Clinical trial NCT00487279: DEfibrillators To REduce Risk by MagnetIc ResoNance Imaging Evaluation
Official title: DEfibrillators To REduce Risk by MagnetIc ResoNance Imaging Evaluation
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: NA
Conditions: Coronary Artery Disease
Left Ventricular Dysfunction
Sudden Cardiac Death
Keywords: Coronary
Artery
Disease
Sudden
Cardiac
Death
ICD
Lead sponsor: Abbott Medical Devices
Sponsor class: INDUSTRY
Collaborators: name: Northwestern University
First posted: 2007-06-18
Enrollment: 81
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This trial is a prospective, multi-center, randomized study of patients with coronary artery disease (CAD) and mild to moderate left ventricular (LV) dysfunction. The primary objective of this study is to test the hypothesis that Implantable Cardioverter Defibrillator (ICD) therapy in combination with medical therapy in patients with an infarct size greater than or equal to 10% of the left ventricular mass improves long term survival compared to medical therapy alone. In addition to the 2-arm randomized trial, the study will also include a non-investigational registry of non-randomized patients.

Detailed description: Detailed Description:

The utilization of ICD therapy has resulted in significant reduction in mortality among those at highest risk of sudden cardiac death, such as survivors of cardiac arrest and patients presenting with symptomatic sustained ventricular arrhythmias. Patients with CAD and advanced LV dysfunction (EF \<35%) also benefit from ICD. However, although at high risk, these patients represent only a small percentage of the population who die suddenly. While there are many tests that have been used for stratification of risk for sudden cardiac death, the two that have documented clinical utility are determination of left ventricular ejection fraction and presence of inducibility of ventricular tachycardia during programmed electrical stimulation performed as part of EP testing. The utility of these tests likely result from their ability to select patients who have the requisite substrate allowing for sustained ventricular tachyarrhythmias. It has been shown that ventricular tachycardia occurs more commonly in the setting of larger infarcts. Ejection fraction has been related to infarct size; presumably, the larger the area of infarction, the lower the ejection fraction. Electrophysiologic testing directly establishes the presence of substrate by the actual induction of ventricular tachycardia.

A major limitation of electrophysiologic programmed stimulation is the high number of false negative findings. Thus, a significant number of patients without inducible arrhythmias remain at risk. CE-MRI provides functional information (EF, LV Volumes, LV mass, etc), which is routine in the initial evaluation of post-MI patients, and in addition provides detailed geometry of scar tissue. There is a clear association between inducible arrhythmias and scar size which until the development of cardiac MRI, could not be seen in humans. Use of cardiac MRI has demonstrated that although most patients with a large MI were inducible, a small but significant number of patients, who remain at risk, were not inducible. There was also an association between death and infarct size in patients with cardiovascular risk factors but no established CAD.

The Center for Medicare Services (CMS) has recently decided in a coverage decision that patients with left ventricular dysfunction, heart failure, and an ejection fraction of \<35% would be eligible to receive an ICD as long as they are enrolled in a prospective registry. Patients with LV ejection fractions greater than 35% or those without heart failure and ejection fractions over 30%, represent a more difficult management dilemma. However, since the majority of out of hospital cardiac arrests occur in patients with EF \>35%, managing these patients is crucial in addressing the epidemiologic problem of sudden cardiac death.

The primary objective of this trial is to test the hypothesis that therapy with an ICD combined with medical therapy improves long-term survival compared to medical therapy alone in patients with CAD, infarct mass greater than or equal to 10% of the left ventricle and left ventricular dysfunction who do not have an indication for ICD by either of the following criteria. Patients must have an EF of \>35% or have an EF of 30-35% and must not have inducible ventricular tachycardia or have NYHA Class II or greater heart failure (Target Population).

The secondary objective is to test the hypothesis that therapy with an ICD combined with medical therapy improves arrhythmic survival compared to medical therapy alone in patients with CAD, infarct mass greater than or equal to 10% and left ventricular dysfunction who do not have an indication for ICD based on the Target Population described above.

Recruitment: All patients who have a history of coronary heart disease (CAD) with documentation of either myocardial infarction (MI) or left ventricular dysfunction (LVD), a preliminary ejection fraction (EF) \> 35% and have previously undergone a contrast-enhanced MRI (CE-MRI) study for clinical diagnostic reasons or as part of the study entry screening procedure may be further evaluated for eligibility for this trial. In addition, patients with an ejection fraction of 30-35% may be eligible for the study if they do not currently have an indication for an ICD based on Target Population criteria described above. These patients may have NYHA Class I heart failure, no non-sustained VT on holter monitor, or if non-sustained VT is present, there is the absence of inducible VT at EP study.

The first 1550 patients who are found to have an EF \>30% with NYHA Class I heart failure or 35% by routine clinical evaluation and who also have an MI involving greater than or equal to 10% of total left ventricular mass will be enrolled in the main randomized portion of the trial. These patients will be randomly assigned to one of two groups: ICD therapy in combination with medical therapy (ICD Group) or medical therapy alone (Control Group).

Follow-Up: Clinic visits are required every 6 months until the completion of the study. Telephone contact is required every six months to assess vital status and obtain new information regarding medical status and/or medical events. The telephone calls alternate with the clinical visits, so that patient contact will occur every 3 months until the completion of the study.

Non-Investigational Registry:

The primary objective of the registry sub-study is to test the hypothesis that infarct mass as measured by contrast enhanced Cardiac MRI (CE-MRI) is a better predictor for sudden cardiac death than LV ejection fraction. The registry will examine infarct mass as measured by Cardiac MRI and LV ejection fraction (EF) as predictors for SCD.

The purpose of the registry is hypothesis generating and no labeling or other indications are anticipated based on registry findings.

Participation in the Registry requires that the patient has undergone a contrast-enhanced cardiac MRI prior to enrollment. In order to ensure consistent infarct mass assessments, the cardiac MRI study submitted to determine eligibility for randomization must meet the following criteria:

1. CE-cardiac MRIs must be obtained using Siemens, General Electric or Phillips equipment.
2. The contrast agent must be gadolinium-based at a dose sufficient to render images of acceptable quality.
3. The CE-cardiac MRI must be available for electronic submission to the MRI Core laboratory for analysis.

If techniques for infarct mass measurement or data acquisition change during the course of the trial, the Core laboratory and the Steering Committee may choose to alter some of the above parameters.

Once consent to participate in the registry has been obtained, the site will forward the CE-MRI study to the CE-MRI core lab for analysis to determine placement in the appropriate registry, baseline demographics characteristics will be collected on all registry patients. This will aid in statistical analysis to verify the generalizability of the findings. The differences in total survival between these groups will also be compared using the same methodology as for the primary end-point. Patients with and without ICD implants will be compared separately. In addition, blood specimens for genetic sampling and biomarker testing will be obtained on all patients in the registry cohort who agree, to determine if any of SCD substrates exist in the DETERMINE registry population.

Study subjects will be contacted by mail by the Endpoint Coordinating Center at Brigham and Women's Hospital in Boston every 6 months to determine vital status and obtain any new information regarding change in medical status or the occurrence of any medical events. This will promote the continued relationship between the study participant and the enrolling center and can also be used to remind the study subject of their next scheduled appointment.

Scope and Duration of the trial:

* Up to 100 sites to screen a total of 10,000 patients will enroll 1550 patients into the randomized study recruited from a total of 10,000 patients contributing data and CE-MRI images to the registries.
* Registry enrollment per site = \~90 subjects
* Randomization per site = 1-3 per month (expected randomized enrollment per site is 20 patients or more )
* Estimated enrollment period: 36 months
* 24 months of follow-up after the last patient is randomized

Eligibility criteria: Inclusion Criteria:

Randomized Arm

1. Evidence of Coronary Artery Disease (CAD)a.
2. Evidence of prior Myocardial Infarction defined by either:

   A. Clinical history of prior myocardial infarction OR B. Mild-moderate systolic LV dysfunction with an EF ≤50%
3. LVEF\>35% by any current standard evaluation technique (e.g., echocardiogram, MUGA, angiography).

   • Patients who have an EF between 30-35% and NYHA Class I heart failure who do not have a history of ventricular tachyarrhythmias, or inducible ventricular tachycardia during electrophysiological (EP) testing can be enrolled (Target Population).
4. CE-MRI measure of infarct mass \> 10% of LV mass (as measured by the MRI core lab)

   • If CE-MRI performed ≤ 40 days after myocardial infarction infarct mass must be ≥ 15% of the LV mass.
5. Patients aged 18 years or above

   1. CAD will be confirmed by evidence of one of the following three (3) criteria 1) Prior myocardial infarction, 2) Significant stenosis of a major epicardial vessel (\>50% proximal or 70% distal) by coronary angiography, 3) Prior revascularization (percutaneous coronary intervention or coronary artery bypass surgery. Patients may not be randomized until 90 days after revascularization.
   2. MI should be documented by the presence of two (2) of the following three (3) criteria: 1) Symptoms consistent with myocardial infarction (i.e. chest pain, shortness of breath), 2) Q-waves on electrocardiogram and 3) Elevated cardiac enzymes (CPK elevation \> two times or troponin elevation \> three times the upper limit of normal for the lab). Patients may not be randomized until 40 days after myocardial infarction.

Exclusion Criteria

1. History of cardiac arrest or spontaneous or inducible sustained VT (15 beats or more at a rate of 120 BPM or greater)\*
2. Unexplained syncope
3. Need for revascularization based on investigator's clinical assessment within the next 12 months (patients may be reevaluated 90 days after revascularization)
4. Currently implanted permanent pacemaker and/or pacemaker/ICD lead
5. Contraindication to a ICD implant (i.e. inadequate venous access, bleeding disorder)
6. Acute or chronic severe renal insufficiency (\< 30mL/min/1.73m2); acute renal insufficiency of any severity due to hepato-renal syndrome
7. Current or planned renal or liver transplant
8. End stage renal disease on hemodialysis or peritoneal dialysis
9. Contraindication to CE-MRI or history of allergy to gadolinium-based contrast dye
10. Metal fragments in the eyes or face, implantation of any electronic devices such as (but not limited to) cardiac pacemakers, cardiac defibrillators, cochlear implants or nerve stimulators, surgery on the blood vessels of the brain, body piercing
11. Recent MI (\<40 days) or revascularization (\<90 days)
12. CVA within 90 days
13. Antiarrhythmic drug therapy for ventricular arrhythmias
14. New York Heart Association CHF functional class IV at enrollment

Non-Investigational Registry Inclusion Criteria

* Evidence of CAD a with either a history of prior myocardial infarction OR any LV dysfunction
* Evidence of LV dysfunction (ejection fraction) as measured by any current standard screening technique (e.g., echocardiogram, MUGA, angiography).c
* Clinical CE-MRI within the past 12 months (scheduled or completed)
* Patients aged 18 years or above
* CAD will be confirmed by evidence of one of the following three (3) criteria 1) Prior myocardial infarction, 2) Significant stenosis of a major epicardial vessel (\>50% proximal or 70% distal) by coronary angiography, 3) Prior revascularization (percutaneous coronary intervention or coronary artery bypass surgery.
* MI should be documented by the presence of two (2) of the following three (3) criteria: 1) Symptoms consistent with myocardial infarction (i.e. chest pain, shortness of breath), 2) Q-waves on electrocardiogram and 3) Elevated cardiac enzymes (CPK elevation \> two times or troponin elevation \> three times the upper limit of normal for the lab).
* Patients can be enrolled in the registry even if they have received or are about to receive an ICD for primary prevention.

Exclusion Criteria

* History of cardiac arrest or spontaneous or inducible sustained VT (15 beats or more at a rate of 120BPM or greater)\*
* Contraindication to CE-MRI or history of allergy to gadolinium-based contrast
* Spontaneous arrhythmia that precludes assessment by cardiac MRI
* Acute or chronic severe renal insufficiency (\<30mL/min/1.73m2); acute renal insufficiency of any severity due to hepato-renal syndrome.
* Current or planned renal or liver transplant
* End stage renal disease on hemodialysis or peritoneal dialysis
* Metal fragments in the eyes or face, implantation of any electronic devices such as (but not limited to) cardiac pacemakers, cardiac defibrillators, cochlear implants or nerve stimulators, surgery on the blood vessels of the brain , body piercing
* Uninterpretable MRI images by core lab criteria
* Any condition other than cardiac disease that, in the investigator's judgment, would seriously limit life expectancy (poor 6-month survival)
* Marked valvular heart disease requiring surgical intervention
* Current alcohol or drug abuse
* Participating in other trials with an active treatment arm (not to exclude patients who are in trials of diagnostic techniques or approved therapies)
* Unwilling or unable to provide informed consent \*Exception: Cardiac arrest or spontaneous VT that occurs during the acute MI event will not be considered an exclusion

Primary outcomes:
measure: All-cause Mortality
timeFrame: Total survival will be evaluated 2 years after the last patient is randomized.
Secondary outcomes:
measure: Arrhythmic Mortality
timeFrame: Total survival will be evaluated 2 years after the last patient is randomized.
Other outcomes:
Locations:
city: Anchorage
country: United States
facility: Alaska Regional Hospital and Alaska Cardiovascular Research Foundation, LLC
state: Alaska
city: Tucson
country: United States
facility: University of Arizona
state: Arizona
city: Glendale
country: United States
facility: Glendale Memorial Hospital and Health Center
state: California
city: Long Beach
country: United States
facility: Long Beach Memorial Medical Center
state: California
city: Los Angeles
country: United States
facility: Hollywood Presbyterian Medical Center
state: California
city: Los Angeles
country: United States
facility: UCLA Medical Center
state: California
city: Newport Beach
country: United States
facility: Hoag Memorial Hospital Presbyterian and Radin Inc.
state: California
city: Sacramento
country: United States
facility: Catholic Healthcare West (d/b/a mercy General Hospital) and Regional Cardiology Associates
state: California
city: Denver
country: United States
facility: Rocky Mountain Cardiovascular Associates
state: Colorado
city: Jacksonville
country: United States
facility: University of Florida-Shands/Jacksonville
state: Florida
city: Orlando
country: United States
facility: Orlando Regional Healthcare System
state: Florida
city: Pensacola
country: United States
facility: Cardiology Consultants of Northwest Florida
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Gainesville
country: United States
facility: Northeast Georgia Heart Center, PC
state: Georgia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Lombard
country: United States
facility: Midwest Heart Foundation
state: Illinois
city: Fort Wayne
country: United States
facility: Lutheran Hospital of Indiana and Northern Indiana Research Alliance of the Heart Center Medical Group
state: Indiana
city: Indianapolis
country: United States
facility: The Care Group
state: Indiana
city: Ashland
country: United States
facility: Kentucky Heart Institute / King's Daughter
state: Kentucky
city: Lexington
country: United States
facility: Baptist Healthcare System Inc. (d/b/a Central Baptist Hospital)
state: Kentucky
city: Baltimore
country: United States
facility: Johns Hopkins
state: Maryland
city: Hyattsville
country: United States
facility: MedStar Research Institute (Washington Hospital Center)
state: Maryland
city: Boston
country: United States
facility: The Brigham and Women's Hospital Inc.
state: Massachusetts
city: Boston
country: United States
facility: Caritas St. Elizabeth's Medical Center
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: Kalamazoo
country: United States
facility: Advanced Cardiac Healthcare (Bronson Methodist Hospital)
state: Michigan
city: Royal Oak
country: United States
facility: William Beaumont Hospital
state: Michigan
city: Minneapolis
country: United States
facility: Minneapolis Heart Institute Foundation/Abbott NW Hospital
state: Minnesota
city: Minneapolis
country: United States
facility: Metropolitan Cardiology Consultants (MCC) / Allina Health System (Mercy & Unity Hospitals)
state: Minnesota
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Ridgewood
country: United States
facility: Valley Hospital
state: New Jersey
city: Brooklyn
country: United States
facility: New York Methodist Hospital
state: New York
city: New York
country: United States
facility: St. Luke's - Roosevelt Hospital Center
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Roslyn
country: United States
facility: St. Francis Hospital
state: New York
city: Greensboro
country: United States
facility: LeBauer Cardiovascular Research Foundation and Moses H. Cone Memorial Hospital
state: North Carolina
city: Cleveland
country: United States
facility: University of Maryland Baltimore and Maryland Medical Center
state: Ohio
city: Cleveland
country: United States
facility: University Hospitals of Cleveland
state: Ohio
city: Cleveland
country: United States
facility: MetroHealth Medical Center
state: Ohio
city: Cleveland
country: United States
facility: The Cleveland Clinic Foundation
state: Ohio
city: Elyria
country: United States
facility: North Ohio Research, Ltd.
state: Ohio
city: Tulsa
country: United States
facility: AHS Hillcrest Medical Center, LLC and Oklahoma Heart Institute
state: Oklahoma
city: Abington
country: United States
facility: Abington Memorial Hospital
state: Pennsylvania
city: Allentown
country: United States
facility: Lehigh Valley Hospital and Health Network
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Allegheny-Singer Research Institute
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Germantown
country: United States
facility: Stern Cardiovascular Center
state: Tennessee
city: Nashville
country: United States
facility: Centennial Medical Center
state: Tennessee
city: Nashville
country: United States
facility: St. Thomas Research Institute, LLC
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt Medical Center
state: Tennessee
city: Houston
country: United States
facility: Methodist Hospital Research Institute
state: Texas
city: Houston
country: United States
facility: St. Luke's Episcopal Hospital
state: Texas
city: Norfolk
country: United States
facility: Sentara Hospitals and Sentara Cardiovascular Research Institute
state: Virginia
city: Virginia Beach
country: United States
facility: Cardiovascular Associates Virginia Beach
state: Virginia
city: Bellingham
country: United States
facility: North Cascade Cardiology
state: Washington
Study officials:
affiliation: Northwestern University
name: Alan Kadish, MD
role: PRINCIPAL_INVESTIGATOR
References: