Clinical trial NCT02618577: Non-vitamin K Antagonist Oral Anticoagulants in Patients With Atrial High Rate Episodes
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Atrial High Rate Episodes
Keywords: Anticoagulation
Atrial High Rate Episodes
Atrial Fibrillation
VKA
NOAC
Lead sponsor: Atrial Fibrillation Network
Sponsor class: OTHER
Collaborators: name: Daiichi Sankyo Europe, GmbH, a Daiichi Sankyo Company
name: Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK)
First posted: 2015-12-01
Enrollment: 2608
Sex: ALL
Minimum age (years): 65
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Phase 3b
Primary purpose: PREVENTION

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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Composite of Stroke, Systemic Embolism, or Cardiovascular Death
timeFrame: 28 months
Secondary outcomes:
measure: Components of the Primary Outcome, Stroke
timeFrame: 28 months
measure: Major Adverse Cardiac Events (MACEs: Cardiac Death, Myocardial Infarction, Acute Coronary Syndrome (ACS)
timeFrame: 28 months
measure: All-cause Death
timeFrame: 28 months
measure: Major Bleeding Events
timeFrame: 28 months
measure: Quality of Life Changes at 12 and 24 Months Compared to Baseline
timeFrame: Baseline, 12 months and 24 months.
measure: Patient Satisfaction at 12 and 24 Months Compared to Baseline
timeFrame: Baseline, 12 months and 24 months.
measure: Cost Effectiveness and Health Resource Utilisation
timeFrame: 28 months
measure: Autonomy Status
timeFrame: Baseline and 24 months
measure: Components of the Primary Outcome, Systemic Embolism
timeFrame: 28 months
measure: Components of the Primary Outcome, Cardiovascular Death
timeFrame: 28 months
Other outcomes:
Locations:
city: Multiple Locations
country: Austria
facility: Several Sites
city: Multiple Locations
country: Belgium
facility: Several Sites
city: Multiple Locations
country: Bulgaria
facility: Several
city: Multiple Locations
country: Czechia
facility: Several
city: Multiple Locations
country: Denmark
facility: Several
city: Multiple Locations
country: France
facility: Several
city: Multiple Locations
country: Germany
facility: Several Sites
city: Multiple Locations
country: Greece
facility: Several
city: Multiple Locations
country: Hungary
facility: Several
city: Multiple Locations
country: Italy
facility: Several
city: Multiple Locations
country: Netherlands
facility: Several
city: Multiple Locations
country: Poland
facility: Several
city: Multiple Locations
country: Portugal
facility: Several
city: Multiple Locations
country: Romania
facility: Several
city: Multiple Locations
country: Spain
facility: Several
city: Multiple Locations
country: Sweden
facility: Several
city: Multiple Locations
country: Ukraine
facility: Several
city: Multiple Locations
country: United Kingdom
facility: Several
Study officials:
affiliation: University Clinic of Hamburg-Eppendorf, Hamburg, Germany
name: Paulus Kirchhof, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bertaglia E, Blank B, Blomstrom-Lundqvist C, Brandes A, Cabanelas N, Dan GA, Dichtl W, Goette A, de Groot JR, Lubinski A, Marijon E, Merkely B, Mont L, Piorkowski C, Sarkozy A, Sulke N, Vardas P, Velchev V, Wichterle D, Kirchhof P. Atrial high-rate episodes: prevalence, stroke risk, implications for management, and clinical gaps in evidence. Europace. 2019 Oct 1;21(10):1459-1467. doi: 10.1093/europace/euz172.
citation: Kirchhof P, Blank BF, Calvert M, Camm AJ, Chlouverakis G, Diener HC, Goette A, Huening A, Lip GYH, Simantirakis E, Vardas P. Probing oral anticoagulation in patients with atrial high rate episodes: Rationale and design of the Non-vitamin K antagonist Oral anticoagulants in patients with Atrial High rate episodes (NOAH-AFNET 6) trial. Am Heart J. 2017 Aug;190:12-18. doi: 10.1016/j.ahj.2017.04.015. Epub 2017 May 3.