New study and accompanying editorial suggest that warfarin may be indicated in fewer patients, but (as usual) issues remain

Henry I. Bussey, Pharm.D., FCCP, FAHA
January, 2010

Singer and colleagues provided an expert reviewed data analysis of 13,559 patients with atrial fibrillation and concluded that the risk of hemorrhagic stroke off-set a good deal of the benefit of warfarin anticoagulation to reduce ischemic stroke.¹ They also suggest that the rate of ischemic stroke in untreated atrial fibrillation may be less than in the past possibly due to improved hypertension control. An accompanying editorial by two other experts, Robert Hart and Jonathan Halperin, provides additional commentary on this analysis.² I elected to take the opportunity to submit a letter to the editor which is reproduced below:

Calculating net clinical benefit of warfarin therapy in atrial fibrillation is an important concept.^1,2 Three other issues, however, should be considered in the future:

First, warfarin therapy affects other major events and may substantially reduce myocardial infarction and death.³

Second, because INR control varies in different settings, and because a 10% improvement in INR time in therapeutic range (TTR) has been associated with a greater than 10% reduction in event rates,^3,4 the relationship between INR control and event rates needs to be more thoroughly defined if one is going to be able to determine how INR control may affect the net clinical benefit in his/her own setting. Veeger, et al. found that the bottom quartile of approximately 4,000 patients was in range only 10 to 20% of the time and accounted for more than half of the major events.⁵ Jones, et al found that the bottom quartile of 2,223 patients was in range only about 28% of the time.⁴ Further, since event rates increase exponentially as the INR moves further out of range, being slightly out of the target range may have little impact, while being at the extremes (INR < 1.5 or INR > 5) may carry a very high risk. Therefore, one needs to know what the event rates were when the INR was within the target range, TTR +/- 0.3 INR units, below an INR of 1.5 and above an INR of 5.0 if one is going to estimate the net clinical benefit in his/her own setting.

Third, one needs to consider how evolving methods to improve INR control may alter the net clinical benefit. As noted by Hart and Halperin, the TTR of 65% reported by Singer, et al is often considered "high".² By combining INR self-testing and computer management, however, Harper, et al reported an 80% TTR with no INRs > 5.⁶ An interim analysis of our similar study found a TTR of 78.9% that increased to 94% when the range was expanded slightly by +/- 0.3 INR units.⁷ Approximate TTR values were 90% for the top quartile and 60% for the lowest quartile, and percent time > 5 or < 1.5 was only 0.27%. Such improved INR control is estimated to yield a 30 to 50% reduction in both thromboembolic and major bleeding events compared to "typical" management; changes that should have a substantial impact on the net clinical benefit of warfarin.

References

1. Singer DE, Chang Y, Fang MC, et al. The net clinical benefit of warfarin anticoagulation in atrial fibrillation. Annals of Internal Medicine 2009; 151:297-305.



2. Hart RG and Halperin JL. Do current guidelines result in overuse of warfarin anticoagulation in patients with atrial fibrillation? Annals of Internal Medicine 2009; 151:355-356.



3. White HD, Gruber M, Feyzi J, Kaatz S, et al. Comparison of outcomes among patients randomized to warfarin therapy according to anticoagulant control: results from SPORTIF III and V. Archives of Internal Medicine 2007; 167:239-245.



4. Jones M, McEwan P, Morgan CL, Peters JR, Goodfellow J, Currie CJ. Evaluation of the pattern of treatment, level of anticoagulation control, and outcome of treatment with warfarin in patients with non-valvar atrial fibrillation: a record linkage study in a large British population. Heart 2005; 91:472-477.



5. Veeger NJ, Piersma-Wichers M, Hillege HL, Crijns HJGM, van Der Meer J. Early detection of patients with a poor response to vitamin K antagonists: the clinical impact of individual time within target range in patients with heart disease. Journal of Thrombosis and Haemostasis 2006; 4:1625-1627.



6. Harper PL and Pollock D. Anticoagulation self-management using near patient testing and decision support software provided via an Internet Website improved anticoagulation control in patients on long-term warfarin. Blood 2008; 112: Abstract 278.



7. Bussey HI, Walker MB, Bussey-Smith KL, Frei CR. Interim analysis of triple intervention to improve International Normalized Ratio (INR) in warfarin-treated patients. (abstract PP-MO-469) International Society of Thrombosis and Haemostasis Congress, July, 2009 (online at http://isth2009.com/abstract_submission.html)