Cardiac Resynchronization in Atrial Fibrillation Trial - a Pilot Study (Pilot-CRAfT)

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

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.

Study Overview

• Status: Unknown
• Conditions: Heart Failure; Atrial Fibrillation
• Intervention / Treatment: Drug: Amiodarone; Procedure: External electrical cardioversion (EEC); Drug: Pharmacotherapy to slow and control ventricular rate; Procedure: Atrioventricular junction ablation (AVJA)

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 60
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Jan B Ciszewski, MD; Phone Number: +48 223434050; Email: jciszewski@ikard.pl

Study Locations

• Poland
  • Warsaw, Poland, 02-637
    • Recruiting
    • Institute of Cardiology, II Dept. of Coronary Heart Disease
    • Contact: Jan B Ciszewski, MD; Phone Number: +48 223434050; Email: jciszewski@ikard.pl
    • Principal Investigator: Jan B Ciszewski, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Rhythm control; 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; 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.; Other Names: Cordarone; Pacerone; Amiodaron; Aratac; Cardinorm; Rithmik; Arycor; Atlansil; Tachyra; Procedure: External electrical cardioversion (EEC); 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.
ACTIVE_COMPARATOR: Rate control; 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; 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%; Other Names: amiodarone; beta-blockers; digitalis; Procedure: Atrioventricular junction ablation (AVJA); 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.

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Identification of the factors predicting the response to the rhythm control strategy	Identification of the patients which benefit the most from the rhythm control strategy and comparison of their baseline characteristics with the whole group. Identification of non-responders to the rhythm control strategy and comparison of their baseline characteristics with the whole group. (multiple regression analysis).	1 year

Collaborators and Investigators

• Sponsor: Institute of Cardiology, Warsaw, Poland
• Investigators: Principal Investigator: Jan B Ciszewski, MD, Institute of Cardiology, Warsaw, Poland; Study Chair: Maciej Sterlinski, MD, PhD, Institute of Cardiology, Warsaw, Poland

Publications and helpful links

General Publications

• Ciszewski J, Maciag A, Kowalik I, Syska P, Lewandowski M, Farkowski MM, Borowiec A, Chwyczko T, Pytkowski M, Szwed H, Sterlinski M. Comparison of the rhythm control treatment strategy versus the rate control strategy in patients with permanent or long-standing persistent atrial fibrillation and heart failure treated with cardiac resynchronization therapy - a pilot study of Cardiac Resynchronization in Atrial Fibrillation Trial (Pilot-CRAfT): study protocol for a randomized controlled trial. Trials. 2014 Oct 4;15:386. doi: 10.1186/1745-6215-15-386.

Study record dates

Study Major Dates

• Study Start: October 1, 2013
• Primary Completion (ANTICIPATED): December 1, 2016
• Study Completion (ANTICIPATED): March 1, 2017

Study Registration Dates

• First Submitted: April 22, 2013
• First Submitted That Met QC Criteria: May 6, 2013
• First Posted (ESTIMATE): May 9, 2013

Study Record Updates

• Last Update Posted (ESTIMATE): March 10, 2015
• Last Update Submitted That Met QC Criteria: March 9, 2015
• Last Verified: March 1, 2015

More Information

Terms related to this study

• Keywords: Atrial fibrillation; Heart failure; Cardiac resynchronization therapy; Rhythm control strategy
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Heart Failure; Atrial Fibrillation; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Vasodilator Agents; Enzyme Inhibitors; Membrane Transport Modulators; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Sodium Channel Blockers; Cytochrome P-450 CYP2D6 Inhibitors; Cytochrome P-450 CYP1A2 Inhibitors; Cytochrome P-450 CYP2C9 Inhibitors; Potassium Channel Blockers; Amiodarone
• Other Study ID Numbers: IK-NP-0021-47/1378/13