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Not all functional mitral regurgitation (MR) is the same, according to researchers who proposed taking proportionality of MR severity into account when identifying patients who might benefit from the MitraClip procedure.

Milton Packer, MD, and Paul Grayburn, MD, both of Baylor Scott & White Heart and Vascular Hospital in Dallas, argued that functional MR should be split into two types "to address the pathophysiologic characteristics as well as the severity of MR":

• Proportionate MR: classic secondary MR that can be explained by left ventricular end-diastolic volume (LVEDV)

• Disproportionate MR: where MR severity exceeds that predicted by LVEDV

This approach was prompted by the discordant findings reported from MITRA-FR and COAPT, two randomized trials of transcatheter edge-to-edge repair in patients with severe functional (or secondary) MR. MitraClip therapy was associated with decreased risk of death and hospitalization for heart failure in COAPT -- but had little clinical benefit in MITRA-FR.

Proportionate vs Disproportionate MR

Categorizing MR into proportionate and disproportionate types would "explain the diverse range of responses to drug and device interventions that have been observed," Packer and Grayburn stated in their published online in JAMA Cardiology.

For example, the small group of COAPT participants that appeared to have proportionate MR, similar to the MITRA-FR cohort, did not respond favorably to transcatheter mitral valve repair, the duo noted.

Classification by proportionate and disproportionate MR would help clinicians give the right therapies to the right patients, according to Packer and Grayburn: interventions that improve LV function for patients with proportionate MR; and interventions directed at the mitral valve apparatus for patients with disproportionate MR.

"Both the U.S. and European guidelines rely on the calculation of the EROA [effective regurgitant orifice area], even though it is based on assumptions about the geometry of the regurgitant jet and is influenced by the transvalvular pressure gradient and the LV ejection fraction," the authors wrote. "Unfortunately, the classic framework ignored the fact that the mitral valve consisted not only of the leaflets but the entire supporting apparatus, which included the annulus, chordae, and papillary muscles."

"We describe the evolution of a conceptual framework that classifies patients with functional MR according to the causal mechanism rather than the severity of the regurgitant lesion and thus distinguishes patients in whom MR is a biomarker from those in whom MR is an appropriate therapeutic target," Packer and Grayburn said.

The Difference in Proportionality Questioned

Based on proportionality analyses, however, another group suggested that the severity of MR was not necessarily all that different between COAPT and MITRA-FR.

One MR proportionality coefficient, the ratio of EROA to EDV, was doubled in COAPT compared with MITRA-FR, suggesting that the COAPT study had patients with more severe MR, according to a from a team led by William Gaasch, MD, of Lahey Hospital and Medical Center in Burlington, Massachusetts, published in the same issue of JAMA Cardiology.

In contrast, the ratio of mitral regurgitant volume to EDV was similar (slightly lower, if anything) in COAPT compared with MITRA-FR, which would indicate that the proportional mitral regurgitant volume was comparable between the two clinical trials.

"The results of proportionality analyses based on EROA differ from those based on a volume analysis. This disparity casts doubt on the notion that an EROA analysis alone can explain the different results of the two randomized clinical trials," Gaasch and colleagues wrote, adding that the results still leave unanswered the question of how to reliably identify a subgroup of patients who might best respond to mitral valve repair.

Putting It All Together

Like Packer and Grayburn, Gaasch and colleagues formed their theory based on assumptions because of missing trial data. Both groups used COAPT volume measurements, which have been questioned for their reliability.

"At the 2019 Transcatheter Cardiovascular Therapeutics meeting, the reported total stroke volume (TSV) was 51 mL and the regurgitant volume was 60 mL, which is obviously not possible and suggests either underestimation of EDV or overestimation of the EROA and regurgitant volume," noted Rebecca Hahn, MD, of the Cardiovascular Research Foundation and NewYork-Presbyterian Hospital/Columbia University Medical Center in New York City.

"The accuracy of the EROA and EDV in COAPT may then be the major limitation for any theoretical construct attempting to explain trial differences based on MR severity and LV size," she wrote in an .

Moreover, the two groups' attempts to normalize the standard quantitative measures of MR severity to LV size still leave room for alteration by chamber compliance and loading conditions, Hahn added. "Regurgitation fraction [RF] normalizes for these hemodynamic and functional parameters by including TSV and should be a measure of the hemodynamic burden of MR for these diverse groups of patients without requiring further adjustment for LV size or function."

To better identify secondary MR patients who are likely to respond to transcatheter repair, a patient-level meta-analysis of COAPT and MITRA-FR is now planned, Hahn noted. "It is possible that with greater transparency of trial data, one could determine which normalized measure, EROA:EDV or regurgitant volume to EDV or RF, has the greatest prognostic value for outcomes."