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Page 8 of 12 Belluschi et al. Mini-invasive Surg 2020;4:58 I http://dx.doi.org/10.20517/2574-1225.2020.48

for percutaneous and surgical treatment, respectively; P = 0.01), especially when residual MR (12.3% vs.
[40]
1.8%; P = 0.02) and reoperation (27.9% vs. 8.9%; P = 0.003) rates were examined . However, the need for
surgery after the index procedure occurred mainly in the first 6 months of follow-up (78%) and mortality
rates did not differ significantly at 5 years (20.8% vs. 26.8%; P = 0.4). Unfortunately, it must be stated that
the MitraClip cases included in this study were performed at the very beginning of the experience with this
new percutaneous approach, thus the learning curve may have played a pivotal role affecting the outcomes
reported.

In addition, the small amount of secondary MR patients reported in this study and the enrollment of
operable patients only did not reflect the real-world scenario. Two registries, the ACCESS-EU in Northern
Europe and the REALISM in United States, enrolled older patients with more comorbidities, mostly
[41]
with ischemic MR and depressed LVEF . More recently, two large randomized clinical trials analyzed
specifically patients with secondary MR: the MITRA-FR and the COAPT trials. Despite randomization,
these studies are still strongly debated by the scientific community for their contrasting outcomes. First,
the MITRA-FR study enrolled severe symptomatic secondary MR patients (defined as effective regurgitant
orifice area of > 20 mm or a regurgitant volume of > 30 mL per beat) with LV dysfunction (LVEF between
2
15% and 40%). After 1:1 randomization to medical therapy alone or medical therapy associated to
percutaneous edge-to-edge repair, no difference was found in the primary composite outcome of any-cause
death or unplanned hospitalization for heart failure at 1 year (55% vs. 51% for the intervention and the
[42]
control group, respectively; OR: 1.16; 95%CI: 0.73-1.84; P = 0.53) .
Conversely, the COAPT trial showed opposite results. In this study 614 severe symptomatic secondary MR
patients were 1:1 randomized to maximal doses of guideline-directed medical therapy vs. Mitraclip plus
medical treatment . Both primary and secondary endpoints at 24 months favored the MitraClip cohort,
[43]
with a hospitalization rate for heart failure of 36% vs. 68% per patient-year (HR: 0.53; 95%CI: 0.40-0.70; P <
0.001) and any-cause death rate of 29% vs. 46% for device and control group, respectively (HR: 0.62; 95%CI:
0.46-0.82; P < 0.001).

Nevertheless, the contrasting results of these two trials can at least in part be explained by analyzing the
major differences between them. The number of clips implanted per-patient was higher in the COAPT,
which may justify the lower 1-year rate of severe residual MR as compared to MITRA-FR (5% vs. 17%,
respectively). In addition, the COAPT Trial used the definition of ischemic MR severity according to the
American Guidelines, resulting in more severe MR at baseline as compared to the MITRA-FR study, which
enrolled the patients according to the European Guidelines (mean EROA 31 mm vs. 41 mm ). Furthermore,
2
2
2
indexed left ventricular end-diastolic volumes were larger in the MITRA-FR trial (135 ± 35 mL/m
2
vs. 101 ± 34 mL/m ). Generally speaking, it seems that patients with more severe secondary MR and not
very advanced LV remodeling/dysfunction, may benefit from MR correction/reduction when they remain
symptomatic despite optimal guideline-directed medical therapy. Careful selection of the candidates
[44]
to MitraClip therapy is therefore mandatory. As proposed by Grayburn et al. , the identification of
proportionate or disproportionate MR could help in the decision-making process for the optimal treatment
of secondary MR in patients with chronic heart failure and systolic dysfunction. Indeed, according to the
Gorlin formula, patients of the MITRA-FR trial appeared to have proportionate MR since the severity
of MR was proportionate to the degree of LV dilatation. Contrarily, participants of the COAPT trial had
more severe MR (ERO 0.3-0.4 cm ) but less dilated LV (Left Ventricle End Diastolic Volume 160-200 mL),
2
resulting in disproportionate MR. These specific and selected patients with disproportionate MR seemed to
respond better to interventions targeting the mitral valve, like MitraClip. Finally, differences in adherence
to optimal guideline-directed medical therapy may have played a role too in influencing the different
results of these two studies.