New <scp>ESC</scp>/<scp>EACTS</scp> guideline recommendations for the treatment of secondary mitral regurgitation: reflections on the evidence
Authors: Christian Frerker, Nicole Karam, Rebecca T. Hahn, Holger Thiele, Gregg W. Stone, Hendrik Treede, Jörg Hausleiter
Journal: European Journal of Heart Failure (2022)

In general, guideline recommendations reflect, summarize and interpret the latest available evidence for assisting health care professionals in proposing the best treatment strategy for groups of patients. Changes in guidelines are usually based on new data from randomized clinical trials (RCTs) or large registry studies supporting new recommendations or the up- or downgrading of existing recommendations with their respective level of evidence (LoE). The currently published 2021 European Society of Cardiology (ESC)/European Association of Cardio-Thoracic Surgery (EACTS) guidelines for the management of valvular heart disease introduced several important new recommendations on secondary mitral regurgitation (SMR).1 The fact that the joint European guidelines are endorsed by two societies of different disciplines, strengthens the role of shared decision-making within a heart team. However, challenges in reconciling the differences in outcomes from the COAPT and MITRA-FR RCTs2, 3 resulted in significant uncertainty. In the following viewpoint, we discuss several major guideline changes and recommendations for the evaluation and treatment of patients with SMR that have raised some concerns about the appropriate management of these complex patients. Although a multi-parametric integrative echocardiographic approach using qualitative, semi-quantitative and quantitative assessments is recommended to determine the severity of SMR,4, 5 the difference in COAPT and MITRA-FR effective regurgitant orifice area (EROA) inclusion criteria, which were based on different guideline recommended cut-offs for severe SMR, has been cited as a major explanation for the discordant outcomes. An EROA ≥20 mm2 defined severe SMR in the 2012 and 2017 ESC/EACTS guidelines, when both trials recruited SMR patients. Incorporating both trial results, the 2021 ESC/EACTS guidelines doubled the EROA threshold fo severe SMR definition to an EROA ≥40 mm2, but they also state that ‘… an EROA ≥30 mm2 by two-dimensional proximal isovelocity surface area (PISA) likely corresponds to severe SMR. In contrast, whether an EROA ≥20 mm2 defines severe SMR remains controversial.’ There are two main controversies: (1) whether the inherent limitations of the PISA method (known to underestimate SMR severity because of the ‘cresent’ shape of the orifice) would translate to a larger EROA by other methods; and (2) whether we should be defining severity based on the quantity of regurgitation, or the prognosis of regurgitation. These two issues are inter-related since if PISA EROA underestimates true regurgitant severity, then a PISA EROA of 20 mm2 could translate to a true EROA of 40 mm2, and the adverse prognosis of SMR would occur at the quantitative grade of severe; prognosis and quantitative severity would be consistent. A number of studies have confirmed the underestimation of EROA by PISA6-8 (Table 1) and an EROA of <30 mm2 could represent severe mitral regurgitation (MR) by either quantitative Doppler method or three-dimensional methods. This known underestimation of PISA EROA as well as the multiple studies documenting a linear relationship between MR severity and outcomes for SMR beginning at ‘mild’,9 led the American echocardiographic guideline4 as well as societal guideline,10 to revert back to the quantitative cut-offs for ‘severe MR’, irrespective of aetiology.11 Furthermore, it is important to realize that other important differences beyond EROA might have influenced the discordant outcomes of COAPT and MITRA-FR and the failure to show improved outcomes with moderate MR repair in surgical trials.12, 13 With the linear association between MR severity and adverse outcomes, the cut-off which defines the early increase in hazard may not be the same cut-off which defines improved outcomes for hard clinical endpoints with intervention. Accordingly, the appropriate cut-off for mitral interventions remains an open question. The second controversy is further complicated by the use of three parameters to quantify the severity of SMR (EROA, regurgitant volume and regurgitant fraction) that clearly become more discordant with larger, more dysfunctional ventricles as well as with alterations in chamber compliance and loading conditions. It seems likely that the prognostic utility of the three parameters may differ based on this interaction of left ventricular (LV) size and function, and haemodynamic load. The regurgitant fraction normalizes for these haemodynamic and functional parameters by quantifying the severity of MR as a fraction of the total stroke volume; thus, representing the haemodynamic burden of SMR for a diverse group of patients without requiring further adjustment for LV size or function. In the MITRA-FR trial, LV dimensions and volumes were larger (a comorbidity that may also play a role in outcomes) with a smaller EROA compared to the COAPT trial, but regurgitant fractions were ∼40% and ∼50% in COAPT and MITRA-FR, respectively14; however, outcomes in the two trials remain different likely because MR severity in isolation, without also considering LV size/function and haemodynamics, will not be sufficient to explain clinical outcomes in these heterogeneous patient populations. Imaging guidelines suggest MR is severe when the regurgitant fraction exceeds 50% of the total stroke volume4, 5 and recent studies have confirmed adverse outcomes associated with this metric.4, 15 In fact, the regurgitant fraction appears to have a continuous hazard of increased mortality whereas the other measures of severity (EROA, regurgitant volume) flatten their risk prediction beyond their cut-offs for ‘moderate’. Most likely this observation is related to the effect of the low inotropic force in patients with heart failure with reduced ejection fraction (HFrEF). In three recent surgical or interventional RCTs2, 16, 17 and the large EuroSMR registry18 of HFrEF patients and severe SMR, the stroke volumes were approximately 65 ml (LV end-diastolic volumes: 170–200 ml; LV ejection fraction: 31%–41%), resulting in a regurgitant volume of >32 ml and an EROA of ∼0.2 cm2, which would correspond to ‘moderate MR’ by current criteria. However, this regurgitant volume and EROA would represent a regurgitant fraction ∼50% which would fulfil the criteria for severe MR and which is likely to drive adverse outcomes. The value of regurgitant fraction is further highlighted in the 2022 EACVI position paper which states that regurgitant fraction is preferred over EROA for SMR grading, when EROA is of borderline significance.19 Acknowledging the lack of a control group in EuroSMR, the 2-year survival rates after mitral valve transcatheter edge-to-edge repair (M-TEER) did not differ between patients with EROAs >30 mm2 (a patient cohort with similarities to COAPT) and patients with EROAs ≤30 mm2.2, 18 A post hoc analysis showed that ‘MITRA-FR type’ patients within the COAPT trial had significant improvements in “patient-centred” outcomes (i.e. quality of life and walk distance) following M-TEER.20 Thus, using EROA, especially when determined by the PISA method, as the parameter to determine the appropriateness of intervention seems flawed. Accordingly, the assessment of MR severity by the heart team should incorporate quantitative parameters such as regurgitation fraction, PISA EROA, Doppler EROA and three-dimensional vena contracta area (Figure 1) for clinical decision making – especially in patients with borderline MR severity. The current ESC/EACTS guidelines also state that M-TEER in SMR patients fulfilling the COAPT entry criteria should be limited to patients who are not eligible for surgery (class IIa/LoE B).1 In the absence of respective RCTs comparing surgery for isolated SMR with guideline-directed medical therapy or other interventional approaches, such a limitation of M-TEER to non-surgical patients seems inappropriate. Indeed, the prognosis of heart failure patients with SMR in COAPT was markedly improved regardless of whether they were low or high surgical risk,2 and no RCT has shown an improved prognosis after surgical treatment of isolated SMR in HFrEF patients. In contrast to the ESC/EACTS guidelines, the 2020 American valvular guideline recommends that patients with SMR fulfilling the COAPT echo criteria should be treated by M-TEER – independently of the surgical risk (class IIa).10 Indeed, based on the superior M-TEER outcomes in COAPT and the lack of comparable RCT data for isolated mitral valve surgery, the evidence suggests that it might be more reasonable to reserve valve surgery only for patients with isolated SMR, who are non-eligible for M-TEER or in whom no significant reduction of MR severity can be achieved. Clearly, determining the appropriate patients for surgery or transcatheter intervention is a nuanced decision-making process. A recent study in fact showed that shared decision-making with a dedicated heart team was associated with a 29% lower mortality than for the general heart team, irrespective of whether an intervention was performed.21 Guidelines should thus emphasize the need to refer all patients with moderate or severe SMR, particularly those with a PISA EROA ≥20 mm2 who have a likelihood of quantitatively severe disease by other methods, to a dedicated heart team22 and the recommendations should be consistent for all surgical risk strata and for all interventions. In summary, although the new 2021 ESC/EACTS valvular guideline has introduced new important recommendations for diagnosing and treating HFrEF patients with severe SMR, the difficulties in the interpretation of the conflicting study results of COAPT and MITRA-FR in addition to the scarce surgical literature on SMR have resulted in guideline changes and recommendations that may limit the ability of a dedicated heart team to make appropriate management decisions, thereby potentially denying patients an appropriate and potentially life-saving intervention. The current viewpoint hopes to emphasize the need for a comprehensive scientifically driven assessment of patients with HFrEF and SMR, which may be refined by new evidence and hopefully adopted widely throughout Europe and beyond. Conflict of interest: C.F. reports grants and personal fees from Abbott Vascular, personal fees from Edwards Lifesciences, outside the submitted work. N.K. reports personal fees from Edwards Lifesciences, Medtronic Inc, Abbott Vascular, outside the submitted work. R.T.H. reports speaker fees from Abbott Structural, Baylis Medical, Edwards Lifesciences, and Philips Healthcare; she has institutional consulting contracts for which she receives no direct compensation with Abbott Structural, Boston Scientific, Edwards Lifesciences, Medtronic and Novartis; she has stock options with Navigate; and is Chief Scientific Officer for the Echocardiography Core Laboratory at the Cardiovascular Research Foundation for multiple industry-sponsored trials, for which she receives no direct industry compensation. H.T. has nothing to disclose. G.W.S. reports personal fees from Cook, TherOx, Vascular Dynamics, Robocath, HeartFlow, Gore, Ablative Solutions, Miracor, Neovasc, V-wave, Abiomed, Shockwave, Vectorious, Cardiomech, Elucid Bio, Occlutech, Infraredx, CorFlow, Apollo Therapeutics, Impulse Dynamics Amgen, other from Applied Therapeutics, Xenter, Biostar family of funds, Aria, Cardiac Success, Cagent, SpectraWave, Orchestra Biomed, personal fees and other from Valfix, Ancora, outside the submitted work; and institutional conflicts: Mount Sinai receives research grants from Abbott, Shockwave, Vascular Dynamics, Phillips, Cardiovascular Systems Inc., Biosense Webster, Bioventrix, V-wave, Phillips. Dr. Stone's daughter is an employee at Medtronic. H.T. reports grants and personal fees from Abbott Vascular and Edwards Lifesciences outside the submitted work. J.H. reports grants and personal fees from Abbott Vascular and Edwards Lifesciences, outside the submitted work.