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ORIGINAL PAPER

Clinical effects of long-term cardiac contractility modulation (CCM) in subjects with heart failure caused by left ventricular systolic dysfunction

D. Müller1 • A. Remppis1 • P. Schauerte2 • S. Schmidt-Schweda3 •

D. Burkhoff4 • B. Rousso5 • D. Gutterman6 • J. Senges7 • G. Hindricks8 •

K.-H. Kuck9

Received: 19 December 2016 / Accepted: 30 June 2017 / Published online: 6 July 2017

� The Author(s) 2017. This article is an open access publication

Abstract

Introduction Heart failure is a major cause of morbidity

and mortality throughout the world. Despite advances in

therapy, nearly half of patients receiving guideline-directed

medical therapy remain limited by symptoms. Cardiac

contractility modulation (CCM) can improve symptoms in

this population, but efficacy and safety in prospective

studies has been limited to 12 months of follow-up. We

report on the first 2 year multi-site evaluation of CCM in

patients with heart failure.

Methods One hundred and forty-three subjects with heart

failure and reduced ejection fraction were followed via

clinical registry for 24 months recording NYHA class,

MLWHFQ score, 6 min walk distance, LVEF, and peak

VO2 at baseline and 6 month intervals as clinically indi-

cated. Serious adverse events, and all cause as well as

cardiovascular mortality were recorded. Data are presented

stratified by LVEF (all subjects, LVEF \35%, LVEF C35%).

Results One hundred and six subjects from 24 sites com-

pleted the 24 month follow-up. Baseline parameters were

similar among LVEF groups. NYHA and MLWHFQ

improved in all 3 groups at each time point. LVEF in the

entire cohort improved 2.5, 2.9, 5.0, and 4.9% at 6, 12, 18,

and 24 months, respectively. Insufficient numbers of sub-

jects had follow-up data for 6 min walk or peak VO2 assessment, precluding comparative analysis. Serious

adverse events (n = 193) were observed in 91 subjects and

similarly distributed between groups with LVEF\35% and LVEF C35%, and similar to other device trials for heart

failure. Eighteen deaths (7 cardiovascularly related) over

2 years. Overall survival at 2 years was 86.4% (95% con-

fidence intervals: 79.3, 91.2%).

Conclusion Cardiac contractility modulation provides safe

and effective long-term symptomatic and functional

improvement in heart failure. These benefits were inde-

pendent of baseline LVEF and were associated with a

safety profile similar to published device trials.

Keywords Heart failure � CCM � Human � Clinical � Registry � Electrical stimulation � Survival � NYHA � LVEF � MLWHFQ

Introduction

In patients with moderate to severe chronic heart failure

and reduced ejection fraction (HFrEF), the mainstay of

guideline directed medical therapy (GDMT) includes use

of beta-adrenergic blockers, angiotensin converting

enzyme inhibitors (ACE-I) or angiotensin receptor block-

ing (ARB) agents, and aldosterone antagonists. Combina-

tion therapy with an ARB and neprolysin inhibitor

(LCZ696) may be substituted for the ACE-I/ARB in

& A. Remppis ba.remppis@hgz-bb.de

1 Heart and Vascular Center (HGZ), Bad Bevensen, Germany

2 University Hospital Aachen RWTH, Berlin, Germany

3 Georg August University of Gottingen, Gottingen, Germany

4 Columbia University, New York, NY, USA

5 Impulse Dynamics, Hod Hasharon, Israel

6 Medical College of Wisconsin, Milwaukee, WI, USA

7 Institut für Herzinfarktforschung, Ludwigshafen, Germany

8 Heart Center Leipzig, Leipzig, Germany

9 Asklepios Klinik St. Georg, Hamburg, Germany

123

Clin Res Cardiol (2017) 106:893–904

DOI 10.1007/s00392-017-1135-9

relevant patients, and Ivabradine is indicated in select

subjects with persistent sinus rates over 70 bpm. However,

despite optimizing GDMT, up to 50% of patients remain

symptomatic with limitation in exertional capacity, and

deterioration of NYHA class, exercise endurance, and

general well-being [1]. Of these, 35% have prolonged QRS

duration or LBBB and are candidates for cardiac resyn-

chronization therapy (CRT) [2]. The remaining 65% have a

narrow QRS or RBBB and CRT is not less frequently

indicated [3]. For these patients, cardiac contractility

modulation (CCM) offers functional improvement, greater

exercise tolerance, and symptomatic benefit [4–6].

Recently, CCM therapy was reviewed in the European

Society of Cardiology’s guidelines on acute and chronic

heart failure (2016) where it was stated that ‘‘CCM may be

considered in selected patients with HF’’ [1].

The Optimizer TM

system (Impulse Dynamics, Orange-

burg, NY, USA), which delivers the CCM therapy, consists

of commercially available implantable leads and an

externally chargeable impulse generator that delivers non-

excitatory biphasic electrical signals to two sites in the RV

septum (spaced a few centimeters apart). Impulses are

delivered during the absolute refractory period thereby

avoiding ventricular capture. When applied this way for

5–12 h/day [4, 7, 8], CCM has been shown to elicit both

pathophysiological and clinical benefits. CCM impulse

delivery produces an instantaneous enhancement in con-

tractility leading to an acute rise in LVEF over a few hours.

This is associated with improved cardiac biochemistry

especially in relation to cardiomyocyte calcium handling

with upregulation of SERCA-2A, increased phosphoryla-

tion of phospholamban, normalization of the sodium-cal-

cium exchanger, and a decrease in BNP [9–11]. These

changes are associated with adaptive local remodeling, and

a decrease in LVEDP and LVEDD which collectively drive

the observed clinical improvement in patients treated with

CCM. The clinical benefit includes an increase in LVEF,

improved quality of life (Minnesota living with heart fail-

ure questionnaire; MLWHFQ), fewer symptoms (NYHA

classification), and longer six minute walk test (6 MW), as

well as an increase in peak VO [5, 7, 24]. The Optimizer TM

system is compliant with available regulations and is

commercially available in countries that recognize the CE

Mark including the European Union, Russia, Brazil, India,

and Australia. Despite substantial clinical experience with

over 3000 implants, few reports with small numbers of

subjects in specific sites have evaluated the benefit of CCM

beyond one year [12–14].

The present registry was established as a means to

follow patients originally enrolled in a clinical trial

comparing CCM to a control group. Difficulties in

recruiting matched control subjects prompted conversion

to a prospective registry after 143 subjects had been

implanted. The goal was to evaluate long-term (2 years)

effects of CCM in each of the 143 symptomatic subjects

with HFrEF including several with mid-range ejection

fractions (HFmEF). Data acquisition continued until all

subjects had completed baseline evaluation and follow-up

at 6 months intervals for 2 years (total of 5 evaluations:

baseline, 6 months, 12 months, 18 months and

24 months). These data form the basis of this prospective

observational report. At baseline and at each interval the

impact of CCM on NYHA, MLWHFQ, LVEF, 6 MW,

and peak VO2 were recorded in accordance with data

availability. Data were available at later time points only

if the study was performed for clinical indications. As a

result, the focus for efficacy data was on NYHA,

MLWHFQ, and LVEF since follow-up measurements of

6 MW and pVO2 were infrequently obtained. All cause

mortality was also determined over the 2 year follow-up

period. The present study is the first to report on long-

term (2 years) effects (efficacy and safety) of CCM in

HFrEF and HFmEF in a large cohort of subjects on a

multi-site basis, and is the first to prospectively analyze

the benefit of CCM therapy in cases with baseline LVEF

below and above 35%.

Methods

Patient selection

The CCM-HF investigation included 143 patients with an

Optimizer device implanted for clinical heart failure and

LVEF\45% between April 15, 2010 (date of first implant) and March 25, 2015 (date of last follow-up visit). The

decision to enroll subjects with LVEF[35% was based on the subgroup analysis performed on the FIX-HF-5 study

[4, 7] which suggested that patients with LVEF between

25–45% had greater clinical benefit than those in the

overall cohort. In that study 35% was used as the upper

limit of baseline LVEF based on the site’s evaluation but

the core echo lab determined that in 38 patients, LVEF was

[35% and these subjects were analyzed separately [7]. For this reason we stratified the patients in the registry

according to LVEF (\, C35%), allowing us to determine if clinical effectiveness and safety of CCM were similar in

subjects with baseline LVEF C35% compared to those

with LVEF \35%.

Outcome measures

The following efficacy data were recorded when available:

NYHA classification, MLWHFQ score, ejection fraction,

peak VO2, and 6 min walk distance (6 MW). Safety

parameters were recorded including all-cause mortality

894 Clin Res Cardiol (2017) 106:893–904

123

(primary safety endpoint), cardiac mortality, and rate and

severity of related serious adverse events (SAE).

Efficacy data were collected on electronic case report

forms, and events were collected by the sponsor, adjudi-

cated and reported. The main efficacy data and all safety

data were monitored using an outside vendor. To minimize

or avoid bias, the registry involved multiple centers (28

sites in Germany), and site selection was based upon site’s

experience with heart failure device implants and avail-

ability of an appropriate patient population. The incidence

and nature of protocol deviations were evaluated for

potential introduction of bias into the data analysis. Every

effort was made to follow all subjects to assure the data set

was as complete as possible.

Inclusion and exclusion criteria

Any subject over the age of 18 years who received an

Optimizer system implant and provided informed consent

was eligible for participation in this registry. Only those

subjects who had been taking stable doses of GDMT for at

least 30 days were enrolled. There were no exclusion cri-

teria; every patient receiving an Optimizer system implant

as part of the originally planned cohort study, could par-

ticipate. As described above, 143 patients had CCM devi-

ces implanted at the time the study was converted to a

registry. Only these patients were followed as part of the

registry. All patients remained on their initial heart failure

medications unless clinical circumstances required a

change. There were no restrictions regarding types or doses

of heart failure medications used.

Study procedures and follow-up

Initial baseline measurements included a MLWHFQ

questionnaire, echocardiogram, NYHA assessment, pVO2,

and a six-minute walk test.

The standard implantation protocol of the Optimizer III

System used was generally followed. The precordial region

of the chest (right subclavian area) was prepped and draped

under sterile conditions. After access to the subclavian or

cephalic vein, a lead was placed transvenously into the

right atrium for sensing atrial activity. Two additional leads

were placed transvenously across the tricuspid valve and

secured to the right ventricular septum for sensing ven-

tricular activity and bipolar delivery of CCM signals. After

recovery from the procedure, a chest X-ray was obtained to

exclude pneumothorax and to evaluate lead placement.

The Optimizer TM

pulse generator was activated prior to

hospital discharge for at least 2 h, while monitoring the

subject on telemetry. During this time and device param-

eters were adjusted as needed and at the end of 2 h, the

device was interrogated to ensure proper functioning. At

the discretion of the Principal Investigator, subjects were

discharged sometime after the 2 h monitoring, having

received instructions for recharging the pulse generator

including a recommendation to recharge the device

weekly. Devices were programmed to be active for an

average of 7 ± 1 h/day. A rechargeable battery may help

to match device longevity with life expectancy, a problem

with most implantable devices [15].

All subjects returned for follow-up between two and

four weeks after CCM activation. The pulse generator was

interrogated to determine the number of sensed beats, RV

lead impedances and the percent of CCM signal delivery

(the number of beats actually receiving CCM relative to the

total number of ventricular beats sensed during the time

period when CCM was programmed to be active). Opti-

mizer parameter settings were adjusted according to the

recommendations of the site PI. The patient’s ICD, if

present, was also interrogated to insure absence of cross-

talk with CCM.

Subjects returned to the hospital for follow-up at 6, 12,

18 and 24 months after baseline assessment. At each visit,

the CCM device, and ICD if present, were interrogated to

ensure proper functioning and to assess events. An interval

medical history, including NYHA classification and med-

ications was obtained. A MLWHFQ, exercise study, and a

6 min walk test were administered if clinically indicated.

At the end of the study period (24 months), the patient

and site PI decided whether to maintain the Optimizer in an

activated state. If signal delivery continued, follow-up

visits were continued accordingly.

Data validity and statistical analysis

All efficacy data were entered by each site into a common

electronic database. Adverse events were reported to the

study sponsor and were adjudicated via direct communi-

cation with the investigator and reported into a separate

database along with efficacy data and measurements. Cat-

egorization of serious adverse events (SAE) was done by

the site PI and reviewed by the Medical Director. SAEs

were categorized as arrhythmic, worsening heart failure,

infectious, bleeding, ICD related, Optimizer charging

issues, lead problem, death, neurological dysfunction, and

renal failure. Cardiopulmonary SAEs outside the above

categories were combined under the heading ‘‘general

cardiopulmonary SAE’’, and those related to general

medical events not otherwise described above were clas-

sified as ‘‘general medical SAE’’. Validity checks and data

cleanup rules were applied with the resulting final data set

used for analysis.

Our secondary analysis examined whether the clinical

effects of CCM in patients with baseline LVEF C35% were

no worse than (i.e., is non-inferior to) the clinical effects

Clin Res Cardiol (2017) 106:893–904 895

123

achieved by patients with initial EF \35%. All data col- lected were analyzed comparing the follow-up interval

results with baseline for the entire cohort as well as

between groups, based on baseline LVEF (\35% vs. C35%). Data are presented as mean±SD. The significance

level used was 0.05.

In addition, analysis of the repeated longitudinal mea-

surements was performed using mixed effects models.

Models treated the time point (Baseline, 6 months,

12 months, 18 months, 24 months) as categorically fixed

predictors allowing for an arbitrary average time course.

Intra-subject correlation was accommodated through a

subject-specific intercept and slope. The use of mixed

effects models enables robust analysis, despite missing

values, based on the totality of available data. In testing for

improvement from baseline to follow-up, it was first tested

if there is a (global) difference at any of the four follow-up

times; if so then changes from baseline to specific time

points are tested with allowance for multiple comparisons

using Sidak’s method. Comparisons between the baseline

LVEF groups were made by including an interaction of the

LVEF group indicator and the time variables. These

computations were performed using the XTMIXED pro-

cedure in Stata 13.

Ethical considerations

The protocol was developed in accordance with the Dec-

laration of Helsinki and ISO 14,155, and was based on the

specific characteristics of the patient population under

evaluation.

The study was approved by the Ethics Committee of

Leipzig University (Ethik-Kommission an der Medizinis-

chen Fakultät der Universität Leipzig, Institute for klinik

pharmacology, Härtelstrasse 16-18, 04107, Leipzig, Ger-

many) and was conducted at 28 sites in Germany.

Results

One hundred and forty-three (143) patients treated with

CCM were followed in this registry. Twenty-eight subjects

had baseline LVEF C35% (mean 37.3 ± 3.1%). All but

one had an LVEF \45%. One hundred and fourteen had LVEF \35% (mean 26.1 ± 5.0%) and one patient did not have a baseline LVEF recorded. This patient’s data is

reported in the data analysis for the entire cohort but not in

the subgroup analysis by LVEF.

A total of 106 patients completed the follow-up period

of 2 years in the registry. The remaining 37 either died or

discontinued their participation in the study for other rea-

sons, as detailed below. Results are presented for all 143

patients, except when noted otherwise. Of the thirty-seven

(37) patients who did not complete 24 months follow-up,

nine (9) patients voluntarily withdrew their consent or were

lost to follow-up, ten (10) were withdrawn due to SAE, and

eighteen (18) patients died. SAEs and deaths are further

discussed below.

Baseline characteristics (mean ± SD) are presented in

Table 1. When stratified by baseline LVEF (\ or C35%), there were no statistically significant differences between

the subgroups in any baseline parameter except for the

presence of an ICD and minor differences in QRS duration.

Thus, the subgroups were well-matched.

Using the 3 LVEF stratifications described (EF \35%; LVEF C35%; and all subjects combined), functional and

quality of life (QOL) characteristics were examined at

baseline and throughout the 24 months of CCM therapy.

NYHA

An improvement in NHYA was observed in overall cohort

at each time point during follow-up, compared to baseline

(p \ 0.001), using a mixed effects models analysis (Sidak). A similar and statistically significant improvement in

NYHA was seen in the group with LVEF \35% and the group with LVEF C35% at each follow-up time point when

compared to baseline (Table 2; Fig. 1). The mixed effects

models analysis found no statistical difference in the result

of the subgroups with baseline LVEF \35% vs LVEF C35% (p = 0.25 for interaction).

MLWHFQ

The impact of CCM on MLWHFQ is shown in Table 2 and

Fig. 1. Baseline MLWHFQ scores were similar in all three

LVEF groups. The overall group improved their scores

significantly at 6-months and sustained the improvement

thereafter with a mean improvement of 13.9 at 6-months;

12.2 at 12-months; 11.6 at 18 months; 12.4 at 24-months

(all p \ 0.001). The improvement was of similar magni- tude in the two LVEF groups (p = 0.58 for interaction)

although statistically significant improvement in

MLWHFQ from baseline was observed in the LVEF\35% and not in the LVEF C35% group on a per-time-point

t test, likely due to the lower number of subjects in the

higher LVEF group.

LVEF

Table 2 and Fig. 2 show the changes in LVEF over the

course of the study. In the overall group a statistically

significant increase in ejection fraction was observed at all

time points with an estimated mean improvement in LVEF

of 2.5% at 6-months, p = 0.003; 2.9% at 12-months,

p = 0.001; 5.0% at 18-months, and p \ 0.001; 4.9% at

896 Clin Res Cardiol (2017) 106:893–904

123

24-months, p \ 0.001. The mixed effects model analysis found a similar improvement in LVEF at each follow-up

time point between subgroups (baseline LVEF \35% vs LVEF C35%; p = 0.83 for interaction.

Peak VO2 and 6 min walk distance

Only about a third of the subjects had baseline peak

exercise studies performed and no more than 10 had

measurements at the 12, 18 and 24 month time points.

Fewer than 50 subjects completed the 6 min walk distance

at each follow-up time point, rendering the dataset under-

powered for adequate statistical comparison.

The efficacy of medical therapy for heart failure may be

influenced by the etiology of cardiac dysfunction [16]

although not in all cases [17]. We examined the efficacy of

CCM in the 69 subjects with ischemic heart disease com-

pared with those with dilated cardiomyopathy. Baseline

values for NYHA (2.9 ± 0.5—Isch; 2.8 ± 0.6—DCM),

MLWHFQ (46.8 ± 19.4—Isch; 45.7 ± 17.3—DCM), and

LVEF (29.1 ± 6.9%—Isch; 27.7 ± 6.0—DCM) were

comparable between groups. The improvement over time

in each group was likewise similar (data not shown). Thus,

improvement in functional and symptomatic parameters

with CCM is not dependent upon whether the heart failure

is idiopathic or of ischemic etiology.

Implantation of other devices during the follow-up

period could have influenced clinical responses to therapy.

However, very few such devices were implanted during the

course of the 2 year study. Between 6 and 12 months fol-

low-up, 1 patient received an ICD and another patient

received a CRT-D. In both cases the implantation was a

Table 1 Baseline demographics and

characteristics

All

n (%)

Group with EF C35%

n (%)

Group with EF \35% n (%)

Number of patients 143 28 114

Gender 109 (76%) Male

34 (24%) Female

22 (79%) Male

6 (21%) Female

87 (76%) Male

27 (24%) Female

Age [completed life years] 62 ± 12 65 ± 12 63 ± 12

Subjects with ICD 108 (76%) 16 (57%)* 91 (80%)

Etiology of cardiomyopathy 69 (50%)—Ischemic

57 (41%)—Idiopathic

13 (9%)—other

N = 27

16 (59%)—Ischemic

8 (30%)—Idiopathic

3 (11%)—other

N = 111

52 (47%)—Ischemic

49 (44%)—Idiopathic

10 (9%)—other

History of CABG and/or PCI 76 (57%) N = 14 (50%) N = 61 (56%)

QRS duration (ms) 118 ± 26 (N = 131) N = 24

112 ± 17*

N = 106

119 ± 27

NYHA class

[Class—N (%)]

II—29 (20%)

III—103 (72%)

IV—11 (8%)

II—7 (25%)

III—21 (75%)

IV—0 (0%)

II—22 (19%)

III—81 (71%)

IV—11 (10%)

Hypertension—N (%) 66 (49%) N = 108

14 (54%)

N = 108

51 (47%)

Presence of CRT—N (%) 14 (10%) 2 (7%) 12 (11%)

Cardiac medications N = 133 N = 26 N = 107

Diuretic 104 (78%) 19 (73%) 85 (79%)

ACE-I 82 (62%) 17 (65%) 65 (61%)

ARB 32 (24%) 8 (31%) 24 (22%)

B-Blocker 126 (95%) 24 (92%) 102 (95%)

Aldosterone inhibitor 87 (65%) 18 (69%) 69 (64%)

Digoxin 19 (14%) 4 (15%) 15 (14%)

Other medications

Anticoagulation 49 (37%) 8 (31%) 41 (38%)

Antiplatelet Therapy 78 (59%) 20 (77%) 58 (54%)

Statin 92 (69%) 21 (81%) 71 (66%)

For one subject the baseline EF was not known, hence while the entire cohort is of 143 subjects, the total

number of subjects in both groups (based on baseline EF) combined, is only 142. * p \ 0.05 vs. Group with EF\ 35%

Clin Res Cardiol (2017) 106:893–904 897

123

revision or replacement of an existing device. Two patients

received a new ICD device, one between 12 and

18 months, and one between 18–24 months. All patients

receiving new or revised devices were in the EF \35% group. Eliminating these patients from analysis did not

change the interpretation of the results.

To determine whether improvements in functional class,

quality of life, and EF might have been associated with

increased use of heart failure medications (ACE-I/ARB,

beta-blocker, aldosterone antagonist) we evaluated usage

of these medications (initiation, termination, or mainte-

nance) over the course of the study. Results of this analysis

are shown in Table 4. The data demonstrate that few

patients initiated or stopped heart failure medications over

the 2 year follow-up period. Among those who did change

their medical regimen, similar numbers started and stopped

the medication. For each medication class (beta blockers,

ACE-I/ARBs, and aldosterone antagonists), and at each

time point, 80% or more of patients maintained use of the

same heart failure medications that were prescribed at the

baseline time point. We were not able to accurately

determine changes in doses of each medication class.

Serious adverse events

Throughout the 24 months of follow-up, one hundred and

ninety-three (193) serious adverse events were reported in

ninety-one (91) patients (Table 3). Of these, thirty-two (32)

SAEs in twenty-five (25) patients were classified by the

investigator as definitely or possibly related to the device

and twenty-seven (28) SAEs in twenty (20) patients as

definitely or possibly related to the procedure. In view of

overlap between events reported as device related and

procedure related, in the aggregate there were thirty-four

(34) device and/or procedure related SAEs reported in

twenty-five (25) patients during the study period, most

commonly due to lead migration. SAEs are presented in

Table 3, stratified by baseline ejection fraction (\35% vs. C35%).

Ten (10) patients were withdrawn from the study due to

an SAE after a mean time of 338 days. Of these, 4 events

were classified by the investigators as related or possibly

related to the device and/or procedure: infection in the ICD

pocket (although not in the Optimizer pocket), Optimizer

IPG removal during a CRT implantation, hematoma in IPG

pocket, and IPG pocket infection.

The thirty-two serious adverse events related or possibly

related to the device occurred in 17% of the total study

population over the study period: 17% of those with LVEF

[=35%, and 18% of those with LVEF \35%. The most common of these SAEs was lead migration. During the two

year period, 171 hospitalizations (all cause) occurred.

Deaths

The primary safety end-point of death of any cause

occurred in 18 enrolled subjects during the 24 month fol-

low-up period (average time from enrollment was

Table 2 Impact of CCM on NYHA, MLWHFQ, and LV ejection fraction over time and by EF class

EF group NYHA MLWHFQ LV ejection fraction

Mean (n) Value (n) D from baseline % (n) D from baseline

Baseline EF \35% 2.9 ± 0.5 (114) 45.4 ± 19.6 (104) – 26.1 ± 5.0 (114) – *EF C35% 2.8 ± 0.4 (28) 44.6 ± 17.3 (25) – 37.3 ± 3.1 (28) –

Total 2.9 ± 0.5 (143) 45.0 ± 19.2 (130) – 28.3 ± 6.4 (142) –

6 Months EF \35% 2.3 ± 0.8* (87) 30.0 ± 19.8 (66) -16.4 ± 20.8* 28.2 ± 8.3 (68) 2.6 ± 7.2* EF C35% 1.9 ± 0.8* (21) 37.3 ± 18.8 (18) -9.7 ± 17.9 40.5 ± 6.2 (15) 3.2 ± 6.6

Total 2.2 ± 0.8* (109) 31.4 ± 19.7 (22) -15.1 ± 20.3* 30.5 ± 9.2 (83) 2.7 ± 7.1*

12 Months EF \35% 2.2 ± 0.8* (79) 32.2 ± 21.9 (61) -12.3 ± 22.8* 28.9 ± 8.8 (62) 3.3 ± 7.8* EF C35% 2.4 ± 0.8* (19) 35.3 ± 14.5 (15) -8.9 ± 9.9 39.1 ± 4.3 (17) 2.4 ± 4.7

Total 2.2 ± 0.8* (99) 32.8 ± 20.6 (76) -11.6 ± 20.9* 31.7 ± 13.1 (79) 3.1 ± 7.3*

18 Months EF \35% 2.2 ± 0.7* (70) 32.5 ± 24.3 (59) -13.0 ± 25.6* 31.1 ± 10.3 (55) 5.3 ± 9.8* EF C35% 2.1 ± 0.6* (15) 35.0 ± 16.0 (11) -4.8 ± 15.9 39.3 ± 4.9 (11) 2.4 ± 5.7

Total 2.2 ± 0.7* (86) 32.9 ± 23.1 (70) -11.7 ± 24.5* 32.0 ± 10.5 (66) 4.8 ± 9.3*

24 Months EF \35% 2.2 ± 0.9* (52) 30.8 ± 23.6 (44) -15.0 ± 21.6* 33.0 ± 9.1 (37) 7.5 ± 9.3* EF C35% 2.3 ± 0.7* (15) 34.5 ± 18.7 (14) -9.4 ± 18 40.2 ± 5.6 (13) 3.5 ± 6.0

Total 2.2 ± 0.8* (68) 31.2 ± 22.5 (59) -13.6 ± 20.6* 34.9 ± 8.8 (51) 6.5 ± 8.7*

All data are presented as mean ± SD; n’s reflect numbers of subjects with available data. LV ejection fraction (EF; mean±SD). Means and

standard deviations of available raw data are shown. P values at individual time points were determined by the mixed model using Sidaks method

for multiple comparisons. *p \ 0.05 vs. corresponding baseline

898 Clin Res Cardiol (2017) 106:893–904

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341 ± 240 days (range 27–659 days). Three (3) of these

were among the 29 patients with baseline LVEF C35%. Of

the 18 who died, 7 deaths were classified as cardiovascular,

8 were non-cardiovascular, and in three it was not known.

None of the deaths were classified by investigators as being

related to the device or to the procedure. Kaplan–Meier

analysis of survival estimate for all patients in this study

through 2 years is shown in Fig. 2. The survival propor-

tions and 95% CIs were 94.2% (88.8, 97.1%) for 1 year,

and 86.4% (79.3, 91.2%) for 2 years.

Discussion

This study represents the largest long-term (24 month)

efficacy and safety evaluation of heart failure patients

implanted with an Optimizer device. Prior randomized

trials followed patients for 3, 6 and 12 months [4, 7]. There

are 2 key new findings. First, efficacy and safety of CCM

are observed in patients with symptomatic heart failure for

at least 2 years. Second, when patients are stratified by

baseline LVEF (\35 or C35%), both groups demonstrated a similar improvement in NYHA classification, MLWHFQ

and LVEF at 6, 12, 18, and 24 month follow-up time

points. The rates of SAEs and death were comparable

between groups and consistent with prior studies.

Cardiac contractility modulation is known to be effec-

tive and safe in treating patients with chronic heart failure

with ejection fractions below 35% [4, 6, 7, 18]. Secondary

analysis of data from the FIX-HF-5 sub-study suggests that

the efficacy of CCM is maintained and possibly greater in

patients with LVEF between 25% and 45% [4]. In the

present study, similar improvements in efficacy were

observed when the prospectively defined analysis was

stratified by baseline LVEF above and below 35%.

The importance of evaluating CCM efficacy in these

patients with less severely reduced ejection fractions is

supported by recently published long-term mortality and

hospitalization data suggesting a long-term improved sur-

vival in patients with LVEF between 25–40% compared to

those with LVEF \25% who are treated with GDMT?CCM vs. GDMT alone [14].

NYHA symptoms improved by 0.70 points within

6 months in the entire cohort with similar changes in each

subgroup. This represents a significant improvement on par

with or greater than prior studies involving CCM where

0 6 1 2 1 8 2 4 1 .5

2 .0

2 .5

3 .0

3 .5 E n t i r e C o h o r t

0 6 1 2 1 8 2 4 1 .5

2 .0

2 .5

3 .0

3 .5

4 .0 E F < 3 5 % E F ≥ 3 5 %

NHYA Classifica�on

MLWHFQ Score

** ** ** * *

* *

**

** **

Fig. 1 Effect of CCM on NHYA and MLWHFQ. NHYA classifica- tion and MLWHFQ both showed sustained improvements over the

course of the study. No difference in improvement was seen between

LVEF subgroups. * p \ 0.05 vs. corresponding baseline. Changes from baseline to specific time points are tested with allowance for

multiple comparisons using Sidaks method mixed effects models

Clin Res Cardiol (2017) 106:893–904 899

123

subgroup stratification occurred at LVEF = 25% [19]. In

the present study the markedly improved NYHA score of

0.7 was maintained throughout the 2 years of treatment.

Quality of life, assessed with the validated MLWHFQ,

improved vs. baseline in the entire cohort of patients by

11–15 points throughout the follow-up period of

6–24 months. This compares to FIX-HF-5 study which

showed an improvement of 9.7 points beyond that observed

in the OMT control group at 12 months [19]. In that study,

patients with LVEF C25% showed greater improvement

0 6 1 2 1 8 2 4 2 5

3 0

3 5

4 0 E n t i r e C o h o r t

0 6 1 2 1 8 2 4 2 0

3 0

4 0

5 0 E F < 3 5 % E F ≥ 3 5 %

%

%

Le� Ventricular Ejec�on Frac�on

0 2 0 0 4 0 0 6 0 0 8 0 0 0 .0 0

0 .2 5

0 .5 0

0 .7 5

1 .0 0

S u r v iv o r F u n c tio n9 5 % C I

Kaplan-Meier Survival Es�mate (mortality of any cause)

fr ac

� on

s ur

vi vi

ng

A B

*

*

* *

Fig. 2 Effect of CCM on LV ejection fraction and all cause mortality. a An improvement in LVEF was observed at 6 months compared to baseline and was sustained for 24 months follow-up.

Improvements in LVEF were similar between LVEF subgroups.

b Kaplan–Meier Survival curves for all-cause mortality over the

2 year follow-up. Data are presented as survival function together

with 95% confidence limits. *p \ 0.05 vs. corresponding baseline. Changes from baseline to specific time points are tested with

allowance for multiple comparisons using Sidaks method mixed

effects models

Table 3 Summary of reported Serious Adverse Events

Category All (N = 143) EF C35% (N = 29) EF \35% (N = 113)

Events Patients (%) Events Patients (%) Events Patients (%)

Arrhythmia 20 14 (10) 3 3 (10) 17 13 (12)

General cardiopulmonary 30 23 (16) 3 23 (10) 27 20 (17)

Worsening heart failure 55 37 (26) 11 6 (21) 44 33 (29)

Infection 16 14 (10) 3 3 (10) 13 11 (10)

Bleeding 5 4 (3) 1 1 (3) 4 3 (3)

ICD related 5 5 (3) 1 1 (3) 4 4 (4)

Optimizer IPG malfunction 5 5 (3) 2 2 (7) 3 3 (3)

Lead migration/revision 12 10 (7) 4 3 (10) 8 7 (6)

General medical 41 28 (20) 6 5 (17) 35 23 (20)

Death—unknown cause 4 4 (3) – – 4 4 (4)

SAE probably or possibly related to device 32 25 (17) 6 5 (17) 26 20 (18)

Total 193 91 (64) 34 17 (59) 159 74 (65)

Arrhythmia includes: supraventricular tachyarrhythmia (atrial fibrillation, atrial flutter, supraventricular tachycardia, ectopic atrial tachycardia),

VT, and VF. General cardiopulmonary includes: angina, dyspnea, pericardial effusion/tamponade, pulmonary related (except pneumonia),

syncope, venous thromboembolic disease, and valvular disease. Infection includes: ICD pocket infection, optimizer pocket infection, pneumonia,

and sepsis. General medical includes: renal failure, neurological dysfunction, peripheral arterial disease/event, stroke, and other non-cardiac

medical abnormalities. SAE’s probably or possibly related to the device are included in the total values

900 Clin Res Cardiol (2017) 106:893–904

123

than those with LVEF \25%. The present registry demonstrates that although both subgroups improved over

time, a trend toward greater improvement was seen in the

subgroup with lower LVEF (\35%). The reason for the differences is not clear but the small numbers of patients in

the higher LVEF subgroups, study design biases, or the

different comparators (randomized controls vs. within-

subject baseline values) may be explanatory factors.

Baseline LVEF among all study participants averaged

28.3 ± 6.4% and increased at each time point studied,

reaching 34.9 ± 8.8% at 24 months. Similar and signifi-

cant increases were observed in the subgroup with baseline

LVEF \35%. Many fewer subjects (n = 13) in the group with LVEF C35% had echocardiographic assessment at

2 years follow-up, yet a strong trend toward improvement

in LVEF was observed (LVEF = 40.2 ± 5.6%, p = 0.055

vs. baseline). Lack of statistical significance likely reflects

insufficient power for this parameter. The only prior ran-

domized controlled trial that reported changes in LVEF

over time had interpretable echocardiographic information

in only one half of subjects randomized and saw no change

in control or CCM groups over the course of the 6 month

crossover trial [7].

Previous studies with small numbers of subjects have

observed improvements in LVEF with relatively short-term

CCM. Stix et al. examined the effect of CCM in 23 subjects

with NHYA class III CHF followed for 8 weeks [18]. LVEF

increased from 22 ± 7% to 28 ± 8% (p = 0.0002) over this

time. In a separate study of 13 subjects with NYHA III heart

failure extending to 24 weeks, Pappone reported an

improvement in LVEF during CCM from 22.7 ± 7% to

37 ± 13% (p = 0.004) [20]. A single center long-term fol-

low-up by Kuschyk et al [12] showed sustained improve-

ments in LVEF, similarly to the present study. The current

study is the first prospective multicenter report of sustained

improvement in LVEF in patients with HFrEF and HFmEF

treated with CCM. Interestingly, among the 38 patients with

LVEF \35% at baseline and who had repeat echocardiog- raphy at 24 months, 11 improved their LVEF to[35%. Six of those 11 had improved above the 35% threshold by

6 months. This raises the question of whether CCM added to

GDMT could reduce the number of patients with an indi-

cation for ICD placement.

Although trends toward improvement were observed,

we found no statistically significant improvement in 6 MW

or pVO2 during follow-up, even though other prospective

clinical trials did observe improvement in 6 MW times

[7, 21] at shorter follow-up times. Several factors may

contribute to the lack of statistically significant improve-

ment in 6 MW, including the small number of subjects

from whom data were available (only 41 of 130 completing

the study had 6 MW testing, and 7 had pVO2 measure-

ments at 24 months), and lack of a control group.

Similar to 6 MW, few subjects completed exercise

testing throughout the study. Only 51 performed baseline

exercise testing and data from 7 were available at the

24 month follow-up visit. The low participation rate likely

relates to the fact that testing was done only for clinical

indications since data was obtained as part of a registry. As

a result it is not possible to draw any conclusions about the

effects of CCM on pVO2 in this study. However, this

question has been addressed in prior studies [4, 5, 7, 19]

which demonstrate an improvement in pVO2, especially in

subgroups with higher baseline LVEF [4, 6].

In our study, 14 subjects had already received a CRT

device (13 with CRT-D and one with CRT-P). For most of

these subjects enrollment occurred due to failure of the

CRT to improve symptoms. In each case the CRT device

was turned off when CCM was implanted. Although the

numbers who completed follow-up functional testing are

insufficient to determine efficacy of CCM in this subgroup

(less than � completed 24 month follow-up testing), a prior short-term study indicated that CCM can be effective

in patients who fail CRT [22]. Nagele used CCM to treat

16 patients with severe heart failure who failed to respond

to CRT [22]. After three months of follow-up, LVEF

improved from 28.1 ± 7% to 33 ± 17% (p \ 0.01) [22]. The risk profile for CCM in this study was comparable

to that described previously for patients with HFrEF and

was primarily related to issues with lead malfunction. In

patients with LVEF C35%, SAEs were observed in 59% of

patients after 2 years compared to 38% at 12 months.

Similarly in patients with LVEF \35%, SAE rates were seen in 65% of subjects at 24 months and in 40% of sub-

jects at 12 months. This is comparable to (and potentially

lower than) the largest randomized controlled trial of CCM

(FIX-HF-5) which reported over a 50 week period, SAEs

in 61 and 54% in the study groups [19]. Device related

SAEs occurred in 13% of Optimizer treated patients in

FIX-HF-5 during the 50 week follow-up, and in 17% of

patients in the current study over 2 years. Mortality in the

present study was similar to that observed in prior studies,

although the number of deaths (n = 18 in 2 years) is too

small for statistical comparison. For example in a retro-

spective study in 81 patients [12], Kaplan–Meier curves

over a 2 year period paralleled mortality in the present

study (Fig. 2). Many baseline patient characteristics were

similar between the two studies (age, gender, QRS dura-

tion, NHYA class, and heart failure etiology) although

LVEF was lower in the Kuschyk study (23.1 ± 7.9%)

compared to the present study (28.3 ± 6.4%). Based on all

the above, adverse events reported in current study reflect

an acceptable safety profile consistent with prior experi-

ence using the Optimizer device and commensurate with

other implantable devices in a patient population with

similar acuity.

Clin Res Cardiol (2017) 106:893–904 901

123

Malignant arrhythmia generation is of particular concern

in heart failure since this accounts for a large percentage of

deaths. Implantation of ICDs has improved survival in this

regard. The precise effect of CCM on ventricular arrhyth-

mias has not been directly studied. It is known that appli-

cation of current, sub-threshold for ventricular capture,

applied to the heart during the refractory period can reduce

or terminate ventricular tachycardia [23]. Whether CCM

evokes similar protection has not been systematically

studied although substudy analysis of one clinical trial

suggests that CCM has no effect on PVCs or duration of

VT [24]. In another report by Pappone et al. [20] of 13

patients followed for 8 weeks, CCM was associated with

fewer daily episodes of NSVT and a trend toward a

reduction in PVCs. In the largest randomized prospective

clinical trial of CCM in heart failure, no increase in ven-

tricular arrhythmias or discharge of ICDs was observed

[19]. For patients with an indication for CCM and with

symptomatic PVCs, it will be interesting to see if CCM

might avert the need for PVC ablation [25]. It would also

be of value to examine structural characteristics of the

failing heart that might identify super responders, as has

been done for CRT [26].

Study limitations

There are several potential limitations to this study. Sig-

nificant improvement from baseline over the time course of

this study was observed in several subjective metrics

related to quality of life and symptoms. We believe these

changes to be valid and not substantively influenced by the

prominent placebo effect common with device therapy

since prior studies involving CCM showed that the initial

placebo effect was not sustained beyond 3 months [7]

(FIX-HF-4). An objective outcome measure, ejection

fraction also improved in both the subgroup with LVEF

\35% and in the total cohort at each of the follow-up time points. This further argues against a prominent placebo

effect, and supports real and sustainable benefit of CCM

therapy.

In a registry, follow-up testing is performed based on

clinical need. This factor limited the number of patients

available with outcomes data related to LVEF and exercise

tolerance including 6 min walk test, and peak VO2. Nev-

ertheless, we were able to reliably measure NYHA and

MLWHFQ in a large number of subjects through the entire

2 year follow-up period.

Improvement in NYHA, MLWHFQ, and LVEF could

have resulted from the increased use of pharmacological

treatment of heart failure in these patients. However,

analysis of use of heart failure medications (Table 4)

reveals that very few subjects initiated or terminated heart

failure medicine use over the course of the study. A similar

and small number of patients started and stopped specific

medications with the majority ([80%) maintaining the same regimen used at enrollment. This analysis suggests

that additional medical therapy is not likely the explanation

for improvement in measured parameters over the time

course of this study. We cannot exclude a change in dosage

of heart failure medications as contributing to improved

Table 4 Variation in medication use by subjects over the course of the study

Patients Chronically Treated at Baseline (%) Patient numbers (% of reported data)

Base-6 mo Base—12 mo Base—18 mo Base—24 mo

ACE-I/ARB 112 (84)

Added 3 (3) 4 (4) 6 (7) 6 (8)

Stopped 6 (6) 7 (7) 7 (8) 7 (9)

No change or not used 97 (92) 93 (89) 80 (86) 62 (83)

# of patients with data 134 106 105 95 77

Beta-blocker 127 (95)

Added 1 (1) (2) 2 (2) 2 (3)

Stopped 3 (3) 3 (2) 4 (4) 4 (5)

No change or not used 102 (96) 99 (95) 87 (94) 69 (92)

Aldosterone antagonist 87 (65)

Added 7 (7) 9 (9) 7 (8) 6 (8)

Stopped 8 (7) 12 (11) 11 (12) 7 (9)

No change or not used 91 (86) 83 (80) 75 (80) 62 (83)

The number of patients with reported data at each timepoint is shown (# of patients with data). The number of patients where drug was added,

stopped, or unchanged/not used is shown in columns on the right. There was no difference in medication use from baseline to any of three time

points (6, 12, 18, or 24 months). This was true for all three classes of heart failure medications (ACE-I/ARB, beta-blockers, aldosterone

antagonists)

902 Clin Res Cardiol (2017) 106:893–904

123

outcomes, but, inclusion criteria required stable use of

guideline-directed heart failure therapy for one month prior

to enrollment, thus optimal doses were likely already

achieved at the beginning of the study.

Lack of a control group poses limitations on interpre-

tation of findings. Contemporary and comparable controls

provide rigor in study design to help avoid interference

from unrelated and/or unknown sources that could influ-

ence the outcome measures. Without a control group, the

analysis of this study compared changes over time to

baseline measurements. While this controls for inter-pa-

tient variability, it may create bias against the CCM

intervention since implicit in the analysis it is assumed that

baseline function remains constant over time in untreated

patients. In fact, outcome variables tend to get worse over

time on GDMT, thus the present study might have under-

estimated the benefit of CCM in this population.

Future studies should identify key biomarkers to predict

optimum responsiveness to CCM. Presence of Cheyne-

Stokes respiratory patterns [27], CRP, angiopoetin [28] and

other serum markers should be examined in relation to

CCM efficacy.

Summary

In summary, in patients with heart failure with reduced

LVEF and persistent symptoms despite GDMT, CCM

provides sustained improvement in both cardiac function

and QOL. The benefit is present not only in subjects with

baseline LVEF \35%, but is also in those with LVEF C35%. The extended benefit is not associated with an

adverse impact on safety beyond what is expected with

implantable devices. Consistent with previous clinical

studies, these data suggest that CCM may be beneficial in

select patients with heart failure, narrow QRS, and symp-

toms despite optimal medical management.

Compliance with ethical standards

Disclosures Rousso is employed by Impulse Dynamics, Burkhoff and Gutterman are consults for Impulse Dynamics. Support for this

study was provided by Impulse Dynamics.

Informed consent All subject provided informed consent. Partici- pating investigators and associated clinical research sites in Germany

include: C Restle, C Menz, J Stockinger—Bad Krozingen; Sperzel J,

Bruder O, Blank E, Waidelich L, Keinhorst J, Reuter V, Schmitz D,

Steffen M—Essen; Frommhold M, Meiland R, Wagner A—Bad

Berka; Muller S, Schmidt-Schweda S—Worbis; Schmidt T, Scholl C,

Obergfoll M—Heilbronn; Bucholz M, Gebhardt S, Spencker S,

Atmowihardjo I, Forster S, Szczesnlak S, Stoeckicht Y, Huseyin I—

Berlin; Reith S, Zink M, Heuer G—Aachen; Hohn A, Schwartzmann

L, Hornlein C, Schertel-Grunler B, Brachmann J, Denninger P—

Coburg; Siems M,Latzko C, Müller D, Nickling E—Bad Bevensen;

Maroto Y Jarvinen S, Block M, von Bodman G—Munchen; Beauport

J, Hofmann W, Antz M—Oldenburg; Zander-Wiegmann M,

Bittlinsky A, Prull M—Herne; Andreas K, Przibille O—Frankfurt;

Frohlich-Grimm F, Danschel W—Chemnitz; Aydin A, Wilke I,

Schnapp A—Reinbek; Haacke K, Gunther M—Dresden; Mletzko

R—Hamburg; Karosiene Z, Bernard L, Willms-Weirich N—Luden-

scheid; Brilla K, Minden H—Hennigsdorf; Over M, Hugl B, Fin-

deisen Z, Haufe A, Wessling P—Neuwied.

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://crea

tivecommons.org/licenses/by/4.0/), which permits unrestricted use,

distribution, and reproduction in any medium, provided you give

appropriate credit to the original author(s) and the source, provide a

link to the Creative Commons license, and indicate if changes were

made.

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