Weekly Journal Scan: RESHAPing potential treatment indications for functional mitral regurgitation in heart failure

Comment on ‘Transcatheter valve repair in heart failure with moderate to severe mitral regurgitation’ which was published in The New England Journal of Medicine, https://doi.org/10.1056/NEJMoa2314328. The Randomized Investigation of the MitraClip Device in Heart Failure: Second Trial in Patients with Clinically Significant Functional Mitral Regurgitation (RESHAPE-HF2) is a company-funded, investigator-initiated, multicentre, prospective, randomized controlled trial (RCT) aimed at assessing whether mitral transcatheter edge-to-edge repair (TEER) added to guideline-directed medical therapy improves outcome in patients with heart failure (HF) and moderate to severe (3+ to 4+) functional mitral regurgitation over a 24 months follow-up period, as compared with medical therapy alone.1 Three primary endpoints were considered: (i) the rate of the composite of first or recurrent hospitalization for HF or death from cardiovascular causes during 24 months; (2) the rate of first or recurrent hospitalization for HF during 24 months; and (3) the change from baseline to 12 months in the score on the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS, ranging from 0 to 100, with higher scores indicating better health status). Secondary endpoints included the following: death from any cause during the entire trial period; rate of recurrent hospitalization from any cause within 24 months; mitral regurgitation 2+ or worse; change in 6 min walk distance; and New York Heart Association (NYHA) functional class I or II HF at 12 months. From March 2015 to October 2023, 505 patients with clinically significant functional mitral regurgitation despite optimal therapy underwent randomization at 30 centres in 9 countries (mean age, 70 years; 20% females; 60% NYHA functional class III; 35% non-ischaemic cause of HF). Patients were randomized to either TEER on top of guideline-directed medical therapy (device group, n = 250) or medical therapy alone (control group, n = 255). At enrolment, 29% of patients had cardiac resynchronization therapy devices, and baseline medical therapy [including angiotensin receptor/neprilysin inhibitors (ARNI) in 13% of patients and sodium-glucose cotransporter-2 inhibitors (SGLT-2i) in 9%] was similar in the two groups. The median left ventricular ejection fraction was 31% [interquartile range (IQR), 25 to 37], with a median left ventricular end-diastolic volume (LVEDV) of 205 mL (IQR, 157 to 250), a median effective regurgitant orifice area (EROA) of .23 cm2 (IQR, .20 to .29), and a median regurgitant volume of 36 mL (IQR, 29 to 43). The median KCCQ-OS score was 43 points (IQR, 26 to 63). MitraClip device was deployed in 98% of patients in the device group, and 38 patients (10%) in the control group underwent unplanned TEER. At 24 months, the rate of first or recurrent hospitalization for HF or death for cardiovascular causes was significantly lower in the device group than in the control group [37 events per 100 patient-years vs. 59 events per 100 patient-years, respectively; rate ratio, .64; 95% confidence interval (CI), .48 to .85; P = .002]. The rate of first or recurrent hospitalization for HF was 27 events per 100 patient-years in the device group and 47 events per 100 patient-years in the control group (rate ratio, .59; 95% CI, .42 to .82; P = .002). The mean change from baseline to 12 months in the KCCQ-OS score was 22 ± 27 points in the device group vs. 8 ± 24 points in the control group (mean difference, 11 points; 95% CI, 6.8 to 15.0; P < .001). Among secondary endpoint analyses, no differences were found for all-cause mortality during the entire follow-up (P = .35) and hospitalization for any cause (P = .15). Ninety per cent of patients in the device group and 36% in the control group had a mitral regurgitation severity grade of 2+ or lower at 12 months of follow-up (P < .001). Periprocedural adverse events occurred in four patients (1.6% of the device group). The results of subgroup analyses of the first composite endpoint (considering the cause of HF, EROA, LVEDV, NYHA functional class, or hospitalization within 12 months before randomization) were consistent with the main results. As a consequence of ventricular remodelling and/or atrial dilatation, functional mitral regurgitation is associated with a poorer prognosis, more frequent hospitalizations for HF, and higher mortality proportional to its severity.2 According to current guidelines, optimal medical therapy, together with cardiac resynchronization therapy whenever indicated and the pursuit of sinus rhythm in patients with atrial fibrillation, represents the mainstay treatment.3 Other treatment options for functional mitral regurgitation are still under debate, and while solid evidence supporting mitral valve surgery is still lacking, the TEER approach has been addressed in two large RCTs, with conflicting results, that have significantly influenced clinical practice in recent years: the Percutaneous Repair with the MitraClip Device for Severe Functional/Secondary Mitral Regurgitation (MITRA-FR) and Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation (COAPT) trials.4,5 In the MITRA-FR trial, there were no statistically significant differences in the rates of death or hospitalization after TEER, compared with optimal medical therapy alone.4 Conversely, the COAPT trial demonstrated a substantial reduction in all-cause mortality and hospitalization, along with enhanced quality of life and exercise capacity.5 The beneficial effects of TEER were sustained over a 5-year follow-up.6 Differences in the study design and clinical and echocardiographic characteristics of the enrolled population might at least in part explain the discordant results, with COAPT patients showing greater EROA (.4 cm2) and only mild to moderate left ventricular dilatation (disproportionate mitral regurgitation), while MITRA-FR enrolled patients with less severe mitral regurgitation (mean EROA .31 cm2) and marked left ventricular dilatation (proportionate mitral regurgitation).7 The RESHAPE-HF2 is the third RCT assessing the effects of TEER with MitraClip in patients with symptomatic HF and left ventricular dysfunction.1 The patients enrolled in this trial had less severe functional mitral regurgitation (EROA .2 cm2) than in both previous trials; nonetheless, TEER treatment improved all the three co-primary endpoints. These results could potentially broaden the indications for mitral TEER in the future, reinforcing the recommendation in patients with moderate-to-severe mitral regurgitation and possibly extending the indication to patients with moderate mitral regurgitation. Some important limitations need to be considered while interpreting the RESHAPE-HF2 results. First, the open-label design of these RCTs carries the risk of bias in treatments and event ascertainment. This is particularly true for those endpoints that are prone to subjective evaluation, such as changes in NYHA functional class and KCCQ score. Second, in the long enrolment period (about eight years), optimal HF medical therapy changed, as well as MitraClip devices and operator experience, leading to heterogeneity in the population studied and in the success rate of the procedure. In this regard, only a minority of patients in the trial were under ARNI or SGLT-2, which might also contribute to reducing the consequences of mitral regurgitation severity and have an impact on the results. Third, up to 23% of the enrolled patients had an EROA < .2 cm2, which does not fit the definition of moderate-to-severe or severe mitral regurgitation according to the current guidelines. This might indicate a potential future expansion of the indications for percutaneous mitral repair to patients with less severe mitral regurgitation, although this requires confirmation in future trials. The positive findings of this trial have been mostly driven by the reduced number of HF hospitalizations. However, this did not translate into a decrease in all-cause hospitalization nor in all-cause mortality. A meta-analysis including data from MITRA-FR, COAPT, and RESHAPE-HF2 showed a borderline benefit of TEER on the endpoint of HF hospitalizations through 24 months, without statistically significant effect on all-cause or cardiovascular mortality.8 However, given the heterogeneity of the results, an individual patient-level meta-analysis may help to better identify patients who are most likely to benefit from TEER for functional mitral regurgitation. In conclusion, RESHAPE-HF2 trial reinforces the current recommendation for TEER in patients with moderate-to-severe or severe functional mitral regurgitation. However, the expansion of transcatheter repair indications to patients with less severe mitral regurgitation requires additional randomized evidence in this clinical setting. While timing of intervention remains a major challenge in valvular heart disease, the present study represents a step forward on the way to a broader and tailored application of this treatment option. D.P. received speaker’s fees from Daiichi Sankyo, outside the submitted work and is supported by a research grant from Italian Ministry of Health (grant: ‘Ricerca corrente’). R.V. received consulting or lecturing fees from Abbott Vascular, Amgen, Medtronic, and Terumo, outside the submitted work.