Author + information
- Received June 1, 2020
- Revision received July 15, 2020
- Accepted July 20, 2020
- Published online September 14, 2020.
- Alan John Camm, MDa,∗ (, )@TRI_Thrombosis,
- Frank Cools, MDb,
- Saverio Virdone, MScc,
- Jean-Pierre Bassand, MDc,d,
- David Andrew Fitzmaurice, MDe,
- Keith Alexander Arthur Fox, MBChBf,
- Samuel Zachary Goldhaber, MDg,
- Shinya Goto, MD, PhDh,
- Sylvia Haas, MD, PhDi,
- Lorenzo Giovanni Mantovani, MScj,k,
- Gloria Kayani, BScc,
- Alexander Graham Grierson Turpie, MDl,
- Freek Willem Antoon Verheugt, MD, PhDm,
- Ajay Kumar Kakkar, MBBS, PhDc,n,
- for the GARFIELD-AF Investigators∗
- aCardiology Clinical Academic Group Molecular & Clinical Sciences Research Institute, St. George’s University of London, London, United Kingdom
- bDepartment of Cardiology, AZ KLINA, Brasschaat, Belgium
- cDepartment of Clinical Research, Thrombosis Research Institute, London, United Kingdom
- dDepartment of Cardiology, Besançon, Besançon, France
- eWarwick Medical School, University of Warwick, Coventry, United Kingdom
- fCentre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom
- gDepartment of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
- hDepartment of Medicine (Cardiology), Tokai University School of Medicine, Kanagawa, Japan
- iFormerly Department of Medicine, Technical University of Munich, Munich, Germany
- jCenter for Public Health Research (CESP), PostGraduate School of Hygiene and Preventive Medicine, University of Milan Bicocca, Milan, Italy
- kValue-Based Healthcare Unit, IRCCS Multimedica, Sesto San Giovanni, Italy
- lDepartment of Medicine, McMaster University, Hamilton, Ontario, Canada
- mDepartment of Cardiology, Onze Lieve Vrouwe Gasthuis (OLVG), Amsterdam, the Netherlands
- nUniversity College London, London, United Kingdom
- ↵∗Address for correspondence:
Dr. A. John Camm, St. George’s University of London, Division of Clinical Sciences, Cranmer Terrace, Tooting, London SW17 0RE, United Kingdom.
Background The recommended doses for direct oral anticoagulants (DOACs) to prevent stroke and systemic embolism (SE) in patients with atrial fibrillation (AF) are described in specific regulatory authority approvals.
Objectives The impact of DOAC dosing, according to the recommended guidance on all-cause mortality, stroke/SE, and major bleeding, was assessed at 2-year follow-up in patients with newly diagnosed AF.
Methods Of a total of 34,926 patients enrolled (2013 to 2016) in the prospective GARFIELD-AF (Global Anticoagulant Registry in the FIELD-AF), 10,426 patients received a DOAC.
Results The majority of patients (72.9%) received recommended dosing, 23.2% were underdosed, and 3.8% were overdosed. Nonrecommended dosing (underdosage and overdosage combined) compared with recommended dosing was associated with a higher risk of all-cause mortality (hazard ratio [HR]: 1.24; 95% confidence interval [CI]: 1.04 to 1.48); HR: 1.25 (95% CI: 1.04 to 1.50) for underdosing, and HR: 1.19 (95% CI: 0.83 to 1.71) for overdosing. The excess deaths were cardiovascular including heart failure and myocardial infarction. The risks of stroke/SE and major bleeding were not significantly different irrespective of the level of dosing, although underdosed patients had a significantly lower risk of bleeding. A nonsignificant trend to higher risks of stroke/SE (HR: 1.51; 95% CI: 0.79 to 2.91) and major bleeding (HR: 1.29; 95% CI: 0.59 to 2.78) was observed in patients with overdosing.
Conclusions In GARFIELD-AF, most patients received the recommended DOAC doses according to country-specific guidelines. Prescription of nonrecommended doses was associated with an increased risk of death, mostly cardiovascular death, compared with patients on recommended doses, after adjusting for baseline factors. (Global Anticoagulant Registry in the Field-AF [GARFIELD-AF]; NCT01090362)
This work was supported by an unrestricted research grant from Bayer AG (Berlin, Germany) to the Thrombosis Research Institute, which sponsors the GARFIELD-AF registry. The funding source had no involvement in the data collection, data analysis, or data interpretation. Dr. Camm has received institutional grants and personal fees from Bayer, Boehringer Ingelheim, Pfizer/Bristol-Myers Squibb, and Daiichi-Sankyo, outside of the submitted work. Dr. Cools has received speaker fees from Boehringer Ingelheim Pharma, Bayer AG, and Pfizer; and has received speaker fees and modest research grant support from Daiichi-Sankyo Europe. Dr. Fitzmaurice has received personal fees from Bayer outside of the submitted work. Dr. Fox has received grants and personal fees from Bayer, Janssen, and AstraZeneca; and has received personal fees from Sanofi/Regeneron and Verseon outside the submitted work. Dr. Goldhaber has received research support from BiO2 Medical, Boehringer Ingelheim, Bristol-Myers Squibb, Boston Scientific, Daiichi-Sankyo, Janssen, National Heart, Lung, and Blood Institute, and the Thrombosis Research Institute; and has served as a consultant for Agile, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Janssen, Portola, and Zafgen. Dr. Goto has received personal fees from the Thrombosis Research Institute and the American Heart Association; and has received grants from Sanofi, Ono, Bristol-Myers Squibb, the Vehicle Racing Commemorative Foundation, and the Nakatani Foundation for Advancement of Measuring Technologies in Biomedical Engineering. Dr. Haas has received personal fees from Aspen, Bayer, Bristol-Myers Squibb, Daiichi-Sankyo, Portola, and Sanofi outside of the submitted work. Dr. Mantovani has received grants and personal fees from Bayer AG during the conduct of the study; has received grants from Boehringer Ingelheim; has received grants and personal fees from Pfizer; has received personal fees from Daiichi-Sankyo; and has received support from the Italian Ministry of Health Ricerca Corrente-IRCCS MultiMedica outside of the submitted work. Dr. Turpie has received personal fees from Bayer Healthcare, Janssen Pharmaceutical Research & Development LLC, Satilla’s, and Portola. Dr. Verheugt has received grants from Bayer Healthcare; and has received personal fees from Bayer Healthcare, Bristol-Myers Squibb/Pfizer, Daiichi-Sankyo, and Boehringer Ingelheim. Dr. Kakkar has received research support from Bayer AG during the conduct of the study; and has received personal fees from Bayer AG, Janssen Pharma, Sanofi SA, Pfizer, and Verseon outside of the submitted work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC author instructions page.
- Received June 1, 2020.
- Revision received July 15, 2020.
- Accepted July 20, 2020.
- 2020 The Authors