A post hoc analysis of COAPT did not support the proportionality explanation for why patients with secondary (or functional) mitral regurgitation (MR) benefited from the MitraClip procedure in that trial but not in the MITRA-FR study.
In line with the main MITRA-FR results, COAPT’s 56 MITRA-FR-like participants had no reduction in combined all-cause mortality or heart failure hospitalization at 24 months when randomized to transcatheter mitral valve repair (TMVr) versus guideline-directed medical therapy alone (27.8% vs 33.1%, P=0.83).
However, at 12 months, this MITRA-FR-like cohort did show marked significant improvements in quality of life measures, reported a group led by JoAnn Lindenfeld, MD, of Vanderbilt University Medical Center in Nashville, Tennessee, in JAMA Cardiology.
Mean Kansas City Cardiomyopathy Questionnaire (KCCQ) scores rose 18.36 points with the procedure versus 0.43 points with medication alone (P=0.01). Distance on the 6-minute walk test rose a mean of 39.0 m with TMVr vs a decline of 48.0 m (P=0.02).
Overall, the echocardiographic data did not support the proportionate-disproportionate hypothesis that effective regurgitation orifice area (EROA) and left ventricular end-diastolic volume (LVEDV) index can help explain the disparate COAPT and MITRA-FR results.
According to that theory, disproportionate patients with more severe MR and less remodeling are more likely to respond, because TMVr directly reduces MR and only indirectly affects the left ventricle, commented Linda Gillam, MD, MPH, of Morristown Medical Center in New Jersey.
The hypothesis had arisen from the observation that MITRA-FR enrolled people with smaller EROAs (mean 31 vs 41 mm2) and larger ventricles (mean LVEDVi 135 vs 101 ml/m2) compared with COAPT.
In the present analysis, the MITRA-FR-like patients in COAPT had a mean EROA of 0.26 cm2 and LVEDV index of 127.6 ml/m2.
“What can we conclude from this study? First, the difference between the COAPT and MITRA-FR results remain incompletely explained and likely multifactorial. It is not surprising that the proportionality analysis, while appealing in its simplicity, falls short,” Gillam wrote in an accompanying editorial.
“Second, patient selection for TMVr remains problematic and it is not appropriate to select or exclude patients with secondary MR for TMVr based on the EROA to LVEDV ratio, the [regurgitant volume] to LVEDV ratio, or the dichotomization of MR as proportionate or disproportionate,” she continued.
Lindenfeld’s group performed a post hoc secondary analysis of the COAPT trial. Included were 548 symptomatic patients with secondary MR (mean age 71.9 years, 64% men).
Among the 492 non-MITRA-FR-like individuals, those who received the MitraClip had a lower incidence of the combined primary endpoint and greater improvement in the KCCQ summary score compared with controls; their 6-minute walk test results were not significantly better, however.
Lindenfeld’s team acknowledged the post hoc nature of the study. An important limitation was the small sample of MITRA-FR-like patients, of whom only 22 had been randomized to TMVr.
“An analysis of the combined MITRA-FR and COAPT databases is planned and will further clarify the factors associated with TMVr response in patients with secondary MR. Additional studies with larger cohorts and longer follow-up are also necessary to determine whether patients with less severe MR or greater LV dimensions may have a more modest clinical benefit,” according to the group.
Gillam suggested that researchers develop better methods of assessing LV size and MR quantification. “Greater access to existing 2-dimensional echocardiographic trial data will help the conversations continue,” she wrote.
On the basis of COAPT, the MitraClip procedure was FDA approved for secondary MR in 2019. In January 2021, CMS finally came through with a revised National Coverage Determination that covers mitral valve transcatheter edge-to-edge repair for this population.
Lindenfeld reported receiving personal fees from Abbott, Boehringer Ingelheim, CVRx, Impulse Dynamics, Edwards Lifesciences, and VWave; grants and personal fees from AstraZeneca; and grants from Sensible Medical and VoluMetrix.
Gillam disclosed personal fees for serving on the Edwards Lifesciences advisory board; serving on the executive committee of the CLASP IID and IIF pivotal trials; consulting for Edwards Lifesciences; and holding Institutional Core Lab contracts with Edwards Lifesciences, Medtronic, and Abbott.