Clinical trial NCT03996772: PREvention of STroke in Intracerebral haemorrhaGE Survivors With Atrial Fibrillation
Official title: PREvention of STroke in Intracerebral haemorrhaGE Survivors With Atrial Fibrillation (PRESTIGE-AF)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Atrial Fibrillation
Intracerebral Hemorrhage
Keywords: Atrial fibrillation
Arrhythmias
Cardiac
Cerebral Hemorrhage
Brain haemorrhage
Intracerebral hemorrhage
Cerebral haemorrhage
Basal ganglia haemorrhage
Putaminal haemorrhage
Anticoagulants
Oral anticoagulant
Direct oral anticoagulant
New oral anticoagulant
Factor Xa inhibitors
Direct thrombin inhibitor
Dabigatran
Apixaban
Rivaroxaban
Edoxaban
DOAC
NOAC
Intracerebral haemorrhage
Brain hemorrhage
Lead sponsor: Imperial College London
Sponsor class: OTHER
Collaborators: name: Wuerzburg University Hospital
name: Julius-Maximilians University
name: Medical University of Graz
name: University of Liverpool
name: King's College London
name: Hospital Universitari Vall d'Hebron Research Institute
name: University of Bordeaux
name: Azienda Ospedaliera di Perugia
name: Aalborg University
name: STROKE ALLIANCE FOR EUROPE
name: University Hospital Heidelberg
name: Imperial College Healthcare NHS Trust
name: Alfried Krupp Krankenhaus
name: University Hospital, Bordeaux
First posted: 2019-06-25
Enrollment: 319
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: PREvention of STroke in Intracerebral haemorrhaGE survivors with Atrial Fibrillation is a phase 3b investigator-led, multicentre, parallel group, prospective randomised, open, blinded end-point assessment (PROBE) clinical trial comparing direct oral anticoagulants against no anticoagulation in patients with a recent intracerebral haemorrhage (ICH) and comorbid atrial fibrillation (AF).

Randomisation will occur in a 1:1 ratio. Participants will be stratified according to two factors: lobar and non-lobar location of ICH and gender. Choice and dose of direct oral anticoagulant treatment and use of concomitant medication during the study treatment will be at the Principal Investigator´s discretion within the licensed doses for stroke prevention in AF patients in Europe. The control group will receive no anticoagulant but the use of an antiplatelet is at the Principal Investigator´s discretion who will use their clinical judgment to initiate an antiplatelet drug of their choice.
Primary purpose: PREVENTION

Brief summary: Atrial fibrillation (AF) is the most common form of irregular heart rhythm. In people with AF, blood clots often form in the heart, which can travel to the brain. Blockage of brain arteries by these clots is a major cause of stroke. This type of stroke is called an ischaemic stroke and approximately 15% of all ischaemic strokes are caused by AF.

People with AF are often prescribed a medication called an anticoagulant, which makes it less likely for blood clots to form and thus can prevent ischaemic strokes. However, anticoagulants also increase the risk of bleeding, so they are not suitable for everyone.

Some people who have AF have had a different type of stroke which is caused by bleeding in the brain, an intracerebral haemorrhage (ICH). These people are at increased risk of suffering both an ischaemic stroke (due to AF) and another ICH. It is not known whether it is best for these people to take an anticoagulant medication or not, as previous research studies did not include this group of people.

PREvention of STroke in Intracerebral haemorrhaGE survivors with Atrial Fibrillation (PRESTIGE-AF) is a research study on the best stroke prevention in people with atrial fibrillation (AF) who have recently had a bleeding in their brain, (ICH). This is a trial where half of the participants will take an anticoagulant medication, preventing blood clot formation, and half will not receive an anticoagulant. The direct oral anticoagulants (DOACs) that will be used in this trial are all licenced for use in the United Kingdom and within the European Union (EU) to prevent strokes in people with AF. However, the current licence does not extend to use with people who have had an ICH because it has not been tested in this group with a randomised controlled trial. DOACs will be tested in ICH survivors with AF because previous research trials have shown that people are up to 50% less likely to have bleeding complications in the brain with DOACs than with Warfarin (another commonly used anticoagulant).

The aim of PRESTIGE-AF is to answer the question of whether people with ICH and AF should take an anticoagulant medication or if it is better for them to avoid it.

Detailed description: Stroke is one of the largest public health challenges worldwide. Its societal impact is expected to further increase in the coming decades due to the aging of population. Importantly, stroke is a heterogeneous disease comprising various subtypes with distinct mechanisms. The variability of individual risks demands that more specifically targeted and better personalised approaches are developed to tailor stroke prevention for particular stroke types and individual patients.

Intracerebral haemorrhage (ICH) is a particularly severe type of stroke affecting 10-15% of all stroke patients. Importantly, ICH carries even higher mortality and more severe disability than other stroke types. While mechanisms of ICH and ischaemic stroke are distinct, many risk factors are shared and patients are often at increased risk of both ischaemic stroke and ICH.

Atrial fibrillation (AF) is also a growing epidemic in aging populations and a major cause of ischaemic stroke due to thrombus formation in the heart migrating to and occluding intracerebral arteries. At least 20% of ICH survivors also suffer from AF and are, thus, at particularly high risk of ischaemic stroke. While ischaemic stroke in AF patients in general can be much more effectively prevented with oral anticoagulation than with antiplatelet agents (APA) concerns about ICH recurrence in ICH survivors are a major barrier for anticoagulation. The best approach to stroke prevention in ICH patients with AF is presently unknown. Current clinical guidelines, which are largely based on retrospective observational studies investigating anticoagulation with vitamin K antagonists (VKA), either recommend considering anticoagulation only in patients with non-lobar location of ICH or, in the absence of evidence from randomised controlled trials, refrain from making any recommendations at all. Anticoagulation with direct oral anticoagulants (DOAC) has proven efficacy and safety for stroke prevention in AF. DOACs may be a better alternative to VKA particularly in ICH patients because DOACs were associated with a 50% lower risk of ICH than VKA in previous clinical trials of stroke prevention in AF. However, patients with previous ICH were excluded from these trials.

Although thousands of ICH survivors with AF every year worldwide need effective prevention of another stroke, the best antithrombotic therapy for these patients is currently unknown. PRESTIGE-AF will be the first sufficiently powered randomised controlled trial aiming to resolve the dilemma of stroke prevention in this challenging high-risk patient population. Specifically, it will answer the question whether DOAC with their well-documented lower risk of intracranial haemorrhagic complications, compared to VKA, provide both a more effective and an equally safe option for stroke prevention in patients with ICH and AF compared to no anticoagulant. Findings of the Study are expected to change management guidelines and future prevention research for ICH survivors with AF.

PREvention of STroke in Intracerebral haemorrhaGE survivors (PRESTIGE-AF) will test whether preventive therapy with DOACs (intervention group) reduce the rate of ischaemic stroke (superiority) compared to no anticoagulation (control group) without unacceptably increasing the risk of recurrent ICH (non-inferiority) in patients with AF and a previous ICH within 6 months before enrolment.

The Research Question is:

Does preventive therapy with Direct Oral Anticoagulants (intervention group) reduce the rate of ischaemic stroke (superiority) compared to no anticoagulation (control group) without unacceptably increasing the risk of recurrent Intracerebral haemorrhage (non-inferiority) in patients with atrial fibrillation and a previous intracerebral haemorrhage within 6 months before enrolment.

The Objectives of the study are:

The main objective is to perform a randomised controlled trial to resolve the long-standing management dilemma of antithrombotic stroke prevention in intracerebral haemorrhage (ICH) survivors with comorbid atrial fibrillation (AF). Specifically, it will address the question whether direct oral anticoagulants (DOACs, intervention) provide a more effective option for prevention of ischaemic stroke and an equally safe option in terms of recurrence of ICH for antithrombotic stroke prevention in survivors of recent ICH compared to no anticoagulation (i.e. no antithrombotic therapy or antiplatelet therapy at Principal Investigator´s discretion).

The secondary Study objectives are:

* To examine the effect of anticoagulation with DOAC versus no anticoagulation on major cardiovascular outcomes and mortality in ICH patient with AF
* To compare the effect of DOACs versus no anticoagulation on major systemic and intracranial bleeding in this Study population
* To examine the effect of DOACs versus no anticoagulation on net clinical benefit in ICH patients with AF

The exploratory objectives are:

• To explore the impact of DOAC vs. no anticoagulation on quality of life, cognition and psychological morbidity in patients with ICH and AF over time Study Design: PRESTIGE-AF is a phase 3b investigator-led, multicentre, parallel group, prospective randomised, open, blinded end-point assessment (PROBE) clinical trial comparing DOACs (interventional arm) against no anticoagulation (control arm) in patients with a recent ICH and comorbid AF.

Randomisation will occur in a 1:1 ratio. Participants will be stratified according to two factors: lobar and non-lobar location of ICH and sex. Choice and dose of DOAC treatment as well as the use of concomitant medication during the study treatment will be at the Principal Investigator´s discretion within the spectrum of licensed doses labelled for stroke prevention in AF patients in Europe following the Summary of Product Characteristics (SmPC). The control group will receive no anticoagulant but the use of an antiplatelet agent is at the Principal Investigator´s discretion who will use their clinical judgment to initiate (or not) an antiplatelet drug of their choice.

Baseline assessment will include capturing Participant's demographics, clinical characteristics, vital signs, medical history, and concomitant diseases as well as documentation of AF (previous history or newly detected). Results of routine diagnostic tests before Study enrolment will be also collected using an electronic case report form. The routine brain imaging data performed after the ICH and before Study enrolment will also be collected at baseline.

After randomisation, Participants will be followed-up in person at various time points (1, 6, 12, 24, 36 months) for up to 3 years. At each visit, outcome events and adverse events will be captured.

Eligibility criteria: Inclusion Criteria:

* Age ≥ 18 years
* Written informed consent obtained from the patient, or for patients who lack the capacity to consent this can be provided by an appropriate representative as defined in protocol
* Non-traumatic spontaneous ICH during the 12 months before enrolment. Patients become eligible 14 days after the date of their ICH.
* Documented evidence of AF (paroxysmal, persistent or permanent)

Exclusion Criteria:

* Fully dependent (mRS \>4)
* Women who are pregnant, breastfeeding, or plan to become pregnant during the Study period
* Women of childbearing potential (WOCBP see section 12.2 for definition) who are unable or unwilling to take measures for effective contraception (4.9)
* Enrolment occurring before 14 days after the date of ICH
* Enrolment occurring longer than 12 months after the date of ICH
* ICH resulting from trauma or vascular malformation
* Another indication for long-term anticoagulation
* Patient has hypertension, which in the opinion of the investigator, is uncontrollable with medication Any contraindication (except intracerebral haemorrhage) to treatment with apixaban, dabigatran, edoxaban, rivaroxaban as per SmPC. Including any of the following:

  * Hypersensitivity to the active principle or any of the excipients
  * Clinically relevant bleeding in progress
  * Liver disease associated with coagulopathy and a clinically relevant bleeding risk
  * Injuries or conditions such as a significant risk of major bleeding
  * Hepatic impairment or liver disease which can have an impact on survival
  * Exclusion of patients with end-stage renal creatinine clearance CrCL, (CrCL \<15 ml / min) or in patients undergoing dialysis
  * Concomitant treatment with other anticoagulants
  * Patients with a history of thrombosis and antiphospholipid antibody syndrome Special warnings and precautions for use for apixaban, dabigatran, edoxaban, rivaroxaban as per SmPC should also be taken into account at randomisation.
* Absolute need for antiplatelet agent (APA) at enrolment, meaning that a patient randomised to receive DOAC who would require an APA is not eligible (single APA is permitted in control group only, at time of randomisation). Presence of a left atrial appendage occlusion device (LAAO) or plan to implant an LAAO
* Presence of any medical, psychological, or psychiatric condition which in the opinion of the Principal or Co-Investigator would cause participation in the Study to be unwise
* Participation in any clinical study with an Investigational Medicinal Product within the past 30 days or 5 half-lives of the study drug (observational studies are permitted)

Primary outcomes:
measure: Time to the first incident ischemic stroke event.
timeFrame: 3 years
measure: Time to the first recurrent intracerebral haemorrhage event.
timeFrame: 3 years
Secondary outcomes:
measure: Rate of all stroke events
timeFrame: 3 years
measure: Rate of systemic embolism
timeFrame: 3 years
measure: Rate of major adverse cardiac events
timeFrame: 3 years
measure: Rate of all-cause mortality
timeFrame: 3 years
measure: Rate of cardiovascular mortality
timeFrame: 3 years
measure: Rate of major haemorrhage
timeFrame: 3 years
measure: Rate of any intracranial haemorrhage
timeFrame: 3 years
measure: Rates of events (all strokes, systemic embolic event, myocardial infarction, cardiovascular mortality and major bleeding)
timeFrame: 3 years
measure: Rate of myocardial infarction
timeFrame: 3 years
measure: Rate of major bleedings
timeFrame: 3 years
measure: Quality of life: EQ-5D
timeFrame: enrolment visit, 6 months (min follow-up), 12 months, 24 months, 36 months, and End of Treatment Visit (between 6 and 36 Months).
measure: Cognitive function: the Montreal Cognitive Assessment (MoCA)
timeFrame: enrolment visit, 6 months (min follow-up), 12 months, 24 months, 36 months, and End of Treatment Visit (between 6 and 36 Months).
measure: Psychological morbidity: the Hospital Anxiety and Depression Scale (HADS)
timeFrame: enrolment visit, 6 months (min follow-up), 12 months, 24 months, 36 months, and End of Treatment Visit (between 6 and 36 months).
Other outcomes:
Locations:
city: Eisenstadt
country: Austria
facility: Krankenhaus der Barmherzigen Brüder Eisenstadt
city: Graz
country: Austria
facility: Medizinische Universität Graz
city: Klagenfurt
country: Austria
facility: Klinikum Klagenfurt am Wörthersee
city: St. Pölten
country: Austria
facility: Universitätsklinikum St. Pölten
city: Bordeaux
country: France
facility: Centre Hospitalier Universitaire de Bordeaux
city: Caen
country: France
facility: Centre Hospitalier Universitaire de Caen Normandie
city: Aachen
country: Germany
facility: Universitätsklinikum Aachen
city: Altenburg
country: Germany
facility: Klinikum Altenburger Land
city: Augsburg
country: Germany
facility: Universitätsklinikum Augsburg
city: Bad Neustadt An Der Saale
country: Germany
facility: Rhön-Klinikum Campus Bad Neustadt
city: Berlin
country: Germany
facility: Vivantes Hospital Neukolin
city: Bochum
country: Germany
facility: Universitätsklinikum Knappschaftskrankenhaus Bochum
city: Bottrop
country: Germany
facility: Knappschaftskrankenhaus Bottrop
city: Cologne
country: Germany
facility: University Hospital Cologne
city: Dortmund
country: Germany
facility: Klinikum Dortmund
city: Dresden
country: Germany
facility: Technische Universität Dresden
city: Düsseldorf
country: Germany
facility: Universitätsklinikum Düsseldorf
city: Erlangen
country: Germany
facility: University Hospital Erlangen
city: Essen
country: Germany
facility: Alfried Krupp Von Bohlen und Halbach-Krankenhaus
city: Frankfurt
country: Germany
facility: University Hospital Frankfurt
city: Geissen
country: Germany
facility: Universitiaetsklinikum Giessen und Marburg (UKGM) - Standort Giessen
city: Günzburg
country: Germany
facility: Bezirkskrankenhaus Günzburg
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Heidelberg
country: Germany
facility: University Hospital Heidelberg
city: Leipzig
country: Germany
facility: University of Leipzig
city: Luebeck
country: Germany
facility: University Hospital Schleswig-Holstein Campus Luebeck
city: Minden
country: Germany
facility: Johannes Wesling Klinikum Minden
city: Stuttgart
country: Germany
facility: Klinikum der Landeshauptstadt Stuttgart
city: Tübingen
country: Germany
facility: Universitätsklinikum Tübingen
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm
city: Wuerzburg
country: Germany
facility: Universitätsklinikum Wuerzburg
city: Branca
country: Italy
facility: Azienda USL Umbria 1 - Ospedale di Branca-Gubbio
city: Cesena
country: Italy
facility: Ospedale Bufalini di Cesena
city: Città di Castello
country: Italy
facility: Azienda USL Umbria 1 - Ospedale di Città di Castello
city: Foligno
country: Italy
facility: Azienda USL Umbria 2
city: Genova
country: Italy
facility: IRCCS Ospedale Policlinico San Martino
city: Milan
country: Italy
facility: Istituto Clinico Humanitas
city: Napoli
country: Italy
facility: Azienda Ospedaliera di Rilievo Nazionale (A.O.R.N) A. Cardarelli di Napoli
city: Perugia
country: Italy
facility: Azienda Ospedaliera di Perugia
city: Reggio Emilia
country: Italy
facility: Azienda USL IRCCS di Reggio Emilia
city: Rome
country: Italy
facility: Azienda Ospedaliera S Camillo Forlanini
city: Siena
country: Italy
facility: Azienda Ospedaliera Universitaria Senese
city: Almería
country: Spain
facility: Hospital Universitario Torrecárdenas
city: Barcelona
country: Spain
facility: Fundacío Institut d'Investigacío Biomèdica de Bellvitge
city: Barcelona
country: Spain
facility: Hospital Germans Trias I Pujol
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Girona
country: Spain
facility: Hospital Dr Josep Trueta
city: Madrid
country: Spain
facility: Hospital Universitario de la Princesa
city: Santiago
country: Spain
facility: Complejo Hospitalario Universitario de Santiago
city: Seville
country: Spain
facility: Hospital Universitario Virgen del Rocio
city: Seville
country: Spain
facility: Hospital Universitario Virgen Macarena
city: Valladolid
country: Spain
facility: Hospital Clínico Universitario de Valladolid
city: Ashford
country: United Kingdom
facility: East Kent Hospitals University NHS Foundation Trust
city: Ashington
country: United Kingdom
facility: Northumbria Healthcare NHS Foundation Trust
city: Basildon
country: United Kingdom
facility: Basildon and Thurrock University Hospitals NHS Trust
city: Cambridge
country: United Kingdom
facility: Cambridge University Hospitals NHS Trust
city: Chester
country: United Kingdom
facility: Countess of Chester Hospital
city: Hull
country: United Kingdom
facility: Hull and East Yorkshire NHS Trust
city: London
country: United Kingdom
facility: Kings College Hospital NHS Foundation Trust
city: London
country: United Kingdom
facility: Imperial College Healthcare NHS Trust
city: Prescot
country: United Kingdom
facility: St Helens and Knowsley Teaching Hospital NHS Trust
city: Taunton
country: United Kingdom
facility: Taunton and Somerset NHS Foundation Trust
city: Wakefield
country: United Kingdom
facility: Mid Yorkshire Hospitals NHS Trust
city: Watford
country: United Kingdom
facility: West Hertfordshire Hospitals NHS Trust
Study officials:
affiliation: Imperial College London
name: Roland E Veltkamp, FESO
role: PRINCIPAL_INVESTIGATOR
References:
citation: Li L, Poon MTC, Samarasekera NE, Perry LA, Moullaali TJ, Rodrigues MA, Loan JJM, Stephen J, Lerpiniere C, Tuna MA, Gutnikov SA, Kuker W, Silver LE, Al-Shahi Salman R, Rothwell PM. Risks of recurrent stroke and all serious vascular events after spontaneous intracerebral haemorrhage: pooled analyses of two population-based studies. Lancet Neurol. 2021 Jun;20(6):437-447. doi: 10.1016/S1474-4422(21)00075-2.