Analysis shows proportionality fails to account for divergent COAPT and Mitra-FR trials

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MitraClip

A secondary analysis of the COAPT trial, which sought to account for differences in the findings of COAPT and the Mitra-FR trial in patients with secondary mitral regurgitation (MR), has concluded that a divergence between the two studies over inclusion criteria relating to “proportionate and disproportionate” MR did not predict outcomes within the COAPT trial.

COAPT was a randomised trial evaluating transcatheter mitral valve repair with the MitraClip (Abbott) device in patients with heart failure and moderate-to-severe or severe secondary MR who remained symptomatic despite maximally-tolerated guideline directed medical therapy. Results of COAPT showed that at two years, using MitraClip to manage patients with secondary mitral regurgitation was associated with a significant reduction in heart failure hospitalisation.

Controversially however, this was at odds with findings of Mitra-FR, which also compared percutaneous edge-to-edge repair using the MitraClip device with medical therapy alone in patients with secondary mitral regurgitation, concluding that the use of the device does not significantly reduce the composite rate of all-cause death and hospitalisation for heart failure compared with medical therapy.

The analysis by JoAnn Lindenfield (Vanderbilt Heart and Vascular Institute, Nashville, USA), published online this month in JAMA Cardiology, looked to test the “proportionate-disproportionate hypothesis”, which centres the ratio of effective regurgitant orifice area (EROA) to left ventricular end-diastolic volume (LVEDV).

The idea that proportionate and disproportionate MR could reconcile the results of the Mitra-FR and COAPT trials was first put forward by Paul Grayburn (Baylor Heart and Vascular Institute, Dallas, USA), Anna Sannino (Federico II University of Naples, Naples, Italy) and Milton Packer (Baylor Heart and Vascular Institute, Dallas, USA) in an editorial published in JACC: Cardiovascular Imaging in 2019.

Grayburn et al suggested that the Mitra-FR trial enrolled patients who had MR that was proportionate to the degree of left ventricular (LV) dilatation, and during long-term follow-up, the LVEDV and clinical outcomes of these patients did not differ from medically-treated control subjects. In comparison, they noted, patients enrolled in the COAPT trial had an EROA ≈30% higher but LV volumes that were ≈30% smaller, indicative of disproportionate MR. In these patients, transcatheter mitral valve repair reduced the risk of death and hospitalisation for heart failure, and these benefits were paralleled by a meaningful decrease in LVEDV, they wrote, adding that characterisation of MR as proportionate or disproportionate to LVEDV “appears to be critical to the selection of an optimal treatment for patients with chronic heart failure and systolic dysfunction”.

To test this theory, Lindenfeld et al carried out a post hoc secondary analysis of the COAPT trial, evaluating a sub-group of 56 COAPT patients with characteristics consistent with those in Mitra-FR (HF with grade 3+ to 4+ SMR, left ventricular ejection fraction of 20%-50%, and New York Heart Association function class II-IV). These were compared with the remaining 492 COAPT patients using the end point of all-cause mortality or heart failure hospitalisation at 24 months, components of the primary end point, and quality of life (QOL).

The analysis found that in the sub-group of patients consistent with those in the Mitra-FR trial, there was no significant difference in the composite rate of all-cause mortality or heart failure hospitalisation between those receiving the MitraClip plus guideline-directed medical therapy versus medical therapy alone at 24 months (27.8% vs 33.1%, p=0.83) compared with a significant difference at 24 months (31.5% vs 50.2%, p<0.001) in the remaining patients. While this finding supports the hypothesis that disproportionate MR benefits from MitraClip in terms of mortality and HF hospitalisation, all subgroups randomised to receive MitraClip versus those treated with medical therapy alone had significantly greater improvement in QOL at 12 months. The results led Lindenfeld and colleagues to conclude that the benefit of transcatheter mitral valve repair is not fully supported by the proportionate-disproportionate hypothesis.

“It is not surprising that the proportionality analysis, while appealing in its simplicity, falls short,” writes Linda Gillam (Morristown Medical Center/Atlantic Health System, Morristown, USA) in an editorial accompanying the publication of the analysis in JAMA Cardiology.

Gillam notes that the difference between the COAPT and Mitra-FR results remains “incompletely explained and likely multifactorial,” adding that patient selection for transcatheter mitral valve replacement “remains problematic” and it is not appropriate to select or exclude patients with secondary MR based on the EROA to LVEDV ratio, the RV to LVEDV ratio, or the dichotomisation of MR as proportionate or disproportionate.

“In the end, whether additional studies or real-world experience with TMVr for secondary MR more closely reproduce COAPT or Mitra-FR results is perhaps most important and remains to be seen,” Gillam concludes.


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