along with NOACs," for patients with AF. The analysis was not designed to compare outcomes with a NOAC vs well-controlled warfarin therapy, but he agreed with the idea that adherence and other factors related to good INR control "might enhance outcomes for NOACs as well."

Finding the Right Fit?

Of note, the mean time in therapeutic range (TTR) in the registry analysis was 68.6%. That compares with 53.7% in the United States in a 2014 report[2], according to Dr Xiaoxi Yao (Mayo Clinic, Rochester, MN), speaking with heartwire .

Yao, who is not associated with the current study, agreed that factors that promoted good INR control in the Swedish cohort could well do the same for NOACs. And warfarin has well-recognized downsides, she noted. "Warfarin requires regular INR testing, dose adjustments and  has numerous interactions with food and other drugs and adherence is notoriously poor," she said.

"This study underscores the importance of closely monitoring patients with suboptimal warfarin control and those on concomitant treatment of antiplatelet or aspirin," according to Yao.

"It has long been known that European national health systems do a better job with warfarin than we do," said Dr Joseph Alpert (University of Arizona College of Medicine, Tucson), also not involved in the Swedish registry analysis. A warfarin TTR of 55% is considered good in the US, he said in an interview.

"In a national healthcare system, it is likely that patients get better follow-up than in a patchwork-quilt system like in the US," he said. Still, "our patients who do very well chronically on warfarin and are stable can remain on warfarin here as in Europe. Those whose INRs are unstable here in the US should be considered for one of the new anticoagulants."

Real-life Data, Good Safety Profile

To investigate outcomes of well-controlled warfarin therapy, the authors identified 40,449 patients receiving warfarin for nonvalvular AF and were enrolled in Swedish registries, notably the National Registry for Auricular Fibrillation and Anticoagulation (AURICULA), from 2006 to 2011, and had follow-up data until 2015.

More than half of the patients (60%) were men. Overall, the cohort had a mean age of 72 years and mean CHADS2 score of 2.1, similar to that in the NOAC trials, according to the authors.

The annual incidence of intracranial bleeding was 0.44%, which was lower than in the warfarin control groups in the pivotal NOAC trials (0.70%–0.85%) and close to the rate with NOACs (about 0.3%), according to the authors.

Similarly, the annual incidence of all-cause mortality was 2.2%, which is lower than in the warfarin- and NOAC-treated patients in the NOAC trials (3.9%–4.9% and 3.5%–4.5%, respectively).

Patients who received concomitant aspirin had higher annual rates of major bleeding (3.07%) and thromboembolism (4.90%). Patients with renal failure had a 2.25-fold higher risk of intracranial bleeding.

Patients who had an individual TTR below 70% also had higher annual rates of major bleeding (3.81%) and thromboembolism (4.41%), as did patients with high INR variability (3.04% and 3.48%, respectively).

Monitoring May Be "One of the Keys"

"The goal is to find an anticoagulant that fits for [a particular] patient," said Björck. "The need for monitoring in warfarin might be one of the keys in achieving high long-term adherence to treatment, which is crucial for outcome in AF and anticoagulants," he noted. "The question is, how to achieve high adherence with NOACs?"

Where warfarin monitoring is expected to be difficult (for example, a patient may have sporadic contact with the healthcare system or may have communication difficulties due to aphasia), a NOAC may be the drug of first choice, he said.

On the other hand, "our study shows that for patients achieving TTR over 70% and not being treated with additional acetylsalicylic acid, the probability of good outcome on further warfarin treatment is likely."

Björck has disclosed no relevant financial relationships; disclosures for the coauthors are listed in the article. Alexander reports institutional research grants from Boehringer Ingelheim, Bristol-Myers Squibb, CSL Behring, Pfizer, Sanofi, Regado Biosciences, Tenax, and Vivus and consulting fees/honoraria from Bristol-Myers Squibb, CSL Behring, Daiichi Sankyo, GlaxoSmithKline, Janssen, Pfizer, Portola, Sohmalution, and Xoma. Thomas reports institutional research grants from Bristol-Myers Squibb, Pfizer, and Janssen Scientific Affairs. Alpert is the editor in chief of the American Journal of Medicine and reports serving on the data safety and monitoring board for the ROCKET-AF and PIONEER studies, two trials involving rivaroxaban. Yao has disclosed no relevant financial relationships.

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