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Treating symptoms and reversing remodelling: clinical and echocardiographic 1‐year outcomes with percutaneous mitral annuloplasty for mild to moderate secondary mitral regurgitation

To determine the effects of percutaneous mitral annuloplasty on symptoms, walk distance and left ventricular (LV) structure and function in patients with mild or moderate secondary mitral regurgitation (SMR).


Introduction
Secondary mitral regurgitation (SMR) in the presence of left ventricular (LV) systolic dysfunction is directly associated with adverse outcomes, including mortality. 1 Even patients with mild SMR have a higher risk of hospitalization and mortality compared to those without SMR. However, despite this knowledge and consistent data that early medical and cardiac implantable electronic device treatment in heart failure with reduced ejection fraction (HFrEF) improves outcomes, 2 patients with less severe mitral regurgitation (MR) have thus far received little attention regarding treatment.
There are specific challenges to studying and treating patients with milder forms of SMR, despite the recognition of increased risk. From a mechanistic perspective, those with mild SMR have less room for improvement. Moreover, the lesser degree of ventricular and atrial remodelling at baseline and slower progression means that showing improvement or even a stabilization of progression are both more difficult compared to patients with more severe SMR. Identifying a modification of disease progression in clinical trials addressing earlier stages of the disease therefore requires longer patient follow-up and a larger sample size, although this can be somewhat compensated for by true blinding. From a recruitment perspective, there may also be a lack of drive to enrol those less sick into a device study due to perceived procedural risk. Hence, the design of a study to explore the hypothesis that . treating patients with mild SMR is a safe 'preventative' strategy for progressive disease requires a careful assessment of existing data to identify a population at risk of deterioration in whom any procedural risk might be more acceptable. Percutaneous mitral annuloplasty is a novel treatment for SMR in which a device is placed into the coronary sinus to reduce its diameter and allow approximation of the mitral valve leaflets 3 to reduce SMR severity. Studies of percutaneous mitral annuloplasty for SMR are unique since in addition to patients with severe SMR, they also included patients with milder degrees of SMR. Three of these studies, TITAN, 4 TITAN II 5 and REDUCE FMR 6 have follow-up to at least 1 year. The aim of this analysis was to present a post-hoc pooled analysis of the 1-year outcomes in patients with mild or moderate SMR treated with percutaneous mitral annuloplasty.

Methods
This is a pooled analysis of patients with mild or moderate SMR treated with a percutaneous mitral annuloplasty procedure utilizing the coronary sinus-based Carillon device (Cardiac Dimensions, Kirkland, WA, USA) in the TITAN, TITAN II, and REDUCE FMR trials. Ethics committees at each site approved the protocols of each trial, all patients provided written informed consent, and study procedures complied with the Declaration of Helsinki. Patient eligibility in these trials specified ongoing symptomatic heart failure with LV systolic dysfunction, despite guideline-directed medical therapy. Patients with class 1 indications for cardiac resynchronization therapy, or with an LV lead in place, were excluded due to the shared coronary sinus space used by mitral annuloplasty. All three trials targeted enrolment to patients with grade 2+ to 4+ SMR. In TITAN and TITAN II the echo core laboratory pre-screened patients and excluded patients with 1+ SMR. REDUCE FMR was designed as a pragmatic trial and local investigators decided upon eligibility. Blinded core echocardiography laboratory analysis was undertaken only at study end, revealing that several enrolled patients actually had 1+ SMR. Additional inclusion criteria for all trials were LV enlargement defined as >5.5 cm LV end-diastolic diameter and reduced ejection fraction (<40% in TITAN and TITAN II; <50% in REDUCE FMR).
Independent core laboratories read echocardiograms for quantitative parameters blinded to allocation (for REDUCE-FMR) and visit date (TITAN, TITAN II and REDUCE FMR). MR grading was based upon American Society of Echocardiography recommendations. 7 The protocols and complete eligibility criteria have been published previously. [4][5][6] The pooled dataset included baseline patient characteristics and secondary, echocardiographic, and vital status results at 1 year of follow-up. Baseline patient characteristics were summarized with the mean and standard deviation for continuous outcomes and counts and percentage for categorical outcomes. Changes in patient outcomes over 1 year relative to baseline were analysed with paired-samples t-tests and presented with 95% confidence intervals (CI). Fisher's exact test was used for group comparison of categorical outcomes. Survival and freedom from heart failure hospitalization were analysed using Kaplan-Meier methods. Treatment success as a binary outcome variable was characterized by progression-free survival, defined as survival at 1 year without an increase in SMR grade. The association of baseline patient characteristics and echocardiographic results with progression-free survival was analysed with univariable logistic regression and reported as an odds ratio (OR) and 95% CI. Variables that entered the model at P < 0.10 were included in a multivariable model. Although this was a post-hoc analysis, we performed significance testing for information using a P < 0.05 to represent statistical significance. All tests were two-sided. Statistical analyses were performed using Stata v16 (StataCorp, College Station, TX, USA).

Results
The pooled dataset of the three studies included 68 patients treated with percutaneous mitral annuloplasty (52 of whom had been part of REDUCE FMR, 7 had been in TITAN and 9 in TITAN II). Of these patients, 25 had mild and 43 moderate SMR. This represented 51% of device-treated patients enrolled in these trials. The mean patient age was 69 ± 9 years, 75% were male, and HFrEF was predominantly of ischaemic aetiology (68%). All patients were classified as New York Heart Association (NYHA) functional class II (35%) or III (65%). The mean LV ejection fraction at baseline was 32 ± 8% and LV end-diastolic diameter was 6.5 ± 0.8 cm ( Table 1). Table 1 also shows medical therapy at baseline which was commensurate with guidelines for medical therapy for HFrEF at the time of studies.
Patients with moderate SMR had confirmatory quantitative echocardiographic evidence of higher regurgitant volume  SMR also had a lower prevalence of atrial fibrillation (P = 0.03), worse NYHA scores (P = 0.009), and lower ejection fraction (P = 0.03) (online supplementary Table S1).
Procedural device-related safety events occurred in two patients. In one patient, a branch of the circumflex artery was compressed by the device. The compression was judged to be non-significant at the time of procedure; however, the patient developed coronary spasm with electrocardiographic changes 1 day post-procedure. The patient continued in the study through 1-year follow-up with only one further occurrence of angina judged to be due to coronary spasm and treated with medical therapy. The other patient with a safety event had troponin elevation following the procedure, but without clinical evidence of myocardial infarction, which did not require intervention.
During the follow-up period, 7 patients died, and 4 withdrew consent, leaving 57 who returned for the 1-year follow-up visit. As appropriate for patients in whom optimal medical therapy was a requirement of enrolment, medical therapy was unchanged during follow-up in the majority of patients with only five patients either discontinuing or adding a drug category. Four patients discontinued any class of drug (two stopping their diuretic, one stopping their beta-blocker, and one stopping both beta-blocker and angiotensin-converting enzyme inhibitor). In one patient, previously deemed to be intolerant, a beta-blocker was added.
There were statistically significant decreases in regurgitant volume (−7 mL; 95% CI −11 to −3; P < 0.001) ( Figure 1A), vena contracta (−0.11 cm; 95% CI −0.20 to 0.02; P < 0.05), and EROA (−0.03 cm 2 ; 95% CI −0.06 to −0.01; P < 0.05). SMR grade improved in 25% of patients and was maintained in 58% of patients ( Table 2). There was no progression in LV dysfunction; rather a trend to reverse remodelling and a significant reduction in LV end-systolic diameter relative to baseline ( Table 2). significant improvements in both 6-min walk test distance and Kansas City Cardiomyopathy Questionnaire were also observed as soon as 1 month post-procedure and were maintained throughout follow-up ( Figure 2 and Table 2). Relative to the mild SMR group, those with moderate SMR were more likely to experience an improvement in NYHA status (P < 0.01) and MR grade (P = 0.01) (online supplementary Table S2). LV structural and secondary changes are shown in Figure 1B-D.
In the present dataset, survival was not significantly different between those with mild SMR (95.8%) and moderate SMR (85.6%) (log-rank P = 0.22) (Figure 3). Progression-free survival (survival at 1 year without an increase in MR grade), was 70% overall; 82% in those with mild SMR and 63% in those with moderate SMR (P = 0.16). Freedom from heart failure hospitalization was 73.3% over 1 year with no significant differences between the mild and moderate SMR groups (86.5% vs. 66.0%; log-rank P = 0.07).
The number of patients with any heart failure hospitalization in the 12-month period following device implant was significantly lower than those experiencing a heart failure hospitalization in the 12 months prior to the procedure (29.4% vs. 51.4%; P = 0.01).
In a univariable logistic regression model, baseline variables that were associated with better progression-free survival were lower NYHA class (P = 0.10), lower regurgitant volume (P = 0.02), and lower EROA (P = 0.02). In the multivariable model, the  only baseline variable that was independently associated with progression-free survival was lower baseline EROA, with an OR of 3.0 (95% CI 1.21 to 7.39, P = 0.02) for each 0.1 cm 2 decrease ( Table 3).

Discussion
The present data provide the strongest data to date that, in patients with HFrEF with mild or moderate SMR, a transcatheter annular approach can safely reduce SMR and that doing this improves symptoms, exercise tolerance and quality of life and might also attenuate LV remodelling. This finding has potential implications for the large number of patients with less severe SMR that are currently not eligible for percutaneous leaflet clipping. Whether these improvements in surrogate endpoints translate to long-term modification of disease progression requires further work including larger studies and longer follow-up given the background that many other treatments for HFrEF, when applied early, are consistently associated with long-term benefits on outcomes.  The current data complement the results of previous studies demonstrating improvements in echocardiographic and clinical outcomes following percutaneous mitral annuloplasty in patients with, on average, moderate to severe SMR. However, SMR is associated with worse outcomes even when mild. 1 Furthermore, the development of SMR is part of a vicious cycle, whereby SMR leads to further LV dilatation, which in turn results in worsening SMR. Arresting this cycle early on may interrupt a key component of cardiac  deterioration in patients with cardiomyopathy and may play a major role in stabilization of the disease process. Current guidelines, based upon the available evidence, focus on patients with severe SMR stating that mitral valve repair or replacement may be considered for severely symptomatic patients. 8 Due to lacking data, there is little discussion regarding the potential for disease modification and the prevention of progression in patients with lesser degrees of SMR, despite the worse prognosis compared to patients with no SMR. Whether a diagnosis of mild or moderate MR warrants transcatheter or surgical treatment is a topic of debate. What is clear is that early medical and cardiac implantable electronic device treatments demonstrate accumulating benefits over time, principally in a slowing of progression in patients when treated early, [9][10][11][12][13][14] which suggests that early treatment for SMR deserves careful study as well. A key question is to identify those patients in whom SMR is likely to contribute to longer-term deterioration. This will require carefully collected large longitudinal observational datasets, as well as evidence that early treatment is feasible, safe, and delays deterioration. This is therefore the first dataset to explore this hypothesis of the potential benefits of targeted early treatment prior to clinical deterioration. Our analysis suggests that percutaneous mitral annuloplasty in patients with mild or moderate MR is feasible and safe. After 12 months of follow-up, there were improvements in NYHA class and 6-min walk distance, and quality of life. There were also reductions in MR as evidenced by changes in regurgitant volume, vena contracta, and EROA. As anticipated, the magnitude of these changes was less in those with mild vs. moderate SMR but, judging by the concurrent improvements in patient-oriented endpoints, seem nonetheless clinically significant. Given the modest improvements in MR yet equivalent improvements in clinical variables compared to previous datasets, it is possible that especially in this population the device limits exercise-induced worsening of MR. These results suggest that percutaneous mitral annuloplasty may be an effective treatment to provide symptomatic relief in even mild or moderate MR. These data, including the presented survival data, may be used for hypothesis generation in the design and statistical powering of future studies.

Univariable analysis
The challenge with any treatment for HFrEF is the balance of the risks of interventions to reduce SMR with the risks of untreated SMR over the patient's lifetime. The advent of percutaneous treatments with lower upfront risk, has facilitated explorations of the potential lifetime benefits of earlier treatment. Future study designs need to consider the lower event rate in patients with lesser degrees of SMR and the need therefore for high levels of safety of the device, larger sample sizes with longer follow-up, and true blinding. The definitive studies will also need to focus on clinical outcomes consequent to disease progression rather than improvements of surrogate endpoints.

Limitations
This is the first study to describe the outcomes of patients with mild or moderate MR treated with a device to reduce SMR. There are, however, several limitations beyond the uncontrolled, observational nature of the data. data collected at 1 year of follow-up and extended follow-up is needed to characterize the long-term safety and effectiveness of this treatment approach in patients with less severe SMR. Second, comparisons of these results to those with other therapies in patients with mild or moderate MR should be made cautiously owing to possible differences in indications, patient characteristics, and echocardiographic protocols. Third, the sample size in each group was small such that the results should be considered primarily as hypothesis-generating for planning future prospective controlled studies. Fourth, of the included studies, only the randomized, sham-controlled REDUCE FMR study had an untreated (control) arm including 18 patients fulfilling the criteria for inclusion in this post-hoc analysis. An exploratory analysis of outcomes in this group described survival at 1 year of 80.8% compared with a 1-year survival of 89.3% in those allocated the device (data not shown). Such a survival analysis is only hypothesis stimulating but could help power future studies in this group. Fifth, given the pragmatic design of the studies and their focus on structural changes and patient-oriented outcomes, we did not routinely measure plasma-based biomarkers. Finally, MR assessment was undertaken at rest. Stress echocardiography was not performed during these studies. Future studies in those with milder forms of MR could explore whether patients with stress-induced worsening of MR have a greater gain from intervention than those in whom mild MR does not deteriorate with stress.

Conclusions
Among patients with HFrEF and mild or moderate SMR who were symptomatic despite guideline-directed medical therapy, and would not be indicated for currently approved percutaneous treatments, percutaneous mitral annuloplasty is associated with few complications, and could lead to improvements in clinical status and SMR parameters, and a stabilization of LV remodelling.

Supplementary Information
Additional supporting information may be found online in the Supporting Information section at the end of the article.