Gareth S. Dulai

Hepatitis C virus antibody status and survival after renal transplantation: Meta-analysis of observational studies

The natural history of hepatitis C virus (HCV) among patients after renal transplantation (RT) remains incompletely defined. We conducted a systematic review of the published medical literature on the impact of hepatitis C antibody status on survival of patients who received RT. We used the random effects model of DerSimonian and Laird to generate a summary estimate of the relative risk (RR) for mortality and graft loss with HCV seropositivity across the published studies.

Meta‐analysis: interferon for the treatment of chronic hepatitis C in dialysis patients

Background : The efficacy of interferon monotherapy in dialysis patients with chronic hepatitis C remains unclear, although a number of small clinical trials have been published addressing this issue.

Colonic stent vs. emergency surgery for management of acute left-sided malignant colonic obstruction: a decision analysis

BACKGROUND Acute colonic obstruction because of malignancy is often a surgical emergency. Surgical decompression with colostomy with or without resection and eventual re-anastomosis is the traditional treatment of choice. Endoscopic colonic stent insertion effectively decompresses the obstructed colon, allowing for surgery to be performed electively. This study sought to determine the cost-effectiveness of colonic stent vs. surgery for emergent management of acute malignant colonic obstruction. METHODS Decision analysis was used to calculate the cost-effectiveness of two competing strategies in a hypothetical patient presenting with acute, complete, malignant colonic obstruction: (1) emergent colonic stent followed by elective surgical resection and re-anastomosis; (2) emergent surgical resection followed by diversion (Hartmanns procedure) or primary anastomosis. Cost estimates were obtained from a third-party payer perspective. Primary outcome measures were mortality, stoma requirement, and total number of operative procedures. RESULTS Colonic stent resulted in 23% fewer operative procedures per patient (1.01 vs. 1.32 operations per patient), an 83% reduction in stoma requirement (7% vs. 43%), and lower procedure-related mortality (5% vs. 11%). Colonic stent was associated with a lower mean cost per patient (

Meta-analysis: Effect of hepatitis C virus infection on mortality in dialysis.

45,709 vs.

Treatment Alternatives for Chronic Hepatitis B Virus Infection: A Cost-Effectiveness Analysis

49,941). CONCLUSIONS Colonic stent insertion followed by elective surgery appears more effective and less costly than emergency surgery under base-case conditions. This finding remains robust over a wide range of assumptions for clinical inputs in sensitivity analysis. Our findings suggest that colonic stent insertion should be offered, whenever feasible, as a bridge to elective surgery in patients presenting with malignant colonic obstruction.

The Cost-Effectiveness of Cyclooxygenase-2 Selective Inhibitors in the Management of Chronic Arthritis

Background : The natural history of hepatitis C virus infection among patients on long‐term dialysis treatment remains incompletely understood. Efforts to elucidate the natural history of hepatitis C virus in this population are difficult because of the slowly progressive nature of hepatitis C virus with often an unrecognized onset in patients whose life‐expectancy is substantially diminished by end‐stage renal disease.

Randomized trial of argon plasma coagulation vs. multipolar electrocoagulation for ablation of Barrett's esophagus

Context Because current treatment options for chronic hepatitis B virus (HBV) infection have varying effects and costs, choosing among them is often difficult. Contribution Using a third-party payer perspective and lifetime horizon, this costutility analysis found that monotherapy with interferon but not lamivudine or adefovir was cost-effective. A salvage strategy that used adefovir only in case of lamivudine-associated viral resistance also seemed cost-effective. Cautions The findings apply only to patients with persistently elevated aminotransferase levels and no cirrhosis. The authors did not model the cost-effectiveness of nucleoside analogue salvage after interferon therapy failure. The Editors Chronic hepatitis B virus (HBV) infection is a prevalent and expensive condition, affecting 350 million people worldwide and 1.25 million people in the United States (1) at a cost of more than

HBsAg Seropositive Status and Survival After Renal Transplantation: Meta‐Analysis of Observational Studies

700 million annually (2). Chronic HBV infection can progress to cirrhosis, liver failure, and hepatocellular carcinoma and is a major cause of morbidity and mortality (1, 3). Traditional therapy for chronic HBV infection with either interferon-2b (interferon) or lamivudine is difficult and has limited long-term efficacy (4). Interferon has clinically significant side effects and results in durable virologic response in only 15% to 30% of patients (5-8). Lamivudine is easy to administer and is associated with minimal side effects (9-11), but it has a higher rate of viral resistance (12), lower durable response rate (9-11), and greater need for prolonged therapy (9, 11) compared with interferon. The efficacy of both interferon and lamivudine is even more limited in patients with hepatitis B e antigennegative (HBeAg-negative) disease (4). This burgeoning population now accounts for more than half of patients with HBV in the United States (13) and up to 80% of patients with HBV in Asia (14, 15). Data from 2 randomized, controlled trials indicate that adefovir is efficacious in HBeAg-positive and HBeAg-negative patients (16, 17). Adefovir has a low risk for side effects and viral resistance (18) compared with interferon and lamivudine, but it is more expensive (19). Therefore, the improved therapeutic benefits of adefovir in chronic HBV infection may offset its increased cost compared with interferon and lamivudine, therapies that are less effective yet less expensive. The most effective and cost-effective therapeutic approach to chronic HBV infection must be established. Given the uncertainty on how best to initiate therapy in HBV, this information may assist clinicians in everyday clinical decision making. We therefore performed an economic analysis to estimate the cost-effectiveness of 5 competing strategies for managing chronic HBV infection in patients with elevated liver enzyme levels and no evidence of cirrhosisthe most prevalent and clinically relevant presentation of chronic HBV infection in the primary care setting. We sought to determine whether and under what circumstances the improved therapeutic benefits of adefovir offset its increased cost compared with lamivudine or interferon in managing chronic HBV infection. Methods Decision Model Framework Model Overview Using decision analysis software (DATA, version 4.0, TreeAge Software, Inc., Williamstown, Massachusetts), we evaluated a hypothetical cohort of patients 40 years of age with chronic HBV infection, elevated aminotransferase levels, and no clinical or histologic evidence of cirrhosis. To emulate the case mix in clinical practice in the United States (13), we assumed that 55% of the cohort was HBeAg-negative. We subsequently varied this estimate between 0% and 100% in our sensitivity analysis. Patients entered the hypothetical model without previous treatment for HBV infection and received 1 of 5 competing strategies for managing chronic HBV infection: 1) no pharmacologic treatment of chronic HBV infection (do nothing strategy), 2) interferon monotherapy, 3) lamivudine monotherapy, 4) adefovir monotherapy, or 5) lamivudine with crossover to adefovir upon development of viral resistance (adefovir salvage strategy). Because the clinical course, prognosis, and response to therapy vary in patients with HBeAg-positive and HBeAg-negative HBV (4), we stratified our analysis by HBeAg status and assigned separate probability estimates for each group. Patients entering the model received either no treatment (do nothing strategy) or active treatment for chronic HBV infection. We then followed the cohort over a lifetime horizon through a series of Markov cycles governing patient transitions between relevant health states. The Appendix describes the model structure in detail. Competing Strategies Do Nothing Strategy. In this strategy, which served as the referent case for our analysis, we assumed that patients were followed clinically but did not receive pharmacologic therapy for chronic HBV infection. Patients followed the natural history of chronic HBV infection according to their HBeAg status. We further assumed that all patients received regular ongoing care, including hepatocellular cancer screening, and that patients developing cirrhosis were managed for complications, as outlined by published management guidelines (4, 20). We assumed that a proportion of patients with cirrhosis became eligible for liver transplantation and that a subgroup of these patients subsequently underwent liver transplantation at the rate reported by the United Network for Organ Sharing (21). Interferon Monotherapy Strategy. Patients in this strategy received up-front active therapy with interferon, 10 million units subcutaneously 3 times per week. We assumed that HBeAg-positive and HBeAg-negative patients received 4 and 12 months of treatment, respectively, as suggested by published guidelines (4, 20). Patients without virologic response did not receive additional HBV therapy and followed the natural history of chronic HBV infection. Lamivudine Monotherapy Strategy. Patients in this strategy received up-front lamivudine, 100 mg orally once daily. Lamivudine therapy was discontinued 6 months after a virologic response. Patients without virologic response, including those developing viral resistance, continued to receive long-term lamivudine therapy as recommended by published guidelines (4, 20). We then assigned patients to receive lifetime lamivudine therapy and discontinued therapy if patients developed a subsequent virologic response. Adefovir Monotherapy Strategy. Patients in this strategy received up-front adefovir, 10 mg orally once daily. Adefovir therapy was discontinued 6 months after a virologic response. Patients without virologic response, including those developing viral resistance, continued to receive long-term adefovir therapy as recommended by published guidelines (20). We then assigned patients to receive lifetime adefovir therapy and discontinued therapy if patients developed a subsequent virologic response. Adefovir Salvage Strategy (Lamivudine to Adefovir Crossover). A relevant therapeutic alternative available to clinicians is a hybrid strategy of up-front lamivudine followed by adefovir salvage if lamivudine-related viral resistance develops. We assumed that patients in this strategy initially received lamivudine as described in the lamivudine monotherapy strategy. We then crossed patients over to adefovir when they developed viral resistance, and we subsequently managed patients as described in the adefovir monotherapy strategy. Patients without viral resistance continued to receive lamivudine. Therefore, we reserved adefovir therapy only for patients developing viral resistance while they were receiving lamivudine therapy. Tables 1 and 2 and the Appendix describe the probability estimates governing all 5 strategies. Table 1. Base-Case Probability Estimates Table 2. Base-Case Treatment-Related Probability Estimates Model Assumptions The Appendix contains information about our key model assumptions, including base-case patient characteristics, survival assumptions, definition of virologic response, relationship between virologic response or resistance and subsequent health, and effect of treatment-related adverse events. Clinical Probability Estimates Our base-case model incorporated a wide range of estimates governing relevant clinical probabilities in the management and natural history of chronic HBV infection (Tables 1 and 2). To derive these estimates, we systematically reviewed MEDLINE to identify relevant English-language studies published from January 1970 to February 2005. The Appendix describes our systematic review methods. Outcomes Because the main objective of cost-effectiveness analysis is to permit comparisons among different interventions in medicine, and because quality-adjusted life-years (QALYs) are the exchange currency that allows these comparisons to be made, we adopted QALYs as our main outcome (120). Our analysis reports the incremental cost per QALY gained among the competing strategies, along with the respective 2.5th and 97.5th percentiles around the point estimates as generated by a Monte Carlo analysis of 1000 trials (see Sensitivity Analyses section for details). Utilities We incorporated a wide range of relevant health state utilities in our model. Table 1 contains the specific utility estimates, and the Appendix describes these estimates in detail. Cost Estimates We conducted our analysis from the perspective of a third-party payer and incorporated the direct health care costs for many therapies, physician visits, diagnostic tests, and complications of chronic liver disease (Table 3). We obtained costs for physician services and procedures from the 2004 American Medical Association Current Procedural Terminology codebook and the 2004 Medicare Fee Schedule (121) and derived our base-case pharmaceutical costs from the average wholesale prices listed in the 2004 Red Book (19). Because large buying consortiums can often obtain prices lower th

Dysplasia and Risk of Further Neoplastic Progression in a Regional Veterans Administration Barrett's Cohort

Context Relative to nonsteroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase-2 (COX-2) inhibitors have fewer gastrointestinal complications but cost more. The exact tradeoff between cost and effectiveness is unknown. Contribution This analysis suggests that using rofecoxib and celecoxib rather than naproxen to treat chronic arthritis is cost-effective only for patients with a previous bleeding ulcer or if the cost of COX-2 inhibitors were 10% of its current average wholesale price. Implications At current prices, COX-2 inhibitors offer a cost-effective therapeutic option for treating chronic arthritis only for patients with a previous bleeding ulcer. The Editors Osteoarthritis and rheumatoid arthritis are prevalent and clinically significant health care problems in the United States today, affecting 15% of the population (1), resulting in more than 100 000 hospitalizations per year (2), and consuming nearly 2.5% of the annual gross domestic product when both direct and indirect costs are considered (3). Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used to treat chronic arthritis pain, and they account for 3% of the U.S. prescription drug market (4). These agents are a mainstay of treatment despite their association with clinically significant peptic ulcer complications, including symptomatic ulcers, ulcer hemorrhages, and ulcer perforations (5). Moreover, NSAIDs may induce upper-gastrointestinal (GI) dyspeptic symptoms (6, 7), including epigastric pain, bloating, nausea, and heartburn, even in the absence of endoscopic lesions (8). The decision to use NSAIDs to treat patients with chronic arthritis requires a delicate balance between effective pain relief and potential GI complications. Cyclooxygenase-2 selective inhibitors, including rofecoxib and celecoxib (coxibs), have been developed as safer alternatives to nonselective NSAIDs and are widely used in clinical practice. When compared with nonselective NSAIDs, including naproxen and ibuprofen, coxibs achieve equal pain relief while reducing upper GI dyspeptic symptoms by 15% (9) and clinically significant ulcer complications by 50% (10-13). For these reasons, the American Pain Society has recently endorsed coxibs as the drug class of choice for the initial management of moderate to severe arthritis pain, although they cost more than nonselective NSAIDs (14). Despite the significant relative risk reduction in GI complications afforded by coxibs, their absolute risk reduction compared with nonselective NSAIDs is only 1% to 2% for overall ulcer complications and less than 1% for significant ulcer complications (ulcer hemorrhages or perforations) (10-13). In addition, although coxibs reduce GI-related utilization of health care resources compared with nonselective NSAIDs in controlled trials, recent data from clinical practice indicate that patients switching from nonselective NSAIDs to coxibs do not have a concurrent decrease in overall GI-related resource utilization (15, 16). The enthusiasm for coxibs may be further tempered by data suggesting that coxibs are associated with a higher rate of cardiovascular events than nonselective NSAIDs (17). For example, one randomized, controlled trial revealed that for every 333 patients treated with rofecoxib instead of naproxen, there was one additional cardiovascular event, including stroke, unstable angina, or acute myocardial infarction (9). Although the reasoning behind this finding is uncertain and controversial (18), the clinical disparity in significant events was highlighted in a systematic review of coxib trials reporting cardiovascular end points (17). Several U.S. Food and Drug Administration (FDA) reports have also raised this concern (19-21). In light of these data, we sought to determine whether the degree of risk reduction in GI complications seen with coxibs offsets their increased cost compared with generic nonselective NSAIDs in the management of chronic arthritis. We performed an economic analysis to estimate the cost-effectiveness of coxibs versus nonselective NSAIDs in the management of chronic arthritis pain. Methods Decision Model Framework Decision analysis is a quantitative method for estimating the financial costs and clinical outcomes of alternative strategies under conditions of uncertainty (22). By using decision-analysis software (DATA 4.0, TreeAge Software, Inc., Williamstown, Massachusetts), we evaluated two strategies for managing a hypothetical cohort of 60-year-old patients with osteoarthritis or rheumatoid arthritis who were not taking concurrent aspirin and required long-term NSAID therapy for moderate to severe arthritis pain (Figure 1). Patients with a history of ulcer complications were not included in our base-case analysis but were evaluated in a sensitivity analysis. Patients who entered the hypothetical model did not have GI symptoms and were initially treated with either a coxib (celecoxib, 200 mg once daily, or rofecoxib, 25 mg once daily) or a nonselective NSAID at the maximum FDA-approved dose (modeled after naproxen, 500 mg twice daily). Over the course of a lifetime horizon, the patients either developed a GI complication (nonulcer dyspepsia, symptomatic ulcer, ulcer hemorrhage, or ulcer perforation) or remained free of GI adverse events. Patients without complications continued taking their prescribed therapy, and those with complications required further evaluation. To make our model clinically realistic, we required patients to develop symptoms or clinically significant adverse outcomes to prompt further evaluation. We based our assumptions about patient and physician behavior on patient-centered outcomes rather than surrogate end points, such as endoscopic lesions or ulcer healing rates. To capture the full range of downstream costs generated by each strategy, we included the ongoing cost of care associated with GI events and the probability of developing recurrent events over the course of a lifetime in the model. Figure 1. Truncated decision model. A Model Assumptions To systematically bias our analysis in favor of the coxib strategy, we designed our model to explicitly support a study hypothesis that coxibs are more cost-effective than nonselective NSAIDs. This best case model for coxibs was based on four assumptions (Figure 1). First, all patients developing upper-GI dyspeptic symptoms, including epigastric pain, bloating, nausea, or heartburn, were required to undergo upper endoscopy and were prescribed once-daily proton-pump inhibitor (PPI) therapy for the remainder of their lifetimes, regardless of whether an ulcer was identified. Although many patients who develop GI symptoms while taking NSAIDs do not receive endoscopy or long-term PPI therapy, our exaggerated assumption was designed to impart a significant economic penalty for the presence of upper GI symptoms. This assumption economically favors coxibs because they are associated with substantially fewer dyspeptic symptoms than nonselective NSAIDs (9). Second, all patients receiving a nonselective NSAID who developed an upper-GI dyspeptic symptom were also required to discontinue their therapy and switch to a coxib for the remainder of their lifetimes, regardless of whether an ulcer was found on endoscopy. Third, all symptomatic patients found to have an ulcer by upper endoscopy were required to undergo endoscopic biopsy and rapid urease testing for Helicobacter pylori and subsequently received a 14-day course of eradication therapy if positive for H. pylori. Although the role of H. pylori in the pathogenesis of NSAID-related ulcers is controversial (23), we purposely required all patients to be tested and treated for H. pylori to incur an additional economic penalty for the presence of ulcers, therefore biasing the model in favor of coxibs. Finally, although data indicate that nonselective NSAIDs are associated with more GI adverse events than coxibs, a recent FDA review indicates that the incidence of overall serious adverse events is lower with nonselective NSAIDs than with coxibs (7.8% vs. 9.3%) (20). However, to bias our model in favor of coxibs, our base-case analysis included only GI-related adverse events and did not model the observed disparity in adverse events for other organ systems (20). Clinical Data Our base-case model incorporated 23 probability estimates derived from a systematic review of the medical literature (Table 1). We performed a structured search of published reports from the MEDLINE bibliographic databases and hand-searched published abstracts from two major subspecialty journals (Arthritis & Rheumatism and Gastroenterology) to identify English-language publications from January 1985 to December 2002 that pertained to our 23 clinical inputs. We targeted randomized, controlled trials with one or more arms that investigated the use of either nonselective NSAIDs or coxibs in managing chronic arthritis pain and selected trials that reported clinically significant GI complications. Where available, we used summary estimates derived from published systematic reviews and meta-analyses. Where there was a range of data without previous meta-analysis, we used meta-analysis software (RevMan 4.1, Cochrane Collaboration, Oxford, United Kingdom) to establish point estimates for use in the decision tree. Table 1. Base-Case Clinical Probability Estimates Clinical Probability Estimates Upper Gastrointestinal Dyspeptic Symptoms Patients Receiving Nonselective NSAID. Upper-GI dyspeptic symptoms include epigastric pain, bloating, nausea, and heartburn. A recent meta-analysis of randomized, controlled NSAID trials reporting upper-GI dyspeptic symptoms as an outcome derived a pooled prevalence of dyspeptic symptoms of 10.9% in the large exposure studies (sample size > 1000 patients); we adopted this as our base-case value (7). Because the precision of this estimate is unlikely to be reproduced among different populations and may vary with duration of therapy, we varied it from 5% to

Meta-analysis: the effect of age on immunological response to hepatitis B vaccine in end-stage renal disease

BACKGROUND Endoscopic ablation of Barretts esophagus has been described in which various thermocoagulation modalities are used in combination with a high dose of a proton pump inhibitor. No randomized comparison of ablation strategies has been published. METHODS Referred patients were screened to identify those with Barretts esophagus 2 to 7 cm in length, without high-grade dysplasia or cancer. Included patients received pantoprazole (40 mg twice a day), followed by randomization to treatment with argon plasma coagulation (APC) or multipolar electrocoagulation (MPEC). The primary outcome measure was the number of treatment sessions required for endoscopic ablation. RESULTS Of 235 patients screened, 52 were randomized. The mean length of Barretts esophagus was 3.1 cm in the MPEC group vs. 4.0 cm in the APC group (p = 0.03). Otherwise, the treatment groups were similar with regard to baseline characteristics. The mean number of treatment sessions required for endoscopic ablation was 2.9 for MPEC vs. 3.8 for APC (p = 0.04) in an intention-to-treat analysis (p = 0.249, after adjustment for the difference in length of Barretts esophagus). The proportion of patients in which ablation was endoscopically achieved proximal to the gastroesophageal junction was 88% for the MPEC group vs. 81% for the APC group (p = 0.68) and histologically achieved in 81% for MPEC vs. 65% for APC (p = 0.21). The mean time required for the first treatment session was 6 minutes with MPEC vs. 10 minutes with APC (p = 0.01) in per protocol analysis. There was no serious adverse event, but transient moderate to severe upper-GI symptoms occurred after MPEC in 8% vs. 13% after APC (p = 0.64). Conclusions Although there were no statistically significant differences, ablation of Barretts esophagus with pantoprazole and MPEC required numerically fewer treatment sessions, and endoscopic and histologic ablation was achieved in a greater proportion of patients compared with treatment with pantoprazole and APC.