Impact of regurgitation on health-related quality of life in gastro-oesophageal reflux disease before and after short-term potent acid suppression therapy.

OBJECTIVE: Limited data exist on the impact of regurgitation on health-related quality of life (HRQOL) in gastro-oesophageal reflux disease (GORD). We assessed the relationship between regurgitation frequency and HRQOL before and after acid suppression therapy in GORD. METHOD: We used data from two randomised trials of AZD0865 25-75 mg/day versus esomeprazole 20 or 40 mg/day in non-erosive reflux disease (NERD) (n=1415) or reflux oesophagitis (RO) (n=1460). The Reflux Disease Questionnaire was used to select patients with frequent and intense heartburn for inclusion and to assess treatment response. The Quality of Life in Reflux and Dyspepsia (QOLRAD) questionnaire was used to assess HRQOL. RESULTS: At baseline, 93% of patients in both the NERD and RO groups experienced regurgitation. Mean QOLRAD scores were similar for NERD and RO at baseline and at week 4 and disclosed decremental HRQOL with increasing frequency of regurgitation; a clinically relevant difference of >0.5 in mean QOLRAD scores was seen with regurgitation ≥4 days/week versus <4 days/week. The prevalence of frequent, persistent regurgitation (≥4 days/week) at week 4 among heartburn responders (≤1 day/week of mild heartburn) was 28% in NERD and 23% in RO. QOLRAD scores were higher among heartburn responders. There was a similar pattern of impact related to regurgitation frequency in heartburn responders compared with the group as a whole. CONCLUSIONS: Frequent regurgitation was associated with a clinically relevant, incremental decline in HRQOL beyond that associated with heartburn before and after potent acid suppression in both NERD and RO. CLINICAL TRIAL NUMBERS: NCT00206284 and NCT00206245.

Regurgitation is less responsive to acid suppression than heartburn in patients with gastroesophageal reflux disease.

BACKGROUND & AIMS: Although most patients with gastroesophageal reflux disease (GERD) achieve substantial symptom relief with acid suppression, many have some residual symptoms. We evaluated the responsiveness of regurgitation, characterized by the reflux disease questionnaire (RDQ) to potent acid suppression. METHODS: We analyzed data from 2 randomized controlled trials of AZD0865 (a potassium-competitive acid blocker) 25-75 mg/day vs esomeprazole 20-40 mg/day for the treatment of nonerosive reflux disease (NERD, n = 1460) or reflux esophagitis (RE, n = 1514). Inclusion criteria for both studies were high-severity substernal burning (≥4 days per week of at least moderate intensity) during the week before enrollment. Pooled data from all treatment arms were used to ascertain the response of the reflux disease questionnaire regurgitation items to potent acid suppression during the fourth week of treatment. RESULTS: When the study began, 93% of patients with NERD or RE had either "acid taste in the mouth" (regurgitation-taste) or "unpleasant movement of material upwards from the stomach" (regurgitation-movement). Either or both symptoms were present and severe in 53% of NERD (n = 717) and 54% of RE patients (n = 751) for the main study outcome. During week 4 of therapy, patients with severe "regurgitation-taste" and "regurgitation-movement" responded significantly less well than patients with NERD and high severity "substernal burning" (34% and 26% vs 49%) or those with RE (44% and 33% vs 55%). There were no differences in symptom response between patients with healed and nonhealed RE. CONCLUSIONS: Regurgitation was less responsive to acid suppression than heartburn in patients with gastroesophageal reflux disease, indicating that persistent regurgitation is a common cause of incomplete treatment response.

Concomitant symptoms itemized in the Reflux Disease Questionnaire are associated with attenuated heartburn response to acid suppression.

OBJECTIVES: The Reflux Disease Questionnaire (RDQ) contains six symptom items for diagnosing and gauging gastroesophageal reflux disease (GERD) severity. However, clinical trials have generally focused only on the "substernal burning" item and limited data exist on the effect of concomitant items on the treatment response of "substernal burning". METHODS: Data from two large randomized trials of AZD0865 25-75 mg/day vs. esomeprazole 20 or 40 mg/day in patients with GERD defined by moderate to severe (≥ 4 days per week) "substernal burning" (non-erosive reflux disease (NERD), N = 1,460; reflux esophagitis (RE), N = 1,514) were re-analyzed. As no differences were found between drugs or doses in treatment response of "substernal burning", pooled data were used to determine the impact of additional RDQ items on the response of "substernal burning" to acid suppression. RESULTS: At baseline, patients reported an average of four RDQ items. "Substernal burning" was the most responsive to therapy in the 3.3% of individuals with this as their only baseline RDQ symptom. The report of any other RDQ item was associated with a reduction in the responsiveness of "substernal burning" to acid suppression (e.g., RE patients with high severity "dyspepsia-pain" had an odds ratio of 0.20 for an improvement in "substernal burning" to treatment). CONCLUSIONS: Other concomitant RDQ items, particularly "substernal pain" or "dyspepsia-pain", were associated with a reduced treatment effect of acid suppression on "substernal burning". These findings support the use of a more comprehensive assessment of disease state and treatment response in GERD trials and clinical practice.

Systematic review: symptom assessment using patient-reported outcomes in gastroesophageal reflux disease and dyspepsia.

OBJECTIVE: The importance of symptom assessment using patient-reported outcomes (PROs) is becoming increasingly recognized in the management of upper gastrointestinal (GI) disease. The authors aimed to review systematically the methodological aspects of PRO instrument development and use in the GERD or dyspepsia literature, and to assess these instruments' properties in light of the Food and Drug Administration's (FDA) guidance. MATERIAL AND METHODS: Systematic PubMed and Embase searches (using terms based on the FDA guidance) identified studies that reported methodological aspects in developing or using PRO instruments for GERD or dyspepsia symptom measurement. RESULTS: Ten studies were identified (six systematically and four from citation lists). Studies reported the development or use of a relevant PRO instrument, with a focus on methodological aspects that the FDA guidance describes as important for patient understanding. Studies demonstrated heterogeneity of recall periods, symptoms and response options. Two studies demonstrated that a lack of consistent vocabulary may contribute to discrepancy in symptom reporting between investigators and patients. Two studies indicated that symptoms must be described in a manner that is relevant to patients. One study described the development of a PRO instrument separately in two languages, acknowledging linguistic and cultural differences between populations. One study demonstrated changes in symptom severity based on the recall period. CONCLUSIONS: There is considerable heterogeneity in the methodology used to develop PRO instruments for upper GI disease. Adherence to best practices in PRO development and validation may improve the quality and utility of these measures, leading to improved communication in clinical practice.

Patient satisfaction with medication for gastroesophageal reflux disease: a systematic review.

BACKGROUND: Patient satisfaction is increasingly regarded as an important aspect of measuring treatment success in individuals with gastroesophageal reflux disease (GERD). OBJECTIVE: To review how satisfied patients with GERD are with their medication, and to analyze the usefulness of patient satisfaction as a clinical end point by comparing it with symptom improvement. METHODS: Systematic searches of the PubMed and EMBASE databases identified clinical trials and patient surveys published between 1966 and 2009. RESULTS: Twelve trials reported that 56% to 100% of patients were 'satisfied' or 'very satisfied' with proton pump inhibitor (PPI) treatment for GERD. Patient satisfaction levels were higher for PPIs than other GERD medications in two trials. The sample-size-weighted average proportion of patients 'satisfied' with their PPI after four weeks of treatment in trials was 93% (95% CI 87% to 99%), with 73% (95% CI 62% to 83%) being 'very satisfied'. In four surveys, the average proportion of patients 'satisfied' with their PPI treatment was 82% (95% CI 73% to 90%) and 62% (95% CI 48% to 75%) were 'very satisfied'. Seven trials found a positive association between patient satisfaction and symptom improvement, and two surveys between satisfaction and improved health-related quality of life. Three trials found that continuous treatment yielded higher rates of satisfaction than on-demand therapy. CONCLUSIONS: More than one-half of patients were satisfied with their PPI medication in trials, and more patients were satisfied with PPIs than other medication types. An association between patient satisfaction and symptom resolution was found, suggesting that patient satisfaction is a useful end point for evaluating GERD treatment success.

Response of unexplained chest pain to proton pump inhibitor treatment in patients with and without objective evidence of gastro-oesophageal reflux disease.

INTRODUCTION: Unexplained chest pain is potentially attributable to gastro-oesophageal reflux disease (GORD) or oesophageal motility disorders. Reflux chest pain may occur without heartburn. We explored the response of unexplained chest pain to proton pump inhibitor (PPI) therapy in randomised clinical trials (RCTs), differentiating patients with and without objective evidence of GORD. METHODS: PubMed and Embase were systematically searched for RCTs that reported chest pain response to PPIs in patients who had had pH-monitoring and/or endoscopy to differentiate GORD-positive from GORD-negative subpopulations. Heterogeneity among studies was assessed using the Cochran Q and I(2) statistics, and a fixed effect model was applied. Possible publication bias was assessed by Egger's test. RESULTS: Six RCTs met the inclusion criteria. All used 24 h pH monitoring and/or endoscopy to define GORD-positive patients and improvement in chest pain to define response (five used ≥50%; one used ≥ 20%). The therapeutic gain of >50% improvement with PPIs relative to placebo was 56-85% in GORD-positive and 0-17% in GORD-negative patients. The RR of >50% improvement in chest pain with PPI versus placebo was 4.3 (95% CI 2.8 to 6.7; p<0.0001) for GORD-positive and 0.4 (95% CI 0.3 to 0.7; p=0.0004) for GORD-negative patients. Concomitant heartburn varied among trials from being an exclusion criterion to being essentially concordant with GORD-positive status. CONCLUSIONS: Unexplained chest pain in patients with endoscopic or pH-monitoring evidence of GORD tends to improve, but not resolve, with PPI therapy, whereas GORD-negative patients have little or no response. Heartburn was a poor predictor of whether patients with chest pain were GORD-positive or GORD-negative by objective testing.

Response of regurgitation to proton pump inhibitor therapy in clinical trials of gastroesophageal reflux disease.

OBJECTIVES: The typical symptoms of gastroesophageal reflux disease (GERD) are heartburn and regurgitation. Extensive analysis has characterized heartburn and its responsiveness to proton pump inhibitor (PPI) therapy, but regurgitation has received relatively little attention. This study aimed to evaluate the response of regurgitation to PPI therapy in GERD trials. METHODS: Studies were identified by systematic searches in PubMed and Embase, as well as searching congress abstracts and the reference lists of Cochrane reviews. RESULTS: Regurgitation was not an entry criterion or the primary end point in any of the 31 clinical trials reporting the response of regurgitation to PPI treatment in GERD. The definitions of regurgitation and responsiveness varied among trials and over half used investigator assessment of response. Owing to these inconsistencies, no meta-analysis was attempted. In seven placebo-controlled trials of PPI therapy, the therapeutic gain for regurgitation response averaged 17% relative to placebo and was >20% less than that observed for heartburn. Studies comparing PPIs with histamine-2 receptor antagonists or prokinetics found the comparator drug response similar to the placebo response rates seen in the placebo-controlled trials. CONCLUSIONS: The therapeutic gain with PPIs over placebo or comparator agents for the relief of regurgitation is modest, and considerably lower than for heartburn. Thus, regurgitation is likely to be an important factor for determining incomplete response to PPI treatment in GERD. Future trials would benefit from using regurgitation as a primary end point, applying an unambiguous definition of the symptom and of a positive treatment response, and using a validated patient-reported instrument for regurgitation assessment.

Human mesenchymal stem cell differentiation to NP-like cells in chitosan-glycerophosphate hydrogels.

Intervertebral disc (IVD) degeneration is one of the major causes of low back pain. As current clinical treatments are aimed at restoring biomechanical function and providing symptomatic relief, interest in methods focused on biological repair has increased. Several tissue engineering approaches using different cell types and hydrogels/scaffolds have been proposed. Owing to the unsuitable nature of degenerate cells for tissue engineering attention has focused on the use of mesenchymal stem cells (MSCs). Additionally, while rigid scaffolds have been demonstrated to allow MSC differentiation to the chondrocyte-like cells of the IVD, hydrogels are being increasingly studied as they allow minimally invasive implantation without extensive damage to the IVD. Here, we have studied the temperature-sensitive hydrogel chitosan-glycerophosphate (C/Gp), seeded with human MSCs and cultured for 4 weeks in standard medium. We have analysed the gene and protein expression profile of the MSCs and compared it to that of both nucleus pulposus (NP) cells and articular chondrocytes cultured in C/Gp. Gene expression analysis for chondrocytic-cell marker genes demonstrated differentiation of MSCs to a phenotype which showed similarities to both articular chondrocytes and NP cells. Conventional PCR demonstrated a lack of expression of osteogenic marker genes and the hypertrophic marker gene type X collagen. MSCs also secreted both proteoglycans and collagens in a ratio, which more closely resembled that of NP cells than articular chondrocytes. These results therefore suggest that MSC-seeded C/Gp gels could be used clinically for the regeneration of the degenerate human IVD.

Response of chronic cough to acid-suppressive therapy in patients with gastroesophageal reflux disease.

BACKGROUND: Epidemiologic and physiologic studies suggest an association between gastroesophageal reflux disease (GERD) and chronic cough. However, the benefit of antireflux therapy for chronic cough remains unclear, with most relevant trials reporting negative findings. This systematic review aimed to reevaluate the response of chronic cough to antireflux therapy in trials that allowed us to distinguish patients with or without objective evidence of GERD. METHODS: PubMed and Embase systematic searches identified clinical trials reporting cough response to antireflux therapy. Datasets were derived from trials that used pH-metry to characterize patients with chronic cough. RESULTS: Nine randomized controlled trials of varied design that treated patients with acid suppression were identified (eight used proton pump inhibitors [PPIs], one used ranitidine). Datasets from two crossover studies showed that PPIs significantly improved cough relative to placebo, albeit only in the arm receiving placebo fi rst. Therapeutic gain in seven datasets was greater in patients with pathologic esophageal acid exposure (range, 12.5%-35.8%) than in those without (range, 0.0%-8.6%), with no overlap between groups. CONCLUSIONS: A therapeutic benefit for acid-suppressive therapy in patients with chronic cough cannot be dismissed. However, evidence suggests that rigorous patient selection is necessary to identify patient populations likely to be responsive, using physiologically timed cough events during reflux testing, minimal patient exclusion because of presumptive alternative diagnoses, and appropriate power to detect a modest therapeutic gain. Only then can we hope to resolve this vexing clinical management problem.