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)

Miklos Rohla, Thomas W Weiss, Ladislav Pecen, Giuseppe Patti, Jolanta M Siller-Matula, Renate B Schnabel, Richard Schilling, Dipak Kotecha, Markus Lucerna, Kurt Huber, Raffaele De Caterina, Paulus Kirchhof, Miklos Rohla, Thomas W Weiss, Ladislav Pecen, Giuseppe Patti, Jolanta M Siller-Matula, Renate B Schnabel, Richard Schilling, Dipak Kotecha, Markus Lucerna, Kurt Huber, Raffaele De Caterina, Paulus Kirchhof

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.

Keywords: anticoagulation; atrial fibrillation; major bleeding; risk stratification; thromboembolism.

Conflict of interest statement

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).

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
Risk factors for thromboembolic events in anticoagulated atrial fibrillation patients, presented as ORs with 95% CIs (PREvention oF thromboembolic events - European Registry in Atrial Fibrillation derivation cohort). *Concomitant therapy with antiplatelet agents or non-steroidal anti-inflammatory drugs. INR, international normalised ratio; TIA, transient ischaemic attack.
Figure 2
Figure 2
Risk factors for major bleeding events in anticoagulated atrial fibrillation patients, presented as ORs with 95% CIs (PREvention oF thromboembolic events - European Registry in Atrial Fibrillation derivation cohort). *Concomitant therapy with antiplatelet agents or non-steroidal anti-inflammatory drugs. INR, international normalised ratio.

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