ABSTRACT

Aims: We assessed long-term effects of cardiac contractility modulation delivered by the Optimizer Smart system on quality of life, left ventricular ejection fraction (LVEF), mortality and heart failure and cardiovascular hospitalizations.

Methods and Results: CCM-REG is a prospective registry study including 503 patients from 51 European centres. Effects were evaluated in three terciles of LVEF (≤25%, 26–34% and ≥35%) and in patients with atrial fibrillation (AF) and normal sinus rhythm (NSR). Hospitalization rates were compared using a chi-square test. Changes in functional parameters of New York Heart Association (NYHA) class, Minnesota Living with Heart Failure Questionnaire (MLWHFQ) and LVEF were assessed with Wilcoxon signed-rank test, and event-free survival by Kaplan–Meier analysis. For the entire cohort and each subgroup, NYHA class and MLWHFQ improved at 6, 12, 18 and 24 months (P <0.0001). At 24 months, NYHA class, MLWHFQ and LVEF showed an average improvement of 0.6±0.7, 10±21 and 5.6±8.4%, respectively (all P <0.001). LVEF improved in the entire cohort and in the LVEF ≤25% subgroup with AF and NSR. In the overall cohort, heart failure hospitalizations decreased from 0.74 [95% confidence interval (CI) 0.66–0.82] prior to enrolment to 0.25 (95% CI 0.21–0.28) events per patient-year during 2-year follow-up (P <0.0001). Cardiovascular hospitalizations decreased from 1.04 (95% CI 0.95–1.13) events per patient-year prior to enrolment to 0.39 (95% CI 0.35–0.44) events per patient-year during 2-year follow-up (P <0.0001). Similar reductions of hospitalization rates were observed in the LVEF, AF and NSR subgroups. Estimated survival was significantly better than predicted by MAGGIC at 1 and 3 years in the entire cohort and in the LVEF 26–34% and ≥35% subgroups.

Conclusions: Cardiac contractility modulation therapy improved functional status, quality of life, LVEF and, compared to patients’ prior history, reduced heart failure hospitalization rates. Survival at 1 and 3 years was significantly better than predicted by the MAGGIC risk score.

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ABSTRACT

Aims: Prior studies of cardiac contractility modulation (CCM) employed a 3-lead Optimizer system. A new 2-lead system eliminated the need for an atrial lead. This study tested the safety and effectiveness of this 2-lead system compared with the 3-lead system.

Methods: Patients with New York Heart Association III/IVa symptoms despite medical therapy, left ventricular ejection fraction 25% to 45%, and not eligible for cardiac resynchronization therapy could participate. All subjects received an Optimizer 2-lead implant. The primary end point was the estimated difference in the change of peak VO2 from baseline to 24 weeks between FIX-HF-5C2 (2-lead system) subjects relative to control subjects from the prior FIX-HF-5C (3-lead system) study. Changes in New York Heart Association were a secondary end point. The primary safety end point was a comparison of device-related adverse events between FIX-HF-5C2 and FIX-HF-5C subjects.

Results: Sixty subjects, 88% male, 66±9 years old with left ventricular ejection fraction 34±6% were included. Baseline characteristics were similar between FIX-HF-5C and FIX-HF-5C2 subjects except that 15% of FIX-HF-5C2 subjects had permanent atrial fibrillation versus 0% in FIX-HF-5C. CCM delivery did not differ significantly between 2- and 3-lead systems (19 892±3472 versus 19 583±4998 CCM signals/day, CI of difference [−1228 to 1847]). The change of peak VO2 from baseline to 24 weeks was 1.72 (95% Bayesian credible interval, 1.02–2.42) mL/kg per minute greater in the 2-lead device group versus controls. 83.1% of 2-lead subjects compared with 42.7% of controls experienced ≥1 class New York Heart Association improvement (P<0.001). There were decreased Optimizer-related adverse events with the 2-lead system compared with the 3-lead system (0% versus 8%; P=0.03).

Conclusions: The 2-lead system effectively delivers comparable amount of CCM signals (including in subjects with atrial fibrillation) as the 3-lead system, is equally safe and improves peak VO2 and New York Heart Association. Device-related adverse effects are less with the 2-lead system.

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ABSTRACT

Aims: Cardiac contractility modulation (CCM) improves symptoms and exercise tolerance and reduces heart failure (HF) hospitalizations over 6-month follow-up in patients with New York Heart Association (NYHA) class III or IV symptoms, QRS <130 ms and 25%≤left ventricular ejection fraction (LVEF)≤45% (FIX-HF-5C study). The current prospective registry study (CCM-REG) aimed to assess the longer-term impact of CCM on hospitalizations and mortality in real-world experience in this same population.

Methods and Results: A total of 140 patients with 25%≤LVEF≤45% receiving CCM therapy (CCM-REG25-45) for clinical indications were included. Cardiovascular and HF hospitalizations, Minnesota Living with Heart Failure Questionnaire (MLHFQ) and NYHA class were assessed over 2 years. Mortality was tracked through 3 years and compared with predictions by the Seattle Heart Failure Model (SHFM). A separate analysis was performed on patients with 35%≤LVEF≤45% (CCM-REG35-45) and 25%≤LVEF<35% (CCM-REG25-34). Hospitalizations decreased by 75% (from 1.2/patient-year the year before, to 0.35/patient-year during the 2 years following CCM, P <0.0001) in CCM-REG25-45 and by a similar amount in CCM-REG35-45 (P <0.0001) and CCM-REG25-34. MLHFQ and NYHA class improved in all three cohorts, with progressive improvements over time (P <0.002). Three-year survival in CCM-REG25-45 (82.8%) and CCM-REG24-34 (79.4%) were similar to those predicted by SHFM (76.7%, P =0.16; 78.0%, P =0.81, respectively) and was better than predicted in CCM-REG35-45 (88.0% vs. 74.7%, P =0.046).

Conclusion: In real-world experience, CCM produces results similar to those of previous studies in subjects with 25%≤LVEF≤45% and QRS <130 ms; cardiovascular and HF hospitalizations are reduced and MLHFQ and NYHA class are improved. Overall mortality was comparable to that predicted by the SHFM but was lower than predicted in patients with 35%≤LVEF≤45%

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ABSTRACT

Objectives: The authors sought to confirm a subgroup analysis of the prior FIX-HF-5 (Evaluate Safety and Efficacy of the OPTIMIZER System in Subjects With Moderate-to-Severe Heart Failure) study showing that cardiac contractility modulation (CCM) improved exercise tolerance (ET) and quality of life in patients with ejection fractions between 25% and 45%.

Background: CCM therapy for New York Heart Association (NYHA) functional class III and IV heart failure (HF) patients consists of nonexcitatory electrical signals delivered to the heart during the absolute refractory period.

Methods: A total of 160 patients with NYHA functional class III or IV symptoms, QRS duration <130 ms, and ejection fraction $25% and #45% were randomized to continued medical therapy (control, n ¼ 86) or CCM (treatment, n ¼ 74, unblinded) for 24 weeks. Peak VO2 (primary endpoint), Minnesota Living With Heart Failure Questionnaire, NYHA functional class, and 6-min hall walk were measured at baseline and at 12 and 24 weeks. Bayesian repeated measures linear modeling was used for the primary endpoint analysis with 30% borrowing from the FIX-HF-5 subgroup. Safety was assessed by the percentage of patients free of device-related adverse events with a pre-specified lower bound of 70%.

Results: The difference in peak VO2 between groups was 0.84 (95% Bayesian credible interval: 0.123 to 1.552) ml O2/kg/min, satisfying the primary endpoint. Minnesota Living With Heart Failure questionnaire (p < 0.001), NYHA functional class (p < 0.001), and 6-min hall walk (p ¼ 0.02) were all better in the treatment versus control group. There were 7 device-related events, yielding a lower bound of 80% of patients free of events, satisfying the primary safety endpoint. The composite of cardiovascular death and HF hospitalizations was reduced from 10.8% to 2.9% (p ¼ 0.048).

Conclusions: CCM is safe, improves exercise tolerance and quality of life in the specified group of HF patients, and leads to fewer HF hospitalizations. (Evaluate Safety and Efficacy of the OPTIMIZER System in Subjects with Moderate-to-Severe Heart Failure; NCT01381172)

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ABSTRACT

Background: Cardiac contractility modulation (CCM) is an electrical-device therapy for patients with heart failure with reduced ejection fraction (HFrEF). Patients with left ventricular ejection fraction (LVEF) ≤35% also have indication for an implantable cardioverter-defibrillator (ICD), and in some cases subcutaneous ICD (S-ICD) is selected.

Hypothesis: CCM and S-ICD can be combined to work efficaciously and safely. Methods: We report on 20 patients with HFrEF and LVEF ≤35% who received CCM and SICD. To exclude device interference, patients received intraoperative crosstalk testing, S-ICD testing, and bicycle exercise testing while CCM was activated. Clinical and QOL measures before CCM activation and at last follow-up were analyzed. S-ICD performance was evaluated while both CCM and S-ICD were active.

Results: Mean follow-up was 34.3 months. NYHA class improved from 2.9  0.4 to 2.1  0.7 (P < 0.0001), Minnesota Living With Heart Failure Questionnaire score improved from 50.2  23.7 to 29.6  22.8 points (P < 0.0001), and LVEF improved from 24.4%  8.1% to 30.9%  9.6% (P = 0.002). Mean follow-up time with both devices active was 22 months. Three patients experienced a total of 6 episodes of sustained ventricular tachycardia, all successfully treated with first ICD shock. One case received an inappropriate shock unrelated to the concomitant CCM. One patient received an LVAD, so CCM and S-ICD were discontinued.

Conclusions: CCM and S-ICD can be successfully combined in patients with HFrEF. S-ICD and CCM remain efficacious when used together, with no interference affecting their function.

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ABSTRACT

Aims: To analyze long-term efficacy and survival in patients with chronic heart failure treated with cardiac contractility modulation.

Methods: 81 patients implanted with a CCM device between 2004 and 2012 were included in this retrospective analysis. Changes in NYHA class, ejection fraction (EF), Minnesota Living with Heart Failure Questionnaire, NTproBNP and peak VO2 were analyzed during a mean follow up of 34.2 ± 28 months (6–123 months). Observed mortality rate was compared with that predicted by the MAGGIC Score.

Results: Patients were 61 ± 12 years old with EF 23 ± 7%. Heart failure was due to ischemic (n = 48, 59.3%) or idiopathic dilated (n = 33, 40.7%) cardiomyopathy. EF increased from 23.1 ± 7.9 to 29.4 ± 8.6% (p b 0.05), mean NT-proBNP decreased from 4395 ± 3818 to 2762 ± 3490 ng/l (p b 0.05) and mean peak VO2 increased from 13.9 ± 3.3 to 14.6 ± 3.5 ml/kg/min (p = 0.1). The overall clinical responder rate (at least 1 class improvement of NYHA within 6 months or last follow-up) was 74.1%. 21 (25.9%) patients died during follow up, 11 (52.4%) due to cardiac conditions and 10 (47.6%) due to non-cardiac conditions. Mortality rates at 1 and 3 years were 5.2% and 29.5% compared to mortality rates estimated from the MAGGIC risk score of 18.4% (p b 0.001) and 40% (p = ns), respectively. Log-Rank analysis of all events through 3 years of follow-up, however, was significantly less than predicted (p = 0.022).

Conclusions: CCM therapy improved quality of life, exercise capacity, NYHA class, EF and NT-proBNP levels during long-term follow up. Mortality rates appeared to be lower than estimated from the MAGGIC score.

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ABSTRACT

Objectives: The objective of this study was to test whether cardiac contractility modulation (CCM) electric signals induce reverse molecular remodeling in myocardium of patients with heart failure.

Background Heart failure is associated with up-regulation of myocardial fetal and stretch response genes and down regulation of Ca2 cycling genes. Treatment with CCM signals has been associated with improved symptoms and exercise tolerance in heart failure patients. We tested the impact of CCM signals on myocardial gene expression in 11 patients.

Methods: Endomyocardial biopsies were obtained at baseline and 3 and 6 months thereafter. The CCM signals were delivered in random order of ON for 3 months and OFF for 3 months. Messenger ribonucleic acid expression was analyzed in the core lab by investigators blinded to treatment sequence. Expression of A- and B-type natriuretic peptides and -myosin heavy chain (MHC), the sarcoplasmic reticulum genes SERCA-2a, phospholamban and ryanodine receptors, and the stretch response genes p38 mitogen activated protein kinase and p21 Ras were measured using reverse transcription-polymerase chain reaction and bands quantified in densitometric units.

Results: The 3-month therapy OFF phase was associated with increased expression of A- and B-type natriuretic peptides, p38 mitogen activated protein kinase, and p21 Ras and decreased expression of -MHC, SERCA-2a, phospholamban, and ryanodine receptors. In contrast, the 3-month ON therapy phase resulted in decreased expression of A- and B-type natriuretic peptides, p38 mitogen activated protein kinase and p21 Ras and increased expression of -MHC, SERCA-2a, phospholamban, and ryanodine receptors.

Conclusions: The CCM signal treatment reverses the cardiac maladaptive fetal gene program and normalizes expression of key sarcoplasmic reticulum Ca2 cycling and stretch response genes. These changes may contribute to the clinical effects of CCM.

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ABSTRACT

Aims: We performed a randomized, double blind, crossover study of cardiac contractility modulation (CCM) signals in heart failure patients.

Methods and Results: One hundred and sixty-four subjects with ejection fraction (EF) , 35% and NYHA Class II (24%) or III (76%) symptoms received a CCM pulse generator. Patients were randomly assigned to Group 1 (n ¼ 80, CCM treatment 3 months, sham treatment second 3 months) or Group 2 (n ¼ 84, sham treatment 3 months, CCM treatment second 3 months). The co-primary endpoints were changes in peak oxygen consumption (VO2,peak) and Minnesota Living with Heart Failure Questionnaire (MLWHFQ). Baseline EF (29.3+6.7% vs. 29.8+7.8%), VO2, peak (14.1+3.0 vs. 13.6+2.7 mL/kg/min), and MLWHFQ (38.9+27.4 vs. 36.5+27.1) were similar between the groups. VO2,peak increased similarly in both groups during the first 3 months (0.40+3.0 vs. 0.37+3.3 mL/kg/min, placebo effect). During the next 3 months, VO2,peak decreased in the group switched to sham (20.86+3.06 mL/kg/min) and increased in patients switched to active treatment (0.16+2.50 mL/kg/min). MLWHFQ trended better with treatment (212.06+15.33 vs. 29.70+16.71) during the first 3 months, increased during the second 3 months in the group switched to sham (þ4.70+16.57), and decreased further in patients switched to active treatment (20.70+15.13). A comparison of values at the end of active treatment periods vs. end of sham treatment periods indicates statistically significantly improved VO2,peak and MLWHFQ (P ¼ 0.03 for each parameter).

Conclusion: In patients with heart failure and left ventricular dysfunction, CCM signals appear safe; exercise tolerance and quality of life (MLWHFQ) were significantly better while patients were receiving active treatment with CCM for a 3-month period.

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