Gastroprotective strategies in chronic NSAID users: a cost-effectiveness analysis comparing single-tablet formulations with individual components.

OBJECTIVES: To evaluate the cost-effectiveness of competing gastroprotective strategies, including single-tablet formulations, in the prevention of gastrointestinal (GI) complications in patients with chronic arthritis taking nonsteroidal anti-inflammatory drugs (NSAIDs). METHODS: We performed a cost-utility analysis to compare eight gastroprotective strategies including NSAIDs, cyclooxygenase-2 inhibitors, proton pump inhibitors (PPIs), histamine-2 receptor antagonists, misoprostol, and single-tablet formulations. We derived estimates for outcomes and costs from medical literature. The primary outcome was incremental cost per quality-adjusted life-year gained. We performed sensitivity analyses to assess the effect of GI complications, compliance rates, and drug costs. RESULTS: For average-risk patients, NSAID + PPI cotherapy was most cost-effective. The NSAID/PPI single-tablet formulation became cost-effective only when its price decreased from €0.78 to €0.56 per tablet, or when PPI compliance fell below 51% in the NSAID + PPI strategy. All other strategies were more costly and less effective. The model was highly sensitive to the GI complication risk, costs of PPI and NSAID/PPI single-tablet formulation, and compliance to PPI. In patients with a threefold higher risk of GI complications, both NSAID + PPI cotherapy and single-tablet formulation were cost-effective. CONCLUSIONS: NSAID + PPI cotherapy is the most cost-effective strategy in all patients with chronic arthritis irrespective of their risk for GI complications. For patients with increased GI risk, the NSAID/PPI single-tablet formulation is also cost-effective.

Gastroprotection in low-dose aspirin users for primary and secondary prevention of ACS: results of a cost-effectiveness analysis including compliance.

PURPOSE: Low-dose aspirin (ASA) increases the risk of upper gastrointestinal (GI) complications. Proton pump inhibitors (PPIs) reduce these upper GI side effects, yet patient compliance to PPIs is low. We determined the cost-effectiveness of gastroprotective strategies in low-dose ASA users considering ASA and PPI compliance. METHODS: Using a Markov model we compared four strategies: no medication, ASA monotherapy, ASA+PPI co-therapy and a fixed combination of ASA and PPI for primary and secondary prevention of ACS. The risk of acute coronary syndrome (ACS), upper GI bleeding and dyspepsia was modeled as a function of compliance and the relative risk of developing these events while using medication. Costs, quality adjusted life years and number of ACS events were evaluated, applying a variable risk of upper GI bleeding. Probabilistic sensitivity analyses were performed. RESULTS: For our base case patients using ASA for primary prevention of ACS no medication was superior to ASA monotherapy. PPI co-therapy was cost-effective (incremental cost-effectiveness ratio [ICER] €10,314) compared to no medication. In secondary prevention, PPI co-therapy was cost-effective (ICER €563) while the fixed combination yielded an ICER < €20,000 only in a population with elevated risk for upper GI bleeding or moderate PPI compliance. PPI co-therapy had the highest probability to be cost-effective in all scenarios. PPI use lowered the overall number of ACS. CONCLUSIONS: Considering compliance, PPI co-therapy is likely to be cost-effective in patients taking low dose ASA for primary and secondary prevention of ACS, given low PPI prices. In secondary prevention, a fixed combination seems cost-effective in patients with elevated risk for upper GI bleeding or in those with moderate PPI compliance. Both strategies reduced the number of ACS compared to ASA monotherapy.

Functional GI disorders: from animal models to drug development.

Despite considerable efforts by academic researchers and by the pharmaceutical industry, the development of novel pharmacological treatments for irritable bowel syndrome (IBS) and other functional gastrointestinal (GI) disorders has been slow and disappointing. The traditional approach to identifying and evaluating novel drugs for these symptom-based syndromes has relied on a fairly standard algorithm using animal models, experimental medicine models and clinical trials. In the current article, the empirical basis for this process is reviewed, focusing on the utility of the assessment of visceral hypersensitivity and GI transit, in both animals and humans, as well as the predictive validity of preclinical and clinical models of IBS for identifying successful treatments for IBS symptoms and IBS-related quality of life impairment. A review of published evidence suggests that abdominal pain, defecation-related symptoms (urgency, straining) and psychological factors all contribute to overall symptom severity and to health-related quality of life. Correlations between readouts obtained in preclinical and clinical models and respective symptoms are small, and the ability to predict drug effectiveness for specific as well as for global IBS symptoms is limited. One possible drug development algorithm is proposed which focuses on pharmacological imaging approaches in both preclinical and clinical models, with decreased emphasis on evaluating compounds in symptom-related animal models, and more rapid screening of promising candidate compounds in man.

The cost-effectiveness and budget impact of competing therapies in hepatic encephalopathy - a decision analysis.

BACKGROUND: Treatment options for hepatic encephalopathy have disparate risks and benefits. Non-absorbable disaccharides and neomycin are limited by uncertain efficacy and common dose-limiting side effects. In contrast, rifaximin is safe and effective in hepatic encephalopathy, but is more expensive. METHODS: We conducted a decision analysis to calculate the cost-effectiveness of six strategies in hepatic encephalopathy: (i) no hepatic encephalopathy treatment, (ii) lactulose monotherapy, (iii) lactitol monotherapy, (iv) neomycin monotherapy, (v) rifaximin monotherapy and (vi) up-front lactulose with crossover to rifaximin if poor response or intolerance of lactulose ('rifaximin salvage'). The primary outcome was cost per quality-adjusted life-year gained. RESULTS: Under base-case conditions, 'do nothing' was least effective and rifaximin salvage was most effective. Lactulose monotherapy was least expensive, and rifaximin monotherapy was most expensive. When balancing cost and effectiveness, lactulose monotherapy and rifaximin salvage dominated alternative strategies. Compared to lactulose monotherapy, rifaximin salvage cost an incremental US$2315 per quality-adjusted life-year-gained. The cost of rifaximin had to fall below US$1.03/tab in order for rifaximin monotherapy to dominate lactulose monotherapy. CONCLUSIONS: Rifaximin monotherapy is not cost-effective in the treatment of chronic hepatic encephalopathy at current average wholesale prices. However, a hybrid salvage strategy, reserving rifaximin for lactulose-refractory patients, may be highly cost-effective.

Differences in the management of Crohn's disease among experts and community providers, based on a national survey of sample case vignettes.

BACKGROUND: When faced with the same set of facts, healthcare providers often make different diagnoses, employ different tests and prescribe disparate therapies. AIM: To perform a national survey to measure process of care and variations in decision-making in Crohn's disease, and the compared results between experts and community providers. METHODS: We constructed a survey with five vignettes to elicit provider beliefs regarding the appropriateness of diagnostic tests and therapies in Crohn's disease. We measured agreement between community gastroenterologists and Crohn's disease experts, and measured variation within each group using the RAND Disagreement Index (DI), which is a validated measure of provider variation. RESULTS: We received 186 responses (42% response rate). Experts and community providers generally agreed on diagnostic testing decisions in Crohn's disease. However, there was a significant disagreement between groups for several decisions (use of 5-aminosalicylate in particular), and there was evidence of 'extreme variation' (defined as DI > 1.0) within groups across a range of decisions. CONCLUSIONS: Although experts and community providers are in general consensus about diagnostic decision-making in Crohn's disease, extreme variation exists both between and within groups for key therapeutic decisions in Crohn's disease. We must understand and decrease this variation prior to future efforts of creating explicit quality indicators in Crohn's disease.

Gastrointestinal symptom severity in irritable bowel syndrome, inflammatory bowel disease and the general population.

BACKGROUND: Irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) patients report similar gastrointestinal (GI) symptoms, yet comparisons of symptom severity between groups and with the general population (GP) are lacking. METHODS: We compared Patient-Reported Outcomes Measurement Information System (PROMIS® ) GI symptom scales measuring gastro-esophageal reflux (GER), disrupted swallowing, diarrhea, bowel incontinence, nausea/vomiting, constipation, belly pain, and gas/bloating in: (i) USA GP sample, (ii) IBS patients, and (iii) IBD patients from tertiary care and community populations. Symptom severity scores were based on T-score metric with mean 50±10 (standard deviation) relative to the GP. KEY RESULTS: Of 1643 patients enrolled, there were 253 IBS patients (68% F, mean age 45±15 years), 213 IBD patients (46% F, mean age 41±14 years), and 1177 GP subjects (57% F, mean age 46±16 years). IBS patients reported greater severity of GER, disrupted swallowing, nausea/vomiting, belly pain, gas/bloating, and constipation symptoms than their IBD counterparts (all P<.05). Compared to the GP, IBD patients had worse belly pain, gas/bloating, diarrhea, and bowel incontinence, but less severe GER and disrupted swallowing (all P<.05), and IBS patients had more severe nausea/vomiting, belly pain, gas/bloating, and constipation (all P<.05). Women had more severe belly pain and gas/bloating than men, whereas men had more severe bowel incontinence (all P<.05). CONCLUSION & INFERENCES: IBS and IBD are associated with more severe GI symptoms compared to the GP excluding esophageal symptoms. Unlike IBD, IBS is not characterized by observable GI inflammation but patients report more severe upper and lower GI symptoms.

A comparison of liver transplantation outcomes in the pre- vs. post-MELD eras.

BACKGROUND: The model for end stage liver disease (MELD)-based organ allocation system is designed to prioritize orthotopic liver transplantation (OLT) for patients with the most severe liver disease. However, there are no published data to confirm whether this goal has been achieved or whether the policy has affected long-term post-OLT survival. AIM: To compare pre-OLT liver disease severity and long-term (1 year) post-OLT survival between the pre- and post-MELD eras. METHODS: Using the United Network of Organ Sharing database, we compared two cohorts of adult patients undergoing cadaveric liver transplant in the pre-MELD (n = 3857) and post-MELD (n = 4245) eras. We created multivariable models to determine differences in: (i) pre-OLT liver disease severity as measured by MELD; and (ii) 1-year post-OLT outcomes. RESULTS: Patients undergoing OLT in the post-MELD era had more severe liver disease at the time of transplantation (mean MELD = 20.5) vs. those in the pre-MELD era (mean MELD = 17.0). There were no differences in the unadjusted patient or graft survival at 1 year post-OLT. This difference remained insignificant after adjusting for a range of prespecified recipient, donor, and transplant centre-related factors in multivariable survival analysis. CONCLUSIONS: Although liver disease severity is higher in the post- vs. pre-MELD era, there has been no change in long-term post-OLT patient or graft survival. These results indicate that the MELD era has achieved its primary goals by allocating cadaveric livers to the sickest patients without compromising post-OLT survival.

Endoscopy for acute nonvariceal upper gastrointestinal tract hemorrhage: is sooner better? A systematic review.

BACKGROUND: While the effectiveness of upper endoscopy has been established for acute nonvariceal upper gastrointestinal tract hemorrhage, its optimal timing has not been clearly defined. Early endoscopy has been advocated for its ability to achieve prompt diagnosis, risk stratification, and therapeutic hemostasis. OBJECTIVE: To determine whether early vs delayed endoscopy improves patient and economic outcomes for all risk groups with nonvariceal upper gastrointestinal tract hemorrhage. METHODS: A systematic review of 3 computerized databases (MEDLINE, HEALTHSTAR, and Cochrane Database of Systematic Reviews) was performed along with hand searching of published abstracts to identify English-language citations from 1980 to 2000. RESULTS: Twenty-three studies met explicit inclusion criteria. The highest-quality study examining outcomes in low-risk patients found no significant complications at 1-month follow-up for any outpatients managed with early endoscopy. The largest randomized trial of high-risk patients showed no mortality benefit but a significant decrease in transfusion requirements with early endoscopy. Seven of the 8 studies examining the effect of early endoscopy on length of stay as a measure of resource utilization demonstrated a significant reduction compared with that of delayed endoscopy. However, most included studies were found to suffer from 1 or more potentially significant methodologic shortcomings. CONCLUSIONS: The overwhelming majority of existing data suggest that early endoscopy is safe and effective for all risk groups. The clinical and economic outcomes of early endoscopy should be confirmed in additional well-designed randomized controlled trials. Given the strength of the evidence, efforts to develop a more standardized and time-sensitive approach to acute nonvariceal upper gastrointestinal tract hemorrhage should be undertaken.

Traditional Chinese medicine based subgrouping of irritable bowel syndrome patients.

Partly from lack of effective conventional therapeutics, patients with irritable bowel syndrome (IBS) turn to complementary and alternative approaches, including Traditional Chinese Medicine (TCM). Key to TCM's approach to IBS is individualized therapies targeted at subgroups. Subgroups represent distinct patterns of dysregulation (e.g. "excess" or "deficiency") identified by both intestinal and extra-intestinal symptoms. Our objective was to identify operational criteria supporting the existence of TCM-based subgroups in IBS and to assess reliability and validity of these criteria. Using TCM principles, items were selected on face validity from conventional questionnaires. TCM practitioners evaluated items for content and face validity. Symptom items and a set of patient cases with item responses were validated by examining patient's pattern of response to items and assessing the consistency with which practitioners diagnosed patients on the spectrum of an "excess" or "deficiency" syndrome. Standard correlation analysis revealed 33 intestinal and extra-intestinal symptom items. There was high degree of practitioner agreement in assessing individual items to particular patterns. External validation by practitioners of cases showed high internal consistency among practitioners (Cronbach's alpha coefficients of 0.91 and 0.87 for excess and deficiency, respectively) and high correlation of average practitioner rating to original questionnaire generated scores (Pearson correlation coefficients of 0.94 and 0.92 for excess and deficiency, respectively). This pilot study provides preliminary support for a methodology to identify novel subgroups of IBS patients related to the TCM classification, which may differ in underlying pathophysiology and treatment responses.

Meta-analysis: do irritable bowel syndrome symptoms vary between men and women?

BACKGROUND: Studies suggest that sex and gender-related differences exist in irritable bowel syndrome (IBS), but data is often conflicting. AIM: To evaluate gender differences and the effect of menstrual cycle and menopausal status on IBS symptoms. METHODS: We performed a systematic review of MEDLINE to search for studies comparing IBS symptoms between gender, menstrual cycle phases and menopausal states in IBS and/or healthy individuals. We performed meta-analyses to compare the relative risk (RR) of individual IBS symptoms between men and women. RESULTS: Twenty-two studies measured gender differences in IBS symptoms. Women were more likely to report abdominal pain (RR = 1.12, 95% CI: 1.02, 1.22) and constipation-related symptoms (RR = 1.12, 95% CI: 1.02, 1.23) than men (all P < 0.05). However, men with IBS were more likely to report diarrhoea-related symptoms than women with IBS (RR = 0.84, 95% CI: 0.75, 0.94, P < 0.05). A systematic review of 13 studies demonstrated that both IBS and healthy women reported increased IBS symptoms during menses vs. other phases. There were insufficient data to determine the effect of menopause and hormone supplementation on IBS symptoms. CONCLUSIONS: In the general and IBS populations, gender differences in IBS symptoms exist, although these differences are modest. Studies suggest that female sex hormones influence the severity of IBS symptoms, but more studies are needed.

The development and validation of a Nocturnal Gastro-oesophageal Reflux Disease Symptom Severity and Impact Questionnaire for adults.

BACKGROUND: Current questionnaires for assessing gastro-oesophageal reflux disease (GERD) symptoms are limited in their ability to capture nocturnal symptoms. AIM: To develop and validate an instrument, the Nocturnal Gastro-oesophageal Reflux Disease Symptom Severity and Impact Questionnaire (N-GSSIQ), to assess severity and impact of nocturnal GERD symptoms. METHODS: Two focus groups and 16 cognitive debriefing interviews were conducted among GERD patients to identify key issues about nocturnal symptoms. A draft instrument was tested in 196 patients at 11 clinics in the US to evaluate psychometric properties. Exploratory factor and item response theory analyses were conducted to finalize items and subscales. Internal consistency reliability, reproducibility and construct validity were examined. RESULTS: Mean age was 45 (s.d. = 13.8) years; 76% were female and 68% were Caucasian. Patient-rated severity was mild-moderate for 69% of participants; 48% reported symptoms on two to three nights the past week. The final questionnaire includes 20 items and three subscales: Nocturnal GERD Symptoms, Morning Impact of Nocturnal GERD and Concern about Nocturnal GERD. The subscales demonstrated internal consistency reliability (Cronbach's alpha 0.84-0.94) and were significantly correlated with similar measures and disease severity (0.41-0.81; P < 0.0001). CONCLUSION: The results support the reliability and validity of the N-GSSIQ as a measure of severity, morning impact and concern about nocturnal GERD.

Measuring symptoms in the irritable bowel syndrome: development of a framework for clinical trials.

BACKGROUND: There is uncertainty about how to measure patient-reported outcomes (PROs) in IBS. The Food and Drug Administration (FDA) emphasizes that PROs must be couched in a conceptual framework, yet existing IBS PROs were not based on such a framework. AIM: To perform qualitative analyses to inform a new conceptual framework for IBS symptoms. METHODS: Following FDA guidance, we searched the literature for extant IBS questionnaires. We then performed interviews in IBS patients to learn about the illness experience in their own words. We cultivated vocabulary to inform a conceptual framework depicted with domains, sub-domains, and item categories, per FDA guidance. RESULTS: We identified 13 questionnaires with items encompassing 18 symptoms. We recruited 123 IBS patients for cognitive interviews. Major themes included: pain and discomfort are different - asking about discomfort is nonspecific and should be avoided in future PROs; bowel urgency is multifaceted - PROs should measure bowel immediacy, controllability, and predictability; and PROs should divide bloating into how it feels vs. how it looks. Symptom experience may be determined by 35-item categories within five domains: (i) pain; (ii) gas/bloat; (iii) diarrhoea; (iv) constipation; and (v) extraintestinal symptoms. CONCLUSIONS: We applied FDA guidance to develop a framework that can serve as the foundation for developing a PRO for IBS clinical trials.

Characterizing abdominal pain in IBS: guidance for study inclusion criteria, outcome measurement and clinical practice.

BACKGROUND: Although irritable bowel syndrome (IBS) is a multisymptom disorder, abdominal pain drives illness severity more than other symptoms. Despite consensus that IBS trials should measure pain to define study entry and determine efficacy, the optimal method of measuring pain remains uncertain. AIM: To determine whether combining information from multiple pain dimensions may capture the IBS illness experience more effectively than the approach of measuring 'pain predominance' or pain intensity alone. METHODS: Irritable bowel syndrome patients rated dimensions of pain, including intensity, frequency, constancy, predominance, predictability, duration, speed of onset and relationship to bowel movements. We evaluated the impact of each dimension on illness severity using multivariable regression techniques. RESULTS: Among the pain dimensions, intensity, frequency, constancy and predictability were strongly and independently associated with illness severity; the other dimensions had weaker associations. The clinical definition of 'pain predominance', in which patients define pain as their most bothersome symptom, was insufficient to categorize patients by illness severity. CONCLUSIONS: Irritable bowel disease pain is multifaceted; some pain dimensions drive illness more than others. IBS trials should measure various pain dimensions, including intensity, constancy, frequency and predictability; this may improve upon the customary use of measuring pain as a unidimensional symptom in IBS.

Adherence to best practice guidelines in dyspepsia: a survey comparing dyspepsia experts, community gastroenterologists and primary-care providers.

BACKGROUND: Although 'best practice' guidelines for dyspepsia management have been disseminated, it remains unclear whether providers adhere to these guidelines. AIM: To compare adherence to 'best practice' guidelines among dyspepsia experts, community gastroenterologists and primary-care providers (PCPs). METHODS: We administered a vignette survey to elicit knowledge and beliefs about dyspepsia including a set of 16 best practices, to three groups: (i) dyspepsia experts; (ii) community gastroenterologists and (iii) PCPs. RESULTS: The expert, community gastroenterologist and PCP groups endorsed 75%, 73% and 57% of best practices respectively. Gastroenterologists were more likely to adhere with guidelines than PCPs (P < 0.0001). PCPs were more likely to define dyspepsia incorrectly, overuse radiographic testing, delay endoscopy, treat empirically for Helciobacter pylori without confirmatory testing and avoid first-line proton pump inhibitors (PPIs). PCPs had more concerns about adverse events with PPIs [e.g. osteoporosis (P = 0.04), community-acquired pneumonia (P = 0.01)] and higher level of concern predicted lower guideline adherence (P = 0.04). CONCLUSIONS: Gastroenterologists are more likely than PCPs to comply with best practices in dyspepsia, although compliance remains incomplete in both groups. PCPs harbour more concerns regarding long-term PPI use and these concerns may affect therapeutic decision making. This suggests that best practices have not been uniformly adopted and persistent guideline-practice disconnects should be addressed.

Evaluating the process of care in nonvariceal upper gastrointestinal haemorrhage: a survey of expert vs. non-expert gastroenterologists.

BACKGROUND: When faced with the same facts, physicians often make different decisions. Aim To perform a survey to measure the process of care and variations in decision-making in nonvariceal upper gastrointestinal tract haemorrhage (NVUGIH) and compare results between experts and non-experts. METHODS: We administered a vignette survey to elicit knowledge and beliefs about NVUGIH, including 13 'best practice' guidelines. We compared guideline compliance between experts and non-experts. RESULTS: One hundred and eighty-eight gastroenterologists responded (46%). Experts endorsed more 'best practices' than non-experts (93% vs. 85%; P = 0.002). Non-experts were more likely to endorse incorrectly bolus dosing vs. continuous infusion of intravenous proton pump inhibitors (PPIs; 92% vs. 64%; P = 0.005) and to select standard-channel vs. large-channel endoscopes in high-risk bleeding (100% vs. 85%; P = 0.04). There were wide variations within groups regarding the timing of nasogastric lavage, use of promotility agents, use of hemoclips and appropriateness of snaring clots overlying ulcers. CONCLUSIONS: Experts are more likely to comply with NVUGIH guidelines. Non-experts diverge from experts in the dosing of PPIs and choice of endoscope in high-risk bleeding. Moreover, there are wide variations in key practices even within groups. This suggests that best practices have been generally well disseminated, but that persistent disconnects exist that should be further investigated.

Prospective validation of the short form liver disease quality of life instrument.

BACKGROUND: Despite the realization that health-related quality of life (HRQOL) is an important outcome in patients with liver disease, there is scarcity of disease-targeted HRQOL measures that have undergone prospective evaluation. AIM: To validate prospectively the short form of liver disease quality of life instrument (the SF-LDQOL) in patients with advanced liver disease. METHODS: The SF-LDQOL includes 36 disease-targeted items representing nine domains: symptoms of liver disease, effects of liver disease, memory/concentration, sleep, hopelessness, distress, loneliness, stigma of liver disease and sexual problems. We administered the SF-LDQOL to 156 advanced liver disease patients at baseline and at 6-month follow-up. We estimated internal consistency reliability for multi-item scales, item discrimination across scale and evaluated construct validity by estimating the associations of SF-LDQOL scores with SF-36 scores, symptom severity and disability days. To evaluate the SF-LDQOL's responsiveness, we compared HRQOL changes for patients who received with those who did not receive liver transplantation (LT). RESULTS: The internal consistency reliability coefficients were > or = 0.70 for seven of nine scales in baseline and for all scales in follow-up administration. The SF-LDQOL correlated highly with SF-36 scores, symptom severity, disability days and global health. Patients undergoing LT reported improved HRQOL compared with patients without LT and the responsiveness indices were excellent. CONCLUSIONS: This study provides support for the reliability and validity of the SF-LDQOL in patients with advanced chronic liver disease. This instrument may be useful in everyday clinical practice and in future clinical trials.