- Email: [email protected]
Gender based differences in management and outcomes of cholecystitis
The American Journal of Surgery (2013) 206, 641-646
Association of Women Surgeons: Clinical Science
Gender based differences in management and outcomes of cholecystitis Anahita Dua, M.D.a,b, Arshish Dua, B.S.a, Sapan S. Desai, M.D., M.B.A., Ph.D.f,g, SreyReath Kuy, D.P.M.c, Rishika Sharma, M.D.b, Sarah E. Jechow, B.S.d, Jason McMaster, M.D.e, Bhavin Patel, B.S.a, SreyRam Kuy, M.D., M.H.S.a,* a
Department of Surgery, Medical College of Wisconsin, 9200 W Wisconsin Avenue, Milwaukee, WI 53226, USA; bCenter for Translational Injury Research, Department of Surgery, University of Texas–Houston, Houston, TX, USA; cUniversity General Hospital, Houston, TX, USA; dUniversity of Texas Medical School at Houston, Houston, TX, USA; eDepartment of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI, USA; fDepartment of Cardiothoracic and Vascular Surgery, University of Texas Medical School at Houston, Houston, TX, USA; gDepartment of Surgery, Duke University, Durham, NC, USA
KEYWORDS: Outcomes; Gender; Cholecystectomy; Biliary disease
Abstract BACKGROUND: During the reproductive years, women have a 4-fold higher prevalence of gallstones than men, making gallbladder disease a critically important topic in women’s health. Among agematched women and men hospitalized for cholecystitis, gender based differences in demographics, management, and economic and clinical outcomes were identified. METHODS: A cross-sectional study was conducted using the Nationwide Inpatient Sample. Outcomes were mortality, complications, length of stay, and cost. RESULTS: Women accounted for 65% of admissions for cholecystitis, with women more likely to have shorter time to surgery (1.6 vs 1.9 days) and laparoscopy (86 vs 76%) (P , .05). After cholecystectomy, women had lower mortality (.6% vs 1.1%), fewer complications (16.9 vs 24.1), shorter lengths of stay (4.2 vs 5.4 days), and lower costs ($10,556 vs $13,201) (P , .05). On multivariate analysis of age-matched patients, women had lower odds of mortality (odds ratio [OR], .75), complications (OR, .86), length of stay (OR, .95), and cost (OR, .93). Longer time to surgery and open cholecystectomy were independent predictors of worse outcomes. CONCLUSIONS: In cholecystitis and cholecystectomy, women have better clinical and economic outcomes then age-matched men. Ó 2013 Elsevier Inc. All rights reserved.
This work was presented at the Academy Health 2009 Annual Research Meeting and Women’s Health 2009 Annual Congress. The data acquisition was funded by the Robert Wood Johnson Clinical Scholars Program at Yale University School of Medicine and the US Department of Veterans Affairs. The authors declare no conflicts of interest. * Corresponding author. Tel.: 11-210-535-2877; fax: 11-414-805-8641. E-mail address: [email protected] Manuscript received May 17, 2013; revised manuscript July 29, 2013 0002-9610/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjsurg.2013.07.011
Gallstone disease accounts for $650 billion in health care expenditures annually in the United States,1 making it the second most costly digestive disease in the United States.2 With .700,000 cholecystectomies performed annually in the United States, gallbladder disease is the single most common indication for abdominal surgery in the United States.1 Among patients initially diagnosed with
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gallstones, 35% eventually experience recurrent symptoms or complications leading to cholecystectomy.3 The National Health and Nutrition Examination Survey estimates that 6.3 million men and 14.2 million women in the United States have gallbladder disease,4 with a prevalence as high as 26% in certain population. Among women, the general prevalence of gallstone disease is more than twice that of men.1,5 However, during the reproductive years, women have a 4-fold higher prevalence of gallstones than their male counterparts.3 As a result of the disproportionate burden of disease among women, gallbladder disease is a critically important topic in women’s health. Small single-institution studies have suggested that cholecystitis is a ‘‘different disease’’ in women compared with men,6,7 and the published data show conflicting results as to whether gender affects outcomes after cholecystectomy.8–11 There is currently a lack of consensus on whether gender affects the management of cholecystitis and the outcomes of cholecystectomy for cholecystitis. However, prior work has clearly shown that older age independently has a negative impact on outcomes after cholecystectomy.12 Therefore, to determine whether gender is an independent predictor of outcome, we examined a national sample of patients hospitalized with cholecystitis over an 8-year period, age matched to account for the effect of age, and identified gender-based differences in demographics of patients hospitalized with cholecystitis, measured clinical and economic outcomes of women compared with men who underwent cholecystectomy during that admission for cholecystitis, and identified patient-level and providerlevel predictors of outcomes.
Methods This was a retrospective, cross-sectional analysis of hospital discharge data from 1999 to 2006 using the Healthcare Cost and Utilization Project (HCUP) Nationwide Inpatient Sample (NIS) database, which is a stratified 20% sample of all inpatient admissions to nonfederal, acute care hospitals maintained by the Agency for Healthcare Research and Quality. It is the largest all-payer inpatient database in the United States, with records from approximately 8 million hospital stays each year.13 Records were limited to adults aged 18 to 100 years who were hospitalized with diagnoses of cholecystitis, as identified by International Classification of Diseases, Ninth Revision (ICD-9), codes and Clinical Classifications Software. ICD-9 procedure codes were used to identify all patients who underwent cholecystectomy as the primary procedure during hospitalization (open and laparoscopic). Previous work has demonstrated that age is an independent predictor of worse in-hospital outcomes after cholecystectomy.12 Therefore, to eliminate the effect of age and focus on gender, women were matched to men by 5-year age intervals for the multivariate analysis.
Independent variables The primary independent variable was gender. Patientlevel covariates included race and ethnicity (white, black, Hispanic, or other), age, insurance status, and median household income quartile for patient home ZIP code ($1 to $24,999, $25,000 to $34,999, $35,000 to $44,999, R$45,000). Clinical covariates included type of cholecystectomy (open vs laparoscopic), time from admission to cholecystectomy, admission urgency (elective vs nonelective), number of comorbidities (calculated using ICD9 codes and the Charlson comorbidity index and stratified as 0, 1, or R2), and number of biliary diagnoses. The biliary diagnoses were calculated using ICD-9 codes and grouped into cholelithiasis, cholecystitis, cholangitis, biliary pancreatitis, or other biliary diagnoses. All patients included in the analysis carried diagnoses of cholecystitis. The number of biliary diagnoses was used as a proxy for severity of illness and stratified into 1, 2, or R3 diagnoses, as previously described by Kuy et al.12 Provider-level covariates included hospital size, hospital location, hospital teaching status, hospital region, hospital location (rural vs urban), and year of admission.
Outcome variables Outcomes of interest were (1) in-hospital mortality; (2) in-hospital complications; (3) mean length of stay (LOS); and (4) mean total inpatient hospital costs. In-hospital complications were calculated for patients who underwent cholecystectomy and were categorized as cardiac, postoperative shock, gastrointestinal, hematologic, renal, pulmonary, infection, thrombosis or embolism, bile duct injury or repair, and other complications after a procedure. Complications were treated as dichotomous variables (0 vs 1). Mean total in-hospital costs were calculated using the HCUP NIS hospital-specific cost-to-charge ratios (available for 2001 to 2005), and using the US Bureau of Labor Statistics Medical Consumer Price Index, they were standardized to 2005 dollars.14
Statistical analysis Bivariate analysis of the independent variables by outcomes was performed using chi-square tests for categorical variables and analysis of variance for continuous variables. Multivariate linear regression incorporated the patient-level and hospital-level variables described in Table 1 and was used to model continuous outcomes (LOS and total inpatient costs), and multivariate logistic regression was used to model mortality and complication rates. The distributions of LOS and cost were skewed. Therefore, they were log transformed to achieve a more normal distribution and are reported as adjusted LOS and adjusted cost. Data analysis and management were
A. Dua et al.
Gender based differences in cholecystitis outcomes
Table 1 National demographics of women compared with men hospitalized with cholecystitis in the United States
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performed using SAS version 9.1 (SAS Institute Inc, Cary, NC). Statistical significance was set at P % .05.
Patient characteristic
Women
Men
P
Mean age (y) Race/ethnicity White Black Hispanic Asian Native American Other Admission type (urgent/emergent) Admission source ER Transfer from another facility Home Insurance status Medicare Medicaid Private/HMO Uninsured Other Income Quartile 1 (lowest) Quartile 2 Quartile 3 Quartile 4 (highest) Number of biliary diagnoses 1 2 R3 Charlson comorbidity score 0 1 2 3 4 R5 Hospital size Small Medium Large Location Rural Urban Teaching hospital Hospital region Northeast Midwest South West
54
61
,.0001
Results
68.0% 10.7% 16.0% 2.0% 0.5% 2.9% 73.0%
75.6% 6.8% 12.1% 2.4% 0.5% 2.6% 76.0%
,.0001
Gender differences in outcomes of hospitalizations for cholecystitis
55.6% 2.7%
58.6% 3.6%
41.7%
37.8%
34.2% 13.5% 42.3% 6.5% 3.5%
48.1% 6.0% 37.2% 5.4% 3.4%
,.0001
17.6%
16.6%
,.0001
27.4% 25.7% 29.3%
27.0% 25.9% 30.6%
80.1% 18.8% 1.2%
77.6% 20.7% 1.8%
,.0001
66.5% 19.8% 7.5% 2.6% 1.0% 2.6%
49.2% 26.3% 12.5% 4.9% 2.2% 4.8%
,.0001
13.1% 28.0% 58.9%
12.9% 27.3% 59.8%
,.0001 ,.0001
Among adults hospitalized with acute cholecystitis, adult women (n 5 518,665) compared with adult men (n 5 276,366) accounted for the majority of all admissions for cholecystitis, at 65% versus 35%, respectively. Compared with men, women were younger (mean age, 54 vs 61 years) were more likely to be black (11% vs 7%) or Hispanic (16% vs 12%) but less likely to have multiple comorbidities and less likely to require an urgent admission (73% vs 76%) (P , .05 for all; Table 1). Women admitted with cholecystitis had lower in-hospital mortality than men (1.4% vs 2.5%), shorter LOS (5 vs 6.5 days), and lower cost of hospitalization ($11,898 vs $15,606) (P , .05 for all). Women were more likely than men to undergo cholecystectomy (75% vs 70%) during that admission and to experience a shorter time from admission to surgery (1.6 vs 1.9 days after admission) and less likely to undergo open cholecystectomy (14% vs 24%) (P , .05 for all).
Gender differences in outcomes of cholecystectomy Among patients who underwent cholecystectomy as the primary procedure during that hospitalization, women were younger, less likely to have multiple comorbidities than men (10% vs 18.9%), less likely to require an urgent admission (74% vs 77%), but more likely to be of nonwhite race or ethnicity (32% vs 24%) (P ,.05 for all). Among patients who underwent cholecystectomy, women had lower mortality (.6% vs 1.1%), fewer complications (16.9 vs 24.1), shorter 30
All p <.05
,.0001
24.1
25 20 16.9
15
17.6% 82.4% 35.2%
18.1% 81.9% 35.3%
18.4% 20.4% 40.3% 20.8%
18.6% 21.4% 40.6% 19.4%
13.2
,.0001
10.6
Women Men
10
NS ,.0001
ER 5 emergency room; HMO 5 health maintenance organization.
4.2
5
5.4
0.6 1.1 0 Mortality
Complications Length of stay Cost (%) (days) (thousands $)
Figure 1 Gender differences in outcomes after cholecystectomy, 1999 to 2006.
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Mortality Adjusted* OR (95% CI) 0.75 (0.69-0.82)
Complications
Length of Stay
0.86 (0.84-0.88) 0.95 (0.95-0.96)
Cost 0.93 (0.93-0.94)
*Age matched sample; Male gender = reference value (OR 1); adjusted for clinical characteristics (age, race, number of biliary diagnoses, type of procedure, admission urgency, comorbidities, time to surgery), year and hospital characteristics (size, teaching status, region, rural or urban location); CI = confidence interval
Figure 2 Associations between female gender and outcomes of cholecystectomy in the United States, 1999 to 2006. * Age-matched sample; male gender 5 reference value (OR, 1); adjusted for clinical characteristics (age, race, number of biliary diagnoses, type of procedure, admission urgency, comorbidities, time to surgery), year, and hospital characteristics (size, teaching status, region, rural or urban location).
LOS (4.2 vs 5.4 days), and lower cost ($10,556 vs $13,201) (P , .05 for all; Fig. 1) On multivariate analysis of age-matched women and men who underwent cholecystectomy, women had lower adjusted odds of mortality (odds ratio [OR], .75; 95% confidence interval [CI], .69 to .82), complications (OR, .86; 95% CI, .84 to .88), LOS (OR, .95; 95% CI, .95 to .96), and cost (OR, .93; 95% CI, .93 to .94) (Fig. 2). In a separate subgroup regression analysis of only patients with no comorbidities, women still had better outcomes after cholecystectomy for all outcomes measured. Longer time from admission to surgery was an independent predictor for mortality (OR, 1.09; 95% CI, 1.08 to 1.10), complications (OR, 1.14; 95% CI, 1.13 to 1.15), longer LOS (OR, 1.14; 95% CI, 1.13 to 1.14), and higher cost (OR, 1.11; 95% CI, 1.10 to 1.11). Furthermore, open cholecystectomy was also an independent predictor of mortality (OR, 3.01; 95% CI, 2.75 to 3.29), complications (OR, 2.50; 95% CI, 2.43 to 2.58), longer LOS (OR, 1.61; 95% CI, 1.60 to 1.63), and higher cost (OR, 1.44; 95% CI, 1.42 to 1.47).
Comments In this study, women clearly constitute the majority of hospitalizations for cholecystitis in the United States and are more likely to undergo surgical management during their hospitalization. Multiple studies have demonstrated a female propensity for gallstone disease. Increased body fat in women and elevated serum triglyceride in both men and women have been associated with an increased risk for cholelithiasis.15 Cholesterol gallstones form as a result of either a deficiency of bile acids or excessive secretion of cholesterol in bile, which contributes to precipitation of cholesterol in supersaturated bile. Women have been found to have a smaller total chenodeoxycholic bile acid pool size than men, which has been theorized to contribute to the greater prevalence of gallstones among women.16 Other risk factors for gallstone disease include advancing age, obesity, diabetes mellitus, estrogen or pregnancy status, cirrhosis, American Indian ethnicity, glucose-6-phosphate dehydrogenase, and hemolytic diseases.1,3,9,11,17–19 Other studies have found that men undergoing cholecystectomy are significantly older and more likely to have coexisting conditions, previous abdominal surgery, previous hospitalization for pancreatitis and cholecystitis, and
severe disease.8,10,11,18 However, these studies have conflicted in demonstrating differences in outcomes after cholecystectomy for women and men, which may be accounted for by differences in age, disease severity, and comorbidities. By age matching and adjusting on multivariate analysis for number of biliary diagnoses, comorbidities, and ethnicity, we were able to demonstrate in this national study over an 8-year period that women have better outcomes after cholecystectomy than men on all outcomes measured. Open cholecystectomy is an independent predictor of mortality, complications, longer LOS, and higher cost, which has been demonstrated in previous studies.20–22 Longer time from admission to surgery was also an independent predictor of worse outcomes. Women experience a shorter time from admission to surgery and are less likely to undergo an open procedure. This fact should spur health care providers to explore with further research whether men experience a delay in diagnoses that contributes to the longer time from admission to surgery. A delay in surgery may also contribute to the higher need for open cholecystectomy seen in the male group. However, after adjusting for time to surgery, open cholecystectomy, and the number of biliary diagnoses, women still experienced better outcomes for all outcomes measured. This study contributes to the literature by identifying that on a national level, among all patients admitted with cholecystitis, women do more favorably on variables known to affect outcomes: women are younger, and they are more likely to undergo laparoscopic procedures. Age is not a variable that can be altered. In addition, we cannot tease out in this administrative database the reasons for a longer time from admission to surgery experienced by men, such as a delay in diagnosis, need to medically stabilize or optimize a patient, or the duration from onset of symptoms to when the patient actually presented for care. However, the choice of procedure, laparoscopic versus open cholecystectomy, is a potentially modifiable variable that women clearly did better on, with lower rates of open cholecystectomy than men. Although we cannot delineate in this study the operative or clinical factors that potentially could influence the type of procedure, such as whether the gallbladder was gangrenous, whether there were significant adhesions, or whether the patient had prior abdominal surgeries contributing to the decision to perform an open cholecystectomy, it is clear that women are less likely to
A. Dua et al.
Gender based differences in cholecystitis outcomes
have an open procedure. These factors together, that women are younger, have a shorter time from admission to surgery, and are less likely to undergo open cholecystectomy, are potentially important contributors to the finding that women hospitalized with cholecystitis have better outcomes than men. Further research into these areas, such as time to diagnosis and time to surgery, may yield an ideal time window for diagnosing and treating patients with gallbladder disease before the more debilitating aspects of the disease manifest. Studies such as these will provide more insight into the approach to diagnosis and treatment of cholecystitis.
Limitations There are limitations inherent to any administrative database such as the HCUP NIS. There can be coding errors, leading to missed diagnoses and procedures, as well as a lack of coding, leading to missing data. The HCUP NIS is a wellvalidated and rigorously maintained database, and its error rate has been low.23 Readmissions and postdischarge mortality are not captured; therefore, it is likely that the study underestimates perioperative morbidity and mortality. Multivariate regression was used to adjust for confounding factors; alternative methods, such as propensity scores, could be used but have not been shown to be superior.24 This study used an administrative database and identified patient-level and hospital-level characteristics from ICD-9 codes. The limitation with this database is we that cannot identify clinical variables such as how many days men, compared with women, were having symptoms before presenting to providers, whether gangrenous cholecystitis was seen intraoperatively, if extensive adhesiolysis was required, or operative details such as the length of operative time, which all have the potential to contribute to the difference observed in outcomes between women and men. These are variables are clinically important, which could potentially be studied in a retrospective chart review or a prospective trial. These are significant limitations of using the NIS database. However, the strength of our study is that we were able to examine a large population on a national level treated by providers at both academic centers and community hospitals and provide an epidemiologic snapshot of outcomes of cholecystectomy.
Conclusions This study revealed a gender-based difference in both management of cholecystitis and clinical and economic outcomes of the disease. Women constitute the majority of hospitalizations for cholecystitis, are younger, are more likely to undergo surgical management during their hospitalization, have surgery earlier, and are more likely to undergo laparoscopic procedures than men. On multivariate analysis of age-matched women and men, adjusting for other characteristics, female gender is associated with better outcomes after cholecystectomy. Days from
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admission to surgery and type of procedure are independent predictors of outcome. Unlike age and gender, laparoscopy and timing of surgery are modifiable variables. Identifying these modifiable characteristics associated with outcomes will help providers and patients in treatment decision making and aid policy makers in identifying ways to improve the outcomes of patients with cholecystitis.
References 1. Shaffer EA. Gallstone disease: epidemiology of gallbladder stone disease. Best Pract Res Clin Gastroenterol 2006;20:981–96. 2. Richter JE. The enormous burden of digestive diseases on our healthcare system. Curr Gastroenterol Rep 2003;5:93–4. 3. Schirmer BD, Winters KL, Edlich RF. Cholelithiasis and cholecystitis. J Long Term Eff Med Implants 2005;15:329–38. 4. Everhart JE, Khare M, Hill M, et al. Prevalence and ethnic differences in gallbladder disease in the United States. Gastroenterology 1999; 117:632–9. 5. Shaffer EA. Epidemiology and risk factors for gallstone disease: has the paradigm changed in the 21st century? Curr Gastroenterol Rep 2005;7:132–40. 6. Bates D, Girvin G. Biliary tract disease: is there a difference in men? Am J Surg 1987;153:532–4. 7. Ammori B, Larvin M, McMahon J. Elective laparoscopic cholecystectomy: preoperative prediction of duration of surgery. Surg Endosc 2001;15:297–300. 8. Russell JC, Walsh SJ, Reed-Fourquet L, et al. Symptomatic cholelithiasis: a different disease in men? Connecticut Laparoscopic Cholecystectomy Registry. Ann Surg 1998;227:195–200. 9. Carbonell AM, Lincourt AE, Kercher KW, et al. Do patient or hospital demographics predict cholecystectomy outcomes? A nationwide study of 93,578 patients. Surg Endosc 2005;19:767–73. 10. Botaitis S, Polychronidis A, Pitiakoudis M, et al. Does gender affect laparoscopic cholecystectomy? Surg Laparosc Endosc Percutan Tech 2008;18:157–61. 11. Lee HK, Han HS, Min SK, et al. Sex-based analysis of the outcome of laparoscopic cholecystectomy for acute cholecystitis. Br J Surg 2005; 92:463–6. 12. Kuy S, Sosa J, Roman S, et al. Age matters: a study of clinical and economic outcomes following cholecystectomy in elderly Americans. Am J Surg 2011;201:789–96. 13. Agency for Healthcare Research and Quality. Healthcare Cost and Utilization Project–Nationwide Inpatient Sample. Available at: http:// www.hcup-us.ahrq.gov/nisoverview.jsp#Whatis. Accessed August 22, 2013. 14. Economagic. Series title: CPI: U.S. city average; medical care; 1982– 845100; NSA. Available at: http://www.economagic.com/em-cgi/ data.exe/blscu/CUUR0000SAM. Accessed December 23, 2008. 15. Persson G, Sko¨ld S, Thulin A. Physical constitution and biochemical characteristics of patients with electively diagnosed gallstone disease. Eur J Surg 1991;157:473–6. 16. Bennion L, Drobny E, Knowler W, et al. Sex differences in the size of bile acid pools. Metabolism 1978;27:961–9. 17. Stinton LM, Shaffer EA. Epidemiology of gallbladder disease: cholelithiasis and cancer. Gut Liver 2012;6:172–87. 18. Nikfarjam M, Harnaen E, Tufail F, et al. Sex differences and outcomes of management of acute cholecystitis. Surg Laparosc Endosc Percutan Tech 2013;23:61–5. 19. Meloni T, Forteleoni G, Noja G, et al. Increased prevalence of glucose6-phosphate dehydrogenase deficiency in patients with cholelithiasis. Acta Haematol 1991;85:76–8. 20. NIH consensus conference. Gallstones and laparoscopic cholecystectomy. JAMA 1993;269:1018–24.
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21. Gallstones and laparoscopic cholecystectomy: NIH Consensus Development Panel on Gallstones and Laparoscopic Cholecystectomy. Surg Endosc 1993;7:271–9. 22. Zacks SL, Sandler RS, Rutledge R, et al. A population-based cohort study comparing laparoscopic cholecystectomy and open cholecystectomy. Am J Gastroenterol 2002;97:334–40.
23. Agency for Healthcare Research and Quality. Hospital inpatient statistics 1996. Available at: http://www.hcup-us.ahrq.gov/reports/natstats/ his96/clinclas.htm. Accessed January 5, 2009. 24. Bosco JLF, Silliman RA, Thwin SS, et al. A most stubborn bias: no adjustment method fully resolves confounding by indication in observational studies. J Clin Epidemiol 2010;63:64–74.
Association of Women Surgeons: Clinical Science
Gender based differences in management and outcomes of cholecystitis Anahita Dua, M.D.a,b, Arshish Dua, B.S.a, Sapan S. Desai, M.D., M.B.A., Ph.D.f,g, SreyReath Kuy, D.P.M.c, Rishika Sharma, M.D.b, Sarah E. Jechow, B.S.d, Jason McMaster, M.D.e, Bhavin Patel, B.S.a, SreyRam Kuy, M.D., M.H.S.a,* a
Department of Surgery, Medical College of Wisconsin, 9200 W Wisconsin Avenue, Milwaukee, WI 53226, USA; bCenter for Translational Injury Research, Department of Surgery, University of Texas–Houston, Houston, TX, USA; cUniversity General Hospital, Houston, TX, USA; dUniversity of Texas Medical School at Houston, Houston, TX, USA; eDepartment of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI, USA; fDepartment of Cardiothoracic and Vascular Surgery, University of Texas Medical School at Houston, Houston, TX, USA; gDepartment of Surgery, Duke University, Durham, NC, USA
KEYWORDS: Outcomes; Gender; Cholecystectomy; Biliary disease
Abstract BACKGROUND: During the reproductive years, women have a 4-fold higher prevalence of gallstones than men, making gallbladder disease a critically important topic in women’s health. Among agematched women and men hospitalized for cholecystitis, gender based differences in demographics, management, and economic and clinical outcomes were identified. METHODS: A cross-sectional study was conducted using the Nationwide Inpatient Sample. Outcomes were mortality, complications, length of stay, and cost. RESULTS: Women accounted for 65% of admissions for cholecystitis, with women more likely to have shorter time to surgery (1.6 vs 1.9 days) and laparoscopy (86 vs 76%) (P , .05). After cholecystectomy, women had lower mortality (.6% vs 1.1%), fewer complications (16.9 vs 24.1), shorter lengths of stay (4.2 vs 5.4 days), and lower costs ($10,556 vs $13,201) (P , .05). On multivariate analysis of age-matched patients, women had lower odds of mortality (odds ratio [OR], .75), complications (OR, .86), length of stay (OR, .95), and cost (OR, .93). Longer time to surgery and open cholecystectomy were independent predictors of worse outcomes. CONCLUSIONS: In cholecystitis and cholecystectomy, women have better clinical and economic outcomes then age-matched men. Ó 2013 Elsevier Inc. All rights reserved.
This work was presented at the Academy Health 2009 Annual Research Meeting and Women’s Health 2009 Annual Congress. The data acquisition was funded by the Robert Wood Johnson Clinical Scholars Program at Yale University School of Medicine and the US Department of Veterans Affairs. The authors declare no conflicts of interest. * Corresponding author. Tel.: 11-210-535-2877; fax: 11-414-805-8641. E-mail address: [email protected] Manuscript received May 17, 2013; revised manuscript July 29, 2013 0002-9610/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjsurg.2013.07.011
Gallstone disease accounts for $650 billion in health care expenditures annually in the United States,1 making it the second most costly digestive disease in the United States.2 With .700,000 cholecystectomies performed annually in the United States, gallbladder disease is the single most common indication for abdominal surgery in the United States.1 Among patients initially diagnosed with
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gallstones, 35% eventually experience recurrent symptoms or complications leading to cholecystectomy.3 The National Health and Nutrition Examination Survey estimates that 6.3 million men and 14.2 million women in the United States have gallbladder disease,4 with a prevalence as high as 26% in certain population. Among women, the general prevalence of gallstone disease is more than twice that of men.1,5 However, during the reproductive years, women have a 4-fold higher prevalence of gallstones than their male counterparts.3 As a result of the disproportionate burden of disease among women, gallbladder disease is a critically important topic in women’s health. Small single-institution studies have suggested that cholecystitis is a ‘‘different disease’’ in women compared with men,6,7 and the published data show conflicting results as to whether gender affects outcomes after cholecystectomy.8–11 There is currently a lack of consensus on whether gender affects the management of cholecystitis and the outcomes of cholecystectomy for cholecystitis. However, prior work has clearly shown that older age independently has a negative impact on outcomes after cholecystectomy.12 Therefore, to determine whether gender is an independent predictor of outcome, we examined a national sample of patients hospitalized with cholecystitis over an 8-year period, age matched to account for the effect of age, and identified gender-based differences in demographics of patients hospitalized with cholecystitis, measured clinical and economic outcomes of women compared with men who underwent cholecystectomy during that admission for cholecystitis, and identified patient-level and providerlevel predictors of outcomes.
Methods This was a retrospective, cross-sectional analysis of hospital discharge data from 1999 to 2006 using the Healthcare Cost and Utilization Project (HCUP) Nationwide Inpatient Sample (NIS) database, which is a stratified 20% sample of all inpatient admissions to nonfederal, acute care hospitals maintained by the Agency for Healthcare Research and Quality. It is the largest all-payer inpatient database in the United States, with records from approximately 8 million hospital stays each year.13 Records were limited to adults aged 18 to 100 years who were hospitalized with diagnoses of cholecystitis, as identified by International Classification of Diseases, Ninth Revision (ICD-9), codes and Clinical Classifications Software. ICD-9 procedure codes were used to identify all patients who underwent cholecystectomy as the primary procedure during hospitalization (open and laparoscopic). Previous work has demonstrated that age is an independent predictor of worse in-hospital outcomes after cholecystectomy.12 Therefore, to eliminate the effect of age and focus on gender, women were matched to men by 5-year age intervals for the multivariate analysis.
Independent variables The primary independent variable was gender. Patientlevel covariates included race and ethnicity (white, black, Hispanic, or other), age, insurance status, and median household income quartile for patient home ZIP code ($1 to $24,999, $25,000 to $34,999, $35,000 to $44,999, R$45,000). Clinical covariates included type of cholecystectomy (open vs laparoscopic), time from admission to cholecystectomy, admission urgency (elective vs nonelective), number of comorbidities (calculated using ICD9 codes and the Charlson comorbidity index and stratified as 0, 1, or R2), and number of biliary diagnoses. The biliary diagnoses were calculated using ICD-9 codes and grouped into cholelithiasis, cholecystitis, cholangitis, biliary pancreatitis, or other biliary diagnoses. All patients included in the analysis carried diagnoses of cholecystitis. The number of biliary diagnoses was used as a proxy for severity of illness and stratified into 1, 2, or R3 diagnoses, as previously described by Kuy et al.12 Provider-level covariates included hospital size, hospital location, hospital teaching status, hospital region, hospital location (rural vs urban), and year of admission.
Outcome variables Outcomes of interest were (1) in-hospital mortality; (2) in-hospital complications; (3) mean length of stay (LOS); and (4) mean total inpatient hospital costs. In-hospital complications were calculated for patients who underwent cholecystectomy and were categorized as cardiac, postoperative shock, gastrointestinal, hematologic, renal, pulmonary, infection, thrombosis or embolism, bile duct injury or repair, and other complications after a procedure. Complications were treated as dichotomous variables (0 vs 1). Mean total in-hospital costs were calculated using the HCUP NIS hospital-specific cost-to-charge ratios (available for 2001 to 2005), and using the US Bureau of Labor Statistics Medical Consumer Price Index, they were standardized to 2005 dollars.14
Statistical analysis Bivariate analysis of the independent variables by outcomes was performed using chi-square tests for categorical variables and analysis of variance for continuous variables. Multivariate linear regression incorporated the patient-level and hospital-level variables described in Table 1 and was used to model continuous outcomes (LOS and total inpatient costs), and multivariate logistic regression was used to model mortality and complication rates. The distributions of LOS and cost were skewed. Therefore, they were log transformed to achieve a more normal distribution and are reported as adjusted LOS and adjusted cost. Data analysis and management were
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Gender based differences in cholecystitis outcomes
Table 1 National demographics of women compared with men hospitalized with cholecystitis in the United States
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performed using SAS version 9.1 (SAS Institute Inc, Cary, NC). Statistical significance was set at P % .05.
Patient characteristic
Women
Men
P
Mean age (y) Race/ethnicity White Black Hispanic Asian Native American Other Admission type (urgent/emergent) Admission source ER Transfer from another facility Home Insurance status Medicare Medicaid Private/HMO Uninsured Other Income Quartile 1 (lowest) Quartile 2 Quartile 3 Quartile 4 (highest) Number of biliary diagnoses 1 2 R3 Charlson comorbidity score 0 1 2 3 4 R5 Hospital size Small Medium Large Location Rural Urban Teaching hospital Hospital region Northeast Midwest South West
54
61
,.0001
Results
68.0% 10.7% 16.0% 2.0% 0.5% 2.9% 73.0%
75.6% 6.8% 12.1% 2.4% 0.5% 2.6% 76.0%
,.0001
Gender differences in outcomes of hospitalizations for cholecystitis
55.6% 2.7%
58.6% 3.6%
41.7%
37.8%
34.2% 13.5% 42.3% 6.5% 3.5%
48.1% 6.0% 37.2% 5.4% 3.4%
,.0001
17.6%
16.6%
,.0001
27.4% 25.7% 29.3%
27.0% 25.9% 30.6%
80.1% 18.8% 1.2%
77.6% 20.7% 1.8%
,.0001
66.5% 19.8% 7.5% 2.6% 1.0% 2.6%
49.2% 26.3% 12.5% 4.9% 2.2% 4.8%
,.0001
13.1% 28.0% 58.9%
12.9% 27.3% 59.8%
,.0001 ,.0001
Among adults hospitalized with acute cholecystitis, adult women (n 5 518,665) compared with adult men (n 5 276,366) accounted for the majority of all admissions for cholecystitis, at 65% versus 35%, respectively. Compared with men, women were younger (mean age, 54 vs 61 years) were more likely to be black (11% vs 7%) or Hispanic (16% vs 12%) but less likely to have multiple comorbidities and less likely to require an urgent admission (73% vs 76%) (P , .05 for all; Table 1). Women admitted with cholecystitis had lower in-hospital mortality than men (1.4% vs 2.5%), shorter LOS (5 vs 6.5 days), and lower cost of hospitalization ($11,898 vs $15,606) (P , .05 for all). Women were more likely than men to undergo cholecystectomy (75% vs 70%) during that admission and to experience a shorter time from admission to surgery (1.6 vs 1.9 days after admission) and less likely to undergo open cholecystectomy (14% vs 24%) (P , .05 for all).
Gender differences in outcomes of cholecystectomy Among patients who underwent cholecystectomy as the primary procedure during that hospitalization, women were younger, less likely to have multiple comorbidities than men (10% vs 18.9%), less likely to require an urgent admission (74% vs 77%), but more likely to be of nonwhite race or ethnicity (32% vs 24%) (P ,.05 for all). Among patients who underwent cholecystectomy, women had lower mortality (.6% vs 1.1%), fewer complications (16.9 vs 24.1), shorter 30
All p <.05
,.0001
24.1
25 20 16.9
15
17.6% 82.4% 35.2%
18.1% 81.9% 35.3%
18.4% 20.4% 40.3% 20.8%
18.6% 21.4% 40.6% 19.4%
13.2
,.0001
10.6
Women Men
10
NS ,.0001
ER 5 emergency room; HMO 5 health maintenance organization.
4.2
5
5.4
0.6 1.1 0 Mortality
Complications Length of stay Cost (%) (days) (thousands $)
Figure 1 Gender differences in outcomes after cholecystectomy, 1999 to 2006.
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Mortality Adjusted* OR (95% CI) 0.75 (0.69-0.82)
Complications
Length of Stay
0.86 (0.84-0.88) 0.95 (0.95-0.96)
Cost 0.93 (0.93-0.94)
*Age matched sample; Male gender = reference value (OR 1); adjusted for clinical characteristics (age, race, number of biliary diagnoses, type of procedure, admission urgency, comorbidities, time to surgery), year and hospital characteristics (size, teaching status, region, rural or urban location); CI = confidence interval
Figure 2 Associations between female gender and outcomes of cholecystectomy in the United States, 1999 to 2006. * Age-matched sample; male gender 5 reference value (OR, 1); adjusted for clinical characteristics (age, race, number of biliary diagnoses, type of procedure, admission urgency, comorbidities, time to surgery), year, and hospital characteristics (size, teaching status, region, rural or urban location).
LOS (4.2 vs 5.4 days), and lower cost ($10,556 vs $13,201) (P , .05 for all; Fig. 1) On multivariate analysis of age-matched women and men who underwent cholecystectomy, women had lower adjusted odds of mortality (odds ratio [OR], .75; 95% confidence interval [CI], .69 to .82), complications (OR, .86; 95% CI, .84 to .88), LOS (OR, .95; 95% CI, .95 to .96), and cost (OR, .93; 95% CI, .93 to .94) (Fig. 2). In a separate subgroup regression analysis of only patients with no comorbidities, women still had better outcomes after cholecystectomy for all outcomes measured. Longer time from admission to surgery was an independent predictor for mortality (OR, 1.09; 95% CI, 1.08 to 1.10), complications (OR, 1.14; 95% CI, 1.13 to 1.15), longer LOS (OR, 1.14; 95% CI, 1.13 to 1.14), and higher cost (OR, 1.11; 95% CI, 1.10 to 1.11). Furthermore, open cholecystectomy was also an independent predictor of mortality (OR, 3.01; 95% CI, 2.75 to 3.29), complications (OR, 2.50; 95% CI, 2.43 to 2.58), longer LOS (OR, 1.61; 95% CI, 1.60 to 1.63), and higher cost (OR, 1.44; 95% CI, 1.42 to 1.47).
Comments In this study, women clearly constitute the majority of hospitalizations for cholecystitis in the United States and are more likely to undergo surgical management during their hospitalization. Multiple studies have demonstrated a female propensity for gallstone disease. Increased body fat in women and elevated serum triglyceride in both men and women have been associated with an increased risk for cholelithiasis.15 Cholesterol gallstones form as a result of either a deficiency of bile acids or excessive secretion of cholesterol in bile, which contributes to precipitation of cholesterol in supersaturated bile. Women have been found to have a smaller total chenodeoxycholic bile acid pool size than men, which has been theorized to contribute to the greater prevalence of gallstones among women.16 Other risk factors for gallstone disease include advancing age, obesity, diabetes mellitus, estrogen or pregnancy status, cirrhosis, American Indian ethnicity, glucose-6-phosphate dehydrogenase, and hemolytic diseases.1,3,9,11,17–19 Other studies have found that men undergoing cholecystectomy are significantly older and more likely to have coexisting conditions, previous abdominal surgery, previous hospitalization for pancreatitis and cholecystitis, and
severe disease.8,10,11,18 However, these studies have conflicted in demonstrating differences in outcomes after cholecystectomy for women and men, which may be accounted for by differences in age, disease severity, and comorbidities. By age matching and adjusting on multivariate analysis for number of biliary diagnoses, comorbidities, and ethnicity, we were able to demonstrate in this national study over an 8-year period that women have better outcomes after cholecystectomy than men on all outcomes measured. Open cholecystectomy is an independent predictor of mortality, complications, longer LOS, and higher cost, which has been demonstrated in previous studies.20–22 Longer time from admission to surgery was also an independent predictor of worse outcomes. Women experience a shorter time from admission to surgery and are less likely to undergo an open procedure. This fact should spur health care providers to explore with further research whether men experience a delay in diagnoses that contributes to the longer time from admission to surgery. A delay in surgery may also contribute to the higher need for open cholecystectomy seen in the male group. However, after adjusting for time to surgery, open cholecystectomy, and the number of biliary diagnoses, women still experienced better outcomes for all outcomes measured. This study contributes to the literature by identifying that on a national level, among all patients admitted with cholecystitis, women do more favorably on variables known to affect outcomes: women are younger, and they are more likely to undergo laparoscopic procedures. Age is not a variable that can be altered. In addition, we cannot tease out in this administrative database the reasons for a longer time from admission to surgery experienced by men, such as a delay in diagnosis, need to medically stabilize or optimize a patient, or the duration from onset of symptoms to when the patient actually presented for care. However, the choice of procedure, laparoscopic versus open cholecystectomy, is a potentially modifiable variable that women clearly did better on, with lower rates of open cholecystectomy than men. Although we cannot delineate in this study the operative or clinical factors that potentially could influence the type of procedure, such as whether the gallbladder was gangrenous, whether there were significant adhesions, or whether the patient had prior abdominal surgeries contributing to the decision to perform an open cholecystectomy, it is clear that women are less likely to
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have an open procedure. These factors together, that women are younger, have a shorter time from admission to surgery, and are less likely to undergo open cholecystectomy, are potentially important contributors to the finding that women hospitalized with cholecystitis have better outcomes than men. Further research into these areas, such as time to diagnosis and time to surgery, may yield an ideal time window for diagnosing and treating patients with gallbladder disease before the more debilitating aspects of the disease manifest. Studies such as these will provide more insight into the approach to diagnosis and treatment of cholecystitis.
Limitations There are limitations inherent to any administrative database such as the HCUP NIS. There can be coding errors, leading to missed diagnoses and procedures, as well as a lack of coding, leading to missing data. The HCUP NIS is a wellvalidated and rigorously maintained database, and its error rate has been low.23 Readmissions and postdischarge mortality are not captured; therefore, it is likely that the study underestimates perioperative morbidity and mortality. Multivariate regression was used to adjust for confounding factors; alternative methods, such as propensity scores, could be used but have not been shown to be superior.24 This study used an administrative database and identified patient-level and hospital-level characteristics from ICD-9 codes. The limitation with this database is we that cannot identify clinical variables such as how many days men, compared with women, were having symptoms before presenting to providers, whether gangrenous cholecystitis was seen intraoperatively, if extensive adhesiolysis was required, or operative details such as the length of operative time, which all have the potential to contribute to the difference observed in outcomes between women and men. These are variables are clinically important, which could potentially be studied in a retrospective chart review or a prospective trial. These are significant limitations of using the NIS database. However, the strength of our study is that we were able to examine a large population on a national level treated by providers at both academic centers and community hospitals and provide an epidemiologic snapshot of outcomes of cholecystectomy.
Conclusions This study revealed a gender-based difference in both management of cholecystitis and clinical and economic outcomes of the disease. Women constitute the majority of hospitalizations for cholecystitis, are younger, are more likely to undergo surgical management during their hospitalization, have surgery earlier, and are more likely to undergo laparoscopic procedures than men. On multivariate analysis of age-matched women and men, adjusting for other characteristics, female gender is associated with better outcomes after cholecystectomy. Days from
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admission to surgery and type of procedure are independent predictors of outcome. Unlike age and gender, laparoscopy and timing of surgery are modifiable variables. Identifying these modifiable characteristics associated with outcomes will help providers and patients in treatment decision making and aid policy makers in identifying ways to improve the outcomes of patients with cholecystitis.
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