Reducing Decompensation Events Utilizing Intracardiac Pressures in Patients With Chronic Heart Failure (HF) (REDUCEhf)

Study Overview
=================
Brief Summary
-----------------
The purpose of this clinical research study is to evaluate the safety and effectiveness of the investigational implantable hemodynamic monitor (IHM), and of the IHM in combination with an implantable cardioverter defibrillator (ICD). The investigational IHM has the ability to record and report the force with which the heart pumps blood (heart pressures). When combined with the ICD, the device has the additional ability to send a strong electrical impulse, or shock, to the heart when it detects dangerously fast heartbeats to return it to a normal rhythm. The IHM and IHM/ICD are implanted surgically just under the skin in the upper chest area. This study will also determine how doctors use the information related to heart pressures in the management of heart failure.

Official Title
-----------------
Reducing Decompensation Events Utilizing Intracardiac Pressures in Patients With Chronic HF (REDUCEhf)

Conditions
-----------------
Heart Failure

Intervention / Treatment
-----------------
* Device: Implantable Hemodynamic Monitor (Chronicle® IHM), and IHM in combination with single chamber ICD (Chronicle ICD)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subjects with heart failure that only sometimes interferes with daily activities (New York Heart Association [NYHA] Class II (1)) or subjects with heart failure which severely limits daily activities (NYHA Class III (2)) at baseline Subject has appropriate medical therapy for heart failure (such as diuretic, angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) and beta blocker) for at least three months prior to the baseline evaluation. Subject has been on stable medications maximized to the subject's tolerance of ACE or ARB and beta blockers as determined by the study investigator for at least 30 days prior to baseline evaluation. (Stable is defined as no more than a 100% increase or a 50% decrease in dose.) If a subject is intolerant of ACE, ARB or beta blockers documented evidence must be available. Subject has had at least one heart failure-related hospitalization or at least one heart failure-related emergency department or urgent care visit necessitating heart failure-related intravenous therapy (e.g. diuretic administration) within 12 months prior to the baseline evaluation To be considered for Chronicle ICD: Subject has, or is at risk of having, a heart beat that is too fast and his/her doctor has determined he/she needs an implantable cardioverter defibrillator (ICD). Class II Subjects with cardiac disease resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or angina. Class III Subjects with cardiac disease resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes fatigue, palpitation, dyspnea, or angina. Exclusion Criteria: Subjects with severe heart failure who should always be resting (NYHA Class IV(3)) or Stage D(4) refractory heart failure. Subjects with severe renal dysfunction. Subjects with severe non-cardiac condition limiting 12-month survival. Subjects in concurrent studies that may confound the results. (3)Class IV Subjects with cardiac disease resulting in inability to carry on any physical activity without discomfort. Symptoms of heart failure or the anginal syndrome may be present even at rest. If any physical activity is undertaken, discomfort is increased. (4)Stage D refractory heart failure: Patients who have marked symptoms at rest despite maximal medical therapy (e.g., those who are recurrently hospitalized or cannot be safely discharged from the hospital without specialized interventions)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Arm<br>Physicians have access to device-based hemodynamic monitor information to guide patient management | Device: Implantable Hemodynamic Monitor (Chronicle® IHM), and IHM in combination with single chamber ICD (Chronicle ICD)<br>* Surgical implantation of hemodynamic device (IHM), or IHM/ICD, and intracardiac leads.<br>* Other names: Chronicle® IHM, Chronicle® ICD;|
| Placebo Comparator: Control Arm<br>Physicians do not have access to device-based hemodynamic monitor information to guide patient management | Device: Implantable Hemodynamic Monitor (Chronicle® IHM), and IHM in combination with single chamber ICD (Chronicle ICD)<br>* Surgical implantation of hemodynamic device (IHM), or IHM/ICD, and intracardiac leads.<br>* Other names: Chronicle® IHM, Chronicle® ICD;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of Subjects With an Attempted Implant of the Chronicle ICD System Free From System-related Chronicle ICD Complications at 6-months Post-implant. | A Chronicle ICD system-related complication was defined as any system-related adverse event that occurred during the clinical investigation which is (1) treated with invasive means (including intravenous drug therapy), (2) results in death or serious injury of subject, (3) results in the explant of any Chronicle ICD component,and/or (4) causes permanent loss of significant function of the implanted system. | Within 6 months post-implant | 
| Percent of Subjects With an Attempted Chronicle IHM Implant Free From Chronicle IHM System-related Complications at 6-months Post-implant | A Chronicle IHM system-related complication was defined as any system-related adverse event that occurred during the clinical investigation which is (1) treated with invasive means (including intravenous drug therapy), (2) results in death or serious injury of subject, (3) results in the explant of any Chronicle IHM component,and/or (4) causes permanent loss of significant function of the implanted system. | 6 months post implant | 
| Relative Risk Reduction of All Heart Failure Related Events in the Treatment Group Compared to the Control Group | The rate of HF-related events (hospitalizations >24h, hospitalizations <24h with IV therapy, ED visits with IV therapy, and urgent clinic visits with IV therapy) during the 12-month randomized follow-up period was compared between the Chronicle and Control groups. | 12 months post-implant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative Days in the Hospital for Heart Failure | The endpoint for this objective was defined as the cumulative days in hospital for heart failure (HF) expressed as a percentage of hospital free follow-up days during the 12-month randomized period. The relatedness of the events was based on the primary reason for which the subject was originally admitted to the hospital or seen in the emergency department or at an urgent visit, not on the development of new events that occur during hospitalization. | 12 months post-implant | 
| Relative Risk Reduction of Cardiovascular Related Events in the Treatment Group Compared to the Control Group | The rate of CV-related events (hospitalizations >24h, hospitalizations <24h with IV therapy, ED visits with IV therapy, and urgent clinic visits with IV therapy) during the 12-month randomized follow-up period was compared between the Chronicle and Control groups. | 12 months post-implant | 
| Freedom From All Cause Death or Heart Failure Hospitalization | Death from any cause or heart failure related hospitalization greater than 24 hours during the 12-month randomized period | 12 months post-implant | 
| Relative Risk of All-cause Events | All-cause events were defined as hospitalizations, hospitalizations <24 hours necessitating intravenous therapy, emergency department visits necessitating intravenous therapy or urgent visits necessitating intravenous therapy. | 12 months post-implant | 
| Percentage of Randomized Subjects at Each Level of the Composite Response Endpoint Between the Treatment Arm and the Control Arm. | The definitions of worsened, improved, and unchanged are as follows: Worsened: Subject dies, is hospitalized for worsening heart failure, permanently discontinues blinded randomized assignment and has worsening heart failure at time of study discontinuation, demonstrates worsening NYHA Class at LOCF, or moderate-marked worsening of global assessment score at LOCF. Improved: Subject has not worsened, and demonstrates improvement in NYHA class and/or moderate-marked improvement in subject global assessment score. Unchanged: Subject is neither worsened nor improved. | 12 months post implant | 
| Characterize Health Resource Utilization | Percentage of randomized days spent in the intensive care unit for heart failure. Reason for hospitalization was determined by the adverse event adjudication committee. | 12 months post implant | 
| Characterize Randomized Days Alive Out of Hospital | Randomized days alive outside of the hospital was computed for each subject as the total number of randomized days minus the number of randomized days spent in the hospital for any cause. | 12 months post implant | 
| Characterize Subject Survival | Death from any cause during the 12-month randomization period | 12 months post implant | 
| Characterize Medication Usage | The rate of change of cardiovascular medications in changes per subject month were computed and compared between treatment groups. | 12 months post implant | 
| Characterize Intracardiac Pressure | The average daily median estimated pulmonary arterial diastolic pressure (ePAD) was computed for each subject with at least 90 days of ePAD data available and compared between the Treatment and Control arms. | 12 months post implant | 
| Characterize Intracardiac Pressure Changes in Response to Subject Clinical Signs and Symptoms of Heart Failure Events | The average daily median estimated pulmonary arterial diastolic pressure (ePAD) was computed for each subject with at least 90 days of ePAD data available and compared between the Control Arm subjects with and without a heart failure related event during the 12-month randomized period. | 12 months post implant | 
| Characterize NYHA Functional Class | The outcome is the change in NYHA functional class between the baseline visit and the 12-month follow-up visit. At baseline subjects were required to be NYHA functional class II or III. The outcome will show the percentage of subjects that were functional class II and III at baseline and functional class I, II, III, or IV at the 12-month visit. The percent improvement from baseline is calculated as the percentage of subjects with a lower NYHA functional class at the 12-month visit compared to their NHYA functional class at baseline. | baseline to 12 months post implant | 
| Characterize Distance Walked in Six Minutes | The outcome is the change in distance walked in 6-minutes in meters between the baseline visit and the 12-month follow-up visit. The change in distance walked was calculated within each subject as the distance walked in 6-minutes at the 12-month visit minus the distance walked in 6-minutes at the baseline visit. Positive values indicate an increase in the distance walked in 6-minutes from baseline. | baseline to 12 months post implant | 
| Characterize Renal Function at the Baseline and 12-month Visit | Change in estimated glomerular filtration rate (eGFR) from baseline to the 12-month follow-up visit. eGFR was estimated using the MDRD forumula from the National Kidney Foundation (American Journal of Kidney Diseases 39: S1-299). Change in eGFR was computed as the 12-month eGFR value minus the baseline eGFR value. Positive values indicate an increase in eGFR from baseline and negative values indicate a decrease in eGFR from baseline. | baseline to 12 months post implant | 
| Characterize Intracardiac Pressure Monitoring Following Defibrillation Testing (Chronicle ICD Subjects Only) | Intracardiac pressure monitoring was deemed successful following defibrillation testing if physiological pressure waveforms were present following defibrillation testing. | implant | 
| Characterize Defibrillation Threshold Testing Efficacy (Chronicle ICD Subjects Only) | The outcome measure is the percentage of subjects implanted with the Chronicle ICD who completed defibrillation testing and had a 10 Joule safety margin | Implant | 
| Characterize Quality of Life at Baseline and 12-month Visit | The outcome is the change in the Minnesota Living with Heart Failure® (MNLWHF) questionnaire response from baseline to the 12-month follow-up visit. The MNLWHF questionnaire is a 21 question questionnaire scored from zero (no impact of heart failure) to 5 (severe impact of heart failure). The composite MNLWHF score ranges from 0 (no impact of heart failure) to 105 (severe impact of heart failure). Change in MNLWHF score was computed as the 12-month minus the baseline score. | baseline to 12 months post implant | 
| Characterize Arrhythmic Events | The rate of spontaneous VT (ventricular tachycardia)/VF (ventricular fibrillation) episodes during the 12-month follow-up period in episodes per subject month was compared between the Treatment Arm and the Control Arm | 12 months post implant | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Implantable cardioverter defibrillator, Intracardiac pressures