Clinical trial NCT01522898: Cardiac Resynchronisation Therapy and AV Nodal Ablation Trial in Atrial Fibrillation Patients (CAAN-AF)
Official title: Cardiac Resynchronisation Therapy and AV Nodal Ablation Trial in Atrial Fibrillation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Heart Failure
Atrial Fibrillation
Keywords: Heart Failure
Atrial Fibrillation
Lead sponsor: University of Adelaide
Sponsor class: OTHER
Collaborators: name: Medtronic
name: Abbott Medical Devices
name: Boston Scientific Corporation
First posted: 2012-02-01
Enrollment: 145
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: All-cause mortality and non-fatal heart failure events
timeFrame: Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)
Secondary outcomes:
measure: All-cause mortality
timeFrame: Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)f recruitment
measure: Cardiovascular mortality
timeFrame: Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)
measure: Non-Fatal Heart Failure Events
timeFrame: Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)
measure: 6-minute walking distance
timeFrame: Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)
measure: Quality of Life questionnaires
timeFrame: Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)
measure: Unplanned Hospitalization
timeFrame: Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)
measure: Ventricular arrhythmias requiring device therapy
timeFrame: Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)
Other outcomes:
measure: Inappropriate shocks
timeFrame: Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)
measure: Cardiovascular MRI prediction of response
timeFrame: Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)
measure: Depression
timeFrame: Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)
measure: Ventricular reverse remodelling
timeFrame: Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)
Locations:
city: Canberra
country: Australia
facility: Canberra Hospital
state: Australian Capital Territory
city: Concord
country: Australia
facility: Concord Hospital
state: New South Wales
city: New Lambton
country: Australia
facility: John Hunter Hospital
state: New South Wales
city: Randwick
country: Australia
facility: Prince of Wales Hospital
state: New South Wales
city: Sydney
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Sydney
country: Australia
facility: Royal Prince Alfred Hospital
state: New South Wales
city: Murdoch
country: Australia
facility: Fiona Stanley
state: Perth, WA
city: Brisbane
country: Australia
facility: Royal Brisbane Hospital
state: Queensland
city: Chermside
country: Australia
facility: Prince Charles Hospital
state: Queensland
city: Douglas
country: Australia
facility: Townsville Hospital and Health Service
state: Queensland
city: Southport
country: Australia
facility: Gold Coast University Hospital
state: Queensland
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Bedford Park
country: Australia
facility: Flinders Medical Centre
state: South Australia
city: Hobart
country: Australia
facility: Royal Hobart Hospital
state: Tasmania
city: Clayton
country: Australia
facility: Monash Medical Centre
state: Victoria
city: Geelong
country: Australia
facility: Geelong Hospital
state: Victoria
city: Heidelberg
country: Australia
facility: Austin Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Melbourne Private Hospital
state: Victoria
city: Melbourne
country: Australia
facility: The Alfred Hospital
state: Victoria
city: Parkville
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: Perth
country: Australia
facility: Sir Charles Gairdner Hospital
state: Western Australia
city: Perth
country: Australia
facility: Royal Perth Hospital
state: Western Australia
city: Mainz
country: Germany
facility: Universitätsmedizin Mainz
state: Gebäude 401/k
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg-Eppendorf
state: Martinistr. 52 Gebäude Ost 50, 8. OG, Raum 842
city: Cologne
country: Germany
facility: University Clinic of Cologne
city: St Georg
country: Germany
facility: Asklepios Hospital
city: Kuala Lumpur
country: Malaysia
facility: National Heart Institute
city: Tauranga
country: New Zealand
facility: Tauranga Hospital
state: Bay Of Plenty
city: Auckland
country: New Zealand
facility: Auckland City Hospital
city: Hamilton
country: New Zealand
facility: Waikato Hospital
city: Wellington
country: New Zealand
facility: Wellington Hospital
city: Middlesbrough
country: United Kingdom
facility: James Cook University Hospital
Study officials:
affiliation: University of Adelaide
name: Prashanthan Sanders, MBBS PhD
role: PRINCIPAL_INVESTIGATOR
References: