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Cardiac Resynchronization Therapy is an Important Advancein the Management of Congestive Heart Failure

CHRISTOPHE LECLERCQ, M.D., PH.D., and J. CLAUDE DAUBERT, M.D.

From the Departement de Cardiologie et Maladies Vasculaires, Centre Cardio-Pneumologique,Centre Hospitalier Universitaire, Rennes, France

Cardiac Resynchronization Therapy for CHF. Cardiac resynchronization therapy (CRT) is anemerging therapy that improves symptoms and exercise tolerance in patients with advanced heart failure,left ventricular systolic dysfunction, and intraventricular conduction delay. By correcting the AV, inter-ventricular, and intraventricular dyssynchrony induced by conduction disorders, controlled studies haveshown that CRT improved functional status, decreased heart failure hospitalization rate, and might havea positive effect on left ventricular remodeling. Recent and preliminary data from the COMPANION trialsuggest that CRT alone or in association with defibrillator capacity significantly reduced total mortalityand hospitalization and that total mortality was significantly reduced only in the CRT plus implantablecardioverter defibrillator (ICD) group. Many questions remain unanswered, particularly the selection ofresponder patients. (J Cardiovasc Electrophysiol, Vol. 14, pp. S27-S29, September 2003, Suppl.)

biventricular pacing, cardiac resynchronization therapy, heart failure

Introduction

Cardiac resynchronization therapy (CRT) is a new therapythat improves hemodynamics and symptoms in patients withadvanced heart failure (HF), left ventricular (LV) systolicdysfunction, and intraventricular conduction delay.1 Resyn-chronization pacing may influence hemodynamics by im-proving mechanical AV synchrony, but also interventricularand intraventricular synchrony. Biventricular pacing devices,first implanted in 1994, were approved by the US Food andDrug Administration in 2001, and current devices may alsohave ventricular defibrillation capacity. The clinical bene-fits of CRT were shown in several controlled clinical trials(Table 1),2-4 which together demonstrate that CRT improvessymptoms and exercise tolerance in medically treated pa-tients with persistent, moderate-to-severe symptoms of HF,poor LV function, and intraventricular conduction delay.

Cardiac Consequences of AV and VentricularDyssynchrony

Both AV and intraventricular conduction delays alter LVfunction in patients with underlying cardiomyopathies.5,6

Cardiac dyssynchrony impairs systolic function, reduces car-diac output, and increases end-systolic volume and wallstress.7 Moreover, conductions disorders, estimated to affect30% to 50% of patients with advanced HF,7,8 progress overtime and are considered an independent risk for mortality.9

Interestingly, preliminary data also suggested that regionalmolecular modifications were observed in dyssynchronouscontracting myocardium.10

Benefits of CRT

Acute Hemodynamic Studies

Atrio-biventricular or LV pacing alone improves hemo-dynamics in patients with HF and left bundle branch block,

Address for correspondence: Christophe Leclercq, M.D., Departement deCardiologie et Maladies Vasculaires, CHU Pontchaillou, 2, rue Henri leGuilloux, 35033 Rennes cedex 09, France. Fax: 33-2-99-28-25-10; E-mail:christophe.leclercq@chu-rennes.fr

increasing cardiac output and reducing ventricular fillingpressures.11 Moreover, CRT is associated with a decreasein sympathetic nervous activity, suggesting that it also mayhave a favorable neurohormonal effect.7 Importantly, CRTimproves systolic function without increasing cardiac oxy-gen consumption, unlike inotropic drugs.11

Controlled Clinical Studies

To date, three placebo controlled studies have been pub-lished: PATH-CHF (Pacing Therapies for Congestive HeartFailure), MUSTIC (Multisite Stimulation In Cardiomyopa-thy), and MIRACLE (Multicenter InSync Randomized Clin-ical Evaluation) (Table 1), comprising a totality of evidencefrom 605 patients. MUSTIC SR,3 a cross-over trial, andMIRACLE,2 a placebo controlled study, both demonstratedimproved New York Heart Association (NYHA) class, exer-cise tolerance (6-minute walk test and peak VO2), and qualityof life (Minnesota Living with Heart Failure Questionnaire)due to CRT.

However, theses studies were not designed to assess theimpact of CRT on morbidity, principally hospitalization, andmortality. Recently, a meta-analysis included 809 patientswith CRT versus 825 without CRT showed that CRT reducedHF-associated mortality by 51% (odds ratio [OR] 0.49; 95%confidence interval [CI] 0.25–0.93) and hospitalization by29% (OR 0.71; 95% CI 0.53–0.96). Neither all-cause mor-tality (OR 0.77; 95% CI 0.51–1.18) nor non-HF deaths (OR1.15; 95% CI 0.65–2.02) were statistically reduced by CRT.12

Today there are two important ongoing mortality/morbiditytrials: CARE-HF (Cardiac Resynchronization in Heart Fail-ure Study) conducted in Europe (inclusion completed inMarch 2003) and COMPANION (Comparison of MedicalTherapy, Pacing and Defibrillator in Chronic Heart Failure)13

in the United States (which has been terminated early by theData Safety and Monitoring Board after the enrollment of1,600 of the 2,200 patients planned due to early benefit asso-ciated with CRT with or without implantable cardioverter de-fibrillator [ICD]). Preliminary results of the COMPANIONtrials, recently presented at the 52nd American College ofCardiology meeting, showed that CRT alone and CRT plusICD significantly decreased the occurrence of the primary

S28 Journal of Cardiovascular Electrophysiology Vol. 14, No. 9, Supplement, September 2003

TABLE 1

Published Controlled Studies with Cardiac Resynchronization Therapy

Follow-Up NYHA QRS Duration LVEFStudy Randomized (months) Class SR/AF (msec) (%) Clinical Results

PATH-CHF4 Yes 3 III/IV SR 175 ± 32 21 ± 7 +22% in 6WT; +43% QOL; +20% peak VO2(N = 42)

MUSTIC SR3 Yes/cross-over 3/3 III SR 176 ± 19 23 ± 7 +23% in 6WT; +32% QOL; 8% peak VO2(N = 67)

MUSTIC AF19 Yes/cross-over 3/3 III AF 207 ± 17 26 ± 10 +9.3% in 6WT; 13% peak VO2(N = 43)

MIRACLE2 Yes/parallel 6 III/IV SR 165 ± 20 22 ± 6 +13% in 6WT; 13% in QOL(N = 453)

AF = atrial fibrillation; LVEF = left ventricular ejection fraction; NYHA = New York Heart Association; QOL = quality of life; 6WT = 6-minute walktest; SR = sinus rhythm.

endpoint events (by 19%, death and hospitalization for allcause. However, only CRT plus ICD reduced significantlythe total mortality by 43%, whereas the reduction observedwith CRT alone (−23%) was not statistically significant.

Both MUSTIC and MIRACLE demonstrated reduced HFhospitalization rates. In MUSTIC, the 1-year monthly hospi-talization rate was reduced from 14% to 2% in the periods ofbiventricular pacing compared to the inactive pacing periods.In the MIRACLE trial, CRT reduced the risk of hospitaliza-tion for HF from 15% to 8% and the total days hospitalizedfor worsening HF over 6 months from 363 to 83. This wasconfirmed in the meta-analysis recently published.12

LV remodeling is an important target in HF treatment. Sev-eral noncontrolled and controlled studies showed that CRTwas associated with reverse LV remodeling, decreased LVend-systolic and end-diastolic volumes, and increased LVejection fraction, and that these benefits were pacing depen-dent.2,14-16

Technical Aspects of CRT

The technology of CRT is still evolving. With improv-ing catheter and lead designs, implantation success has risenfrom ∼50% to >90%.7 The major complications of LVlead implantation as reported by the MIRACLE investigators(n = 453) are death (n = 2); complete heart block (n = 2);coronary sinus dissection (n = 23) or perforation (n = 12);and need to reposition (n = 20), replace (n = 10), or remove(n = 7) pacing leads (2). The LV lead implantation successrate was 92%.2 Optimization of LV lead position (usually butnot always in the mid-lateral or posterolateral LV wall) is acrucial issue in the clinical benefit of CRT.7 New generationsof biventricular pacemaker will provide independent LV andright ventricular ports to program an interventricular intervaland perhaps to optimize ventricular resynchronization.17 Fi-nally, whether simultaneous pacing of both ventricles is nec-essary remains questionable, because hemodynamic studiessuggest that LV pacing alone may improve mechanical syn-chrony even without electrical synchrony.18

Summary

CRT clearly is an extremely promising and effective strat-egy to improve hemodynamic performance in patients withadvanced HF, LV systolic dysfunction, and intraventricu-lar conduction delay. Several studies have demonstrated thatCRT can restore synchrony and improve cardiac performance

without the cost of increased myocardial oxygen consump-tion. This hemodynamic benefit rapidly translates into im-proved patient well-being as evidenced by enhanced exercisecapacity and reduced utilization of inpatient care. New un-published studies and meta-analyses suggest that CRT doeshave a mortality benefit, but this must be proven with specif-ically designed and powered studies.

Several questions remain unanswered or must be clari-fied: the effect of CRT in permanent atrial fibrillation pa-tients (up to 40% of HF patients); how to define and howto select responders; and the impact of echocardiographyand new imaging technologies on the selection and evalu-ation of CRT patients. Finally, the cost-effectiveness of thistherapy, especially in CRT-ICD combination, remains to beevaluated.

References

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