Chronic Ischemic Mitral Regurgitation: Randomized Trials or Observational Studies?

Comparison of Outcomes following Mitral Valve Repair versus Replacement for Chronic Ischemic Mitral Regurgitation: A Meta-Analysis

The correct treatment of chronic ischemic mitral regurgitation (CIMR) is still not well established. Even if the benefit of revascularization in patients with depressed left ventricular (LV) function is well known, patients with a substantial amount of dysfunctional but viable myocardium may not improve ejection fraction (EF) or prognosis after revascularization alone. Lack of recovery in patients with a considerable amount of viable tissue may be related to increased LV volume due to ventricular remodeling. The onset of secondary mitral regurgitation (MR) is the main factor that may induce progressive LV dilatation, affecting survival and functional status. The vicious circle related to the appearance of MR results in further LV remodeling with subsequent increase in MR grade. Nevertheless, there is still no clear evidence that correction of CIMR could have a clear benefit in terms of survival, even if there are many evidences that CIMR correction improves symptoms of heart failure if compared with patients with same CIMR grade, but uncorrected.[1] [2]

Although there is general agreement to correct severe CIMR, the problem of correction of moderate CIMR has been recently addressed by a randomized study[3] including patients with moderate CIMR who needed coronary artery bypass grafting (CABG). Two groups were randomized, one with CABG alone and one with CABG + mitral valve repair (MVr). Results showed that, after 1 year, adding MVr to CABG was not beneficial with the exception of fewer patients with moderate or severe CIMR at follow-up. However, this study, which could provide answers, added only confusion. Strangely, 35.8% of patients in the CABG-only group and 31.3% in the CABG + MVr group had no previous acute myocardial infarction (AMI), going against the rationale of CIMR correction, that is, revascularization alone is not able to improve CIMR (by definition, related to the consequences of a AMI). This aspect made the results inconsistent. The EF of the patients was on the high side. The mean was 41.2% ± 11.6 in CABG alone and 39.3% ± 10.9 in CABG + MVr, but the standard deviation was such that approximately 50% of the patients had an EF of 40% or more, identifying patients in whom indication to CIMR correction, in prospective, is doubtful: our group demonstrated that correction of less than severe CIMR does not influence 10-year outcome in treated or untreated patients when EF is >40%.[4]

On the other side, in approximately 16% of the patients, EF was >52.8% in CABG alone and >50.2% in CABG + MVr. Evaluating left ventricular end-systolic volume index (LVESVi) (54.8 ± 24.9 in CABG alone group and 59.6 ± 25.7 in CABG + MVr), approximately 16% of the patients had a LVESVi of 33.5 or less and 33.9 or less in CABG alone group and CABG + MVr group, respectively. Practically, this study includes a reasonable number of patients with normal EF and normal or mildly increased LVESVi. Moreover, overall approximately 60% of the patients had no or mild sign of heart failure. It is noteworthy that the diagnosis of ischemic MR was confirmed perioperatively by transesophageal echocardiography on a negative basis “to confirm the absence of a mitral-valve structural abnormality” and not because of the presence of subvalvular abnormalities specific of CIMR, such as chordal tethering and so on. All these considerations cast a shadow on the way the study was built and on its conclusions.

Another unsolved problem is the most appropriate surgical technique. MVr has always been considered the best strategy to correct CIMR and over-reductive annuloplasty was considered to be the gold standard. Even if other techniques, such as chordal cutting and papillary muscle(s) repositioning, have been proposed, they still do not have a precise role in MVr.[5] MV replacement (MVR), in the past considered a bailout technique with high mortality, has been reevaluated and is widely used now. During the past decade, some studies appeared where the optimal indications for repair or replacement (more precisely prosthesis insertion maintaining chords and subvalvular apparatus) were proposed. Among these, our group proposed to use the coaptation depth (CD the ideal point where both mitral leaflets meet at end systole) as a mirror of the underlying displacement of the papillary muscles.[6] A cutoff of 10 mm was considered as a limit for MVr. Even if higher CD was related mostly to higher CIMR grade, even patients with lower CIMR grade could have CD higher than 10 mm, necessitating MVR. Other studies with other indexes appeared later, all proposing surgical indications to repair or replacement.[7] [8] [9] Since then, MVR was used more routinely, and results improved in such a way that a randomized study was proposed to compare the outcome of surgery for severe CIMR.[10] One-year results, as expected, were similar, but with a more durable correction in case of MVR. However, analysis of data showed that 21.4% of the patients in MVr group and 29.6% in MVR group had no previous AMI. Moreover, EF was 42.2% ± 12.0 in MVr group and 40.0% ± 11.0 in MVR group. This means that in around 16% of the patients, EF was >52.4% in MVr group and >51.0% in MVR group, values certainly too high for what is the current clinical practice, questioning if the diagnosis of secondary MR could be correct. Furthermore, analyzing the LVESVi, we found that around 16% of the patients had values <34.9 mL/m² and <38.3 mL/m², respectively. MVr encompassed higher MR recurrence, but indications to repair or replacement did not include any analysis of the grade of chordal tethering which, in a post hoc analysis, was found to be the cause[11] of recurrent MR.

What did we learn from these randomized studies? Not a lot. In both studies, recruitment per center was low, two to three per year. High EF and lack of AMI in a consistent number of patients puzzle about the generalization of the results which surely will follow. Another issue is making the problem more complicated, if possible. In these two randomized studies, the definition of CIMR severity was coherent with the previous guidelines.[12] Moderate secondary MR included effective regurgitant orifice (ERO) 0.20 to 0.39 cm², vena contracta 0.3 to 0.69 cm, and color Doppler jet area from 20 to 40% of the left atrial (LA) area.[3] Severe secondary MR included ERO ≥0.4 cm² or other criteria such as vena contracta, jet area/LA ratio, and others.[10] However, recently the gradation of severity for CIMR changed. What was called moderate (ERO ≥0.2 cm²) now became severe,[13] [14] and moderate CIMR is defined as progressive MR (grade B), with ERO <0.20 cm², regurgitant volume <30 mL, or regurgitant fraction <50%.[14] Some of the previous criteria disappeared, making difficult to draw any valid conclusion.

Another important point remains unexplained. Mean ERO was 0.2 ± 0.1 cm² in both the groups in the study by Smith et al[3] and 0.4 ± 0.17 and 0.39 ± 0.11 cm² (groups MVr and MVR, respectively) in the study by Acker et al.[10] According to the properties of the standard deviation, 50% of the patients had ERO <0.2 cm² in the first study and <0.4 and <0.39 cm² in the second one. Furthermore, 16% of the patients had ERO 0.1 cm² or less,[3] 0.27 cm² or less, and 0.28 cm² or less.[10] How the core laboratory was able to confirm that 93 and 96%, respectively, of the patients had moderate and severe secondary MR remains difficult to understand.

Randomized studies have always been considered the gold standard, as they are able to isolate the effect from the confounding factors and to assure the homogeneity of the samples. However, often we forget that randomized studies have intrinsic limitations. Selection of patients depends on inclusion criteria, which are restrictive, often leading to a small recruitment. In the study on moderate CIMR,[3] a total of 6,676 patients were screened but only 301 (4.5%) were randomized. In the study on severe CIMR,[10] a total of 3,458 patients were screened and 251 (7.3%) randomized. Results, however, are extrapolated to the entire population.

Having lost the opportunity to learn from these two randomized studies, how can we logically move in this complex and not well-established field? We have to start from what we surely know: the presence of secondary MR worsens survival and symptoms in patients who had an AMI. It then seems logical that, if we are able to correct CIMR without increasing in-hospital mortality, patients can have a benefit or, at worse, remain unchanged. Even in the randomized study on moderate CIMR, results in patients who had MVr were similar, but not worse than in patients who had not. Replacing blindly all MV if CIMR is severe is a mistake. Severe CIMR in a patient with ischemic and moderately enlarged LV, with a CD <10 mm, can have a good midterm result after MVr. A dilated LV with moderate CIMR and a CD >10 mm deserves MVR, as, after MVr, MR return is foreseeable in the short run. We think that it is impossible to make precise rules, as patients are different from each other (in both randomized trials if CIMR was symmetric or asymmetric[15] was not taken into account) and MR return of any grade has a different weight in patients with EF of 20% if compared with EF of 45%.

In this scenario, experiences coming from single- or multicenter observational studies, summarized by meta-analyses, are by far more important for decision making than randomized studies, the results of which have been questionable and inconclusive.

• References

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