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Trial Summary MADIT-RIT

Title: Multicenter Automatic Defibrillator Implantation Trial–Reduce Inappropriate Therapy
Trial Sponsor: Boston Scientific
Year Presented: 2012
Year Published: 2012
Topic(s): Arrhythmias, Cardiac Rhythm Management, Heart FailureTransplant
Summary Posted: 11/6/2012
Writer: Dharam J. Kumbhani, MD, SM, F.A.C.C.
Author Disclosure:   CONSULTING FEES/HONORARIA: American College of Cardiology(SIGNIFICANT)
Reviewer: Deepak L. Bhatt, M.D., M.P.H., F.A.C.C.
Reviewer Disclosure: CONSULTING FEES/HONORARIA: Elsevier Practice Update Cardiology(MODEST) RESEARCH/RESEARCH GRANTS: Roche(SIGNIFICANT), Bristol Myers Squibb(SIGNIFICANT), Amarin(SIGNIFICANT), The Medicines Company(SIGNIFICANT), Astra Zeneca(SIGNIFICANT), Sanofi Aventis(SIGNIFICANT), Eisai(SIGNIFICANT), Ethicon(SIGNIFICANT), Medtronic(SIGNIFICANT), FlowCo(NONE), Takeda(NONE), PLx Pharma(NONE) OTHER FINANCIAL BENEFIT: WebMD(SIGNIFICANT), Journal of Invasive Cardiology(SIGNIFICANT), Slack Publications/Cardiology Research Foundation(SIGNIFICANT), Belvoir Publications(SIGNIFICANT), Regado Biosciences(NONE), Medscape Cardiology(NONE), Clinical Cardiology(NONE)

Description:

Although implantable cardioverter-defibrillators (ICDs)/cardiac resynchronization therapy devices (CRT-Ds) have a significant role in preventing sudden cardiac death in high-risk patients, especially for secondary prevention, inappropriate ICD shocks are common (8-40%). They are associated with high morbidity as well.

Hypothesis:

Programming ICDs to a higher rate or increased monitoring delays before therapy administration would be safe and efficacious as compared with conventional programming.

Drugs/Procedures Used:

Patients undergoing ICD implantation were randomized in a 1:1:1 fashion to three different settings. Patients in the conventional arm had two detection zones: one at 170-199 bpm for ventricular tachycardia (VT) with a 2.5-second delay, and the second at ≥200 bpm with a 1-second delay, before administration of therapy. Patients in the high-rate group had a monitoring-only zone between 170 and 199 bpm, and therapy zone at ≥200 bpm with a 2.5-second monitoring delay. Patients in the delayed-therapy arm had three different zones: 1 at 170-199 bpm with rhythm detection on and a 60-second delay before administering therapy, the second at ≥200 bpm with rhythm detection on and a 12-second delay before administering therapy, and the third at ≥250 bpm with a 2.5-second delay before administering therapy. Therapy could be either antitachycardia pacing (ATP) or shock in all devices (sequentially).

Concomitant Medications:

Beta-blockers (94%), angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers (67%), digitalis (13%)

Principal Findings:

A total of 1,500 patients were randomized, 514 to conventional therapy, 500 to high-rate therapy, and 486 to delayed therapy. Baseline characteristics were fairly similar between the three arms. About 53% had a history of ischemic cardiomyopathy. Atrial fibrillation (AF) was present in about 11%, and the resting heart rate was approximately 72 bpm. Approximately 50% of the devices were ICDs, and the other half were CRT-Ds.

High-rate therapy vs. conventional programming: The primary endpoint of first occurrence of inappropriate therapy was significantly lower in the high-rate therapy arm as compared with the conventional programming arm (4% vs. 20%, hazard ratio [HR] 0.21, 95% confidence interval [CI] 0.13-0.34, p < 0.001). This was mainly due to a significant reduction in inappropriate ATP (2% vs. 17%, p < 0.001); inappropriate shocks were similar (2% vs. 4%, p = 0.12). Similarly, the first occurrence of appropriate therapy was significantly lower in the high-rate therapy arm as compared with the conventional programming arm (9% vs. 22%, p < 0.001). This was mainly due to a significant reduction in appropriate ATP (5% vs. 18%, p < 0.001); appropriate shocks were similar (4% vs. 4%, p = 0.68). All-cause mortality was significantly reduced in the high-rate therapy arm (3.2% vs. 6.6%, HR 0.45, 95% CI 0.24-0.85, p = 0.01). The incidence of first syncope was similar (4.4% vs. 4.5%, p = 0.39).

Delayed therapy vs. conventional programming: The primary endpoint of first occurrence of inappropriate therapy was significantly lower in the delayed therapy arm as compared with the conventional programming arm (5% vs. 20%, HR 0.24, 95% CI 0.15-0.40, p < 0.001). This was mainly due to a significant reduction in inappropriate ATP (3% vs. 17%, p < 0.001); inappropriate shocks were similar (3% vs. 4%, p = 0.28). Similarly, the first occurrence of appropriate therapy was significantly lower in the delayed therapy arm as compared with the conventional programming arm (6% vs. 22%, p < 0.001). This was mainly due to a significant reduction in appropriate ATP (2% vs. 18%, p < 0.001); appropriate shocks were similar (3% vs. 4%, p = 0.74). All-cause mortality was numerically lower in the delayed therapy arm (4.3% vs. 6.6%, HR 0.56, 95% CI 0.30-1.02, p = 0.06). The incidence of first syncope was similar (4.5% vs. 4.5%, p = 0.80).

The most common reason for delivery of inappropriate therapy was regular supraventricular tachycardia, followed by AF/atrial flutter.

Interpretation:

The results of the MADIT-RIT trial indicate that programming ICDs either at a higher rate (≥200 bpm) or with a longer delay (as long as 60 seconds in the 170-199 bpm zone) is superior to conventional programming with a 2.5-second delay in the 170-199 bpm zone in reducing inappropriate ICD therapies (mostly ATP). There was also a reduction in appropriate therapies (suggesting that a lot of slower VTs are self-limiting) without an increase in adverse clinical outcomes. In fact, all-cause mortality was reduced with high-dose therapy as compared with conventional programming. These results are hypothesis generating and need further study. The majority of literature on inappropriate ICD therapy has been about the high morbidity associated with inappropriate shocks. The current trial suggests that ATP may also be associated with adverse clinical outcomes in these patients, and raises the question of whether routine ATP settings are necessary in all patients.

Study Design:

Blinded. Parallel. Placebo Controlled. Randomized. Stratified.

Primary Endpoints:

  • First occurrence of inappropriate therapy (i.e., therapy for nonventricular tachyarrhythmias)

Secondary Endpoints:

  • All-cause mortality
  • First episode of syncope

Patient Population:

  • Primary prevention patients with no history of VT/ventricular fibrillation
  • Sinus rhythm at enrollment
  • Patient on stable, optimal pharmacologic therapy
  • Age >21 years

    Number of enrollees: 1,500
    Duration of follow-up: 2.5 years
    Mean patient age: 63 years
    Percentage female: 30%
    Ejection fraction: 26%
    New York Heart Association (NYHA) class: II/III (98%)

Exclusions:

  • Patient with pacemaker, ICD, or CRT-D device
  • CABG or PTCA in past 3 months
  • Myocardial infarction or AF in past 3 months
  • Second- or third-degree heart block
  • NYHA class IV
  • Chronic AF
  • Renal disease: blood urea nitrogen >50 mg/dl or creatinine >2.5 mg/dl

References:

Moss AJ, Schuger C, Beck CA, et al. Reduction in inappropriate therapy and mortality through ICD programming. N Engl J Med 2012;Nov 6:[Epub ahead of print].

Presented by Dr. Arthur Moss at the American Heart Association Scientific Sessions, Los Angeles, CA, November 6, 2012.

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