Arrhythmic Risk Stratification in Nonischemic Dilated Cardiomyopathy

Dilated Cardiomyopathy Clinical Trial

— ReCONSIDER  

Official title:

Arrhythmic Risk Stratification in Nonischemic Dilated Cardiomyopathy: The ReCONSIDER Study. A Two-step, Multifactorial, Electrophysiology-inclusive Approach

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04246450
• Other study ID #: HIPPO-RECO
• Status: Recruiting
• Phase: N/A
• Start date: September 1, 2020
• Est. completion date: May 1, 2025

Study information

• Verified date: April 2021
• Source: University of Athens
• Contact: Konstantinos A Gatzoulis, MD
• Phone: 00306944580369
• Email: kgatzoul[@]med.uoa.gr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Nonischemic dilated cardiomyopathy is a heterogeneous disease often associated with increased rates of sudden cardiac death. Although many algorithms have been proposed, risk stratification remains suboptimal, and implantable cardioverter-defibrillators are currently recommended only in patients with poor left ventricular function. However, most cases of sudden cardiac death occur at earlier stages, in patients with relatively preserved left ventricular function and exercise capacity, for which device-therapy is currently not indicated. Several noninvasive risk factors have been associated with increased arrhythmic risk, including clinical history (syncope), imaging (fibrosis on cardiac magnetic resonance imaging and left ventricular dimensions in echocardiography) and electrocardiographic parameters (ventricular arrhythmic burden, late potentials, heart rate variability and repolarization abnormalities).

The investigators hypothesized that the encouraging findings of studies assessing more sophisticated stratification-algorithms in patients with ischemic heart disease could be extrapolated in patients with nonischemic dilated cardiomyopathy. Thus, combining noninvasive risk factors with programmed ventricular stimulation may risk-stratify such patients more accurately. In this regard, the prospective observational multicenter ReCONSIDER study aims to integrate several approaches to arrhythmic risk stratification in nonischemic dilated cardiomyopathy in a tiered, multifactorial, approach, in which noninvasive risk factors are combined with electrophysiologic studies. This approach may pave the way for a more comprehensive risk stratification algorithm in patients with nonischemic dilated cardiomyopathy, leading to more rational device-therapy, and, ultimately to lower mortality.

Description:

1. Study hypothesis There is an urgent need for reconsidering risk stratification approaches to DCMP patients, in addition to LVEF in order to identify subgroups at high arrhythmic risk that could benefit from ICD. This task could be achieved either by imaging and/or noninvasive, ECG-related, risk stratification techniques. In this direction, the investigators recently introduced a two-step multifactorial, noninvasive ECG findings leading to programmed ventricular stimulation (PVS), electrophysiology study (EP)-inclusive approach, to modify and protect the truly high risk post-myocardial infarction (MI) CAD patients with a LVEF≥40%. Based on the fact that those DCMP patients inducible on PVS into sustained ventricular tachycardia/fibrillation (VT/Vf) are the ones most likely to receive appropriate ICD therapy regardless of the degree of left ventricular contractile dysfunction or/and the presence of complex ventricular ectopy, the investigators now propose a similar two-step, multifactorial, noninvasive, EP-inclusive approach among the DCMP population with either relatively preserved (35%60mm on echocardiography

3. LGE presence (qualitative approach - dichotomous value)

4. >30 premature ventricular complexes/hour on 24-hour electrocardiography

5. Presence of non-sustained ventricular tachycardia on 24-hour electrocardiography

6. 2/3 positive criteria for late potentials, either conventional or modified43

7. QTc derived from 24-hour electrocardiography >440ms (men) or >450ms (women)44 according to the Fridericia formula from a signal recorded in 3 pseudo-orthogonal leads

8. Ambulatory T-wave alternans ≥65μV in 2 Holter channels20, 45

9. Standard deviation of normal RR intervals ≤75ms on ambulatory electrocardiography

10. Deceleration capacity ≤4.5ms and heart rate turbulence onset ≥0% and heart rate turbulence slope ≤2.5ms46 ii. Cardiac MRI protocol Cardiac MRI protocol will entail the following: All patients recruited will undergo cMRI in a 1.5 Tesla system. All sites of cMRI fulfil the requirements of expertise and equipment to be involved in the trial. Each participating centre has approval by their respective Ethics Committee. Analysis will be performed with dedicated computer software.

Measurements will consist of the end-diastolic and end-systolic right and left ventricular volumes, the ejection fraction of both ventricles, and will be provided by analysing cine-sequences performed on both ventricles. Endocardium and epicardium will be contoured both in end-diastole and end-systole to define end-diastolic and end-systolic volumes and subsequently LV stroke volume, ejection fraction, and myocardial mass. All parameters will be indexed to body surface area.

Additionally, cardiac MRI studies will include late images after gadolinium infusion, using inversion recovery sequence, with late gadolinium-enhanced area expressed as percentage of the left ventricular mass. Presence of LGE in any extent will constitute a positive study in terms of NIRF presence. LGE localization and pattern will also be recorded for further analysis.

iii. Programmed ventricular stimulation protocol PVS protocol will consist of up to 3 extrastimuli being introduced from 2 different right ventricular sites, preferably the apex and outflow tract. These extrastimuli will follow a drive train consisting of 6 stimuli at 2 cycle lengths (550msec and 400msec) at the first site and at a single cycle length (400msec) at the second site. Coupling intervals between extrastimuli will be shortened by 10msec intervals until refractoriness or an interval of 200msec is reached - whichever occurs first. Additionally, once the procedure is completed,β-agonist infusion (isoproterenol) will commence at rates 1-4μg/min. Once baseline heart rate increases to >120bpm the protocol will be repeated, using 3 extrastimuli from a single site and with a driving train cycle length of 400msec. Patients will be considered inducible and the protocol terminated prematurely if monomorphic ventricular tachycardia (VT - either sustained - >30sec in duration - or requiring termination due to hemodynamic instability) or ventricular fibrillation (Vf) is induced at any stage.

iv. Patient Groups

Based on the above, 6 patient subgroups will be available for comparison:

1. Group A patients - 35%95%). Extra visits will be scheduled in cases of device activation and clinical events.

E. Power analysis i. Assumptions Thus, 60% of Group A patients are expected to have no NIRFs detected (Group 1-A), 30% to have at least one NIRF present yet be noninducible upon PVS (Group 2-A) and 10% to both have NIRF(s) present and be inducible. On the other hand, 10% of Group B patients are expected to both have no NIRFs and be noninducible (Group 1-B), 60% to have at least 1 NIRF while being noninducible (Group 2-B) and 30% to have both NIRF(s) present and be inducible (Group 3-B).

The investigators hypothesize a corresponding incidence of MAEs ranging from as high as 50% (Group 3-B, annual incidence 12.5%), down to 25% (Group 3-A, annual incidence 8.3% - similar to the 8.2% annual rate observed in the high risk cohort of the PRESERVE EF study), 10% (Group 2-B - annual incidence 2.5%) and even 0% (Groups 1-A, and 1-B), in the high, intermediate, and low risk groups, respectively.

ii. Sample size calculation Based on the above assumptions, power analysis suggests that, in order to achieve 80% power (β=0.2) at a significance level (α) of 0.05, with an allocation ratio [high risk subgroup to all group patients, i.e. subgroup 3:(1+2+3) of 0.1 for Group A patients (35%

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 675
• Est. completion date: May 1, 2025
• Est. primary completion date: May 1, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

ALL of the following criteria must be fulfilled:

1. Dilated cardiomyopathy diagnosis based on the ESC proposed criteria1: Dilation based on left ventricular end-diastolic diameter or volume >2SD larger than age, gender, and body surface area adjusted normal values, hypokinesia based on left ventricular ejection fraction =50%, not attributable to loading conditions or coronary artery disease. In cases of LVEF<45%, otherwise unexplained, and no evident ventricular dilation, the diagnosis of hypokinetic, nondilated CMP will be made

2. Patients will have to have been diagnosed >6 months prior to enrolment in order to exclude reversible myocarditis cases

3. Be on sinus rhythm or with paroxysmal atrial fibrillation to facilitate noninvasive risk factor (NIRF) presence assessment

4. Age >18 years and <80 years

5. On optimal medical therapy for at least 3 months

Exclusion Criteria:

A patient will be excluded from the study if any of the following criteria are present:

1. Significant ventricular extrasystole burden (>10,000/24hrs or >10% PVCs) on 24hr ambulatory ECG (PVC-induced cardiomyopathy)38, 39, persisting even after all pharmacologic and/or interventional (ablation) attempts

2. Permanent atrial fibrillation

3. More than moderate left-sided valvular heart disease

4. Epicardial vessel lumen stenoses >70% detected on coronary angiogram36 in a major coronary artery

5. Expected survival <12months

6. Pregnancy (planned and accidental)

7. Stage IIIb chronic kidney disease (estimated glomerular filtration rate <30ml/hr). This mainly relates to the non-tachycardic SCD mechanisms in this population (bradycardia/pulseless electrical activity)40-42, not amenable to antitachycardic ICD interventions

8. NYHA IV functional class

9. Participation in another study with an active treatment arm

10. Contraindication to either MRI performance or insertion of a transvenous ICD system

Related Conditions & MeSH terms

• Arrhythmias, Cardiac
• Cardiomyopathies
• Cardiomyopathy, Dilated
• Death
• Death, Sudden, Cardiac
• Dilated Cardiomyopathy
• Sudden Cardiac Death Due to Cardiac Arrhythmia

Intervention

Device:
• Implantable Cardioverter Defibrillator (ICD) insertion
Implantation of ICD when arrhythmic risk is deemed high in those with LVEF between 35%-50%, and to all with LVEF<35%. Aim to determine whether risk stratification accuracy can be improved more than that of the current approach regarding primary prevention of sudden cardiac arrhythmic death in nonischemic dilated cardiomyopathy patients (no ICDs to those with LVEF between 35%-50% and ICDs to all with LVEF <35%. In patients in the LVEF <35% groups, ICDs will be used as implantable recorders, to determine whether occurrence of major arrhythmic events (MAEs) can be better predicted by NIRFs/PVS than by LVEF alone.

Locations

Country	Name	City	State
Greece	Hippokrateion General Hospital of Athens	Athens	Attica

Sponsors (1)

Lead Sponsor	Collaborator
University of Athens

Country where clinical trial is conducted

Greece, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Major arrhythmic event (MAE) occurrence (ICD activation ± sudden cardiac death ± sustained ventricular tachycardia/ventricular fibrillation)	Sustained ventricular arrhythmias necessitating ICD therapy ± sudden cardiac death ± sustained ventricular tachycardia/ventricular fibrillation	48 months (total follow up duration)
Secondary	Mortality (all-cause and heart failure-related) - Heart failure-related hospitalization	All cause mortality, mortality due to heart failure, determined by death certificates	48 months (total follow up duration)
Secondary	Device-related complications	Infections - pocket and lead related, as well as inappropriate therapies. Determined by reports of implanting physicians.	48 months (total follow up duration)