Design of Treatment Trials for Functional Gastrointestinal Disorders.

This article summarizes recent progress and regulatory guidance on design of trials to assess the efficacy of new therapies for functional gastrointestinal disorders (FGIDs). The double-masked, placebo-controlled, parallel-group design remains the accepted standard for evaluating treatment efficacy. A control group is essential, and a detailed description of the randomization process and concealed allocation method must be included in the study report. The control will most often be placebo, but for therapeutic procedures and for behavioral treatment trials, respectively, a sham procedure and control intervention with similar expectation of benefit, but lacking the treatment principle, are recommended. Investigators should be aware of, and attempt to minimize, expectancy effects (placebo, nocebo, precebo). The primary analysis should be based on the proportion of patients in each treatment arm who satisfy a treatment responder definition or a prespecified clinically meaningful change in a patient-reported outcome measure. Data analysis should use the intention-to-treat principle. Reporting of results should follow the Consolidated Standards for Reporting Trials guidelines and include secondary outcome measures to support or explain the primary outcome and an analysis of harms data. Trials should be registered in a public location before initiation and results should be published regardless of outcome.

Rectal 5-aminosalicylic acid for maintenance of remission in ulcerative colitis.

BACKGROUND: 5-Aminosalicylic acid (5-ASA) is a first-line therapy for inducing and maintaining remission of mild and moderately active ulcerative colitis (UC). When the proximal margin of inflammation is distal to the splenic flexure, 5-ASA therapy can be delivered as a rectal suppository, foam or liquid enema. OBJECTIVES: The primary objective was to assess the efficacy and safety of rectal 5-ASA for maintaining remission of distal UC. SEARCH METHODS: We searched MEDLINE (1966 to August 2012), the Cochrane Library (August 2012), abstracts from major gastroenterology meetings (1997-2011) and bibliographies of relevant publications to identify relevant studies. SELECTION CRITERIA: Eligible studies were randomized controlled trials comparing rectal 5-ASA to placebo or another active treatment for a minimum duration of six months. Symptom scores needed to be assessed in at least one study outcome. Patients had to be at least 12 years of age with disease extent less than 60 cm from the anal verge or distal to the splenic flexure, as determined by barium enema, colonoscopy or sigmoidoscopy. Patients were expected to be in remission prior to the treatment trial. DATA COLLECTION AND ANALYSIS: Study eligibility was independently assessed by three authors. Data were extracted using standardized forms by two independent reviewers, with inter-rater agreement assessed using Cohen's Kappa and disagreements resolved by consensus. In cases where clarification of study results or methodology was needed, corresponding authors were contacted. The methodological quality of each trial was assessed by the Cochrane risk of bias tool and by a 30-point scale developed and used previously by the authors. Pooled risk ratios (RR) and corresponding 95% confidence intervals (CI) for continued clinical, endoscopic and histologic remission were estimated for comparisons between rectal 5-ASA and placebo or oral 5-ASA, and for comparisons among 5-ASA doses. Heterogeneity was assessed using the Chi(2) test and visual inspection of forest plots. If no significant heterogeneity was identified (P > 0.10 for Chi(2)) a fixed-effect model (Mantel-Haenstzel) was used. If heterogeneity was significant, a random-effects model was used. MAIN RESULTS: Nine studies (484 patients) met the pre-specified inclusion criteria (Kappa 1.00). Six studies were rated as low risk of bias. Three studies were rated as high risk of bias due to blinding (two open label and one single-blind). The total daily dose of rectal 5-ASA ranged from 0.5 g to 4 g, and dose frequency ranged from once to three times daily. 5-ASA was delivered as liquid enema in five studies or as a suppository in four studies. Follow-up ranged from 6 to 24 months. Rectal 5-ASA was significantly superior to placebo for maintenance of symptomatic remission over a period of 12 months.Sixty-two per cent of patients in the rectal 5-ASA group maintained symptomatic remission compared to 30% of patients in the placebo group (4 studies; 301 patients; RR 2.22, 95% CI 1.26 to 3.90; I(2) = 67%; P < 0.01). A GRADE analysis indicated that the overall quality of the evidence for the primary outcome was low due to imprecision (i.e. sparse data 144 events) and inconsistency (i.e. unexplained heterogeneity). Rectal 5-ASA was significantly superior to placebo for maintenance of endoscopic remission over a 12 month period. Seventy-five per cent of patients in the rectal 5-ASA group maintained endoscopic remission compared to 15% of patients in the placebo group (1 study; 25 patients; RR 4.88, 95% CI 1.31 to 18.18; P < 0.05). There was no statistically significant difference in the proportion of patients who experienced at least one adverse event. Sixteen per cent of patients in the rectal 5-ASA group experienced at least one adverse compared to 12% of placebo patients (2 studies; 160 patients; RR 1.35, 95% CI 0.63 to 2.89; I(2) = 0%; P = 0.44). The most commonly reported adverse events were anal irritation and abdominal pain. No statistically significant differences between rectal and oral 5-ASA were identified for either symptomatic or endoscopic remission over a period of six months. Eighty per cent of patients in the rectal 5-ASA group maintained symptomatic remission compared to 65% of patients in the oral 5-ASA group (2 studies; 69 patients; RR 1.24, 95% CI 0.92 to 1.66; I(2) = 0%; P = 0.15). A GRADE analysis indicated that the overall quality of the evidence for the primary outcome was low due to imprecision (i.e. sparse data 50 events) and high risk of bias (i.e. both studies in the pooled analysis were open label). Eighty per cent of patients in the rectal 5-ASA group maintained endoscopic remission compared to 70% of patients in the oral 5-ASA group (2 studies; 91 patients; RR 1.14, 95% CI 0.90 to 1.45; I(2) = 0%; P = 0.26). In two small trials, one comparing 2 g/day 5-ASA enemas to 4 g/day 5-ASA enemas and the other comparing 0.5 g/day 5-ASA suppositories to 1 g/day 5-ASA suppositories no dose response relationship was observed. AUTHORS' CONCLUSIONS: The limited data available suggest that rectal 5-ASA is effective and safe for maintenance of remission of mild to moderately active distal UC. Well designed randomized trials are needed to establish the optimal dosing regimen for rectal 5-ASA, to compare rectal 5-ASA with rectal corticosteroids and to identify subgroups of patients who are more or less responsive to specific rectal 5-ASA regimens. The combination of oral and rectal 5-ASA appears to be more effective than either oral or rectal monotherapy for induction of remission. The efficacy of combination therapy for maintenance of remission has not been assessed and could be evaluated in future trials.

Quality of life in patients with immune-mediated inflammatory diseases.

There is no doubt that patients with immune-mediated inflammatory diseases (IMID) have a significantly impaired quality of life (QOL). Pain and disability often leave these patients helpless and frustrated. The recognition that addressing physical and psychological functioning plays a significant role in an overall treatment approach led to the inclusion of QOL measures as secondary outcomes in clinical trials with IMID patients. To that end, both generic and disease-specific instruments have been utilized. Measurement of health-related QOL (HRQOL) and patient-reported outcomes (PRO) in a controlled manner allows for better understanding of the correlation between different aspects of disease activity and QOL. In addition, the effects of different therapeutic options on HRQOL-related outcomes can be further evaluated. This 3-part section describes key QOL-related complaints of patients with IMID affecting joints, skin, or gut. An overview of the strengths and weaknesses of various commonly used HRQOL instruments is provided. Finally, the influence of anti-tumor necrosis factor-α agents on HRQOL outcomes, as assessed in recent clinical trials, is highlighted.

Rectal 5-aminosalicylic acid for induction of remission in ulcerative colitis.

BACKGROUND: 5-Aminosalicylates (5-ASA) are considered a first-line therapy for inducing and maintaining remission of mild to moderately active ulcerative colitis (UC). When inflammation in UC is limited to the distal colon, 5-ASA can also be administered rectally as a suppository, enema or foam. OBJECTIVES: A systematic review was undertaken to evaluate the efficacy of rectal 5-ASA for treating active distal UC. SEARCH STRATEGY: Electronic searches of the MEDLINE database (1966-2008), the Cochrane Central Register of Controlled Trials and the Cochrane IBD/FBD Group Specialized Trials Register were supplemented by manual reviews of reference listings and conference proceedings. SELECTION CRITERIA: Randomized trials comparing rectal 5-ASA to placebo or another active therapy were eligible for inclusion. Eligible trials enrolled patients with a distal disease margin less than 60 cm from the anal verge or distal to the splenic flexure. Trials that enrolled subjects less than 12 years of age were excluded. DATA COLLECTION AND ANALYSIS: Eligibility was assessed by three authors. Data were extracted by two authors using standardized forms. Pooled odds ratios (POR) for inducing improvement and remission by symptomatic, endoscopic and histologic criteria were calculated using an intention to treat principle. Fixed effects models were used unless heterogeneity was encountered within groups (P < 0.10), where random effects models were used. All statistical analyses were performed using RevMan 5. Where sufficient data were available, subgroup analyses were performed for disease extent, total daily 5-ASA dose, 5-ASA formulation (enema,suppository, foam) and the type of control intervention (placebo or another active therapy). MAIN RESULTS: Thirty-eight studies fulfilled the inclusion criteria. Rectal 5-ASA was superior to placebo for inducing symptomatic, endoscopic and histological improvement and remission, with POR for symptomatic improvement 8.87 (8 trials, 95% CI: 5.30 to 14.83; P < 0.00001), endoscopic improvement 11.18 (5 trials, 95% CI 5.99 to 20.88; P < 0.00001), histologic improvement 7.69 (6 trials, 95% CI 3.26 to 18.12; P < 0.00001), symptomatic remission 8.30 (8 trials, 95% CI 4.28 to 16.12; P < 0.00001), endoscopic remission 5.31 (7 trials, 95% CI 3.15 to 8.92; P < 0.00001), and histologic remission 6.28 (5 trials, 95% CI 2.74 to 14.40; P < 0.0001). Rectal 5-ASA was superior to rectal corticosteroids for inducing symptomatic improvement and remission with POR 1.56 (6 trials, 95% CI 1.15 to 2.11; P = 0.004) and 1.65 (6 trials, 95% CI 1.11 to 2.45; P = 0.01), respectively. Rectal 5-ASA was not superior to oral 5-ASA for symptomatic improvement (POR 2.25; 95% CI 0.53 to 19.54; P = 0.27). Neither total daily dose nor 5-ASA formulation affected treatment response. AUTHORS' CONCLUSIONS: Rectal 5-ASA should be considered a first-line therapy for patients with mild to moderately active distal UC. The optimal total daily dose and dose frequency of 5-ASA remain to be determined. Future research should define differences in efficacy among patient subgroups defined by proximal disease margin and disease activity. There is a strong need for consensus standardization of outcome measurements for clinical trials in ulcerative colitis.

Gastroscopy following a positive fecal occult blood test and negative colonoscopy: systematic review and guideline.

BACKGROUND: A sizeable number of individuals who participate in population-based colorectal cancer (CRC) screening programs and have a positive fecal occult blood test (FOBT) do not have an identifiable lesion found at colonoscopy to account for their positive FOBT screen. OBJECTIVE: To evaluate the evidence and provide recommendations regarding the use of routine esophagogastroduodenoscopy (EGD) to detect upper gastrointestinal (UGI) cancers in patients participating in a population-based CRC screening program who are FOBT positive and colonoscopy negative. METHODS: A systematic review was used to develop the evidentiary base and to inform the evidence-based recommendations provided. RESULTS: Nine studies identified a group of patients who were FOBT positive and colonoscopy negative. Three studies found no cases of UGI cancer. Four studies reported cases of UGI cancer; three found UGI cancer in 1% or less of the population studied, and one study found one case of UGI cancer that represented 7% of their small subgroup of FOBT-positive/colonoscopy-negative patients. Two studies did not provide outcome information that could be specifically related to the FOBT-positive/colonoscopy-negative subgroup. CONCLUSION: The current body of evidence is insufficient to recommend for or against routine EGD as a means of detecting gastric or esophageal cancers for patients who are FOBT positive/colonoscopy negative, in a population-based CRC screening program. The decision to perform EGD should be individualized and based on clinical judgement.

Survey of access to gastroenterology in Canada: the SAGE wait times program.

BACKGROUND: Assessment of current wait times for specialist health services in Canada is a key method that can assist government and health care providers to plan wisely for future health needs. These data are not readily available. A method to capture wait time data at the time of consultation or procedure has been developed, which should be applicable to other specialist groups and also allows for assessment of wait time trends over intervals of years. METHODS: In November 2008, gastroenterologists across Canada were asked to complete a questionnaire (online or by fax) that included personal demographics and data from one week on at least five consecutive new consultations and five consecutive procedure patients who had not previously undergone a procedure for the same indication. Wait times were collected for 18 primary indications and results were then compared with similar survey data collected in 2005. RESULTS: The longest wait times observed were for screening colonoscopy (201 days) and surveillance of previous colon cancer or polyps (272 days). The shortest wait times were for cancer-likely based on imaging or physical examination (82 days), severe or rapidly progressing dysphagia or odynophagia (83 days), documented iron deficiency anemia (90 days) and dyspepsia with alarm symptoms (99 days). Compared with 2005 data, total wait times in 2008 were lengthened overall (127 days versus 155 days; P<0.05) and for most of the seven individual indications that permitted data comparison. CONCLUSION: Median wait times for gastroenterology services continue to exceed consensus conference recommended targets and have significantly worsened since 2005.

Urinary potassium is a clinically useful test to detect a poor quality diet.

Poor eating habits, a strong predictor of health outcomes, are not objectively assessed in routine clinical practice. In this study, we evaluated the use of urinary potassium (K(+)) as a means to identify people consuming a poor quality diet. Consecutive patients with kidney stones (n = 220), aged 18-50 y, from a population-based lithotripsy unit, collected a single 24-h urine sample to assess urinary K(+). They also completed a FFQ to derive the recommended foods score (RFS), an index of overall diet quality, and had their blood pressure, heart rate, weight, and height measured. Urinary K(+) was related positively with the intake of recommended food items, including vegetables, fruit, whole grains, low-fat dairy products, fish and poultry, and wine and negatively to those not recommended by current dietary guidelines, including red meat, fast food, and high-energy drinks. Urinary K(+) was also correlated with the RFS (r = 0.226; P < 0.001). Using a receiver operating characteristic curve, K(+) excretion values below the gender-specific median (men, 60 mmol/d; women, 41 mmol/d) were identified as the optimal cutoff values for a poor quality diet, indicated by the RFS. Higher urinary K(+) was inversely related to adjusted BMI (P-trend = 0.03), diastolic blood pressure (P-trend = 0.04) and heart rate (P-trend = 0.006), after controlling for potential confounders. Urinary K(+) provides a summary measure of diet quality, is significantly related to BMI, blood pressure, and heart rate, and may be useful clinically to detect poor dietary habits and monitor response to dietary interventions.

Quality of life of patients with ulcerative colitis: past, present, and future.

Quality of life (QoL) is vitally important to patients with chronic illnesses such as ulcerative colitis (UC) and has been assessed in observational, cross-sectional, and cohort studies. However, relatively few clinical trials have evaluated the QoL of patients with UC. Recently, greater availability of the necessary tools has facilitated the undertaking of studies showing that QoL of patients with UC is reduced significantly compared with that of the general population. Studies using disease-specific instruments have identified disease severity as the strongest predictor of QoL, with other disease-related predictors including type of medical or surgical treatment and the efficacy, tolerability, and acceptability to patients of particular types of medical or surgical treatments. Other factors, such as comorbid medical or psychosocial problems and adherence to treatment, also affect QoL. Combined use of generic and disease-specific instruments in clinical trials can ensure that all clinically relevant unexpected events (generic instrument) and important improvement or deterioration (disease-specific instrument) are captured. For accurate outcomes assessment, the use of comprehensively validated instruments is critical. The need for the development and evaluation of new instruments will be determined by the mechanisms and targets of novel therapies. Ultimately, QoL assessment of effective therapies will play a strong role in pharmacoeconomic evaluations, providing health policy makers with the evidence to support the treatments that can most effectively normalize QoL through complete symptom resolution, minimal side effects, and convenient administration.

Recommendations on chronic constipation (including constipation associated with irritable bowel syndrome) treatment.

While chronic constipation (CC) has a high prevalence in primary care, there are no existing treatment recommendations to guide health care professionals. To address this, a consensus group of 10 gastroenterologists was formed to develop treatment recommendations. Although constipation may occur as a result of organic disease, the present paper addresses only the management of primary CC or constipation associated with irritable bowel syndrome. The final consensus group was assembled and the recommendations were created following the exact process outlined by the Canadian Association of Gastroenterology for the following areas: epidemiology, quality of life and threshold for treatment; definitions and diagnostic criteria; lifestyle changes; bulking agents and stool softeners; osmotic agents; prokinetics; stimulant laxatives; suppositories; enemas; other drugs; biofeedback and behavioural approaches; surgery; and probiotics. A treatment algorithm was developed by the group for CC and constipation associated with irritable bowel syndrome. Where possible, an evidence-based approach and expert opinions were used to develop the statements in areas with insufficient evidence. The nature of the underlying pathophysiology for constipation is often unclear, and it can be tricky for physicians to decide on an appropriate treatment strategy for the individual patient. The myriad of treatment options available to Canadian physicians can be confusing; thus, the main aim of the recommendations and treatment algorithm is to optimize the approach in clinical care based on available evidence.

Functional gastrointestinal disorders and mood disorders in patients with inactive inflammatory bowel disease: prevalence and impact on health.

BACKGROUND: Symptoms of functional gastrointestinal disorders (FGID) associated with mood disorders (MD), such as depression and anxiety, occur in some patients with quiescent inflammatory bowel disease (IBD) and could be caused by changes in gut motility, visceral hypersensitivity, or psychological dysfunction. We assessed the prevalence of FGID symptoms and mood disorders in ambulatory patients with quiescent IBD and examined their impact on health-related quality of life (HRQOL) and use of health resources. METHODS: Consecutive ambulatory patients with IBD completed a survey of Rome II criteria for FGID, the Hospital Anxiety and Depression Survey, HRQOL indices, and health resource utilization. Logistic and linear regression analyses tested for predictors of FGID and HRQOL. RESULTS: Of 361 patients surveyed, 149 (44 ulcerative colitis [UC] and 105 Crohn's disease [CD]) had inactive IBD during the previous 12 months. Symptoms of at least 1 FGID occurred in 81.9%. Functional anorectal disorders were the most prevalent (53.7%) followed by functional bowel disorders (51.7%), and both were of greater prevalence than in the Canadian population (41.6% and 22.6%, respectively). Irritable bowel syndrome symptoms were more common in inactive CD than in UC (26% versus 9.1%, P = .01) and functional constipation was more common in inactive UC than in CD (26.2% versus 5.8%, P < .01). MD occurred in 27.3% of UC and 31.3% of CD patients. Age > or =40 years and anxiety independently predicted an FGID. Both FGID symptoms and MD were associated with impaired HRQOL and increased use of health services. CONCLUSIONS: Many patients with inactive IBD have symptoms compatible with FGID. Both FGID-like symptoms and MD are associated with impaired HRQOL and increased health resource utilization. Recognition and treatment of FGID and MD could potentially improve daily functioning of IBD patients.

Measurement and expression of risk: optimizing decision strategies.

A significant proportion of the >6 million articles published annually present data in terms of risk and risk reduction. While the measurement of risk and risk reduction is often straightforward, there are a variety of ways that risk may be expressed. Risk is defined as the rate of an occurrence of a particular disease or adverse event and is determined by the number of events divided by the person-years or number of individuals in the at-risk population. The portrayal of risk can be achieved using different techniques but is typically provided in demographic maps, time-trend charts, or incidence bar graphs. Risk can be expressed in relative terms such as relative risk or absolute measures such as attributable risk or number needed to treat. Understanding risk determination as well as the differences in risk depiction and expression is necessary to ascertain the relevance of the data to one's clinical practice as well as to make optimal clinical and pharmacoeconomic treatment decisions. A review of terms, together with examples, is presented, such that clinicians evaluating the medical literature will be able to identify differences in the way that risk-related results are expressed and optimize the application of such evidence to their practice.

Providing disease-related information worsens health-related quality of life in inflammatory bowel disease.

BACKGROUND: Patients with inflammatory bowel disease (IBD) have identified a need for more information about their disease. PURPOSE: To assess the effect of an educational intervention on health-related quality of life (HRQOL) in patients with IBD. METHODS: Consecutive ambulatory IBD patients were randomized to receive four IBD-specific educational booklets or usual care. Subjects completed two disease-specific HRQOL questionnaires-the Inflammatory Bowel Disease Questionnaire (IBDQ) (range 1-poor to 7-excellent) and the Quality Index in Crohn's and Colitis (QuICC) (range 1-excellent to 5-poor) at entry and after 2 weeks. The mean change in HRQOL scores at follow-up was compared between the education and control groups. RESULTS: 59 subjects participated, with a mean age of 40.0 +/- 11.9 years. 34 were given educational booklets and 25 received standard care. 6 patients (10%) did not complete the study. Mean IBDQ scores became significantly worse in the education group with a change of -0.17 +/- 0.49 compared with controls at +0.28 +/- 0.62 (p = 0.006). This could be explained by worsened disease activity in the education group. There was no significant change in the QuICC scores (p = 0.61). Education group patients who had not received prior educational material had improved mean IBDQ scores of +0.24 +/- 0.47 compared with education patients who had received educational material prior to this study, with a score change of -0.25 +/- 0.46 (p = 0.09). CONCLUSIONS: The addition of educational booklets to IBD patients in a tertiary center does not improve, and may worsen, short-term HRQOL. Education of newly diagnosed or less informed patients should be studied further.

Ischemic colitis after weight-loss medication.

BACKGROUND: Previous weight-loss medications have received cautious support due to their association with pulmonary hypertension and valvular heart disease. However, newer drugs are increasingly being recommended as potentially safer and more efficacious. We report a case of ischemic colitis possibly linked to the use of a weight-loss drug, and review the literature to highlight an important latent consequence of these medications. CASE REPORT: A 59-year-old obese woman presented to the emergency room with rectal bleeding and suprapubic abdominal pain. Her medical history was unremarkable for risk factors for bowel ischemia. An appetite suppressant, phentermine 15 mg daily, had been prescribed, and had resulted in a 12 kg weight loss over 10 weeks. Colonoscopy and biopsies both demonstrated findings typical of mild ischemia at the splenic flexure. DISCUSSION: Phentermine, an amphetamine-derived sympathomimetic, acts centrally to suppress appetite. While there are no published reports linking the use of phentermine as a single agent to ischemic colitis, phentermine alone has been associated with ischemic neurological events and, when used in combination with fenfluramine, has been implicated in a single case of acute ischemic colitis. Other sympathomimetics, such as cocaine, have been clearly linked with ischemic colitis. CONCLUSIONS: This report describes a temporal association with the use of phentermine and the development of ischemic colitis. Heightened awareness and appropriate surveillance is warranted to determine whether the use of weight-loss drugs, such as phentermine, can lead to ischemic colitis.

Self-reported awareness and use of the International Classification of Diseases coding of inflammatory bowel disease services by Ontario physicians.

RATIONALE: Population and health services research can be performed by linkage analysis of administrative data. However, the robustness of study results is determined by the accuracy of the diagnostic coding. OBJECTIVES: To estimate the awareness, use and accuracy of the International Classification of Diseases, Ninth Revision (ICD-9) coding by physicians providing services for patients with Crohn's disease (CD) and ulcerative colitis (UC). METHODS: All Ontario gastroenterologists and a 10% random sample of internists, pediatricians, pediatric or general surgeons, and family physicians were surveyed by postal questionnaire to estimate the frequency and 95% CI of using codes 555 or 556 when billing for CD- and UC-related services, respectively. c2 tests were used for between-group comparisons. RESULTS: Of the physicians who were surveyed, 67.7% (416 of 614) responded; 258 of 391 (66%) who were still practising in Ontario saw patients with inflammatory bowel disease (IBD), and 54% had more than 10 IBD patients; 86.5% (95% CI 82.4% to 90.6%) were familiar with ICD-9 codes, and 91.4% (95% CI 88.1% to 95.6%) used the codes 555 (CD) or 556 (UC) for billing. Rates of ICD-9 use did not differ by sex but were used more frequently by those graduating after 1981 (P<0.02). Gastroenterologists used ICD-9 IBD codes 555 or 556 significantly more often than all other physicians (P=0.001). Most (more than 75%) Ontario physicians used ICD-9 IBD codes always or frequently when billing for IBD-related services. Few (10%) used these codes to bill for non-IBD-related problems. CONCLUSIONS: These data suggest that there is acceptable use and accuracy of ICD-9 diagnostic coding for CD and UC services - comparable with results from studies of other diseases. Administrative data may thus be used to undertake epidemiological studies in IBD in Ontario.

Diagnosis of constipation in family practice.

BACKGROUND: Patients who complain of constipation to their family doctor may not be truly constipated. Variability in stool frequency and consistency, and perception of symptoms may lead to inaccurate patient reporting or diagnosis of constipation. OBJECTIVES: To determine whether patients visiting their family doctor with a complaint of, or diagnosed with, constipation fulfilled the Rome II criteria for functional constipation and had stool characteristics of constipation. METHODS: A random sample of Canadian family physicians were recruited to enroll a series of adults who complained of, or had received a diagnosis of, constipation during an office visit. Patients were advised of the survey. Those providing written consent were contacted by an independent research firm and forwarded a survey questionnaire that included the Rome II gastrointestinal questionnaire, questions regarding their medical history and questions regarding their demographics. Patients also completed a four-week daily diary recording their bowel habits using the Bristol Stool Form Scale, medication use and satisfaction with treatment. Questionnaire and diary responses were retrieved by telephone. RESULTS: One hundred eighty-four family physicians enrolled 311 patients, of whom 220 completed the questionnaire. Females comprised 79.5% of the sample and had a mean age of 54.2 years (males 61.6 years; P<0.05). According to the Rome II criteria, 37.3% had functional constipation and 46.8% had irritable bowel syndrome (IBS). Whole gut transit times estimated using the Bristol Stool Scale were similar among those with self-reported constipation, those with Rome II functional constipation and those with Rome II IBS (79.3 h, 85.8 h and 77.4 h, respectively). Almost half of the patients with IBS or functional constipation were taking a pain medication, while nearly one-fifth took antidepressants. Of the medications or remedies taken to treat constipation, patients rated 49.8% of the doses as satisfactory. CONCLUSIONS: A large proportion of Canadian primary care patients whose presenting complaint or diagnosis was constipation satisfied the Rome II criteria for IBS, with a smaller number defined as functionally constipated. IBS patients tended to be younger than those with functional constipation, and whole gut transit times did not differentiate IBS from functional constipation. Careful questioning of patients who complain of constipation may reveal constipating medication, diarrhea symptoms or IBS.

Assessing heterogeneity in meta-analyses of Helicobacter pylori infection-related clinical studies: a critical appraisal.

OBJECTIVE: To critically assess the meta-analyses of Helicobacter pylori infection-related clinical studies, particularly the handling of between-study heterogeneity. METHODS: A qualitative, all-language, systematic literature search was performed in Medline, PubMed, BioMed Central and Embase up to February 2003, supplemented by a manual search of major relevant journals. Assessment was according to modified criteria for literature searching, eligibility criteria, validity assessment, data extraction and presentation. Five parameters were used to assess the quality of the meta-analyses in handling between-study heterogeneity. RESULTS: Of 84 potentially relevant citations, 47 were systematic reviews and of them 38 were meta-analyses. Of these 38 studies, 15 (39.5%) had conducted a literature search of multiple databases and 34 (89.5%) had conducted a supplementary manual search. The eligibility criteria were clearly presented in 81.6% of studies, but the quality of the primary studies was assessed in only 26.3%. The process and strategy for data extraction was reported in 57.9% of all studies; 19 (50%) studies planned statistical tests of between-study homogeneity and the results were reported in 18, but the level of statistical significance was reported in only 11 (57.9%). The selection of and justification for a statistical model was presented in 39.5% and 26.3% of studies, respectively. Among the 11 meta-analyses in which statistical between-study heterogeneity was reported, 54.5% ignored the statistical findings and proceeded to pool the study results. The implications of between-study heterogeneity were discussed in only 8 studies. CONCLUSIONS: Many methodological flaws were identified in the meta-analyses of H. pylori-related clinical studies, particularly for assessing, reporting and interpreting between-study heterogeneity. This warrants consistent and urgent adherence by reviewers and journal editors to the methodological guidelines for meta-analyses.

Canadian cost-utility analysis of initiation and maintenance treatment with anti-TNF-α drugs for refractory Crohn's disease.

OBJECTIVES: Crohn's disease (CD) is a chronic inflammatory disease of the gastrointestinal tract. Symptoms include but are not limited to abdominal pain, nausea, emesis, and diarrhea. Anti-TNF-α drugs are increasingly being used in patients with CD who have inadequate response to conventional therapy. However, these medications are quite expensive. The objective of this study is to evaluate the cost-utility of two anti-TNF-α drugs (infliximab, adalimumab) for refractory CD. METHODS: A Markov model was used to estimate the costs and QALYs of three treatments (usual care, infliximab, adalimumab) over a 5 year time horizon. After initial treatment, patients achieve remission, achieve treatment response or remain in the drug refractory health state. Patients who achieve remission or treatment response are at risk of relapse each 3 month model cycle. Patients in the drug refractory health state either remain in the health state or have surgery in each cycle. Different costs and utility values were assigned to the various model health states. Model input parameters including initial response rates, relapse rates, utility values were derived from published literature. RESULTS: Usual care had both the lowest expected costs ($17,017) and QALYs (2.555), while infliximab had both the highest expected costs ($54,084) and QALYs (2.721). The incremental cost per QALY moving from usual care to adalimumab and from adalimumab to infliximab was estimated to be to be $193,305 and $451,165, respectively. CONCLUSIONS: Based on common willingness to pay thresholds, ant-TNF-α drugs would not be perceived as a cost effective treatment for refractory CD.

Development of the Crohn's disease digestive damage score, the Lémann score.

Crohn's disease (CD) is a chronic progressive destructive disease. Currently available instruments measure disease activity at a specific point in time. An instrument to measure cumulative structural damage to the bowel, which may predict long-term disability, is needed. The aim of this article is to outline the methods to develop an instrument that can measure cumulative bowel damage. The project is being conducted by the International Program to develop New Indexes in Crohn's disease (IPNIC) group. This instrument, called the Crohn's Disease Digestive Damage Score (the Lémann score), should take into account damage location, severity, extent, progression, and reversibility, as measured by diagnostic imaging modalities and the history of surgical resection. It should not be "diagnostic modality driven": for each lesion and location, a modality appropriate for the anatomic site (for example: computed tomography or magnetic resonance imaging enterography, and colonoscopy) will be used. A total of 24 centers from 15 countries will be involved in a cross-sectional study, which will include up to 240 patients with stratification according to disease location and duration. At least 120 additional patients will be included in the study to validate the score. The Lémann score is expected to be able to portray a patient's disease course on a double-axis graph, with time as the x-axis, bowel damage severity as the y-axis, and the slope of the line connecting data points as a measure of disease progression. This instrument could be used to assess the effect of various medical therapies on the progression of bowel damage.

Patient outcomes after anti TNF-alpha drugs for Crohn's disease.

Crohn's disease (CD) is a chronic inflammatory bowel disease with a relatively high prevalence rate in North America. More than 50% of CD patients require surgery at some stage of their disease. Anti-TNF-alpha drugs are increasingly being used in patients with CD who have had an inadequate response to conventional therapy. Treatment with anti-TNF-alpha agents aims at improving symptom control and reducing the need for hospitalization and surgery. This review examines the clinical effectiveness of three anti-TNF-alpha agents (infliximab, adalimumab and etanercept) in moderate and severe CD. The review further considers the evidence for the harms and benefits associated with switching from one anti-TNF-alpha agent to another and strategies to optimize the timing of therapy.

Design of treatment trials for functional gastrointestinal disorders.

This document addresses the design of trials to assess the efficacy of new treatments for functional gastrointestinal disorders (FGID), emphasizing trials in irritable bowel syndrome and dyspepsia, because most research has been undertaken in these conditions. The double-blind, randomized, placebo-controlled, parallel group trial remains the preferred design. Randomized withdrawal designs, although encouraged by the European Agency for the Evaluation of Medicinal Products, have the same potential disadvantages as a crossover design, including carryover effects, unmasking (unblinding), and overestimation of the potential benefit for clinical practice. Innovative trial designs that evaluate intermittent (on demand) treatment are likely to become more common in the future. Investigators should include as broad a spectrum of patients as possible and should report recruitment strategies, inclusion/exclusion criteria, and attrition data. The primary analysis should be based on the proportion of patients in each treatment arm who satisfy an a priori treatment responder definition, or a prespecified clinically meaningful change in a patient-reported symptom improvement measure. Such measures of improvement are psychometrically validated subjective global assessments or a change from baseline in a validated symptom severity questionnaire. It is unethical to change the responder definition after a trial begins. Data analysis should address all patients enrolled, using an intention-to-treat principle. Reporting of results should follow the Consolidated Standards for Reporting Trials guidelines and include an analysis of harms data and secondary outcome measures to support or explain the primary outcome. Trials should be registered in a public location, prior to initiation, and should be published even if the results are negative or inconclusive.