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Summary

  1. Top of page
  2. Summary
  3. Background
  4. Gastric pH and oesophagitis healing
  5. Factors affecting gastric pH
  6. Gastric pH and proton pump inhibitors
  7. Oesophagitis healing and proton pump inhibitors
  8. Endoscopy-negative reflux disease and proton pump inhibitors
  9. Conclusions
  10. References

In patients with gastro-oesophageal reflux disease, the pH of refluxed gastric contents has a direct bearing on disease severity and oesophageal damage. A pH of 4 has been defined as a threshold below which refluxed gastric contents become injurious to the oesophagus. Studies in patients with erosive oesophagitis have shown that the 8-week healing rates produced by acid suppressive therapy are related to the duration of time over a 24-h period that the intragastric pH > 4. The most effective agents, providing more hours with gastric pH > 4 and higher healing rates in erosive oesophagitis patients, are the proton pump inhibitors. The intragastric pH is often used to gauge the efficacy of acid suppressive therapies. There are several factors, however, that may affect the clinical relevance of such data, and these should be taken into account when comparing the effectiveness of different therapies. Firstly, because of inter-individual variation, studies comparing therapies should be of a crossover design, so that responses to therapy are measured in the same individuals. Secondly, the Helicobacter pylori status of the individual should be known, as H. pylori infection has been shown to increase intragastric pH readings when examining the effect of acid suppressive therapy. Other factors, such as positioning of the pH electrode and the duration of previous therapy, also need to be standardized when using intragastric pH to assess the efficacy of different therapies. Crossover studies comparing standard doses of different proton pump inhibitors have shown that esomeprazole 40 mg produces a significantly greater amount of time at intragastric pH > 4 on day 5 of treatment than standard doses of other proton pump inhibitors. The correlation between greater efficacy in acid suppression and clinical benefit is supported by the findings that esomeprazole 40 mg is the only proton pump inhibitor to provide greater 8-week healing rates in patients with erosive oesophagitis than both omeprazole and lansoprazole. These data all suggest strongly that intragastric pH monitoring is an effective surrogate marker and a relevant predictor of outcome in gastro-oesophageal reflux disease.


Background

  1. Top of page
  2. Summary
  3. Background
  4. Gastric pH and oesophagitis healing
  5. Factors affecting gastric pH
  6. Gastric pH and proton pump inhibitors
  7. Oesophagitis healing and proton pump inhibitors
  8. Endoscopy-negative reflux disease and proton pump inhibitors
  9. Conclusions
  10. References

The pathogenesis of gastro-oesophageal reflux disease (GERD) is multifactorial. The reflux of gastric contents into the oesophagus is frequently a consequence of abnormal function at the level of the lower oesophageal sphincter,1 but it can also be related to impaired oesophageal or gastric motility and the presence of a hiatus hernia. However, typical reflux symptoms, such as heartburn and regurgitation, and the development of oesophageal injury in patients with erosive reflux oesophagitis are due predominantly to the reflux of acidic gastric contents into the oesophagus.2 It is not known whether it is the acid itself, or the acidic milieu in conjunction with pepsin,3 that causes reflux symptoms and oesophageal injury, but there is no doubt that a reduction in oesophageal acidity is beneficial in GERD.

The relationship between the reduction in oesophageal acid exposure and healing is evident when comparing classes of medication that clearly differ in their ability to reduce gastric acidity,4 but there are fewer data to indicate whether smaller differences in acid suppression potency are relevant predictors of clinical efficacy when comparing different medications within the same class.

Clinically, the efficacy of medications must be judged on the basis of their ability to produce an improvement in reflux symptoms or a decrease in oesophageal damage; however, first-generation proton pump inhibitors are so effective in the treatment of acid-related disorders that a study intended to assess the clinical superiority of one proton pump inhibitor over another would have to recruit many hundreds or even thousands of patients to demonstrate the expected increment in clinical efficacy. It is therefore critical to identify a surrogate marker of efficacy to determine whether or not a new medication is likely to achieve the desired clinical end-point. Given that oesophageal symptoms and injury in GERD are related to the degree of oesophageal acid exposure, it would be logical to assume that one could measure oesophageal acidity and its response to therapy as a surrogate marker for clinical efficacy when evaluating a new medication for the treatment of GERD. However, in practice, this is not the case, probably because gastro-oesophageal reflux is an intermittent phenomenon leading to greater day-to-day and inter-individual variability of oesophageal acid exposure (in health and in disease) than is the case for gastric acidity. The reduction in oesophageal acid exposure produced by acid suppressive medication is therefore likely to be less predictable than the underlying reduction in gastric acidity. Furthermore, the reproducibility of oesophageal pH assessment is affected by the fact that the measured pH is highly dependent on accurate positioning of the pH electrode relative to the lower oesophageal sphincter.5 As a consequence, the efficacy of acid suppressive medications has been assessed primarily on the basis of their effect on gastric acidity.

Gastric pH and oesophagitis healing

  1. Top of page
  2. Summary
  3. Background
  4. Gastric pH and oesophagitis healing
  5. Factors affecting gastric pH
  6. Gastric pH and proton pump inhibitors
  7. Oesophagitis healing and proton pump inhibitors
  8. Endoscopy-negative reflux disease and proton pump inhibitors
  9. Conclusions
  10. References

Ambulatory 24-h gastric pH recordings, acquired using an intragastric pH electrode connected to an electronic data recorder, usually register a pH measurement every 2–6 s. These recordings therefore generate many thousands of data points, and it is necessary to calculate a summary measure that facilitates comparison of the results of different recordings. The most common summary measures for gastric pH recordings are the median pH and the mean pH for the overall 24-h recording period,6 supplemented by the calculation of the median or mean pH values for other, shorter periods of interest, such as night-time or meal times. A series of meta-analyses, examining treatment effect in patients with duodenal ulcer7 and gastric ulcer,8 have shown that the healing of these lesions, and the time to healing, is related to the period of time that acid suppressive treatment can increase the gastric pH above thresholds of 2.0, 3.0, 4.0 and 5.0. In peptic ulcer disease, pH 4.0 was considered to be the most relevant threshold. Subsequent meta-analyses, summarizing the relative efficacy of antacids, histamine-2 receptor antagonists (H2RAs) and proton pump inhibitors in reflux disease, have shown that there is a direct relationship between oesophagitis healing rates at 8 weeks and the time during which the oesophageal pH > 4.0. Not surprisingly, there is also a direct relationship between the healing rates and the time during which the gastric pH > 4.0.4 In this meta-analysis, the degree of acid suppression achieved was calculated as the number of hours during which the gastric pH > 4.0. The highest degrees of acid suppression, ranging up to 16–18 h per 24-h period during which the gastric pH > 4.0, were achieved by proton pump inhibitors, which also achieved significantly higher healing rates than H2RAs or antacids (Figure 1).

image

Figure 1. Relationship between healing of erosive oesophagitis after 8 weeks and the magnitude of acid suppression, characterized as the percentage of the 24-h recording period during which the gastric pH > 4.0, for antacids (open circles), histamine-2 receptor antagonists (grey circles) and proton pump inhibitors (black circles). Modified, by permission of S. Karger, AG Basel, from Bell et al.4

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Factors affecting gastric pH

  1. Top of page
  2. Summary
  3. Background
  4. Gastric pH and oesophagitis healing
  5. Factors affecting gastric pH
  6. Gastric pH and proton pump inhibitors
  7. Oesophagitis healing and proton pump inhibitors
  8. Endoscopy-negative reflux disease and proton pump inhibitors
  9. Conclusions
  10. References

The development of gastric acidity measurement techniques has been an important step in the assessment of therapy for acid-related disorders since the introduction of H2RAs nearly 30 years ago. Gastric acidity is, however, subject to a number of factors, which can affect the interpretation of studies conducted using ambulatory gastric pH recording techniques (Table 1). The effects of these factors on gastric pH have not been defined fully, but they should all be considered or controlled for when designing gastric pH studies or assessing the effects of different interventions on gastric acidity.

Table 1.  Factors affecting the results of gastric pH recordings
Inter-individual variability
 Baseline, off therapy
 On therapy
Duration of previous therapy
Subject's health status
 Healthy
 Peptic ulcer disease or gastro-oesophageal reflux disease
 Systemic illness (e.g. intensive care unit patient)
Helicobacter pylori status
Feeding status
 Fasted
 Regular food
 Enteral/parenteral nutrition
Position of pH electrode in the stomach
 Body
 Antrum
Type of pH electrode
 Glass
 Antimony
 Ion-sensitive field effect transistor (ISFET)

Although marked inter-individual variation exists with respect to baseline gastric acidity, off therapy there is good intra-individual reproducibility for recordings repeated in the same subject in the absence of acid suppressive medication.9 Thus, the effect of medications on gastric pH should be evaluated in a crossover, repeated-measure study design, rather than by comparing the effects of different medications in separate groups of subjects. This is particularly important when comparing the effects of two medications that are similar in potency, as the inter-individual variation attributable to differences in baseline gastric acidity may be greater than the postulated difference between the two compounds. For this reason, it is also preferable to obtain a baseline 24-h gastric pH recording before the assessment of a treatment effect, to ensure that there are no underlying abnormalities of gastric acidity in individual subjects. Thereafter, the duration of therapy prior to the gastric pH recordings is important; the effect of H2RAs can decrease rapidly over the first few days of therapy,10, 11 whereas the effects of proton pump inhibitors take up to 4 days to reach a representative steady state.12 Generally, pH data obtained from day 5 of treatment or after are taken to be indicative of the effect of a proton pump inhibitor at steady state.

Some inter-individual variability may be attributable to associated diseases, and it has been proposed, therefore, that gastric pH recordings are most relevant if they are performed in subjects who suffer from the condition under consideration. For example, as duodenal ulcer patients generally show higher gastric acid secretion than gastric ulcer patients, the effect of acid suppression on duodenal ulcer healing may be better predicted using data from gastric pH recordings in duodenal ulcer patients than from recordings in normal subjects, GERD patients or gastric ulcer patients. There is no direct proof that this is the case, although there are data to indicate that Helicobacter pylori affects gastric acidity,13 and the effect of an acid suppressant in a duodenal ulcer patient may therefore be different from that observed in a healthy subject.14–16 Specifically, there are no data to indicate that GERD patients have significantly greater acid secretion or a lower gastric pH than healthy subjects. Patients with systemic disease or multi-organ dysfunction, such as patients in an intensive care unit, may have significant changes in gastric acidity or response to therapy, but this is not generally relevant to GERD patients.

The type of food and the manner of its delivery are important determinants of gastric pH, and can vary in effect between the gastric corpus and gastric antrum. Thus, it is important that meals and meal times are standardized and that the pH electrode is located at the same distance from the lower oesophageal sphincter or cardia for all gastric pH recordings. Technically, it is preferable that gastric pH recordings be performed using glass pH electrodes, as they are less susceptible to drift and the effects of other luminal contents than are antimony electrodes17 or ion-sensitive field effect transistor electrodes.18

Gastric pH and proton pump inhibitors

  1. Top of page
  2. Summary
  3. Background
  4. Gastric pH and oesophagitis healing
  5. Factors affecting gastric pH
  6. Gastric pH and proton pump inhibitors
  7. Oesophagitis healing and proton pump inhibitors
  8. Endoscopy-negative reflux disease and proton pump inhibitors
  9. Conclusions
  10. References

The measurement of the gastric pH came to the fore with the development of the H2RAs and confirmation of the role of medical acid suppressive therapy in the treatment of peptic ulcers and GERD. The subsequent development of omeprazole and other proton pump inhibitors was founded on the demonstration that they produced profound suppression of gastric acid secretion and significant increases in gastric pH.19

A series of comparative studies in healthy volunteers or patients with GERD have shown that esomeprazole 40 mg daily produces higher 24-h median pH values (Figure 2) than standard doses of omeprazole, pantoprazole and rabeprazole on days 1 and 5 of drug administration.20–24 Similarly, esomeprazole 40 mg daily produced a higher mean percentage of the 24-h recording period during which the gastric pH > 4.0 (Figure 3) than omeprazole 20 mg, omeprazole 40 mg, lansoprazole 30 mg, pantoprazole 40 mg or rabeprazole 20 mg daily,20–26 and esomeprazole 20 mg daily produced greater acid suppression than lansoprazole 15 mg daily.27 The results of these crossover studies, which compared esomeprazole with one other proton pump inhibitor, are supported by a more recent gastric pH monitoring study in H. pylori-negative patients with GERD.28 Within this crossover study, the effects of esomeprazole 40 mg on gastric pH were compared directly with those of four other proton pump inhibitors, given at the standard initial therapy dose for oesophagitis patients. Esomeprazole 40 mg daily produced a greater percentage of the 24-h recording period during which the gastric pH > 4 on day 5 of drug administration than lansoprazole 30 mg daily, omeprazole 20 mg daily, pantoprazole 40 mg daily or rabeprazole 20 mg daily (Figure 4). Another recent crossover study in healthy subjects confirmed that there is a dose–response effect for both esomeprazole and lansoprazole with respect to the control of gastric pH,29 and demonstrated also that esomeprazole 40 mg daily produced more prolonged acid suppression than lansoprazole 30 mg or 60 mg daily (Figure 5). Thus, there is good evidence from these, and other publications,30 to indicate that measurement of the steady state (day 5 of administration) gastric pH can differentiate between different proton pump inhibitors. It should be noted, however, that the relevance of differences in gastric pH recorded on the first day of therapy to oesophageal healing and symptom relief has not been established.

image

Figure 2. Median 24-h pH values on day 5 of drug administration in patients with gastro-oesophageal reflux disease, comparing esomeprazole 40 mg daily with esomeprazole 20 mg daily and omeprazole 20 mg daily,20 omeprazole 40 mg daily,21 pantoprazole 40 mg daily22 and rabeprazole 20 mg daily.23

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image

Figure 3. Mean percentages of the 24-h recording periods, on day 5 of drug administration, during which the gastric pH > 4.0 in patients with gastro-oesophageal reflux disease20–23, 25 and healthy subjects.24, 26, 27 All studies were conducted as crossover studies comparing esomeprazole (40 mg or 20 mg) with one other proton pump inhibitor in Helicobacter pylori-negative subjects.

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image

Figure 4. Mean percentages of the 24-h recording periods, on day 5 of drug administration, during which the gastric pH > 4.0 in 34 Helicobacter pylori-negative patients with gastro-oesophageal reflux disease in an open-label, five-way crossover study comparing esomeprazole 40 mg, rabeprazole 20 mg, omeprazole 20 mg, lansoprazole 30 mg and pantoprazole 40 mg daily.28

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image

Figure 5. Mean percentages of the 24-h recording periods, on day 5 of drug administration, during which the gastric pH > 4.0 in healthy Helicobacter pylori-negative subjects in an open, six-way crossover study comparing esomeprazole (20 mg, 40 mg and 80 mg daily) with lansoprazole (15 mg, 30 mg and 60 mg daily).29

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Oesophagitis healing and proton pump inhibitors

  1. Top of page
  2. Summary
  3. Background
  4. Gastric pH and oesophagitis healing
  5. Factors affecting gastric pH
  6. Gastric pH and proton pump inhibitors
  7. Oesophagitis healing and proton pump inhibitors
  8. Endoscopy-negative reflux disease and proton pump inhibitors
  9. Conclusions
  10. References

Numerous studies and meta-analyses have confirmed the superiority of proton pump inhibitors over H2RAs for the healing of erosive oesophagitis,31 and this outcome is due to the acid antisecretory effect of proton pump inhibitors. The superiority of proton pump inhibitors was established initially in studies with omeprazole, and there is no convincing evidence that the subsequent three proton pump inhibitors — lansoprazole, pantoprazole and rabeprazole — are significantly more effective in healing erosive oesophagitis.32 However, recent clinical studies in patients with endoscopically confirmed erosive oesophagitis have provided further evidence of the relationship between acid suppression and oesophagitis healing.

Esomeprazole, the optical (S)-isomer of omeprazole, has been shown to produce greater areas under the plasma drug concentration–time curve (AUC) than equivalent doses of omeprazole as a result of its decreased first-pass hepatic metabolism33 in both slow and fast metabolizers. The greater AUC for esomeprazole is associated with greater suppression of gastric acid secretion20 and higher gastric pH. Although AUC values are not necessarily directly comparable between different proton pump inhibitors, there are accumulating data to show that, when compared with other proton pump inhibitors, the greater AUC of the esomeprazole serum concentration curve translates into higher healing rates for reflux oesophagitis and better symptom control.34–40

The first randomized controlled studies with esomeprazole reported that it produced healing of erosive oesophagitis, at doses of 40 mg daily and 20 mg daily, in a greater proportion of patients than omeprazole 20 mg daily34, 35 after 8 weeks of therapy (Table 2), and that esomeprazole 40 mg daily was more effective than omeprazole 20 mg daily at 4 weeks.

Table 2.  Eight-week healing rates for esomeprazole 40 mg and 20 mg daily compared with omeprazole 20 mg daily or lansoprazole 30 mg daily in patients with erosive oesophagitis34–36
TreatmentKahrilas et al.34Richter et al.35Castell et al.36
Remission % (95% CI)nRemission % (95% CI)nRemission % (95% CI)n
  • CI, confidence interval.

  • *

    P < 0.001 vs. omeprazole 20 mg.

  • P < 0.05 vs. omeprazole 20 mg.

  • P < 0.001 vs. lansoprazole 30 mg.

Esomeprazole 40 mg94.1* (92.2–96.0)65493.7* (92.3–95.1)121692.6 (91.5–93.6)2624
Esomeprazole 20 mg89.9 (87.5–92.3)656
Omeprazole 20 mg86.9 (84.2–89.6)65084.2 (82.1–86.3)1209
Lansoprazole 30 mg88.8 (87.5–90.0)2617

A subsequent acute study comparing esomeprazole 40 mg daily with lansoprazole 30 mg daily demonstrated that esomeprazole was more effective in healing erosive oesophagitis (Table 2) and relieving reflux symptoms,36 and that the difference in effect was more marked for patients who had more severe (Los Angeles grades C and D) erosive oesophagitis.

There are, to date, no published studies comparing esomeprazole with rabeprazole for the treatment of erosive oesophagitis, but early data from a study comparing esomeprazole 40 mg daily and pantoprazole 40 mg daily also indicate that the greater acid suppression documented with esomeprazole12, 28 is associated with higher healing rates.37

Endoscopy-negative reflux disease and proton pump inhibitors

  1. Top of page
  2. Summary
  3. Background
  4. Gastric pH and oesophagitis healing
  5. Factors affecting gastric pH
  6. Gastric pH and proton pump inhibitors
  7. Oesophagitis healing and proton pump inhibitors
  8. Endoscopy-negative reflux disease and proton pump inhibitors
  9. Conclusions
  10. References

The relationship between the level of acid suppression and symptom relief produced by different proton pump inhibitors has not, as yet, translated into demonstrated benefit in patients with endoscopy-negative reflux disease. It is possible that success in this patient subgroup requires a lower threshold of effect on gastric pH than in oesophagitis patients. In addition, although the majority of patients with endoscopy-negative reflux disease enrolled in clinical trials appear to have heartburn-dominant symptoms that are acid reflux related,41–45 a significant minority may have ‘functional heartburn’,46 unrelated to the presence of acid in the oesophagus. Such patients may not respond either to acid suppression or to the greater acid suppression produced by esomeprazole or by increased doses of esomeprazole or other proton pump inhibitors.47

Conclusions

  1. Top of page
  2. Summary
  3. Background
  4. Gastric pH and oesophagitis healing
  5. Factors affecting gastric pH
  6. Gastric pH and proton pump inhibitors
  7. Oesophagitis healing and proton pump inhibitors
  8. Endoscopy-negative reflux disease and proton pump inhibitors
  9. Conclusions
  10. References

For patients with erosive oesophagitis, the greater degree of acid suppression produced by proton pump inhibitors, compared with H2RAs, is associated with higher healing rates as well as greater and more rapid symptom relief. Recent studies with esomeprazole 40 mg have indicated that it produces significantly greater acid suppression than comparator, standard, once-daily proton pump inhibitors, and clinical studies that have compared esomeprazole with omeprazole and lansoprazole have indicated that the greater effects of esomeprazole 40 mg on gastric pH translate into higher healing rates for erosive oesophagitis. This provides good support for the hypothesis that gastric pH, whether analysed as the time with gastric pH > 4.0 or as the median 24-h pH, is the most relevant predictor of proton pump inhibitor treatment efficacy in patients with GERD. The relationship between gastric pH during therapy and treatment outcome is most clearly evident in patients with erosive oesophagitis, in whom lesions and symptoms appear to be closely related to oesophageal acid exposure. More research is needed into both baseline and ‘on-therapy’ gastric and oesophageal pH patterns, with correlation of these patterns to symptom outcome data, in patients with endoscopy-negative reflux disease, in order to better understand the outcomes of proton pump inhibitor therapy in this patient group.

References

  1. Top of page
  2. Summary
  3. Background
  4. Gastric pH and oesophagitis healing
  5. Factors affecting gastric pH
  6. Gastric pH and proton pump inhibitors
  7. Oesophagitis healing and proton pump inhibitors
  8. Endoscopy-negative reflux disease and proton pump inhibitors
  9. Conclusions
  10. References
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