An observational study in Symptomatic Congestive Heart Failure, sponsored by Quovadis Associazione. Recruiting at 13 sites in Italy. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2025-07-29.
Sponsored by Quovadis Associazione · Observational
The goal of this observational cohort study, which is both retrospective and prospective, is to evaluate the long-term clinical and instrumental response to Cardiac Contractility Modulation (CCM) treatment in adult subjects suffering from symptomatic heart failure (HF) due to systolic left ventricular dysfunction, despite adequate medical therapy. Based on the response to stress echocardiography with preimplantation low-dose Dobutamine, the main questions it aims to answer are:
-Introductory summary When no other therapeutic options are available, CCM can be a helpful complement to treating heart failure, improving quality of life, and prolonging survival. Still, the high cost and availability of implants in qualified centers limit their use.
Then, searching for indicators that maximize the benefit/risk ratio is appropriate. According to the study's proponents, the contractile reserve of the left ventricle assessed by stress echo to low-dose Dobutamine may be among the most promising indicators for this purpose.
Introduction Heart failure (H.F.) has a very poor prognosis in terms of mortality, quality of life, and functional capacity. It is one of the most important cardiovascular diseases in terms of global prevalence and healthcare costs. Despite appropriate medical care, many patients experience frequent hospitalizations and limitations in daily activities (1).
The prevalence of heart failure ranges between 1% and 3% in the general adult population in industrialized countries. It is expected to increase substantially due to the availability of better diagnostic tools and medical treatments that prolong life after diagnosis of HF (2).
The latest international guidelines on the management of reduced ejection fraction H.F. recommend a timely approach with the simultaneous introduction of the four main categories of drugs (ACE inhibitors or ARNIs, beta-blockers, mineralocorticoid receptor antagonists (MRAs), and SGLT2 inhibitors). If drug therapy alone is not sufficient or not well tolerated by the subject, or if there is a disorder in the conduction of the electrical impulse (in particular, a left bundle branch block), it is possible to associate it with electrical therapy, which consists of the implantation of biventricular cardiac devices (pacemakers or defibrillators) that resynchronize cardiac contraction (cardiac resynchronization therapy, CRT). These devices work in close synergy with anti-decompensation drugs to curb the progression of heart failure and, in some cases, restore normal cardiac contractility. Cardiac resynchronization therapy, combined with drug therapy, has been shown to improve survival and quality of life by reducing the symptoms of heart failure, increasing exercise capacity, and enabling subjects to resume many of their daily activities.
Cardiac Contractility Modulation (CCM) CRT is indicated for patients with a large QRS (>130 ms and evidence of left bundle branch block)3; however, the percentage of individuals who do not respond to CRT varies between studies, usually between 25% and 33% (4). Randomized clinical trials have shown that Cardiac Contractility Modulation (CCM) is a treatment option5 for patients with symptomatic heart failure despite optimized medical therapy and not eligible for CRT. CCM therapy has also been evaluated in patients who have not responded to CRT (6) therapy.
The implanted device for CCM consists of an implantable pulse generator (like a pacemaker) equipped with a transcutaneously rechargeable battery connected to two ventricular leads that transmit high-energy electrical impulses within the absolute refractory period of the myocardial action potential. The device has no pacing or antiarrhythmic functions and is designed to work even in patients already implanted with pacemakers or defibrillators.
The FIX-HF-47, FIX-HF-58,9, and FIX-HF-5C10 trials demonstrated the safety and efficacy of the CCM device concerning the following end-points:
The CCM has been shown to improve myocardial contractility (11) by improving cardiomyocyte management of intracellular calcium. It exerts short- and long-term effects and positively modulates cardiac cell gene expression.
The Optimizer Smart system has been approved in countries where the C.E. mark applies since October 3, 2016.
The OPTIMIZER Smart System is indicated for use in patients over 18 who have symptomatic heart failure due to systolic left ventricular dysfunction despite medical and interventional therapy. CCM therapy delivered by the OPTIMIZER system has been shown to improve the clinical status, functional capacity, and quality of life and prevent hospital admissions in symptomatic patients with left heart failure who are carefully selected and followed by cardiologists experienced in the treatment of heart failure (12).
The Optimizer Smart device was FDA-approved on March 21, 2019, for delivering Cardiac Contractility Modulation (CCM) therapy. This approval is unique in that it is the first device to be granted "Breakthrough Device" status by the FDA and to have been included in the FDA's review panel for cardiovascular devices - where it received a unanimous recommendation for approval due to its favorable benefit/risk ratio and then obtained PMA approval by the FDA (12).
In the 2021 ESC guidelines for diagnosing and treating acute and chronic heart failure (13), CCM is an "under evaluation" therapy in NYHA class III/IV patients, with LVEF between 25% and 45% and QRS duration \<130 ms.
In the consensus paper published in 2024 by the Heart Failure Association (HFA) and the European Heart Rhythm Association (EHRA) of the European Society of Cardiology (ESC)(14), CCM is suggested as a therapy that experienced operators who cooperate in a multidisciplinary team for heart failure should consider if symptoms persist.
It has been evaluated that, for heart failure patients with reduced ejection fraction, the addition of CCM therapy could be more convenient than OMT alone (i.e., the combined use of five classes of drugs that, individually, have already been shown to improve the prognosis of infarcted patients: acetylsalicylic acid, beta-blockers, statins, antagonists of the renin-angiotensin system, and thienopyridines), if a time horizon of the whole life is considered (15, 16).
In selected cases, and when no other therapeutic options are available, CCM can be adjunct in patients who do not respond to CRT29.
In a recent study (30), CCM significantly improved H.F. in patients with reduced ejection fraction (HFrEF), NYHA class III, and moderately prolonged QRS of 120-149 ms.
Pharmacological stress echocardiography Pharmacological stress echocardiography is indicated for the diagnosis and treatment of suspected ischemic heart disease or left ventricular dysfunction of suspected ischemic origin. The examination consists of performing an echocardiogram during the infusion of increasing drug doses that stimulate the sympathetic nervous system, stimulating the heart with an effect similar to physical exertion. The heart reacts with increased contraction force and frequency; sometimes, blood pressure can also increase. The examination helps to recognize the possible presence of stress-induced myocardial ischemia.
Other indications of stress echocardiography include quantifying contractile reserve in cardiomyopathies, evaluating cardiac valvulopathy and congenital heart disease, and evaluating diastolic function and pulmonary hypertension. The main advantages of stress echocardiography are its simplicity, low cost, wide availability, and absence of radiation (17, 18).
The most used drugs in this procedure are Dobutamine or dipyridamole. Dobutamine is a synthetic catecholamine that primarily stimulates β1 adrenergic receptors and, to a lesser extent, α1 and β2 receptors.
The protocol for standard dobutamine examination was defined in the American Society of Echocardiography (ASE) guidelines of 2007 (19). A graduated dobutamine infusion is usually administered at a 5 μg/kg starting dose per minute. The dobutamine infusion aims to achieve a heart rate of 85% of the maximum heart rate predicted for the person's age. The dose of Dobutamine is increased every 3-5 minutes to 10, 20, 30, and finally to 40 μg/kg per minute (20).
On the other hand, the "low-dose" dobutamine stress echocardiography (LDDSE) test is optimal for detecting ischemia and assessing viability by searching for the "biphasic response." A myocardial area increases its contraction at a low dose of inotropic but later becomes hypokinetic or akinetic at higher doses of dobutamine (20).
During the low-dose dobutamine stress echocardiography, the subject is stressed with Dobutamine by standardized incremental infusions of 5, 10, and 20 μg/kg/min. Each infusion dose is administered for a maximum of five minutes (18, 20, 21, 22).
As assessed by low-dose dobutamine stress echo, left ventricular contractile reserve is a helpful marker for predicting functional improvement of the left ventricle and determining long-term prognosis in patients with dilated heart disease (23).
Low-dose dobutamine stress echocardiography has proven to be a simple and effective procedure for selecting patients who are candidates for CRT, having demonstrated the correlation between contractile reserve and response to subsequent resynchronization therapy (24). The assay was also used to quantify the degree of remodeling after CRT (25) therapy.
Many CRT studies have evaluated left ventricular reverse remodeling by echocardiographic testing with low-dose Dobutamine. A positive response criterion is a reduction of left ventricular end-systolic volume (LVESV) greater than or equal to 15% (26, 27, 28).
6,331 studies on the registry are indexed under Heart Failure; 1,396 are open to participants now.
This study's planned enrollment of 120 is below the median of 200 across 1,983 observational studies indexed under Heart Failure.
Browse Heart Failure studies →Quovadis Associazione is the lead sponsor of 7 studies on the registry; 3 are open to participants now.
Counted across the registry records on this site, refreshed daily.
Enrollable subjects who, in the participating Clinical Centers, received a CCM implant from July 1, 2024, to the start of the study will be part of the retrospective cohort, while subsequent subjects of the prospective cohort.
Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
The study doctor’s estimate of how long someone is likely to live. Criteria use it so that people can stay in the study long enough for it to answer its question.
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
An allergy, or another reaction of the immune system, to a substance. “Hypersensitivity to the study drug” means a known allergic reaction to it — not every side effect a medicine can have.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Life expectancy
The study doctor’s estimate of how long someone is likely to live. Criteria use it so that people can stay in the study long enough for it to answer its question.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraindication
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Hypersensitivity
An allergy, or another reaction of the immune system, to a substance. “Hypersensitivity to the study drug” means a known allergic reaction to it — not every side effect a medicine can have.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Subjects showing a reduction of 15% or more in LVESV through pre-implant low-dose dobutamine echocardiography stress testing
Device: Cardiac Contractility Modulation (CCM) implant
Subjects showing a reduction of less than 15% in LVESV through pre-implant low-dose dobutamine echocardiography stress testing
Device: Cardiac Contractility Modulation (CCM) implant
Subjects participating in the study carry or will carry the Cardiac Contractility Modulation (CCM) medical device "OPTIMIZER Smart Mini" by Impulse Dynamics (USA). It is indicated for use in patients over 18 years of age with symptomatic heart failure due to systolic left ventricular dysfunction, despite appropriate medical treatment. The OPTIMIZER Smart Mini Implantable Pulse Generator is a programmable device with an internal battery and telemetry functions. The OPTIMIZER Smart Mini is connected to two or three implantable leads, two of which are implanted in the right ventricle and one, optionally, in the right atrium.
New York Heart Association class variation
The proportion of subjects with clinical response to CCM therapy at 12 months, defined as a reduction of at least 1 class of the New York Heart Association Classification of the functional status of the heart (minimum value I, better outcome, and maximum value IV, worse outcome)
Time frame: From enrollment to the end of follow-up, 12 months
Hospitalizations
Change in the number of hospitalizations, visits to the Emergency Department, or access to day hospital facilities for more than 4 hours (e.g., by intravenous infusion of cardiac inotropic drugs) compared to the year before the study.
Time frame: From enrollment to the end of follow-up, 12 months
Minnesota LIVING WITH HEART FAILURE Questionnaire score variation
Change in the quality-of-life score estimated with the "Minnesota LIVING WITH HEART FAILURE Questionnaire" MLHFQ (minimum value 0, better outcome, and maximum value 105, worse outcome),
Time frame: From enrollment to the end of follow-up, 12 months
6MWT variation
Change in walk distance between baseline and end of follow-up in the walk test (6MWT)
Time frame: From enrollment to the end of follow-up, 12 months
NT-proBNP variation
Change in NT-proBNP level between baseline and end of follow-up
Time frame: From enrollment to the end of follow-up, 12 months
LVESV change
The proportion of subjects with LVESV decreased by ≥ 15% on echocardiography at end-of-follow-up compared to preimplantation
Time frame: From enrollment to the end of follow-up, 12 months
VTI change
The proportion of subjects with increased integral velocity time (VTI) ≥ 20% between preimplantation and end-of-follow-up echocardiography,
Time frame: From enrollment to the end of follow-up, 12 months
LVEF change
The proportion of subjects with a 20% increase in ejection fraction (LVEF) between preimplantation and end-of-follow-up echocardiography
Time frame: From enrollment to the end of follow-up, 12 months
MR change
The proportion of subjects with progression or, conversely, improvement in Mitral Regurgitation (M.R.; classified as mild, moderate, or severe).
Time frame: From enrollment to the end of follow-up, 12 months
CRT implant
The proportion of subjects who, during follow-up, will be evolved to cardiac resynchronization system (CRT) implantation
Time frame: From enrollment to the end of follow-up, 12 months
LVAD implant
The proportion of subjects who, during follow-up, will be evolved to left ventricular assist device (LVAD) implantation,
Time frame: From enrollment to the end of follow-up, 12 months
Cardiac Transplant
The proportion of subjects who will have received a cardiac transplant during follow-up
Time frame: From enrollment to the end of follow-up, 12 months
HF death
The proportion of subjects who will die from H.F. during follow-up
Time frame: From enrollment to the end of follow-up, 12 months
AE
Rate of all procedure-related adverse events.
Time frame: From enrollment to the end of follow-up, 12 months
Re-Operation
Rate of re-operations (lead revision/replacement/infection)
Time frame: From enrollment to the end of follow-up, 12 months
Not enrolling at this site.
PDFs hosted by the registry, ClinicalTrials.gov.
Plan to share: No
Started Jul 2025 (actual). Primary completion is estimated for Dec 2028, 41 months after the start.
Of 793 non-industry observational studies under Heart Failure, half reached primary completion within 45 months of starting (the median), counting those still running; a quarter within 23 and three quarters within 99. This study's planned 41 months is close to that.
Counting every sponsor, half of 975 studies reached it within 41 months; a quarter within 23 and three quarters within 89.
How these figures are worked out, and which studies are left out of them.
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