Abstract
Background: The MADIT-CRT trial was designed to determine whether cardiac-resynchronization therapy (CRT) with biventricular pacing would reduce the risk of death or heart-failure events in patients with mild cardiac symptoms, a reduced ejection fraction, and a wide QRS complex.
Methods: During a 4.5-year period, the investigators enrolled and followed 1820 patients with ischemic or nonischemic cardiomyopathy, an ejection fraction of 30% or less, a QRS duration of 130 msec or more, and New York Heart Association class I or II symptoms. Patients were randomly assigned in a 3:2 ratio to receive CRT plus an implantable cardioverter–defibrillator (ICD) (1089 patients) or an ICD alone (731 patients). The primary end point was death from any cause or a nonfatal heart-failure event (whichever came first). Heart-failure events were diagnosed by physicians who were aware of the treatment assignments, but they were adjudicated by a committee that was unaware of assignments.
Results: During an average follow-up of 2.4 years, the primary end point occurred in 187 of 1089 patients in the CRT–ICD group (17.2%) and 185 of 731 patients in the ICD-only group (25.3%) (hazard ratio in the CRT–ICD group, 0.66; 95% confidence interval [CI], 0.52 to 0.84; P=0.001). The benefit did not differ significantly between patients with ischemic cardiomyopathy and those with nonischemic cardiomyopathy. The superiority of CRT was driven by a 41% reduction in the risk of heart-failure events, a finding that was evident primarily in a prespecified subgroup of patients with a QRS duration of 150 msec or more. CRT was associated with a significant reduction in left ventricular volumes and improvement in the ejection fraction. There was no significant difference between the two groups in the overall risk of death, with a 3% annual mortality rate in each treatment group. Serious adverse events were infrequent in the two groups.
Conclusions: CRT combined with ICD decreased the risk of heart-failure events in relatively asymptomatic patients with a low ejection fraction and wide QRS complex. (ClinicalTrials.gov number, NCT00180271.)
Full Citation
Published at www.nejm.org September 1, 2009 (10.1056/NEJMoa0906431)
The attached publication discusses the results from the MADIT-CRT Trial.
The following information is provided in accordance with FDA’s Guidance Document, Good Reprint Practices for the Distribution of Medical Journal Articles and Medical or Scientific Reference Publication s on Unapproved Uses of Approved Drugs and Approved or Cleared Medical Devices, dated January 2009.
MADIT-CRT was supported by a research grant from Boston Scientific Co. Only commercially available transvenous devices were used. All devices used were from Boston Scientific. Financial interest of the authors of this study can be found on page 9 of the NEJM publication.
St. Jude Medical does not have any interest in the Boston Scientific devices used in this study. St. Jude Medical does manufacture cardiac resynchronization therapy (CRT) devices.
Current indications for St. Jude Medical pulse generators are as follows (see attached users manual):
St. Jude Medical ICD and CRT devices, including the Current®, Current® Plus, Promote®, and Promote® Plus pulse generators, are intended to provide ventricular antitachycardia pacing and ventricular defibrillation for automated treatment of life-threatening ventricular arrhythmias.
AF Suppression™ pacing is indicated for suppression of paroxysmal or persistent atrial fibrillation in patients with the above ICD indication and sinus node dysfunction.
In patients indicated for an ICD, the Promote and Promote Plus pulse generators are also intended:
• To provide a reduction of the symptoms of moderate to severe heart failure (NYHA Functional Class III or IV) in those patients who remain symptomatic despite stable, optimal medical therapy and have a left ventricular ejection fraction less than or equal to 35% and a prolonged QRS duration
• To maintain synchrony of the left and right ventricles in patients who have undergone an AV nodal ablation for chronic (permanent) atrial fibrillation and have NYHA Class II or III heart failure
Contraindications for use of the pulse generator system include ventricular tachyarrhythmias resulting from transient or correctable factors such as drug toxicity, electrolyte imbalance, or acute myocardial infarction.
In the MADIT-CRT study, risks with CRT-D implantation in this patient population were consistent with the risks present in typical CRT-D implants. Specifically in the MADIT-CRT patient population, in the 30 days after device implantation, the following percentages of patients had serious adverse events: pneumothorax (1.7% in the CRT-ICD group and 0.8% in the ICD-only group), infection (1.1% in the CRT-ICD group and 0.7% in the ICD-only group), and pocket hematoma requiring evacuation (3.3% in the CRT-ICD group and 2.5% in the ICD-only group). Also, during CRT-ICD implantation, coronary venous dissection with pericardial effusion occurred in 5 patients (0.5%) and the left ventricular coronary-vein lead was repositioned during the first 30 days for a variety of reasons in 44 patients (4.0%). Finally, during long-term follow-up after the first 30 days, serious device-related adverse events occurred with a frequency of 4.5 per 100 device-months in the CRT-ICD group and of 5.2 per 100 device-months in the ICD-only group.
A number of other potential adverse events can be associated with CRT systems and are listed in the device manuals including but not limited to acceleration of arrhythmias (caused by device), air embolism, allergic reaction, bleeding, cardiac tamponade, chronic nerve damage, death, erosion, exacerbation of heart failure, excessive fibrotic tissue growth, extracardiac stimulation (phrenic nerve, diaphragm, chest wall), extrusion, fluid accumulation, formation of hematomas or cysts, inappropriate shocks, infection, keloid formation, lead abrasion and discontinuity, lead migration/dislodgment, myocardial damage, pneumothorax, shunting current or insulating myocardium during defibrillation with internal or external paddles, potential mortality due to inability to defibrillate or pace, thromboemboli, venous occlusion, venous or cardiac perforation.
Patients susceptible to frequent shocks despite antiarrhythmic medical management may develop psychological intolerance to an ICD or CRT-D system that may include dependency, depression, fear of premature battery depletion, fear of shocking while conscious, fear of losing shock capability, imagined shocking (phantom shock).
An editorial published by Mariell Jessup regarding the MADIT-CRT Trial results discusses recent trials such as RethinQ which have studied the impact of CRT on patients with mechanical dyssynchrony and a narrow QRS duration. The RethinQ study found that CRT had no benefit on heart failure events at 6 months in these narrow QRS patients. In addition, both the REVERSE trial and MADIT-CRT showed that clinical benefit occurred primarily in the subgroup of patients with a QRS > 150 ms. Therefore, these trials suggest that CRT-D may be most beneficial for NYHA Class I or II patients with low EF and QRS widths > 150 ms.
For additional publications regarding the use of CRT-D in Class I/II HF patients, review the bibliographies at the back of the attached publications. Information regarding the REVERSE study can be found in JACC: Randomized trial of cardiac resynchronization in mildly symptomatic heart failure patients and in asymptomatic patients with left ventricular dysfunction and previous heart failure symptoms. J Am Coll Cardiol. 2008 Dec 2;52(23):1834-43. Epub 2008 Nov 7.
Information regarding the RethinQ study can be found in the NEJM:
Cardiac-resynchronization therapy in heart failure with narrow QRS complexes. N Engl J Med. 2007 Dec 13;357(24):2461-71. Epub 2007 Nov 6.
View a presentation on the MADIT-CRT trial, Reduction in the risk of heart failure with preventive cardiac resynchronization therapy: MADIT-CRT Trial.
To review the full text publication, click on the link below. In accordance with the FDA’s Good Reprint Practice Guidance dated January 2009, please review the memo linked below when accessing the article. Please print and attach the memo to any printed copies of the full text publication as well.
View memo link
View Jessup editorial