Left Cardiac Sympathetic Denervation for Cardiomyopathy Feasibility Pilot Study (LCSD)

Left Cardiac Sympathetic Denervation (LCSD) for Cardiomyopathy Feasibility Pilot Study

A randomized controlled trial to test the potential safety and efficacy of LCSD in patients with heart failure due to non-ischemic and ischemic cardiomyopathy at the University of Cape Town. Left Cardiac Sympathetic Denervation (LCSD) is a surgical intervention that modulates the autonomic innervation of the cardiac system. This is important because: a] sympathetic and parasympathetic tone has a profound effect on the threshold for ventricular tachyarrhythmias-the main cause of sudden cardiac death in this population; and b] autonomic dysfunction (which is characterized by an imbalance between sympathetic and parasympathetic activation), plays an important detrimental role in the pathophysiology and progression of heart failure.

Study Overview

• Status: Suspended
• Conditions: Dilated Cardiomyopathy; Ischemic Cardiomyopathy; Non-ischemic Cardiomyopathy
• Intervention / Treatment: Procedure: Left Cardiac Sympathetic Denervation (LCSD); Other: Optimal Medical Therapy

Detailed Description

STUDY SUMMARY

TITLE Left Cardiac Sympathetic Denervation (LCSD) for Cardiomyopathy Study DESIGN Phase II feasibility parallel randomised controlled trial (RCT) AIMS Assess the feasibility and safety of LCSD in patients with cardiomyopathy and heart failure OUTCOME MEASURES Recruitment rates, retention, follow-up and safety POPULATION 30 patients with heart failure secondary to cardiomyopathy ELIGIBILITY Adult participants with ischemic and non-ischemic cardiomyopathy DURATION 18 months follow up

METHODS:

Participants will be randomized to receive LCSD in addition to optimal medical therapy in the intervention arm (15 patients) and optimal medical therapy in the active control arm (15 patients). Participants would be recruited from both inpatient and outpatient general medical and cardiology wards and clinics at Groote Schuur Hospital where patients with the syndrome of heart failure are frequently referred for subspecialty evaluation and management. Eligible patients who meet the inclusion criteria would be randomized to undergo LCSD in addition to optimal medical therapy (intervention arm) or receive standard optimal medical therapy (active placebo). Optimal therapy for patients with cardiomyopathy and heart failure currently consists of an ace-inhibitor or angiotensinogen receptor blocker, beta-blocker, mineralocorticoid receptor antagonist with or without a loop diuretic, and digoxin. All patients in the study would receive an implantable loop recorder to allow for the accurate determination of episodes of symptomatic and asymptomatic ventricular tachyarrhythmias. In order not to lose all of the clinical outcome information obtained in the pilot phase of the study, we would propose only assessing the pre-specified feasibility and safety aspects of the study and keeping the data on efficacy outcomes blinded for inclusion in the fully powered main study.

The LCSD procedure The procedure involves the surgical removal of the lower half of the left stellate ganglion (T1) and thoracic ganglia (T2-T4), thereby removing the pro-arrhythmic noradrenergic input to the ventricles (3). LCSD raises the ventricular fibrillation threshold without impairing cardiac contractility or reducing heart rate. LCSD results in pre-ganglionic denervation, thus preventing re-innervation and producing permanent antifibrillatory effects. This procedure can be performed by video-assisted thoracoscopic surgery (VATS) usually in less than 45 minutes and will be conducted by thoracic surgeons at Groote Schuur Hospital. The lead thoracic surgeon (J.R.) has a large experience in performing this procedure for the indication of hyperhidrosis in over 200 patients (personal communication). This experienced thoracic surgeon will lead a team of thoracic surgeons (T.P., L.M.) to perform the procedure.

Implantable loop recorder (ILR) insertion The implantable loop recorder is a small device that will be inserted at the end of the LCSD procedure by the thoracic surgeon or after enrolment in the optimal medical therapy arm by a cardiologist. This loop recorder is inserted under sterile conditions in the catheter laboratory or operating theatre. In the catheter laboratory, the device is inserted under local anaesthetic, subcutaneously over the left precordium and usually takes less than 15 minutes. The implantable loop recorder is a well-established device to quantify and detect atrial and ventricular tachyarrhythmias with an excellent safety record. The device has a battery life of up to 3 years and can be removed via a small skin incision at the end of the study. Implantable loop recorder insertion does not carry risk of known major complications. There is a minimal risk (<1%) of complications (infection, bleeding) as the device is implanted subcutaneously. Potential complications include superficial skin infections that readily responds to antibiotics. Device removal is easy to perform and is seldom required.

Optimal Medical Therapy

All eligible patients with heart failure and depressed left ventricular systolic function will receive guideline and evidence based optimal tolerated medical therapy. The level of risk associated with optimal medical therapy is considered very low. For the majority of patients with heart failure and depressed left ventricular systolic function this will include:

1. A renin angiotensin system blocker at highest tolerated doses (e.g., enalapril 10mg twice daily or equivalent)
2. A mineralocorticoid receptor antagonist (e.g., Spironolactone 25-50mg daily or equivalent)
3. A Beta-blocker (e.g., Carvedilol 25mg twice daily or equivalent)
4. The use of a loop diuretic and digitalis will be clinically driven and used at the discretion of the attending clinician

• Study Type: Interventional
• Enrollment (Anticipated): 30
• Phase: Phase 2

Contacts and Locations

Study Locations

• South Africa
  • Western Cape
    • Cape Town, Western Cape, South Africa, 7925
      • University of Cape Town

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• At least 18 years of age
• New York Heart Association (NYHA) II/III stable heart failure due to an ischemic or non-ischemic cardiomyopathy with a Left Ventricular Ejection Fraction <=35% based on Echocardiogram, ERNA or MRI performed in the last 12 months. For the purpose of this study, Ischemic cardiomyopathy will be defined as Left Ventricular systolic dysfunction (Ejection Fraction <35%) associated with 75% narrowing of at least 1 of the 3 major coronary arteries, a documented history of a ST elevation myocardial infarction or significant regional wall motion abnormality on an echocardiogram. Non-ischemic cardiomyopathy will be defined as Left Ventricular systolic dysfunction <35% in the absence of known coronary artery disease or regional wall motion abnormality on echocardiography.
• No history of a prior cardiac arrest or sustained (>30 seconds or <30s if haemodynamically unstable) ventricular tachyarrhythmia.
• Signed informed consent forms will be available in IsiXhosa, Afrikaans and English.

Exclusion Criteria:

• History of prior unexplained syncope, sudden cardiac arrest or ventricular arrhythmia
• Peripartum cardiomyopathy or cardiomyopathy associated with thyrotoxicosis
• History of coronary revascularization or percutaneous intervention in the preceding 3 months
• Myocardial infarction in the preceding 1 month
• NYHA IV at enrollment
• Patient taking an antiarrhythmic drug (not including beta-blockers)
• Pregnancy
• Any non-cardiac condition that is associated with a high likelihood of death during the trial such as major organ dysfunction or malignancy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Left Cardiac Sympathetic Denervation (LCSD); Left Cardiac Sympathetic Denervation (LCSD) in addition to Optimal Medical Therapy (OMT)	Procedure: Left Cardiac Sympathetic Denervation (LCSD); The procedure involves the surgical removal of the lower half of the left stellate ganglion (T1) and thoracic ganglia (T2-T4), thereby removing the pro-arrhythmic noradrenergic input to the ventricles; Other: Optimal Medical Therapy; All eligible patients with heart failure and depressed left ventricular systolic function will receive guideline and evidence based optimal tolerated medical therapy. The level of risk associated with optimal medical therapy is considered very low. For the majority of patients with heart failure and depressed left ventricular systolic function this will include: A renin angiotensin system blocker at highest tolerated doses (e.g., enalapril 10mg twice daily or equivalent); A mineralocorticoid receptor antagonist (e.g., Spironolactone 25-50mg daily or equivalent); A Beta-blocker (e.g., Carvedilol 25mg twice daily or equivalent); The use of a loop diuretic and digitalis will be clinically driven and used at the discretion of the attending clinician
Other: OMT only; Optimal Medical Therapy (OMT) only	Other: Optimal Medical Therapy; All eligible patients with heart failure and depressed left ventricular systolic function will receive guideline and evidence based optimal tolerated medical therapy. The level of risk associated with optimal medical therapy is considered very low. For the majority of patients with heart failure and depressed left ventricular systolic function this will include: A renin angiotensin system blocker at highest tolerated doses (e.g., enalapril 10mg twice daily or equivalent); A mineralocorticoid receptor antagonist (e.g., Spironolactone 25-50mg daily or equivalent); A Beta-blocker (e.g., Carvedilol 25mg twice daily or equivalent); The use of a loop diuretic and digitalis will be clinically driven and used at the discretion of the attending clinician

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Feasibility of recruiting	Recruitment rate	36 months
Feasibility of performing the procedure in recruited patients	Patient retention	36 months
Procedure related complications	Measured by:• Horner's syndrome in those under going LCSD • Pneumothorax in those undergoing LCSD • Implantable loop recorder site sepsis	36 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality and morbidity	Measured by: All cause mortality; Heart failure related mortality; Hospital admissions; Ventricular arrhythmias;	36 months
Functional capacity: Measured by 6 minute walk test Quality of life at 6 months Admission to hospital for heart failure Functional Capacity	Measured by 6 minute walk test	6 monthly for 36 months
Functional capacity: Quality of life (EQ-5D questionnaire) Quality of life at 6 months Admission to hospital for heart failure Functional Capacity	Quality of life (EQ-5D questionnaire)	6 monthly for 36 months
End Systolic and Diastolic volumes	End Systolic and Diastolic volumes as determined by Echocardiography	6 monthly for 36 months

Collaborators and Investigators

• Sponsor: University of Cape Town
• Collaborators: Medtronic

Study record dates

Study Major Dates

• Study Start (Actual): November 24, 2016
• Primary Completion (Anticipated): November 1, 2021
• Study Completion (Anticipated): February 1, 2022

Study Registration Dates

• First Submitted: February 24, 2017
• First Submitted That Met QC Criteria: March 1, 2017
• First Posted (Actual): March 7, 2017

Study Record Updates

• Last Update Posted (Actual): May 6, 2021
• Last Update Submitted That Met QC Criteria: May 2, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: Cardiomyopathy; Left Cardiac Sympathetic Denervation
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Genetic Diseases, Inborn; Cardiomegaly; Laminopathies; Cardiomyopathies; Cardiomyopathy, Dilated
• Other Study ID Numbers: 001001001

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No