Infectious Complications and Mortality after Noncardiac Surgery Associated with CHA2DS2-VASc Score: A Retrospective Cohort Study Based on a Real-world Database

Background: Little was know about the association between the CHA2DS2-VASc score and postoperative outcomes. Our purpose is to evaluate the effects of CHA2DS2-VASc score on the perioperative outcomes in patients with atrial brillation (AF). Methods: We identied 47,402 patients with AF over the age of 20 years who underwent noncardiac surgeries between 2008 and 2013 from claims data of the National Health Insurance in Taiwan. The CHA2DS2-VASc score was used to evaluate postoperative complications, mortality and the consumption of medical resources by calculating adjusted odds ratios (ORs) and 95% condence intervals (CIs). Results: Compared with patients with a CHA2DS2-VASc score of 0, patients with scores ≥ 5 had an increased risk of postoperative pneumonia (OR 1.81, 95% CI 1.30-2.51), septicemia (OR3.24, 95% CI 2.36-4.43), urinary tract infection (OR 1.64, 95% CI 1.20-2.25), intensive care (OR 2.94, 95% CI 2.46-3.51), and mortality (OR 2.07, 95% CI 1.17-3.64). There was a signicant positive correlation between risk of postoperative complication and the CHA2DS2-VASc score (P<0.0001). Conclusion: The CHA2DS2-VASc score was highly associated with postoperative infection and 30-day mortality among AF patients. Cardiologists and surgical care teams may consider using the CHA2DS2-VASc score to evaluate perioperative outcome risks in patients with AF. considering the signicance and magnitude of the observed effects, it is unlikely that these limitations compromised the results. Second, comorbidity severities (such as CHA2DS2-VASc score components) and coexisting medical conditions were dened by registered diagnosis codes, not by laboratory data, image studies or clinical evaluations. In addition, because the study cohort included only Taiwanese patients with AF, the results may not be generalizable to other populations. Finally, our investigation was a retrospective observational study, which had certain methodological limitations. Understanding the causal inference between the CHA2DS2-VASc score and perioperative outcomes requires future prospective studies. In conclusion, the CHA2DS2-VASc scoring system is an important independent predictor for postoperative major infections, 30-day mortality, and consumption of medical resources in patients with AF undergoing noncardiac surgeries. Our study suggests that perioperative care teams could apply CHA2DS2-VASc scores preoperatively for AF patients receiving noncardiac surgeries. Future studies are needed to assess the application of CHA2DS2-VASc scores to AF patients undergoing noncardiac surgeries.


Introduction
Atrial brillation (AF) is the most common sustained cardiac arrhythmia with an estimated ve million incident cases worldwide [1,2]. The 2010 global burden of disease study reported that there were 33.5 million patients with AF globally, constituting approximately 0.5% of the total world population [2]. The incidence of AF increases dramatically with age and is higher in men than women [3]. Numerous studies have reported a lifetime risk of developing AF among those aged ≥ 40 years of approximately 20%-25% [3]. Furthermore, this prevalence is likely underestimated since a large number of asymptomatic individuals and those having transient symptoms remain undiagnosed. AF is associated with an increased risk of thromboembolic stroke, acute coronary syndrome, heart failure, chronic kidney disease, hospitalization and all-cause mortality, as well as higher medical costs and a reduced quality of life [1,[4][5][6].
The CHA2DS2-VASc score for stroke risk assessment in patients with AF is well validated and has been widely applied and adopted in the U.S. and European clinical guidelines, as well as in the Asia Paci c Heart Rhythm Society, as a basic risk assessment tool [7][8][9][10][11]. The CHA2DS2-VASc score may predict adverse cardiovascular events and mortality in subsets of certain populations with high accuracy [12][13][14]. Moreover, the CHA2DS2-VASc score has also been shown to be useful in predicting ischemic stroke even among individuals without AF [12,15].
Since the number of people with AF is increasing, more AF patients will require risk strati cation before surgery [1,2]. Clinical guidelines for perioperative risk assessment focus on coronary artery disease rather than AF as an important risk factor for adverse outcomes [16,17]. In a population-based data analysis of 38,047 consecutive patients, the 30-day postoperative mortality rate was signi cantly higher in patients with AF than in those with coronary heart disease [18].
Infectious complications are the major causes of postoperative morbidity and mortality in noncardiac surgery, which merits increased attention and intervention [19]. Some studies have also reported that AF is strongly associated with hospital-acquired pneumonia or postoperative infection [20]. However, limited information is available regarding the potential application of the CHA2DS2-VASc score to adverse outcomes in AF patients receiving noncardiac surgeries. Thus, we used reimbursement claims from the Taiwan Health Insurance Research Database to conduct a population-based cohort study to investigate whether the CHA2DS2-VASc score is associated with the relative risk of postoperative adverse events in patients with AF when receiving noncardiac surgeries.
We used the International Classi cation of Diseases, Ninth Revision, Clinical Modi cation (ICD-9-CM) and administration codes to identify physician diagnoses of disease histories and complications after surgery in the Taiwan Health Insurance Research Database. Based on our previous studies, we included surgical patients' current medical conditions and their history of diseases such as mental disorders, chronic obstructive pulmonary disease, cancer, chronic kidney disease, hyperlipidemia, renal dialysis, Parkinson's disease, and liver cirrhosis as covariates in this study. Postoperative infection-related complications, such as pneumonia, septicemia, and urinary tract infection, were also identi ed. The consumption of medical resources including admission to an intensive care unit, length of hospital stay, and medical expenditure were considered as study outcomes.

Statistical analysis
We used chi-square tests to compare categorical variables (summarized using frequency and percentage) between AF patients with a CHA2DS2-VASc score of 0 and ≥ 1. Continuous variables were compared using a t-test (summarized using mean±SD). We used multivariate logistic regression to calculate the odds ratios (ORs) and 95% con dence intervals (CIs) of the CHA2DS2-VASc score associated with postoperative pneumonia, septicemia, urinary tract infection, intensive care unit stay, and in-hospital mortality. Multiple linear regressions were used to evaluate the relationship between the CHA2DS2-VASc score and length of hospital stay and medical expenditure. Adjusted ORs (95% CIs) of postoperative adverse events for patients with each component of the CHA2DS2-VASc score were also calculated. Multiple logistic regressions were also used to calculate adjusted ORs (95% CIs) of the CHA2DS2-VASc score associated with postoperative adverse events in the subgroups of male gender, number of medical conditions and types of anesthesia.

Results
Among 47,402 surgical patients with AF (Table S1), 45,639 (96.3%) had a CHA2DS2-VASc score of ≥ 1. Compared with AF patients with a CHA2DS2-VASc score of 0 (Table 1), those with score of ≥ 1 had higher incidences of mental disorders (P < 0.0001), liver cirrhosis (P < 0.0001), chronic obstructive pulmonary disease (P < 0.0001), chronic kidney disease (P = 0.003), and Parkinson's disease (P < 0.0001). The incidence of low income was higher in AF patients with scores of 0 compared with AF patients with scores of ≥ 1 (P = 0.0004). Postoperative infection-related complications, such as pneumonia (P < 0.0001), septicemia (P < 0.0001), and urinary tract infection (P < 0.0001) were associated with the CHA2DS2-VASc score with a biological gradient trend. Compared to AF patients with a CHA2DS2-VASc score of 0 (  Table 3, CHA2DS2-VASc score of ≥ 5 was also associated with stay in the intensive care unit (OR = 2.94; 95% CI: 2.46-3.51) and in-hospital mortality (OR = 2.07; 95% CI: 1.17-3.64) with signi cant trends (P for trend were < 0.0001 for both).   In Table S2, the average hospital stay length (P < 0.0001) and medical expenditure (P < 0.0001) were higher in surgical patients with a CHA2DS2-VASc score of ≥ 5 compared to surgical patients with a CHA2DS2-VASc score of 0. After adjusting for covariates in the multiple regression analysis, the CHA2DS2-VASc score was signi cantly associated with the length of hospital stay (beta = 1.25, P < 0.0001) and medical expenditure (beta = 256, P < 0.0001).

Discussion
This study is the rst population-based study to report the application of the CHA2DS2-VASc score to assessments of perioperative of noncardiac surgery outcomes in patients with AF. The CHA2DS2-VASc score was highly associated with postoperative major infection, intensive care unit stay, and 30-day mortality. Prolonged length of hospital stay and elevated medical expenditures were also noted in patients with higher CHA2DS2-VASc scores. The biological gradient effects existed in the CHA2DS2-VASc score associated with postoperative infections and mortality. The association between CHA2DS2-VASc score and postoperative adverse events remained signi cant for various subgroups.
Preoperative AF was independently associated with higher postoperative complications in patients undergoing noncardiac surgery [18]. In the current clinical settings, the Revised Cardiac Risk Index or the American College of Surgeons National Surgical Quality Improvement Program risk model calculator were used to assess the cardiovascular risk in all patients who were scheduled to undergo noncardiac surgeries [38]. According to the clinical practice guidelines, electrocardiogram and echocardiography are common tools for assessing perioperative outcomes that are not recognized as risks in aforementioned risk model calculators [16,17,38]. However, the comprehensive assessment of preoperative risk strati cation in AF population has not been ideally established.
Therefore, our study examined the possibility of applying the CHA2DS2-VASc score to surgical patients in order to assess infectious complications and mortality.
A retrospective population-based cohort study was conducted to investigate which risk score for perioperative outcomes prediction in patients with AF undergoing noncardiac surgery and concluded that the CHA2DS2-VASc score provides acceptable preoperative risk strati cation for major perioperative events including mortality [26]. Compared with our study, the authors did not adjust some possible potential confounding factors into their analysis (such as socioeconomic status, hyperlipidemia, liver cirrhosis and types of anesthesia). Additionally, the patient cohort in our study was larger and from a more recent time period compared with the previous cohort study [26]. Furthermore, the present study provides evidence that patients with AF with an increased CHA2DS2-VASc score have an increased risk for postoperative adverse events compared to patients with AF only. With these results, clinicians can precisely access the risk of adverse outcomes and allocate medical resources in AF patients with coexisting medical conditions when they undergo noncardiac surgeries.
This study had several inherent limitations. First, several unmeasured factors, such as the type of AF (paroxysmal or non-paroxysmal), frailty, various perioperative AF medication management strategies, drug compliance, alcohol consumption, body mass index, cigarette smoking, physical activity level, and perioperative heart rate status, were unavailable in our database. Failure to consider the aforementioned variables may have led to a certain degree of residual bias. However, considering the signi cance and magnitude of the observed effects, it is unlikely that these limitations compromised the results. Second, comorbidity severities (such as CHA2DS2-VASc score components) and coexisting medical conditions were de ned by registered diagnosis codes, not by laboratory data, image studies or clinical evaluations. In addition, because the study cohort included only Taiwanese patients with AF, the results may not be generalizable to other populations. Finally, our investigation was a retrospective observational study, which had certain methodological limitations.
Understanding the causal inference between the CHA2DS2-VASc score and perioperative outcomes requires future prospective studies.
In conclusion, the CHA2DS2-VASc scoring system is an important independent predictor for postoperative major infections, 30-day mortality, and consumption of medical resources in patients with AF undergoing noncardiac surgeries. Our study suggests that perioperative care teams could apply CHA2DS2-VASc scores preoperatively for AF patients receiving noncardiac surgeries. Future studies are needed to assess the application of CHA2DS2-VASc scores to AF patients undergoing noncardiac surgeries.