Journal of Cardiac Failure Vol. 16 No. 4 2010

Conventional Versus Biventricular Pacing in Heart Failureand Bradyarrhythmia: The COMBAT Study

MARTINO MARTINELLI FILHO, MD, PhD,1 SERGIO FREITAS DE SIQUEIRA, BS,1 ROBERTO COSTA, MD, PhD,1

OSWALDO T. GRECO, MD,2 LUIZ FELIPE MOREIRA, MD, PhD,1 ANDRE D’AVILA, MD, PhD,3 AND E. KEVIN HEIST, MD, PhD4

Sao Paulo, Brazil; New York, New York; Boston, Massachusetts

From the 1PacePaulo Medical SchSao Paulo, BrazilNew York, NY anHospital, Harvard

Manuscript receNovember 30, 200

Reprint requestsCor-HC/FMUSP, A000-Brazil. Tel.:

martino@incor.uspMedtronic Com

search support, spMedical (speaker)otronik (research sSt. Jude Medical (Medtronic (consuMedical (consulta(speaker), Boston(speaker), Medtrospeaker, consultan

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ABSTRACT

Background: Worsening in clinical and cardiac status has been noted after chronic right ventricular pacing,but it is uncertain whether atriobiventricular (BiVP) is preferable to atrio-right ventricular pacing (RVP).Conventional versus Multisite Pacing for BradyArrhythmia Therapy study (COMBAT) sought to compareBiVP versus RVP in patients with symptomatic heart failure (HF) and atrioventricular (AV) block.Methods and Results: COMBAT is a prospective multicenter randomized double blind crossover study.Patients with New York Heart Association functional class (FC) II-IV, left ventricular ejection fraction(LVEF) !40%, and AV block as an indication for pacing were enrolled. All patients underwent biventric-ular system implantation and then were randomized to receive successively (group A) RVP-BiVP-RVP, or(group B) BiVP-RVP-BiVP. At the end of each 3-month crossover period, patients were evaluated accord-ing to Quality of Life (QoL), FC, echocardiographic parameters, 6-Minute Walk Test (6MWT), and peakoxygen consumption (VO2max). Sixty patients were enrolled, and the mean follow-up period was 17.5 6

10.7 months. There were significant improvements in QoL, FC, LVEF, and left ventricular end-systolicvolume with BiVP compared with RVP. The effects of pacing mode on 6MWT and VO2max were not sig-nificantly different. Death occurred more frequently with RVP.Conclusion: In patients with systolic HF and AV block requiring permanent ventricular pacing, BiVP issuperior to RVP and should be considered the preferred pacing mode. (J Cardiac Fail 2010;16:293e300)Key Words: Chronic conventional right ventricular pacing, cardiac resynchronization therapy, heart fail-ure, AV block.

The prevalence of intraventricular conduction delay in 120 ms in the CHF population has been associated with

patients with congestive heart failure (CHF) is substantial,estimated at 27% to 53%.1 A QRS duration greater than

maker Clinic, Heart Institute (InCor), University of Saoool, Brazil; 2Hospital de Base de Sao Jose do Rio Preto,; 3Cardiac Arrhythmia Service, Mount Sinai Hospital,d 4Cardiac Arrhythmia Service, Massachusetts GeneralMedical School, Boston, MA.ived September 10, 2009; revised manuscript received9; revised manuscript accepted December 10, 2009.: Martino Martinelli, MD, Clinica de Marcapasso do In-v. Eneas de Carvalho Aguiar, 44, Sao Paulo-SP, 05403-þ55 11 3069 5516; Fax: þ55 11 3081 7148; E-mail:

.brercial Ltd supported this study. M.M.F.: Biotronik (re-eaker), Medtronic (research support, speaker), St. Jude. S.F.d.S.: Part-time St Jude Medical employee. R.C.: Bi-upport, speaker), Medtronic (research support, speaker),speaker). O.T.G.: Medtronic (research support). A.d.’A.:ltant and speaker), Boston Scientific (speaker), St. Judent, speaker and research support). K.H.: Biotronik

Scientific (research support, speaker), ELA/Sorinnic (speaker), St. Jude Medical (research support,t).ee front matterr Inc. All rights reserved.rdfail.2009.12.008

293

dyssynchrony of left ventricular (LV) systole and diastoleas well as reduced LV contractility, greater mitral regurgi-tation, and increased cardiac events and mortality.2-4 Theefficacy of cardiac resynchronization therapy (CRT) inthe correction of ventricular dyssynchrony for patientswith intraventricular conduction delay and refractory sys-tolic CHF, with improvement in echocardiographic param-eters, CHF symptoms, and mortality has been extensivelydocumented.5-11 Based on the results from these studies,CRT has been widely adopted for patients with currentlyaccepted CRT indications, which typically include NewYork Heart Association functional class (NYHA) III-IVCHF, LV ejection fraction (LVEF) #35% and QRS duration$120 ms. Right ventricular (RV) apical pacing can elicitLV dyssynchrony similar to that described in the settingof intrinsic left bundle branch block.12-14 Experimentaland clinical observations have demonstrated worsening ofcardiac function and clinical status after chronic RVpacing.15

Leon et al reported improvements in LV function and heartfailure symptoms during biventricular pacing, when com-pared with RV apical stimulation, in patients with chronic

Phase I (Pre-implantation)

Implantation

Randomization (1:1)

Phase II (crossover) Echocardiography AVI Optimization

First evaluation*

Intermediate evaluation*

Final evaluation*

Phase III evaluation*

Selection of Patients

group-B

DDD/DDDR BiV programming group-A

DDD/DDDR RV programming

DDD/DDDR BiV programming DDD/DDDR RV programming

DDD/DDDR RV programming DDD/DDDR BIV programming

Chronic Programming according to best individual adaptation

DDDR Biventricular System

Fig. 1. Clinical study flow chart.

294 Journal of Cardiac Failure Vol. 16 No. 4 April 2010

atrial fibrillation and left ventricle ejection fraction #35%.16

Similarly, in the Multicenter Automatic Defibrillator Implan-tation Trial II (MADIT II) and Dual Chamber and VVIImplantable Defibrillator (DAVID) trials, patients who re-ceived a large percentage of RV apical pacing were morelikely to develop significant impairment of the LV functionand worsening of NYHA class compared with patients re-quiring less pacing.17,18 For these reasons, it is generally ac-cepted that RV pacing should be minimized in patientsreceiving pacemakers or implanted cardiac defibrillatorswho have intact atrioventricular (AV) conduction.18,19

Considering that up to 15% of patients with cardiomyop-athy and heart failure may require substantial ventricularpacing because of bradycardia resulting from AV block,20

it is important to determine the optimal pacing mode forthis specific cohort. The objective of the Conventional ver-sus Multisite Pacing for BradyArrhythmia Therapy study(COMBAT) was to compare the effects of atrio-biventricu-lar pacing (BiVP) to atrio-right ventricular pacing (RVP) inpatients with LV dysfunction and AV block requiring ven-tricular pacing to treat bradycardia. The COMBAT rationaleand study design has been previously published.21

Methods

COMBAT is a prospective, multicenter, randomized, doubleblinded, and double crossover clinical study. Patients were

enrolled at 4 Brazilian Centers. Enrollment began in January2004 and ended in May 2006. The investigation conforms withthe principles outlined in the Declaration of Helsinki (Br Med J1964;ii:177). The study was approved by the National EthicsCommittee, and all centers had the study protocol approved bytheir respective local ethics committees. Written, informed con-sent was obtained for all patients enrolled. Inclusion criteria in-cluded patients with AV block resulting in a Class I indicationfor DDD/DDDR pacemaker implantation according to the Brazil-ian and the American College Cardiology/American Heart Associ-ation Guidelines,22,23 NYHA Class II-IV, and LVEF #40% understable optimal medical therapy for at least 30 days.

Exclusion criteria included the following: patients younger than18 years of age or with the following conditions: isolated sicksinus syndrome; unstable angina; acute myocardial infarction; cor-onary artery bypass grafting or percutaneous transluminal coro-nary angioplasty within 3 months of enrollment; cerebrovascularaccident or recent transient ischemic attacks (!3 months); previ-ous pacemaker implant; the requirement for intravenous inotropicdrugs; inability to undergo pacemaker implantation for any rea-son; plasma creatinine O3 mg/dL; primary pulmonary disease,chronic atrial arrhythmias including atrial fibrillation or flutter;life expectancy !9 months; and pregnancy.

Study Design

The COMBAT included 3 discrete phases (Fig. 1).Phase I: patient selection, BiVP system implantation for all

patients.

Heart Failure and Bradyarrhythmia Pacing � Filho et al 295

Phase II: double-blind randomization of pacemaker program-ming into 2 groups:

C group A: device was initially programmed to RVP, crossed toBiVP and crossed back to RVP.

C group B: device was initially programmed to BiVP, crossed toRVP and crossed back to BiVP.

At the end of each period, lasting at least 3 months, the patientswere evaluated.

Phase III: an extended period of clinical follow-up. In this phase,the device was individually programmed to the best pacing modeusing the quality of life results from each patient from Phase II.

Pacemaker System Implantation

All patients received Medtronic InSync III pacemakers (Med-tronic Corp, Minneapolis, MN); the RV lead was implanted atthe mid or lower portion of the interventricular septal wall. Theright atrial lead was placed in the right atrial appendage or lateralright atrium based on operator discretion. LV lead placement wasperformed with the aid of coronary sinus venography. The LV lead(Medtronic Attain) was placed in a branch of the coronary sinusover the posterolateral or lateral LV wall.

Randomization and Pacing System Optimization

Double-blinded randomization was performed in a 1:1 fashionwithin 7 days of successful system implantation. The AV pacinginterval was individually adjusted for all patients (for both RVPand BiVP pacing modes) based on echocardiography in order toobtain optimal E and A waves.24 During BiVP, simultaneous RVand LV pacing was programmed in all patients.

Crossover

To minimize effects of prior pacing mode, a crossover period ofat least 3 months was required in each pacing mode before anal-ysis of primary and secondary end points.

Double Blind Configuration

Clinical investigators and patients remained blinded to pacingmode throughout the entire study. Only research personnel ap-pointed for pacemaker evaluations were aware of the programmedpacing mode.

Premature Crossover

All efforts were made to avoid premature crossover. Consider-ation was given to premature crossover in the setting of worseningof clinical heart failure, the development of atrial fibrillation, orpacing system dysfunction.

Evaluations

The patients’ evaluations, performed at the end of each cross-over period (lasting at least 3 months), included: quality of lifeas assessed by the Minnesota Living with Heart Failure question-naire (QoL), clinical evaluation of NYHA Class, 6-minute walktest (6MWT), peak oxygen uptake during cardiopulmonary exer-cise test (VO2max), and echocardiographic variables.

End Points of the Study

Primary end points were QoL and NYHA Class. Secondary endpoints were: 6MWT, V02max, mortality and echocardiographic

assessment of LV ejection fraction, ventricular volumes (systolicand diastolic), and grade of mitral regurgitation.

Statistical Analysis

Continuous variables, expressed as means 6 standard deviation,and their distribution were analyzed through the Shapiro-Wilkstest of normality and categorical variables, expressed in numbersand percentages were analyzed by Fisher exact test and chi squaretest. Comparisons between groups were performed with 2-wayanalysis of variance and the Bonferroni test. All statistical testswere 2-tailed, and a P value of less than .05 was considered to in-dicate statistical significance.

Results

Sixty-eight patients met the inclusion criteria and con-sented to enrollment in this study. Of these, 4 patientswere excluded because of unsuccessful BiVP pacemakerimplantation and 4 patients were lost to follow-up beforeevaluation of the first crossover phase. Of the remaining60 patients, 31 were randomized to group A, and 29 togroup B. The mean follow-up among these 60 patientswas 17.5 6 10.7 months. The average time in each cross-over period was 4.7 6 2.2 months. Seventeen patientswere followed for more than 24 months. The clinical andepidemiological characteristics of the 60 patients enrolledin the study are shown in Table 1. Most patients enrolledhad complete or high-grade AV block, often with a widecomplex escape rhythm.

Primary Study End Points: Quality of Life and HeartFailure Functional Class

The primary study end points of QoL and NYHA Classbehavior were both significantly improved with BiVP com-pared with RVP (interaction P value for each variable!.0001). Both QoL and NYHA Class were consistentlyand significantly improved with BiVP compared withRVP at all crossover points within the study (P ! .01)(Fig. 2, 3; Table 2A). At the end of the second crossover,33 patients were programmed to BiVP based on improvedQoL score, whereas 9 reached best QoL score with RVP.

Secondary Clinical End Points

There were not statistically significant overall differencesbetween BiVP and RVP for the end points of 6MWT andV02max (Table 2A), although nonsignificant trends gener-ally favored BiVP compared with RVP for these end points.At the final study phase, a significant benefit of BiVP com-pared to RVP was noted for V02max (P 5 .026).

Echocardiographic Outcomes

BiVP resulted in significant improvements comparedwith RVP in regard to the echocardiographic endpoints ofLVEF and LV end-systolic volume (P 5 .0225 and .0460,respectively) (Fig. 4, Table 2B). There was a nonsignificantstatistical trend toward reduced mitral regurgitation withBiVP compared with RVP (P 5 .061). LV end-diastolic

Table 1. Baseline Characteristics of the Patients

Variables Group A Group B P

Gender .65Male 21 (67.7%) 18 (62.7%)Female 10 (32.3%) 11 (37.9%)

Mean age (y) 57.4 6 15.0 59.3 6 13.3 .60Cardiomyopathy .12

Chagasic 16 (51.6%) 15 (51.7%)Ischemic 7 (22.6%) 3 (10.3%)Idiopathic 6 (19.4%) 11 (37.9%)Hypertrophic 2 (6.5%) 0 (0.0%)

Drug therapyb-blockers 17 (54.8%) 12 (41.4%) .18Antiarrhythmic 14 (45.2%) 10 (34.5%) .40Diuretics 28 (90.3%) 28 (96.6%) .61Cardiac glycoside 19 (61.3%) 24 (82.8%) .065ACE 28 (90.3%) 24 (82.8%) .40Aldactone 7 (22.6%) 1 (3.4%) .03ARB 0 (0%) 1 (3.4%) .31

NYHA class .89II 5 (16.1%) 5 (17.3%)III 16 (51.6%) 15 (51.7%)IV 10 (32.3%) 9 (31.0%)

ECG findingsComplete heart block 15 (48.4%) 15 (51.7%) .61Type II AV block 9 (29.0%) 10 (34.5%) .47Advanced heart block* 7 (22.6%) 4 (13.8%) .61QRS duration (ms) 154 6 13.1 148 6 16.4 .14

Echocardiographic measurementsLVEF (%) 29.2 6 7.4 30.1 6 9.2 .68LVESV 226 6 129 218 6 114 .82LVEDV 313 6 130 292 6 95 .52LVESD 6.04 6 0.99 5.88 6 0.75 .52LVEDD 6.98 6 1.01 6.82 6 0.71 .48Mitral regurgitation .50Mild 12 (40.0%) 8 (27.6%)Moderate 11 (36.7%) 11 (37.9%)Severe 7 (23.3%) 10 (34.5%)

ACE, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker.LVEF, left ventricular ejection fraction; LVESV, left ventricular endsystolic volume; LVEDV, left ventricular end-diastolic volume; LVESD, left ventricular end-systolic diameter; LVEDD, left ventricular end-diastolic diam-eter; NYHA class, New York Heart Association functional class;

*Wide QRS and atrioventricular relationO50%.

Fig. 2. Comparative results of the Quality of Life (QoL) score ac-cording to the group randomization at each study end point. GroupA, right ventricular pacing - atriobiventricular - right ventricularpacing; group B, atriobiventricular - right ventricular pacing -atriobiventricular.

296 Journal of Cardiac Failure Vol. 16 No. 4 April 2010

volume was not significantly different between BiVP andRVP (P 5 .30).

Clinical Events

During the study period, 15 deaths (25% of total studypatients) occurred. At the time of death, the stimulationmode was RVP in 13 (86.7%) patients and BiVP in 2(13.3%) patients. Death occurred significantly more fre-quently during periods of RVP compared with BiVP(P 5 .012).

A variety of additional clinical events occurred duringthe study, as detailed in Table 3. These include atrial fibril-lation (2), worsening of CHF requiring unplanned crossoverfrom RVP to BiVP (4), CHF hospitalization (7), heart trans-plantation (1), the need for LV lead repositioning (2),pacing system infection (1), and automobile accident (1).

Discussion

The COMBAT study has produced several importantfindings. In regard to the important primary functionalend points, there was a significant and consistent benefit

of BiVP compared with RVP in regard to QoL andNYHA Class. BiVP also demonstrated a significant benefitcompared with RVP in the echocardiographic endpoints of

Fig. 3. Comparative results of New York Heart Association Func-tional Class based on group randomization, including the baselinefunctional class. Group A, right ventricular pacing - atriobiventric-ular - right ventricular pacing; group B, atriobiventricular - rightventricular pacing - atriobiventricular.

Heart Failure and Bradyarrhythmia Pacing � Filho et al 297

LVEF and LV end-systolic volume, with a statistical trendfavoring BiVP in regard to reduction in mitral regurgitation.There were not consistently significant improvements in LVend-diastolic volume, 6MWT, or VO2max with BiVP com-pared with RVP, although nonsignificant trends generallyfavored BiVP for these end points. Additionally, the mortal-ity rate in COMBAT was significantly higher during periodsof RVP than during periods of BiVP.

Biventricular pacing has been shown to improve heartfailure symptoms in multiple published studies of patientswith CHF, LV systolic dysfunction, and a wide QRS com-plex.7-12 Substantial RV pacing has been shown to be harm-ful, especially among patients with LV dysfunction.18,25 Forpatients with intact AV conduction who undergo dualchamber pacemaker/defibrillator implantation, it is clearthat unnecessary RV pacing should be avoided, whichmay be accomplished by programming long AV delays.19

Furthermore, for patients with refractory atrial arrhythmiaswho undergo AV nodal ablation producing iatrogenic com-plete AV block requiring obligate ventricular pacing, it hasbeen demonstrated that BiVP is superior to RVP in regard

Table 2A. Results of the Studied Variables Obtained During

Variables QoL

Evaluation Phase Groups (Score)

Initial A (RVP) 19.79 6 8.15B (BiVP) 35.24 6 18.01

P .008Intermediate A (BiVP) 31.89 6 18.81

B (RVP) 15.67 6 8.21P !.001

Final A (RVP) 14.59 6 5.10B (BiVP) 30.17 6 19.43

P .004Group interaction P !.0001

QoL, Quality of Life; NYHA class, New York Heart Association functional clasright ventricular pacing; BiVP, biventricular pacing.

to 6MWT and LVEF, especially among patients with im-paired LVEF or CHF before ablation.27 The question thathas remained, however, is whether BiVP is preferred overRV pacing for patients with CHF who present with brady-cardia from AV block likely to necessitate a large percent-age of ventricular pacing. The COMBAT study wasdesigned to directly address this question with a crossoverdesign similar to that employed in the MUSTIC study,which allowed each patient to act as his or her own controlfor the effects of BiVP versus RVP.8

Despite being a relatively small trial, the positive find-ings in MUSTIC helped to establish BiVP as part of clinicalpractice for patients with systolic CHF and a broad QRScomplex.8 COMBAT demonstrates a similar and significantclinical benefit in QoL, NYHA Class, and LVEF with BiVPcompared with RVP at all crossover periods for patientspresenting with AV block likely to require substantial ven-tricular pacing and systolic heart failure. Because QoL andNYHA Class are highly relevant and important endpointsfor patients with CHF, this should be taken as evidence ofa benefit of BiVP in this population likely to be of consider-able importance to patients. Because COMBAT was a cross-over trial with multiple secondary end points and timepoints of analysis, it is not surprising that statistical signif-icance of BiVP versus RVP was not demonstrated for allsecondary end points and at all crossover periods. It shouldbe noted, however, that RVP was not significantly betterthan BiVP for any end point, and overall trends in second-ary end points that did not reach statistical significance gen-erally favored BiVP.

A reduction in mortality with CRT has been demon-strated in prior published studies, including CardiacResynchronization-Heart Failure and meta-analyses ofother published CRT trials.10,11 This mortality differencehas generally required long periods of evaluation with largenumbers of patients to achieve statistical significance. Sur-prisingly, despite being a relatively small study, COMBATdemonstrated significantly greater mortality during periodsof RVP compared with BiVP. This finding may be related tothe detrimental impact of RVP18 in addition to the benefit ofBiVP. Most published CRT trials used placebo (no pacing)

Each Evaluation According to Group Randomization

6MWT VO2max

NYHA Class (m) (mL$kg$min)

2.5 6 0.60 430 6 124 16.3 6 8.21.8 6 0.6 428 6 131 19.6 6 4.5

.006 .385 .2341.91 6 1.9 444 6 120 19.6 6 8.72.45 6 0.5 439 6 129 18.1 6 6.0

.009 .484 .82.67 6 0.7 380 6 127 15.8 6 6.01.89 6 0.6 442 6 122 20.8 6 4.8

.001 .163 .026!.0001 .4509 .1288

s; SMWT, 6-minute walking test; VO2max, peak oxygen consumption; RVP,

Fig. 4. Comparative results of echocardiographic variables. (A) Left ventricular ejection fraction. (B) Left ventricular end systolic volume.(C) Left ventricular end diastolic volume; based on group randomization. Group A, right ventricular pacing - atriobiventricular - right ven-tricular pacing; group B, atriobiventricular - right ventricular pacing - atriobiventricular.

298 Journal of Cardiac Failure Vol. 16 No. 4 April 2010

rather than RVP in the control arm, because most of thesetrials excluded patients with AV block. Placebo was notan alternative in COMBAT, because these patients requiredventricular pacing due to AV nodal disease. It is possiblethat intrinsic ventricular conduction with a broad QRS com-plex (the control group in most published CRT studies) dif-fers in regard to mortality compared with incessant rightventricular pacing that was present in the RVP crossoverperiods of COMBAT, and that obligate RVP may lead toa particularly high mortality rate. Consistent with this hy-pothesis, the Post AV Nodal Ablation Evaluation (PAVE)trial, which also compared BiVP with RVP (patients werepacemaker dependent because of AV nodal ablation),

Table 2B. Results of the Studied Echocardiograph Variables Obtaine

Variables LVESV

Evaluation Phase Groups (mL)

Initial A (RVP) 224 6 51B (BiVP) 160 6 59

P .084Intermediate A (BiVP) 199 6 80

B (RVP) 185 6 66P .582

Final A (RVP) 256 6 68B (BiVP) 147 6 49

P .002Group interaction P .0460

LVESV, left ventricular end-systolic volume; LVEDV, left ventricular end-diasventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; RVP,

Mitral regurgitation attributed values: Absent 1; Mild 2; Moderate 3; Severe 4

demonstrated a substantial, although statistically insignifi-cant, difference in mortality between BiVP and RVP(hazard ratio 2.3, mortality 18% RVP versus 8% BiVP,P 5 .16).26 Ongoing noncrossover studies including Bio-Pace27 and BLOCK HF28 will provide additional informa-tion on mortality when comparing BiVP versus RVP forHF patients with AV conduction diseases.

Another trial, Homburg Biventricular Pacing Evaluation(HOBIPACE),29 has also reported clinical and echocardio-graphic benefits of BiVP compared with RVP for patientswith bradycardia requiring pacing and LV systolic dysfunc-tion, and is the only other published trial with inclusioncriteria similar to COMBAT. HOBIPACE differs from

d During Each Evaluation According to Group Randomization

LVEDV LVEF

(mL) (%) Mitral Regurgitation

272 6 51 21.9 6 7.9 2.73 6 0.94237 6 90 30.4 6 7.2 2.55 6 0.89

.388 .018 .378264 6 89 28.7 6 8.6 2.41 6 1.01254 6 94 25.8 6 7.7 2.60 6 1.05

.938 .411 .436295 6 78 22.5 6 8.1 3.11 6 0.76214 6 68 29.3 6 6.9 2.33 6 0.59

.018 .04 .002.3013 .0225 .0611

tolic volume; LVESD, left ventricular end-systolic diameter; LVEDD, leftright ventricular pacing; BiVP, biventricular pacing..

Table 3. Follow-up Complications Observed During the Study Follow-up

Pacing Mode at Event (n)

Occurrence BiVP RVP Therapy/Comments

Atrial fibrillation d 2 Reverted to sinus rhythm and restarted the evaluation timeAnticipated crossover d 4 (RVP crossed to BiVP) because of heart failure worseningICD indication d 2 Recurrence of syncope and induced ventricular tachycardia (1);

reverted ventricular fibrillation during six minute walked test (1)Heart failure hospitalization 3 4 Required vasoactive drugs (4) and heart transplantation (1)Left ventricular pacing threshold increase 2 d Lead repositioning (1)

Output energy reprogramming (1)Pacing generator pocket infection 1 d Conventional system was replacedAutomobile accident 1 d Disability precluding functional analysis

ICD, implantable cardioverter defibrillator; BiVP, biventricular pacing; RVP, right ventricular pacing.

Heart Failure and Bradyarrhythmia Pacing � Filho et al 299

COMBAT in several important ways, however. First,HOBIPACE was single-blinded and thus potentially subjectto greater bias than the double-blinded design of COMBAT.Second, HOBIPACE included patients with atrial fibrilla-tion (accounting for 1/3 of all patients enrolled), whereasCOMBAT excluded these patients and focused solely on pa-tients in sinus rhythm with AV block. Third, HOBIPACEallowed less optimal anterolateral LV pacing lead locations(present in 1/3 of patients); whereas COMBAT requiredlateral or posterolateral LV leads. Finally, HOBIPACE isa somewhat smaller trial than COMBAT, and HOBIPACEdid not detect a significant mortality difference betweenBiVP and RVP.

Limitations

COMBAT included a relatively large proportion of pa-tients with Chagas cardiomyopathy compared with mostCRT trials, and it is possible that the effects of RVP versusBiVP could differ based on the cause of cardiomyopathy.Given the crossover nature of COMBAT, the effects oflong-term, continuous RVP versus BiVP on functional,echocardiographic, and mortality end points cannot be fullyassessed by these data, and 3-month intervals may not haveprovided sufficient time to assess the full benefits of CRT. Itis also possible that an implanted LV lead (programmedoff) could have been harmful during periods of conven-tional right ventricular pacing. The COMBAT study onlyrequired stable medicines for 30 days before enrollment,and this could have impacted the ultimate response to pac-ing compared with longer periods of stable medical regi-men. Finally, COMBAT was not powered to detectdifferences in response to pacing mode between subgroupssuch as NYHA Class II, III, and IV CHF.

Conclusions

For patients with systolic heart failure, sinus rhythm, andAV block requiring permanent ventricular pacing, BiVP issuperior to RVP with regard to QoL, NYHA Class, LVEF,and LV end-systolic volume. These data support an expan-sion in the indication for BiVP to patients who fit theCOMBAT inclusion criteria (NYHA Class II-IV, LVEF

!40%, and sinus rhythm with AV block likely to requireconsistent ventricular pacing).

References

1. Aaronson K, Schwartz S, Chen T, Goin JE, Wong K, Mancini DM.

Development and prospective validation of a clinical index to predict

survival in ambulatory patients referred for cardiac transplant evalua-

tion. Circulation 1997;95:2660e7.

2. Xiao HB, Lee CH, Gibson DG. Effect of the left bundle branch block

on diastolic function in dilated cardiomyopathy. Br Heart J 1991;66:

443e7.

3. Grines CL, Bashore TM, Boudoulas H, Olson S, Shafer P, Wooley CF.

Functional abnormalities in isolated left bundle branch block. The ef-

fect of intraventricular asynchrony. Circulation 1989;79:845e53.

4. Shamim W, Francis DP, Yousufuddin M, Varney S, Pieopli MF,

Anker SD, et al. Intraventricular conduction delay: a prognostic

marker in chronic heart failure. Int J Cardiol 1999;70:171e8.

5. Blanc JJ, Etienne Y, Gillard M, Mansourati J, Munier S, Boschat J,

et al. Evaluation of different ventricular pacing sites in patients with

severe heart failure: results of an acute hemodynamic study. Circula-

tion 1997;96:3273e7.

6. Gras D, Mabo P, Tang T, Luttikuis O, Chatoor R, Pedersen AK, et al.

Multisite pacing as a supplemental treatment of congestive heart fail-

ure: preliminary results of the Medtronic Inc. InSync Study. Pacing

Clin Electrophysiol 1998;21:2249e55.

7. Auricchio A, Stellbrink C, Block M, Sack S, Vogt J, Bakker P, et al. Ef-

fect of pacing chamber and atrioventricular delay on acute systolic

function of paced patients with congestive heart failure: the Pacing

Therapies for Congestive Heart Failure Study Group. The Guidant Con-

gestive Heart failure Research Group. Circulation 1999;99:2993e3001.

8. Cazeau S, Leclercq C, Lavergne T, Walker S, Varma C, Linde C, et al.

Effects of multisite biventricular pacing in patients with heart failure

and intraventricular conduction delay. N Engl J Med 2001;344:873e80.

9. Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E,

et al. Cardiac resynchronization in chronic heart failure. N Engl J Med

2002;346:1845e53.

10. Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De

Marco T, et al. Comparison of Medical Therapy, Pacing and Defibril-

lation in Heart Failure (COMPANION) Investigators. Cardiac-

resynchronization therapy with or without an implantable defibrillator

in advanced chronic heart failure. N Engl J Med 2004;350:2140e50.

11. Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D,

Kappenberger L, et al. Cardiac Resynchronization-Heart Failure

(CARE-HF) Study Investigators. The effect of cardiac resynchroniza-

tion on morbidity and mortality in heart failure. N Engl J Med 2005;

14(352):1539e49.

12. Gold MR, Peters RW. Permanent peacemakers in patients with dilated

cardiomyopathy. Cardiac Electrophysiol Rev 1999;2:381e3.

300 Journal of Cardiac Failure Vol. 16 No. 4 April 2010

13. Prinzen FW, Peschar M. Relation between the pacing induced

sequence of activation and left ventricular pump function in animals.

PACE 2002;25:484e98.

14. Giudici MC, Thornburg GA, Buck DL, Coyne EP, Walton MC,

Paul DL, et al. Comparison of right ventricular outflow tract and apical

lead permanent pacing on cardiac output. Am J Cardiol 1997;79:

209e12.

15. Saxon LA, Stevenson WG, Middlekauff HR, Stevenson LW. Increased

risk of progressive hemodynamic deterioration in advanced heart fail-

ure patients requiring permanent pacemakers. Am Heart J 1993;125:

1306.

16. Leon AR, Greenberg JM, Kanuru N, Baker CM, Mera FV, Smith AL,

et al. Cardiac resynchronization in patients with congestive heart fail-

ure and chronic atrial fibrillation: effect of upgrading to biventricular

pacing after chronic right ventricular pacing. JACC 2002;39.

1258e63.

17. Moss AJ, Zareba W, Hall WJ, Klein H, Wilber DJ, Cannom DS, et al.

Multicenter Automatic Defibrillator Implantation Trial II Investiga-

tors. Prophylactic implantation of a defibrillator in patients with myo-

cardial infarction and reduced ejection fraction. N Engl J Med 2002;

346:877e83.

18. Wilkoff BL, Cook JR, Epstein AE, Greene HL, Hallstrom AP, Hsia H,

et al. Dual chamber pacing or ventricular backup pacing in patients

with an implantable defibrillator. JAMA 2002;288:3115e23.

19. Olshansky B, Day JD, Moore S, Gering L, Rosenbaum M,

McGuire M, et al. Is dual-chamber programming inferior to single-

chamber programming in an implantable cardioverter-defibrillator?

Results of the INTRINSIC RV (Inhibition of Unnecessary RV Pacing

with AVSH in ICDs) study. Circulation 2007;115:9e16.

20. Hope UC. Beta-blocker induced bradycardiadshould we pace? Eur J

Heart Fail 2004;6:449e51.

21. Martinelli M, Costa R, de Siqueira SF, Ramires JA. COMBAT - con-

ventional versus multisite pacing for bradyarrhythmia therapy: ratio-

nale of a prospective randomized multicenter study. Eur J Heart Fail

2005;7:219e24.

22. Brazilian Guidelines for Evaluation and Treatment of Patients with

Cardiac Arrhythmias. Arq Bras Cardiol 2002;79(Suppl V):37e42.

23. Gregoratos G, Abrams J, Epstein AE, Freedman RA, Hayes DL,

Hlatky MA, et al. American College of Cardiology/American Heart

Association Task Force on Practice Guidelines American College of

Cardiology/American Heart Association/North American Society for

Pacing and Electrophysiology Committee. ACC/AHA/NASPE 2002

guideline update for implantation of cardiac pacemakers and antiar-

rhythmia devices: summary article. A report of the American College

of Cardiology/American Heart Association Task Force on Practice

Guidelines (ACC/AHA/NASPE Committee to Update the 1998 Pace-

maker Guidelines). J Cardiovasc Electrophysiol 2002;13:1183e99.

24. Lane RE, Chow AW, Chin D, Mayet J. Selection and optimization of

biventricular pacing: the role of echocardiography. Heart 2004;90:

vi10e6.

25. Hoijer CJ, Meurling C, Brandt J. Upgrade to biventricular pacing in pa-

tients with conventional pacemakers and heart failure: a double-blind,

randomized crossover study. Europace 2006;8:51e5.

26. Doshi RN, Daoud EG, Fellows C, Turk K, Duran A, Hamdan MH, et al.

Left ventricular based cardiac stimulation post AV nodal ablation eval-

uation (the PAVE study). J Cardiovasc Electrophysiol 2005;16:1160e5.

27. Funck RC, Blanc J, Mueller H, Schade-Brittinger C, Bailleul C,

Maisch B, et al. Biventricular stimulation to prevent cardiac desynch-

ronization: rationale, design, and endpoints of the ‘Biventricular Pac-

ing for Atrioventricular Block to Prevent Cardiac Desynchronization

(BioPace)’ study. Europace 2006;8:629e35.

28. Curtis AB, Adamson PB, Chung E, Sutton MS, Tang F, Worley S.

Biventricular versus right ventricular pacing in patients with AV block

(BLOCK HF): clinical study design and rationale. J Cardiovasc

Electrophysiol 2007;18:965e71.

29. Kindermann M, Hennen B, Jung J, Geisel J, Bohm M, Frohlig G. Bi-

ventricular versus conventional right ventricular stimulation for

patients with standard pacing indication and left ventricular dysfunc-

tion: the Homburg Biventricular Pacing Evaluation (HOBIPACE).

J Am Coll Cardiol 2006;47:1927e37.