Effect of Initiation of Warfarin Therapy on the Risk of Ischemic Stroke

Study Methodology and Population

The study utilized the UK’s Clinical Practice Research Datalink (CPRD), which contains information on more than 12 million patients registered with 650 general practitioners. The study included 70,766 individuals over 18 years old who were diagnosed with atrial fibrillation between January 1, 1993, and December 31, 2008. Patients with paroxysmal atrial fibrillation, mitral or aortic valve replacement, and those treated for hyperthyroidism were excluded from the study.

The average age of the subjects was 74.1 years, and patients were followed for an average of 3.9 years. During the follow-up, 5,519 patients experienced an ischemic stroke. The remaining 55,022 individuals were included in the control group. The case and control groups, matched based on similar clinical characteristics, were compared regarding the incidence of stroke upon warfarin use, depending on the duration from the start of use and compared to stroke incidence without warfarin use. Other risk factors for cardiovascular complications (alcoholism, smoking, obesity, CHADS₂ score, peripheral artery disease, coronary heart disease, cancer, venous thrombosis, valvular diseases, and the use of ACE inhibitors, AT₁ receptor blockers, antidepressants, antipsychotics, nonsteroidal anti-inflammatory drugs, and statins) were also considered for each patient.

Results

A 71% increased risk of developing ischemic stroke was noted within 30 days after starting warfarin compared to no antithrombotic therapy, with the highest risk 3 days after therapy initiation (adjusted relative risk [RR] 2.33; 95% confidence interval [CI] 1.50–3.61). The association of stroke development with warfarin use was modulated by the history of ischemic stroke before the study recruitment.

In patients with a prior history of ischemic stroke, an increased risk was recorded during the first 30 days after starting warfarin (RR 2.45; 95% CI 1.72–3.49). There was no proven association between the 30th and 90th days of use (RR 0.96; 95% CI 0.49–1.86), and beyond 90 days of therapy, the risk was reduced (RR 0.54; 95% CI 0.43–0.68).

For patients without prior ischemic stroke, an increased risk was also demonstrated during the first 30 days after starting warfarin (RR 1.30; 95% CI 1.04–1.63), but with longer therapy, the risk was reduced (RR 0.43; 95% CI 0.27–0.68 for 30-90 days of use and RR 0.62; 95% CI 0.56–0.69 for > 90 days of use). 

Discussion

The study results suggest that the risk of developing ischemic stroke approximately doubles during the first 30 days of warfarin use. Warfarin inhibits not only coagulation factors II, VII, IX, and X but also proteins C and S. This inhibition could lead to a transient hypercoagulable state, potentially resulting in thromboembolic complications.

This study is the first large-scale population-based study of its kind. However, one limitation may be the absence of evidence that patients actually took the prescribed medications. Furthermore, due to occasional incomplete information in the database regarding the type of stroke, some hemorrhagic strokes might have been mistakenly included. Given the overwhelming incidence of ischemic strokes (> 80%), this error's impact on the study results is expected to be minimal.

Several models verifying the influence of other factors on ischemic stroke development were created; however, none showed relevant deviations from the study’s findings. Theoretically, the increased risk of stroke development could also be due to inadequate monitoring after starting warfarin therapy, but this cannot be proven as the CPRD database does not consistently include INR values.

Conclusion

The study demonstrated an association between initiating anticoagulant therapy with warfarin and an increased risk of developing ischemic stroke in patients with atrial fibrillation. Whether this increased risk is due to a transient hypercoagulable state induced by warfarin and whether temporary heparin administration could help reduce this risk should be topics for further research.

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Source: Azoulay L., Dell Anielo S., Simon T. et al. Initiation of warfarin in patients with atrial fibrillation: early effects on ischaemic strokes. Eur Heart J 2014; 35: 1881–1887, doi: 10.1093/eurheartj/eht499.