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PREvention of STroke in Intracerebral haemorrhaGE survivors with Atrial Fibrillation

Periodic Reporting for period 3 - PRESTIGE-AF (PREvention of STroke in Intracerebral haemorrhaGE survivors with Atrial Fibrillation)

Reporting period: 2020-12-01 to 2022-05-31

Stroke is one of the leading causes of death and long-term disability worldwide, but its impact is expected to increase even further with the aging of populations. Strokes that are caused by bleeding in the brain (Intracerebral haemorrhage or ICH) account for only 10-15% of all strokes but they are associated with a higher risk of disability and death compared to strokes caused by a blood clot (ischaemic stroke). At least 20% of ICH survivors suffer from an irregular heartbeat called atrial fibrillation (AF) which can cause blood clots to form in the heart, and therefore is a major risk factor for ischaemic stroke. In patients with AF, ischaemic stroke can be effectively prevented by taking medications called oral anticoagulants which lower the risk of a blood clots forming. However, survivors of ICH have a substantially increased risk of suffering another ICH, and there is a concern that starting anticoagulants may increase the risk of them having another ICH. Consequently, stroke prevention in ICH patients with AF is an unresolved dilemma.
The first objective of the project is to determine whether ICH patients who have AF should be treated with anticoagulants for stroke prevention or not. PRESTIGE-AF will assess whether treatment with direct oral anticoagulants (DOACs) is more effective in preventing ischaemic stroke (compared to not taking an anticoagulant) without substantially increasing the risk of ICH recurrence.
The second objective of the study is to improve the individual predictability of stroke in ICH patients with AF. We intend to personalise the preventive strategy to individual patients using the results of risk modelling.
The third objective is to address public health and health economic implications by estimating the effects of the trial data to the general stroke population. Using large-scale European and Asian registry data, we will model outcomes with effect sizes of the DOACs in different ICH patient populations and will model the replication of the trial
findings within real-life settings.
The fourth objective is to investigate patient-centred aspects of preventive medicine in stroke patients. We will study the potential impact that patient’s attitudes towards antithrombotic therapy, and their psychosocial status, have on adherence to medication and on clinical outcomes. Participant’s adherence to their medication will be monitored throughout the trial using questionnaires and blood drug levels. We will also strive to identify physician and patient factors that may underlie the under-representation of women in stroke prevention trials to inform future trials of cardiovascular prevention.
The PRESTIGE-AF Study includes the main randomised clinical trial and 3 optional substudies. The trial protocol has been approved by the authorities and ethics committees in all 6 participating European countries. All aspects of the trial infrastructure including data entry platforms, safety reporting, event adjudication, data monitoring, and delivery of supplies, are firmly established. The criteria to take part in the clinical trial has been amended so that patients who have cognitive decline, and are not able to make decisions for themselves, can be included with the agreement of their next of kin. This means that our results will be more representative of the patient group because cognitive decline is common after ICH. It is a great success of the project that this has been approved in 5 countries as some authorities are reluctant to approve this in prevention studies.

As of 31st May 2022, PRESTIGE-AF has 134 participants enrolled into the trial. The team have worked hard to boost recruitment, which has been successful, with the average monthly recruitment in March-May 2022 being more than twice the recruitment rate of the same period in 2021. More than two thirds of our sites have recruited participants, with 9 sites having recruited 5 or more. Of the 70 hospitals where the trial was opened, 63 are still recruiting and a further 4 are in setup to replace sites that have closed. Each participant is extensively characterised at the start of the trial, including collection of their medical history and brain imaging. They are offered participation in the following substudies, which provide further valuable data:

The Predictive Modelling of Risk Substudy where participants have blood-based biomarkers and genetic samples collected, has recruited 49 participants.

The Longitudinal Neuroimaging Substudy has recruited 35 participants, each will have an additional MRI brain scan at 12 months after inclusion.

The Pharmacology Substudy, which uses dried blood spots to look at the levels of DOAC in a participant’s blood, has recruited 24 participants.

To address public health impact, the project is using previously collected information from the Global Burden of Disease study and data sets from three registers of patients who have had strokes: the South London Stroke Register, the European Registers of Stroke, and the UK Sentinel Stroke National Audit Programme. We have conducted analyses and have preliminary estimates of risk, outcomes, and future projections of ICH in the EU over the next 30 years, which are being written up for publication.

An interesting question that is being explored is why women are underrepresented in stroke prevention trials. Over half of the required respondents have taken part in a survey given to doctors exploring if bias affects which patients are offered clinical trials. This will also be explored in a survey given to patients and with interviews with both groups. Another substudy has examined the attitudes of doctors towards management of AF patients who have survived an ICH. Doctors described the process of deciding on stroke prevention in patients with AF post-ICH as ‘challenging’ due to considerable ‘clinical equipoise’ - meaning that there is not yet a good basis for choice between different care options. The findings of the study were presented at the International Stroke Conference in February 2021, and the full results are to be published in the journal, Thrombosis and Haemostasis, in June 2022. This team are now focusing on another study which is exploring patients views on the same subject.
Over the course of the project, PRESTIGE-AF has produced 11 publications, taken part in 26 conferences and events, published 21 news stories on its website, and amassed 212 Twitter followers.
PRESTIGE-AF addresses an important unmet need for developing prevention concepts in a highly vulnerable group of stroke patients, namely those with ICH and AF. Effective prevention of recurrent strokes in these patients will prevent the devastating consequences for the individual and their families and will reduce societal and healthcare costs. PRESTIGE-AF will deliver new guidance on effective treatment of ICH patients with AF. It will establish a personalised approach of individual risk prediction that integrates the knowledge of clinical characteristics as well as biological data including biomarkers, genetics, and neuroimaging. The project will also simulate the population impact of the trial using data from large-scale registries derived from real life settings and perform health economic modelling. PRESTIGE-AF will investigate patient-centred aspects such as adherence to medication, patients’ and physicians´ attitudes towards anticoagulation, and gender aspects in stroke prevention research.