Who Benefits From the MitraClip?
論文ID: CJ-21-0924
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論文ID: CJ-21-0924
Whether using the MitraClip for patients with severe secondary mitral regurgitation (sMR) reduces rehospitalization due to heart failure (HF) and improves prognosis remains unclear. In the 2018 COAPT trial, a randomized controlled trial (RCT) that compared the MitraClip plus guideline directed medical therapy (GDMT) to GDMT alone for patients with moderate-to-severe or severe sMR, the MitraClip was effective at improving the all-cause death (29.1% in the MitraClip+GDMT group and 46.1% in the GDMT alone group, P<0.001) and HF rehospitalizations at 24 months (35.8% per patient-year in the MitraClip+GDMT group and 67.9% in the GDMT alone group, P<0.001). On the other hand, another RCT, MITRA-FR, failed to demonstrate the same composite endpoint at 24 months (63.8% all-cause death or hospitalization in the MitraClip+GDMT group and 67.1% in the GDMT alone group).1–3 These conflicting results have been debated in various ways. The differences in the severity of sMR and left ventricular (LV) remodeling, procedural outcomes, and the baseline GDMT between these 2 RCTs have been discussed through post-hoc analyses of these studies (Table).4,5 Among these differences, the different grades of MR and of LV remodeling/dysfunction were highlighted, and the concept of proportionate and disproportionate MR was proposed as a framework to distinguish the subset of patients who respond to correction of sMR with the MitraClip. This approach originated from deep understanding of the degree of sMR in connection with LV end-diastolic volume (LVEDV) reported by Grayburn et al in 2014.6 The main idea behind the concept is that the effective regurgitant orifice area (EROA) and regurgitant volume (RVol) values in severe sMR, defined as regurgitant fraction (RF) ≥50%, depend on the LVEDV. If the degree of MR (EROA is utilized as a parameter of the degree of MR) is significantly higher than that presumed from the degree of LV remodeling/dysfunction (LVEDV is used as a parameter of LV remodeling/dysfunction), the condition is defined as disproportionate MR. If EROA is equal to that presumed from the LVEDV, the condition is defined as proportionate MR (Figure).6 Therefore, EROA/LVEDV or RVol/LVEDV is adopted to judge the proportionality of sMR to find the responder to the MitraClip. As shown in the Figure, the ratio in the COAPT study was higher than that in MITRA-FR, suggesting that the MitraClip is beneficial for patients with disproportionate MR. In contrast, if RVol/LVEDV is applied to judge the proportionality of sMR in these studies, the ratio in both studies is <0.2, suggesting proportionate MR (Table). Considering that TTE-derived EROA is often influenced by various echocardiographic parameters, the EROA analysis alone should not be used to interpret these studies.7
| MITRA-FR | COAPT | Japan PMS study | |
|---|---|---|---|
| Severe MR entry criteria | EROA >0.2 cm2 or RV >30 mL/beat |
EROA ≥0.3 cm2 or RV >45 mL/beat |
EROA ≥0.3 cm2 or RV >45 mL/beat |
| EF (%) | 33±7 | 31±9 | 40±11 |
| EROA (cm2) | 0.31±0.10 | 0.41±0.15 | 0.36±0.21 |
| LVEDV (mL) | 252±67 | 192±67 | 176±79 |
| ERO/LVEDV (mm2/mL) | 0.13 | 0.21 | 0.20 |
| RVol/LVEDV | 0.18 | 0.15 | 0.20 |
| GDMT at baseline (device arm) |
On-site heart team decision |
Controlled to maximum dose by central eligibility committee |
On-site heart team decision |
| Diuretics | 99.3% | 89.4% | 87.3% |
| β-blockers | 88.2% | 91.1% | 76.4% |
| ACE/ARB | 73.0% | 67.6% | 62.5% |
| ARNI | 10.0% | 4.3% | 0.0% |
| SGLT2 | 0.0% | 0.0% | 0.0% |
| Acute result: No clip/≥ +3MR | 9% | 5% | 5% |
| 12-month MitraClip ≥ +3MR | 17% | 5% | 10% |
ACE, angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor blocker; ARNI, angiotensin receptor-neprilysin inhibitor; EF, ejection fraction; EROA, effective regurgitant orifice area; GDMT, guideline directed medical therapy; LVEDV, left ventricular end-diastolic volume; MR, mitral regurgitation; RV, right ventricular; RVol, regurgitant volume; SGLT2, sodium-glucose cotransporter-2 (inhibitor).
Concept of proportionate and disproportionate mitral regurgitation (MR). The relationship between effective regurgitant orifice area (EROA) and left ventricular end-diastolic volume (LVEDV) is determined using the Gorlin hydraulic formula (EROA, y-axis; LVEDV, x-axis) with the following assumptions: LV ejection fraction (LVEF) 30%, regurgitant fraction (RF) 50%, ejection time 300 ms, and LV-LA pressure gradients of 64, 100 and 144 mmHg. Upper, middle, and lower solid lines were drawn on the assumption of LV-LA pressure gradients of 64, 100, and 144 mmHg, respectively. Based on this assumption, patients having disproportionate severe secondary MR, proportionate severe secondary MR, and non-severe MR are shown in the orange, white, and green areas, respectively. The black circles represent the mean EROA and LVEDV from the COAPT, MITRA-FR, and Japan Post-Marketing Surveillance studies. The area between the two dotted lines shows the range of proportionate severe MR under the assumption of LVEF 40%. (Reproduced with permission from Grayburn PA, et al.4)
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In this issue of the Journal, Matsumoto et al8 demonstrate the safety and efficacy of the MitraClip by analyzing the Japan Post-Marketing Surveillance study (Japan PMS study). They report a very low single-leaflet device attachment rate at 30 days and a high acute procedural success rate at discharge, irrespective of MR etiology and the operator’s expertise. They also show a sustainable reduction in the MR degree and a reduction in the New York Heart Association functional class of HF throughout the 1-year follow-up. This is the first publication to show the safety and efficacy of the MitraClip in Japanese clinical practice.
However, to determine the effect of the MitraClip for sMR on death and rehospitalization, the data in this study must be cautiously interpreted in comparison with that of the COAPT and MITRA-FR trials. First, as the authors note in the limitations, a left ventricular ejection fraction (LVEF) <30% was excluded; therefore, the mean LVEF was higher in this study than in the MITRA-FR and COAPT trials (mean LVEF 40% vs. 33% vs. 31%, respectively). The higher LVEF in this study should be considered when considering the proportionality of sMR. The EROA/LVEDV ratio (mm2/mL) in this study was approximately 0.20 (Table), suggesting that the patients enrolled in this study were likely to have disproportionate MR, as in the COAPT trial (Figure, black circle).8 However, the range of proportionate severe MR (Figure, white area) was generated by calculating the EROA by adopting the Gorlin hydraulic formula using the assumptions described in the figure legend. When using the same assumptions, except for changing the LVEF to 40%, the range of severe proportionate MR shifts upwards (Figure, black dotted lines). Moreover, when the volume analysis, RVol/LVEDV, was calculated on the assumption of RF 50%, it was 0.20 in the Japan PMS study, similar to MITRA-FR. Considering these facts, the better 1-year mortality rate and lower rehospitalization rate might be explained by the relatively preserved LVEF rather than by disproportionate MR. Second, the GDMT was not strictly controlled in this study. The usage of β-blockers at baseline was relatively low, even though β-blockers in a well-tolerated dose range are the key GDMT to promote LV reverse remodeling and MR reduction. The lower usage rate of β-blockers makes it more difficult to compare and interpret the results of this study with those of other studies. Recently, it has been demonstrated that angiotensin receptor-neprilysin inhibitors (ARNI) and sodium-glucose cotransporter-2 (SGLT2) inhibitors improve prognosis and decrease HF rehospitalization rates in patients with HF with reduced EF (EF ≤40%), and these medications are listed in the current guidelines as contemporary GDMT.9 The effect of these new HF medications on sMR should be further investigated.
In conclusion, this is the first publication showing that transcatheter mitral valve repair with the MitraClip has commenced safely and effectively in Japanese clinical practice. Further studies that incorporate the concept of proportionate/disproportionate MR and contemporary GDMT should be conducted to establish the true response to using the MitraClip.
I.M. received scholarship funds from Edwards Lifesciences Japan, Boston Scientific Japan, and Abbott Medical Japan.
