3. MADIT & Multicenter Unsustained Tachycardia Trial (MUSTT): Demonstrated a
benefit from ICD implantation in patients with CAD, reduced ventricular function,
unsustained ventricular tachycardia, and inducible ventricular tachycardia on EP
testing.
In MADIT II: No EP study required, inclusion criteria included a prior MI at least 30
days previous to implantation, and EF of 30% or less.
MADITT randomized 1232 patients from 71 US centers and 5 European centers to
receive either an ICD, or to continue on conventional medical therapy
3 to 4 million patients fit the entry criteria
400,000 new cases annually
4. • Heart failure remains a significant health concern; a heart failure event is associated with a
five-fold increase in mortality in 5 years.
• Cardiac resynchronization therapy with defibrillation (CRT-D) has been demonstrated to
reduce mortality and hospitalizations, improve symptoms, and increase exercise capacity.
• Prior to MADIT-CRT, Boston Scientific CRT-Ds were indicated by FDA for the treatment of
patients with the following conditions:
– Moderate to severe heart failure (NYHA Class III/IV) despite optimal pharmacological
therapy
– Reduced systolic function (LVEF 35%)
– Wide QRS (QRS duration ≥ 120 ms)
5. RATIONALE FOR UNDERTAKING MADIT-CRT
• Currently, patients with severe left ventricular systolic dysfunction, a wide QRS complex,
and asymptomatic or mildly symptomatic heart failure are indicated for prophylactic ICD
therapy without CRT
• Although ICD therapy is effective for the prevention of sudden cardiac arrest, it does not
slow the progression of heart failure
However, progression of heart failure in these patients is associated with increased mortality
and diminished quality of life
• Retrospective studies of CRT-D in NYHA Class I/II patients reported improvement in
echocardiographic variables, suggesting a potential role for CRT-D earlier in the disease
process
• Accordingly, MADIT-CRT was undertaken to determine if early intervention with CRT-D in
patients with asymptomatic or mild heart failure could reduce death and heart failure
events
6. • Primary:
It was hypothesized that CRT-D would reduce the risk of the combined endpoint of all-
cause mortality or heart failure event, whichever came first, when compared with ICD in
patients with asymptomatic or mildly symptomatic heart failure with left ventricular
dysfunction and wide QRS
• A heart failure event was defined as a patient having signs and symptoms of heart failure,
with either:
• Intravenous decongestive therapy in an outpatient setting, or
• Augmented intravenous or oral decongestive therapy during in-hospital stay
• Secondary:
Evaluate the effects of CRT-D, relative to ICD, on the patient-specific rates of recurrent
heart failure events over the full study period
MADIT-CRT Primary/Secondary Effectiveness Hypotheses
7. Study Design
• Designed to detect a 25% reduction in the risk of the primary end
point
• Wang-Tsiatis group-sequential design
• 95% power at a two-sided significance level of 5%
• Sample size requirement of 1820 patients
• Randomized controlled trial
• Randomization on a 3:2 basis to CRT-D/ICD
• Stratified by ischemic status and clinical center
• Data analyzed on an intention-to-treat basis
8. Inclusion Criteria
• Ischemic heart disease (NYHA Class I or II) or non-ischemic heart
disease (NYHA Class II) for at least three months prior to entry
• Optimal pharmacologic therapy
• Beta blockers, ACE/ARB, and statins (ischemic patients) unless not
tolerated or contraindicated
• Left ventricular ejection fraction ≤ 30%
• QRS duration ≥ 130 ms
• Sinus rhythm
9. Exclusion Criteria
• Currently implanted pacemaker, ICD, or CRT device
• Current indication for CRT
• Atrial fibrillation within one month of entry
• NYHA Class III/IV within three months of entry
• CABG, PCI, or MI within three months of entry
10. 10
MADIT-CRT: Methods
Largest randomized NYHA
Class I/II CRT-D trial to date
• Enrollment
• 1820 patients, 110 centers, 14
countries
• Average follow-up
• 34.3 months
• Commercially available devices provided by
Boston Scientific were used
Moss AJ, et al. N Engl J Med. 2009;361:1329-1338.
Baseline Evaluation
To document inclusion/exclusion criteria and establish
baseline heart statusa
Randomization (3:2 CRT-D:ICD)
Stratified by center and ischemic status
Clinic Follow-up Visits
1 month post-enrollment/randomization, 3 months post-
randomization, and quarterly thereafter to a common study
closure dateb
CRT-D + OPT
(1089 patients)
ICD + OPT
(731 patients)
aBaseline evaluation includes history and physical exam, electrocardiogram, and echocardiogram. Patients are randomized and then
baseline testing is completed including BNP (US only), quality-of-life assessment, 6-minute walk test, and Holter monitor recording (CRT-
D patients only).
bThe 12-month follow-up visit includes echocardiogram, BNP (US only), 6-minute walk test, Holter monitor recording (CRT-D patients only),
and device interrogation. Other follow-up visits include history and physical exam, clinical events, and device interrogation. Quality-of-
life assessments were conducted at 6-month intervals.
11. 11
Study Milestones
• Primary endpoint was met on June 22, 2009
• Results were published online on Sep. 1, 2009, in the NEJM and
presented as a late-breaker at ESC
• Published in print in the NEJM on Oct. 1, 2009
• FDA requested updated results through Dec. 31, 2009
• FDA panel took place on Mar. 18, 2010, and there was unanimous
recommendation for approval of the expanded CRT-D indication for
the MADIT-CRT left bundle branch block (LBBB) sub-population
12. 12
Previously Published and Updated Results
• MADIT-CRT met its endpoint in June 2009
and results were published in the
September 2009 NEJM online addition.
• Results showed that CRT-D was
associated with a 34% reduction in the
relative risk of the primary endpoint
• Primary effectiveness endpoint achieved
• The FDA requested to see additional 6 months
of data analyzed (through December 2009)
• It was subsequently discovered and validated
that in the LBBB subgroup, patients received
substantial benefit from CRT-D. Non-LBBB
patients did not show evidence of benefit. The
LBBB sub-group made up approximately 70%
of the total MADIT-CRT population.
N Engl J Med. 2009 Oct 1;361(14):1329-38. Epub 2009 Sep 1. Cardiac-resynchronization therapy for the prevention of heart-failure events.
Moss AJ, Hall WJ, Cannom DS, Klein H, Brown MW, Daubert JP, Estes NA 3rd, Foster E, Greenberg H, Higgins SL, Pfeffer MA, Solomon SD, Wilber D, Zareba W; MADIT-CRT Trial Investigators.
34% 57%
15. 15
Exploratory Analysis - Hypothesis Generating Only:
LBBB Echocardiographic Outcomes
CRT therapy was ON during echocardiographic measurements and may have influenced the results.
16. 16
16
Results
In asymptomatic or mild heart failure, patients with wide QRS, LV
dysfunction, and LBBB on stable optimal heart failure pharmacologic
therapy, CRT-D, as compared to ICD, was significantly associated with:
• An acceptable safety profile
• Primary endpoint showed:
57% reduction (p < 0.001) in the risk of a composite of all-cause mortality
or heart failure events. This was driven by:
• 35% reduction (p = 0.048) in the risk of all-cause mortality, and a
• 63% reduction (p < 0.001) in the risk of heart failure events
– Secondary endpoint showed:
43% reduction (p = 0.001) in the risk of recurrent heart failure events
17. 17
17
New Boston Scientific CRT-D Indication
Boston Scientific Cardiac Resynchronization Therapy Defibrillators (CRT-
Ds) are indicated for patients with heart failure who receive optimal
pharmacologic therapy (OPT) for heart failure and who meet any one of
the following classifications:
• Moderate to severe heart failure (NYHA Class III/IV) with EF ≤ 35% and QRS
duration ≥ 120 ms
• Left bundle branch block with QRS ≥ 130 ms, EF ≤ 30% and mild (NYHA Class
II) ischemic or nonischemic heart failure or asymptomatic (NYHA Class I)
ischemic heart failure
