Patients more vulnerable in first 30 days on warfarin

Patients with atrial fibrillation who initiate warfarin therapy may have a two-fold risk of ischemic stroke in the first 30 days of use compared with nonusers, according to a study published online Dec. 18 in the European Heart Journal.

Post-hoc analyses of the clinical trials ROCKET-AF and ARISTOTLE, which compared novel oral anticoagulants with warfarin to prevent thromboembolism in patients with atrial fibrillation, found increased risk of ischemic stroke or systemic embolism in the first 30 days when the warfarin groups were transitioned to warfarin. But the short bridging time in the trials may not have been sufficient to achieve adequate anticoagulation, wrote lead author Laurent Azoulay, MD, of Jewish General Hospital in Montreal, and colleagues.

They designed a population-based study using the Clinical Practice Research Datalink database in the U.K. to assess the association between warfarin initiation and an increased risk of ischemic stroke. The study included 70,766 adult patients newly diagnosed with atrial fibrillation between 1993 and 2008 with a mean follow-up of 3.9 years. The overall ischemic stroke rate was 2 percent annually.

They did a nested case-control analysis, with cases consisting of patients who had ischemic stroke during follow-up. Compared with nonusers, warfarin users had a 71 percent increased risk of ischemic stroke during the first 30 days of initiation of the therapy. The risk was highest in the first week. After 30 days, the risk decreased significantly.

“The paradoxical procoagulant effect of warfarin observed in the early days of the treatment is biologically plausible,” Azoulay et al wrote. “While warfarin blocks the activation of clotting factors II, VII, IX, and X, it also deactivates protein C and protein S, two endogenous anticoagulants. Protein C has a short half-life (8 h), and thus rapid depletion of this protein can theoretically lead to a transient hypercoagulable state.”

In a release, Azoulay emphasized that physicians should continue prescribing warfarin but they should be vigilant during the initiation period. He called for studies to identify the subset of patients who are at risk.

The authors also recommended more research be done to confirm their findings and investigate whether a bridging strategy using heparin in the initial treatment period reduces risk.

Their study was observational and may be biased by confounding. The database included information about written prescriptions but it did not gauge adherence and it did not include information about international normalized ratio with warfarin use.