Prospective Assessment of Premature Ventricular Contractions Suppression in Cardiomyopathy(PAPS)

NCT ID: NCT03228823

Last Updated: 2021-04-14

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE4
• Total Enrollment: 5 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-08-01
• Study Completion Date: 2021-08-31

Brief Summary

Premature ventricular contractions (PVCs) coexist in patients with heart failure (HF) and LV dysfunction. Frequent PVCs have shown to induce a reversible cardiomyopathy (PVC-CM).

This clinical pilot study will enroll 36 patients with frequent PVCs (burden >10%) and CM (LVEF <45%) and randomize them to either: 1) RFA or 2) AADs. Prior to treatment, patients will undergo a baseline cardiac MR if clinically indicated followed by 3-month observation period (optimal HF medical therapy). Changes in LV function/scar, PVC burden/arrhythmias and clinical/functional status (QOL, HF symptoms and admissions, NYHA class) and adverse events will be assessed throughout the observation period and compare with PVC suppression strategies (RFA or AAD). Similar comparison will be made between RFA and AAD treatment groups during a 12-month follow up using a Prospective Randomized Open, Blinded End-point (PROBE) study design. The treatment regimens will be compared in an intention-to-treat analysis. In addition, a total of 20,000 consecutive ambulatory ECG Holter monitors from all participating centers will be screened to identify all patients with probable diagnosis of PVC-CM.

This pilot study is intended to estimate the prevalence of this clinical entity and pave the way for a large full scale randomized trial to identify best treatment strategy for patients with PVC-CM. Treating and reversing this underestimated PVC-CM may improve patient's health and subsequently decrease HF healthcare spending.

Detailed Description

Rationale. Frequent PVCs have shown to induce a reversible cardiomyopathy (PVC-CM). Yet, it is unclear why some patients develop PVC-CM, while others do not. Appropriate diagnosis and treatment of patients with PVC-CM is believed to carry significant benefits, improving quality of life (QOL), HF symptoms / admissions and life expectancy. Currently, these patients are offered radiofrequency ablation (RFA), antiarrhythmic drugs (AADs) or no treatment depending on physician's experience and resources. Nevertheless, no randomized-prospective study exists to support the benefit of RFA. Thus, a large-scale multicenter randomized clinical trial entitled "Prospective Assessment of PVC Suppression in Cardiomyopathy (PAPS)"' study has been planned to compare these treatment strategies. However, a PAPS pilot study is proposed to better estimate the potential affected patient population, limitations of enrollment, rate of clinical outcomes, potential crossover and drop out. This pilot study is key to better design and power the large-scale multicenter PAPS trial.

Objective. PAPS pilot study is a randomized clinical trial to assess the feasibility of enrolling, randomizing treatment strategies and retaining participants with frequent PVCs and associated CM.

Hypotheses. Our main hypotheses of the PAPS pilot study are:

1. A large-scale randomized PAPS clinical study is feasible with minimal barriers of enrollment, treatment crossover and drop out due to a unique design including a short observation period and PVC suppression strategy in all participants.

2. The rate of responders (defined as improvement of LVEF ≥ 10% points) with HF medical therapy alone during observation period will be less than 15%. In contrast, RFA and AADs will have a responder rate of at least 35% in the same population. Furthermore, RFA will have a greater 1-year response rate when compared to AAD therapy.

3. RFA will have a lower rate of composite adverse events (worsening NYHA class, HF admission, treatment side effects & complications, and death), arrhythmia burden and a better long-term tolerance than AADs.

Methods. A prospective clinical pilot study is planned to prove the feasibility of a large-scale multicenter clinical trial (PAPS study) of patients with probable PVC-CM. This pilot study will enroll 36 patients with frequent PVCs (burden ≥10%) and CM (LVEF ≤45%) and randomize them to either: 1) RFA or 2) AADs. Prior to treatment, all patients will undergo a baseline cardiac MR if clinically indicated and be allowed a 3-month observation period (optimal HF medical therapy). To assess the effects of PVC suppression, changes in LV function, rate of responders (defined above), PVC burden/arrhythmias and clinical/functional status (QOL, HF symptoms and admissions, NYHA class) and adverse events will be compared between observation period and both PVC suppression strategies (RFA or AAD). To identify the best PVC suppression strategy, similar comparisons between RFA and AAD treatment groups will be performed at 12-month follow up using a Prospective Randomized Open, Blinded End-point (PROBE) study design. The treatment regimens will be compared in an intention-to-treat analysis.

In summary, the multicenter PAPS pilot study is intended to better estimate the prevalence of PVC-CM, prove feasibility and rates of clinical outcomes. This pilot study with a multidisciplinary approach will pave the way for a large-scale randomized PAPS trial to identify the best treatment strategy for patients with PVC-CM. Treating and reversing PVC-CM with its associated HF morbidity and mortality will impact not only healthcare spending, but most importantly it will improve patient's health, quality of life and long-term prognosis.

Conditions

Ventricular Premature Beats, Contractions, or Systoles; Cardiomyopathies

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Radiofrequency Ablation

Radiofrequency ablation (RFA) will be performed after 3-month observation period. EPS and RFA will be performed using standard techniques and protocols similar to those patients that do not participate in this clinical study. In the event of polymorphic PVCs, all morphologies are to be targeted for ablation

Group Type: ACTIVE_COMPARATOR

Radiofrequency ablation

Intervention Type: PROCEDURE

RFA to achieve PVC suppression will be performed using standard techniques and protocols similar to those patients that do not participate in this clinical study.

Antiarrhythmic Drug

Antiarrhythmic drugs (AADs) will be only initiated after 3-month observation period. AAD therapy of choice is amiodarone. Amiodarone loading dose of 10 grams is recommended, followed by maintenance dose of 200-400mg daily to achieve successful PVC suppression. Investigators define successful PVC suppression only if ≥ 80% absolute reduction in PVC burden is achieved after a drug or intervention. Alternatively, sotalol and/or propafenone could be considered at discretion of electrophysiologists (sotalol dose of at least 120mg twice daily, propafenone 150-300mg tid) if there is a significant concern of safety profile of amiodarone.

Group Type: ACTIVE_COMPARATOR

Amiodarone (Antiarrhythmic drug)

Intervention Type: DRUG

AAD therapy of choice is amiodarone. Amiodarone loading dose of 10 grams is recommended, followed by maintenance dose of 200-400mg daily to achieve successful PVC suppression. Alternatively, sotalol and/or propafenone could be considered at discretion of electrophysiologists (sotalol dose of at least 120mg twice daily, propafenone 150-300mg tid) if there is a significant concern of safety profile of amiodarone.

Interventions

Radiofrequency ablation

RFA to achieve PVC suppression will be performed using standard techniques and protocols similar to those patients that do not participate in this clinical study.

Intervention Type: PROCEDURE

Amiodarone (Antiarrhythmic drug)

AAD therapy of choice is amiodarone. Amiodarone loading dose of 10 grams is recommended, followed by maintenance dose of 200-400mg daily to achieve successful PVC suppression. Alternatively, sotalol and/or propafenone could be considered at discretion of electrophysiologists (sotalol dose of at least 120mg twice daily, propafenone 150-300mg tid) if there is a significant concern of safety profile of amiodarone.

Intervention Type: DRUG

Other Intervention Names

Ablation; Amiodarone

Eligibility Criteria

Inclusion Criteria

• LV dysfunction (calculated LVEF < or equal to45% based on Echo) within 150 days of Enrollment (Day 0)
• PVC burden > or equal to 10% by at least a 24-hr ambulatory Holter monitor (within 150 days of Enrollment (Day 0)

Exclusion Criteria

• Age < 18 years old
• Current amiodarone use or within last 2 months
• Current use of antiarrhythmic drugs class I or III
• Contraindication to amiodarone use or any other class III antiarrhythmic
• Severely symptomatic PVCs (unable to complete 3-month observation period)
• Severe/significant CAD with planned revascularization in the near future
• Complete AV block and pacemaker dependent
• Pacemaker or ICD with >10% RV pacing
• Severe valvular heart disease or planned valvular/cardiac surgery
• Uncontrolled / untreated endocrinopathies
• Uncontrolled HTN, (systolic BP >180mmHg or diastolic >110 mmHg)
• Hypertrophic cardiomyopathy
• Systemic infiltrative and immune disorders
• Family history of dilated CM in a first degree relative
• Alcohol abuse or illicit drug use
• Contraindication to short-term acute anticoagulation (due to possible randomization to ablation)
• Atrial fibrillation and flutter with rapid ventricular response with possible tachycardia-induced cardiomyopathy
• Possible infectious etiology of cardiomyopathy
• Pregnant or lactating women
• Previous PVC ablation

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Virginia Commonwealth University

OTHER

Sponsor Role: collaborator

University of California, San Francisco

OTHER

Sponsor Role: collaborator

University of Calgary

OTHER

Sponsor Role: collaborator

Washington University School of Medicine

OTHER

Sponsor Role: collaborator

Wake Forest University Health Sciences

OTHER

Sponsor Role: collaborator

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

Hunter Holmes Mcguire Veteran Affairs Medical Center

FED

Sponsor Role: lead

Responsible Party

Jose Huizar

Director, Arrhythmia and Device Clinic

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Jose F Huizar, M.D.

Role: STUDY_DIRECTOR

McGuire VA Medical Center

Locations

University of California Los Angeles Medical Center

Los Angeles, California, United States

University of California, San Francisco

San Francisco, California, United States

James A. Haley Veterans' Hospital

Tampa, Florida, United States

Rush University Medical Center

Chicago, Illinois, United States

Roxbury VA Medical Center

West Roxbury, Massachusetts, United States

Northwell Health System-Staten Island University Hospital

Staten Island, New York, United States

University of Pennsylvania Medical Center

Philadelphia, Pennsylvania, United States

University of Virginia

Charlottesville, Virginia, United States

McGuire VA Medical Center

Richmond, Virginia, United States

Virginia Commonwealth University

Richmond, Virginia, United States

Libin Cardiovascular Institute, University of Calgary

Calgary, Alberta, Canada

Countries

United States; Canada

References

Torrado J, Sima A, Comstuck C, Kaszala K, Tan A, Koneru J, Frankel DS, Marchlinski F, Kowalski M, Sharma P, Gerstenfeld EP, Vaseghi M, Shivkumar K, Malhotra R, Morillo C, Ellenbogen KA, Huizar JF. Prevalence of frequent premature ventricular contractions and left-ventricular systolic dysfunction in patients receiving Holter monitoring. J Cardiovasc Electrophysiol. 2025 Jan;36(1):54-61. doi: 10.1111/jce.16478. Epub 2024 Oct 24.

Reference Type: DERIVED

PMID: 39445764 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

R34HL138110-01

Identifier Type: NIH

Identifier Source: secondary_id

View Link

NIH ID 9372611

Identifier Type: -

Identifier Source: org_study_id