Abbreviations CABG coronary artery bypass grafting IABP intra-aortic balloon pump MI myocardial infarction PCI percutaneous coronary intervention VSD ventricular septal defect 1 INTRODUCTION

Ventricular septal defect (VSD) due to ischemic septal rupture represents a rare event complicating ST-elevation myocardial infarction (MI). There has been a significant decrease in the incidence of this dreaded complication, from 1% to 3% in the prethrombolysis eras to 0.2%–0.34% in the latest years.1 However, this event is still associated with very poor clinical outcomes. The mortality rate is as high as 94% after medical treatment whereas surgical repair of VSD has been reported to have an operative mortality higher than 30% and it varies largely according to the timing of surgery. Currently, there is no consensus on which is the optimal timing for the repair of VSD as patients undergoing surgery early after the MI show worse outcomes while patients in which surgical repair is attempted after 2–3 weeks after the culprit MI have the lowest operative mortality.2, 3

More recently, the use of percutaneous devices to close the septal defect has emerged as a potential alternative to surgical repair. Although interventional VSD closure is associated with a more rapid correction of the interventricular shunt, it still remains impacted by high mortality and morbidity and therefore, surgical repair remains in the majority of cases the gold standard for these patients.4

This study aimed to provide a clinical benchmark for the treatment of post-MI VSD by reporting on the outcomes of VSD repair over a 23-year period and identify risk factors associated with worse short-term outcomes after surgical repair.

2 METHODS

The study is part of a research project approved by the Health Research Authority (HRA) and Health and Care Research Wales. Patient consent was waived (HCRW) (IRAS ID: 278171) in accordance with the research guidance. This study complies with the Declaration of Helsinki.

2.1 National adult cardiac surgery audit (NACSA) dataset

A complete extract of prospectively collected data from the NACSA was obtained from the National Institute of Cardiovascular Outcomes Research (NICOR) central cardiac database and retrospectively analyzed. The definitions of the database variables used for this study are available at https://www.nicor.org.uk/national-cardiac-audit-programme/adult-cardiac-surgery-surgery-audit/. The NICOR registry prospectively collects demographic, as well as pre- and postoperative clinical information, including mortality, for all major adult cardiac surgery procedures performed in the UK. The flow of the data from surgeon-input to analysis has been described elsewhere.5 Missing data are resolved during the validation stages of the data transfer from individual centers. Missing and conflicting data for in-hospital mortality status are backfilled and validated via record linkage to the Office for National Statistics census database. The overall percentage of missing data for baseline information is very low (1.7%). Missing categorical or dichotomous variable data were imputed with the mode while missing continuous variables data imputed with the median. For the present analysis, from the NACSA registry we identified patients undergoing surgical repair for post-MI VSD from January 1996 to December 2018 in England, Scotland and Wales. Information on the anatomical position of the defect (anterior vs. posterior) was not available in the dataset.

2.2 Outcomes

The primary outcome was in-hospital mortality. Secondary outcomes investigated were postoperative cerebrovascular events, need for postoperative dialysis, deep sternal wound infection, reexploration for bleeding, insertion of intra-aortic balloon pump (IABP) or ventricular assist devices and length of stay.

2.3 Statistical analysis

Categorical variables are presented as count and proportion and were compared using the Pearson's Chi-squared test or Fisher's exact test, as appropriate, whereas continuous variables were reported as median and interquartile range and were compared using Wilcoxon rank sum test.

Patients characteristics were reported in the overall sample and were stratified by patient status at discharge (survivor vs. nonsurvivors). Predictors of operative mortality were investigated using a multivariable, generalized linear mixed model, which included the patient characteristics found significant at the univariable analysis as fixed effect covariates. A clustering effect was anticipated for patients operated in the same hospital or by the same surgeon and therefore these two variables were included in the model as random intercepts. As surgical outcomes may have improved in the last decade, year of surgery was also included as random intercept. Effect estimates for fixed effect covariates were reported as odds ratio (OR) and 95% confidence interval (CI). The marginal R-squared considers only the variance of the fixed effects, while the conditional R-squared takes both the fixed and random effects into account.6

The primary outcome was also investigated according to the time interval from MI to the surgery, and according to the procedure performed (isolated VSD repair, concomitant CABG or CABG plus mitral valve surgery).

p value <.05 was considered significant in all the analysis. Statistical analysis was performed using R version 4.0.0 using the packages sjplot, lme4, lmertest, gtsummary.

3 RESULTS

From 1996 to 2018, 1010 patients underwent surgical repair of post-MI VSD in 42 centres by 370 surgeons. Over the 23-year period, the number of VSD undergoing surgical repair remained stable after an initial upsurge in the first 5 years (Figure 1) and ranged from 41 to 67 cases per year. The overall median number of VSD repairs per surgeon was 2 (1–3) and the overall median hospital volume 24 (13–36). On average, each centre operated 3 (2–4) patients each year and each surgeon operated on 1 (1–2) patients annually.

Number of postmyocardial infarction ventricular septal defect (VSD) surgically repaired over time

Patient characteristics are presented in Table 1. The median age was 70 (62–75 years) and most of the patients were men (66%). Surgical repair of VSD was mainly performed in the timespan of 1–30 days after the culprit MI (69%), whereas the least patients were operated on within the first 6 h after the MI (2.4%). Half of the patients had a critical preoperative state presenting with cardiogenic shock (54%) and/or inotropic support (41%). A total of 252 (25%) patients had a previous percutaneous coronary intervention (PCI). Repair of the post-MI VSD was urgent or emergent in 88% of the cases. The median interval time from hospital admission to surgery was 1 (0–5) day.

Table 1. Baseline characteristics of patients undergoing surgical repair of postmyocardial infarction ventricular septal defect in the overall cohort and between survivors and nonsurvivors Characteristic Overall, N = 1010a Survivors, N = 617a Nonsurvivors, N = 393a p valueb Age (years) 70 (62, 75) 68 (61, 74) 71 (64, 76) .002 Index of multiple deprivation 18 (10, 31) 18 (10, 32) 18 (10, 31) .8 Female sex 345 (34%) 207 (34%) 138 (35%) .6 CCS Class 3 or 4 546 (54%) 300 (49%) 246 (63%) <.001 NYHA Class 3 or 4 771 (76%) 471 (76%) 300 (76%) >.9 Interval between MI and surgical repair <.001 <6 h 24 (2.4%) 6 (1.0%) 18 (4.6%) 6–24 h 155 (15%) 60 (9.7%) 95 (24%) 1–30 days 695 (69%) 436 (71%) 259 (66%) ≥31 days 136 (13%) 115 (19%) 21 (5.3%) PCI <.001 No 758 (75%) 487 (79%) 271 (69%) <24 h, same index admission 80 (7.9%) 23 (3.7%) 57 (15%) >24 h, same index admission 130 (13%) 75 (12%) 55 (14%) >24 h, previous admission 42 (4.2%) 32 (5.2%) 10 (2.5%) Previous heart surgery 45 (4.5%) 32 (5.2%) 13 (3.3%) .2 Diabetes 137 (14%) 76 (12%) 61 (16%) .15 Hypertension 511 (51%) 304 (49%) 207 (53%) .3 Smoking .5 Never smoker 342 (34%) 201 (33%) 141 (36%) Former smoker 418 (41%) 259 (42%) 159 (40%) Current smoker 250 (25%) 157 (25%) 93 (24%) COPD 130 (13%) 75 (12%) 55 (14%) .4 Previous cerebrovascular accidents .3 TIA 22 (2.2%) 14 (2.3%) 8 (2.0%) CVA with recovery 14 (1.4%) 7 (1.1%) 7 (1.8%) CVA with deficit 9 (0.9%) 8 (1.3%) 1 (0.3%) PVD 72 (7.1%) 45 (7.3%) 27 (6.9%) .8 Preoperative AF 54 (5.3%) 31 (5.0%) 23 (5.9%) .6 Preoperative VF 15 (1.5%) 9 (1.5%) 6 (1.5%) >.9 3-vessel coronary artery disease 234 (23%) 141 (23%) 93 (24%) .8 LVEF <.001 <30% 356 (35%) 187 (30%) 169 (43%) 30%–50% 456 (45%) 318 (52%) 138 (35%) ≥50% 198 (20%) 112 (18%) 86 (22%) Cardiogenic shock 542 (54%) 271 (44%) 271 (69%) <.001 Inotropic support 414 (41%) 211 (34%) 203 (52%) <.001 UA 556 (55%) 313 (51%) 243 (62%) <.001 Preoperative ventilation 90 (8.9%) 40 (6.5%) 50 (13%) <.001 Urgency <.001 Elective 31 (3.1%) 29 (4.7%) 2 (0.5%) Urgent 333 (33%) 271 (44%) 62 (16%) Emergency 551 (55%) 283 (46%) 268 (68%) Salvage 95 (9.4%) 34 (5.5%) 61 (16%) BMI 26.0 (23.7, 28.4) 26.0 (23.7, 28.4) 26.0 (23.8, 28.7) 0.3 CKD 181 (18%) 81 (13%) 100 (25%) <.001 Days from admission to surgery 1 (0, 5) 2 (1, 8) 1 (0, 2) <.001 Abbreviations: AF, atrial fibrillation; BMI, body mass index; CCS, Canadian Cardiovascular Society; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; CVA, cerebrovascular accidents; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NYHA, New York Heart Association; PCI, percutaneous coronary intervention; PVD, peripheral vessel disease; TIA, transient ischemic attack; UA, unstable angina; VF, ventricular fibrillation.

The median cardiopulmonary bypass time was 135 (104, 171 min) and the median cross-clamp time 88 (62–116 min) (Table 2). Fifty-four percent of patients underwent concomitant surgical revascularization, with a median number of grafts of 2 (1–2), and 2.5% underwent concomitant mitral valve procedures (Table 2).

Table 2. Operative characteristics in the overall cohort and according to the operative mortality outcome Characteristic Overall, N = 1010a Survivors, N = 617a Nonsurvivors, N = 393a p valueb Cardiopulmonary bypass time (min) 135 (104, 171) 128 (97, 162) 146 (115, 201) <0.001 Cross-clamp time (min) 88 (62, 116) 83 (60, 112) 90 (64, 130) <0.001 Concomitant CABG 543 (54%) 334 (54%) 209 (53%) 0.8 Concomitant MVP 25 (2.5%) 15 (2.4%) 10 (2.5%) 0.9 Number of grafts 1 (1–2) 1 (1–2) 1 (1–2) 0.4 Abbreviations: CABG, coronary artery bypass grafting; IQR, interquartile range; MVP, mitral valve procedures.

The overall operative mortality was 38.9% (n = 393) (Table 3). Patients who died were more likely to be older, have an impaired left ventricular and renal function, and present with unstable angina. Also, nonsurvivors tended to have undergone a previous PCI and be more critically ill presenting with cardiogenic shock, inotropic support and preoperative ventilation. VSD repair was more likely to be nonelective and take place within the first 24 h after MI in patients who died (Table 1). Over the years, the operative mortality ranged from 27.8% to 48.8% and did not change significantly (Figure 2). When the primary outcome was analysed according to the interval between MI and the surgical repair, the operative mortality was significantly higher in patients undergoing surgery within the first 24 h (75% and 61.3% if operated within 6 h or between 6 and 24 h, respectively) compared to patients with a delayed repair (Figure 3). Moreover, operative mortality did not differ significantly when isolated VSD repair was compared to VSD repaired with concomitant CABG and mitral valve surgery (Figure 4).

Table 3. In-hospital outcomes of patients undergoing surgical repair of postmyocardial infarction ventricular septal defect Characteristic Overall, N = 1010a Survivors, N = 617a Nonsurvivors, N = 393a p valueb Mortality 393 (38.9%) 0 (0) 393 (100%) Postoperative CVA .2 TIA 10 (1.1%) 8 (1.5%) 2 (0.6%) Stroke 29 (3.3%) 14 (2.6%) 15 (4.5%) Postoperative dialysis 244 (28%) 84 (15%) 160 (48%) <.001 Postoperative DSWI 3 (1.1%) 2 (1.2%) 1 (1.0%) >.9 Postoperative IABP 159 (37%) 85 (33%) 74 (43%) .035 Postoperative VAD 7 (1.9%) 2 (0.9%) 5 (3.3%) .12 Length of stay, days 11 (5, 21) 15 (9, 26) 3 (1, 10) <.001 Return to theatre due to bleeding 84 (8.3%) 43 (7.0%) 41 (10%) .05 Abbreviations: CVA, cerebrovascular accident; DSWI, deep sternal wound infection; IABP, intra-aortic balloon pump; IQR, interquartile range; TIA, transient ischemic attack; VAD, ventricular assist device.

Mortality rates over time following ventricular septal defect surgical repair

Operative mortality following ventricular septal defect surgical repair according to the interval between myocardial infarction (MI) and surgery

Operative mortality following surgical repair of ventricular septal defect (VSD) according to the type of procedure (isolated VSD repair; VSD and coronary artery bypass grafting [CABG]; VSD repair and CABG and mitral valve [MV] surgery). CABG, coronary artery bypass grafting; MV, mitral valve; VSD, ventricular septal defect

Patients presenting with deteriorated clinical conditions (e.g., cardiogenic shock) had a double rate of operative mortality compared to patients with stable hemodynamic (50.0% vs. 26.1%; p < .001). Among patients with cardiogenic shock, 125 (23%) received preoperative IABP, 36 also had an Impeller implanted and 1 a ventricular assist device. The operative mortality of patients with cardiogenic shock and supported by mechanical devices was not significantly different from the mortality of patients without mechanical support (49.6% vs. 50.1%; p = 1.0).

The multivariable regression model confirmed the trend towards a lower risk of operative mortality with delayed surgery, in particular surgical repair of VSD between 1 and 30 days after MI had an OR of 0.35 (95% CI: 0.12–0.99) and after 30 days the OR was 0.25 (95% CI: 0.08–0.80). Other risk factors associated with a worst mortality were older age, cardiogenic shock, renal failure and urgent or emergent operations (Table 4). PCI performed within 24 h of the index surgery was associated with a more than twofold higher odds of operative mortality (Table 4).

Table 4. Results of the generalized linear mixed effect model for the identification of risk factors associated with in-hospital mortality Mortality Predictors Odds ratios CI p (Intercept) 0.02 0.00–0.16 <.001 Age 1.03 1.02–1.05 <.001 CCS class 3 or 4 1.27 0.90–1.79 .173 MI < h Ref MI 6–24 h 0.58 0.20–1.69 .317 MI 1–30 days 0.35 0.12–0.99 .047 MI > 31 days 0.25 0.08–0.80 .019 No PCI Ref <24 h, same admission 2.38 1.34–4.23 .003 >24 h, same admission 1.66 1.07–2.59 .024 >24 h, previous admission 0.94 0.41–2.18 .887 Diabetes 1.30 0.85–1.99 .234 Poor LVEF (<30%) Ref Moderate LVEF (30%–50%) 0.67 0.48–0.94 .021 Normal LVEF (>50%) 1.28 0.84–1.96 .245 Cardiogenic shock 1.55 1.09–2.19 .014 Inotropic support 1.05 0.74–1.49 .779 Unstable angina 0.88 0.62–1.25 .478 Ventilation preoperatively 1.04 0.61–1.77 .877 Elective Ref Urgency 2.61 0.58–11.70 .211 Emergency 7.32 1.63–32.87 .009 Salvage 11.82 2.43–57.57 .002 CKD 1.72 1.18–2.53 .005 CABG 1.10 0.81–1.48 .544 MVP 1.40 0.50–3.92 .524 Random effects σ2 3.29 τ00 Consultant 0.03 τ00 HospCode 0.09 τ00 Year 0.00 ICC 0.03 N Consultant 379