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When well-managed, warfarin (Coumadin) therapy is still a valid alternative for preventing stroke associated with atrial fibrillation (afib), with a low risk of complications and all-cause mortality, researchers said.

Findings from a retrospective Swedish cohort study showed that the annual incidence of , Fredrik Björck, MD, of Umeå University in Sundsvall, Sweden, and colleagues reported online in JAMA Cardiology.

The annual incidence of intracranial bleeding was 0.44%.

Warfarin therapy should be closely monitored for patients with renal failure, concomitant aspirin use, and poor international normalized ratio (INR) control, the investigators added.

"Patients receiving concomitant aspirin had higher bleeding and thromboembolic rates, and patients with individual times in a therapeutic range (iTTRs) of less than 70% or high INR variability had an increased rate of complications," they wrote. "The iTTR is a strong indicator of probability for both bleeding and thromboembolic events and should be maintained at 70% or greater."

In an accompanying editorial, , and , both of Duke Clinical Research Institute in Durham, N.C., cautioned that clinicians should not use these findings to guide their treatment decisions.

"The analysis of outcomes in a retrospective cohort with well-controlled warfarin cannot inform treatment decisions that are made without knowledge of the future," Alexander and Thomas wrote, noting that Sweden has a in patients with afib.

"The real danger is that physicians and patients will use these findings to guide treatment decisions among warfarin-experienced or, worse, warfarin-naive patients. It would be easy to inappropriately extrapolate these data because the results are consistent with the expectation that INR control matters and because other sources of information related to INR control (i.e., historic measurements or center-level INR control) are commonly available."

There are a number of reasons why this analysis can't be used to determine prognosis for patients with afib or to determine which anticoagulation strategy would be best, they said.

Because patients with better INR control are generally a lower-risk group than patients with poor INR control, the association between INR control and outcomes may not be causal. This can't be assessed without a non-vitamin K oral anticoagulant (NOAC) comparator group, the editorialists pointed out.

On the other hand, even if the association were entirely causal, it couldn't be prognostic. "It requires information that can only be known after the outcomes themselves are known," they said.

"The observation likely involves a self-fulfilling prophecy," they explained. Since the cohort was defined retrospectively, "periods of good INR control during follow-up are more likely in the absence of procedures, interruptions, and clinical events."

What might be generalizable from this study are the findings that renal dysfunction and concomitant antiplatelet therapy are associated with worse outcomes in anticoagulated patients with afib, said the editorialists.

These findings replicated of randomized comparisons of event rates among patients receiving NOACs and warfarin, they pointed out.

"Perhaps the most attractive finding [from this study] is that patients with consistently well-controlled warfarin have very low rates of subsequent complications or death," Alexander and Thomas added.

The multicenter study was carried out between Jan. 1, 2006, and Dec. 31, 2011, using data from Swedish national registries, especially AuriculA, a quality register for afib and oral anticoagulation. A total of 40,449 patients were included, 40.0% of whom were female. Mean age was 72.5 years.

The mean CHA₂DS₂-VASc (cardiac failure or dysfunction, hypertension, age ≥75 years [doubled], diabetes mellitus, stroke [doubled]–vascular disease, age 65-74 years, and sex category [female]) score was 3.3 at baseline, the investigators reported.

Patients receiving concomitant aspirin had annual rates of any major bleeding of 3.07% and thromboembolism of 4.90%, the study showed. In addition, patients with renal failure were at higher risk of intracranial bleeding (hazard ratio 2.25; 95% confidence interval 1.32-3.82).

After adjustments, the additional risk for bleeding associated with aspirin was 36% for any major bleeding, 59% for gastrointestinal tract bleeding, and 33% for other major bleeding, the researchers said.

Annual rates of any major bleeding and any thromboembolism in iTTR less than 70% were 3.81% and 4.41%, respectively, and, in high INR variability, were 3.04% and 3.48%, respectively. For patients with iTTR 70% or greater, event rates weren't altered by the level of INR variability.