Improvement of long-term survival by cardiac contractility modulation in heart failure patients: A case–control study

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Abstract

Introduction

Cardiac contractility modulation (CCM) has been shown to be effective in improving symptoms and cardiac function in heart failure (HF). However, there is limited data on the role of CCM on long-term survival, which was explored in the present study.

Methodology

Forty-one consecutive HF patients with left ventricular ejection fraction (EF) < 40% received CCM and were followed for approximately 6 years. They were compared with another 41 HF patients who were enrolled into the HF registry in the same period, and had similar age, gender, EF and etiology of HF. The primary end-point was all cause-mortality. This was stratified by EF. Secondary end-points included HF hospitalization, cardiovascular death, and the composite outcome of death or heart failure hospitalization.

Results

The CCM and control groups were well balanced for demographic data, medications and baseline left ventricular EF (27 ± 6 vs 27 ± 7%, p = NS). The mean follow-up duration was 75 ± 19 months in the CCM group and 69 ± 17 months in the control group. All-cause mortality was lower in the CCM group than the control group (39% vs. 71%, respectively; Log-rank χ2 = 11.23, p = 0.001). Of note, the improvement of all-cause mortality is more dramatic in patients with EF  25–40% (36% vs. 80%, Log-rank χ2 = 15.8, p < 0.001) than those with EF < 25% (50% vs. 56%, p = NS), CCM vs. control respectively. Similar results were shown for the benefit of CCM in the secondary endpoints of cardiovascular death, and the composite outcome of death or heart failure hospitalization. The occurrence of HF hospitalization showed no significant difference between CCM and control groups in the whole cohort (41% vs. 49%, p = NS), but was significantly lower with CCM in subjects with EF  25–40% at baseline (36% vs. 64%, Log-rank χ2 = 7.79, p = 0.005).

Conclusion

CCM resulted in significant improvement of long-term survival, in particular in those with EF  25–40%. A reduction in heart failure hospitalizations was also seen in this group of patients with less severely reduced EF.

Introduction

The incidence of heart failure is increasing in part due to more aggressive treatment of acute coronary syndromes, leaving more survivors who have had significant loss of cardiac function. The growing incidence of heart failure is expected to continue, especially in China where Westernization has propelled the prevalence of cardiovascular disease over 230 million and rank it as the commonest cause of death [1]. As a result the number of patients in China with heart failure is expected to increase rapidly from its current prevalence of 4.2 million.

Even though therapies for chronic heart failure have advanced significantly in the past two decades, an enlarging number of patients with ejection fractions (EF) < 45% on optimal medical therapy experience life-style limiting symptoms. For these subjects, several types of device-linked therapies are potentially available including implantable cardiac defibrillators (ICD), cardiac resynchronization therapy (CRT), and cardiac contractility modulation (CCM). Although many of these patients are candidates for the life-prolonging effects of ICDs, in the subset of patients with EF < 35%, this therapy does not improve symptoms or functional status. Use of ICDs has regional variability across the globe. About one fourth of this group of patients with heart failure has left bundle branch block or otherwise prolonged QRS duration and benefits from CRT [2], [3]. However for the remaining majority, who do not have QRS widening, CRT does not help or may be detrimental [4]. In this group, CCM (Optimizer device, Impulse Dynamics) has proven to be safe and effective, improving peak VO2, New York Heart Association (NYHA) classification, symptoms and well-being (Minnesota Living with Heart Failure questionnaire), 6-Minute Hall Walk test and EF [5], [6], [7].

CCM delivers a biphasic high voltage signal to the right ventricular septum during the absolute refractory period, triggered by detecting the tissue depolarization within the QRS complex with a timed delay. CCM acutely increases EF by about 5% and over time improves other parameters of cardiac function and symptoms. The mechanism of action involves improvement of cardiac calcium handling through upregulation of phospholamban, sarcoendoplasmic reticulum calcium transport ATPase, and L-type calcium channels both locally near the CCM signal delivery site and remotely throughout the heart [6]. CCM use also elicits left ventricular reverse remodeling of the fetal gene program towards that seen in normal hearts with elevation of myosin heavy chain-α and reduction in B-type Natriuretic Peptide levels [8]. While the acute and short term benefits (months) are well-established, much less data exist regarding longer term benefits including effects on mortality and hospitalization. This report provides long-term follow-up on 41 consecutive symptomatic subjects with EF < 40% in whom an Optimizer device was implanted and compared to a matched control group from a local heart failure registry of selected patients who did not receive CCM.

Section snippets

Methods

The study group consisted of forty-one consecutive patients with NYHA III symptomatic heart failure and EF < 40% who were on stable doses of heart failure medications and in whom an Optimizer III device was deployed. Patients were recruited from a University teaching hospital from 2005 to 2012. The protocol was approved by the local ethics board and all study subjects provided written informed consent. The comparator group consisted of 41 heart failure patients enrolled in the same hospital's

Results

Forty-one patients implanted with CCM between July 6, 2005 and June 6, 2012 were enrolled and followed through 31st August 2013. Baseline characteristics of these subjects and the matched controls are shown in the Table. There were no differences between groups within the matching criteria (age, gender, medications at baseline, left ventricular EF at baseline, follow-up duration, and etiology of heart failure). Only two subjects had an ICD implanted and both were in the group receiving CCM.

Discussion

The primary finding in this case–control study is that CCM added to medical therapy is associated with better survival than medical therapy alone. This is the first demonstration of long-term benefit of CCM in a population of Chinese patients. Cumulative survival at 80 months was 29% in the control group and 61% in the CCM treated group. The separation in survival curves occurred within the first few months and was maintained throughout the study thus the benefit of CCM starts early and is

Conflict of interest

Dr. Shlomo is the founder of Impulse Dynamics. Dr. Burkhoff and Dr. Gutterman are consultants to Impulse Dynamics. Dr. Rousso is an employee of Impulse Dynamics.

Funding

The study was partly supported by a research grant by Impulse Dynamics

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