Correspondence to Dr An-Hsun Chou; [email protected]
Strengths and limitations of this study
This study investigates the sex differences in outcomes after different major cardiac surgeries, and subgroup analyses of different valve types were also investigated.
The follow-up course was a relatively long-term period (a maximum of 14-year time period).
This population-based cohort study was large-scale enough to analyse the outcomes we focused on by using the Taiwan National Health Insurance Research Database (NHIRD).
Some detailed information was absent in the NHIRD, including laboratory data, echocardiographic reports, physical status and perioperative data such as types of valve prosthesis, surgical technique used and indications.
Although this study provides adequate short-term and long-term outcomes with properly well-controlled propensity score matching, the database is slightly outdated (2000 to 2013).
Introduction
Sex differences in major cardiac surgery, including clinical presentation, disease management, complications and survival outcomes, have been widely studied.1–3 Nevertheless, fierce debates on sex-related differences are ongoing. Most adult cardiac procedures include coronary artery bypass graft (CABG) and single or multiple valvular surgery.4 In the past, female sex was recognised as a vulnerable factor for operation risk and prognosis.1 2 4 This theory was based on the physical frailty of female patients and profound disease severity when undergoing an operation.1
Previous published studies revealed a preference for surgical outcomes for male patients undergoing adult cardiac surgery.3 4 Most articles have discussed CABG, but the outcomes of valvular surgeries have been less frequently mentioned. In addition, there has been no strong agreement on the prognosis of valve surgery as compared with that of CABG.5–10 Although some studies demonstrated the outcome of single-valve surgery,5 7–10 other conditions remain to be investigated, such as multiple-valve surgery and concomitant CABG and valve surgery.
A comprehensive understanding of sex differences in major adult cardiac surgery could provide better knowledge of risk factors, management strategy and short-term or long-term outcomes. The aim of the present study was to demonstrate the effects of sex differences on demographics, clinical and surgical characteristics and outcomes using information obtained from a national database in Taiwan.
Materials and methods
Data source
This retrospective, nationwide, population-based cohort study was implemented on the basis of data obtained from the Taiwan National Health Insurance Research Database (NHIRD). Covering almost 99% of the Taiwan residents, the National Health Insurance (NHI) programme was established on 1 March 1995, and NHIRD was derived from the government-operated single-payer NHI programme. The costs of all examinations (physical or imaging), laboratory tests, medications, interventional procedures and surgeries were reimbursed via Taiwan’s Bureau of NHI. Because the NHIRD contains the details of major cardiac surgery, such as the type of procedure, demographic distribution and in-hospital and long-term follow-up, this database provides a practical way to analyse the outcomes in which we were interested. Constraints imposed by the Computer-Processed Personal Data Protection Law and associated NHI regulations ensured that the investigators’ access to the database was limited to research purposes only. Detailed information about the NHIRD is included in previous articles.11
Study population
Using the Taiwan NHI reimbursement codes, we identified hospitalisation records with any cardiac surgeries (isolated CABG, isolated valve or CABG +valve) between 1 January 2000 and 31 December 2013. For patients with multiple cardiac surgeries, the first cardiac surgery during the study period was assigned as the index surgery. Patients with missing demographics and those aged <20 years were excluded. After selection, 66 326 patients were eligible for analysis. These patients were subsequently categorised into the following three groups: isolated CABG, isolated valve surgery and concomitant CABG and valve surgery. All three groups were further stratified into male and female patients (figure 1).
Comorbidities
Covariates included age, monthly income, urbanisation level, history of previous cardiac surgery, presence of urgent surgery, 10 comorbidities (diabetes mellitus, hypertension, heart failure, coronary arterial disease, prior myocardial infarction, peripheral arterial disease, prior stroke, chronic obstructive pulmonary disease, liver cirrhosis and malignancy), Charlson Comorbidity Index score, hospital level of the index cardiac surgery, cumulative hospital volume of cardiac surgeries (CABG or valve) between 2000 and 2013, surgical type (isolated CABG, isolated valve or CABG+ valve), surgical details of CABG and valve surgeries, type of valve surgery and concomitant maze procedure. The International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM), diagnostic codes were used to detect diseases (online supplemental table 1). Comorbidities were identified using at least two outpatient diagnoses or any single inpatient diagnosis in the previous year of the index cardiac surgery. Previous cardiac surgery, surgical details and concomitant surgeries were detected using the Taiwan NHI reimbursement codes from the inpatient claims data. The type of valve surgery was identified using ICD-9-CM procedural codes (online supplemental table 2)12–14
Outcomes
Outcomes included both in-hospital (perioperative) complications and late outcomes. In-hospital outcomes were in-hospital mortality, new-onset stroke and new-onset dialysis during the admission for the index surgery. Late outcomes were all-cause mortality, major adverse cardiovascular events (MACE) and all-cause readmission during follow-up. Death was defined as a withdrawal from the NHI program.15 MACE included any one of the following: cardiovascular death, revascularisation, acute myocardial infraction or ischaemic stroke during follow-up. Cardiovascular death was considered when the criteria of the Standardized Definitions for Cardiovascular and Stroke Endpoint Events in Clinical Trials by the US Food and Drug Administration in the USA were met. The occurrence of acute myocardial infraction and ischaemic stroke was defined as the principal diagnosis of admission. Revascularisation was identified using the Taiwan NHI reimbursement codes of inpatient claims data. The ICD-9-CM and NHI codes were provided in the supplement (online supplemental table 2). For the analysis of late outcome, each patient was followed from the index cardiac surgery to the date of death, the date of outcome occurrence or 31 December 2013, whichever came earlier.
Statistical analysis
We tested the trend of sex distribution in receiving isolated CABG or isolated valve surgeries across the study period, using the Cochran–Armitage χ2 test. The primary analysis was performed to compare sex differences in the risks of outcomes using the raw data for real-world practice without propensity score matching (PSM). The secondary analysis was based on the propensity score-matched cohort. The propensity score was the predicted probability to be woman given the values of covariates (except for follow-up year, in-hospital and late outcomes) using the multivariable logistic regression without considering interaction effects. The follow-up year is related to long-term outcomes and, therefore, the admission date of the index surgery was included in the propensity score calculation instead. Each woman was matched to a man. PSM was conducted separately for different surgical types: isolated CABG, isolated valve and CABG combined with valve. The matching was processed using a greedy nearest neighbour algorithm with a calliper of 0.2 times the SD of the logit of the propensity score, with random matching order and without replacement. Sex differences in demographics as well as clinical and surgical characteristics were assessed using the standardised difference, in which an absolute value of the standardised difference <0.1 was considered a negligible difference, and a value ranging from 0.1 to 0.2 was considered a small difference.
Sex differences in in-hospital outcomes were compared using logistic regression analysis for the binary outcome. Using the Cox proportional hazard model, we compared sex differences in the risks of fatal late outcomes (ie, all-cause mortality and MACE). The sex differences in the risks of time to nonfatal late outcomes (ie, all-cause readmission) were compared using the Fine and Gray subdistribution hazard model, which considered all-cause mortality a competing risk. In the secondary analysis based on the PSM cohort, the within-pair clustering of outcomes among the matched pairs was accounted for using a robust SE in all of the aforementioned regression analyses.
To focus on the population of isolated valve surgery, we performed a subgroup analysis according to several prespecified subgroup variables: isolated aortic valve replacement (AVR), isolated mitral valve (MV) repair, isolated MV replacement and number of intervened valves on in-hospital mortality and all-cause mortality. The subgroup analysis was conducted for both the raw data for real-world practice and the PSM cohort. The aforementioned subgroup analysis was performed based on interaction models. A two-sided p value <0.05 was considered statistically significant. However, the Bonferroni adjustment for type I error inflation was also made due to there were six outcomes in this study, and, therefore, the corrected significance was p value <0.0083. Statistical analyses were performed using SAS V.9.4 (SAS Institute, Cary, North Carolina).
Patient and public involvement
No patient was involved in this study.
Results
Epidemiology of isolated cardiac surgery in Taiwan
Among the population with isolated cardiac surgery, the proportion of female patients decreased gradually over the study period (p for trend=0.004; figure 2A). On the other hand, among the population receiving isolated valve surgery, the proportion of female patients increased gradually across the years (p for trend=0.073; figure 2B).
Enlarge this image.Figure 2. Sex distribution of patients undergoing isolated CABG (A) and isolated valve surgeries (B) across the study years in Taiwan. CABG, coronary artery bypass graft.
Baseline characteristics
Table 1 and online supplemental table 3 summarise the baseline characteristics between sexes after combining the data of different cardiac surgeries. Women tended to be slightly older, had lower socioeconomical status and had more comorbid conditions such as diabetes mellitus and heart failure. Male patients had more vascular-associated conditions such as coronary arterial disease and prior myocardial infarction. Male patients were more likely to undergo isolated CABG surgery, whereas female patients had more isolated valve surgeries. Among patients who underwent CABG, women had a lower number of bypassed vessels (2.8±0.8). With regards to valve surgeries, female patients tended to have a greater number of intervened valves (1.5±0.6). Men more frequently underwent aortic valve repair or replacement as compared with women. Female patients more frequently received MV replacement and tricuspid repair than male patients did. Finally, all sex differences in patient baseline characteristics were negligible after PSM. The detailed complete version of table 1 is provided as online supplemental table 3. Online supplemental tables 4–6 list the detailed baseline characteristics between sexes for each surgical type both before and after PSM.
Table 1Brief demographics, clinical and surgical characteristics of the female and male patients
| Variable | Before matching | After matching | STD | |||
| Female (n=20 078) | Male (n=46 248) | STD | Female (n=18 720) | Male (n=18 720) | ||
| Age (years) | 64.4±12.8 | 63.2±12.3 | 0.09 | 64.4±12.8 | 64.1±12.8 | 0.02 |
| Previous cardiac surgery | 290 (1.4) | 515 (1.1) | 0.03 | 251 (1.3) | 271 (1.4) | −0.01 |
| Urgent surgery | 2046 (10.2) | 5701 (12.3) | −0.07 | 1994 (10.7) | 1995 (10.7) | <0.01 |
| Comorbid conditions | ||||||
| 8761 (43.6) | 17 887 (38.7) | 0.10 | 8389 (44.8) | 8351 (44.6) | <0.01 | |
| 12 102 (60.3) | 28 883 (62.5) | −0.04 | 11 619 (62.1) | 11 501 (61.4) | 0.01 | |
| 6071 (30.2) | 10 226 (22.1) | 0.19 | 5390 (28.8) | 5455 (29.1) | −0.01 | |
| 13 632 (67.9) | 38 438 (83.1) | −0.36 | 13 200 (70.5) | 13 128 (70.1) | 0.01 | |
| 2732 (13.6) | 9447 (20.4) | −0.18 | 2699 (14.4) | 2656 (14.2) | 0.01 | |
| 981 (4.9) | 2204 (4.8) | 0.01 | 919 (4.9) | 932 (5.0) | <0.01 | |
| 2894 (14.4) | 6227 (13.5) | 0.03 | 2693 (14.4) | 2714 (14.5) | <0.01 | |
| 1096 (5.5) | 4614 (10.0) | −0.17 | 1068 (5.7) | 1102 (5.9) | −0.01 | |
| 297 (1.5) | 910 (2.0) | −0.04 | 274 (1.5) | 307 (1.6) | −0.01 | |
| 796 (4.0) | 1571 (3.4) | 0.03 | 722 (3.9) | 683 (3.6) | 0.01 | |
| 2.6±2.3 | 2.3±2.2 | 0.09 | 2.6±2.3 | 2.6±2.3 | <0.01 | |
| Surgical type | ||||||
| 9849 (49.1) | 32 303 (69.8) | −0.43 | 9818 (52.4) | 9818 (52.4) | 0 | |
| 8573 (42.7) | 10 487 (22.7) | 0.44 | 7374 (39.4) | 7374 (39.4) | 0 | |
| 1656 (8.2) | 3458 (7.5) | 0.03 | 1528 (8.2) | 1528 (8.2) | 0 | |
| CABG details (n=47 266) | ||||||
| Number of bypassed vessels | ||||||
| 999 (8.7) | 1894 (5.3) | 0.13 | 952 (8.4) | 683 (6.0) | 0.09 | |
| 2264 (19.7) | 6077 (17.0) | 0.07 | 2224 (19.6) | 1987 (17.5) | 0.05 | |
| 6692 (58.2) | 22 392 (62.6) | −0.09 | 6635 (58.5) | 6945 (61.2) | −0.06 | |
| 1550 (13.5) | 5398 (15.1) | −0.05 | 1535 (13.5) | 1731 (15.3) | −0.05 | |
| Number of bypassed vessels | 2.8±0.8 | 2.9±0.7 | −0.15 | 2.8±0.8 | 2.9±0.7 | −0.11 |
| Type of CABG: on pump | 9468 (82.3) | 29 181 (81.6) | 0.02 | 9333 (82.3) | 9333 (82.3) | <0.01 |
| Valve surgery details (n=24 174) | ||||||
| Number of involved valves | ||||||
| 5907 (57.7) | 9132 (65.5) | −0.16 | 5484 (61.6) | 5484 (61.6) | <0.01 | |
| 3645 (35.6) | 4066 (29.2) | 0.14 | 2905 (32.6) | 2905 (32.6) | <0.01 | |
| 677 (6.6) | 747 (5.4) | 0.05 | 513 (5.8) | 513 (5.8) | <0.01 | |
| 1.5±0.6 | 1.4±0.6 | 0.15 | 1.4±0.6 | 1.4±0.6 | <0.01 | |
| Type of valve surgery | ||||||
| 4085 (39.9) | 7011 (50.3) | −0.21 | 3897 (43.8) | 3897 (43.8) | <0.01 | |
| 3173 (31.0) | 3881 (27.8) | 0.07 | 2612 (29.3) | 2612 (29.3) | <0.01 | |
| 5634 (55.1) | 5857 (42.0) | 0.26 | 4504 (50.6) | 4504 (50.6) | <0.01 | |
| 1295 (12.7) | 1256 (9.0) | 0.12 | 953 (10.7) | 953 (10.7) | <0.01 | |
| 330 (3.2) | 395 (2.8) | 0.02 | 232 (2.6) | 232 (2.6) | <0.01 | |
| 4.8±4.0 | 5.1±3.9 | −0.06 | 4.9±4.0 | 4.8±3.9 | 0.01 | |
Values are given as number (%) or mean±SD.
CABG, coronary artery bypass graft; STD, standardised difference.
In-hospital (short-term) outcomes
Table 2 demonstrates the sex difference of the in-hospital outcomes before and after PSM. Among patients who received isolated CABG, women tended to have a greater risk in in-hospital mortality (8.8% vs 6.5%; OR 1.37, 95% CI 1.26 to 1.49; p<0.001). Besides, women after CABG also had higher rate of new-onset stroke and dialysis during admission. In contrast, among the population who underwent isolated valve surgery, women had a lower risk of new-onset stroke during admission. Nevertheless, women had slightly higher risks of in-hospital mortality (6.8% vs 6.2%; OR 1.10, 95% CI 0.98 to 1.24; p=0.094) among those undergoing isolated valve surgery, although not statistically significant. Among patients who had combined CABG and valve surgery, women had greater risks of in-hospital mortality (15.8% vs 13.6%; OR 1.19, 95% CI 1.01 to 1.40; p=0.036) and new-onset dialysis during admission. Secondary analysis in the PSM cohort revealed less significant results as compared with the primary analysis because of the smaller sample size. Noticeably, several results turned to be insignificant after adjustment for type I error inflation.
Table 2In-hospital outcomes of the female versus male patients before and after propensity score matching
| Cohort/outcome/surgical type | Female | Male | OR/HR/SHR for female (95% CI) | P |
| Before matching | ||||
| In-hospital mortality during admission | ||||
| Isolated CABG | 862 (8.8) | 2111 (6.5) | 1.37 (1.26 to 1.49) | <0.001* |
| Isolated valve | 582 (6.8) | 649 (6.2) | 1.10 (0.98 to 1.24) | 0.094 |
| CABG+valve | 262 (15.8) | 471 (13.6) | 1.19 (1.01 to 1.40) | 0.036 |
| New onset stroke during admission | ||||
| Isolated CABG | 332 (3.4) | 872 (2.7) | 1.26 (1.11 to 1.43) | 0.001* |
| Isolated Valve | 241 (2.8) | 352 (3.4) | 0.83 (0.71 to 0.98) | 0.031 |
| CABG+valve | 65 (3.9) | 136 (3.9) | 1.00 (0.74 to 1.35) | 0.989 |
| New onset dialysis during admission | ||||
| Isolated CABG | 974 (9.9) | 2383 (7.4) | 1.38 (1.28 to 1.49) | <0.001* |
| Isolated valve | 506 (5.9) | 599 (5.7) | 1.04 (0.92 to 1.17) | 0.575 |
| CABG+valve | 264 (15.9) | 414 (12.0) | 1.40 (1.18 to 1.65) | <0.001* |
| After matching | ||||
| In-hospital mortality during admission | ||||
| Isolated CABG | 853 (8.7) | 770 (7.8) | 1.12 (1.01 to 1.24) | 0.031 |
| Isolated Valve | 500 (6.8) | 422 (5.7) | 1.20 (1.05 to 1.37) | 0.008* |
| CABG+valve | 234 (15.3) | 227 (14.9) | 1.04 (0.85 to 1.26) | 0.723 |
| New onset stroke during admission | ||||
| Isolated CABG | 330 (3.4) | 297 (3.0) | 1.11 (0.95 to 1.31) | 0.182 |
| Isolated valve | 203 (2.8) | 254 (3.4) | 0.79 (0.66 to 0.96) | 0.016 |
| CABG+valve | 57 (3.7) | 67 (4.4) | 0.84 (0.58 to 1.22) | 0.370 |
| New onset dialysis during admission | ||||
| Isolated CABG | 966 (9.84) | 967 (9.85) | 1.00 (0.91 to 1.10) | 0.981 |
| Isolated valve | 419 (5.7) | 421 (5.7) | 1.00 (0.87 to 1.14) | 0.943 |
| CABG+valve | 228 (14.9) | 187 (12.2) | 1.26 (1.02 to 1.55) | 0.031 |
*Significant after Bonferroni adjustment for type I error inflation (p<0.0083).
CABG, coronary artery bypass graft; SHR, subdisribution HR.
Late follow-up (long-term) outcomes
Table 3 presents the comparison of sex differences in the long-term outcomes for each surgical type using real-world data before and after PSM. Among patients who received isolated CABG, women tended to have a greater risk in all-cause mortality (44.8% vs 37.5%; HR 1.26, 95% CI 1.22 to 1.31; p<0.001), all-cause readmission and MACE during late follow-up. Nevertheless, women who underwent isolated valve surgery had a lower risk of all-cause mortality (29.2% vs 31.6%; HR 0.92, 95% CI 0.87 to 0.97; p=0.001) and MACE during follow-up. Finally, among patients who had concurrent CABG and valve surgery, women had greater risks of all-cause mortality during follow-up (52.5% vs 47.6%; HR 1.14, 95% CI 1.05 to 1.24; p=0.002). Secondary analysis in the PSM cohort demonstrated results similar to the primary analysis. However, it is noted that several results turned to be insignificant after adjustment for type I error inflation.
Table 3Long-term outcomes of the female versus male patients before and after propensity score matching
| Variable | Female | Male | OR/ HR/SHR for female (95% CI) | P |
| Cohort/outcome/surgical type | ||||
| All-cause mortality during follow-up | ||||
| Isolated CABG | 4408 (44.8) | 12 109 (37.5) | 1.26 (1.22 to 1.31) | <0.001* |
| Isolated valve | 2502 (29.2) | 3317 (31.6) | 0.92 (0.87 to 0.97) | 0.001* |
| CABG+valve | 869 (52.5) | 1647 (47.6) | 1.14 (1.05 to 1.24) | 0.002* |
| MACE during follow-up† | ||||
| Isolated CABG | 3569 (36.2) | 10 438 (32.3) | 1.22 (1.18 to 1.27) | <0.001* |
| Isolated valve | 1603 (18.7) | 2114 (20.2) | 0.92 (0.86 to 0.98) | 0.009 |
| CABG+valve | 445 (26.9) | 990 (28.6) | 0.97 (0.87 to 1.09) | 0.641 |
| All-cause readmission during follow-up | ||||
| Isolated CABG | 6923 (70.3) | 21 540 (66.7) | 1.12 (1.09 to 1.15) | <0.001* |
| Isolated valve | 4945 (57.7) | 6079 (58.0) | 0.99 (0.96 to 1.03) | 0.729 |
| CABG+valve | 1002 (60.5) | 2110 (61.0) | 0.99 (0.91 to 1.06) | 0.683 |
| After matching | ||||
| All-cause mortality during follow-up | ||||
| Isolated CABG | 4380 (44.6) | 4453 (45.4) | 0.98 (0.95 to 1.02) | 0.429 |
| Isolated valve | 2112 (28.6) | 2299 (31.2) | 0.91 (0.86 to 0.96) | 0.001* |
| CABG+valve | 786 (51.4) | 759 (49.7) | 1.05 (0.95 to 1.15) | 0.345 |
| MACE during follow-up† | ||||
| Isolated CABG | 3559 (36.2) | 3446 (35.1) | 1.050 (1.002 to 1.100) | 0.040 |
| Isolated valve | 1364 (18.5) | 1527 (20.7) | 0.88 (0.81 to 0.94) | <0.001* |
| CABG+valve | 406 (26.6) | 440 (28.8) | 0.91 (0.80 to 1.04) | 0.175 |
| All-cause readmission during follow-up | ||||
| Isolated CABG | 6907 (70.4) | 6823 (69.5) | 1.03 (0.99 to 1.06) | 0.125 |
| Isolated valve | 4220 (57.2) | 4302 (58.3) | 0.96 (0.92 to 1.00) | 0.059 |
| CABG+valve | 928 (60.7) | 939 (61.5) | 0.96 (0.88 to 1.05) | 0.377 |
*Significant after Bonferroni adjustment for type I error inflation (p<0.0083).
†Including anyone of cardiovascular death, revascularisation, acute myocardial infraction or ischaemic stroke.
CABG, coronary artery bypass graft; MACE, major adverse cardiovascular events; SHR, subdisribution HR.
Subgroup analysis of mortality outcomes
To focus on the population who received isolated valve surgery, we performed subgroup analysis on in-hospital (short-term) mortality and all-cause mortality (long-term). Sex differences in in-hospital mortality were more apparent when isolated MV repair (p for interaction=0.088) was conducted. Female patients tended to have non-favourable in-hospital mortality (HR 1.70; 95% CI 1.01 to 2.87) when undergoing isolated MV repair (figure 3A). The secondary analysis under the PSM cohort revealed similar but less significant results as compared with the primary analysis (figure 3B).
Enlarge this image.Figure 3. Subgroup analysis of the comparison of sex differences in the risks of in-hospital mortality using the whole data (A) or the propensity score-matched cohort (B). AVR, aortic valve replacement; MV, mitral valve.
On the other hand, sex differences in all-cause mortality were more obvious when isolated AVR (p for interaction=0.091) was conducted. Female patients tended to have a more favourable outcome of all-cause mortality (HR 0.90; 95% CI 0.84 to 0.96) when isolated AVR was not undergone (figure 4A). The secondary analysis in the PSM cohort demonstrated similar results as that of the primary analysis (figure 4B).
Enlarge this image.Figure 4. Subgroup analysis of the comparison of sex differences in the risks of all-cause mortality during follow-up using the whole data (A) or the propensity score-matched cohort (B). AVR, aortic valve replacement; MV, mitral valve.
Discussion
Main findings
In both the group undergoing isolated CABG and concomitant CABG/valve surgery, female patients had a higher rate of in-hospital mortality during admission and all-cause mortality during follow-up. In terms of complications, female patients undergoing CABG tended to suffer from new-onset stroke, dialysis and even MACE. Second, female patients undergoing isolated valve surgery had better outcomes in all-cause mortality during follow-up and fewer complications such as new-onset stroke and MACE, although their rate of in-hospital mortality was slightly higher than that of men. After obtaining real-world data, we demonstrated a PSM to determine whether sex was a predictor of surgical outcomes. Matching revealed that the findings were generally similar to the primary analysis in the three groups. Finally, we performed the subgroup analysis to investigate the details of the outcomes of different intervened single valvular procedures. Female patients tended to have non-favourable in-hospital mortality after undergoing isolated MV repair. The outcomes of all-cause mortality in women who did not undergo isolated AVR were better as compared with those in men.
Sex differences in procedures including coronary bypass surgery
This present study reveals that both isolated CABG and concomitant CABG/valve surgery were associated with worse early and late outcomes in women. This result could be mainly attributed to the involvement of coronary bypass surgery. Female patients undergoing coronary surgical bypass are older, have a smaller body surface area, have more underlying comorbidities and have a greater need for urgent or emergent surgical intervention.3 16 17 Female patients more frequently present with atypical or non-anginal symptoms, which likely contributes to delays in the diagnosis, treatment and recognition of surgical coronary disease.17 18 Moreover, the worse clinical outcomes can be explained by factors such as smaller coronary arteries, fewer internal mammary artery grafts, fewer bypass grafts and graft–coronary mismatch.17 19 In addition, the fear of surgery may result in delayed referral for CABG in female patients.1 Figure 2 shows that the number of female patients undergoing isolated CABG are decreasing. This fact might be related to the advancement in percutaneous coronary intervention procedures, resulting in a decrease in referral to CABG for female patients who are older, are frail, or have multiple comorbidities.4 A recent analysis reported by Soham et al demonstrated that women after CABG surgery had greater risk of in-hospital death and 30-day and 90-day readmission compared with men.17 They also described that women continue to have worse outcomes even though the current clinical practice has been modified to reduce sex difference. And these points and finding supported our study results.
Few studies have investigated the outcomes of sex differences after combined CABG/valve surgery.2 20–22 As compared with the better knowledge of outcomes of isolated CABG, there is no strong agreement on whether there are sex differences in the outcomes of combined CABG/valve surgery. In this study, the data between isolated CABG and combined CABG/valve surgery were similar. These data indicate the increase in morbidity and mortality and relate to late presentation or referral. Therefore, the worse outcomes among female patients undergoing simultaneous CABG/valve surgery could be explained by the involvement of coronary bypass surgery rather than the valve operation itself. Earlier studies comparing the outcomes of different types of valve surgery (single or multiple) with or without concurrent CABG also support this perspective.20–23 Sinead et al recently reported their analysis that women undergoing major cardiac surgery had much more chance to receive allogeneic transfusions compared with men, especially in non-White races. Moreover, allogeneic transfusions were associated with a higher likelihood of in-hospital mortality.24
Sex differences in intervened valve procedure
As mentioned in the previous section, female sex may not always be a vulnerable factor of surgical outcomes. Our study results indicated that women undergoing isolated valve surgeries had lower rates of all-cause mortality, new-onset stroke during admission and MACE. However, there are few published articles based on a retrospective large population data to clarify this issue. Johnston et al3 found no significant difference in 30-day mortality or in long-term follow-up after isolated valve surgery (single-valve and multiple-valve surgery). The isolated valve surgeries received by patients were composed of different types of intervened valves, and some involved more than one valve. Therefore, the different types of valve surgery were stratified for subgroup analysis in this study.
There was no obvious sex difference in in-hospital mortality among patients undergoing isolated AVR. In addition, female patients tended to have more favourable all-cause mortality when they did not receive isolated AVR. The clinical outcomes of isolated AVR between women and men are controversial, without strong consensus. An earlier study by Aranki et al20 found that sex was not a predictor of operative mortality among those undergoing isolated AVR. Mokhles et al8 also reported that men and women had comparable in-hospital mortality (OR 1.20, 95% CI 0.90 to 1.61; p=0.220). Nevertheless, some studies have demonstrated that women have worse in-hospital mortality following AVR as compared with men5 or even higher late mortality.6 These findings, therefore, provide a perspective of advocating for transcatheter AVR in women with a lower threshold. A recent retrospective article showed no difference in overall survival between women and men after adjusting for preoperative risk factors,25 which supports our results after PSM. Female sex itself may not be a predictor in isolated AVR, and it could be related to the worse perioperative profile of women.
In this present study, female patients underwent MV replacement more frequently than male patients did. The number of patients receiving MV repair were comparable between women and men. Our data show that female patients undergoing isolated MV repair had higher rates of in-hospital mortality but not all-cause mortality. The outcomes of MV replacement in early and late mortality were comparable between women and men. On the other hand, Johnston et al3 documented that male patients undergoing MV repair had higher rates of long-term survival, whereas female patients undergoing MV replacement had higher rates of long-term survival. Another recent nationwide cohort study reported no significant differences between men and women in-hospital mortality with both MV repair and MV replacement.7 In contrast, Vassileva et al26 found a higher mortality rate in female patients undergoing MV surgery. Because there is no strong agreement of the outcomes on isolated MV surgery, further research is needed. As with other cardiac surgical procedures, female patients who underwent isolated MV surgery were older and had a more profound disease severity when presenting for the operation.7 Studies have reported a delayed detection of severe MV disease and late referral to surgical intervention in women.27 28 This is compatible with the current condition of female patients in Taiwan, who have relatively low socioeconomic status and are afraid to undergo surgery. A delay in surgery might partially explain our results of higher in-hospital mortality in female patients, and female sex may not to be a predictor of long-term outcomes of isolated MV surgery.
Limitations
Because this current study is inherent to the NHIRD, some detailed information was absent, including physical examination, vital signs, laboratory data, echocardiographic reports and heart failure symptoms. Some intraoperative and postoperative data were also not able to be retrieved from the database such as length of cardiopulmonary bypass, types of valve prosthesis, surgical technique used, indications, perioperative use of inotropes or intra-aortic balloon pump and postoperative cardiogenic shock.17 Besides, although we performed a large-scale nationwide cohort, the results may not represent generalisation to other Asian or non-Asian populations.17 In addition, misclassification and coding errors might have occurred during the analysis of the NHIRD data, which is based on ICD-9-CM codes. Nevertheless, the NHI programme has strict regulations regarding surgery, examination and medication reimbursements. Comprehensive reviews of all medical records including imaging studies and laboratory data ensure that specific examinations or interventions are granted only to patients who are indicated. Therefore, the use of Taiwan’s Taiwan NHI reimbursement codes for major cardiac-related diagnoses and procedures is precise and has been validated.29 Despite this study provides short-term and long-term outcomes with properly well-controlled PSM, the database is slightly outdated (2000 to 2013), and clinical practice may have changed in past years. Nevertheless, our study focused on the long-term outcomes of sex difference, and the sex-based disparity is inherent. Gupta et al17 documented their recent study results and revealed that despite efforts in reducing the sex disparity, women still have worse outcomes in current era. Therefore, we assume that the extension of the follow-up period may have limited impact to our conclusion. Finally, although medical costs might be important in some regions where health insurance is not readily available, we did not calculate these costs.
Conclusions
We conducted a nationwide, population-based cohort study to determine the sex-related differences in clinical outcomes after major adult cardiac surgery. Female patients who underwent procedures involving coronary bypass surgery (with or without concurrent valvular intervention) generally had worse outcomes. However, the results of isolated valve surgery were variable on the basis of the type of the intervened valve. Understanding the male–female differences in demographics, clinical and surgical characteristics and outcomes could modify the physician’s practice and improve the quality of management.
We thank Alfred Hsing-Fen Lin and Ben Yu-Lin Chou for their assistance in the statistical analysis.
Data availability statement
No data are available.
Ethics statements
Patient consent for publication
Not applicable.
Ethics approval
This cohort study was evaluated and approved via the NHIRD research committee and the institutional review board of Chang Gung Memorial Hospital and waived the need for individual informed consent (registration number: 104-7990B).
F-CC and S-WC contributed equally.
Contributors F-CC: conceptualisation; data curation; methodology; investigation; validation; writing—original draft. S-WC: conceptualisation; data curation; methodology; formal analysis; validation; writing—original draft. Y‐HC: methodology; formal analysis; investigation; resources; writing—review and editing. C-PL: conceptualisation; formal analysis; data curation; resources; validation; writing—review and editing. VC-CW: data curation; formal analysis; writing—review and editing. Y-TC: conceptualisation; data curation; formal analysis; supervision. D-YC: conceptualisation; formal analysis; software. K-CH: data curation; methodology; software. P-HC: methodology; data curation; resources; supervision; writing—review and editing. A-HC: conceptualisation; investigation; project administration; funding acquisition; validation; writing—review and editing. All authors give final approval of the version to be submitted and any revised version.
Funding The study was supported by a grant from the Chang Gung Medical Research Project (BMRPC19，CMRPG3K1431，CFRPG3K0071). The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.
1 Vaccarino V, Abramson JL, Veledar E, et al. Sex differences in hospital mortality after coronary artery bypass surgery: evidence for a higher mortality in younger women. Circulation 2002; 105: 1176–81. doi:10.1161/hc1002.105133 http://www.ncbi.nlm.nih.gov/pubmed/11889010
2 Doenst T, Ivanov J, Borger MA, et al. Sex-specific long-term outcomes after combined valve and coronary artery surgery. Ann Thorac Surg 2006; 81: 1632–6. doi:10.1016/j.athoracsur.2005.11.052 http://www.ncbi.nlm.nih.gov/pubmed/16631648
3 Johnston A, Mesana TG, Lee DS, et al. Sex differences in long-term survival after major cardiac surgery: a population-based cohort study. J Am Heart Assoc 2019; 8: e013260. doi:10.1161/JAHA.119.013260 http://www.ncbi.nlm.nih.gov/pubmed/31438770
4 Buth KJ, Gainer RA, Legare J-F, et al. The changing face of cardiac surgery: practice patterns and outcomes 2001-2010. Can J Cardiol 2014; 30: 224–30. doi:10.1016/j.cjca.2013.10.020 http://www.ncbi.nlm.nih.gov/pubmed/24373760
5 Chaker Z, Badhwar V, Alqahtani F, et al. Sex differences in the utilization and outcomes of surgical aortic valve replacement for severe aortic stenosis. J Am Heart Assoc 2017; 6 doi:10.1161/JAHA.117.006370 28935681
6 Elhmidi Y, Piazza N, Mazzitelli D, et al. Sex-related differences in 2197 patients undergoing isolated surgical aortic valve replacement. J Card Surg 2014; 29: 772–8. doi:10.1111/jocs.12442 http://www.ncbi.nlm.nih.gov/pubmed/25264220
7 Mokhles MM, Siregar S, Versteegh MIM, et al. Male-female differences and survival in patients undergoing isolated mitral valve surgery: a nationwide cohort study in the Netherlands. Eur J Cardiothorac Surg 2016; 50: 482–7. doi:10.1093/ejcts/ezw151 http://www.ncbi.nlm.nih.gov/pubmed/27174553
8 Mokhles MM, Soloukey Tbalvandany S, Siregar S, et al. Male-female differences in aortic valve and combined aortic valve/coronary surgery: a national cohort study in the Netherlands. Open Heart 2018; 5: e000868. doi:10.1136/openhrt-2018-000868 http://www.ncbi.nlm.nih.gov/pubmed/30228910
9 Onorati F, D'Errigo P, Barbanti M, et al. Different impact of sex on baseline characteristics and major periprocedural outcomes of transcatheter and surgical aortic valve interventions: results of the multicenter Italian OBSERVANT registry. J Thorac Cardiovasc Surg 2014; 147: 1529–39. doi:10.1016/j.jtcvs.2013.05.039 http://www.ncbi.nlm.nih.gov/pubmed/23856202
10 Veen KM, Mokhles MM, Braun J, et al. Male-female differences in characteristics and early outcomes of patients undergoing tricuspid valve surgery: a national cohort study in the Netherlands. Eur J Cardiothorac Surg 2019; 55: 859–66. doi:10.1093/ejcts/ezy390 http://www.ncbi.nlm.nih.gov/pubmed/30517619
11 Hsing AW, Ioannidis JPA. Nationwide population science: lessons from the Taiwan National health insurance research database. JAMA Intern Med 2015; 175: 1527–9. doi:10.1001/jamainternmed.2015.3540 http://www.ncbi.nlm.nih.gov/pubmed/26192815
12 Chen S-W, Wu VC-C, Lin Y-S, et al. Propensity score matched analysis of mechanical vs. bioprosthetic valve replacement in patients with previous stroke. Circ J 2018; 82: 2041–8. doi:10.1253/circj.CJ-18-0003 http://www.ncbi.nlm.nih.gov/pubmed/29794401
13 Lee H-A, Cheng Y-T, Wu VC-C, et al. Nationwide cohort study of mitral valve repair versus replacement for infective endocarditis. J Thorac Cardiovasc Surg 2018; 156: 1473–83. doi:10.1016/j.jtcvs.2018.04.064 http://www.ncbi.nlm.nih.gov/pubmed/29843917
14 Wong W-K, Chen S-W, Chou A-H, et al. Late outcomes of valve repair versus replacement in isolated and concomitant tricuspid valve surgery: a nationwide cohort study. J Am Heart Assoc 2020; 9: e015637. doi:10.1161/JAHA.119.015637 http://www.ncbi.nlm.nih.gov/pubmed/32301369
15 Wu C-Y, Chen Y-J, Ho HJ, et al. Association between nucleoside analogues and risk of hepatitis B virus–related hepatocellular carcinoma recurrence following liver resection. JAMA 2012; 308: 1906–14. doi:10.1001/2012.jama.11975 http://www.ncbi.nlm.nih.gov/pubmed/23162861
16 Faerber G, Zacher M, Reents W, et al. Female sex is not a risk factor for post procedural mortality in coronary bypass surgery in the elderly: a secondary analysis of the GOPCABE trial. PLoS One 2017; 12: e0184038. doi:10.1371/journal.pone.0184038 http://www.ncbi.nlm.nih.gov/pubmed/28854266
17 Gupta S, Lui B, Ma X, et al. Sex differences in outcomes after coronary artery bypass grafting. J Cardiothorac Vasc Anesth 2020; 34: 3259–66. doi:10.1053/j.jvca.2020.04.030 http://www.ncbi.nlm.nih.gov/pubmed/32507458
18 Parvand M, Rayner-Hartley E, Sedlak T. Recent developments in sex-related differences in presentation, prognosis, and management of coronary artery disease. Can J Cardiol 2018; 34: 390–9. doi:10.1016/j.cjca.2018.01.007 http://www.ncbi.nlm.nih.gov/pubmed/29571423
19 Koch CG, Nussmeier NA. Gender and cardiac surgery. Anesthesiol Clin North Am 2003; 21: 675–89. doi:10.1016/S0889-8537(03)00048-8 http://www.ncbi.nlm.nih.gov/pubmed/14562572
20 Aranki SF, Rizzo RJ, Couper GS, et al. Aortic valve replacement in the elderly. Effect of gender and coronary artery disease on operative mortality. Circulation 1993; 88: Ii17–23. http://www.ncbi.nlm.nih.gov/pubmed/8222150
21 Ibrahim MF, Paparella D, Ivanov J, et al. Gender-related differences in morbidity and mortality during combined valve and coronary surgery. J Thorac Cardiovasc Surg 2003; 126: 959–64. doi:10.1016/S0022-5223(03)00355-6 http://www.ncbi.nlm.nih.gov/pubmed/14566232
22 Thourani VH, Weintraub WS, Craver JM, et al. Influence of concomitant CABG and urgent/emergent status on mitral valve replacement surgery. Ann Thorac Surg 2000; 70: 778–83. doi:10.1016/S0003-4975(00)01641-6 http://www.ncbi.nlm.nih.gov/pubmed/11016309
23 Gehlot A, Mullany CJ, Ilstrup D, et al. Aortic valve replacement in patients aged eighty years and older: early and long-term results. J Thorac Cardiovasc Surg 1996; 111: 1026–36. doi:10.1016/S0022-5223(96)70379-3 http://www.ncbi.nlm.nih.gov/pubmed/8622300
24 O'Shaughnessy S, Tangel V, Dzotsi S. Non-white race/ethnicity and female sex are associated with increased allogeneic red blood cell transfusion in cardiac surgery patients: 2007-2018. J Cardiothorac Vasc Anesth 2021 doi:10.1053/j.jvca.2021.11.021 34969561
25 Ter Woorst JF, Hoff AHT, van Straten AHM, et al. Impact of sex on the outcome of isolated aortic valve replacement and the role of different preoperative profiles. J Cardiothorac Vasc Anesth 2019; 33: 1237–43. doi:10.1053/j.jvca.2018.08.196 http://www.ncbi.nlm.nih.gov/pubmed/30245111
26 Vassileva CM, McNeely C, Mishkel G, et al. Gender differences in long-term survival of Medicare beneficiaries undergoing mitral valve operations. Ann Thorac Surg 2013; 96: 1367–73. doi:10.1016/j.athoracsur.2013.04.055 http://www.ncbi.nlm.nih.gov/pubmed/23915585
27 Mirabel M, Iung B, Baron G, et al. What are the characteristics of patients with severe, symptomatic, mitral regurgitation who are denied surgery? Eur Heart J 2007; 28: 1358–65. doi:10.1093/eurheartj/ehm001 http://www.ncbi.nlm.nih.gov/pubmed/17350971
28 Chandrasekhar J, Dangas G, Mehran R. Valvular heart disease in women, differential remodeling, and response to new therapies. Curr Treat Options Cardiovasc Med 2017; 19: 74. doi:10.1007/s11936-017-0573-z http://www.ncbi.nlm.nih.gov/pubmed/28895061
29 Cheng C-L, Chien H-C, Lee C-H, et al. Validity of in-hospital mortality data among patients with acute myocardial infarction or stroke in national health insurance research database in Taiwan. Int J Cardiol 2015; 201: 96–101. doi:10.1016/j.ijcard.2015.07.075 http://www.ncbi.nlm.nih.gov/pubmed/26292275
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Details
; Shao-Wei, Chen 2 ; Yi‐Hsin Chan 3 ; Chia-Pin, Lin 3 ; Victor Chien-Chia Wu 3 ; Yu-Ting, Cheng 4 ; Dong-Yi, Chen 3 ; Kuo-Chun, Hung 3 ; Pao-Hsien Chu 3
; Chou, An-Hsun 1
1 Department of Anesthesiology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan
2 Division of Thoracic and Cardiovascular Surgery, Department of Surgery, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan; Center for Big Data Analytics and Statistics, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan
3 Department of Cardiology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan
4 Division of Thoracic and Cardiovascular Surgery, Department of Surgery, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan