Author + information
- Received February 21, 2018
- Revision received April 3, 2018
- Accepted April 17, 2018
- Published online July 9, 2018.
- Anthony P. Kent, MDa,
- Martina Brueckmann, MDb,c,
- Mandy Fraessdorf, PhDb,
- Stuart J. Connolly, MDd,
- Salim Yusuf, MD, DPhild,
- John W. Eikelboom, MDd,
- Jonas Oldgren, MD, PhDe,
- Paul A. Reilly, PhDf,
- Lars Wallentin, MD, PhDe and
- Michael D. Ezekowitz, MD, PhDg,∗ (, )@TJUHospital@JeffersonUniv@LIMR
- aDepartment of Internal Medicine, Bridgeport Hospital, Yale New Haven Health, Bridgeport, Connecticut
- bBoehringer Ingelheim GmbH & Co KG, Ingelheim, Germany
- cUniversity of Heidelberg, Mannheim, Germany
- dMcMaster University and Hamilton Health Sciences, Population Health Research Institute, Hamilton, Ontario, Canada
- eUppsala Clinical Research Center and Department of Medical Sciences, Uppsala University, Uppsala, Sweden
- fClinical Development, Cardiology, Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut
- gSidney Kimmel Medical College at Thomas Jefferson University and Lankenau and Bryn Mawr Hospitals, Philadelphia, Pennsylvania
- ↵∗Address for correspondence:
Dr. Michael D. Ezekowitz, Department of Cardiology, Bryn Mawr Hospital and Lankenau Medical Center, 830 Lancaster Road, Suite 301, Bryn Mawr, Pennsylvania 19010.
Background Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used medications that can potentially increase the risk of bleeding and thrombosis.
Objectives This study quantified the effect of NSAIDs in the RE-LY (Randomized Evaluation of Long Term Anticoagulant Therapy) trial.
Methods This was a post hoc analysis of NSAIDs in the RE-LY study, which compared dabigatran etexilate (DE) 150 and 110 mg twice daily (b.i.d.) with warfarin in patients with atrial fibrillation. Treatment-independent, multivariate-adjusted Cox regression analysis assessed clinical outcomes by comparing NSAID use with no NSAID use. Interaction analysis was obtained from treatment-dependent Cox regression modeling. Time-varying covariate analysis for NSAID use was applied to the Cox model.
Results Among 18,113 patients in the RE-LY study, 2,279 patients used NSAIDs at least once during the trial. Major bleeding was significantly elevated with NSAID use (hazard ratio [HR]: 1.68; 95% confidence interval [CI]: 1.40 to 2.02; p < 0.0001). NSAID use did not significantly alter the risk of major bleeding for DE 150 or 110 mg b.i.d. relative to warfarin (pinteraction = 0.63 and 0.93, respectively). Gastrointestinal major bleeding was significantly elevated with NSAID use (HR: 1.81; 95% CI: 1.35 to 2.43; p < 0.0001). The rate of stroke or systemic embolism (stroke/SE) with NSAID use was significantly elevated (HR: 1.50; 95% CI: 1.12 to 2.01; p = 0.007). The use of NSAIDs did not significantly alter the relative efficacy on stroke/SE for DE 150 or 110 mg b.i.d. relative to warfarin (pinteraction = 0.59 and 0.54, respectively). Myocardial infarction rates were similar with NSAID use compared with no NSAID use (HR: 1.22; 95% CI: 0.77 to 1.93; p = 0.40). Patients were more frequently hospitalized if they used an NSAID (HR: 1.64; 95% CI: 1.51 to 1.77; p < 0.0001).
Conclusions The use of NSAIDs was associated with increased risk of major bleeding, stroke/SE, and hospitalization. The safety and efficacy of DE 150 and 110 mg b.i.d. relative to warfarin were not altered. (Randomized Evaluation of Long Term Anticoagulant Therapy [RE-LY]; NCT00262600)
The RE-LY clinical trial was funded by Boehringer Ingelheim GmbH & Co KG, Ingelheim, Germany. The post hoc analysis did not have a funding source. Dr. Connolly has received grants and personal fees from Boehringer Ingelheim, Bristol-Myers Squibb, Sanofi, and Bayer; has received personal fees from Portola; has received grants from Boston Scientific; and has received an institutional research grant from Boehringer Ingelheim. Dr. Yusuf has received grants, honoraria, and travel reimbursements for speaking engagements from Boehringer Ingelheim, Bayer, and Bristol-Myers Squibb; and has received a research grant from Boehringer Ingelheim. Dr. Eikelboom has received consulting fees and/or honoraria and grant and/or in-kind support from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly, GlaxoSmithKline, Pfizer, Janssen, and Sanofi. Dr. Oldgren has been a consultant (including steering and data monitoring committees) and has received lecture fees from Bayer, Bristol-Myers Squibb/Pfizer, Boehringer Ingelheim, Daichii-Sankyo, and Sanofi; and has been a member of the advisory board for Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, and Sanofi. Dr. Wallentin has received institutional research grants from AstraZeneca, Bristol-Myers Squibb/Pfizer, Merck & Co., Roche, GlaxoSmithKline, and Boehringer Ingelheim; and has received consulting fees from Abbott. Dr. Ezekowitz has received consulting fees from Boehringer Ingelheim, Pfizer, Bristol-Myers Squibb, Portola, Daiichi-Sankyo, and Armetheon; and has received grant support from Boehringer Ingelheim and Pfizer. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received February 21, 2018.
- Revision received April 3, 2018.
- Accepted April 17, 2018.