NOAH: Non-vitamin K Antagonist Oral Anticoagulants in Patients With Atrial High Rate Episodes

Sponsor

Atrial Fibrillation Network (Other)

Overall Status

Recruiting

CT.gov ID

NCT02618577

Collaborator

Daiichi Sankyo Europe, GmbH, a Daiichi Sankyo Company (Industry), Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK) (Other)

2,538

Enrollment

Locations

Arms

88.9

Anticipated Duration (Months)

149.3

Patients Per Site

1.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

NOAH is an investigator-initiated, prospective, parallel-group, double-blind, randomised, multi-centre trial. The objective of the trial is to demonstrate that oral anticoagulation using the NOAC edoxaban is superior to current therapy to pre-vent stroke, systemic embolism, or cardiovascular death in patients with AHRE and at least two stroke risk factors but without AF. The trial will be conducted in several European countries.

Condition or Disease	Intervention/Treatment	Phase
Atrial High Rate Episodes	Drug: Edoxaban Drug: ASA	Phase 3

Detailed Description

Atrial fibrillation (AF) is a common cause of stroke, especially ischemic stroke. So far, all available data that demonstrate a beneficial effect of oral anticoagulation for stroke prevention have been collected in populations with AF documented by conventional ECG recordings. It is well established that a large proportion of AF episodes remain undiagnosed ("silent AF"), and many of these patients present with a stroke as the first clinical sign of AF. Earlier initiation of anticoagulation could prevent such events. Continuous monitoring of atrial rhythm by implanted devices could close this diagnostic gap. Pacemakers, defibrillators, and cardiac resynchronisation devices already provide automated algorithms alerting to the occurrence of highly organised atrial tachyarrhythmia episodes, also called "subclinical atrial fibrillation" or, more commonly, "atrial high rate episodes" (AHRE). Data from large prospectively followed patient cohorts demonstrated that stroke rate is increased in patients with AHRE. A sizeable portion of these patients develops clinically detected AF over time. In these patients, AHRE can be considered as an early manifestation of paroxysmal AF. A few AHRE patients do not develop clinically overt AF, and the absolute stroke rates are lower in patients with AHRE when compared to stroke rates in patients with clinically diagnosed AF. In light of the bleeding complications associated with oral anticoagulant therapy, there is thus uncertainty about the optimal antithrombotic therapy in patients with AHREs.

The Non-vitamin K antagonist Oral anticoagulants (NOACs) provide similar or slightly better stroke prevention, and appear slightly safer compared to vitamin K antagonists (VKAs). In addition, no individual therapy adjustment of NOACs has to be performed. Edoxaban, a newly introduced NOAC, at a dose regime of 60 mg once daily (OD) has a favourable profile compared to dose-adjusted VKA therapy: In the ENGAGE-TIMI 48 trial, edoxaban prevented strokes at least as effectively as VKA therapy but caused less major bleeding events than VKA therapy.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

2538 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Phase 3bPhase 3b

Masking:

Double (Participant, Investigator)

Primary Purpose:

Prevention

Official 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

Actual Study Start Date :

Feb 1, 2016

Anticipated Primary Completion Date :

Jun 30, 2022

Anticipated Study Completion Date :

Jun 30, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Edoxaban Edoxaban will be applied in NOAH at the therapeutic dose approved for stroke prevention in non-valvular AF, i.e. 60 mg OD with a reduction of dose to 30 mg OD in patients with one of the following characteristics: Impaired renal function (CrCl 15-50 ml/min), or low body weight (≤60 kg), or patients receiving the glycoprotein p inhibitors cyclosporin, dronedarone, erythromycin, or ketoconazole.	Drug: Edoxaban Edoxaban will be applied at the therapeutic dose approved for stroke prevention in non-valvular AF, i.e. 60 mg OD with a reduction of dose to 30 mg OD in patients with one of the following characteristics: Impaired renal function (CrCl 15-50 ml/min), or low body weight (≤60 kg), or patients receiving the glycoprotein p inhibitors cyclosporin, dronedarone, erythromycin, or ketoconazole. Other Names: Lixiana Savaysa
Active Comparator: ASA or Placebo 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	Drug: ASA ASA 100 mg tablets or Placebo Other Names: ASS

Arm

Intervention/Treatment

Experimental: Edoxaban

Edoxaban will be applied in NOAH at the therapeutic dose approved for stroke prevention in non-valvular AF, i.e. 60 mg OD with a reduction of dose to 30 mg OD in patients with one of the following characteristics: Impaired renal function (CrCl 15-50 ml/min), or low body weight (≤60 kg), or patients receiving the glycoprotein p inhibitors cyclosporin, dronedarone, erythromycin, or ketoconazole.

Drug: Edoxaban

Edoxaban will be applied at the therapeutic dose approved for stroke prevention in non-valvular AF, i.e. 60 mg OD with a reduction of dose to 30 mg OD in patients with one of the following characteristics: Impaired renal function (CrCl 15-50 ml/min), or low body weight (≤60 kg), or patients receiving the glycoprotein p inhibitors cyclosporin, dronedarone, erythromycin, or ketoconazole.

Other Names:

Lixiana

Savaysa

Active Comparator: ASA or Placebo

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

Drug: ASA

ASA 100 mg tablets or Placebo

Other Names:

ASS

Outcome Measures

Primary Outcome Measures

Time from randomisation to the first occurrence of stroke, systemic embolism, or cardiovascular death [28 months]

Secondary Outcome Measures

Components of the primary outcome [28 months]
All-cause death Major bleeding events according to the ISTH definitions Quality of life changes at 12 and 24 months compared to baseline Patient satisfaction at 12 and 24 months compared to baseline Cost effectiveness and health resource utilisation Patient autonomy changes at 12 and 24 months compared to baseline including chronic consequences of stroke (aphasia, hemianopia ("mild stroke")) Cognitive function at 12 and 24 months compared to baseline
Major Adverse Cardiac Events (MACEs: cardiac death, myocardial infarction, acute coronary syndrome (ACS), PCI, CABG) [28 months]
All-cause death [28 months]
Major bleeding events according to the International Society on Thrombosis and Haemostasis (ISTH) definitions (60, 61), (Appendix IV) [28 months]
Quality of life changes at 12 and 24 months compared to baseline (assessed by EQ-5D including its visual-analogue scale and by the Karnofsky scale) [28 months]
Patient satisfaction at 12 and 24 months compared to baseline (assessed by modified EHRA score (36) and PACT-Q (43)) [28 months]
Cost effectiveness and health resource utilisation estimated by quantification of relevant events, interventions, nights spent in hospital and cardiovascular therapies [28 months]
Changes of autonomy status in patients with stroke during study participation, potentially assessed at each FU visit by modified Rankin scale; a maximum of 2 subsequent assessments in FU per patient with stroke should be performed [28 Months]
Cognitive function (MoCA) at 12 and 24 months compared to baseline [28 months]

Eligibility Criteria

Criteria

Ages Eligible for Study:

65 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Pacemaker, defibrillator or insertable cardiac monitor implanted for any reason with feature of detection of AHRE, implanted at least 2 months prior to randomisation
AHRE detection feature activated for adequate detection of AHRE (refer to Appendix XIII)
AHRE (≥ 170 bpm atrial rate and ≥ 6 min duration) documented by the implanted device via its atrial lead and stored digitally. Any AHRE episode recorded is potentially eligible, but AHRE episodes detected in the first 2 months after implantation of a new device involving placement or repositioning of atrial electrodes are not eligible. 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 atrial electrodes, are eligible
Provision of signed informed consent
Age ≥ 65 years

In addition, at least one of the following cardiovascular conditions leading to a modified

CHA2DS2VASc score of 2 or more:

Age ≥ 75 years
Heart failure (clinically overt or LVEF < 45%)
Arterial hypertension (chronic treatment for hypertension, estimated need for continuous antihyper-tensive therapy or resting blood pressure > 145/90 mmHg)
Diabetes mellitus
Prior stroke or transient ischemic attack (TIA)
Vascular disease (previous myocardial infarction, peripheral, carotid/cerebral, or aortic plaques on transesophageal echocardiogram [TEE])
Provision of signed informed consent

Exclusion Criteria:

Any disease that limits life expectancy to less than 1 year
Participation in another controlled clinical trial, either within the past two months or still ongoing
Previous participation in the present trial NOAH - AFNET 6
Drug abuse or clinically manifest alcohol abuse
Any history of overt AF or atrial flutter
Indication for oral anticoagulation (e.g. deep venous thrombosis)
Contraindication for oral anticoagulation in general
Contraindication for edoxaban as stated in the current SmPC
Indication for long-term antiplatelet therapy other than acetylsalicylic acid or a need for treatment with any antiplatelet agent in addition to edoxaban, especially dual antiplatelet therapy (DAPT). 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
Acute coronary syndrome, coronary revascularisation (PCI or bypass surgery), or overt stroke within 30 days prior to randomisation
End stage renal disease (creatinine clearance (CrCl) < 15 ml/min as calculated by the Cockcroft-Gault method)
All persons exempt from participation in a clinical trial by law

Contacts and Locations

Locations

	Site	City	Country
1	Several Sites	Multiple Locations	Austria
2	Several Sites	Multiple Locations	Belgium
3	Several	Multiple Locations	Bulgaria
4	Several	Multiple Locations	Czechia
5	Several	Multiple Locations	France
6	Several Sites	Multiple Locations	Germany
7	Several	Multiple Locations	Greece
8	Several	Multiple Locations	Hungary
9	Several	Multiple Locations	Italy
10	Several	Multiple Locations	Netherlands
11	Several	Multiple Locations	Poland
12	Several	Multiple Locations	Portugal
13	Several	Multiple Locations	Romania
14	Several	Multiple Locations	Spain
15	Several	Multiple Locations	Sweden
16	Several	Multiple Locations	Ukraine
17	Several	Multiple Locations	United Kingdom