Clinical impact of changes in mitral regurgitation severity after medical therapy optimization in heart failure

Background Few data are available regarding changes in mitral regurgitation (MR) severity with guideline-recommended medical therapy (GRMT) in heart failure (HF). Our aim was to evaluate the evolution and impact of MR after GRMT in the Biology study to Tailored treatment in chronic heart failure (BIOSTAT-CHF). Methods A retrospective post-hoc analysis was performed on HF patients from BIOSTAT-CHF with available data on MR status at baseline and at 9-month follow-up after GRMT optimization. The primary endpoint was a composite of all-cause death or HF hospitalization. Results Among 1022 patients with data at both time-points, 462 (45.2%) had moderate-severe MR at baseline and 360 (35.2%) had it at 9-month follow-up. Regression of moderate-severe MR from baseline to 9 months occurred in 192/462 patients (41.6%) and worsening from baseline to moderate-severe MR at 9 months occurred in 90/560 patients (16.1%). The presence of moderate-severe MR at 9 months, independent from baseline severity, was associated with an increased risk of the primary endpoint (unadjusted hazard ratio [HR], 2.03; 95% confidence interval [CI], 1.57–2.63; p < 0.001), also after adjusting for the BIOSTAT-CHF risk-prediction model (adjusted HR, 1.85; 95% CI 1.43–2.39; p < 0.001). Younger age, LVEF ≥ 50% and treatment with higher ACEi/ARB doses were associated with a lower likelihood of persistence of moderate-severe MR at 9 months, whereas older age was the only predictor of worsening MR. Conclusions Among patients with HF undergoing GRMT optimization, ACEi/ARB up-titration and HFpEF were associated with MR improvement, and the presence of moderate-severe MR after GRMT was associated with worse outcome. Graphical abstract Supplementary Information The online version contains supplementary material available at 10.1007/s00392-022-01991-7.

The aim of this study was to evaluate the evolution and prognostic impact of MR after up-titration of GRMT in patients included in Biology Study to Tailored Treatment in Chronic Heart Failure (BIOSTAT-CHF), a prospective observational multicentre study enrolling patients with worsening chronic or new-onset HF undergoing GRMT optimization [32][33][34].

Study population
The index cohort of BIOSTAT-CHF recruited 2516 patients from 69 centres in 11 European countries between 2010 and 2014. Included patients had symptoms of new-onset or worsening chronic HF, with either a left ventricular ejection fraction (LVEF) ≤ 40% or B-type natriuretic peptide (BNP) > 400 pg/mL and/or N-terminal pro-BNP (NT-proBNP) > 2000 pg/mL and were treated with oral or intravenous furosemide ≥ 40 mg/day or equivalent at inclusion. Patients should not have been previously treated with ACEi/ ARBs and/or β-blockers or should have received ≤ 50% of the target doses of these drugs at inclusion, with an anticipated initiation or up-titration of ACEi/ARBs and/or 1 3 β-blockers by the treating physician. In the first 3 months (optimization phase), initiation or up-titration of ACEi/ ARBs and/or β-blockers was specified according to the 2008 European Society of Cardiology (ESC) guidelines [35]. In the subsequent 6 months (stabilization phase), no further treatment optimization was required, except in case of changes in clinical status. At 9 month, a mandated followup visit was performed, including clinical evaluation and echocardiography. Subsequent follow-up was performed at 6 month intervals by means of clinical visit or phone contact, until the end of follow-up on April 1, 2015. The study was approved by the ethics committees of all participating centres and all patients provided written informed consent.
For the purposes of the present study, patients from the index cohort with available MR data at both baseline and 9 months (n = 1022) were included. The study flowchart is shown in Supplementary Fig. 1.

Study definitions and endpoints
Patients underwent two-dimensional transthoracic echocardiography at baseline and at 9-month follow-up using a commercially available echocardiography (3.5 MHz probe). According to the study protocol, MR was evaluated using two-dimensional and color Doppler echocardiography [36], and the presence of moderate or severe MR (as compared to no or mild MR) was recorded. Left ventricular (LV) diameters, LVEF according to the modified Simpson rule, and left atrium diameter were also quantified and reported. Baseline clinical characteristics, quality-of-life (QoL) measures and laboratory data at inclusion and 9 months, and clinical outcomes at follow-up were also assessed.
The primary endpoint was the composite of all-cause mortality or HF hospitalization. Secondary endpoints were all-cause mortality, cardiovascular (CV) mortality and HF hospitalization as individual outcomes.

Statistical analyses
Continuous variables are presented as mean ± standard deviation or median (interquartile range, IQR), as appropriate, and were compared with the unpaired Student's t test or the Mann-Whitney U test, respectively. Categorical variables are presented as number and percentages and were compared with the χ 2 test. Baseline clinical characteristics, echocardiography data, laboratory data, QoL indexes, primary and secondary endpoints were compared between patients with vs. without 9-month moderate-severe MR and between the following four groups defined according to baseline and 9 month moderate-severe MR: patients without moderatesevere MR at baseline and 9 months (unchanged); patients with moderate-severe MR at baseline and without moderate-severe MR at 9 months (improved); patients without moderate-severe MR at baseline and with moderate-severe MR at 9 months (worsened); and patients with moderatesevere MR at baseline and 9 months (unchanged). The Kaplan-Meier method (log-rank test) was used to evaluate the first occurrence of primary and secondary endpoint in patients with or without 9-month moderate-severe MR and in the four groups describing MR evolution (censoring follow-up at 2 years). Cox proportional hazards regression analysis was also performed to evaluate the prognostic impact of 9-month moderate-severe MR on primary and secondary endpoints. Univariable analysis and multiple multivariable models were performed to adjust the presence of 9 month MR for the several clinical, laboratory, and echocardiographic covariates of interest, including the previously validated BIOSTAT-CHF risk prediction models (model 5) [33]. Results of the Cox regression analyses are reported as unadjusted or adjusted hazard ratio (HR) and 95% confidence interval (CI). Multivariable binary logistic regression analysis was also performed to identify independent predictors of moderate-severe MR at 9-month follow-up. Variables with a univariate p value < 0.10 or variables judged to be of clinical relevance were included into the final multivariable model. Results of the binary logistic regression are presented as odds ratio with 95% CI. The C statistic and Hosmer-Lemeshow goodness-of-fit test were used to evaluate the discrimination, calibration and fit of the multivariable model.
All reported p values are two sided, and p < 0.05 was considered statistically significant.

Results
Among the 1,022 patients included in the present study ( Supplementary Fig. 1

Patients' characteristics
Detailed clinical, echocardiographic, laboratory, and QoL characteristics across the four groups defined according to baseline and 9-month MR are reported in Supplementary Tables 1 and 2. Baseline clinical characteristics among patients included as compared to those excluded from the study are reported in Supplementary Table 3.
Compared to patients with no or mild MR, patients with moderate-severe MR at 9 months were older, had lower body mass index, and were more likely to have a history of chronic kidney disease, prior cardiac device therapy, and worsening chronic HF as cause of the baseline visit (Table 1). These patients also had more advanced symptoms (NYHA class) at 9 months and lower systolic blood pressure at baseline and 9 months compared to patients with no or mild MR. The percentage of patients who achieved the ACEi/ARB target dose at 3 months and the mean ACEi/ARB optimal dose fraction at 3 months were lower in patients with moderatesevere MR at 9 months. These differences were not observed for β-blockers.
Median LVEF at 9 months was lower in patients with 9-month moderate-severe MR compared to those with no or mild MR (Table 2). Hence, patients with 9 month moderatesevere MR were more likely to have HFrEF at 9 months (LVEF < 40%) rather than HF with mid-range (HFmrEF; LVEF 40-49%) or preserved LVEF (HFpEF; LVEF ≥ 50%). Moreover, median LV end-diastolic diameter, LV end-systolic diameter, and left atrium diameter at baseline and at 9 months were all higher in patients with as compared to those without 9-month moderate-severe MR. Patients with 9-month moderate-severe MR had lower baseline eGFR and higher baseline and 9-month plasma NT-proBNP levels compared to patients with no or mild MR. All QoL measures assessed at 9 months were lower in these patients ( Table 2).

Impact of changes in MR severity and 9-month moderate-severe MR on clinical outcomes
After a median follow-up of 405 (IQR 254-554) days, the primary endpoint occurred in 114 patients (31.7%) with, and in 119 patients (18.0%) without, moderate-severe MR at 9 months (unadjusted HR 2.03, 95% CI 1.57-2.63). By Kaplan-Meier analysis, the incidence of the 2-year primary endpoint was higher in patients with, as compared to those without, moderate-severe MR at 9 months (log-rank p < 0.0001; Fig. 1A). Patients with worsened MR from baseline to 9 months and those with persistent moderatesevere MR at both baseline and 9 months had a similar incidence of the 2-year primary endpoint, which was higher compared to patients whose MR improved from baseline to 9 months and to those who had no or mild MR at both time-points (log-rank p < 0.0001; Fig. 1B Supplementary Fig. 5, the higher risk of the primary endpoint in patients with 9-month moderate-severe MR was observed both in patients with LVEF < 40% and in those with LVEF ≥ 40% (p value for interaction = 0.803).

Predictors of 9-month significant MR
At multivariable binary logistic regression analysis (Table 4), the presence of moderate-severe MR at baseline and older age were associated with an increased risk of 9 month moderate-severe MR, whereas HFpEF (LVEF ≥ 50% at baseline) and treatment with a higher fraction of ACEi/ARB optimal dose at 3 months were associated with a lower risk of 9 month moderate-severe MR. The C statistic (0.77) and Hosmer-Lemeshow goodness-of-fit test p value (0.48) confirmed good discrimination and fit of the multivariable model.
Regarding the prediction of changes in MR severity, among the 462 patients with moderate-severe MR at baseline, younger age, HFpEF, and treatment with a higher fraction of ACEi/ARB optimal dose at 3 months were associated with a lower likelihood of persistence of moderate-severe MR at 9 months (Supplementary Table 4). Among the 560 patients with no or mild MR at baseline, older age was the only independent predictor of worsening MR at 9 months (Supplementary Table 5).

Discussion
The main findings of our study on patients with worsening or new-onset HF are as follows: (1) MR may dynamically change after attempted implementation of GRMT, with an improvement observed in a consistent proportion of patients with moderate-severe MR at baseline (41.6%), and MR development or worsening observed in a lower proportion of patients with no or mild MR at baseline (16.1%); (2) moderate-severe MR persists or develops despite GRMT in a substantial proportion of patients (35.2%) and has a strong prognostic impact even after adjusting for several other variables related to HF severity; (3) older age and presence of significant MR at baseline were associated with a greater risk of moderate-severe MR after GRMT optimization, whereas HFpEF and treatment with higher doses of ACEi/ ARB were associated with a lower likelihood of moderatesevere MR after GRMT. In our study, prevalence of 9 month moderate-severe MR after GRMT optimization in patients with HF was 35.2%, a figure that seems in line with prior studies not strictly focusing on GRMT optimization and reporting rates of moderate-severe MR ranging from 29 to 53% [1-3, 10, 13, 15, 16]. Furthermore, we found that MR severity was unchanged after GRMT optimization in 46.0% of patients without moderate-severe MR and in 26.4% of patients with moderate-severe MR, whereas MR improved in 18.8% and worsened in 8.8% of patients from baseline to 9 months. These results are in line with previous smaller studies reporting the evolution of MR in HFrEF patients receiving GRMT [37][38][39][40]. Compared to these studies [37][38][39][40], our analysis was performed on a much larger study group, including a broader HF population with HFrEF, HFmrEF and HFpEF patients. Despite the percentages of patients with improving or worsening MR were slightly lower in our study (18.8% and 8.8%, respectively) as compared to those reported by Nasser et al. (38% and 18%, respectively), both studies confirmed the prognostic impact of both persistent significant or worsening MR after GRMT optimization [38]. Of note, the Pharmacological Reduction of Functional, Ischemic Mitral Regurgitation (PRIME) trial randomized 118 patients with HF, LVEF < 50%, significant functional MR and optimized medical therapy with ACEi/ARBs or β-blockers to ARNI or valsartan, demonstrating a greater reduction in MR severity with ARNI at 1-year follow-up [28]. Although the benefits of ARNI could exceed those associated with ACEi/ARBs or β-blockers in terms of functional MR reduction, our study was performed before the introduction of ARNI into the routine clinical management of HF patients and, therefore, we could not evaluate the impact of this therapy. Several reasons could explain a lack of MR improvement or even MR worsening in a relevant proportion of patients (35.2%) in our study, including a more advanced stage of HF in terms of symptoms, clinical profile and echocardiographic findings, and lower odds of achieving higher GRMT doses during the optimization phase (see Supplementary Tables 1-2 for  details). Biological variables, such as kidney dysfunction, hyperkalemia and low blood pressure may, on the other hand, cause lack of GRMT initiation or up-titration [41][42][43].
Our study demonstrates that both persistent significant MR and worsening MR after GRMT optimization in patients with HF are associated with an increased risk of all-cause death or HF hospitalization. The prognostic impact of moderate-severe MR after GRMT was particularly strong   [38,39]. Furthermore, a recent sub-analysis of the COAPT trial reported that MR improvement at 30 days was associated with better clinical outcomes and improved quality of life among HF patients, regardless of whether such improvement was achieved through transcatheter mitral valve repair or GRMT [44].
Since GRMT represents the first crucial therapeutic step in patients with HF and significant MR, [20,21] our study may have clinically relevant implications in the management of patients with MR. Our data suggest that the optimal timing to evaluate interventional procedures for MR correction in HF should be after an adequate period of GRMT optimization since the prognostic impact of persistent significant MR after such period is particularly strong. In line with this concept, the COAPT trial demonstrated the prognostic benefit of percutaneous mitral valve repair in a carefully selected population of symptomatic patients with HF and persistent MR despite GRMT up-titration to maximally tolerated doses, as evaluated by a dedicated central committee [19,24,25]. Our study seems in line with this strategy of GRMT optimization before planning potential interventions for MR correction in HF.
Interestingly, ACEi/ARB up-titration was associated with a lower likelihood of persistence of moderate-severe MR in our study and, therefore, with MR improvement after the optimization phase. Prior randomized studies have already demonstrated that ACEi are effective in reducing functional MR in HFrEF [29]. Similarly, as already mentioned, sacubitril/valsartan was more effective than valsartan in reducing functional MR among 118 patients with HFrEF or HFmrEF enrolled in the PRIME trial [28]. Furthermore, among patients undergoing percutaneous mitral valve repair for secondary MR, in addition to a "COAPT-like" Data are presented as n (%) and median (Q25-Q75). Bold values represent significant p-values (p < 0.05) 6MWT 6 min walking test; CKD-EPI chronic kidney disease epidemiology collaboration; eGFR estimated glomerular filtration rate; EQ-5D EuroQol-5 dimension; HFmrEF heart failure with mid-range ejection fraction; HFpEF heart failure with preserved ejection fraction; HFrEF heart failure with reduced ejection fraction; KCCQ Kansas city cardiomyopathy questionnaire; LVEDD left ventricular end-diastolic diameter; LVEF left ventricular ejection fraction; LVESD left ventricular end-systolic diameter; MR mitral regurgitation; NT-proBNP N-terminal pro-B-type natriuretic peptide; QoL quality-of-life; VAS visual analogue scale in four patients' groups according to baseline and 9-month moderatesevere MR after GRMT optimization (panel B). GRMT guidelinedirected medical therapy; HF heart failure; MR mitral regurgitation echocardiographic and clinical profile, GRMT was found to be a powerful predictor of 5 year survival [45]. Several mechanisms could explain the benefit of RAAS inhibitors on MR in HF, including reverse LV remodelling, afterload reduction and beneficial effects on valve leaflet remodelling [46,47]. However, from the present study, we cannot assess whether the association between better up-titration of ACEi/ ARB and a lower likelihood of persistence of moderatesevere MR was causally related. Furthermore, we found that HFpEF was associated with a lower likelihood of moderate-severe MR after the optimization phase of GRMT up-titration. The different mechanisms and pathogenesis of MR in patients with normal or reduced LVEF could play a role in the different MR evolution in patients with HFrEF and HFpEF after GRMT optimization [48,49]. Of note, atrial functional MR, typically associated with HFpEF and atrial fibrillation, has emerged as a distinct entity from "ventricular" secondary MR, typically associated with HFrEF [50]. Despite the better prognosis of patients with HFpEF as compared to those with HFrEF [51], significant functional MR has been associated with worse clinical outcomes both in HFpEF and in HFrEF patients [12]. However, the interplay between ACEi/ARB or β-blockers up-titration and persistence of significant MR in HFpEF needs to be further explored in dedicated studies.

Limitations
Our study is a post hoc retrospective analysis of a prospective multicentre registry and, therefore, has all the usual Table 3 Cox regression models for the impact of 9-month moderate-severe MR on the combined endpoint (all-cause death or HF hospitalization), all-cause death, CV death and HF hospitalization Data are presented as HR and 95% CI. Bold values represent significant p-values (p < 0.05) ACEi angiotensin-converting enzyme inhibitor; ARB angiotensin receptor blocker; CI confidence interval; CV cardiovascular; eGFR estimated glomerular filtration rate; HF heart failure; HR hazard ratio; MR mitral regurgitation; LVEF left ventricular ejection fraction; NYHA New York Heart Association; NT-proBNP N-terminal pro-B-type natriuretic peptide * In multivariable model 5, 9-month moderate-to-severe MR was adjusted for the BIOSTAT-CHF risk prediction models, including the following covariates: age, HF hospitalization in last year, systolic blood pressure, peripheral oedema, log-NT-proBNP, haemoglobin, sodium, high-density lipoprotein, and use of β-blockers at baseline for the combined endpoint; age, log-urea, log-NT-proBNP, haemoglobin, and use of β-blockers at baseline for all-cause death and CV death; age, HF hospitalization in last year, systolic blood pressure, peripheral oedema, and estimated glomerular filtration rate for HF hospitalization limitations associated with this design. The main limitation is the lack of core-laboratory analysis of echocardiographic data and the consequent lack of detailed information regarding MR severity and aetiology. Furthermore, no independent adjudication of clinical events was performed. Of note, BIOSTAT-CHF was performed before the introduction of sodium-glucose cotransporter-2 inhibitors and ARNI in the treatment of HFrEF, hence the impact of these therapies on MR evolution and prognosis could not be evaluated. Moreover, the proportion of patients with HFpEF in our study was relatively small (4.2%), thus preventing from definitive conclusions for this disease entity, and no specific recommendations regarding GRMT were available for HFpEF at time of BIOSTAT-CHF enrolment [35].

Conclusions
In patients with worsening or new-onset HF enrolled in BIOSTAT-CHF, MR severity may dynamically change after a dedicated period of GRMT optimization. The presence of moderate-severe MR after GRMT optimization, either persistent moderate-severe or worsening MR from baseline, has a strong prognostic impact, regardless of relevant variables of interest and from an already validated risk prediction model. Higher ACEi/ARB up-titration and HFpEF were associated with a higher likelihood of MR improvement after GRMT optimization. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes ACEi angiotensin-converting enzyme inhibitor; ARB angiotensin receptor blocker; CI confidence interval; CKD-EPI chronic kidney disease epidemiology collaboration; eGFR estimated glomerular filtration rate; HF heart failure; HFmrEF heart failure with mid-range ejection fraction; HFpEF heart failure with preserved ejection fraction; HFrEF heart failure with reduced ejection fraction; LVEF left ventricular ejection fraction; MR mitral regurgitation; NYHA New York Heart Association; NT-proBNP N-terminal pro-B-type natriuretic peptide; OR odds ratio were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/.