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