An increased risk of stroke has been observed in two atrial fibrillation (AF) trials of oral factor Xa inhibitors, when patients were transitioned to open label warfarin at the end of the study.
This nested case–control study examined whether initiation of warfarin is linked to an increased risk of stroke in patients with AF using data from the UK Clinical Practice Research Datalink (CPRD). The cohort consisted of 70,766 patients with AF between 1993 and 2008. Stroke cases were matched with up to 10 controls. Overall, 5519 patients experienced a stroke during follow-up. Warfarin was associated with an increased risk of stroke in the first 30 days of use (rate ratio: 1.71, 95% CI: 1.39–2.12), while decreased risks were observed with initiation >30 days before the event (31–90 days: RR: 0.50, 95% CI: 0.34–0.75 and >90 days: RR: 0.55, 95% CI: 0.50–0.61, respectively).
The researchers conclude that the findings of this large population-based study suggest that the initiation of warfarin is associated with an increased risk of ischaemic stroke; and these results corroborate with those observed in post hoc analyses of two large trials of novel oral anticoagulants.
However they note various limitations to their study:
• The drug information in the CPRD represents written prescriptions, thus it is unknown whether these prescriptions were actually dispensed and used by the patient. As a result, it is possible that some unexposed patients were misclassified as exposed which would have biased the estimates.
• Stroke events may be underreported in the CPRD, which would lead to an underestimation of the treatment effects.
• Because of the observational nature of the study, confounding by indication needs to be considered,in particular, the baseline stroke risk may be higher among treated compared with non-treated patients.
• The initial increased risk observed may have been due to inadequate warfarin control, and thus it would have been informative to correlate INR fluctuations with outcome during each exposure time period. However, this was not possible because INRs are not consistently recorded in the CPRD.
They add that while the findings support the biological plausibility of warfarin in inducing a transient hypercoagulable state at the start of the treatment, additional well conducted studies are needed to confirm these findings and determine whether a heparin bridging strategy at the initial phase of the treatment reduces this risk.