Non-vitamin K antagonist oral anticoagulants in patients with atrial high rate episodes
| ISRCTN | ISRCTN17309850 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN17309850 |
| EudraCT/CTIS number | 2015-003997-33 |
| ClinicalTrials.gov number | NCT02618577 |
| Secondary identifying numbers | NOAH - AFNET 6 |
- Submission date
- 08/12/2015
- Registration date
- 29/01/2016
- Last edited
- 30/01/2024
- Recruitment status
- No longer recruiting
- Overall study status
- Stopped
- Condition category
- Circulatory System
Plain English summary of protocol
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 December 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 Vincent Beuger, vincent.beuger@af-net.eu
2. Prof Paulus Kirchof, p.kirchhof@uke.de
Contact information
Public
Atrial Fibrillation NETwork (AFNET)
Mendelstrasse 11
Muenster
48149
Germany
| Phone | +49 (0)251 9801333 |
|---|---|
| vincent.beuger@af-net.eu |
Scientific
Universitäres Herz- und Gefäßzentrum Hamburg
Klinik für Kardiologie
Universitätsklinikum Hamburg-Eppendorf
Martinistraße 52
Gebäude Ost 70
Hamburg
20246
Germany
 ORCID ID |
0000-0002-1881-0197 |
|---|---|
| Phone | +49 (0)40 7410-52438 |
| p.kirchhof@uke.de |
Study information
| Study design | Prospective randomised double-blind multi-centre trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised parallel trial |
| Study setting(s) | Hospital |
| Study type | Prevention |
| Participant information sheet | Not available in web format, please use the contact details to request a patient information sheet |
| 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 |
| Study acronym | NOAH |
| Study objectives | 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(s) | 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 |
| Health condition(s) or problem(s) studied | 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 |
| Pharmaceutical study type(s) | |
| Phase | Phase III/IV |
| Drug / device / biological / vaccine name(s) | Edoxaban, acetylsalicylic acid (ASA, aspirin) |
| 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 study start date | 01/02/2016 |
| Completion date | 31/12/2022 |
| Reason abandoned (if study stopped) | The reason for early termination is an observed trend towards futility for efficacy combined with expected safety concerns. |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Senior |
| Lower age limit | 65 Years |
| Sex | Both |
| Target number of participants | 2538 |
| Total final enrolment | 2535 |
| Key inclusion criteria | Current participant inclusion criteria as of 19/03/2020: 1. Implanted pacemaker, defibrillator or insertable cardiac monitor with feature of detection of AHRE, implanted at least 2 months prior to randomization 2. AHRE detection feature activated adequately according to "Suggestions for optimal programming of devices for adequate detection of AHRE" 3. AHRE (≥ 170 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: a. Age ≥ 75 years b. Heart failure (clinically overt or LVEF < 45%) c. Arterial hypertension (chronic treatment for hypertension, estimated need for continuous antihypertensive therapy or resting blood pressure > 145/90 mmHg) d. Diabetes mellitus e. Prior stroke or transient ischemic attack (TIA) f. 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 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 |
| Key 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) |
| Date of first enrolment | 01/02/2016 |
| Date of final enrolment | 08/09/2022 |
Locations
Countries of recruitment
- Austria
- Belgium
- Bulgaria
- Czech Republic
- Denmark
- France
- Germany
- Greece
- Hungary
- Italy
- Netherlands
- Poland
- Portugal
- Romania
- Spain
- Sweden
- Ukraine
- United Kingdom
Study participating centre
Münster
48149
Germany
Sponsor information
Other
Mendelstraße 11
Münster
48149
Germany
| Phone | +49 (0)251 9801340 |
|---|---|
| info@kompetenznetz-vorhofflimmern.de |
Funders
Funder type
Industry
No information available
Government organisation / Research institutes and centers
- Alternative name(s)
- Deutsches Zentrum für Herz-Kreislaufforschung e.V., German Centre for Cardiovascular Research, DZHK Germany, Zentrum HerzKreislaufForschung, Deutsches Zentrum für Herz-Kreislauf-Forschung e.V., DZHK, DZHK e.V.
- Location
- Germany
Results and Publications
| Intention to publish date | 31/08/2023 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request, Published as a supplement to the results publication |
| Publication and dissemination plan | Planned publication of study results in a peer-reviewed journal. |
| IPD sharing plan | The datasets generated during and/or analysed during the current study are/will be available upon request from the Chief Investigator Prof Paulus Kirchhof, p.kirchhof@uke.de, and will be published as a supplement to the results publication. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Protocol article | protocol | 01/08/2017 | Yes | No | |
| Results article | 25/08/2023 | 29/08/2023 | Yes | No | |
| Statistical Analysis Plan | version 4.0 | 21/03/2023 | 30/01/2024 | No | No |
Additional files
Editorial Notes
30/01/2024: The following changes were made:
1. Statistical analysis plan uploaded.
2. The individual participant data (IPD) sharing plan and summary were added.
29/08/2023: Publication reference added.
05/06/2023: The following changes were made to the trial record:
1. The intention to publish date was changed from 31/12/2023 to 31/08/2023.
2. Denmark was added to the countries of recruitment.
3. A contact's details were updated.
4. The study was stopped.
5. The total final enrolment was changed from 2545 to 2535.
27/09/2022: The following changes were made to the trial record:
1. The recruitment end date was changed from 31/08/2022 to 08/09/2022.
2. The overall end date was changed from 31/08/2023 to 31/12/2022.
3. The total final enrolment was added.
4. The plain English summary was updated to reflect these changes.
25/08/2022: The public contact was updated.
01/07/2022: The following changes were made to the trial record:
1. The recruitment end date was changed from 30/04/2022 to 31/08/2022.
2. The overall trial end date was changed from 31/07/2023 to 31/08/2023.
3. IPD sharing statement added.
21/12/2020: The following changes have been made:
1. The recruitment end date has been changed from 31/12/2020 to 30/04/2022.
2. The overall trial end date has been changed from 31/03/2022 to 31/07/2023.
3. The intention to publish date has been changed from 31/12/2022 to 31/12/2023.
4. The target number of participants has been changed from 2686 to 2538.
09/07/2020: The trial contact details have been made publicly visible.
19/03/2020: The following changes have been made:
1. The participant inclusion criteria have been updated.
2. The countries of recruitment "Greece" and "Romania" have been added.
28/09/2018: The contact details were updated.
27/09/2018: The following changes were made to the trial record:
1. The plain English summary was updated
2. The secondary outcomes were updated
3. The overall trial end date was updated from 01/09/2019 to 31/03/2022
4. The inclusion criteria was updated
5. The target number of participants and total target enrolment were updated from 3400 to 2686
6. The recruitment end date was updated from 01/05/2019 to 31/12/2020
7. The countries of recruitment were updated
8. Publication reference added
9. The intention to publish date was updated from 31/12/2019 31/12/2022
