Randomised controlled trial of pantoprazole versus ranitidine for the treatment of uninvestigated heartburn in primary care

Gastro-oesophageal reflux disease (GORD) is frequent in the Australian community, and a very common reason for general practice visits. Data from the United States and the United Kingdom suggest that heartburn and acid regurgitation may occur weekly in up to 20% of the population and monthly in up to 40%.1-3 Similarly high rates have been observed in Australia and New Zealand.4,5

The value of lifestyle measures and antacids in managing GORD remains poorly documented, and their effectiveness is probably limited.6 There has been considerable debate as to whether treatment of patients with GORD should be initiated with H2-receptor antagonists and "stepped up" to more effective agents if treatment fails, or if it should commence with proton-pump inhibitors, currently the most effective therapy, and then be "stepped down" when symptom control is achieved.7,8

GORD is usually relapsing or chronic, and most patients require long-term medical management. Half-dose proton-pump inhibitor treatment represents a potentially attractive long-term option as it is less expensive than full-dose treatment.6 However, there are no Australian data on the long-term effects of low-dose proton-pump inhibitors compared with those of full-dose H2-receptor antagonists in patients with symptomatic GORD. Indeed, few international studies have compared these approaches in primary care.6,7,9

We therefore conducted a randomised, multicentre study to test the hypothesis that low-dose pantoprazole (20 mg once daily) would produce superior symptomatic remission rates than standard-dose ranitidine (150 mg twice daily) in patients presenting to general practitioners with symptoms of GORD.

Patients were eligible for the study if they reported experiencing heartburn (defined as "a burning feeling rising from the stomach or lower chest towards the neck"6,10) at least twice a week as the predominant upper-gastrointestinal complaint. Antacid medication and concomitant medications for intercurrent or chronic diseases were permitted during the study. Exclusion criteria are listed in Box 1.

Patients were allocated to treatment groups on the basis of a computer-generated randomisation list administered by participating Divisions of General Practice. The allocation sequence was blinded. No stratification methods were used.

A total of 76 general practitioners recruited 307 patients who entered the random-allocation phase; 154 were assigned to the pantoprazole arm and 153 to the ranitidine arm (Box 2). A total of 184 patients completed the study: 101 in the pantoprazole treatment group and 83 in the ranitidine group.

Significantly more patients withdrew from the ranitidine group than the pantoprazole group (70 v 53; P = 0.04), with lack of efficacy being the most common reason. Nineteen (12%) of the pantoprazole group and 22 (14%) of the ranitidine group withdrew because of adverse events, thought to be related to the study medication in 11 patients in each group.

Baseline demographic and clinical characteristics were well matched between the two groups (Box 3). Eighty-eight per cent of the pantoprazole and 85% of the ranitidine group reported moderate to very severe heartburn on entry into the study, with 46% and 53%, respectively, having experienced daily heartburn. Ninety per cent of participants were compliant with the study treatment.

Patients with endoscopy-negative GORD represent the largest subgroup presenting to primary care with chronic reflux symptoms. Of the remainder, most patients have only mild grades of reflux oesophagitis.6 Both low-dose proton-pump inhibitors and full-dose H2-receptor antagonists are usually inadequate for symptom control in severe grades of oesophagitis, but this factor probably accounted for only a few failures in either treatment arm.6 It is more likely that non-responders were mainly patients with endoscopy-negative disease, who probably represent a heterogeneous group.

Few data are available comparing maintenance proton-pump inhibitor therapy with standard H2-receptor antagonist therapy in primary care. In a trial conducted in patients with endoscopy-negative reflux disease, 60% of those receiving omeprazole (10 mg) achieved symptomatic remission at 24 weeks, compared with 24% of those receiving cimetidine.12 Our trial provides direct evidence that, in patients with uninvestigated reflux, low-dose proton-pump inhibitor therapy was superior to full-dose ranitidine, and provided symptom control in 40% of patients within one month and 71% at six months, with a therapeutic gain of 15% at six months. Eighty-six per cent of patients receiving pantoprazole had achieved sufficient symptom control at six months. Pantoprazole was clearly superior to ranitidine in the first month of therapy, although many had not responded by then to either therapy.

Our trial did not examine whether all patients require maintenance treatment. However, another study has assessed intermittent treatment over one year in patients with endoscopy-proven symptomatic reflux disease in a randomised controlled trial.13 Patients initially received standard-dose omeprazole, low-dose omeprazole, or standard-dose ranitidine. Those who became asymptomatic or mildly symptomatic were then followed for 12 months and any recurrences of heartburn were treated with the dose that was successful in initially controlling symptoms. In all treatment groups, about half of the patients did not need any treatment for at least six months. Such data support a management approach based on self-directed "on-demand" therapy as an alternative to continuous therapy, as patients will often apply this approach by taking medication only when troubled by symptoms.6 Randomised placebo-controlled trials have shown that on-demand therapy is effective and well tolerated in patients with endoscopy-negative GORD.13,14

Safety is a key issue for first-line proton-pump inhibitor therapy for symptomatic reflux disease in general practice. We identified no serious adverse events related to misdiagnosis or treatment in our study after one year of follow-up. The clinical relevance of eradicating Helicobacter pylori in those infected before initiating suppression remains controversial, so we did not determine H. pylori status in our present study. Longer-term treatment with a proton-pump inhibitor has been associated with a small, though definite, increase in the incidence of gastric corpus mucosal atrophy in patients infected with H. pylori. In a study of patients with refractory reflux oesophagitis prescribed omeprazole at standard or higher doses, annual incidences of gastric corpus mucosal atrophy among patients positive and negative for H. pylori were 4.7% and 0.7%, respectively.15 Notably, this increase occurred mainly in those who were elderly and had moderate or severe gastritis at baseline. Other investigators have shown that H. pylori eradication prevents this increase in corpus gastritis, although it is unclear whether it also prevents the progression to gastric atrophy.16 An increased incidence of benign fundic gland polyps has been observed in patients taking proton-pump inhibitors, but does not appear to be clinically significant.17 Although rebound acid hypersecretion occurs after ceasing proton-pump inhibitor therapy, it appears to be restricted to patients negative for H. pylori and is related to the degree of pH elevation during treatment.18,19 Moreover, the clinical relevance of this finding is unclear, and is likely to be small.

Potential failure to identify serious underlying disease is another issue for empirical treatment in patients who have not undergone endoscopy. There is some concern that lesions may be missed or misdiagnosed in patients who are subsequently investigated while receiving proton-pump inhibitor therapy. Case studies have documented failure to recognise early gastric cancers during endoscopy in patients prescribed proton pump inhibitors.20,21 However, curable cancer is rarely identified, and endoscopy in patients with GORD is generally considered to contribute only minimally to its diagnosis. For example, a Canadian study of 742 patients who underwent endoscopy for reflux symptoms found that, regardless of the grade of oesophagitis detected, the most frequent resultant management decisions were dose maintenance or increase in those already receiving a proton-pump inhibitor, and switching to proton-pump inhibitor therapy in those receiving an H2-receptor antagonist. Furthermore, no oesophageal cancers were identified and the prevalence of Barrett's oesophagus was very low.22

Overall, the literature suggests that the risk of serious disease is minimal in patients with reflux attending primary care. Furthermore, there is no evidence that oesophagitis grade worsens over a 10-year period, regardless of treatment.6 While patients who have or develop symptoms such as weight loss, vomiting or bleeding require prompt evaluation, preferably before treatment is started, the current data suggest an empirical trial of therapy is generally safe and acceptable in the absence of such symptoms.

Pantoprazole (20 mg daily) has been demonstrated elsewhere to provide adequate long-term maintenance therapy for patients with GORD in whom remission had already been achieved with standard-dose proton-pump inhibitor therapy.23 It has also been demonstrated to be effective and well tolerated in the treatment of patients with ulcerative oesophagitis.24 In our study, low dose pantoprazole was shown to be effective treatment in patients with symptomatic gastro-oesophageal reflux disease in the general practice setting.

In conclusion, low-dose pantoprazole appears to be an effective alternative to a standard dose of ranitidine in the long-term management of symptomatic GORD. An empirical treatment strategy also appears to be safe in general practice, assuming patients with alarm symptoms are excluded.

2: Establishing the study population for a randomised controlled trial of pantoprazole (20 mg once daily) versus ranitidine (150 mg twice daily) for the treatment of heartburn

a) Recruitment and random allocation

b) Reasons for patient withdrawal*

	Pantoprazole	Ranitidine
Total patients	154	153
Number withdrawn†	53 (34%)	70 (46%)
Consent withdrawn	19 (12%)	12 (8%)
Poor efficacy	16 (10%)	36 (24%)
Adverse event(s) related to study medication	11 (7%)	11 (7%)
Adverse event(s) not related to study medication	8 (5%)	11 (7%)
Protocol deviation	3 (2%)	8 (5%)
Lost to follow-up	1 (1%)	3 (2%)
Other	5 (3%)	8 (5%)
* Difference between withdrawal rates of pantoprazole and ranitidine treatments significant at P = 0.04. † Patients are counted only once in the "Number withdrawn" row, but may have withdrawn for multiple reasons, and are included in the count for each applicable reason for withdrawal.

4: Time to first complete symptom control