Multicenter Automatic Defibrillator Implantation Trial–Cardiac Resynchronization Therapy - MADIT-CRT


Currently, an implantable cardioverter defibrillator (ICD) is indicated for primary prevention in patients with ischemic (ICM) or nonischemic cardiomyopathy (NICM), with a left ventricular ejection fraction (LVEF) <35%, despite optimal medical management. Cardiac resynchronization therapy (CRT) with or without an ICD (CRT-D) is indicated for symptom improvement in patients with chronic systolic heart failure, with prolonged intraventricular conduction delay (QRS duration ≥120 ms), and New York Heart Association (NYHA) class III/IV symptoms, despite optimal medical therapy. The current trial sought to determine the utility of CRT-D in reducing all-cause mortality and congestive heart failure (CHF) events in patients meeting criteria for an ICD, but with NYHA class I/II symptoms.


CRT-D would reduce the risk of mortality or CHF events in high-risk CHF patients, who are relatively asymptomatic (NYHA class I/II), compared with an ICD alone.

Study Design

  • Randomized
  • Blinded
  • Parallel
  • Stratified

Patients Enrolled: 1,820
NYHA Class: ICM (NYHA I: 14.6%, II: 40.3%), NICM (NYHA II: 45.1%)
Mean Follow Up: 2 years; long-term 7 years
Mean Patient Age: 64.6 years
Female: 25%
Mean Ejection Fraction: 24%

Patient Populations:

  • Age >21 years
  • LVEF ≤30% by angiographic, radionuclide, or echocardiographic methods within 1 year prior to enrollment and measured during the enrollment echocardiogram obtained within 14 days prior to randomization to confirm eligibility (recommended)
  • Stable optimal medical therapy
  • QRS ≥130 ms
  • Normal sinus rhythm
  • NYHA class I or II (ICM), class II (NICM)


  • Existing indication for CRT therapy
  • Implanted pacemaker
  • Implanted ICD or CRT device
  • NYHA class I with NICM
  • NYHA class III or IV in the past 90 days 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 90 days prior to enrollment
  • Enzyme-positive myocardial infarction within the past 90 days prior to enrollment
  • Angiographic evidence of coronary disease sufficient to be a candidate for coronary revascularization and likely to undergo coronary artery bypass graft surgery or percutaneous coronary intervention in the foreseeable future
  • Second- or third-degree heart block
  • Irreversible brain damage from pre-existing cerebral disease
  • Women who are pregnant or plan to become pregnant during the course of the trial (women of child-bearing potential must have a negative pregnancy test within 7 days of enrollment)
  • Reversible NICM such as acute viral myocarditis or discontinuation of alcohol in alcohol-induced heart disease
  • Chronic AF
  • 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 >70 mg/dl or creatinine >3.0 mg/dl), liver failure, etc.

Primary Endpoints:

All-cause mortality or CHF events (signs and symptoms consistent with CHF that is responsive to intravenous decongestive therapy on an outpatient basis, or an augmented decongestive regimen with oral or parenteral medications during an in-hospital stay)

Secondary Endpoints:

  • Change in LVESV from baseline
  • Change in LVEDV from baseline
  • Subject-specific rates of multiple CHF events

Drug/Procedures Used:

All patients received Boston Scientific devices (who were the trial sponsors). Patients were randomized in a 3:2 fashion to receive either CRT-D or ICD alone. CRT was programmed to maximize biventricular programming, and atrioventricular delay was optimized using the latest optimization techniques. Single- or dual-chamber ICD devices were implanted, with a goal to minimize RV pacing.

Ventricular tachycardia zone was set at 180 bpm, and the ventricular fibrillation zone at 210 bpm. The programmed mode in the CRT-ICD arm was DDD with a lower rate of 40 bpm, with hysteresis off. In the ICD only arm, the programmed mode was VVI or DDI for single- and dual-chamber units, respectively, with a lower rate of 40 bpm, with hysteresis off.

Concomitant Medications:

Beta-blockers (93.3%), angiotensin-converting enzyme inhibitors (77%), angiotensin-receptor blockers (20.5%), amiodarone (7.1%), aldosterone antagonist (31.6%), diuretic (74.3%), and statin (67.4%)

Principal Findings:

A total of 1,820 patients were enrolled from 110 hospitals in the United States and Europe, of which 1,089 received CRT-D, and 731 received ICD alone. The trial was terminated early, owing to a benefit noted in the CRT-D arm versus the ICD arm, which reached the prespecified efficacy boundary for interim analysis.

Baseline characteristics were fairly similar between the two arms. Patients enrolled in the trial were predominantly white (90.5%). About 55% had ICM, and about 10% of the patients had NYHA class III/IV symptoms >3 months prior to enrollment. The mean LVEF was 24%, with a mean 6-minute walk distance of about 361 ms. Atrial fibrillation (AF) was noted in about 12% of the patients, and diabetes in about 30.4%. The majority of patients had a left bundle branch block on electrocardiogram (70.6%), and a QRS width ≥150 ms (64.6%). The mean LV end-systolic volume (LVESV) and LV end-diastolic volume (LVEDV) were 177 and 248 ml, respectively. Device implantation was successful in 98.4% of the patients, with 95.4% receiving the device to which they had been assigned. The device was removed in about 1% of the patients during follow-up.

The primary endpoint of death or nonfatal CHF events was less frequent in the CRT-D arm, compared with the ICD arm (17.2% vs. 25.3%, hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.52-0.84, p = 0.001), driven predominantly by a reduction in CHF events (13.9% vs. 22.8%, p < 0.001), with no difference in all-cause mortality (6.8% vs. 7.3%, p = 0.99). This was true of patients with both ICM and NICM. Subgroup analyses demonstrated a greater benefit in women than in men (p = 0.01), in those with a QRS duration ≥150 msec (p = 0.001), and those with an LBBB (p < 0.001). LVEF improved to a greater extent compared with baseline in the CRT-D arm (0.11 vs. 0.03, p < 0.001). Similarly, LVESV and LVEDV both reduced significantly compared to baseline in the CRT-D arm (57 ml vs. 18 ml, and 52 ml vs. 15 ml, respectively; p < 0.001 for both).

Adverse events in the 30 days after implantation were numerically higher in the CRT-D arm compared to the ICD arm, including pneumothorax (1.7% vs. 0.8%), infection (1.1% vs. 0.7%), and pocket hematoma needing evacuation (3.3% vs. 2.5%). Approximately 4% of patients in the CRT-D arm needed coronary vein/sinus lead revision in the first 30 days.

Long-term follow-up: Of the 1,691 surviving patients at the end of the trial, 854 were enrolled in post-trial registries (527 to CRT-D and 327 to ICD only). At 7 years of follow-up, all-cause mortality in patients with LBBB was significantly lower among those who received CRT-D compared with those who did not (HR 0.59, 95% CI 0.43-0.80, p < 0.0001). Similarly, there were significant reductions in nonfatal HF (HR 0.38, 95% CI 0.30-0.48, p < 0.0001) and CHF/death (HR 0.45, 95% CI 0.37-0.56, p < 0.0001). Paradoxically, all-cause mortality was increased with CRT-D in non-LBBB morphologies (HR 1.57, 95% CI 1.03-2.39, p = 0.04) (p value for interaction < 0.001). Landmark analyses showed similar findings.


The results of the MADIT-CRT trial indicate that CRT-D implantation in patients with systolic CHF (LVEF ≤30%), with a wide QRS, and NYHA class I/II symptoms (asymptomatic or mildly symptomatic patients) is associated with a significant reduction in the primary endpoint of CHF events or mortality, as compared with ICD implantation alone, primarily due to a reduction in CHF events. Further, CRT-D implantation is associated with a significant albeit modest improvement in LVEF and LV volumes, as measured by echocardiography in a subgroup of patients. There is significant effect modification by QRS morphology – patients with LBBB had a significant benefit on long-term follow-up to 7 years, while patients with non-LBBB morphologies had suggestion of harm.

Improvements in LV dimensions with CRT in mildly asymptomatic CHF patients have been noted earlier in the MIRACLE ICD-II and REVERSE trials. However, no significant difference in clinical endpoints was noted in these trials. MADIT-CRT is the largest trial on this topic, and noted an improvement in clinical endpoints, primarily CHF events.

One criticism is that investigators adjudicating on baseline functional status, and therapy or admission for CHF were not blinded to study group assignments, and could thus have biased the results toward a benefit in the CRT-D arm. Further, at least 10% of the patients in both arms had NYHA class III/IV symptoms >3 months prior to enrollment, and would thus have qualified for CRT-D, based on current criteria. The inclusion of these patients could also have biased the results in favor of the CRT-D arm.

Other considerations include analyzing the cost-effectiveness of CRT-D compared with ICD in future trials, since CRT-D implantation is significantly more expensive than ICD implantation alone.


Moss AJ, Hall WJ, Cannom DS, et al. Cardiac-resynchronization therapy for the prevention of heart-failure events. N Engl J Med 2009;361;1329-1338.

Goldenberg I, Kutyifa V, Klein HU, et al. Survival with cardiac-resynchronization therapy in mild heart failure. N Engl J Med 2014;Mar 30:[Epub ahead of print].

Presented by Dr. Ilan Goldenberg at the American College of Cardiology Scientific Session, Washington, DC, March 30, 2014.

Keywords: Follow-Up Studies, Radioisotopes, Pneumothorax, Ventricular Fibrillation, Hematoma, Electrocardiography, Heart Failure, Systolic, Primary Prevention, Cardiac Resynchronization Therapy, Registries, Tachycardia, Ventricular, Cardiac Pacing, Artificial, Research Personnel, Cardiomyopathies, Bundle-Branch Block, Stroke Volume, Confidence Intervals, Coronary Vessels, Defibrillators, Implantable, Diabetes Mellitus, Echocardiography, ACC Annual Scientific Session

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