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Preoperative heart disease and risk for postoperative complications after pancreatoduodenectomy

  • Patrik Larsson
    Correspondence
    Correspondence: Patrik Larsson, Department of Surgery, Skelleftea County Hospital, Skelleftea, Sweden.
    Affiliations
    Department of Surgery, Skelleftea County Hospital, Skelleftea, Sweden

    Department of Clinical Science, Intervention and Technology (CLINTEC), Division of Surgery, Karolinska Institutet, Stockholm, Sweden
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  • Kari Feldt
    Affiliations
    Department of Medicine, Unit of Cardiology, Karolinska Institutet, Stockholm, Sweden

    Heart and Vascular Theme, Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden
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  • Marcus Holmberg
    Affiliations
    Department of Clinical Science, Intervention and Technology (CLINTEC), Division of Surgery, Karolinska Institutet, Stockholm, Sweden

    Department of Upper Abdominal Diseases, Karolinska University Hospital, Stockholm, Sweden
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  • Oskar Swartling
    Affiliations
    Department of Medicine, Clinical Epidemiology Division, Karolinska Institutet, Stockholm, Sweden
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  • Ernesto Sparrelid
    Affiliations
    Department of Clinical Science, Intervention and Technology (CLINTEC), Division of Surgery, Karolinska Institutet, Stockholm, Sweden

    Department of Upper Abdominal Diseases, Karolinska University Hospital, Stockholm, Sweden
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  • Fredrik Klevebro
    Affiliations
    Department of Clinical Science, Intervention and Technology (CLINTEC), Division of Surgery, Karolinska Institutet, Stockholm, Sweden

    Department of Upper Abdominal Diseases, Karolinska University Hospital, Stockholm, Sweden
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  • Poya Ghorbani
    Affiliations
    Department of Clinical Science, Intervention and Technology (CLINTEC), Division of Surgery, Karolinska Institutet, Stockholm, Sweden

    Department of Upper Abdominal Diseases, Karolinska University Hospital, Stockholm, Sweden
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Open AccessPublished:July 07, 2022DOI:https://doi.org/10.1016/j.hpb.2022.07.002

      Abstract

      Background

      Comorbidities increase the risk for postoperative complications after pancreatoduodenectomy. The importance of different categories of heart disease on postoperative outcomes has not been thoroughly studied.

      Methods

      Patients aged ≥18 years undergoing pancreatoduodenectomy between 2008 and 2019 at Karolinska University Hospital, Sweden were included. Heart disease was defined as a preoperatively established diagnosis, and subcategorized into ischaemic, valvular, heart failure and atrial fibrillation. Postoperative outcome was analysed by multivariable regression.

      Results

      Out of 971 patients, 225 (23.3%) had heart disease. Heart disease was associated with an increased risk for complications; Clavien–Dindo score ≥ IIIa (Odds Ratio [OR] 1.53, 95% confidence interval [CI] 1.07–2.18; p = 0.019), intensive care unit admissions (OR 3.20, 95% CI 1.81–5.66; p < 0.001) and longer hospitalizations (median 14 vs. 11 days; p < 0.001). Although heart disease was not associated with 90-day mortality, it conferred a shorter median overall survival (22 vs. 32 months; p < 0.001). Atrial fibrillation and heart failure were each associated with increased risk for postoperative complications, whereas ischaemic and valvular heart disease were not.

      Conclusion

      Atrial fibrillation and heart failure were independently associated with increased risk for postoperative complications. Despite no association with early postoperative mortality, heart disease negatively affected long-term survival.

      Introduction

      Pancreatoduodenectomy is a complex procedure used to treat malignancies in the pancreatic head.
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      It is associated with significant post-operative risks and 90-day mortality is reported to be 1–8 per cent.
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      The 90-day mortality after pancreatectomy for cancer is double the 30-day mortality: more than 20,000 resections from the national cancer data base.
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      • et al.
      Age comorbidity scores as risk factors for 90-day mortality in patients with a pancreatic head adenocarcinoma receiving a pancreaticoduodenectomy: a National Population-Based Study.
      In spite of surgical resection, the prognosis remains dismal with a five-year survival rate ranging from 25 to 40 per cent.
      • Strobel O.
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      • Büchler M.W.
      Optimizing the outcomes of pancreatic cancer surgery.
      Although the risk for postoperative complications has decreased in the last decades due to advances in perioperative management,
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      • Rosemurgy A.
      Has survival improved following resection for pancreatic adenocarcinoma?.
      the risks associated with pancreatoduodenectomy remain high. Therefore, it is challenging to determine if the possible benefits of surgery outweigh the risks.
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      • Fisher W.E.
      Pancreatic cancer: advances in treatment.
      Preoperative assessment of comorbidities offers an avenue of treatment optimization which may decrease risks associated with surgery.
      • Tateosian V.S.
      • Richman D.C.
      Preoperative cardiac evaluation for noncardiac surgery.
      Some comorbidities, including heart disease, increase the risk of postoperative complications after pancreatic surgery.
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      • Lin C.P.
      • Kelly K.J.
      • Cho C.S.
      • Winslow E.R.
      • et al.
      Impact of cardiac comorbidity on early outcomes after pancreatic resection.
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      • D'Ambra M.
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      • et al.
      Pancreatic resection in patients 80 years or older: a meta-analysis and systematic review.
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      • Rajamanickam V.
      • Wan Y.
      • Hanson T.
      • Rettammel R.
      • et al.
      Preoperative factors predict perioperative morbidity and mortality after pancreaticoduodenectomy.
      There are several formulae designed to estimate the effect of comorbidities on complications, one being Charlson Comorbidity Index.
      • Charlson M.E.
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      • Ales K.L.
      • MacKenzie C.R.
      A new method of classifying prognostic comorbidity in longitudinal studies: development and validation.
      Many of these preoperative risk estimation models are, however, mainly dichotomous and do not account for different types of heart disease.
      • Asano T.
      • Yamada S.
      • Fujii T.
      • Yabusaki N.
      • Nakayama G.
      • Sugimoto H.
      • et al.
      The Charlson age comorbidity index predicts prognosis in patients with resected pancreatic cancer.
      • Hill J.S.
      • Zhou Z.
      • Simons J.P.
      • Ng S.C.
      • McDade T.P.
      • Whalen G.F.
      • et al.
      A simple risk score to predict in-hospital mortality after pancreatic resection for cancer.
      • Shah R.
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      • Syed Z.
      • Swartz A.
      • Rubinfeld I.
      Limitations of patient-associated co-morbidity model in predicting postoperative morbidity and mortality in pancreatic operations.
      • Joliat G.R.
      • Petermann D.
      • Demartines N.
      • Schäfer M.
      External assessment of the early mortality risk score in patients with adenocarcinoma undergoing pancreaticoduodenectomy.
      The aim of this study was to investigate the impact of different categories of heart disease on morbidity and mortality after pancreatoduodenectomy.

      Methods

      Study population

      All adult patients (age ≥ 18 years) treated with pancreatoduodenectomy, regardless of indication, between January 2008 and June 2019 at Karolinska University Hospital, Stockholm, Sweden, a tertiary referral centre for pancreatic surgery, were included. Patients with prior pancreatic surgery were excluded. Data were systematically and prospectively collected via electronic health records, and thereafter retrospectively controlled and classified.
      The study was reported in accordance to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines
      • von Elm E.
      • Altman D.G.
      • Egger M.
      • Pocock S.J.
      • Gøtzsche P.C.
      • Vandenbroucke J.P.
      • et al.
      The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies.
      and approved by the National Ethical Review Agency (registration number: 2020/05238).

      Data variables and definitions

      Baseline characteristics

      Data were collected on age, Body Mass Index (BMI), sex, estimated glomerular filtration rate (eGFR), American Society of Anaesthesiologists – Physical Status (ASA-PS) classification,
      • Hurwitz E.E.
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      • Minhajuddin A.
      • et al.
      Adding examples to the ASA-physical status classification improves correct assignment to patients.
      Eastern Cooperative Oncology Group (ECOG) Performance Status,
      • Kelly C.M.
      • Shahrokni A.
      Moving beyond Karnofsky and ECOG performance status assessments with new technologies.
      preoperative smoking status, history of hypertension and diabetes, pathological report on operative specimen and ejection fraction (EF) on preoperative echocardiography, if present.

      Heart disease

      The data on cardiac diagnosis/heart disease were based on systematic review of the patients' electronic health records. Heart disease was defined as a preoperatively established cardiac diagnosis, and was coded according to the International Statistical Classification of Diseases and Related Health Problems (ICD) 10th version,
      • Brämer G.R.
      International statistical classification of diseases and related health problems.
      or classified according to pathological findings on preoperative echocardiography, not older than 6 months at the time of surgery. Heart disease was a priori categorized into four groups; ischaemic heart disease, atrial fibrillation, heart failure and valvular heart disease.
      Ischaemic heart disease was defined as preoperative myocardial infarction, previous percutaneous coronary intervention, a diagnosis of angina pectoris or chronic coronary disease. Heart failure was defined as presence of a preoperatively established heart failure diagnosis, or a left ventricular ejection fraction less than 40 per cent on a preoperative echocardiography, if available. For patients without an available echocardiography, either symptoms of heart failure requiring medical treatment or elevated biochemical markers (such as natriuretic peptides) had to be present. Valvular disease was defined as a preoperative established diagnosis of aortic stenosis or an aortic valve continuous doppler flow velocity of >2.5 m/s, or a diagnosis of mitral regurgitation, or at least moderate mitral regurgitation on a pre-operative echocardiography. Atrial fibrillation was defined as any preoperative history of diagnosed atrial fibrillation, whether paroxysmal, persistent or permanent. For a detailed list of ICD-codes and echocardiographic criteria, see the supplementary material (Table S1). Any case of de novo peri- or postoperative heart disease diagnosis without recorded preoperative clinical findings supporting that diagnosis preoperatively was not classified as a preoperative condition.

      Outcomes

      The primary outcome measure was postoperative complication defined as Clavien–Dindo (CD) score ≥ IIIa.
      • Dindo D.
      • Demartines N.
      • Clavien P.A.
      Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey.
      Secondary outcomes were 30-day, 90-day and overall mortality, 1-, 3- and 5-year survival, intensive care unit (ICU) admission, length of stay in the ICU and length of stay in hospital. Delayed gastric emptying, postoperative pancreatic fistula, postoperative pancreatic haemorrhage and bile leakage were also considered secondary outcomes and classified according to the International Study Group of Pancreatic Surgery (ISGPS) and International Study Group of Liver Surgery (ISGLS) guidelines; only grade B and C complications were considered to be of clinical relevance.
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      • Adham M.
      • et al.
      The 2016 update of the International Study Group (ISGPS) definition and grading of postoperative pancreatic fistula: 11 years after.
      • Wente M.N.
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      • Gouma D.J.
      • et al.
      Postpancreatectomy hemorrhage (PPH): an international study group of pancreatic surgery (ISGPS) definition.
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      • Fingerhut A.
      • Gouma D.J.
      • Izbicki J.R.
      • et al.
      Delayed gastric emptying (DGE) after pancreatic surgery: a suggested definition by the International Study Group of Pancreatic Surgery (ISGPS).
      • Shukla P.J.
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      • Fingerhut A.
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      • Dervenis C.
      • et al.
      Toward improving uniformity and standardization in the reporting of pancreatic anastomoses: a new classification system by the International Study Group of Pancreatic Surgery (ISGPS).

      Statistical analysis

      Categorical variables were analysed using Chi-square test or Fisher's exact test and presented as counts with percentages. Continuous data were analysed with independent samples t-test or Mann–Whitney U test and presented as medians with interquartile range (i.q.r). Normality was tested using the Shapiro–Wilk test.
      Survival was analysed using the Kaplan–Meier method and analysed with the log rank test. Multivariable logistic regressions were performed to analyse the association between heart disease and postoperative complications. Results of the logistic regression analyses were presented in odds ratio (OR) and 95 per cent confidence intervals (CI). Variables in the multivariable logistic regression model were decided a priori and included: age (continuous), sex (male, female), smoking (never, active, previous), hypertension (no, yes), BMI (continuous), diabetes mellitus (no, yes), pulmonary disease (any degree of chronic obstructive pulmonary disease or pulmonary fibrosis) and eGFR (continuous). Statistical significance was considered as two-tailed p-value <0.050. All analyses were performed with StataCorp. 2013. Stata Statistical Software: Release 13. College Station, TX: StataCorp LP.

      Results

      In total, 971 patients met the inclusion criteria, of which 225 (23.2 per cent) had at least one preoperative cardiac diagnosis (Fig. 1). The median follow-up time was 6.2 years (i.q.r 3.5 years–8.9 years). Among all patients, 122 (12.6 per cent) had atrial fibrillation, 107 (11.0 per cent) had ischaemic heart disease, 52 (5.4 per cent) had heart failure and 25 (2.6 per cent) had valvular heart disease. Patients with heart disease were older, predominantly male and had higher ASA-PS and ECOG-levels. Additionally, hypertension and diabetes were more prevalent among patients with heart disease (Table 1). Also, patients with heart disease were more often evaluated with a preoperative echocardiography than those without heart disease. There was no difference in the proportion of malignant histopathology in the postoperative specimens when comparing patients with and without heart disease. All patients with valvular heart disease had an available standard transthoracic echocardiography.
      Table 1Baseline characteristics of patients with and without heart disease undergoing pancreatoduodenectomy
      No heart disease (n = 746)Heart disease (n = 225)Overall (n = 971)p value†
      Age (years)
      Indicates median (interquartile range).
      67.3 (60.6–74.0)72.1 (67.1–77.1)68.4 (62.0–74.8)<0.001‡
      BMI (kg/m2)
      Indicates median (interquartile range).
      24.3 (21.6–27.0)24.8 (22.2–27.4)24.4 (21.8–27.0)0.110‡
      Sex<0.001
       Men366 (49.1)152 (67.6)518 (53.4)
       Women380 (50.9)73 (32.4)453 (46.7)
      eGFR (ml/min/1.73 m2)
      Indicates median (interquartile range).
      90 (78–102)90 (78–102)90 (78–102)0.913‡
      ASA grade<0.001
       1102 (13.7)6 (2.7)108 (11.1)
       2459 (61.5)91 (40.4)550 (56.6)
       3180 (24.1)118 (52.4)298 (30.7)
       45 (0.7)10 (4.4)15 (1.5)
      ECOG performance status0.001
       0482 (64.6)112 (49.8)594 (61.2)
       1107 (14.3)45 (20.0)152 (15.7)
       225 (3.4)16 (7.1)41 (4.2)
       33 (0.4)3 (1.3)6 (0.6)
       Missing129 (17.3)49 (21.8)178 (18.3)
      Smoking0.511
       Never546 (73.2)158 (70.2)704 (72.5)
       Currently141 (18.9)44 (19.6)185 (19.1)
       Former59 (7.9)23 (10.2)82 (8.4)
      Hypertension193 (25.9)125 (55.6)318 (32.8)<0.001
      Diabetes107 (14.3)73 (32.4)180 (18.5)<0.001
      Malignant histology570 (76.4)182 (80.9)752 (77.5)0.159
      Preoperative echocardiography57 (7.6)90 (40.0)147 (15.1)<0.001
      Ejection fraction<0.001
       ≥40%55 (96.5)73 (81.1)128 (87.1)
       <40%0 (0.0)17 (18.9)17 (11.6)
       Missing2 (3.5)0 (0.00)2 (1.4)
      Values in parenthesis are percentages unless indicated otherwise. p-value indicates difference between patients with and without heart disease. †χ2 test, except ‡Mann–Whitney U-test.
      a Indicates median (interquartile range).
      Postoperative outcomes are presented in Table 2. The proportion of patients with severe complications, defined as CD score ≥ IIIa (32.9 per cent vs. 24.7 per cent, p = 0.014) and delayed gastric emptying grade B–C (38.7 per cent vs. 28.2 per cent, p = 0.003), was higher among patients with heart disease compared to patients without heart disease. The median hospital length of stay was longer (14 days vs. 11 days, p < 0.001) and the proportion of ICU admission higher (14.2 per cent vs. 4.7 per cent, p < 0.001) compared to patients with no heart disease.
      Table 2Postoperative morbidity and mortality according to the presence of heart disease at baseline
      No heart disease (n = 746)Heart disease (n = 225)Overall (n = 971)p value†
      CD grade IIIa-V184 (24.7)74 (32.9)258 (26.6)0.014
      30-day mortality13 (1.7)5 (2.2)18 (1.9)0.640
      90-day mortality22 (3.0)13 (5.8)35 (3.6)0.046
      Median survival (months)
      Values are median (interquartile range).
      31.6 (10.5–52.7)21.8 (5.7–37.9)28.7 (8.2–49.2)<0.001‡
      1-year survival615 of 746 (82.4)172 of 225 (76.4)787 of 971 (81.1)0.044
      3-year survival325 of 601 (54.1)69 of 186 (37.1)394 of 787 (50.1)<0.001
      5-year survival175 of 431 (40.6)38 of 148 (25.7)213 of 579 (36.8)<0.01
      Days of hospital stay
      Values are median (interquartile range).
      11 (7–15)14 (8–20)12 (8–16)<0.001‡
      Days in hospital<0.001
       1–13 days470 (63.0)111 (49.3)581 (59.8)
       ≥14 days276 (37.0)114 (50.7)390 (40.2)
      ICU admission35 (4.7)32 (14.2)67 (6.9)<0.001
      Days of ICU stay
      Values are median (interquartile range).
      5 (0–10)5.5 (1–10)5 (0–10)0.875‡
      Days in ICU<0.001
       0 days711 (95.3)193 (85.8)904 (93.1)
       1–6 days21 (2.8)19 (8.4)40 (4.1)
       7–13 days6 (0.8)6 (2.7)12 (1.2)
       ≥14 days8 (1.1)7 (3.1)15 (1.5)
      DGE grade B–C210 (28.2)87 (38.7)297 (30.6)0.003
      POPF grade B–C126 (16.9)48 (21.3)174 (17.9)0.128
      PPH grade B–C81 (10.9)35 (15.6)116 (12.0)0.057
      Bile leakage grade B–C24 (3.2)11 (4.9)35 (3.6)0.238
      CD, Clavien–Dindo; ICU, intensive care unit; DGE, delayed gastric emptying, POPF, postoperative pancreatic fistula; PPH, post pancreatectomy haemorrhage. Values in parenthesis are percentages unless indicated otherwise. †χ2 test, except ‡Student's t test.
      a Values are median (interquartile range).
      In a multivariable logistic regression analysis, heart disease was associated with increased risk for severe complications with CD score ≥ IIIa (OR 1.53, 95% CI 1.07–2.18, p = 0.019), ICU admission, hospital stay ≥14 days and delayed gastric emptying grade B–C compared to patients with no heart disease (Table 3).
      Table 3Multivariable logistic regressions for postoperative complications according to categories of heart disease at baseline
      Heart diseaseAtrial fibrillationIschaemic heart diseaseHeart failureValvular heart disease
      Odds ratioOdds ratioOdds ratioOdds ratioOdds ratio
      CD grade IIIa-V1.53 (1.07–2.18)1.53 (1.00–2.32)1.55 (0.97–2.46)2.25 (1.25–4.02)0.84 (0.33–2.15)
      30-day mortality0.87 (0.28–2.68)1.33 (0.40–4.42)0.79 (0.17–3.72)1.44 (0.30–6.79)1
      90-day mortality1.62 (0.75–3.49)1.36 (0.55–3.33)1.37 (0.52–3.62)1.23 (0.35–4.29)2.00 (0.44–8.98)
      ICU admission3.19 (1.81–5.63)2.44 (1.32–4.53)2.55 (1.31–5.00)3.02 (1.39–6.55)1.09 (0.25–4.77)
      Hospital stay ≥ 14 days1.65 (1.19–2.28)1.70 (1.15–2.53)1.08 (0.70–1.67)1.92 (1.08–3.42)1.09 (0.49–2.44)
      DGE grade B–C1.45 (1.03–2.04)1.33 (0.88–2.00)1.42 (0.91–2.22)1.79 (1.00–3.18)0.98 (0.41–2.32)
      POPF grade B–C1.27 (0.84–1.94)1.44 (0.89–2.34)0.67 (0.35–1.25)0.81 (0.37–1.77)0.37 (0.08–1.62)
      PPH grade B–C1.56 (0.97–2.52)1.59 (0.91–2.76)1.71 (0.95–3.08)1.29 (0.58–2.89)1.39 (0.46–4.18)
      Bile leakage grade B–C1.70 (0.75–3.86)1.81 (0.72–4.51)0.24 (0.03–1.82)1.71 (0.48–6.07)1.16 (0.15–8.98)
      CD, Clavien–Dindo; ICU, intensive care unit; DGE, delayed gastric emptying, POPF, postoperative pancreatic fistula; PPH, post pancreatectomy haemorrhage. Values in parenthesis are 95 per cent confidence interval. The following covariates were included in the multivariable logistic regression models: age, sex, BMI, eGFR, diabetes mellitus, hypertension, smoking status, pulmonary disease.
      Multivariable logistic regression analyses showed that atrial fibrillation and heart failure were independent risk factors for severe complications with CD score ≥ IIIa, and hospital length of stay ≥14 days. Also, ischaemic heart disease, atrial fibrillation and heart failure were associated with increased risk of ICU admission. Heart failure was associated with increased risk for DGE grade B–C (Table 3).
      There was no difference in 30-day mortality rate when comparing patients with and without heart disease (Table 2). The 90-day mortality rate was higher for patients with heart disease compared to patients without heart disease (5.8 per cent vs. 3.0 per cent, p = 0.046). However, there was no association between heart disease and risk of 90-day mortality in a multivariable adjusted logistic regression analysis (Table 3). Overall, patients with heart disease had a shorter median survival (21.8 months vs. 31.6 months; p < 0.001) and lower rates of 1-, 3- and 5-year survival than patients with no heart disease (Fig. 2). The proportion of malignant diagnosis among patients surviving 5 years or more did not differ significantly between patients with and without heart disease (24 patients, 63.2 per cent vs. 100 patients, 57.1 per cent respectively, p = 0.496).
      Figure 2
      Figure 2Kaplan–Meier overall survival curves in patients undergoing pancreatoduodenectomy, stratified by presence of heart disease. p < 0.001 (log rank test) when comparing groups with malignant histology; p = 0.001 (log rank test) when comparing groups with benign histology

      Discussion

      This high-volume, single centre cohort study, including 971 consecutive patients with a study period of more than ten years, affirms that heart disease is associated with postoperative complications after pancreatoduodenectomy.
      While it has been shown that preoperative heart disease is a risk factor for complications after pancreatic surgery, the reported risks associated with different types of heart disease have varied between studies.
      • Ronnekleiv-Kelly S.M.
      • Greenblatt D.Y.
      • Lin C.P.
      • Kelly K.J.
      • Cho C.S.
      • Winslow E.R.
      • et al.
      Impact of cardiac comorbidity on early outcomes after pancreatic resection.
      ,
      • Asano T.
      • Yamada S.
      • Fujii T.
      • Yabusaki N.
      • Nakayama G.
      • Sugimoto H.
      • et al.
      The Charlson age comorbidity index predicts prognosis in patients with resected pancreatic cancer.
      ,
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      • Zhou Z.
      • Simons J.P.
      • Ng S.C.
      • McDade T.P.
      • Whalen G.F.
      • et al.
      A simple risk score to predict in-hospital mortality after pancreatic resection for cancer.
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      The Charlson age comorbidity index predicts early mortality after surgery for pancreatic cancer.
      Ischaemic heart disease has consequently been a risk factor in these studies, whereas heart failure has not. This may be due to different study designs, definitions of disease, sample sizes and selection bias. In the present study heart failure and atrial fibrillation were each, independently associated with major postoperative complications, whereas ischaemic heart disease and left sided valvular heart disease (mild or moderate degree) were not. Interestingly, the increased risk for major complications was not explained by a higher incidence of specific complications after pancreatic surgery, such as grade B–C postoperative pancreatic fistulas, bile leakage or postoperative pancreatic haemorrhage. Instead, the need of ICU admissions for supportive intensive care, rather than re-operations, constituted one of the most important major complications for patients with heart disease. The association of heart disease with ICU admissions and longer hospital stays, however, did not translate into early postoperative mortality. Despite the increased risk of complications among patients with heart disease, the results imply that these were successfully treated, rendering prolonged hospital stays but no negative effects on early post-operative survival. The association of preoperative atrial fibrillation with an increased risk for major postoperative complications after pancreatoduodenectomy is a novel finding for this patient category, although similar effects have been reported in other surgical settings.
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      Mechanisms, such as an increased need of anticoagulation, heart rate control, and elevated risk of both thromboembolism and bleeding may explain this association.
      To the best of our knowledge there are no reports describing the association between preoperative heart disease and the risk for delayed gastric emptying after pancreatic surgery. Postoperative atrial fibrillation, however, has been found to be a risk factor for delayed gastric emptying after pancreatoduodenectomy.
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      • Steele J.
      • Yu G.
      • Chabot J.A.
      Atrial fibrillation and delayed gastric emptying.
      Moreover, age has been identified as a risk factor for delayed gastric emptying after pancreatic surgery.
      • Hartwig W.
      • Hackert T.
      • Hinz U.
      • Gluth A.
      • Bergmann F.
      • Strobel O.
      • et al.
      Pancreatic cancer surgery in the new millennium: better prediction of outcome.
      ,
      • Casadei R.
      • Ricci C.
      • Lazzarini E.
      • Taffurelli G.
      • D'Ambra M.
      • Mastroroberto M.
      • et al.
      Pancreatic resection in patients 80 years or older: a meta-analysis and systematic review.
      However, the mechanism between age and delayed gastric emptying is not fully understood: whether age itself or diseases associated with ageing are responsible for this association remains unclear. Here, we report an association between heart disease – a major disease group of ageing – and postoperative delayed gastric emptying.
      We found that heart disease was associated with an increased risk for long-term all-cause postoperative mortality after pancreatoduodenectomy, whereas no such association with short-term mortality was detected. The long-term survival among patients with malignant histology should, however, be interpreted with caution as there was no data on the tumour stage nor administration of adjuvant chemotherapy. However, there was no difference in the prevalence of malignant diagnosis between patients with or without heart disease, and the proportion of patients surviving with a malignant diagnosis decreased at equal rates in these two groups during follow-up. These findings imply that with modern perioperative treatment and postoperative surveillance, patients with and without heart disease have similar risks for short-term complications. However, over time, patients with heart disease have an increased risk for overall mortality. This indicates that heart disease and its management might indeed constitute an important competing long-term mortality risk among patients who undergo pancreatoduodenectomy. These results suggest that optimized post-operative management of heart disease may offer an additional avenue towards clinical benefit, possibly even survival.
      This study has several limitations. As with all retrospective cohort analyses, residual confounding may exist. A further limitation was the lack of information on subjects who were excluded from surgery, and the unknown prevalence of heart disease among these patients. Also, de novo cases of heart disease, such as atrial fibrillation occurring post-operatively were not studied. Categorization of heart disease was based on previous diagnostic work up and coding. However, a thorough validation of diagnostic coding was conducted through systematic, case by case review of the patients' electronic health records, including evaluation of discharge notes, office visits, diagnostic or multidisciplinary meetings, echocardiography and radiology reports, notes from procedures, and laboratory/biochemical data. The data collection and review of heart disease variables were conducted by two of the investigators in order to minimize the risk of systematic sampling error in the collection.
      The frequent use of pre-operative echocardiography, and the relatively low prevalence of reduced left ventricular ejection fraction among operated patients with heart disease, point towards a negative selection of more severe forms of left ventricular dysfunction. It is thus likely, that among patients with heart disease only those with higher physiological performance status underwent surgery. In the light of our main findings that atrial fibrillation and heart failure significantly contribute to postoperative complications, this further underlines the importance of a thorough preoperative cardiac assessment, and optimized post-operative care, regardless of surgical indication.

      Conclusions

      In the present study we report that atrial fibrillation and heart failure are each independently associated with an increased risk for early postoperative complications after pancreatoduodenectomy, whereas ischaemic heart disease and valve disease are not. Furthermore, heart disease was associated with significantly worse long-term survival, independent of the underlying histopathology, and thus may constitute an important competing mortality risk among patients who undergo pancreatoduodenectomy.

      Acknowledgements

      No funding was received for this project.

      Declaration of interests

      He authors declare no conflict of interest.

      Appendix A. Supplementary data

      The following is the Supplementary data to this article:

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