Secondary or functional moderate-to-severe MR occurs in about a third of patients with heart failure (HF) and is an independent marker of poor prognosis, typically resulting from left ventricular remodeling. This condition arises from myocardial disease—both ischemic and non-ischemic—that leads to myocardial distortion and reduced mitral leaflet coaptation.

Although surgical management is regarded as the best treatment for severe MR, high-risk patients are often unsuitable for surgery due to fragility, advanced age, left ventricular dysfunction, and comorbidities. Surgery is particularly recommended when combined with coronary revascularization or other valve surgery (recommendation level I B, per the 2021 ESC guidelines on valvular heart disease). On the other hand, isolated mitral valve surgery—whether repair or replacement—yields better outcomes in select populations with early-stage HF (IIb C).

The COAPT study, published in NEJM in 2018, assessed the efficacy and safety of MitraClip® in patients with moderate-to-severe secondary MR. This was a multicenter, open-label, 1:1 randomized study involving 614 patients who received either MitraClip® implantation or optimal medical therapy. The MitraClip® group saw a significant reduction in the primary outcome, which evaluated cumulative HF hospitalizations, and in several pre-specified secondary outcomes, including all-cause mortality at two years.

This article presents the five-year follow-up results of the COAPT study, involving 270 patients (89.4%) in the device group and 264 (84.6%) in the control group. The primary outcome revealed a 47% reduction in cumulative hospitalizations (HR = 0.53) and a 51% reduction in first HF hospitalization (HR = 0.49), with consistency across all pre-specified subgroups. However, this difference disappeared in the post-hoc analysis examining first HF hospitalization beyond the third year of follow-up (HR = 0.85). All-cause mortality also significantly decreased at five years (HR = 0.72), driven by a reduction in cardiovascular mortality (HR = 0.71). Similar to the primary outcome, the post-hoc analysis of total mortality beyond the second follow-up year showed no significant differences.

In terms of device safety, 89.2% of patients remained free of device-related complications. Only four device-related safety events (1.2%) were reported, all within the first 30 days post-implantation. Additionally, although 23 patients (7.6%) in the device group developed severe mitral stenosis, none required mitral surgery. Unplanned mitral valve procedures were more frequent in the control group than in the device group.

The authors conclude that in patients with HF and moderate-to-severe secondary MR who remain symptomatic despite optimal medical therapy, transcatheter edge-to-edge repair is safe and reduces all-cause mortality and HF hospitalizations over a five-year follow-up.

COMMENTARY:

Secondary MR has historically been managed surgically via mitral valve repair. However, transcatheter edge-to-edge repair has emerged as a viable alternative for high-risk patients. Reviewing the literature, only one clinical trial (EVEREST II) directly compares both strategies. At five years, the composite outcome of absence of death, surgery, or residual grade III-IV MR was 44.2% versus 64.3% (p = .01) favoring surgery. This finding was explained by a higher incidence of grade III-IV MR (12.3% vs. 1.8%; p = .02) and increased surgical need (27.9% vs. 8.9%; p = .003). However, five-year mortality rates, functional class improvements, and ventricular function parameters were similar to those in the surgical group.

The latest evidence comes from a 2021 meta-analysis including 12 studies with 4,219 patients (MitraClip®: 1,210; surgery: 3,009). Patients in the MitraClip® group were significantly older, had worse left ventricular function, and a higher proportion were in NYHA class III-IV. In-hospital, medium- and long-term mortality (4-5 years) were similar between groups. Mean hospital stay was shorter in the MitraClip® group, though moderate MR recurrence and reinterventions were significantly lower in the surgery group.

In contrast, the French MITRA-FR registry, published the same week in NEJM, also evaluated MitraClip® versus optimal medical therapy in secondary MR. However, unlike COAPT, it did not find benefits in terms of hospitalizations, cardiovascular mortality, or total mortality. This discrepancy may be due to MITRA-FR’s smaller sample size (307 vs. 614 patients), more severe MR, larger left ventricular dimensions, poorer treatment optimization, and higher procedural complication rates (14.6% vs. 8.5%), indicating greater interventionist experience in COAPT.

Stone et al.’s study has certain limitations and has faced criticism. Firstly, patient loss was higher in the control group (15.4%) than in the device group (10.6%) at five years. Moreover, the MitraClip® device used in the study was first-generation, whereas third- and fourth-generation devices are now more commonly used, potentially affecting generalizability. Another notable limitation was the highly selective recruitment, as only 614 patients from 78 U.S. centers were included over five years (1.5 patients per center annually). Additionally, the study permitted patient crossover from the control to the device group after two years, with edge-to-edge repair performed on 67 control patients, representing 44.9% of the group’s 138 survivors, with similar net benefits to those treated from the outset. This may explain the attenuation in mortality and HF readmission benefits observed beyond two and three years, respectively, under an intention-to-treat analysis.

Ultimately, the COAPT study’s five-year results confirm the trend toward clinical improvement and mortality reduction initially observed in the two-year follow-up, compared with optimal medical therapy alone.

In conclusion, mitral valve repair has proven effective and durable in secondary MR in clinical trials and should remain the first choice when surgical risk is acceptable. Edge-to-edge percutaneous repair is a good alternative for high-risk surgical patients who meet specific anatomical criteria. However, clinical trials are needed to establish long-term efficacy and durability, as well as to understand the impact of moderate-to-severe MR recurrence and high reintervention rates.

REFERENCE:

Stone GW, Abraham WT, Lindenfeld J, Kar S, Grayburn PA, Lim DS, et al.; COAPT Investigators. Five-year follow-up after transcatheter repair of secondary mitral regurgitation. N Engl J Med. 2023 Mar 5. doi: 10.1056/NEJMoa2300213.