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

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ClinicalTrials.gov Identifier: NCT02618577
Recruitment Status : Recruiting
First Posted : December 1, 2015
Last Update Posted : October 8, 2018
Sponsor:
Collaborators:
Daiichi Sankyo Europe, GmbH, a Daiichi Sankyo Company
Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK)
Information provided by (Responsible Party):
Atrial Fibrillation Network

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 Type : Interventional  (Clinical Trial)
Estimated Enrollment : 2686 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Phase 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 : February 2016
Estimated Primary Completion Date : December 31, 2021
Estimated Study Completion Date : March 31, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Blood Thinners
Drug Information available for: Edoxaban

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 Name: ASS




Primary Outcome Measures :
  1. Time from randomisation to the first occurrence of stroke, systemic embolism, or cardiovascular death [ Time Frame: 28 months ]

Secondary Outcome Measures :
  1. Components of the primary outcome [ Time Frame: 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

  2. Major Adverse Cardiac Events (MACEs: cardiac death, myocardial infarction, acute coronary syndrome (ACS)) [ Time Frame: 28 months ]
  3. All-cause death [ Time Frame: 28 months ]
  4. Major bleeding events according to the International Society on Thrombosis and Haemostasis (ISTH) definitions [ Time Frame: 28 months ]
  5. 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) [ Time Frame: 28 months ]
  6. Patient satisfaction at 12 and 24 months compared to baseline (assessed by modified EHRA score (36) and PACT-Q (43)) [ Time Frame: 28 months ]
  7. Cost effectiveness and health resource utilisation estimated by quantification of relevant events, interventions, nights spent in hospital and cardiovascular therapies [ Time Frame: 28 months ]
  8. 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 [ Time Frame: 28 Months ]
  9. Cognitive function (MoCA) at 12 and 24 months compared to baseline [ Time Frame: 28 months ]


Information from the National Library of Medicine

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Ages Eligible for Study:   65 Years and older   (Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Pacemaker or defibrillator 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
  • AHRE (≥ 180 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])

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02618577


Contacts
Contact: Paulus Kirchhof, Prof. Dr. +44 121 414 ext 7042 p.kirchhof@bham.ac.uk
Contact: Benjamin Blank, Dr. 0049 251 980 ext 1340 benjamin.blank@af-net.eu

Locations
Austria
Several Sites Recruiting
Multiple Locations, Austria
Belgium
Several Sites Not yet recruiting
Multiple Locations, Belgium
Bulgaria
Several Recruiting
Multiple Locations, Bulgaria
Czechia
Several Recruiting
Multiple Locations, Czechia
France
Several Recruiting
Multiple Locations, France
Germany
Several Sites Recruiting
Multiple Locations, Germany
Hungary
Several Recruiting
Multiple Locations, Hungary
Italy
Several Recruiting
Multiple Locations, Italy
Netherlands
Several Recruiting
Multiple Locations, Netherlands
Poland
Several Recruiting
Multiple Locations, Poland
Portugal
Several Recruiting
Multiple Locations, Portugal
Spain
Several Recruiting
Multiple Locations, Spain
Sweden
Several Recruiting
Multiple Locations, Sweden
Ukraine
Several Recruiting
Multiple Locations, Ukraine
United Kingdom
Several Recruiting
Multiple Locations, United Kingdom
Sponsors and Collaborators
Atrial Fibrillation Network
Daiichi Sankyo Europe, GmbH, a Daiichi Sankyo Company
Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK)
Investigators
Principal Investigator: Paulus Kirchhof, Prof. Dr. University of Birmingham Centre for Cardiovascular Scienes

Additional Information:
Responsible Party: Atrial Fibrillation Network
ClinicalTrials.gov Identifier: NCT02618577     History of Changes
Other Study ID Numbers: NOAH - AFNET 6
2015-003997-33 ( EudraCT Number )
First Posted: December 1, 2015    Key Record Dates
Last Update Posted: October 8, 2018
Last Verified: October 2018

Keywords provided by Atrial Fibrillation Network:
Anticoagulation
atrial high rate episodes
Atrial Fibrillation
VKA
NOAC

Additional relevant MeSH terms:
Edoxaban
Anticoagulants
Factor Xa Inhibitors
Antithrombins
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action