CardioBrief

Once again a MADIT trial appears poised to shake things up. Results from the MADIT-CRT trial were presented this morning at the ESC and published simultaneously in the New England Journal of Medicine.

In MADIT-CRT, 1,820 patients with cardiomyopathy, EF < 30, QRS > 130 msec, and NYHA class I or II symptoms were randomized in a 3:2 ratio to receive CRT plus an ICD or an ICD alone. Patients were followed for 2.4 years.

The primary endpoint,  all-cause mortality or a nonfatal heart-failure event, was significantly reduced in the ICD plus CRT group. This difference was driven entirely by a dramatic 41% reduction in heart-failure events. The reduction in these events, in turn, occurred mostly in the prespecified subgroup of patients with a QRS duration of > 150 msec.

Primary endpoint (p = 0.001):

• ICD: 25.3%
• ICD + CRT: 17.2%

Heart failure only (p < 0.001):

• ICD: 22.8%
• ICD + CRT: 13.9%

Mortality (p = 0.99):

• ICD: 8.7%
• ICD + CRT: 8.9%

Harlan Krumholz told CardioBrief that MADIT-CRT is a “remarkable study that shows that a large group that are indicated for an ICD will benefit from the use of resynchronization. The challenge is to identify all who may be eligible and to present to them the option of ICD and CRT.”

Regarding the potential expanded indication for CRT, Mariell Jessup, in an accompanying NEJM editorial, asks: “Is this money that could be spent more wisely?” She raises concerns about “‘indication creep’ in patients who are unlikely to derive a mortality benefit” and concludes:

“Given the sobering facts about the costs of health care confronting us now and in the future, it appears prudent that any expanded indication for CRT in less symptomatic patients should be confined to patients with a QRS duration of more than 150 msec and in whom previous marked symptoms have been controlled with optimal medical therapy.”

Many in the EP community and industry are hoping that MADIT-CRT will help reverse the effect of several years of negative news about ICDs, which resulted in decreased confidence in ICDs among both consumers and physicians, yielding declines in new implants. According to one industry source, there are approximately 160,000 NYHA class I and II patients in the US who have a QRS interval greater than 130 msec. This number declines to about 100,000 if the cutoff point is raised to 150 msec.

Here is the ESC press release:

Early intervention with cardiac resynchronization therapy defibrillators (CRT-D) in mild heart failure slows the progression of heart failure, producing significant reductions in death and heart failure interventions, conclude preliminary results from the MADIT-CRT study.

“We are very encouraged by these initial positive results, and are hopeful MADIT-CRT will lead to a wider population of heart failure patients being treated with CRT-D therapy,” commented Prof. Panos E. Vardas, President of the European Heart Rhythm Association (EHRA). “Early use of CRT-D in milder heart failure patients might be beneficial in improving left ventricular (LV) function, leading to a reduction in symptoms, hospitalizations, and mortality.“

Half of all patients will die suddenly

Around half of all patients with heart failure die suddenly due to ventricular arrhythmias, leading to the placement of implantable cardioverter defibrillators (ICDs) being recommended as secondary prevention in these patients in both European (ESC) and US (ACC/AHA) clinical practice guidelines issued in 2005, and joint ESC/ACC/AHA guidelines published in 2006. Furthermore, about one third of patients with low ejection fractions (EF) and New York Heart Association (NYHA) functional Class III to IV heart failure have abnormal electrical activation of the left ventricle (defined as aQRS  duration greater than 120 ms). The result is dyssynchronous contraction of the walls of the left ventricle, leading to suboptimal ventricular filling, decreased stroke volume facilitation of mitral regurgitation, increased wall stress, and delayed relaxation, which has been associated with increased morbidity and mortality.  Cardiac resynchronization therapy (CRT) is achieved by simultaneously pacing both the left and right ventricles in a synchronized manner, resulting in acute haemodynamic benefits.

Benefits of CRT-D versus ICD

The Multicentre Automatic Defibrillator Implantation Trial-CRT, (MADIT-CRT), sets out to investigate whether patients with mild heart failure do better if they get implanted with a CRT-D device (combining cardiac resynchronization therapy with defibrillation), than if they only receive   the traditional ICD defibrillator. CRT-Ds have already been approved for use in patients with severe heart failure (NYHA class III/IV).  In the study, led by Professor Arthur J Moss, from the University of Rochester Medical Centre, New York, 1820 patients with NYHA functional Class II (with non-ischemic or ischemic cardiomyopathy) and NYHA functional Class I (with ischemic cardiomyopathy, left ventricular dysfunction (ejection fraction [EF] < or = 0.30), and prolonged intraventricular conduction (QRS duration > or = 130 ms)) were enrolled from 110 centres in 14 countries and randomised to receive either CRT-D or ICD. All patients received optimal medical therapy.

The preliminary results, announced by Boston Scientific in June, demonstrated that CRT-D was associated with a significant 29 % reduction (p=0.003) in death or heart failure interventions when compared to traditional ICD. The MADIT-CRT Executive Committee stopped the trial on 22 June 2009, when the trial achieved its primary end point.

22 million people worldwide suffer from heart failure

“MADIT-CRT is providing insight into the potential of CRT-D therapy to intervene earlier in the natural progression of heart failure,” says Prof. Vardas, adding that approximately 60% of all heart failure patients in Europe fall into the NYHA Class I or II population enrolled into the study and that nearly 22 million people worldwide currently suffer from some form of heart failure.

“Patients with milder heart failure symptoms have less functional limitation, better quality of life, fewer hospitalizations and a lower mortality rate. However, many of these patients have severe LV systolic dysfunction and prolonged QRS duration with mechanical dyssynchrony, and require aggressive heart failure medical therapy. Early resynchronization may prevent progression of disease and retard or may even reverse the process of LV remodelling”, said Prof. Vardas, stressing that the results are preliminary and needed to be validated by publication in a peer-review journal.

Professor Vardas expressed concern that if the results of MADIT -CRT are validated it may prove difficult to get the CRT-D technology implemented throughout Europe. “Currently, huge differences exist in the implementation of the guidelines from country to country. More education is needed, making the recommendations available at the right time. EHRA must organise a professional policy for the proper implementation of the existing guidelines. A local implementation strategy also is needed in each country,” he said.

Notes to editor

The MADIT-CRT study is the latest in the series of MADIT trials, which have been described as practice changing:

• MADIT proved for the first time that prophylatic implantable cardioverter defibrillator (ICD) therapy can dramatically improve survival in high risk patients. In the study ICDs were found to reduce the overall mortality by 54% and arrhythmic mortality by 75% compared with conventional medical therapy. New England Journal of Medicine 1996;335:1933-40

• MADIT II proved heart attack survivors with left ventricular ejection fractions of 30% or less, without any other risk stratification, benefit from ICD therapy. During an average follow-up of 20 months, the ICD therapy resulted in a 31% reduction in the risk of all cause mortality and a 67% reduction in Sudden Cardiac Death. As a result of MADIT II, patients no longer have to undergo invasive electrophysiological testing to receive the ICD therapy.  New England Journal of Medicine 2002; 346:877-883.

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