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Trial registered on ANZCTR


Registration number
ACTRN12613000444785
Ethics application status
Not yet submitted
Date submitted
3/04/2013
Date registered
18/04/2013
Date last updated
8/03/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
Implications of aggressive cardiac risk factor management on the catheter ablation for atrial fibrillation
Scientific title
Implications of aggressive cardiac risk factor management on the catheter ablation for atrial fibrillation
Secondary ID [1] 282236 0
NIL
Universal Trial Number (UTN)
Trial acronym
ARREST -AF
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Metabolic Syndrome 288752 0
Atrial Fibrillation 288753 0
Condition category
Condition code
Diet and Nutrition 289110 289110 0 0
Obesity
Cardiovascular 289201 289201 0 0
Other cardiovascular diseases
Metabolic and Endocrine 289202 289202 0 0
Metabolic disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The study will be a multi-center prospective randomized controlled study evaluating the effect of a structured weight and cardio-metabolic risk factor management program on multiple outcomes pertinent to Atrial Fibrillation. The project will incorporate two distinct studies with respective primary and secondary outcomes.

Phase 1 will primarily assess the impact of intervention on objectively measured AF burden and electroanatomical remodelling and or reverse remodelling of heart along with autonomic and thrombotic parameters.This will be first 6 months after enrolment.

Phase 2 will evaluate the impact of intervention on success of catheter ablation along with autonomic and thrombotic parameters and will be from time of ablation until 60 months.
The two phases of the program, weight loss and weight maintenance, will follow a previously described approach.

This regime has been successfully used by another study from our group and was assessed and approved by the RAH REC.

Weight loss will be achieved by using structured physician-led motivational and goal-directed face-to-face visits every 3 months. In addition, patients will be encouraged to utilize support counseling and schedule more frequent reviews, as they required. The intervention cohort will be subjected to periodic intensive one-on-one supportive counseling that will review goals achieved and further incremental goal setting. Nutritional behavior reflection, barriers to goal achievement and nutritional decision coaching will be the pillars of the 20-40 minute counseling sessions. Subsequent to barrier identification, verbal and written tailored educational material will be provided. The participant could schedule additional intervening visits and/or physician at will in the event of an impending relapse. When additional support is required, 24-hour email and telephone contact will be available.

Initial weight reduction will be attempted by a meal plan and behavior modification program. Participants will be required to maintain a diet and activity diary. Meals will consist of high protein and low glycemic index, calorie controlled foods. If the patients did not loose 3% of weight after first 3 months they will then be prescribed very-low-calorie meal replacement sachets (Prima health solutions or Nestle Health Science) for 1-2 meals a day. The initial goal will be to reduce body weight by 10% from baseline. Patients on meal replacement supplement will undergo weight loss in two distinct phases.

Weight loss phase : Weight loss will be induced over 8 weeks using a modified very low calorie diet (VLCD) (800-1200 Cal/day). Patients will be prescribed VLCD meal replacement diet for 1-2 of their daily meals. Remaining meal will consist of high animal and plant protein, and low glycemic index (GI), calorie controlled foods.

Weight maintenance phase : After patients achieved initial goal the meal replacement will be replaced with high protein and low glycemic index, calorie controlled foods. Further weight loss with diet will be attempted if indicated with a target BMI of 25 kg/m2. This phase will focus on slower weight loss and maintenance. This will occupy the remainder of the follow up period. During this phase, VLCD meal supplements will be gradually phased out and replaced with a low GI meal plan with emphasis on education for permanent lifestyle changes and behavior modification program.


Lifestyle Journal - Participants in the intervention group only are instructed to maintain a self-monitoring lifestyle journal detailing food type, preparation method and amount consumed. Patients are advised to review the journal on a weekly basis on their own and to reflect on nutritional behavioral patterns. The journal functions to indicate, in addition to nutritional habits, blood pressure patterns (documented 2-3 times daily, see below) and estimated energy expenditure. The maintenance of the journal is a dynamic process, whereby it may be relaxed when significant clinical (and anthropometric) progress is made and re-initiated when healthy lifestyle divergence is evident or a weight re-gain is impending.

Exercise – In the intervention group, physical activity is prescribed initially at 20 minutes of low intensity (walking and/or aqua-aerobics) thrice weekly and titrated over phase 1 to reach 45 minutes thrice weekly finally increasing to at least 200 min of moderate-intensity physical activity in a week. Type of activity and duration is logged into the journal. Control group participants are not required to maintain a lifestyle journal and education regarding activity levels is issued in the form of specific written material. Low intensity exercise was prescribed initially for 20 minutes thrice weekly

Control Group - Standard care (control) group participants are issued with once off written and verbal advice regarding health nutrition and exercise guidelines at commencement of their participation and weight management is a self-directed process. Completion of a diet and activity diary was not requested. Follow-up will scheduled three monthly for a 20-40 minute physician-led major assessment, as for the intervention group.

Cardio-metabolic risk assessment and managements (All Groups) - Coexistent risk factors of hypertension, hyperlipidemia, glucose intolerance, obstructive sleep apnea, alcohol and tobacco use are identified through historical patient records and fasting plasma testing (see below). Following identification, optimal management in accordance with current established best practice guidelines is undertaken by the identifying physician and by referral to a specialist management clinic (diabetes and sleep disordered breathing) for that particular risk factor. Both intervention and control cohorts undergo comprehensive risk assessment and management.

Glucose tolerance and hyper-insulinemia -If fasting glucose was between 100 and 125mg/dL, a 2-hour oral glucose tolerance test will be performed. Impaired glucose tolerance (IGT) will be managed with lifestyle measures such as diet and aerobic exercise. If patients were unable to maintain glycosylated hemoglobin values below 6.5 percent after three months, metformin will be started. Patients in both groups with poor glycemic control (HbA1c>7%) will be referred to diabetes clinic.

Hyperlipidemia – Management of dyslipidemia will be in accordance with the guidelines. Initial management will be with lifestyle measures. If patients were unable to achieve LDL-Cholesterol of less than 100mg/dL after 3 months then statin will be initiated. Fibrates will be used for isolated cases of hypertriglyceridemia (TG > 500mg/dL) or added to statin therapy if TG> 200mg/dL and non-HDL cholesterol was >130mg/dL after 3 months of therapeutic life style changes.

Hypertension – Patients in RF Mx or intensive arm group will be asked to measure blood pressure (BP) twice daily using home-automated monitor and an appropriate sized cuff. In addition, exercise stress testing will be performed to determine the presence of exercise-induced hypertension. Increase in blood pressure to over 200/100 with exercise will be considered further evidence to optimize control. Initial therapeutic advice will include dietary salt restriction and weight loss with increase in aerobic physical activity, in keeping with current guidelines. Pharmacotherapy will be initiated using angiotensin-aldosterone axis active agents by preference, and other agents where necessary to achieve a target BP of <130/80mmHg on at least 80% of random patient acquired blood pressure readings as listed above. These will also be corroborated by in-office readings and 24-hour ambulatory blood pressure monitors as required. In addition, echocardiography be be used to monitor and to ensure the resolution of any left ventricular hypertrophy as objective evidence of end-organ injury. Changes in the dose and number of anti-hypertensive agents will be recorded at each 3 monthly visit.

Sleep apnea - All subjects will be referred to the same dedicated sleep disorders unit for inpatient or home overnight polysommnography. Continuous positive airway pressure will be prescribed in the presence of a clinically compatible history of sleep apnea and sleep study results (RDI and desaturation levels). Generally, for an RDI of 15-30 continued lifestyle measures may be pursued with periodic evaluation and for an RDI >30, CPAP will be prescribed.

Smoking: The “5A” (Ask, Assess, Advice, Assist and Arrange follow up) structured smoking cessation framework was adapted. Smokers were offered help and follow-up, with access to clinic for behavioral support.

Alcohol: Written and verbal counseling was provided with regular supportive follow up for alcohol reduction (=2 drinks for men and =1 for female) with abstinence as ultimate goal.


Pharmacotherapy – Major clinical review, assessment of lifestyle journal and 12-lead ECG will be performed on all enrolled patients. Patient response and tolerance of all prescribed pharmacotherapy will be assessed. Medication addition, cessation and dosage titration is undertaken and documented at each 3-month visit. Anti-arrhythmic medications, for rate and/or rhythm control will be prescribed at the discretion of the attending physician and guided by the clinical response and symptomatology of the patient. Electrical cardioversion may be performed as a last resort, in preference for pharmacologic cardioversion.

ABLATION PROCEDURE

There is no alteration of the clinical procedure as part of the study protocol.
All patients less than 65 yrs. old will undergo Electrophysiology study to rule out supra ventricular tachycardia (SVT) as a cause for atrial fibrillation (Standard Practice in RAH) If found then this tachycardia will be ablated. At a later date if the patient needs AF ablation, an EP study will be done with activation mapping of both atrium and then wide encircling pulmonary vein antrum isolation will be performed with the aid of electroanatomic mapping and 3-D LA geometry construction. Radiofrequency current from irrigated tip catheters will be the used as the ablation energy. A stepwise approach to LA ablation, with linear lesion formation, coronary sinus isolation and possible fractionated electrogram targeting, will be utilised based on the discretion of the operator. This is based on the frequency and duration of attacks and chronicity of the disease. Pre-procedural anti-coagulation will be managed in accordance with local guidelines.
Within the 60 months of follow-up, patients may undertake a repeat or consolidative AF procedure as clinically required.
Post Ablation Care : Anticoagulation management will be as for standard clinical care, using post procedural heparin, flowed by enoxaparin while warfarin loading takes place.

During the follow-up visits, patients will undergo face-to-face counseling and feedback based on anthropometric measures and lifestyle journal. Patients will have access to 24 hour email and telephone support in addition to additional counseling sessions if required. The periodicity of follow-up data recording is as follows: 1:Follow up review (40 min) every 3 months in both groups.In intensive arm this can be more frequent if required. 2.BMI, Waist Circumference(WC), blood pressure, 12-lead ECG (baseline and three monthly) 3.7 day Holter recording (baseline and 12 months,24months,36months,48months,60months) 4.Exercise stress testing (baseline and 12 months,24months,36months,48months,60months) 5.Head up tilt table testing (baseline and 12 months,24months,36months,48months,60months) 6.Transthoracic echocardiography (baseline and 12 months,24months,36months,48months,60months) 7.Delayed enhancement Cardiac MRI (baseline and 12 months,24months,36months,48months,60months) 8.Fasting plasma biochemistry (baseline and 12 months,24months,36months,48months,60months)
Intervention code [1] 286857 0
Treatment: Surgery
Intervention code [2] 286858 0
Prevention
Intervention code [3] 286931 0
Lifestyle
Comparator / control treatment
Standard care (control) group participants are issued with once off written and verbal advice regarding health nutrition and exercise guidelines at commencement of their participation and weight management is a self-directed process. Follow-up will scheduled three monthly for a 20-40 minute physician-led major assessment, as for the intervention group.Total follow up will be for 60 months
Control group
Active

Outcomes
Primary outcome [1] 289233 0
*AF burden on loop recorder before AF ablation(%)
Timepoint [1] 289233 0
Baseline, 3, 6, 9, 12 ,24,36,48,60 MONTHS
Primary outcome [2] 289234 0
*Percentage of patients free from AF on loop recorder after AF ablation. The AF burden will be assessed by loop recorder data.
Timepoint [2] 289234 0
Baseline,3,6,9,12,24,36,48,60 months
Primary outcome [3] 289314 0
*Electrophysiological changes in conduction velocity/ERP: EP study will be done at baseline and at the time of AF ablation. Electrophysiology study using diagnostic EP catheter.

Atrial effective refractory period (ERP) will be evaluated at cycle lengths (CL) of 600 and 450 ms with an 8-beat drive followed by an extra- stimulus, starting with an extra-stimulus coupling interval of 150 ms increasing in 10-ms increments. The ERP will be defined as the longest coupling interval failing to propagate to the atrium. At each site the ERP will be measured 3 times during each CL and averaged. If ERP varied by >10 ms, an additional 2 measurements were made, and the total number was averaged. The ERP was measured from the following sites: 1) distal-CS; 2) proximal-CS; 3) low lateral RA; 4) high lateral RA; 5) high septal RA.

Isochronal activation maps (5-ms intervals) of the atria will be created and regional conduction velocity determined in the direction of the wave-front propagation (least isochronal crowding). An approximation of conduction velocity will be determined by expressing the distance between 2 points as a function of the difference in local activation time. Mean conduction velocity for each region will be determined by averaging the conduction velocity between 5 pairs of points, as previously described. For the purposes of evaluating regional conduction differences, each atrium will be segmented as noted in the preceding text.

AF inducibility will be assessed using a standardized protocol of burst pacing in the proximal followed by distal coronary sinus and during programmed extra stimuli from the same sites. Pacing will be started at 200 ms and will be decreased in 5-ms intervals until either AF initiates or there is loss of 1:1 capture. A fixed rate of decrement will be used at 5 ms per 3 seconds to ensure consistency. AF is defined as rapid irregular atrial rhythm lasting longer than 2 seconds. This protocol of induction will be repeated 10 times. Mean AF duration will be obtained from the average of all induced AF episodes. If AF persists beyond 5 minutes, no further induction will be tried.
Timepoint [3] 289314 0
Baseline,3,6,9,12,24,36,48,60 months
Secondary outcome [1] 302078 0
*Autonomic remodeling assessed by heart rate variability and NA spillover. Will be assessed by Holter data, EST, Tilt table, Sleep study results.
Timepoint [1] 302078 0
Baseline,3,6,9,12,24,36,48,60 months
Secondary outcome [2] 302079 0
*Physical functioning, health-related quality of life (HRQoL) in patients post AF ablation. Will be assessed by AFSS scoring and SF36 data.
Timepoint [2] 302079 0
Baseline,3,6,9,12,24,36,48,60 months
Secondary outcome [3] 302227 0
*Platelet function and endothelial function.
*Endothelial Function tested by : Endo PAT, ADMA,ET-1
*Platelet Function tested by MPV,TAT,P-Selectin,ADP,Collagen,Thrombin,Serotonin
Timepoint [3] 302227 0
Baseline,3,6,9,12,24,36,48,60 months
Secondary outcome [4] 302228 0
Re-hospitalisation- from history
Timepoint [4] 302228 0
at 24,26 and 60 months
Secondary outcome [5] 302333 0
All-cause mortality – From History
Timepoint [5] 302333 0
At 24,26 and 60 months

Eligibility
Key inclusion criteria
Paroxysmal and persistent AF
BMI>27
Waist circumference >100 (male), >90 (female)
Highly symptomatic AF
Age >18 years and <65 years
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Serious underlying medical disorder
Malabsorption disorder
Unstable INR
Moderate-severe impaired LV systolic function
Insulin-dependent diabetes
Moderate-severe cardiac valvulopathy
Inability to provide informed consent
Endocrinopathy including subclinical thyroid disease
Recent (within 3 months) participation in a structured weight management program
Significant psychiatric disorder

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Screening of all the patients referred for catheter ablation of atrial fibrillation for drug-refractory paroxysmal and persistent symptomatic AF (not secondary to an acute reversible medical cause) AF ablation will be offered entry into this study if they meet above inclusion criteria. These patients will be referred to clinic where they will be then randomised to either of the group using a computerised randomisation tool.Upon enrolment and randomization, a unique numerical identifier code will be allocated to each patient for entry into the database.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomization between 0 (control) and 1 (active) using an electronic random number generator.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Follow up for 60 mnths
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/05/2013
Actual
30/05/2013
Date of last participant enrolment
Anticipated
1/01/2014
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
150
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 836 0
The Royal Adelaide Hospital - Adelaide
Recruitment postcode(s) [1] 6652 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 287007 0
University
Name [1] 287007 0
The university of Adelaide
Country [1] 287007 0
Australia
Funding source category [2] 287008 0
Hospital
Name [2] 287008 0
The Royal Adelaide Hospital
Country [2] 287008 0
Australia
Primary sponsor type
Hospital
Name
Royal Melbourne Hospital
Address
Grattan St Parkville VIC 3050
Country
Australia
Secondary sponsor category [1] 285792 0
Hospital
Name [1] 285792 0
The Royal Adelaide Hospital
Address [1] 285792 0
The Royal Adelaide Hospital
North Terrace, Adelaide, SA, 5000
Country [1] 285792 0
Australia

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 289049 0
Royal Adelaide Hospital Ethics Committee
Ethics committee address [1] 289049 0
Ethics committee country [1] 289049 0
Australia
Date submitted for ethics approval [1] 289049 0
03/04/2013
Approval date [1] 289049 0
Ethics approval number [1] 289049 0
AU/1/E6E1110

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 38946 0
Prof Prashanthan Sanders
Address 38946 0
Centre For Heart Rhythm Disorder
Level 5 McEwin Building
The Royal Adelaide Hospital
North Terrace
Adelaide, SA, 5000
Country 38946 0
Australia
Phone 38946 0
+61 8 82222723
Fax 38946 0
+61 8 82222722
Email 38946 0
Rajeev.Pathak@adelaide.edu.au
Contact person for public queries
Name 38947 0
Prashanthan Sanders
Address 38947 0
Centre For Heart Rhythm Disorder
Level 5 McEwin Building
The Royal Adelaide Hospital
North Terrace
Adelaide, SA, 5000
Country 38947 0
Australia
Phone 38947 0
+61 8 82222723
Fax 38947 0
+61 8 82222722
Email 38947 0
prash.sanders@adelaide.edu.au
Contact person for scientific queries
Name 38948 0
Prashanthan Sanders
Address 38948 0
Centre For Heart Rhythm Disorder
Level 5 McEwin Building
The Royal Adelaide Hospital
North Terrace
Adelaide, SA, 5000
Country 38948 0
Australia
Phone 38948 0
+61 8 82222723
Fax 38948 0
+61 8 82222722
Email 38948 0
Rajeev.Pathak@adelaide.edu.au

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbasePrevention and regressive effect of weight-loss and risk factor modification on atrial fibrillation: The reverse-af study - Authors' reply.2019https://dx.doi.org/10.1093/europace/euz050
N.B. These documents automatically identified may not have been verified by the study sponsor.