Randomised clinical trial: addition of alginate-antacid (Gaviscon Double Action) to proton pump inhibitor therapy in patients with breakthrough symptoms.

BACKGROUND: Symptomatic breakthrough in proton pump inhibitor (PPI)-treated gastro-oesophageal reflux disease (GERD) patients is a common problem with a range of underlying causes. The nonsystemic, raft-forming action of alginates may help resolve symptoms. AIM: To assess alginate-antacid (Gaviscon Double Action, RB, Slough, UK) as add-on therapy to once-daily PPI for suppression of breakthrough reflux symptoms. METHODS: In two randomised, double-blind studies (exploratory, n=52; confirmatory, n=262), patients taking standard-dose PPI who had breakthrough symptoms, assessed by Heartburn Reflux Dyspepsia Questionnaire (HRDQ), were randomised to add-on Gaviscon or placebo (20 mL after meals and bedtime). The exploratory study endpoint was change in HRDQ score during treatment vs run-in. The confirmatory study endpoint was "response" defined as ≥3 days reduction in the number of "bad" days (HRDQ [heartburn/regurgitation] >0.70) during treatment vs run-in. RESULTS: In the exploratory study, significantly greater reductions in HRDQ scores (heartburn/regurgitation) were observed in the Gaviscon vs placebo (least squares mean difference [95% CI] -2.10 [-3.71 to -0.48]; P=.012). Post hoc "responder" analysis of the exploratory study also revealed significantly more Gaviscon patients (75%) achieved ≥3 days reduction in "bad" days vs placebo patients (36%), P=.005. In the confirmatory study, symptomatic improvement was observed with add-on Gaviscon (51%) but there was no significant difference in response vs placebo (48%) (OR (95% CI) 1.15 (0.69-1.91), P=.5939). CONCLUSIONS: Adding Gaviscon to PPI reduced breakthrough GERD symptoms but a nearly equal response was observed for placebo. Response to intervention may vary according to whether symptoms are functional in origin.

Systematic review: quality of trials on the symptomatic effects of the low FODMAP diet for irritable bowel syndrome.

BACKGROUND: The low Fermentable Oligo-, Di- Monosaccharides, and Polyoles (FODMAP) diet is a new treatment option for irritable bowel syndrome (IBS). Experts refer to the diet as supported by high level of evidence, but an evaluation of the quality of trials is lacking. AIM: To provide a systematic review of the quality of trials on the symptomatic effects of the low FODMAP diet for IBS. METHODS: Pubmed and EMBASE were searched for randomised controlled trials (RCTs) reporting effect of the low FODMAP diet on IBS symptoms. The quality of trials was evaluated by estimating risk of bias and assessing trial methodology. RESULTS: Nine RCTs were eligible, including 542 patients. The intervention period was from 2 days to 6 weeks and one trial included a 6-month follow-up. Three trials intervened by providing meals, controlling with a diet high in FODMAP content. In six trials, the intervention was instruction by a dietician and a variety of control interventions were used, all with limited established efficacy. Domains with a high risk of bias were identified for all the trials. High risk of bias dominated domains regarding blinding, with only one trial double-blinded. CONCLUSIONS: The RCTs on the low FODMAP diet are characterized by high risk of bias. The diet has not been studied in a randomised, controlled setting for more than 6 weeks and trials examining the effect of the important reintroduction period are lacking. There is a risk that the symptomatic effects reported in the trials are driven primarily by a placebo response.

The epidemiology of irritable bowel syndrome: Symptom development over a 3-year period in Denmark. A prospective, population-based cohort study.

BACKGROUND: We aimed to explore the natural history of irritable bowel syndrome (IBS) in Denmark over 3 years by studying development of IBS symptoms and associated factors. METHODS: A cohort study was carried out using a web panel representative of the Danish general population 18-50 years. The survey, including a questionnaire based on the Rome III criteria for IBS, was conducted in January 2010, January 2011, and March 2013. KEY RESULTS: The prevalence of IBS was 15.4% (920/5986). The incidence was 10.3%, and was three times higher for persons with unspecific gastrointestinal (GI) symptoms compared to asymptomatic persons. Of respondents with IBS symptoms in both 2010 and 2011, 69% (131/191) also reported symptoms of IBS in 2013, which was significantly more compared to respondents with IBS symptoms in 2010 reporting to be asymptomatic or having unspecific GI symptoms in 2011 (20% and 39%, respectively, P<.001). Being diagnosed with IBS predicted fulfilling the criteria for IBS 3 years later (OR: 2.59, 95% CI: 1.11-6.10). Fulfilling criteria for IBS after 1 year also led to a high risk of IBS symptoms 3 years later in asymptomatic persons and persons with unspecific symptoms at baseline. CONCLUSIONS & INFERENCES: The vast majority of persons fulfilling criteria for IBS report GI symptoms after one and 3 years. Fulfilling IBS criteria after 1 year led to a high risk of reporting IBS symptoms after 3 years. In the general population having an IBS diagnosis predicts persistently fulfilling the Rome III criteria for IBS 3 years later.

Randomised clinical trial: alginate (Gaviscon Advance) vs. placebo as add-on therapy in reflux patients with inadequate response to a once daily proton pump inhibitor.

BACKGROUND: Many reflux patients remain symptomatic on a standard dose of proton pump inhibitor (PPI). Alginates decrease the number of reflux events by forming a raft on top of the stomach content and thus offer a supplemental mechanism of action to acid suppression. AIM: To assess the efficacy of an alginate (Gaviscon Advance, Reckitt Benckiser, Slough, UK) on reflux symptoms in patients with persistent symptoms despite once daily PPI. METHODS: This was a multicentre, randomised, placebo-controlled, 7-day double-blind trial preceded by a 7-day run-in period. Reflux symptoms were assessed using the Heartburn Reflux Dyspepsia Questionnaire (HRDQ). Based on symptom score during run-in, eligible patients were randomised to Gaviscon Advance 10 mL four times a day or placebo in addition to a once daily PPI. The primary endpoint was change in HRDQ score post-treatment compared to baseline. RESULTS: One hundred and thirty-six patients were randomised. Change in HRDQ reflux score was significantly greater for Gaviscon Advance (mean: -5.0, s.d.: 4.7) than for placebo (mean: -3.5, s.d.: 5.5) with an LS mean difference of 1.6 [95% CI -3.1 to -0.1], P = 0.03. A decrease in the mean (s.d.) number of nights with symptoms was observed from 3.6 (2.8) to 3.0 (3.0) in the placebo group and from 3.9 (2.8) to 2.2 (2.7) for the Gaviscon Advance group. This reduction was significantly greater in the Gaviscon Advance group than in the placebo group [LS mean difference = -0.9, 95% CI (-1.6 to -0.2), P < 0.01]. CONCLUSION: In patients with residual reflux symptoms despite PPI treatment, adding an alginate offers additional decrease in the burden of reflux symptoms (EudraCT/IND Number: 2011-005486-21).

Use of acid-suppressive therapy before anti-reflux surgery in 2922 patients: a nationwide register-based study in Denmark.

BACKGROUND: Guidelines recommend that patients with gastro-oesophageal reflux disease are adequately treated with acid-suppressive therapy before undergoing anti-reflux surgery. Little is known of the use of acid-suppressive drugs before anti-reflux surgery. AIM: To determine the use of proton pump inhibitors and H2 -receptor antagonists in the year before anti-reflux surgery. METHODS: A nationwide retrospective study of all patients aged ≥18 undergoing first-time anti-reflux surgery in Denmark during 2000-2012 using data from three different sources: the Danish National Register of Patients, the Danish National Prescription Register, and the Danish Person Register. RESULTS: The study population thus included 2922 patients (median age: 48 years, 55.7% male). The annual proportion of patients redeeming ≥180 DDD of acid-suppressive therapy increased from 17.0% 5 years before anti-reflux surgery to 64.9% 1 year before. The probability for inadequate dosing 1 year before surgery (<180 DDD) was significantly increased for younger patients, patients operated in the period 2000-2003, patients who had not undergone pre-surgical manometry, pH- or impedance monitoring, and patients who had not redeemed prescriptions on NSAID or anti-platelet drugs. CONCLUSION: Compliance with medical therapy should be evaluated thoroughly before planning anti-reflux surgery, as a high proportion of patients receive inadequate dosing of acid-suppressive therapy prior to the operation.

Partial symptom-response to proton pump inhibitors in patients with non-erosive reflux disease or reflux oesophagitis - a post hoc analysis of 5796 patients.

BACKGROUND: Although most patients with gastro-oesophageal reflux disease (GERD) benefit from proton pump inhibitor (PPI) therapy, some experience only partial symptom relief. AIM: To determine the prevalence of partial heartburn response to PPIs and its impact on health-related quality of life. METHODS: Four randomised, double-blind studies in adults with reflux disease compared esomeprazole 40 mg/day or 20 mg/day with omeprazole 20 mg/day, or esomeprazole 40 mg/day with pantoprazole 40 mg/day. Patients with heartburn on ≥4 days during the 1-week recall period at baseline were included. Partial response was defined as heartburn on ≥3 days during the last treatment week and reduced heartburn frequency after 4 weeks of treatment compared with baseline. RESULTS: The analysis included 2645 patients with non-erosive reflux disease (mean age: 48.8 years; 54.4% women) and 3151 patients with reflux oesophagitis (mean age: 50.6 years; 37.1% women). At baseline, most patients reported heartburn on 5-7 days (non-erosive reflux disease: 82.2%; reflux oesophagitis: 86.8%). Partial heartburn response occurred in 19.9% of patients with non-erosive reflux disease and 14.0% with reflux oesophagitis. Defining partial response as heartburn on ≥2 days increased these rates to 26.2% and 19.3%, respectively; defining partial response as heartburn of moderate or severe intensity on ≥3 days decreased these rates to 6.4% and 5.3%, respectively. Nonresponse to PPIs was rare (non-erosive reflux disease: 2.4%; reflux oesophagitis: 1.4%). CONCLUSION: Using our conservative definition, partial heartburn response to proton pump inhibitor therapy occurred in 14-20% of gastro-oesophageal reflux disease patients, more commonly in non-erosive reflux disease than in reflux oesophagitis.

The Rome II and Rome III criteria identify the same subtype-populations in irritable bowel syndrome: agreement depends on the method used for symptom report.

BACKGROUND: For comparing trials using different classifications for irritable bowel syndrome (IBS) subtypes, it is important to know whether these identify the same sub-populations. Our aim was to determine the agreement between Rome II and Rome III subtypes, and to explore whether agreement depends on the symptom reporting method. METHODS: Rome II IBS patients from two identical, randomized placebo-controlled trials of probiotics were included. Retrospective subtypes were based on the Rome II questionnaire. Prospective subtypes were based on diary cards for 2 weeks of run-in. Agreement was determined between: (i) retrospective Rome II and Rome III, (ii) prospective Rome II and Rome III, (iii) retrospective Rome II and prospectively Rome III, (iv) retrospective and prospective Rome II, and (v) retrospective and prospective Rome III. KEY RESULTS: A total of 126 patients, 72% women, mean age 46 ± 15 years, were included. The agreement between subtypes using the same symptom reporting method was: (i) 90.3% (κ = 0.85) for retrospective subtypes, and (ii) 84% (κ = 0.76) for prospective subtypes. The agreement between subtypes using different symptom reporting methods was, (iii) 49% (κ = 0.23) for retrospective Rome II and prospective Rome III, (iv) 51% (κ = 0.26) for Rome II subtypes, and (v) 41% (κ = 0.25) for Rome III subtypes. CONCLUSIONS & INFERENCES: Agreement between Rome II and Rome III subtypes is good to very good when using the same symptom reporting method. When mixing methods, agreement is only fair even within the same classification. This has implications for comparison of trials using different symptom reporting methods for subtyping.

Short-term stability of subtypes in the irritable bowel syndrome: prospective evaluation using the Rome III classification.

BACKGROUND: In irritable bowel syndrome (IBS) subtyping is used in research and clinical practice. Knowledge of subtype stability is needed for proper design of trials and treatment strategies. AIMS: To evaluate the stability of Rome III IBS subtypes over time and to determine the optimal time period for prospective, diary-based subtyping. METHODS: Rome III IBS patients aged 18-70 years enrolled in two identical, randomised, placebo-controlled trials of probiotics, were included. No difference was found on stool pattern, thus patients were analysed as one group. Patients scored defaecations according to Bristol Stool Form Scale for 10 weeks. IBS subtypes were determined for all 1- and 2-week periods. Subtype distribution and stool pattern over time were determined. The proportions of patients having the same subtype all weeks (stable patients) or having a predominant subtype (same subtype ≥60% of time) were determined. RESULTS: A total of 126 patients, mean age 46 ± 15 years, 72% women were included. Subtype distribution was similar over time with IBS with constipation, IBS with diarrhoea and IBS unsubtyped constituting one-third of the population each. Even though only 18-35% had the same subtype all weeks, the majority of patients had the same subtype for ≥60% of time (82-98%). Sixty-nine per cent had the same predominant and baseline subtypes. Two-week data increased the proportion of stable patients, of patients with a predominant subtype, and of patients who had similar baseline and predominant subtype. CONCLUSIONS: Most IBS patients change subtype over time. However, an underlying stool pattern stability was demonstrated in the majority of patients. To increase stability, we recommend 2-week data for IBS subtyping.

Randomised clinical trial: identification of responders to short-term treatment with esomeprazole for dyspepsia in primary care - a randomised, placebo-controlled study.

BACKGROUND: Response to proton pump inhibitor (PPI) treatment in dyspepsia is unpredictable. AIM: To identify symptoms associated with response to esomeprazole in order to target patients for empirical treatment. METHODS: Eight hundred and five uninvestigated, primary care patients with upper GI symptoms that were considered to be acid-related were randomised to 2 weeks' treatment with esomeprazole 40 mg or placebo. The study population was divided into a model sample (N = 484) and a validation sample (N = 321). We developed a therapeutic index to predict PPI response from the model sample and tested this in the validation sample. RESULTS: Response to PPI was found in 68% of patients (44% in placebo arm). Bothersome heartburn and early satiety were associated with increased likelihood of PPI response, whereas dull abdominal pain, pain relieved by bowel movements and nausea in women were associated with a decreased likelihood of PPI response. Patients in the validation sample could be classified as having a 'very high' (n = 55), 'high' (n = 123), 'medium' (n = 78) or 'low' (n = 65) probability of PPI response. The therapeutic gains over placebo were 55%, 31%, 20% and 22%, respectively. CONCLUSIONS: In patients with uninvestigated dyspepsia, PPI responders can be reliably identified by a simple pocket chart using symptoms and patient characteristics (ClinicalTrials.gov NCT00318968).

Clinical trial: long-term use of proton pump inhibitors in primary care patients - a cross sectional analysis of 901 patients.

BACKGROUND: The use of proton pump inhibitors (PPIs) is extensive. While the incidence of new treatments remains stable, the prevalence of long-term treatment is rising. Studies have shown that up to 70% of patients on chronic acid suppression lack a verified indication for treatment. AIMS: To investigate primary care patient characteristics associated with long-term use of PPIs. METHODS: A cross-sectional analysis of 42,634 patients registered with 22 general practitioners was performed. Patients with prescriptions of > or =120 tablets/year were defined as long-term users. A survey of a subgroup of patients without verified indication was performed. RESULTS: In all, 901 (2.1%) patients were long-term treated. Verified indications for treatment were identified for 247/901 (27%). An upper GI endoscopy had been performed in 418 patients (46%). Of the 194/654 without verified indication who participated in the survey, 71% reported heartburn/acid regurgitation as the reason for therapy. On-demand therapy was reported by 43/194 (22%) and previous attempts to withdraw by 119/194 (61%). CONCLUSIONS: The prevalence of PPI long-term treatment among primary care patients is 2.1%. The main reason for treatment is reflux symptoms or verified GERD. Rationalization of use of PPIs is possible as daily treatment without attempts to discontinue is frequently observed.

Appropriateness of colonoscopy in Europe (EPAGE II). Screening for colorectal cancer.

BACKGROUND AND STUDY AIMS: To summarize the published literature on assessment of appropriateness of colonoscopy for screening for colorectal cancer (CRC) in asymptomatic individuals without personal history of CRC or polyps, and report appropriateness criteria developed by an expert panel, the 2008 European Panel on the Appropriateness of Gastrointestinal Endoscopy, EPAGE II. METHODS: A systematic search of guidelines, systematic reviews, and primary studies regarding colonoscopy for screening for colorectal cancer was performed. The RAND/UCLA Appropriateness Method was applied to develop appropriateness criteria for colonoscopy in these circumstances. RESULTS: Available evidence for CRC screening comes from small case-controlled studies, with heterogeneous results, and from indirect evidence from randomized controlled trials (RCTs) on fecal occult blood test (FOBT) screening and studies on flexible sigmoidoscopy screening. Most guidelines recommend screening colonoscopy every 10 years starting at age 50 in average-risk individuals. In individuals with a higher risk of CRC due to family history, there is a consensus that it is appropriate to offer screening colonoscopy at < 50 years. EPAGE II considered screening colonoscopy appropriate above 50 years in average-risk individuals. Panelists deemed screening colonoscopy appropriate for younger patients, with shorter surveillance intervals, where family or personal risk of colorectal cancer is higher. A positive FOBT or the discovery of adenomas at sigmoidoscopy are considered appropriate indications. CONCLUSIONS: Despite the lack of evidence based on randomized controlled trials (RCTs), colonoscopy is recommended by most published guidelines and EPAGE II criteria available online (http://www.epage.ch), as a screening option for CRC in individuals at average risk of CRC, and undisputedly as the main screening tool for CRC in individuals at moderate and high risk of CRC.

Clinical trial: the glucagon-like peptide-1 analogue ROSE-010 for management of acute pain in patients with irritable bowel syndrome: a randomized, placebo-controlled, double-blind study.

BACKGROUND: There is currently no treatment available to manage acute pain attacks in IBS patients regardless of subtype. AIMS: To evaluate efficacy and safety of the GLP-1 analogue ROSE-010 in patients with irritable bowel syndrome (IBS) through a randomized, double-blind, placebo-controlled study. METHODS: Eligible patients (n = 166) meeting Rome II criteria were randomly assigned to receive single subcutaneous injections of ROSE-010 100 microg, 300 microg and placebo in a cross-over design. Safety was assessed from spontaneously reported adverse events and measurement of vital signs. Patient-rated pain relief and intensity were measured on a 100-mm visual analogue scale. The primary efficacy variable was proportion of patients with >50% maximum total pain relief response from 10 to 60 min after treatment. Secondary endpoints included the maximum summed pain intensity difference, time to meaningful pain relief and patient ratings of satisfaction with treatment. RESULTS: Twice as many patients were responders in the primary efficacy endpoint after both ROSE-010 injections compared to placebo (24%P = 0.011, 23%P = 0.005, and 12% after 300 microg, 100 microg and placebo injections, respectively). Similar results were obtained for the proportion of patients with total pain intensity response. Times to meaningful and total pain relief were shorter for both doses of ROSE-010 compared with placebo. Compared with placebo, more patients (P < 0.05) were satisfied with ROSE-010 and considered ROSE-010 better than previous IBS medications used. CONCLUSION: ROSE-010 was well tolerated and provided fast and effective relief of acute pain attacks on demand in IBS patients.

Clinical trial design in adult reflux disease: a methodological workshop.

BACKGROUND: The development of well-tolerated acid suppressant drugs has stimulated substantial growth in the number of trials assessing therapy options for gastro-oesophageal reflux disease (GERD). AIM: To develop consensus statements to inform clinical trial design in adult patients with GERD. METHODS: Draft statements were developed employing a systematic literature review. A modified Delphi process including three rounds of voting was used to reach consensus. Between voting, statements were revised based on feedback from the Working Group and additional literature reviews. The final vote was at a face-to-face meeting that included discussion time. Voting was conducted using a six-point scale. RESULTS: At the last vote, 93% of the final 102 statements achieved consensus (defined a priori as being supported by >or=75% of the votes). The Working Group strongly supported the development of validated patient-reported outcome instruments. Symptom assessments carried out by the investigator were considered unacceptable. There was agreement that exclusion from clinical trials should be minimized to improve generalizability, that prospective evaluation ideally requires electronic timed/dated methods and that endoscopists should be blinded to patient symptom status. CONCLUSIONS: Implementation of the consensus statements will improve the quality and comparability of trials, and make them compatible with regulatory requirements.

The validity of a symptom diary in ratings of dyspepsia measured against a detailed interview: do patients and clinicians agree in their assessment of symptoms?

BACKGROUND: Patients' self-assessment of symptoms is central in drug treatment trials of functional dyspepsia. The validity of such ratings is important. AIM: To validate a diary for monitoring severity and duration of dyspepsia. METHOD: We compared the diary-cards with two clinicians' ratings of the patient's open-ended responses to the same questions administered by interview. Agreements were evaluated by estimation of the overall agreement and weighted kappa values (Kw). RESULTS: Forty-six patients were evaluated. The Kw between the two clinicians rating severity and duration of symptoms were 0.59 and 0.86, respectively. Overall agreement between patients' diary rating and clinicians' consensus rating of severity were 52%, and a moderate agreement with Kw of 0.49 was found. For duration of symptoms the overall agreement and Kw were 67% and 0.59, respectively. Qualitative data revealed useful insight in the possible causes of suboptimal agreement between patients and clinicians. CONCLUSIONS: We found a moderate to good agreement between patient and observer ratings, indicating that patients to a reasonable extent interpret severity and duration of dyspeptic symptoms in the same way as do investigators. A ceiling effect of the duration scale indicates suboptimal response categories, which should be adjusted before further use.

Impact of an information video before colonoscopy on patient satisfaction and anxiety - a randomized trial.

BACKGROUND AND STUDY AIMS: Anxiety before colonoscopy may have adverse consequences and increase requirements for sedation and analgesics. We aimed to examine the effects of adding an information video to our usual preprocedural information. PATIENTS AND METHODS: 162 colonoscopy patients were randomly assigned to video (72) or no video (90) groups. Patients in the video group watched a video on colonoscopy procedures and cleansing. The patients' situational anxiety was measured using the State-Trait Anxiety Inventory (STAI) questionnaire. Patients rated pain and overall satisfaction related to the procedure. The colonoscopist and the endoscopy nurse, who were blinded to the patient's allocation, completed questionnaires on use of medication, procedure outcome, and their assessments of patient pain and toleration of the procedure. RESULTS: There were no differences between the two groups concerning situational anxiety (mean STAI-State score 45.0 +/- 13.3 vs. 45.9 +/- 12.9, P = 0.7), rating of pain, tolerability of the procedure, or the willingness to undergo a future colonoscopy. The staff rated the outcomes equally in the two groups. There was no difference in use of midazolam, but patients, who had seen the video used higher doses of fentanyl ( P < 0.02). Situational anxiety ratings were significantly higher in women, and they found the procedure significantly more painful ( P = 0.001) and were less satisfied ( P < 0.05). CONCLUSIONS: An information video shown to patients preparing for colonoscopy had no impact on tolerability or anxiety. Colonoscopy is less tolerable and more painful for women and this is probably related to a higher degree of anxiety. Endoscopy personnel should be aware of these gender differences and adjust information and medication accordingly.