Author + information
- Paul A. Reilly, PhD∗ (, )
- Stuart J. Connolly, MD,
- Salim Yusuf, MD, DPhil,
- John W. Eikelboom, MBBS,
- Michael D. Ezekowitz, MD, PhD,
- Lars Wallentin, MD, PhD,
- RE-LY Investigators
- ↵∗Clinical Development, Boehringer Ingelheim Pharmaceuticals, 900 Ridgebury Road, Ridgefield, Connecticut 06877
We would like to respond to Dr. Rao's questions concerning our paper (1). First, it is incorrect to state that any data on dabigatran and plasma levels were suppressed. This information has been submitted to all regulatory authorities as part of the original registration process of dabigatran etexilate for reduction of stroke in patients with atrial fibrillation. These data have also been in the public domain since the U.S. Food and Drug Administration (FDA) Advisory Committee meeting in September 2010, before marketing approval (2).
Our paper, which investigated the exposure–response relationship, documents plasma concentration as one factor affecting clinical outcomes (1). Whether we could specify and defend a single optimal concentration range for all patients was the subject of extensive discussions among the coauthors. We ultimately came to the conclusion that there is no single range that fits all patients, because individual patient demographics (e.g., age, renal function, and prior stroke) are at least as important as the plasma concentrations in assessing benefit–risk and confound the association between drug levels and outcomes. Even with the high plasma concentrations of dabigatran observed in patients with renal dysfunction, the FDA has concluded there is a positive benefit–risk balance for patients (3). Further, RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) is the only trial of a new oral anticoagulant that has published extensive data regarding blood concentrations. It is likely that other anticoagulants will also exhibit variability in blood concentrations.
Although it may appear attractive to monitor concentrations and adjust dosing to improve outcomes, given the complex interactions between plasma concentrations, demographics, and outcomes, we cannot make recommendations on how to do this. In fact, without routine testing in the RE-LY trial, dabigatran produces a clear net benefit over warfarin. The safety compared with warfarin has also been confirmed in post-marketing analyses by the FDA (4).
Please note: The RE-LY trial was funded by Boehringer Ingelheim. Dr. Reilly is a full-time employee of Boehringer-Ingelheim. Drs. Connolly, Yusuf, Eikelboom, Ezekowitz, and Wallentin have received grant support/honoraria/consulting fees from Boehringer-Ingelheim.
- American College of Cardiology Foundation
- Reilly P.A.,
- Lehr T.,
- Haertter S.,
- et al.,
- on behalf of the RE-LY Investigators
- ↵Advisory Committee briefing document for dabigatran Etexilate, section 4.6. Available at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/UCM226009.pdf. Accessed April 2, 2014.