Cardiac Resynchronization in Atrial Fibrillation Trial - a Pilot Study

Study Overview
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Brief Summary
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The purpose of this prospective randomized study is to determine whether patients on cardiac resynchronization therapy with concomitant long-standing persistent or permanent atrial fibrillation would benefit from a strategy to restore and maintain sinus rhythm (rhythm control strategy) in comparison to a rate control strategy in terms of higher biventricular paced beats percentage.

Detailed Description
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Due to a lack of sufficient data the present guidelines on treatment of patients with atrial fibrillation (AF) and cardiac resynchronization therapy (CRT) devices are of low scientific evidence. The efficacy of CRT in AF patients is limited by the percentage of the effective biventricular paced beats (BiVp%), which should exceed 95%-98% - a goal which is seldom obtained by means of pharmacological rate control strategy. The only treatment strategy which effect is scientifically established is an atrioventricular junction ablation (AVJA) but the use of this method is limited. On the other hand, about 10% of patients with persistent forms of AF experience a spontaneous sinus rhythm (SR) resumption after CRT implantation. Moreover, SR resumption and it's maintenance by means of single external electrical cardioversion in AF patients has been proven feasible. A strategy of rhythm control in AF patients on CRT could provide high BiVp% and improve the efficacy of CRT in this group of patients. To show superiority of the rhythm control strategy over the rate control strategy a sample size of 60 patients was calculated based on following assumptions: two-tailed test, a type I error of 0.05, a power of 80%, efficacy (mean BiVp%) of rate control strategy 90%, efficacy (mean BiVp%)of rhythm control strategy 98% and 8% drop-out rate to fulfill the criteria of intention-to-treat analysis. Due to presumed lack of statistical power the secondary end points and safety endpoints will be considered exploratory.

Official Title
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Comparison of a Rhythm Control Treatment Strategy Versus a Rate Control Strategy in Patients With Permanent or Long-term Persistent Atrial Fibrillation and Heart Failure Treated With Cardiac Resynchronization Therapy - a Pilot Study

Conditions
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Atrial Fibrillation, Heart Failure

Intervention / Treatment
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* Drug: Amiodarone
* Procedure: External electrical cardioversion (EEC)
* Drug: Pharmacotherapy to slow and control ventricular rate
* Procedure: Atrioventricular junction ablation (AVJA)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Permanent or long-standing persistent atrial fibrillation (definitions according to the latest European Society of Cardiology guidelines on AF) At least 3 months after a procedure of a CRT device implantation A CRT device with a presence of a right atrial electrode Age: ≥18 years old Effectively biventricular paced captured beats <95% Effective therapy with oral anticoagulants for at least 3 months Written informed consent Exclusion Criteria: Reversible causes of AF Significant valve disease Advanced A-V block (including: AVJA) Contraindications to amiodarone (hyperthyroidism, not compensated hypothyroidism, drug intolerance, QT>460ms for men, QT>450 for women) Long-QT syndrome Decompensation of the heart failure within 48 hours before the qualification Cardiac transplantation in 6 months Life expectancy less than 1 year Chronic dialysis LA diameter >6cm Alcohol abuse Pregnancy/lack of effective contraceptive therapy (in case of females in the reproductive age) Participation in other clinical trial

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rhythm control<br>In this group a strategy to restore and maintain SR, including amiodarone and an external electrical cardioversion (EEC), is implemented. A procedure of AF ablation is possible but not obligatory. At baseline, patients assigned to the group undergo a standard 12-lead ECG, a 6-minute walk test (6MWT), a cardiopulmonary exercise test(CPX), an echocardiography(ECHO), a standard device control; a serum thyroid -stimulating hormone (TSH) level is assessed and patients fill the Minnesota Living With Heart Failure Questionnaire (MLHFQ). Control visits are performed every 3 months including a 12-lead ECG measurement and a device control. On the visits in the 3rd and 12th month an ECHO, a CPX, a 6MWT are performed and a MLHFQ is filled; control TSH levels are assessed every 6 months. | Drug: Amiodarone<br>* The pharmacological treatment in the rhythm control strategy consist of amiodarone given orally including the loading dose up to 600mg daily - for the first 4 weeks. Then, a maintenance dose of 200mg/daily is prescribed. The use of other anti-arrhythmic agents is possible unless they are contraindicated. The introduction of amiodarone must not be performed unless the patient is treated effectively with oral anticoagulants for 3 weeks at least. Discontinuation of amiodarone results neither in withdrawal from the study nor in change of the treatment arm.<br>* Other names: Tachyra;Procedure: External electrical cardioversion (EEC)<br>* The first EEC is performed after the loading dose of amiodarone has been administered. A maximal number of shocks during one cardioversion is 3. The amount of the energy delivered during shocks is left at discretion of a physician performing the EEC. The EEC must be performed in accordance with the present guidelines on EEC and post-procedural care and the state of art. If atrial fibrillation reoccur, the patient should undergo a next EEC as soon as possible but preserving the safety time margins (i.e. effective anticoagulation period). The maximal no. of EEC procedures is 3. If sinus rhythm resumption or its maintenance is impossible or AF reoccur after the 3rd EEC, a strategy of rhythm control is discontinued and a rate control strategy is implemented.<br>|
| Active Comparator: Rate control<br>In the latter group a pharmacotherapy to slow and control ventricular rate by means of pharmacotherapy and an atrio-ventricular junction ablation (AVJA) is implemented. At baseline, each patient assigned to the rate control group undergoes a standard 12-lead ECG, a 6MWT, a CPX, an ECHO, a standard device control and a serum TSH level assessed. Moreover, the patient fills the Minnesota Living With Heart Failure Questionaire (MLHFQ). The control visits are performed for one year, every 3 months including a standard 12-lead ECG measurement and standard control of the device. On the visits in the 3rd and 12th month additionally an ECHO, a CPX, a 6MWT are performed and a MLHFQ is filled. The control TSH levels are assessed every 6 months. | Drug: Pharmacotherapy to slow and control ventricular rate<br>* The pharmacotherapy should be consistent with current guidelines. It should include negative chronotropic and negative dromotropic agents such as beta-blockers, digitalis and amiodarone (the use of other, less popular agents, is also possible). The choice of the agents as well as their dosages are left at discretion of the treating physician. The goal of the therapy is to obtain BiVp% >95%<br>* Other names: amiodarone;Procedure: Atrioventricular junction ablation (AVJA)<br>* The procedure of atrioventricular junction ablation is dedicated to the patients in the rate control group in who the rate control is unsatisfactory. An AVJA procedure is not obligatory. The decision to perform an AVJA should be discussed with the patient and should be made collectively by the therapeutic team.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| BiVp% | Percentage of effective biventricular paced beats during 1st year (mean percentage from baseline to the control visit in 12th month) . | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 6MWT distance | 6 minute walk test distance (in meters)measured at 1 year from baseline | 1 year | 
| peak VO2 | Peak oxygen uptake (peak VO2) measured by means of cardiopulmonary exercise test at 1 year from baseline | 1 year | 
| NYHA class | Heart failure (HF) symptoms escalation measured in New York Heart Association (NYHA) classes at 1 year from baseline | 1 year | 
| Ejection fraction | Ejection fraction (EF) [%] assessed in ECHO at 1 year from baseline | 1 year | 
| LVEDD reduction from baseline at 1 year | Change from baseline in left ventricle end-diastolic diameter (LVEDD) in ECHO at 1 year | baseline and 1 year | 
| LVEDV reduction from baseline at 1 year | Change from baseline in left ventricle end-diastolic volume (LVEDV) in ECHO at 1 year | baseline and 1 year | 
| LVESD reduction from baseline at 1 year | Change from baseline in left ventricle end-systolic diameter (LVESD) in ECHO at 1 year | baseline and 1 year | 
| LVESV reduction froma baseline at 1 year | Change from baseline in left ventricle end-systolic volume (LVESV) in ECHO at 1 year | baseline and 1 year | 
| Reduction of LA diameter at 1 year | Change from baseline in left atrium diameter assessed in ECHO at 1 year | baseline and 1 year | 
| Reduction of mitral regurgitation at 1 year | Change from baseline in mitral regurgitation measured in ECHO at 1 year | baseline and 1 year | 
| Heart failure exacerbations | Number of heart failure exacerbations in the treatment arm in 1 year time from baseline | up to 1 year | 
| Mortality | Numer of deaths assesed in 1 year follow-up | up to 1 year | 
| Stroke/TIA | Stroke or transient ischemic attack (TIA) during a year follow-up | up to 1 year | 
| CV mortality | Death due to cardiovascular (CV) causes during a year follow-up | up to 1 year | 
| Cardiovascular hospitalizations | Number of hospitalizations due to cardiovascular causes during a year follow-up | up to 1 year | 
| Quality of Life | The quality of life measured with the Minnesota Living with Heart Failure Questionaire (MLHFQ) at 1 year from baseline | 1 year | 
| AF prevalence | Measurement of the prevalence of atrial fibrillation (precentage of participants with AF) at 1 year from baseline | 1 year | 
| Ventricular arrhythmia | Number of ventricular arrhythmias (VF/Torsade de Pointes VT/sVT/nsVT) during the first year from basline | up to 1 year | 
| Electrotherapy | The number of high-energy interventions (shocks) including separately: adequate shocks, inadequate shocks, electrical storm applies only to the patients with CRT-D device during the first year from baseline | up to 1 year | 
| Side effects | Overall number of side effects cases and complications cases of the treatment strategies related to: the device, the pharmacotherapy, the electrotherapy during the first year from baseline. | 1 year | 
| 6MWT distance | 6 minute walk test distance (in meters) at 3 months from baseline | 3 months | 
| peak VO2 | Peak oxygen uptake (peak VO2) measured by means of cardiopulmonary exercise test at 3 months from baseline | 3 months | 
| NYHA class | Heart failure (HF) symptoms escalation measured in New York Heart Association (NYHA) classes at 3 months from baseline | 3 months | 
| Ejection fraction | Ejection fraction (EF) [%] assessed in ECHO at 3 months from baseline | 3 months | 
| LVEDD reduction | Change from baseline in left ventricle end-diastolic diameter (LVEDD) reduction in ECHO at 3 months | baseline and 3 months | 
| LVEDV reduction | Change from baseline in left ventricle end-diastolic volume (LVEDV) reduction in ECHO at 3 months | baseline and 3 months | 
| Reduction of LA area | Change from baseline in left atrium area assessed in ECHO at 1 year | baseline and 1 year | 
| Reduction of LA diameter | Change from baseline in left atrium diameter assessed in ECHO at 3 months | baseline and 3 months | 
| Reduction of mitral regurgitation | Change from baseline in mitral regurgitation measured in ECHO at 3 months | baseline and 3 months | 
| Stroke/TIA | Stroke or transient ischemic attack (TIA) during the first 3 months from baseline | up to 3 months | 
| Quality of Life | The quality of life measured with the Minnesota Living with Heart Failure Questionaire (MLHFQ) at 3 months from baseline | 3 months | 
| BiVp% | Percentage of effective biventricular paced beats during first 3 months from baseline. | 3 months | 
| AF prevalence | Measurement of the prevalence of atrial fibrillation (precentage of participants with AF) at 3 month from baseline | 3 months | 
| Electrotherapy | The number of high-energy interventions (shocks) including separately: adequate shocks, inadequate shocks, electrical storm applies only to the patients with CRT-D device during first 3 months from baseline | up to 3 months | 
| Ventricular arrhythmia | Number of ventricular arrhythmias (VF/Torsade de Pointes VT/sVT/nsVT) during the first 3 months from basline | up to 3 months | 
| Side effects | Overall number of cases of side effects and complications of the treatment strategies related to: device, pharmacotherapy, electrotherapy during the first 3 months from baseline. | 3 months | 
| Reduction of LA area | Change from baseline in left atrium area assessed in ECHO at 3 months | baseline and 3 month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Atrial fibrillation, Cardiac resynchronization therapy, Heart failure, Rhythm control strategy