CRT-P or CRT-D in Dilated Cardiomyopathy

The ICD-Reality study is a non-commercial, investigator-led, multicenter, prospective, randomized, controlled trial. We aim to determine the effect of CRT-D or CRT-P implantation in non-ischemic cardiomyopathy and heart failure patients.

The reason why we initiated this trial is the lack of evidence-based treatment for the significant number of these patients. In these patients, 5-year mortality remains as high as 20% despite recent therapeutic advances. Based on currently available evidence, because of a significant decrease in mortality due to modern pharmacotherapy, it is not certain which of these patients should receive a CRT-P and who should receive a CRT-D. No dedicated and adequately powered trial has addressed this important question.

We hypothesize that patients with symptomatic HF, LVEF ≤35%, without left ventricular mid-wall fibrosis on LGE-CMR, will not benefit from CRT-D implantation compared with CRT-P only implantation.

If our hypothesis is confirmed, this could provide evidence for the management of these patients with a significant impact on common daily praxis and health care expenditures.

We aim to enroll 600 patients in the trial. 924 patients are needed to be screened for these 600 patients to be randomized.

Patients with non-ischemic HF visiting an out-patient department and possibly eligible for the trial will have their pharmacotherapy optimized.

Patients with a significant amount of fibrosis will be excluded from the study and treated according to local practice with an emphasis on ICD implantation to prevent SCD.

After fulfilling all eligibility criteria, including maximally tolerated pharmacotherapy, subjects will be randomized by the physicians who enrolled them in a 1:1 ratio to receive CRT-D or CRT-P implantation.

All patients will be followed-up for at least 3 years after the implantation.

The trial goals The ICD-Reality study is an investigator-led, multicenter, prospective, randomized, controlled trial. We aim to determine the effect of CRT-D or CRT-P implantation in non-ischemic cardiomyopathy and heart failure patients. The reason why we initiated this trial is the lack of evidence-based treatment for the significant number of these patients. In these patients, 5-year mortality remains as high as 20% despite recent therapeutic advances. Based on currently available evidence, because of a significant decrease in mortality due to modern pharmacotherapy, it is not certain which of these patients should receive an ICD. We hypothesize that patients with symptomatic HF, LVEF ≤35%, without left ventricular mid-wall fibrosis on LGE-CMR, will not benefit from CRT-D implantation compared with CRT-P only implantation. If our hypothesis is confirmed, this could provide evidence for the management of these patients with a significant impact on common daily praxis and health care expenditures.

Clinical hypothesis:

Patients with symptomatic HF, with LVEF ≤35% and without LV mid-wall fibrosis on late gadolinium enhancement cardiovascular magnetic resonance imaging (CMR), will not benefit from CRT-D implantation compared with CRT-P only implantation.

Estimated number of patients needed to be screened and randomized:

600 patients are needed to be randomized according to the study power analysis. Since 35 % of patients are estimated to be LG-E positive and thus excluded from randomization, 924 patients are needed to be screened.

Pre-screening:

Patients with non-ischemic HF visiting an out-patient department and possibly eligible for the trial will have their pharmacotherapy optimized. A screening visit in an out-patient department will be scheduled in 1-2 months after pharmacotherapy optimization since the qualifying LVEF and NT-proBNP level has to be measured after a maximal tolerated pharmacotherapy of heart failure has been achieved.

Screening:

After the signing of informed consent, screening examination will be performed. The informed consent will be obtained by attending physician in every center and a signed original will be stored in each individual center for the whole duration of the study. The screening examination will include medical history, documentation of underlying cardiac disease. The following co-morbidities will be specifically documented: peripheral arterial disease, cerebral vascular disease, pulmonary disease, diabetes mellitus, hypertension, sleep apnea, tobacco use, and any malignant disease within the last 5 years. Physical exam with vital signs, NYHA functional class, pulse rate, resting blood pressure will be performed. Cardiovascular pharmacological treatment will be documented. Standard laboratory parameters are recorded, including creatinine, estimated glomerular filtration rate, liver tests, TSH, NT-proBNP. Transthoracic echocardiography will be done to confirm LVEF ≤35% using biplane Simpson's method. Documented will be LV end-systolic and end-diastolic diameters and volumes, thickness of ventricular septum and LV posterior wall, stroke volume, cardiac output, indexed left atrial volume, presence and grade of valvular heart disease, right ventricle diameter, TAPSE, presence and grade of pulmonary hypertension. Selective coronarography will be performed if it was not done before to exclude patients with a severe coronary heart disease. LGE-CMR imaging will be performed by an operator blinded to all other clinical data to evaluate left ventricular mid-wall fibrosis.

Patients with a significant amount of fibrosis will be excluded from the study and treated according to local practice with an emphasis on ICD implantation to prevent SCD.

Randomization:

After fulfilling all eligibility criteria, including maximally tolerated pharmacotherapy, subjects will be randomized by the physicians who enrolled them in a 1:1 ratio to receive CRT-D or CRT-P implantation. Randomization will be carried out by physicians enrolling patients through a stand-alone web-based CRF managed by an independent biomedicine and statistics center, independent on all randomizing personnel. The web-CRF-based allocation sequence will be based on computer-generated random numbers and will be concealed until the type of intervention is assigned.

Treatment:

After randomization, devices will be implanted as soon as possible (within 2 weeks). The ICD will be programmed with anti-tachycardia pacing and shock therapy as per common praxis.

Follow-up:

All patients will be followed-up for at least 3 years after the implantation. After the implantation, all patients will be examined every 6 months in an out-patient department with the assessment of medical history, vital signs, physical exam, and NT-proBNP as in the screening visit. A device control will be performed every 6 months.

After device implantation the concomitant care and all possible concomitant interventions will be carried out as per common praxis.

Patients will be evaluated for possible end-points. Deaths and hospitalizations for heart failure, stroke or arrhythmias will be recorded throughout the study duration.

Quality of life (QoL) is assessed at baseline and annually during follow-up. Patients will fill out the SF-36 Questionnaire for general QoL, the MacNew Questionnaire for disease specific QoL.

An Endpoint Classification Committee will adjudicate hospitalizations and deaths for causality. An independent Data Monitoring Committee will periodically review mortality data throughout the study.

For safety reasons, all patients will be followed using a daily ECG monitoring and analysis. ECG from the Home-monitoring units will be evaluated in a dedicated center. This center will evaluate the ECGs sent from the Home-monitoring units with respect to patient safety and the study end-points. If the Home-monitoring unit reveals any rhythm disturbance they will contact the patient's physician and make a record in the CRF. If a sustained ventricular tachyarrhythmia is documented on a Home-monitoring in a CRT-P patient, a decision will be made and documented about a possible crossover to CRT-D as soon as possible.

Patients who will deviate from intervention protocols (e.g. crossover to CRT-D implantation) will continue to be followed-up.

Blinding:

Trial participants will be blinded to the device type for the whole duration of the trial.

The randomizing and implanting physicians will not be blinded to the type of the device. These physicians will not take care in the subsequent patients' follow-up and sign a declaration of confidentiality.

The same will be true for the physicians / technicians attending to the device interrogation during follow-up visits. The device type will be hidden and physicians will sign a declaration of confidentiality. The patients' documentation will not reveal the device type.

A maximum effort will be done to hide the type of the implanted device. The implantation will be intramuscular and the device interrogation follow-up visits will not reveal the device type.

The physicians attending the follow-up visits and entering all patients' data into web-based CRF will be blinded to the implanted device type.

In case of an emergency with a need to reveal the type of the device, i.e. lead fracture, infection in the place of implantation, ventricular tachycardia, the site principal investigator will decide to unblind the patient. This will be documented in the CRF.

Eligibility Criteria:
Inclusion Criteria:

* ≥ 18 years of age at the time of screening
* Documented non-ischemic HF with an LVEF ≤ 35
* QRS≥130ms; NYHA class II-IV
* Signed written informed consent
* NT-proBNP above 200 pg/ml

Exclusion Criteria:

* Uncorrected congenital heart disease or valve obstruction
* obstructive cardiomyopathy
* active myocarditis
* constrictive pericarditis
* untreated hypothyroidism or hyperthyroidism
* adrenal insufficiency
* active vasculitis due to collagen vascular disease
* Presence on the urgent waiting list for a heart transplant (UNOS category 1A or 1B, or equivalent)
* Patients on the non-urgent waiting list for a heart transplant (UNOS category 2 or 7, or equivalent) are eligible for inclusion in the study
* Recipient of any major organ transplant (e.g., lung, liver, heart)
* Receiving or has received cytotoxic or cytostatic chemotherapy and/or radiation therapy for treatment of a malignancy within 6 month before randomization or clinical evidence of current malignancy, with the following exceptions: basal or squamous cell carcinoma of the skin, cervical intraepithelial neoplasia, prostate cancer (if stable localized disease, with a life expectancy of \> 2.5 years in the opinion of the investigator)
* Known to be human immunodeficiency virus positive with an expected survival of less than 5 years due to HIV
* Chronic kidney disease with glomerular filtration rate \<30 ml/min
* Chronic dialysis treatment
* Recent (within 3 months) history of alcohol or illicit drug abuse disorder, based on self-report
* Any condition (e.g., psychiatric illness) or situation that, in the investigator's opinion, could put the subject at significant risk, confound the study results, or interfere significantly with the subject's participation in the study
* Unwilling to participate

Additional information related to inclusion and exclusion criteria:

* The qualifying LVEF and NT-proBNP level has to be measured after a maximal tolerated pharmacotherapy of heart failure has been achieved.
* A non-ischemic cause of HF has to be determined by coronary angiography. Patients could be included even if they will have one or two coronary arteries with stenosis, if the extent of coronary artery disease will not be considered to be sufficient to account for the reduced LVEF. Patients with a significant coronary heart disease (CAD) will be excluded.
* Patients with an existing conventional pacemaker could be included if they will be willing to have the device changed or upgraded.
* Patients with any form of atrial fibrillation will not be excluded.