Author + information
- Lawrence Gage, MD⁎ ()
- ↵⁎Rochester General Hospital, Rochester Cardiopulmonary Group, P.C., 1445 Portland Avenue, Suite 104, Rochester, New York 14621
In the “2011 ACCF/AHA/HRS Focused Update on the Management of Patients With Atrial Fibrillation (Update on Dabigatran)” (1), the writing committee provides a Class IB recommendation for dabigatran as a useful “alternative to warfarin” in most patients with nonvalvular atrial fibrillation.
The guideline, like the manufacturer's prescribing information, implies that a patient with creatinine clearance 15 to 30 ml/min is a candidate for dabigatran 75 mg twice daily (bid), despite the fact that patients with creatinine clearance <30 ml/min were excluded from the RE-LY trial (2), on which the recommendation is primarily based. We do not know, in fact, that dabigatran 75 mg bid is safe in these fragile patients or that it is effective in anyone.
How did the 75-mg dose come about? The U.S. Food and Drug Administration (FDA) Division of Cardiovascular and Renal Products explains, but hardly reassures: “Based on pharmacokinetic modeling, comparing pharmacokinetic data from RE-LY with data from a small study of subjects with compromised renal function, a dosing regimen of 75 mg bid appears appropriate for patients with estimated CrCL 15 to 30 mL/min” (3).
Although it is encouraging that intracranial hemorrhage was less frequent with dabigatran than with warfarin in RE-LY, most seasoned clinicians will recall any number of patients who presented with overwhelming, fatal hemorrhagic diatheses, with or without intracranial hemorrhage, as a result of over-anticoagulation. Compared with warfarin, dabigatran has the advantage—and the disadvantage—of not being subject to periodic monitoring and titration; it is eliminated by an organ whose function routinely varies remarkably in the elderly, and it has no antidote. As I contemplate using 150 mg bid, effectively within a one-size-fits-all paradigm, my concern is that we may begin to collect more such tragic vignettes.
The “average” patient in RE-LY was 71 years of age, weighed 83 kg, and had a creatinine clearance (by the Cockcroft-Gault method) of 106 ml/min. An 80-year-old woman who weighs 60 kg and has a serum creatinine level of 1.3 has an estimated creatinine clearance of 33 ml/min. It is generally agreed that formulas for calculating glomerular filtration rate are fraught with error, but assuming 33 ml/min is correct, what dose of dabigatran is right for her? Here is the FDA's advice: “Patients with CrCL ≥31 mL/min should receive 150 mg bid” (3).
It appears that we are to assume that this woman's risk of serious bleeding with dabigatran 150 mg bid exceeds that of the more robust “average” patient only by a small, clinically acceptable margin, but, in fact, we do not know what that margin is. What is more, although she qualifies for 150 mg bid (according to the manufacturer, the FDA, and the new guideline) a week from now, when her serum creatinine level chances to be 1.5 and her creatinine clearance 28 ml/min, she will not qualify. She will instead be relegated to an untested dose that seemed “appropriate” on pharmacokinetic grounds.
In summary, the recommendation to use dabigatran 75 mg bid in patients with atrial fibrillation is Class IIb at best, and Level C; there is no randomized trial. The recommendation for 150 mg bid, although Level B, is Class IIa: “additional studies with focused objectives are needed.” The nearly unqualified endorsement of Class I status is not warranted.
- American College of Cardiology Foundation
- Wann L.S.,
- Curtis A.B.,
- Ellenbogen K.A.,
- et al.
- ↵Center for Drug Evaluation and Research, Application number 22-512, Summary Review, Deputy Office Director Decisional Memo, October 19, 2010: page 15. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022512Orig1s000SumR.pdf. Accessed March 28, 2011.