A model of healing of Los Angeles grades C and D reflux oesophagitis: is there an optimal time of acid suppression for maximal healing?

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1 Alimentary Pharmacology and Therapeutics A model of healing of Los Angeles grades C and D reflux oesophagitis: is there an optimal time of acid suppression for maximal healing? P. O. Katz*, D. A. Johnson à, D. Levine,K.Röhss, O. Junghard,, M. Åstrand & P. Nagy *Albert Einstein Medical Center, Philadelphia, PA, USA. à Eastern Virginia Medical School, Norfolk, VA, USA. AstraZeneca Pharmaceuticals LP, Wilmington, DE, USA. AstraZeneca R&D, Mölndal, Sweden. Correspondence to: Prof. P. O. Katz, Albert Einstein Medical Center, Klein Bldg, Suite 363, 5501 Old York Road, Philadelphia, PA 19141, USA. katzp@einstein.edu Deceased. Publication data Submitted 8 February 2010 First decision 22 February 2010 Resubmitted 18 May 2010 Accepted 18 May 2010 Epub Accepted Article 22 May 2010 SUMMARY Background In patients with Los Angeles (LA) grade C or D oesophagitis, a positive relationship has been established between the duration of intragastric acid suppression and healing. Aim To determine whether there is an apparent optimal time of intragastric acid suppression for maximal healing of reflux oesophagitis. Methods Post hoc analysis of data from a proof-of-concept, double-blind, randomized study of 134 adult patients treated with esomeprazole (10 or 40 mg od for 4 weeks) for LA grade C or D oesophagitis. A curve was fitted to pooled 24-h intragastric ph (day 5) and endoscopically assessed healing (4 weeks) data using piecewise quadratic logistic regression. Results Maximal reflux oesophagitis healing rates were achieved when intragastric ph >4 was achieved for approximately 50 70% (12 17 h) of the 24-h period. Acid suppression above this threshold did not yield further increases in healing rates. Conclusion After 4 weeks acid-suppressive therapy for LA grade C or D oesophagitis, successful healing appears to reach a threshold above which improvements are unlikely to be achieved despite an increase in number of hours with intragastric ph >4. Aliment Pharmacol Ther 2010; 32: doi: /j x

2 P. O. Katz et al. INTRODUCTION Symptoms typical of gastro-oesophageal reflux disease (GERD), heartburn and or regurgitation, are common among the general population and approximately 40 60% of patients with GERD symptoms daily 1 or for a duration of 1 month 2 show evidence of reflux (erosive) oesophagitis (RO) on endoscopy. Excessive exposure of the oesophagus to reflux of gastric contents with a ph 4 is an important factor in the pathogenesis of such injury. 3, 4 Consequently, it has been suggested that healing of RO is optimal and directly related to the duration for which intragastric ph is maintained above this threshold with acid-suppressive therapy (i.e. percentage of time with intragastric ph >4). 5, 6 Proton pump inhibitors (PPIs), which provide potent acid suppression, therefore provide healing in patients with RO superior to that of H 2 -receptor antagonists. 7 In patients with moderate-to-severe RO [Los Angeles (LA) grades C and D 8 ], a positive relationship between the duration of intragastric acid suppression provided by esomeprazole and the proportion of patients with complete healing of RO has been demonstrated previously in a prospective, proof-of-concept study. 9 As part of an exploratory analysis, we sought to characterize this relationship further, in terms of whether there is an apparent optimal time of acid suppression for maximal probability of healing. METHODS This post hoc analysis used data from a prospective, proof-of-concept, multicentre, double-blind, randomized study in patients with RO (ClinicalTrials.gov identifier: NCT ; study code: D9612L00062). Full details of study methods are published elsewhere. 9 Briefly, men and women (aged years) had to have oesophagogastroduodenoscopy (EGD)-diagnosed RO (LA grade C or D) within 7 days prior to study entry. Patients were excluded if they had clinically relevant gastrointestinal bleeding, non-acid-related oesophagitis, history of gastric or oesophageal surgery, bleeding disorders, abnormal laboratory values or the presence of any condition likely to compromise safety and efficacy assessments. To achieve a range of intragastric ph levels, patients were randomized to receive esomeprazole (AstraZeneca Pharmaceuticals LP, Wilmington, DE, USA) 10 or 40 mg once daily for 4 weeks. Study medication was to be taken 30 min before breakfast. Rescue antacids (Gelusil; Warner-Lambert Consumer Healthcare, Morris Plains, NJ, USA) were allowed for relief of acute, intolerable GERD symptoms. On day 5 of treatment, 24-h intragastric ph monitoring was completed using a transnasal, dual-channel, microelectrode catheter attached to a GERD-check data logger (Sandhill Scientific, Highlands Ranch, CO, USA), as previously described. 9 In brief, the ph probe was positioned so that respectively the proximal and distal channels were 5 cm above and 7 10 cm below the manometrically defined lower oesophageal sphincter. The ph values were recorded at 5-s intervals throughout the 24-h study period. Intragastric ph data were reviewed by an investigator blinded to drug dosage or healing status and were considered evaluable if there were more than 20 h of data within the ph range 0 9, <1 continuous hour outside this range and no technical failures. Healing of RO was assessed by EGD after 4 weeks of acid-suppressive therapy. An absence of mucosal breaks indicated healing of RO. Maximal healing rates were defined as the highest mean percentage of patients completely healed. The present analysis included all patients with evaluable healing data and 24-h intragastric ph monitoring on day 5 of the study (intent-to-treat analysis). Point summaries using 10% increments of percentage of time with ph >4 were calculated, and a curve was fitted to ph and healing data using piecewise quadratic logistic regression (4 degrees of freedom). Thereafter, the apparent optimal time of acid suppression for maximal healing was visually estimated from the fitted curve. RESULTS From a total of 169 randomized patients in the original study by Katz et al. (of whom 103 were included in the corresponding per-protocol analysis), patients (mean age, 49 years) had evaluable RO healing data and had undergone 24-h intragastric ph monitoring on day 5 of the study and were therefore included in the present intent-to-treat analysis. Of the evaluable population, 67 patients were treated with esomeprazole 10 mg and 67 patients were treated with esomeprazole 40 mg. Overall, 66% of patients were men, 91% had LA grade C and 9% LA grade D oesophagitis and 9% were positive for Helicobacter pylori. Relationship between intragastric ph and healing of reflux oesophagitis A non-linear pattern was observed between percentage of time with intragastric ph >4 and RO healing and therefore a non-linear curve was fitted (Figure 1). Visual estimation showed that maximal healing rates were attained when intragastric ph >4 was achieved for approximately 444 Aliment Pharmacol Ther 2010; 32:

3 Acid suppression and healing of reflux oesophagitis Healing of Oesophagitis (%) n=6 n=5 n=19 n=23 n=12 n=14 n=18 n=17 n=12 n= Mean time with intragastric ph > 4 (%) Figure 1 Reflux oesophagitis healing in 10% intervals of time vs. time with intragastric ph >4 (fitted curve plus 95% confidence region). Error bars indicate standard error of the mean % (12 17 h) of the 24-h period. The positive predictive value for 70% of time with ph >4 (number of patients with healed oesophagitis and 70% of time with ph >4 divided by number of patients with 70% of time with ph >4) was 73% (33 of 45 patients). Thus, healing of RO was observed in 73% of patients who had more than 70% of mean time with ph >4 compared with 46% (23 of 50 patients) of those who had <50% of mean time with ph >4 for the 24-h period. The difference was statistically significant (P = 0.007, Chi-square-test). Acid suppression above 70% of the 24-h period did not yield further increases in healing rates. For 50% of time with ph >4, the positive predictive value was 76% (65 of 85 patients). Similar findings were apparent when the small number of H. pylori-positive patients was excluded from the analysis [above 70%: 69% healed (27 of 39 patients); below 50%: 48% healed (22 of 46 patients); P = 0.047, Chi-square-test]. DISCUSSION This exploratory post hoc analysis aimed to characterize further the relationship between acid suppression (percentage of time with intragastric ph >4 in a 24-h period) with PPI therapy and healing of oesophagitis, specifically patients with LA grade C or grade D oesophagitis. Overall, the findings indicate an apparent optimal time of acid suppression for maximal healing in such patients, in that an increase in the time with intragastric ph >4 beyond 50 70% (12 17 h) of a 24-h period did not improve healing rates. The findings of the present study add to the recognized importance of ph suppression in healing of RO, 10 and indicate that new acid-suppressive agents that rely solely on an increase in the number of hours of ph control over currently available PPIs most likely will not result in improved healing. For example, comparative studies of AZD0865 [a member of a new class of acidsuppressive therapy (potassium-competitive acid blockers)] found that whilst AZD0865 provided a longer duration of acid suppression compared with esomeprazole, there was no incremental clinical benefit in terms of either improved RO healing or symptom control. 11, 12 In addition, dexlansoprazole, a dual delayed-release PPI which in doses of 60 mg once daily kept intragastric ph >4 for 71% of the 24-h period, does not appear to provide an increased healing rate. 13 One possible explanation for an increase in acid suppression (intragastric ph >4) above the 50 70% threshold not translating into additional clinical benefit, at least in the present study, is that gastric acid suppression is perhaps an imprecise surrogate for what is more directly contributory to the healing process: diminished oesophageal acid exposure. In this regard, factors such as the rate of epithelial cell turnover 11 and mucosal inflammation 14 are important; duodenogastro-oesophageal reflux may also impact on healing rates. 15 However, further research is warranted to establish whether factors other than specific levels of ph control affect RO healing, including bile pepsin reflux, nocturnal acid breakthrough, presence of hiatal hernia and obesity. ph-impedance studies may add to such research, although in the present study ph-impedance information is unlikely to have changed the overall conclusion. The ability of patients to achieve the apparent optimal time of acid suppression for healing (reported in the current study) when using commercially available PPIs is of interest. Indeed, analysis of pooled data from comparative pharmacodynamic studies showed that the proportion of patients who achieved at least 70% mean time with intragastric ph >4 was substantially higher with esomeprazole 40 mg (32%) compared with healing doses of all currently available PPIs (lansoprazole 30 mg, 13%; omeprazole 20 mg, 15%; pantoprazole 40 mg, 4% and rabeprazole 20 mg, 18%), while the proportion of patients with at most 50% mean time with ph >4 was substantially lower with esomeprazole 40 mg (15%) compared with healing doses of all currently available PPIs (lansoprazole 30 mg, 56%; omeprazole 20 mg, 52%; pantoprazole 40 mg, 64% and rabeprazole 20 mg, 53%). This may explain the clinical findings of comparative studies in which esomeprazole proved superior healing efficacy to these other PPIs Aliment Pharmacol Ther 2010; 32:

4 P. O. Katz et al. It is surprising that the healing curve appears to decline once the apparent threshold of 50 70% time with intragastric ph >4 is achieved, and this may simply reflect a chance finding in view of the small sample size. Another potential limitation of the current study is that it only included patients with moderate-to-severe RO (LA grade C or D), in whom other co-factors such as reflux of bile and pepsin may be pathologically important. Consequently, the results might not be generalizable to those with milder disease (LA grade A or grade B), but in these patients, it would be expected that a lower ph threshold exists for successful healing of erosions given that the severity of RO generally relates to the duration of oesophageal acid exposure. 26 It also has to be considered that the ph threshold is limited to healing of oesophagitis, and may not extend to symptom control. Unfortunately, it was not possible to study symptom control in view of the small sample size, this endpoint having been part of the secondary analysis in the original proof-of-concept study. Further studies in a larger number of patients are therefore warranted to determine whether the latter relationship exists. Finally, we did not perform baseline evaluations of acid secretion by ph-metry, which may have enabled an evaluation of healing in terms of intra-individual changes with acid-suppressive therapy. However, there is no reason to believe that the typical GERD patient would have anything but normal intragastric ph-metry at baseline, and therefore the relevance of baseline evaluations of acid secretion in terms of the healing endpoint remains debatable. In conclusion, after 4 weeks of treatment targeted at acid suppression, the healing of RO (LA grade C or grade D) appears to reach a threshold above which improved healing cannot be achieved despite an increase in number of hours with intragastric ph >4. An apparent optimal time of acid suppression for maximal healing indicates that prolonged acid suppression with new and emerging anti-secretory compounds may not offer an advantage over current therapies. Further clinical study with a larger patient group and more extended treatment follow-up is warranted. ACKNOWLEDGEMENTS Declaration of personal interests: Philip O. Katz has received consultancy fees from AstraZeneca, Takeda and XenoPort, along with speaker fees from Takeda. He is also an adjudicator for Eisai. David A. Johnson has received consultancy fees from AstraZeneca, Novartis and Takeda, along with speaker fees and clinical research support from AstraZeneca and Takeda. 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