Long-term fate of moderate aortic regurgitation left untreated at the time of mitral valve surgery

Abstract

 

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OBJECTIVES

The appropriateness of moderate aortic regurgitation treatment during mitral valve (MV) surgery remains unclear. The goal of this study was to evaluate the immediate and long-term outcomes of patients with moderate aortic regurgitation at the time of MV surgery.

METHODS

We included 183 patients admitted to our institution for elective treatment of MV disease between 2004 and 2018, in whom moderate aortic regurgitation was diagnosed during preoperative evaluation. One hundred and twenty-two patients underwent isolated MV surgery (study group) whereas 61 patients underwent concomitant MV surgery and aortic valve replacement (control group).

RESULTS

One death (0.8%) occurred in the study group, and 3 deaths (4.8%) occurred in the control group (P = 0.52). The rate of the most common postoperative complication was similar between the 2 groups. At 12 years, the cumulative incidence function of cardiac death, with non-cardiac death as a competing risk, was 4.7 ± 2.8% in the study group; no cardiac deaths were observed in the control group (P = 0.078). At 6 and 12 years, in the study group, the cumulative incidence function of aortic valve reintervention, with death as a competing risk, was 2.5 ± 1.85% and 19 ± 7.1%, respectively.

CONCLUSIONS

The appropriate management of moderate aortic regurgitation at the time of MV surgery deserves a careful evaluation by balancing the reintervention rate with the age, the operative risk and the life expectancy of the patient. Our findings suggest that a patient-tailored approach is the key to achieving the best clinical outcome for each individual patient.

INTRODUCTION

Multivalvular heart disease is a highly prevalent clinical condition that comprises 14.6% of the patients undergoing valvular surgery [1]. Specifically, aortic valve regurgitation (AR) can be present in a considerable proportion of patients undergoing mitral valve (MV) surgery. In the Society of Thoracic Surgeons database, concomitant aortic and mitral surgery accounted for 57.8% of the total multivalvular procedures with an unadjusted mortality rate of 10.7% [2].

When both the aortic and MVs exhibit severe disease, concomitant valve surgery is well-accepted by the surgical community and supported by current guidelines [3–4]. On the other hand, when the aortic valve (AV) shows only moderate regurgitation, which would not be surgically treated if singly present, the appropriate management of the AV pathology at the time of MV surgery is still under debate.

The American College of Cardiology guidelines state that aortic valve replacement (AVR) is reasonable (class IIa) in patients with moderate AR (stage B) while undergoing surgery on the ascending aorta, a coronary artery bypass graft or MV surgery (level of evidence: C) [3]. Conversely, the latest European Society of Cardiology guidelines on valvular heart disease [4] define as controversial the decision to treat the AV in patients with moderate AR who undergo MV surgery, considering the slow progression of this disease [5–8]. In this group of patients, they advocate a heart team approach that will take into account the aetiology of AR, the life expectancy of the patient, the operative risk and other clinical factors.

This disagreement may lead to uncertainty about how patients with less than severe AR should be managed during MV surgery, especially considering the burden of double-valve surgical procedures.

The goal of this study was to evaluate the immediate and long-term outcomes, including the need for a new procedure on the AV, in patients with moderate AR at the time of MV surgery.

MATERIALS AND METHODS

Ethical statement

Our institutional ethics committee approved this retrospective study and waived individual consent from the patients (approval number 53/INT/2021).

Study population

We studied 183 patients admitted to the San Raffaele University Hospital in Milan for elective treatment of MV disease between 2004 and 2018, in whom moderate AR was present. One hundred and twenty-two patients underwent MV surgery alone and represent the study group (AVR neglected). These patients were compared with 61 patients who underwent concomitant MV surgery and AVR for moderate AR, who represent the control group (AVR performed).

The diagnosis of moderate AR was made during the preoperative transoesophageal echocardiography examination following a multiparametric approach. In the first years of our experience, the grading of the severity of AR was based mostly on structural and qualitative Doppler parameters (e.g. jet width in the left ventricular outflow tract using colour flow, flow convergence, jet density, jet deceleration time and diastolic flow reversal in the descending aorta). Recently, according to the latest European Association of Cardiovascular Imaging and the American Society of Echocardiography guidelines [9–10], semi-quantitative and quantitative parameters such as vena contracta width, regurgitant fraction and effective regurgitant orifice area, have been used to ensure the most accurate diagnosis.

The decision to perform or avoid AVR was made by the operating surgeon, or, in the last 10 years, by the heart team, after considering various factors. First, attention was given to the echocardiographic characteristics of the diseased AV, such as fibrotic and hypomobile leaflets or calcifications. The patient risk profile and overall patient frailty were also assessed, considering both cardiac risk and the burden of concomitant non-cardiac pathologies. Furthermore, patient life expectancy played an important role in the decision-making process. Given the slow progression rate of AR [5–8], the heart team generally agreed on the practice of not performing AVR in patients with an estimated residual life span of <10 years compared with the life expectancy of the general population.

To minimize the confounding factors, patients with the following conditions were not included: any degree of aortic stenosis, severe dilatation of the left ventricle (end-diastolic diameter ≥ 65 mm), left ventricular ejection fraction (LVEF) <35%, urgent or emergency operations, infective endocarditis, history of mediastinal radiation therapy, ascending aorta aneurysm, planned aortic root surgery and previous AV repair or ascending aorta surgery. The preoperative, intraoperative and postoperative data were reviewed retrospectively from our hospital database.

Follow-up

All patients underwent transthoracic echocardiography right before hospital discharge. Follow-up data were collected from our institutional outpatient clinic visits or by means of telephone interviews with the patients and the referring cardiologists. We focused on survival, causes of death, incidence of treatment of the AV disease either with surgery or by the percutaneous approach (transcatheter AV implantation), progression of the AR, clinical status and symptoms and echocardiographic data. If the patient was rehospitalized, a copy of the discharge letter was obtained in order to understand the cause of the hospitalization. All the patients were asked to send a copy of their last echocardiographic scan if it was performed outside our hospital. We conducted follow-up examinations in the same period for all patients, irrespective of the time since the operation occurred (common closing date method).

The cause of death was determined from death certificates or from information from the physician who was caring for the patient at that time. Follow-up was 97% complete. The median follow-up time was 6.9 years [4.6; 11.6] with a maximum follow-up time of 16.2 years.

Statistical analyses

This retrospective study was conducted without a pre-specified primary end-point and without adjustment for multiple testing, but as an analysis that was exploratory in nature. Categorical data were described as absolute and percentage (%) frequency values and compared with the χ² or the Fisher exact tests, as appropriate. The Shapiro–Wilk test was used to assess whether the distribution was normal or not-normal. Continuous normal distributed variables were expressed as mean ± standard deviation and compared with results from the unpaired t-test, whereas continuous not-normal variables were reported as median and [25th percentile; 75th percentile] compared with the Mann–Whitney test.

Kaplan–Meier estimates were used to analyse long-term survival and presented as mean ± standard error. Predictors associated with death were assessed with Cox proportional hazard models.

All the covariates of medical interest with a P-value <0.1 at the univariate analysis were added to the multivariable model with stepwise selection. The variable of interest (comparison between the 2 groups) was forced into the multivariable model. To assess the proportional hazards assumption of the Cox model, a global test and Schoenfeld residuals were used.

The cumulative incidence function was computed for cardiac death with non-cardiac death as a competing risk and for reintervention on the AV with death as a competing risk. The Fine–Gray model for competing risk analysis was used to identify predictors of cardiac death with non-cardiac death as a competing risk and for reoperation on the AV with death as a competing risk. Covariates with a P-value <0.1 at univariate analysis were included in the multivariable model.

The Pepe-Mori non-parametric test was used to assess differences between the 2 groups.

A P-value of <0.05 was used to define statistical significance. All the analyses were performed with Stata software version 15 (StataCorp LP, College Station, TX, USA).

RESULTS

The preoperative clinical characteristics of the patients of both groups did not show significant statistical differences (Table 1). The median age was 67 years [interquartile range (IQR) 61–75] in the study group and 64.5 years (IQR 55–70) in the control group (P = 0.35). Fifty patients (41%) in the study group and 24 patients (38.7%) in the control group were in New York Heart Association functional class III or IV (P = 0.73). The median LVEF was 60% in both groups, and the median left ventricular end-diastolic diameter was 54 mm (IQR 49–58) in the study group and 55.5 mm (IQR 49–59) in the control group (P = 0.50).

All patients in both groups were affected by concomitant moderate AR. One hundred and fourteen patients (93.5%) in the study group and 57 patients (91.9%) in the control group were affected by moderate-to-severe or severe MR (P = 0.78). In the study group, 40 patients (32.8%) had MV stenosis of any degree, whereas in the control group it was observed in 28 patients (45.2%) (P = 0.10). Rheumatic disease was the cause of valvular dysfunction in 38 patients (31.1%) in the study group and in 27 patients (43.5%) in the control group (P = 0.096). More-than-mild tricuspid valve regurgitation was present in 71 patients (58.2%) in the study group and in 29 patients (46.7%) in the control group (P = 0.22). Twelve patients (9.8%) in the study group and 9 patients (14.5%) in the control group were redo cases (P = 0.35).

MV replacement was performed in 69 patients (56.6%) from the study group and 38 patients (61.3%) from the control group (P = 0.54). A mechanical prosthesis was implanted in the mitral position in 33 patients (48%) from the study group and in 26 patients (68%) from the control group (P = 0.034). Among patients from the control group, an aortic mechanical prosthesis was employed in 49% (n = 30) of the cases. Seventy-eight patients (64%) in the study group and 36 (59%) in the control group underwent concomitant procedures (P = 0.52). Operative characteristics, including the details of the adjunctive procedures, are shown in Table 2.

In-hospital outcomes

There was 1 in-hospital death (0.8%) in the study group, whereas 3 patients (4.8%) in the control group died before discharge; this difference did not reach statistical significance (P = 0.11). The most common postoperative complications are compared in Table 3.

Fourteen patients (11.5%) in the study group and 10 patients (16.1%) in the control group experienced low cardiac output syndrome requiring prolonged inotropic support (P = 0.32). Forty-three patients (35.2%) in the study group and 29 (46.8%) in the control group developed atrial fibrillation during postoperative hospitalization (P = 0.080), whereas pacemaker implants were necessary in 4 patients (3.3%) in the study group and in 1 patient (1.6%) in the control group (P = 0.99). The median length of postoperative hospitalization was 6 days in both groups.

Follow-up outcomes

At 12 years, 8 patients in the study group and 2 in the control group had died. Among the patients in the study group, 3 deaths were cardiac-related (1 acute exacerbation of chronic heart failure in the context of severely depressed LV function; 2 out-of-hospital cases of sudden cardiac arrest), whereas none in the control group were cardiac related. The causes of death of the other patients were cancer (3 patients), internal haemorrhage (1 patient), septic shock (1 patient), head trauma (1 patient) and bronchopneumonia (1 patient). The overall 12-year survival (Fig. 1) was similar between the 2 groups (89 ± 3.90% in the study group and 93.7 ± 4.58% in the control group; P = 0.41). At multivariable analysis with the Cox model, age was the only factor influencing long-term survival [hazard ratio = 1.29; 95% CI (1.13–1.47); P < 0.001].

At 12 years, the cumulative incidence function of cardiac death, with non-cardiac death as a competing risk, was 4.7 ± 2.8% in the study group, whereas no events were registered in the control group (Fig. 2). However, this difference did not reach statistical significance (P = 0.078).

At multivariable analysis with the Fine–Gray model, lower LVEF (subdistribution hazard ratio =0.81; P = 0.004) and increased systolic pulmonary artery pressure (subdistribution hazard ratio =1.08; P = 0.011) were the only predictors of cardiac death at follow-up (Table 4).

During follow-up, 7 patients in the study group (6.3%) had progression of AV disease to severe AR and consequently were treated. Five patients underwent AVR and 2 patients underwent transcatheter AV implantation. On the other hand, no reoperation was registered in the control group.

At 6 and 12 years, in the study group, the cumulative incidence function of AV reintervention, with death as a competing risk, was 2.5 ± 1.85% and 19 ± 7.1%, respectively (Fig. 3). The difference between the 2 groups was statistically significant (P = 0.006). Multivariable analysis with the Fine–Gray model, however, failed to identify predictors of reintervention at follow-up (Table 5).

At the last follow-up, only 3 patients in the study group (2.9%) and 2 patients (4%) in the control group were in New York Heart Association functional class III/IV. The median LVEF was 58% [55–60] in the study group and 56% [51–60] in the control group (P = 0.057); the median left ventricular end-diastolic diameter was 49 mm [47–52] in the study group and 48 mm [47–51.5] in the control group (P = 0.55). In the study group, when we excluded the 7 patients in whom AV disease was treated, all the remaining patients had moderate or less AR.

DISCUSSION

In patients affected by severe MV disease, the concomitant involvement of the AV is a fairly frequent clinical condition [11], with rheumatic heart valve disease considered the predominant cause for a long time [12]. Even though the incidence of rheumatic fever has declined sharply over the past 50 years [13], a concomitant decrease in the prevalence of multivalvular disease has not been observed [14]. This finding is mainly due to the growth of degenerative valve disease in developed countries as a result of the ageing of the population [13, 15].

When the MV is severely diseased, the pathophysiological effect of concomitant AR can be extremely variable depending on the type of the MV disorder. The association of mitral stenosis and aortic regurgitation results in inverse loading conditions on the left ventricle with both left ventricular end-diastolic and end-systolic volume lower than in case of isolated AR. On the other hand, the association of MR and AR is characterized by severe left ventricular volume overload, which may cause a severe left ventricular dilatation with eccentric hypertrophic remodelling. Usually, this condition is poorly tolerated by the patients [16].

Both these associations present some caveats in the echocardiographic evaluation, principally due to the strict interdependence of the blood flow throughout the diseased valves [11, 16]. In this scenario, a multiparametric evaluation of the AR is key to determining if the AV needs to be treated.

AVR is by far the most commonly performed surgical treatment for AR [17–20]. In the context of moderate AR, whether prophylactic replacement of the AV at the time of MV surgery has beneficial effects over time is still unclear. As proof of this observation, the latest European and American guidelines [3–4] provide different recommendations for treatment of moderate AR at the time of MV surgery.

Indeed, the association of AVR during MV surgery is burdened by an increased in-hospital mortality [2], which was also found in this study, although the difference did not reach statistical significance. This well-established evidence imposes the need for a careful evaluation before exposing the patient to the potential immediate and long-term risks of the unnecessary replacement of the AV. The alternative is to follow these patients closely, considering that some of them may require a procedure on the AV in the future. In this scenario, determining the clinical impact and evolution of moderate AR left untreated at the time of the first MV surgery becomes crucial.

Several reports addressed the issue of the progression of mild AV disease in patients with rheumatic valve pathology. Vaturi et al. [21] analysed patients with mild AR at the time of MV surgery and reported an extremely slow progression rate of the AR at follow-up. Similarly, Hwang et al. [22] showed a rare progression of mild AR of up to 20 years after MV surgery. Moreover, the group of patients who underwent concomitant AV surgery, either repair or replacement, did not have a better outcome in terms of freedom from AV-related events.

One of the main findings of our study is that, at long-term follow-up, the overall survival and rate of cardiac death were comparable if moderate AR was left untreated or was treated during the first intervention on the MV. Likewise, Ha et al. [23] showed an excellent survival rate at 12-years of follow-up among patients with mild-to-moderate AV disease left untreated at the time of MR surgery. Both those findings presumably reflect the fact that moderate AR per se does not have a substantial impact on long-term survival. In our population, the cumulative incidence of AV reintervention was 2.5 ± 1.85% at the 6-year and 19 ± 7.1% at the 12-year follow-up. We did not identify predictors of reintervention, probably due to the limited number of events. At follow-up, all the procedures on the AV (either surgical or percutaneous) were performed because moderate AR had progressed to severe AR. Apart from those cases, the remaining patients showed stable moderate AR at the last follow-up and were in excellent clinical condition. Our observed progression rate to severe AR is in line with the rate reported by Weisemberg et al. at the midterm follow-up. They showed an average progression rate of 1.9% per year but, in contrast to our findings, only 3 of their patients were referred for AVR during the follow-up period (yearly rate 0.3%). Based on our findings and on those of previous published studies, when to perform concomitant AVR for moderate AR during MV surgery must be properly thought-out.

In the decision-making process, 2 main concerns have to be taken into consideration and linked to the characteristics of the individual patient: (i) the early and long-term risks of adjunctive AVR when not clearly needed; and (ii) the potential need for a future procedure on the AV and its risk.

Concomitant AVR for moderate AR may be neglected at the time of MV surgery in older patients who are at increased surgical risk and/or have a reduced life expectancy. Under these circumstances, the drawbacks of the double-valve surgery are most likely to exceed the risk of progression of the AR over time. In addition, one must also consider that the technical progress related to modern percutaneous devices will enable the treatment of pure AR in the near future [24].

Conversely, the opportunity to perform a prophylactic AVR at time of the first MV operation in younger patients should be seriously considered. The aetiology and the types of lesions of both the mitral and AVs should play a central role in guiding this choice. In patients with degenerative disease, in whom there is a high likelihood of a successful and durable MV repair, if the AV is suitable for a reconstructive procedure, it should probably be carried out [18], though the adoption of repair AV surgery is still far from being widespread.

On the other hand, whenever AVR seems to be the only option for treatment (e.g. rheumatic valve disease, complex valvular lesions, calcifications), the clinical scenario should be carefully discussed with the patient. Indeed, the choice of a biological or a mechanical prosthesis and the increased risk of double-valve surgery should be carefully balanced with the risk of the progression of untreated AR. From this perspective, the contribution from our series is that in a middle-aged population the need for AV reintervention for untreated moderate AR will approach 20% at 12 years, which should be carefully considered.

CONCLUSIONS

Whether to treat moderate AR during MV surgery is still the object of an ongoing debate. Certainly, an adjunctive procedure on the AV increases the operative risk, thereby imposing a focused analysis before proceeding. However, as shown by our study, the risk of progression of moderate AR is not negligible and should be taken into consideration. Definitive recommendations, therefore, cannot be provided. A patient-tailored approach, including operative risk, age and life expectancy, is mandatory to try to achieve the best clinical outcome for each patient. Definitively, randomized studies with a longer follow-up are needed to better define the progression of moderate AR over time.

Limitations

First, our study is retrospective in nature and therefore subject to the inherent weaknesses of a retrospective analysis (influence of confounding factors, selection and information bias, missed data). Second, in the first years of our experience, the final decision to treat moderate AR was made exclusively by the operating surgeon. Further research is needed to develop a solid protocol to help the surgeon decide when a concomitant AVR during MV surgery is really necessary. Finally, echocardiographic follow-up was partially performed outside our hospital; this fact could have influenced AR quantification but not the rate of AV reintervention.

Presented at the 34th Annual Meeting of the European Association for Cardio-Thoracic Surgery, Barcelona, Spain, 8–10 October 2020.

ACKNOWLEDGEMENTS

We thank the Alfieri Heart Foundation for supporting data collection and analysis of this research.

Conflict of interest: none declared.

Author contributions

Benedetto Del Forno: Conceptualization; Data curation; Methodology; Writing—original Draft. Guido Ascione: Data curation; Formal analysis; Visualization; Writing—original draft. Arturo Bisogno: Data curation; Formal analysis; Visualization; Writing—original draft. Davide Carino: Visualization. Elisabetta Lapenna: Visualization. Alessandro Verzini: Visualization. Marta Bargagna: Visualization. Stefania Ruggeri: Data curation; Formal analysis; Investigation. Davide Schiavi: Data curation; Software. Roberta Meneghin: Data curation; Software. Eustachio Agricola: Visualization. Fabrizio Monaco: Visualization. Ottavio Alfieri: Supervision. Alessandro Castiglioni: Supervision. Michele De Bonis: Project administration; Supervision; Validation; Writing—review & editing.

Reviewer information

European Journal of Cardio-Thoracic Surgery thanks Graham J. Cooper, Patrick Klein, Kazumasa Orihashi and the other anonymous reviewer(s) for their contribution to the peer review process of this article.

REFERENCES

ABBREVIATIONS

 
• AR

  Aortic valve regurgitation

 
• AV

  Aortic valve

 
• AVR

  Aortic valve replacement

 
• IQR

  Interquartile range

 
• LVEF

  Left ventricular ejection fraction

 
• MV

  Mitral valve