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

Prospective Assessment of Premature Ventricular Contractions Suppression in Cardiomyopathy(PAPS): A Pilot Study

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Cardiomyopathies; Ventricular Premature Beats, Contractions, or Systoles
• Intervention / Treatment: Procedure: Radiofrequency ablation; Drug: Amiodarone (Antiarrhythmic drug)

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.

• Study Type: Interventional
• Enrollment (Anticipated): 5
• Phase: Phase 4

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 2T9
      • Libin Cardiovascular Institute, University of Calgary
• United States
  • California
    • Los Angeles, California, United States, 90095
      • University of California Los Angeles Medical Center
    • San Francisco, California, United States, 94143
      • University of California, San Francisco
  • Florida
    • Tampa, Florida, United States, 33612
      • James A. Haley Veterans' Hospital
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
  • Massachusetts
    • West Roxbury, Massachusetts, United States, 02132
      • Roxbury VA Medical Center
  • New York
    • Staten Island, New York, United States, 10305
      • Northwell Health System-Staten Island University Hospital
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania Medical Center
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University
    • Richmond, Virginia, United States, 23249
      • McGuire VA Medical Center

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:

• 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

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: 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	Procedure: 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.; Other Names: Ablation
Active Comparator: 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.	Drug: 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.; Other Names: Amiodarone

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Improvement of left ventricular ejection fraction after PVC suppression	Compare the overall improvement or change in LVEF between RFA and AAD groups.	12 months
Responders to PVC suppression strategy	Assessment of the number of responders (delta LVEF ≥ 10%) after PVC suppression strategies will assess the effectiveness of RFA and AADs to reverse or improve cardiomyopathy induced by frequent PVCs.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Successful PVC suppression	Efficacy of Radiofrequency ablation vs. Antiarrhythmic drugs to achieve successful PVC suppression (defined as a reduction of PVC burden greater than ≥80%).	12 months
Composite Adverse Events	Composite end-point of adverse events, including worsening in NYHA functional class (I-IV), number of HF and cardiac-related admissions, RFA complications and AAD adverse effects and cardiovascular death.	12 months
Composite Arrhythmia Burden	Composite end-point of arrhythmia burden, including PVC recurrence, non-sustained (< 30sec) and sustained (> 30sec) ventricular arrhythmias and arrhythmic sudden cardiac death	12 months

Collaborators and Investigators

• Sponsor: Hunter Holmes Mcguire Veteran Affairs Medical Center
• Collaborators: Washington University School of Medicine; National Heart, Lung, and Blood Institute (NHLBI); Wake Forest University Health Sciences; University of California, San Francisco; University of Calgary; Virginia Commonwealth University
• Investigators: Study Director: Jose F Huizar, M.D., McGuire VA Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2018
• Primary Completion (Anticipated): August 31, 2021
• Study Completion (Anticipated): August 31, 2021

Study Registration Dates

• First Submitted: July 18, 2017
• First Submitted That Met QC Criteria: July 22, 2017
• First Posted (Actual): July 25, 2017

Study Record Updates

• Last Update Posted (Actual): April 14, 2021
• Last Update Submitted That Met QC Criteria: April 13, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Keywords: Cardiomyopathy; Premature Ventricular contractions
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Cardiac Conduction System Disease; Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Premature Birth; Cardiomyopathies; Cardiac Complexes, Premature; Ventricular Premature Complexes; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Enzyme Inhibitors; Membrane Transport Modulators; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Sodium Channel Blockers; Cytochrome P-450 CYP2D6 Inhibitors; Cytochrome P-450 CYP1A2 Inhibitors; Cytochrome P-450 CYP2C9 Inhibitors; Potassium Channel Blockers; Amiodarone; Anti-Arrhythmia Agents
• Other Study ID Numbers: NIH ID 9372611; R34HL138110-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: This is solely a pilot study of frequent PVCs and cardiomyopathy. Results of this preliminary data will not provide final definitive data, yet investigators will make it available. However, investigators will make clear that this pilot data is not intended to answer benefits of different PVC suppression strategies to avoid misinterpretation or inaccurate conclusions based solely on preliminary data.
• IPD Sharing Time Frame: 3-6 months after pilot study has been completed
• IPD Sharing Supporting Information Type: Clinical Study Report (CSR)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes