Transcatheter mitral valve repair for primary and secondary mitral regurgitation: new insights from a nationwide registry

This article refers to ‘Italian Society of Interventional Cardiology (GIse) registry Of Transcatheter treatment of mitral valve regurgitaTiOn (GIOTTO): impact of valve disease aetiology and residual mitral regurgitation after MitraClip implantation’ by F. Bedogni et al., published in this issue on pages 1364–1376. Mitral regurgitation (MR) is the most frequent heart valve disease in the community and the second most frequent cause of hospital referral.1-3 The distinction between primary and secondary MR is of utmost importance since they differ not only in the mechanism causing valve failure but also in their prevalence, prognosis and treatment. Primary MR is caused by leaflet and/or chordae anomalies, and surgery improves the prognosis of symptomatic patients or those with haemodynamic consequences. Secondary MR is caused by a disease of the left ventricle or the left atrium (or both), is frequent in the community4 and is associated with lower event-free survival than primary MR of similar magnitude.5 While medical treatment and resynchronization improve prognosis, uncertainty remains regarding the benefit of surgery in these patients.6 Edge-to-edge transcatheter mitral valve repair (TMVr) has been largely adopted in clinical practice. Likewise surgery, there is uniform agreement that TMVr is indicated in patients with primary MR at high risk for surgery as stated in current guidelines.6, 7 More questionable is the benefit of TMVr in patients with secondary MR, with major discordances between the two randomized trials MITRA-FR and COAPT.8, 9 Nonetheless, there is no doubt that TMVr has strengthened interest in secondary MR since the possibility of less invasive intervention appears particularly attractive for this disease subject to concerns on the risk–benefit ratio of interventions on the mitral valve. Indeed, previous European registries have shown a predominance of secondary MR in patients treated with TMVr. The analysis of the GIOTTO registry published in this issue of the Journal confirms this observation with 59% of patients presenting with secondary MR.10 This finding is probably the consequence of the selection of high-risk patients for TMVr and illustrates the reluctance of practitioners to consider mitral valve surgery in patients with secondary MR in whom there is no strong evidence that the clinical benefits outweigh the operative risk. The GIOTTO registry is a nationwide registry including 1659 patients treated with TMVr between 2016 and 2020 in Italy. These results further demonstrate the feasibility and safety of this therapy in patients with either primary or secondary MR with a high rate of procedural success (84% at 30 days) and a low risk of early morbidity and mortality (4% at 30 days) in a ‘real-life’ setting and provides valuable information regarding the use of medical therapy in patients with MR. Indeed, medical therapy was underused in patients with secondary MR, in particular inhibitors of the renin–angiotensin system which were prescribed in only a third of these patients although the vast majority of them had reduced ejection fraction (91% with ejection fraction <50%) and severe symptoms (83% in New York Heart Association class III or IV). It should be highlighted that optimized guideline-directed medical therapy was a prerequisite for inclusion in the COAPT trial and the most stringent criteria applied in the COAPT trial are one of the reasons put forward to explain the differences with the MITRA-FR trial. Conversely, a striking finding of this study is the high rate of prescription of drug therapy in patients with primary MR, which is indicated only in the presence of heart failure with reduced ejection fraction. While only 30% of patients with primary MR in the GIOTTO registry had ejection fraction <50%, beta-blockers were prescribed in 73% of them and inhibitors of the renin–angiotensin system in 32%. Unfortunately, the underuse of evidence-based therapies in patients with secondary MR and its overuse in primary MR are consistent with previous studies and have also been observed in a survey based on clinical scenarios performed among general practitioners, cardiologists and cardiac surgeons.11 Although adherence to class I recommendations for interventions in patients with MR improved over time, it remains suboptimal and inferior to aortic valve diseases.1 Many efforts are therefore needed in terms of education of health care professionals and patients. Importantly, secondary MR itself was an independent predictor of 1-year mortality after TMVr in the GIOTTO registry. Although results were adjusted on left ventricular ejection fraction and dimensions, other potential confounders as right ventricular dysfunction were not considered in this analysis. Indeed, a low right ventricle–pulmonary artery coupling, which represents the relationship between right ventricular contractility and afterload, has recently been identified as a strong predictor of adverse outcome after TMVr in patients with secondary MR regurgitation.12 In fact, this has been raised as a potential explanation of the discrepancies between both randomized trials13 since patients with right ventricular dysfunction and severe pulmonary hypertension were excluded from COAPT but not from MITRA-FR. One of the main results of the GIOTTO registry is the impact of residual MR on mid-term outcome after TMVr. In this study, in both primary and secondary MR, a grade 1+ residual MR was a protective factor for 1-year mortality and patients with grade 3+/4+ residual MR were at high risk of early death (within 60 days) with 50% of deaths at 1 year. While the reduced risk of death associated with a grade 1+ residual MR was expected for primary MR, in which left ventricular dysfunction is the consequence of MR, this is less obvious for secondary MR, in which MR is not the cause but the consequence of left ventricular dysfunction. Although there is agreement that secondary MR worsens the prognosis of left ventricular dysfunction, there has been a longstanding debate on the clinical benefit of the correction of secondary MR. Observational series led to discrepant results and the only randomized trial on ischaemic MR did not show a benefit of adding mitral surgery to coronary artery bypass grafting.14 The discordant conclusions of the COAPT and MITRA-FR trials precluded a definite answer to the question, although a lower degree of residual MR in COAPT than in MITRA-FR has been proposed as one of the reasons for discordant results with regard to clinical benefit. Although appealing, in particular in the setting of secondary MR, this has to be confirmed in future randomized trials. Nonetheless, these findings support efforts for reducing the degree of residual MR. The advent of new generation devices (extended clip arms), growing experience and the evolution of the technique will probably result in reduced residual MR after TMVr. Although the high risk of early death in patients with grade 3+/4+ residual MR is not fully explainable, this suggests that all efforts should be done to improve patient selection and TMVr results in order to avoid futile interventions. Whether a proportion of these patients should have been denied therapy due to too advanced heart disease is unknown. However, the results of the GIOTTO registry should be interpreted having in mind the limitations of the study. Whether the evaluation of MR was qualitative or quantitative, which is recommended nowadays, is unknown. The lack of echo core lab is of particular importance in the graduation of the severity of residual MR, which is not standardized and particularly difficult on a double orifice and thus subject to variability between studies. Finally, the rate of patients lost to follow-up, in particular at 2 years, and the presence of missing data are inherent to large multicentre registries but may limit the relevance of certain analyses. The possibility of linking large registries with administrative databases is a promising perspective which will enhance the relevance of registries by increasing the quality of late clinical follow-up.15 The advent of transcatheter interventions have not only revolutionized the management of heart valve disease but also paved the way for a much better assessment of interventions through complementary randomized trials and large registries. Besides randomized trials, which are of course mandatory to develop evidence-based recommendations, nationwide registries are complementary to evaluate the applicability and results of innovative techniques in a real-life setting. The GIOTTO nationwide registry represents thus a new contribution expanding the knowledge on TMVr in high-risk patients with either primary or secondary MR (Figure 1). Conflict of interest: B.I.: consultancy for Edwards Lifesciences. M.U. has nothing to disclose.