Good Warfarin Management Prevents Complications in A-fib Patients, Swedish Study Contends

In recent years a new crop of anticoagulants has sprung up, offering patients alternatives that require less monitoring and a lower risk of complications than the old standby, warfarin. But new findings from Sweden suggest that with vigilant control, the cheaper agent can be used successfully, resulting in longer time in therapeutic range and low annual rates of bleeding and death. 

Using data from a Swedish registry, Fredrik Björck, MD (Umea University, Umea, Sweden), and colleagues examined outcomes in 40,449 A-fib patients who were started on warfarin therapy and monitored. All documentation regarding patients’ warfarin therapy is tracked and updated every 24 hours by the registry, which also offers a clinical-decision tool that uses an algorithm to aid in determining warfarin dosage. If certain criteria are met, the algorithm can give a dose suggestion that can be accepted or manually changed.

The researchers found low annual rates of all-cause mortality (2.19%) and intracranial bleeding (0.44%) in the overall population. Complications were higher in those taking concomitant aspirin (any major bleeding 3.07%, thromboembolism 4.90%) and in those with renal failure, in whom the risk of intracranial bleeding was more than doubled. Results remained consistent after adjustment for age, sex, and other risk factors.

“The strongest indicator of the probability for intracranial bleeding in our study was renal failure, which is a well-known risk factor for bleeding events in general but, to our knowledge, has not previously been linked to intracranial bleeding during oral anticoagulation therapy,” Björck and colleagues write.

Patients taking aspirin also had a 59% higher risk of gastrointestinal tract bleeds compared with patients taking no additional antiplatelet therapy.

Poor warfarin control (defined as time in therapeutic range < 70%) and a high degree of variability in international normalized ratio (INR) also contributed to higher annual rates of any major bleeding and any thromboembolism.

A ‘Valid Alternative’

For patients in the study who had a history of prior stroke, the risk of intracranial bleeding was 58% higher than for those with no prior stroke, and for patients with hypertension, intracranial bleeding risk was 37% higher than in those without hypertension. Additionally, the risk of intracranial bleeding increased with increasing age and was lower in women than in men.

According to the study authors, global, randomized trials such as ARISTOTLE, RE-LY, ENGAGE AF-TIMI 48, and ROCKET AF that have compared warfarin with the newer non-vitamin K antagonist oral anticoagulants (NOACs) have demonstrated time in the therapeutic range for warfarin of 55.2% to 64.9%, compared with a mean of 68.6% in the current analysis. They also note that the annual incidence of both all-cause mortality and intracranial bleeding in warfarin-treated patients is lower in the current study than in those global NOAC trials, providing support for the idea that carefully managed warfarin therapy “is a valid alternative in patients with [A-fib] who require anticoagulant treatments.”

A limitation of Björck and colleagues’ study is the all-Swedish cohort, consisting of mostly white European patients in a high-income country, making extrapolation of the findings to  low-income countries or other ethnic groups difficult. 

In an email, Björck said the national quality registry used in the study, known as AuriculA, is an important tool for clinicians in Sweden and “includes and displays all INR values and previous warfarin dosages, making future dosages easier.” Additionally, he said the computerized algorithm helps clinicians better control INR because “the suggestion from the algorithm is often better than the clinicians’ manually performed suggestions.”

Generalizability and Differences

Another issue when considering how generalizable the results are to patients outside of Sweden, say John H. Alexander, MD, and Laine E. Thomas, PhD (Duke Clinical Research Institute, Durham, NC), in an accompanying editorial, is that Sweden has historically had the best INR control in the world.

Björck concurred, telling TCTMD: “In Sweden there is a longstanding tradition in warfarin treatment, with well-organized anticoagulation clinics and primary healthcare centers, including trained nurses.”

Still, Alexander and Thomas say some aspects of the study are useful, including the findings that renal dysfunction and concomitant antiplatelet therapy are associated with worse outcomes in anticoagulated A-fib patients, confirming data from prior analyses.

“These important subgroups do help inform treatment decisions, particularly given the randomized comparisons of event rates among patients receiving NOACs and warfarin,” they write. “Perhaps the most attractive finding is that patients with consistently well-controlled warfarin have very low rates of subsequent complications or death.”

But, Alexander and Thomas say, it is unlikely that the association between warfarin control and outcomes is entirely causal, since it has been demonstrated in studies such as RE-LY, ARISTOTLE and ROCKET AF that patients with better INR control are different and generally lower risk in comparison to those with worse INR control. Furthermore, features related to good INR control, including adherence, lack of interruptions, and better health care, might also contribute to good outcomes with NOACs, leaving open the question of whether patients with better INR control might also be expected to have better outcomes with NOACs, they say.

To TCTMD, Björck noted that the study was not designed to answer that question and that further studies are needed, preferably with long-term follow-up. He concluded that well-controlled warfarin therapy “might be one of the keys in achieving high long-term adherence” to warfarin, but achieving similarly high levels of adherence with the various NOACs is still challenging.

• Björck F, Renlund H, Lip GYH, et al. Outcomes in a warfarin-treated population with atrial fibrillation. JAMA Cardiol. 2016;Epub ahead of print. 
• Alexander JH, Thomas LE. Using data to guide anticoagulation in patients with atrial fibrillation: does the analysis fit the question? JAMA Cardiol. 2016;Epub ahead of print. 

Disclosures:

• Björck reports no relevant conflicts of interest. 
• 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. 

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