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COMBAT—conventional versus multisite pacing for bradyarrhythmia

therapy: rationale of a prospective randomized multicenter study

Martino Martinellia,*, Roberto Costab, Sergio Freitas de Siqueiraa, Jose A. Ramiresc

aPacemaker Clinic, Heart Institute-InCor, University of Sao Paulo, Sao Paulo, BrazilbSurgery of Pacemaker, Heart Institute-InCor, University of Sao Paulo, Sao Paulo, Brazil

cDirector of Heart Institute-InCor, University of Sao Paulo, Sao Paulo, Brazil

Received 4 August 2003; received in revised form 28 May 2004; accepted 23 June 2004

Available online 26 January 2005

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Abstract

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.

D 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.

Keywords: Atrio-biventricular stimulation; Pacemaker; Heart failure; Pacemaker indication

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1. Introduction

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].

1388-9842/$ - see front matter D 2004 European Society of Cardiology. Publishe

doi:10.1016/j.ejheart.2004.06.008

* Corresponding author. Clınica de Marcapasso do InCor-HC/FMUSP,

Av. Eneas de Carvalho Aguiar, 44, Sao Paulo-SP, 05403-000-Brazil. Tel.:

+55 11 3069 5321; fax: +55 11 3081 7148.

E-mail addresses: martino@incor.usp.br, siqueira@incor.usp.br

(M. Martinelli).

13

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 COMPAN-

ION 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)

Failure 7 (2005) 219–224

d by Elsevier B.V. All rights reserved.

M. Martinelli et al. / The European Journal of Heart Failure 7 (2005) 219–224220

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function and CHF symptoms during biventricular pacing

compared to RVAS, in patients with chronic atrial fibrillation

(AF) and left ventricle ejection fraction V35%. 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.

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2. Objective of the study

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 pace-

maker implantation.

2.1. Primary endpoints

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! 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

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! 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

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 Sao 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

AgeN18 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 V40% by echocardiogram;

Stable optimal medical therapy, including h-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 (b3 months)

Cerebrovascular accident or recent transitory ischemic

attacks (b3 months)

Previous pacemaker implantation

Administration of intravenous inotropic drugs

Restriction for cardiac pacemaker implantation

Plasma creatinine N3 mg/dl

Primary pulmonary disease

Chronic atrial arrhythmia

Life expectancy b9 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 conven-

tional 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 interven-

tricular 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.

M. Martinelli et al. / The European Journal of Heart Failure 7 (2005) 219–224 221

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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 conven-

tional right ventricular or biventricular DDD or DDD,R

pacing modes.

3.8. Study design

This is a multicenter, prospective, randomized, cross-

over, 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 biven-

tricular 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).

Optimal pacing mode will be defined arbitrarily, accord-

ing 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 exer-

cise text), (2) left ventricular ejection fraction (echocardio-

gram) 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 individu-

ally 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 interfer-

ence 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

bmode switchQ function will be turned bonQ for all

patients, in case of recurrent paroxysmal or persistent

(N24 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 Pace-

maker Center Team will be responsible for electronic

evaluation of the device.

Fig. 1. Clinical study flow chart.

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3.14. Evaluations

After 3, 6, 9 and 24 months of randomization, all patients

will be submitted to:

Clinical evaluation: CHF symptoms and NYHA func-

tional class.

Echodopplercardiogram: Left ventricular ejection frac-

tion, end systolic and diastolic dimensions, mitral

regurgitation and pacing system optimization.

24-h Holter monitoring: Register of density and com-

plexity 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 consump-

tion 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 continu-

ous variables (left ventricle ejection fraction, quality of

life score, etc.) or through relative and absolute frequen-

cies for classifying variables (sex, cardiomyopathy etiol-

ogy, etc.).

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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 tachyar-

rhythmia, stroke, LV lead displacement, phrenic stim-

ulation 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 a 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 Coracao-InCor/HCFMUSP, Sao Paulo,

SP: Martino Martinelli Filho, MD, PhD; Roberto Costa,

MD, PhD; Sergio Freitas de Siqueira, ENG; Jose Carlos

Tavares Costa Junior, MD; Thacila Regina Mozzaquatro,

RN; Beneficencia Portuguesa, Sao Paulo SP: Medical

Team 1: Silas dos Santos Galvao, MD; Cecılia Monteiro

Boya Barcellos, MD; Jose Tarcısio M. de Vasconcelos,

MD; Alexandre C. Rabello, MD; Medical Team 2:

Vicente Avila Neto, MD; Fernando Sergio Oliva de

Souza, MD; Universidade Federal de Uberlandia, Uber-

landia, MG: Elias Esber Kanaan, MD; Petronio Ranchel

Salvador Junior, MD; Hospital de Base da Faculdade de

Medicina, Sao Jose do Rio Preto, SP: Medical Team 1:

Osvaldo Tadeu Greco, MD; Marcelo Jose Ferreira Soares,

MD; Adolberto Lorga Filho, MD; Augusto Cardinalli

Neto, MD; Rosana Andreia Mazzo, psychologist; Medical

Team 2: Domingo M Braile, MD; Valeria Braile, MD;

Hospital Universitario, UFRJ, Rio de Janeiro, RJ: Jacob

Atie, 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 Antonio Mesquita, MD; Marcia

Maria Vitorino Sampaio, RN; Santa Casa de Goiania,

Goiania, GO: Antonio Malan, MD; Zander Bastos

Rocha, MD; Luiz Antonio Sa, MD; Hosp. do Coracao

de Natal, Natal, RN: Sylton Arruda de Melo, MD; Flavio

Jose Bezerra de Oliveira, MD.

Clinical Events Review Committee: Martino Martinelli

Filho, MD (Chair); Roberto Costa, MD; Sergio Freitas de

Siqueira, ENG; Andre Luiz Buchele D’Avila, MD.

Safety Monitoring Board: Jose Carlos Silva de Andrade

(Chair), MD; Luiz Felipe Pinho Moreira, MD.

Acknowledgements

This study will be partially supported by Medtronic

Comercial (Brazil).

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