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Risk factors for thromboembolic and bleeding events in anticoagulated patients with atrial fibrillation: the prospective, multicentre observational PREvention oF thromboembolic events - European Registry in Atrial Fibrillation (PREFER in AF)
  1. Miklos Rohla1,2,
  2. Thomas W Weiss2,3,
  3. Ladislav Pecen4,
  4. Giuseppe Patti5,
  5. Jolanta M Siller-Matula6,
  6. Renate B Schnabel7,
  7. Richard Schilling8,
  8. Dipak Kotecha9,
  9. Markus Lucerna10,
  10. Kurt Huber1,3,
  11. Raffaele De Caterina11,
  12. Paulus Kirchhof9
  1. 1 3rd Medical Department, Cardiology and Intensive Care Medicine, Wilhelminen Hospital, Vienna, Austria
  2. 2 Institute for Cardiometabolic Diseases, Karl Landsteiner Society, St. Pölten, Austria
  3. 3 Cardiology, Sigmund Freud University, Medical School, Vienna, Austria
  4. 4 Cardiology, Medical Faculty Pilsen, Charles University, Pilsen, Czech Republic
  5. 5 Department of Cardiovascular Sciences, Campus Bio-Medico University of Rome, Rome, Italy
  6. 6 Department of Cardiology, Medical University of Vienna, Vienna, Austria
  7. 7 University Heart Center Hamburg, Clinic for General and Interventional Cardiology, Hamburg, Germany and DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Luebeck, Hamburg, Germany
  8. 8 Department of Cardiology, St Bartholomew’s Hospital, London, UK
  9. 9 University of Birmingham Institute of Cardiovascular Sciences, University of Birmingham, UHB and SWBH NHS Trusts, Birmingham, UK
  10. 10 Daiichi Sankyo Europe, Munich, Germany
  11. 11 University of Pisa and Division of Cardiology, Pisa University Hospital, Pisa, Italy
  1. Correspondence to Dr Paulus Kirchhof; p.kirchhof{at}bham.ac.uk

Abstract

Objectives We identified factors associated with thromboembolic and bleeding events in two contemporary cohorts of anticoagulated patients with atrial fibrillation (AF), treated with either vitamin K antagonists (VKA) or non-VKA oral anticoagulants (NOACs).

Design Prospective, multicentre observational study.

Setting 461 centres in seven European countries.

Participants 5310 patients receiving a VKA (PREvention oF thromboembolic events - European Registry in Atrial Fibrillation (PREFER in AF), derivation cohort) and 3156 patients receiving a NOAC (PREFER in AF Prolongation, validation cohort) for stroke prevention in AF.

Outcome measures Risk factors for thromboembolic events (ischaemic stroke, systemic embolism) and major bleeding (gastrointestinal bleeding, intracerebral haemorrhage and other life-threatening bleeding).

Results The mean age of patients enrolled in the PREFER in AF registry was 72±10 years, 40% were female and the mean CHA2DS2-VASc Score was 3.5±1.7. The incidence of thromboembolic and major bleeding events was 2.34% (95% CI 1.93% to 2.74%) and 2.84% (95% CI 2.41% to 3.33%) after 1-year of follow-up, respectively.

Abnormal liver function, prior stroke or transient ischaemic attack, labile international normalised ratio (INR), concomitant therapy with antiplatelet or non-steroidal anti-inflammatory drugs, heart failure and older age (≥75 years) were independently associated with both thromboembolic and major bleeding events.

With the exception of unstable INR values, these risk factors were validated in patients treated with NOACs (PREFER in AF Prolongation Study, 72±9 years, 40% female, CHA2DS2-VASc 3.3±1.6). For each single point decrease on a modifiable bleeding risk scale we observed a 30% lower risk for major bleeding events (OR 0.70, 95% CI 0.64 to 0.76, p<0.01) and a 28% lower rate of thromboembolic events (OR 0.72, 95% CI 0.66 to 0.82, p<0.01).

Conclusion Attending to modifiable risk factors is an important treatment target in anticoagulated AF patients to reduce thromboembolic and bleeding events. Initiation of anticoagulation in those at risk of stroke should not be prevented by elevated bleeding risk scores.

  • atrial fibrillation
  • anticoagulation
  • thromboembolism
  • major bleeding
  • risk stratification

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

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Footnotes

  • Contributors MR contributed to the statistical analysis and prepared the manuscript draft. TWW contributed to the statistical analysis and reviewed the manuscript draft. LP performed the statistical analysis. GP contributed to the design of the present analysis and reviewed the manuscript draft. JMSM contributed to the design of the present analysis and reviewed the manuscript draft. RBS contributed to the design of the present analysis and reviewed the manuscript draft. RS was involved in the conduct of the PREFER in AF study, contributed to the design of the present analysis and reviewed the manuscript draft. DK contributed to the design of the present analysis including statistical consideration and reviewed the manuscript draft. ML was involved in the funding and conduct of the PREFER in AF study and the present analysis. KH contributed to the design of the present analysis and reviewed the manuscript draft. RDC was involved in the conduct of the PREFER in AF study, contributed to the design of the present analysis and reviewed the manuscript draft. PK was involved in the conduct of the PREFER in AF study, contributed to the design of the present analysis including statistical consideration and reviewed the final manuscript draft.

  • Funding The PREFER in AF study was supported by Daiichi-Sankyo Europe.

  • Competing interests MR received advisory fees from Daiichi Sankyo and Novarits and lecutring fees from Biotronik and Takeda Pharma. TWW received lecturing fees and advisory honoraria from Daiichi Sankyo, Boehringer Ingelheim and Pfizer/BMS. LP consultant fees from Daiichi-Sankyo, SOTIO, Beckman Coulter, Novartis. GP speaker/consultant/advisory board for Amgen, Sanofi, Bayer, Boehringer-Ingelheim, BMS-Pfizer, Daiichi Sankyo, Astra Zeneca, Sigma-Tau, Malesci, PIAM and MSD. JMSM lecture or consultant fees from AstraZeneca, Daiichi Sankyo, Eli Lilly, Bayer and research grant from Roche Diagnostics. Menarini and lecture fees from AtriCure, all outside the submitted workML is affiliated with the sponsor. KH received lecturing fees and advisory honoraria from Boehringer Ingelheim, Pfizer/BMS, Bayer, Daiichi Sankyo, Sanofi-Aventis, AstraZeneca, and Eli Lilly. RDC received research grants from Boehringer-Ingelheim, Bayer and BMS/Pfizer. Honoraria for lecturing and participation to Advisory Boards from Boehringer-Ingelheim, Bayer and BMS/Pfizer, Daiichi-Sankyo, Lilly, AstraZeneca, Merck, Novartis, Roche. PK has received research support from European Union, British Heart Foundation, Leducq Foundation, Medical Research Council (UK), and German Centre for Heart Research, from several drug and device companies active in atrial fibrillation, and has received honoraria from several such companies. PK is listed as inventor on two patents held by University of Birmingham (Atrial Fibrillation Therapy WO 2015140571, Markers for Atrial Fibrillation WO 2016012783).

  • Ethics approval Ethics committees in the respective seven participating European countries, as listed in the online supplementary appendix.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement Main results from the PREFER in AF study are accessible from DOI 10.1093/europace/eut263.

  • Patient consent for publication Not required.

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