Proportionate and Disproportionate MR: A ‘Framework’ for MitraClip and Medical Therapy

Among ongoing efforts to identify the heart failure patient who will benefit the most from device-based therapies like MitraClip (Abbott), a heart failure expert has teamed up with a valvular heart disease imager to posit a “framework” that they believe can help guide the most appropriate therapy in any given patient.

Milton Packer, MD, and Paul Grayburn, MD, have offices a mere 100 feet apart at Baylor University Medical Center in Dallas, TX, Packer explained to TCTMD. They “met in the middle”—figuratively and literally (there is a conference room halfway between their two offices)—to share their understanding of the pathophysiology of heart failure and severe mitral regurgitation (MR).

“We actually went to a white board and started making diagrams,” Packer said. “I made my diagrams and he made his, and in a couple hours we saw that the diagrams actually made much more sense if they were considered together than if they were considered separately.”

The resulting paper, which went online last week in Circulation, is a companion to a paper published earlier this year in JACC: Cardiovascular Imaging that was more specifically targeted at cardiac imagers. Together, the papers lay out the concept of “proportionate” and “disproportionate” MR as determined by the relationship between effective regurgitant orifice area (EROA) and left ventricular end-diastolic volume (LVEDV).

In patients with proportionate MR, Packer said, the left ventricular enlargement and remodeling are responsible for the changes to the mitral valve and supporting structures and explain the degree of mitral regurgitation. In other words, there is a linear relationship between LVEDV and the EROA for a given ejection fraction. These patients, the authors argue, will benefit principally from drugs that improve LV function.

The concept makes total sense, at least in part explains the COAPT/MITRA-FR differences, and is a logical path to pursue going forward. Michael Mack

By contrast, in patients with LV dysfunction related to pathology at the level of the mitral valve and supporting structures, the relationship is nonlinear and the resulting mitral regurgitation is disproportionate to the LV geometry. In these patients, “you have to actually correct the problem in the valve mechanically, and there are two ways of doing that,” Packer said. “One is, in selected patients, a cardiac resynchronization device will be a good first step. And secondly a MitraClip might be an equally logical step for individuals whose primary problem is with the mitral valve and [whom] we can identify by showing that they have disproportionate MR.”

Proportional Representation

While the terms are relatively new, the “framework” proposed by Packer and Grayson is in-line with theories other experts have advanced to explain the apparent differences between the negative MITRA-FR and positive COAPT trials. Commenting on the paper for TCTMD, both COAPT co-principal investigators agreed that Packer and Grayburn’s proposal fits with the conclusions reached by COAPT investigators.

“The concept makes total sense, at least in part explains the COAPT/MITRA-FR differences, and is a logical path to pursue going forward,” Michael Mack, MD (The Heart Hospital Baylor, Plano, TX), told TCTMD in an email. “However, it still needs validation, and the ability to accurately calculate this on every patient in every institution is going to be problematic.”

Gregg Stone, MD (NewYork-Presbyterian/Columbia University Irving Medical Center), had a similar perspective. “I think it’s a very useful construct to start to conceptualize the relative contribution of the mitral regurgitation disease process versus the severity of LV dysfunction,” he told TCTMD. “What is missing, though, is how to apply this to the individual patients.”

In their paper, Packer and Grayburn use population means, abstracted from major HF clinical trials, to plot where specific heart failure therapies fall on the spectrum of severe and disproportionate MR, severe and proportionate MR, and mild-to-moderate MR, Stone noted. The problem with this approach is that it uses aggregate data rather than patient-level data. “What is lacking so far is a prospective or even retrospective validation that this approach can be applied to individual patients to predict which ones will benefit and which will not,” Stone said.

What is lacking so far is a prospective or even retrospective validation that this approach can be applied to individual patients to predict which ones will benefit and which will not. Gregg Stone

He also believes that there are other factors, in addition to the concepts of proportionate and disproportionate MR, that should play a role in deciding whether medical therapy or valve repair/replacement is the best approach.

“It may be that when the left ventricle gets too large, even if you have very severe MR, that the patients may not be able to respond—the ventricle may not be able to recover—suggesting that maybe you should treat earlier,” Stone said. “And conversely, even if the ventricle is quite small, it may be that lesser degrees of MR (what they call proportionate or even slightly less proportionate MR) may be able to respond. And then finally they are very prescriptive about proportionate mitral regurgitation primarily being treated with heart failure medications and other such therapies, whereas disproportionate MR should primarily be treated with devices like the MitraClip or cardiac resynchronization therapy [CRT], and I don’t think we have that data at all.”

Stone maintains there are likely patients with severe MR, both proportionate and disproportionate, who will respond to MR reduction therapies and CRT. By the same token, even patients with disproportionate MR can benefit from heart failure therapies—that’s underscored by the fact that COAPT patients had to be maximized on best medical therapy before being considered for enrollment in the trial.

“So, I don’t think the therapeutic implications are quite as straightforward as they imply,” said Stone, “but I think that this is a great framework to then start exploring, on an individual patient basis, what patients might benefit more by heart failure therapies versus CRT versus MR reduction devices.”

More Data to Come

Packer himself stressed that the proposed framework is principally an attempt to get physicians thinking about the underlying pathophysiology and to use this to make sense of what, on the surface, are the conflicting COAPT and MITRA-FR results.

This is a framework and its whole intent is to stimulate people to come up with new data to either confirm or refute it. Milton Packer

“This is a framework and its whole intent is to stimulate people to come up with new data to either confirm or refute it,” Packer said. “Five years from now it could be that all of the data that's collected during that period of time confirms our framework and so people are solidly behind it, but it could be that a lot of new data is inconsistent with the framework and we will have to revise it. The framework isn't put forward as an ultimate solution. The framework is being put forward as the best possible explanation based on what we already know.”

According to Stone, the COAPT and MITRA-FR investigators are already moving forward with plans to get more information, having agreed to pool their data and reanalyze the echocardiograms from MITRA-FR using the COAPT core lab. “So, we’ll have all of the parameters measured exactly the same, and then we’ll be able to create subsets of patients that we can classify as proportionate versus disproportionate versus nonsevere MR and see if those subsets benefit or don’t benefit from the MitraClip,” said Stone. “And I think that will be very useful to identify individual patients with criteria that can be used in practice.”

On a related noted, Stone disclosed that new COAPT data are slated for release at the upcoming EuroPCR meeting. The analysis is looking at the relationship between MR reduction at 30 days and long-term outcomes, regardless of treatment allocation.