John M. Inadomi

Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document

bacterial peritonitis (SBP) is a fre- quent and severe complication of cirrhotic patients with ascites. Much information regarding SBP has ap- peared during recent years, particularly on aspects in- volving the management of this complication. There- fore, the International Ascites Club (IAC) com- missioned a panel of experts to prepare a consensus on the diagnosis, therapy and prophylaxis of SBI? A draft consensus document, drawn up by the panel members, was presented and discussed at the regular Meeting of the IAC held during the 33rd Annual Meeting of the European Association for the Study of the Liver, in Lisbon in April 1998, after which a final consensus was reached. This article represents the final consensus document and is divided into three separate sections concerning the diagnosis, treatment and prophylaxis of SBI? Speci- fic recommendations are formulated and each recom- mendation is rated on the basis of strength and quality according to guidelines from the Practice Guidelines Committee of the American Association for the Study of Liver Diseases, with some modifications (1). The rating system is summarized in Table 1.

National Institutes of Health consensus development conference statement: management of hepatitis B.

National Institutes of Health (NIH) consensus and stateof-the-science statements are prepared by independent panels of health professionals and public representatives on the basis of 1) the results of a systematic literature review prepared under contract with the Agency for Healthcare Research and Quality (AHRQ); 2) presentations by investigators working in areas relevant to the conference questions during a 2-day public session; 3) questions and statements from conference attendees during open discussion periods that are part of the public session; and 4) closed deliberations by the panel during the remainder of the second day and morning of the third. This statement is an independent report of the panel and is not a policy statement of the National Institutes of Health or the U.S. government. The statement reflects the panel’s assessment of medical knowledge available at the time the statement was written. Thus, it provides a “snapshot in time” of the state of knowledge on the conference topic. When reading the statement, keep in mind that new knowledge is inevitably accumulating through medical research. Hepatitis B is a major cause of liver disease worldwide, ranking as a substantial cause of cirrhosis and hepatocellular carcinoma. The development and use of a vaccine for hepatitis B virus (HBV) has resulted in a substantial decline in the number of new cases of acute hepatitis B among children, adolescents, and adults in the United States. However, this success has not yet been duplicated worldwide, and both acute and chronic HBV infection continue to represent important global health problems. Seven treatments are currently approved for adult patients with chronic HBV infection in the United States: interferon-, pegylated interferon-, lamivudine, adefovir dipivoxil, entecavir, telbivudine, and tenofovir disoproxil fumarate. Interferon- and lamivudine have been approved for children with HBV infection. Although available randomized, controlled trials (RCTs) show encouraging short-term results— demonstrating the favorable effect of these agents on such intermediate markers of disease as HBV DNA level, liver enzyme tests, and liver histology— limited rigorous evidence exists demonstrating the effect of these therapies on important long-term clinical outcomes, such as the development of hepatocellular carcinoma or a reduction in deaths. Questions therefore remain about which groups of patients benefit from therapy and at which point in the course of disease this therapy should be initiated.

Cost-effectiveness of Colonoscopy in Screening for colorectal cancer

With its high incidence and mortality, colorectal cancer constitutes a public health burden in most industrialized countries. In the United States, colorectal cancer is the second leading cause of death among cancers from all sites, exceeded only by lung cancer (1). Because of its high prevalence, its long asymptomatic phase, and the presence of a treatable precancerous lesion, colorectal cancer ideally meets the criteria for screening. Fecal occult blood testing and colonoscopy represent the extremes of a wide spectrum of potential screening strategies. The first method is characterized by simplicity and low price, the second by efficacy and thoroughness. Previous studies of the cost-effectiveness of colorectal cancer screening have shown colonoscopy, flexible sigmoidoscopy, and fecal occult blood testing to be cost-effective screening alternatives (2-7). Since the publication of these analyses, new studies have become available to assess the protective influence of endoscopic procedures against future development of colorectal cancer (8-11). The cost structure for reimbursement of gastrointestinal procedures has undergone several changes. The guidelines for screening have been revised to recommend colonoscopy every 10 years instead of 5 years (7). We sought to take these recent changes into account and reassess the cost-effectiveness of screening programs for colorectal cancer based on fecal occult blood testing, flexible sigmoidoscopy, or colonoscopy as the primary screening method. In contrast to most previous studies, our decision analysis tests the influence of different compliance rates with the three screening methods. Fecal occult blood testing, flexible sigmoidoscopy, and colonoscopy are compared with respect to the number of prevented cases of colorectal cancer and the costs spent per 1 life-year saved from cancer-related mortality. Methods General Assumptions of the Markov Model The cost-effectiveness of fecal occult blood testing, flexible sigmoidoscopy, and colonoscopy were compared by using computer models based on a Markov process (12). Medical events are modeled as transitions of patients among a predefined set of health states; the occurrence of each transition is governed by a probability value (Appendix Figure). The time frame of the analysis is divided into equal increments of 1 year, during which patients may cycle from one state to another. Only the gray and black ovals of the Appendix Figure show states in the true sense of a Markov process, because patients remain in these states for at least a full 1-year cycle. The white ovals represent the intermediate states of screening procedures. Patients can enter and leave these intermediate states during one cycle before settling in a true Markov state. In the first model of screening by fecal occult blood testing, the initial population comprises 100 000 patients 50 years of age who are offered the test. Depending on the initial compliance rate and the outcome of the test (positive or negative), patients then undergo colonoscopy or enter the pool of patients waiting for their next fecal occult blood test in 1 years time. In the case of normal results on colonoscopy (no adenomatous polyp), annual fecal occult blood testing is resumed 10 years after colonoscopy. If an adenomatous polyp is found, surveillance colonoscopy is repeated every 3 years until adenomatous polyps are no longer found. Patients with a positive result on fecal occult blood testing who decline colonoscopy or those who decline to have repeated fecal occult blood testing after 1 year enter the state of noncompliance. Patients in any Markov state can develop colorectal cancer; the probability stems from the age-specific incidence rate. The likelihood of developing cancer is reduced in patients after colonoscopy plus polypectomy, depending on the rate of preventive efficacy assigned to the procedure. The length of time for which colonoscopy plus polypectomy protects against colorectal cancer is equal to the screening interval. In addition to the states shown in the Appendix Figure, the population in each state is also subjected to natural attrition by the annual age-specific death rate of the U.S. population (13). Screening with flexible sigmoidoscopy is modeled similarly to fecal occult blood testing (Appendix Figure). The simulation is started with 100 000 patients being offered screening with flexible sigmoidoscopy. The transitions out of this intermediate state depend on whether a polyp is found during sigmoidoscopy. After normal flexible sigmoidoscopy without adenomatous polyps, patients stay in the pool waiting for the next screening sigmoidoscopy in 5 years. The remainder of the model is similar to that of fecal occult blood testing. Screening with colonoscopy is modeled by using a Markov process similar to that used for the two previous strategies, except that all states associated with a different screening test other than colonoscopy are eliminated (Appendix Figure). All three models were simulated by using Excel spreadsheets (Microsoft Corp., Redmond, Washington). Transition Probabilities The transition probabilities built into the model and the ranges tested in the sensitivity analyses are shown in the Appendix Table. Most large prospective trials of fecal occult blood testing used nonrehydrated slides. The sensitivity and specificity of testing for colorectal cancer varied from 30% to 50% and 90% to 99%, respectively (14, 15, 24-28). Estimates of 40% and 97.5% for the two parameters are supported by data from a recent large prospective trial comprising more than 8000 participants (15). The rate of positive results on fecal occult blood testing was calculated as the sum of true-positive and false-positive results. Screening intervals were chosen to agree with the most recent set of recommendations (7). Three types of compliance rates are built into the model; screened patients must be compliant with the initial screening procedure, each repeated screening, and colonoscopy after a positive result on fecal occult blood testing or flexible sigmoidoscopy. Under baseline conditions, all compliance rates were assumed to be 100%. In the sensitivity analysis, the rates of initial, repeated, and follow-up compliance were varied according to estimates published for the three screening methods (9, 24, 29-34). The prevalence of adenoma per 10-year age group was available from autopsy studies (16, 17). An annual incidence of 1% was calculated as the average difference between the prevalence rates of two consecutive age groups. In the sensitivity analysis, the annual incidence of adenomatous polyps was varied from 1% to 6%. The Markov model uses the polyp rate to calculate the number of polypectomies and repeated colonoscopies after polypectomy. The number of cases of cancer prevented was calculated from the age-specific incidence rates of colorectal cancer. About 45% of all polyps are within the reach of flexible sigmoidoscopy (18, 22, 35). The annual age-specific incidence rate of colorectal cancer is taken from published statistics of the Surveillance, Epidemiology, and End Results Program (36). Depending on the type of historical control group chosen, the National Polyp Study showed an efficacy of colonoscopy in reducing the incidence of colorectal cancer ranging from 76% to 90% (9). Because other studies have suggested an efficacy of only 49% to 59% (8, 10, 11), we chose a median value of 75% as the baseline rate. Effectiveness and Costs Effectiveness of screening is measured in terms of life-years saved through prevention of colorectal cancer and improved survival of earlier cancer stages. Without screening, 40% of all colorectal cancers were assumed to result in death within 5 years (36). Because detection of colorectal cancer at earlier stages improves the overall 5-year survival rate, survival after annual screening was adjusted to reduce mortality from colorectal cancer by 18% (37). The life-years lost by the age-dependent proportions of patients dying prematurely of colorectal cancer are accumulated for each cycle during the entire expected lifetime. The number of life-years saved because of screening corresponds to the difference in life-years lost from cancer-related deaths between a Markov model with and one without screening. Medical, surgical, and diagnostic services were assigned Current Procedural Terminology or diagnosis-related group codes to identify the health care resources utilized for each patient (19, 20). These codes were converted into costs for each health care resource utilization (Table 1). The costs represent the average payments allowed for each coded procedure by the U.S. Health Care Finance Administration during fiscal year 1998. The costs also include the possibility of hospitalization for bleeding or perforation after endoscopy with or without polypectomy (21, 38-43). Published cost estimates for the medical care of patients with colorectal cancer range from

Screening and surveillance for Barrett esophagus in high-risk groups: a cost-utility analysis.

25 000 to

ACG practice guidelines: Esophageal reflux testing

45 000 (4, 7, 23, 44). We used the most recent data available from a study by Lee and colleagues (44). All future costs arising from screening or care of colorectal cancer and all future life-years saved through screening are discounted at an annual rate of 3% (45). Table 1. Costs Based on Medicare Payments in 2000 Role of the Funding Sources Dr. Delcs salary was supported by a grant from the Swiss Foundation for Grants in Medicine and Biology. Drs. Inadomi and Sonnenberg were full-time employees of the Department of Veterans Affairs. The funding sources had no role in the collection, analysis, or interpretation of the data or in the decision to submit the paper for publication. Results Baseline Assumptions Table 2 shows the outcomes of modeling four programs to prevent colorectal cancer. Future life-years saved and the costs associated with various items reflect the effect of an annual discount rate of 3%. Without screening, the cohort of 50-year-old persons will experience

Consensus Statements for Management of Barrett's Dysplasia and Early-Stage Esophageal Adenocarcinoma, Based on a Delphi Process

Context Barrett esophagus, a complication of gastroesophageal reflux disease (GERD), is associated with an increased risk for esophageal cancer. Some have proposed endoscopic screening for Barrett esophagus, followed by surveillance for cancer in patients with the disorder. Contribution The authors modeled the cost-effectiveness of screening 50-year-old white men with GERD. Screening followed by surveillance in patients with Barrett esophagus and dysplasia cost

Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis

10 440 per quality-adjusted life-year (QALY). Surveillance of patients with Barrett esophagus but no dysplasia every 5 years would cost an additional

Lansoprazole treatment of patients with chronic idiopathic laryngitis: a placebo-controlled trial

596 000 per QALY. Implications One-time screening for Barrett esophagus in 50-year-old men with GERD is reasonably cost-effective if surveillance is limited. The Editors Current guidelines from the American College of Gastroenterology recommend surveillance to detect cancer and dysplasia in patients with Barrett esophagus, a columnar-cell metaplasia that replaces the native squamous-cell epithelium of the distal esophagus (1). The costs and benefits of surveillance have been evaluated in retrospective studies (2-5) and formal decision analyses (6, 7). Barrett esophagus alone does not cause symptoms that would prompt endoscopic evaluation, and the question of whether screening strategies to detect Barrett esophagus are reasonable and, if so, in which patients is unresolved (8). Adding to the uncertainty is emerging evidence from prospective studies that the incidence of cancer in patients with Barrett esophagus may be considerably lower than previously reported (9, 10). In the absence of randomized, controlled trials of screening and surveillance in Barrett esophagus, the costs and benefits of strategies to decrease mortality rates from cancer are unknown. We used decision analysis to determine whether current recommendations for screening of patients with gastroesophageal reflux disease (GERD) represent cost-effective care. The cohort that we modeled consisted of white men 50 years of age who have symptoms of GERD, because this group is at high risk on the basis of epidemiologic evidence demonstrating an increased risk for esophageal adenocarcinoma compared with other groups [11-14]. Specifically, we examined strategies for screening patients with symptoms of GERD for the presence of Barrett esophagus, dysplasia, or cancer and compared these strategies with no screening for Barrett esophagus. Secondary objectives were 1) to determine whether more benefit was provided by the initial screening examination or by subsequent surveillance, 2) to evaluate different intervals of surveillance in patients with Barrett esophagus, and 3) to identify clinical variables critical to the determination of cost-effectiveness. Methods Patients The hypothetical cohort consisted of white men 50 years of age who had symptoms consistent with GERD (heartburn or acid regurgitation). These patients were assumed not to have symptoms or signs that would otherwise prompt endoscopic evaluation (dysphagia, anemia, weight loss, or bleeding) and had not been previously screened for Barrett esophagus. The analysis assumed that Barrett esophagus was defined by salmon-colored mucosa of any length at endoscopy and intestinal metaplasia on histologic examination. Intestinal metaplasia of the gastroesophageal junction in the absence of endoscopic identification of Barrett esophagus was not examined. It was assumed that all patients modeled for participation in screening and surveillance would be surgical candidates for esophagectomy and would consent to undergo this operation if esophageal cancer was diagnosed. The analysis followed the cohort until 80 years of age or death. Model A decision analysis model was created by using DATA 4.0 software (TreeAge, Williamstown, Massachusetts). A Markov model was used to analyze patients with symptomatic GERD (15, 16). Figure 1 shows a simplified outline of the structure of the Markov model. The actual model contains more than 7000 nodes (branch points) that encompass the natural history of patients with GERD compared to strategies of screening and surveillance for Barrett esophagus, dysplasia, and cancer. (The Appendix provides further information on model assumptions, including structure, transitions, utilities, and sensitivity analysis.) Figure 1. Markov model. Natural History Costs and quality-adjusted life-years (QALYs) without screening and surveillance for Barrett esophagus and adenocarcinoma of the esophagus were examined. Cancer would be diagnosed only if symptoms (dysphagia, weight loss, bleeding, or pain) prompted endoscopic evaluation. Depending on the stage of cancer at the time of diagnosis, palliation (esophageal stent or chemoradiation) or surgical resection could be attempted. Patients with unresectable disease accrued costs of hospice or palliative care. Patients in whom resection was attempted could die after the procedure or survive. Patients who survived surgery could be cured of cancer or experience persistent or recurrent cancer, rates of which depended on the stage of cancer at diagnosis. Death from causes other than adenocarcinoma of the esophagus was incorporated in an age-dependent manner. Screening and Surveillance The natural history analysis was compared to screening with two surveillance strategies. Both strategies used screening endoscopy at 50 years of age and biopsy done to confirm Barrett esophagus if abnormalities were seen at endoscopy. Identification of adenocarcinoma by the initial screening examination prompted esophagectomy or palliation, depending on the stage of tumor. Palliation was associated with costs of endoscopic stenting or chemotherapy and radiation. Surgery could result in perisurgical death, persistent or recurrent cancer, or cure. The first strategy limited surveillance to patients with Barrett esophagus with dysplasia at the initial examination. White men with symptoms of GERD would undergo screening endoscopy at 50 years of age; if Barrett esophagus without dysplasia or no Barrett esophagus was diagnosed, further surveillance would not be performed. Patients with Barrett esophagus with dysplasia would undergo surveillance endoscopy every 6 months for low-grade dysplasia or every 3 months for high-grade dysplasia as long as dysplasia was noted at least once during the preceding 12 months. Detection of cancer would prompt esophagectomy or palliation, depending on stage of disease at diagnosis. The second strategy also evaluated screening of white men with symptoms of GERD at 50 years of age. Patients with Barrett esophagus with dysplasia underwent surveillance as in the first strategy; however, those with Barrett esophagus without dysplasia were separately modeled to undergo surveillance endoscopy at intervals of 2, 3, 4, or 5 years. If intestinal metaplasia was not found on two consecutive surveillance endoscopies, surveillance ceased. Cancer was managed as in the first strategy. Endoscopy and biopsy was modeled to be an imperfect test: that is, false-positive and false-negative results would occur, thereby missing some cases of dysplasia or cancer and overdiagnosing other states. Procedure-related morbidity and mortality for surgery and endoscopy were included in the analysis. Adjustment for patient preferences for the various health states (utilities) was incorporated into the model. Differential rates of cure from cancer were assigned depending on the stage at diagnosis. Death from causes other than adenocarcinoma of the esophagus was incorporated in an age-dependent manner. All costs and benefits were discounted at 3% annually (0% to 5% annually in the sensitivity analysis). Transitions Transitions between health states of the Markov model were derived from the published literature. To assess key variables, the MEDLINE and EMBASE databases from 1970 to 2001 and abstracts from major gastroenterological scientific meetings from 1999 to 2001 were searched by using the terms Barretts esophagus, esophageal neoplasms, adenocarcinoma, precancerous conditions, and gastroesophageal reflux disease. If no data existed for a specified transition, the authors reached consensus. In addition to the base-case scenario, sensitivity analyses were performed using variations around each of the transitions supported by the literature (Table 1). Table 1. Model Assumptions Costs and Utilities Costs, not charges, were the basis for inputs used in this analysis. Costs included direct costs of care for delivery of services and were derived from published literature and 2001 data from the Health Care Financing Administration. Data on inpatient resource use from the Health Care Financing Administration were based on diagnosis-related groups and Current Procedural Terminology codes, whereas outpatient data were based on ambulatory payment classification and Current Procedural Terminology codes. Costs of endoscopy included biopsies and histologic interpretation. Costs are shown in Table 1. A third-party insurer perspective was taken (58-60). Patient preferences for different health states (utilities) were derived from the published literature, and outcomes were adjusted to derive QALYs (6, 7). Utilities were derived from expert opinion by using a time-tradeoff technique (7) and from responses by patients who had undergone esophagectomy for high-grade dysplasia or cancer (6). Costs of time lost from work and support required from family or friends and intangible losses due to pain and suffering were not incorporated. Sensitivity Analysis All assumptions for the model were varied over a wide range of values in a series of one-way sensitivity analyses. Published rates from the literature were used if available. In the absence of published data, baseline rates were halved and doubled with adjustment by consensus from the authors. Monte Carlo simulation was used to create a multi-way sensitivity analysis. Surgery for High-Grade Dysplasia In the base-case strategy, the diagnosis

A Cost-Utility Analysis of Ablative Therapy for Barrett's Esophagus

Investigations and technical advances have enhanced our understanding and management of gastroesophageal reflux disease. The recognition of the prevalence and importance of patients with endoscopy-negative reflux disease as well as those refractory to proton pump inhibitor therapy have led to an increasing need for objective tests of esophageal reflux. Guidelines for esophageal reflux testing are developed under the auspices of the American College of Gastroenterology and its Practice Parameters Committee and approved by the Board of Trustees. Issues regarding the utilization of conventional, catheter-based pH monitoring are discussed. Improvements in the interpretation of esophageal pH recordings through the use of symptom-reflux association analyses as well as limitations gleaned from recent studies are reviewed. The clinical utility of pH recordings in the proximal esophagus and stomach is examined. Newly introduced techniques of duodenogastroesophageal reflux, wireless pH capsule monitoring and esophageal impedance testing are assessed and put into the context of traditional methodology. Finally, recommendations on the clinical applications of esophageal reflux testing are presented.

Projections of demand and capacity for colonoscopy related to increasing rates of colorectal cancer screening in the United States.

BACKGROUND & AIMS Esophageal adenocarcinoma (EA) is increasingly common among patients with Barretts esophagus (BE). We aimed to provide consensus recommendations based on the medical literature that clinicians could use to manage patients with BE and low-grade dysplasia, high-grade dysplasia (HGD), or early-stage EA. METHODS We performed an international, multidisciplinary, systematic, evidence-based review of different management strategies for patients with BE and dysplasia or early-stage EA. We used a Delphi process to develop consensus statements. The results of literature searches were screened using a unique, interactive, Web-based data-sifting platform; we used 11,904 papers to inform the choice of statements selected. An a priori threshold of 80% agreement was used to establish consensus for each statement. RESULTS Eighty-one of the 91 statements achieved consensus despite generally low quality of evidence, including 8 clinical statements: (1) specimens from endoscopic resection are better than biopsies for staging lesions, (2) it is important to carefully map the size of the dysplastic areas, (3) patients that receive ablative or surgical therapy require endoscopic follow-up, (4) high-resolution endoscopy is necessary for accurate diagnosis, (5) endoscopic therapy for HGD is preferred to surveillance, (6) endoscopic therapy for HGD is preferred to surgery, (7) the combination of endoscopic resection and radiofrequency ablation is the most effective therapy, and (8) after endoscopic removal of lesions from patients with HGD, all areas of BE should be ablated. CONCLUSIONS We developed a data-sifting platform and used the Delphi process to create evidence-based consensus statements for the management of patients with BE and early-stage EA. This approach identified important clinical features of the diseases and areas for future studies.