Sex-specific differences and postoperative outcomes of minimally invasive and sternotomy valve surgery

Abstract   OBJECTIVES Female sex is an established risk factor for postoperative complications after heart surgery, but the influence of sex on outcomes after minimally invasive cardiac surgery (MICS) for valvular replacement/repair remains controversial. We examined whether the role of sex as a risk factor varies by surgical approach [MICS vs conventional sternotomy (ST)] and further assessed outcomes among female patients including in-hospital mortality and postoperative complications by surgical approach. METHODS We analysed data from a multicentre registry for patients who underwent isolated aortic valve and mitral surgery with MICS or ST. The primary outcome was in-hospital mortality. Propensity score matching was used to minimize between-group differences. RESULTS Among the 15 155 patients included in the study, 7674 underwent MICS (50.6%). Female sex was equally distributed in the MICS and ST groups (47.3% vs 47.6%, respectively). Risk for surgery was higher in the ST group than in the MICS group {EuroSCORE II: 4.0 [standard deviation (SD): 6.8] vs 3.7 [SD: 6.4]; P = 0.005}, including among female patients only [ST vs MICS 4.6 (SD: 6.9) vs 4.2 (SD: 6.3); P = 0.04]. Mortality did not significantly vary by procedure among women [MICS vs ST, 2.4% vs 2.8%; hazard ratio 1.09, 95% confidence interval 0.71–1.73; P (surgical approach × sex) = 0.51]. The results also did not vary after adjusting for confounders. CONCLUSIONS Female sex was associated with higher mortality in patients undergoing valve surgery, regardless of surgical approach. In female patients, MICS did not provide any benefits over ST in terms of in-hospital deaths or postoperative complications. Subject collection 117, 125.


INTRODUCTION
Female sex is a strong, independent risk factor for mortality after cardiac surgery, and it is included in the Society of Thoracic Surgeons [1] and EuroSCORE II risk models [2]. Yet, women are historically under-represented in cardiovascular trials, and analyses of registry data [3] suggest that, compared to men, women are less likely to undergo valvular surgery and have worse outcomes [3].
Minimally invasive cardiac surgery (MICS) for aortic or mitral repair or replacement is thought to produce better postoperative outcomes compared to conventional sternotomy (ST), including reduced blood loss, shorter hospital stays and higher patient satisfaction [4,5]. On this premise, MICS may be particularly suited to patients who are at risk for surgery [6][7][8].
In this study, we hypothesized that MICS may be advantageous compared to conventional ST for female patients in terms of in-hospital mortality, operative parameters and postoperative complications. To this end, the goal of the study was to assess whether female sex as a risk factor for poor outcome after valve repair or replacement is a function of surgical approach (MICS or ST).

MATERIALS AND METHODS
This study was an observational analysis of data from 9 cardiac units in Italy. Centre specifications are reported in the Supplementary Materials. The analysis included all patients who underwent isolated mitral (± tricuspid repair) or aortic valve surgery (repair and replacement) with ST or MICS from 31 December 2010 to 31 December 2019. Patients who required combined procedures (other than tricuspid repair) were excluded.
All centres entered cardiac surgery-related data into a common registry that was subject to review by a centralized clinical governance unit who checked data for accuracy and completeness on a monthly basis. In the present analysis, the primary outcome of interest was mortality defined as in-hospital mortality. Secondary outcomes included cardiopulmonary bypass (CPB) and cross-clamp (CC) times, postoperative renal failure, disabling stroke, need for blood transfusions, mechanical ventilation time and length of stay in the intensive care unit (ICU).

Ethical statement
All patients provided written informed consent for the clinical and administrative storage of medical data. Given the observational nature of this study, the local ethics committee waived the need for patients' consent to analyse the data from the registry.

Minimally invasive surgical techniques
The decision to perform valve repair or replacement via a minimally invasive approach was based on the preference of the surgeon. All of the included cardiac units adopted a similar approach for minimally invasive aortic and mitral valve surgery as described previously [9,10] and as reported in the Supplementary Materials. The types of valves implanted and the types of mitral valve repairs are also reported in the Supplementary Materials.

Statistical analyses
Anonymized data were exported in a .csv sheet and uploaded in an Rstudio environment. Data distributions were checked for normality before further analysis with the Shapiro-Wilk test. Continuous data are presented as the mean and standard deviation (SD) or median and interquartile range. Unpaired t-tests or Wilcoxon rank sum tests were used for statistical comparisons. Categorical data are presented as proportions and were compared using the v 2 tests.
To balance the distribution of measured baseline covariates and given the observational nature of the data, we used a nearest neighbour 1:1 propensity score matching analysis (greedy matching) with a calliper of 0.2, based on the surgical approach (MICS or ST). We calculated standardized mean differences for each covariate in the propensity model to assess residual imbalances between the groups. A standardized mean difference of ±0.1 of SD units or less indicated an irrelevant difference.
Survival was analysed using the Kaplan-Meier method, and corresponding survival curves were built by plotting all observations. Comparisons of survival estimates for different patient strata were performed with the log-rank statistic.
A Cox proportional hazard regression model was constructed to identify factors associated with mortality and to assess the statistical interaction of the covariate 'sex' and 'surgical approach' on mortality in the general population. Covariates included in the regression model are specified in the Supplementary materials.
Risk factor distributions in each group were plotted using a random effects model and reported as risk ratios before and after matching. All statistical analyses were performed with RStudio Team (2020) (RStudio: Integrated Development for R. RStudio, PBC, Boston, MA, USA; URL http://www.rstudio.com/).

Baseline patient characteristics
A total of 15 155 patients underwent isolated valve surgery at 9 Italian cardiac centres during the study period; of these, 7674 patients underwent MICS (50.6%). Overall population baseline characteristics and those for female subpopulations are reported in Table 1. Proportions of female patients were similar between the MICS and ST groups (47.3% vs 47.6%, respectively; P = 0.76). Relevant differences in baseline characteristics are shown in

Propensity score matched cohort
Propensity score matching generated 4485 matched pairs for a total sample size of 8970 patients (Table 3) Operative and postoperative details are provided in Table 4.

Subgroup analysis: isolated aortic and mitral surgery
There were no significant statistical interactions between sex and surgical approach for in-hospital mortality in the aortic surgery [HR 0.79, 95% CI 0.37-1.7; P (surgical approach Â sex) = 0.55] or mitral surgery subpopulations [HR 0.88, 95% CI 0.57-1.4; P (surgical  Values are reported as mean ± SD or number and frequency (%).  Table S4).

DISCUSSION
This study found that female mortality rates did not differ for MICS and ST. Even after adjusting for baseline covariates, a MICS approach did not mitigate the influence of sex on in-hospital mortality or postoperative complications after valve surgery. The data do, however, suggest that MICS is not inferior to ST in terms of safety for female patients.
To the best of our knowledge, this is the first study to investigate the interaction of sex and surgical access on mortality and postoperative complications in the context of valve repair or replacement. Compared to men, women tend to have a higher burden of comorbidity conditions such as diabetes mellitus, hypertension, heart failure, cerebrovascular disease and anaemia. They also have smaller body surface area and generally are more 'medically complex' and frail than men [11]. Moreover, women with cardiovascular disease often experience a delay in diagnosis and treatment compared to men, which may partly explain the more advanced coronary or valvular disease at the time of surgery reported in the literature [12].
We have previously reported that MICS for valve repair or replacement is safe and effective including among high-risk patients [6]. Female sex is a factor included in most of the risk score computation methods for most of the risk scores [1,2], especially for coronary artery bypass grafting surgery and combined/mixed cardiac procedures [11]. However, the exact role of sex in surgical risk for isolated valve procedures (repair and replacement) remains controversial.
In a nationwide study of all patients undergoing mitral valve surgery in the Netherlands between 2007 and 2011 (N = 3411 patients, 42% women), Mokhles et al. [13] reported no sexspecific differences in terms of early mortality; however, the study did not include any late outcomes. Chan et al. [14] analysed 743 Canadian patients (28% women) who underwent mitral valve repair for degenerative mitral regurgitation between 2001 and 2014 and similarly observed no specific sex differences in early and 5-year survival.
At the same time, a large study of Medicare beneficiaries (N = 183 792 patients) found significant sex-specific differences for early mortality (7.7% for women and 6.1% for men; P < 0.0001) after mitral surgery, repair and replacement; nevertheless, long-term survival was similar [15]. They also found that women were more likely to have their mitral valves replaced rather than repaired, and that repair restored life expectancy for men but not for women [15].
Kulik et al. [16] performed a retrospective analysis of 3118 patients (40.4% women) who had mitral or aortic valve replacement in Canada between 1976 and 2006 and found that women had worse long-term outcomes (including survival) after valve replacement surgery than men. Johnston et al. [11] reported that female sex did not influence early mortality; however, life expectancy after mitral valve repair was higher among men whereas that after mitral valve replacement was higher among women. The authors reported no sex differences with regard to aortic valve surgery.
In the Cardiothoracic Surgical Trial Network study that focused on secondary mitral regurgitation treated in 251 patients (38.2% women), women had higher mortality and worse quality of life after mitral surgery (both repair and replacement) than men [17]. A large cohort study of patients who underwent isolated leftsided valve surgery similarly found that women experienced higher in-hospital complications including all-cause mortality than men but that improvements in in-hospital clinical outcomes were observed over time for both sexes [18]. Seeburger et al. [19] also reported that men had better long-term survival than women after mitral valve repair.
Finally, with regard to isolated aortic valve replacement, findings from the OBSERVANT (Observational Study of Effectiveness of SAVR-TAVI Procedures for Severe Aortic Stenosis Treatment) trial showed that female sex was a risk factor for mortality and for postoperative blood transfusions [20].
Another important finding arising from our analysis was that the number of patients undergoing mitral valve repair was higher in the MICS group compared to the ST group, whereas tricuspid associated procedures were more frequent in the ST group. One potential explanation is that physicians elected to perform ST in more complex patients requiring replacement and associated tricuspid procedures. Nevertheless, female patients had the same likelihood of undergoing mitral valve repair as the general population (MICS: 76% vs 75.5% and 60% vs 58%, respectively).

Limitations
Our study had several limitations. First, observed sex-specific differences in outcomes may be representative of surgical practice in Italy; accordingly, our findings require validation in other settings and countries to confirm their generalizability. Second, most isolated mitral valve procedures were valve repairs, and we did not differentiate between primary and secondary mitral valve regurgitation. Neither did we explore the influence of valve type (e.g. mechanical, tissue) on outcomes. The number of sutureless valves implanted was extremely low (<1%), such that it may be hypothesized that increased use of sutureless valves in a MICS context would result in better postoperative outcomes [21]. Third, the use of both ministernotomy and minithoracotomy approaches for aortic valve replacement in our study [9] may have produced a degree of clinical heterogeneity. Some of the baseline patient characteristics (i.e. history of coronary artery disease, need for rethoracotomy or conversion to ST) were not included in the analysis. Follow-up data were not recorded. Importantly, such findings should be interpreted also in the light of newer technologies such as transcatheter approaches.
Lastly, the study was subject to some bias and confounding because it was an observational study.

CONCLUSION
Being female was associated with higher mortality in patients undergoing valve surgery. Minimal access cardiac surgery in female patients was safe; however, it did not provide any benefit in terms of reduced mortality or postoperative complications compared to standard ST.

SUPPLEMENTARY MATERIAL
Supplementary material is available at EJCTS online.