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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 investigate the efficacy of a low dose of pantoprazole, a gastric proton pump inhibitor, for the relief of symptoms and healing of lesions in mild gastro-oesophageal reflux disease (GERD), and to compare it with the efficacy of ranitidine.

Methods:

Patients with endoscopically established GERD (Stage I, Savary–Miller classification) were enrolled into a randomized, double-blind, parallel-group and multicentre study (intention-to-treat n = 209, age range 19–82 years). They were treated once daily with oral pantoprazole 20 mg or ranitidine 300 mg, for up to 8 weeks. End-point parameters included relief of symptoms (heartburn, acid regurgitation, pain on swallowing) and the healing of GERD lesions. Relief from symptoms was assessed after 2 and 4 weeks, and endoscopically confirmed healing of lesions after 4 and 8 weeks.

Results:

The proportion of patients reporting complete relief from symptoms after 2 weeks was greater in the pantoprazole than in the ranitidine group (69 vs. 48%, < 0.01), with further improvements seen in the pantoprazole group after 4 weeks (80 vs. 65%, < 0.05, Cochran–Mantel/Haenszel test). Healing of lesions was confirmed in 70/87 (80%) patients after 4 weeks (pantoprazole group), as compared with 55/86 (64%) patients (ranitidine group) (< 0.05, per protocol population); after 8 weeks the respective results were 78/87 (90%) and 63/86 (73%) patients (< 0.01). Both study medications were well tolerated.

Conclusion:

Low-dose pantoprazole (20 mg) is clinically superior to ranitidine (300 mg) in providing fast relief from symptoms and healing of lesions in patients with mild GERD.


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 multifactorial clinical condition affecting a large proportion of the population. It is characterized by reflux of gastric acid into the oesophagus, which can cause inflammation of the oesophageal mucosa.[1][2]1–3 The disease can present with a range of symptoms and several degrees of oesophageal damage classified (according to Savary and Miller4) as GERD I, II, III or IV.1–3, 5 Even in mild GERD (Stage I), the patients perceive painful symptoms, the most common of these being heartburn, followed by acid regurgitation and pain on swallowing;2 erythematous lesions are detectable endoscopically above the mucosal junction. In the more advanced stages (Stage II to IV), the lesions tend to progress and become confluent or cover the whole circumference of the oesophagus.

Inhibition of gastric acid secretion appears to be the most successful therapeutic approach in the management of GERD.1–3, 5 Histamine-receptor (H2-receptor) antagonists such as ranitidine and famotidine have been used previously to modulate the gastric acid secretion in this clinical condition.6 However, during the last decade, inhibitors of the gastric proton pump, H+,K+-ATPase (omeprazole, lansoprazole and pantoprazole) have clearly demonstrated their clinical superiority over the H2-receptor antagonists in the treatment of this gastric acid-related disorder.1, 3, 5, 7–10

Recent clinical studies have showed that 40 mg oral pantoprazole taken once daily (o.d.) is superior to H2-receptor antagonists (ranitidine and famotidine)7, 1115 and is equivalent to other proton pump inhibitors such as omeprazole1618 and lansoprazole19 for the treatment of moderate and severe GERD (Stage II and III, respectively).11, 13, 1519 These observations were extended further in the present study by testing the hypothesis that a low dose of pantoprazole (20 mg o.d.) may be sufficient to relieve symptoms and achieve high healing rates in patients with mild GERD.

PATIENTS AND METHODS

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

This study was a randomized, multicentre, double-blind and parallel-group comparison of pantoprazole 20 mg o.d. (taken before breakfast) and ranitidine 300 mg o.d. (taken at bedtime), involving 24 centres in Germany. The study was conducted according to the Good Clinical Practice guidelines and the protocol was approved by the State Ethics Committee (Baden-Württemberg, Stuttgart, Germany). All patients gave their written informed consent to their participation in the study.

Inclusion criteria

Male and female patients were enrolled into the study (intention-to-treat patient population, n = 209, age range 19–82 years). All had mild GERD which was diagnosed endoscopically within 3 days prior to the start of the study treatment and rated as Stage I according to the Savary–Miller classification.4 GERD Stage I was defined as the presence of an erythematous, oval or linear erosion (usually 1–1.5 cm) above the mucosal junction. Progressive appearance of further multiple lesions may be seen, however the lesions must not become confluent. In addition to the erythematous lesions, the presence of at least one of the primary symptoms of GERD, namely acid regurgitation, heartburn or pain on swallowing, was required for inclusion into the study.

Exclusion criteria

The exclusion criteria were: the presence of GERD Stage II, III or IV according to the Savary–Miller classification,4 peptic ulcer or Zollinger–Ellison syndrome; intake of substituted benzimidazoles within 3 days prior to the start of the study; intake of glucocorticoids or non-steroidal anti-inflammatory drugs, a concomitant treatment with drugs whose absorption is pH dependent, such as sucralfate, antacids, ketoconazole, prokinetic drugs and oral anticoagulants. Other exclusion criteria were pregnancy, lactation, females not using reliable contraception, severe concomitant disease, any history of allergic drug reactions, alcohol or drug abuse, any clinically relevant deviations in routine laboratory variables on entry to the study and non-compliance with either the study medication or attendance at the follow-up visits, as defined below.

Treatment

The double-blind design of the study was ensured by using a double-dummy technique for the study medications. Patients were randomized into two treatment groups to receive tablets containing the active drug—either 20 mg pantoprazole or 300 mg ranitidine. They also received dummy tablets which were identical in appearance to the respective active drug. Pantoprazole was taken once daily before breakfast, ranitidine once daily at bedtime. The treatment lasted for 4 weeks and, if the healing was not complete, continued for an additional 4 weeks.

Assessments

Symptoms of reflux oesophagitis.

The presence and severity of the principal symptoms of reflux oesophagitis, i.e, acid regurgitation, heartburn and pain on swallowing, were assessed after 2 and 4 weeks. The symptoms were defined as follows: heartburn—substernal pain or burning sensation in the epigastrium, possibly rising to the pharynx; acid regurgitation—backward flow of small amounts of the contents of the stomach, possibly rising to the pharynx and attributed to gastric acid; sometimes occurring together with coughing or choking; pain on swallowing (also referred to as dysphagia by some investigators)—clear pain upon swallowing the associated with retrosternal tightness.20, 21 Patients were asked at each visit to classify the severity of their symptoms as none, mild (barely noticeable), moderate (clearly noticeable symptoms, but tolerable without immediate relief) or severe (overwhelming discomfort, urgent desire for immediate relief). During these visits, other gastrointestinal symptoms (epigastric pain, retrosternal pain, retrosternal tightness, regurgitation of air, nausea, retching and vomiting) were also assessed according to the same scale.

Healing of reflux oesophagitis.

The efficacy of oesophagitis healing was defined as a complete epithelialization of the erythematous lesions that were observed at entry into the study. Endoscopic examinations were performed on entry into the study, after 4 weeks and, if appropriate, after 8 weeks of treatment.

Safety.

Safety of the study treatments was assessed by recording any adverse events. Information regarding such events was obtained by questioning patients during the study visits. Determination of haematological and biochemical parameters and dipstick urine analysis were performed at the individual study centres before the start of the treatment (baseline) and after 4 weeks and, if appropriate, after 8 weeks of treatment.

Compliance.

Compliance with the study medication was required to be greater than 70% between two study visits; this was checked by counting the returned tablets. Patients whose visit dates fell – 3 or + 7 days (weeks 2 and 4) and – 3 or + 8 days (weeks 6 and 8) outside the scheduled study visits were excluded from the per protocol analysis.

Statistics

The sample size was calculated to detect a 25% difference between the treatment groups in the healing of lesions after 4 weeks (55:80%; Fisher’s exact test as an approximation to the Cochran–Mantel/Haenszel test); 160 patients were required to detect this difference based on a two-sided test at a 5% level of significance and a power of 90%. The Cochran–Mantel/Haenszel test, which provided the estimation and confidence interval for the odds ratio, was used for the statistical analysis of data regarding the healing after 4 and 8 weeks, and freedom from symptoms after 2 and 4 weeks of treatment.

The statistical analysis of results was performed in the patient populations intention-to-treat, per protocol and key-point-available. The intention-to-treat population represents patients who ingested at least one dose of the study medication. This population was used for the statistical analysis of demographic data, baseline comparisons, tolerability and healing of erythematous lesions. The per protocol population included patients who: (i) completed the entire treatment regimen according to the protocol or (ii) discontinued the study for reasons attributed to the study medication, i.e. for adverse events assessed as probably or definitely related to the study medication or for lack of efficacy. These drop-out patients were considered as treatment failures in the analyses of the healing of erythematous oesophageal lesions. For analysis of symptoms, the per protocol and key-point-available approach included all patients who were per protocol and who provided valid data for the respective ‘key’ time points.

RESULTS

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

Patient populations

The details regarding the patients’ treatment groups, drop-outs and protocol violators, as well as the different populations used for the statistical analysis of data are summarized in a flow chart (Figure 1).

Intention-to-treat.

A total of 209 patients were enrolled into the study (intention-to-treat population). Their demographic and baseline characteristics are listed in Table 1. These patients were randomized according to a computer-generated randomization list to receive pantoprazole or ranitidine (Figure 1). The median age in the ranitidine group (54 years) was greater than in the pantoprazole group (47 years; < 0.05). This difference in age was unlikely to have had a clinically relevant effect upon the outcome of the study. Other baseline and demographic characteristics were comparable.

Per protocol.

The per protocol study population consisted of 87 patients who received pantoprazole and 86 who received ranitidine. Thirty-six patients (18 each from the pantoprazole and ranitidine treatment groups) were classified as protocol violators and were excluded from the per protocol analysis. The reasons for excluding patients from the per protocol data analysis were: poor compliance with either the study visits (n = 20) or study medications (n = 6), study tests, i.e. endoscopies performed more than 3 days before start of study treatment (n = 2), discontinuation of treatment due to adverse events not related to study treatment (n = 4), request for discontinuation (n = 3) and clinically relevant elevated liver enzymes at baseline (n = 1). A total of eight patients were classified as drop-outs and these were included in the per protocol population (n = 3 in the pantoprazole group and n = 5 in the ranitidine group). They discontinued the study prematurely due either to adverse events which were rated by the investigator as possibly related to the study medication or to lack of efficacy (Figure 1).

Per protocol and key-point-available.

For the evaluation of symptom relief, the only patients included in the analysis were those who were classified as per protocol in the healing rates analyses and for whom results of the symptom status was available at the respective assessment visits after week 2 or 4 of treatment (Figure 1). Thus, according to this definition a patient was excluded from the analysis at week 2 but was included for the analysis at week 4 because he missed the visit at week 2 but attended at week 4 and provided valid data for that time point.

Treatment efficacy

Symptom relief.

As shown in Figure 2, after 2 weeks of treatment 58/84 (69%) patients in the pantoprazole group were completely free of all primary symptoms, i.e, acid regurgitation, heartburn, pain on swallowing. This compared with 41/85 (48%) patients in the ranitidine group (P < 0.01, Cochran–Mantel/Haenszel test). After 4 weeks, 68/85 (80%) patients in the pantoprazole group and 55/84 (65%) patients in the ranitidine group were free from these symptoms (P < 0.05) (per protocol and key-point-available population).

Healing of oesophageal lesions.

In the per protocol population healing of lesions in patients with mild GERD are presented in Figure 3. After 4 weeks, complete healing was evident in 80% (70/87) of patients in the pantoprazole group and in 64% (55/86) of patients in the ranitidine group (per protocol analyses). After 8 weeks, the cumulative healing rates were 90% (78/87) of patients in the pantoprazole group and 73% (63/86) of patients in the ranitidine group. The differences in the healing rates between the two treatment groups were statistically significant after 4 (P < 0.05) and 8 (P < 0.01) weeks.

In the intention-to-treat population, when protocol violators were included in the analyses as non-responders, the healing after 4 weeks was 67% (70/105) of patients in the pantoprazole group and 53% (55/104) of patients in the ranitidine group (< 0.05). After 8 weeks the healing was 74% (78/105) and 61% (63/104), respectively (< 0.05).

Safety

Both study medications were generally well tolerated. Thirty adverse events were reported by 19/105 (18%) patients receiving pantoprazole, while 45 adverse events were reported by 22/104 (21%) patients in the ranitidine group. Of these, 17 events in the pantoprazole group and 32 events in the ranitidine group were classified by the investigators as not related to the study medication. Those adverse events that were not excluded from a causal relationship with the study medications involved 8/105 (8%) patients treated with pantoprazole and 9/104 (9%) patients treated with ranitidine. Diarrhoea, dizziness and nausea were reported at an incidence of about 3% each in the group receiving pantoprazole; in the ranitidine group these events were reported at an incidence of 3, 4 and 2%, respectively. The severity of these events was judged to be mild or moderate.

There were no consistent or clinically significant differences between the median values for haematology and biochemistry parameters at baseline and weeks 4 or 8.

DISCUSSION

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

Numerous controlled clinical studies have shown that the proton pump inhibitors (omeprazole, lansoprazole and pantoprazole) provide an obvious therapeutic benefit in the treatment of the more advanced forms of GERD (Stage II, III, IV) over H2-receptor antagonists (ranitidine, cimetidine or famotidine).1, 2, 5, 6, 11, 12, 22–27 In previous investigations it was noted that 40 mg pantoprazole o.d. achieved better healing rates and relief from symptoms in patients with the moderate (Stage II) as compared to the severe (Stage III) form of reflux oesophagitis.12, 1517 Only a few studies, however, have examined the efficacy of these medications in the mild form (Stage I) of this clinical condition.12, 21, 28 The aim of the current study was to establish the therapeutic efficacy of a low dose of oral pantoprazole (20 mg o.d.) in comparison to ranitidine (300 mg o.d) in patients with mild GERD. A large homogeneous population of patients with a confirmed gastrointestinal complaint (mild GERD) was assessed at predefined key time points during the treatment period.

The results from this study showed that significantly more patients with mild GERD were free of all symptoms after only 2 (69 vs. 48%, < 0.01) and 4 (80 vs. 65%, < 0.05) weeks when treated with pantoprazole as compared to those in the ranitidine group (Figure 2). With respect to heartburn, 82 vs. 61% (< 0.01) patients were free of this primary symptom after 2 weeks of treatment in the pantoprazole and ranitidine groups, respectively (results not shown). Endoscopically confirmed healing was also achieved more effectively in patients treated with the low-dose pantoprazole as compared to ranitidine (80 vs. 64%, < 0.05 after 4 weeks and 90 vs. 73%, < 0.01 after 8 weeks).

Comparison of the results from the present study with those from other trials is difficult, however. This is mainly due to differences in (i) the study design, (ii) assessment times, (iii) medications, (iv) medication dose and (iv) involvement of a heterogeneous patient population with various stages of GERD in the other trials.[12][21]12, 21, 29 Specifically, in these studies, summarized by Bader and Delchier,12 the number of patients with mild GERD was relatively small, so that the overall results reported with 40 mg pantoprazole reflected the efficacy of the treatment in patients who had predominantly moderate to severe forms of GERD. These results are nonetheless in agreement with other studies for the predominant clinical indications involved.7, 11, 13, 1519

Despite the many factors which may contribute to GERD, the role of gastric acid is considered essential to the eventual mucosal damage. In particular, the duration of the suppressed gastric acid secretion, achieved over a 24-h period, is considered a fundamental parameter in the pathogenesis of this common clinical condition.[3]3, 5 The superior results observed even with a low dose of pantoprazole over ranitidine therefore emphasize the ability of pantoprazole to achieve a more effective and longer-lasting suppression of acid secretion in patients with mild GERD.

The value of lifestyle modifications in patients with GERD has been a topic of several reviews.2, 5, 21, 30 It is accepted that, as part of an anti-reflux regimen, these patients should be advised of the simple measures of weight loss, dietary control, smoking and raising the head of the bed. However, the benefits of lifestyle changes is apparent or achievable only after some time. In addition, a consistent implementation of the suggested lifestyle modifications is often difficult to impose or to control. Symptoms, even those associated with mild GERD, can seriously affect performance and the quality of life of those affected. The fast resolution of discomfort and pain that can be attained with medications such as pantoprazole is therefore a welcome alternative. Indeed, the so-called ‘on demand’ or ‘intermittent’ schedules with pantoprazole for these patients may turn out to be a new option for managing patients with mild GERD.21, 31

In conclusion, the results of the present study show clearly that even low-dose pantoprazole (20 mg o.d.) is therapeutically superior to ranitidine (300 mg o.d.) in achieving rapid relief from the primary symptoms of GERD and in promoting the healing of lesions. The results also provide new information regarding safe management options for patients with mild GERD.

ACKNOWLEDGEMENTS

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

The authors gratefully acknowledge Dr Kathy B. Thomas (Byk Golden, Konstanz) for helpful suggestions during the preparation and editing of this manuscript.

This work was supported by a grant from Byk Gulden Pharmaceuticals, Konstanz, Germany.

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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