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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. References

Background

: H2-receptor antagonists are widely used in patients with gastro-oesophageal reflux disease (GERD) and are frequently continued when symptoms persist. Aim: To compare the efficacy of omeprazole 20 mg once daily with that of ranitidine 150 mg twice daily in relieving GERD symptoms, in patients who remained symptomatic following a 6-week course of ranitidine therapy.

Methods

: Patients with heartburn on at least 4 days/week but who did not have endoscopy to assess oesophageal mucosa could participate. This two-phase, prospective trial included a 6-week open-label phase (phase I), followed by an 8-week double-blind phase (phase II). Patients still symptomatic following treatment with ranitidine 150 mg twice daily (phase I) were randomized to double-blind treatment (phase II) with either omeprazole 20 mg once daily or ranitidine 150 mg twice daily. The primary efficacy variable was the proportion of patients with heartburn resolution during weeks 4 and 8 of phase II.

Results

: Of the 533 patients with GERD who received ranitidine in phase I, 348 patients (65%) were still symptomatic. A total of 317 patients (59%) were randomized to double-blind treatment (phase II). At week 8, a significantly (< 0.0004) greater proportion of omeprazole-treated patients (70%) experienced no more than mild heartburn compared with ranitidine-treated patients (49%). Complete resolution of heartburn also occurred in a significantly (< 0.00001) greater proportion of omeprazole-treated patients (46% vs. 16% of the ranitidine group at week 8).

Conclusions

: After 6 weeks of ranitidine treatment, the majority of patients with GERD were still experiencing moderate to severe heartburn. Omeprazole was significantly more effective than ranitidine in resolving heartburn in this group of patients.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. References

Gastro-oesophageal reflux disease (GERD) is the term used to describe symptoms of varying severity, with or without endoscopically determined mucosal damage and histopathologic changes, resulting from episodes of gastro-oesophageal reflux. The most common symptom of GERD is heartburn, but acid regurgitation is also frequently seen.1[2]–3 However, symptoms do not necessarily predict the presence of oesophageal damage, nor do patients with reflux oesophagitis always suffer from heartburn.1 The pathophysiology of GERD is multifactorial and may include transient lower oesophageal sphincter (LES) relaxation, incompetence of the LES, reduced oesophageal clearance, and impaired resistance of the oesophageal mucosa.4[5]–6 GERD is common; in the United States, it is estimated that 7% of adults have daily heartburn, 14% have weekly heartburn, and 40% have monthly heartburn.1, 7, 8 However, precise epidemiologic data are difficult to obtain owing to the relatively broad definition of GERD and variability in diagnostic criteria.1 It is estimated that approximately one-third of patients with symptoms of GERD also have endoscopic signs of erosive reflux oesophagitis.3, 9, 10 Treatment of GERD is important because it is a chronic, recurring disease, which, if not successfully managed, may sometimes lead to complications such as oesophageal stricture, oesophageal ulcer and bleeding, and Barrett's oesophagus.8, 11, 12

The treatment of GERD was advanced by the introduction, in the mid-1970s, of the H2-receptor antagonists (H2RAs). These drugs are widely used; however, while standard doses of ranitidine (150 mg b.d.) may result in improvement of GERD symptoms in up to 82% of patients, using the more stringent criterion of complete symptom resolution, success rates are less than 50%.4 Thus, based on symptom resolution rates, a large number of patients do not have an adequate response to this therapy.13

Oesophageal acid exposure has been shown to be a key factor in the pathogenesis of GERD,14 and the frequency of GERD symptoms is positively correlated with acid exposure time.2, 3, 5 It has been demonstrated in numerous clinical trials that increasing suppression of gastric acid secretion, thereby reducing oesophageal acid exposure, is associated with improved symptom relief in GERD.14, 15 The proton pump inhibitor (PPI) omeprazole, which blocks the final step in the formation of hydrochloric acid by specifically inhibiting the H + /K + -ATPase enzyme system in the gastric parietal cell, effectively suppresses both basal and meal-stimulated gastric acid secretion. The greater symptomatic response observed in patients treated with omeprazole compared with H2RAs may be related to the higher degree of acid suppression provided by the proton pump inhibitors,15 particularly during food-stimulated acid secretion.14

Based on its greater efficacy in reducing acid secretion, it is expected that omeprazole should be more efficacious than ranitidine in the treatment of symptomatic GERD. Therefore, the goal of this double-blind study was to investigate the efficacy and safety of omeprazole 20 mg o.d. compared with the commonly used practice of continuing with ranitidine 150 mg b.d. for the resolution of GERD symptoms in patients poorly responsive to a standard course of open-label ranitidine therapy (150 mg b.d. for 6 weeks).

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. References

Patient selection

Patients aged 18 years or older with a history of heartburn for at least 6 months and having current episodes of moderate to severe heartburn on at least 4 of the last 7 days prior to study entry were eligible to participate. Endoscopy was not performed and therefore the degree of mucosal damage was not assessed, to mimic the situation as presented to the primary care physician. Female participants could be included if they were postmenopausal, surgically sterilized, or using an acceptable method of birth control. Women with the potential for childbearing were required to have a negative urine pregnancy test at baseline.

A potential study participant was excluded for any of the following: a history or current evidence of oesophageal stricture, Barrett's metaplasia, or oesophageal, gastric, or duodenal ulcers; Zollinger–Ellison syndrome; evidence of gastrointestinal bleeding within 3 days of entry into the open-label study phase; use of a proton pump inhibitor within the month prior to entry into the open-label phase; prior daily use of an H2RA within the 2 weeks before entry into the open-label phase. Also excluded were patients with an anticipated need for concomitant medication with anticholinergics, motility drugs, prostaglandin analogs, or sucralfate. Use of non-steroidal anti-inflammatory drugs (NSAIDs), including salicylates, was not permitted, except for low-dose aspirin (≤ 165 mg daily). Patients with a history of inflammatory bowel disease, malabsorption, pancreatitis, severe pulmonary or liver disease, renal disease, any active malignancy (except for superficial skin disease), unstable diabetes mellitus, cerebral vascular disease, any bleeding disorder, or any condition that might require surgery during the study were not enrolled.

During the last week of the open-label phase, patients experiencing at least one episode of moderate to severe heartburn were eligible for the double-blind phase. They were also required to have taken at least nine ranitidine tablets during the week prior to randomization.

Written informed consent was obtained from all patients. The protocol was approved by the Institutional Review Board for each centre prior to the start of the study.

Study design

This was a 2-phase (open-label, followed by double-blind) multicentre, prospective, randomized study. Patients were recruited from 32 US centres, which included gastroenterology and family medicine practices. In the open-label phase (phase I), symptomatic GERD patients were treated with ranitidine 150 mg b.d. for 6 weeks; at the end of the 6 weeks, symptomatic response to treatment was assessed. Patients who experienced at least one episode of moderate to severe heartburn during week 6 (the week prior to randomization) and who also took at least nine ranitidine tablets during that week were classified as ‘poorly responsive’ to ranitidine treatment; these patients were randomized to double-blind treatment (phase II) with either omeprazole 20 mg o.d. or ranitidine 150 mg b.d. for 8 weeks. A double-dummy technique was used.

Baseline evaluation included a general medical history (including a history of GERD and use of alcohol, caffeine and tobacco); review of previous and concurrent medication; physical examination; and blood and urine samples. Patients were not assessed endoscopically either at entry or during the study.

During the open-label phase, patients were instructed to take one ranitidine tablet with a glass of water before breakfast, and again in the evening before bedtime. During the double-blind phase, patients were instructed to take one tablet and one capsule with a glass of water each morning, and one tablet each evening before bedtime.

Patients received antacid tablets (Gelusil, Parke-Davis, Morris Plains, NJ) as rescue medication for relief of heartburn, sour stomach, acid indigestion and symptoms of gas, up to a maximum of six tablets per day. Patients were not permitted to take any other antacid, H2RA, or proton pump inhibitor during either the open-label or the double-blind phase of the study. Patients recorded their antacid consumption on diary cards.

The primary efficacy variable was the proportion of patients with resolution of moderate to severe heartburn (i.e. no heartburn or only mild heartburn) during weeks 4 and 8 of the double-blind phase. Secondary efficacy variables from the double-blind phase included the proportion of patients with complete resolution of heartburn (defined as no heartburn of any type), mean change from baseline in the average frequency of heartburn, mean change from baseline in the number of Gelusil tablets consumed, and the percentage of heartburn-free days. Additionally, time-to-event variables were also analysed across the double-blind period. These included time to resolution of moderate to severe heartburn (no heartburn or only mild heartburn), time to complete resolution of heartburn, and time to first heartburn-free day. Time to resolution of moderate to severe heartburn was defined as the first day in which there was no heartburn, or the severity of all subsequent episodes of heartburn was mild. Time to complete resolution of heartburn was defined as the first day on which there were no episodes of heartburn on that day and on all subsequent days until the completion of the study.

Symptom assessment

To be included in the study, patients had to have had episodes of moderate to severe heartburn on a least 4 of the 7 days before entry into the open-label phase. Patients recorded the frequency and severity of their heartburn on diary cards during the last week of the open-label phase and then for the duration of the double-blind phase. Heartburn severity was classified as none (no heartburn); mild (awareness, but easily tolerated); moderate (discomforting heartburn, causing interference with normal daily activities); or severe (incapacitating heartburn preventing performance of normal daily activities). Mean change from baseline in the average number of Gelusil tablets taken, the percentage of heartburn-free days, and the three time-to-event variables were also calculated based on diary card entries.

Other specific symptoms possibly associated with GERD that were evaluated by the investigator at baseline and at each subsequent visit were acid regurgitation, dysphagia, and epigastric pain. As with heartburn, the severity of these symptoms was classified as none, mild, moderate or severe.

Safety assessment

Safety was evaluated by clinical adverse events and laboratory data. During each visit, patients reported any adverse events that had occurred since the previous visit. Any significant deterioration in clinical status was considered to be an adverse event and was recorded on the case report form.

Statistical analyses

Data analyses were based on an intention-to-treat population, i.e. all patients who were randomized and took at least one dose of study medication.

Following randomization, the proportions of patients in each treatment group who experienced no heartburn or only mild heartburn, as well as complete resolution of heartburn, were compared through the Mantel–Haenzel statistic, with adjustment for the investigator's geographical region. A two-way analysis of variance model was used to assess differences between means (change-from-baseline variables and percentage of heartburn-free days); treatment and investigator regions were main effects, and there was no interaction term. For all analyses designed to assess differences between treatment groups in the time-to-event variables, the log-rank statistic was used. Because there were no differences between the two randomized treatment groups based on demographic characteristics, no adjustment for baseline variables was deemed necessary. Fisher's exact test was used to analyse the safety data. All tests were two-tailed with a significance level (α) of 0.05.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. References

Only 35% (185 patients) of the 533 patients who entered the open-label phase were classified as responders (i.e. they had no heartburn or only mild heartburn during the last week of phase I) after 6 weeks of ranitidine treatment. The remaining 65% (348 patients) were poorly responsive; of these, 317 (315 plus two responders erroneously classified as poorly responsive), i.e. 59%, were randomized to double-blind treatment—156 received omeprazole 20 mg o.d. and 161 received ranitidine 150 mg b.d. (Table 1). The two groups were comparable with regard to demographics (age, race, sex), consumption of caffeine and alcohol, and smoking.

Table 1.  . Characteristics of patient groups Thumbnail image of

Twenty-three patients who were randomized to double-blind treatment did not complete the study, including eight patients in the omeprazole group and 15 patients in the ranitidine group. The reasons most frequently cited for study discontinuation were ‘lost to follow-up’ (four patients) in the omeprazole group and ‘adverse experience’ (four patients) and ‘consent withdrawn’ (four patients) in the ranitidine group.

Compliance with treatment (defined as consumption of at least 75% of study medication) was 94% in both treatment groups.

Resolution of symptoms

The proportion of patients who experienced no heartburn or only mild heartburn during double-blind treatment was significantly greater in the omeprazole group than in the ranitidine group both at week 4 (66% vs. 40%, = 0.00001) and week 8 (70% vs. 49%, = 0.0004), as shown in Figure 1. The omeprazole group also had a significantly higher proportion of patients with complete resolution of heartburn (no heartburn) at week 4 (31% vs. 11%, < 0.00001) and week 8 (46% vs. 16%, < 0.00001). The percentage of heartburn-free days was significantly (< 0.0001) higher in the omeprazole-treated patients than in the ranitidine-treated patients both at week 4 (69% and 48%, respectively) and week 8 (76% and 56%, respectively), as shown in Figure 2. The mean reduction from baseline in both the frequency of heartburn episodes and number of Gelusil tablets taken at weeks 4 and 8 was significantly (≤ 0.02) greater in the omeprazole group than in the ranitidine group.

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Figure 1. .  Resolution of heartburn in patients poorly responsive to open-label ranitidine therapy.

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Figure 2. .  Percentage of heartburn-free days in patients poorly responsive to open-label ranitidine therapy.

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Relief of heartburn symptoms was more rapid in the omeprazole-treated patients than in the ranitidine-treated patients as demonstrated by the earlier occurrences in heartburn reduction in the omeprazole group. Figure 3 shows that the omeprazole group, on average, achieved resolution of heartburn (i.e. they had no heartburn or only mild heartburn) in week 5, ≈ 11 days faster than did the ranitidine group (week 7). The omeprazole group reached complete resolution of heartburn ≈ 9 days faster (week 7) than the ranitidine group (week 8). On average, the omeprazole-treated patients had their first heartburn-free days by day 7 compared with day 9 for the ranitidine-treated patients.

image

Figure 3. .  Mean time to resolution of heartburn in patients poorly responsive to open-label ranitidine therapy.

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Mean reductions in epigastric pain scores were significantly greater in omeprazole-treated patients than in ranitidine-treated patients at weeks 4 and 8 (≤ 0.001). There were no significant differences between the two treatment groups in mean reduction of acid regurgitation and dysphagia.

Safety and tolerability

There were no significant differences between the omeprazole and ranitidine groups in the overall incidence and types of clinical adverse events during the double-blind phase (Table 2). In the omeprazole group, 48% of patients experienced an adverse event, compared with 50% in the ranitidine group. Adverse events that were possibly, probably, or definitely drug related occurred in 10% of the omeprazole group and 7% of the ranitidine group; this difference was not significant. Seven serious adverse events were reported during the study (one patient during the open-label phase, one patient randomized to omeprazole, and five patients randomized to ranitidine). None was considered to be drug related. There were no deaths during this study. Of the six patients who withdrew from the double-blind phase of the study because of clinical adverse experiences, four had received ranitidine and two, omeprazole.

Table 2.  . Most common clinical adverse experiences (incidence ≥ 5%) observed during double-blind treatment Thumbnail image of

Six patients (three in the omeprazole group and three in the ranitidine group) had one or more abnormal laboratory values that were considered clinically significant and thus classified as adverse events.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. References

In the treatment of GERD, symptomatic response to therapy is an important measure of clinical success, as this is the effect most likely to be of greatest consequence to the patient. Our study was the first well-controlled US trial designed to assess two different agents for the treatment of GERD symptoms in a patient population demonstrated to be poorly responsive to ranitidine. The issue of refractoriness of GERD to H2RA therapy is emerging as a highly important clinical consideration in the treatment of this disorder. Resistance to H2RA therapy has been estimated to occur in anywhere from 10% to 50% of GERD patients; 16, 17 however, in the present study, 59% of GERD patients responded poorly to ranitidine, which underscores the inadequacy of ranitidine therapy in many patients.

In our study, the proportion of patients with no heartburn or only mild heartburn was significantly greater with omeprazole than with ranitidine both at week 4 (66% vs. 40%, respectively) and week 8 (70% vs. 49%, respectively). Complete resolution of heartburn was also significantly higher in the omeprazole group than in the ranitidine group both at week 4 (31% vs. 11%, respectively) and week 8 (46% vs. 16%, respectively). There was also a greater proportion of heartburn-free days in the omeprazole group (76%) than in the ranitidine group (56%) at week 8.

The findings of our study are consistent with those from previous studies in which patients who had responded poorly to therapy with ranitidine or another H2RA achieved greater resolution of GERD symptoms with omeprazole 20 mg than with continued ranitidine therapy (150 mg b.d.).4, 16 However, there were differences between the design of our study and those of previous studies which underscore the significance of our findings. In a study conducted by Richter et al.,4 treatment was not continuous; there was a break of up to 5 days between initial treatment with ranitidine (150 mg b.d.) and subsequent randomization. Thus, those randomized either continued to have symptoms after stopping treatment, or had a recurrence of symptoms. In our study, only those who continued to have symptoms while being actively treated were randomized. Moreover, in the study conducted by Richter et al. the randomized groups were not blinded. In a study conducted by Bianchi Porro and colleagues,16 patients determined to be refractory to H2RA therapy could have been treated with any one of three different agents. In addition, refractoriness was determined by grade of oesophagitis, and not by the presence or absence of heartburn.

In their study of patients symptomatic after treatment with ranitidine 150 mg b.d. for 8 weeks, Richter et al.4 observed complete resolution of GERD symptoms in 64% of omeprazole-treated patients by week 8, compared with 29% of ranitidine-treated patients. Likewise, the percentage of heartburn-free days was significantly higher for the omeprazole group (70% to 73%) than for the ranitidine group (34% to 44%) over the course of the study. As in our study, the omeprazole group became heartburn free significantly faster than the ranitidine group. Bianchi Porro and colleagues16 treated patients resistant to standard doses of ranitidine, cimetidine, or famotidine with omeprazole 20 mg o.d. or ranitidine 150 mg b.d. for up to 8 weeks. Again, resolution of symptoms by week 4 was more rapid in the omeprazole group, 60% of whom were heartburn free, compared with only 21% of the ranitidine group. These data indicate that omeprazole is an attractive clinical option for the treatment of GERD in H2RA-resistant patients. Furthermore, omeprazole has been approved as first-line treatment for heartburn and other GERD-associated symptoms. The high frequency of H2RA failures in our trial suggests that omeprazole should be considered at an earlier step in the GERD treatment algorithm.

The results of this study also confirm the findings of previous comparative studies13, 18, 19 conducted in patients with GERD who were not necessarily resistant to H2RA therapy. These studies demonstrated that omeprazole 20 mg o.d. is superior to ranitidine 150 mg b.d. in the symptomatic treatment of GERD and, when present, in healing reflux oesophagitis.13, 18, 19 Interestingly, symptom resolution rates with ranitidine in these studies, where patients may or may not have been resistant to H2RA therapy, were no higher than in our study. In these previous studies, omeprazole produced greater and more rapid rates of symptom resolution than did ranitidine, regardless of the differences in the patient populations (related to presence or absence of erosive oesophagitis) and variability in the definition of endpoints. Omeprazole also provided symptom relief in GERD patients irrespective of the presence or absence of endoscopic evidence of reflux oesophagitis. The findings underscore not only the greater efficacy of omeprazole in the treatment of GERD symptoms, but the clinical challenge of achieving complete symptom resolution in these patients. Doubling the dose of ranitidine to 300 mg b.d. does not appear to significantly affect the response rate. In a recent study,20 investigators found significantly higher rates of symptom relief in the GERD patients treated with omeprazole 20 mg o.d. 61% and 74% at weeks 4 and 8, respectively than in those treated with ranitidine 300 mg b.d. (31% and 50% at weeks 4 and 8, respectively).

The design of this study is noteworthy in that it mirrors the way heartburn is generally treated in the primary care setting, where the primary goal is symptom reduction, and where the status of the patient's oesophageal mucosa is generally unknown. Two studies conducted in the primary care setting 21, 22 support our finding of the superior efficacy of omeprazole 20 mg vs. ranitidine 150 mg b.d. for the relief of heartburn. In one study, 21 59% of omeprazole-treated patients vs. 26% of ranitidine-treated patients were free of heartburn at week 4, and the onset of symptom relief was significantly more rapid in the omeprazole group. Moreover, patients with more severe symptoms were more likely to obtain relief with omeprazole than with ranitidine. In the second study,22 relief of heartburn was also achieved in significantly more omeprazole-treated patients 61% than in ranitidine-treated patients (40%). These findings are consistent with those of our study, which included patients not only from primary care, but from gastroenterology practices. Moreover, data from three decision-analysis modelling studies,23[24]–25 based on patients with erosive GERD, have also shown that therapy with a proton pump inhibitor is preferable to treatment with an H2RA both for healing 23 and for symptom resolution.24, 25 Surgical therapy should be reserved for patients with complicated GERD or a defective LES, or for patients who have failed to respond to pharmacotherapy, because of the direct costs involved and the reasonably high probability of complications and/or treatment failure.26[27]–28

In conclusion, more than half of patients with GERD who received a standard course of ranitidine therapy remain symptomatic. In this poorly responsive group, omeprazole treatment was significantly more effective than continued treatment with ranitidine in resolving heartburn.

ACKNOWLEDGEMENTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. References

The authors would like to thank the following investigators for their contributions to this study: Richard Aaronson, M.D., Chicago Heights, IL; Raymond Bell, M.D., Mobile, AL; Charles Birbara, M.D., Worcester, MA; Milan Brandon, M.D., F.A.C.A., San Diego, CA; Gregory Collins, M.D., Charlotte, NC; Charles Cox, M.D., Reno, NV; Alan Cutler, M.D., Detroit, MI; Stephen Daniels, D.O., Houston, TX; Howard Goldberg, M.D., F.A.C.P., F.A.C.G., Wheaton, MD; Ronald Gove, M.D., Pleasantville, NJ; Pradeep Gupta, M.D., Arlington, VA; Vernon Hee, M.D., Vancouver, WA; Dan Henry, M.D., Salt Lake City, UT; Ray Keate, M.D., Scottsdale, AZ; Byron Kolts, M.D., Jacksonville Beach, FL; Frank Lushine, M.D., Minneapolis, MN; John Morganstern, M.D., Lexington, KY; Daniel Pambianco, M.D., Charlottesville, VA; Martin Poleski, M.D., La Jolla, CA; Gary Ruoff, M.D., Kalamazoo, MI; Seymour Sabesin, M.D., Chicago, IL; Shariar Safavi, M.D., Irving, TX; Earl Scheidler, D.O., Cincinnati, OH; John Schoenberger, M.D., Redwood City, CA; Barry Scott, M.D., Baton Rouge, LA; Nimish Vakil, M.D., Milwaukee, WI; Lawrence Wruble, M.D., Memphis, TN; Paul Zachary, M.D., St. Louis, MO; Thomas Zarchy, M.D., Hawthorne, CA; Alvin Zfass, M.D., Richmond, VA.

We also thank Vivian Alderfer, PhD for performing the statistical analyses and Joyce Weiner, PhD for editorial assistance.

Funding for this study was provided by Astra Merck Inc., Wayne, Pennsylvania.

References

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. References
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