Treatment Of Atrial Fibrillation In Preserved Cardiac Function Heart Failure

Study Overview
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Brief Summary
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Heart failure (HF) with preserved left ventricular function (pEF) is difficult clinical syndrome to treat effectively with few evidence based therapies. Atrial fibrillation (AF) is now an important co-morbidity being observed in 43% of patients with HFpEF. Rhythm control has not been studied in this population. Catheter ablation and antiarrhythmic drugs are rhythm control therapies that have been used for treatment of AF without HF or HF with reduced systolic function but have not been widely applied in HFpEF. No controlled comparative evaluation has been performed in HFpEF. The introduction of wireless pulmonary artery hemodynamic monitoring has permitted optimization of HF therapy in patients with chronic HF with reduced and preserved EF. Reduction in HF hospitalizations has been observed in post hoc analyses of HFpEF patients but has not been systematically applied in AF patients with HFpEF. In this study, we propose to study both rhythm control and optimized HF therapeutic approaches in an AF with HFpEF study population in a pilot study using a sequential two phase randomized controlled clinical trial design.

Detailed Description
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This is a prospective pilot study utilizing a randomized comparative sequential evaluation of these two therapeutic approaches in two consecutive phases: Phase 1 will examine an initial catheter ablation strategy versus an initial antiarrhythmic drug (AAD) therapy strategy for safety and efficacy in patients with atrial fibrillation with preserved systolic cardiac function, heart failure hospitalization in the past year or one or more documented HF events. Phase 2 will examine optimized rhythm control therapy with and without wireless pulmonary artery pressure hemodynamic monitoring for HF therapy optimization in the same patients as in Phase 1 with documented atrial fibrillation with preserved systolic cardiac function, prior HF hospitalization and class III heart failure. This is an open label two phase study in which patients will be randomized in a 1:1 ratio to either ablation or AAD with a pilot phase 1 that will consist to 100 patients enrolled at 10 centers. They will be followed for a minimum of 6 months, after a three month blanking period, for event rates of the primary endpoint as well as safety and efficacy. Phase 2 will randomize patients completing Phase 1 to hemodynamic monitoring with a wireless pulmonary artery sensor insertion and guided HF therapy or empiric standard of care HF therapy. They will be followed for a minimum of 6 months, after a three month blanking period for optimization of rhythm and HF therapies. This study is a sequential randomized, open label, active-controlled trial, designed to compare a composite clinical outcomes endpoint of heart failure hospitalization and/or cardiovascular mortality among these patients randomized to each of these treatment strategies. This endpoint will be employed in both pilot trial phases to assess event rates, as well as safety endpoints. This data will form the basis of a larger pivotal trial

Official Title
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A Phase 4, Randomized, Open Label, Multicenter Prospective Comparative Study To Evaluate The Treatment Of Atrial Fibrillation In Preserved Cardiac Function Heart Failure

Conditions
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Atrial Fibrillation, Heart Failure, Diastolic Heart Failure

Intervention / Treatment
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* Device: Catheter ablation
* Drug: Rate or Rhythm control antiarrhythmic drugs for atrial fibrillation
* Device: Insertion of CardioMems Hemodynamic monitor
* Drug: Empiric heart failure drug therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient with symptomatic Heart Failure with preserved systolic cardiac function & paroxysmal or persistent atrial fibrillation who meet the following criteria Subjects must be willing and able to give written informed consent Outpatients ≥ 50 years of age, male or post- menopausal female patients; premenopausal female patients who are on and will maintain continuous birth control therapy during the study. Subjects must have documented HFpEF & paroxysmal or persistent AF and satisfy one of the following inclusion criteria a) Consecutive patients with AF, symptomatic heart failure requiring diuretic therapy for at least 30 days prior to study entry b) Hospitalization for HF and/or AF in the past 12 months prior to catheter ablation with documented NT-pro BNP >200pg/ml for patients not in AF or > 600 pg/ml for patients in AF on screening ECG or NYHA class 2, 3 or ambulatory class 4 heart failure documented NT-pro BNP >300pg/ml for patients not in AF or > 900 pg/ml for patients in AF on screening ECG c).Evidence of structural heart disease defined as by at least 1 of the following echocardiography findings (any local measurement made during the screening epoch or within the 6 months prior to screening visit): 1) LA enlargement defined by at least 1 of the following: LA width (diameter) >3.8 cm or LA length >5.0 cm or LA area >20 cm2 or LA volume >55 ml or LA volume index >29 ml/m2 2) LVH defined by septal thickness or posterior wall thickness >1.1 cm d).Left ventricular ejection fraction > 45% using standard imaging techniques at enrollment for study or in prior 6 months e).ECG documented paroxysmal or persistent atrial fibrillation f).Patients are candidates for a clinically indicated catheter ablation procedure, and Rate or Rhythm control antiarrhythmic drug therapy Patients should be on one or more standard heart failure drug therapy (ies) for heart failure with preserved cardiac function for at least 30 days Written informed consent for the clinically indicated study procedures Patients must be candidates for long-term OAC therapy based on clinical practice guidelines for treatment of AF. Guidelines for GFR as established for DOACSs will be applicable to all subjects. Exclusion Criteria: Patients with HFpEF who were not on any drug therapy for HF or have uncontrolled hypertension defined as systolic BP >180 mm Hg at screening or >150 mm Hg on three or more antihypertensive drugs Patients with QRS duration of >120 ms and intraventricular conduction defects who are or maybe candidates for or have received ventricular resynchronization therapy Recent (<1 month) myocardial infarction or acute coronary syndrome Recent (<3 months) coronary revascularization procedures Documented LA thrombus on TEE or any LVEF measurement <40% Patients who are not candidates for Rate or Rhythm control drug therapy for AF Dilated cardiomyopathy due to potentially reversible cause e.g. myocarditis Contraindications to anticoagulant therapy or adverse event with prior Warfarin or DOAC therapy Creatinine clearance <30ml/min or >95ml/min Advanced hepatic disease, pulmonary disease clinically significant congenital heart disease, clinically significant pericardial constriction, hypertrophic cardiomyopathy, infiltrative cardiomyopathy, decompensated valvular heart disease likely to require surgical or percutaneous intervention during the trial Recent stroke (<3 months) or thromboembolic event, transient ischemic attack or carotid angioplasty in the prior 3 months Recent (<3 months) intracranial or other major bleeding event Candidates for heart or any other organ transplantation or left ventricular assist devices, recent (< 3 months) valve or other cardiac surgery Patients requiring ACE inhibitor or ARB drug therapy for any reason History of hypersensitivity to antiarrhythmic drugs Patients with other clinically significant medical condition that precludes study participation Patients with life expectancy < 1 year Premenopausal female patients, who are not on continuous birth control therapy or are likely to discontinue it at any time during the entire duration of study enrollment. Pregnant or nursing lactating mothers or women of childbearing potential who are not on effective contraceptive therapy Patients who have been noncompliant with medical regimens or have social or other issues precluding regular follow up, history of alcohol or drug abuse in past 12 months.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a prospective pilot study utilizing a randomized comparative sequential evaluation of two therapeutic approaches in two consecutive phases. Phase 1 will examine an initial catheter ablation strategy versus an initial antiarrhythmic drug (AAD) therapy strategy for safety and efficacy in patients with atrial fibrillation with preserved systolic cardiac function, heart failure hospitalization in the past year or one or more documented HF events. Phase 2 will examine optimized rhythm control therapy with and without wireless pulmonary artery pressure hemodynamic monitoring for HF therapy optimization in the same patients as in Phase 1 with documented atrial fibrillation with preserved systolic cardiac function, prior HF hospitalization and class III heart failure.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Phase 1 Catheter Ablation<br>Patients with atrial fibrillation and heart failure with preserved systolic function will be enrolled after informed consent. They randomly assigned to catheter ablation as one arm. They will undergo a catheter ablation procedure within 14 days of randomization. This procedure will include isolation of all four pulmonary veins in the antrum using catheter delivered radiofrequency current, cryothermal or laser ablation energy with standard FDA approved ablation catheter systems used in atrial fibrillation ablation. Patients will be monitored for a minimum period of 9 months after the catheter ablation intervention. | Device: Catheter ablation<br>* Delivery of physical energy from external energy source via percutaneously inserted electrophysiologic catheter to destroy heart tissue in the human atrium and adjoining vasculature<br>* Other names: Ablation;|
| Active Comparator: Phase 1 Antiarrhythmic drug therapy<br>Patients with atrial fibrillation and heart failure with preserved systolic function will be enrolled after informed consent. They will be randomly assigned to antiarrhythmic drug therapy for Rate or Rhythm control in this arm. They will undergo drug dose titration within 14 days of randomization. . Patients will be monitored for a minimum period of 9 months after the AAD therapy initiation | Drug: Rate or Rhythm control antiarrhythmic drugs for atrial fibrillation<br>* Administration of antiarrhythmic drug to achieve either rate control or restoration of sinus rhythm for management of atrial fibrillation<br>* Other names: Antiarrhythmic Drug;|
| Active Comparator: Phase 2 Guided Heart Failure Therapy<br>Patients with atrial fibrillation and heart failure with preserved systolic function will be enrolled after informed consent and completion of Phase 1. They will be randomly assigned to insertion of an implantable hemodynamic monitor in this arm and heart failure therapy guided by wireless hemodynamic monitoring. Patients will be monitored for a minimum period of 9 months after the implantable hemodynamic monitor insertion on guided drug therapy | Device: Insertion of CardioMems Hemodynamic monitor<br>* Insertion of wireless hemodynamic monitor to provide hemodynamic data to guide heart failure therapy to achieve heart failure improvement.<br>* Other names: IPM;|
| Active Comparator: Phase 2 Empiric Heart Failure Therapy<br>Patients with atrial fibrillation and heart failure with preserved systolic function will be enrolled after informed consent and completion of Phase 1. They will be randomly assigned to heart failure management with empirical selection of heart failure therapy. Patients will be monitored for a minimum period of 9 months after the initiation of empirically selected heart failure drug therapy | Drug: Empiric heart failure drug therapy<br>* Administration of heart failure drug therapy based on clinical evaluation to achieve heart failure improvement.<br>* Other names: HFDrug;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Composite of Heart failure hospitalizations and/or Cardiovascular mortality | Time to either first of Heart failure hospitalization and/or mortality due to cardiovascular etiology | From date of randomization until the date of first documented heart failure hospitalization or date of death from cardiovascular causes, whichever came first, assessed up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All cause Mortality | Time to mortality due to any cause | From date of randomization until the date of death from any cause, assessed up to 12 months | 
| MACE events | Time to major adverse cardiovascular event | From date of randomization until the date of first documented major adverse cardiovascular event, assessed up to 12 months | 
| Cardiovascular Hospitalization | Time to first hospitalization due to cardiovascular causes | From date of randomization until the date of first documented hospitalization due to cardiovascular causes , assessed up to 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Atrial fibrillation, Heart failure, Diastolic heart failure, Catheter Ablation, Antiarrhythmic Drugs