Regurgitant volume to LA volume ratio in patients with secondary MR: the COAPT trial

Abstract

Aims

The conceptual framework of proportionate vs. disproportionate mitral regurgitation (MR) translates poorly to individual patients with heart failure (HF) and secondary MR. A novel index, the ratio of MR severity to left atrial volume (LAV), may identify patients with ‘disproportionate’ MR and a higher risk of events. The objectives, therefore, were to investigate the prognostic impact of MR severity to LAV ratio on outcomes among HF patients with severe secondary MR randomized to transcatheter edge-to-edge repair (TEER) with the MitraClip™ device plus guideline-directed medical therapy (GDMT) vs. GDMT alone in the COAPT trial.

Methods and results

The ratio of pre-procedural regurgitant volume (RVol) to LAV was calculated from baseline transthoracic echocardiograms. The primary endpoint was 2-year covariate-adjusted rate of HF hospitalization (HFH). Among 567 patients, the median RVol/LAV was 0.67 (interquartile range 0.48–0.91). In patients randomized to GDMT alone, lower RVol/LAV was independently associated with an increased 2-year risk of HFH (adjHR: 1.77; 95% CI: 1.20–2.63). RVol/LAV was a stronger predictor of adverse outcomes than RVol or LAV alone. Treatment with TEER plus GDMT compared with GDMT alone was associated with lower 2-year rates of HFH both in patients with low and high RVol/LAV (P_interaction = 0.28). Baseline RVol/LAV ratio was unrelated to 2-year mortality, health status, or functional capacity in either treatment group.

Conclusion

Low RVol/LAV ratio was an independent predictor of 2-year HFH in HF patients with severe MR treated with GDMT alone in the COAPT trial. TEER improved outcomes regardless of baseline RVol/LAV ratio.

Clinical Trial Registration

Trial Name: Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation (The COAPT Trial) (COAPT)

ClinicalTrial.gov Identifier NCT01626079

URL https://clinicaltrials.gov/ct2/show/NCT01626079

Graphical Abstract

Impact of baseline RVol/LAV ratio on HFH in patients with heart failure and severe mitral regurgitation in the COAPT trial. A lower ratio of RVol to LAV was associated with an increased adjusted risk of HFH within 2 years in patients with heart failure with severe mitral regurgitation enrolled in the COAPT trial and treated with GDMT alone. *Per 10 mL increase. GDMT, guideline-directed medical therapy; HFH, heart failure hospitalization; HR, hazard ratio; LAV, left atrial volume; RVol, regurgitant volume; TEER, transcatheter edge-to-edge therapy.

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Introduction

The presence of secondary mitral regurgitation (SMR) is associated with increased mortality in patients with heart failure (HF).^1,2 The Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation (COAPT) trial demonstrated that transcatheter edge-to-edge repair (TEER) with the MitraClip™ system (Abbott, Santa Clara, CA) is safe,^3,4 reduces adverse outcomes, and improves functional status and quality-of-life beyond treatment with guideline-directed medical therapy (GDMT) alone in selected HF patients with severe SMR.^5–8 Conversely, the MITRA-FR trial showed no benefit of TEER in an ostensibly similar patient population.⁹ The concept of disproportionate mitral regurgitation (MR), i.e. greater MR severity relative to left ventricular (LV) volume, has been proposed to partially explain these discrepancies in outcomes, with COAPT enrolling a greater percentage of patients with disproportionate MR than MITRA-FR.^9,10 However, within the COAPT population, the ratio between MR severity, as assessed by effective regurgitant orifice area (EROA), and LV end-diastolic volume (LVEDV) was not a major discriminator of treatment outcomes.¹¹ Moreover, in other studies, the conceptual framework of proportionate vs. disproportionate MR has been difficult to translate to individual patients with HF to identify those who will benefit from MR correction.^12–16

Left atrial (LA) size and function are also markers of disease severity and are related to worse outcomes in SMR.¹⁷ In addition, because MR increases LA volume (LAV) overload, the effects of disproportionate (severe) MR might be especially pronounced on the LA. To our knowledge, no previous studies have examined the effects of proportionate vs. disproportionate MR on the LA. We hypothesized that the ratio between MR severity and LAV is associated with outcomes in HF patients with SMR, and therefore aimed to explore the prognostic impact of this ratio in HF patients with severe SMR enrolled in the COAPT trial.

Methods

Study design

Details of the COAPT trial protocol and design have been published previously.⁴ In brief, the COAPT trial was a multicentre, randomized, open-label clinical trial of TEER with the MitraClip device in HF patients with moderate-to-severe (3+) or severe (4+) SMR who remained symptomatic despite maximally-tolerated GDMT and cardiac resynchronization therapy when applicable. Eligibility criteria included LV ejection fraction (LVEF) between 20% and 50%, LV end-systolic diameter ≤ 70 mm, and absence of severe pulmonary hypertension [defined as systolic pulmonary artery pressure (SPAP) > 70 mmHg despite vasodilator therapy] or moderate or severe symptomatic right ventricular failure. Eligible patients were randomized in a 1:1 ratio to either MitraClip in addition to GDMT or to GDMT alone.

Transthoracic echocardiograms were obtained at baseline and were analysed by an independent core laboratory (MedStar Health Research Institute, Washington, DC).¹⁸ The severity of MR was graded according to US American Society of Echocardiography guidelines.¹⁹ RVol in COAPT was determined using the proximal isovelocity hemispheric area method on 3 consecutive beats whenever available (5 consecutive beats if the patient was in atrial fibrillation) and the average was reported. The intraclass correlation and 95% confidence interval (CI) for interobserver variability were 0.84 (95% CI: 0.51–0.96). LAV was assessed by using Simpson’s biplane method if possible; otherwise, Simpson’s monoplane method was used. Institutional review board/ethics committee approval was obtained from all sites that participated in the COAPT trial, and all patients signed informed consent. The authors had full access to all data in the study and accept responsibility for the article’s integrity, the data analysis, and the decision to publish. The data from this study may be made available to support additional studies; such requests should be made to the COAPT publications committee ([email protected]).

Study endpoints

The primary endpoint for this analysis was time to the first occurrence of HF hospitalization (HFH) within 2 years. Secondary endpoints were time to cardiovascular mortality, and the composite of cardiovascular mortality or HFH. Additional analyses were performed to assess quality-of-life and functional status, including 6-minute walk distance (6MWD), the Kansas City Cardiomyopathy Questionnaire overall summary score, and New York Heart Association functional class. Missing values for the 6MWD were imputed according to the protocol.⁴ Subjects who expired due to an adjudicated HF death before the 2-year follow-up time or were unable to walk due to cardiac reasons were included in the analysis and assigned a follow-up 6MWD of zero.¹¹

Statistical analysis

Patients were divided into two groups according to RVol/LAV ratio (<median vs. ≥median). Categorical variables are reported as counts and corresponding proportions and were compared with the χ² test or the Fisher’ exact test, as appropriate. Continuous variables are described as mean ± standard deviation (SD) if the data were normally distributed or as median [interquartile range (IQR)] if non-normally distributed and were compared with two-sided Student’s t-test (parametric test) or the Wilcoxon rank sum test (non-parametric test), respectively. The rates of HFH and cardiovascular death were estimated using the Kaplan–Meier method and were compared with the log rank test. Hazard ratio (HRs) and 95% CIs were determined using Cox proportional hazards regression with adjustment for age, sex, diabetes, hypertension, history of atrial fibrillation/flutter, estimated glomerular filtration rate, LVEF, LV global longitudinal strain (LV GLS), LVEDV, and right ventricular systolic pressure. RVol/LAV ratio, RVol alone, and LAV alone were included with these covariates in separate multivariable models, and their predictive capacity was compared using the Akaike Information Criterion (AIC). As a sensitivity analysis, unadjusted and adjusted clinical outcomes in all patients and by treatment group were examined according to the median EROA/LAV ratio. A two-sided P-value of <0.05 was considered to indicate statistical significance. All statistical analyses were performed with SAS software, version 9.4 (SAS Institute, Cary, NC).

Results

Study population

Among 614 patients enrolled in the COAPT trial, RVol could not be measured in 47 patients because of suboptimal echogenicity or jet eccentricity that precluded alignment with the regurgitant jet for calculation of the RVol using the PISA method. The remaining 567 patients (84.1%) with evaluable baseline RVol and LAV measures comprise the analytic cohort. The median baseline RVol/LAV ratio was 0.67 [IQR 0.48–0.91]. Characteristics of the study population stratified according to the median RVol/LAV ratio are depicted in Table 1. Compared with subjects with RVol/LAV ratio ≥ 0.67, those with lower RVol/LAV were less likely to be women and to have diabetes, and more frequently had a history of atrial fibrillation or flutter. Echocardiographic characteristics according to median RVol/LAV ratio are presented in Table 2. As expected, patients with low RVol/LAV had smaller RVols and larger LAVs than those with higher RVol/LAV. There were no differences between groups regarding LVEF, SPAP, tricuspid regurgitation grade ≥ 2+, or right ventricular function assessed by right ventricular free wall longitudinal strain. LV GLS was lower (i.e. better) in patients with a higher RVol/LAV. There was no correlation between RVol and LAV (Spearman’s correlation coefficient = 0.066; P = 0.10, Figure 1). Baseline clinical and echocardiographic characteristics stratified according to baseline EROA/LAV ratio were consistent with the RVol/LAV results (see Supplementary data online, Tables S1 and S2, Supplementary data online, Figure S1). Correlation between RVol/LAV and LVEDVi, LVEF, LV GLS, SPAP, age, and natriuretic peptide levels are provided in Supplementary data online, Figure S2.

Relationship between baseline RVol/LAV ratio and clinical outcomes

At 2 years, HFH occurred in 230 patients (44.8%), cardiovascular death occurred in 150 patients (28.8%), and the composite outcome of cardiovascular death or HFH occurred in 279 patients (51.7%) (Table 3). In unadjusted analyses, patients with a low baseline RVol/LAV ratio were at higher risk of HFH in the GDMT alone group, but not in the TEER plus GDMT group. There was no significant association between RVol/LAV ratio and 2-year cardiovascular death in either treatment group. After multivariable adjustment, a low RVol/LAV was associated with higher 2-year rates of HFH (adjusted HR: 1.77; 95% CI: 1.20 to 2.63; P = 0.004, Figure 2A) and the composite of cardiovascular death or HFH (adjusted HR: 1.75; 95% CI: 1.22 to 2.52; P = 0.02, Figure 2B) in the GDMT alone group, but not with cardiovascular death alone. There was no association between RVol/LAV ratio and outcomes in the TEER plus GDMT group. In patients randomized to GDMT alone, the RVol/LAV ratio, but not RVol or LAV alone, was an independent predictor of HFH and resulted in the lowest AIC among the three multivariable models (Graphical Abstract and Table 4). Spline regression analyses of RVol/LAV ratio and clinical outcomes are shown in Supplementary data online, Figure S3. Clinical outcomes at 2 years according to the median RVol/LAV ratio in patients with moderate-to-severe (3+) and severe (4+) MR are presented separately in Supplementary data online, Table S3. The results were consistent with the overall population.

Effect of TEER according to baseline RVol/LAV ratio

Compared with GDMT alone, treatment with TEER improved the 2-year rates of HFH in patients with high (31.9% vs. 49.6%; HR: 0.55; 95% CI: 0.37–0.82) and low (34.0% vs. 63.3%; HR: 0.40; 95% CI: 0.28–0.58) baseline RVol/LAV (P_interaction = 0.28, Figure 2A). TEER also reduced rates of cardiovascular death and the composite of cardiovascular death or HFH in both RVol/LAV groups (Figure 2B and C). These results were consistent in sensitivity analyses using the EROA/LAV ratio (see Supplementary data online, Table S4 and Supplementary data online, Figures S3–S6), for which the P-values for interaction between EROA/LAV ratio and treatment for the 2-year rates of HFH, cardiovascular death, and the composite of cardiovascular death or HFH were 0.12, 0.70, and 0.23, respectively.

Finally, there were no significant differences between patients in the low and high RVol/LAV groups regarding 2-year health status measurements (see Supplementary data online, Table S5).

Discussion

This study is the first to investigate the prognostic utility of the ratio between MR severity and LAV in HF patients with SMR. The major findings from the present sub-study from the COAPT trial are: (i) a low RVol/LAV ratio identified a group of patients treated with GDMT alone who were at higher risk of HFH; (ii) this ratio performed better than either of its individual components in predicting HFH events; (iii) treatment with TEER mitigated the increased risk of HFH among patients with a low RVol/LAV ratio, and improved survival and health status (as well as HFH) regardless of the RVol/LAV ratio; and (iv) the results were generally similar when patients were stratified according to the EROA/LAV ratio.

The concept of disproportionate vs. proportionate MR was proposed by Grayburn et al.¹⁰ as a conceptual framework that might reconcile the conflicting results between the COAPT and MITRA-FR trials of TEER with the MitraClip device compared with GDMT alone in HF patients with severe SMR.^4,9 This pathophysiologic hypothesis using the mitral EROA/LVEDV ratio suggested that patients with proportionate MR, i.e. an EROA expected according to the LVEDV by the Gorlin equation to represent severe MR (regurgitant fraction of 50%), would benefit less from TEER compared with patients with a higher EROA/LVEDV ratio (i.e. regurgitant fraction > 50%, representing ‘very severe’ MR). From examination of the mean group EROA and LVEDV values from COAPT and MITRA-FR, it was evident that COAPT enrolled more patients in whom the EROA was greater and the LVEDV was smaller than in MITRA-FR, despite similar mean LVEFs in the two trials. However, applying this concept to select individual HF patients with MR who should clearly undergo TEER has not been straightforward.

LA enlargement has been proposed as a barometer of LV diastolic dysfunction and a prognostic marker in chronic HF patients independent of LV function.^20,21 However, few studies have examined the link between MR severity and LA volume or function in HF patients with SMR. Stassen et al.¹⁷ recently showed that LA function, evaluated using speckle-tracking echocardiography, was independently associated with all-cause mortality in patients with significant SMR and has incremental prognostic value beyond LV GLS. Using morphomic and functional network profiling in 383 HF patients treated with GDMT alone, Bartko et al.²² identified novel phenotypes of SMR that incorporated both LV and LA remodelling in predicting the prognosis of SMR.

Data on the relationship between LA size and outcomes after TEER in patients with SMR are scarce. A sub-study of the TRAMI registry in patients with primary and secondary MR reported that LA enlargement on echocardiography was an independent predictor of adverse long-term outcomes after TEER.²³ More recently, a sub-study from the EuroSMR registry reported that LAV index was modestly associated with adverse outcomes after TEER and that the association of LA size with mortality was more pronounced in patients with less severe SMR, reinforcing the idea to explore LA adaptability in this population.²⁴ Of note, a linear increase of LAV in patients with up to moderate SMR but without further increase in those with greater MR severity has been previously reported.²⁵ These findings are consistent with our results that show no relationship between RVol or EROA and LAV in HF patients, all of whom had at least moderate-to-severe SMR. Our results showed that HF patients with lower RVol and larger LA have higher rates of HFH compared with patients with higher RVol and smaller LA. It may be hypothesized that LA adaptability plays a preponderant and more important role than regurgitation, as suggested by Iliadis et al.²⁴ Beyond a certain degree of LA dilation, the ability of the LA to prevent pulmonary congestion by damping pressure swings between the LV and the pulmonary vasculature is significantly impaired. In the COAPT trial, the severity of LA disease (increased LAV) seemed to be a stronger driver of clinical outcomes than the severity of MR (increased RVol) in patients treated with GDMT. The RVol/LAV ratio, which includes both components, might be useful to discriminate those patients at higher risk of pulmonary congestion and HFH.

Regardless, the present results suggest that the ratio of RVol/LAV is a stronger predictor of HFH in GDMT-treated HF patients with severe SMR than either RVol or LAV alone. These findings suggest that a lower RVol/LAV ratio identifies a group of patients in whom the severity of LA dysfunction dictates the prognosis more so than the degree of SMR. However, no significant interaction was present between the baseline RVol/LAV ratio and treatment with TEER vs. GDMT alone on the 2-year risk of HFH. It is also noteworthy that the RVol/LAV ratio was not predictive of cardiovascular mortality, QOL, or functional capacity in either treatment group.

We chose to investigate the RVol/LAV ratio for our primary analysis rather than the EROA/LAV ratio because EROA is only one determinant of the regurgitant volume (the others being the magnitude and duration of the pressure gradient across the mitral orifice).¹⁶ Moreover, Gaasch et al. hypothesized that the RVol/LVEDV ratio may be more predictive of outcomes in SMR than the EROA/LVEDV ratio because it is the volume overload from MR that causes symptoms and progressive LV dysfunction. These considerations notwithstanding, our results were generally similar when patients were stratified according to the EROA/LAV ratio. Further studies are warranted to determine which metric (RVol/LVEDV or RVol/LAV) is more reproducible and predictive of outcomes in HF patients with severe SMR treated with GDMT alone and TEER plus GDMT.

Study limitations

First, while the present findings support the relationship between RVol and LAV as a determinant of future HFH in patients with SMR treated with GDMT alone, the relative reduction in HFH was similar in COAPT patients treated with TEER plus GDMT and GDMT alone. Thus, the present study does not support use of the RVol/LAV ratio as a discriminator to identify higher-risk patients who might benefit from TEER to a relatively greater vs. lesser degree. However, the COAPT trial enrolled a relatively homogenous cohort of patients, excluding those with marked LV dilatation or dysfunction and severe pulmonary hypertension or right heart disease. Further studies are required to determine whether the RVol/LAV ratio can identify patients particularly likely to benefit from TEER. Secondly, these results cannot necessarily be generalized to patients with characteristics that did not meet the COAPT criteria. Thirdly, the echocardiograms of the COAPT trial were assessed by an independent expert core laboratory. The reproducibility and feasibility of quantifying MR severity using RVol, especially in patients with SMR, might be less in clinical practice settings. Fourthly, we acknowledge that LA strain is a better surrogate of LAV function than LA volume. However, we chose to use the ratio between RVol and maximal LA volume because these two volumes are assessed at the same time of the cardiac cycle and because LAV quantification is widely performed, reproducible, and feasible in most cases. Finally, information regarding the proportion of patients meeting ASE/EACVI guideline criteria for optimal LA quantification by 2D echocardiography was not available. The lack of dedicated views and single-plane quantification may have led to LA volume underestimation.

Conclusions and clinical implications

In the COAPT trial, a low baseline RVol/LAV ratio was an independent predictor of 2-year HFH in patients with HF and severe SMR treated with GDMT alone, whereas neither RVol nor LAV alone were predictive of outcomes. In contrast, cardiac mortality, QOL, and functional capacity were unrelated to RVol/LAV in the overall COAPT population or in either treatment group. Finally, TEER reduced the 2-year risks of HFH and mortality to a similar extent regardless of baseline RVol/LAV ratio.

Based on these findings, a low RVol/LAV ratio may have utility as a novel risk factor for increased HFH in patients with HF and SMR. This ratio could therefore be useful to identify high-risk HF patients not eligible for TEER with MitraClip at increased risk for HFH in whom medical therapy intensification and close monitoring is warranted. However, this ratio does not identify a subgroup of ‘disproportionately severe’ SMR patients who are especially likely to benefit from TEER. Future studies are needed to validate the utility of the RVol/LAV (and EROA/LAV) ratio, to define its optimal cut-off to predict events, and to explore whether it has a role in patients with primary MR. Finally, the search for a method to reliably identify disproportionate SMR in individual patients continues.

Supplementary data

Supplementary data are available at European Heart Journal - Cardiovascular Imaging online.

Funding

The COAPT trial was funded by Abbott (Santa Clara, CA).

Data availability

The data from this study will not be made publicly available. However, the authors are interested in collaborating with other groups on related projects. Please contact the corresponding author for more information.

References

Author notes