The MADIT-CRT Trial Results: Interview With Arthur Moss, MD

In this interview, we discuss the recent results of the MADIT-CRT trial. Dr. Arthur Moss is located at the University of Rochester Medical Center in Rochester, New York.

Tell us about the MADIT-CRT trial. What were the study findings? Why are these findings significant? How did gender play a role — did women or men fare better?

From our previous studies in MADIT I and MADIT II, we realized that heart failure was a frequent accompaniment in the long term for these patients, and also that heart failure was frequently a risk factor for cardiac arrhythmias. We found that events in patients who had New York Heart Association (NYHA) Class 1 or II heart failure were often associated with subsequent ICD firing for ventricular tachycardia and ventricular fibrillation. We researched this further and became aware of the indications for cardiac resynchronization therapy (CRT) for patients with NYHA Class III and IV heart failure, low ejection fraction and wide QRS complex. Our executive committee met and decided that what was needed was a definitive trial of a large group of patients with Class I and Class II heart failure with wide QRS and low ejection fraction, involving patients with both ischemic and nonischemic heart disease: this was the MADIT-CRT trial. The findings from MADIT-CRT were more dramatic than what we had expected or anticipated. There was a 34 percent reduction in the primary endpoint of heart failure or death, whichever comes first. Because this was a relatively low risk group, the actual mortality rate was quite low — less than 3 percent per year — thus, we could look at the other secondary endpoint, which was heart failure. That is where we found a 44 percent reduction in heart failure events. This is a very important finding, because several different studies have shown that the heart failure events are associated over the next 5 years with a 5- to 8-fold increase in mortality. This was the background and the primary findings of the study. We did have additional findings that showed patients with a wider QRS complex did better than patients with a narrower QRS complex. Even more important, we found out that women in this trial did significantly better than the men, although the men in the trial also got a significant result, which was about a 23 percent reduction in the primary endpoint. The women had approximately a 67 percent reduction in the primary endpoint, and this was significantly different between the men and women. Other aspects worthy of note is that we did echocardiograms at baseline and at 1 year in the 2 treatment groups — a CRT-D group versus the ICD-only group — and the patients who had the CRT-D had significantly greater reductions in heart volumes and improvements in ejection fractions than did the group with the ICD only.

Was there also a difference in benefits between Class 1 and Class II patients?

Actually, no there were not. Only about 15 percent of patients were considered Class I and about 85 percent were Class II, and as we reported in the New England Journal of Medicine, there was no significant difference in the benefit between the 2 treatment groups, although Class II seemed to have a little better of a result than Class I, but the number of patients in Class I was smaller.

How does this data help our understanding of heart failure in Class I and II patients?

It is very clear that patients with NYHA Class I and II heart failure do get benefit from resynchronization therapy — it significantly reduces the progression to heart failure, and this will eventually transfer into reduced mortality. There was a 44 percent reduction in heart failure events, and this is in addition to ACE inhibitors, beta blockers, diuretics, and everything else. So the findings are showing there is a new and effective therapy to prevent heart failure events. This is very important.

Do you anticipate there will be an expanded indication for CRT-D devices for Class I or II heart failure patients?

I believe so. We do not want to provide bias, but this result is from a large study of 1,820 patients randomized. The findings from the previous REVERSE trial showed fundamentally the same thing — a significant reduction in heart volumes and improvements in ejection fraction. Therefore, I think that in view of the echocardiographic findings, the size of the trial, and the fact that there is another similar trial with the same pattern, I think there will be new guidelines. However, that usually takes about a year or so.

Do you expect an increase in the number of CRT device implantations?

Yes, I think so. We tend to follow general guidelines that are based on good clinical trials and an understanding of pathophysiology, and heart failure is a big problem — it is the major cause of hospitalizations for adult patients with heart disease. Actually, in MADIT-CRT we also found a reduction in repetitive hospitalizations for heart failure, and we’ll be reporting on that later. So yes, I think there will be an increase in the utilization. If you were to ask me at what magnitude, I couldn’t guess that. I can only say that this is effective therapy, and since the data are not from an isolated or standalone trial, I think it makes sense that this will advance the science of clinical cardiology and will be utilized appropriately. We were pretty stringent in our eligibility — that is, we used a 130-millisecond QRS cutoff and low ejection fraction of 30 percent or less, and we evaluated both ischemic and nonischemic adults — so this was an at-risk group. Therefore, I think there will be a considerable increase in utilization of this therapy.

How has this trial data been received?

I think it has been favorably received overall. Anytime you come out with something new, there are always the sort of naysayers. For example, the editorial in the New England Journal of Medicine raised the issue of cost effectiveness, in which they made some assumptions that weren’t true. They thought 10 percent of the patients had been in Class IV at some time in the past, but in fact that was just simply wrong, and if they had read the article more carefully it was actually 3 percent. This group didn’t do quite as well, although they got a hazard ratio of 0.77 which would be a 23 percent reduction in events. If we had removed that group they would have obtained an even better result, a hazard ratio of 0.63 or a 37 percent reduction in the primary event. One always expects critical comments, but the overall response from the vast majority of people has been very favorable.

How does these trial results impact both the patient and electrophysiologist?

I think the most important thing is that it impacts these at-risk patients in a very favorable way. In terms of electrophysiologists, I suspect there will be an increased referral of these at-risk patients; it won’t take place overnight, but will gradually become more available.

What further research is still needed?

As in any therapy that is initiated, there is always the need for improved selection. For instance, if you were to look back to the original introduction of the ACE inhibitors, which were a big step forward back then, there were 2 main trials for the Enalapril drug. One was for the treatment of Class III and IV heart failure, and the other was for the heart failure prevention trial of Class I and II. This showed a significant reduction in heart failure events, and this was followed up 4-5 years later by looking at the reduction in long-term mortality. Ours is a relatively asymptomatic yet at-risk group, so I think that this therapy will become progressively accepted as people see and experience the benefits from it.