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European Journal of Heart Failure 2005 7(2):219-224; doi:10.1016/j.ejheart.2004.06.008
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© 2005 European Society of Cardiology

COMBAT—conventional versus multisite pacing for bradyarrhythmia therapy: rationale of a prospective randomized multicenter study

Martino Martinellia,*, Roberto Costab, Sérgio Freitas de Siqueiraa and José A. Ramiresc

a Pacemaker Clinic, Heart Institute-InCor, University of São Paulo São Paulo, Brazil
b Surgery of Pacemaker, Heart Institute-InCor, University of São Paulo São Paulo, Brazil
c Director of Heart Institute-InCor, University of São Paulo São Paulo, Brazil

* Corresponding author. Clónica de Marcapasso do InCor-HC/FMUSP, Av. Enéas de Carvalho Aguiar, 44, São Paulo-SP, 05403-000-Brazil. Tel.: +55 11 3069 5321; fax: +55 11 3081 7148. E-mail address: martino{at}incor.usp.br, E-mail address: siqueira{at}incor.usp.br


   Abstract
Top
 Abstract
1. Introduction
 2. Objective of the...
 3. Patients and methods
 References
 
COMBAT is a prospective, multicenter, randomized, blinded clinical study, with crossover design. The main objective is the comparative evaluation of atrio-biventricular versus conventional atrioventricular stimulation (atrio and right ventricle) in patients with heart failure and bradycardia as the primary indication for pacemaker implantation. After successful atrio-biventricular system implantation, patients will be randomized into two groups: group A—atrioventricular conventional pacing and group B—atrio-biventricular pacing. Both groups will be programmed in DDD mode with AV delay optimized by echocardiogram. After 3 months, New York Heart Association functional class, ventricular arrhythmia density and complexity, echocardiography outcomes, 6-min hall walk distance, quality of life and peak oxygen consumption will be assessed in all patients. Then, all patients will crossover to the other pacing regimen, with an additional AV delay adjustment by echo. Patients will be followed up for another 3 months at the end of which all evaluations will be repeated. Patients will then crossover back to their original pacing regimen for a further 3 months. At the end of this 9-month period, patients will be reprogrammed according to their optimal pacing regime.

In an extended follow-up, patient survival will be evaluated after 24 months of the optimal pacing therapy.

Key Words: Atrio-biventricular stimulation • Pacemaker • Heart failure • Pacemaker indication

Received August 4, 2003; Revised May 28, 2004; Accepted June 23, 2004


   1. Introduction
Top
 Abstract
 1. Introduction
2. Objective of the...
 3. Patients and methods
 References
 
The prevalence of intraventricular conduction delay (IVCD) in patients with congestive heart failure (CHF) is around 35–50% [1,2]. A QRS interval longer than 120 ms leads to uncoordination of left ventricular contraction and relaxation phases, dP/dt reduction as well as worsening of mitral regurgitation [3,4]. Specifically, left bundle branch block (LBBB) is frequently associated with poor clinical prognosis and high mortality [5].

The ability of cardiac resynchronization therapy (CRT) to correct ventricular asynchrony in patients with IVCD and refractory CHF has been reported [6–8]. Results of the PATH-CHF, MUSTIC and MIRACLE trials have shown an improvement in cardiac function, exercise capacity, New York Heart Association (NYHA) functional class and quality of life [8–10]. A reduction in all-cause mortality and hospitalization by CRT, when compared to optimal medical therapy, was recently observed in the COMPANION trial [11].

Similarly to LBBB, right ventricular apical stimulation (RVAS) provokes left ventricular asynchrony [12–14]. Many clinical and experimental observations have demonstrated worsening cardiac function and clinical status after chronic conventional ventricular pacing, that is RVAS [15–17]. Leon et al. [18] reported improvement in left ventricular (LV) function and CHF symptoms during biventricular pacing compared to RVAS, in patients with chronic atrial fibrillation (AF) and left ventricle ejection fraction ≤35%. The same behavior was observed in the MADIT II and DAVID trials; patients who required RVAS for bradycardia therapy had significant left ventricular functional and NYHA functional class impairment [19,20].

In view of these findings and the fact that up to 15% of patients with cardiomyopathy and CHF need permanent pacing due to symptomatic bradycardia, we propose the use of biventricular stimulation as a primary treatment option in this specific patient cohort.


   2. Objective of the study
Top
 Abstract
 1. Introduction
 2. Objective of the...
3. Patients and methods
 References
 
The aim of the COMBAT study is to compare atrio-biventricular pacing with conventional atrioventricular stimulation to treat patients with left ventricular dysfunction in whom bradycardia is the primary indication for pacemaker implantation.

2.1. Primary endpoints

• New York Heart Association functional class;
• Quality of life according to the Minnesota Living with heart failure score;
• 6-min hall walk distance;
• Peak oxygen consumption.

2.2. Secondary endpoints

• Left ventricular ejection fraction, end systolic and diastolic dimension and grade of mitral regurgitation by echocardiogram;
• Clinical and pacing system follow-up complications
•atrial fibrillation, ventricular arrhythmia and stroke
•LV lead displacement, phrenic stimulation and exit block

• Mortality: rate and causes.


   3. Patients and methods
Top
 Abstract
 1. Introduction
 2. Objective of the...
 3. Patients and methods
References
 
3.1. Study population
Ten Brazilian centers will select at least 60 patients, according to the sample size estimation (see statistical analysis). The Coordination Center will be the Heart Institute of University of São Paulo Medical School (InCor). All centers will have the study protocol approved by the local and National Ethics Committee. Written informed consent will be obtained from all patients. A permanent Review Board Committee will follow the comparative endpoint results in order to safeguard the ethical principles of the study.

3.2. Inclusion criteria

Age>18 years; class I indication for DDD/DDDR pacing implantation for persistent bradyarrhythmia according to the Brazilian or American College of Cardiology/American Heart Association Guidelines [21,22];
NYHA functional classes II, III, IV and/or ejection fraction ≤40% by echocardiogram;
Stable optimal medical therapy, including β-blockers, ACE inhibitors and aldosterone antagonists according to patient tolerance, for at least 30 days, will be required as a routine approach for all patients.

3.3. Exclusion criteria

Isolated sick sinus syndrome
Unstable angina, acute myocardial infarction, CABG or PTCA (<3 months)
Cerebrovascular accident or recent transitory ischemic attacks (<3 months)
Previous pacemaker implantation
Administration of intravenous inotropic drugs
Restriction for cardiac pacemaker implantation
Plasma creatinine >3 mg/dl
Primary pulmonary disease
Chronic atrial arrhythmia
Life expectancy <9 months
Pregnancy

3.4. Pacemaker system implantation
Atrio-biventricular pacemakers will be implanted using transvenous access. If it is impossible to obtain reliable left ventricular stimulation, the patient will undergo conventional DDD pacemaker implantation and will be excluded from the study.

3.5. Right atrial and ventricular leads
Conventional endocardial bipolar leads will be implanted through cephalic or subclavian access. For atrial pacing, the right appendage or the right atrial lateral wall will be preferred. The right ventricular lead will be implanted at the mid or lower portion of the interventricular septal wall.

3.6. Left ventricular lead
After coronary sinus venography, a Medtronic Attain lead, model 2187 or 4193, will be implanted, according to the shape and size of the lateral vein. Only veins of the lateral wall will be accessed. The interventricular, anterior or posterior branches of the coronary sinus will not be considered for left ventricular lead implantation.

3.7. Pulse generator
A Medtronic InSync III pulse generator will be used in all patients, placed in a subcutaneous or subpectoral pocket. This pulse generator permits reprogramming to conventional right ventricular or biventricular DDD or DDD,R pacing modes.

3.8. Study design
This is a multicenter, prospective, randomized, crossover, blinded clinical study which includes three distinct phases:

Phase I: patient selection, written informed consent and atrio-biventricular pacing system implantation;
Phase II: randomization into groups A and B; clinical and functional evaluations after 3, 6 and 9 months of randomization (two crossover phases) and identification of the best pacing mode;
Phase III: a 24-month follow-up after initiation of the best pacing mode as defined at the end of phase II.

All patients will receive the same atrio-biventricular device. Subsequently, they will be randomized into two groups, as follows: group A—patients will start the study with the system programmed to conventional DDD mode and after 3 months will be reprogrammed to the biventricular DDD mode, which will be maintained for 3 months. Then, patients will return to the initial programming (conventional DDD mode), which will be continued for another 3 months. Group B—patients will start the study in biventricular DDD mode and after 3 months they will be reprogrammed to conventional DDD mode. After another 3 months, they will return to the initial programming (biventricular DDD mode), which will be kept until the end of phase II. For patients with concomitant sick sinus syndrome, the pacing mode will be DDDR.

In phase III, the device will be programmed according to the optimal pacing mode observed for each patient during phase II and patients will be followed for 2 additional years (Fig. 1).


Figure 1
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  		Fig. 1 Clinical study flow chart.

 
Optimal pacing mode will be defined arbitrarily, according to the best QOL score. If this evaluation is inconclusive, a decision will be made based on the following variables: (1) maximum oxygen consumption (cardiopulmonary exercise text), (2) left ventricular ejection fraction (echocardiogram) and (3) researcher decision.

3.9. Randomization and pacing system optimization
Centralized randomization with a 1:1 distribution rate will be made up to 7 days after successful atrio-biventricular system implantation.

Paced and sensed AV delay (AVD) will be individually adjusted, guided by the echocardiography and analysis of the mitral valve flow, in order to obtain the best coupling between A and E waves and mitral valve closing.

3.10. Crossover
Since all patients included in this study will have symptomatic bradycardia, it is not possible to use the preoperative data as baseline. In this sense, pacing discontinuation to avoid previous pacing mode interference was not included in Phase II (crossover). In order to minimize previous therapy effects, a long and arbitrary crossover period of 3 months was included in the study.

3.11. Blind configuration
Clinical investigators and patients will be blinded to the pacing regime and will not have access to the programmed pacing mode. Only researchers appointed for pacemaker evaluations will inevitably know the device programming.

3.12. Premature crossover
Premature crossover will not be permitted unless:

• Clinical aggravation: In case of clinical worsening refractory to medical therapy, patients will undergo the 3-month follow-up tests earlier than planned, and the device will be reprogrammed to the next pacing mode. In these situations, patients will continue participating in the study, for end-point calculations.
• Atrial fibrillation (AF) occurrence: Although the "mode switch" function will be turned "on" for all patients, in case of recurrent paroxysmal or persistent (>24 h) AF, medical therapy for maintenance of sinus rhythm should be introduced to avoid exclusion from the study.
• Pacing system dysfunction: Lead or pulse generator malfunctions must be corrected by reprogramming or a surgical approach. If a malfunction occurs during phase II, the crossover period will be restarted after correction. If correction is impossible, the patient will be excluded from the study.

3.13. Clinical and electronic follow-up
Clinical and electronic follow-up will be made in phases II and III (Fig. 1). A team of cardiologists will perform clinical follow-up and heart failure drug therapy optimization. However, in order to maintain the blind clinical follow-up and pacemaker programming, a Pacemaker Center Team will be responsible for electronic evaluation of the device.

3.14. Evaluations
After 3, 6, 9 and 24 months of randomization, all patients will be submitted to:

Clinical evaluation: CHF symptoms and NYHA functional class.
Echodopplercardiogram: Left ventricular ejection fraction, end systolic and diastolic dimensions, mitral regurgitation and pacing system optimization.
24-h Holter monitoring: Register of density and complexity of supraventricular and ventricular arrhythmia.
Minnesota living with heart failure questionnaire: Evaluation of every day quality of life, which should be preferably be performed by a member of the nursing team.
6-min hall walk distance: Evaluation of functional capacity, which must be performed by an investigator blinded to the patients pacing regime (i.e. researchers not involved with pacemaker programming).
Cardiopulmonary exercise test: Peak oxygen consumption evaluation and definition of aerobic and anaerobic threshold.

3.15. Statistical data analysis
Data will be initially evaluated as descriptive form according to means and standard deviations for continuous variables (left ventricle ejection fraction, quality of life score, etc.) or through relative and absolute frequencies for classifying variables (sex, cardiomyopathy etiology, etc.).

Findings of the studied variables at 3, 6 and 9 months will be statistically evaluated by analysis of variance to repeated measurements.

In order to compare findings of primary and secondary endpoints, the following variables will be analyzed:

• New York Heart Association functional class;
• Quality of life according to the Minnesota Living with Heart Failure Score;
• Distance walked, by 6-min hall walk distance test;
• Peak oxygen consumption, by ergoespirometric test;
• Left ventricular ejection fraction, end systolic and diastolic dimensions and grade of mitral regurgitation by transthoracic echocardiogram;
• Incidence rate of atrial fibrillation, ventricular tachyarrhythmia, stroke, LV lead displacement, phrenic stimulation and mortality.

3.16. Sample size estimation
To estimate the study sample size, it was necessary to assume a difference between means of a continuous variable (quality of life score was chosen) of 3 units and a standard deviation equal to this difference, that is 3, which defines a detectable difference rate of 1.00. A desired power of 90% with {alpha} value of 0.05 for a three times observational designed study with a minimal correlation between times of 0.1 was also considered. Those assumptions lead to a sample size of 26 patients for each group. Therefore, the enrollment of 60 patients will be required for a total dropout rate estimation added to follow-up loss of 10% (total number.) [23].

3.17. Participating centers, investigators and committees
Instituto do Coração-InCor/HCFMUSP, São Paulo, SP: Martino Martinelli Filho, MD, PhD; Roberto Costa, MD, PhD; Sérgio Freitas de Siqueira, ENG; José Carlos Tavares Costa Júnior, MD; Thacila Regina Mozzaquatro, RN; Beneficência Portuguesa, São Paulo SP: Medical Team 1: Silas dos Santos Galvão, MD; Cecília Monteiro Boya Barcellos, MD; José Tarcísio M. de Vasconcelos, MD; Alexandre C. Rabello, MD; Medical Team 2: Vicente Ávila Neto, MD; Fernando Sérgio Oliva de Souza, MD; Universidade Federal de Uberlândia, Uberlândia, MG: Elias Ésber Kanaan, MD; Petrônio Ranchel Salvador Júnior, MD; Hospital de Base da Faculdade de Medicina, São José do Rio Preto, SP: Medical Team 1: Osvaldo Tadeu Greco, MD; Marcelo José Ferreira Soares, MD; Adolberto Lorga Filho, MD; Augusto Cardinalli Neto, MD; Rosana Andreia Mazzo, psychologist; Medical Team 2: Domingo M Braile, MD; Valéria Braile, MD; Hospital Universitário, UFRJ, Rio de Janeiro, RJ: Jacob Atié, MD; Silvia Martelo, MD; Luiz G. B. Moraes, MD; Hospital de Messejana, Fortaleza, CE: Stela Maria Vitorino Sampaio, MD; Luiz Eduardo Montenegro Camanho, MD; Neyle Caveiro, MD; Waldemiro Carvalho Junior, MD; Fernando Antônio Mesquita, MD; Márcia Maria Vitorino Sampaio, RN; Santa Casa de Goiânia, Goiania, GO: Antônio Malan, MD; Zander Bastos Rocha, MD; Luiz Antônio Sá, MD; Hosp. do Coração de Natal, Natal, RN: Sylton Arruda de Melo, MD; Flávio José Bezerra de Oliveira, MD.

Clinical Events Review Committee: Martino Martinelli Filho, MD (Chair); Roberto Costa, MD; Sérgio Freitas de Siqueira, ENG; André Luiz Buchele D'Avila, MD.

Safety Monitoring Board: José Carlos Silva de Andrade (Chair), MD; Luiz Felipe Pinho Moreira, MD.


   Acknowledgements
 
This study will be partially supported by Medtronic Comercial (Brazil).


   References
Top
 Abstract
 1. Introduction
 2. Objective of the...
 3. Patients and methods
 References
 

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