Plain English Summary
Plain English summary as of 27/09/2018:
Background and study aims
Atrial fibrillation (AF) is a common heart condition, affecting millions of people worldwide. When a person is suffering from AF, the electrical signals that control the heartbeat fire chaotically, causing the heart to beat irregularly and often very fast (arrhythmia). Studies have shown that AF can increase a persons’ risk of stroke, particularly ischaemic stroke (a condition in which the arteries that supply the brain with oxygen (carotid arteries) become narrowed or blocked, causing severely reduced blood flow). Many recent studies have shown that even very early stages of AF, so called "atrial high rate episodes" (AHRE), are linked with an increased risk of stroke. A large portion of these patients also develop AF over time. Stroke prevention from patients with AF is usually done using vitamin K antagonists (VKAs). These are anti-clotting medications which prevent blood clots from forming by interfering with the action of vitamin K (which plays a key role in blood clotting). These bear the risk of bleeding events and need to be dose-adjusted for each individual depending on blood values taken repetitively. Non-vitamin K antagonist oral anticoagulants (NOACs) have been introduced into clinical practice in recent years as an alternative, appearing safer than VKAs and being administered in a fixed dose. The aim of this study is to find out whether long-term treatment with Edoxaban (a NOAC) is more effective than the current strategy of no oral anticoagulation treatment in AHRE patients who present with an additional risk factor for stroke but who do not have diagnosed AF.
Who can participate?
Adults aged 65 or over with an implanted pacemaker or defibrillator that can detect AHRE.
What does the study involve?
Participants are randomly allocated to one of two groups. Those in the first group are given 60mg Edoxaban tablets to take every day for at least 12 months (which can later be reduced to 30mg a day if appropriate). Participants are also given a placebo (dummy) tablet to take which looks the same as a 100mg aspirin tablet to take once a day for the same length of time. Those in the second group are given a placebo (dummy) tablet that looks the same as a 60mg Edoxaban tablet and are either given a 100mg aspirin tablet to take every day (if the doctor feels they could benefit from it) or a placebo (dummy) tablet to take which looks the same as a 100mg aspirin tablet to take every day for at least 12 months. All participants are monitored throughout the study in order to record the amount who have suffered from a stroke or have died.
What are the possible benefits and risks of participating?
There is not expected to be any direct benefits from taking part in the study. The risks involves with participating are expected to be low as edoxaban has a clinical licence for stroke prevention in patients with atrial fibrillation.
Where is the study run from?
The study is run from the Atrial Fibrillation Competence Network e . V. (Germany)
When is the study starting and how long is it expected to run for?
February 2016 to March 2022
Who is funding the study?
1. Daiichi Sankyo Europe GmbH (Germany)
2. German Centre for Cardiovascular Research (Germany)
Who is the main contact?
1. Dr Benjamin Blank (Public)
2. Professor Paulus Kirchof
Previous plain English summary:
Background and study aims
Atrial fibrillation (AF) is a common heart condition, affecting millions of people worldwide. When a person is suffering from AF, the electrical signals that control the heartbeat fire chaotically, causing the heart to beat irregularly and often very fast (arrhythmia). Studies have shown that AF can increase a persons’ risk of stroke, particularly ischaemic stroke (a condition in which the arteries that supply the brain with oxygen (carotid arteries) become narrowed or blocked, causing severely reduced blood flow). Many recent studies have shown that even very early stages of AF, so called "atrial high rate episodes" (AHRE), are linked with an increased risk of stroke. A large portion of these patients also develop AF over time. Stroke prevention from patients with AF is usually done using vitamin K antagonists (VKAs). These are anti-clotting medications which prevent blood clots from forming by interfering with the action of vitamin K (which plays a key role in blood clotting). These bear the risk of bleeding events and need to be dose-adjusted for each individual depending on blood values taken repetitively. Non-vitamin K antagonist oral anticoagulants (NOACs) have been introduced into clinical practice in recent years as an alternative, appearing safer than VKAs and being administered in a fixed dose. The aim of this study is to find out whether long-term treatment with Edoxaban (a NOAC) is more effective than the current strategy of no oral anticoagulation treatment in AHRE patients who present with an additional risk factor for stroke but who do not have diagnosed AF.
Who can participate?
Adults aged 65 or over with an implanted pacemaker or defibrillator that can detect AHRE.
What does the study involve?
Participants are randomly allocated to one of two groups. Those in the first group are given 60mg Edoxaban tablets to take every day for 24 months (which can later be reduced to 30mg a day if appropriate). Participants are also given a placebo (dummy) tablet to take which looks the same as a 100mg aspirin tablet to take once a day for the same length of time. Those in the second group are given a placebo (dummy) tablet that looks the same as a 60mg Edoxaban tablet and are either given a 100mg aspirin tablet to take every day (if the doctor feels they could benefit from it) or a placebo (dummy) tablet to take which looks the same as a 100mg aspirin tablet to take every day for 24 months. All participants are monitored throughout the study in order to record the amount who have suffered from a stroke or have died.
What are the possible benefits and risks of participating?
There is not expected to be any direct benefits from taking part in the study. The risks involves with participating are expected to be low as edoxaban has a clinical licence for stroke prevention in patients with atrial fibrillation.
Where is the study run from?
The study is run from the Atrial Fibrillation Competence Network e . V. (Germany)
When is the study starting and how long is it expected to run for?
February 2016 to September 2019
Who is funding the study?
1. Daiichi Sankyo Europe GmbH (Germany)
2. German Centre for Cardiovascular Research (Germany)
Who is the main contact?
1. Dr Benjamin Blank (Public)
2. Professor Paulus Kirchof
Trial website
Contact information
Type
Public
Primary contact
Dr Benjamin Blank
ORCID ID
Contact details
Kompetenznetz Vorhofflimmern e.V.
Mendelstrasse 11
Muenster
48149
Germany
Type
Scientific
Additional contact
Prof Paulus Kirchhof
ORCID ID
http://orcid.org/0000-0002-1881-0197
Contact details
The University of Birmingham
Vincent Drive
Edgbaston
Birmingham
B15 2TT
United Kingdom
Additional identifiers
EudraCT number
2015-003997-33
ClinicalTrials.gov number
NCT02618577
Protocol/serial number
NOAH - AFNET 6
Study information
Scientific title
Non-vitamin K Antagonist Oral Anticoagulants in patients with atrial high rate episodes - an investigator-driven, prospective, randomised, double-blind, multi-centre trial initiated by the European Society of Cardiology and AFNET
Acronym
NOAH
Study hypothesis
The aim of the trial is to demonstrate that oral anticoagulation using the NOAC edoxaban is superior to current therapy to prevent stroke, systemic embolism, or cardiovascular death in patients with AHRE and at least two stroke risk factors but without AF.
Ethics approval
Technische Universität Dresden, Ethikkommission, 20/05/2016, Number: EK 144042016 Pilotprojekt-Nr. PB 0008
All other centres received ethics approval before recruitment of the first participant
Study design
Prospective randomised double-blind multi-centre trial
Primary study design
Interventional
Secondary study design
Randomised parallel trial
Trial setting
Hospitals
Trial type
Prevention
Patient information sheet
Not available in web format, please use the contact details to request a patient information sheet
Condition
Atrial high rate episodes
Intervention
The investigational medicinal product being tested is the Non-vitamin K antagonist oral anticoagulant edoxaban. The IMP used as a comparator is acetylsalicylic acid or placebo. The patients will randomly be assigned to the “NOAC” or to the comparator group.
NOAC group: Participants will receive anticoagulation therapy with edoxaban. Edoxaban will be used at the therapeutic dose approved for stroke prevention in non-valvular AF, i.e. 60 mg OD or with a reduction of dose to 30 mg OD in patients.
In the “NOAC” group one edoxaban tablet plus one placebo tablet matching in colour, weight, form and size to ASA 100 mg will be administered per day irrespective of stratum according to indication for use of antiplatelet therapy. The use of edoxaban eliminates the necessity of parallel intake of ASA 100 mg in case of an indication for use of antiplatelet therapy.
Usual Care group: Participants will receive either acetylsalicylic acid (ASA) or no antithrombotic therapy depending on the indication for use of antiplatelet therapy (stratification at the time of randomisation). In the “Usual Care” group either one tablet of ASA 100 mg plus one placebo tablet matching in colour, form and size to edoxaban 60 mg or one placebo tablet matching in colour, weight, form and size to ASA 100 mg plus one placebo tablet matching in colour, form and size to edoxaban 60 mg will be administered per day depending on the indication for use of antiplatelet therapy as assessed by the responsible investigator. A documented change of indication for use of antiplatelet therapy in follow-up will lead to blinded exchange of double-dummy study drug according to actual indication.
Treatment is starting at baseline. Based on the sample size estimation, the expected mean follow-up time will be about 28 months per patient with a minimum follow-up time of 12 months and a maximum follow-up time of presumably 44 months until end of final visit after required number of endpoints has been reached. Every patient will be followed-up until global end of study. The exact duration of follow-up will be determined by the accrual of events (event-driven study).
Intervention type
Drug
Phase
Phase III/IV
Drug names
1. Edoxaban
2. ASA
Primary outcome measure
Time from randomisation to the first occurrence of stroke, systemic embolism, or cardiovascular death
Secondary outcome measures
Secondary outcome measures as of 27/09/2018:
1. Components of the primary outcome
2. Major Adverse Cardiac Events (MACEs: cardiac death, myocardial infarction, acute coronary syndrome (ACS))
3. All-cause death
4. Major bleeding event rate (according to the International Society on Thrombosis and Haemostasis (ISTH) definitions)
5. Quality of life assessed using the EQ-5D including its visual-analogue scale and the Karnofsky scale at baseline
6. Patient satisfaction is measured using the modified EHRA score and PACT-Q
7. Cost effectiveness and health resource utilisation is estimated using quantification of relevant events, interventions, nights spent in hospital and cardiovascular therapies
8. Patient autonomy
9. Cognitive function is measured using the Montreal Cognitive Assessment (MoCA)
Previous secondary outcome measures:
1. All cause death is determined at 24 months
2. Major bleeding event rate (according to the International Society on Thrombosis and Haemostasis (ISTH) definitions) is determined at 24 months
3. Quality of life assessed using the EQ-5D including its visual-analogue scale and the Karnofsky scale at baseline, 12 and 24 months
4. Patient satisfaction is measured using the modified EHRA score (36) and PACT-Q (43) at baseline, 12 and 24 months
5. Cost effectiveness and health resource utilisation is estimated using quantification of relevant events, interventions, nights spent in hospital and cardiovascular therapies is determined at 24 months
6. Patient autonomy is measured at baseline, 12 and 24 months
7. Cognitive function is measured using the Montreal Cognitive Assessment (MoCA) baseline, 12 and 24 months
Overall trial start date
01/02/2016
Overall trial end date
31/03/2022
Reason abandoned (if study stopped)
Eligibility
Participant inclusion criteria
Participant inclusion criteria as of 27/09/2018:
1. Implanted pacemaker or defibrillator with feature of detection of AHRE, implanted at least 2 months prior to randomisation
2. AHRE detection feature activated adequately according to "Suggestions for optimal programming of devices for adequate detection of AHRE"
3. AHRE (≥ 180 bpm atrial rate and ≥ 6 min duration) documented by the implanted device via its atrial lead and stored digitally. AHRE episodes detected in the first 2 months after implantation of a new device involving placement or repositioning of electrodes are not counted. AHRE episodes recorded in the first two months after a simple "box change" operation, i.e. exchange of a pacemaker or defibrillator device without exchange or repositioning of electrodes, are eligible.
4. Aged 65 years or over
5. In addition, at least one of the following cardiovascular conditions leading to a modified CHA2DS2VASc score of 2 or more:
5.1. Age ≥ 75 years;
5.2. Heart failure (clinically overt or LVEF < 45%);
5.3. Arterial hypertension (chronic treatment for hypertension, estimated need for continuous antihyper-tensive therapy or resting blood pressure > 145/90 mmHg);
5.4. Diabetes mellitus;
5.5. Prior stroke or transient ischemic attack (TIA);
5.6. Vascular disease (previous myocardial infarction, peripheral, carotid/cerebral, or aortic plaques on transesophageal echocardiogram [TEE]).
6. Provision of signed informed consent
Previous participant inclusion criteria:
1. Implanted pacemaker or defibrillator with feature of detection of AHRE, implanted at least 2 months prior to randomisation
2. AHRE detection feature activated adequately according to "Suggestions for optimal programming of devices for adequate detection of AHRE"
3. AHRE (≥ 180 bpm atrial rate and ≥ 6 min duration) documented by the implanted device via its atrial lead and stored digitally. AHRE episodes detected in the first 2 months after implantation of a new device involving placement or repositioning of electrodes are not counted. AHRE episodes recorded in the first two months after a simple "box change" operation, i.e. exchange of a pacemaker or defibrillator device without exchange or repositioning of electrodes, are eligible.
4. Aged 65 years or over
5. In addition, at least one of the following cardiovascular conditions leading to a CHA2DS2VASc score of 2 or more:
5.1. Heart failure (clinically overt or LVEF < 45%)
5.2. Arterial hypertension (chronic treatment for hypertension, estimated need for continuous antihypertensive therapy or resting blood pressure > 145/90 mmHg)
5.3. Diabetes mellitus
5.4. Prior stroke or transient ischemic attack (TIA)
5.5. Vascular disease (peripheral, carotid/cerebral, or aortic plaques on transesophageal echocardio-gram [TEE])
6. Provision of signed informed consent
Participant type
Patient
Age group
Senior
Gender
Both
Target number of participants
2686
Participant exclusion criteria
1. Any disease that limits life expectancy to less than 1 year
2. Participation in another controlled clinical trial, either within the past two months or still ongoing
3. Previous participation in the present trial NOAH
4. Drug abuse or clinically manifest alcohol abuse. Exclusion criteria related to a cardiac condition
5. Any history of overt AF or atrial flutter
6. Indication for oral anticoagulation (e.g. deep venous thrombosis)
7. Contraindication for oral anticoagulation in general
8. Contraindication for edoxaban as stated in the current SmPC
9. Indication for long-term antiplatelet therapy other than acetylsalicylic acid, especially dual antiplatelet therapy (DAPT) with acetylsalicylic acid and one of the following agents: clopidogrel, prasugrel, or ticagrelor. Patients with a transient requirement for DAPT (e.g. after receiving a stent) will be eligible when the need for DAPT is no longer present
10. Acute coronary syndrome, coronary revascularisation (PCI or bypass surgery), or overt stroke within 30 days prior to randomisation
11. End stage renal disease (creatinine clearance (CrCl) < 15 ml/min as calculated by the Cockcroft-Gault method)
Recruitment start date
01/02/2016
Recruitment end date
31/12/2020
Locations
Countries of recruitment
Austria, Belgium, Bulgaria, Czech Republic, France, Germany, Hungary, Italy, Netherlands, Poland, Portugal, Spain, Sweden, Ukraine, United Kingdom
Trial participating centre
Kompetenznetz Vorhofflimmern e. V.
Mendelstraße 11
Münster
48149
Germany
Funders
Funder type
Industry
Funder name
Daiichi Sankyo Europe GmbH
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Funder name
Deutsches Zentrum für Herz-Kreislaufforschung
Alternative name(s)
Deutsches Zentrum für Herz-Kreislaufforschung e.V., Deutsches Zentrum für Herz-Kreislauf-Forschung e. V., German Centre for Cardiovascular Research, DZHK
Funding Body Type
private sector organisation
Funding Body Subtype
Other non-profit
Location
Germany
Results and Publications
Publication and dissemination plan
Planned publication of study results in a peer reviewed journal.
Intention to publish date
31/12/2022
Participant level data
Other
Basic results (scientific)
Publication list
2017 protocol in: https://www.ncbi.nlm.nih.gov/pubmed/28760205