Dr P. O. Katz, Albert Einstein Medical Center, 5501 Old York Road, Philadelphia, PA 19141 USA. E-mail: email@example.com
Background : Patients with chronic heartburn but with no endoscopic evidence of erosive oesophagitis require gastric acid suppression to relieve symptoms.
Aim : To assess the efficacy and safety of esomeprazole in patients with frequent heartburn for ≥ 6 months and no evidence of erosive oesophagitis on endoscopy.
Methods : Two randomized, double-blind, 4-week, multi-centre trials with identical methodology compared once-daily esomeprazole, 40 mg (n = 241) or 20 mg (n = 234), with placebo (n = 242) for the rigorous end-point of complete resolution of heartburn. Secondary end-points included the percentage of heartburn-free days and the time to first and sustained resolution of heartburn.
Results : Patients treated with either dose of esomeprazole were two to three times more likely to achieve complete resolution of heartburn than patients treated with placebo (P < 0.001). The percentage of heartburn-free days was significantly higher with esomeprazole 40 mg (63%, 66%) or 20 mg (63%, 68%) than with placebo (46%, 36%; P ≤ 0.001) in each of the two studies. Esomeprazole was associated with a significantly shorter mean time to first (6–7 days) and sustained (12–17 days) resolution of heartburn compared with placebo (first, 10–12 days; sustained, 21–22 days; P ≤ 0.008). The spectrum and frequency of adverse events with esomeprazole were similar to those with placebo.
Conclusions : Esomeprazole, at daily doses of 40 mg or 20 mg, is effective and safe for the treatment of chronic heartburn in patients without erosive oesophagitis.
Chronic, persistent heartburn, the most common symptom of erosive and non-erosive forms of gastro-oesophageal reflux disease (GERD),1 affects 20–40% of the adult population in Western countries.2,3 Approximately one-half of patients with GERD have erosive oesophagitis or other mucosal damage, whereas the remaining half have no endoscopic evidence of oesophageal pathology.4 Because the severity of symptoms cannot reliably predict the presence of oesophageal erosions,5,6 endoscopy is the only method that can distinguish between erosive and non-erosive disease.
Acid reflux is the cause of heartburn in most patients with or without endoscopic evidence of oesophageal injury.1 Indeed, acid control with a proton pump inhibitor provides the highest level of efficacy when treating patients with endoscopy-negative reflux disease.7–9 However, between 33% and 40% of patients with endoscopy-negative disease have normal results on 24-h oesophageal pH monitoring, suggesting that even physiological acid exposure can trigger typical heartburn in some patients.8,10,11 Moreover, in a minority of patients, heartburn may be caused by pathologies unrelated to acid reflux.12
Esomeprazole is the first proton pump inhibitor to demonstrate improved effectiveness compared with other proton pump inhibitors for the treatment of patients with erosive GERD. In several multi-centre, double-blind, comparative trials, esomeprazole 40 mg was more effective than omeprazole 20 mg13,14 or lansoprazole 30 mg15 in achieving the resolution of heartburn and healing of erosions after up to 8 weeks of treatment in patients with endoscopically confirmed erosive oesophagitis. For maintenance therapy, esomeprazole 20 mg maintained healing in a higher percentage of patients compared with lansoprazole 15 mg following 6 months of treatment.16
These findings suggest that esomeprazole may also be effective for symptomatic relief in patients with chronic heartburn and a normal endoscopy (a disorder also referred to as non-erosive reflux disease or symptomatic GERD). Two double-blind, 4-week, randomized controlled clinical trials with identical methodology were conducted to evaluate the efficacy and safety of esomeprazole for the treatment of chronic heartburn in patients without erosive oesophagitis.
Materials and methods
Males and non-pregnant, non-lactating females between the ages of 18 and 75 years, with at least a 6-month frequent history of heartburn and no evidence of erosive oesophagitis, as confirmed by oesophago-gastro-duodenoscopy performed within 10 days of study randomization, were eligible for the study. Patients who had experienced episodes of heartburn for 4 days or more during the 7 days prior to baseline were included in the study. Females needed to be postmenopausal, surgically sterilized or using a medically acceptable form of birth control throughout the study.
Patients were excluded from the study if they had endoscopic evidence of Barrett's oesophagus or significant dysplastic changes in the oesophagus; any bleeding disorder or signs of gastrointestinal bleeding at the time of the screening oesophago-gastro-duodenoscopy or within 3 days prior to randomization; a past or current history of endoscopically confirmed erosive oesophagitis; a history of gastric or oesophageal surgery (except for simple closure of perforated ulcer); and past or current evidence of significant gastrointestinal disease (Zollinger–Ellison syndrome, primary oesophageal motility disorders, oesophageal stricture, duodenal or gastric ulcer, inflammatory bowel disease, upper gastrointestinal malignancy, pancreatitis or malabsorption) or other significant medical diseases. Other exclusion criteria included the use of a proton pump inhibitor within 28 days prior to the baseline visit; the use of H2-receptor antagonists daily during the 2 weeks prior to the screening oesophago-gastro-duodenoscopy and study enrolment (occasional use less than daily was permissible); and the need for continuous concurrent therapy within 1 week of randomization with quinidine, diazepam, diphenylhydantoins, mephenytoin, warfarin, anticholinergic agents, prostaglandin analogues, antineoplastic agents, salicylates (unless ≤ 165 mg daily for cardiovascular prophylaxis), corticosteroids, promotility drugs, sucralfate or non-steroidal anti-inflammatory drugs. Patients with a known hypersensitivity to esomeprazole or Gelusil were also excluded.
Two clinical studies, hereafter labelled ‘Study 1’ and ‘Study 2’, used identical study designs. Both were multi-centre, double-blind, randomized, placebo-controlled, parallel-group trials conducted at 26 and 27 centres, respectively, in the USA. Both studies were conducted in accordance with the principles of the Declaration of Helsinki and in compliance with good clinical practices regulations and guidance issued by the US Food and Drug Administration. The study protocols were reviewed and approved by local institutional review boards. All study participants provided written informed consent prior to study enrolment.
Three hundred and sixty-eight patients in Study 1 and 349 patients in Study 2 were randomized in a double-blind fashion to one of three treatment groups: esomeprazole 40 mg, esomeprazole 20 mg or placebo, administered orally once daily in the morning for up to 4 weeks. Blind blocks of six allocation numbers in a 1 : 1 : 1 ratio were used for randomization. To ensure the integrity of blinding, the three study drugs were identical in appearance. Investigators were provided with individually sealed and blind randomization envelopes indicating the treatment allocation for each patient, and all envelopes were collected and checked at the end of the study. Aluminium/magnesium hydroxide antacid therapy (Gelusil tablets) was permitted as rescue medication for acute breakthrough GERD symptoms, to a maximum of six tablets per day. Compliance was monitored by counting the amount of unused study drug returned at each follow-up visit.
Within 7 days prior to randomization, patients fulfilling the inclusion and exclusion criteria underwent the following baseline procedures: medical history, physical examination, vital signs, oesophago-gastro-duodenoscopy, gastric biopsy to determine Helicobacter pylori status (negative or positive), pregnancy test (females), GERD symptom assessment and standard clinical laboratory testing (serum chemistry, urinalysis and haematology).
Primary efficacy end-point. The proportion of patients with complete resolution of heartburn at the end of the study served as the primary efficacy end-point in both Study 1 and Study 2. Complete resolution of heartburn was defined as no episodes of heartburn during the last seven consecutive days of treatment and was documented by patients using daily heartburn diary cards. Patients were instructed to assess heartburn each morning during the study period, and record the severity of their worst heartburn episode during the 24-h period prior to that morning's study medication dose. Heartburn was graded on a four-point scale: none (no symptoms); mild (aware of symptoms, but easily tolerated); moderate (discomforting, sufficient to interfere with normal activities, including sleep); or severe (incapacitating, with inability to perform normal activities, including sleep). The presence of nocturnal heartburn was also recorded on the diary card. Patients submitted their daily heartburn diary cards at return visits (weeks 2 and 4).
Secondary efficacy end-points. Patients' diary cards were used to evaluate the percentage of heartburn-free days and nights, the time to first resolution of heartburn (defined as the first heartburn-free day using the diary assessment) and the time to sustained resolution of heartburn (defined as the time to the first of seven consecutive study days with no heartburn) and nocturnal heartburn (defined as the time to the first of seven consecutive study days with no nocturnal heartburn). In addition, efficacy was measured at weeks 2 and 4 by investigator assessment of the presence and severity of heartburn and acid regurgitation during the 7 days preceding the visit, and then compared with the same assessment performed at baseline. The severity of heartburn was graded using the same scale (none, mild, moderate, severe) as described above.
Overall treatment evaluation was another secondary assessment variable. At weeks 2 and 4, patients completed a questionnaire on which they were asked to rate their upper abdominal pain and/or discomfort as ‘better’, ‘about the same’ or ‘worse’, compared with the start of treatment. Patients reporting improvement rated the degree of change using a seven-grade scale: ratings ranged from ‘almost the same, hardly better at all’ to ‘a very great deal better’ for improvement. A similar seven-grade scale was completed by patients reporting worsening, ranging from ‘almost the same, hardly worse at all’ to ‘a very great deal worse.’ Patients reporting improvement or worsening also completed a seven-grade scale rating the importance of the improvement or worsening in carrying out their daily activities (from ‘not important’ to ‘extremely important’). For analysis, the questionnaire was combined into a 15-point scale comprising the seven-point improvement scale, the ‘about the same’ scale and the seven-point worsening scale.
Both studies used identical safety assessment parameters. All patients who received at least one dose of study medication were evaluated for adverse events, changes from baseline in vital signs at each follow-up visit and changes from baseline in laboratory test and physical examination results at week 4. Investigators assessed the relationship of each adverse event to the study drug as probable, possible or unlikely, and the intensity of each adverse event as mild, moderate or severe.
For each study, a sample size of 100 patients per treatment arm was calculated to have 95% power to detect a difference in resolution rates of 60% for esomeprazole treatment and 30% for placebo treatment. This calculation assumed a two-sided test using the arcsine transformation, and an alpha level of 0.025. In both studies, all summaries and analyses were performed using the statistical software package SAS System, Version 6.12 (SAS Institute, Cary, NC, USA).
For the primary efficacy analysis, a chi-square test was used to analyse differences between each esomeprazole dosage regimen and placebo, applying the Hochberg procedure to correct for multiple comparisons and maintain the level of significance at alpha = 0.05. For investigator-assessed GERD symptoms, between-group differences for the percentage of patients with symptom resolution were analysed using a Cochran–Mantel–Haenszel chi-squared test, stratified by baseline severity for each symptom.
A life-table approach was used to analyse the ‘time to’ variables, and a two-way analysis of variance (anova) model was used to analyse between-group differences for the percentage of heartburn-free days (24-h period) or heartburn-free nights. A log-rank test was used to evaluate between-group differences regarding the time to first and sustained heartburn resolution. A Wilcoxon rank sum test was used to analyse overall treatment evaluation results.
The demographic and baseline characteristics of the patient populations were similar in the two studies and between the treatment groups within each study (Table 1). In addition to heartburn, 90% of all patients had acid regurgitation at baseline.
Table 1. Demographics and baseline characteristics of the intention-to-treat study populations
Esomeprazole 40 mg (n = 123)
Esomeprazole 20 mg (n = 121)
Placebo (n = 124)
Esomeprazole 40 mg (n = 118)
Esomeprazole 20 mg (n = 113)
Placebo (n = 118)
GERD, gastro-oesophageal reflux disease.
Data were missing for three patients in Study 1 (two in the esomeprazole 20 mg group and one in the placebo group) and for two patients in Study 2 (one in the esomeprazole 40 mg group and one in the esomeprazole 20 mg group).
Three hundred and forty-four of 368 patients (93.5%) completed Study 1, and 320 of 349 patients (91.7%) completed Study 2. The most frequent reasons for study discontinuation were withdrawal of consent (Study 1, n = 9; Study 2, n = 4) and occurrence of an adverse event (Study 1, n = 3; Study 2, n = 8). In both studies, more than 90% of the patients in each treatment group had medication compliance rates of greater than 80%.
In both Study 1 and Study 2, a significantly higher percentage of patients treated with esomeprazole exhibited complete resolution of heartburn for the final 7 days of the study than those treated with placebo (Figure 1; P < 0.001).
Esomeprazole was significantly more effective than placebo for all secondary end-points evaluating heartburn resolution at week 4 (Figure 2 and Table 2). Analysis of the patients' diary data showed a higher mean percentage of heartburn-free days at week 4 (Figure 2) in patients receiving esomeprazole than in those receiving placebo (P ≤ 0.001). A significantly higher percentage of heartburn-free nights was observed in patients receiving esomeprazole 40 mg (87.7% and 88.5% in Study 1 and Study 2, respectively) or esomeprazole 20 mg (87.7% and 89.9% in Study 1 and Study 2, respectively) vs. patients receiving placebo (78.7% and 79.5% in Study 1 and Study 2, respectively; P ≤ 0.006). The time to the first resolution of heartburn was significantly shorter with esomeprazole than placebo (Table 2; P ≤ 0.008 vs. placebo in Study 1; P = 0.001 vs. placebo in Study 2). At day 7, the following percentages of patients in the esomeprazole 40 mg, esomeprazole 20 mg and placebo groups had recorded their first resolution of heartburn: 70.7%, 77.7% and 58.1% of patients, respectively, in Study 1, and 72.0%, 77.9% and 51.7% of patients, respectively, in Study 2.
Table 2. End-points at week 4 in patients with symptomatic, endoscopy-negative gastro-oesophageal reflux disease (intention-to-treat population) treated with once-daily esomeprazole 40 mg, esomeprazole 20 mg or placebo
E 40 mg (n = 123)
E 20 mg (n = 121)
PBO (n = 124)
E 40 mg (n = 118)
E 20 mg (n = 113)
PBO (n = 118)
E 40 mg, esomeprazole 40 mg; E 20 mg, esomeprazole 20 mg; PBO, placebo.
Treatment with esomeprazole also provided a significantly shorter mean time to the sustained resolution of heartburn than did placebo (Table 2; P ≤ 0.001; log-rank test). At week 4, a higher cumulative percentage of patients in the esomeprazole 40 mg and esomeprazole 20 mg groups in both Study 1 and Study 2 reported the sustained resolution of heartburn (50.4% and 47.9%, and 50.8% and 55.8%, respectively) than those in the placebo group (29.8% and 20.3%, respectively). The cumulative percentage of patients achieving the sustained resolution of heartburn by diary day is presented in Figure 3. In addition, the sustained resolution of nocturnal heartburn occurred significantly sooner in patients receiving esomeprazole than in those receiving placebo (P ≤ 0.02 vs. placebo in both studies; log-rank test). At week 4, a significantly higher percentage of patients treated with esomeprazole had investigator-assessed resolution of heartburn and acid regurgitation compared with patients receiving placebo (P ≤ 0.003, Table 3).
Table 3. Percentage of patients with the resolution of investigator-assessed gastro-oesophageal reflux disease (GERD) symptoms at week 4 treated once daily with esomeprazole 40 mg, esomeprazole 20 mg or placebo (intention-to-treat population)
GERD symptoms (% of patients)
E 40 mg (n = 117)
E 20 mg (n = 114)
PBO (n = 117)
E 40 mg (n = 114)
E 20 mg (n = 104)
PBO (n = 110)
E 40 mg, esomeprazole 40 mg; E 20 mg, esomeprazole 20 mg; PBO, placebo.
0.003 vs. placebo (Cochran–Mantel–Haenszel test stratified by baseline rating of the symptom).
Analysis of the patient questionnaire responses for the degree of change in abdominal pain or discomfort and its impact on the performance of daily activities showed a significant between-treatment difference in favour of esomeprazole vs. placebo in attaining an improvement in upper abdominal discomfort at week 4 (P < 0.001 for each esomeprazole dose in both studies). The majority of patients receiving esomeprazole who rated their condition as ‘improved’ also rated the importance of this change between ‘important’ and ‘extremely important’ in performing their activities of daily living (esomeprazole 40 mg, 78–88%; esomeprazole 20 mg, 79–91%).
Safety and tolerability
The safety analysis included 365 patients in Study 1 and 345 patients in Study 2. Esomeprazole was well tolerated at both doses. In the two studies, similar percentages of patients in the esomeprazole 40 mg (41.0% and 43.1%), esomeprazole 20 mg (35.0% and 42.9%) and placebo (39.0% and 40.2%) groups reported at least one adverse event, regardless of its relationship to treatment. Across the two studies, all-cause adverse events resulted in the discontinuation of treatment in three patients in the esomeprazole 40 mg group, five patients in the esomeprazole 20 mg group and three patients in the placebo group. Of the patients who discontinued esomeprazole therapy because of an adverse event, gastrointestinal symptoms (n = 4) and headache (n = 1) were the only adverse events assessed by the investigator as being possibly or probably related to esomeprazole. Adverse events that occurred in ≥ 5% of patients in any treatment group, regardless of causality, are summarized in Table 4. The most common adverse events considered by the investigator to be possibly or probably related to study treatment were headache, nausea, abdominal pain and diarrhoea. No clinically meaningful mean changes from baseline in any laboratory test parameter or vital sign were observed in either study.
Table 4. Adverse events of all causes occurring in ≥ 5% of patients in any treatment group
Adverse event (% of patients)
E 40 mg (n = 122)
E 20 mg (n = 120)
PBO (n = 123)
E 40 mg (n = 116)
E 20 mg (n = 112)
PBO (n = 117)
BT, below threshold; E 40 mg, esomeprazole 40 mg; E 20 mg, esomeprazole 20 mg; PBO, placebo.
These two large independent trials demonstrated that treatment with esomeprazole for 4 weeks produced more rapid and complete resolution of heartburn in patients with no evidence of erosive oesophagitis compared with placebo. Patients receiving 4 weeks of treatment with esomeprazole 40 mg daily were free of heartburn for 63% and 66% of the study days in Study 1 and Study 2, respectively, rates similar to but slightly lower than those reported with esomeprazole 40 mg daily in patients with erosive oesophagitis (73–75%).13–15
Esomeprazole also provided significantly more heartburn-free days, and significantly shortened the time to the initial and sustained resolution of heartburn over a 24-h period and during the night, compared with placebo. The investigators' assessments of heartburn resolution at week 4 were consistent with the patients' assessments, showing statistically significant differences between esomeprazole and placebo. The investigators also found esomeprazole to be significantly more effective than placebo in resolving acid regurgitation, another common symptom of GERD. Esomeprazole was well tolerated, with an adverse effect profile indistinguishable from that of placebo.
Esomeprazole resolved chronic heartburn at daily doses of either 20 mg or 40 mg, i.e. doses considered to be therapeutic for the treatment of patients with non-erosive disease (symptomatic GERD) and for the healing of erosive oesophagitis, respectively. In other studies assessing the efficacy of two different therapeutic doses of a proton pump inhibitor (lansoprazole 15 and 30 mg), significant clinical improvement was observed with either dose in patients with heartburn but without erosive oesophagitis, and no significant additional benefit was seen with the higher dose.9 However, a therapeutic dose of 20 mg of omeprazole offered significantly more efficacy than a subtherapeutic dose of 10 mg for the resolution of heartburn, and both doses of omeprazole were more effective than placebo.8 These observations confirm the importance of daily full therapeutic doses of acid suppressive treatment in providing for the relief of chronic heartburn.
Irrespective of endoscopic findings, chronic heartburn decreases the quality of life.17–19 From the patient's perspective, complete resolution of persistent heartburn is highly desirable, as it can quickly restore the quality of life to normal or near-normal levels.17,19 The majority of patients in the present studies rated the improvement of heartburn observed with esomeprazole as being ‘important’ or ‘extremely important’ to their daily functioning in the overall treatment evaluation, thus confirming the observation that heartburn relief contributes substantially to the improvement in the quality of life.
Patients with chronic heartburn but no oesophageal erosions require therapeutic doses of long-term acid suppressive therapy to achieve consistently effective symptom relief, similar to those with erosive GERD.20 However, in clinical practice, no presenting symptom can reliably predict the presence of erosive disease. Moreover, there is no correlation between the severity of heartburn and the severity of oesophageal erosions.5,6 Indeed, many patients complaining of only mild heartburn may have severe erosive disease. Most patients treated in accordance with current practice guidelines will receive empirical treatment without an endoscopic evaluation to assess the baseline severity of disease.21 Thus, treatment with highly effective agents that relieve symptoms and heal erosions, regardless of their baseline severity, appears to be a rational therapeutic approach. In clinical trials, up to 8 weeks of treatment with esomeprazole 40 mg produced higher healing rates across all grades of severity of erosive disease than did omeprazole 20 mg or lansoprazole 30 mg, and these differences became greater with more severe disease.13–15 Similarly, 6 months of daily treatment with esomeprazole 20 mg maintained high rates of remission of oesophagitis, regardless of the severity of disease at baseline, whereas the efficacy of lansoprazole decreased to a greater degree with increasing severity of oesophagitis.16
In conclusion, once-daily treatment with esomeprazole was superior to placebo in achieving complete resolution of chronic heartburn in patients with no endoscopic evidence of erosive disease. These data support the use of esomeprazole as empirical treatment for patients with chronic heartburn, provided that concomitant alarm symptoms are absent.
The authors would like to acknowledge Christopher Rains, Karen van Hoeven and Caroline Spencer for their editorial assistance.