MADIT-CRT: Multicenter Automatic Defibrillator Implantation With Cardiac Resynchronization Therapy

• Sponsor: Boston Scientific Corporation (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00180271
• Collaborator: University of Rochester (Other)
• Enrollment: 1,820
• Location: 1
• Arms: 2
• Duration (Months): 69
• Patients Per Site Per Month: 26.4

Study Details

Study Description

Brief Summary

The MADIT-CRT trial is designed to determine if combined implantable cardiac defibrillator (ICD)-cardiac resynchronization therapy (CRT-D) will reduce the risk of mortality and heart failure (HF) events by approximately 25%, in subjects who are in New York Heart Association (NYHA) functional Class II with non-ischemic or ischemic cardiomyopathy and subjects who are in NYHA functional Class I with ischemic cardiomyopathy, left ventricular dysfunction (ejection fraction [EF] < or = 0.30), and prolonged intraventricular conduction (QRS duration

or = 130 ms).

Condition or Disease	Intervention/Treatment	Phase
Tachycardia; Congestive Heart Failure	Device: Cardiac resynchronization therapy with defibrillation; Device: Implantable Cardioverter Defibrillator (ICD)	N/A

Detailed Description

In this study, subjects will be randomized to CRT-D or ICD-only. Randomization will be stratified by clinical center and ischemic status. Approximately 60% of the subjects will be randomly assigned to receive a CRT-D with biventricular pacing, and 40% will receive an ICD only. Optimal pharmacological therapy for heart failure will be required in both treatment arms. Length of follow-up for each subject will depend on the date of entry into the study, since all subjects will be followed to a common study termination date.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1820 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy
• Study Start Date: Dec 1, 2004
• Actual Primary Completion Date: Jun 1, 2009
• Actual Study Completion Date: Sep 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: CRT-D CRT-D: Cardiac resynchronization therapy with defibrillation.	Device: Cardiac resynchronization therapy with defibrillation; Boston Scientific Corporation Market Released Cardiac Resynchronization therapy with defibrillation
Active Comparator: ICD ICD: Implantable cardioverter defibrillator	Device: Implantable Cardioverter Defibrillator (ICD); Boston Scientific Corporation Market Released Implantable Cardioverter Defibrillator

Outcome Measures

Primary Outcome Measures

1. Mortality From Any Cause or First Heart Failure (HF) Event [Outcome measured at average follow-up duration of 2.4 years.]

   MADIT-CRT was an event-driven trial in which patients were monitored for all-cause mortality and HF events. An HF event was defined as either hospitalization for symptoms and/or signs consistent with congestive HF and: administration of intravenous decongestive therapy that does not involve formal in-patient hospital admission, regardless of the setting (i.e. in an emergency room setting, in the physician's office, etc.), or administration of an augmented HF regimen with oral or intravenous medications during an in-hospital stay.

Secondary Outcome Measures

1. Recurrent Heart Failure Events [Time of event, DSMB review]

   The MADIT-CRT secondary outcome evaluated the effects of CRT-D, relative to ICD, on the recurrence of heart failure events over the full study period An HF event was defined as either hospitalization for symptoms and/or signs consistent with congestive HF and: administration of intravenous decongestive therapy that does not involve formal in-patient hospital admission, regardless of the setting (i.e. in an emergency room setting, in the physician's office, etc.), or administration of an augmented HF regimen with oral or intravenous medications during an in-hospital stay.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Ischemic heart disease defined as:

• NYHA Class I or II for the past 3 calendar months prior to, and at the time of, enrollment;

• one or more clinically documented (Q wave or enzyme positive) prior myocardial infarctions, but not within 3 calendar months of enrollment; and/or

• one or more prior coronary artery bypass graft surgeries or percutaneous coronary interventions (balloon and/or stent angioplasty) but not within 3 calendar months of enrollment.

OR

• Non-ischemic heart disease including dilated cardiomyopathy characterized by a low ejection fraction and increased ventricular volume, with ventricular compliance that is normal or increased

• NYHA Class II for the past 3 calendar months prior to, and at the time of, enrollment

AND all of the following:

• Stable optimal pharmacologic therapy.

• An ejection fraction < or = 0.30 by angiographic, radionuclide, or echocardiographic methods within one year prior to enrollment and measured during the enrollment echocardiogram obtained within 14 days prior to randomization to confirm eligibility (recommended)

• Resting QRS duration > or = 130 ms on print-out of a current electrocardiogram (ECG) obtained within 14 days prior to randomization.

• Sinus rhythm by ECG (including right bundle branch block [RBBB] and first degree heart block with PR < 250 ms.)

• Men and women 21 years of age or older (no upper-age cut off)

Exclusion Criteria:

• Existing indication for CRT

• Subjects with an implanted pacemaker

• Subjects with an existing ICD or CRT device

• Subjects in NYHA Class I with non-ischemic cardiomyopathy

• Subjects in NYHA Class III or IV in the past 3 calendar months prior to, or at the time of, enrollment

• Coronary artery bypass graft surgery or percutaneous coronary intervention (balloon and/or stent angioplasty) within the past 3 calendar months prior to enrollment

• Enzyme-positive myocardial infarction within the past 3 calendar months prior to enrollment

• Subjects with angiographic evidence of coronary disease who are candidates for coronary revascularization and are likely to undergo coronary artery bypass graft surgery or percutaneous coronary intervention in the foreseeable future

• Subjects with second or third degree heart block

• Subjects with irreversible brain damage from preexisting cerebral disease

• Women who are pregnant or plan to become pregnant during the course of the trial. Women of childbearing potential must have a negative pregnancy test within 7 days prior to enrollment.

• Reversible non-ischemic cardiomyopathy such as acute viral myocarditis or discontinuation of alcohol in alcohol-induced heart disease

• Subjects with chronic atrial fibrillation within one month prior to enrollment

• Presence of any disease, other than the subject's cardiac disease, associated with a reduced likelihood of survival for the duration of the trial, e.g., cancer, uremia (blood urea nitrogen [BUN] > 70 mg/dl or creatinine > 3.0 mg/dl), liver failure, etc.

• Subjects participating in any other clinical trials

• Subjects unwilling or unable to cooperate with the protocol

• Subjects who live at such a distance from the clinic that travel for follow-up visits would be unusually difficult

• Subjects who do not anticipate being residents of the area for the scheduled duration of the trial

• Subjects unwilling to sign the consent for participation

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Multiple locations in the US and international	Rochester	New York	United States	14642

Sponsors and Collaborators

• Boston Scientific Corporation
• University of Rochester

Investigators

• Principal Investigator: Arthur J Moss, MD, University of Rochester, NY

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Boston Scientific Corporation
• ClinicalTrials.gov Identifier: NCT00180271
• Other Study ID Numbers: Clinicals0003; MADIT-CRT
• First Posted: Sep 16, 2005
• Last Update Posted: Dec 19, 2018
• Last Verified: Nov 1, 2018

• Keywords provided by Boston Scientific Corporation: Defibrillator; Cardiac Resynchronization Therapy; MADIT
• Additional relevant MeSH terms: Heart Failure; Tachycardia

Study Results

Participant Flow

Recruitment Details	The study enrolled 1820 patients from 110 hospital centers (88 in the United States, 2 in Canada, and 20 in Europe) between December 22, 2004 and April 23, 2008. Follow-up continued thereafter until trial termination.
Pre-assignment Detail	Data from all patients enrolled were analyzed on an intention-to-treat basis.

Arm/Group Title	Cardiac Resynchronization Therapy + Defibrillator	Implantable Cardioverter Defibrillator Alone
Arm/Group Description	Patients randomized to cardiac resynchronization therapy with backup defibrillation (CRT-D) in addition to optimal pharmacologic therapy (as administered by the primary care physician). CRT-D devices both deliver shocks to terminate potentially lethal ventricular arrhythmias and pace both ventricles in patients with ventricular dyssynchrony.	Patients randomized to implantable cardioverter defibrillator (ICD) in addition to optimal pharmacologic therapy (as administered by the primary care physician). ICDs deliver shocks to terminate potentially lethal ventricular arrhythmias.
Period Title: Overall Study
STARTED	1089	731
COMPLETED	1089	731
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Cardiac Resynchronization Therapy + Defibrillator	Implantable Cardioverter Defibrillator Alone	Total
Arm/Group Description	Patients randomized to cardiac resynchronization therapy with backup defibrillation (CRT-D) in addition to optimal pharmacologic therapy (as administered by the primary care physician). CRT-D devices both deliver shocks to terminate potentially lethal ventricular arrhythmias and pace both ventricles in patients with ventricular dyssynchrony.	Patients randomized to implantable cardioverter defibrillator (ICD) in addition to optimal pharmacologic therapy (as administered by the primary care physician). ICDs deliver shocks to terminate potentially lethal ventricular arrhythmias.	Total of all reporting groups
Overall Participants	1089	731	1820
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	543 49.9%	380 52%	923 50.7%
>=65 years	546 50.1%	351 48%	897 49.3%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	65 (11)	64 (11)	65 (11)
Sex: Female, Male (Count of Participants)
Female	275 25.3%	178 24.4%	453 24.9%
Male	814 74.7%	553 75.6%	1367 75.1%
Region of Enrollment (participants) [Number]
United States	757 69.5%	514 70.3%	1271 69.8%
Canada	14 1.3%	8 1.1%	22 1.2%
Czech Republic	17 1.6%	11 1.5%	28 1.5%
Denmark	22 2%	13 1.8%	35 1.9%
France	13 1.2%	9 1.2%	22 1.2%
Germany	98 9%	61 8.3%	159 8.7%
Hungary	16 1.5%	10 1.4%	26 1.4%
Israel	45 4.1%	30 4.1%	75 4.1%
Italy	15 1.4%	12 1.6%	27 1.5%
Netherlands	34 3.1%	24 3.3%	58 3.2%
Poland	14 1.3%	10 1.4%	24 1.3%
Spain	36 3.3%	24 3.3%	60 3.3%
Switzerland	4 0.4%	2 0.3%	6 0.3%
United Kingdom	4 0.4%	3 0.4%	7 0.4%

Outcome Measures

1. Primary Outcome

Title	Mortality From Any Cause or First Heart Failure (HF) Event
Description	MADIT-CRT was an event-driven trial in which patients were monitored for all-cause mortality and HF events. An HF event was defined as either hospitalization for symptoms and/or signs consistent with congestive HF and: administration of intravenous decongestive therapy that does not involve formal in-patient hospital admission, regardless of the setting (i.e. in an emergency room setting, in the physician's office, etc.), or administration of an augmented HF regimen with oral or intravenous medications during an in-hospital stay.
Time Frame	Outcome measured at average follow-up duration of 2.4 years.

Outcome Measure Data

Analysis Population Description

Analysis was performed on an intention-to-treat basis and counted the time to first event. The category "Patients with Death at Any Time", includes deaths that occurred after the first heart failure event.

Arm/Group Title	Cardiac Resynchronization Therapy + Defibrillator	Implantable Cardioverter Defibrillator Alone
Arm/Group Description	Patients randomized to cardiac resynchronization therapy with backup defibrillation (CRT-D) in addition to optimal pharmacologic therapy (as administered by the primary care physician). CRT-D devices both deliver shocks to terminate potentially lethal ventricular arrhythmias and pace both ventricles in patients with ventricular dyssynchrony.	Patients randomized to implantable cardioverter defibrillator (ICD) in addition to optimal pharmacologic therapy (as administered by the primary care physician). ICDs deliver shocks to terminate potentially lethal ventricular arrhythmias.
Measure Participants	1089	731
Patients who are Event Free	901 82.7%	543 74.3%
Patients with Death or Heart Failure Event	188 17.3%	188 25.7%
Patients with Heart Failure Event Alone	152 14%	170 23.3%
Patients with Death at Any Time	74 6.8%	53 7.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cardiac Resynchronization Therapy + Defibrillator, Implantable Cardioverter Defibrillator Alone
	Comments	The trial utilized a Wang-Tsiatis (delta=0.1) group-sequential design with 95% power to detect a hazard ratio of 0.75 at a two-sided significance level of 0.05. Primary analysis based on statistical evaluation comparing the life-table event-free survival time graphs for CRT-D and ICD-only arms of the trial. Stratified Cox proportional-hazards regression was used to estimate a hazard ratio and statistical significance was evaluated with the log-rank test. Stratified by center and ischemic status.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments	The trial involved prespecified event monitoring at up to 20 successive periods by an independent DSMB to permit trial termination if the CRT-D was superior to, inferior to, or not different from ICD according to prespecified stopping rules.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.66
	Confidence Interval	(2-Sided) 95%; 0.52 to 0.84
	Parameter Dispersion	Type: Value:
	Estimation Comments	A Hazard ratio < 1.0 would indicate that the result favors CRT-D.

2. Secondary Outcome

Title	Recurrent Heart Failure Events
Description	The MADIT-CRT secondary outcome evaluated the effects of CRT-D, relative to ICD, on the recurrence of heart failure events over the full study period An HF event was defined as either hospitalization for symptoms and/or signs consistent with congestive HF and: administration of intravenous decongestive therapy that does not involve formal in-patient hospital admission, regardless of the setting (i.e. in an emergency room setting, in the physician's office, etc.), or administration of an augmented HF regimen with oral or intravenous medications during an in-hospital stay.
Time Frame	Time of event, DSMB review

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	CRT-D	ICD: Implantable Cardioverter Defibrillator
Arm/Group Description	CRT-D: Cardiac resynchronization therapy with defibrillation. Cardiac resynchronization therapy with defibrillation: Boston Scientific Corporation Market Released Cardiac Resynchronization therapy with defibrillation	ICD: Implantable cardioverter defibrillator Implantable Cardioverter Defibrillator (ICD): Boston Scientific Corporation Market Released Implantable Cardioverter Defibrillator
Measure Participants	1089	731
Participants with 0 events	928 85.2%	545 74.6%
Participants with 1 event	93 8.5%	107 14.6%
Participants with 2 or more events	68 6.2%	79 10.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cardiac Resynchronization Therapy + Defibrillator, Implantable Cardioverter Defibrillator Alone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments
	Method	Andersen-Gill
	Comments	Andersen-Gill model performed, adjusted for a previous HF event in the study, stratified by ischemic status and using robust variance estimation.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.67
	Confidence Interval	(2-Sided) 95%; 0.53 to 0.86
	Parameter Dispersion	Type: Value:
	Estimation Comments	Model adjusted for previously experienced heart failure event in the study. Hazard Ratio (95% CI) comparing patients with a previous heart failure event to those patients without a prior heart failure event equaled 8.84 (6084, 11.43), p<0.001.

Adverse Events

Time Frame	91 Days
Adverse Event Reporting Description	The primary outcome was performed on an intention-to-treat basis and all participants were followed. However, the number of participants at risk for adverse events is fewer than the total number in the primary outcome. Some participants did not undergo the surgical procedure for device implant and were therefore not subjected to risk.
Arm/Group Title	Cardiac Resynchronization Therapy + Defibrillator		Implantable Cardioverter Defibrillator Alone
Arm/Group Description	Patients randomized to cardiac resynchronization therapy with backup defibrillation (CRT-D) in addition to optimal pharmacologic therapy (as administered by the primary care physician). CRT-D devices both deliver shocks to terminate potentially lethal ventricular arrhythmias and pace both ventricles in patients with ventricular dyssynchrony.		Patients randomized to implantable cardioverter defibrillator (ICD) in addition to optimal pharmacologic therapy (as administered by the primary care physician). ICDs deliver shocks to terminate potentially lethal ventricular arrhythmias.
All Cause Mortality
	Cardiac Resynchronization Therapy + Defibrillator		Implantable Cardioverter Defibrillator Alone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Cardiac Resynchronization Therapy + Defibrillator		Implantable Cardioverter Defibrillator Alone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	164/1079 (15.2%)		55/712 (7.7%)
Blood and lymphatic system disorders
Thromboembolic Events	8/1079 (0.7%)	8	4/712 (0.6%)	4
Cardiac disorders
Lead Dislodgment, Left Ventricular	46/1079 (4.3%)	51	1/712 (0.1%)	1
Lead Dislodgment, Right Atrial	33/1079 (3.1%)	33	10/712 (1.4%)	10
Extracardiac Stimulation, Left Ventricular	11/1079 (1%)	11	0/712 (0%)	0
Lead Dislodgment, Right Ventricular	8/1079 (0.7%)	8	5/712 (0.7%)	5
Elevated Threshold, Right Ventricular	6/1079 (0.6%)	6	3/712 (0.4%)	3
Inadvertent Ventricular Tachyarrhythmia	4/1079 (0.4%)	4	2/712 (0.3%)	2
Elevated Defibrillation Thresholds	6/1079 (0.6%)	6	8/712 (1.1%)	8
Inappropriate Tachyarrhythmia Therapy	2/1079 (0.2%)	2	1/712 (0.1%)	1
Early Elective Replacement Indicator	2/1079 (0.2%)	2	1/712 (0.1%)	1
Insulation Breach, Left Ventricular Lead	2/1079 (0.2%)	2	0/712 (0%)	0
Inadvertent Supraventricular Tachyarrhythmia	2/1079 (0.2%)	2	0/712 (0%)	0
Worsening Heart Failure	2/1079 (0.2%)	2	1/712 (0.1%)	1
Elevated Threshold, Left Ventricular	1/1079 (0.1%)	1	0/712 (0%)	0
Difficulty Measing Impedance/Amplitude	1/1079 (0.1%)	1	0/712 (0%)	0
Elevated Shock Impedance	1/1079 (0.1%)	1	0/712 (0%)	0
Bigeminy	1/1079 (0.1%)	1	0/712 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pleural Effusion	1/1079 (0.1%)	1	0/712 (0%)	0
Skin and subcutaneous tissue disorders
Hemorrhage, Pocket	2/1079 (0.2%)	2	1/712 (0.1%)	1
Surgical and medical procedures
Pneumothorax	15/1079 (1.4%)	15	5/712 (0.7%)	5
Hematoma, Pocket	14/1079 (1.3%)	14	5/712 (0.7%)	5
Atrioventricular Block	6/1079 (0.6%)	6	2/712 (0.3%)	2
Adverse Reaction	6/1079 (0.6%)	6	7/712 (1%)	7
Infection, Post Surgical	9/1079 (0.8%)	9	2/712 (0.3%)	2
Renal Failure	4/1079 (0.4%)	4	0/712 (0%)	0
Pericardial Effusion	3/1079 (0.3%)	4	1/712 (0.1%)	1
Myocardial Perforation with Tamponade	3/1079 (0.3%)	3	1/712 (0.1%)	1
Arterial Perforation	1/1079 (0.1%)	1	0/712 (0%)	0
Venous Occlusion	1/1079 (0.1%)	1	0/712 (0%)	0
Seroma, Pocket	1/1079 (0.1%)	1	0/712 (0%)	0
Pulse Generator Migration	1/1079 (0.1%)	1	0/712 (0%)	0
Set Screws Not Tightened	0/1079 (0%)	0	3/712 (0.4%)	3
Post Surgical Wound Discomfort	0/1079 (0%)	0	1/712 (0.1%)	1
Other (Not Including Serious) Adverse Events
	Cardiac Resynchronization Therapy + Defibrillator		Implantable Cardioverter Defibrillator Alone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	126/1079 (11.7%)		0/712 (0%)
Cardiac disorders
Extracardiac Stimulation, Left Ventricular	70/1079 (6.5%)	77	0/712 (0%)	0
Pacemaker Mediated Tachycardia	56/1079 (5.2%)	67	0/712 (0%)	0

Limitations/Caveats

The FDA Circulatory Devices advisory panel recommended approval for the patient subpopulation with left bundle branch block (LBBB) only. Consequently, FDA has restricted indications for use to LBBB.

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.