Meta-analysis Teases Out What Drives Success in M-TEER

As a whole, the data from the three large, randomized trials of mitral transcatheter edge-to-edge repair (M-TEER)—MITRA-FR, COAPT, and RESHAPE-HF2—confirm that the intervention reduces 24-month rates of death and hospitalization due to heart failure in patients with symptomatic moderate-to-severe functional mitral regurgitation (FMR), the authors of a new meta-analysis say.

However, they stress that the results emphasize how important it is to select the right cases when pursuing M-TEER.

The meta-analysis included the 2018 MITRA-FR trial, which dampened enthusiasm by showing negative results for M-TEER, as well as the positive COAPT trial released months later. It also included RESHAPE-HF2, a third trial that, when released 6 years after those conflicting results, provided somewhat mixed findings.

Senior author Davide Capodanno, MD, PhD (University of Catania, Italy), told TCTMD that their new paper reveals what may be driving the inconsistent results among the trials.

“One may say, ‘Okay, we know the information from the three trials. We don’t need to put them together.’ But for me, it is a good way to look critically at the differences between the three trials,” Capodanno explained, pointing out that heterogeneity was high, in the ballpark of 80%. “You need to find the sources of the heterogeneity. By looking at the characteristics of the populations [in each trial], you discover why this procedure works well in some patients and works less well in other patients.

“I think, in the end, the message is powerful,” he continued, “because it tells you if you select carefully the patients and mirror the characteristics that were in COAPT and RESHAPE, you may get the best from this procedure.” On the other hand, if M-TEER is performed in patients with dilated ventricles and less MR, the results are closer to what’s seen in MITRA-FR, said Capodanno.

Without additional research that reflects current medical therapy, “the jury is still out” on M-TEER, said Capodanno. “It’s important to have a critical approach to the data, because . . . sometimes the full picture is clear but in other cases you [must not] miss the nuances. This is one field of interventional cardiology where the nuances are very important in the full story.”

Led by Nicola Ammirabile, MD (University of Catania), the meta-analysis was published in the January 2026 issue of EuroIntervention.

It’s important to have a critical approach to the data, because . . . sometimes the full picture is clear but in other cases you [must not] miss the nuances. Davide Capodanno

David Messika-Zeitoun, MD, PhD (University of Ottawa Heart Institute, Canada), a MITRA-FR investigator who has explored how that trial diverged from COAPT, commented to TCTMD that the new paper doesn’t offer any surprises based on what the studies originally found. “To be frank, the added value is limited,” he said. “It’s not unexpected. . . . What is interesting is that the different methodologies they used [in the meta-analysis] gave different results.”

Still, “what is clear is the clip is beneficial in the population of patients with ventricular functional mitral regurgitation,” Messika-Zeitoun added. “The [totality] of the three different trials shows that not everyone is benefitting from intervention, but so far we only have vague indicators regarding who will benefit.”

In line with this, the latest European guidelines for valvular heart disease “provide some support, but in fact [are] very vague,” he noted.

Messika-Zeitoun said it’s likely no additional large RCTs are on the way that will guide patient selection, given that MitraClip (Abbott) has long been on the market. The best approach, he stressed, would be combining individual patient data from COAPT and MITRA-FR, a project that has been explored but not yet come to fruition.

“Transcatheter intervention is very low risk, and because it’s very low risk, we [sometimes] do it because we can, not always because we should,” Messika-Zeitoun said. When selecting patients, currently “everybody is in a gray zone and [trying] to use common sense.”

MITRA-FR lead investigator Jean-François Obadia, MD (formerly of Hôpital Cardiovasculaire Louis Pradel, Bron, France), told TCTMD that there’s only so much to be gleaned from meta-analyses in this area.

“Not being a statistician, but rather a clinician long involved in the management of functional mitral regurgitation, my interpretation of the MITRA-FR, COAPT, and RESHAPE-HF2 trials is primarily clinical and pathophysiological,” he wrote via email. “Recent meta-analyses provide useful information; however, they sometimes place on the same level studies whose designs, patient populations, and organizational contexts differ substantially, thereby limiting the relevance of conclusions based solely on an overall average treatment effect.”

Obadia pointed out that the three trials’ discrepant results stem from the diversity of their designs.

“Taken together, these trials have nonetheless played a crucial role in improving our pathophysiological understanding of functional mitral regurgitation and in confirming what surgeons have long observed: some patients clearly benefit from correction of the regurgitant lesion, whereas in others ventricular disease overwhelmingly determines clinical outcome,” he said.

The Meta-analysis

Altogether, the MITRA-FR, COAPT, and RESHAPE-HF2 trials enrolled 1,422 patients with symptomatic FMR assigned to M-TEER plus guideline-directed medical therapy (GDMT) or GDMT alone. Parameters including sex, LV end-diastolic volume, FMR severity, atrial fibrillation, and GDMT varied across the studies.

Yet “the quality of trials was high overall and, except for a possible bias due to the unfeasibility of masking, there were no significant concerns,” the paper notes.

The researchers looked at the data from two perspectives, as a one-stage analysis based on reconstructed time-to-first event individual patient data and as a two-stage random-effects analysis.

Death or first HF hospitalization at 24 months, the meta-analysis’ primary endpoint, was lower with M-TEER versus GDMT in the one-stage analysis (HR 0.72; 95% CI 0.56-0.92). The two-stage analysis was less compellingly in favor of M-TEER, however (HR 0.72; 95% CI 0.51-1.00), with substantial heterogeneity (I² = 80.3%; P = 0.006). With the random-effects model plus 95% CI correction using the Hartung-Knapp method, the difference was no longer significant (HR 0.72, 95% CI 0.34-1.50).

HF hospitalization as an individual endpoint was lower with M-TEER in both the one-stage (HR 0.65; 95% CI 0.48-0.88) and two-stage (HR 0.66; 95% CI: 0.45-0.96) analyses, again with much heterogeneity (I² = 81.2%; P = 0.005). The addition of 95% CI correction again rendered nonsignificant results with the random-effects model (HR 0.66; 95% CI 0.29-1.52).

There were no differences in all-cause death and CV death at 24 months when considering all three trials, though when the researchers performed a leave-one-out analysis excluding MITRA-FR, the results were positive. Using data only from COAPT and RESHAPE-HF2, there was a lower risk of death with M-TEER versus GDMT alone (HR 0.66; 95% CI 0.53-0.83) and a lower risk of CV death (HR 0.68, 95% CI: 0.49-0.96).

“The leave-one-out analysis confirmed that the exclusion of either the COAPT trial or the RESHAPE-HF2 trial led to nonsignificant differences between treatment groups, and the exclusion of the MITRA-FR trial rendered heterogeneity no longer detectable,” Ammirabile and colleagues note.

The researchers acknowledge that it’s hard to reconcile the discrepancies between MITRA-FR and COAPT.

“In the COAPT trial, FMR severity was assessed by a core laboratory, and an independent multidisciplinary committee, including heart failure specialists, verified the eligibility of inclusion of each patient based on whether heart failure treatments at the maximum tolerated dose were employed without tangible clinical improvements and excluded a reduction in mitral regurgitation severity during the intensified run-in phase,” they explain. In contrast, for the MITRA-FR trial, “less standardized procedures may have led to a more liberal selection of patients.”

These imbalances may have led to imbalances in FMR stage, medical therapy, and proportion of patients on cardiac resynchronization therapy. Additionally, “patients enrolled in the MITRA-FR trial showed larger left ventricular end-diastolic volumes and lower effective regurgitant orifice areas [on echocardiography] compared with those enrolled in the COAPT trial,” the paper points out.

M-TEER Guidelines

For M-TEER to be at its best, Capodanno advised, interventionalists must partner with echocardiographers. Imagers “are instrumental in selecting the right patients,” he said. “They offer clues in guiding the procedure, because of course they are in the cath lab with us, and the follow-up is also key in order to see whether there is [recurrence] or failure.”

An editorial by Christian Besler, MD, and Dirk Westermann, MD (both from University of Freiburg, Germany), asserts that the new paper, while useful, demonstrates the intricacies of the statistical methods involved in conducting meta-analyses. “Importantly, the results remind us that designing trials in this heterogeneous patient population is complex both in terms of patient selection and statistics, as results may differ markedly depending on patient characteristics, disease stage, composition of clinical endpoints, or length of follow-up,” Besler and Westermann write.

Everybody is in a gray zone and [trying] to use common sense. David Messika-Zeitoun

The 2025 European guidelines give M-TEER a class I recommendation in patients who have severe FMR but no coronary artery disease when HF symptoms persist despite optimized GDMT, the editorialists highlight. “However, apart from guideline recommendations, the spectrum of patients with ventricular FMR in everyday practice is broad, and there is still often substantial debate in multidisciplinary heart teams on when to apply M-TEER, in whom to apply it, and what results to expect.”

Thus, they conclude, “acknowledging the fact that there are subgroups across the broad spectrum of FMR patients who derive less or no improvement in clinical outcome is crucial in moving the field forward. . . . Efforts to refine M-TEER by addressing specific ventricular FMR phenotypes, earlier mitral regurgitation disease stages, or patients with not yet uptitrated guideline-directed heart failure therapy hold promise in maximizing its benefit for patient outcomes and should be explored.”

Obadia agreed that, for now, “attempts to robustly identify a clearly defined target subpopulation remain insufficiently satisfactory, highlighting the need for new, better-phenotyped studies.” While a meta-analysis based on individual patient data could assist in this effort, he added, “such an approach would be extremely costly and dependent on substantial funding.”

It’s important to weigh the available evidence carefully, he advised, noting that “the central question is probably no longer whether percutaneous repair of functional mitral regurgitation works, but rather in which patients it truly represents an intervention capable of modifying the natural history of the disease.” 

He stressed the need for “careful clinical phenotyping, consideration of the medico-economic context, and multidisciplinary heart team decision-making” as essential ingredients that help the field “avoid excessive expansion of indications and to optimize real patient benefit.”