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

NCT ID: NCT01522898

Last Updated: 2020-11-13

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 145 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-03-31
• Study Completion Date: 2020-08-31

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.

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.

Conditions

Heart Failure; Atrial Fibrillation

Keywords

Heart Failure; Atrial Fibrillation

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: ACTIVE_COMPARATOR

Medical Ventricular Rate Control

Intervention Type: DRUG

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

AV nodal ablation

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

Group Type: EXPERIMENTAL

AV nodal ablation

Intervention Type: PROCEDURE

Percutaneous catheter ablation of the AV node.

Interventions

AV nodal ablation

Percutaneous catheter ablation of the AV node.

Intervention Type: PROCEDURE

Medical Ventricular Rate Control

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

Intervention Type: DRUG

Other Intervention Names

His Bundle Ablation, AV junctional ablation

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Medtronic

INDUSTRY

Sponsor Role: collaborator

Abbott Medical Devices

INDUSTRY

Sponsor Role: collaborator

Boston Scientific Corporation

INDUSTRY

Sponsor Role: collaborator

University of Adelaide

OTHER

Sponsor Role: lead

Responsible Party

Prashanthan Sanders

Director, Centre for Heart Rhythm Disorders, University of Adelaide and Royal Adelaide Hospital

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Prashanthan Sanders, MBBS PhD

Role: PRINCIPAL_INVESTIGATOR

University of Adelaide

Locations

Canberra Hospital

Canberra, Australian Capital Territory, Australia

Concord Hospital

Concord, New South Wales, Australia

John Hunter Hospital

New Lambton, New South Wales, Australia

Prince of Wales Hospital

Randwick, New South Wales, Australia

Royal North Shore Hospital

Sydney, New South Wales, Australia

Royal Prince Alfred Hospital

Sydney, New South Wales, Australia

Fiona Stanley

Murdoch, Perth, WA, Australia

Royal Brisbane Hospital

Brisbane, Queensland, Australia

Prince Charles Hospital

Chermside, Queensland, Australia

Townsville Hospital and Health Service

Douglas, Queensland, Australia

Gold Coast University Hospital

Southport, Queensland, Australia

Princess Alexandra Hospital

Woolloongabba, Queensland, Australia

Royal Adelaide Hospital

Adelaide, South Australia, Australia

Flinders Medical Centre

Bedford Park, South Australia, Australia

Royal Hobart Hospital

Hobart, Tasmania, Australia

Monash Medical Centre

Clayton, Victoria, Australia

Geelong Hospital

Geelong, Victoria, Australia

Austin Hospital

Heidelberg, Victoria, Australia

Melbourne Private Hospital

Melbourne, Victoria, Australia

The Alfred Hospital

Melbourne, Victoria, Australia

Royal Melbourne Hospital

Parkville, Victoria, Australia

Sir Charles Gairdner Hospital

Perth, Western Australia, Australia

Royal Perth Hospital

Perth, Western Australia, Australia

Universitätsmedizin Mainz

Mainz, Gebäude 401/k, Germany

Universitätsklinikum Hamburg-Eppendorf

Hamburg, Martinistr. 52 Gebäude Ost 50, 8. OG, Raum 842, Germany

University Clinic of Cologne

Cologne, , Germany

Asklepios Hospital

St. Georg, , Germany

National Heart Institute

Kuala Lumpur, , Malaysia

Tauranga Hospital

Tauranga, Bay of Plenty, New Zealand

Auckland City Hospital

Auckland, , New Zealand

Waikato Hospital

Hamilton, , New Zealand

Wellington Hospital

Wellington, , New Zealand

James Cook University Hospital

Middlesbrough, , United Kingdom

Countries

Australia; Germany; Malaysia; New Zealand; United Kingdom

Other Identifiers

RAH-HREC-Protocol-#111234

Identifier Type: -

Identifier Source: org_study_id