Surgical treatment of hypertrophic obstructive cardiomyopathy in relatively elderly patients: Short- and long-term outcomes

Abstract

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OBJECTIVES

Our goal was to assess the short- and long-term outcomes of surgical treatment for hypertrophic obstructive cardiomyopathy in patients ≥65 years of age compared to patients < 65 years of age.

METHODS

Sixty-four patients aged ≥65 years, surgically treated for symptomatic hypertrophic obstructive cardiomyopathy, were compared to a control group of 125 patients <65 years.

RESULTS

Patients aged ≥65 years were less frequently male (36% vs 68%, P < 0.001) and had higher EuroSCORE II scores [1.4 (1.1–2.2) vs 0.8 (0.7–1.2), P < 0.001], lower risk of sudden death, higher pulmonary artery pressure [40 (30–50) vs 30 (30–43), P = 0.04) and more mitral annulus calcifications (44% vs 14%, P < 0.001) compared to younger patients.

Hospital death was 1%, with no difference between the 2 groups (1.5% vs 0.8%, P = 0.9).

Patients aged ≥65 years had more concomitant coronary bypass grafting (12% vs 5%, P = 0.05) and a higher incidence of blood transfusions (50% vs 17%, P < 0.001) and postoperative atrial fibrillation (19% vs 8%, P = 0.02).

Follow-up was 98% complete [median 8.3 (5.3–12.8) years]. The 13-year survival in the group aged ≥65 was 54 (SD: 9) % vs 83 (SD: 5) % in the control group (P < 0.001), but it was comparable to that expected in the age-sex matched general national population.

At 13 years, the cumulative incidence function of cardiac death in the elderly group was 19 (SD: 7)%, mostly unrelated to hypertrophic cardiomyopathy causes.

At the last follow-up, 90% of patients were in New York Heart Association functional class I-II and 68% were in sinus rhythm.

CONCLUSIONS

Selected elderly symptomatic patients with hypertrophic obstructive cardiomyopathy can benefit from surgery, with low hospital mortality and morbidity, relief of symptoms and late survival comparable to that expected in the age-sex matched general population.

INTRODUCTION

Surgery is the gold standard for the treatment of severe symptomatic refractory hypertrophic obstructive cardiomyopathy (HOCM) because it relieves symptoms related to left ventricular outflow tract (LVOT) obstruction and affects quality of life and survival at the long-term follow-up [1].

However, it has been suggested that surgical candidacy decreases with increasing age due to the higher surgical risk related to the fragility of tissues and the attendant comorbidities [2–3]. Therefore, the percutaneous alternative has historically been the most favoured in elderly patients [4–5].

Few data are available on the outcome of the surgical treatment of this specific subgroup [6–8].

The goal of this study was to assess the short- and long-term outcomes of surgical treatment for HOCM in patients ≥ 65 years of age compared to those <65 years of age.

MATERIALS AND METHODS

Ethical statement

The San Raffaele Hospital Institutional Ethic Committee approved this study on 16 September 2020 (id : 154/INT/2020) and waived individual consent for this retrospective analysis.

Study population

From 1999 to 2019, a total of 64 consecutive patients aged ≥65 years were surgically treated for symptomatic HOCM at our institution and were compared to a control group of 125 patients with HOCM aged <65 years who were operated on in the same time frame (Fig. 1). The cut-off of 65 years was chosen because in the majority of the articles in the literature, septal myectomy has historically been considered the most appropriate approach in patients <65 years of age.

Left ventricular hypertrophy was assessed according to the current guidelines [3], and the diagnosis of HOCM was based on echocardiographic evidence of a hypertrophied, non-dilated left ventricle in the absence of any other primary cardiac or systemic aetiology [3]. Therefore, for the purpose of this study, we excluded patients with a previous septal myectomy or a prior mitral valve (MV) operation including the MitraClip procedure and those who underwent concomitant aortic valve replacement or subaortic membrane removal. On the other hand, we included patients with hypertension when the degree and duration of hypertension were not deemed significant enough to result in the amount of left ventricular hypertrophy seen in these patients [9].

Surgery was indicated when a resting or provoked (with Valsalva or exercise) LVOT peak instantaneous gradient of ≥50 mmHg was detected [3]. The severity and mechanism of mitral regurgitation were established by transthoracic and transoesophageal echocardiography using multiple criteria. The degree of mitral regurgitation was measured by Doppler colour flow imaging and defined as mild (1+/4+), moderate (2+/4+), moderate-to-severe (3+/4+) and severe (4+/4+).

Because there is no specific surgical risk calculator for septal myectomy, we used the EuroSCORE II and the Society of Thoracic Surgeons (STS) Adult Cardiac Surgery Risk Calculator for Aortic Valve Replacement in case of isolated septal myectomy and for MV repair or MV replacement (MVR) in case of concomitant MV surgery, with and without associated coronary artery bypass grafts, as appropriate.

The primary outcomes of the study were survival and the cumulative incidence function (CIF) of cardiac death. Secondary outcomes included postoperative complications, reoperation, clinical functional status and the LVOT gradient at the long-term follow-up.

For the purpose of this study, the preoperative, intraoperative, postoperative and follow-up data were prospectively entered into a dedicated database and reviewed retrospectively.

Follow-up

All patients underwent transthoracic echocardiography before discharge. Clinical and echocardiographic follow-ups were performed mainly in our institutional outpatient clinic. The cause of death was determined from death certificates or information from the physician who was caring for the patient at that time.

Statistical analysis

Statistical analyses were performed using Stata software version 16 (StataCorp LP, College Station, TX, USA). Categorical data were presented as number and percentage (%) values and compared using the χ² test or the Fisher exact test, as appropriate. Normal distribution of continuous variables was assessed by the Kolmogorov-Smirnov test. Continuous normal distributed variables were reported as mean (standard deviation) (SD) and compared with results from the Student t-test, whereas continuous not-normal data were expressed as median [25th percentile–75th percentile] and compared with results from the Mann–Whitney U test. Baseline and last follow-up measurements of continuous, normally distributed data were compared using the paired t-test whereas the not normally distributed data were compared using the Wilcoxon signed-rank test for related samples. Missing data were handled by their exclusion.

To evaluate the observed and expected outcomes predicted by the STS score and the EuroSCORE II, variables were compared using 1-sample comparisons of the proportions test using the average predicted risk in the sample as the hypothesized risk with a type I error of 0.05.

Kaplan–Meier estimates were used for analysing long-term survival, and comparison to the general age- and sex-matched national population was performed. The log-rank test was used to compare survival among groups. Predictors associated with death were assessed in the multivariable Cox proportional hazard model. The variables were chosen using the stepwise selection, a combination of forwards and backwards selection. In the first phase, we started with the absence of predictors, then sequentially we added the most contributive predictors. In the second phase, after adding each new variable, we removed any variables that no longer provided a significant improvement in the model fit.

Mortality rates were calculated for each individual and combined to form an expected summary curve for the general population. Expected survival was calculated according to age- and gender-specific mortality rates obtained from the Istituto Nazionale di Statistica (ISTAT). Expected and observed mortality rates were compared using the one-sample log-rank test, which provides a standardized mortality ratio and the 95% confidence interval (CI).

CIF were computed for time to cardiac death, with non-cardiac death as the competing risk and for time to reoperation with death as the competing risk. For actuarial estimates, data were presented as failure probability ± standard error. Equality across groups was tested with the Pepe and Mori test. Fine and Gray models were adopted for the assessment of factors associated with cardiac death (with non-cardiac death as the competing risk). All variables with a P-value <0.1 at univariable analysis were retained in the multivariable model. A P-value <0.05 was used to define statistical significance.

RESULTS

Patient characteristics

The preoperative clinical and echocardiographic characteristics of the patients are listed in Table 1. At hospital admission, half of the patients were in New York Heart Association (NYHA) functional class III or IV, and 11% of them had been hospitalized due to pulmonary oedema. The peak LVOT gradient at rest was 72 [50–96] mmHg whereas the maximum intraventricular gradient was provoked in 94 (50%) patients and reached 101(SD: 37) mmHg with no difference between the 2 groups (P = 0.7).

Patients over the age of 65 had a median age of 71 years, were less frequently male (36% vs 68%, P < 0.001) and had higher STS/EuroSCORE II [1(0.8–1.7)/1.4 (1.1–2.2) vs 0.5 (0.4–0.7)/0.8 (0.7–1.2), P < 0.001] values, lower European Society of Cardiology hypertrophic cardiomyopathy (HCM) risk-sudden cardiac death [2.3 (1.8–3.3) vs 3.4 (2.3–4.2), P = 0.003] scores, higher systolic pulmonary artery pressure (SPAP) [40 (30–50) vs 30 (30–43), P = 0.04] and more mitral annulus calcifications (44% vs 14%, P < 0.001) compared to younger patients.

Procedural data

All patients were operated on through a conventional median sternotomy. Standard cardiopulmonary bypass (CPB) with the patient on moderate hypothermia and cardioplegic arrest were applied. To correct outflow obstruction, 137 (72%) patients underwent transaortic septal myectomy alone, which was combined with a transapical approach in 9 cases. In 52 (28%) patients, associated MV surgery was performed (Table 2). The mitral valve was repaired whenever indicated, using the edge-to-edge technique, as previously described [10]. In the case of MV replacement, low profile mechanical (19 patients) or biological (5 patients) prostheses were used.

After weaning from CPB and under optimal haemodynamic and filling conditions, transoesophageal echocardiography was routinely performed to assess the LVOT and the final result of the repair/replacement, as appropriate.

As listed in Table 2, concomitant procedures were performed in 62 patients (33%). Patients aged ≥65 years had more concomitant CABG (12% vs 5%, P = 0.05). Median CPB and cross-clamp times were 60 [45–7] min and 40 [30–58] min, respectively, with no difference between groups (P = 0.7).

Clinical hospital outcomes

The overall hospital mortality was 1% (2/189 patients) with no difference between the 2 age groups (1.5% vs 0.8%, P = 0.9) (Table 2). The patient who died in the elderly group had preoperative refractory heart failure, and the cause of death was low cardiac output syndrome followed by multiorgan failure. The other patient, who was 62 years old, died of neurological complications.

There was no difference between observed mortality and that predicted by the STS or EuroSCORE II (P = 0.4, P = 0.9).

Postoperative complications are reported in Table 2. In particular, patients aged ≥65years had a higher incidence of blood transfusions (50% vs 17%, P < 0.001) and postoperative atrial fibrillation (AF) (19% vs 8%, P = 0.02). No significant differences were observed in terms of pacemaker implants (6% vs 4%, P = 0.3) between the 2 groups. There were no cases in either group of perioperative acute myocardial infarction or respiratory failure requiring tracheostomy. Three patients had postoperative ventral septal defect: 1 patient was treated with the Amplatzer septal occluder device a few days after the operation, whereas the other 2 cases did not need treatment because the shunt was deemed not to be haemodynamically significant.

At hospital discharge, a significant reduction in the resting intraventricular gradient [median 10 (0–22) mmHg] compared to baseline (P < 0.001) was documented in all patients.

Follow-up

Follow-up was 98% complete, median 8 [5.3–12.8] years. The follow-up index was 0.94 (SD: 0.15).

Long-term survival and cardiac death

During the follow-up period, 41 patients died (41/184, 22%), 25 in the elderly group (25/62, 40%) and 16 in the control group (16/122, 13%). The 13-year survival time was 54 (SD: 8.8)%, 95% CI [35.57–69.49] in the group aged ≥65 compared to 83 (SD: 5)%, 95% CI [70.62–90.86] in the control group (P < 0.001) (Fig. 2A), but it was comparable to that expected in the age- and sex-matched general national population (P = 0.4) (Fig. 2B). On multivariable Cox proportional-hazard regression, only age ≥ 65 was identified as an independent predictor of death [hazard ratio (HR)  = 2.44, 95% CI (1.10–5.42), P = 0.028]. In particular, among the variables considered in the univariable Cox proportional hazard regression, the presence of anomalous muscle bundles, the associated transapical myectomy, MV repair and MV replacement were not identified as predictors of death (HR = 1.83, 95% CI 0.64–5.22, P = 0.256; HR = 0.79, 95% CI 0.11–5.82, P = 0.819; HR = 1.50, 95% CI 0.57–3.95, P = 0.411; and HR = 1.18, 95% CI 0.57–2.44, P = 0.659, respectively). Moreover, survival in the subgroup of patients undergoing concomitant mitral valve surgery was not significantly different from that in the myectomy alone group, in both age groups (the log-rank P-value was 0.501 in the group aged <65 years and the log-rank P-value was 0.571 in the group aged ≥65).

In the group aged ≥65, late deaths occurred at a median age of 82 [76–86] years. The causes of death are reported in Table 3.

At 13 years, the CIF of cardiac death, with non-cardiac death as the competing risk, was 19 (SD: 7)%, 95% CI [8.09–33.93] in the group aged ≥65, compared to 2 (SD: 1)%, 95% CI [0.33–5.41] in the control group, P = 0.07 (Fig. 3). Fine and Gray models identified female sex and preoperative history of AF as factors associated with cardiac death (HR = 13.16, 95% CI 1.89–91.33, P = 0.009; HR = 4.53, 95% CI 1.61–12.68, P = 0.004, respectively) at multivariable analysis (Table 4).

However, HOCM-related deaths occurred only in 6 patients (6/184, 3.3%), representing 15% of all deaths (6/41) (Table 3).

Reoperation

During follow-up, 6 patients (6/184, 3.3%) in the whole series underwent reoperation. One 45-year-old patient underwent MV repair 1 month after surgery because of severe mitral regurgitation related to flail of the A1 scallop of the mitral valve. Two patients who had had previous MV repair and myectomy required MV replacement due to persistent LVOT obstruction related to anterior displacement of the anterolateral papillary muscle. One patient who had had a septal myectomy through a transaortic and transapical approach underwent the MitraClip procedure 10 years after the previous operation, and 1 other patient had a TAVI implant 7 years later due to aortic regurgitation. Finally, 1 patient with MV replacement needed a reoperation 15 years later due to a prosthesis leak.

The 13-year CIF of reoperation, with death as the competing risk, was 8.2 (SD: 4.05)% (95% CI 2.55–18.34) in patients aged ≥65 years and 2.7 (SD: 2.01)% (95% CI 0.44–8.98) in younger patients (P = 0.13).

Fine and Gray models identified preoperative SPAP (HR = 1.05, 95% CI 1.01–1.10, P = 0.027) and left atrial volume (HR = 1.01, 95% CI 1.00–1.01, P = 0.004) as predictors of reoperation, at multivariable analysis.

Clinical outcomes

During the follow-up period, 5 patients (3%) developed heart failure, 1 patient underwent percutaneous transluminal coronary angioplasty, and 5 patients had catheter ablation of AF. Stroke occurred in 4 (2%) patients and major bleeding events in 1 (0.5%) patient (cerebral haemorrhage). Two patients (3%) in the elderly group and 9 (7%) in the younger group received an implantable cardioverter-defibrillator because of resuscitated cardiac arrest, ventricular tachyarrhythmia or as primary prevention (P < 0.001). Moreover, 8/184 (4%) patients required a permanent pacemaker due to bradi-AF (4 patients), ablate and pace therapy (2 patients) or atrioventricular block (2 patients), with no difference between groups (P = 0.50). Finally, 2 patients in permanent AF underwent transcatheter occlusion of the left atrial appendage with the St. Jude Medical Amplatzer device.

At the last follow-up, 90% of patients were in NYHA functional class I-II and 68% in sinus rhythm, with no difference between the groups (P = 0.69 and P = 0.55, respectively).

At the last echocardiographic examination, the median resting LVOT gradient decreased to 10 mmHg [0–20] (P < 0.001 vs preoperative values) and the LVEF remained stable at 60 [55–63]% (P = 0.50 vs preoperative values), with no difference between the 2 groups (P = 0.47 and P = 0.19, respectively). The SPAP of the whole series was reduced to 32 [28–40] mmHg (P = 0.01 vs baseline) and in particular was 35 [32–39] mmHg in the elderly group and 30 [25–40] mmHg in the younger group (P = 0.03).

DISCUSSION

The present study reports the short- and long-term clinical and echocardiographic outcomes of a series of relatively elderly patients surgically treated for HOCM compared to patients aged <65 years of age (the control group).

The major findings are that (i) in selected elderly symptomatic patients with HOCM, surgery can be performed with low hospital mortality and morbidity; (ii) patients ≥ 65 years of age benefit from surgical treatment with relief of severe symptoms and an overall survival comparable to that expected in the age- and sex-matched general national population; (iii) cardiac death in patients aged ≥65 was mostly unrelated to HOCM causes.

Once regarded as a disease most relevant to the young, HOCM is being increasing identified in older patients with some distinct clinical characteristics [6, 11]. Alashi et al. [6] found in 1100 elderly patients with HCM, a higher prevalence of female sex, traditional cardiovascular risk factors and atrial arrhythmia, whereas HCM-related sudden death risk factors were lower. Indeed, our series of surgically treated patients with HOCM confirmed the previous findings, showing that patients aged ≥65 years were mostly female, had higher risk factors as documented by the STS/EuroSCORE II values, lower European Society of Cardiology HCM 5-year SCD-risk scores, higher SPAP and more mitral annulus calcifications compared to younger patients.

Surgery is the gold standard for the treatment of severe symptomatic refractory HOCM, providing excellent long-term survival and freedom from symptoms [1]. With improvements in the operative technique, the mortality risk associated with an isolated septal myectomy is now less than 1% at experienced surgical centres, with only rare complications of heart block, ventricular septal defect and aortic valve regurgitation [12]. However, few data are available on the surgical outcome of the specific subgroup of elderly patients with HOCM [6–8]. It has been suggested that surgical candidacy decreases with increasing age due to the higher surgical risk related to fragility of tissues and attendant comorbid conditions that contribute to surgical mortality and morbidity [2–3]. Therefore, historically, the percutaneous alternative (alcohol septal ablation) has been most favoured in elderly patients [4–5]. However, although relatively older age requires a closer preoperative evaluation to delineate other comorbid conditions, it would be difficult to accept a cut-off age value, since many of these patients are still good candidates for surgery [13]. Additionally, surgery for older patients can sometimes give further benefits, allowing one to address at the same time other associated diseases, such as coronary disease and atrial fibrillation, which are more frequent in the elderly. Indeed, in our series, concomitant procedures, such as coronary artery bypass graft and AF ablation, were performed in 37% of patients aged ≥65years.

The hospital death rate in the elderly group was 1.5%, and it was comparable to the 0.8% in the younger cohort and to that expected by the STS score and the EuroSCORE II prediction. Similarly, no higher incidence of major postoperative complications was detected in the elderly, who showed only a higher rate of blood transfusions and postoperative AF compared to the younger cohort. No significant difference in terms of pacemaker implants was observed. Indeed, in our series of elderly patients with HOCM, surgery has been just as safe as it was for the younger cohort. However, the elderly patients in our series had relatively low surgical risk scores, which may have positively affected the perioperative results. Because those patients were referred for surgery, we cannot exclude the fact that such satisfactory outcomes could have been driven by the selection of lower-risk elderly individuals.

Lemor et al. [7] recently described the in-hospital mortality and complication rate of 2113 patients who had septal myectomies (18% were > 65 years), reporting hospital deaths of 6.7% in patients >65 years, compared to 1.5% in the younger group. Interestingly, they documented the fact that patients aged >65 years who underwent surgery in high-volume centres had a hospital mortality lower than those operated on in low-volume centres (3.5% vs 7.1%). Indeed, as underscored by guideline expert consensus panels [2, 14], septal myectomy has to be performed preferably in high-volume centres staffed by skilled surgeons experienced with the complex left ventricular outflow tract anatomy in HCM rather than in low-volume institutions in which this operation is rarely performed. Higher patient volume and more experience link to lower operative risk. Therefore, it has to be emphasized that any suggestion of performing surgery in an elderly patient must be balanced against procedural risk and overall experience of the centre at managing these complex patients.

Currently, data on the long-term age-specific outcomes after surgery in patients with HOCM are scarce [6, 8]. Because surgery provides excellent long-term survival and freedom from recurrent symptoms in “standard” younger patients with HOCM, it would be intuitive to think that similar observations would hold true in elderly patients [6, 13].

Recently, Alashi et al. [6] described the clinical outcomes of a subgroup of 195 elderly (aged >75 years) patients with HOCM undergoing septal reduction therapy, 154 patients by means of surgical myectomy±MV surgery and 41 patients by alcohol septal ablation. The 5-year survival was 84%, and it was similar to a normal age-sex matched United States population.

Our study confirmed the previous findings even in the longer term, showing that in a selected group of elderly patients with symptomatic HOCM, surgery was associated with a survival similar to that expected for the age-sex matched general national population.

As would be expected, cardiac death in the elderly was unrelated to HOCM causes, being mostly due to patient comorbidity rather than to the HOCM itself. Indeed, female sex and preoperative history of AF were identified as factors associated with cardiac death on multivariable analysis.

Recently, Nguyen et al. [15], in a large cohort of patients (median age, 56 years) undergoing surgery for HOCM, documented that most of the patients did not die of HCM, because HCM was identified as the primary cause of death in less than 20%, suggesting a protective effect of surgery. In our series, the incidence of HOCM-related deaths was even lower (3.3%). Interestingly, Maron et al. [11] showed in a series of 428 patients ≥60 years of age with HCM that only 3.7% of the patients died of HCM-related causes, including embolic stroke (consequence of atrial fibrillation), progressive heart failure (associated with the dilated phase of the cardiomyopathy) and arrhythmic sudden death. Our experience was consistent with those findings, confirming that non-cardiac or other cardiac comorbidities pose a far greater threat to long-term survival than HOCM itself.

Finally, our study documented a remarkable symptomatic improvement in the whole series with 90% of patients in NYHA functional class I-II and 68% in sinus rhythm in the long term.

In conclusion, the current study showed that in selected elderly symptomatic patients with HOCM, surgery can be performed with low hospital mortality and morbidity. In addition, it is associated with relief of symptoms and long-term survival similar to that of the general age-sex matched national population.

Study limitation

This study has several limitations. Although the data were obtained from a prospectively collected database, it was a retrospective, single-centre study and therefore subject to its intrinsic limitations. The inclusion period is long; therefore, the variability of the indications, care and management might have affected the results. Furthermore, the small sample size could undermine the statistical power of our analysis. Moreover, because these patients were referred for surgery, it was not possible to exclude intrinsic selection bias of lower-risk elderly patients. Future studies, with larger numbers of patients, may lead to more robust conclusions and may help to identify the optimal strategy for this challenging population.

In our series, cardiac magnetic resonance imaging, which is an important examination to complete as part of the preoperative evaluation of patients with HOCM, has been performed only in more recent patients due to the long time frame taken into consideration. Furthermore, in our clinical practice, genetic testing is currently not part of the routine assessment of older patients with HOCM. Finally, due to the retrospective nature of the study, some echocardiographic measurements such as the length of the anterior leaflet, the mitroaortic angle, the coaptation-septum distance and details about localization of hypertrophy in the midventricular portion, were not systematically recorded and therefore could not be analysed.

We would like also to acknowledge that for some covariates analysed in our series, the lack of statistically significant differences between the 2 groups might be due to low statistical power, which should be considered when looking at our results.

Finally, we cannot be certain that these data are entirely representative and generalizable for non-tertiary referral centres with less experience in the surgical management of HOCM.

Presented at the 35th EACTS Annual Meeting, Barcelona, Spain, 13-16 October 2021.

ACKNOWLEDGEMENT

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

Funding

None.

Conflict of interest: none declared.

Data Availability Statement

The data underlying this article will be shared on reasonable request to the corresponding author. Moreover, the data set for the general national population was derived from sources in the public domain: Istituto Nazionale di Statistica (ISTAT), http://dati.istat.it/Index.aspx?DataSetCode=DCIS_MORTALITA1

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