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

Heart Failure Clinical Trial

— CAAN-AF  

Official title:

Cardiac Resynchronisation Therapy and AV Nodal Ablation Trial in Atrial Fibrillation

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01522898
• Other study ID #: RAH-HREC-Protocol-#111234
• Status: Completed
• Phase: N/A
• Start date: March 2013
• Est. completion date: August 31, 2020

Study information

• Verified date: November 2020
• Source: University of Adelaide
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 145
• Est. completion date: August 31, 2020
• Est. primary completion date: August 31, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Atrial Fibrillation
• Heart Failure

Intervention

Procedure:
• AV nodal ablation
Percutaneous catheter ablation of the AV node.

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

Locations

Country	Name	City	State
Australia	Royal Adelaide Hospital	Adelaide	South Australia
Australia	Flinders Medical Centre	Bedford Park	South Australia
Australia	Royal Brisbane Hospital	Brisbane	Queensland
Australia	Canberra Hospital	Canberra	Australian Capital Territory
Australia	Prince Charles Hospital	Chermside	Queensland
Australia	Monash Medical Centre	Clayton	Victoria
Australia	Concord Hospital	Concord	New South Wales
Australia	Townsville Hospital and Health Service	Douglas	Queensland
Australia	Geelong Hospital	Geelong	Victoria
Australia	Austin Hospital	Heidelberg	Victoria
Australia	Royal Hobart Hospital	Hobart	Tasmania
Australia	Melbourne Private Hospital	Melbourne	Victoria
Australia	The Alfred Hospital	Melbourne	Victoria
Australia	Fiona Stanley	Murdoch	Perth, WA
Australia	John Hunter Hospital	New Lambton	New South Wales
Australia	Royal Melbourne Hospital	Parkville	Victoria
Australia	Royal Perth Hospital	Perth	Western Australia
Australia	Sir Charles Gairdner Hospital	Perth	Western Australia
Australia	Prince of Wales Hospital	Randwick	New South Wales
Australia	Gold Coast University Hospital	Southport	Queensland
Australia	Royal North Shore Hospital	Sydney	New South Wales
Australia	Royal Prince Alfred Hospital	Sydney	New South Wales
Australia	Princess Alexandra Hospital	Woolloongabba	Queensland
Germany	University Clinic of Cologne	Cologne
Germany	Universitätsklinikum Hamburg-Eppendorf	Hamburg	Martinistr. 52 Gebäude Ost 50, 8. OG, Raum 842
Germany	Universitätsmedizin Mainz	Mainz	Gebäude 401/k
Germany	Asklepios Hospital	St Georg
Malaysia	National Heart Institute	Kuala Lumpur
New Zealand	Auckland City Hospital	Auckland
New Zealand	Waikato Hospital	Hamilton
New Zealand	Tauranga Hospital	Tauranga	Bay Of Plenty
New Zealand	Wellington Hospital	Wellington
United Kingdom	James Cook University Hospital	Middlesbrough

Sponsors (4)

Lead Sponsor	Collaborator
University of Adelaide	Abbott Medical Devices, Boston Scientific Corporation, Medtronic

Countries where clinical trial is conducted

Australia,  Germany,  Malaysia,  New Zealand,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Inappropriate shocks	The clinical events committee will review clinical records to ascertain if device therapies are appropriate or inappropriate.	Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)
Other	Cardiovascular MRI prediction of response	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.	Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)
Other	Depression	Depression will be evaluated in all patients at specified clinical follow-up visits with the Center for Epidemiologic Studies Depression Scale (CES-D questionnaire).	Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)
Other	Ventricular reverse remodelling	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.	Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)
Primary	All-cause mortality and non-fatal heart failure events	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	Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)
Secondary	All-cause mortality	All-cause mortality will be determined after adjudication committee review of clinical records, and death certificate data.	Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)f recruitment
Secondary	Cardiovascular mortality	Cardiovascular deaths will be classified in terms of suddenness and arrhythmic mechanism according to the Hinkle-Thaler criteria.	Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)
Secondary	Non-Fatal Heart Failure Events	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	Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)
Secondary	6-minute walking distance	6-minute walking distance will be measured according to standard criteria.	Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)
Secondary	Quality of Life questionnaires	Quality of life as assessed by the Short Form 36 (SF-36) questionnaire and Minnesota Living with Heart Failure Questionnaire	Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)
Secondary	Unplanned Hospitalization	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	Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)
Secondary	Ventricular arrhythmias requiring device therapy	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).	Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)