Evaluating the MADIT-CRT Trial

Dear Readers, Heart failure therapies are typically tested first in the sickest patients, because it is easier to detect a benefit if the therapy works. For example, angiotensin-converting enzyme inhibitors were first tested in patients with advanced heart failure. After being found to be effective, they were evaluated in the SOLVD prevention trial in asymptomatic patients with left ventricular dysfunction. Studies of cardiac resynchronization pacing therapy (CRT) are evolving similarly. Early acute hemodynamic studies were followed by studies of chronically implanted device-based therapy in patients with severe heart failure and severe dyssynchrony. The therapy was quickly adopted at many centers in the late 1990s even before there were devices designed and approved to deliver CRT, by using modified tined leads placed in the coronary veins and attached to the pacing device with an adapter. As data came in showing benefit, studies like COMPANION were designed to test CRT in less sick patients with less severe electrical dyssynchrony. The technology has evolved such that implantation of a left ventricular pacing lead has become almost routine. However, an important remaining issue has been how worse off a patient really needs to be to get benefit from CRT. When a patient with ventricular dysfunction and an intraventricular conduction delay is being evaluated for a primary prevention defibrillator, it is sometimes difficult to decide if CRT should be recommended, recognizing that placement of an additional lead is associated with more cost, more hardware, and a longer implant duration, as well as recognizing that patients can go back and forth between heart failure classifications. The first available data from a large clinical trial of CRT that evaluated patients with less severe heart failure was from the Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction (REVERSE) trial sponsored by Medtronic.1 This trial showed that CRT can improve cardiac structure and function through reverse left ventricular remodeling. Although this study was exciting, it did not have much effect on clinical practice and has not affected practice guidelines. The long-awaited results of the third MADIT trial, the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT), sponsored by Boston Scientific, were published in September 2009 in the New England Journal of Medicine.2 This study enrolled almost 2,000 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 an ICD that delivered CRT (CRT-D) or an ICD alone. The primary endpoint was death from any cause or a nonfatal heart failure event. After an average of 2.4 years, many fewer patients who received CRT reached the primary endpoint (17% vs. 25%). In addition, the risk of heart failure events was reduced by 41% and the benefit was most notable in those with a QRS duration of ≥ 150 msec. MADIT-CRT is a very important study that will likely have an impact on how we practice. However, despite the encouraging results of this landmark study, Dr. Mariell Jessup drew attention to the rising costs of health care in her accompanying NEJM editorial,3 emphasizing that costs should be considered before expanding the indications for CRT. She made the point that 12 patients would need to be treated to prevent a single heart failure event in the MADIT-CRT trial. What was not emphasized was that these patients already have an indication for an implantable defibrillator. From the patient’s perspective, the addition of a left ventricular lead at the time of implantation is very different than undergoing a procedure at all. It was also not emphasized that the benefit was shown after only two and a half years of follow-up, a duration that is about half of the longevity of most current CRT devices. Given the major costs and negative experiences associated with a hospital admission for patients with congestive heart failure, any therapy found to reduce the risk of heart failure events by 41% should be embraced. Patients should not have to wait until they are drowning to ask for this life preserver.