Cardiac Resynchronisation Therapy and AV Nodal Ablation Trial in Atrial Fibrillation Patients (CAAN-AF)

Sponsor
University of Adelaide (Other)
Overall Status
Completed
CT.gov ID
NCT01522898
Collaborator
Medtronic (Industry), Abbott Medical Devices (Industry), Boston Scientific Corporation (Industry)
145
33
2
90
4.4
0

Study Details

Study Description

Brief Summary

Cardiac resynchronization therapy (CRT) is a treatment for heart failure in patients who also suffer from ventricular dyssynchrony, a form of uncoordinated contraction of the ventricle (lower pumping chamber of the heart). In the past decade, CRT has become an established treatment for heart failure patients who are in normal rhythm, called sinus rhythm. An important subset of heart failure patients are those with atrial fibrillation (AF), who make up around 1 in 4 HF patients, and are over-represented amongst HF patients with more advanced symptoms. In heart failure patients with AF, CRT has proven not to be as effective as in sinus rhythm, due to competition between beats generated by the CRT device and beats conducted from the heart's own electrical conduction system. In the current study, we aim to test the hypothesis that ablating the AV node, which controls electrical conduction from the heart's atria (top chamber) to its ventricles (lower chambers), will improve survival and heart failure symptoms in CRT patients with co-existent AF. The results are important, because they will provide a way of passing on the benefits of CRT, such as improved survival, less heart failure symptoms, and better quality of life, to heart failure patients who also suffer from AF.

Condition or Disease Intervention/Treatment Phase
  • Procedure: AV nodal ablation
  • Drug: Medical Ventricular Rate Control
N/A

Detailed Description

Background: Cardiac Resynchronization Therapy (CRT) is an established treatment in heart failure (HF) patients with ventricular dyssynchrony who remain in sinus rhythm. Available clinical data has shown inferior outcomes of CRT in HF patients with co-existent atrial fibrillation (AF), who comprise up to 27% of HF patients, and are over-represented in advanced HF classes. We hypothesize, based on the results of a systematic review we recently published in the Journal of the American College of Cardiology, that AV nodal ablation may improve survival, heart failure and functional outcomes in CRT recipients with co-existent AF.

Design: This study will be a multicentre, prospective, randomized controlled trial. Patients with ischemic or nonischemic cardiomyopathy heart failure (NYHA II, III or ambulatory class IV), left ventricular dysfunction (EF ≤ 35%), prolonged intraventricular conduction (QRS duration ≥ 120ms), and persistent or permanent AF will be considered for the study. Persistent AF will be defined as patients where obtaining and maintaining sinus rhythm is deemed either not worthwhile, or to be ineffective in the long term, or where both the patient and the physician accept the presence of AF, where rhythm control intervention is, by definition, no longer pursued. Permanent AF is defined as AF where sinus rhythm cannot be restored.

Eligible subjects will be randomized into one of two arms: (1) CRT-D plus AV nodal ablation ("AV nodal ablation arm [AVNA]") or (2) CRT-D alone ("rate control arm").

Enrollment: 590 subjects, with 295 subjects in the AV node ablation arm and 295 subjects in the control arm, will be enrolled. Study patients will undergo stratified randomization at ≥ 30 days after CRT implant. Participants in will sign informed consent and be screened prior to randomisation. After CRT implant, patients will have at least 30 days for optimisation of heart failure therapy, prior to randomisation.

Randomisation: A computer-generated web-based randomisation schedule will be used. Randomisation will be stratified by trial centre. Randomisation is considered the trial entry point.

Outcomes: The primary endpoint is a composite of all cause mortality and non-fatal heart failure events. Secondary endpoints include all-cause mortality, cardiovascular mortality (including classification in terms of suddenness and arrhythmic mechanism by prespecified Hinkle-Thaler criteria), non-fatal heart failure events, 6-minute walking test distance, quality of life, unplanned hospitalization, and ventricular arrhythmias requiring device therapy, inappropriate shocks, cardiovascular MRI prediction of response, percentage pacing and prediction of response to therapy, ventricular reverse remodeling.

Statistical Plan: The study is powered to find a 25% relative reduction in event rate, with sample sizes calculated assuming a two-tailed α=0.05,1-β=0.80, and 10% sample size increment allow for to drop in the event rate (AV nodal ablation arm), drop out or cross-over (feasibly, control to AVNA arm only). It is planned to perform three interim (0.25, 0.5 0.75 information fractions) and a final analysis requiring 295 patients per arm with a final P-value at ≤ 0.045; stopping rules according to the method of O'Brien and Fleming. The boundaries (z scores: ±4.332, ±2.963, ±2.359, ±2.014; and nominal P-values: 0.000015, 0.0031, 0.014, 0.044)) were derived using the statistical package PASS (V12). Outside of these defined analyses, the Data Safety Monitoring Board (DSMB) will have access to data reports and will be able to stop the trial at any time.

All analyses will be based on the intention-to-treat principle. The primary (binary) mortality-outcome will be analysed using the Cochran-Mantel-Haenszel statistic and logistic regression with pre-specified (baseline) covariates. Time-to-event analyses will be initially undertaken by the Kaplan-Meier survival analysis approach. Key secondary outcomes such as all-cause mortality, cardiovascular mortality, unplanned hospitalisation, and rates of ventricular arrhythmia episodes will be analysed using either Cox proportional hazards models or Fine and Gray competing risks regression as appropriate. Continuous secondary outcomes such as the 6-minute walking distance, Short Form 36 (SF36) scores, Minnesota Living with Heart Failure (MLWHF) score will be compared between randomised groups over time using linear mixed effects models.

Significance and Impact: The study will answer a central clinical question directly impacting the care of HF patients with AF, and will be expected to change current HF management guidelines.

Study Design

Study Type:
Interventional
Actual Enrollment :
145 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Cardiac Resynchronisation Therapy and AV Nodal Ablation Trial in Atrial Fibrillation
Study Start Date :
Mar 1, 2013
Actual Primary Completion Date :
Aug 31, 2020
Actual Study Completion Date :
Aug 31, 2020

Arms and Interventions

Arm Intervention/Treatment
Active Comparator: Medical Rate Control

Medical Rate Control aimed at ventricular rate target of 90 beats per minute. Specific medical therapy to be determined for each patient by individual clinician.

Drug: Medical Ventricular Rate Control
Ventricular Rate Control with target ventricular rate of 90 beats per minute.

Experimental: AV nodal ablation

AV node ablation performed by percutaneous catheter ablation, with endpoint of complete heart block.

Procedure: AV nodal ablation
Percutaneous catheter ablation of the AV node.
Other Names:
  • His Bundle Ablation, AV junctional ablation
  • Outcome Measures

    Primary Outcome Measures

    1. All-cause mortality and non-fatal heart failure events [Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)]

      This is a composite of all-cause mortality and non-fatal heart failure events. All-cause mortality will be determined by a designated clinical events committee. Heart Failure events will be documented by clinical data from the hospital In CAAN-AF, a subject will be described as having a "Heart Failure Event" when the subject has symptoms and/or signs consistent with congestive heart failure and: responsive to parenteral diuretic or inotropic support as an outpatient responsive to oral or parenteral diuretic or inotropic support during an inpatient stay

    Secondary Outcome Measures

    1. All-cause mortality [Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)f recruitment]

      All-cause mortality will be determined after adjudication committee review of clinical records, and death certificate data.

    2. Cardiovascular mortality [Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)]

      Cardiovascular deaths will be classified in terms of suddenness and arrhythmic mechanism according to the Hinkle-Thaler criteria.

    3. Non-Fatal Heart Failure Events [Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)]

      Heart Failure events will be documented by clinical data from the hospital In CAAN-AF, a subject will be described as having a "Heart Failure Event" when the subject has symptoms and/or signs consistent with congestive heart failure and: responsive to parenteral diuretic or inotropic support as an outpatient responsive to oral or parenteral diuretic or inotropic support during an inpatient stay

    4. 6-minute walking distance [Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)]

      6-minute walking distance will be measured according to standard criteria.

    5. Quality of Life questionnaires [Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)]

      Quality of life as assessed by the Short Form 36 (SF-36) questionnaire and Minnesota Living with Heart Failure Questionnaire

    6. Unplanned Hospitalization [Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)]

      Unplanned hospital admissions will be assessed by a combination of patient self-report, hospital record and/or treating physician interrogation. The reason, date and duration of hospitalization will be recorded Planned hospitalizations (hospital visits for elective or planned medical interventions) will excluded from this outcome

    7. Ventricular arrhythmias requiring device therapy [Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)]

      Ventricular arrhythmias requiring device therapy will be determined by implantable Cardioverter Defibrillator (ICD) interrogation records and clinical records. At each site, the number, duration and type (VT/VF) of device recorded arrhythmias will be recorded, as well as the need for device therapy (anti-tachycardia pacing and/or ICD shocks).

    Other Outcome Measures

    1. Inappropriate shocks [Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)]

      The clinical events committee will review clinical records to ascertain if device therapies are appropriate or inappropriate.

    2. Cardiovascular MRI prediction of response [Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)]

      Cardiovascular MRI will be performed in subjects eligible for this procedure prior to implantation of CRT device, when available. Cardiovascular MRI data will be evaluated for the ability to predict clinical CRT response.

    3. Depression [Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)]

      Depression will be evaluated in all patients at specified clinical follow-up visits with the Center for Epidemiologic Studies Depression Scale (CES-D questionnaire).

    4. Ventricular reverse remodelling [Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)]

      Left ventricular reverse remodeling will be assessed by echocardiographic parameters including left ventricular end systolic volume, left ventricular ejection fraction. An echocardiography core laboratory has been established to process images from individual trial sites for this purpose.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Age ≥ 18 years old

    • Persistent (≥ 1 month) or permanent atrial fibrillation. Persistent AF will be where obtaining and maintaining sinus rhythm is deemed either not worthwhile, or to be ineffective in the long term, or where both the patient and physician accept the presence of AF, where rhythm control intervention is, by definition no longer pursued. Permanent AF is defined as atrial fibrillation where sinus rhythm cannot be restored.

    • NYHA class II , III or ambulatory class IV heart failure

    • Left Ventricular Ejection Fraction (LVEF) ≤ 35% by objective criteria such as echocardiography, or cardiac MRI

    • QRS duration on 12-lead ECG ≥ 120ms

    • Able and willing to comply with all pre-, post- and follow-up testing and requirements.

    Exclusion Criteria:
    • age < 18 years

    • pregnancy

    • previous AV nodal ablation

    • Second or third degree AV block

    • Inability to provide informed consent

    • life expectancy less than 24 months due to co-morbid illness other than heart failure erg cancer, end-stage renal disease, liver failure

    • Paroxysmal Atrial Fibrillation that self terminates within 7 days

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Canberra Hospital Canberra Australian Capital Territory Australia 2605
    2 Concord Hospital Concord New South Wales Australia
    3 John Hunter Hospital New Lambton New South Wales Australia 2305
    4 Prince of Wales Hospital Randwick New South Wales Australia 2031
    5 Royal North Shore Hospital Sydney New South Wales Australia 2065
    6 Royal Prince Alfred Hospital Sydney New South Wales Australia
    7 Fiona Stanley Murdoch Perth, WA Australia 6150
    8 Royal Brisbane Hospital Brisbane Queensland Australia 4209
    9 Prince Charles Hospital Chermside Queensland Australia 4032
    10 Townsville Hospital and Health Service Douglas Queensland Australia 4814
    11 Gold Coast University Hospital Southport Queensland Australia 4213
    12 Princess Alexandra Hospital Woolloongabba Queensland Australia 4102
    13 Royal Adelaide Hospital Adelaide South Australia Australia 5000
    14 Flinders Medical Centre Bedford Park South Australia Australia 5042
    15 Royal Hobart Hospital Hobart Tasmania Australia 7000
    16 Monash Medical Centre Clayton Victoria Australia 3168
    17 Geelong Hospital Geelong Victoria Australia 3220
    18 Austin Hospital Heidelberg Victoria Australia 3084
    19 Melbourne Private Hospital Melbourne Victoria Australia
    20 The Alfred Hospital Melbourne Victoria Australia
    21 Royal Melbourne Hospital Parkville Victoria Australia 3050
    22 Sir Charles Gairdner Hospital Perth Western Australia Australia 6009
    23 Royal Perth Hospital Perth Western Australia Australia
    24 Universitätsmedizin Mainz Mainz Gebäude 401/k Germany 55131
    25 Universitätsklinikum Hamburg-Eppendorf Hamburg Martinistr. 52 Gebäude Ost 50, 8. OG, Raum 842 Germany 20246
    26 University Clinic of Cologne Cologne Germany D-50936
    27 Asklepios Hospital St Georg Germany 20099
    28 National Heart Institute Kuala Lumpur Malaysia 50400
    29 Tauranga Hospital Tauranga Bay Of Plenty New Zealand 3143
    30 Auckland City Hospital Auckland New Zealand 1142
    31 Waikato Hospital Hamilton New Zealand 3240
    32 Wellington Hospital Wellington New Zealand 6021
    33 James Cook University Hospital Middlesbrough United Kingdom

    Sponsors and Collaborators

    • University of Adelaide
    • Medtronic
    • Abbott Medical Devices
    • Boston Scientific Corporation

    Investigators

    • Principal Investigator: Prashanthan Sanders, MBBS PhD, University of Adelaide

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Prashanthan Sanders, Director, Centre for Heart Rhythm Disorders, University of Adelaide and Royal Adelaide Hospital, University of Adelaide
    ClinicalTrials.gov Identifier:
    NCT01522898
    Other Study ID Numbers:
    • RAH-HREC-Protocol-#111234
    First Posted:
    Feb 1, 2012
    Last Update Posted:
    Nov 13, 2020
    Last Verified:
    Nov 1, 2020
    Keywords provided by Prashanthan Sanders, Director, Centre for Heart Rhythm Disorders, University of Adelaide and Royal Adelaide Hospital, University of Adelaide
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Nov 13, 2020