Discussion

In contrast to industry-sponsored randomized controlled trials, the present study is entirely independent of commercial funding and free of sponsor-driven endpoint selection. Drawing on routine claims data from BARMER, covering approximately 10 % of the German population, our analysis reflects unselected, real-world clinical practice. This is of relevance, as it enables the inclusion of patient subgroups — such as the very elderly and those with significant frailty or multimorbidity — who are frequently underrepresented in sponsored trials yet constitute a substantial proportion of patients encountered in daily clinical practice. Our analysis of a large real-world patient cohort undergoing M-TEER shows comprehensively that age, frailty and comorbidities significantly influence long-term survival. These aspects are often interrelated and should be considered when it comes to patient selection.

Age

M-TEER plays a pivotal role in the treatment of patients with MR who have a prohibitive risk for surgery and has evolving clinical implications. Age alone is not necessarily a factor why patients are referred for transcatheter mitral valve repair, but comorbidities and frailty increase with age and are linked to adverse health care outcomes. In a primary care cohort of aging people, prevalence of multimorbidity was consistently high (89.3%) throughout all age groups, while frailty almost quadrupled (23.5% to 82.8%) from 65 to 99 years of age. [15]

Our real-world data sample shows that M-TEER is most used to treat very old (>80 years) and old (70–79 years) patients in Germany; and in very-old patients excess mortality is observed. Some randomized controlled trials [10], [16] and registry data [17] did not show that survival was significantly influenced by age. For example, in the COAPT trial, no two-year survival difference was found in-between the defined age groups (< 75 years, ≥ 75 years). However, in older patients HFH were reduced to a lesser extend as compared to younger patients. [16] On the other hand, in an analysis from the EuroSMR registry age, next to other criteria (i.e. renal failure, residual MR after M-TEER, NYHA class, left ventricular ejection fraction, and COAPT trial eligibility) age was an independent predictor for long-term survival. [12]

A relative survival analysis, as performed by the MitraSwiss registry investigators, may give more granular information in this context: the investigators showed that M-TEER in very-old patients with primary MR was able to restore the predicted life expectancy (described as relative survival, defined by the ratio between post M-TEER survival and expected survival in a matched age-, sex- and calendar period), whereas in patients with secondary MR life expectancy was bound to procedural success. [18] However, in daily clinical practice, M-TEER might be considered as a therapeutical option to primarily improve soft endpoints (i.e., amelioration of symptoms and reduction of HFH) rather than restoring relative survival, particularly in very old patients who might have already surpassed the mean predicted life-span of their age cohort.

Frailty

Frailty is a theoretical construct not linked to organ function but rather describes the age-related loss of haemostasis and resilience against stressors. [15], [19] It is considered to be one of the most problematic expression of population aging [20], although it lacks a uniform definition. Among individuals aged ≥75 years, frailty is present in 20–30% of individuals. [21] Hence, the majority of M-TEER patients is affected by frailty and several investigations elucidated on the role of frailty, although data on long-term outcomes remains scarce. An analysis from the Japanese multi-centre OCEAN trial used the clinical frailty scale [22] to show that all-cause mortality at 24-months is significantly linked to increased impairment of independence and abilities, and residual MR grade ≥ 2 after the intervention. [23] A variety of studies focuses on the association of frailty and short-term outcomes after M-TEER: Rios et al. [24] reviewed the national in-patient sample from the United States and could show that frailty was associated with increased in-hospital mortality, greater resource use, and incremental health care costs during the index hospitalization. A small-scale German study [25] (n = 213 patients, median follow-up: 1.17 years) showed that M-TEER can be performed with equal procedural success in frail and non-frail patients, and the procedure leads to short-term functional improvement.

Our data is in line with the current body of evidence, and is the first real-world, large patient sample showing that a gradual decrease in independence and abilities is linked to increased long-term mortality. The number of patients officially needing assistance due to impairments of independence and abilities seems rather small (25.15%).

It must be noted that in patients with very advanced age combined with significant functional deficits (care levels 3–5), the survival benefit of M-TEER may be attenuated, and that these findings should be considered in the heart team decision-making process. We emphasize that a comprehensive geriatric assessment — already reflected in the Pflegegrad system — should be an integral part of patient selection to avoid futile interventions, while also acknowledging the potential benefit in terms of symptom relief and quality of life, which is beyond the scope of the current dataset.

Comorbidities and demographic aspects

The high prevalence of multiple chronic conditions, defined as having two or more chronic diseases that last a year and require ongoing medical attention or limit activities of daily living, is the major driver for increased health care utilization in the elderly. [26], [27] In clinical practice, a certain overlap of frailty and multimorbidity exists: fewer multimorbid individuals also present with frailty, while most frail ones are also multimorbid. [28] Both, frailty and multimorbidity, are linked to poor health outcomes, increased mortality, and excessive health care costs. [29], [30], [31], [32] Multimorbidity has been investigated to a lesser extend in M-TEER patients. The Charlson comorbidity index is a widely used tool to estimate multimorbidity in patients and was able to predict mortality and clinical long-term outcomes. [33] The German Transcatheter Mitral Valve Intervention (TRAMI) registry (n = 722 patients, median follow-up time: 2.84 years) identified previous aortic valve implantation, prior cardiac decompensation, previous HFH, NYHA class IV, chronic kidney disease and a left ventricular ejection fraction below 30% as most predictive for long-term mortality. [17] Fewer studies investigate the influence of non-cardiac comorbidities, and mostly data on short-term survival after M-TEER is available. [34], [35]

In our analysis, female sex seems to be protective, however the current body of evidence is not conclusive: Agrawal et al. investigated that females have better adjusted long-term outcomes after M-TEER as compared to men. [36] In an analysis from the MitraSwiss registry both sexes had comparable 5-year outcomes, and M-TEER completely restored normal life expectancy in female patients with primary MR, which was not the case in women with secondary MR. Hence, further in-depth investigations are needed. [7] Additionally, obesity turned out to have a protective effect, although recent studies suggest that obesity-survival paradox does not exist and new anthropometric measures like the waist-to-height ratio may be more appropriate than the body mass index to predict adverse outcomes. [37]

Regarding cardiac co-morbidities, right heart failure at baseline proved to have a significant impact on long-term survival, which is in-line with several already published investigations. [38], [39], [40] Other well-known factors like ischemic cardiomyopathy, previous valve intervention, pulmonary artery pressure and tricuspid regurgitation [41] have not been further investigated in our patient sample.

Health economic aspects

With an aging population, health care systems are confronted with increasing health care demands. M-TEER has been proven to be cost-effective in different jurisdictions, such as the United Kingdom and as part of the COAPT trial in the United States of America. [42], [43] So far, no data is available for Germany. Our investigation could show that overall treatment costs for M-TEER patients is high and cannot be significantly reduced by transcatheter treatment of MR. Doctor patient contacts in the ambulatory setting remained unchanged, however HFH could be reduced, potentially leading to released pressure of hospitals facing diminished staff and financial resources.

With respect to clinical practice, we recommend that age, frailty (as assessed by structured tools such as the Pflegegrad or equivalent validated instruments), and the burden of non-cardiac comorbidities be systematically integrated into the heart team discussion prior to M-TEER. With respect to future investigations, we suggest that prospective studies incorporating quality-of-life endpoints alongside survival data are needed — particularly in the very elderly and frail — to more comprehensively inform the risk-benefit assessment of M-TEER in these populations.