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Abstract

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

Aim

: To observe the natural course of gastro-oesophageal reflux disease (GERD) in patients without oesophagitis following effective symptom relief, and to determine the place of acid pump inhibitor therapy in the long-term management of these patients.

Methods

: We investigated the efficacy of on-demand therapy with omeprazole 20 mg or 10 mg, or placebo in a double-blind, randomized multicentre trial. It involved 424 patients with troublesome heartburn without endoscopic evidence of oesophagitis in whom heartburn had been resolved with short-term treatment. Patients were told to take study medication on demand once daily on recurrence of symptoms until symptoms resolved over a 6-month period. They also had access to antacids. The primary efficacy variable was time to discontinuation of treatment, due to unwillingness to continue.

Results

: According to life-table analysis, after 6 months the remission rates were 83% (95% CI: 77–89%) with omeprazole 20 mg, 69% (61–77%) with omeprazole 10 mg, and 56% (46–64%) with placebo (< 0.01 for all intergroup differences). The mean (s.d.) number of study medications used per day in these groups was 0.43 (0.27), 0.41 (0.27) and 0.47 (0.27), respectively. The use of antacids was highest in the placebo group and lowest in the omeprazole 20 mg group. Treatment failure was associated with more than a doubling of antacid use, and a deterioration in patient quality of life.

Conclusions

: Approximately 50% of patients with heartburn who do not have oesophagitis need acid inhibitory therapy in addition to antacid medication to maintain a normal quality of life. On-demand therapy with omeprazole 20 mg, is an effective treatment strategy in these patients.


INTRODUCTION

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

Gastro-oesophageal reflux disease (GERD) is a major healthcare problem in the adult population1 and has a significant negative impact on patient quality of life.2 The disease is diagnosed by symptom analysis, endoscopy and, in selected cases, by ambulatory 24-h pH metry. Endoscopic assessment has its limitations, however, because while it identifies those patients with reflux oesophagitis, over 50% of patients with chronic GERD lack macroscopic evidence of damage to the oesophageal mucosa.3 The difficulties in accurately diagnosing the disease are further compounded by the lack of relationship between the severity, frequency and duration of symptoms and the severity of endoscopically evident erosive lesions.4

Heartburn, the classical symptom of GERD, is generally caused by excess acid reflux into the oesophagus5 and thus inhibiting gastric acid secretion has become the mainstay of medical therapy for the disease. The efficacy of the acid pump inhibitor omeprazole in relieving the symptoms of reflux oesophagitis and in healing the underlying lesion is well documented.6[7]–8 More recently, omeprazole has been shown to have similar efficacy in relieving symptoms in GERD patients without oesophagitis as in those with reflux oesophagitis.9

However, the clinical course of GERD in patients without oesophagitis following symptom relief with short-term omeprazole therapy has not been determined, and in addition, the need for, and efficacy of, long-term acid pump inhibitor therapy needs to be addressed in these patients. Long-term medical therapy of reflux oesophagitis relies largely on continuous maintenance strategies. However, it is a generally held view that GERD without oesophagitis is accompanied by less acid reflux than in patients with reflux oesophagitis.10 Intermittent omeprazole therapy taken on demand is thus an attractive potential long-term management strategy in GERD patients without oesophagitis.

The aim of the present study therefore was to assess the clinical course of GERD in patients without oesophagitis, following symptom relief with short-term therapy, and to compare the long-term efficacy of omeprazole, 20 mg and 10 mg, taken on demand, in a placebo-controlled, randomized, long-term trial.

PATIENTS AND METHODS

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

Patients

Patients of both sexes, aged 18 years or older, who had been suffering from heartburn as their predominant dyspeptic symptom for at least 12 months and who did not have endoscopic signs of oesophagitis were included in the study. Patients with resolution of heartburn following short-term treatment11 entered the long-term on-demand study. The exclusion criteria prior to short-term treatment were: erosive, ulcerative or complicated oesophagitis; peptic ulcer disease; concurrent disease likely to complicate the evaluation of the study treatment; clinically significant abnormal values in the prestudy laboratory screen; treatment with any investigational compound or with antisecretory agents in ulcer healing doses within the previous month; alcohol or drug abuse; pregnancy or lactation; or need for an interpreter.

Study design

The study was double-blind, randomized, placebo-controlled, and multicentre, performed in 25 centres in Denmark and Sweden. All patients were endoscoped and oesophageal acid exposure was determined by 24-h ambulatory intraoesophageal pH monitoring prior to receiving short-term treatment for their heartburn. The result of the pH monitoring was not used as a selection criterion for inclusion in the trial, and was not made available either to the investigator or to the patient during the course of the trial. Patients in whom heartburn was resolved during short-term treatment for 4 or 8 weeks were re-randomized to on-demand treatment with either omeprazole 20 mg, omeprazole 10 mg, or placebo for up to 6 months.

All patients were seen in the outpatient clinic 2, 4, and 6 months after randomization or at any time if unwilling to continue in the trial due to either uncontrolled symptoms, an unacceptable adverse event or some other reason. At each visit patients were asked: ‘Does the study medication give sufficient control of your heartburn’? If the answer was ‘No’, they were asked whether they wanted to continue in the trial or not. Any adverse events were also recorded at each visit.

The study was conducted in accordance with the principles stated in the Declaration of Helsinki and was approved by the local ethics committees.

On-demand treatment

On experiencing heartburn, patients were to take their medication o.d. until they experienced relief of the symptom. They returned to the clinic at the stated intervals, as well as if heartburn control was inadequate and/or they wanted to stop treatment. Medication was given in bottles with a cap containing an electronic device (Medication Event Monitoring System [MEMS], APREX Limited, CH-6304 Zug, Switzerland)12 which automatically recorded the date and time of day that the bottle was opened and closed. New study drug was given at each clinic visit, but each patient retained a single electronic cap throughout the study. Patients were also provided with antacid tablets for pain relief if needed. Returned study drug and antacids were counted at each visit.

Quality of life assessment

Prior to treatment and at 6 months, patients completed two questionnaires which assessed quality of life and gastrointestinal symptoms. These questionnaires had also been completed before inclusion in the short-term treatment study. The Psychological General Well-Being index (PGWB) was used to assess perceived health and well-being, the range being 22–132 with a higher score indicating better well-being.13 The Gastrointestinal Symptom Rating Scale (GSRS) was used to assess subjective symptoms in relation to five common gastrointestinal complaints (indigestion, diarrhoea, constipation, abdominal pain, and reflux), the range being 1–7 and the lower the score the better the patient.14

Statistics

The primary data analysis used the ‘all patients treated’ (APT) method, and a ‘per protocol’ (PP) analysis was also performed. The primary efficacy variable, time to discontinuation due to unwillingness to continue, and a secondary efficacy variable, time to discontinuation due to inadequate relief of heartburn, were analysed by life table methods and treatment differences tested with the log rank test. Pre-treatment oesophageal acid exposure was assessed as a possible prognostic factor for time to discontinuation by use of a Cox′ regression model. Descriptive statistics were used to validate differences in dosing habits.

RESULTS

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

Study population

Baseline demographic details for the 424 patients randomized to on-demand treatment are given in Table 1. Treatment groups were well matched, with slight imbalances with respect to smoking habits and gender, but these had no influence on treatment outcome. Further, there was no difference regarding initial short-term treatment between the groups.

Table 1.  . Baseline demographics by treatment group Thumbnail image of

All patients were included in the APT analysis of crude remission rates. In Figure 1 it is shown the number of patients and reasons for discontinuing the study. For the APT life table analysis, 10 patients were censored for reasons other than the primary end-point. With respect to each treatment group (omeprazole 20 mg/omeprazole 10 mg/placebo), the reasons were adverse events (1/3/0), lost to follow up (1/2/1), erroneous delivery of study medication (0/1/0), and pregnancy (0/0/1).

image

Figure 1. . Flow chart for patients in the study.

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Outcome of treatment

According to life table analysis of the APT cohort, after 6 months of on-demand therapy, 83% of patients treated with omeprazole, 20 mg, were in remission (i.e. willingness to continue in the study), compared with 69% of those who received omeprazole 10 mg, and 56% who took placebo. The crude APT remission rates were almost identical (Table 2). The differences were significant between all three treatment groups in both the APT and PP analyses. The life table analysis of time to study discontinuation due to unwillingness to continue in the APT cohort is shown in Figure 2. The corresponding curves for the PP cohort and for the time to study discontinuation due to inadequate relief of heartburn were almost identical. Indeed, of the 129 patients who left the study due to unwillingness to continue, 91% were due to inadequate relief of heartburn. Pre-treatment oesophageal acid exposure was not a prognostic factor for time to discontinuation.

Table 2.  . Patients in remission after 6 months of on-demand treatment (ATP analysis) Thumbnail image of
image

Figure 2. . Life-table analysis of time to discontinuation due to unwillingness to continue randomized treatment on demand (APT cohort).

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Quality of life

Prior to receiving on-demand therapy, when patients had completed a short-term course of therapy and their heartburn was resolved, their quality of life as assessed by the PGWB index was raised above the mean score found in the normal, healthy population (approximately 103).15 When the index scores according to the clinical outcome of treatment after 6 months of on-demand therapy were examined, patients in remission still had quality of life scores above that of the normal population ( Figure 3). However, treatment failure was associated with a fall in PGWB scores to the low levels observed prior to short-term treatment. Additionally, a difference was observed between treatment groups in the pattern of PGWB scores in patients who relapsed. The PGWB score was already markedly low (96.6) prior to receiving on-demand therapy in patients who subsequently relapsed on omeprazole 20 mg, compared with those who subsequently relapsed on omeprazole 10 mg (108.3) and on placebo (108.8; Figure 3).

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Figure 3. The quality of life as assessed by the mean Psychological General Well-Being score (range 22–132) in patients who completed and who discontinued 6 months on demand treatment (S–E). For comparison the mean scores before the short-term treatment are also shown (P). The vertical lines represent the 95% confidence interval. The horizontal line indicates the level of a healthy population (mean PGWB score = 103. ). (P = Pre-treatment, S = Start of on-demand therapy, E = End of on-demand therapy)

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There were no significant differences between treatments in the total rating of gastrointestinal symptoms according to the GSRS. However, for the reflux dimension the deterioration in the score during the study was greater in the placebo group compared to both omeprazole groups. The difference between placebo and omeprazole 20 mg, was 0.58 (95% CI: 0.30–0.86) and between placebo and omeprazole 10 mg, 0.39 (95% CI: 0.11–0.67). The difference between the two omeprazole doses 0.19 (95% CI: 0.09–0.47) was not significantly different.

Dosing habits

The consumption of study drug, as assessed by the electronic device in the container caps, was similar in all three treatment groups. The mean (s.d.) number of omeprazole 20 mg, omeprazole 10 mg, and placebo capsules used per day was 0.43 (0.27), 0.41 (0.27) and 0.47 (0.27), respectively.

Antacid consumption increased with decreased symptom control, and correlated with the use of study drug ( Figure 4). Antacid use was thus highest in patients receiving placebo study medication. The mean (s.d.) number of antacid tablets used per day in patients taking omeprazole 20 mg, omeprazole 10 mg and placebo, respectively, was 0.77 (0.69), 0.91 (0.92) and 1.15 (1.03). Treatment failure was associated with increased drug consumption and more than a doubling of antacid use. The mean (s.d.) number of antacid tablets used per day in treatment failures was 1.63 (1.21) in patients receiving placebo, 1.49 (0.74) in the omeprazole 20 mg group and 1.50 (1.16) in the omeprazole 10 mg group. The corresponding figures for those who continued in the study were 0.78 (0.66), 0.62 (0.58) and 0.67 (0.67).

image

Figure 4. . The percentage of treatment failures (left) and the use of antacid tablets (right) in the three treatment groups according to the amount of study drug used. Data from seven patients in each treatment group is missing.

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According to the electronic registration, 58% of the study drug was taken between 06.00 and 12.00 hours, and use was equally distributed between the different days of the week. More than half of the patients (54%) used the drug for at least one consecutive period of 7 days or more, 26% for 14 days or more, and 13% for 28 days or more. Time to the first consecutive treatment period of 7 days or more for the median patient treated with omeprazole 20 mg, omeprazole 10 mg, and placebo was 164, 126 and 61 days, respectively.

DISCUSSION

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

The natural history of GERD in patients without oesophagitis is largely unknown.16 In the present study, with the reservation that patients were allowed to take antacids, the natural history of the disease is illustrated by the outcome in the placebo-treated patients. The results indicate that within 6 months, approximately 50% of patients experience an unacceptable degree of symptomatic relapse which is not controlled by antacid use, despite more than doubling of antacid intake by patients who relapsed.

The present study also shows that acid inhibition with omeprazole taken on demand is an effective strategy in these patients. The effect of omeprazole was dose-dependent with 83% of patients kept in remission over a 6-month period using omeprazole 20 mg, on demand, and 69% in remission with omeprazole 10 mg. Moreover, the use of omeprazole was associated with reduced antacid use compared with placebo, and a longer period before study medication was taken for a consecutive period of 7 days or more. Additionally, the superiority of omeprazole over placebo was reflected in the greater deterioration in the reflux dimension of the GSRS in patients who took placebo.

A number of trials have previously assessed low dose omeprazole regimens in the long-term management of GERD. When maintenance of healing has been assessed in a broad sample of patients with reflux oesophagitis,17 there has been a significant dose response effect using maintenance therapy with 10 mg and 20 mg omeprazole, given o.d. However, an intermittent dosing schedule using omeprazole 20 mg o.d. for 3 consecutive days (‘weekend therapy’) has been shown not to be effective in maintaining healing in patients with reflux oesophagitis. Furthermore, in patients with reflux oesophagitis, a numerical but not statistically significant difference has been found between maintenance treatment with omeprazole 10 mg and omeprazole 20 mg o.d., in the time to symptomatic relapse.18 The proportion of patients in symptomatic remission after 6 months continuous treatment with omeprazole 10 mg or 20 mg, was higher than in the present study, but the proportion of patients with relapse in the placebo group was similar to our result. This may be explained by a greater heterogeneity in patient selection in this study compared to studies using unequivocal endoscopic criteria for inclusion, and a different definition of treatment failure, which in the present study was based on the patients’ unwillingness to continue due to unsufficient control of heartburn or any other reasons patients were unsatisfied with.

Tailoring acid inhibition to disease severity in acid related disorders is an attractive approach, which potentially minimizes drug consumption, and this approach was initially investigated by Pounder et al.19 in patients with duodenal ulcer. For heartburn patients without oesophagitis, effective symptom control is their priority, and on-demand treatment as applied in this study individualizes drug usage to the actual need of the patient. In contrast to maintenance therapy with a fixed daily dose, on-demand therapy allows symptoms to recur, but one important conclusion from the current study is that the majority of patients accept this as long as effective therapy is readily available. The long-term safety of omeprazole given as maintenance therapy at high doses is well established, but on-demand therapy achieves the aim of minimal intervention, which is to be strived for with any medical therapy.

Because of the way in which patients were included, GERD was firstly defined in the study on the basis of typical symptoms of reflux. Secondly, patients were selected who did not have mucosal breaks at endoscopy, and finally, on-demand therapy was only given to patients who were satisfied with their initial short-term therapy, which included placebo. Thus the study population did not include all patients with GERD, as symptoms other than heartburn, such as epigastric pain or regurgitation, sometimes predominate, albeit less frequently.20 However, it should be emphasized that the simple selection process makes our results readily applicable in general practice. Additionally, although heartburn is a rather specific symptom of GERD, it is not infallible, and may not have been elicited by acid reflux in some of the patients included in the study. The initial short-term therapy may have eliminated some patients who did not have true GERD, but not all; the resulting heterogeneity would have tended to diminish the treatment effect.

Contrary to the findings during initial treatment with omeprazole where a higher response rate was found in patients with higher pre-treatment levels of oesophageal acid exposure,11 the magnitude of acid reflux did not significantly influence the time to discontinuation during on-demand therapy. Several studies have demonstrated a close, although not absolute, correlation between the level of acid exposure and the endoscopic severity of oesophagitis, but a similar relationship between intensity of symptoms and the magnitude of reflux has been difficult to demonstrate.10, 21 Furthermore, a proportion of patients with chronic reflux symptoms have normal oesophageal acid exposure,22 and there is a large overlap in acid exposure between patients with different severities of GERD.23 These observations suggest that mechanisms within the epithelial barrier of the oesophageal mucosa may be important for the development of oesophageal injury and symptoms in some patients with GERD.24 It is therefore not surprising that we did not find a clear relationship between the magnitude of acid reflux and failures to on-demand therapy.

Patient quality of life, safety and cost are also relevant issues when considering long-term management strategies. On-demand therapy minimizes drug use and thus cost. Additionally, the present study demonstrates that while patients are maintained in symptomatic remission, quality of life as assessed by the PGWB scale is kept at a normal level. In contrast, symptomatic relapse results in a significant deterioration in patient well-being, underlining the value, and necessity of effective therapy given on demand.

The PGWB results show that treatment failures on omeprazole 20 mg differed from failures on omeprazole 10 mg and placebo. Patients who failed on omeprazole 20 mg did not show any improvement in their quality of life during the initial short-term treatment and remained on the lower score through the study. This further emphasizes that heterogeneity in patient selection is likely to have had a negative impact on treatment effect.

In conclusion, approximately half the patients presenting with heartburn as the primary symptom of GERD who do not have oesophagitis will need effective acid inhibitory therapy in addition to antacid medication. Failure to provide this results in symptomatic relapse with a concomitant negative impact on patient quality of life. On-demand therapy with omeprazole is an attractive treatment strategy in GERD patients without oesophagitis who need acid suppression, and the 20 mg dose is superior to 10 mg in keeping these patients in remission.

ACKNOWLEDGEMENTS

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

The study was funded by Astra Hässle, Mölndal, Sweden.

References

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