Double-blind, randomized controlled study to assess the effects of lansoprazole 30 mg and lansoprazole 15 mg on 24-h oesophageal and intragastric pH in Chinese subjects with gastro-oesophageal reflux disease

Authors


Dr K. C. Lai, Department of Medicine, University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong S.A.R., China.
E-mail: kclai@hku.hk

Summary

Background : Previous studies have suggested that the acid secretory capacity of the Chinese population is lower than that of the Western population.

Aim : To compare the effect of lansoprazole 30 mg and 15 mg once daily on the 24-h oesophageal and intragastric pH profiles in Chinese patients with gastro-oesophageal reflux disease.

Methods : Forty-four patients (male to female ratio, 27 : 17; mean age, 53 years; 55% with oesophagitis) with gastro-oesophageal reflux disease were randomized to receive lansoprazole 30 mg or 15 mg once daily for 4 weeks. Measurement of the 24-h oesophageal and intragastric pH, gastro-oesophageal reflux disease symptoms and quality of life was performed at baseline and during the last week of each dosing period.

Results : Lansoprazole 30 mg maintained an intragastric pH > 4 for 10.5 h vs. 9.6 h for lansoprazole 15 mg (P = 0.44). The percentage total time at oesophageal pH < 4 was similar for lansoprazole 30 mg and 15 mg (2.0% vs. 2.3%, P = 0.30). The proportion of patients with complete cure of heartburn and acid regurgitation and the quality of life assessment were similar for lansoprazole 30 mg and 15 mg. Both dosages of lansoprazole were well tolerated and the compliance was 100% in both groups.

Conclusion : Lansoprazole dosages of 30 mg and 15 mg once daily provide a satisfactory decrease for oesophageal acid exposure and are equally effective for the treatment of gastro-oesophageal reflux disease in the Chinese population.

Introduction

Acid control plays a key role in the management of gastro-oesophageal reflux disease (GERD), and the control of GERD symptoms is highly pH dependent.1–4 There are reasons to believe that, in the Chinese population, the degree of acid suppression required for the control of GERD symptoms may be different from that in the Western population. Firstly, the prevalence of GERD is around 20% in the Western population,5 which is much higher than the prevalence of 2.5% found in a recently conducted population survey in the Chinese population.6 Secondly, erosive oesophagitis, oesophageal stricture and Barrett's oesophagus are rarely encountered in the Chinese population.7 Thirdly, the Chinese population has a lower acid secretory capacity than the Western population.8 As long-term acid suppression may be associated with potential side-effects,9, 10 a lower dose is advisable if clinically efficacious.

Thus, the aims of this study were to determine the following in Chinese patients with GERD: (i) the 24-h oesophageal and intragastric pH profiles with lansoprazole 30 mg (standard dose) vs. 15 mg (low dose) daily; (ii) the degree of symptomatic relief with lansoprazole 30 mg vs. 15 mg daily; and (iii) the quality of life assessment with lansoprazole 30 mg vs. 15 mg daily. We hypothesized that the two dosages of lansoprazole would be equally effective for the management of Chinese patients with GERD.

Patients and methods

Patient population

Consecutive Chinese patients with symptoms of suspected (satisfied the diagnostic criteria of a validated Chinese GERD questionnaire) or confirmed (erosive oesophagitis by upper endoscopy) GERD, with at least weekly reflux symptoms, who were referred to the endoscopy unit of Queen Mary Hospital, University of Hong Kong between January 2002 and June 2003, were assessed for their suitability to enter the study.7, 11 The Chinese GERD questionnaire was a seven-item instrument which evaluated the frequency and severity of heartburn, frequency and severity of acid regurgitation, frequency and severity of a feeling of acidity in the stomach and frequency of antisecretory drug usage for GERD symptoms. It had a sensitivity of 82% and a specificity of 84% for the diagnosis of GERD.11

Patients were excluded if they had a past history of gastrointestinal surgery, peptic ulcer disease or connective tissue disorder, or had taken H2-receptor blockers, bismuth or proton pump inhibitors in the preceding 4 weeks. Patients with symptoms of gastrointestinal bleeding or a history of alcoholism, drug abuse or significant concomitant diseases likely to interfere with the results of the study were also excluded. Furthermore, pregnant or nursing women and those not likely to be using adequate contraceptive measures during the course of the study were excluded. Informed written consent was obtained from all patients participating in the study.

All patients received an upper endoscopy. During endoscopy, two antral biopsies and one corpus biopsy were taken. One antral biopsy was used for rapid urease test and the rest were sent for histological examination of Helicobacter pylori status by haematoxylin and eosin stains and Giemsa stain if necessary. Specimens were read by experienced pathologists who were blind to all clinical information, including the rapid urease test results. The definition of H. pylori infection required both tests to be positive. This approach has been validated previously in our centre with an accuracy of 100%, and less than 0.3% of cases cannot be diagnosed by this approach.12

Study design and treatment

This was a double-blind, randomized, cross-over study comprising two 4-week dosing periods separated by a washout interval of 2 weeks. Eligible patients were randomized to receive either lansoprazole 30 mg daily for 4 weeks or lansoprazole 15 mg daily for 4 weeks, and then crossed over to the other arm after a washout period of 2 weeks. Randomization was performed by drawing a sealed envelope that contained a pre-assigned randomized treatment generated by computer on entry to the study. Both the investigators and patients were blind to the assigned treatment throughout the study. The lansoprazole 30-mg and 15-mg capsules were identical in appearance.

All drugs were administered 30 min before breakfast. The 24-h oesophageal and intragastric pH results were obtained at baseline and during the last week of treatment of each dosing period. The study was approved by the ethics committee of the University of Hong Kong.

Symptom assessment and Short Form-36

Each patient was assessed by a locally validated questionnaire which evaluated the symptoms of GERD; this consisted of 20 items, including heartburn, acid regurgitation, chest pain, dysphagia, dyspepsia, belching, globus, hoarseness of voice, chronic cough and feeling of acidity in the stomach, graded on a five-point Likert scale.11 The clinical response of each subject was assessed at the follow-up visit. A pre-treatment symptom was considered to be ‘cured’ if the severity changed from mild, moderate, severe or very severe to absent. A symptom was considered to be ‘improved’ if it changed from a higher grading to a lower grading. A symptom was considered to be a ‘failure’ if it stayed the same or worsened. The condition was considered to be ‘indeterminate’ if the symptom was not assessed during follow-up. If a symptom was absent at baseline, it was not included in the end-of-treatment analysis.

The quality of life was assessed by a locally validated version of the Short Form-36 (SF-36) questionnaire.13 The SF-36 consists of 11 items measuring eight aspects of psychological general well-being (physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional and mental health). The symptom score and SF-36 were assessed at baseline and after each dosing period.

Twenty-four-hour oesophageal and intragastric pH

Twenty-four-hour ambulatory oesophageal pH monitoring was performed on an out-patient basis directly after stationary manometry. The location of the lower oesophageal sphincter was first determined using a low-compliance pneumo-hydraulic capillary infusion system (Dentsleeve Pty Ltd, Belair, Australia) and the station pull-through technique. A sleeve catheter with 5 cm spacing was used (Dentsleeve Pty Ltd, Belair, Australia). The upper border of the lower oesophageal sphincter was defined as the pressure point. Two-channel antimony pH probes with internal references were spaced 15 cm apart. The pH electrode was calibrated using buffers of pH 1.0 and pH 7.0. The pH electrode was passed transnasally and the proximal channel was positioned 5 cm above the proximal border of the manometrically identified lower oesophageal sphincter. Thus, the distal channel was about 10 cm below the lower oesophageal sphincter. Simultaneous pH recordings were obtained from the oesophagus (proximal channel) and the stomach (distal channel). A diary card and an event recorder button were used to record the time of symptoms during the 24-h ambulatory period. The transducers were calibrated before each procedure and re-calibrated after the procedure to look for drift. The recording end of the pH catheter was connected to an ambulatory recording device (Synectics Medical, Stockholm, Sweden), which sampled pH activity at a rate of 4 Hz. On completion, data were transferred from the recorder to an IBM-compatible personal computer for graphical display and numerical analyses using commercially available software (Multigram 6.31, Gastrosoft Inc., Stockholm, Sweden).

All recordings were checked visually for technical quality to exclude artefacts. A reflux episode was defined as any fall in distal gastro-oesophageal pH below a threshold of pH 4.0 for at least 5 s. The following oesophageal parameters were measured: (i) percentage of the total 24-h period when the oesophageal pH was below pH 4; (ii) percentage of the total upright period when the oesophageal pH was below pH 4; (iii) percentage of the total supine period when the oesophageal pH was below pH 4; (iv) total number of reflux episodes; (v) duration of the longest reflux episode; (vi) number of reflux episodes greater than 5 min; (vii) median oesophageal pH. The normal oesophageal parameters in the healthy Chinese population are: percentage total time pH < 4, 4.6%; percentage upright time pH < 4, 7.0%; percentage supine time pH < 4, 4.5%; number of reflux episodes, 73; number of reflux episodes with pH < 4 for > 5 min, 4; longest single acid exposure episode, 11.2 min.14 The percentage of time at intragastric pH > 4, total duration at intragastric pH > 4 and median intragastric pH were also determined.

To ensure consistency of the results, the food and beverage intake was standardized throughout each day of oesophageal and intragastric pH measurements for all patients. Standardized meals were served at the same times and in the same sequence during each cross-over period. Xanthine-containing food and beverages were prohibited during the study periods. All tracings were reviewed by two gastroenterologists (WMW and KCL) who were blind to the clinical information of the patients.

Outcome measure

The oesophageal and intragastric pH profiles, symptom scores and quality of life assessments of the two different doses of lansoprazole were compared with each other and also with the baseline measurements.

Statistical analysis

The differences between the effects of lansoprazole 30 mg and 15 mg on the oesophageal and intragastric pH profiles and SF-36 assessment were analysed using a mixed-mode analysis of variance, with fixed effects for period, carry-over and treatment and a random effect for patients. Symptom assessments between lansoprazole 30 mg and 15 mg were compared using the chi-squared test. The differences in the oesophageal and intragastric pH measurements between the two dosages and the baseline values, and between erosive reflux disease and non-erosive reflux disease, were compared using Student's t-test. A P value of 0.05 or less was considered to be statistically significant. All P values were two-sided.

Results

Forty-four consecutive patients with GERD (24 with erosive oesophagitis and 20 with symptomatic GERD diagnosed by a validated GERD questionnaire) were recruited.7, 11 The demographic data of the 44 patients are listed in Table 1. Compliance by pill counting was 100% in all patients. No patient discontinued treatment due to adverse effects. In general, the medications were well tolerated in both groups.

Table 1.  Demographic data of the study subjects (n = 44)
  1. NSAID, non-steroidal anti-inflammatory drug.

Mean age (± s.d.) (years)53 ± 12
Male/female27/17
Smoking (%)5 (11)
Alcohol (%)8 (18)
Coffee (%)14 (32)
Use of NSAIDs (%)9 (21)
Mean body mass index (± s.d.) (kg/m2)23.9 ± 3.1
Heartburn and/or acid regurgitation > 3 times/week (%)23 (52)
Endoscopic findings (%)
 Normal20 (45)
 Los Angeles grade A oesophagitis9 (21)
 Los Angeles grade B oesophagitis15 (34)
H. pylori positivity (%)14/30 (32)

Twenty-four-hour oesophageal and intragastric pH parameters

Thirty-four patients had baseline oesophageal pH data available for evaluation, with 21 (62%) having at least one abnormal reflux parameter.14 Of the remaining 13 patients, four had erosive oesophagitis on upper endoscopy and nine fulfilled the diagnostic criteria of GERD by the validated GERD questionnaire. These nine patients probably had non-erosive reflux disease. There were significant changes in oesophageal pH parameters from baseline for both lansoprazole groups (Table 2). All the abnormal oesophageal parameters returned to normal values after either dosage of lansoprazole.14 The percentage total time at oesophageal pH < 4 was similar between lansoprazole 30 mg and 15 mg (2.0% vs. 2.3%, P = 0.30). The other oesophageal pH measurements were similar between the two groups.

Table 2.  Results of 24-h ambulatory oesophageal and intragastric pH monitoring in the 44 patients with gastro-oesophageal reflux disease at baseline, after 4 weeks of lansoprazole 30 mg daily and after 4 weeks of lansoprazole 15 mg daily. All data are presented as the mean value ± S.E.M.
  Baseline§Lansoprazole 30 mgLansoprazole 15 mg
  • *

     P < 0.05 when compared with baseline.

  • † 

    P < 0.01 when compared with baseline.

  • ‡ 

    P < 0.001 when compared with baseline.

  • § 

    10 patients had no baseline oesophageal pH results.

Percentage of time pH < 4
 Total6.3 ± 1.12.0 ± 0.432.3 ± 0.46
 Supine7.6 ± 2.41.8 ± 0.56*2.2 ± 0.78*
 Upright6.4 ± 1.32.1 ± 0.482.6 ± 0.56
Total number of episodes52 ± 8.228.0 ± 5.4*36.7 ± 6.4
Number of episodes > 5 min3.0 ± 0.541.4 ± 0.35*1.1 ± 0.27
Longest reflux episode (min)29.3 ± 7.25.8 ± 1.38.1 ± 1.8*
24-h median oesophageal pH6.3 ± 0.126.2 ± 0.136.2 ± 0.13
Mean duration (h) at intragastric pH > 44.2 ± 0.3710.5 ± 0.969.6 ± 0.98
Mean percentage of 24-h period at intragastric pH > 4 (95% CI)18.4 ± 1.645.2 ± 4.140.9 ± 4.2
24-h median intragastric pH1.4 ± 0.14.2 ± 0.353.3 ± 0.36

Similarly, there were no significant differences in the changes from baseline of the median intragastric pH, mean duration at intragastric pH > 4 and mean percentage of the 24-h period at intragastric pH > 4 between the lansoprazole 30 mg and 15 mg groups by mixed-mode analysis of variance. Lansoprazole 30 mg maintained an intragastric pH > 4 for 10.5 h vs. 9.6 h for lansoprazole 15 mg (P = 0.44). The mean percentage of the 24-h period at intragastric pH > 4 was similar in the two groups (45% vs. 41%, P = 0.40). There was no difference in the median intragastric pH between the two groups (pH 4.2 vs. pH 3.3, P = 0.44). Carry-over effects were not significant for any of the measurement variables (data not shown).

Effect of H. pylori

The oesophageal and intragastric pH parameters were similar in H. pylori-positive and H. pylori-negative patients with GERD at baseline, after lansoprazole 30 mg and after lansoprazole 15 mg (data not shown).

Erosive vs. non-erosive reflux disease

The intragastric pH measurements were similar in patients with erosive reflux disease (oesophagitis) and non-erosive reflux disease at baseline, after lansoprazole 30 mg and after lansoprazole 15 mg. In the oesophageal pH baseline assessment, patients with erosive reflux disease had a higher mean longest acid reflux than those with non-erosive reflux disease (44.8 min vs. 11.9 min, P = 0.018). After lansoprazole 30 mg, the percentage total time at oesophageal pH < 4 (2.8% vs. 0.88%, P = 0.014) (Figure 1a), percentage upright time at oesophageal pH < 4 (3% vs. 1%, P = 0.03) (Figure 1b) and number of reflux episodes > 5 min (2.1 vs. 0.5, P = 0.012) (Figure 1c) were higher in patients with erosive reflux disease than in those with non-erosive reflux disease. There was no significant difference in oesophageal pH measurements between patients with oesophagitis and those with non-erosive reflux disease after lansoprazole 15 mg (Figure 1a–c).

Figure 1.

(a) Percentage total time oesophageal pH < 4 in patients with erosive oesophagitis (EE) and non-erosive reflux disease (NERD) after lansoprazole 30 mg (filled bars) and lansoprazole 15 mg (open bars). (b) Percentage upright time oesophageal pH < 4 in patients with EE and NERD after lansoprazole 30 mg (filled bars) and lansoprazole 15 mg (open bars). (c) Number of reflux episodes > 5 min in patients with EE and NERD after lansoprazole 30 mg (filled bars) and lansoprazole 15 mg (open bars). *P < 0.05 when compared with patients with EE.

Symptom assessment and Short Form-36

The proportions of patients with complete cure of heartburn (71% vs. 66%, P = 0.86) and acid regurgitation (51% vs. 57%, P = 0.74) were similar in the lansoprazole 30 mg and 15 mg groups (Table 3). The proportions of patients with improvement and failure were similar between the two groups. There was significant improvement in the bodily pain domain after lansoprazole 30 mg and 15 mg (Table 4). However, the other domains of SF-36 remained unchanged after treatment. The 24-h oesophageal pH measurements were similar in patients with complete cure of heartburn and acid regurgitation symptoms and in those without complete cure of reflux symptoms (data not shown).

Table 3.  Clinical response after 4 weeks of lansoprazole 30 mg daily and after 4 weeks of lansoprazole 15 mg daily
 Lansoprazole 30 mg*Lansoprazole 15 mg*P value
  • *

     Patients with no symptoms at baseline were not included in the end-of-treatment analysis.

Severity of heartburn (%)
 Cure22 (71)19 (66) 
 Improvement 3 (10) 5 (17) 
 Failure 6 (20) 4 (14) 
 Indeterminate 0 (0) 1 (3)0.376
Frequency of heartburn (%)
 Cure22 (71)19 (66) 
 Improvement 4 (13) 5 (17) 
 Failure 5 (16) 4 (14) 
 Indeterminate 0 (0) 1 (3)0.711
Severity of acid regurgitation (%)
 Cure22 (51)24 (57) 
 Improvement 8 (19) 9 (21) 
 Failure12 (28) 8 (19) 
 Indeterminate 1 (2) 1 (2)0.817
Frequency of acid regurgitation (%)
 Cure22 (51)24 (57) 
 Improvement11 (26)11 (26) 
 Failure 9 (21) 6 (14) 
 Indeterminate 1 (2) 1 (2)0.879
Severity of chest pain (%)
 Cure15 (58)14 (54) 
 Improvement 4 (15) 5 (19) 
 Failure 7 (27) 6 (23) 
 Indeterminate 0 (0) 1 (4)0.748
Frequency of chest pain (%)
 Cure15 (56)14 (54) 
 Improvement 6 (22) 6 (23) 
 Failure 5 (19) 4 (15) 
 Indeterminate 1 (4) 2 (8)0.928
Table 4.  Short Form-36 (mean ± S.E.M.) at baseline, after 4 weeks of lansoprazole 30 mg daily and after 4 weeks of lansoprazole 15 mg daily
 BaselineLansoprazole 30 mgLansoprazole 15 mg
  • P = 0.011 when compared with baseline.

  • † 

    P = 0.005 when compared with baseline.

Physical functioning85.0 ± 2.085.7 ± 2.183.2 ± 2.6
Role physical72.2 ± 5.869.1 ± 6.375.0 ± 6.4
Bodily pain57.5 ± 3.365.1 ± 3.5*70.8 ± 3.9
General health48.2 ± 3.049.9 ± 3.646.7 ± 3.2
Vitality51.3 ± 2.947.6 ± 2.850.3 ± 3.2
Social functioning76.4 ± 2.973.9 ± 3.576.0 ± 3.1
Role emotional68.9 ± 5.466.7 ± 7.374.8 ± 5.7
Mental health67.9 ± 2.569.4 ± 3.170.4 ± 2.6

Discussion

Acid inhibition with antisecretory therapy is a key factor in the management of acid-related disorders. Proton pump inhibitors are the most effective treatment for the initial and maintenance therapy of GERD.1, 3, 4 The prevalence of GERD and GERD-related complications is lower in the Asian population.2, 7 Thus, it is reasonable to assume that the dosage of proton pump inhibitor required for the satisfactory control of reflux symptoms may be lower in the Asian population. Previous pharmacodynamic studies of proton pump inhibitors have usually been performed in healthy volunteers rather than in patients with GERD.15 The duration of treatment has usually been short and simultaneous oesophageal and intragastric pH measurements have not been performed. Furthermore, few pharmacodynamic studies of proton pump inhibitors have been carried out in the Chinese population. Thus, we were stimulated to perform the current study in order to evaluate the optimal dosage for the treatment of GERD in the Chinese population. We have shown that lansoprazole 15 mg is as effective as lansoprazole 30 mg for the reduction of oesophageal acid exposure in patients with GERD. The proportions of patients with complete cure of heartburn and acid regurgitation were similar in the two groups, implying that physiological measurements can be translated into clinical efficacy.

The median intragastric pH was 4.2 after lansoprazole 30 mg and 3.3 after lansoprazole 15 mg. It may be argued that the optimal intragastric pH that can be used to distinguish between aggressive and non-aggressive reflux is pH 4.0.1, 15 However, the comparable duration at intragastric pH > 4 and the similar therapeutic response observed after lansoprazole 30 mg and lansoprazole 15 mg suggest that this is not a major problem. Furthermore, there is concern about the effect of potent, long-term acid suppression in patients with GERD, which may lead to pre-neoplastic changes in the gastric mucosa. This issue is of particular importance in Asian countries, which have a high prevalence of gastric cancer.16, 17 A lower dosage of proton pump inhibitor with less suppression of intragastric pH, but with a satisfactory reduction in oesophageal acid exposure, may theoretically be ideal for the treatment of acid-related disorders in a population with a high risk of gastric cancer development. Furthermore, there is a potential cost saving in terms of drug costs with low-dose proton pump inhibitors. The percentage of time at intragastric pH > 4 after 5 days of lansoprazole 30 mg was approximately 53–65% in previous studies.18–21 The mean percentage of the 24-h period at intragastric pH > 4 after lansoprazole 30 mg was lower in the current study than in previous studies. The reason for this difference is not clear, but may be related to differences in H. pylori status, age, gender, smoking and genetic differences in hepatic metabolism.15

Although lansoprazole 15 mg was as effective as lansoprazole 30 mg for the reduction of oesophageal acid exposure in this study, caution should be used when applying our data to patients with more severe GERD, such as Los Angeles grade C/D oesophagitis, as all the patients recruited in this study had milder disease. Nevertheless, the data presented here should be applicable to the majority of Chinese patients with reflux disease, in whom severe GERD is relatively uncommon.7 The plasma concentration of lansoprazole was not measured in this study as the primary aim was to investigate the pharmacodynamic effects of lansoprazole in Chinese patients with GERD using simultaneous 24-h oesophageal and intragastric pH monitoring. Furthermore, lansoprazole accumulates in the parietal cell and binds irreversibly to proton pumps, making the plasma concentration a less reliable predictor of pharmacodynamic effects.

By SF-36 assessment, only the bodily pain domain improved significantly during treatment. In a large US study to assess the effect of rabeprazole on the health-related quality of life in patients with erosive GERD, the highest improvement was also observed in the bodily pain domain.22 Similar findings have been reported in a recent prospective, randomized, double-blind study from Canada, in which the bodily pain domain significantly improved after 4 weeks of pantoprazole treatment.23

In conclusion, lansoprazole 30 mg once daily and lansoprazole 15 mg once daily provide a similar reduction in oesophageal acid exposure and are equally effective for the treatment of GERD in the Chinese population.

Acknowledgements

The authors thank Nurse Specialist Ms M. Chong and Endoscopy Nurses Ms K. W. Wong, Vera S. Y. Tang, Diana K. K. Chang and W. P. Yung for assistance. This study was supported by the Simon K. Y. Lee Gastroenterology Research Fund, Peptic Ulcer Research Fund, a research grant from the Department of Medicine, University of Hong Kong, Hong Kong Society of Gastroenterology and an unrestricted grant from Takeda Chemical Industries (Taiwan), Ltd.

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