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- PATIENTS AND METHODS
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.6–8 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.
- Top of page
- PATIENTS AND METHODS
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.