Randomized Controlled Trials of Proton-Pump Inhibitors in Nighttime GERD

Abstract

Purpose: To assess heterogeneity in enrollment criteria, methodology and methodological quality, and outcomes across randomized-controlled clinical trials (RCTs) evaluating the efficacy of proton-pump inhibitors (PPIs) in controlling nighttime symptoms of gastroesophageal reflux disease (GERD). Methods: MEDLINE and EMBASE databases from 1990 to June 2007 were searched. Studies were included if the design was a RCT, at least one treatment arm was PPI, the subjects were adults with nighttime GERD, and nighttime symptoms were assessed. The methodological quality of trials was evaluated using the score devised by Jadad et al (ranging from 1 = low to 5 = high). We also assessed nighttime criteria used for patient enrollment, nighttime outcomes measured, and the nighttime definition used. Results: Thirty-two RCTs compared the efficacy of PPI with placebo only (N = 7), H2-receptor antagonist only (N = 12), another PPI only (N = 11) or both placebo and H2-receptor antagonist (N = 2) in controlling nighttime GERD. Methodological quality of trials was high with 28 of the 32 trials attaining a Jadad score of at least 3 points. Source of data collection was patient daily diaries across all studies. The majority of studies assessed nighttime symptoms as a secondary outcome; erosive esophageal healing was usually the primary endpoint. Most studies assessed efficacy at 8 weeks or less; only 3 studies measured the long-term efficacy of PPI (pantoprazole [N = 2] and rabeprazole [N = 1]) for a year. Criteria for enrolling nighttime GERD patients (frequency and/or severity of nighttime symptoms) lacked consistency. Thirty studies (94%) assessed nighttime heartburn; few studies evaluated overall nighttime symptoms (N = 4) and only one study evaluated regurgitation as an independent outcome. Nighttime heartburn outcomes measured were percentage of patients without nighttime heartburn (N = 18), percentage of heartburn-free nights (N = 15), heartburn severity score (N = 11) or time to heartburn relief (N = 6). The time window for the assessment of nighttime symptoms was reported in only 3 studies (9%) and was not based on specific hours but on sleep or posture (retiring or lying down to sleep). Conclusion: RCTs of PPI therapy in nighttime GERD are of high methodological quality but are heterogeneous with respect to their definition of nighttime symptoms and outcomes. Consensus on diagnostic criteria for nighttime GERD would be anticipated to increase generalizability of results and guide the diagnosis and management of nighttime symptoms. Long-term observational studies may be helpful in translating the efficacy of PPI observed in clinical trials to real-world patients.