The onset of functional (or secondary) mitral regurgitation (MR), a common complication associated with left ventricular remodeling and left atrial dilation during the progression of heart failure (HF), significantly worsens the prognosis of affected patients. 

Current therapies for treating functional MR include mitral valve surgery and transcatheter edge-to-edge repair (TEER). In recent years, the percutaneous option has gained prominence due to evidence from clinical trials such as COAPT, MITRA-FR, and the newly published RESHAPE-HF2 study in 2024. 

This year, a meta-analysis was published in JACC analyzing the comprehensive evidence provided by these three studies on percutaneous repair of functional MR in patients with heart failure receiving optimal medical therapy. 

Firstly, this meta-analysis evaluated a total population of 1,423 patients comparing percutaneous mitral regurgitation repair using the Abbott MitraClip® device plus optimal medical therapy against optimal medical therapy alone. The common endpoints assessed across these trials over two years of follow-up included HF hospitalizations, recurrent rehospitalization events or all-cause death, all-cause mortality, cardiovascular mortality, and changes in the six-minute walk test (6MWT) after one year. 

Baseline patient characteristics represented a broad spectrum of moderate-to-severe functional MR. The median age ranged between 70 and 72 years, with all patients exhibiting left ventricular systolic dysfunction and an ejection fraction around 31–33%. Comorbidities associated with heart failure were similarly distributed. The severity of MR, measured by effective regurgitant orifice area (EROA), ranged from 0.25 to 0.40 cm². Similarly, HF progression, estimated by left ventricular end-diastolic volume index (LVEDVI), ranged from 192 to 252 mL. 

The results showed statistically significant benefits for the Abbott MitraClip® in HF hospitalizations (HR = 0.69; p = .0324), recurrent rehospitalization events or all-cause death (HR = 0.71; p = .0486), and the change in the six-minute walk test at one year. However, while a positive trend was observed, differences in all-cause and cardiovascular mortality were not statistically significant. It is worth mentioning that this meta-analysis did not include safety outcomes, but the safety profile reported across the studies was excellent, with a low proportion of procedural failures or related complications. 

In conclusion, this meta-analysis suggests that percutaneous repair of moderate-to-severe functional MR combined with optimal medical therapy is beneficial for patients with symptomatic heart failure. 

COMMENTARY: 

The natural history of heart failure represents a feedback cycle leading to left chamber dilation and subsequent functional mitral regurgitation, which, in turn, exacerbates heart failure. For this reason, achieving benefits from addressing a valvular disease secondary to the natural progression of another condition has been historically challenging. 

The COAPT and MITRA-FR clinical trials recruited opposing patient populations but shared moderate-to-severe mitral regurgitation as a common feature. These studies laid the foundation at the end of the last decade to define criteria selecting MR cases disproportionately more severe than ventricular dilation, which predicted the benefit of repair. These findings were reflected in European and American guidelines, granting edge-to-edge therapies a class IIa recommendation and establishing an international EROA threshold of 0.30 cm² for intervention consideration. 

In this context, the 2024 RESHAPE-HF2 study provides evidence defining a broader range of patients benefiting from this therapy, encompassing MR grades as low as 0.25 cm² EROA and ventricular dilation up to 211 mL. This is particularly important as prior evidence suggested no clinical benefit from treating moderate MR, such as findings from a trial on ischemic MR repair with mitral annuloplasty in patients undergoing coronary bypass surgery. 

However, one major limitation of the meta-analysis is the significant heterogeneity in patient populations, especially regarding optimal medical therapy. For example, RESHAPE-HF2 patients received superior medical treatment, with a higher proportion using beta-blockers, angiotensin receptor blockers, and neprilysin inhibitors. Notably, 80% of these patients were treated with mineralocorticoid receptor antagonists, compared to only 50% in the other two studies. 

Another pertinent critique is the lack of surgical risk assessment across studies, except for COAPT, where 42% of patients had an STS score ≥8%, indicating high surgical risk. This omission precludes evaluating whether mitral valve surgery might have been feasible in low-risk surgical cases. 

Looking forward, given the heterogeneity of both the studies and secondary mitral regurgitation itself—with phenotypes exhibiting distinct responses to medical and interventional treatments—future trials may benefit from focusing on “patient type” rather than “mitral regurgitation grade” to identify the most representative and benefitting patient groups. 

Overall, there seems to be sufficient evidence to recommend transcatheter repair for patients with symptomatic heart failure and moderate-to-severe secondary mitral regurgitation. Nevertheless, further studies specifically designed for moderate MR are needed to establish robust recommendations in this scenario. 

REFERENCE: 

Anker MS, Porthun J, Schulze PC, Rassaf T, Landmesser U. Percutaneous Transcatheter Edge-to-Edge Repair for Functional Mitral Regurgitation in Heart Failure: A Meta-Analysis of 3 Randomized Controlled Trials. J Am Coll Cardiol. 2024 Dec 10;84(24):2364-2368. doi: 10.1016/j.jacc.2024.08.026.