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Should we be treating fewer patients with warfarin (Coumadin)?

Henry I. Bussey, Pharm.D., FCCP, FAHA
March, 2007

Reference: Flaherty ML, Kissela B, Woo D, et. al. The increasing incidence of anticoagulant-associated intracerebral hemorrhage. Neurology. 2007 Jan 9;68(2):116-21.

This article is one of several key studies* that are raising important questions about the future role of warfarin therapy, especially in patients with atrial fibrillation.


Is the expanded use of warfarin causing more harm than good, and should we reduce our use of anticoagulation in atrial fibrillation?

Should we be using warfarin to treat more, rather than fewer, patients with atrial fibrillation?

Does improving INR control beyond that typically reported in clinical trials yield an improved risk/benefit ratio? If so, what can be done to improve INR control further? If we can optimize INR control, will there be a need for newer anticoagulants currently in development?

What is the adherence rate of warfarin patients managed in an anticoagulation clinic, and are there clinical consequences of non-adherence in such patients?


The study by Flaherty et. al. found that a dramatic increase in the use of warfarin over the previous decade was associated with an even more dramatic increase in warfarin-related intracerebral hemorrhage but without a decrease in cardioembolic stroke. Does this mean we should be treating fewer patients with warfarin?

Flaherty and colleagues examined the rate of anticoagulation-related intracerebral hemorrhage (ICH) and cardioembolic stroke in the Cincinnatti, Ohio area during three time periods (1988, 1993-94, and 1999). Their data were combined with US census data and data regarding the increased use of warfarin that followed the publication of the pivotal trials of anticoagulation in atrial fibrillation. The results of their study revealed that a four to five fold increase in the use of warfarin had occured, that ICH had increased even more than had the use of warfarin, but that cardioembolic stroke had not declined. At first read, one might conclude from these data that the ICH risk of warfarin therapy outweighs the benefit, but there is good reason to not embrace that conclusion based to some degree on the following:

First, although the risk of cardioembolic stroke did not decline with the increased use of warfarin, recent data have found that the incidence of atrial fibrillation has increased sharply over the recent past and actually affects more than twice as many individuals as previously described (see http://www.clotcare.com/clotcare/atrialfibrillationincreasing.aspx). Therefore, the fact that the incidence of cardioembolic stroke did not change may actually be a result of warfarin effectively preventing an increase in stroke of a magnitude similar to the increase in atrial fibrillation that has been reported.

Second, others also have reported an increase in major bleeding over time but attributed the increase to additional factors. ClotCare editorial board member, Dr. Samuel Z. Goldhaber and his group from Harvard Medical School reported an increase in warfarin-related major hemorrhage over time at their institution. (see http://www.clotcare.com/clotcare/warfarinbleeding.aspx). In their report, however, they suggested that at least some of the increase in bleeding rates was likely due to the fact that, over time, more of their warfarin patients were found to be hypertensive, had experienced a prior stroke, and/or were receiving antiplatelet therapy. Considering that the use of coronary artery stenting also was increasing during the period of Flaherty's study, and the fact that stents require dual antiplatelet therapy, it is highly probable that at least some of the increase in bleeding is due to the use of combined antiplatelet therapy in conjunction with warfarin. The fact that 33% of the ICH in Flaherty's study occurred with INRs less than 2 would suggest that there probably were other contributing factors (such as antiplatelet therapy, hypertension, advanced age, etc.). In fact, almost 60% of their ICHs occurred at an INR of 3 or less while in many reports the risk of major bleeding did not increase substantially until the INR exceeded a value of about 4.5 to 5.0. Such a large percent of ICHs occurring below an INR of 3.0 would suggest that factors other than warfarin alone were involved.

Third, although the extent of increase in ICH is quite impressive, the absolute number of ICH events should be viewed in relation to the number of cardioembolic strokes that may have been prevented. For example, for the entire study group, the annual incidence of warfarin-related ICH increased from 0.8 per 100,000 in 1988 to 4.4 per 100,000 in 1999. Although that is more than a five fold increase in ICH (at a time when the use of warfarin increased by about 4 fold), the absolute increase is 3.6 events per 100,000. If we estimate that 3% of the population has atrial fibrillation with an average risk of stroke of 5% per year, then that same population of 100,000 would have about 3,000 A. Fib patients and, without anticoagulation, about 150 of those would have a stroke each year (3,000 x 0.05 = 150). With appropriate anticoagulation, approximately 90 to 120 of the 150 stokes would be prevented each year (based on a 60% to 80% reduction in stroke with warfarin; the difference being dependent on whether one uses intention to treat or on treatment analysis of pivotal trials).1, 2 Therefore, preventing approximately 100 cardioembolic strokes at the risk of causing fewer than 4 ICH would seem to suggest that the benefit outweighs the risk.

Finally, new data have confirmed that major events rates - both major bleeding and thromboembolism - are substantially lower in atrial fibrillation patients whose anticoagulation is well controlled.3 Data on INR control were not provided in the Flaherty study, but it would be reasonable to suspect that at least some of the ICH might have been avoided with tighter INR control, especially in those 80 years of age and older. This group had by far the greatest increase in ICH events over time, and tight INR control has been shown to be especially important in older patients.

Additional Questions About Warfarin's Future

  1. Should we be treating more patients with warfarin (Coumadin)?

  2. Can better INR control be achieved, and if so, how will new anticoagulants compare to warfarin (Coumadin)?

Additional References

  1. Albers GW, Sherman DG, Gress DR, Paulseth JE, Petersen P. Stroke prevention in nonvalvular atrial fibrillation: a review of prospective randomized trials. Ann Neurol. 1991 Oct;30(4):511-8.

  2. Atwood JE, Albers GW. Anticoagulation and atrial fibrillation. Herz. 1993 Feb;18(1):27-38.

  3. White HD, Gruber M, Feyzi J, et. al. Comparison of outcomes among patients randomized to warfarin therapy according to anticoagulant control: results from SPORTIF III and V. Arch Intern Med. 2007 Feb 12;167(3):239-45.
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Saturday, August 19, 2017