Long-term outcome of patients undergoing re-exploration for bleeding following cardiac surgery: a SWEDEHEART study

Abstract

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OBJECTIVES

Excessive bleeding leading to re-exploration is a severe complication of cardiac surgical procedures, associated with early postoperative morbidity and mortality. Less is known about the long-term outcome of these patients. We evaluated the impact of re-exploration after cardiac surgery on peri- and postoperative morbidity and mortality, as well long-term mortality, in a well-defined nationwide population.

METHODS

In this retrospective study, 48 060 consecutive patients undergoing coronary artery bypass grafting (CABG) and/or valve surgery from 2006 to 2015 were analysed. Multivariable logistic regression was used to identify factors associated with re-exploration, morbidity and mortality. Cox regression analysis was implemented to explore the association between re-exploration and long-term mortality. The mean follow-up time was 4.6 years (range 0–10 years) with follow-up time set at 31 December 2015.

RESULTS

Overall, 2371 patients (4.9%) underwent re-exploration. Factors associated with re-exploration included advanced age, procedures other than isolated CABG and acute surgery. Re-explored patients had an increased risk of unadjusted mortality at 30, 90 and beyond 90 days (all P < 0.001). Significance was maintained after adjustment at 30 days [odds ratio: 3.94, 95% confidence interval (CI): 3.19–4.85, P < 0.001] and 90 days (odds ratio: 3.79, 95% CI: 3.14–4.55, P < 0.001), but not with long-term mortality (hazard ratio: 1.02, 95% CI: 0.91–1.15, P = 0.712). Furthermore, re-exploration was independently associated with other postoperative complications, e.g. prolonged hospital stay, stroke and renal injury.

CONCLUSIONS

Patients who are re-explored for bleeding within 24 h have almost four-fold higher odds of mortality within 3 months post-procedure. However, the increased risk of death following re-exploration is not maintained in the long term.

INTRODUCTION

Perioperative bleeding is a severe complication of cardiac surgical procedures, with reported re-exploration rates ranging between 2% and 7% in different studies [1–5]. The risk of re-exploration for bleeding has been associated with various patient-related and intraoperative factors, such as advanced age, small body surface area, renal insufficiency, type and extent of procedure, greater number of distal anastomoses, emergency status and preoperative exposure to platelet inhibitors [2, 3, 5]. Excessive bleeding and re-exploration have been linked to a substantially increased incidence of postoperative complications including myocardial infarction (MI), acute kidney injury (AKI), stroke, infections (including deep sternal wound infection), transfusion-related events and increased length of hospital stay and hospital costs [1–3, 5–7]. Correspondingly, numerous studies have shown a strong association between re-exploration for bleeding and early mortality, with a reported two- to six-fold increased risk of death in the early (within 30 days) postoperative period [1–5, 7–9]. Much less, however, is known about the long-term outcomes of these patients.

The aim of this study was therefore to analyse the associations between re-exploration for bleeding and early- and long-term morbidity and mortality following the most common cardiac surgical procedures in a large, whole-nation cohort of patients.

MATERIALS AND METHODS

Ethics statement

The study was approved by the Regional Ethics committee Board of Gothenburg (approval number 139-16, approved 4 April 2016), which waived the need for consent from individual patients. The study was performed in accordance with the 1975 Declaration of Helsinki To ensure anonymity and all personal identifiers were replaced by codes in the data set before analysis. The authors declare that the Strengthening the Reporting of Observational Studies in Epidemiology guidelines were followed in the creation of this manuscript [10].

Study population

The Swedish Cardiac Surgery Registry, which is a part of the Swedish Web System for Enhancement and Development of Evidence-Based care in Heart disease Evaluated According to Recommended Therapies (SWEDEHEART) registry [11] was used to identify all patients >18 years, who underwent cardiothoracic surgery from January 2006 to 31 December 2015. Surgical procedures that were included were coronary artery bypass grafting (CABG), valve replacement, valve repair or combined CABG and valve procedures. Surgery for congenital cardiac diseases or arrhythmias, heart transplantations and surgery of the thoracic or thoraco-abdominal aorta were excluded. The patients were identified in the SWEDEHEART registry using codes from the NOMESCO Classification of Surgical procedures, version 1.16 (Supplementary Material, Table S1). The final study size was 48 060.

Only re-exploration for excessive bleeding or tamponade within the first 24 h from the primary operation was included. In the SWEDEHEART registry, re-exploration for bleeding is a separate entity and does not include other causes of re-exploration. The decision to re-explore the patient was under the discretion of the attending surgeon. Patients who underwent re-exploration for bleeding were compared to patients who did not.

Data sources

In this population-based retrospective study, data were merged from 3 nationwide registries through a personal identification number, unique for all Swedish citizens. The SWEDEHEART registry contains information about pre-, intra-, and postoperative information for all patients who have undergone cardiac surgery in Sweden since 1992 with a coverage of 99% [12, 13]. From this registry, information about sex, age, body mass index (BMI), left ventricular ejection fraction (LVEF), history of a recent MI (i.e. within 90 days before surgery), previous percutaneous coronary intervention, preoperative serum creatinine (SCr), preoperative haemoglobin, European System for Cardiac Operative Risk Evaluation (EuroSCORE) I, preoperative use of aspirin [acetylsalicylic acid (ASA)] or other platelet inhibitors (i.e. within 5 days before surgery) was collected. Additional data of intraoperative variables were also collected from SWEDEHEART, i.e. type of surgical procedure, extracorporeal circulation, number of distal anastomoses, use of internal mammary artery whether the operation was acute and whether the patient was re-explored for bleeding. Acute operation was defined as surgery performed before the beginning of the next working day.

Information on the patient’s medical history such as history of diabetes, hypertension, dyslipidaemia, atrial fibrillation, heart failure, renal failure, history of bleeding (gastrointestinal, intracranial, pericardial or pulmonary haemorrhage), stroke, transient ischaemic attack and history of cancer was collected from the Swedish National Inpatient Register [14]. Diagnoses are based on the 10th revision of the International Classification of Diseases system (Supplementary Material, Table S2). Information on preoperative SCr was also obtained.

Data on morbidity were collected from the SWEDEHEART register. Information on date of death was collected from the Swedish Cause of Death Register [15]. Information on missing data can be found in Supplementary Material, Table S3. Missing values were not imputed and were handled with listwise deletion as missing values were determined to be missing at random and sufficient power was still maintained.

Outcomes

Outcome variables for which data were collected included length of stay at the hospital in days, perioperative AKI, perioperative stroke, postoperative atrial fibrillation and need for dialysis, extended mechanical ventilation or circulatory support postoperatively. Perioperative AKI was defined as a two-fold increase in SCr from preoperative status according to RIFLE criteria [16].

Mortality data included 30-day mortality, 90-day mortality and long-term mortality. Patients who died up to 30 days postoperatively were included in the data for 90-day mortality. Long-term mortality was defined as death occurring >90 days post-operatively (until the end of follow-up) with survival time being counted from the date of the operation. Patients who died before 90 days were excluded in this case, to remove the bias of early death on long-term analysis. The final follow-up date was 31 December 2015, with mean follow-up time being 4.6 ± 2.9 years (range 0–10 years; median 4.6 years; Q₁–Q₃ 2.2–7.1 years). Follow-up was 99.6% complete regarding mortality.

Statistical methods

Statistical analyses were performed in RStudio for Windows, version 4.0.4 (R Foundation for Statistical Computing, Vienna, Austria). Statistical significance was set at the 0.05 probability level. Categorical variables were described as proportions and continuous variables were described using means ± standard deviations or medians with Q₁–Q₃. The association of each variable with re-exploration for bleeding was evaluated using the appropriate statistical tests. For continuous variables, t tests or the nonparametric Wilcoxon–Mann–Whitney test was used, depending on whether or not the data were normally distributed. Due to sample size, the Anderson–Darling test was used to assess for sample normality for continuous variables. For categorical variables, the χ² test was applied as the minimum expected cell value was over 5 for all variables.

Multivariable logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the relationship between re-exploration for bleeding and various pre- and perioperative variables to identify predictors of re-exploration for bleeding, as well assessing the association between re-exploration and adverse outcomes other than mortality. A subset of the database including years 2013–2015 was used in the analysis of possible predictors of re-exploration; this is because the most recent years of the database included more complete data for some of the preoperative variables. Variable selection for the final models was based on factors associated with re-exploration for bleeding reported in previous literature. Crude and adjusted ORs are reported with 95% CIs and P-values. Similarly, for 30- and 90-day mortality, multivariable logistic regression was used with the aforementioned method and ORs with 95% CIs were reported. The final multivariable models both included 80.2% of the cohort.

Furthermore, long-term mortality was analysed with multivariable Cox proportional hazard regression. An identical stepwise selection method as mentioned above was utilized in Cox regression analysis, to find the best final model. All variables in the final model met the requirements of proportional hazards. The final model included 79.3% of the patients in the cohort. The adjusted hazard ratio (HR) from the final analysis, along with its 95% CI and P-value, is reported. Excluded from long-term mortality analysis were foreign citizens who were operated on acutely when visiting Sweden.

RESULTS

Overall, the cohort consisted of 74.2% males with a median age of 69.0 years (first to third quartile [Q₁–Q₃] 62–76; mean 68.1 ± 10.5 years). Of the 48 060 patients, 30 390 (63.2%) underwent isolated CABG, 11 899 (24.8%) underwent valve replacement or repair and 4653 (9.7%) had combined CABG and valve surgery.

The incidence of re-exploration for bleeding within the first 24 h was 4.9% (n = 2371). Patients in the re-exploration group differed in several ways from the control group, as shown in Table 1. A higher proportion of them were males, were older and had lower BMI, lower LVEF, higher EuroSCORE, higher preoperative SCr and lower haemoglobin (all P < 0.001). Re-explored patients were also more likely to have had various comorbidities such as recent MI (P = 0.005), heart failure (P < 0.001), renal failure (P < 0.001), atrial fibrillation (P = 0.012) and a history of bleeding (P < 0.001). Re-explored patients had a lower incidence of diabetes mellitus (P = 0.046). Preoperative use of platelet inhibitors other than ASA within 5 days before surgery was more common (6.3% vs 4.7%, P < 0.001) in re-explored patients. The 2 groups did not differ significantly regarding preoperative use of ASA (P = 0.916).

The re-exploration rates for different types of surgery were 4.1% (n = 1253), 5.2% (n = 619) and 8.9% (n = 412) for CABG, valvular surgery and CABG and valvular surgery combined, respectively. Re-explored patients were more likely to have undergone combined CABG and valve surgery than non-reexplored patients (P < 0.001). Compared to the non-reexplored group, fewer re-explored patients underwent CABG surgery (P < 0.001). Acute operations (4.0% of all cases) were also more common among re-explored patients, 9.5% (n = 183) of acutely operated patients underwent re-exploration for bleeding, as compared with 4.7% (n = 1945) of patients who had elective or urgent surgery (P < 0.001).

Factors associated with re-exploration for bleeding

Table 2 shows crude odds ratio (OR) for each variable and the adjusted OR for independent risk factors of re-exploration for bleeding in the final multivariable model. Independent risk factors for re-exploration were advanced age, exposure to platelet inhibitors other than ASA within 5 days before surgery, increased preoperative SCr, surgical procedure other than isolated CABG, greater number of distal anastomoses and acute surgery. Female sex, on the other hand, was identified as a protective factor regarding re-exploration for bleeding (OR 0.76, CI: 0.61–0.95, P = 0.017). Preoperative use of aspirin, history of bleeding and the use of extracorporeal circulation were not identified as independent predictors for re-exploration. A subanalysis of CABG patients (i.e. isolated CABG and CABG with valve surgery) is presented in Supplementary Material, Table S4.

Peri- and postoperative morbidity

The outcomes of logistic regression analysis evaluating the impact of re-exploration for bleeding on other adverse outcomes are shown in Table 3. Re-exploration for bleeding was significantly associated with an increased unadjusted risk of complications in the peri- and postoperative period, e.g. stroke, AKI, new-onset atrial fibrillation, and postoperative need for dialysis, extended mechanical ventilation and the need for circulatory support. Re-exploration was also independently associated with prolonged hospital stay (≥10 days), with median length of stay postoperatively being 12 days (Q₁–Q₃ 8–20 days) for re-explored patients compared to 9 days (Q₁–Q₃ 7–14 days) for controls (P < 0.001). After adjustment the association remained significant for each of these adverse outcomes for patient characteristics, type and acuteness of surgery and comorbidities at baseline.

Mortality

Overall, 7862 patients (16.4%) died during the study period (mean 4.6 years), 83.2% of whom (n = 6540) died >90 days postoperatively. Nine hundred and forty-three patients (2.0%) died within the first 30 postoperative days, and 1322 patients (2.8%) died within the first 90 days. As shown in Fig. 1, unadjusted mortality rates were significantly higher among patients who underwent re-exploration at both 30 and 90 days postoperatively, but not beyond 90 days.

Early mortality

Unadjusted 30-day mortality was over four-fold higher in the re-exploration group than in the non-re-exploration group (7.4% vs 1.7%, OR 4.66, 95% CI: 3.92–5.51, P < 0.001). In Fig. 2, outcomes of the final multivariable model are presented. After adjustment, the OR of re-exploration for bleeding for 30-day mortality was 3.94 (95% CI: 3.19–4.85, P < 0.001). As for 30-day mortality, the unadjusted 90-day mortality rate was also over four-fold higher among re-explored patients (9.6% vs 2.4%, OR 4.43, 95% CI: 3.73–5.02, P < 0.001). Results of the final multivariable model are shown in Fig. 3, where the OR of re-exploration for bleeding for 90-day mortality was 3.69 (95% CI: 3.01–4.51; P < 0.001) after adjustment. Other independently associated factors for 30- and 90-day mortality were included advanced age, female sex, BMI >30, LVEF <50%, diabetes, hypertension, higher preoperative SCr, higher EuroSCORE, surgical procedure other than isolated CABG and acute operations. A subanalysis of only those patients who underwent CABG (i.e. isolated CABG and CABG with valve surgery), with regard to short-term mortality, is included in Supplementary Material, Tables S5 and S6.

Long-term mortality

At 1 year following surgery, unadjusted cumulative survival was 88.3% for re-explored patients compared to 96.0% for controls (P < 0.001). Unadjusted cumulative survival at 5 and 10 years for re-explored patients was 76.9% and 61.1%, respectively, compared to 85.9% and 68.2% for controls (P < 0.001, log-rank test). The unadjusted HR for re-exploration for bleeding was 1.23 (95% CI: 1.11–1.38, P < 0.001) during the study period. The adjusted analysis for long-term mortality (with mortality before 90 days excluded) is shown in Fig. 4. Independent factors at baseline associated with long-term mortality were advanced age, BMI above or below the ‘overweight’ range, LVEF ≤50%, diabetes, hypertension, history of cancer, higher preoperative SCr, high EuroSCORE, valve surgery or combined CABG and valve surgery, perioperative AKI and perioperative stroke. Re-exploration, however, was not associated with a significantly increased hazard of death in the long term after adjustment, with an HR of 1.02 (95% CI: 0.91–1.15, P = 0.712). Supplementary Material, Table S7 includes a subanalysis on the long-term mortality of only those patients who underwent CABG (i.e. isolated CABG and CABG with valve surgery).

DISCUSSION

In this large, nationwide observational study of cardiac surgical patients, the main finding was that re-exploration for bleeding after cardiac surgery was associated with a sigificantly increased adjusted risk for early mortality but not for mortality beyond 90 days.

In the present study, 4.9% of CABG and/or valve surgery patients underwent re-exploration because of major bleeding. This figure is comparable to or higher than reported in most previous studies on the subject where it most often ranges from 2% to 7% [1–5]. However, previous studies are almost exclusively single-centre studies, with an obvious risk for reporting bias (i.e. it is more common that centres with low incidences of re-exploration publish their results). In contrast, the present study is a nationwide study based on a registry where it is mandatory to report re-explorations, which may, at least partially, explain the higher figure. Numerous factors may influence the decision to re-explore, including the amount of bleeding, the clinical status of the patients and echocardiographic findings as well as institutional traditions.

In alignment with previous studies on this subject, the present study showed that there were strong associations between re-exploration for bleeding after cardiac surgery and early complications, including early mortality [1–5, 7–9]. However, the causality between re-exploration for bleeding and poor early outcome remains incompletely understood [4, 5, 7]. Several factors may contribute, including loss of blood, excess transfusion of blood products and volume expanders, repeat sternotomy, and, in severe cases, the effects of cardiac tamponade with resulting hypotension and hypovolaemia [17]. Unfortunately, the present registry-based study lacks detailed information about these factors and hence cannot solve the causality issue. As is shown in Table 1, patients who underwent re-exploration had a higher burden of comorbidities, a higher EuroSCORE, and were more likely to have undergone acute surgery and surgery other than isolated CABG. These are all factors that have been shown increased mortality. However, in the final analysis, we tried to isolate the effect of re-exploration on mortality by correcting for the most important comorbidities and operative factors in the final models, as shown in Figs 2–4.

In contrast to the many studies that have focused on the association between re-exploration and early mortality and morbidity in cardiac surgery patients, the present study included the associations with long-term outcome, on which there is a paucity of studies. Brown et al. [9] investigated in a single-centre study 10 824 patients out of whom 292 (2.7%) were reexplored for bleeding. After exclusion of patients who died before discharge, the authors found that the re-exploration group had a significantly increased long-term risk of death, as compared to the group not requiring re-exploration (adjusted HR 1.59, 95% CI: 1.21–2.09). Similar results were reported in another single-center study by Fröjd and Jeppsson [5] of 5362 patients, of who 320 (6.0%) were re-explored and the mortality risk beyond 90 days was increased in re-explored patients [adjusted HR 1.72 (95% CI 1.14–2.61)]. In contrast to these studies, Marteinsson et al. [18] showed in a nationwide study from Iceland that included 130 re-explorations in 2060 patients (6.1%) no difference in adjusted long-term mortality. Their findings are in line with the current study that included multiple centres in a nationwide cohort of 2371 re-explorations in 48 060 patients (4.9%), with almost complete follow-up. Both these latter studies therefore show that there is no significant association between re-exploration and long-term adjusted mortality risk in patients who survived 90 days after the index operation. Thus, the difference in survival stems mainly from short-term mortality rates, whereas if re-explored patients survive beyond the first 90 days, their survival is comparable to those who were not re-explored.

Strengths and limitations

This study has both limitations and strengths. As in all retrospective observational studies, there is an inherent risk of selection bias and residual confounding. Hence, the findings are associative and our results should be interpreted as hypothesis generating rather than conclusive. Only first-time procedures were included in our database, to have a homogenous study population and, therefore, the results may not be valid in re-sternotomies. Furthermore, the criteria for re-exploration may differ between institutions and even between individual surgeons at a centre, which may introduce bias. Also, in the SWEDEHEART registry, re-exploration for bleeding is defined as a procedure that is performed within 24 h. Re-explorations after 24 h are hence not registered, which may lead to an underestimation of the number of re-explorations, but a previous study by Smarason et al. [19] showed that later re-explorations for bleeding are rare (<3%). Finally, although we used validated registries, underreporting and misreporting may influence results in registry studies. The strengths include a large study population in a real-world setting, the long and extensive follow-up, the nationwide coverage with a high degree of data completeness and a primary end point (all-cause mortality) not subjected to bias.

CONCLUSION

In conclusion, cardiac surgery patients with postoperative bleeding that necessitates re-exploration have a significantly increased risk for early complications, including almost four-fold higher odds of early mortality. The long-term mortality risk in re-explored patients surviving beyond 3 months, however, is not different to patients who have not undergone re-exploration. Therefore, if re-explored patients survive the early postoperative period, their long-term prognosis is as good as for non-reexplored patients.

SUPPLEMENTARY MATERIAL

Supplementary material is available at EJCTS online.

Funding

The authors received no funding for the research, authorship or publication of this article.

Conflict of interest: The authors have no conflicts of interest to declare that are relevant to the content of this article.

Data Availability Statement

The data underlying this article was provided by SWEDEheart and national healthcare registries in Sweden. Data will be shared after approval from the SWEDEHEART registry and the Swedish Board of Health and Welfare and on reasonable request to the corresponding author.

Author contributions

Alexandra A. Heimisdottir: Conceptualization; Formal analysis; Investigation; Methodology; Software; Visualization; Writing—original draft. Susanne J. Nielsen: Data curation; Methodology; Writing—review & editing. Martin Karlsson: Writing—review & editing. Anders Jeppsson: Conceptualization; Formal analysis; Investigation; Methodology; Supervision; Validation; Visualization; Writing—original draft; Writing—review & editing. Tomas Gudbjartsson: Conceptualization; Formal analysis; Investigation; Methodology; Project administration; Supervision; Validation; Visualization; Writing—review & editing.

Reviewer information

European Journal of Cardio-Thoracic Surgery thanks Monica Contino, Walter J. Gomes, Fabio Miraldi and the other, anonymous reviewer(s) for their contribution to the peer review process of this article.

Presented at the 35th Annual Meeting of the European Association for Cardio-Thoracic Surgery, Barcelona, Spain, 13–16 October 2021.

REFERENCES

ABBREVIATIONS

ABBREVIATIONS
 
• AKI

  Acute kidney injury

 
• ASA

  Acetylsalicylic acid

 
• BMI

  Body mass index

 
• CABG

  Coronary artery bypass grafting

 
• CI

  Confidence interval

 
• EuroSCORE

  European System for Cardiac Operative Risk Evaluation

 
• HR

  Hazard ratio

 
• LVEF

  Left ventricular ejection fraction

 
• MI

  Myocardial infarction

 
• OR

  Odds ratio

 
• SCr

  Serum creatinine

 
• SWEDEHEART

  Swedish Web System for Enhancement and Development of Evidence-Based care in Heart disease Evaluated According to Recommended Therapies