# Direct oral anticoagulants versus no anticoagulation for the prevention of stroke in survivors of intracerebral haemorrhage with atrial fibrillation (PRESTIGE-AF): a multicentre, open-label, randomised, phase 3 trial

Roland Veltkamp, Eleni Korompoki, Kirsten H Harvey, Emily R Harvey, Cornelia Fiessler, Uwe Malzahn, Viktoria Rucker, Joan Montaner, Valeria Caso, Igor Sibon, et al.

► To cite this version:

Roland Veltkamp, Eleni Korompoki, Kirsten H Harvey, Emily R Harvey, Cornelia Fiessler, et al. Direct oral anticoagulants versus no anticoagulation for the prevention of stroke in survivors of intracerebral haemorrhage with atrial fibrillation (PRESTIGE-AF): a multicentre, open-label, randomised, phase 3 trial. The Lancet, 2025, 405 (10482), pp.927-936. 10.1016/s0140-6736(25)00333-2. hal-05030487

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# Direct oral anticoagulants versus no anticoagulation for the prevention of stroke in survivors of intracerebral haemorrhage with atrial fibrillation (PRESTIGE-AF): a multicentre, open-label, randomised, phase 3 trial

Roland Veltkamp, Eleni Korompoki, Kirsten H Harvey, Emily R Harvey, Cornelia Fießler, Uwe Malzahn, Viktoria Rücker, Joan Montaner, Valeria Caso, Igor Sibon, Peter Ringleb, Omid Halse, Klemens Hügen, Sabine Ullmann, Carolin Schuhmann, Gabriele Putz Todd, Kirsten Haas, Elena Palà, Stéphanie Debette, Morgane Lachaize, Tim D'Aoust, Christian Enzinger, Stefan Ropele, Simon Fandler-Höfler, Melanie Haidegger, Yanzhong Wang, Hatem A Wafa, Virginia Cancelloni, Maria Giulia Mosconi, Gregory Y H Lip, Deirdre A Lane, Walter E Haefeli, Kathrin I Foerster, Viktoria S Wurmbach, Peter Brønnum Nielsen, Karim Hajjar, Patrick Müller, Sven Poli, Jan Purrucker, Mona Laible, Lucio D'Anna, Yolanda Silva, Reyes de Torres Chacon, Patricia Martínez-Sánchez, Marion Boulanger, Bo Norrving, Guillaume Paré, Rolf Wachter, George Ntaios, Charles D A Wolfe, Peter U Heuschmann, on behalf of the PRESTIGE-AF Consortium*

## Summary

**Background** Direct oral anticoagulants (DOACs) reduce the rate of thromboembolism in patients with atrial fibrillation but the benefits and risks in survivors of intracerebral haemorrhage are uncertain. We aimed to determine whether DOACs reduce the risk of ischaemic stroke without substantially increasing the risk of recurrent intracerebral haemorrhage.

**Methods** PRESTIGE-AF is a multicentre, open-label, randomised, phase 3 trial conducted at 75 hospitals in six European countries. Eligible patients were aged 18 years or older with spontaneous intracerebral haemorrhage, atrial fibrillation, an indication for anticoagulation, and a score of 4 or less on the modified Rankin Scale. Patients were randomly assigned (1:1) to a DOAC or no anticoagulation, stratified by intracerebral haemorrhage location and sex. Only the events adjudication committee was masked to treatment allocation. The coprimary endpoints were first ischaemic stroke and first recurrent intracerebral haemorrhage. Hierarchical testing for superiority and non-inferiority, respectively, was performed in the intention-to-treat population. The margin to establish non-inferiority regarding intracerebral haemorrhage was less than 1·735. The safety analysis was done in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, NCT03996772, and is complete.

**Findings** Between May 31, 2019, and Nov 30, 2023, 319 participants were enrolled and 158 were randomly assigned to the DOAC group and 161 to the no anticoagulant group. Patients' median age was 79 years (IQR 73–83). 113 (35%) of 319 patients were female and 206 (65%) were male. Median follow-up was 1·4 years (IQR 0·7–2·3). First ischaemic stroke occurred less frequently in the DOAC group than in the no anticoagulant group (hazard ratio [HR] 0·05 [95% CI 0·01–0·36]; log-rank p<0·0001). The rate of all ischaemic stroke events was 0·83 (95% CI 0·14–2·57) per 100 patient-years in the DOAC group versus 8·60 (5·43–12·80) per 100 patient-years in the no anticoagulant group. For first recurrent intracerebral haemorrhage, the DOAC group did not meet the prespecified HR for the non-inferiority margin of less than 1·735 (HR 10·89 [90% CI 1·95–60·72]; p=0·96). The event rate of all intracerebral haemorrhage was 5·00 (95% CI 2·68–8·39) per 100 patient-years in the DOAC group versus 0·82 (0·14–2·53) per 100 patient years in the no anticoagulant group. Serious adverse events occurred in 70 (44%) of 158 patients in the DOAC group and 89 (55%) of 161 patients in the no anticoagulant group. 16 (10%) patients in the DOAC group and 21 (13%) patients in the no anticoagulant group died.

**Interpretation** DOACs effectively prevent ischaemic strokes in survivors of intracerebral haemorrhage with atrial fibrillation but a part of this benefit is offset by a substantially increased risk of recurrent intracerebral haemorrhage. To optimise stroke prevention in these vulnerable patients, further evidence from ongoing trials and a meta-analysis of randomised data is needed, as well as the evaluation of safer medical or mechanical alternatives for selected patients.

**Funding** European Commission.

**Copyright** © 2025 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.

## Introduction

Intracerebral haemorrhage is a devastating type of stroke. An estimated 25% of survivors of intracerebral haemorrhage have atrial fibrillation, most of whom are

anticoagulated at the time of the event.¹,² Survivors of intracerebral haemorrhage with atrial fibrillation are at an especially high risk of ischaemic stroke and cardiovascular events.³,⁴ Although there is strong evidence that oral

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oa
OPEN ACCESS

Lancet 2025; 405: 927–36

Published Online
February 26, 2025
https://doi.org/10.1016/
S0140-6736(25)00333-2

This online publication has
been corrected. The corrected
version first appeared at
thelancet.com on
March 13, 2025

See Comment page 872

*Members of the PRESTIGE-AF
Consortium are listed in the
appendix (p 2)

Department of Brain Sciences,
Imperial College London,
London, UK

(Prof R Veltkamp MD,
E Korompoki PhD,
K H Harvey MRes, E R Harvey BSc,
O Halse MD, L D'Anna PhD);

Department of Neurology,
Alfred-Krupp Krankenhaus,
Essen, Germany

(Prof R Veltkamp, K Hajjar MD,
P Müller MD); Department of
Neurology, Heidelberg
University Hospital,
Heidelberg, Germany
(Prof R Veltkamp,
Prof P Ringleb MD,
Prof J Purrucker MD);

Department of Clinical
Therapeutics, National and
Kapodistrian University of
Athens, Alexandra Hospital,
Athens, Greece (E Korompoki);
Clinical Trial Center Würzburg,
University Hospital Würzburg,
Würzburg, Germany
(C Fießler PhD, U Malzahn PhD,
K Hügen MSc, S Ullmann MSc,
C Schuhmann, G Putz Todd PhD,
Prof P U Heuschmann MD);

Institute of Clinical
Epidemiology and Biometry,
University of Würzburg,
Würzburg, Germany
(V Rücker PhD, K Haas PhD, Prof P U Heuschmann); Instituto de Biomedicina de Sevilla, Centro Superior Investigaciones Científicas/Universidad de Sevilla, Seville, Spain (J Montaner MD); Department of Neurology, Hospital Universitario Virgen Macarena, Seville, Spain (J Montaner); Neurovascular Research Laboratory, Vall d'Hebron Institute of Research, Hospital Vall d'Hebron, Barcelona, Spain (J Montaner, E Palà PhD); Stroke Unit—Internal, Vascular and Emergency Medicine, University of Perugia, Santa Maria della Misericordia Hospital Perugia, Perugia, Italy (V Caso MD, V Cancelloni MD, M G Mosconi MD); Institut de Neurosciences Cognitives et Intégratives d'Aquitaine, and Bordeaux Neurocampus (I Sibon PhD), UMR 1219 Bordeaux Population Health Center (Prof S Debette PhD, M Lachaize MSc, T D'Aoust MSc), University of Bordeaux, Bordeaux, France; Stroke Unit (I Sibon), and Department of Neurology, Institute for Neurodegenerative Diseases (Prof S Debette, M Lachaize), Bordeaux University Hospital, Bordeaux, France; Department of Stroke and Neuroscience, Charing Cross Hospital, Imperial College Healthcare NHS Trust, London, UK (O Halse, L D'Anna); Department of Neurology, Medical University of Graz, Graz, Austria (Prof C Enzinger MD, S Ropele PhD, S Fandler-Höfler MD PhD, M Haidegger MD); School of Life Course and Population Sciences, King's College London, London, UK (Y Wang PhD, H A Wafa PhD, C D A Wolfe MD); Danish Center for Health Services Research, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark (Prof G Y H Lip MD, Prof D A Lane PhD, P Brønnum Nielsen PhD); Liverpool Centre for Cardiovascular Science, University of Liverpool, Liverpool John Moores University and Liverpool Heart & Chest Hospital, Liverpool, UK (Prof G Y H Lip, Prof D A Lane); Cardiovascular and Metabolic Medicine, Institute of Life

Research in context

Evidence before this study

Direct oral anticoagulants (DOACs) reduce the rate of thromboembolism in patients with atrial fibrillation but their benefits and risks in survivors of intracerebral haemorrhage are uncertain. In meta-analyses of observational studies, anticoagulation reduced the risk of ischaemic stroke without increasing the risk of recurrent intracerebral haemorrhage; however, these data were prone to selection bias and confounding by indication. We searched MEDLINE, Embase, Cochrane library, EudraCT, and ClinicalTrials.gov from database inception to January, 2025, for randomised controlled trials comparing anticoagulation with no anticoagulation using the key search terms "intracerebral haemorrhage", "atrial fibrillation", and "oral anticoagulation", with no language restrictions. We found an individual patient data meta-analysis on survivors of intracerebral haemorrhage with atrial fibrillation and data from the ELDERCARE-AF trial (NCT02801669). The meta-analysis reported uncertain effects of oral anticoagulation on the risk of any stroke, cardiovascular mortality, and haemorrhagic major adverse events but suggested ischaemic adverse cardiovascular events were reduced and data from larger randomised trials were needed to resolve the remaining uncertainty.

Added value of this study

The PRESTIGE-AF trial is the first completed phase 3 trial of antithrombotic stroke prevention in survivors of intracerebral

anticoagulation prevents ischaemic strokes in patients with atrial fibrillation with no previous intracerebral haemorrhage,⁵,⁶ the optimal preventive management of stroke among survivors of intracerebral haemorrhage with atrial fibrillation is uncertain because patients with intracerebral haemorrhage have been excluded from trials.

In 2017, systematic reviews and meta-analyses of observational studies suggested a benefit of oral anticoagulants (mostly vitamin K antagonists) for the prevention of ischaemic stroke in survivors of intracerebral haemorrhage,⁷,⁸ and one large national register-based study showed a 45% reduction in mortality in patients receiving anticoagulants.⁹ Anticoagulation was not associated with a significant increase in recurrent intracranial haemorrhage in these studies.⁷ Subsequent pilot-phase, randomised controlled trials¹⁰,¹¹ using direct oral anticoagulants (DOACs), which confer about half the risk of intracranial haemorrhages compared with vitamin K antagonists, and an individual patient data meta-analysis of randomised controlled data¹² reported inconclusive effects of oral anticoagulation on the risk of any stroke, cardiovascular mortality, and haemorrhagic adverse events, but suggested a reduction of ischaemic adverse cardiovascular events. Hence, additional evidence from larger trials was needed to identify the best preventive management in survivors of intracerebral haemorrhage with atrial fibrillation.¹² We aimed to assess the efficacy and safety of DOACs compared

haemorrhage with atrial fibrillation that compared the effects of DOACs versus no anticoagulation. Participants assigned to DOACs had significantly fewer ischaemic strokes than those assigned to no anticoagulation. This benefit was partly offset by a significantly increased risk of recurrent intracerebral haemorrhage and other major bleedings. Nevertheless, trends in favour of DOAC were observed for the prespecified secondary endpoint of all stroke and systemic embolism as well as for cardiovascular and all-cause mortality consistent with previous observations in pilot-phase trials.

Implications of all the available evidence

Anticoagulation with DOACs substantially reduces the risk of ischaemic stroke and other major ischaemic adverse outcomes in survivors of intracerebral haemorrhage with atrial fibrillation. However, a part of this benefit is offset by an increased risk of recurrent intracerebral haemorrhage and other major haemorrhagic complications. To optimise stroke prevention in these vulnerable patients, further evidence from ongoing trials and a meta-analysis of randomised data is needed. Potentially safer medical or mechanical alternatives are also being investigated in ongoing research including randomised trials.

with no anticoagulation in survivors of intracerebral haemorrhage with atrial fibrillation.

Methods

Study design

The PRESTIGE-AF trial was a multicentre, open-label, randomised, phase 3 trial done at 75 hospitals with stroke units in six countries in Europe (UK, Germany, Austria, Spain, Italy, and France). Details of the trial design have been published previously.¹³ The trial followed the principles of the Declaration of Helsinki and the Council for International Organizations of Medical Sciences International Ethical Guidelines. Research ethics committees and authorities in each participating country approved the trial protocol (version 3; Oct 5, 2018, lead ethics approval in the UK 18/LO/1186) and subsequent amendments (appendix pp 6–7). The trial steering committee and sponsor approved the final version of the trial protocol (version 7; May 4, 2023; appendix) and the statistical analysis plan (final version 1.5; April 18, 2024, before database lock and analysis; appendix). This trial is registered with ClinicalTrials.gov, NCT03996772, and is complete.

Participants

Eligible patients were aged 18 years or older with a spontaneous intracerebral haemorrhage, atrial
fibrillation, an indication for anticoagulation, and a score of 4 or less on the modified Rankin Scale.¹⁴ Enrolment occurred from 14 days to 12 months (initially 6 months) after the index intracerebral haemorrhage. Exclusion criteria included intracerebral haemorrhage resulting from vascular malformation or trauma and the presence of or the plan to implant a left atrial appendage occlusion device. Full eligibility criteria are presented in the appendix (p 7). Eligible patients or their legal representatives were approached by local investigators. Written informed consent was obtained from the patient or their legal representative (after an amendment) if the patient lacked capacity to consent.

## Randomisation and masking

Patients were randomly assigned (1:1) to receive a DOAC or no anticoagulation using a central web-based randomisation system (secuTrial), stratified according to intracerebral haematoma location (lobar vs non-lobar, determined by each site) and sex. Haematoma location and volume were reassessed by the imaging core laboratory (Medical University of Graz) using the Cerebral Haemorrhage Anatomical RaTing instrument.¹⁵

Treatment allocation was known to patients, treating clinicians, and investigators including patients into the trial and completing follow-up. Outcome events were assessed by an event adjudication committee masked to treatment allocation, drug use, and participant identity, by redaction of source documents.

## Procedures

Patients assigned to the DOAC group received apixaban, dabigatran, edoxaban, or rivaroxaban at the discretion of local investigators. A dose licensed for stroke prevention in atrial fibrillation by the European Medicines Agency was prescribed. All DOACs were labelled by the central pharmacy (Heidelberg University Hospital). Patients in the no anticoagulation group received antiplatelet medication (eg, aspirin 100 mg once per day) or no antiplatelet medication as decided by local investigators. The use of dual antiplatelets was not permitted at enrolment but was allowed during follow-up if clinically warranted (appendix p 8).

At screening and enrolment, demographics, cardiovascular risk factors, medical history, concomitant medication, and vital signs were recorded. Data were collected to calculate the risk of stroke using the CHA₂DS₂-VASc score (for which points are assigned for the following risk factors: congestive heart failure, hypertension, age ≥75 years [doubled], diabetes, previous stroke [doubled], vascular disease, and female sex), with scores ranging from 1 to 9 and higher scores indicating a greater risk of stroke. Risk of major bleeding was calculated using the HAS-BLED score (for which points are assigned for the following risk factors: uncontrolled hypertension or systolic blood pressure >160 mm Hg, abnormal renal or liver function, previous stroke,

bleeding history or predisposition, labile international normalised ratio, age >65 years, concomitant drugs, and alcohol use), with scores ranging from 0 to 9 and higher scores indicating a greater risk of bleeding.

Patients were followed up for at least 6 months, and up to 36 months, with in-person follow-up visits scheduled at 1, 6, 12, 24, and 36 months. Off-site or remote visits were permitted if the patient was unable to attend the site. Essential procedures included blood pressure measurements, blood sample collection, outcome and adverse event recording, and drug accountability. All sites with enrolled patients underwent repeated on-site monitoring with source data verification. Trial conduct, data quality, and patient safety were centrally monitored throughout the study.

## Outcomes

The two coprinary binary endpoints were first incident ischaemic stroke and first recurrent intracerebral haemorrhage (definitions of all endpoints and outcomes are provided in the appendix pp 8–10). Prespecified secondary endpoints were all stroke and systemic embolism, major adverse cardiac events, cardiovascular mortality, all-cause mortality, and net clinical benefit comprising all stroke and systemic embolism, myocardial infarction, cardiovascular mortality, and major bleeding.¹⁶ Secondary safety endpoints were all events of intracranial haemorrhage and all events of major bleeding according to the International Society on Thrombosis and Haemostasis classification.¹⁷ All prespecified primary and secondary endpoints were centrally assessed by the event adjudication committee. All serious adverse events were reviewed centrally by the sponsor and presented periodically to the independent data safety monitoring board.

## Statistical analysis

The original sample size calculation was based on a meta-analysis of observational studies in which patients mostly received vitamin K antagonists as anticoagulants.⁷ The calculation yielded a total of 654 participants (327 per group in a 1:1 randomisation). A revision of the power analysis was performed in 2022 after data from two pilot-phase trials became available.¹⁰,¹¹ This power analysis also accounted for the slower than expected recruitment rate and considered different recruitment scenarios during the remaining funding period (full details are provided in the appendix). The different recruitment scenarios resulted in 294–340 participants in total. For the coprinary endpoint of ischaemic stroke, the corresponding power analysis calculated more than 80% power at a significance level of 0·05 for hazard ratios (HRs) less than 0·348, assuming a 10% dropout rate and a 5% change of treatment regimen. The scenario considered most realistic was a recruitment rate of 12 participants per month, yielding an expected sample size of 312 participants.

Course and Medical Sciences, University of Liverpool, Liverpool, UK (Prof D A Lane); Internal Medicine IX (Prof W E Haefeli, V S Wurmbach PhD) and Cooperation Unit Clinical Pharmacy (Prof W E Haefeli, K I Foerster PhD, V S Wurmbach), Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Heidelberg, Germany; Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark (P Brønnum Nielsen); Department of Neurology & Stroke (S Poli MD), and Hertie Institute for Clinical Brain Research (S Poli), University of Tübingen, Tübingen, Germany; Department of Neurology, University of Ulm, Ulm, Germany (M Laible MD); Department of Neurology, Hospital Universitari Dr José Trueta, IDIBGI, Girona, Spain (Y Silva PhD); Servicio de Neurología, Hospital Universitario Virgen Macarena, Seville, Spain (R de Torres Concha MD); Department of Neurology, Torrecárdenas University Hospital, University of Almería, Almería, Spain (P Martínez-Sánchez MD); Neurology Department, Caen University Hospital, Caen, France (M Boulanger PhD); Department of Clinical Sciences and Department of Neurology, Skåne University Hospital, Lund University, Lund, Sweden (Prof B Norrving MD); Thrombosis and Atherosclerosis Research Institute, ON, Canada (G Paré) MD; McMaster University, Hamilton, ON, Canada (G Paré); Hamilton Health Sciences, Hamilton, ON, Canada (G Paré); Population Health Research Institute, Hamilton, ON, Canada (G Paré); Department of Cardiology, University Hospital Leipzig, Leipzig, Germany (R Wachter MD); First Propedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece (Prof G Ntaios PhD); NIHR Applied Research Collaboration South London, London, UK (C D A Wolfe); Institute for Medical Data Science, University Hospital Würzburg,
Würzburg, Germany
(Prof P U Heuschmann)

Correspondence to:
Prof Roland Veltkamp,
Department of Brain Sciences,
Imperial College London,
London W6 8RP, UK

r.veltkamp@imperial.ac.uk

See Online for appendix

Within the primary analysis, statistical tests for the two coprprimary endpoints were combined by a fixed sequence hierarchical test procedure (ie, the null hypothesis for recurrent intracerebral haemorrhage was only tested if the null hypothesis for incident ischaemic stroke could be rejected at a significance level of 0.05). Therefore, the overall significance level of the analyses of 0.05 was preserved. The primary efficacy statistical test procedure for the first coprprimary endpoint was a two-sided log-rank test for the time from randomisation to the first incident ischaemic stroke. The hypothesis for the second coprprimary endpoint was tested with a non-inferiority log-rank test for the time from randomisation to the first event of recurrent intracerebral haemorrhage. Assignment to the DOAC group was assessed as non-inferior compared with the no anticoagulant group if the absolute increase in hazard rate was no more than 0.03 (ie, hazard rate in no anticoagulant group was 0.0408 vs 0.0708 in DOAC group). Non-inferiority could be concluded if the upper limit of a two-sided 90% CI for

the HR was less than the non-inferiority boundary of 1.735.

All patients randomly assigned to treatment groups were included in the intention-to-treat population and were tested for superiority. To establish non-inferiority, a significant result was required from the intention-to-treat analysis and the per-protocol analysis. Patients with no follow-up examination with documentation of drug administration or who permanently crossed over treatments, or those who never started the assigned treatment or with other protocol violations were excluded from the per-protocol analysis.

As randomisation was stratified according to two dichotomous factors (lobar or non-lobar location of index intracerebral haemorrhage and sex), variables were adjusted for in sensitivity analyses. For both coprprimary endpoints, Cox proportional hazards regression was performed for the time-to-first ischaemic stroke or first recurrent intracerebral haemorrhage, with treatment group as the main factor and location of index intracerebral haemorrhage, sex, and age (<80 years vs ≥80 years) as covariates. Additionally, event rates (per 100 person-years) of all primary endpoint events were calculated as a sensitivity analysis. Within another sensitivity analysis, the variability of the treatment effect across hospitals was estimated by using frailty models incorporating a random centre effect within the hazard function. A sensitivity analysis using a risk-score imputation approach was also conducted to censor patient information by creating multiple imputations of event times for patients whose event times were censored non-administratively.

Secondary endpoints were compared between treatment groups by calculating estimates for event rates (per 100 patient-years) and event rate ratios with accompanying 95% CIs. For adjusted results, Cox proportional hazards regression with treatment group as the main factor and location of index intracerebral haemorrhage, sex, and age as covariates was used for both mortality endpoints. Similarly, count data regression models with treatment group as the main factor, location of index intracerebral haemorrhage, sex, and age as covariates, and individual time under observation as an offset term were used for all other secondary and safety endpoints.

The proportional hazards assumption for Cox regression analyses was affirmed by graphical methods. For all secondary endpoints and sensitivity analyses of the coprprimary endpoints, the width of the CI around the risk estimates were not adjusted for multiplicity and should not be used in place of hypothesis testing. All statistical analyses were performed using R version 4.4.1.

## Role of the funding source

The funder of this study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report.

<figure><img src="image_3.png" /><figcaption>**Figure 1: Trial profile**
DOAC=direct oral anticoagulant.</figcaption></figure>
## Results

Between May 31, 2019, and Nov 30, 2023, 319 patients were enrolled; 158 were assigned to the DOAC group and 161 to the no anticoagulant group (figure 1). Of 158 patients in the DOAC group, 85 (54%) received apixaban, 33 (21%) received dabigatran, 29 (18%) received

edoxaban, nine (6%) received rivaroxaban, and two (1%) did not receive any anticoagulant (appendix p 11). Of 161 patients in the no anticoagulant group, 53 (33%) received antiplatelet therapy and 108 (67%) received no antithrombotic treatment. 266 (83%) of 319 patients were included in the per-protocol analysis. No patients were lost to follow-up.

Baseline characteristics were similar between groups (table 1; appendix p 11). The median age of patients was 79 years (IQR 73–83); 113 (35%) of 319 patients were women and 206 (65%) were men. Median time from index intracerebral haemorrhage to enrolment was 49 days (IQR 31–93). Based on central assessment, the index intracerebral haemorrhage was in non-lobar locations in 224 (70%) of 319 patients and in lobar locations in 95 (30%) of 319 patients. Median haematoma volume was 4.2 mL (IQR 1.4–8.9) in the DOAC group and 3.2 mL (1.1–10.2) in the no anticoagulant group. The median length of follow-up was 1.4 years (0.7–2.3). 11 patients underwent left atrial appendage closure during follow-up (appendix p 12). There were no key variables with missing data. Blood pressure was well controlled in both groups at baseline and during follow-up (appendix p 12).

First ischaemic stroke occurred significantly less frequently in the DOAC group than in the no anticoagulant group (HR 0.05 [95% CI 0.01–0.36]; log-rank p<0.0001; table 2; figure 2). The rate of all ischaemic stroke events was 0.83 (95% CI 0.14–2.57) per 100 patient-years in the DOAC group versus 8.60 (5.43–12.80) per 100 patient-years in the no anticoagulant group (appendix p 12). Treatment with a DOAC was associated with an absolute reduction in the event rate of ischaemic stroke by 7.77 events per 100 patient-years resulting in a number needed to treat of 13 patients to prevent one ischaemic stroke per year. Treatment effects from Cox regression models including a random centre effect revealed no indication for a possible variability in the treatment effect across hospitals. The effect size estimates from the sensitivity analysis addressing informative censoring yielded similar results as in the primary efficacy analyses (appendix p 13).

The comparison of the first recurrence of intracerebral haemorrhage between the DOAC group and the no anticoagulant group did not meet the prespecified non-inferiority margin (HR 10.89 [90% CI 1.95–60.72];

<table><thead><tr><th></th><th>DOAC group (n=158)</th><th>No anticoagulant group (n=161)</th></tr></thead><tbody><tr><td>Age, years</td><td>78 (73-83)</td><td>79 (73-84)</td></tr><tr><td>Sex</td><td></td><td></td></tr><tr><td>Female</td><td>56 (35%)</td><td>57 (35%)</td></tr><tr><td>Male</td><td>102 (65%)</td><td>104 (65%)</td></tr><tr><td>Ethnicity*</td><td></td><td></td></tr><tr><td>White</td><td>153 (97%)</td><td>153 (95%)</td></tr><tr><td>Mixed</td><td>1 (1%)</td><td>1 (1%)</td></tr><tr><td>Asian</td><td>0</td><td>1 (1%)</td></tr><tr><td>Black</td><td>0</td><td>1 (1%)</td></tr><tr><td>Unknown</td><td>4 (3%)</td><td>5 (3%)</td></tr><tr><td>Medical history</td><td></td><td></td></tr><tr><td>Hypertension</td><td>151 (96%)</td><td>154 (96%)</td></tr><tr><td>Diabetes</td><td>41 (26%)</td><td>38 (24%)</td></tr><tr><td>Myocardial infarction</td><td>10 (6%)</td><td>16 (10%)</td></tr><tr><td>Ischaemic stroke</td><td>32 (20%)</td><td>30 (19%)</td></tr><tr><td>Transient ischaemic attack</td><td>9 (6%)</td><td>7 (4%)</td></tr><tr><td>ICH†</td><td>6 (4%)</td><td>8 (5%)</td></tr><tr><td>Other major bleeding†</td><td>13 (8%)</td><td>20 (12%)</td></tr><tr><td>Modified Rankin Scale score</td><td>3 (1-3)</td><td>3 (2-3)</td></tr><tr><td>CHA<sub>2</sub>DS<sub>2</sub>-VASc score‡</td><td>4 (3-6)</td><td>4 (3-6)</td></tr><tr><td>HAS-BLED score§</td><td>3 (2-3)</td><td>3 (2-3)</td></tr><tr><td>Blood pressure at enrolment, mm Hg</td><td></td><td></td></tr><tr><td>Systolic</td><td>129 (15)</td><td>128 (16)</td></tr><tr><td>Diastolic</td><td>76 (11)</td><td>75 (10)</td></tr><tr><td>Time from index ICH to enrolment, days</td><td>48 (29-96)</td><td>49 (32-91)</td></tr><tr><td>Location of ICH¶</td><td></td><td></td></tr><tr><td>Lobar</td><td>53 (34%)</td><td>42 (26%)</td></tr><tr><td>Non-lobar</td><td>105 (66%)</td><td>119 (74%)</td></tr><tr><td>ICH volume, mL¶||</td><td>4.2 (1.4-8.9)</td><td>3.2 (1.1-10.2)</td></tr><tr><td>Antithrombotic medication before index ICH</td><td></td><td></td></tr><tr><td>Anticoagulant agent</td><td>135 (85%)</td><td>133 (83%)</td></tr><tr><td>Antiplatelet agent</td><td>8 (5%)</td><td>8 (5%)</td></tr><tr><td>Anticoagulant and antiplatelet agent</td><td>3 (2%)</td><td>3 (2%)</td></tr><tr><td>No antithrombotic medication</td><td>12 (8%)</td><td>17 (11%)</td></tr></tbody></table>

Data are median (IQR), n (%), or mean (SD). DOAC=direct oral anticoagulant. ICH=intracerebral haemorrhage. *Percentages do not add up to 100 due to rounding. †Before index intracerebral haemorrhage. ‡CHA<sub>2</sub>DS<sub>2</sub>-VASc score (for which points are assigned for the following risk factors: congestive heart failure, hypertension, age ≥75 years [doubled], diabetes, previous stroke [doubled], vascular disease, and female sex). §HAS-BLED score (for which points are assigned for the following risk factors: uncontrolled hypertension or systolic blood pressure >160 mm Hg, abnormal renal or liver function, previous stroke, bleeding history or predisposition, labile international normalised ratio, aged >65 years, and concomitant drugs and alcohol use). ¶Based on central reading by the imaging core laboratory. ||Index ICH volume could not be determined in nine participants (two in the DOAC group and seven in the no anticoagulant group).

<table><caption>**Table 1: Patient baseline characteristics**</caption><thead><tr><th></th><th>DOAC group (n=158)</th><th>No anticoagulant group (n=161)</th><th>Unadjusted HR (95% or 90% CI)*</th><th>Adjusted HR† (95% or 90% CI)*</th></tr></thead><tbody><tr><td>Ischaemic stroke</td><td>1</td><td>20</td><td>0.05 (0.01-0.36)</td><td>0.05 (0.01-0.38)</td></tr><tr><td>Recurrent intracerebral haemorrhage</td><td>11</td><td>1</td><td>10.89 (1.95-60.72)</td><td>11.2 (2.01-62.86)</td></tr></tbody></table>

Data are number of events, unless otherwise specified. DOAC=direct oral anticoagulant. HR=hazard ratio. *95% CI for ischaemic stroke, 90% CI for intracerebral haemorrhage as the hypothesis for intracerebral haemorrhage endpoint was non-inferiority. †Adjusted for location of index intracerebral haemorrhage, sex, and age.

<caption>**Table 2: Copriginary endpoints during follow-up**</caption>
<figure><img src="image_4.png" /><figcaption>**Figure 2:** Kaplan-Meier analysis of first incident ischaemic stroke
DOAC=direct oral anticoagulant. HR=hazard ratio.</figcaption></figure>

<figure><img src="image_5.png" /><figcaption>**Figure 3:** Kaplan-Meier analysis of first recurrent intracerebral haemorrhage
DOAC=direct oral anticoagulant. HR=hazard ratio.</figcaption></figure>

log-rank p=0.96; table 2; figures 3, 4). The rate of all intracerebral haemorrhage was 5.00 (95% CI 2.68–8.39) per 100 patient-years in the DOAC group compared with 0.82 (0.14–2.53) per 100 patient-years in the no anticoagulant group (appendix p 12). DOACs increased the event rate of recurrent intracerebral haemorrhage by 4.18 events per 100 patient-years resulting in a number needed to harm of 24 patients to cause one more intracerebral haemorrhage per year. Differential risks of

<figure><img src="image_6.png" /><figcaption>**Figure 4:** Intracerebral haemorrhage in relation to prespecified non-inferiority margin
DOAC=direct oral anticoagulant. HR=hazard ratio.</figcaption></figure>

recurrent intracerebral haemorrhage based on haematoma location were not identifiable (appendix p 13).

Point estimates for event rates for secondary mortality endpoints were lower in the DOAC group than in the no anticoagulant group (6.67 events vs 8.60 events per 100 patient-years for all-cause mortality and 2.92 events vs 5.73 events per 100 patient-years for cardiovascular mortality; table 3). The secondary safety endpoints of any intracranial bleeding (6.25 events per 100 patient-years vs 0.82 per 100 patient-years) and any major bleeding (8.75 vs 2.05) occurred more often in the DOAC group than in the no anticoagulant group (table 3; appendix p 13). Fewer patients in the DOAC group met the secondary composite endpoint of all stroke and systemic embolism than patients in the no anticoagulant group (5.83 events per 100 patient-years vs 11.06 events per 100 patient-years; table 3). Similarly, fewer patients in the DOAC group met the net clinical benefit endpoint (all stroke and systemic embolism, myocardial infarction, cardiovascular mortality, and major bleeding) than in the no anticoagulant group (19.20 vs 26.52). Kaplan-Meier estimates for time to first event of the composite endpoints showed lower risks for patients in the DOAC group than the no anticoagulant group (appendix pp 4–5).

The HR for the rate of first recurrent intracerebral haemorrhage in the per-protocol population was 7.42 (90% CI 1.30–42.50). The results of a post-hoc sensitivity analysis, excluding eight patients who had left atrial appendage occlusion without having a previous primary outcome event, were not different to the results from the intention-to-treat analysis (appendix p 15).

A post-hoc power calculation for the endpoint ischaemic stroke on the final sample size of 319 patients resulted in a power of 84.7%. In post-hoc analyses, the event rate of recurrent intracerebral haemorrhage did not seem to be higher in patients with lobar location than non-lobar location of the index intracerebral haemorrhage, as assessed by core laboratory reading. Serious adverse events occurred in 70 (44%) of 158 patients in the DOAC group and 89 (55%) of 161 patients in the no anticoagulant group. 16 (10%) patients in the DOAC and 21 (13%) in the no anticoagulant group died (appendix p 13).
<table><thead><tr><th rowspan="2"></th><th colspan="2">DOAC group (n=158)</th><th colspan="2">No anticoagulant group (n=161)</th><th rowspan="2">Unadjusted HR or event rate ratio (95% CI)</th><th rowspan="2">Adjusted HR or event rate ratio* (95% CI)</th></tr><tr><th>Number of events</th><th>Event rate per 100 patient-years</th><th>Number of events</th><th>Event rate per 100 patient-years</th></tr></thead><tbody><tr><td>All-cause mortality</td><td>16</td><td>6.67</td><td>21</td><td>8.60</td><td>0.78 (0.41-1.49)</td><td>0.81 (0.42-1.55)</td></tr><tr><td>Cardiovascular mortality</td><td>7</td><td>2.92</td><td>14</td><td>5.73</td><td>0.51 (0.21-1.27)</td><td>0.52 (0.21-1.28)</td></tr><tr><td>Major adverse cardiac events</td><td>9</td><td>3.75</td><td>15</td><td>6.14</td><td>0.61 (0.27-1.40)</td><td>0.60 (0.25-1.36)</td></tr><tr><td>Any major bleeding†</td><td>21</td><td>8.75</td><td>5</td><td>2.05</td><td>4.27 (1.74-12.80)</td><td>4.47 (1.82-13.44)</td></tr><tr><td>Any intracranial bleeding</td><td>15</td><td>6.25</td><td>2</td><td>0.82</td><td>7.63 (2.15-48.43)</td><td>7.53 (2.11-47.87)</td></tr><tr><td>All stroke and systemic embolism</td><td>14</td><td>5.83</td><td>27</td><td>11.06</td><td>0.53 (0.27-0.99)</td><td>0.55 (0.28-1.04)</td></tr><tr><td>Net clinical benefit‡</td><td>32</td><td>19.20</td><td>45</td><td>26.52</td><td>0.67 (0.33-1.36)</td><td>0.69 (0.33-1.40)</td></tr></tbody></table>

DOAC=direct oral anticoagulant. HR=hazard ratio. *Adjusted for location of index intracerebral haemorrhage, sex, and age. †Definition according to International Society on Thrombosis and Haemostasis bleeding assessment tool. ‡All stroke and systemic embolism, myocardial infarction, cardiovascular mortality, and major bleeding.

<caption>**Table 3:** Prespecified secondary endpoints during follow-up by treatment allocation</caption>

Discussion

In this multicentre, randomised, phase 3 trial, survivors of intracerebral haemorrhage with atrial fibrillation assigned to no anticoagulation had a high event rate of ischaemic strokes. Treatment with DOACs substantially decreased the risk of ischaemic stroke but also increased the risk of recurrent intracerebral haemorrhage and other types of major bleeding.

PRESTIGE-AF is the first completed phase 3 trial showing a significant reduction in the risk of ischaemic stroke using DOACs in survivors of intracerebral haemorrhage with atrial fibrillation. The reduction in ischaemic stroke was consistent with the efficacy of anticoagulation in trials using DOACs in patients with atrial fibrillation without previous intracerebral haemorrhage.¹⁸,¹⁹ A meta-analysis of observational trials in survivors of intracerebral haemorrhage with atrial fibrillation found a 53% risk reduction of ischaemic stroke with vitamin K antagonists.⁷ The pilot-phase, randomised APACHE-AF trial did not find any effect of apixaban on the risk of ischaemic stroke.¹¹ A meta-analysis of randomised data¹² encompassing the SoSTART trial¹⁰ reported a reduction of major adverse cardiovascular events including ischaemic stroke, consistent with the effects of DOACs seen in the PRESTIGE-AF trial.

A meta-analysis of observational data suggested that vitamin K antagonists do not increase the risk of recurrent intracerebral haemorrhage in patients with intracerebral haemorrhage and atrial fibrillation.⁷ In prevention trials in patients without previous intracerebral haemorrhage, DOAC use conferred a 50% lower risk of intracerebral haemorrhage than vitamin K antagonists.¹⁹ Two pilot-phase trials in survivors of intracerebral haemorrhage with atrial fibrillation reported unadjusted HRs of 2.31 (95% CI 0.69-7.68) to 4.12 (0.46-36.94) for the risk of recurrent intracerebral haemorrhage associated with DOACs.¹⁰,¹¹ In a meta-analysis of randomised data,¹² use of anticoagulants was not associated with a significant

increase in haemorrhagic major adverse cardiovascular events compared with DOACs (15 [7%] of 212 vs nine [5%] of 200; pooled HR 1.80 [95% CI 0.77-4.21]) but the investigators expressed a need for data from larger studies. PRESTIGE-AF tested the non-inferiority hypothesis that DOACs do not substantially increase the risk of recurrent intracerebral haemorrhage compared with no anticoagulation. However, PRESTIGE-AF did not show non-inferiority but instead found a higher risk (HR 10.89) of recurrent intracerebral haemorrhage in patients assigned to the DOAC group than the no anticoagulant group. Moreover, the event rate of all major haemorrhages was higher in the DOAC group, which was largely driven by recurrent intracerebral haemorrhage. Taken together, these findings suggest that use of DOACs in survivors of intracerebral haemorrhage is associated with a substantially increased risk of severe bleeding complications compared with no anticoagulation. This higher risk difference between treatment groups versus previous studies might be explained by the low rate of recurrent intracerebral haemorrhage in the no anticoagulant group, which might be attributed to close and structured follow-up during PRESTIGE-AF, which was conducted as a clinical trial with investigational medicinal products.²⁰

Whether haematoma location should affect the decision to start anticoagulation in patients with intracerebral haemorrhage with atrial fibrillation is controversial. Lobar haemorrhages were associated with a two-fold to three-fold higher risk of recurrent intracerebral haemorrhage than non-lobar haematomas in observational studies.¹,²¹ An observational study pooling data from three registries reported a similar benefit of anticoagulation in lobar and non-lobar intracerebral haemorrhage and no differential effect on major bleedings.²² An interim safety analysis of the ongoing ENRICH-AF trial (NCT03950076) found an excessive risk of recurrent intracerebral haemorrhage in patients receiving anticoagulation treatment with lobar intracerebral haemorrhage.²³ Consequently, the
steering committee discontinued anticoagulation in patients with lobar intracerebral haemorrhage and excluded further enrolment of such patients.²³ By contrast, a meta-analysis of the SoSTART and APACHE-AF trials found no clear dependency of the safety of anticoagulation on haematoma location.¹² Similarly, in PRESTIGE-AF, the increased risk of recurrent intracerebral haemorrhage in patients in the no anticoagulant group did not seem to depend on haematoma location (appendix p 13) but there are too few events for intracerebral haemorrhage recurrence to draw definitive conclusions.

The benefits and risks of anticoagulation should be carefully balanced in patients with intracerebral haemorrhage and atrial fibrillation. The Kaplan–Meier analyses in this trial might suggest a particular benefit of DOACs for prevention of ischaemic strokes in the first year after the index event, whereas the risk of intracerebral haemorrhage recurrence in the DOAC group appeared to continue thereafter. However, this finding should be interpreted with caution due to the short observation time. Another approach to balance the opposing risks is to use composite endpoints. The composite of all (ischaemic and haemorrhagic) strokes and systemic embolism has been widely used as a primary endpoint in trials of stroke prevention in patients with atrial fibrillation without previous intracerebral haemorrhage.¹⁹,²⁴ The present study found a reduction in risk of all strokes and systemic embolism in patients who were assigned to receive a DOAC. The composite endpoint of net clinical benefit occurred less frequently in the DOAC group. A large observational study suggested that anticoagulation might reduce the mortality of patients with atrial fibrillation.⁹ A meta-analysis of randomised data did not find a significant benefit of DOACs on cardiovascular or all-cause mortality.¹² In the PRESTIGE-AF trial, point estimates for mortality were lower in the DOAC group. However, the findings regarding all secondary endpoints should be interpreted with caution due to the wide CIs of effect estimates, which were not adjusted for multiplicity, and should not be used in place of hypothesis testing.

In view of the opposing risks that survivors of intracerebral haemorrhage with atrial fibrillation face with and without anticoagulation, individual patient preferences should be considered in shared decision making.²⁵ This discussion should include the different effects of ischaemic versus haemorrhagic types of stroke. The establishment of tools including clinical, neuroimaging, and genetic patient features for enhancing individualised risk prediction is desirable. New anticoagulants with a lower bleeding risk²⁶ or mechanical interventions, such as left atrial appendage occlusion, might become better alternatives to DOACs, at least for selected patients;²⁷ however, their efficacy and safety in survivors of intracerebral haemorrhage remains to be established (A3ICH NCT03243175; STROKECLOSE NCT02830152; CLEARANCE NCT04298723).

This study has some limitations. The low number of primary outcome events and short follow-up period resulting in broad CIs surrounding effect estimates limit the overall interpretation and clinical impact of the results. The study had an open design, but outcome events were adjudicated by independent experts masked to treatment allocation and potential under-reporting of events was addressed by prespecified procedures including monitoring. Furthermore, the study was not powered for secondary endpoints, and any trends suggesting a potential net benefit require confirmation in larger ongoing trials. The putatively differential impact of ischaemic strokes and recurrent intracerebral haemorrhages on disability were difficult to determine because the event rates were low and the levels of disability at the time of enrolment varied. The generalisability of the trial to different ethnicities and other systems of stroke care might be limited and requires assessment in ongoing trials (ENRICH-AF NCT03950076; ASPIRE NCT03907046). For example, only 113 (35%) of 319 participants were female, indicating that women are under-represented as in many other cardiovascular and stroke prevention trials. Recruitment of patients into PRESTIGE-AF was slowed by the COVID-19 pandemic, as in other trials in cardiovascular medicine.²⁸ This lower than expected recruitment rate led to a revised power calculation in view of a planned sample size reduction, resulting in a minimum power of 80% for the primary endpoint of ischaemic stroke. Additionally, a post-hoc power calculation on the final sample size of 319 patients resulted in a power of 84·7%. The trial protocol excluded the enrolment of survivors of intracerebral haemorrhage with severe disability, which might have led to the enrolment of patients with small haematoma volumes²⁹ limiting the study's generalisability. The number of patients with lobar intracerebral haemorrhage was slightly different between groups due to different interpretations of local and core imaging of available brain scans. A supplementary analysis stratified by DOAC type (accounting for uneven prescription frequencies in the study cohort) was not possible due to the small number of events. Subgroup analyses were not reported as stated in the original protocol, as only one event of first ischaemic stroke was observed in the DOAC group and one event of first recurrent intracerebral haemorrhage was observed in the no anticoagulation group. 33 (10%) of 319 participants crossed over to the opposite treatment. However, this rate was lower than anticipated in our sample size calculations, and the results of the per-protocol analysis were consistent with the intention-to-treat analysis. Finally, 11 (3%) participants underwent left atrial appendage closure for various reasons, but in most cases, this occurred at later timepoints during follow-up. This study has several strengths including rigorous study conduct, adequate power, regulatory standards of clinical trials of investigational medicinal products followed, performed across six countries with a homogeneous standard of care, and no patients lost to follow-up.
In conclusion, DOACs are effective in preventing ischaemic strokes in survivors of intracerebral haemorrhage with atrial fibrillation. However, this benefit is partly offset by an increased risk of intracerebral haemorrhage and other major bleeding complications. To further improve stroke prevention in these vulnerable patients, additional evidence is needed from ongoing trials and the COCROACH meta-analysis of randomised data, as well as the evaluation of safer medical or mechanical alternatives for selected patients.

### Contributors

RV composed the first draft of the manuscript. RV, PUH, JM, CE, and DAL formulated the overarching research goals and aims. KHH, ERH, CF, UM, GPT, CS, SU, CE, SF-H, VR, KHaa, SR, and RdTC curated the data. RV and CF directly accessed and verified the underlying data. CF, UM, SR, SD, and TD completed the formal analysis. EK, PUH, JM, GYHL, DAL, WEH, KIF, VSW, PBN, CDAW, and IS acquired funding. RV, EK, JM, GPT, CS, SU, CE, SF-H, DAL, WEH, KIF, VSW, PBN, SP, LD, JP, MB, RW, GN, EP, PM, MH, YS, RdTC, CDAW, IS, KHaj, MGM, MLai, OH, PM-S, SD, TD, VCas, VCan, PR, and SR conducted the trial. RV, EK, PUH, UM, CE, DAL, WEH, PBN, BN, VR, KHaa, and YW developed and designed the methodology. RV, KHH, ERH, KHü, GPT, CS, SU, CE, GYHL, WEH, KIF, VSW, CDAW, EP, MLac, PM, RdTC, IS, MGM, OH, VCas, VCan, and PR were responsible for the management and coordination of the research planning and execution. RV, EK, KHH, ERH, CF, UM, KHü, GPT, CS, SU, CE, SP, LD, YS, SR, IS, MGM, SD, TD, VCas, VCan, and PR provided resources. RV, KHH, ERH, PUH, JM, PR, KHü, CE, BN, GP, CDAW, RdTC, IS, SP, MLai, VCas, and WEH were responsible for the oversight and leadership for the research activity planning and execution. CF, UM, RV, EK, GPT, CS, SU, SP, RW, VR, YS, and RdTC validated the overall results and research outputs. RV, KHH, ERH, CF, and PM prepared, created, and presented the draft manuscript. RV, EK, KHH, ERH, CF, and JM wrote the original draft. All authors reviewed and edited the manuscript. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.

### Declaration of interests

RV reports research support from Bayer, BMS-Pfizer, Boehringer Ingelheim, Daiichi Sankyo, Medtronic, and Biogen; honoraria for consultancies and lectures from AstraZeneca, Bayer, BMS-Pfizer, Javelin, and Portola; and being an investigator of the Imperial BRC. EK reports honoraria for lectures or participation on advisory boards from Amgen, AstraZeneca, Bayer, Elpen, Innovis, Pfizer, and Sanofi. VCas reports consultancy work for Bayer as a member of the Steering Committee for OCEANIC-AF; speakers bureau for Bayer, BMS-Pfizer alliance, and Daiichi-Sankyo; and a leadership role for WSO Treasurer. PR reports payment to the institution for consulting from Bayer and Boehringer Ingelheim; lecture fees paid to the institution from Bayer, Boehringer Ingelheim, and Pfizer; travel support from Boehringer Ingelheim; participation on a data and safety monitoring board or advisory board for the NISCI study and Closure-AF study. VR reports grants or contracts from the University Hospital Wuerzburg, Universitätsklinikum Essen. TD reports funding from PIA3 for the Digital Public Health Program. SF-H reports lecture fees from AstraZeneca. YW and HAW report grants for applied research from the National Institute for Health and Care Research. DAL reports investigator-initiated quality improvement grants from Bristol-Myers Squibb and Pfizer (paid to the institution); being a co-applicant on the AFFIRMO project on multimorbidity in atrial fibrillation, ARISTOTELES project on artificial intelligence for management of chronic long term conditions, and the TARGET project on digital twins for personalised management of atrial fibrillation and stroke, all of which are funded by the Horizon Europe Research & Innovation programme; and being a co-chair of European Heart Rhythm Association Advocacy, Quality Improvement, and Health Economics Committee. WEH reports grants or contracts from ABDA—Bundesvereinigung Deutscher Apothekerverbände, ABF Pharmaceutical Services, AOK Thüringen und Sachsen, Bayoonet,

BioNTech, Boehringer Ingelheim, Bundesinstitut für Arzneimittel und Medizinprodukte, Bundesministerium für Bildung und Forschung, Bundesverwaltungsamt, Chiesi, Christophsbad, Daiichi Sankyo, Deutsche Forschungsgemeinschaft, Deutsches Krebsforschungszentrum, Dietmar Hopp Stiftung, Dosing, Dr Falk Pharma, Else Kröner-Fresenius Stiftung, Förderinitiative Pharmazeutische Betreuung, Goethe Universität Frankfurt, Gilead, Heidelberg ImmunoTherapeutics, Hepatera, Innovationsfonds des Gemeinsamen Bundesausschusses, Innovative Molecules, Janssen, Kassenärztliche Vereinigung Baden-Württemberg, Landesapothekerkammer Baden-Württemberg, Lesmüller-Stiftung, Martin-Luther Universität Halle, Medizinische Fakultät Heidelberg, MYR, Parexel Intern, Pharmtrace Klinische Entwicklung, Röchling, Sanofi, and Universität Maastricht; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Deutsches Ärzteblatt, Landgericht Hannover, Landesapothekerkammer Baden-Württemberg, Med Fakultät Heidelberg, Regierungspräsidium Stuttgart, Thieme Verlag, and Thieme Compliance; support for attending meetings or travel from Abschiedssymposium Basel and Universitätsklinikum Dresden; patents planned, issued, or pending from Universitätsklinikum Heidelberg, LipOra, Universitätsklinikum Heidelberg, Doxapram, Universitätsklinikum Heidelberg, and Task-1-Inhibitoren zur Behandlung von atrialer Arrhythmie; and participation on a data and safety monitoring board for MYR safety advisory committee. PBN reports research grants and consultant fees from Daiichi-Sankyo, grants from BMS/Pfizer, and grants and consultant fees from Bayer. SP reports grants or contracts from BMS/Pfizer (for the ATTICUS trial), Boehringer-Ingelheim (REVISION trial), Daiichi Sankyo (SPOCT-DOAC 1 study), European Union (PROOF trial), German Federal Joint Committee Innovation Fund (APICES project), German Federal Ministry of Education and Research (APICES project), German Federal Ministry of Education and Research (REVISION trial), Helena Laboratories (SPOCT-DOAC 1 study), and Werfen (SPOCT-DOAC 1 study); consulting fees from Alexion, AstraZeneca, Daiichi Sankyo, and Werfen; and non-significant payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Alexion, Bayer, Boehringer-Ingelheim, BMS/Pfizer, and Portola. JP reports grants or contracts and payment for lecture fees from Abbott, Akcea, Daiichi Sankyo, and BMS Pfizer, and grants from the Federal Joint Committee. MLai reports lecture fees from AstraZeneca. PM-S reports lecture fees from Daiichi Sankyo. BN reports personal honoraria for work on a data and safety monitoring board from Simbec-Orion. GP reports research grants from Sanofi and Bayer and honoraria and consulting fees from Amgen, Bayer, Novartis, and Sanofi. RW reports research grants from Bundesministerium für Bildung und Forschung, Deutsche Forschungsgemeinschaft, European Union, and Medtronic to his institution and personal honoraria for lectures or participation on advisory boards from AstraZeneca, Bayer, BMS, Boehringer Ingelheim, CVRX, Daiichi Sankyo, Medtronic, Novartis, Pfizer, and Servier. GN reports honoraria for lectures or participation on advisory boards from AstraZeneca, Bayer, Ferrer, Javelin, Novartis, Pfizer, Sanofi, and Winmedica (all paid to the University of Thessaly). PUH reports research grants from the European Union, German Ministry of Research and Education, German Research Foundation, Federal Joint Committee (G-BA) within the Innovation fund, German Cancer Aid, German Heart Foundation, Bavarian State, Robert Koch Institute, and University Hospital Heidelberg (within RASUNOA-prime); support from an unrestricted research grant to the University Hospital Heidelberg from Bayer, BMS, Boehringer-Ingelheim, and Daiichi Sankyo; and participation on a data and safety monitoring board in publicly funded studies (by German Research Foundation, German Ministry of Research, and Foundations). All other authors declare no competing interests.

### Data sharing

The data which can be made publicly available will be compiled and deposited in the OpenAIRE's Zenodo (https://zenodo.org/) 6 months after publication. Data which cannot be made openly available will be available to researchers upon request to the corresponding author (r.veltkamp@imperial.ac.uk) and will be subject to approval by an independent review committee identified for this purpose.
Acknowledgments

This study was sponsored by Imperial College London and was
funded by the European Commission as part of the Horizon 2020
research and innovation programme (grant 754517). We thank all
participants, their relatives and carers, the outcome event
adjudicators, the trial steering committee, the external ethics advisory
committee, the scientific advisers, and the data safety and monitoring
board.

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