Early Versus Delayed Cholecystectomy for Acute Calculous Cholecystitis

Early Versus Delayed Cholecystectomy for Acute Calculous Cholecystitis

by

Charles William Armand de Mestral

A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Graduate Department of the Institute of Medical Science

University of Toronto

© Copyright by Charles William Armand de Mestral 2013

ii

Early Versus Delayed Cholecystectomy for

Acute Calculous Cholecystitis

Charles de Mestral

Doctor of Philosophy

The Institute of Medical Science University of Toronto

2013

ABSTRACT

Introduction: Despite evidence in favour of cholecystectomy early during first presenting

admission for most patients with acute calculous cholecystitis, variation in the timing of

cholecystectomy remains evident worldwide. This dissertation characterizes the extent of

variation within a large regional healthcare system, as well as addresses gaps in our current

understanding of the clinical consequences and costs associated with early versus delayed

cholecystectomy for acute cholecystitis.

Methods: A population-based retrospective cohort of patients admitted emergently with acute

cholecystitis was identified from administrative databases for the province of Ontario, Canada.

First, the extent of variation across hospitals in the performance of early cholecystectomy (within

7 days of emergency department presentation) was characterized. Second, among patients

discharged without cholecystectomy following index admission, the risk of recurrent gallstone

symptoms over time was quantified. Third, operative outcomes of early cholecystectomy were

compared to those of delayed cholecystectomy. Finally, a cost-utility analysis compared

healthcare costs and quality-adjusted life-year gains associated with three management strategies

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for acute cholecystitis: early cholecystectomy, delayed cholecystectomy and watchful waiting,

where cholecystectomy is performed urgently if recurrent gallstone symptoms arise.

Results: The rate of early cholecystectomy varied widely across hospitals in Ontario (median

rate 51%, interquartile range 25-71%), even after adjusting for patient characteristics (median

odds ratio 3.7). Among patients discharged without cholecystectomy following an index

cholecystitis admission, the probability of a gallstone-related emergency department visit or

hospital admission was 19% by 12 weeks following discharge. Early cholecystectomy was

associated with a lower risk of major bile duct injury (0.28% vs. 0.53%, RR=0.53, 95% CI 0.31–

0.90, p=0.025). No significant differences were observed in terms of open cholecystectomy (15%

vs. 14%, RR=1.07, 95% CI 0.99–1.16, p=0.10) or in conversion among laparoscopic cases (11%

vs. 10%, RR=1.02, 95% CI 0.93–1.13, p=0.68). Early cholecystectomy was on average less

costly ($6,905 per person) and more effective (4.20 QALYs per person) than delayed

cholecystectomy ($8,511; 4.18 QALYs per person) or watchful waiting ($7,274; 3.99 QALYs

per person).

Conclusions: Early cholecystectomy offers a benefit over delayed cholecystectomy in terms of

major bile duct injury, mitigates the risk of recurrent symptoms, and is associated with the

greatest QALY gains at the least cost.

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Acknowledgments

I wish to thank the following people and organizations who generously provided invaluable

support for my thesis work:

My supervisor Dr. Avery Nathens, for consistently using his experience, enthusiasm and

resources to support my success over the last 3 years.

My thesis committee members, Dr. Jeffrey Hoch, Dr. Andreas Laupacis and Dr. Ori Rotstein, for

their steadfast support and sound advice.

Brandon Zagorksi, for helping me navigate the complexities of accessing and analyzing ICES

data.

My fellow graduate students Barbara Haas, David Gomez, Marvin Hsiao, Sunjay Sharma, Aziz

Alali, Chethan Sathya and Debbie Li as well as our lab’s research manager Jennifer Bridge, for

the insightful input on my work and for creating a great work environment.

Harindra Wijeysundera and Murray Krahn, for their help with my Markov model.

The University of Toronto Department of Surgery, Division of General Surgery, Dr. George

Hiraki and the Clinician Investigator Program, for supporting my training in the Surgeon-

Scientist Training Program.

The Canadian Association of General Surgeons, Physician Services Inc. Foundation and the

Institute for Clinical Evaluative Sciences for financially supporting this thesis work.

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Funding

This graduate work was financially supported by an Ontario Doctoral Award, the Chikai

and Sawa Hiraki Surgeon-Scientist fellowship, a Clinician-Investigator Program Award from the

Ontario Ministry of Health as well as funds from the Division of General Surgery and

Department of Surgery of the University of Toronto.

Operating costs were covered by a grant from the Canadian Surgical Research Fund and a

Resident Research Grant from Physician Services Inc. Foundation. In addition, this work was

supported by the Institute for Clinical Evaluative Sciences, which is funded by an annual grant

from the Ontario Ministry of Health and Long-Term Care. The opinions, results and conclusions

reported in this thesis are those of the author and are independent from the funding sources. No

endorsement by the Canadian Institutes of Health Research, the Institute for Clinical Evaluative

Sciences or the Ontario Ministry of Health and Long-Term Care is intended or should be

inferred.

The author has no other financial disclosures or any conflict of interest to declare.

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Table of Contents

Abstract ............................................................................................................................................ ii

Acknowledgments........................................................................................................................... iv

Funding ............................................................................................................................................ v

Table of Contents ............................................................................................................................ vi

List of Tables ................................................................................................................................... x

List of Figures ................................................................................................................................ xii

List of Abbreviations .....................................................................................................................xiii

Chapter 1 - Thesis Overview, Hypotheses and Specific Aims ........................................................1

1.1 Thesis Overview ..................................................................................................................2

1.2 Rationale ..............................................................................................................................2

1.3 Hypotheses ...........................................................................................................................3

1.4 Research Aims .....................................................................................................................4

1.4 Contributions........................................................................................................................5

Chapter 2 - Background ...................................................................................................................6

2.1 Epidemiology of Gallstone Disease and Acute Cholecystitis..............................................7

2.2 Pathogensis of Gallstones and Acute Calculous Cholecystitis ............................................8

2.3 Diagnosis and Severity.......................................................................................................10

2.4 Surgical Management of Acute Cholecystitis....................................................................11

2.4.1 Rationale for Surgical Management of Acute Cholecystitis..................................11

2.4.2 Surgical Approach..................................................................................................12

2.4.3 Complications of Cholecystectomy .......................................................................13

2.4.4 Laparoscopic Cholecystectomy in the Setting of Acute Cholecystitis ..................15

2.4.5 Timing of Cholecystectomyfor Acute Cholecystitis..............................................16

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2.4.6 Timing of Cholecystectomy and Clinical Outcomes...........................................17

2.4.7 Timing of Cholecystectomy and Economic Outcomes .........................................18

2.5 Management Guidelines for Acute Cholecystitis ..............................................................20

2.6 Variation in Practice Worldwide........................................................................................21

2.7 Summary of Gaps in Current Knowledge..........................................................................22

2.7 Tables for Chapter 2...........................................................................................................24

2.8 Figures for Chapter 2 .........................................................................................................27

Chapter 3 - General Methods .........................................................................................................29

3.1 Strengths of Ontario's Administrative Health Data ...........................................................30

3.2 Description of Data Sources ..............................................................................................31

3.3 Data Validity ......................................................................................................................33

3.4 Approach to Costing with Ontario's Administrative Data .................................................35

3.5 Analytic Considerations .....................................................................................................36

Chapter 4 - Variation in Early Cholecystectomy for Acute Cholecystitis in Ontario ...................42

4.1 Summary ............................................................................................................................43

4.2 Background ........................................................................................................................44

4.3 Methods..............................................................................................................................45

4.4 Results ................................................................................................................................50

4.5 Discussion ..........................................................................................................................52



Chapter 5 - The Risk of Recurrent Symptoms if Cholecystectomy is Delayed .............................62

5.1 Summary ............................................................................................................................63

5.2 Background ........................................................................................................................64

5.3 Methods..............................................................................................................................65

5.4 Results ................................................................................................................................68

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5.5 Discussion ..........................................................................................................................70



Chapter 6 - Comparative Operative Outcomes of Early and Delayed Cholecystectomy ..............78

6.1 Summary ............................................................................................................................79

6.2 Background ........................................................................................................................80

6.3 Methods..............................................................................................................................82

6.4 Results ................................................................................................................................87

6.5 Discussion ..........................................................................................................................89


6.7 Figures for Chapter 4 .......................................................................................................100

Chapter 7 - Cost-utility Analysis of Alternative Timeframes of Cholecystectomy for Acute Cholecystitis ............................................................................................................................101

7.1 Summary ..........................................................................................................................102

7.2 Background ......................................................................................................................103

7.3 Methods............................................................................................................................104

7.4 Results ..............................................................................................................................112

7.5 Discussion ........................................................................................................................114

7.6 Tables for Chapter 7.........................................................................................................117

7.7 Figures for Chapter 7 .......................................................................................................120

7.8 Supplemental data for Chapter 7......................................................................................128

Chapter 8 - General Discussion ...................................................................................................136

8.1 Thesis summary ...............................................................................................................137

8.2 Implications......................................................................................................................139

8.3 Thesis Limitations............................................................................................................141

Chapter 9 - Future Directions.......................................................................................................144

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9.1 Understanding the Context-Specific Determinants of Management ...............................145

9.2 Knowledge Translation Plan ............................................................................................146

9.3 Ongoing Evaluation of Patient Outcomes and Preference...............................................147

References ....................................................................................................................................149

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List of Tables

Table 2.1 - Acute cholecystitis severity classification from the Tokyo Guidelines......................24

Table 2.2 . Major sources of morbidity and resource utilization to consider when comparing

early to delayed cholecystectomy………………………………………………………………..25

Table 2.3 - Summary of randomized controlled trials comparing early to delayed

cholecystectomy for acute cholecystitis……………………………………………………….....26

Table 4.1 - Distribution of patient characteristics……………………………………………….56

Table 4.2 - Distribution of hospital characteristics……………………………………………...57

Table 4.3 - Multilevel multivariable logistic regression results showing association of patient and

hospital characteristics with early cholecystectomy ………………………………………….....58

Table 5.1 - Probability of a gallstone-related event by time from discharge……………………73

Table 5.2 - Multivariable time to event analysis showing adjusted risk of gallstone-related event

across patient characteristics………………………………….………………………………….74

Table 5.3 - Probability of a gallstone-related event by time from discharge in competing risk

time-to-event analysis……………………………………………………………………………75

Table 5.4- Probability of a gallstone-related event by 12 weeks across age groups in competing

risk time-to-event analysis ………………………………………………………………………76

Table 6.1 - Baseline characteristics of patients and their surgeon before matching…………….93

Table 6.2 - Baseline characteristics of patients and their surgeon after matching………………94

Table 6.3 - Outcome frequency and relative risk before and after matching ……………….......95

Table 6.4 - Baseline characteristics of patients and their surgeon in synthetic cohort after

weighting on the inverse probability of treatment received………………………………...........96

Table 6.5 - Relative risk of outcome after weighting on inverse probability of treatment……...97

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Table 6.6 - Relative risk of outcomes when defining early cholecystectomy as occurring within 3

days of emergency department presentation……………………………………………………..98

Table 6.7 - Relative risk of outcome when excluding delayed cholecystectomy later than 1 year

after discharge……………………………………………………………………………………99

Table 7.1 - Model parameter inputs with sources and threshold analysis results……………...117

Table 7.2 - Average costs and quality-adjusted life-year gains and associated increments..…..119

Table 7.S1 - Baseline characteristics of patients and their surgeon before matching………….130

Table 7.S2 - Baseline characteristics of patients and their surgeon after matching……………131

Table 7.S3 - Baseline characteristics of patients before matching……………………………..132

Table 7.S4 - Baseline characteristics of patients after matching……………………………….133

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List of Figures

Figure 2.1 - Depiction of anatomy of gallbladder, cystic duct and common bile duct………….27

Figure 2.2 - Depiction of laparoscopic and open cholecystectomy………………….………….28

Figure 4.1 - Patient eligibility flowchart………………………………………………………...59

Figure 4.3 - Variation in the rate of early cholecystectomy across hospitals (N=24,437 patients,

106 hospitals)…………………………………………………………………………………….60

Figure 4.4 - Variation in the rate of early cholecystectomy rate across hospitals among young

(<50 years) healthy patients without concurrent biliary tract obstruction or pancreatitis (N=2,894

patients, 102 hospitals)…………………………………………………………………………...61

Figure 5.1 - Unadjusted probability of a gallstone-related event across age groups in the first

year following discharge…………………………………………………………………….…...77

Figure 6.1 - Patient eligibility flowchart……………………………………………………….100

Figure 7.1 - Simplified representation of model state transition diagram……………………...120

Figure 7.2 - Cost-effectiveness plane of Monte-Carlo probabilistic analysis results (10,000

iterations)……………………………………………………………………………………….122

Figure 7.3 - Incremental cost-effectiveness plane comparing early to delayed

cholecystectomy………………………………………………………………………………...124

Figure 7.4 - Cost-effectiveness acceptability curve derived from Monte-Carlo probabilistic

sensitivity analysis……………………………………………………………………………...126

Figure 7.S1 - Example of two-way sensitivity analysis results …………………………….....134

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List of Abbreviations

ADG - Aggregated Diagnosis Group

QALY - Quality-Adjusted Life-Year

CBD - Common Bile Duct

CI - Confidence Interval

CIHI - Canadian Institute for Health Information

CPWC - Cost Per Weighted Case

DAD - Discharge Abstract Database

ED - Emergency Department

ICES - Institute for Clinical Evaluative Sciences

IQR - Interquartile Range

ISPOR - International Society for Pharmacoeconomics and Outcomes Research

KM - Kaplan Meier

MOR - Median Odds Ratio

NACRS - National Ambulatory Care Reporting System

NMB - Net Monetary Benefit

OHIP - Ontario Health Insurance Plan

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OR - Odds Ratio

PSA - Probabilistic Sensitivity Analysis

RIW - Resource Intensity Weight

RPDB - Registered Person Database

RR - Relative Risk

SD - Standard Deviation

SMDM - Society for Medical Decision Making

WTP - Willingness-To-Pay

1

Chapter 1

Thesis Overview, Hypotheses, and Specific Aims

The purpose of this chapter is to:

I. Provide an overview of the thesis structure

II. Describe the rationale for the thesis focus

III. Provide the research hypotheses

IV. List the overarching objective and specific aims

V. Detail all contributions to this thesis work

2

1.1 Thesis Overview

In Chapter 1, I outline the structure of this dissertation as well as present the rationale,

hypotheses and specific aims of the thesis. In Chapter 2, I detail the relevant epidemiology,

pathophysiology and severity classification of acute cholecystitis. I then review the rationale for

surgical management of acute cholecystitis as well as the historical and clinical context of the

controversy concerning the optimal timing of cholecystectomy for acute cholecystitis. Existing

evidence comparing the clinical and economic outcomes of early and delayed cholecystectomy

are then described followed by a description of practice worldwide. Chapter 3 is a discussion of

general methods applicable to all specific aims. First, details on the contents and validity of

administrative databases utilized are provided. Second, major analytic concepts relevant to each

specific aim are discussed. Chapters 4, 5, 6 and 7 reflect the four specific aims of this thesis in

manuscript format. The final two chapters summarize the thesis results, place the implications in

the context of general limitations, and proposes ideas for future directions.

Chapter 4 has been accepted for publication by the Canadian Medical Association Journal

Open and Chapter 5 has been published in the Journal of Trauma and Acute Care Surgery.

Chapter 6 is currently under review by Annals of Surgery.

1.2 Rationale

As detailed in Chapter 2, cholecystectomy early on first admission is recommended over

delayed elective cholecystectomy for most patients with acute cholecystitis, based on

randomized trials and meta-analyses. However, recent reports reveal inconsistency in following

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this recommendation internationally, suggesting that the timing of cholecystectomy remains

controversial.

In order to generate local solutions for quality improvement, a setting-specific

understanding of the extent and potential underlying etiology for the inconsistent application of

early cholecystectomy is required. In addition, important limitations of current knowledge should

be addressed in order to better inform best practice with regards to the surgical care of acute

cholecystitis. In fact, randomized trials comparing early to delayed surgery suffer from limited

contemporary external validity and no study to date has been large enough to compare rare but

serious operative complications such as bile duct injury or death. Large population-based

analyses undertaken in this thesis offer the unique opportunity to address these limitations.

Finally, given the constrained nature of healthcare budgets, costs should be considered alongside

the clinical consequences of alternative management strategies being considered. Setting-specific

economic evaluations incorporating contemporary data will provide critical supplemental

evidence with which to inform decision making.

1.3 Hypotheses

We first hypothesize that there is considerable variation in the rate of early

cholecystectomy for acute cholecystitis across hospitals in Ontario. Second, we hypothesize that

early cholecystectomy is associated with similar operative outcomes as delayed cholecystectomy

but confers less morbidity by mitigating the risk of recurrent gallstone-related symptoms.

Finally, we hypothesize that in Ontario, early cholecystectomy is cost saving and is associated

with greater quality-adjusted life year gains compared to delayed laparoscopic cholecystectomy.

4

1.4 Research Aims

The overarching research objective of this thesis is to investigate the clinical outcomes

and costs associated with early and delayed cholecystectomy for acute cholecystitis, using a

population-based approach.

Given our overarching objective and hypotheses, this thesis is structured around the

following four specific aims:

Specific Aim #1: To characterize the extent and potential sources of variation in the

performance of early cholecystectomy for acute cholecystitis in Ontario.

Specific Aim #2: To determine the probability of gallstone-related complications in patients

discharged home without cholecystectomy on first admission.

Specific Aim #3: To compare the frequency of operative outcomes between early and

delayed cholecystectomy.

Specific Aim #4: To conduct an economic evaluation comparing different timeframes of

cholecystectomy for acute cholecystitis.

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1.5 Contributions

My contributions

I was involved in every stage of this thesis work with the support and guidance of my

program advisory committee. I developed the specific research aims with my supervisor and

program advisory committee. I was responsible for creating the population-based cohorts with

assistance from an analyst at the Institute for Clinical Evaluative Sciences (ICES). Based on the

previous work and input of ICES scientists, I performed and take responsibility for all statistical

analyses and the accuracy of the reports. I created the Markov model used in the economic

evaluation with input from experts in medical decision modeling and my program advisory

committee members. I am the first author of all four manuscripts resulting from this thesis.

Specific contribution of others to each specific aim

Avery Nathens, Ori Rotstein, Andrea Laupacis, Jeffrey Hoch contributed to the design of

all four specific aims. Brandon Zagorski was involved in helping me create the cohorts for each

specific aim. Input on statistical analysis was provided by Barbara Haas (specific aim 1), David

Gomez (specific aim 1), Aziz Alali (specific aim 3), Jeffrey Hoch (specific aims 1,3,4), Brandon

Zagorki (specific aims 1,2,3) and Avery Nathens (all specific aims). Harindra Wijeysundera and

Murray Krahn provided input in the development of the Markov model for specific aim 4. All

co-authors provided critical revisions on manuscripts.

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Chapter 2

Background


I. Describe the epidemiology, pathogenesis and severity classification of acute cholecystitis

II. Review the role of surgery for acute cholecystitis

III. Review current knowledge with respect to the impact of timing of cholecystectomy on

clinical outcomes and healthcare costs.

IV. Describe the extent of variation in the timing of cholecystectomy worldwide.

V. Provide a summary of gaps in current knowledge

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2.1 Epidemiology of gallstone disease and acute cholecystitis

Large screening ultrasound studies have shown that gallstones are present in 5% to 20%

of adults1-3. The prevalence ranges widely across ethnicities1,3 and is approximately twice as high

in women as in men 4-6. In addition to the important influence of ethnicity and sex on prevalence,

other non-modifiable risk factors for gallstones include older age, family history and genetic

predisposition2. Modifiable risk factors include obesity, rapid weight loss and a high calorie diet.

Furthermore, certain drugs (e.g. estrogen replacement therapy, thiazide diuretics) promote

gallstone formation2 whereas others such as statins, inhibitors of HMG-CoA reductase, have

been shown to reduce the risk of gallstone disease 7-9.

The previously mentioned risk factors are most applicable to the formation of cholesterol

gallstones, which account for 90% of gallstones in Western nations10. Pigment stones are more

common in eastern Asia and more frequently present as stones in the bile duct

(choledocholithiasis) as opposed to in the gallbladder (cholelithiasis)2,10. Pigment stones are

associated with states of increased bilirubin excretion (e.g. hemolysis, cirrhosis, bile salt

malabsorption) in the case of black pigment stones, or with biliary tract infection and

inflammation (cholangitis) in the case of brown pigment stones2,10.

The large majority of patients with gallstones will remain asymptomatic. However, 1% to

3% of patients per year will develop symptoms of gallstone disease11,12. Symptomatic gallstone

disease can present as biliary colic, a short-lived episode of right upper quadrant abdominal pain

due to temporary obstruction of outflow from the gallbladder by a gallstone. Acute cholecystitis

is a more severe manifestation of cholelithiasis and results from prolonged gallbladder outflow

obstruction giving rise to an inflammatory reaction described in the next section. Patients present

8

with pain of longer duration than biliary colic and with local and system signs of inflammation.

Stones can also escape the gallbladder into the biliary tract (choledocholithiasis) leading to

obstruction of the common bile duct with or without infection (cholangitis) or to an

inflammatory process in the pancreas (gallstone pancreatitis).

The incidence of acute cholecystitis decreased by 18% in Canada in the 1990s as elective

laparoscopic cholecystectomy was increasingly performed for symptomatic gallstones13.

However, acute cholecystitis remains prevalent and is in fact the most common reason for

hospitalization among all digestive diseases in the United States14.

Between 90% and 95% of cases of acute cholecystitis are due to gallstones, more

accurately referred to as acute calculous cholecystitis10,15. Gallbladder outflow obstruction may

however also occur due to malignancy, gallbladder polyps and parasites16. More commonly,

acalculous cholecystitis arises in association with predisposition to gallbladder ischemia or

instances of reduced gallbladder motility (e.g. critical illness, sepsis, burns, major surgery, total

parenteral nutrition)10,16. This thesis work focuses on the management of acute cholecystitis due

to gallstones.

2.2 Pathogenesis of gallstones and acute calculous cholecystitis

Gallstones form from the precipitation of bile solutes. Bile is produced in the liver by

hepatocytes and is stored in the gallbladder (Figure 2.1). After ingestion of a meal, neuro-

hormonal signals lead to contraction of the gallbladder and excretion of bile into the

gastrointestinal tract where it functions to facilitate the digestion of fats by emulsifying lipids

9

into micelles. In its role as a reservoir for bile, the gallbladder is the primary site of gallstone

formation.

The major solutes of bile include cholesterol, water-soluble bile salts and water-insoluble

phospholipids (lecithins)10. The formation of cholesterol gallstones is promoted by a number of

processes. First, cholesterol precipitates into crystals when its concentration in bile exceeds the

solubilizing capacity of bile salts and phospholipids. Bile stasis with gallbladder hypomotility

supports the nucleation of cholesterol crystals and mucous hypersecretion by the gallbladder

epithelium facilitates the formation of stones10,17,18.

Acute calculus cholecystitis develops as a result of gallstone obstruction of the cystic

duct leading to impaired bile outflow from the gallbladder and increased pressure within the

gallbladder. Gallbladder wall inflammation results from progressive mucosal ischemia

exacerbated by the release of inflammatory prostaglandins, leading to the compromise of the

glycoprotein mucous layer protecting the gallbladder epithelium10. While infection is not present

at the onset of acute cholecystitis, secondary superinfection is identified on biliary or gallbladder

cultures in 29% to 54% of cases of acute cholecystitis19. Gram negative organisms (E. coli,

Klebsiella spp., Pseudomonas spp., Enterobacter spp.) are most frequently involved as well as

anaerobes (Bacteroides, Clostridium) and gram positive cocci (Enterococcus, Streptococcus)

16,19.

Acute cholecystitis therefore includes a pathologic spectrum ranging from mild

inflammation with sterile bile to gangrenous cholecystitis with necrosis, empyema of the

gallbladder or emphysematous cholecystitis from gas-forming organisms. Untreated acute

cholecystitis can also progress to perforation of the gallbladder leading to bile peritonitis or a

10

pericholecystic abscess15. The formation of a biliary fistula between the gallbladder and

duodenum is also a well-documented complication15.

2.3 Diagnosis and severity

In an effort to standardize nomenclature, inform best practices and facilitate research

efforts, an international consensus conference focusing on the topics of acute cholecystitis and

cholangitis was organized in Toyko, Japan, in 2006. A panel of international experts in surgery,

internal medicine (including infectious diseases and gastroenterology), critical care and

radiology participated in performing systematic reviews and discussions ultimately leading to a

guidelines on the diagnosis and management of acute cholecystitis in 2007. This series of

publications, known as the Tokyo guidelines, were updated in January 2013, and lay out

diagnostic criteria and a clinical severity classification system for acute cholecystitis20.

As per the 2013 Toyko guidelines, the diagnosis of acute cholecystitis can be ‘suspected’

given one local sign of gallbladder inflammation (either Murphy’s sign on physical exam or right

upper quadrant mass/pain/tenderness) and one systemic sign of inflammation (either fever, an

elevated C reactive protein or a white blood cell count >12,000/mm3)20. A ‘definite’ diagnosis is

achieved when, in addition to the two previous criteria, imaging findings characteristic of acute

cholecystitis are present20. In a retrospective validation study, these criteria had a 91% sensitivity

and 97% specificity for a definite diagnosis of acute cholecystitis20.

The pathologic spectrum of acute cholecystitis mentioned previously is reflected by a

range in severity of clinical presentation. In patients with acute cholecystitis, the Tokyo

guidelines describe three levels of severity (Table 2.1). Mild cholecystitis involves meeting the

11

cholecystitis diagnostic criteria without any markers of greater severity. Moderate cholecystitis

reflects a greater degree of inflammation as suggested by a patient’s history, physical exam or

investigations. Finally, the definition of severe cholecystitis mirrors that of severe sepsis in so far

as the criteria are all markers of organ dysfunction. Approximately 95% of patients with acute

cholecystitis have mild or moderate cholecystitis21.

Several patient characteristics are frequently cited as associated with more severe

cholecystitis. However, no published studies have identified predictors of greater cholecystitis

severity in the context of the Toyko guidelines severity classification system. Furthermore, the

conclusion of an association between a patient characteristic and “more severe cholecystitis” has

been based on a range of metrics including clinical presentation, pre-operative imaging findings,

intraoperative findings, pathology or operative outcomes. With these caveats in mind, the

characteristics most consistently associated with more severe cholecystitis include older age,

male sex and diabetes22-27.

2.4 Surgical Management of Acute Cholecystitis

2.4.1 Rationale for surgical management of acute cholecystitis

Current management of acute cholecystitis is predominantly surgical for two main

reasons. First, cholecystectomy is the only definitive management of acute cholecystitis since it

manages the inflamed organ and, by removing the site of gallstone formation, prevents recurrent

symptoms. Second, the advent of laparoscopic cholecystectomy in 1990 has reduced the

12

morbidity associated with surgery thereby increasing the proportion of patients to whom

definitive surgery can be offered13.

The majority of cases of acute cholecystitis, if managed non-operatively, will settle.

In these patients, the need for definitive management is justified based on the risk of recurrent

gallstone-related symptoms. In the era when open cholecystectomy was the only surgical

approach, alternatives to cholecystectomy such as gallstone lithotripsy and pharmacologic

dissolution were extensively investigated for patients with symptomatic gallstones, outside of the

acute setting28. A high rate of recurrent or residual stones, high cost, applicability to only a small

proportion of patients and, ultimately, the advent of laparoscopic technique limited the uptake of

these nonsurgical treatments29-31. Laparoscopic cholecystectomy therefore became the

predominant treatment of symptomatic gallstone disease and the number of cholecystectomies

performed annually rose significantly in the 1990s13.

In a small proportion of cases of acute cholecystitis initially managed non-

operatively, symptoms will fail to settle and worsening sepsis, gangrenous cholecystitis, or

gallbladder perforation may ensue. Urgent surgical intervention is justified in these cases. An

alternative to surgery in the acute phase for patients with severe or worsening cholecystitis is

gallbladder decompression, generally via placement of a percutaneous drain known as a

cholecystostomy drain. Cholecystostomy placement is very effective in settling the acute

inflammation however, unlike surgery, does not prevent recurrence of symptom in the future32,33.

2.4.2 Surgical approach

Historically, cholecystectomy was performed via a subcostal incision (open

approach). Since the advent of laparoscopy in the late 1980s, laparoscopic cholecystectomy,

13

performed through 5-10mm incisions, has become the standard surgical approach (Figure 2.2). In

the non-emergent setting, the benefits of laparoscopic over open cholecystectomy include a

shorter hospital stay, faster return to work as well as better cosmesis, less post-operative pain and

a reduced incidence of surgical site infection34-36. As a result, by year 2000, over 90% of elective

cholecystectomies were started via a laparoscopic approach in Ontario13. However, in the event

of technical difficulty, conversion from laparoscopic to standard open technique is safe practice.

2.4.3 Complications of cholecystectomy

Removing the gallbladder first involves entering the abdominal cavity, either through an

open subcostal incision or laparoscopic instrument port placement (Figure 2.2), and dissecting

off omentum or bowel that is adherent to the gallbladder due to the inflammatory process. The

cystic duct, which connects the gallbladder to the common bile duct, and the cystic artery, which

supplies blood to the gallbladder, are then carefully identified, ligated and then divided (Figure

2.1). The gallbladder is then free to be dissected off the liver bed.

As with any invasive surgery, cholecystectomy carries certain risks. Operation-specific

complications include surgical site infection, bile leak, bile duct injury, bowel injury, vascular

injury and vasculo-biliary injuries. Medical complications include myocardial infarction,

pneumonia, urinary tract infection and venous thromboembolism. While rare, death may result

from any of these or other rarer complications.

The frequency of surgical site infection ranges from 1% to 10% and the risk is related to

surgical approach (laparoscopic or open cholecystectomy) and the degree of contamination (e.g.

gangrenous cholecystitis, leakage of infected bile, occurrence of a bile duct or bowel injury)37.

More specifically, when characterized according to the Center for Disease Control’s levels of

14

surgical site infection, the frequency of infection is 1% - 5%, 0.1% - 1% and 0.3% - 2.5% for

superficial incisional surgical site infection, deep incisional surgical site infection and organ

space surgical site infection respectively37,38. Appropriate management is usually based on the

nature and severity of infection. Antibiotics or simply opening the surgical wound will treat a

superficial surgical site infection. Percutaneous drainage or re-operation and washout are

required for more extensive or deep organ-space infections.

Bile leaks and bile duct injuries represent a spectrum of injury to the biliary tract.

Strasberg et al. proposed a classification system most applicable to the laparosopic era that

classifies injuries based on the length, circumference and level of the injury involved and

whether the main duct (common hepatic and common bile duct) versus an accessory or the cystic

duct are injured39. With respect to associated morbidity and impact on quality of life, injury to

the biliary tract can be considered in two broad categories: bile leaks and bile duct injuries

requiring operative intervention. Leaks may result from injury to a side branch of the biliary tree,

the cystic duct stump or a non-circumferential injury to the main ductal system. These may be

managed with endoscopic cholangiopancreatography and stent placement, possibly in association

with percutaneous drainage40. Major bile duct injuries require operative repair or reconstruction

of the biliary tract and are therefore associated with the greatest morbidity40. In fact bile duct

injuries are associated with reduced long term survival and are a major cause of litigation against

general surgeons40-43. Leaks occur in approximately 1-3% of laparoscopic cholecystectomies

whereas injuries complicate only 0.3-0.5% of cholecystectomies41,44-48. In addition, vasculo-

biliary injuries have recently received greater attention and refer to an extreme case of major bile

duct injury that occurs in conjunction with injury to a hepatic artery and/or portal vein 49,50. This

devastating injury accounts for only 2% of major bile duct injuries51.

15

The frequency of bowel injuries is not well characterized but results from dissection of

the colon, small bowel or duodenum adhered to an inflamed gallbladder or from inadvertent

cautery burn. Primary repair is generally possible if recognized early; otherwise, patients will

present later with peritonitis necessitating a return visit to the operating room.

A small proportion of cholecystectomies for symptomatic gallstones lead to medical

complications. Based on data from the National Surgery Quality Improvement Program (NSQIP)

of the American College of Surgeons, a procedure-specific registry, medical complications such

as myocardial infarction, pneumonia, urinary tract infection and venous thromboembolism

respectively occur in 0.2%-1%, 0.4%-4%, 0.7%-2% and 0.2%-1% patients respectively37. The

frequency of such complications might reasonably be expected to be higher in patients operated

on for acute cholecystitis.

Finally, mortality for patients with acute cholecystitis is under 1%15 and mortality

attributable to cholecystectomy (within 30 days or same admission) ranges between 0.3% and

3%15,37,52,53.

2.4.4 Laparoscopic cholecystectomy in the setting of acute cholecystitis

The initial experience with laparoscopic cholecystectomy was in the elective setting for

patients suffering from biliary colic, where transient gallbladder outflow obstruction occurs

without gallbladder inflammation. In fact, acute cholecystitis was initially considered a

contraindication to laparoscopic surgery based on the argument that laparoscopy in the setting of

acute inflammation would translate into high rates of operative complications54. High common

bile duct injury rates (5.5%) and high rates of conversion to open approach (15%-33%) were

indeed initially seen with laparoscopic cholecystectomy in the setting of acute cholecystitis54-56.

16

However, in a randomized trial comparing laparoscopic to open cholecystectomy in the setting of

acute cholecystitis, laparoscopy was associated with less morbidity, shorter hospital stay and

more rapid return to work57. More recent evidence suggests an improvement in rates of bile duct

injury as surgeons’ experience and comfort with laparoscopy has grown. In fact, large scale

analyses of laparoscopic cholecystectomy in patients with prior acute cholecystitis showed a

0.3% common bile duct injury rate with conversion rates remaining high in the order of 15%58.

Given the benefits of laparoscopy over an open approach, as well as evidence of improvement in

outcomes with experience, laparoscopic cholecystectomy has become the standard initial

surgical approach for acute cholecystitis.

As mentioned previously, in the event of operative difficulty, conversion from

laparoscopic to an open approach should be undertaken to prevent complications such as bile

duct injury. A number of preoperative factors have been associated with an increased probability

of conversion from laparoscopic to open surgery. These include male sex, older age, the presence

or history of obstructive jaundice, an elevated white blood cell count and a longer duration of

symptoms 22,49. Nevertheless, the degree of inflammation encountered intra-operatively

(particularly in the area known as Calot’s triangle, where the cystic duct, cystic artery and

common hepatic duct are found) remains challenging to predict preoperatively. Furthermore, the

surgeon’s comfort with difficult laparoscopic cholecystetomy is also a critical determinant of the

probability of conversion.

2.4.5 Timing of cholecystectomy for acute cholecystitis

While laparoscopic cholecystectomy was established as superior to open

cholecystectomy for patients with acute cholecystitis, the timing of operative intervention in the

laparoscopic era remained controversial in the late 1990s. Two broad strategies exist: urgent

17

early cholecystectomy and delayed elective cholecystectomy. Early cholecystectomy, while

variably defined throughout the surgical literature, most generally refers to cholecystectomy

performed on the initial admission within up to 7 days from symptom onset 22,59,60. With delayed

intervention, acute inflammation is allowed to settle before proceeding with cholecystectomy

some 6 to 12 weeks after the initial admission.

In the pre-laparoscopy era, early open cholecystectomy for acute cholecystitis was

supported by randomized prospective trials59,61,62. However with laparoscopy, it was not initially

known how conversion rates and operative complications would compare between early and

delayed cholecystectomy. Performing a delayed cholecystectomy when the gallbladder is no

longer acutely inflamed and friable might reasonably be safer. Conversely, if delayed

cholecystectomy allows for the formation of fibrosis in and around Calot’s triangle, the operation

may prove more difficult resulting in a higher rate of conversion and complications. Also,

patients managed with the intention of delayed cholecystectomy, who are discharged home once

their acute symptoms improve, remain at risk of recurrent gallstone-related symptoms until their

scheduled elective cholecystectomy. Table 2.2 lists the major sources of morbidity and resource

use to consider when comparing early to delayed cholecystectomy.

2.4.6 Timing of cholecystectomy and clinical outcomes

Starting in the late 1990s multiple studies prospectively examined the timing of

laparoscopic cholecystectomy in acute cholecystitis. Five randomized prospective trials compare

the outcomes of laparoscopic cholecystectomy performed on first presentation compared to a

delayed procedure and are synthesized in Table 2.3. The results of these trials show that

laparoscopic cholecystectomy within 7 days of symptom onset or diagnosis is associated with a

significantly reduced total hospital stay and a similar conversion rate as delayed cholecystectomy

18

46,63-67. Furthermore, with respect to the clinical course of patients managed with delayed

cholecystectomy, trial data and retrospective studies of selected patient samples suggest that

delayed management is associated with a 0% to 38% readmission rate for gallstone related

complications 46,63-70. This range of estimates also provides insight into our contemporary

understanding of the natural history of untreated acute cholecystitis.

As such, early cholecystectomy for most patients with acute cholecystitis has been

promoted based on the findings of a similar conversion rate, shorter hospital length of stay and

avoidance of recurrent gallstone symptoms. However, the randomized trials suffer from many

limitations. First, they were published from 1998 to 2004 and certain exclusion criteria such as

suitability for laparoscopy are unlikely to apply today as experience with difficult laparoscopic

cholecystectomy has grown. Second, the trials were powered to compare conversion rates in the

order of 20% but were too small to compare rare but devastating complications such as bile duct

injury or mortality. A recent meta-analysis of the trials’ data remains underpowered to offer a

conclusive comparison of the frequency of bile duct injury (1 in 232 early cases versus 3 in 219

delayed cases)71. Finally, the studies originate from single academic centers and therefore may

not provide estimates of outcomes and recurrent gallstone symptoms that can be generalized to a

broader sphere of practice. The only published population-based data on recurrent gallstone

complication rates, in patients discharged home without cholecystectomy, is limited to capturing

admissions in patients over the age of 6569.

2.4.7 Timing of cholecystectomy and economic outcomes

The timing of laparoscopic cholecystectomy for acute cholecystitis has important

ramifications in terms of resource utilization and associated costs. Clinical studies suggest lower

healthcare costs with early cholecystectomy based on a reduction in total hospital length of

19

stay46,69. However, only two formal economic evaluations have focused on the timing of

cholecystectomy in acute cholecystitis. A complete economic evaluation requires consideration

of both the costs and clinical consequences of alternative management strategies72. The results of

an economic evaluation can help a decision maker, such as a third party payer, decide whether

the clinical benefit of one treatment over the other is worth any additional cost. Furthermore,

quantifying the amount of uncertainty around the results is an integral component of economic

evaluations and remains relevant even in situations where a treatment is more effective and less

costly than its alternative.

In the first published economic evaluation on this topic, Wilson et al. undertook a cost-

utility analysis using a decision tree framework to compared early cholecystectomy, performed

within up to 7 days symptom onset, to delayed elective cholecystectomy73. Costs were calculated

from the perspective of the United Kingdom Ministry of Health and the metric of clinical

effectiveness was the quality-adjusted life-year (QALY). Their analysis showed that early

laparoscopic cholecystectomy was less costly (−£820 per patient) and associated with greater

QALY gains (+0.05QALYs per patient) for patients with acute cholecystitis. On probabilistic

sensitivity analysis, they reported an 80% probability that early laparoscopic cholecystectomy

was cost-effective given a Ministry of Health willingness-to-pay £20,000 per additional quality-

adjusted life-year. In a similar cost-utility analysis, Johner and colleagues reached the same

conclusion, but included only costs from the perspective of a single academic hospital in British

Columbia, Canada74. However, the outcomes probabilities that informed both group’s decision

tree models input parameters were derived from the existing randomized trials comparing early

to delayed cholecystectomy. As a result, both studies are hindered by the previously mentioned

limited contemporary external validity and constraints related to the small sample size of the

trials.

20

In addition to these two similar model-based studies, a person-level cost-utility analysis

was also published by MaCafee et al. that compared early to delayed cholecystectomy for

patients with biliary or acute cholecystitis75. They performed a small randomized trial capturing

patients’ quality of life 30-35 days after surgery as well as costs from a National Health Service

and societal perspective. Although no significant differences in costs or quality of life were

observed, the marginally higher quality of life 30 days after delayed surgery (vs. early surgery)

was associated with minimal additional cost. Since the risk of operative complications and

recurrent symptoms is lower with biliary colic than acute cholecystitis, the lack of a subgroup

analysis focused on patients with acute cholecystitis limits direct application of these results to

the central question of this thesis. Furthermore, temporary reductions in quality of life while

awaiting delayed elective cholecystectomy were not captured in Macafee’s analysis and are a

critical consideration.

2.5 Management guidelines for acute cholecystitis

The previously described Tokyo consensus guidelines represent the most detailed

guidelines for the management of acute cholecystitis 49. Based on existing evidence and

consensus among the expert panel members, the 2013 Tokyo guidelines support early surgery on

first presenting admission as the optimal management strategy for patients with non-severe acute

cholecystitis. This recommendation is also consistent with the Society of American

Gastrointestinal and Endoscopic Surgeon’s (SAGES) guidelines for the clinical application of

laparoscopic biliary surgery76. While much less detailed, SAGES endorses early laparoscopic

cholecystectomy within 24 to 72 hours of diagnosis for patients with acute cholecystitis.

21

The Tokyo guidelines also provide recommendations specific to the grade of cholecystitis

severity. Since the severity classification system was published relatively recently, grade-specific

recommendations do not have a strong evidence base. However, the recommendations are

informed by consensus of international experts that participated in the development of these

guidelines. Patients with mild (grade I) acute cholecystitis should be managed with

cholecystectomy early on first presenting admission. For patients with moderate cholecystitis

(grade II), early cholecystectomy is also recommended as the preferred management strategy.

However, the 2013 version of the guidelines, more so than the 2007 version, stresses the point

that, at the surgeon-level, delaying surgery may be reasonable if the surgeon is not comfortable

with difficult laparoscopic cholecystectomy where severe local inflammation is encountered.

Conversely, the point is also made that a minority of cases of moderate cholecystitis involving

gallbladder perforation, grangrenous cholecystitis or emphysematous cholecystitis may require

urgent early surgery or gallbladder drainage. Finally, for patients with severe cholecystitis,

intervention is required given the organ dysfunction resulting from the acute cholecystitis.

Percutaneous cholecystostomy followed by delayed cholecystectomy is recommended as the

optimal management for these patients.

2.6 Variation in practice

As described, best available evidence can be interpreted as supportive of early

cholecystectomy for most patients with acute cholecystitis based on a similar conversion rate,

shorter total hospital length of stay and elimination of the risk of recurrent gallstone symptoms

associated with delayed cholecystectomy. While the clinical trials were published between 1998

22

and 2004, practice patterns have not universally followed suit. In studies published between 2004

and 2007, only 11% to 55% of surgeons surveyed in the UK, Japan and Australia reported

having a preference for early laparoscopic cholecystectomy77-80. Further support in the literature

for early cholecystectomy was provided in 2006-2007 when a Cochrane Collaborative meta-

analysis of the randomized trial data was published as well as the Tokyo consensus guidelines

for the management of acute cholecystitis. However, studies published between 2006 and 2012

in the USA, UK and Japan have shown that 36-88% of patients with acute cholecystitis actually

undergo early cholecystectomy69,70,80-83. Clearly practice patterns remain variable across

hospitals worldwide. However, because of differences in the setting and cohort characteristics

across published studies, our understanding of the extent and underlying etiology of the

inconsistent application of early cholecystectomy remains circumstantial.

2.7 Summary of gaps in knowledge

In summary, important gaps remain in the clinical evidence comparing early to delayed

cholecystectomy for acute cholecystitis. The main gaps include:

(1) The need for a contemporary comparison of the rate of conversion from

laparoscopic to open cholecystectomy in real world practice.

(2) The lack of an accurate comparison of rare but devastating operative

complications including bile duct injury and death.

(3) The need for estimates of the risk of recurrent symptoms if cholecystectomy is

delayed, that can be generalized to a broad range of patients.

23

Furthermore, published reports suggest variation in the application of early

cholecystectomy across different contexts of care. Therefore, in order to effectively translate

clinical evidence into practice within a given healthcare system such as Ontario’s, a detailed

understanding of the local context of practice is required.

Finally, given the constrained nature of healthcare budgets, economic evaluations can

provide useful information for decision making by explicitly presenting the costs of alternative

treatments relative to the associated clinical consequences. Setting-specific cost estimates as well

as clinical outcome estimates addressing previously mentioned knowledge gaps will best inform

decision making.

24

2.8 Tables for Chapter 2

Table 2.1 – Acute cholecystitis severity classification from the Tokyo Guidelines20

Severity level Criteria

Mild cholecystitis Not meeting criteria for moderate or severe cholecystitis

Moderate cholecystitis

Any one of the following conditions: 1. Elevated WBC count (>18,000/mm3) 2. Palpable tender mass in the right upper abdominal

quadrant 3. Duration of complaints > 72 hours 4. Marked local inflammation (gangrenous cholecystitis,

pericholecystic abscess, hepatic abscess, biliary peritonitis, emphysematous cholecystitis)

Severe cholecystitis

Dysfunction in any one of the following organs/systems: 1. Cardiovascular dysfunction: Hypotension requiring

treatment with dopamine ≥5 lg/kg per min, or any dose of norepinephrine

2. Neurological dysfunction: Decreased level of consciousness

3. Respiratory dysfunction: PaO2/FiO2 ratio < 300 4. Renal dysfunction: Oliguria, creatinine> 2.0 mg/dl 5. Hepatic dysfunction: PT-INR>1.5 6. Hematological dysfunction Platelet

count<100,000/mm3

25

Table 2.2– Major sources of morbidity and resource utilization to consider when comparing early and delayed cholecystectomy

Early cholecystectomy Delayed cholecystectomy

1) Operative events:

- Conversion to open cholecystectomy - Major bile duct injury (requiring

surgical reconstruction) - Bile leak (requiring endoscopic

intervention) - Other complications: surgical site

infection, vascular injury, bowel injury, medical complications

- Death 2) Hospital length of stay

1) Operative events:

- Conversion to open cholecystectomy - Major bile duct injury (requiring

surgical reconstruction) - Bile leak (requiring endoscopic

intervention) - Other complications: surgical site

infection, vascular injury, bowel injury, medical complications

- Death 2) Gallstone-related symptoms while

awaiting elective operation: - Biliary colic, recurrent cholecystitis,

gallstone pancreatitis, choledocholithiasis, cholangitis, gallstone ileus

3) Hospital length of stay

Delayed group

Study Country Early Delayed (weeks) Exclusions Surgeons’

experienceNumber of patients

(Early / delayed)Conversion (%) -

1ry outcomeMajor bile

duct injury (N)

Total hospital length of stay in days (median)

Non-resolving or recurrent

symptoms (%)

Kolla, 2004 India 48hrs from randomization 6-12

* Symptoms for >96hrs * Prior upper abdominal surgery * Unfit for laparoscopic surgery *concurrent CBD stones

NR 20 / 20 25 vs. 25 1 vs. 0 4 vs. 10 0%

Johansson, 2003 Sweden 48hrs from randomization 6-8 Symptoms for > 7 days >25 LCs 74 / 71 31 vs. 29 0 vs. 1 5 vs. 8 25%

Davila, 1999 Spain 4 days from symptom onset 8 NR NR 36 / 27 4 vs. 17 0 vs. 1 1.6 vs. 2.7 13%

Lai, 1998Hong Kong, China

24hrs from randomization 6-8

* Symptoms > 1 week * Prior upper abdominal surgery * Unfit for laparoscopic surgery * Concurrent CBD stones

>50 LCs 53 / 51 21 vs. 24 0 vs. 0 8 vs. 12 17%

Lo, 1998Hong Kong, China

72 hrs from admission 8-12

* Symptoms > 7days * Prior upper abdominal surgery * unfit for laparoscopic surgery * Concomittant malignancy

>300 LCs 49 / 50 10 vs. 20 0 vs. 1 6 vs. 11 37%

LC=laparoscopic cholecystectomies, CBD= common bile duct, NR=Not reported

Outcomes

Early vs. Delayed Study characteristics

Table 2.3- Summary of randomized controlled trials comparing early to delayed laparoscopic cholecystectomy for acute cholecystitis

Charles

Text Box

26

27

2.9 Figures for Chapter 2

Figure 2.1 - Depiction of anatomy of gallbladder, cystic duct and common bile duct (copyright

A.D.A.M)

28

Figure 2.2 - Depiction of laparoscopic and open cholecystectomy

29

Chapter 3

General Methods


I. Describe the strengths of using Ontario’s population-based administrative databases for

this thesis work

II. Present details on the data sources and data validity

III. Provide an overview of the major analytic considerations for each chapter

30

There is no large population-based study to date that compares early to delayed

cholecystectomy for acute cholecystitis. As detailed previously, trials comparing these

management strategies suffer from limited sample size and limited contemporary external

validity. Analysis of a large population-based cohort of patients with acute cholecystitis is

uniquely suited to address these limitations and offer added value to decision making. The need

for such studies has in fact been echoed in a number of published reports 84-86.

While retrospective analysis of population-based administrative databases offers several

unique strengths, important methodological considerations are necessary. In view of this fact,

this chapter discussed the major strengths associated with the use of Ontario’s administrative

data to address the specific aims of this thesis. I then provide details on each of the databases

utilized as well as their validity for the purposes of this thesis. Finally, major analytic concepts

relevant to each specific aim are presented.

31

3.1 Strengths of Ontario’s Administrative Health Data

Administrative health data for the province of Ontario are housed and consolidated at

the Institute for Clinical Evaluative Sciences (ICES), Toronto. The strengths of Ontario’s

administrative health data for the purposes of this thesis include the provision of a large study

sample, its population-based nature, the broad scope of services captured, the longitudinal span

of the data supported by deterministic linkage and a data collection framework supporting data

validity.

3.1.1 Large sample size

Canada’s most populous province, Ontario has a population of over 13 million persons

contributing to the administrative data sources utilized for this thesis87. Studying a large sample

of patients with acute cholecystitis drawn from this population allows the detection of rare

operative complications such as bile duct injury or death as well as rare gallstone-related

complications such as gallstone ileus.

3.1.2 Unselected population-based sample

A number of large databases worldwide have been utilized for the purpose of studying

gallstone disease. Procedure-specific registries exists such as the U.S. National Surgical Quality

Improvement Program37, the Swiss Association of Laparoscopic and Thoracoscopic Surgery

Database53 or the population-based Swedish Gallrisk registry42. These registries do not support

the disease-specific analysis required for the specific aims of this thesis since episodes of care

not involving surgery are not captured. Disease-specific cohorts of patient with acute

cholecystitis can be defined from many large administrative databases, however most are

32

restricted to a selected patient group (e.g. patients over 65 years of age in U.S. Medicare data69)

or a selection of hospitals (e.g. U.S. Nationwide Inpatient Sample88, the Health Episode Statistics

database in the U.K.89). In part due to the fact that there are no private general hospitals in

Ontario, the data sources utilized in this thesis offer the important advantage of including all

residents within the province with a valid health card. Therefore, a population-based disease-

specific cohort of all patients with acute cholecystitis can be studied and generate results

generalizable to a wide range of patients and settings.

3.1.3 Longitudinal span supported by deterministic data linkage

Administrative records held at ICES data back as far as the late 1980s in some cases and

new records are added on an annual basis. These databases are linkable across episodes of care

and fiscal year using an encrypted unique patient identifier based on a patient’s Ontario Health

Card Number. This deterministic linkage supports longitudinal follow-up with loss of follow-up

occurring only in the case where patients lose their status as residents of Ontario.

3.1.4 Broad scope of services captured

As can be appreciated below in the descriptions of the individual databases, the scope of

services and information captured in Ontario’s administrative data is broad. Records cover all

hospitalizations, day surgeries, emergency rooms visits, physician billing as well as information

on hospitals and physicians. The scope of health services captured and deterministic linkage of

individual records at the patient-level allows a detailed understanding of patients’ clinical course.

33

3.2 Description of Data Sources

3.2.1 Discharge Abstract Database

The Discharge Abstract Database (DAD) at ICES includes data on all hospital admissions

and same day surgeries in Ontario. Each record of a hospital stay includes patient demographics,

diagnostic and procedural data as well as disposition. Prior to processing at ICES, the data is

collected as part of a national DAD by the Canadian Institute for Health Information (CIHI) and,

with the exception of Québec, is submitted directly to CIHI by individual hospitals. A DAD

abstraction manual, describing province-specific mandatory fields, as well as required testing of

abstraction software supports a standardized abstraction process90. When data errors at an

individual hospital are identified during initial processing, CIHI is able to request that corrected

data be resubmitted. DAD was used to capture the index acute cholecystitis admission as well as

day surgeries for cholecystectomy and gallstone-related admissions.

3.2.2 National Ambulatory Care Reporting System

Records from the National Ambulatory Care Reporting System (NACRS) also originate

from a national database collected and maintained by CIHI that includes all emergency

department visits. NACRS records are processed at ICES to allow direct linkage to an associated

DAD record. For the purposes of this thesis, entry via the emergency department prior to the

index cholecystitis admission was confirmed through linkage with NACRS. In addition,

gallstone-related emergency department visits were identified in NACRS.

34

3.2.3 Registered Person Database

The registered person database (RPDB) is provided to ICES by the Ontario Ministry of

Health and includes basic demographic information (age, sex) and vital statistics (date of birth,

date of death) on residents of Ontario with a valid health card. Date of death and patient

demographic information are preferentially identified from RPDB as is standard with ICES

projects.

3.2.4 Ontario Health Insurance Plan Billing Database

The Ontario Health Insurance Plan (OHIP) Billing Database contains records of all

physician billing claims paid by the Ontario Ministry of Health and Long Term Care. Each

record contains a fee code, a fee suffix reflecting the type of physician service (e.g. performing a

surgical procedure vs. assisting with a surgical procedure) as well as an encrypted physician

number and the ICES patient key number for linkage to other databases. A diagnosis code is also

included. However, this field is of uncertainty validity and may reflect broad disease categories

rather than specific diseases. The OHIP Billing Database was used to derive a comorbidity index

as well as identify cholecystectomies and biliary tract repair for major bile duct injury.

3.2.5 ICES Physicians Database

The ICES Physician Database contains information on physicians in Ontario that is

linkable to the encrypted physician billing number included in the OHIP Billing Database. From

this database year of medical school graduation was obtained and used as a reflection of a

surgeon’s number of years in practice.

35

3.3 Data validity

The validity of the above-mentioned databases can be an important strength or a serious

limitation depending on the research question. The data held at ICES has been validated for the

identification of a variety of diagnoses including congestive heart failure91, acute myocardial

infarction91, chronic obstructive pulmonary disease92, hypertension93, diabetes94 and infection

with human immunodeficiency virus95. In addition to these specific diagnoses, referencing a

patient’s inpatient and outpatients records in DAD, NACRS and the OHIP billing database

support the derivation of a comorbidity index predictive of 1 year mortality in a general cohort of

adult Ontarians96,97. Finally, the accuracy of DAD coding for a broader range of diagnoses as

well as procedures was examined in an ICES-funded multicenter re-abstraction study98. This

study was the largest of its kind in Canada, including over 14,000 records across 18 hospitals in

Ontario. Juurlink and coauthors reported consistently high sensitivity and specificity of

procedure coding in administrative records. While variation across disease areas was observed,

coding of the diagnosis most responsible for hospitalization was generally accurate.

Of specific relevance to this thesis, almost perfect agreement (kappa= 0.83 (0.76 to 0.90))

and high sensitivity (0.85 (0.74 to 0.92)) was found for gallstone disease as the most responsible

diagnosis98. However, it should be noted that the accuracy of coding of specific types of

gallstone disease (e.g. cholelithiasis with cholecystitis versus cholelithiasis without cholecystitis

versus cholecystitis with choledocholithiasis) was not examined. With respect to the accuracy of

cholecystectomy coding, almost perfect agreement (kappa= 0.97 (0.95 to 0.99)) and very high

sensitivity (0.98 (0.93 to 1.00)) were found in Ontario’s DAD98.

36

3.4 Approach to costing with Ontario’s administrative data

Methods of cost estimation using administrative data in Canada are becoming

increasingly refined and were outlined in a 2009 report by the Canadian Agency for Drugs and

Technologies in Health99. Based on this methodology, an ICES-specific person-level costing

approach has been described in a recent report that includes database-specific considerations100.

Hospital costs are estimated using the Resource Intensity Weight (RIW) method 18. Each

ED visit, hospital admission and day surgery is assigned an RIW value, which when multiplied

by the provincial average cost per weighted case (CPWC), estimates the cost of the given patient

visit. The RIW value for a given admission for example reflects a patient`s level of resource

utilization during that admission and is based on the patient`s major diagnosis, age, comorbidity

burden, interventions received and length of stay. The CPWC values are year and visit type

specific (e.g. inpatient stay in fiscal year 2009), and they are derived from the allocation of

global hospital budgets across all patients (total annual budget of inpatient care divided by sum

of all inpatients’ RIWs). Both direct medical and overhead hospital costs associated with relevant

ED visits, inpatient stays and day surgery are captured within this costing approach.

The cost of physician services relevant to this thesis work fall outside the scope of the

RIW method since general surgery physician services in Ontario are largely directly paid by the

Ministry of Health on a fee-for-service basis. The costs specific to physician claims can therefore

be derived based on the fee schedule known as the Ontario Health Insurance Plan schedule of

benefits for physician services101.

37

3.5 Analytic consideration

3.5.1 Clustered data

Data and variables included in large administrative databases generally reflect

patients treated within given structures of care (e.g. patients cared for by specific physicians,

working within specific hospitals). In other words patients can be considered clustered within

structures of healthcare delivery. Furthermore, when studying a large cohort, it is reasonable in

many cases to expect that patients within the same cluster (e.g. cared for at the same hospital) are

more similar to one another than to patients within a distinct cluster (e.g. cared for at another

hospital). However, standard multivariable regression techniques (i.e. generalized linear models)

to account for confounding assume that all observations are independent102. The impact of this

assumption is most important when interpreting the association of cluster-level characteristics

(e.g. hospital teaching status) with a given outcome 103. For example, when considering the

association between patient and hospital level characteristics with the receipt of early

cholecystectomy as we do in Specific Aim 1, standard regression will tend increase the precision

of the association between hospital-level characteristics and the outcome. This occurs because

instead of comparing for example 25 teaching hospitals to 127 non-teaching hospitals, teaching

status is attributed to the person-level such that the comparison of teaching status now involves

comparing approximately 13,000 patients at teaching hospitals to approximately 10,000 patients

at non-teaching hospitals104. Multilevel regression overcomes this analytic fallacy by attributing

an additional measure of effect in the regression equation for each higher-level unit and also

supports further understanding of outcome variation across high-level units. While the magnitude

of change in the direction and significance of effects when accounting for clustering cannot

always be predicted, the impact is generally greatest on higher-level characteristics. In other

38

words, the estimate (e.g. odds ratio) and the confidence limits around this estimate are more

likely to change for hospital teaching status or a hospital volume metric than for patient age or

sex104.

3.5.2 Standard versus competing risks in time-to-event analysis

Specific Aim 2 focuses on quantifying the risk of recurrent gallstone-related

symptoms among patients discharged without cholecystectomy following an index cholecystitis

admission. The outcome of interest is occurrence of the first gallstone-related emergency

department visit or hospital admission. In calculating the probability of this outcome at clinically

meaningful time intervals after discharge, time-to-event (survival analysis) is appropriate in

order to account for the different individual periods of follow-up as well as considering the fact

that patients’ follow-up may be censored. Censoring means that follow-up is cut short before the

outcome is observed. Reasons a patient’s follow-up may be censored include end of the

observation window, death or end of the period where the patient is at risk of the outcome (e.g. a

patient has their gallbladder removed so is no longer at risk of recurrent acute cholecystitis). The

reasons patients are censored as well as the clinical question are important considerations when

deciding on an appropriate analytic approach.

Standard univariable time-to-event analysis using the Kaplan-Meier method considers

that censoring is non-informative105.The assumption of non-informative censoring means that

patients who undergo a censoring event (e.g. cholecystectomy) should not be at greater or lesser

risk of a subsequent outcome event (e.g. gallstone-related complication) as compared to the

remaining patients with a similar event-free (“survival”) time. When censoring is an informative

competing risk (e.g. a large proportion of deaths at home are due to gallstone disease), the

Kaplan-Meier method will overestimate the probability of the outcome 106,107. The cumulative

39

incidence approach has been developed as an alternative analytic approach that accounts for the

competing nature of a censoring event107,108.

However, both approaches can be interpreted as presenting valid information, even in

the context of informative censoring by a competing risk. On one hand, the Kaplan-Meier results

reflect the probability of the outcome over time among patients who would not be affected by the

competing risk. Alternatively, the cumulative incidence approach describes the probability of the

outcome as actually observed in the study cohort. Therefore it is important to consider to whom

the results are meant to apply. Ultimately, the magnitude of the difference between the two

approaches will be minimal in cases where the competing risk is rare, as is the case for death

among patients being offered delayed elective cholecystectomy. Given these considerations, as

detailed in Chapter 5, we performed standard time-to-event analysis as our primary approach.

The cumulative incidence function of a gallstone-related event was also calculated as a

secondary approach.

3.5.3 Accounting for selection bias in comparative effectiveness studies

By the very nature of non-experimental studies, treatment selection bias is a critical

consideration when comparing two treatment alternatives using administrative data. Standard

regression techniques are most often used and are an accessible tool to non-statisticians given the

ease of implementation in most statistical software and rapidly increasing processing power.

Nevertheless, regression techniques also offer the opportunity to perform an analysis without

seeing explicit evidence that the results reflect a less biased estimate of an exposure-outcome

association. Propensity score methods were first developed by Rosenbaum and Rubin as an

alternative to regression methods109. The propensity value is the probability of exposure based on

observed covariates109. When conditioning on the propensity score, a comparison of similar

40

patients is possible. Four methods of using the propensity score to reduce bias have been

described: direct adjustment, stratification, matching and inverse probability of treatment

weighting110. The first involves including the propensity score value as a continuous independent

variable in a regression model. The second involves creating strata based on the propensity score

within which a less biased outcome comparison can be made. The third involves matching

patients in exposure groups based on the propensity score and the fourth methods weighs each

patient based on the inverse of the probability of treatment received. The third and fourth

methods have been shown to most effectively reduce bias given a binary outcome measure 111.

Matching has the added benefit of a being more transparent approach since balance before and

after matching of exposure groups is presented and, similarly to the first table of baseline

characteristics in a randomized trial, requires minimal statistical training to appreciate. Matching

on the propensity score was therefore employed as the primary analytic technique to minimize

bias related to observed covariates when comparing the operative outcomes of early and delayed

cholecystectomy for acute cholecystitis in Specific Aim 3. Inverse probability of treatment

weighting was also undertaken as a secondary approach.

3.5.4 Best modeling practices in economic evaluation

The final paper of this thesis is a model-based cost-utility analysis comparing

alternative timeframes of cholecystectomy for acute cholecystitis. Economic evaluation such as

cost-utility or cost-effectiveness analyses can either be person-level or model-based72. Since

simultaneous collection of all relevant clinical outcomes probabilities, health-related quality of

life and costs relevant to a decision is rare, modeling is most often required. Based on decision

analysis methods, a model-based economic evaluation can support the comparison of many

alternative treatment strategies and should be informed by best available evidence, often drawn

41

from multiple difference sources. Given the complexity of many economic models as well as the

subjective nature of model construction, the Society for Medical Decision Making (SMDM) and

International Society for Pharmacoeconomics and Outcomes Research (ISPOR) created a Task

Force on best modeling practices112. Recommendations were made with respect to model

structure, integration of outcomes, model evaluation as well as sensitivity analyses. The

recommendations stress the role of decision/economic models as a means to support decision

making by explicitly considering all clinical consequences (and costs for economic evaluations)

of alternative management strategies. Another critical recommendation is that model structure be

based on the relevant clinical and economic consequences as opposed to available data (e.g. from

the newest randomized controlled trial) and that best available data consistent with principles of

evidence-based medicine should inform the model. Finally, sensitivity analyses, including

probabilistic sensitivity analysis, are considered essential to evaluate model input parameter

uncertainty. These and other recommendations of the SMDM-ISPOR Task Force were

considered in completing Specific Aim 4.

42

Chapter 4

Variation in early cholecystectomy for acute cholecystitis in Ontario


I. Characterize the extent of variation in early cholecystectomy across hospitals in Ontario.

II. Identify patient and hospital characteristics associated with performing early

cholecystectomy

Preamble

The contents of this chapter have been accepted for publication in CMAJOpen:

De Mestral C, Laupacis A, Rotstein OD, Hoch JS, Haas B, Gomez D, Zagorski B, Nathens AB.

Early Cholecystectomy for Acute Cholecystitis: A Population-based Retrospective Cohort Study

of Variation in Practice. CMAJ Open. In press. 2013

Copyright for this manuscript in CMAJOpen is retained by the authors for noncommercial use.

43

4.1 Summary

Background

Despite evidence in favour of early cholecystectomy for most patients with acute

cholecystitis, variation in practice has been reported across hospitals worldwide. We sought to

characterize the extent and potential sources of variation in the performance of early

cholecystectomy for acute cholecystitis, within a large regional healthcare system.

Methods

We used a population-based retrospective cohort design. The cohort was limited to adults

with a first episode of acute cholecystitis, admitted through the emergency department. Patients

were identified using administrative databases comprising all emergency department visits and

hospital admissions in Ontario, Canada, from 2004 to 2010. Patient and hospital-level

characteristics associated with early cholecystectomy (within 7 days of emergency department

presentation) were identified using multilevel logistic regression.

Results

We identified 24,437 patients admitted to 106 hospitals with a first episode of acute

cholecystitis. A majority (58%, N=14,286) underwent early cholecystectomy. Rates of early

cholecystectomy varied widely across hospitals (median 51%, IQR 25%-72%), even among 18-

49 year old healthy patients with uncomplicated cholecystitis (median 74%, IQR 41%-88%). On

multivariable multilevel analysis, hospitals in the top quartile for acute cholecystitis admission

44

volume had the highest adjusted odds of early cholecystectomy and hospital effects accounted

for half of the explained variation in early cholecystectomy.

Conclusion

Across a large regional healthcare system’s hospitals, similar patients with acute

cholecystitis did not receive comparable care. Hospital-level factors, independent of patient

characteristics, appear strongly related to practice.

4.2 Background

Acute cholecystitis is a ubiquitous cause of hospitalization for gastrointestinal disease

and is definitively managed with cholecystectomy14,113.Randomized controlled trials, meta-

analyses and expert consensus support a practice of early laparoscopic cholecystectomy on first

hospital admission for most patients with acute cholecystitis, without severe sepsis49,60,76,84,114. In

fact, when compared to delaying cholecystectomy, early laparoscopic cholecystectomy within up

to 7 days of symptom onset is associated with a shorter total hospital length of stay and a similar

risk of conversion to open cholecystectomy60. Further support for early intervention can be

drawn from reports showing an approximately 20% risk of recurrent gallstone-related symptoms,

if delaying cholecystectomy15,60.

In spite of this evidence favouring early intervention, inconsistency in delivering what

many consider best practice has been reported worldwide. In fact, reports out of the United

Kingdom, Japan and the United States show rates of early cholecystectomy ranging from 36% to

88%69,70,81,82,88. However, because of differences in the setting and patient sample characteristics

across published studies, our understanding of the extent and underlying etiology of the

45

inconsistent application of early cholecystectomy remains circumstantial. We postulated that a

better understanding of the factors associated with the performance of early cholecystectomy

would provide opportunities to address the gap between evidence and practice. Our objective

was therefore to evaluate the extent of variation across hospitals in a large regional healthcare

system and, to identify patient and hospital characteristics associated with performing early

cholecystectomy.

4.3 Methods

Study design

This is a population-based retrospective cohort study of all adults with a first episode of

acute cholecystitis emergently admitted to an acute care hospital between April 1, 2004 and

March 31, 2010, in the province of Ontario, Canada. We compared rates of early

cholecystectomy across hospitals and used multivariable multilevel logistic regression to identify

patient and hospital characteristics associated with performing early cholecystectomy. This study

was approved by the Research Ethics Board of Sunnybrook Health Sciences Center.

Setting

This study used data from Ontario, Canada’s most populous province with over 13

million persons across 918,000 square kilometres. All hospital and physician services for Ontario

residents are paid by the provincial Ministry of Health. There are no private general hospitals in

Ontario.

Data sources

46

Patients were identified from the Canadian Institute for Health Information Discharge

Abstract Database, which contains demographic, diagnostic and procedural information on all

hospitalizations in Ontario. Admission via the emergency department was confirmed through

linkage to the National Ambulatory Care Reporting System database, which captures all

emergency department visits. To derive certain covariates (patient comorbidities and hospital

after-hours procedure volume), the Discharge Abstract Database was supplemented with data

from the Ontario Health Insurance Plan billing database that contains all physician claims. These

datasets were deterministically linked through a unique encrypted patient identifier and have

been validated for a variety of exposures and comorbidities91-94,98. In a multicenter validation

study, almost perfect agreement was found between Ontario’s Discharge Abstract Database and

reabstracted data for cholecystectomy coding and coding of gallstone disease as the most

responsible diagnosis98.

Study cohort

The cohort included residents of Ontario, 18 years of age or older, who were admitted to

hospital via the emergency department with a most responsible diagnosis of acute cholecystitis

(ICD-10-CA codes K80.0, K80.1, K80.4, K81.0, K81.8, K81.9). We restricted our analysis to

those with a first episode of acute cholecystitis and without other prior gallstone-related

admissions or emergency department visits in the two years preceding their index admission. We

also excluded patients directly admitted to an intensive care unit. Intensive care unit admission

was considered a surrogate for cholecystitis with severe sepsis, consistent with the Tokyo

guidelines definition of severe cholecystitis20. Patients who underwent cholecystostomy tube

placement were also excluded since this may suggest either severe cholecystitis, acalculous

47

cholecystitis or significant comorbidity that might preclude operative intervention at any time.

Less than 0.5% of patients were excluded due to missing covariate information.

There were two exclusions at the hospital level. First, we wished to exclude hospitals

where there was no general surgeon, because patients presenting to these hospitals could not

have had an early cholecystectomy. Since data on the availability of physicians at specific

hospitals were not directly available, we excluded hospitals where no appendectomy was

recorded over the six year study period. Appendectomy was chosen as the surrogate for surgeon

availability since appendicitis is common and is managed in the vast majority of cases with

urgent appendectomy if surgical expertise is available. Finally, to provide more robust estimates

of rates, we also excluded hospitals with fewer than 5 patients meeting entry criteria per study

year. These two criteria resulted in the exclusion of 52 of 158 hospitals.

Outcome measure

The primary outcome of interest was early cholecystectomy, defined as cholecystectomy

within 7 days of emergency department presentation.

Patient and hospital-level characteristics

Several patient and hospital-level characteristics were considered as potential explanatory

variables influencing the performance of early cholecystectomy. Patient-level characteristics

included age, sex, income level, comorbidity level, concomitant common bile duct obstruction

and pancreatitis. Income quintile was used as crude surrogate for socioeconomic status and was

derived from the median household income of the patient’s postal code of residence based on

2001 and 2006 census data115. Comorbidity level was captured using the John Hopkins

Aggregated Diagnosis Group scoring system116.Using inpatient and outpatient records in the two

48

years preceding the index admission, an Aggregate Diagnosis Group-based comorbidity index

was calculated according to an algorithm validated for the prediction of 1 year mortality in a

large cohort of adult Ontarians96,97.

The hospital-level characteristics we considered included teaching status (academic

teaching / non-teaching) as recognized by the Ontario Ministry of Health117, annual volume of

acute cholecystitis admissions (quartiles) and, annual volume of elective cholecystectomies

(quartiles). We also considered the possibility that a hospital’s policy regarding the use of

operating room resources after hours (evenings, nights and weekends) or operating room

availability might influence the likelihood of early cholecystectomy. Therefore, as a standardized

measure of operating room utilization after hours, we derived a variable corresponding to the

ratio of total after-hours operative cases (for all surgical specialties) divided by the number of

all-cause emergency department visits. Lower values are indicative of lesser after-hours

operating room utilization.

Statistical analysis

Exploration of variation across hospitals

We first calculated the crude rate of early cholecystectomy at each hospital for all

patients. To better understand the source of variation, we also explored rates across hospitals for

young healthy patients (<50 years old in lowest comorbidity quartile) with uncomplicated

disease (without common bile duct obstruction or pancreatitis). Variation across hospitals is

presented using funnel plots in which each hospital’s early cholecystectomy rate is plotted

against their volume of acute cholecystitis admissions. The funnel plots graphically show

whether the variation in the rate of early cholecystectomy across hospitals is in excess or within

49

the range expected based on chance alone. Ninety-nine percent control limits frame the range of

random variation around the overall cholecystectomy rate and are defined as exact binomial

confidence intervals that vary as a function of the volume of acute cholecystitis admissions118. A

hospital outside the control limits is therefore interpreted as having an early cholecystectomy rate

outside the range of random variation that would be expect based on chance alone.

Exploration of factors associated with early cholecystectomy

We then evaluated the association of patient and hospital characteristics with early

cholecystectomy using multilevel (two-level) logistic regression, which accounted for the non-

independence of patients admitted to the same hospital104. Model calibration was examined

through observed versus predicted outcome plots and discrimination was quantified with the c-

statistic.

To evaluate the relative importance of hospital characteristics and patient case-mix, we

compared the proportion of explained outcome variation in the multilevel logistic model with

patient and hospital-level characteristics to a standard logistic model containing only the patient-

level covariates. Each model’s respective proportion of explained outcome variation was

calculated as the squared Pearson correlation coefficient between the probabilities of early

cholecystectomy predicted by the model and the observed outcomes119,120.

In addition, the multilevel model was used to quantify the extent of variation between

hospitals, adjusted for differences in patient case-mix, by calculating the median odds ratio121.

The median odds ratio is the median value of all possible ratios of the odds of cholecystectomy

in two patients with the same covariates admitted to two randomly selected, distinct hospitals. By

convention, the odds of the patient at the hospital with the highest propensity for

50

cholecystectomy is used as the numerator of the ratio, such that the median odds ratio is always

greater or equal to 1. As an example, a median odds ratio of 3.0 suggests a threefold median

difference in the odds of early cholecystectomy for two similar patients admitted to distinct

randomly selected hospitals. The median odds ratio can also be directly compared to the fixed

effects in the study (e.g. patient age, sex, etc.) thereby informing a meaningful interpretation of

its magnitude.

All analyses were performed using SAS 9.2. Given the large sample size, a two-tailed α

<0.01 was considered statistically significant.

4.4 Results

Study cohort

We identified 24,437 patients admitted to 106 hospitals with a first episode of acute

cholecystitis who met inclusion criteria (figure 4.1). The median number of patients per hospital

was 196 (IQR 71 – 357). Teaching hospitals comprised 13% of all hospitals and cared for 21%

of all patients. The cohort was evenly distributed across study years. Over half of patients were

female (59%) and the mean age was 56±18 years. Concurrent common bile duct obstruction and

pancreatitis were present in 11% and 5% of patients, respectively. Overall, 14,286 (58%)

patients underwent early cholecystectomy.

Variation in the rate of early cholecystectomy across hospitals

There was marked variation in the rate of early cholecystectomy across hospitals: median

51%, IQR 25% to 72%. This variation remained evident even when limited to young (<50 years)

51

healthy (lowest comorbidity quartile) patients with uncomplicated disease (without CBD

obstruction or pancreatitis): median early cholecystectomy rate 74%, IQR 41%-88%. In the full

cohort and in the younger healthy subgroup, the variation in early cholecystectomy was in excess

of that expected by chance alone as evidenced by the large number of hospitals lying outside the

ninety-nine percent control limits shown in the funnel plots (figures 4.2 and 4.3). In other words,

the funnel plots suggest that factors other than chance explain the extent of variation. As expect,

there was less variation within the more homogeneous younger subgroup as evidenced by a

smaller proportion of hospitals lying outside the control limits (figure 4.3).

A broad range in early cholecystectomy rates was also seen across hospitals with similar

characteristics: teaching hospitals (median 47%, IQR 27%-54%), hospitals in the top volume

quartile of elective cholecystectomies (median 54%, IQR 35%-79%) and, hospitals in the top

quartile of OR utilization after hours (median 60%, IQR 46%-77%).

Association of patient and hospital-level characteristics with early cholecystectomy

On univariable analysis, patients who were younger, female, with a lower comorbidity

burden and without common bile duct obstruction were more likely to undergo early operative

intervention (Table 4.1). As well, patients admitted to non-teaching hospitals, hospitals that had

high operating room utilization after hours and, hospitals that had a high institutional volume of

acute cholecystitis admissions and elective cholecystectomies, were more likely to undergo early

cholecystectomy (Table 4.2).

On multivariable multilevel analysis, the same patient-level associations with early

cholecystectomy remained and, at the hospital level, a high volume of acute cholecystitis

admissions was associated with increased odds of early cholecystectomy (Table 4.3). Albeit

52

significant, the level of OR utilization after hours showed an inconsistent association with

performance of early cholecystectomy. The model showed good discrimination (c-statistic=0.80)

and calibration.

We then used the multilevel model to quantify the extent of variability between hospitals,

adjusted for differences in patient case-mix, by calculating the Median Odds Ratio (MOR). The

MOR for the model was 3.7, which can be interpreted as a nearly 4-fold median difference in the

odds of early cholecystectomy for two similar patients admitted to randomly selected hospitals.

Finally, we apportioned the explained outcome variation between patient and hospital

level effects as described in the methods section. Our multilevel model explained 53% of the

variation in the frequency of early cholecystectomy. Of this explained variation, about half

(27%) could be attributed to hospital-level effects, and half (26%) to patient-level effects.

4.5 Discussion

In this population-based study evaluating the practice of early cholecystectomy for acute

cholecystitis, we demonstrated significant variation across hospitals, even when considering only

young, healthy patients with uncomplicated disease. Our analysis suggests that two similar

patients presenting to randomly selected hospitals have an almost 4-fold median difference in

their respective odds of early cholecystectomy. Furthermore, hospital effects, as opposed to

patient effects, accounted for half of the explained variation in early cholecystectomy. Admission

to a hospital with a high acute cholecystitis admission volume was associated with the highest

rate of early intervention.

53

Best available evidence supports early over delayed laparoscopic cholecystectomy for

most patients with acute cholecystitis, based on findings of a shortened total hospital stay, a

similar conversion rate and the elimination of the risk of recurrent gallstone symptoms associated

with delayed elective cholecystectomy60.While trials comparing early to delayed

cholecystectomy were published between 1998 and 2005, inconsistency in the practice of early

cholecystectomy remains evident across different practice environments internationally, with

reported early cholecystectomy rates ranging from 36% to 88%69,70,81,82,88. Previous studies have

also shown that, in those 66 years of age or older, early cholecystectomy is less likely in patients

of greater age and comorbidity level and that early cholecystectomy is less likely with limited

insurance status in the United States69,88.Other determinants of management identified in surveys

of physicians include the surgeon’s competing elective clinical obligations, the surgeon’s

comfort with laparoscopy, as well as the availability of hospital resources for emergency

surgery77,78,122.While we found patient characteristics associated with management that are

consistent with the prior literature, our study also described the wide extent of variation across

hospitals within a large regional healthcare system and quantified the importance of hospital-

level effects as a source of variation in practice.

While many hospitals are providing early cholecystectomy for most patients in Ontario,

we have shown that similar patients managed at different hospitals did not receive comparable

care. We postulate that these results may in part be related to logistic barriers to early

cholecystectomy at certain institutions. Variation across hospitals in the management of acute

cholecystitis may be reduced in the future because of a recent focus on the efficient delivery of

emergency surgical care. This focus includes the American College of Surgeons’ support for the

emerging field of acute care surgery as well as the Royal College of Surgeons of England’s

promotion of the separation of emergency and elective surgery practice123,124. Initiatives targeting

54

better delivery of emergency surgical care, including a dedicated service for emergency surgery

referrals, a surgeon-of-the-week practice model, and operating room time during the day

dedicated to emergency cases, are likely to facilitate early cholecystectomy. In fact, recent

evidence supports a dedicated emergency surgery team as the catalyst for more efficient

management of gallstone disease125-129.

In addition, variation in practice may in part reflect the need to address remaining gaps in

the evidence comparing the outcomes of early and delayed cholecystectomy. In fact, one of the

factors hindering the uptake of early cholecystectomy may be concern that early intervention is

associated with a higher rate of major bile duct injury, a rare but devastating operative

complication. Adequately powered studies assessing whether this is true, as well as a comparison

of real world rates of conversion from laparoscopic to open cholecystectomy are required.

Strengths and limitations

The main strengths of this study include its population-based scope, the quality of the

data sources, as well as the study setting - a health care system where emergency surgical care is

only accessed through single-payer funded public hospitals. However, the study also has

limitations. The first is potential residual confounding related to the severity of cholecystitis. We

attempted to reduce this potential bias by excluding patients with severe cholecystitis and prior

gallstone disease. While a gradient of severity (captured by duration of symptoms, white blood

cell count, gallbladder wall thickness on ultrasound) is likely present in our study cohort, it is

reasonable to expect that this gradient be similarly distributed across hospitals, particularly after

adjusting for age, sex, socioeconomic status and comorbidity level. Furthermore, we believe the

extent of variation across hospital is too large to be fully explained by unmeasured differences in

cholecystitis severity. The second limitation is that we are unable to identify the decision-making

55

surgeon in our data sources. Nevertheless, many surgeon characteristics such as physician

practice type and cholecystectomy volumes would be expected to overlap with the hospital

characteristics we included. As such, the measured hospital effects are likely partly attributable

to the hospital’s surgeons and characterizing the relative importance of surgeon-level variation in

practice merits further investigation. Despite this limitation, understanding variation at the

hospital-level remains a constructive starting point to generate solutions for quality

improvement. Finally, definitions of the timeframe for early cholecystectomy range in the

literature between 24 hours and 7 days from symptom onset or diagnosis. While we chose a

broad timeframe definition (within 7 days from emergency department presentation), when we

defined early cholecystectomy as occurring within 3 days of emergency department presentation,

we found the same extent of variation and similar associations on multivariable analysis.

In conclusion, we have presented a population-based analysis of the management of acute

cholecystitis within a geographic region where all emergency surgical care is accessed from a

single public payer. We have found considerable variation in the rate of early cholecystectomy

across hospitals and also shown that, across these hospitals, similar patients with acute

cholecystitis did not receive comparable care. Hospital-level factors, independent of patient

characteristics, appear strongly related to practice.

56


Table 4.1 - Distribution of patient characteristics

Early cholecystectomy

N=14,286

No early cholecystectomy

N=10,151

P value

Age (years) <0.001 18 – 35 2791 (20) 1200 (12) 36 – 50 3859 (27) 1863 (18) 51 – 65 3857 (27) 2447 (24) 66 – 80 2990 (21) 2975 (29) >80 809 (6) 1666 (17)

Female sex 8,810 (62) 5,553 (55) <0.001 Income quintile 0.02

1 (lowest) 3,165 (22) 2,119 (22) 2 3,017 (21) 2,234 (22) 3 2,754 (19) 2,086 (21) 4 2,802 (20) 1,887 (19) 5 2,548 (18) 1,745 (17)

ADG Comorbidity index quartile <0.001 1(lowest) 4,132 (29) 2,134 (21) 2 3,799 (27) 2,370 (24) 3 3,339 (23) 2,330 (23) 4 3,016 (21) 3,317 (32)

Common bile duct obstruction 1,119 (8) 1,539 (16) <0.001 Pancreatitis 659 (5) 464 (5) 0.88 All values are presented as N(%)

57

Table 4.2 - Distribution of hospital characteristics

Early cholecystectomy

N=14,286

No early cholecystectomy

N=10,151

P value

Teaching status <0.001 Academic teaching 2,467 (17) 2720 (27) Non-teaching 11,819 (83) 7,431 (73)

After-hours operating room utilizationa (quartile) <0.001

1(lowest) 1,036 (7) 1,238 (12) 2 2,712 (18) 2,156 (21) 3 4,505 (31) 3,154 (31) 4 6,033 (44) 3,603 (36)

Annual volume of acute cholecystitis admissions (quartile)

<0.001

5-17 502 (3) 2,119 (9) 18-39 1,935 (14) 2,234 (17) 40-65 3,799 (27) 2,086 (33) 66-164 8,050 (56) 1,887 (41)

Annual volume of elective cholecystectomies (quartile) <0.001

0-74 938 (7) 1,364 (13) 75-159 2,515 (18) 1,700 (17) 160-279 4,481 (31) 2,712 (27) 280-905 6,352 (44) 4,375 (43)

All values are presented as N(%) a Ratio of total after-hours operative cases (for all surgical specialties) divided by the number of all-cause emergency department visits

58

Table 4.3 - Multilevel multivariable logistic regression results showing association of patient and hospital characteristics with early cholecystectomy

Characteristic Adjusted Odds Ratio (99% CI)

Patient Age (years)

18 – 35 Reference 36 – 50 0.92 (0.81 – 1.05) 51 – 65 0.69 (0.61 – 0.79) 66 – 80 0.46 (0.40 – 0.53) >80 0.21 (0.18 – 0.25)

Male sex 0.87 (0.80 – 0.95) Income quintile

1(lowest) Reference 2 0.98 (0.87 – 1.10) 3 0.93 (0.82 – 1.05) 4 1.06 (0.94 – 1.21) 5 1.12 (0.98 – 1.27)

ADG Comorbidity index quartile 1(lowest) Reference 2 0.90 (0.80 – 1.01) 3 0.89 (0.79 – 1.00) 4 0.67 (0.60 – 0.75)

Common bile duct obstruction 0.41 (0.36 – 0.47) Pancreatitis 1.14 (0.94 – 1.37) Hospital Annual volume of acute cholecystitis admissions (quartile)

5-17 0.53 (0.35 – 0.78) 18-39 0.67 (0.52 – 0.87) 40-65 0.84 (0.72 – 0.97) 66-164 Reference

After-hours operating room utilizationa (quartile) 1(lowest) 0.97 (0.72 – 1.30) 2 0.84 (0.66 – 1.07) 3 0.79 (0.64 – 0.97) 4 Reference

Annual volume of elective cholecystectomies (quartile) 0-74 1.02 (0.63 – 1.63) 75-159 1.15 (0.82 – 1.60) 160-279 1.11 (0.91 – 1.35) 280-905 Reference

Academic teaching hospital 0.71 (0.27 – 1.85) aRatio of total after-hours operative cases (for all surgical specialties) divided by the number of all-cause emergency department visits

N=33,102 adults admitted with acute cholecystitis via the emergency

department

N=25,382 at 158 hospitals

N=24,437 at 106 hospitals

N=6,179 excluded given prior emergency department visit or admission for gallstone disease

N=1,393 excluded given Intensive Care Unit admission or cholecystostomy

N=148 excluded given missing covariates

52 hospitals without a general surgeon or with <5 patients excluded (N=945 patients)

FIGURES

Figure 1. Exclusion flowchart

Charles

Rectangle

Charles

Text Box


Charles

Text Box

Figure 4.1 - Patient eligibility flowchart

Charles

Text Box

59

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 100 200 300 400 500 600 700 800

Ear

ly c

hole

cyst

ecto

my

rate

Count of acute cholecystitis admissions

Hospital Cohort average 99% Control limits

Figure 2A. Variability in the rate of early cholecystectomy across hospitals (N=24,437 patients, 106 hospitals)

Charles

Rectangle

Charles

Text Box

60

Charles

Text Box

Figure 4.2 - Variation in the rate of early cholecystectomy across hospitals (N=24,437 patients, 106 hospitals)

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 20 40 60 80 100 120 140 160

Ear

ly c

hole

cyst

ecto

my

rate

Count of acute cholecystitis admissions

Hospital Cohort average 99% Control limits

Figure 2B. Variability in the rate of early cholecystectomy rate across hospitals among young (<50 years) healthy patients without concurrent biliary tract obstruction or pancreatitis (N=2,894 patients, 102 hospitals)

Charles

Rectangle

Charles

Text Box

61

Charles

Text Box

Figure 4.3 - Variation in the rate of early cholecystectomy rate across hospitals among young (<50 years) healthy patients without concurrent biliary tract obstruction or pancreatitis (N=2,894 patients, 102 hospitals)

62

Chapter 5

Risk of Recurrent Symptoms if Cholecystectomy is Delayed


I. Present the frequency of recurrent gallstone-related symptoms if discharged without

cholecystectomy.

II. Identify patient subgroups at highest risk of recurrent symptoms.

Preamble

The contents of this chapter have been published in the Journal of Trauma and Acute Care

Surgery:

de Mestral C, Rotstein OD, Laupacis A, Hoch JS, Zagorksi B, Nathens AB. The clinical course

of 10,304 patients with acute cholecystitis discharged without cholecystectomy. Journal of

Trauma and Acute Care Surgery. 2013; 74: 26-31

© Wolters Kluwer. The use of the manuscript is by permission of the copyright holder.

63

5.1 Summary

Background

Randomized trials and expert opinion support early laparoscopic cholecystectomy for

most patients with acute cholecystitis; however, practice patterns are variable worldwide and

delayed cholecystectomy remains a common practice. We therefore present a population-based

analysis of the risk of recurrent gallstone-related symptoms in patients with acute cholecystitis

discharged without cholecystectomy.

Methods

Using administrative databases capturing all ED visits and hospital admissions within a

geographic region encompassing 13 million persons, we identified adults with a first emergency

admission for uncomplicated acute cholecystitis over the period of 2004-2011. In those

discharged without cholecystectomy, the probability of a subsequent gallstone-related event

(gallstone-related ED visit or hospital admission) was evaluated using the Kaplan-Meier method.

The association of patient characteristics with time to first gallstone related event after discharge

was explored through multivariable time-to-event analysis.

Results

10,304 of 25,397 patients with acute cholecystitis (41%) did not undergo

cholecystectomy on first admission. The probability of a gallstone-related event by 6 weeks, 12

weeks and 1 year after discharge was 14%, 19% and 29% respectively. Of these events, 30%

were for biliary tract obstruction or pancreatitis. When controlling for sex, income and

comorbidity level, the risk of a gallstone-related event was highest in patients 18 to 34 years old.

64

Conclusions

In patients who do not undergo cholecystectomy on first admission for acute

cholecystitis, the probability of a gallstone-related ED visit or hospital admission within 12

weeks of discharge is 19%. The increased risk in younger patients reinforces the value of early

cholecystectomy in the non-elderly.

5.2 Background

Randomized trials and expert opinion support early laparoscopic cholecystectomy within

up to 7 days of symptom onset for most patients with acute cholecystitis22,60,65-67,114,130.

Nevertheless, early cholecystectomy rates reported worldwide vary from 36% to 88%,

suggesting that delayed cholecystectomy remains a common practice at many

institutions69,70,81,82,88. One of the strongest arguments against delayed cholecystectomy is that, in

the interval between discharge and delayed elective cholecystectomy, patients are at risk of

recurrent gallstone-related symptoms. Existing data suggest that the frequency of recurrent

symptoms post discharge is in the range of 0% to 38% 65-67,69,130,131. Small study samples, single

centre analyses and data sources limited to specific patient subgroups are limitations of these

studies65-67,69,130,131. Accurate estimates that can be generalized to a broad population of adults are

needed to inform clinical and resource allocation decisions about the management of acute

cholecystitis. Therefore, the objectives of this study were to determine the frequency of recurrent

gallstone-related symptoms using population-based data, as well as to identify patient subgroups

at highest risk of recurrent symptoms.

65

5.3 Methods

Study design and setting

This is a population-based retrospective cohort study of the clinical course of adults

admitted with a first episode of acute cholecystitis and discharged without undergoing

cholecystectomy. We used data from Ontario, Canada’s most populous province with over 13

million residents. Funding for all medically necessary hospital and physician services accessed

by Ontario residents is solely provided by the provincial Ministry of Health. This study was

approved by the Research Ethics Board of Sunnybrook Health Sciences Center.

Data sources

The cohort was identified from administrative datasets housed and consolidated at the

Institute for Clinical Evaluative Sciences, Toronto, Canada. Diagnostic and procedural

information was obtained from the Discharge Abstract Database (DAD) that contains data about

all hospital admissions in Ontario, and the National Ambulatory Care Reporting System

(NACRS) that includes data about all Emergency Department (ED) visits and same day

surgeries. Demographic data and date of death were obtained from the Registered Person

Database (RPDB). An encrypted unique patient identifier allows these datasets to be

deterministically linked, thereby providing an accurate record of patients’ clinical trajectories.

Cohort

66

All Ontario residents, admitted via the ED from April 2004 to March 2011 with a most

responsible diagnosis of acute cholecystitis (ICD-10-CA codes K80.00, K80.01, K80.10,

K80.11, K81.0, K81.8, K81.9) were considered for inclusion in the cohort. We identified patients

with a first episode of AC by excluding those with an ED visit or hospital admission for

gallstone disease in the 2 years preceding the index admission. We also excluded patients with

complicated cholecystitis, namely: those with a concurrent diagnosis of pancreatitis or common

bile duct obstruction, those with severe cholecystitis as evidence by direct admission to an

intensive care unit and those who underwent cholecystostomy tube placement. The remaining

patients that survived to hospital discharge and did not undergo cholecystectomy on their index

admission comprised the final cohort.

Outcome

The outcome of interest was time to first gallstone-related event. A gallstone-related

event was defined as any ED visit or hospital admission for biliary colic, recurrent acute

cholecystitis, choledocholithiasis, cholangitis, biliary pancreatitis or gallstone ileus. All ED visits

and hospital admissions between the date of hospital discharge and date of maximum follow-up

were searched. Identification of gallstone-related events was limited to the main diagnosis field

for ED visits and to the most responsible and post-admission comorbidity fields for hospital

admissions. If a hospital admission included two or more gallstone diagnoses (e.g. cholecystitis

and pancreatitis), the gallstone-related event was classified based on the diagnosis with greatest

potential morbidity (i.e. pancreatitis).

67

Patient characteristics

Risk of recurrent gallstone-related symptoms across patient subgroups was examined

based on the following patient characteristics: age, sex, comorbidity level and income quintile.

Used as a crude proxy for socioeconomic status, income quintile reflects the median household

income in a patient’s postal code of residence based on 2001 or 2006 Canada census data 115.

The John Hopkins Aggregate Diagnosis Groups (ADG) system was used to quantify the level of

comorbidity based on inpatient and outpatient records in the 2 years preceding the index

cholecystitis admission116. From this grouping system, an ADG-based comorbidity index was

calculated according to an algorithm validated for the prediction of 1 year mortality in a large

cohort of adult Ontarians96,97.

Statistical Analysis

First, the probability of a gallstone-related event by clinically meaningful time points

following discharge was calculated using the Kaplan-Meier method (1 minus the product limit

value). Patients who underwent elective cholecystectomy, who died or who reached the maximal

follow-up date prior to any gallstone-related event were censored. Cholecystectomy was

considered elective if performed as same day surgery, or on an inpatient admission without an

associated ED visit. Any admission for gallstone disease involving a cholecystectomy but with

an associated ED visit was considered an admission for a recurrent gallstone-related event.

Second, in order to understand which patient subgroups might be at greater risk of

recurrent gallstone symptoms, we performed univariable comparisons with the log-rank test as

well as developed a Cox proportional-hazard model. This multivariable time to event analysis

68

was used to describe the association of all the previously listed patient characteristics with time

to first gallstone-related event. The proportional hazards assumption was evaluated graphically

by plotting logarithm-minus-logarithm survival curves105. Given the large sample size, alpha was

set at 0.01.

As a secondary analytic approach, competing risk time-to-event analysis was undertaken.

In doing so the cumulative incidence method was used to derive the probability of a gallstone-

related event over time. As discussed in Chapter 3, unlike the Kaplan-Meier method, the

cumulative incidence approach accounts for the competing nature of a censoring event107,108. In

this secondary analysis, death and elective cholecystectomy were treated as informative

competing risks.

5.4 Results

Study cohort

Of 25,397 patients admitted with a first episode of uncomplicated acute cholecystitis

meeting inclusion criteria, 10,304 (41%) were discharged without undergoing cholecystectomy.

The majority (54%, N=5,550) were female and the median age was 62 years (IQR 47-76 years).

The cohort was evenly distributed across study years.

Median follow-up was 3.4 years (IQR 1.7-5.1). Over the interval of follow-up, 2,479

(24%) patients had an observed gallstone-related ED visit or admission. Median time to first

event was 78 days with 88% (N=2,177) of events occurring within 1 year of discharge. A total of

4,617(45%) underwent elective cholecystectomy and an additional 733 (7%) patients died prior

69

to any gallstone-related event. Median times to elective cholecystectomy and death were 8 weeks

(IQR 5-13 weeks) and 14 months (IQR 4-30 months) respectively.

Frequency of gallstone-related ED visit or admission

The probability of a gallstone-related event by 6 and 12 weeks following discharge was

14% and 19% respectively (Table 5.1). Of the patients with a gallstone-related event within 12

weeks of discharge, over two thirds presented with recurrent cholecystitis or biliary colic (70%)

with the remaining patients presenting with biliary tract obstruction (24%) or pancreatitis (6%).

A similar distribution of event type was found by 1 year, with an additional small proportion of

first gallstone-related ED visits or admissions (<1%) due to gallstone ileus. In those patients

readmitted for AC or biliary colic and in those with pancreatitis, biliary obstruction or gallstone

ileus, in-hospital mortality was 1.6% and 1.4% respectively (p=0.77).

Risk of gallstone-related ED visit or admission

Differences in the risk of a gallstone-related event were found across age groups (Figure

5.1). For example, the probability of a first gallstone-related event by 12 weeks following

discharge was 30% in patients between the ages of 18 and 35, compared to only 14% in those 80

years of age or older (p<0.001). No difference in the type of gallstone-related event was seen

across age groups. On multivariable analysis, when controlling for sex, comorbidity level and

income, younger patients remained at greatest risk throughout the first year following discharge

from hospital (Table 5.2). No difference in the probability of recurrent gallstone symptoms was

seen between sexes or across comorbidity and income levels.

70

Secondary analysis

When treating death and elective cholecystectomy as competing risks, the probability of a

gallstone-related event over time was not meaningfully different from the primary analysis

(Table 5.3) and a higher risk of a gallstone-related event was also observed in younger patients

(Table 5.4).

5.5 Discussion

This study of the clinical course of patients with acute cholecystitis discharged without

cholecystectomy demonstrates three main findings. First, by 12 weeks from discharge, the time

interval conventionally used for delayed elective cholecystectomy after an episode of acute

cholecystistis, the risk of a gallstone-related ED visit or hospital admission was 19%. Second, in

those who had recurrent symptoms, nearly 30% presented with biliary tract obstruction or

pancreatitis, diseases with greater morbidity potential than the initial cholecystitis episode. Third,

the risk of recurrent gallstone-related ED visit or hospital admission decreased with age.

In randomized trials comparing early to delayed intervention, 0% to 37% of patients

randomized to delayed treatment had non-resolving or recurrent gallstone symptoms65-67,130,131.

In a large cohort study of patients with acute cholecystitis aged 65 and older, Riall and

colleagues reported a 38% probability of gallstone-related readmission by 2 years after

discharge69. The same study also demonstrated a higher risk of recurrent symptoms in the

youngest patients of the cohort.

71

Our results are consistent with the existing literature, but provide estimates of the risk of

recurrent symptoms that were derived from a broad population of adults with acute cholecystitis.

Furthermore, this analysis demonstrates that a relatively large proportion of patients return with

biliary tract obstruction or pancreatitis, which carry significant potential for added morbidity.

These data are critical for informed decision-making with patients, concerning delayed

cholecystectomy as a management strategy. That an age-related gradient in risk of recurrent

symptoms was also found by Riall reinforces the validity of our similar finding, although our

data cannot explain the underlying reasons for such differences in risk across ages. It may be that

diet, genetics and anatomy contribute to the development of acute cholecystitis early in life in

these younger patients, who then remain at increased risk of recurrent symptoms. Another

possible explanation is that younger patients were more prone to seek medical attention. The

higher risk of symptomatic disease in younger patients, and the lower risk in those older than 80

years of age, can inform decision making about the benefits and risks of early cholecystectomy

in these patients. Most clearly, these results reinforce the value of early cholecystectomy in the

non-elderly.

Strengths of this study are its population-based scope, large sample size and the capture

of emergency department visits in addition to admissions. However, its limitations must be

recognized. First, the increased risk of recurrent gallstone disease in younger patients may be

partially attributable to unmeasured characteristics such as dietary intake, body mass index,

genetic factors, biliary anatomy or differences in cholecystitis severity. Second, our results may

slightly overestimate the probability of recurrent gallstone disease if pre-admission cholecystitis

was erroneously coded as a post-admission comorbidity on a subsequent visit. However, when

we restricted the outcome definition to only the most-responsible diagnosis field for subsequent

emergency department visits and admissions, the estimates of recurrent symptoms were not

72

meaningfully lower from those in table 5.1 and adjusted risks across patient characteristics were

similar to those presented in table 5.2. Finally, while we were able to capture all emergency

department visits and hospitals admissions in Ontario, we did not capture outpatient clinic visits

to a family physician for gallstone-related symptoms and therefore may slightly underestimate

the probability of recurrent symptoms.

In conclusion, this population-based analysis characterizes the risk of recurrent gallstone

symptoms in a large cohort of patients who presented with a first episode of acute cholecystitis

and were discharged without cholecystectomy. The probability of a gallstone-related emergency

department visit or hospital admission within 12 weeks of discharge was 19%. The increased risk

in younger patients reinforces the value of early cholecystectomy in the non-elderly.

73


Table 5.1 - Probability of a gallstone-related event by time from discharge

Time from discharge

Probability of gallstone-related event by time from

discharge (99% CI) a

No. of patients remaining at risk of

gallstone-related event

6 weeks 14.0% (13.1% – 14.9%) 7,126

12 weeks 18.9% (17.7% - 19.9%) 4,877

6 months 24.2% (22.9% - 25.5%) 3,340

1 year 28.8% (27.4% - 30.3%) 2,552

2 years 33.9% (32.2% - 35.6%) 1,745

3 years 37.6% (35.7% - 39.5%) 1,191

4 years 39.8% (37.8% - 41.9%) 789

5 years 40.8% (38.7% - 43.1%) 471

aProbability is conditional on surviving and not undergoing elective cholecystectomy prior to time from discharge

74

Table 5.2 - Multivariable time-to-event analysis showing adjusted risk of gallstone-related event across patient characteristics

Patient characteristic Hazard Ratio (99% CI)

Age - years 18 – 35 (N=1,133) 36 – 50 (N=1,958) 51 – 65 (N=2,473) 66 – 80 (N=2,988) >80 (N=1,752)

2.23 (1.82 – 2.74) 1.57 (1.29 – 1.90) 1.26 (1.05 – 1.51) 1.16 (0.98 – 1.39)

Reference Sex

Female (N=5,564) Male (N=4,740)

0.97 (0.87 – 1.09)

Reference Income quintile

1a (N=1,855) 2 (N=1,958) 3 (N=2,061) 4 (N=2,164) 5 (N=2,262)

1.11 (0.93 – 1.33) 1.12 (0.94 – 1.34) 1.03 (0.86 – 1.24) 1.00 (0.83 – 1.21)

Reference ADG comorbidity index quartile

1† (N=2,483) 2 (N=2,669) 3 (N=2,545) 4 (N=2,607)

0.94 (0.80 – 1.11) 0.88 (0.75 – 1.03) 0.89 (0.76 – 1.04)

Reference a 1 reflects lowest income and comorbidity level

75

Table 5.3 - Probability of a gallstone-related event by time from discharge in competing risk time-to-event analysis

Time from discharge

Probability of gallstone-related event by time from

discharge

6 weeks 13.3%

12 weeks 16.8%

6 months 19.7%

1 year 21.2%

2 years 23.7%

3 years 25.0%

4 years 25.8%

5 years 26.1%

76

Table 5.4- Probability of a gallstone-related event by 12 weeks across age groups in competing risk time-to-event analysis

Age group (years)

Probability of gallstone-related event by 12 weeks

from discharge

18 – 35 25.2%

36 – 50 19.0%

51 – 65 16.0%

66 – 80 15.1%

> 80 13.3%

77


Figure 5.1 - Unadjusted probability of a gallstone-related event across age groups in the first year following discharge

78

Chapter 6

Comparative Operative Outcomes of Early and Delayed

Cholecystectomy for Acute Cholecystitis


I. Present the comparative frequency of rare operative complications between early and

delayed cholecystectomy in a large population-based cohort.

II. Present the comparative frequency of open cholecystectomy and conversion among

laparoscopic cases between early and delayed cholecystectomy in a large population-

based cohort.

Preamble

The contents of this chapter are currently under review with Annals of Surgery:

De Mestral C, Rotstein OD, Laupacis A, Hoch JS, Zagorksi B, Alali A, Nathens AB.

Comparative operative outcomes of early and delayed cholecystectomy for acute

cholecystitis: A population-based propensity score analysis.

79

6.1 Summary

Background

Randomized trials comparing early to delayed cholecystectomy for acute cholecystitis

have limited contemporary external validity. Furthermore, no study to date has been large

enough to assess the impact of timing of cholecystectomy on the frequency of serious rare

complications including bile duct injury and death. We sought to compare the operative

outcomes of early and delayed cholecystectomy for acute cholecystitis in a large population-

based cohort.

Methods

This is a retrospective cohort study of patients emergently admitted to hospital with acute

cholecystitis and managed with cholecystectomy over the period of April 1, 2004 to March 31,

2011. We used administrative records for the province of Ontario, Canada. Patients were divided

into two exposure groups: those who underwent cholecystectomy within 7 days of emergency

department presentation on index admission (early cholecystectomy) and those whose

cholecystectomy was delayed. The primary outcome was major bile duct injury requiring

operative repair within 6 months of cholecystectomy. Secondary outcomes included major bile

duct injury or death, 30-day post-cholecystectomy mortality, completion of cholecystectomy

with an open approach and, among laparoscopic cases, conversion from a laparoscopic to an

open approach. Propensity score methods were used to address confounding by indication.

Results

80

From 22,202 patients, a well-balanced matched cohort of 14,220 patients was defined.

Early cholecystectomy was associated with a lower risk of major bile duct injury (0.28% vs.

0.53%, RR=0.53, 95% CI 0.31–0.90, p=0.025), of major bile duct injury or death (1.36% vs.

1.88%, RR=0.72, 95% CI 0.56–0.94, p=0.016) and, albeit not significant, of 30-day post-

operative mortality (0.46% vs. 0.64%, RR=0.73, 95% CI 0.47–1.15, p=0.21). No significant

differences were observed in terms of open cholecystectomy (15% vs. 14%, RR=1.07, 95% CI

0.99–1.16, p=0.10) or in conversion among laparoscopic cases (11% vs. 10%, RR=1.02, 95% CI

0.93–1.13, p=0.68).

Conclusion

These results support the benefit of early over delayed cholecystectomy for patients with

acute cholecystitis.

6.2 Background

Acute cholecystitis is the most common cause of hospitalization for gastrointestinal

disease14. While cholecystectomy is the definitive management, the timing of surgery in relation

to the first episode of acute cholecystitis remains an area of considerable practice variation.

Operative intervention is either undertaken early on first presenting admission or, may be

delayed 6 to 12 weeks after initial non-operative management to allow the acute inflammation to

resolve. Several randomized controlled trials have shown that early laparoscopic

cholecystectomy (within up to 7 days of symptom onset) is associated with a shorter total

hospital length of stay and a similar rate of conversion to an open procedure, when compared to

delayed cholecystectomy60. Furthermore, early surgery precludes the risk of recurrent gallstone-

81

related symptoms, estimated to affect approximately 20% of patients15,60,132. However, despite

this evidence as well as expert consensus supporting early laparoscopic cholecystectomy, rates of

early surgery remain variable.

Practice patterns may not be consistent with best available evidence because concern

remains that rare but serious complications such as major bile duct injury or death may occur

more frequently in the setting of emergency surgery on an acutely inflamed gallbladder22. Major

bile duct injury occurs in 0.3-0.5%41,53of cholecystectomies and is a serious complication

associated with reduced long term survival41,42 and high litigation rates43. No study to date has

been large enough to compare major bile duct injury or mortality rates between early and


Furthermore, the trials comparing early to delayed surgery were derived from single

specialized centres and included patients recruited between 1993 and 200265-67,130,131.

Consequently, these data may not be generalizable to a broader range of hospitals or to current

practice characterized by greater expertise with laparoscopic surgery. Understanding

comparative rates of open cholecystectomy and conversion in the laparoscopic era is important

since, while conversion to an open approach is safe practice in the face of operative difficulty,

open cholecystectomy is associated with greater post-operative pain, an increased incidence of

surgical site infection and a longer hospital stay34-36.

To address these evidence gaps, we compared the operative outcomes of early and

delayed cholecystectomy in a contemporary, population-based cohort of patients with acute

cholecystitis.

82

6.3 Methods

Design

This is a retrospective cohort study of patients emergently admitted to hospital with acute

cholecystitis who were subsequently managed with cholecystectomy over the period of April 1,

2004 to March 31, 2011. Operative outcomes were compared between patients who underwent

cholecystectomy within 7 days of emergency department (ED) presentation on index admission

(early cholecystectomy) and patients whose cholecystectomy was delayed. The research ethics

board of Sunnybrook Health Sciences Centre, Toronto, Canada, approved this study.

Setting

We used administrative records for the province of Ontario, Canada. Medically necessary

hospital and physicians services for Ontario’s over 13 million residents are universally accessible

and funded by the provincial Ministry of Health and Long Term Care.

Data sources

Population-based datasets that include all ED visits, hospital admissions, outpatient

surgeries and physician billing claims in Ontario were deterministically linked using an

encrypted unique patient identifier. The index cholecystitis admission was identified in the

Discharge Abstract Database (DAD) and, linkage to the National Ambulatory Care Reporting

System confirmed entry via the ED. Patient characteristics were derived from DAD

83

supplemented with data from the Ontario Health Insurance Plan (OHIP) physician claims

database. Surgical procedure data and surgeon characteristics were also available through linkage

of DAD and the OHIP claims database. Date of death was obtained from the Registered Persons

Database. These datasets have been validated for a variety of diagnoses91-94,98 and, a multicenter

validation study showed almost perfect agreement on the most responsible diagnosis between

DAD and re-abstracted records for gallstone-related admissions98.

Cohort

Adults admitted through the ED with a most responsible diagnosis of acute cholecystitis

(ICD-10-CA: K80.0, K80.1, K80.4, K81.0, K81.8, K81.9) and without prior symptomatic

gallstone disease – no ED visit or hospital admission for gallstone disease in the two preceding

years – were considered for inclusion in the cohort. Patients admitted directly to the intensive

care unit or managed with a cholecystostomy drain (ICD-10-CA: 1.OD.52) were excluded

because they were considered to have cholecystitis with severe sepsis or significant comorbidity

precluding operation. Patients who underwent cholecystectomy were identified based on having

an inpatient or outpatient record of cholecystectomy (ICD-10-CA: 1.OD.57, 1.OD.89) and an

associated OHIP claim for cholecystectomy (S287). Finally, given the primary outcome

definition described below, we excluded patients without at least 6 months of post-operative

follow-up, as well as patients with a diagnosis of biliary tract malignancy or cyst (ICD-10-

CA:C23, C22.1, C24, Q44.4) within 6 months of cholecystectomy (figure 1).

Exposure

84

The main exposure was early cholecystectomy, defined as cholecystectomy within 7 days

of ED presentation on index admission.

Outcomes

The primary outcome was major bile duct injury. Patients who underwent operative

repair of the biliary tract (OHIP billing claim: S281, S285 – choledochoenterostomy; S292 –

repair of common duct) within 6 months of cholecystectomy were considered to have suffered a

major bile duct injury. There were four secondary outcomes: (1) a composite outcome of major

bile duct injury or death – included because of potential for censoring of the primary outcome by

death before biliary tract repair within 6 months; (2) 30-day post-cholecystectomy mortality; (3)

completion of cholecystectomy through an open approach – whether started open or via

laparoscopy; (4) conversion to open cholecystectomy among laparoscopic cases.

Identification of major bile duct injury in administrative data through physician billing

claims for surgical repair of the biliary tract has been previously utilized41 with injury rates

consistent with prospective cholecystectomy and gallstone registries42,53. It is also unlikely that

differences exist between exposure groups in the sensitivity and specificity of OHIP repair

claims for the identification of major bile duct injury. ICD-10 procedure coding was used to

differentiate open from laparoscopic cases and an attribute status code was used to identify

conversion among laparoscopic cases. A multicentre validation study found almost perfect

agreement on surgical approach (open vs. laparoscopic) between administrative and re-abstracted

records across a range of abdominal surgical procedures98. Substantial agreement was also

85

reported regarding conversion during laparoscopic appendectomy, indirectly supporting the

validity of conversion in this study98.

Covariates

Several characteristics of the patient and surgeon might confound the relationship

between the timing of cholecystectomy and operative outcomes. We considered patient age, sex,

income level, comorbidity burden, and pancreatitis or biliary tract obstruction on index

admission as potential confounders. A crude proxy for socioeconomic status, income quintiles

were based on the median income of a patient’s postal code of residence115. Comorbidity level

was calculated using the John Hopkins Aggregated Diagnostic Groups (ADG) system116 with a

2-year look-back at inpatient and outpatient records. The ADG system was used to derive a

comorbidity index validated for the prediction of 1-year mortality in a general cohort of adult

Ontarians96,97. At the physician level, we considered the number of cholecystectomies a surgeon

had performed in the year prior to the index cholecystectomy, as well as the number of years

since medical school graduation.

Analytic approach

We used propensity score methods to account for selection bias. Matching on the

propensity score was the primary analytic approach employed111.

First, each patient’s probability of receiving early cholecystectomy (propensity score)

was derived from a logistic regression model where all of the previously mentioned potential

86

confounders were regressed onto the binary outcome of early or delayed cholecystectomy.

Continuous variables (age, comorbidity index, surgeon’s number of cholecystectomies and years

since medical school graduation) were modeled using smoothing cubic splines to allow for

departures from linearity133.

Propensity score matching was then performed using a nearest-neighbour, 1-to-1 pair

match within 0.2 standard deviations (caliper) of the logit of the propensity score and without

replacement111,134. Thus, in random sequence, a patient in the early group was selected and then

matched to a patient in the delayed group with the closest propensity score, within the defined

caliper range. Covariate balance after matching was quantified by calculating the standardized

difference of the mean or proportion for each covariate, with a standardized difference of <10%

indicative of good balance between groups135,136. The distributions of continuous variables were

also compared graphically through cumulative density and quantile-quantile plots136. In addition

to matching on the propensity score, given that older age and male sex have been associated with

greater severity of cholecystitis22-24, matched pairs were required to be of the same sex and have

an age difference of at most 5 years. Within the matched sample, outcome frequency differences

were tested with the McNemar chi-square. A relative risk and 95% confidence interval was also

calculated for each outcome, taking account of the sample’s matched nature137.

A variety of sensitivity analyses were undertaken. First, we employed an alternate

propensity score approach that used the entire study cohort: inverse probability of treatment

weighting. Weighting each patient on the inverse probability of treatment received produces a

synthetic study sample balanced on observed covariates111,138. The relative risk for each outcome

was calculated from a weighted log binomial regression model with robust variance

estimation110. Second, given the variable definition of timing of early cholecystectomy across the

87

literature, we reanalyzed the data using cholecystectomy within 3 days of ED presentation as the

exposure. Finally, we examined the results after excluding patients who underwent

cholecystectomy later than 1 year after discharge from index admission, considering that they

were less likely to have been discharged with the intention of delayed cholecystectomy.

6.4 Results

A total of 22,202 patients were emergently admitted across 154 hospitals with a first

episode of acute cholecystitis and ultimately managed with cholecystectomy from 2004 to 2011.

The mean age was 54±18 years and most were women (60%, n=13,376). Common bile duct

obstruction and pancreatitis were present on admission in 10% (n=2,243) and 5% (n=1,058) of

patients, respectively. The majority of cholecystectomies (67%, n=14,948) were early. The

median time to delayed cholecystectomy was 8 weeks (IQR 4-12 weeks) from ED presentation.

Overall, there were 77 (0.35%) major bile duct injuries and 100 (0.45%) deaths within 30 days of

cholecystectomy. A total of 2,861 of the 22,202 cholecystectomies (13%) were completed open

(started open or converted). Among the 21,280 cases started via laparoscopy, 1,939 (9%) were

converted to an open approach.

Patients undergoing early cholecystectomy were younger, more frequently female, less

likely to have biliary tract obstruction and had a lower comorbidity burden (table 6.1). These

patients were also operated on by surgeons earlier in their career and with a larger recent

cholecystectomy experience when compared to patients receiving delayed cholecystectomy.

Matching on the propensity score, sex and age created 7,110 distinct pairs. After matching, all

patient and surgeon characteristics were well balanced (Table 6.2).

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Within the matched sample, early cholecystectomy was associated with half the risk of

major bile duct injury and a lower risk of the composite outcome of major bile duct injury or

death (Table 6.3). While 30-day post-cholecystectomy mortality was lower in the early group,

this observation did not reach statistical significance (Table 6.3). The frequencies of open

cholecystectomy or conversion among laparoscopic cases were similar between the two groups

(table 6.3).

While 98% of patients managed with delayed cholecystectomy were included in the

matched sample, a majority (52%) of patients managed with early cholecystectomy were not

matched. Among the early cholecystectomy group, unmatched patients reflect those with a

higher propensity for early cholecystectomy than matched patients (mean propensity score 0.73

vs. 0.64, p<0.001) as well as similar or better outcomes (major bile duct injury 0.28% vs. 0.23%,

p=0.53; major bile duct injury or death 0.85% vs. 1.36%, p=0.002; cholecystectomy completed

open 9% vs. 15%, p<0.001).

Sensitivity analyses included an alternate analytic approach (inverse probability of

treatment weighting), a change in the exposure definition (early surgery within 3 days of ED

presentation) and a restricted timeframe for delayed cholecystectomy (within 12 months of

discharge). First, with inverse probability of treatment weighting, the probability of treatment

received for each patient is calculated and corresponds to the propensity score for early group or,

1 minus the propensity score for the delayed group. Weighting on the inverse of the probability

of treatment received created a synthetic study sample that was well-balanced with respect to

observed covariates (Table 6.4). The outcome results from the weighted analysis were similar to

the matched analysis (Table 6.5).

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Second, when narrowing the timeframe for early cholecystectomy to 3 days from ED

presentation, 13,087 (59% of 22,202) were considered to have undergone early cholecystectomy.

Using the same propensity score model and matching algorithm as the primary analysis, 7,865

well-balanced matched pairs were formed. The results with the new exposure definition

remained consistent with the primary analysis (Table 6.6).

Third, when excluding patients who underwent delayed cholecystectomy later than 1 year

after discharge, the cohort was reduced to 21,937 patients. Applying the same propensity score

model and matching algorithm as the primary analysis resulted in 6,864 well-balanced matched

pairs. The results for this cohort were similar to the primary analysis (Table 6.7).

6.5 Discussion

In this population-based analysis of over 20,000 patients with acute cholecystitis, early

cholecystectomy was associated with half the risk of major bile duct injury, a lower risk of major

bile duct injury or death, and a reduction, albeit non-significant, in 30-day post-cholecystectomy

mortality. Furthermore, no significant differences between management strategies were observed

in terms of open cholecystectomy or conversion. That early cholecystectomy is associated with

improved operative outcomes substantiates the need for a paradigm shift in the management of

acute cholecystitis.

Based on best available evidence, early cholecystectomy is supported by many expert

groups49,76 but practice patterns remain variable. Given the limited external validity and small

sample size of existing trials, concern remained that a higher frequency of rare but serious

operative complications might result from early surgery in the setting of acute inflammation22,49.

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Meta-analysis of randomized trials failed to show a difference in rates of bile duct injury (1/222

in early group vs. 3/216 in delayed group)71. Our study is the first comparison of these strategies

with the power to detect a benefit associated with early surgery in terms of major bile duct

injury. The development of fibrosis in and around Calot’s triangle following resolution of the

initial bout of acute cholecystitis is a reasonable pathologic explanation supporting a causal

association between delayed surgery and a higher risk of major bile duct injury130,131.

Furthermore, recurrent acute cholecystitis which may occur prior to the delayed cholecystectomy

may also contribute to the increased average risk of major bile duct injury. With respect to post-

cholecystectomy mortality, the trials provide little insight since no deaths occurred71. Our

analysis showed a lower 30-day mortality following early surgery, although it is very possible

that this observation occurred due to chance. It is also plausible that patients deemed unfit for

surgery because of a perceived mortality risk were less likely to undergo early cholecystectomy.

To examine the possibility of residual confounding of mortality, we compared the proportion of

patients who underwent elective hip and knee replacement surgery within two years of

cholecystectomy. The rates of these elective procedures, performed to improve quality of life,

were not significantly different between early and delayed groups (hip: 0.38% vs. 0.42%,

p=0.79; knee: 0.72% vs. 0.82%, p=0.57), suggesting that residual confounding is an unlikely

explanation for the observed lower mortality.

This study is consistent with trial data in showing a similar frequency of conversion to an

open procedure between early and delayed cholecystectomy. By addressing this comparison

across a population-based cohort of patients and general surgeons, our analysis alleviates the

concern of limited external validity of the randomized trials. While the trials showed conversion

rates in the order of 20%, the conversion rate in this contemporary cohort approximated 10%.

Given that these trials recruited patients between 1993 and 2002, the observed decrease has face

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validity and is consistent with increased training and experience with laparoscopic

cholecystectomy over time.

In addition to the benefit of early surgery in terms of major bile duct injury, early surgery

is also favoured based on the considerable risk of recurrent gallstone symptoms if

cholecystectomy is delayed. In a meta-analysis of existing trials, 17.5% of patients randomized

to delayed cholecystectomy suffered non-resolving or recurrent symptoms71. In the work

described in Chapter 4 of this thesis, 19% of patients with acute cholecystitis who were

discharged without cholecystectomy, either returned to the ED or were readmitted to hospital for

gallstone disease within 12 weeks of discharge132. These results and the present study therefore

both support early over delayed surgery for most patients.

Strengths of this study include the large sample size, the use of a validated 1-year

mortality risk index and a sophisticated analytic approach to address confounding by indication.

However, several limitations exist. First, propensity score methods only account for confounding

related to observed covariates. Thus residual confounding due to differences in cholecystitis

severity or surgeon characteristics may partially explain the observed difference in major bile

duct injury. For a number of reasons we feel that differences in cholecystitis severity between

exposure groups is unlikely. First, we excluded patients likely to have severe cholecystitis or

severe comorbidity. Second, although information about time delay between symptom onset and

hospital presentation (a widely cited marker of greater cholecystitis severity20) was not available,

because all emergency care is universally accessible without copayment in Ontario, prolonged

delay in seeking medical attention for cholecystitis symptoms is unlikely. Furthermore,

controlling for age, sex and comorbidity can reasonably be expected to minimize differences

between exposure groups with respect to cholecystitis severity22-24. Finally, the performance of

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an intraoperative cholangiogram may be indicative of severe inflammation or fibrosis in Calot’s

triangle and was identified in 3% (n=604) of cholecystectomies. We did not include this

characteristic in deriving the propensity score since it could also reflect the consequence of a bile

duct injury. However, before and after matching, the frequency of cholangiogram was similar in

the early and delayed groups, offering further support for the premise that cholecystitis severity

was not meaningfully different. With respect to surgeon characteristics, two potentially

important unmeasured factors are whether the surgeon had subspecialty training in hepato-biliary

or minimally invasive surgery, and whether a trainee was involved in the operation. However,

even if residual confounding exists related to surgeon characteristics, these results suggest that

early cholecystectomy can confer improved operative outcomes. Thus, surgeons uncomfortable

with offering early laparoscopic surgery should consider seeking the expertise of colleagues with

more experience in difficult laparoscopic cholecystectomy before recommending initial non-

operative management and delayed cholecystectomy. Second, we were unable to capture bile

leaks managed with percutaneous or endoscopic intervention since the date of these procedures,

undertaken outside the operating room, was inconsistently available. However, major bile duct

injuries requiring operative repair remain most clinically important given high associated

morbidity. Finally, the cause of death was unavailable, precluding an understanding of the

proportion of post-operative deaths that could be attributed to cholecystectomy.

In conclusion, these data are consistent with randomized controlled trials but also provide

considerable added value for decision making. The results offer strong support for a practice of

early over delayed cholecystectomy for most patients with acute cholecystitis.

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Table 6.1 - Baseline characteristics of patients and their surgeon before matching

Characteristic Early

cholecystectomy (n=14,948)

Delayed cholecystectomy

(n=7,254) P valuea

Patient characteristics Age, years

mean (SD) 53 (18) 56 (17) <0.001 ≥65 years, no. (%) 4,210 (28) 2,686 (37) <0.001

Female sex, no. (%) 9,241 (62) 4,135 (57) <0.001 Income Quintile, no. (%) 0.72

1 3,227 (22) 1,560 (22) 2 3,196 (21) 1,584 (22) 3 2,895 (19) 1,440 (20) 4 2,943 (20) 1,403 (19) 5b 2,687 (18) 1,267 (17)

ADG comorbidity index mean (SD) 3±13 4±13 <0.001 highest quartile, no. (%) 3,407 (23) 2,037 (28) <0.001

Common bile duct obstruction, no. (%) 1,168 (8) 1,075 (15) <0.001 Pancreatitis, no. (%) 670 (4) 388 (5) 0.004

Surgeon characteristics Years since medical school graduation

mean (SD) 21(10) 22(10) <0.001 highest quartile (≥29) , no. (%) 3,251 (22) 2,018 (28) <0.001

Number of cholecystectomies in preceding year

mean (SD) 75(52) 67 (40) <0.001 highest quartile (≥90), no. (%) 4,201 (28) 1,384 (19) <0.001

aA chi-square test was used for categorical variables and a t-test was used for continuous variables bHighest income level

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Table 6.2 - Baseline characteristics of patients and their surgeon after matching

Characteristic a Early



(n=7,110) Patient characteristics

Age, y mean (SD) 56 (18) 56 (17) ≥65 years, no. (%) 2,581 (36) 2,598 (37)

Female sex, no. (%) 4,057 (57) 4,057 (57) Income Quintile, no. (%)

1 1,519 (21) 1,524 (21) 2 1,569 (22) 1,547 (22) 3 1,419 (20) 1,408 (20) 4 1,338 (19) 1,381 (19) 5b 1,265 (18) 1,250 (18)

ADG comorbidity index mean (SD) 4±13 4±13 highest quartile, no. (%) 1,919 (27) 1,960 (28)

Common bile duct obstruction, no. (%) 900 (13) 944 (13) Pancreatitis, no. (%) 368 (5) 369 (5)


mean (SD) 22(10) 22(10) highest quartile (≥29) , no. (%) 1,864 (26) 1,927 (27)


mean (SD) 67 (41) 67 (41) highest quartile (≥90), no. (%) 1,417 (20) 1,383 (20)

aAll characteristics were well balanced (standardized differences of at most 2% as well as similar distributions of continuous variables when verified graphically). bHighest income level

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Table 6.3 - Outcome frequency and relative risk before and after matching

Outcomea Early Cholecystectomy b

Delayed Cholecystectomy b Relative Risk b P value

Major bile duct injury

Unmatched 38 (0.25) 39 (0.54) 0.47 (0.30 – 0.74) 0.001

Matched 20 (0.28) 38 (0.53) 0.53 (0.31 - 0.90) 0.025

Major bile duct injury or death

Unmatched 163 (1.09) 141 (1.94) 0.56 (0.45 – 0.70) <0.001

Matched 97 (1.36) 134 (1.88) 0.72 (0.56 – 0.94) 0.016 30-day post-cholecystectomy mortality

Unmatched 52 (0.35) 48 (0.66) 0.53 (0.36 – 0.78) <0.001

Matched 33 (0.46) 45 (0.64) 0.73 (0.47 – 1.15) 0.21

Cholecystectomy completed open

Unmatched 1822 (12) 1039 (14) 0.85 (0.79 – 0.91) <0.001

Matched 1078 (15) 1008 (14) 1.07 (0.99 – 1.16) 0.10

Conversion among laparoscopic cases

Unmatched 1220 (9) 719 (10) 0.82 (0.75 – 0.90) <0.001

Matched 679 (11) 664 (10) 1.02 (0.93 – 1.13) 0.68

a Unmatched results reflect outcomes among entire study sample (N=22,202 of which 21,936 were laparoscopic cases). Matched results reflect outcomes among the matched sample(7,110matched pairs of which 6,457 pairs were laparoscopic cases). b Outcome frequencies are presented as number (%). Relative risk (early compared to delayed cholecystectomy) is presented with the corresponding 95% confidence interval.

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Table 6.4 - Baseline characteristics of patients and their surgeon in synthetic cohort after weighting on the inverse probability of treatment received





Age, y mean (SD) 54 (21) 54 (31) ≥65 years, no. (%) 4,700 (31) 2,252 (31)


1 3,207 (21) 1,563 (22) 2 3,219 (22) 1,563 (22) 3 2,939 (20) 1,419 (20) 4 2,922 (20) 1,419 (20) 5 b 2,661 (18) 1,290 (18)

ADG comorbidity index mean (SD) 3.2±16.3 3.2±23.3 highest quartile, no. (%) 3,697 (25) 1,772 (24)

Common bile duct obstruction, no. (%) 1522 (10) 736 (10) Pancreatitis, no. (%) 709 (5) 344 (5)


mean (SD) 21±12 21±17 highest quartile (≥29) , no. (%) 3,731 (25) 1,711 (24)



a All characteristics were well balanced (standardized differences of at most 3% as well as similar distributions of continuous variables when verified graphically). bHighest income level

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Table 6.5 - Relative risk of outcome after weighting on inverse probability of treatment

a Total study sample (n=22,202) included in analysis. Conversion was compared within the 21,936 laparoscopic cases b Relative risk (early compared to delayed cholecystectomy) is presented with the corresponding 95% confidence interval.

Outcome a Relative risk b

Major bile duct injury 0.56 (0.36 – 0.89)

Major bile duct injury or death 0.71 (0.56 – 0.90)

30-day post-cholecystectomy mortality 0.67 (0.45 – 1.01)

Cholecystectomy completed open 1.03 (0.98 – 1.08)

Conversion among laparoscopic cases 0.99 (0.91 – 1.08)

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Table 6.6 - Relative risk of outcomes when defining early cholecystectomy as occurring within 3 days of emergency department presentation

a The outcome results reflect 7,865 well-balanced matched pairs from a total study sample of 22,202. Conversion was compared within the 7,165 well-balanced matched pairs that began with a laparoscopic approach. b Relative risk (early compared to delayed cholecystectomy) is presented with the corresponding 95% confidence interval.







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Table 6.7 - Relative risk of outcome when excluding delayed cholecystectomy later than 1 year after discharge

a The outcome results reflect 6,864 well-balanced matched pairs from a starting sample of 21,937. Conversion was compared between the 6,242 well-balanced matched pairs that began with a laparoscopic approach. b Relative risk (early compared to delayed cholecystectomy) is presented with the corresponding 95% confidence interval.







N=31,667 adults admitted with acute cholecystitis via the emergency department (ED), without a prior ED visit or hospital admission for gallstone disease

N=23,979

N=22,202

N=1,677 excluded given severe cholecystitis (Intensive care unit admission or cholecystostomy)

N=5,908 excluded given no cholecystectomy

N=103 excluded given missing income quintile

N=1,742 excluded without at least 6 months of post-operative follow-up

N=35 excluded with biliary malignancy or cyst

FIGURES

Figure 1. Patient eligibility flowchart

Charles

Text Box


Charles

Text Box

Figure 6.1 - Patient eligibility flowchart

Charles

Rectangle

Charles

Text Box

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101

Chapter 7

Cost-utility Analysis Comparing Alternative Timeframes of

Cholecystectomy for Acute Cholecystitis


I. Compare the clinical effectiveness and costs associated with three alternative timeframes

of cholecystectomy for acute cholecystitis

II. Characterize the level of uncertainty around these estimates through probabilistic

sensitivity analysis

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7.1 Summary

Background

The constrained nature of healthcare budgets mandates careful consideration of costs,

relative to the clinical consequences of alternative treatments. We performed a cost-utility

analysis comparing alternative timeframes of cholecystectomy for acute cholecystitis.

Methods

A Markov decision analytic model with a 5 year time horizon was developed to compare

costs and quality-adjusted life-years (QALY) gained from three alternative management

strategies: early cholecystectomy (within 7 days of presentation), delayed elective

cholecystectomy (8 to 12 weeks from presentation) and watchful waiting, where

cholecystectomy is performed urgently if recurrent symptoms arise. Model inputs were selected

to reflect patients with uncomplicated acute cholecystitis – without concurrent common bile duct

obstruction, pancreatitis or severe sepsis. Outcome probabilities and costs from the perspective

of a third party payer were derived from analysis of population-based administrative databases

for the province of Ontario, Canada. QALY values were based on directly elicited utilities

identified in the literature. Parameter uncertainty was evaluated through probabilistic sensitivity

analyses.

Results

Early cholecystectomy was less costly ($6,905 per person) and more effective (4.20

QALYs per person) than delayed cholecystectomy ($8,511; 4.18 QALYs per person) or watchful

waiting ($7,274; 3.99 QALYs per person), and therefore was the dominant alternative. In

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probabilistic analysis, early cholecystectomy was most likely to be the optimal management

strategy, regardless of the decision maker’s willingness-to-pay for one additional QALY.

Conclusion

This cost-utility analysis provides further support for early cholecystectomy as the

optimal management of uncomplicated acute cholecystitis since early surgery offered the best

outcomes at the least cost.

7.2 Background

Gallstone disease affects as many as 20% of adults and is associated with an estimated

cost of over 6 billion dollars annually in the United States1. Furthermore, among all diseases of

the gastrointestinal tract, acute calculous cholecystitis is the leading cause of hospitalization14.

The only definitive management of acute cholecystitis remains cholecystectomy since surgery

manages the inflamed organ and, by removing the site of gallstone formation, prevents recurrent

symptoms. However, the timing of cholecystectomy remains contentious. Randomized

controlled trials and analyses in the previous chapters suggest a benefit to early urgent

cholecystectomy (within up to 7 days of symptom onset) over delaying cholecystectomy.

Specifically, early surgery is associated with a lower risk of major bile duct injury, a similar risk

of conversion from laparoscopic to open cholecystectomy, a shorter total hospital length of stay

and, unlike delayed surgery, does not leave the patient at risk of recurrent gallstone

symptoms22,71,114,132.

Despite the publication of the trials starting in the late 1990s, the application of early

cholecystectomy remains inconsistent across hospitals worldwide, with contemporary early

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cholecystectomy rates ranging from 36% to 88%69,82,88,139,140. While clinical evidence continues

to grow in support of early surgery, very few formal economic evaluations have been published

comparing alternative timeframes of cholecystectomy in acute cholecystitis. A formal economic

evaluation involves estimating the relative costs and clinical consequences of alternative

treatments as well as characterizing uncertainty around the joint distribution of both outcomes72.

Furthermore, the economic evaluations that exist are based on data from small randomized trials

of limited contemporary external validity73,74. Given the constrained nature of healthcare

budgets, such analyses can provide important supplemental data for decision makers to consider

alongside clinical efficacy and effectiveness studies. We therefore performed an economic

evaluation comparing different timeframes of cholecystectomy for acute cholecystitis.

7.3 Methods

Study design

This is a model-based cost-utility analysis that compared three treatment strategies for

patients admitted to hospital with a first presentation of acute cholecystitis. The strategies were:

(1) early cholecystectomy, performed within 7 days of presentation, (2) delayed

cholecystectomy, performed electively 8 to 12 weeks following presentation, and (3) watchful

waiting, with cholecystectomy performed urgently, should recurrent symptoms arise.

Outcomes, time horizon and perspective

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The outcomes of interest were quality-adjusted life-years (QALYs) and costs. Not

infrequently used in surgical literature141-143, QALYs combine the quality of life associated with

a particular health state and the duration of that health state into a single measure72. All costs

were converted to 2011 Canadian dollars using the consumer price index for health care in

Ontario144.

Outcomes were quantified over a 5 year time horizon starting at the time of first

presentation. A 5 year horizon was chosen over a lifetime horizon since acute cholecystitis and

cholecystectomy on average only have a short term impact on quality of life and mortality.

Furthermore, based on the analysis from Chapter 5, 95% of emergency department visits or

readmissions for recurrent gallstone symptoms occur within 2 years of discharge132. Therefore,

nearly all the impact of the modeled decision on quality of life and mortality would reasonably

be expected to occur within a 5 year time period.

Costs were considered from the perspective of a third party payer, the Ontario Ministry of

Health and Long Term Care. Therefore, patients’ out of pocket costs were not included in the

analysis. As per Canadian cost-effectiveness guidelines, costs and QALYs were discounted at a

rate of 5% per year145.

Model Structure

The underlying framework of the analysis was a Markov cohort decision analytic model,

used to derive the average cost and QALY gains of each management strategy, for a hypothetical

cohort of patients. Decision analysis provides an explicit framework to inform decision making

based on best available evidence. While defining a model structure necessarily involves a

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simplification of reality, the model should reflect all important clinical consequences and costs

associated with the disease process and management strategies72. Thus, the initial cholecystitis

admission, recurrent gallstone-related symptoms if discharged without cholecystectomy and

complications resulting from cholecystectomy were modeled. Patients’ clinical course was

represented through a Markov process involving a series of mutually exclusive health states

(Figure 7.1). Over the 5 year time horizon of the analysis, patients transition from one health

state (e.g. acute cholecystitis) to another (e.g. asymptomatic awaiting elective cholecystectomy)

according to defined transition probabilities and at time intervals dictated by the defined cycle

length (1 month in our model).

As modeled, cholecystectomy could be undertaken via a laparoscopic or open (either

started open or converted to open) approach and cholecystectomy-related outcomes were

incorporated as: major bile duct injury requiring operative reconstruction, bile leak requiring

endoscopic intervention, other complications and no complication. In the base case analysis,

major bile duct injury, bile leak and other complications were modeled as impacting on quality

of life for 6, 2, and 1 month, respectively. Finally, gallstone-related symptoms were modeled as

biliary colic or recurrent cholecystitis, choledocholithiasis with or without cholangitis, and

pancreatitis. In both the delayed cholecystectomy and watchful waiting strategies, if a patient

suffered a gallstone-related symptom after their initial cholecystitis admission, they were

admitted and cholecystectomy was performed urgently on the same admission. Mortality was

incorporated in all stages of the model.

Model Inputs

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The required model inputs include transition probabilities, costs, and utilities associated

with each health state or trajectory between health states. The input values were selected to be

representative of a hypothetical cohort of adult patients, emergently admitted with a first episode

of uncomplicated acute cholecystitis – without concurrent severe sepsis, common bile duct

obstruction or pancreatitis.

Probabilities

The analyses detailed in Chapters 5 and 6 provided the foundation for deriving most of

the model probabilities (Table 7.1).

Briefly, a cohort of patients with acute cholecystitis was first defined from

deterministically-linked population-based databases including all ED visits, hospitals admissions

and day surgeries in Ontario, Canada. All adults admitted to hospital from April, 2004 to March

2011, with a most responsible diagnosis of acute cholecystitis were identified. The cohort was

restricted to patients admitted through the ED and without prior gallstone disease – no gallstone-

related ED visit or hospital admission in the preceding 2 years. We excluded patients with biliary

tract obstruction or pancreatitis on the index admission in addition to patients considered to have

severe cholecystitis, defined as those directly admitted to an intensive care unit or whose disease

was treated with a cholecystostomy tube.

From this cohort, outcome probabilities specific to each of the three modeled

management strategies were derived. To do so, three propensity-score matched groups were

defined: (1) patients managed with early cholecystectomy – within 7 days of ED presentation,

(2) patients managed with delayed cholecystectomy – between 7 days from ED presentation and

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1 year following discharge, and (3) patients discharged from the initial cholecystitis admission

without cholecystectomy. The first and second matched groups were used to determine the

frequency of operative outcomes and mortality for all three strategies. The third matched group

was used to calculate the risk of recurrent gallstone-related symptoms, relevant only to the

delayed and watchful waiting strategies.

As per the approach described in Chapter 6, patients managed with early and delayed

cholecystectomy were matched on propensity of treatment (early or delayed cholecystectomy),

age (within 5 years) and sex in order to control for factors that might have confounded the

relationship between timing of cholecystectomy and operative outcomes. The confounders

contributing to the propensity score included patient (age, sex, comorbidity level, income level)

and surgeon (years since medical school graduation and cholecystectomy experience)

characteristics as previously described in chapter 6 (see 7.8 - Supplemental data). The relevant

operative outcomes included the frequency of open cholecystectomy, major bile duct injury and

other complications. When calculating operative outcome probabilities, distinction was made

between delayed urgent cholecystectomy, occurring because of a recurrent gallstone-related

event, and delayed elective cholecystectomy. A cholecystectomy was considered elective if the

operation took place in day surgery or the hospital admission was elective.

Major bile duct injury was identified based on the presence of a billing code for biliary

tract repair or reconstruction within 6 months of cholecystectomy (OHIP billing claim: S281,

S285 – choledochoenterostomy; S292 – repair of common duct) as previously described. Other

cholecystectomy-related complications were identified based on ICD-10-CA diagnosis codes

identified on the same visit as the index cholecystectomy or within 30 days of cholecystectomy

The diagnosis codes considered complications of cholecystectomy included – T81.0

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Haemorrhage and haematoma complicating a procedure, T81.3 Disruption of operation wound

(dehiscence), T81.4 Infection following a procedure, including post-procedural intra-abdominal

abscess, post-procedural wound infection and post-procedural sepsis.

Finally, patients discharged from hospital without cholecystectomy were matched to the

early cholecystectomy group on age (within 5 years), sex and propensity for group membership,

based on patient characteristics only (see 7.8 - Supplemental data). As per the approach

described in Chapter 5, this third matched group provided the probability of recurrent gallstone-

related symptoms (ED visit or hospital admission for gallstone disease)132.

These inputs were supplemented with data from a Cochrane meta-analysis of randomized

trials comparing early to delayed cholecystectomy for acute cholecystitis71. Due to difficulty

ascertaining bile leaks in our administrative data, the relative frequency of this complication was

taken from the meta-analysis. The meta-analysis included five single-center trials and was not

used as the primary data source since the trials have limited contemporary external validity and

lacked power to compare costly major bile duct injuries and death. However, all meta-analysis

outcome estimates were incorporated into one-way sensitivity analysis ranges detailed below.

Costs

Hospital costs were estimated using the Resource Intensity Weight (RIW) method100.

Each ED visit, hospital admission and day surgery is assigned an RIW value, which when

multiplied by the provincial average cost per weighted case (CPWC), estimates the cost of a

patient`s visit. The RIW value for a given admission reflects a patient`s level of resource

utilization during that admission and is based on the patient`s major diagnosis, age, comorbidity

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burden, interventions received and length of stay. The CPWC values are year and visit type

specific (e.g. inpatient stay in fiscal year 2009), and they are derived from the allocation of

global hospital budgets across all patients (total annual budget divided by sum of all patients’

RIWs). Both direct medical and overhead hospital costs associated with relevant ED visits,

inpatient stays and day surgery were thus included in our model. Furthermore, since surgeons’

services are largely reimbursed on a fee-for-service basis in Ontario, hospital costs were

supplemented with the cost of specific physician claims, priced according to the Ontario Health

Insurance Plan schedule of benefits for physician services101 (Table 7.1).

Quality-adjusted life-years

QALY gains over the 5 year time horizon were derived from utility values. A utility is a

numerical measure of preference for a particular health state under conditions of uncertainty, and

is expressed on a scale from 0 (reflecting death) to 1.0 (representing perfect health)72. The

quantity of QALYs associated with an outcome is calculated by multiplying the utility value of

the relevant health state by the duration of time spent in that health state. For example, 6 months

of life with a major bile duct injury requiring operative repair would have a value of 0.32

QALYs (utility value of 0.64 multiplied by 0.5 years). Utilities for our model were obtained from

review of the literature and the Cost-Effectiveness Analysis Registry of the Institute for Clinical

Research and Health Policy Studies, Tufts Medical Center146. When multiple utility values were

identified, those directly elicited under conditions of uncertainty (standard gamble) were used

with the remaining values incorporated in sensitivity analysis. The majority of the utility values

were obtained from a cohort of general medical patients without prior gallstone disease, with

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similar age and sex distributions to the population-based cohort used to derive the outcome

transition probabilities 147(Table 7.1).

Analysis

The model was first evaluated using cohort simulation. Cohort simulation refers to the

process of running a hypothetical cohort of patients from the starting health state (i.e. acute

cholecystitis) through to the end of the time horizon. At each cycle during the cohort simulation,

costs and QALY gains are added to a running total based on the distribution of the cohort across

health states. Changes in the distribution of patients across health states, from one cycle to the

next, are dictated by the defined transition probability point estimates (Table 7.1). The cohort

simulation was run three times, once for each treatment strategy. The final result is an average

per patient total cost and QALY gains over 5 years for each strategy.

We evaluated the robustness of the results through a number of sensitivity analyses.

Parameter uncertainty was first evaluated through one-way and two-way sensitivity analyses.

One-way sensitivity analysis offers an understanding of the sensitivity of the results to individual

input parameters by varying each parameter value one at a time while keeping the others fixed.

For each parameter, the threshold at which the study conclusions changed was reported if one

existed. Two-way sensitivity analysis was also undertaken. Both these analyses confirmed that

changes of input parameters had predictable effects on model outcomes (internal consistency).

Next, in order to evaluate uncertainty of all parameters simultaneously, probabilistic sensitivity

analysis (PSA) was undertaken and involved second-order Monte Carlo simulation (10,000

iterations of the previously described cohort simulation). For every iteration, a new value for

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each input parameter was selected from defined distributions. Beta distributions (bounded by 0

and 1) were used for probabilities and utilities and, given their positive skew, Gamma

distributions were used for costs148. In all cases the distributions were parameterized based on

the mean (point estimate in Table 7.1) and standard error of the inputs. Parameters were treated

as independent and no correlations between parameters were incorporated in the PSA.

Structural uncertainty was also evaluated by testing the sensitivity of the results to

specific changes in the model structure. These changes included varying the timing of delayed

elective cholecystectomy, the duration of time cholecystectomy complications impacted on

quality of life, applying different discount rates recommended by US and UK cost-effectiveness

guidelines 149,150 and exploring time horizons of 1 to 6 years.

7.4 Results

Early cholecystectomy was less expensive and provided greater QALY gains than both

alternate management strategies (Table 6.2). Of the three strategies, watchful waiting provided

the least QALY gains over 5 years due to reduced quality of life from recurrent gallstone

symptoms, relatively poorer outcomes associated with delayed urgent cholecystectomy and

higher mortality. Of the three strategies, delayed cholecystectomy was the most expensive given

the additional cost associated with a second hospitalization or same day surgery visit.

On one-way sensitivity analysis, threshold values were identified for individual

parameters above or below which early cholecystectomy was no longer the optimal strategy

(Table 6.1). A strategy is considered economically attractive if it dominates all alternatives (i.e.

is cheapest and most effective) or is associated with an incremental cost-effectiveness ratio (cost

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per 1 QALY gained from one alternative compared to another) below the decision maker`s

willingness-to-pay (WTP) for an additional QALY. Threshold results were calculated using a

WTP of C$50,000 per QALY, based on local gross domestic product per capita 87,151,152. For

example, were the probability of bile leak following early cholecystectomy greater than 27%, the

additional QALY gains associated with early surgery would cost more than $50,000 per QALY

so early cholecystectomy would no longer represent good value for the additional investment. As

shown in table 1, in virtually all cases thresholds were implausibly extreme values, with the

exception of the cost of the index cholecystitis admission. Two-way sensitivity analysis

confirmed internal consistency of the model (supplemental figure 7.S1).

On PSA, cost varied widely for all three strategies across the 10,000 model iterations:

mean cost per person was $6,994 (SD $3,996) for early cholecystectomy, $7,275 (SD $3,152) for

watchful waiting and $ 8,494 (SD $3,255) for delayed cholecystectomy. However, the ranking

based on total QALYs gained over five years remained consistent: mean QALYs per person was

$4.20 (SD 0.01) for early cholecystectomy, 4.18 (SD 0.01) for delayed cholecystectomy and3.99

(SD 0.08) for watchful waiting Figure 7.2).While QALY gains between early and delayed

cholecystectomy were relatively close in value, when examining the difference in cost and

QALY gains of early compared to delayed cholecystectomy on each iteration, early

cholecystectomy was more often associated with greater QALY gains (figure 7.3). Furthermore,

given a WTP of $50,000 per QALY, early cholecystectomy was cost-effective compared to

delayed cholecystectomy in 72% of iterations. Since the true WTP value is unknown, a cost-

effectiveness acceptability curve was also derived that shows the proportion of the 10,000

Monte-Carlo iterations where a given strategy is the most cost-effective alternative across a

range of WTP values153. Regardless of the decision maker`s willingness-to-pay, early

cholecystectomy had the highest probability of being the optimal strategy (Figure 7.4).

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Finally, the impact of changes to the model structure was also investigated. First,

delayed elective cholecystectomy was scheduled at 4 weeks from the initial cholecystitis episode

reducing the proportions of patients suffering from recurrent symptoms. Second, the duration of

reduced quality of life associated with post-operative complications was varied from 1 to 12

months. Third, discount rates consistent with UK and then US cost-effectiveness guidelines were

applied. In all these cases early remained cheaper and more effective. Finally, when we varied

the time horizon from 1 year to 6 years, early and delayed cholecystectomy accrued all costs and

most QALY losses within the first year. While always least effective, watchful waiting was

cheaper in the short term and continued accruing additional costs between 1 and 6 years, driven

by the cumulating risk of recurrent gallstone symptoms.

7.5 Discussion

This cost-utility analysis shows that patients with acute uncomplicated early cholecystitis

benefit from early cholecystectomy. This strategy is less costly and more effective (greater

QALY gains) than either delayed elective cholecystectomy or watchful waiting. Furthermore,

when considering uncertainty around best available evidence, early cholecystectomy is most

likely to be the optimal management strategy regardless of the decision maker’s willingness-to-

pay for additional health gains.

These results are consistent with existing economic evaluations comparing early to

delayed cholecystectomy for acute cholecystitis. In a model-based cost-utility analysis from the

perspective of the UK Ministry of Health, Wilson et al. found early cholecystectomy to be the

dominant strategy73. Johner and colleagues reached the same conclusion using a similar approach

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but from the perspective of a single hospital74. In both studies, a decision tree model incorporated

outcome probabilities derived mostly from the Cochrane meta-analysis of randomized trials that

have important limitations. Our approach improves on these analyses in a number of ways. First,

we have employed a more complex model structure over a longer time horizon that is more

reflective of patients’ clinical course. Second, we have incorporated new input parameters

derived from person-level, real-world estimates of operative outcomes, mortality and the

probability of recurrent gallstone symptoms. Third, costing using the person-level RIW method

may more accurately reflect the range of cost across patients. Finally, we have also considered a

third management strategy - watchful waiting - that may be considered for patients wishing to

avoid surgery. Despite the differences in study design, the fact that our results are consistent with

other reports reinforces the external validity of the conclusions across different perspectives and

settings. As such, this study has direct implications for the management of patients in Canada,

but the conclusion that early cholecystectomy is economically attractive likely holds across a

wide range of countries. While we have not considered this comparison from a broader societal

perspective, loss of productive working time would be the most important additional

consideration. Since time off work is minimized with early surgery71, taking a societal

perspective would only further underscore the benefit of early surgery.

While this study has a number of strengths, there are potential limitations. For example,

despite employing propensity-score methods, residual confounding may affect the outcome

probabilities derived from administrative data. In addition to this potential bias undermining the

validity of operative outcome frequencies, other complications were captured with a crude

approximation method based on relatively non-specific diagnoses codes. Ultimately however, the

analysis results were not sensitive to the rate and cost of operative complications within plausible

ranges. With respect to potential residual bias of mortality estimates, good balance between

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groups in terms of baseline mortality risk was supported by the use of a morbidity index

validated for the prediction of 1 year mortality in adult Ontarians96,97. Finally, correlations

between parameters were not considering in the PSA. This limitation only affects the

quantification of uncertainty and does not undermine the conclusion that early is on average

more effective and less costly.

In conclusion, early cholecystectomy offered the best outcomes at the least cost, and

therefore should be considered for most patients with uncomplicated acute cholecystitis.

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Table 7.1 - Model parameter inputs with sources and threshold analysis results

Point estimate Sourcea Thresholdb

PROBABILITIES

Early cholecystectomy Open cholecystectomy 15% - >53% Major bile duct injury 0.2% - >8.9% Bile leak 3.1% 71 >27% Other complication 4.1% - >73%

Mortality KM c - >30% increase

Delayed cholecystectomy Open cholecystectomy – elective cholecystectomy 12% - None Major bile duct injury – elective cholecystectomy 0.5% - None Bile leak – elective cholecystectomy 0% 71 None Other complication – elective cholecystectomy 4.4% - None Open cholecystectomy – urgent cholecystectomy 24% - None Major bile duct injury – urgent cholecystectomy 0.5% - None Bile leak – urgent cholecystectomy 0% 71 None Other complication – urgent cholecystectomy 5.2% - None Risk of recurrent gallstone-related symptoms KM c - None

Biliary colic or cholecystitis as recurrent eventd 68% - None Choledocholithiasis as recurrent eventd 25% - None Acute pancreatitis as recurrent eventd 7% - None

Mortality KM c - >30% decrease

Watchful waiting Open cholecystectomy – urgent cholecystectomy 24% - None Major bile duct injury – urgent cholecystectomy 0.5% - None Bile leak – urgent cholecystectomy 0% 71 None Other complication – urgent cholecystectomy 5.2% - None Gallstone-related recurrent symptoms KM c - None

Biliary colic or cholecystitis as recurrent eventd 68% - None Choledocholithiasis as recurrent eventd 25% - None Acute pancreatitis as recurrent eventd 7% - None

Mortality KM c - >85% decrease

UTILITY VALUES Acute cholecystitis admission 0.77 147 None

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Asymptomatic awaiting cholecystectomy 0.96 147 None Asymptomatic watchful waiting 0.96 147 None Post-cholecystectomy major bile duct injury 0.64 147 None Post-cholecystectomy bile leak 0.76 154 None Post-cholecystectomy other complication 0.79 147 None Full recovery post cholecystectomy 0.998 147 <0.92 Post laparoscopic cholecystectomy 0.91 147 None Post open cholecystectomy 0.78 147 None Biliary colic or recurrent cholecystitis 0.77 147 None Choledocholithiasis 0.76 154 None Acute pancreatitis 0.57 155 None Dead 0 - -

COSTS

Early cholecystectomy Cholecystitis admission with cholecystectomy $6,464 - >$8,856 Delayed cholecystectomy and watchful waiting Cholecystitis admission without cholecystectomy $3,738 - <$1,337 Elective Cholecystectomy $3,477 - <$444 ED visit and admission for biliary colic or recurrent cholecystitis and cholecystectomy $8,123 - None

ED visit and admission for choledocholithiasis admission and cholecystectomy $10,880 - None

ED visit and admission for acute pancreatitis and cholecystectomy $9,254 - None

Early, delayed and watchful waiting

Additional cost of major bile duct injury $18,633 - None Additional cost of bile leak $8,321 - >$84,840 Additional cost of other complications $2,645 - >$517,151

a Values without a source reference were derived from analysis of the population-based cholecystitis cohort as described in the methods.

b For each parameter, the threshold at which the study conclusions changed was reported if one existed.

c KM refers to Kaplan-Meier estimates that were derived from the population-based cholecystitis cohort with conditional probabilities estimated for each 1 month interval. In the first 30 days from ED presentation, mortality was 0.4% in the early, delayed and watchful waiting groups. The probability of recurrent gallstone-related symptoms prior to delayed elective cholecystectomy was 20%.

d The distribution of the type of recurrent gallstone-related event was held constant over the time horizon

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Table 7.2 - Average costs and quality-adjusted life-year gains and associated increments

Cost Incremental

Cost

Quality-

adjusted life-

years

Incremental

Quality-

adjusted life-

years

Early cholecystectomy $6,905 4.20

Watchful waiting $7,275 + $370 3.99 - 0.21

Delayed cholecystectomy $8,511 + 1,236 4.18 - 0.02

ACUTE CHOLECYSTITIS

Asymptomatic awaiting cholecystectomy

Asymptomatic - watchful waiting

Recurrent gallstone symptomsand urgent cholecystectomy

Post cholecystectomy states

EARLY CHOLECYSTECTOMY

DELAYED CHOLECYSTECTOMY

WATCHFUL WAITING

Elective cholecystectomy

- Post-cholecystectomy major bile duct injury- Post-cholecystectomy bile leak- Post-cholecystectomy other complication- Full recovery post cholecystectomy

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Figure 7.1 Simplified representation of model state transition diagram 120

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Line

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Figure 7.1 Description of simplified representation of model state transition diagram

A patient’s clinical course in a Markov model is modeled as a series of mutually

exclusive health states (represented by ovals).

All patients start in the acute cholecystitis health state.

Over the 5 year time horizon, patients transition between health states at time intervals

dictated by the defined cycle length (1 month).

Straight arrows represent transitions from a given health state to another health state.

Semi-circular arrows represent transitions from a given health state back to the same

health state.

While not depicted, all health states could lead to death.

Recurrent gallstone symptoms and cholecystectomy are modeled as events occurring

during a transition between health states (therefore are not within an oval).

While not depicted, recurrent gallstone symptoms are modeled as biliary colic or

recurrent cholecystitis, choledocholithiasis with or without cholangitis, and pancreatitis.

While not depicted, 4 temporary post-cholecystectomy health states were modeled: full

recovery, post-cholecystectomy major bile duct injury, post-cholecystectomy bile leak,

post-cholecystectomy other complication

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Figure 7.2 - Cost-effectiveness plane of Monte-Carlo probabilistic analysis results (10,000 iterations) 122

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Figure 7.2 – Description of the cost-effectiveness plane of Monte-Carlo probabilistic analysis

results (10,000 iterations)

For each iteration of the Monte-Carlo simulation, the model is run three times (once for

each management strategy) and a corresponding average QALY gain (x-axis) per person

and average cost per person (y-axis) is obtained for each strategy.

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Figure 7.3 - Incremental cost-effectiveness plane comparing early to delayed cholecystectomy 124

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Callout

Willingness-to-pay threshold of $50,000 per QALY

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I

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II

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III

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IV

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Figure 7.3 – Description of incremental cost-effectiveness plane comparing early to delayed

cholecystectomy

Each point represents one iteration of the Monte-Carlo probabilistic analysis.

The X-axis represents the difference between the average cost of early minus delayed

cholecystectomy.

The Y-axis represents the difference between the average QALY gains from early minus


In quadrants I and IV, early is more effective than delayed cholecystectomy, in quadrants

I and II, early is more expensive than delayed cholecystectomy.

Interpretation: In a majority of Monte-Carlo runs, early cholecystectomy is more

effective than delayed. Given a willingness-to-pay of $50,000 (angled broken line), early

cholecystectomy was cost-effective compared to delayed cholecystectomy in 72% of

iterations.

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Figure 7.4 - Cost-effectiveness acceptability curve derived from Monte-Carlo probabilistic sensitivity analysis 126

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Figure 7.4 – Description of cost-effectiveness acceptability curve derived from Monte-Carlo

probabilistic sensitivity analysis.

For every iteration of the Monte-Carlo probabilistic analysis, a net monetary benefit

(NMB) is calculated for each of the three management strategies. The

NMB=WTP*QALYs-Cost. At a given WTP level (x-axis), the proportions of iterations

where a given strategy has the highest NMB is calculated (y-axis)

Interpretation: At a WTP=0, the average QALY gains do not contribute to NMB (since

if WTP=0 then WTP*QALY=0), therefore the least expensive strategy will have the

highest NMB. As the WTP increases, QALY gains increasingly drive the NMB value.

Since early cholecystectomy is the least expensive and the most effective, it remains most

likely to have the highest NMB (i.e. most likely to be the optimal strategy) across all

values of WTP.

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7.8 Supplemental data for Chapter 7

A total of 31,667 adults were admitted with acute cholecystitis via the emergency

department and did not have a prior ED visit or hospital admission for gallstone disease. Of these

patients, 6,122 were excluded given concurrent severe cholecystitis (i.e. intensive care unit

admission or insertion of a cholecystostomy drain, N=1,677), biliary tract obstruction or

pancreatitis (N=4,313) and missing income level (N=132). Of the remaining 25,545 patients,

19,126 underwent cholecystectomy (either on initial admission of within 1 year of discharge) and

met additional inclusion criteria (at least 6 months of post-cholecystectomy follow-up and no

diagnosis of biliary tract malignancy within 6 months of cholecystectomy).

First and second matched groups: early and delayed cholecystectomy

These 19,126 patients were divided based on having received early (within 7 days of ED

presentation) or delayed cholecystectomy. A propensity score for receipt of early

cholecystectomy was calculated and the two groups were then matched based on the propensity

score, age (within 5 years) and sex. Characteristics of the two groups prior to the match are

presented in Table 7.S1 and characteristics of the matched cohort are presented in Table 7.S2.

Balance in covariates between groups after matching was confirmed by verifying that the

standardized difference was less than 10%. The distributions of continuous variables were also

compared graphically through cumulative density and quantile-quantile plots. All characteristics

were well balanced with standardized differences of at most 3% as well as similar distributions

of continuous variables when verified graphically.

Third matched group: patients discharged without cholecystectomy following initial cholecystitis

admission

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Starting from 25,545 patients described above, 15,162 underwent cholecystectomy on the

index admission. Another 79 patients died during the index admission leaving 10,304 patients

discharged without cholecystectomy. This group was matched to the 5,676 matched early group

previously. The propensity score and matching process was similar to the first match with the

exception that only patient characteristics were used to derive the propensity score.

Characteristics of the two groups prior to the match are presented in Table S3 and characteristics

of the matched cohort are presented in Table S4. All characteristics were well balanced with

standardized differences of at most 2% as well as similar distributions of continuous variables

when verified graphically.

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Table 7.S1 - Baseline characteristics of patients and their surgeon before matching




(n=5,700) P valuea Patient characteristics

Age, year mean (SD) 52 (18) 56 (17) <0.001 ≥65 years, no. (%) 3,594 (28) 2,020 (35) <0.001

Female sex, no. (%) 5,093 (39) 2,487 (44) <0.001 Income Quintile, no. (%) 0.62

1 2,831 (22) 1,194 (21) 2 2,802 (21) 1,243 (22) 3 2,569 (19) 1,141 (20) 4 2,609 (20) 1,121 (19) 5b 2,401 (18) 1,001 (17)



mean (SD) 21(10) 22(10) <0.001 highest quartile (≥29) , no. (%) 2,882 (22) 1,574 (28) <0.001


mean (SD) 74 (52) 66 (40) <0.001 highest quartile (≥90), no. (%) 3,659 (28) 1,077 (19) <0.001


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Table 7.S2 - Baseline characteristics of patients and their surgeon after matching





Age, year mean (SD) 56 (17) 56 (17) ≥65 years, no. (%) 1,991 (35) 2,000 (35)


1 1,141 (20) 1,190 (21) 2 1,251 (22) 1,234 (22) 3 1,134 (20) 1,134 (20) 4 1,142 (20) 1,120 (20) 5b 1,008 (18) 998 (18)



mean (SD) 22(10) 22(10) highest quartile (≥29) , no. (%) 1,477 (26) 1,554 (27)




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Table 7.S3 - Baseline characteristics of patients before matching




(n=10,304) P valuea

Age, year mean (SD) 56 (17) 60 (19) <0.001 ≥65 years, no. (%) 1,991 (35) 4,539 (44) <0.001

Female sex, no. (%) 3,196 (56) 5,559 (54) 0.004 Income Quintile, no. (%) 0.05

1 1,141 (20) 2,253 (22) 2 1,251 (22) 2,270 (22) 3 1,134 (20) 2,025 (20) 4 1,142 (20) 1,927 (18) 5b 1,008 (18) 1,829 (18)



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Table 7.S4 - Baseline characteristics of patients after matching




(n=5,675) Age, y

mean (SD) 56 (17) 56 (17) ≥65 years, no. (%) 1,991 (35) 1,991 (35)


1 1,242 (20) 1,159 (21) 2 1,251 (22) 1,270 (22) 3 1,133 (20) 1,152 (20) 4 1,142 (20) 1,112 (20) 5b 1,009 (18) 982 (17)



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Figure 7.S1 - Example two-way sensitivity analysis results 134

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Figure 7.S1 – Description of example of two-way sensitivity analysis results

The probability of a major bile duct injury(x-axis) was varied simultaneous with the

utility of major bile duct injury (y-axis).

The pink area represents values of both variables where early cholecystectomy is the

optimal strategy given a WTP of $50,000, whereas the blue area represents values for

both variables where delayed cholecystectomy would optimal.

Interpretation: Regardless of the utility of a major bile duct injury, the probability of a

major bile duct injury with early cholecystectomy would need to be unrealistically high

(>6%) to change the conclusion that early cholecystectomy is the optimal management

strategy.

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Chapter 8

General Discussion


I. Provide a summary of the thesis results

II. Discuss the implications

III. Review the general limitations

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8.1 Thesis Summary

This thesis focused on characterizing the clinical outcomes and costs associated with

early and delayed cholecystectomy for acute cholecystitis. The specific aims were defined in

order to address existing gaps in knowledge comparing early to delayed cholecystectomy as well

as to provide insight into the current context of practice in Ontario. We began by characterizing

the extent of variation in early cholecystectomy, then compared early to delayed surgery with

respect to specific clinical outcomes followed by a comparison of both clinical outcomes and

cost within the framework of economic evaluation.

In the Specific Aim 1, the extent of variation in application of early cholecystectomy

(within 7 days of emergency department presentation) across hospitals in Ontario was

characterized. The median early cholecystectomy rate was 51% and wide variation was observed

across hospitals (interquartile range of 25% to 72%), even among 18-49 year old healthy patients

with uncomplicated cholecystitis (median 74%, interquartile range of 41% to 88%). When

accounting for patient characteristics on multivariable analysis, similar patients did not receive

similar care across the province (Median Odds Ratio 3.7). Hospitals seeing higher volumes of

patients with acute cholecystitis were found to confer the highest adjusted odds of early

cholecystectomy and half of the explained variation in early cholecystectomy was related to

hospital-level effects.

In the Specific Aim 2, the risk of recurrent symptoms in patients discharged without

cholecystectomy was derived. In a study sample of 10,304 patients with acute cholecystitis, the

probability of a gallstone-related emergency department visit or hospital admission by 6 weeks,

12 weeks and 1 year after discharge was 14%, 19% and 29% respectively. Of these events, 30%

were for biliary tract obstruction or pancreatitis. A difference in the risk of a gallstone-related

event was also observed across age groups, with the lowest risk observed in the oldest patients.

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In the Specific Aim 3, we sought to address the limitations of small randomized trials

comparing early to delayed cholecystectomy for acute cholecystitis with respect to operative

outcomes. We performed the same comparison in a sample of over 20,000 patients drawn from

Ontario’s population-based administrative databases. We compared rare outcomes including

major bile duct injury and death as well as the rate of open cholecystectomy (started open or

converted) and, among laparoscopic cases, the rate of conversion to an open approach. Early

cholecystectomy was associated with half the risk of major bile duct injury as well as a lower

risk of major bile duct injury or death within six months. Finally the rate of open

cholecystectomy and conversion were not meaningfully different between exposure groups.

The final Specific Aim 4 was to perform a cost-utility analysis comparing three

management strategies for acute cholecystitis: early cholecystectomy (within 7 days of

emergency department presentation), delayed elective cholecystectomy (8 to 12 weeks from

presentation) and watchful waiting, where cholecystectomy is performed urgently only if

recurrent gallstone symptoms arise. The outcomes were costs from the perspective of the Ontario

Ministry of Health and QALYs gained over 5 years. Early cholecystectomy was on average less

costly ($6,905 per person) and more effective (4.20 QALYs per person) than delayed

cholecystectomy ($8,511; 4.18 QALYs per person) or watchful waiting ($7,274; 3.99 QALYs

per person). In probabilistic sensitivity analysis, early cholecystectomy was most likely to be the

optimal management strategy, regardless of the value a decision maker would be willing to pay

for one additional QALY.

These results represent novel data on variation in practice in Ontario as well as clinical

and economic outcomes associated with early to delayed cholecystectomy for acute cholecystitis.

This thesis work therefore offers significant added value to decision making that is applicable to

the province of Ontario and can also be generalized to a wider context of practice.

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8.2 Implications

The implications of this thesis work should be considered when placing these results in

the context of existing best available evidence. We now know that early cholecystectomy offers

multiple benefits over delayed cholecystectomy.

First, delaying surgery is associated with a considerable risk of recurrent symptoms. This

risk is approximately 20% by 3 months following discharge based on existing trials and

observational studies 15,46,89 as well as the Chapter 5 results in this thesis. This risk represents one

of the most convincing arguments against delaying surgery,

Second, based on a similar rate of conversion to open cholecystectomy and low rates of

serious complications in both early and delayed groups in randomized trials, early

cholecystectomy was deemed ‘safe’ given appropriate surgical experience. However, valid

concern remained that urgent early surgery in the setting of acute inflammation might confer a

higher risk of rare but devastating complications such as bile duct injury. This analysis has not

only confirmed that the rate of open cholecystectomy and conversion is similar across a broad

group of patients, but it also shows a benefit of early cholecystectomy in terms of major bile duct

injury. These results therefore support a shift in thinking. Early cholecystectomy should no

longer simply be viewed as safe compared to delayed surgery but, in fact, should be considered

superior to delaying intervention in terms of rare operative outcomes. The development of

fibrosis in and around Calot’s triangle following resolution of the initial bout of acute

cholecystitis may explain the increased risk of major bile duct injury when delaying surgery

130,131. Although bile duct injuries are rare, given the serious morbidity, increased mortality and

high litigation rates associated with this injury, a seemingly subtle shift in thinking may in fact

be the catalyst of a further shift in practice towards early cholecystectomy for most patients.

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Third, randomized controlled trials in both the open and laparoscopic era consistently

showed that early surgery was associated with a shorter total hospital length of stay. Since

hospital stay is the main source of costs associated with the surgical management of acute

cholecystitis, it is reasonable that early surgery would be less costly than delayed surgery. While

the clinical and costs benefits are clear, the formal economic evaluation in this thesis is useful on

multiple grounds. Not only does the cost-utility analysis in this thesis provide economic evidence

most directly relevant to Ontario but the conclusion that early cholecystectomy is the dominant

strategy also hold external validity. This external validity can be based on the fact that the results

are consistent with two other cost-utility analyses using distinct modeling approaches, outcome

probabilities sources, and perspective for costing. In addition, our study as well as that published

by Wilson and colleagues suggests a high probability that early cholecystectomy is the optimal

management strategy when considering uncertainty around clinical outcome and cost estimates.

Overall, the economic evaluation in this thesis should be viewed a suggesting an economic

benefit of early surgery that compliments the evidence of clinical benefit. Such data may be of

particular interest to healthcare administrators striving to support the provision of best clinical

care while containing healthcare spending.

Finally, the variation in practice observed across Ontario suggests inconsistency with best

available evidence at many hospitals. The importance of hospital-level effects in explaining

variation in early cholecystectomy independently of patient-level effects suggests that the

implementation of hospital specific measures to facilitate early cholecystectomy should be

considered.

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8.3 Limitations

8.3.1 Inability to capture variation at the physician-level

The major limitation associated with Specific Aim 1 is the inability to identify the

decision making physician using the administrative data sources. As a result some of the

unexplained variation in practice may be explained by physician-level effects. However, while a

surgeon’s comfort with difficult laparoscopic cholecystectomy might influence management of

some patients, it is unlikely that it would explain the wide range of variation in early

cholecystectomy observed across the province. Furthermore, as mentioned previously the

characteristics of hospitals included in our analysis are closely related to characteristics of the

surgeons working within them. While, future research should focus on identifying and

distinguishing barriers to early cholecystectomy at the physician and hospital level,

understanding variation at the hospital level remains a constructive starting point to generate

solutions for quality improvement.

8.3.2 Differentiating the type of gallstone-related admission

As mentioned in Chapter 3, while ICD-10 coding clearly permits the differentiation of the

different types of gallstone-related complications (e.g. biliary colic, cholecystits,

choledocholithiasis, gallstone pancreatitis, etc.) the accuracy of this differentiation has not been

validated. This limitation has impact in terms of identifying the proportion of patients with

complicated cholecystitis (i.e. same presentation biliary tract obstruction or pancreatitis) for

Specific Aims 1 and 3. Furthermore, it also affects the accuracy around the type of recurrent

gallstone-related event described in Specific Aims 2 and 4. Nevertheless, unlike many other

medical diagnoses, data coders can generally find documentation (i.e. imaging reports, operative

142

reports, pathology reports) to help differentiate the type of gallstone disease, thereby supporting

the likely accuracy of the most responsible diagnosis code.

8.3.3 Limited scope of operative outcomes

The major limitation that applies to the comparison of operative outcomes in Specific

Aim 3 is that only a limited number of specific outcomes can be reasonably captured within

Ontario’s administrative health data. While the validity of mortality, major bile duct injury, open

cholecystectomy and conversion as outcomes can be justified (seen Chapter 6, section 6.2

Methods), other surgical and medical complications cannot be ascertained with certainty.

Contemporary randomized trials or validated registry studies would be useful to understand the

comparative risk of complications such as bile leak, surgical site infection and other medical

complications.

8.3.4 Potential for residual confounding

Residual confounding is the main limitation affecting the comparison of operative

outcomes between early and delayed cholecystectomy. A gradient of cholecystitis severity is

likely the most important source of residual confounding and, as detailed in the chapter 6

discussion, there are number of reason to suggest that any difference in severity gradient between

groups is minimal. Ultimately however, if residual confounding is present, the results are likely

biased against early intervention. Since the definition of early surgery is a wide timeframe (7

days) patients initially managed with an intention of delaying surgery, but whose symptoms did

not resolve, are likely included in the early group. These patients based on the Tokyo guideline

severity classification have moderate as opposed to mild cholecystitis. Furthermore, a subgroup,

143

albeit small, of patients in the early group were likely healthy patients that required emergency

surgery based on the severity of their presentation.

Finally, a surgeon’s inexperience with difficult laparoscopic cholecystectomy may in

practice be reasonable justification for his or her decision not to perform early surgery. However,

from a patient’s perspective, given the benefit now further demonstrated with early

cholecystectomy, it would seem unreasonable to delay surgery if colleagues with appropriate

expertise are available. This point underscores the utility of considering this topic from the

perspective of the hospital or surgical provider group in order to develop solutions that optimize

the efficient management of acute cholecystitis

144

Chapter 9

Future Directions


I. Present possible future directions

145

Including the publications stemming from this thesis, a large body of work now supports

early over delayed cholecystectomy for most patients with acute cholecystitis. Future efforts

should focus on understanding the context-specific determinants of management, knowledge

translation and ongoing evaluation of patient outcomes and preference.

9.1 Understanding the context-specific determinants of

management

In Specific Aim 1, we found that in nearly half of hospitals in Ontario, early

cholecystectomy was only provided to a minority of patients with acute cholecystitis. Efficiently

shifting practice at these institutions will require an understanding of the local determinants of

decision making. At the macro-level, specific barriers to early cholecystectomy within a given

practice setting (e.g. an academic health network, a regional health integration network, the

entire province) could be formally clarified through a mixed methods approach involving

interviews or focus groups as well as survey of the general surgeons. Domains of questioning

could include the surgeon’s interpretation of best available evidence and the importance of

specific barriers to offering early cholecystectomy (e.g. competing elective clinical obligations

when on call, limited operating room time, clinical scope of practice not including laparoscopic

surgery). In addition, a respondent’s opinion could also be sought regarding the utility of specific

measures to facilitate early surgery in their practice setting. These results would provide hospital

or regional administrators valuable information on which to act to facilitate early surgery. At the

micro-level, each hospital’s general surgery division members should reassess their local practice

and be well placed to identify ways to offer early surgery to a greater number of patients.

However, a macro-level assessment may be more likely to promote a universal standard of care.

146

9.2 Knowledge translation plan

A second important future direction is the development and implementation of a

knowledge translation plan. While the preliminary knowledge translation plan detailed below

focuses on efforts in Ontario and Canada, a number of the measures described should also

support knowledge translation across other settings.

The goals of the knowledge translation efforts will be twofold: (1) to disseminate the

new research results presented in this thesis and (2) to promote a shift in practice based on the

broader body of evidence supporting early over delayed cholecystectomy. A simple succinct

message will need to be delivered: “Early cholecystectomy offers superior clinical outcomes

over delayed cholecystectomy and is cost saving for the healthcare system”. The message and

the knowledge translation strategy will be tailored to the targeted audience.

Surgeons will be the primary audience but patients, hospital administrators and Ministry

of Health officials will also be targeted. Publications in peer-reviewed journals and presentations

at scientific meetings will form the basis for engaging clinicians. A number of more specific

measures could also be undertaken. For example, the Canadian Association of General Surgeons

and American College of Surgeons supports an email-based journal club that would be an

excellent way to disseminate these research results of across North America. Another local

measure would be to prepare a research brief summarizing the results and mail it to all general

surgery division heads across the province, in order to stimulate discussion at individual

hospitals. Finally, incorporation of the results from Specific Aims 2, 3 and 4 into the next

147

revision of the Tokyo Guidelines in 2018 could help promote knowledge translation

internationally.

In order to reach patients, the media will be engaged as an effective messenger. Press

releases related to publications and communications via social media (e.g. twitter,

www.healthydebate.ca) may help engage a variety of interested members of the public, the

media as well as various members of the healthcare system.

Finally, the Ontario Ministry of Health will be targeted by engaging contacts at the

Ontario Surgical Wait Times Strategy. In face-to-face discussions, the extent of variation in care

will be emphasized as well as the clinical and economic impetus for favouring early

cholecystectomy. The very successful experience of the Wait Times Strategy staff should be

critical in effectively promoting solutions to facilitate the performance of early cholecystectomy.

9.3 Ongoing evaluation of patient outcomes and preference

Ongoing evaluation of patient outcomes will be warranted as the practice of early

cholecystectomy becomes more broadly implemented. It will also be justified if modified

approaches to cholecystectomy (e.g. single port, robotic, natural orifice) become more popular

and if indications for surgical intervention evolve. The role of early cholecystectomy in moderate

to severe cholecystitis is in fact currently being evaluated in the ongoing CHOCOLATE trial

comparing early cholecystectomy to percutaneous cholecystostomy33.

In addition to capturing traditionally reported outcomes such as conversion, surgical site

infection and bile duct injury, future studies should capture health-related quality of life. A focus

on quality of life may be particularly informative for management decisions in elderly patients in

148

whom recurrent gallstone symptoms or post-operative recovery may have a greater or more

prolonged impact on quality of life.

Regular revision every 5 years of the Tokyo Guidelines should support the synthesis and

dissemination of new data as well as the identification of areas where further research is

required.

149

References 1. Shaffer E. Gallstone disease: Epidemiology of gallbladder stone disease. Best Practice

Research Clinical Gastroenterology. 2006;20(6):981-96.

2. Stinton LM, Shaffer EA. Epidemiology of gallbladder disease: Cholelithiasis and cancer. Gut

Liver. 2012;6(2):172-187.

3. Xu Q, Tao L, Wu Q, et al. Prevalences of and risk factors for biliary stones and gallbladder

polyps in a large chinese population. HPB. 2012;14(6):373-381.

4. Everhart JE, Khare M, Hill M, Maurer KR. Prevalence and ethnic differences in gallbladder

disease in the united states. Gastroenterology. 1999;117(3):632-9.

5. Attili AF, Carulli N, Roda E, et al. Epidemiology of gallstone disease in italy: Prevalence data

of the multicenter italian study on cholelithiasis (M.I.COL.). Am J Epidemiol. 1995;141(2):158-

165.

6. Barbara L, Sama C, Labate AMM, et al. A population study on the prevalence of gallstone

disease: The sirmione study. Hepatology. 1987;7(5):913-917.

7. Tsai CJ, Leitzmann MF, Willett WC, Giovannucci EL. Statin use and the risk of

cholecystectomy in women. Gastroenterology. 2009;136(5):1593-1600.

8. Bodmer M, Brauchli YB, Krahenbuhl S, Jick SS, Meier CR. Statin use and risk of gallstone

disease followed by cholecystectomy. JAMA. 2009;302(18):2001-2007.

150

9. Erichsen R, Froslev T, Lash TL, Pedersen L, Sorensen HT. Long-term statin use and the risk

of gallstone disease: A population-based case-control study. Am J Epidemiol. 2011;173(2):162-

170.

10. Kumar V, Abbas AK, Aster JC, Robbins SL. Robbins basic pathology. 9th ed. Philadelphia,

PA: Elsevier/Saunders; 2013:909.

11. Halldestam I, Enell E-, Kullman E, Borch K. Development of symptoms and complications

in individuals with asymptomatic gallstones. Br J Surg. 2004;91(6):734-738.

12. Friedman GD. Natural history of asymptomatic and symptomatic gallstones. The American

Journal of Surgery. 1993;165(4):399-404.

13. Urbach DR, Stukel TA. Rate of elective cholecystectomy and the incidence of severe

gallstone disease. CMAJ Canadian Medical Association Journal. 2005;172(8):1015-1019.

14. Russo MW, Wei JT, Thiny MT, et al. Digestive and liver diseases statistics, 2004.

Gastroenterology. 2004;126(5):1448-1453.

15. Kimura Y, Takada T, Strasberg S, et al. TG13 current terminology, etiology, and

epidemiology of acute cholangitis and cholecystitis. J Hepatobiliary Pancreat Sci. 2013;20(1):8-

23.

16. Elwood D. Cholecystitis. Surg Clin North Am. 2008;88(6):1241-52,viii.

17. Lammert F, Miquel JF. Gallstone disease: From genes to evidence-based therapy. J Hepatol.

2008;48 Suppl 1:S124-35.

151

18. Paumgartner G, Sauerbruch T. Gallstones: Pathogenesis. The Lancet. 1991;338(8775):1117-

1121.

19. Gomi H, Solomkin JS, Takada T, et al. TG13 antimicrobial therapy for acute cholangitis and

cholecystitis. J Hepatobiliary Pancreat Sci. 2013;20(1):60-70.

20. Yokoe M, Takada T, Strasberg S, et al. TG13 diagnostic criteria and severity grading of

acute cholecystitis (with videos). J Hepatobiliary Pancreat Sci. 2013;20(1):35-46.

21. Yokoe M, Takada T, Strasberg SM, et al. New diagnostic criteria and severity assessment of

acute cholecystitis in revised tokyo guidelines. J Hepatobiliary Pancreat Sci. 2012;19(5):578-

585.

22. Strasberg SM. Clinical practice. acute calculous cholecystitis. N Engl J Med.

2008;358(26):2804-2811.

23. McGillicuddy EA, Schuster KM, Barre K, et al. Non-operative management of acute

cholecystitis in the elderly. Br J Surg. 2012;99(9):1254-1261.

24. Lee HK, Han HS, Min SK, Lee JH. Sex-based analysis of the outcome of laparoscopic

cholecystectomy for acute cholecystitis. Br J Surg. 2005;92(4):463-466.

25. Elwood DR. Cholecystitis. Surg Clin North Am. 2008;88(6):1241-1252.

26. Fagan SP, Awad SS, Rahwan K, et al. Prognostic factors for the development of gangrenous

cholecystitis. The American Journal of Surgery. 2003;186(5):481-485.

152

27. Aydin C, Altaca G, Berber I, Tekin K, Kara M, Titiz I. Prognostic parameters for the

prediction of acute gangrenous cholecystitis. J Hepatobiliary Pancreat Surg. 2006;13(2):155-

159.

28. Sauerbruch T, Paumgartner G. Gallbladder stones: Management. The Lancet.

1991;338(8775):1121-1124.

29. Bateson MC. GALLSTONE DISEASE—PRESENT AND FUTURE. The Lancet.

1986;328(8518):1265-1267.

30. Nealon WH, Urrutia F, Fleming D, Thompson JC. The economic burden of gallstone

lithotripsy. will cost determine its fate? Ann Surg. 1991;213(6):645-9; discussion 649-50.

31. Strasberg SM. Cholelithiasis and acute cholecystitis. Baillieres Clin Gastroenterol.

1997;11(4):643-661.

32. Winbladh A, Gullstrand P, Svanvik J, Sandstrom P. Systematic review of cholecystostomy as

a treatment option in acute cholecystitis. HPB (Oxford). 2009;11(3):183-193.

33. Kortram K, van Ramshorst B, Bollen TL, et al. Acute cholecystitis in high risk surgical

patients: Percutaneous cholecystostomy versus laparoscopic cholecystectomy (CHOCOLATE

trial): Study protocol for a randomized controlled trial. Trials. 2012;13:7.

34. Keus F, Gooszen HG, van Laarhoven CJ. Open, small-incision, or laparoscopic

cholecystectomy for patients with symptomatic cholecystolithiasis. an overview of cochrane

hepato-biliary group reviews. Cochrane Database Syst Rev. 2010;(1):CD008318.

doi(1):CD008318.

153

35. Richards C, Edwards J, Culver D, Emori TG, Tolson J, Gaynes R. Does using a laparoscopic

approach to cholecystectomy decrease the risk of surgical site infection? Ann Surg.

2003;237(3):358-62.

36. The Southern Surgeons Club. A prospective analysis of 1518 laparoscopic

cholecystectomies. the southern surgeons club. New England Journal of Medicine, The.

1991;324(16):1073-8.

37. Ingraham AM, Cohen ME, Ko CY, Hall BL. A current profile and assessment of north

american cholecystectomy: Results from the american college of surgeons national surgical

quality improvement program. J Am Coll Surg. 2010;211(2):176-186.

38. Mangram AJ, Horan TC, Pearson ML, Silver LC, Jarvis WR, The Hospital Infection Control

Practices Advisory Committee. Guideline for prevention of surgical site infection. Infect Control

and Hosp Epidemiol. 1999;20:247-278.

39. Strasberg SM, Hertl M, Soper NJ. An analysis of the problem of biliary injury during

laparoscopic cholecystectomy. J Am Coll Surg. 1995;180(1):101-125.

40. Connor S, Garden OJ. Bile duct injury in the era of laparoscopic cholecystectomy. Br J Surg.

2006;93(2):158-168.

41. Flum DR, Dellinger EP, Cheadle A, Chan L, Koepsell T. Intraoperative cholangiography and

risk of common bile duct injury during cholecystectomy. JAMA. 2003;289(13):1639-1644.

42. Tornqvist B, Stromberg C, Persson G, Nilsson M. Effect of intended intraoperative

cholangiography and early detection of bile duct injury on survival after cholecystectomy:

Population based cohort study. BMJ. 2012;345:e6457.

154

43. Berney CR. Major common bile duct injury and risk of litigation: A surgeon's perspective.

Am J Surg. 2012;204(5):800-802.

44. Barkun AN, Rezieg M, Mehta SN, et al. Postcholecystectomy biliary leaks in the

laparoscopic era: Risk factors, presentation, and management. Gastrointest Endosc.

1997;45(3):277-282.

45. Eisenstein S, Greenstein AJ, Kim U,Divino CM. Cystic duct stump leaks: After the learning

curve. Archives of Surgery. 2008;143(12):1178-1183.

46. Gurusamy KS, Samraj K. Early versus delayed laparoscopic cholecystectomy for acute

cholecystitis. Cochrane Database of Systematic Reviews. 2006(4):005440.

47. Giger U, Ouaissi M, Schmitz SF, Krahenbuhl S, Krahenbuhl L. Bile duct injury and use of

cholangiography during laparoscopic cholecystectomy. Br J Surg. 2011;98(3):391-396.

48. Enochsson L, Thulin A, Österberg J, Sandblom G,Persson G. The swedish registry of

gallstone surgery and endoscopic retrograde cholangiopancreatography (gallriks): A nationwide

registry for quality assurance of gallstone surgery. JAMA Surgery. 2013:1-8.

49. Yamashita Y, Takada T, Strasberg S, et al. TG13 surgical management of acute cholecystitis.

J Hepatobiliary Pancreat Sci. 2013;20(1):89-96.

50. Strasberg SM, Gouma DJ. 'Extreme' vasculobiliary injuries: Association with fundus-down

cholecystectomy in severely inflamed gallbladders. HPB. 2012;14(1):1-8.

51. Strasberg SM, Helton WS. An analytical review of vasculobiliary injury in laparoscopic and

open cholecystectomy. HPB (Oxford). 2011;13(1):1-14.

155

52. Banz V, Gsponer T, Candinas D, Guller U. Population-based analysis of 4113 patients with

acute cholecystitis: Defining the optimal time-point for laparoscopic cholecystectomy. Ann Surg.

2011;254(6):964-970.

53. Giger U, Michel J, Opitz I, Inderbitzin D, Kocher T, Krhenbhl L. Risk factors for

perioperative complications in patients undergoing laparoscopic cholecystectomy: Analysis of

22,953 consecutive cases from the swiss association of laparoscopic and thoracoscopic surgery

database. J Am Coll Surg. 2006;203(5):723-8.

54. Kum CK, Eypasch E, Lefering R, Paul A, Neugebauer E, Troidl H. Laparoscopic

cholecystectomy for acute cholecystitis: Is it really safe?. World J Surg. 1996;20(1):43-48.

55. Jacobs M, Verdeja JC, Goldstein HS. Laparoscopic cholecystectomy in acute cholecystitis. J

Laparoendosc Surg. 1991;1(3):175-7.

56. Flowers JL, Bailey RW, Scovill WA, Zucker KA. The baltimore experience with

laparoscopic management of acute cholecystitis. The American journal of surgery.

1991;161(3):388-92.

57. Kiviluoto T, Siren J, Luukkonen P, Kivilaakso E. Randomised trial of laparoscopic versus

open cholecystectomy for acute and gangrenous cholecystitis. Lancet. 1998;351(9099):321-325.

58. Giger UF. Michel JM. Opitz I. Th Inderbitzin D. Kocher T. Krahenbuhl L. Swiss Association

of Laparoscopic and Thoracoscopic Surgery (SALTS) Study Group. Risk factors for

perioperative complications in patients undergoing laparoscopic cholecystectomy: Analysis of

22,953 consecutive cases from the swiss association of laparoscopic and thoracoscopic surgery

database. J Am Coll Surg. 2006;203(5):723-728.

156

59. Papi C, Catarci M, D'Ambrosio L, et al. Timing of cholecystectomy for acute calculous

cholecystitis: A meta-analysis. Am J Gastroenterol. 2004;99(1):147-155.

60. Gurusamy K, Samraj K, Gluud C, Wilson E, Davidson BR. Meta-analysis of randomized

controlled trials on the safety and effectiveness of early versus delayed laparoscopic


61. Jrvinen HJ, Hstbacka J. Early cholecystectomy for acute cholecystitis: A prospective

randomized study. Ann Surg. 1980;191(4):501-5.

62. Norrby S, Herlin P, Holmin T, Sjdahl R, Tagesson C. Early or delayed cholecystectomy in

acute cholecystitis? A clinical trial. Br J Surg. 1983;70(3):163-5.

63. Lo CM, Liu CL, Fan ST, Lai EC, Wong J. Prospective randomized study of early versus

delayed laparoscopic cholecystectomy for acute cholecystitis. Ann Surg. 1998;227(4):461-467.

64. Lai PB, Kwong KH, Leung KL, et al. Randomized trial of early versus delayed laparoscopic


65. Johansson M, Thune A, Blomqvist A, Nelvin L, Lundell L. Management of acute

cholecystitis in the laparoscopic era: Results of a prospective, randomized clinical trial. Journal

of Gastrointestinal Surgery. 2003;7(5):642-645.

66. Kolla SB, Aggarwal S, Kumar A, et al. Early versus delayed laparoscopic cholecystectomy

for acute cholecystitis: A prospective randomized trial. Surg Endosc. 2004;18(9):1323-7.

67. Davila D, Manzanares C, Picho ML, Albors P, Cardenas F, Fuster E. <br />Experience in the

treatment (earlyvs. delayed) of acute cholecystitis via laparoscopy. Cirugıa Espanola.

1999;66(233).

157

68. Peng WK, Sheikh Z, Nixon SJ, Paterson-Brown S. Role of laparoscopic cholecystectomy in

the early management of acute gallbladder disease. Br J Surg. 2005;92(5):586-91.

69. Riall TS, Zhang D, Townsend CM,Jr, Kuo YF, Goodwin JS. Failure to perform

cholecystectomy for acute cholecystitis in elderly patients is associated with increased morbidity,

mortality, and cost. J Am Coll Surg. 2010;210(5):668-677.

70. Stevens KA, Chi A, Lucas LC, Porter JM, Williams MD. Immediate laparoscopic

cholecystectomy for acute cholecystitis: No need to wait. Am J Surg. 2006;192(6):756-761.

71. Gurusamy K, Samraj K, Gluud C, Wilson E, Davidson BR. Meta-analysis of randomized

controlled trials on the safety and effectiveness of early versus delayed laparoscopic


72. Drummond MF, Drummond MF. Methods for the economic evaluation of health care

programmes. 3rd ed. Oxford ; New York: Oxford University Press; 2005:379.

73. Wilson E, Gurusamy K, Gluud C, Davidson BR. Cost-utility and value-of-information

analysis of early versus delayed laparoscopic cholecystectomy for acute cholecystitis. Br J Surg.

2010;97(2):210-9.

74. Johner A, Raymakers A, Wiseman SM. Cost utility of early versus delayed laparoscopic

cholecystectomy for acute cholecystitis. Surg Endosc. 2013;27(1):256-262.

75. Macafee DAL, Humes DJ, Bouliotis G, Beckingham IJ, Whynes DK, Lobo DN. Prospective

randomized trial using cost-utility analysis of early versus delayed laparoscopic cholecystectomy

for acute gallbladder disease. Br J Surg. 2009;96(9):1031-40.

158

76. Society of American Gastrointestinal and Endoscopic Surgeons. SAGES guidelines for the

clinical application of laparoscopic biliary tract surgery. http://www.sages.org/publication/id/06/.

Updated 2010.

77. Yamashita Y, Takada T, Hirata K. A survey of the timing and approach to the surgical

management of patients with acute cholecystitis in japanese hospitals. J Hepatobiliary Pancreat

Surg. 2006;13(5):409-415.

78. Cameron IC, Chadwick C, Phillips J, Johnson AG. Management of acute cholecystitis in UK

hospitals: Time for a change. Postgrad Med J. 2004;80(943):292-4.

79. Askew J. A survey of the current surgical treatment of gallstones in queensland. ANZ J Surg.

2005;75(12):1086-9.

80. Sekimoto M, Imanaka Y, Hirose M, Ishizaki T, Murakami G, Fukata Y. Impact of treatment

policies on patient outcomes and resource utilization in acute cholecystitis in japanese hospitals.

BMC health services research. 2006;6:40-40.

81. Lee SW, Yang SS, Chang CS, Yeh HJ. Impact of the tokyo guidelines on the management of

patients with acute calculous cholecystitis. Journal of Gastroenterology & Hepatology.

2009;24(12):1857-1861.

82. Casillas RA, Yegiyants S, Collins JC. Early laparoscopic cholecystectomy is the preferred

management of acute cholecystitis. Arch Surg. 2008;143(6):533-537.

83. Greenstein AJ, Moskowitz A, Gelijns AC, Egorova NN. Payer status and treatment paradigm

for acute cholecystitis. Archives of Surgery. 2012;147(5):453-458.

159

84. Strasberg S. Clinical practice. acute calculous cholecystitis. New England Journal of

Medicine, The. 2008;358(26):2804-11.

85. Skouras C, Jarral O, Deshpande R, Zografos G, Habib N, Zacharakis E. Is early laparoscopic

cholecystectomy for acute cholecystitis preferable to delayed surgery?: Best evidence topic

(BET). International Journal Of Surgery. 2012;10(5):250-258.

86. Gananadha S, Fergusson J. Moderate acute cholecystitis: To cut now or to cut later. Journal

of Gastroenterology & Hepatology. 2009;24(12):1806-1807.

87. Statistics Canada. CANSIM table 051-0001 population by year, by province and territory.

http://www.statcan.gc.ca/tables-tableaux/sum-som/l01/cst01/demo02a-eng.htm. Updated 2013.

88. Greenstein AJ, Moskowitz A, Gelijns AC, Egorova NN. Payer status and treatment paradigm

for acute cholecystitis. Arch Surg. 2012.

89. David GG, Al-Sarira AA, Willmott S, Deakin M, Corless DJ, Slavin JP. Management of

acute gallbladder disease in england. Br J Surg. 2008;95(4):472-476.

90. Canadian Institute for Health Information. Quality assurance processes applied to the

discharge abstract and hospital morbidity databases. ottawa: Canadian institute for health

information. . 2007.

91. Austin PC, Daly PA, Tu JV. A multicenter study of the coding accuracy of hospital discharge

administrative data for patients admitted to cardiac care units in ontario. Am Heart J.

2002;144(2):290-296.

160

92. Gershon AS, Wang C, Guan J, Vasilevska-Ristovska J, Cicutto L, To T. Identifying

individuals with physcian diagnosed COPD in health administrative databases. COPD.

2009;6(5):388-394.

93. Tu K, Chen Z, Lipscombe LL, Canadian Hypertension Education Program Outcomes

Research Taskforce. Prevalence and incidence of hypertension from 1995 to 2005: A population-

based study. CMAJ. 2008;178(11):1429-1435.

94. Hux JE, Ivis F, Flintoft V, Bica A. Diabetes in ontario: Determination of prevalence and

incidence using a validated administrative data algorithm. Diabetes Care. 2002;25(3):512-516.

95. Antoniou T, Zagorski B, Loutfy MR, Strike C, Glazier RH. Validation of case-finding

algorithms derived from administrative data for identifying adults living with human

immunodeficiency virus infection. PLoS One. 2011;6(6):e21748.

96. Austin PC, Walraven C. The mortality risk score and the ADG score: Two points-based

scoring systems for the johns hopkins aggregated diagnosis groups to predict mortality in a

general adult population cohort in ontario, canada. Med Care. 2011;49(10):940-947.

97. Austin PC, van Walraven C, Wodchis WP, Newman A, Anderson GM. Using the johns

hopkins aggregated diagnosis groups (ADGs) to predict mortality in a general adult population

cohort in ontario, canada. Med Care. 2011;49(10):932-939.

98. Juurlink D, Preyra C, Croxford R, et al. Canadian institute for health information discharge

abstract database: A validation study. Toronto: Institute for Clinical Evaluative Sciences. 2006.

99. Jacobs P, Yim R. Using canadian administrative databases to derive economic data for health

technology assessments. Ottawa: Canadian agency for drugs and technologies in health. . 2009.

161

100. Wodchis WP, Bushmeneva K, Nikitovic,M., McKillop,I. Guidelines on person-level costing

using administrative databases in ontario. toronto: Health system performance research network.

. 2011.

101. Ontario Ministry of Health and Long Term Care. Schedule of benefits – physician services

under the health insurance act. . September 1, 2011.

102. Kleinbaum DG, Klein M, Pryor ER. Logistic regression. . 2010:701.

103. Austin PC, Goel V, van Walraven C. An introduction to multilevel regression models. Can

J Public Health. 2001;92(2):150-154.

104. Austin PC, Tu JV, Alter DA. Comparing hierarchical modeling with traditional logistic

regression analysis among patients hospitalized with acute myocardial infarction: Should we be

analyzing cardiovascular outcomes data differently? Am Heart J. 2003;145(1):27-35.

105. Kleinbaum DG, Klein M. Survival analysis. . 2005:590.

106. Southern DA, Faris PD, Brant R, et al. Kaplan-meier methods yielded misleading results in

competing risk scenarios. J Clin Epidemiol. 2006;59(10):1110-1114.

107. Satagopan JM, Ben-Porat L, Berwick M, Robson M, Kutler D, Auerbach AD. A note on

competing risks in survival data analysis. Br J Cancer. 2004;91(7):1229-1235.

108. Tai B, Machin D, White I, Gebski V. Competing risks analysis of patients with

osteosarcoma: A comparison of four different approaches. Statist Med. 2001;20(5):661-684.

109. ROSENBAUM PR, RUBIN DB. The central role of the propensity score in observational

studies for causal effects. Biometrika. 1983;70(1):41-55.

162

110. Austin PC. An introduction to propensity-score methods for reducing confounding in

observational studies. Multivariate Behav Res. 2011;46:399-424.

111. Austin PC. The performance of different propensity-score methods for estimating

differences in proportions (risk differences or absolute risk reductions) in observational studies.

Stat Med. 2010;29(20):2137-2148.

112. Caro J, Briggs A, Siebert U, Kuntz K. Modeling good research Practices—Overview: A

report of the ISPOR-SMDM modeling good research practices task Force–1. Medical Decision

Making. 2012;32(5):667-677.

113. Williams JG, Roberts SE, Ali MF, et al. Gastroenterology services in the UK. the burden of

disease, and the organisation and delivery of services for gastrointestinal and liver disorders: A

review of the evidence. Gut. 2007;56(Suppl 1):1-113.

114. Germanos S, Gourgiotis S, Kocher HM. Clinical update: Early surgery for acute

cholecystitis. The Lancet. 2007;369(9575):1774-1776.

115. Wilkins R. Use of postal codes and addresses in the analysis of health data. Health Rep.

1993;5(2):157-177.

116. Johns Hopkins University. Johns hopkins ACG case-mix adjustment system.

http://www.acg.jhsph.edu.

117. Ontario Ministry of Health and Long Term Care. Classification of hospitals.

http://www.health.gov.on.ca/english/public/contact/hosp/group_a.html. Updated 2009.

118. Spiegelhalter DJ. Funnel plots for comparing institutional performance. Stat Med.

2005;24(8):1185-1202.

163

119. Mittlbock M, Schemper M. Explained variation for logistic regression. Stat Med.

1996;15(19):1987-1997.

120. Mittlbock M, Heinzl H. A note on R2 measures for poisson and logistic regression models

when both models are applicable. J Clin Epidemiol. 2001;54(1):99-103.

121. Larsen K, Merlo J. Appropriate assessment of neighborhood effects on individual health:

Integrating random and fixed effects in multilevel logistic regression. Am J Epidemiol.

2005;161(1):81-88.

122. Campbell EJ, Montgomery DA, Mackay CJ. A national survey of current surgical treatment

of acute gallstone disease. Surg Laparosc Endosc Percutan Tech. 2008;18(3):242-247.

123. Hoyt DB. Looking forward. Bulletin of the American College of Surgeons. 2011;96:6.

124. Royal College of Surgeons of England. Separating emergency and elective surgical care:

Recommendations for practice. http://www.rcseng.ac.uk/. Updated 2007.

125. Lau B, Difronzo LA. An acute care surgery model improves timeliness of care and reduces

hospital stay for patients with acute cholecystitis. Am Surg. 2011;77(10):1318-1321.

126. Agrawal S, Battula N, Barraclough L, Durkin D, Cheruvu CV. Early laparoscopic

cholecystectomy service provision is feasible and safe in the current UK national health service.

Ann R Coll Surg Engl. 2009;91(8):660-664.

127. Simpson DJ, Wood AM, Paterson HM, Nixon SJ, Paterson-Brown S. Improved

management of acute gallstone disease after regional surgical subspecialization. World J Surg.

2008;32(12):2690-2694.

164

128. Lehane CW, Jootun RN, Bennett M, Wong S, Truskett P. Does an acute care surgical model

improve the management and outcome of acute cholecystitis? ANZ J Surg. 2010;80(6):438-442.

129. Britt RC, Bouchard C, Weireter LJ, Britt LD. Impact of acute care surgery on biliary

disease. J Am Coll Surg. 2010;210(5):595-9, 599-601.

130. Lo CM, Liu CL, Fan ST, Lai EC, Wong J. Prospective randomized study of early versus

delayed laparoscopic cholecystectomy for acute cholecystitis. Ann Surg. 1998;227(4):461-7.

131. Lai PB, Kwong KH, Leung KL, et al. Randomized trial of early versus delayed laparoscopic


132. de Mestral C, Rotstein OD, Laupacis A, Hoch JS, Zagorski B, Nathens AB. A population-

based analysis of the clinical course of 10,304 patients with acute cholecystitis, discharged

without cholecystectomy. J Trauma Acute Care Surg. 2013;74(1):26-30; discussion 30-1.

133. Durrleman S, Simon R. Flexible regression models with cubic splines. Stat Med.

1989;8(5):551-561.

134. Austin PC. Optimal caliper widths for propensity-score matching when estimating

differences in means and differences in proportions in observational studies. Pharm Stat.

2011;10(2):150-161.

135. Flury BK, Riedwyl H. Standard distance in univariate and multivariate analysis. The

American Statistician. 1986;40(3):249-251.

136. Austin PC. Balance diagnostics for comparing the distribution of baseline covariates

between treatment groups in propensity-score matched samples. Stat Med. 2009;28(25):3083-

3107.

165

137. Agresti A, Min Y. Effects and non-effects of paired identical observations in comparing

proportions with binary matched-pairs data. Statist Med. 2004;23(1):65-75.

138. Lunceford JK, Davidian M. Stratification and weighting via the propensity score in

estimation of causal treatment effects: A comparative study. Statist Med. 2004;23(19):2937-

2960.

139. de Mestral C, Laupacis A, Rotstein OD, et al. Early cholecystectomy for acute cholecystitis:

A population-based analysis fo variation in practice. CMAJOpen. 2013;In press.

140. Lee SW, Yang SS, Chang CS, Yeh HJ. Impact of the tokyo guidelines on the management

of patients with acute calculous cholecystitis. J Gastroenterol Hepatol. 2009;24(12):1857-1861.

141. Ramsey SD, Berry K, Etzioni R, et al. Cost effectiveness of lung-volume-reduction surgery

for patients with severe emphysema. N Engl J Med. 2003;348(21):2092-2102.

142. Constantinides VA, Heriot A, Remzi F, et al. Operative strategies for diverticular

peritonitis: A decision analysis between primary resection and anastomosis versus hartmann's

procedures. Ann Surg. 2007;245(1):94-103.

143. Carradice D, Mekako AI, Mazari FA, Samuel N, Hatfield J, Chetter IC. Randomized

clinical trial of endovenous laser ablation compared with conventional surgery for great

saphenous varicose veins. Br J Surg. 2011;98(4):501-510.

144. Statistics Canada. CANSIM Table 326-0021 consumer price index.

http://www.statcan.gc.ca/start-debut-eng.html. Updated 2013.

166

145. Canadian Agency for Drug and Technologies in Health. Guidelines for the economic

evaluation of health technologies. ottawa: Canadian agency for drugs and technologies in health.

. 2006.

146. Center for the Evaluation of Value and Risk in Health, Tufts University. The cost-

effectiveness analysis registry. www.tufts-nemc.org/cearegistry.

147. Bass EB, Steinberg EP, Pitt HA, et al. Comparison of the rating scale and the standard

gamble in measuring patient preferences for outcomes of gallstone disease. Medical Decision

Making. 1994;14(4):307-314.

148. Briggs AH, Claxton K, Sculpher MJ. Decision modelling for health economic evaluation.

Oxford: Oxford University Press; 2006:237.

149. National Institute for Clinical Excellence. Guidance for manufacturers and sponsors.

national institute for clinical excellence. . 2001.

150. Weinstein MC, Siegel JE, Gold MR, Kamlet MS,Russell LB. REcommendations of the

panel on cost-effectiveness in health and medicine. JAMA. 1996;276(15):1253-1258.

151. World Health Organization. Choosing interventions that are cost effective.

http://www.who.int/choice/costs/CER_levels/en/index.html.

152. Statistics Canada. CANSIM table 384-0038 gross domestic product, expenditure-based .

http://www.statcan.gc.ca/start-debut-eng.html. Updated 2013.

153. Fenwick E, Claxton K, Sculpher M. Representing uncertainty: The role of cost-

effectiveness acceptability curves. Health Econ. 2001;10(8):779-787.

167

154. Gregor JC, Ponich TP, Detsky AS. Should ERCP be routine after an episode of ''idiopathic''

pancreatitis? A cost-utility analysis. Gastrointest Endosc. 1996;44(2):118-123.

155. Arseneau KO, Cohn SM, Cominelli F, Connors AF. Cost-utility of initial medical

management for crohn's disease perianal fistulae. Gastroenterology. 2001;120(7):1640-1656.

156. van Baal MC, Besselink MG, Bakker OJ, et al. Timing of cholecystectomy after mild

biliary pancreatitis: A systematic review. Ann Surg. 2012;255(5):860-866.

157. Falor AE, de Virgilio C, Stabile BE, et al. Early laparoscopic cholecystectomy for mild

gallstone pancreatitis: Time for a paradigm shift. Arch Surg. 2012;147(11):1031-1035.

158. Bouwense SA, Besselink MG, van Brunschot S, et al. Pancreatitis of biliary origin, optimal

timing of cholecystectomy (PONCHO trial): Study protocol for a randomized controlled trial.

Trials. 2012;13:225-6215-13-225.

Early Versus Delayed Cholecystectomy for Acute Calculous Cholecystitis

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