Atrial High Rate Episodes
Conditions
Keywords
Anticoagulation, Atrial High Rate Episodes, Atrial Fibrillation, VKA, NOAC
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.
Interventions
DRUGEdoxaban
Edoxaban will be applied at the therapeutic dose approved for stroke prevention in non-valvular AF
DRUGASA
ASA 100 mg tablets or Placebo, based on accepted indication for the latter, including peripheral or coronary artery disease, a prior myocardial infarction, or a prior stroke.
Sponsors
Daiichi Sankyo Europe, GmbH, a Daiichi Sankyo Company
Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK)
Atrial Fibrillation Network
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Intervention model description
Phase 3b
Eligibility
Sex/Gender
ALL
Age
65 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Composite of Stroke, Systemic Embolism, or Cardiovascular Death | 28 months | Time from randomisation to the first occurrence of stroke, systemic embolism, or cardiovascular death; incidence of first occurence of outcome measure. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Major Adverse Cardiac Events (MACEs: Cardiac Death, Myocardial Infarction, Acute Coronary Syndrome (ACS) | 28 months | PCI, CABG |
| All-cause Death | 28 months | All-cause death |
| Major Bleeding Events | 28 months | according to the International Society on Thrombosis and Haemostasis (ISTH) definitions |
| Quality of Life Changes at 12 and 24 Months Compared to Baseline | Baseline, 12 months and 24 months. | Adjusted mean change from baseline at 12 and 24 months of Quality of life as assessed by the EuroQol Group 5-Dimension 5-Level questionnaire (EQ-5D-5L): The resulting score of the UK index ranges from 1 (for the best state) to - 0.285 (for the worst state), with 5.1% of the states valued as worse than dead. EQ5D- VAS: visual-analogue scale (0 worst to 100 best). Subscales of the UK index score were combined by adding up EQ-5D-5L index values with STATA using the English (ENG) Devlin value set, Version 1.1 (Updated 01/12/2020). Karnofsky Performance Scale is an 11-point scale from 0 to 100 (0 worst to 100 best). |
| Components of the Primary Outcome, Stroke | 28 months | Time from randomisation to the first occurrence of ischemic stroke; incidence of first occurence of outcome measure. |
| Cost Effectiveness and Health Resource Utilisation | 28 months | estimated by quantification of relevant events, interventions, nights spent in hospital and cardiovascular therapies |
| Autonomy Status | Baseline and 24 months | Autonomy status only in patients with stroke during study participation, assessed at 24 month by modified Rankin scale. (Score ranges from 1 to 8, a higher score indicates a higher grade of disability) |
| Components of the Primary Outcome, Systemic Embolism | 28 months | Time from randomisation to the first occurrence of systemic embolism; incidence of first occurence of outcome measure. |
| Components of the Primary Outcome, Cardiovascular Death | 28 months | Time from randomisation to the first occurrence of cardiovascular death; incidence of first occurence of outcome measure. |
| Patient Satisfaction at 12 and 24 Months Compared to Baseline | Baseline, 12 months and 24 months. | Adjusted change from baseline at 12 and 24 months measured by the Perception of Anticoagulant Treatment Questionnaire: For convenience score, a 0 - 100 scale; for satisfaction score a 0 - 100 scale; for both scores, the higher the score, the higher the convenience/satisfaction. |
Countries
Austria, Belgium, Bulgaria, Czechia, Denmark, France, Germany, Greece, Hungary, Italy, Netherlands, Poland, Portugal, Romania, Spain, Sweden, Ukraine, United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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.
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. | 1,270 |
| 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
ASA: ASA 100 mg tablets or Placebo, based on accepted indication for the latter, including peripherial or coronary artery disease, a prior myocardial infarction, or a prior stroke. | 1,264 |
| Total | 2,534 |
Baseline characteristics
| Characteristic | Total | Edoxaban | ASA or Placebo |
|---|---|---|---|
| Age, Continuous | 77.5 years STANDARD_DEVIATION 6.7 | 77.4 years STANDARD_DEVIATION 6.5 | 77.5 years STANDARD_DEVIATION 6.8 |
| Race and Ethnicity Not Collected | 0 Participants | — | — |
| Region of Enrollment Austria | 221 participants | 108 participants | 113 participants |
| Region of Enrollment Belgium | 23 participants | 15 participants | 8 participants |
| Region of Enrollment Bulgaria | 21 participants | 9 participants | 12 participants |
| Region of Enrollment Czechia | 12 participants | 6 participants | 6 participants |
| Region of Enrollment Denmark | 18 participants | 11 participants | 7 participants |
| Region of Enrollment France | 82 participants | 41 participants | 41 participants |
| Region of Enrollment Germany | 685 participants | 340 participants | 345 participants |
| Region of Enrollment Greece | 7 participants | 4 participants | 3 participants |
| Region of Enrollment Hungary | 70 participants | 35 participants | 35 participants |
| Region of Enrollment Italy | 158 participants | 82 participants | 76 participants |
| Region of Enrollment Netherlands | 50 participants | 22 participants | 28 participants |
| Region of Enrollment Poland | 272 participants | 137 participants | 135 participants |
| Region of Enrollment Portugal | 25 participants | 13 participants | 12 participants |
| Region of Enrollment Romania | 14 participants | 7 participants | 7 participants |
| Region of Enrollment Spain | 353 participants | 176 participants | 177 participants |
| Region of Enrollment Sweden | 16 participants | 9 participants | 7 participants |
| Region of Enrollment Ukraine | 351 participants | 179 participants | 172 participants |
| Region of Enrollment United Kingdom | 156 participants | 76 participants | 80 participants |
| Sex: Female, Male Female | 947 Participants | 469 Participants | 478 Participants |
| Sex: Female, Male Male | 1587 Participants | 801 Participants | 786 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 142 / 1,306 | 125 / 1,302 |
| other Total, other adverse events | 718 / 1,306 | 662 / 1,302 |
| serious Total, serious adverse events | 498 / 1,306 | 467 / 1,302 |
Outcome results
Primary
Composite of Stroke, Systemic Embolism, or Cardiovascular Death
Time from randomisation to the first occurrence of stroke, systemic embolism, or cardiovascular death; incidence of first occurence of outcome measure.
Time frame: 28 months
Population: The primary analysis is in the modified intention-to-treat population, consisting of all randomised patients with a qualifying AHRE and intake of at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Edoxaban | Composite of Stroke, Systemic Embolism, or Cardiovascular Death | 3.3 number of new events per 100 pat.-years |
| ASA or Placebo | Composite of Stroke, Systemic Embolism, or Cardiovascular Death | 4.0 number of new events per 100 pat.-years |
p-value: 0.1595% CI: [0.6, 1.08]Cause-spec. Cox Proport. Hazard model
Secondary
All-cause Death
All-cause death
Time frame: 28 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Edoxaban | All-cause Death | 4.3 number of new events per 100 pat.-years |
| ASA or Placebo | All-cause Death | 3.7 number of new events per 100 pat.-years |
p-value: 0.2895% CI: [0.88, 1.53]Cause-spec. Cox Proport. Hazard model
Secondary
Autonomy Status
Autonomy status only in patients with stroke during study participation, assessed at 24 month by modified Rankin scale. (Score ranges from 1 to 8, a higher score indicates a higher grade of disability)
Time frame: Baseline and 24 months
Population: MoCA Stroke Severity in patients with a stroke estimated by the Modified Rankin Scale at FU24.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Edoxaban | Autonomy Status | 3.0 Scores on a scale |
| ASA or Placebo | Autonomy Status | 2.5 Scores on a scale |
Secondary
Components of the Primary Outcome, Cardiovascular Death
Time from randomisation to the first occurrence of cardiovascular death; incidence of first occurence of outcome measure.
Time frame: 28 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Edoxaban | Components of the Primary Outcome, Cardiovascular Death | 2.0 number of new events per 100 pat.-years |
| ASA or Placebo | Components of the Primary Outcome, Cardiovascular Death | 2.2 number of new events per 100 pat.-years |
95% CI: [0.62, 1.31]
Secondary
Components of the Primary Outcome, Stroke
Time from randomisation to the first occurrence of ischemic stroke; incidence of first occurence of outcome measure.
Time frame: 28 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Edoxaban | Components of the Primary Outcome, Stroke | 0.9 number of new events per 100 pat.-years |
| ASA or Placebo | Components of the Primary Outcome, Stroke | 1.1 number of new events per 100 pat.-years |
95% CI: [0.45, 1.39]
Secondary
Components of the Primary Outcome, Systemic Embolism
Time from randomisation to the first occurrence of systemic embolism; incidence of first occurence of outcome measure.
Time frame: 28 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Edoxaban | Components of the Primary Outcome, Systemic Embolism | 0.5 number of new events per 100 pat.-years |
| ASA or Placebo | Components of the Primary Outcome, Systemic Embolism | 1.1 number of new events per 100 pat.-years |
95% CI: [0.27, 0.96]
Secondary
Cost Effectiveness and Health Resource Utilisation
estimated by quantification of relevant events, interventions, nights spent in hospital and cardiovascular therapies
Time frame: 28 months
Secondary
Major Adverse Cardiac Events (MACEs: Cardiac Death, Myocardial Infarction, Acute Coronary Syndrome (ACS)
PCI, CABG
Time frame: 28 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Edoxaban | Major Adverse Cardiac Events (MACEs: Cardiac Death, Myocardial Infarction, Acute Coronary Syndrome (ACS) | 3.6 number of new events per 100 pat.-years |
| ASA or Placebo | Major Adverse Cardiac Events (MACEs: Cardiac Death, Myocardial Infarction, Acute Coronary Syndrome (ACS) | 4.1 number of new events per 100 pat.-years |
95% CI: [0.67, 1.18]
Secondary
Major Bleeding Events
according to the International Society on Thrombosis and Haemostasis (ISTH) definitions
Time frame: 28 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Edoxaban | Major Bleeding Events | 2.1 number of new events per 100 pat.-years |
| ASA or Placebo | Major Bleeding Events | 1.0 number of new events per 100 pat.-years |
p-value: 0.00295% CI: [1.3, 3.38]Cause-spec. Cox Proport. Hazard model
Secondary
Patient Satisfaction at 12 and 24 Months Compared to Baseline
Adjusted change from baseline at 12 and 24 months measured by the Perception of Anticoagulant Treatment Questionnaire: For convenience score, a 0 - 100 scale; for satisfaction score a 0 - 100 scale; for both scores, the higher the score, the higher the convenience/satisfaction.
Time frame: Baseline, 12 months and 24 months.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Edoxaban | Patient Satisfaction at 12 and 24 Months Compared to Baseline | PACT-Q convenience to FU12 | 0.84 scores on a scale (with 95% Confidence I |
| Edoxaban | Patient Satisfaction at 12 and 24 Months Compared to Baseline | PACT-Q convenience to FU24 | 1.35 scores on a scale (with 95% Confidence I |
| Edoxaban | Patient Satisfaction at 12 and 24 Months Compared to Baseline | PACT-Q satisfaction to FU12 | 2.97 scores on a scale (with 95% Confidence I |
| Edoxaban | Patient Satisfaction at 12 and 24 Months Compared to Baseline | PACT-Q satisfaction to FU24 | 3.80 scores on a scale (with 95% Confidence I |
| ASA or Placebo | Patient Satisfaction at 12 and 24 Months Compared to Baseline | PACT-Q satisfaction to FU24 | 4.84 scores on a scale (with 95% Confidence I |
| ASA or Placebo | Patient Satisfaction at 12 and 24 Months Compared to Baseline | PACT-Q convenience to FU12 | 0.96 scores on a scale (with 95% Confidence I |
| ASA or Placebo | Patient Satisfaction at 12 and 24 Months Compared to Baseline | PACT-Q satisfaction to FU12 | 4.01 scores on a scale (with 95% Confidence I |
| ASA or Placebo | Patient Satisfaction at 12 and 24 Months Compared to Baseline | PACT-Q convenience to FU24 | 1.47 scores on a scale (with 95% Confidence I |
Comparison: PACT-Q convenience95% CI: [-1.12, 0.87]
Comparison: PACT-Q satisfaction95% CI: [-2.6, 0.52]
Secondary
Quality of Life Changes at 12 and 24 Months Compared to Baseline
Adjusted mean change from baseline at 12 and 24 months of Quality of life as assessed by the EuroQol Group 5-Dimension 5-Level questionnaire (EQ-5D-5L): The resulting score of the UK index ranges from 1 (for the best state) to - 0.285 (for the worst state), with 5.1% of the states valued as worse than dead. EQ5D- VAS: visual-analogue scale (0 worst to 100 best). Subscales of the UK index score were combined by adding up EQ-5D-5L index values with STATA using the English (ENG) Devlin value set, Version 1.1 (Updated 01/12/2020). Karnofsky Performance Scale is an 11-point scale from 0 to 100 (0 worst to 100 best).
Time frame: Baseline, 12 months and 24 months.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Edoxaban | Quality of Life Changes at 12 and 24 Months Compared to Baseline | EQ-5D-5L UK Index to FU12 | -0.01 adjusted mean change from baseline |
| Edoxaban | Quality of Life Changes at 12 and 24 Months Compared to Baseline | EQ-5D-5L UK Index to FU24 | -0.04 adjusted mean change from baseline |
| Edoxaban | Quality of Life Changes at 12 and 24 Months Compared to Baseline | EQ-5D-5L VAS to FU12 | -0.75 adjusted mean change from baseline |
| Edoxaban | Quality of Life Changes at 12 and 24 Months Compared to Baseline | EQ-5D-5L VAS to FU24 | -1.72 adjusted mean change from baseline |
| Edoxaban | Quality of Life Changes at 12 and 24 Months Compared to Baseline | Karnofsky score to FU12 | -1.14 adjusted mean change from baseline |
| Edoxaban | Quality of Life Changes at 12 and 24 Months Compared to Baseline | Karnofsky score to FU24 | -2.28 adjusted mean change from baseline |
| ASA or Placebo | Quality of Life Changes at 12 and 24 Months Compared to Baseline | Karnofsky score to FU12 | -1.41 adjusted mean change from baseline |
| ASA or Placebo | Quality of Life Changes at 12 and 24 Months Compared to Baseline | EQ-5D-5L UK Index to FU12 | -0.01 adjusted mean change from baseline |
| ASA or Placebo | Quality of Life Changes at 12 and 24 Months Compared to Baseline | EQ-5D-5L VAS to FU24 | -1.68 adjusted mean change from baseline |
| ASA or Placebo | Quality of Life Changes at 12 and 24 Months Compared to Baseline | EQ-5D-5L UK Index to FU24 | -0.03 adjusted mean change from baseline |
| ASA or Placebo | Quality of Life Changes at 12 and 24 Months Compared to Baseline | Karnofsky score to FU24 | -2.55 adjusted mean change from baseline |
| ASA or Placebo | Quality of Life Changes at 12 and 24 Months Compared to Baseline | EQ-5D-5L VAS to FU12 | -0.71 adjusted mean change from baseline |
Comparison: EQ-5D-5L UK Index95% CI: [-0.02, 0.01]
Comparison: EQ-5D-5L VAS, FU 24months95% CI: [-1.46, 1.38]
Comparison: Karnofsky score95% CI: [-0.56, 1.09]