EDITORIAL

The Food and Drug Administration Decision Not to Approve the 110 mg Dose of Dabigatran: Give Us a Way Out
In an article published last spring in the New England Journal of Medicine, Beasley et al1 presented the reasons why the US Food and Drug Administration (FDA) decided not to approve the 110 mg twice per day dosage of dabigatran for stroke prevention in patients with atrial brillation. We want to present the clinical reasons why that decision was specious and has prevented doctors from taking proper care of their patients. On the basis of its superiority and a reduced incidence of intracranial hemorrhages, the 150 mg twice per day dosage received a recommendation for approval by the Cardiorenal Advisory Committee.2 The FDA stated that it could not identify a patient group for whom there was an improvement in benet/risk for the 110 mg dose compared with the 150 mg dose. They concluded that approving the 110 mg dose would have a negative impact on public health. At the same time, based purely on pharmacokinetic data, the FDA approved a 75 mg twice per day dosage for patients with severe renal dysfunction.2 Our concern is that subgroup analyses cannot address the risk/benet ratio across the wide spectrum of patients who could receive dabigatran. There are myriad patient characteristics, concomitant therapies, and comorbidities that affect the choice of dabigatran and its dose. Prevention of a stroke has a high priority and intuitively outweighs a gastrointestinal bleed. However, weighing of harms is empiric, and clinical decisions are frequently based on extrapolations from clinical trials. What is unique in this case is that the FDA usurped clinicians who should be the ultimate treatment arbiters. Nonapproval of the 110 mg dose will prevent a signicant number of patients from receiving a useful drug. We are concerned about patients, particularly the elderly, who cannot maintain a stable level of anticoagulation and yet
Funding: None. Conict of Interest: Drs Kowey and Naccarelli have been fee-forservice consultants to Boehringer-Ingelheim and to other companies developing new anticoagulants for atrial brillation, including Johnson & Johnson, Portola, Merck, Bristol Meyers Squibb, Pzer, AstraZeneca, Sano-Aventis, and Daiichi-Sankyo. Neither holds an equity interest in any of these companies. Authorship: Both authors had access to the data and played a role in writing this manuscript.

have a high bleed risk. Will physicians retreat to warfarin, antiplatelet therapy, or creative dabigatran dosing? The bottom line is that the 110 mg twice per day dosage of dabigatran was noninferior to warfarin.3 This combined with a safety prole and discontinuation rate equal to or better than warfarin would have made the 110 mg dose approvable if studied alone. In effect, we have been deprived of a treatment that might benet some of our patients because another dose of the drug was superior for a particular safety end point. We would remind the FDA that the benet that seems to accrue with the new anticoagulants is the avoidance of hemorrhagic strokes, a safety advantage to be sure. By not approving the 110 mg dose, the FDA deprived patients of a viable treatment option and established an undesirable regulatory precedent. A one-dose-ts-all decision makes little sense for a drug that can cause life-threatening bleeding, has no available assay, and has no antidote. Data from a landmark trial supported approval of both studied doses and contained no data to support an even lower dose that is now being used inappropriately by physicians who are appropriately concerned about bleeding. The FDA made a paternalistic decision that backed physicians into a therapeutic corner. On behalf of our patients, we request a way out. Peter R. Kowey, MD, FHRS, FACC, FAHA
Lankenau Institute for Medical Research, Jefferson Medical College Wynnewood, Pennsylvania

Gerald V. Naccarelli, MD, FHRS, FACC, FAHA

Penn State University Heart and Vascular Institute Hershey, Pennsylvania

References
1. Beasley BN, Unger EF, Temple R. Anticoagulant optionswhy the FDA approved a higher and not a lower dose of dabigatran. N Engl J Med. 2011;364:1788-1790. Epub 2011 Apr 13. 2. FDA-approved drug products. Rockville, MD: Food and Drug Administration. Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index. cfm?fuseaction SearcLabel_ApprovalHistory#apphist. 3. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial brillation. N Engl J Med. 2009;361:1139-1151.

0002-9343/$ -see front matter 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2011.10.035