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Warfarin initiation increased stroke risk within 30 days of use
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Patients with atrial fibrillation have nearly double the risk for stroke in the first 30 days after warfarin initiation compared with nonusers.
According to study results of more than 70,000 patients, risk for stroke was increased by 71% in the first 30 days after warfarin initiation (RR=1.71; 95% CI, 1.39-2.12). After 30 days, risk for stroke was halved among warfarin users (31 to 90 days: RR=0.5; 95% CI, 0.34-0.75; >90 days: RR=0.55; 95% CI, 0.5-0.61).
Researchers analyzed data from 70,766 patients aged at least 18 years who were diagnosed with AF between 1993 and 2008. The study was carried out using the UK Clinical Practice Research Datalink. The researchers followed the patients for up to 16 years until an ischemic stroke, death, end of registration with their primary care practice or the end of the study period, whichever came first.
“To our knowledge, this is the first population-based study to investigate whether the initiation of warfarin is associated with an increased risk of ischemic stroke,” Laurent Azoulay, PhD, assistant professor in the department of oncology at McGill University and project leader at the Centre for Clinical Epidemiology at Lady Davis Institute, Jewish General Hospital, Montreal, said in a press release.
During follow-up, 5,519 patients experienced a stroke (2%/year). According to the study abstract, the highest risk for stroke was in the first week of use, peaking on the third day after warfarin initiation (133%). If patients had a previous history of ischemic stroke, their risk for stroke was increased by 245% during the first 30 days of warfarin treatment.
“There is no question that warfarin is highly effective in preventing strokes in patients with atrial fibrillation. Thus, our finding that the initiation of warfarin may be associated with an increased risk of stroke should not deter physicians and patients from using this drug, since this likely affects a small number of patients.
“Future studies should confirm our results, and identify the small subset of patients who may be at risk. However, the results of our study suggest that physicians should be vigilant when initiating warfarin, particularly in the first week of use,” Azoulay said.
The researchers aim to repeat the study using databases from other countries and settings.
Samy Suissa, PhD, James McGill professor of epidemiology, biostatistics and medicine at McGill University, said it is “imperative to investigate whether the newer, popular anticoagulants also carry this early risk.” Until then, “a bridging strategy using heparin … at the initiation of warfarin treatment could be considered as a way to reduce the increased risk observed in the first 30 days of use.”
Disclosure: Azoulay reports no relevant financial disclosures. Suissa reports receiving research funding and participating in advisory committees for Bayer-Schering, Bristol-Myers Squibb and Boehringer Ingelheim.
Perspective
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Jonathan P. Piccini, MD, MHS, FACC, FHRS
Warfarin is highly effective at preventing stroke and death in patients with atrial fibrillation, but it carries a host of challenges for patients and health care providers. These challenges are well-known and include variable dose-response, multiple drug-drug interactions, and increased risks for bleeding, including intracranial hemorrhage. While the risks for bleeding during warfarin initiation have been well-described (Hylek EM. Circulation. 2007;115:2689-2696), less is known about the risk for stroke early after warfarin initiation.
In a large cohort of 70,766 patients with chronic AF, Azoulay and colleagues found that patients newly started on warfarin experienced a 71% increased risk for stroke in the first 30 days of therapy. The investigators found that the risk for stroke was greatest in the first week of therapy, peaking at 3 days post-initiation. Interestingly, this window of increased risk is similar to the period of risk reported for warfarin skin necrosis, a complication which is hypothesized to be due to differential inhibition of vitamin K-dependent factors that leads to a relative protein C deficiency and a hypercoaguable state. The increased risks reported by Azoulay et al. are also similar to increased risks observed with warfarin initiation following the termination of novel oral anticoagulants at the end of clinical trials (Patel MR. Circulation. 2012;125:2445-7; Granger CB. Eur Heart J. 2012;33(S1):685-686). The study by Azoulay and colleagues also has several notable limitations, including the inability to account for compliance or quality of warfarin anticoagulation and the likely influence of residual confounding (e.g., sicker patients may have been more likely to be treated with warfarin).
Despite several limitations, the data reported by Azoulay and colleagues raise an important hypothesis and enforce the call for vigilance during anticoagulation initiation, transition and withdrawal raised by other recent studies. It is important to remember that the initiation of stroke prevention therapy is a critically important intervention for patients with atrial fibrillation at moderate to high risk for stroke. However, the initiation (and interruption) of warfarin is a period of heightened risk. Future studies should investigate these potential risks and, more importantly, identify methods to mitigate them and improve patient safety.
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