A randomized controlled trial to evaluate the safety and efficacy of cardiac contractility modulation in patients with systolic heart failure: Rationale, design, and baseline patient characteristics

doi:10.1016/j.ahj.2008.05.019

American Heart Journal

Volume 156, Issue 4, October 2008, Pages 641-648.e1

https://doi.org/10.1016/j.ahj.2008.05.019 Get rights and content

Cardiac contractility modulation (CCM) signals are nonexcitatory electrical signals delivered during the cardiac absolute refractory period that enhance the strength of cardiac muscular contraction. Prior research in experimental and human heart failure has shown that CCM signals normalize phosphorylation of key proteins and expression of genes coding for proteins involved in regulation of calcium cycling and contraction. The results of prior clinical studies of CCM have supported its safety and efficacy. A large-scale clinical study, the FIX-HF-5 study, is currently underway to test the safety and efficacy of this treatment. In this article, we provide an overview of the system used to deliver CCM signals, the implant procedure, and the details and rationale of the FIX-HF-5 study design. Baseline characteristics for patients randomized in this trial are also presented.

Section snippets

The OPTIMIZER System and implant procedure

The Optimizer III System (Figure 1) consists of an implantable pulse generator (IPG) with a rechargeable battery that delivers CCM signals (described below), an atrial and 2 ventricular pacing leads, an IPG programmer (similar to a standard pacer/ICD programmer), a hemodynamic monitoring system that calculates the maximal rate of left ventricular pressure generation (LV dP/dt_max) during the system implant, and an IPG charger used by patients at their home. The procedures for device implantation

FIX-HF-5 study overview and objectives

The FIX-HF-5 study is a prospective, randomized, parallel-controlled, trial of optimal medical therapy (OMT) alone (control group) versus OMT plus CCM (treatment group) (Figure 4). The objectives of the FIX-HF-5 study are to evaluate the safety (event-free survival) and efficacy (exercise tolerance and quality of life) of the OPTIMIZER System in subjects with moderate to severe heart failure despite OMT (including drug therapies and an ICD), ejection fraction ≤35%, and no indication for CRT.

Study population

The trial design required randomization of 428 subjects to achieve its prespecified statistical power of 80% to test hypotheses for the safety and efficacy of CCM therapy (detailed below). Subjects were randomized at 50 sites in the United States. Recruitment began in March 2005 and was completed in June 2007.

The inclusion and exclusion criteria are summarized in Table I. In brief, the study recruited patients with EF ≤35% with NYHA class III or IV symptoms despite medical treatment with

Approach to reducing placebo effect and bias

Although a double-blind trial design using an implanted control as used in some implantable device trials (including the prior studies of the Optimizer11, 12) was initially considered, a number of factors made this approach impractical for the present study. To obtain sufficient assurance of device safety, it was deemed necessary to acquire parallel-group controlled safety data over a 1-year period of follow-up. This extended period of follow-up created several challenges. First, the process of

Efforts to ensure cardiopulmonary stress test quality

Several measures were taken to optimize the quality CPX tests at all sites. These measures included the following: (1) on-site training on standardized procedures for conducting CPX tests and electronic transfer of data to the core laboratory; (2) site revalidation every 6 months; and (3) rapid feedback on test quality from the core laboratory (on the day they are performed).

Once obtained, metabolic data are sent to the blinded CPX core laboratory for analysis. Ventilatory anaerobic threshold,

Events Adjudication Committee and Data Safety Monitoring Board

An EAC was established to review records of hospitalizations, deaths, and serious adverse events. This committee is composed of 3 independent cardiologists experienced in the adjudication process (Appendix B available online). The committee ensured consistent designation of events constituting a hospitalization. Specifically, protocol-specified hospitalizations include an admission that results in a calendar date change or is related to an adverse event that causes a prolongation of the index

Statistical considerations and analysis plan

The trial's primary measure of effectiveness is the change from baseline in the VAT on CPX testing. The primary efficacy analysis is a superiority analysis comparing “responder” rates between the treatment and control groups at the 24-week follow-up visit. An individual subject will be considered a responder if VAT increases by ≥20% at 24 weeks compared to their respective baseline value. Responder rates between randomization arms is by a one-sided Fisher exact test with an α of .025. Secondary

Baseline characteristics of enrolled study subjects

Between March 2005 and June 2007, 773 potential study subjects provided informed consent to participate in this study. From among these patients, 428 subjects passed baseline screening and were randomized to either the control group (n = 213) or the treatment group (n = 215). The baseline characteristics of these patients are summarized in Table III. Overall, these characteristics are balanced between groups and are consistent with the study inclusion and exclusion criteria. Medication and ICD

Discussion

Despite major advances in drugs and devices to treat heart failure, many patients have persistent symptoms and exercise intolerance. A minority of patients are eligible for significant CRT, which is arguably, the most important advance in device-based treatment for heart failure over the past decade, and significant CRT nonresponder rates remain a limitation of this therapy. Preliminary studies with CCM suggest that this may be a viable treatment option for many of these patients. The FIX-HF-5

References (19)

LawoT. et al.
Electrical signals applied during the absolute refractory period: an investigational treatment for advanced heart failure in patients with normal QRS duration
J Am Coll Cardiol
(2005)
ImaiM. et al.
Therapy with cardiac contractility modulation electrical signals improves left ventricular function and remodeling in dogs with chronic heart failure
J Am Coll Cardiol
(2007)
ButterC. et al.
Cardiac contractility modulation electrical signals improve myocardial gene expression in patients with heart failure
J Am Coll Cardiol
(2008)
ButterC. et al.
Enhanced inotropic state of the failing left ventricle by cardiac contractility modulation electrical signals is not associated with increased myocardial oxygen consumption
J Card Fail
(2007)
NeelagaruS.B. et al.
Nonexcitatory, cardiac contractility modulation electrical impulses: feasibility study for advanced heart failure in patients with normal QRS duration
Heart Rhythm
(2006)
BristowM.R. et al.
Heart failure management using implantable devices for ventricular resynchronization: Comparison of Medical Therapy, Pacing, and Defibrillation in Chronic Heart Failure (COMPANION) trial. COMPANION Steering Committee and COMPANION Clinical Investigators [In Process Citation]
J Card Fail
(2000)
KuboS.H. et al.
Development and validation of a patient questionnaire to determine New York Heart Association classification
J Card Fail
(2004)
SueD.Y. et al.
Metabolic acidosis during exercise in patients with chronic obstructive pulmonary disease. Use of the V-slope method for anaerobic threshold determination
Chest
(1988)
BlackwelderW.C.
“Proving the null hypothesis” in clinical trials
Control Clin Trials
(1982)

There are more references available in the full text version of this article.

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The role of entirely subcutaneous ICD™ systems in patients with dilated cardiomyopathy
2020, Journal of Cardiology
The subcutaneous implantable-cardioverter defibrillator (S-ICD™, Boston Scientific, Natick, MA, USA) is an important advance in device therapy for the prevention of sudden cardiac death (SCD). Although current guidelines recommend S-ICD™ use, long-term data are still limited, especially in subgroups. Dilated cardiomyopathy (DCM) is a common reason for the implantation of an ICD. However, there are no sufficient data on the performance of the S-ICD™ in this patient cohort.
All S-ICD™ patients with DCM as the main indication for ICD implantation (n = 47 patients) in our large-scaled single-center S-ICD™ registry (n = 294 patients) were included in this study. Baseline characteristics, appropriate and inappropriate shocks, and complications were documented in a mean follow-up of 22.9 ± 18.5 months.
A total of 47 patients with DCM as the underlying structural heart disease received an S-ICD™ in our institution. Mean left ventricular ejection fraction was 37 ± 12% and a 28% had a history of ventricular tachyarrhythmia. During follow-up eight ventricular tachyarrhythmias were adequately terminated in three patients. In four patients, oversensing resulting in an inappropriate shock was observed, which could be managed by changing the sensing vector. There was no need for a change to a cardiac resynchronization (CRT) system while one system was changed to a VVI-ICD due to S-ICD™ wound infection.
The S-ICD™ seems to be a valuable option for the prevention of SCD in patients with DCM and no indication for CRT. As clinically relevant ventricular arrhythmias consisted of ventricular fibrillation or fast ventricular tachycardia in all patients in our cohort, no change to transvenous ICDs for anti-tachycardia pacing delivery was necessary.
A Randomized Controlled Trial to Evaluate the Safety and Efficacy of Cardiac Contractility Modulation
2018, JACC: Heart Failure
This study 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%.
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.
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 = 86) or CCM (treatment, n = 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%.
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 = 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 = 0.048).
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)
Cost minimization analysis of Herceptin subcutaneous versus Herceptin intravenous treatment for patients with HER2+ Breast cancer in Greece
2017, Journal of Cancer Policy
To conduct an economic evaluation comparing Herceptin subcutaneous formulation (Herceptin-SC) with Herceptin intravenous formulation (Herceptin-IV), in the treatment of patients with human epidermal growth factor receptor 2-positive (HER2 + ) early and metastatic breast cancer (EBC-MBC), in the Greek health care setting.
A cost-minimization model was developed to compare the total cost of care, from the hospital perspective, for new and existing patients, over 18 cycles therapy course. Total cost of therapy reflects drug acquisition cost, consumables dispensed, hospital overheads, physician and other staff time. Costing data were obtained from official Government sources (in 2014) and resource utilization data from a local validation of an international time and motion study.
The mean total cost of therapy per patient on Herceptin-IV was estimated at €23,118 compared to €21,870 per patient receiving Herceptin-SC. Drug acquisition costs accounted for €22,311 and €21,738 of total therapy costs for Herceptin-IV and Herceptin-SC, respectively. Following drug acquisition costs, the administration cost was €267 and €64 for Herceptin-IV and Herceptin-SC, respectively. Moreover, the central venous access device cost was €290 and €0 of the total costs of Herceptin IV and Herceptin SC, respectively.
Whilst drug costs are even, from an economic perspective treatment with Herceptin-SC is associated with a lower economic burden in comparison to Herceptin-IV in the management of patients with HER2+ EBC and MBC. Hence, the substitution of Herceptin-IV with Herceptin-SC can produce valuable savings for the Greek health care system, especially in the current economic environment where resources are scarce.
Long-term survival with Cardiac Contractility Modulation in patients with NYHA II or III symptoms and normal QRS duration
2016, International Journal of Cardiology
Citation Excerpt :
In the FIX-CHF-5 study, the safety and efficacy of CCM over six months was examined in 428 randomized patients with moderate to severe heart failure (NYHA functional class III/IV), narrow QRS, on optimal medical treatment (OMT). In a secondary subgroup analysis [13], patients with less severe symptoms and higher EFs (≥ 25%) benefitted more from CCM than the full cohort of patients with lower EF (< 35%). Generally, the patient population of the FIX-HF-5 study had more advanced heart failure than in the present cohort, which explains the difference in overall number of events compared with the FIX-HF-5 study.
Cardiac Contractility Modulation (CCM) is a treatment for heart failure based on electrical signals applied during the absolute refractory period. CCM improves myocardial molecular and biochemical characteristics of heart failure and improves exercise tolerance and quality of life. However, the long term impact on survival has not been described.
Survival was determined retrospectively from a cohort of 68 consecutive heart failure cases with NYHA II or III symptoms and QRS duration ≤ 130 ms, implanted with a CCM device between May 2002 and July 2013 in either Bochum or Ludenscheid, Germany. Results were compared with predicted survival (Seattle Heart Failure Model; SHFM) pre-implant for each patient. Mean follow-up was 4.5 years (range 0.25–10.3 years). Baseline characteristics were as follows: mean age 61 years, 88% male, 68% with ischemic heart disease, 78% with an ICD, mean NYHA class 2.9 ± 0.3, LVEF 26% ± 6% (range 15–40%) and mean QRS duration 106 ± 11 ms. Mortality rates (Kaplan–Meier analysis) at 1-, 2- and 5-years were lower with CCM than predicted by SHFM for the cohort (0% with CCM vs. 6.1% per SHFM, 3.5% vs. 11.8%, and 14.2% vs. 27.7%, respectively, p = 0.007).
Long-term mortality rates in heart failure patients with NYHA (II–III) and QRS ≤ 130 ms are lower when treated by CCM than predicted for the cohort. These findings warrant substantiation in a prospective study.
A randomized controlled trial to evaluate the safety and efficacy of cardiac contractility modulation in patients with moderately reduced left ventricular ejection fraction and a narrow QRS duration: Study rationale and design
2015, Journal of Cardiac Failure
Citation Excerpt :
Patients in the CCM treatment group will continue to be followed at 3-month intervals for device-related serious adverse events, device interrogations, and vital status. While a double-blind trial design employing an implanted control as used in some implantable device trials (including the prior feasibility study of the Optimizer8) was initially considered, this was deemed unfeasible as detailed in the description of the original FIX-HF-5 study.9 In brief, the need for weekly charging of the device with a wand the patient positions over the device would have likely led to significant (if not total) unblinding.
Cardiac contractility modulation (CCM) signals are nonexcitatory electrical signals delivered during the cardiac absolute refractory period that enhance the strength of cardiac muscular contraction. The FIX-HF-5 study was a prospective randomized study comparing CCM plus optimal medical therapy (OMT) to OMT alone that included 428 New York Heart Association (NYHA) functional class III or IV heart failure patients with ejection fraction (EF) ≤45% according to core laboratory assessment. The study met its primary safety end point, but did not reach its primary efficacy end point: a responders analysis of changes in ventilatory anaerobic threshold (VAT). However, in a prespecified subgroup analysis, significant improvements in primary and secondary end points, including the responder VAT end point, were observed in patients with EFs ranging from 25% to 45%, who constituted about one-half of the study subjects. We therefore designed a new study to prospectively confirm the efficacy of CCM in this population. A hierarchic bayesian statistical analysis plan was developed to take advantage of the data already available from the first study. In addition, based on technical difficulties encountered in reliably quantifying VAT and the relatively large amount of nonquantifiable studies, the primary efficacy end point was changed to peak VO₂, with significant measures incorporated to minimize the influence of placebo effect. In this paper, we provide the details and rationale of the FIX-HF-5C study design to study CCM plus OMT compared with OMT alone in subjects with normal QRS duration, NYHA functional class III or IV, and EF 25%–45%. This study is registered on www.clinicaltrials.gov with identifier no. NCT01381172.
Effects of respiratory exchange ratio on the prognostic value of peak oxygen consumption and ventilatory efficiency in patients with systolic heart failure
2013, JACC: Heart Failure
Citation Excerpt :
These cutoffs were pre-determined on the basis of the existing literature. That is, several large-scale, multicenter studies involving patients with HF consider an acceptable “maximal” cutoff to be a RER ≥1.05 (20–22). The third subgroup was derived from recommendations suggesting that a peak RER ≥1.00 is likely acceptable (10,11).
The purpose of this analysis was to evaluate the prognostic characteristics of peak oxygen consumption (Vo₂) and the minute ventilation/carbon dioxide (VE/Vco₂) slope of different peak respiratory exchange ratios (RERs) obtained from cardiopulmonary exercise testing in patients with heart failure (HF).
For patients with HF, peak Vo₂ and the VE/Vco₂ slope are used for assessing prognosis. Peak Vo₂ is assessed in association with peak RER ≥1.10, indicating maximal effort and prognostic sensitivity. Conversely, the VE/Vco₂ slope provides effort-independent prognostic discrimination.
Patients with HF scheduled to undergo cardiopulmonary exercise testing were enrolled. Patients were subclassified by peak RER (RER <1.00, RER 1.00 to 1.04, RER 1.05 to 1.09, RER ≥1.10) and followed for up to 3 years for major cardiac-related events (death, left ventricular assist device implantation, or cardiac transplantation).
Included were 1,728 patients with HF (75% males; 40% ischemic etiology; age: 55 ± 14 years; left ventricular ejection fraction: 28 ± 10%). Two hundred seventy major events occurred, with no proportional differences across the RER subgroups. Multivariate Cox regression analysis indicated that the VE/Vco₂ slope and peak Vo₂ remained prognostic within each subgroup; the VE/Vco₂ slope remained the strongest predictor. Receiver-operating characteristic analysis demonstrated equitable prognostic cutoffs for the VE/Vco₂ slope (range: 34.9 to 35.7; area under the curve [AUC] range: 0.69 to 0.75) and peak Vo₂ (range: 13.8 to 14.0 ml·kg^–1·min^–1; AUC range: 0.68 to 0.75).
Peak Vo₂ provided a sensitive assessment of prognosis in patients with HF in all RER subgroups. The VE/Vco₂ slope provided greater prognostic discrimination in all RER subgroups. Clinical consideration may be warranted for patients with low RER, low peak Vo₂, and an elevated VE/Vco₂ slope.

View all citing articles on Scopus

: Registered randomized clinical trial no. NCT00112125.

: The FIX-HF-5 study is supported by IMPULSE Dynamics. D. Burkhoff is an employee and shareholder in IMPULSE Dynamics.

¹: FIX-HF-5 Investigators and Coordinators listed in Appendix A available online.

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Trial DesignA randomized controlled trial to evaluate the safety and efficacy of cardiac contractility modulation in patients with systolic heart failure: Rationale, design, and baseline patient characteristics

Section snippets

The OPTIMIZER System and implant procedure

FIX-HF-5 study overview and objectives

Study population

Approach to reducing placebo effect and bias

Efforts to ensure cardiopulmonary stress test quality

Events Adjudication Committee and Data Safety Monitoring Board

Statistical considerations and analysis plan

Baseline characteristics of enrolled study subjects

Discussion

J Am Coll Cardiol

J Am Coll Cardiol

J Am Coll Cardiol

J Card Fail

Heart Rhythm

J Card Fail

J Card Fail

Chest

Control Clin Trials

Trial Design
A randomized controlled trial to evaluate the safety and efficacy of cardiac contractility modulation in patients with systolic heart failure: Rationale, design, and baseline patient characteristics