New Data on Warfarin Therapy for Atrial Fibrillation
New Data on Warfarin Therapy for Atrial Fibrillation
Abstract & Commentary
By Michael H. Crawford, MD, Professor of Medicine, Chief of Cardiology, University of California, San Francisco. Dr. Crawford is on the speaker's bureau for Pfizer. This article originally appeared in the October 2009 issue of Clinical Cardiology Alert. It was edited by Michael H. Crawford, MD and peer reviewed by Ethan J. Weiss, MD. Dr. Weiss is Assistant Professor of Medicine, Division of Cardiology and CVRI, University of California, San Francisco; he reports no financial relationships relevant to this field of study.
Source: Singer DE, et al. The net clinical benefit of warfarin anti coagulation in atrial fibrillation. Ann Int Med. 2009;151:297-305.
Current recommendations for stroke prophylaxis with warfarin for patients with atrial fibrillation do not take into account the risks of hemorrhage. Thus, Singer et al from Kaiser Permanente studied more than 13,000 patients with non-valvular atrial fibrillation to estimate the net clinical benefit of warfarin therapy for atrial fibrillation (reduction in thromboembolism minus the increase in intracranial hemorrhage). The mean age of the subjects was 73 years, and 20% had no major risk factors for stroke based upon CHADS2. At entry, about half the patients were receiving warfarin, and tended to have a higher prevalence of stroke risk factors, except for those age > 75 years. Over a median follow-up of six years, there were 1,092 embolic events (1,017 strokes) and 299 intracranial hemorrhage events (193 on warfarin). The annual rate of stroke or systemic embolic events was 2.1% in those not on warfarin and 1.3% in those on warfarin. The annual rate of intracranial hemorrhage was 0.32% in those not on warfarin and 0.58% in those on warfarin. The adjusted net clinical benefit of warfarin was 0.68 adverse events prevented per 100 person years. The benefits of warfarin were observed to increase as the risks for thromboembolism increased, but harm increased only modestly. Prior stroke was the strongest risk factor for subsequent stroke and intracranial hemorrhage. The net clinical benefit increased with the presence of any risk factor except hypertension. Also, net clinical benefit increased with age, being near zero at ages < 75 years and as the CHADS2 score increased above one. Singer et al concluded that a risk assessment that includes the risk of thromboembolism and intracranial hemorrhage provides a better basis for decisions regarding warfarin therapy in patients with non-valvular atrial fibrillation.
Commentary
When faced with starting a patient with atrial fibrillation on warfarin, many physicians demur for a variety of reasons. One is fear of major bleeding. The downsides to warfarin therapy are often applied irrationally to our decision making, as there is no equivalent of the CHADS2 score for the risk of warfarin. Thus, this analysis of the Kaiser Permanente database on warfarin therapy for atrial fibrillation is of interest because it estimates net clinical benefit of warfarin by subtracting the risk of intracerebral hemorrhage, the most serious major bleeding event, from the predicted benefits of treatment based on CHADS2.
There are several clinically useful points made by this analysis. First, the risk of stroke in non-valvular atrial fibrillation is lower now than that observed in the up to 20-year-old prior studies (2% vs. 5%). This makes consideration of adverse effects even more compelling. Second, the risk of stroke increases considerably with increasing CHADS2 score: one point each for congestive heart failure, hypertension, age > 75 years, and diabetes, and 2 points for prior stroke. However, the risk of intracerebral hemorrhage is relatively constant across CHADS2 scores. Thus, the higher the CHADS2 score, the greater the net clinical benefit. In their data, a CHADS2 score of two or more would seem worth considering warfarin therapy. Finally, the net benefits of warfarin increase significantly over age 75 years. Treatment with warfarin should seriously be considered in such individuals, unless there are contraindications to its use.
The strengths of this study include the large population, with ample numbers of events and a relatively long follow-up period. Also, the events were carefully validated. This study represents best practices because in this closed population, INRs were tightly controlled to minimize complications. The major weakness is that it is a non-randomized, observational study. Hence, it is likely that patients at higher risk of stroke and with fewer potential contraindications were treated with warfarin, exaggerating the benefits and minimizing the risks, which will confound the results. Also, concomitant aspirin or other antiplatelet drug use was not recorded for this study, but is estimated to be about half the subjects. Finally, no specific predictors of intracranial bleed were identified, so an estimated net clinical benefit cannot be calculated for each individual. Prior stroke carries a two-point weight in the CHADS2 scoring system because it carries the highest risk of stroke, but this study showed it also carried the greatest risk of an intracranial hemorrhage on warfarin; the proverbial double-edged sword.
My take on this study is that the risk vs. benefit of warfarin is much narrower than previously thought, but warfarin should be seriously considered in those > 75 years old or with a CHADS2 score of two or more, unless they have a prior stroke; then, consultation with a neurologist should be sought before starting warfarin.
Current recommendations for stroke prophylaxis with warfarin for patients with atrial fibrillation do not take into account the risks of hemorrhage. Thus, Singer et al from Kaiser Permanente studied more than 13,000 patients with non-valvular atrial fibrillation to estimate the net clinical benefit of warfarin therapy for atrial fibrillation (reduction in thromboembolism minus the increase in intracranial hemorrhage).Subscribe Now for Access
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