DETERMINE: DEfibrillators To REduce Risk by MagnetIc ResoNance Imaging Evaluation

• Sponsor: Abbott Medical Devices (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT00487279
• Collaborator: Northwestern University (Other)
• Enrollment: 81
• Locations: 56
• Arms: 2
• Duration (Months): 46
• Patients Per Site: 1.4
• Patients Per Site Per Month: 0

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Coronary Artery Disease; Left Ventricular Dysfunction; Sudden Cardiac Death	Device: Defibrillator; Other: Control	N/A

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 81 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: DEfibrillators To REduce Risk by MagnetIc ResoNance Imaging Evaluation
• Study Start Date: Jun 1, 2007
• Actual Primary Completion Date: Dec 1, 2010
• Actual Study Completion Date: Apr 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: ICD Group ICD (Implantable Cardioverter Defibrillator)	Device: Defibrillator; ICD(Implantable Cardioverter Defibrillator); Other Names: Implantable Cardioverter Defibrillator
Other: Control Group Medial Therapy	Other: Control; No Intervention; Other Names: No Intervention

Outcome Measures

Primary Outcome Measures

1. All-cause Mortality [Total survival will be evaluated 2 years after the last patient is randomized.]

Secondary Outcome Measures

1. Arrhythmic Mortality [Total survival will be evaluated 2 years after the last patient is randomized.]

   Arrhythmic mortality was reported as the number of randomized patients who died due to arrhythmic death. Arrhythmic death was defined as death due to arrhythmia or sudden death.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

Randomized Arm

1. Evidence of Coronary Artery Disease (CAD)a.

2. Evidence of prior Myocardial Infarction defined by either:

1. Clinical history of prior myocardial infarction OR B. Mild-moderate systolic LV dysfunction with an EF ≤50%

1. 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).

1. 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.

1. Patients aged 18 years or above

2. 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.

3. 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Alaska Regional Hospital and Alaska Cardiovascular Research Foundation, LLC	Anchorage	Alaska	United States	99508
2	University of Arizona	Tucson	Arizona	United States	85724
3	Glendale Memorial Hospital and Health Center	Glendale	California	United States	91204
4	Long Beach Memorial Medical Center	Long Beach	California	United States	90806
5	Hollywood Presbyterian Medical Center	Los Angeles	California	United States	90027
6	UCLA Medical Center	Los Angeles	California	United States	90095
7	Hoag Memorial Hospital Presbyterian and Radin Inc.	Newport Beach	California	United States	92263
8	Catholic Healthcare West (d/b/a mercy General Hospital) and Regional Cardiology Associates	Sacramento	California	United States	95818
9	Rocky Mountain Cardiovascular Associates	Denver	Colorado	United States	80204
10	University of Florida-Shands/Jacksonville	Jacksonville	Florida	United States	32209
11	Orlando Regional Healthcare System	Orlando	Florida	United States	32806
12	Cardiology Consultants of Northwest Florida	Pensacola	Florida	United States	32501
13	Emory University	Atlanta	Georgia	United States	30365
14	Northeast Georgia Heart Center, PC	Gainesville	Georgia	United States	30501
15	Northwestern University	Chicago	Illinois	United States	60611
16	Midwest Heart Foundation	Lombard	Illinois	United States	60148
17	Lutheran Hospital of Indiana and Northern Indiana Research Alliance of the Heart Center Medical Group	Fort Wayne	Indiana	United States	46804
18	The Care Group	Indianapolis	Indiana	United States	46260
19	Kentucky Heart Institute / King's Daughter	Ashland	Kentucky	United States	41101
20	Baptist Healthcare System Inc. (d/b/a Central Baptist Hospital)	Lexington	Kentucky	United States	40503
21	Johns Hopkins	Baltimore	Maryland	United States	21287
22	MedStar Research Institute (Washington Hospital Center)	Hyattsville	Maryland	United States	20783
23	The Brigham and Women's Hospital Inc.	Boston	Massachusetts	United States	02115
24	Caritas St. Elizabeth's Medical Center	Boston	Massachusetts	United States	02135
25	Henry Ford Health System	Detroit	Michigan	United States	48202
26	Advanced Cardiac Healthcare (Bronson Methodist Hospital)	Kalamazoo	Michigan	United States	49007
27	William Beaumont Hospital	Royal Oak	Michigan	United States	48073
28	Minneapolis Heart Institute Foundation/Abbott NW Hospital	Minneapolis	Minnesota	United States	55407
29	Metropolitan Cardiology Consultants (MCC) / Allina Health System (Mercy & Unity Hospitals)	Minneapolis	Minnesota	United States	55433
30	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198
31	Valley Hospital	Ridgewood	New Jersey	United States	07450
32	New York Methodist Hospital	Brooklyn	New York	United States	11215
33	St. Luke's - Roosevelt Hospital Center	New York	New York	United States	10019
34	Columbia University Medical Center	New York	New York	United States	10032
35	University of Rochester	Rochester	New York	United States	14642
36	St. Francis Hospital	Roslyn	New York	United States	11576
37	LeBauer Cardiovascular Research Foundation and Moses H. Cone Memorial Hospital	Greensboro	North Carolina	United States	27401
38	University of Maryland Baltimore and Maryland Medical Center	Cleveland	Ohio	United States	21201
39	University Hospitals of Cleveland	Cleveland	Ohio	United States	44106
40	MetroHealth Medical Center	Cleveland	Ohio	United States	44109
41	The Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
42	North Ohio Research, Ltd.	Elyria	Ohio	United States	44035
43	AHS Hillcrest Medical Center, LLC and Oklahoma Heart Institute	Tulsa	Oklahoma	United States	74104
44	Abington Memorial Hospital	Abington	Pennsylvania	United States	19001
45	Lehigh Valley Hospital and Health Network	Allentown	Pennsylvania	United States	18103
46	Allegheny-Singer Research Institute	Pittsburgh	Pennsylvania	United States	15212
47	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania	United States	15213
48	Stern Cardiovascular Center	Germantown	Tennessee	United States	38138
49	Centennial Medical Center	Nashville	Tennessee	United States	37203
50	St. Thomas Research Institute, LLC	Nashville	Tennessee	United States	37205
51	Vanderbilt Medical Center	Nashville	Tennessee	United States	37212
52	Methodist Hospital Research Institute	Houston	Texas	United States	77030
53	St. Luke's Episcopal Hospital	Houston	Texas	United States	77030
54	Sentara Hospitals and Sentara Cardiovascular Research Institute	Norfolk	Virginia	United States	23507
55	Cardiovascular Associates Virginia Beach	Virginia Beach	Virginia	United States	23454
56	North Cascade Cardiology	Bellingham	Washington	United States	98225

Sponsors and Collaborators

• Abbott Medical Devices
• Northwestern University

Investigators

• Principal Investigator: Alan Kadish, MD, Northwestern University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Abbott Medical Devices
• ClinicalTrials.gov Identifier: NCT00487279
• Other Study ID Numbers: Determine2007v12
• First Posted: Jun 18, 2007
• Last Update Posted: Feb 5, 2019
• Last Verified: Feb 1, 2019

• Keywords provided by Abbott Medical Devices: Coronary; Artery; Disease; Sudden; Cardiac; Death; ICD
• Additional relevant MeSH terms: Coronary Artery Disease; Ventricular Dysfunction; Death, Sudden, Cardiac; Ventricular Dysfunction, Left; Death

Study Results

Participant Flow

Arm/Group Title	ICD Group	Control Group
Arm/Group Description	ICD (Implantable Cardioverter Defibrillator)in combination with medical therapy	Medical therapy alone
Period Title: Overall Study
STARTED	44	37
COMPLETED	43	35
NOT COMPLETED	1	2

Baseline Characteristics

Arm/Group Title	ICD Group	Control Group	Total
Arm/Group Description	ICD (Implantable Cardioverter Defibrillator)in combination with medical therapy	Medical therapy alone	Total of all reporting groups
Overall Participants	44	37	81
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	24 54.5%	16 43.2%	40 49.4%
>=65 years	20 45.5%	21 56.8%	41 50.6%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62 (11)	65 (12)	63 (12)
Sex: Female, Male (Count of Participants)
Female	11 25%	5 13.5%	16 19.8%
Male	33 75%	32 86.5%	65 80.2%
Region of Enrollment (participants) [Number]
United States	44 100%	37 100%	81 100%

Outcome Measures

1. Primary Outcome

Title	All-cause Mortality
Time Frame	Total survival will be evaluated 2 years after the last patient is randomized.

Outcome Measure Data

Analysis Population Description

Intent to Treat

Arm/Group Title	ICD Group	Control Group
Arm/Group Description	ICD (Implantable Cardioverter Defibrillator)in combination with medical therapy	Medical therapy alone
Measure Participants	44	37
Number [participants]	1 2.3%	0 0%

2. Secondary Outcome

Title	Arrhythmic Mortality
Description	Arrhythmic mortality was reported as the number of randomized patients who died due to arrhythmic death. Arrhythmic death was defined as death due to arrhythmia or sudden death.
Time Frame	Total survival will be evaluated 2 years after the last patient is randomized.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	ICD Group	Control Group
Arm/Group Description	ICD (Implantable Cardioverter Defibrillator)in combination with medical therapy	Medical therapy alone
Measure Participants	44	37
Number [participants]	0 0%	0 0%

Adverse Events

Adverse Event Reporting Description	Serious adverse events were defined as those related to the device or its implantation procedure. Therefore, the control group was not at risk for a serious adverse event. Other adverse events were defined as non-serious adverse events related to the ICD or its implant procedure. The control group was not at risk for an other adverse event.
Arm/Group Title	ICD Group		Control Group
Arm/Group Description	ICD (Implantable Cardioverter Defibrillator)in combination with medical therapy		Medical therapy alone
All Cause Mortality
	ICD Group		Control Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	ICD Group		Control Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/44 (6.8%)		0/0 (NaN)
Injury, poisoning and procedural complications
Lead Dislodgment or Migration	3/3 (100%)	3	0/0 (NaN)	0
Other (Not Including Serious) Adverse Events
	ICD Group		Control Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/44 (4.5%)		0/0 (NaN)
Infections and infestations
Infection	1/1 (100%)	1	0/0 (NaN)	0
Injury, poisoning and procedural complications
Lead Dislodgment or Migration	1/1 (100%)	1	0/0 (NaN)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

All publications must be reviewed by the Sponsor, Executive Sterring Committe and the Publications Committee at least 30 days prior to submittal. In the event that no multi-center study publication occurs within 12 months of study completion, investigators may publish the restuls of the study data from those subjects enrolled in a study at the Institution provided the Sponsor, Executive Steering Committee and Publicaiton Committee review at least 30 days prior to submittal.