Author + information
- Received April 28, 2016
- Revision received April 17, 2018
- Accepted May 10, 2018
- Published online August 6, 2018.
- John D. Horowitz, MBBS, PhDa,∗ (, )@UniofAdelaide,
- Raffaele De Caterina, MD, PhDb,c,
- Tamila Heresztyn, BSca,
- John H. Alexander, MDd,
- Ulrika Andersson, PhDe,
- Renato D. Lopes, MD, PhDd,
- Philippe Gabriel Steg, MDf,g,h,i,
- Elaine M. Hylek, MD, MPHj,
- Puneet Mohan, MD, PhDk,
- Michael Hanna, MDk,
- Petr Jansky, MDl,
- Christopher B. Granger, MDd,
- Lars Wallentin, MD, PhDe,m,
- on behalf of the ARISTOTLE Investigators
- aCardiology Unit, Basil Hetzel Institute, Queen Elizabeth Hospital, University of Adelaide, Adelaide, South Australia, Australia
- bG. d’Annunzio University, Chieti, Italy
- cG. Monasterio Foundation, Pisa, Italy
- dDuke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina
- eUppsala Clinical Research Center, Uppsala, Sweden
- fINSERM-Unité 698, Paris, France; Assistance Publique-Hôpitaux de Paris, Paris, France
- gDépartement Hospitalo-Universitaire FIRE, Hôpital Bichat, Paris, France
- hUniversité Paris-Diderot, Sorbonne-Paris Cité, Paris, France
- iNHLI Imperial College, ICMS, Royal Brompton Hospital, London, United Kingdom
- jBoston University Medical Center, Boston, Massachusetts
- kBristol-Myers Squibb, Princeton, New Jersey
- lCardiovascular Centre, University Hospital Motol, Prague, Czech Republic
- mDepartment of Medical Sciences, Cardiology, Uppsala University, Uppsala, Sweden
- ↵∗Address for correspondence:
Dr. John D. Horowitz, Cardiology and Clinical Pharmacology Unit, Basil Hetzel Institute, Queen Elizabeth Hospital, University of Adelaide, Woodville Road, Woodville, SA 5011 Australia.
Background There is little mechanistic information on factors predisposing atrial fibrillation (AF) patients to thromboembolism or bleeding, but generation of nitric oxide (NO) might theoretically contribute to both.
Objectives The authors tested the hypothesis that plasma levels of the methylated arginine derivatives asymmetric and symmetric dimethylarginine (ADMA/SDMA), which inhibit NO generation, might be associated with outcomes in AF.
Methods Plasma samples were obtained from 5,004 patients with AF at randomization to warfarin or apixaban in the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial. ADMA and SDMA concentrations were measured by high-performance liquid chromatography. Relationships to clinical characteristics were evaluated by multivariable analyses. Associations with major outcomes, during a median of 1.9 years follow-up, were evaluated by adjusted Cox proportional hazards models.
Results Both ADMA and SDMA plasma concentrations at study entry increased significantly with patients’ age, female sex, renal impairment, permanent AF, or congestive heart failure. ADMA and SDMA increased (p < 0.001) with both increased CHA2DS2-VASc and HAS-BLED scores, but decreased in the presence of diabetes. On multivariable analysis adjusting for established risk factors and treatment, tertile groups of ADMA concentrations were significantly associated with stroke/systemic embolism (p = 0.034), and death (p < 0.0001), whereas tertile groups of SDMA were associated with major bleeding and death (p < 0.001 for both). Incorporating ADMA and SDMA into CHA2DS2-VASc or HAS-BLED predictive models improved C-indices for those outcomes. Neither ADMA nor SDMA predicted differential responses to warfarin or apixaban.
Conclusions In anticoagulated patients with AF, elevated ADMA levels are weakly associated with thromboembolic events, elevated SDMA levels with bleeding events and both are strongly associated with increased mortality. These findings suggest that disturbances of NO function modulate both thrombotic and hemorrhagic risk in anticoagulated patients with AF. (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation [ARISTOTLE]; NCT00412984)
The ARISTOTLE trial and this substudy were funded by Bristol-Myers Squibb and Pfizer Inc. Dr. De Caterina has received institutional grant support from Bayer, Boehringer Ingelheim, and Daiichi-Sankyo; honoraria and lecture fees from Bristol-Myers Squibb/Pfizer; consulting fees and honoraria from Bayer, Boehringer Ingelheim, Daiichi-Sankyo, Eli Lilly, Merck, and Novartis; and has served as a steering committee member for Bristol-Myers Squibb/Pfizer. Dr. Alexander has received institutional research grants from Bristol-Myers Squibb, Merck, Pfizer, Boehringer Ingelheim, CSL Behring, National Institutes of Health, Regado Biosciences, Sanofi, Tenax Therapeutics, and Vivus Pharmaceuticals; and consulting fees and honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Merck, Ortho-McNeil-Janssen, Pfizer, Portola Pharmaceuticals, Regado Biosciences, and Sohmalution. Dr. Andersson has received an institutional research grant from Bristol-Myers Squibb/Pfizer. Dr. Lopes has received institutional grant support from Bristol-Myers Squibb and GlaxoSmithKline; consulting fees from Bayer, Boehringer Ingelheim, and Pfizer; and honoraria from Merck and Portola. Dr. Steg has received institutional research grants from Merck, Sanofi, and Servier; honoraria and nonfinancial support from AstraZeneca, Sanofi, and Servier; and honoraria from Amarin, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Medtronic, Janssen, The Medicines Company, CSL-Behring, Regeneron, and GlaxoSmithKline; and is a stockholder in Aterovax. Dr. Hylek has served as an advisory board member for Bayer, Boehringer Ingelheim, Bristol-Myers Squibb Daiichi-Sankyo, Janssen, Medtronic, and Pfizer; and has received symposium lecture fees from Bayer, Boehringer Ingelheim, and Bristol-Myers Squibb. Dr. Mohan is a former employee of Bristol-Myers Squibb. Dr. Hanna is an employee of and has stock ownership in Bristol-Myers Squibb. Dr. Granger has received research grants from GlaxoSmithKline, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Sanofi, Takeda, The Medicines Company, Janssen, Bayer, Medtronics Foundation, Merck & Co., and Armetheon; and personal fees from GlaxoSmithKline, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Sanofi, Takeda, The Medicines Company, Janssen, Bayer, Hoffmann-La Roche, Eli Lilly, AstraZeneca, Daiichi-Sankyo, Ross Medical Corporation, Salix Pharmaceuticals, Gilead, and Medtronic. Prof. Wallentin has received institutional research grants from AstraZeneca, Bristol-Myers Squibb/Pfizer, Boehringer Ingelheim, GlaxoSmithKline, Merck & Co., and Roche; consultancy fees from GlaxoSmithKline, Abbott, AstraZeneca, Bristol-Myers Squibb/Pfizer, and Boehringer Ingelheim; lecture fees and travel support from GlaxoSmithKline, AstraZeneca, Bristol-Myers Squibb/Pfizer, and Boehringer Ingelheim; honoraria from GlaxoSmithKline; and holds 2 patents involving GDF-15. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received April 28, 2016.
- Revision received April 17, 2018.
- Accepted May 10, 2018.
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