Alimentary Pharmacology and Therapeutics
Predictors of either rapid healing or refractory reflux oesophagitis during treatment with potent acid suppression P. J. Kahrilas*, T. Persson†, H. Denison†, B. Wernersson†, N. Hughes‡ & C. W. Howden*
*Division of Gastroenterology and Hepatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. † AstraZeneca R&D, M€ olndal, Sweden. ‡ Research Evaluation Unit, Oxford PharmaGenesis Ltd, Oxford, UK.
Correspondence to: Dr P. J. Kahrilas, Division of Gastroenterology and Hepatology, 676 N. Saint Clair St., Suite 1400, Chicago, IL 60611-2951, USA. E-mail: [email protected]
Publication data Submitted 26 February 2014 First decision 4 March 2014 Resubmitted 6 June 2014 Accepted 25 June 2014 EV Pub Online 15 July 2014 This article was accepted for publication after full peer review.
SUMMARY Background Little is known regarding patient characteristics that influence the speed of reflux oesophagitis (RO) healing. Aim To investigate patient characteristics that may influence RO healing rates. Methods A post hoc analysis of clinical trial data for potent acid suppression treatment of RO (esomeprazole or AZD0865) was conducted. Group A underwent endoscopy at baseline, week 2 and 4, and group B at baseline, week 4 and 8. Group A patients were sub-grouped as ‘rapid’ (healed at 2 weeks) or unhealed at 2 weeks. Group B patients were sub-grouped as ‘slow’ (healed at 8 weeks, not at 4 weeks) or ‘refractory’ (not healed at 8 weeks). Logistic regression analysis was performed only for comparisons within group A. Results At 2, 4 and 8 weeks, RO had healed in 68%, 65% and 61% of patients unhealed at previous endoscopy, respectively. Low-grade [vs. high-grade (C or D)] RO was the only independent predictor of rapid healing in group A after logistic regression analysis. Significantly more rapid healers had low grade RO (A or B) at baseline than patients with refractory RO (84% vs. 49%; P < 0.001), and significantly more refractory patients had frequent regurgitation at baseline than slow healers (80% vs. 63%; P = 0.039). Conclusions Low- (vs. high-) grade RO determines the most rapid benefit from acid suppression. Roughly two-thirds of patients healed with each time increment of potent acid suppression therapy. This suggests that some unhealed patients may still heal with continued therapy and that truly refractory RO is rare. (ClinicalTrials.gov: NCT00206245). Aliment Pharmacol Ther 2014; 40: 648–656
648
ª 2014 John Wiley & Sons Ltd doi:10.1111/apt.12877
Predictors of reflux oesophagitis healing INTRODUCTION Gastro-oesophageal reflux disease (GERD) develops when the reflux of stomach contents causes troublesome symptoms and/or complications. One manifestation of GERD, reflux oesophagitis (RO), is defined endoscopically by visible breaks of the distal oesophageal mucosa.1 Various classification systems have been used to grade the severity of RO but, most recently, the Los Angeles (LA) classification system2 has gained wide clinical acceptance.1 It is well established that healing of RO is effectively promoted by potent acid suppression and there is an association between healing rates and the degree of acid suppression3, 4 Healing rates averaging 83% have been reported after 8 weeks of proton pump inhibitor (PPI) therapy.5–7 However, with the exception of the association between more severe LA grade RO and a lower healing rate, little is known about the patient characteristics that may influence whether RO heals with acid suppression therapy, or how quickly healing occurs. AIMS The aim of this post hoc analysis of clinical trial data was to characterise patients whose RO healed rapidly (within 2 weeks) and those whose RO was unhealed after 8 weeks of potent acid suppression therapy (refractory RO). The patient characteristics assessed were age, sex, prevalence of hiatal hernia, Helicobacter pylori status, body mass index (BMI), LA grade of RO, symptom patterns and health-related quality of life (HRQoL). METHODS We performed a post hoc analysis of a large, randomised trial of AZD0865 (a potassium-competitive acid blocker) 25–75 mg/day vs. esomeprazole 40 mg/day (present as 44.5 mg/day esomeprazole magnesium trihydrate) for up to 4 or up to 8 weeks for the treatment of RO (N = 1514)8 (clinicaltrials.gov identifier: NCT00206245). Endoscopy was performed at baseline; patients included in the clinical trial had LA grade A–D RO, a minimum 6-month history of heartburn (‘burning feeling behind the breastbone’) as their main GERD symptom, and had experienced ≥4 days of at least moderate intensity heartburn in the week before randomisation, as measured by the Reflux Disease Questionnaire (RDQ)9, 10 with a 7-day recall. Most (93%) of the patients also had concomitant regurgitation of some frequency or intensity at baseline. Patients with dominant dyspeptic RDQ symptoms were excluded from the trial.8 The original trial’s primary endpoint was healing of RO at 4 weeks, although healing Aliment Pharmacol Ther 2014; 40: 648-656 ª 2014 John Wiley & Sons Ltd
rates at 2 and 8 weeks were also assessed as secondary variables. To accomplish this while minimising the number of endoscopies performed on each patient, the study population was randomly divided into groups A and B, which were of similar size. Group A patients had endoscopy planned at weeks 2 and 4 and group B at weeks 4 and 8. All patients completed the RDQ by electronic diary twice daily during the first 4 weeks of treatment and the Quality Of Life in Reflux Disease and Dyspepsia (QOLRAD) questionnaire11 at baseline, after 4 weeks (group A only), and after 8 weeks (group B only) of treatment. Higher scores on the 1–7 graded Likert scale indicate better HRQoL. Patients in group A (n = 767) were assigned treatment for up to 4 weeks. Therapy was stopped after 2 weeks in patients whose RO had healed. Patients in group B (n = 747) were assigned treatment for up to 8 weeks. Therapy was stopped after 4 weeks in patients whose RO had healed. No more endoscopies or other types of follow-up were done in patients after their RO had healed. As there was no significant difference between esomeprazole and the various doses of AZD0865 with respect to either the response of heartburn or the healing of RO, we pooled data for all treatment arms in the analysis. Healing of RO in group A was categorised as ‘rapid’ (RO had healed at 2 weeks) or unhealed at 2 weeks. Healing of RO in group B was categorised as ‘slow’ (RO not healed at 4 weeks but healed at 8 weeks) or ‘refractory’ (RO not healed at 8 weeks). Patients in group B who were healed at 4 weeks would also include unidentified ‘rapid healers’ as they did not have endoscopy at 2 weeks. Patients in group B who were healed at 4 weeks were therefore not included in the analysis.
Statistical analysis Proportions were compared by v2 tests. For age, the mean values were compared by t-tests. P-values below 0.05 were considered statistically significant. Variables with more than two categories were collapsed into two categories for comparison (e.g. the proportion of patients with LA grade A + B was compared between groups). Independent predictors of RO healing rate were evaluated by logistic regression analysis. RESULTS Baseline predictors for rapid healing vs. unhealed reflux oesophagitis (after 2 weeks of treatment) Of 767 patients in group A at baseline, 732 had an endoscopy at 2 weeks (i.e. data were missing for 649
35 patients; Figure 1) and were included in the overall analysis. Following 2 weeks of therapy, 68% of patients in group A (495/732) had healed RO (rapid healers) and 32% (n = 237) did not; 65% (153/235) of patients unhealed at 2 weeks were healed at 4 weeks, and 89% (648/730) of patients’ RO had healed by 4 weeks in group A overall since baseline. Of patients with LA grade C or D RO at baseline, 48% (81/170) were healed after 2 weeks compared with 74% (414/562) of patients with LA grade A or B. The proportion of patients with LA grade A or B RO at baseline was significantly higher among rapid healers (414/495, 84%) than among patients who were not healed at 2 weeks (148/237, 62%; P < 0.001) (Table 1, Figure 2). Of those patients who were not healed at 2 weeks, 62% had improved by at least one LA grade since baseline, whereas 38% had the same or a more severe grade. The proportion of patients who were women was also significantly higher among rapid
healers (205/495, 41%) than among patients who were not healed at 2 weeks (77/237, 32%; P = 0.020) (Table 1). The proportion of patients with hiatal hernia at baseline was significantly lower among rapid healers (316/495, 64%) than among patients who were not healed at 2 weeks (171/237, 72%; P = 0.028) (Table 1). The only factor that independently predicted rapid healing, based on logistic regression analysis, was low LA grade (A or B) RO. In the sub-group of patients who had high LA grade (C or D) RO, none of the variables assessed (hiatal hernia, sex, dyspepsia and regurgitation) was a predictor of rapid healing.
Baseline predictors for refractory reflux oesophagitis vs. slow healers Of 747 patients in group B at baseline, 698 had 4-week endoscopy data (i.e. data were missing for 49 patients; Figure 1); 127 of 141 patients unhealed after 4 weeks
Table 1 | Baseline demographics of patients with rapid healing [reflux oesophagitis (RO) healed after 2 weeks] and patients with RO that was not healed after 2 weeks of therapy. All patients were taking AZD0865 25–75 mg/day or esomeprazole 40 mg/day. Comparisons of percentages (means for age)
Baseline demographic
Rapid healers: RO healed at 2 weeks (n = 495)
Age (years) – mean 46.7 (13) (s.d.) Gender – n (%) Men 290 (59) Women 205 (41) Los Angeles grade of RO – n (%) A 192 (39) B 222 (45) C 77 (16) D 4 (1) A+B 414 (84) Hiatal hernia – n (%) 316 (64) H. pylori – n (%) 66 (13) Body mass index – n (%) Underweight 7 (1) Normal weight 96 (19) Overweight 210 (42) Obese 182 (37) Underweight 103 (21) + normal weight RDQ regurgitation – n (%) 0–3 days/week 134 (32) 4–7 days/week 289 (68) RDQ dyspepsia – n (%) 0–3 days/week 371 (81) 4–7 days/week 85 (19)
RO not healed at 2 weeks (n = 237)
P value
47.3 (12)
0.58
160 (68) 77 (32)
0.020
52 96 62 27 148 171 34
(22) (41) (26) (11) (62) (72) (14)
Predictors of either rapid healing or refractory reflux oesophagitis during treatment with potent acid suppression P. J. Kahrilas*, T. Persson†, H. Denison†, B. Wernersson†, N. Hughes‡ & C. W. Howden*
*Division of Gastroenterology and Hepatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. † AstraZeneca R&D, M€ olndal, Sweden. ‡ Research Evaluation Unit, Oxford PharmaGenesis Ltd, Oxford, UK.
Correspondence to: Dr P. J. Kahrilas, Division of Gastroenterology and Hepatology, 676 N. Saint Clair St., Suite 1400, Chicago, IL 60611-2951, USA. E-mail: [email protected]
Publication data Submitted 26 February 2014 First decision 4 March 2014 Resubmitted 6 June 2014 Accepted 25 June 2014 EV Pub Online 15 July 2014 This article was accepted for publication after full peer review.
SUMMARY Background Little is known regarding patient characteristics that influence the speed of reflux oesophagitis (RO) healing. Aim To investigate patient characteristics that may influence RO healing rates. Methods A post hoc analysis of clinical trial data for potent acid suppression treatment of RO (esomeprazole or AZD0865) was conducted. Group A underwent endoscopy at baseline, week 2 and 4, and group B at baseline, week 4 and 8. Group A patients were sub-grouped as ‘rapid’ (healed at 2 weeks) or unhealed at 2 weeks. Group B patients were sub-grouped as ‘slow’ (healed at 8 weeks, not at 4 weeks) or ‘refractory’ (not healed at 8 weeks). Logistic regression analysis was performed only for comparisons within group A. Results At 2, 4 and 8 weeks, RO had healed in 68%, 65% and 61% of patients unhealed at previous endoscopy, respectively. Low-grade [vs. high-grade (C or D)] RO was the only independent predictor of rapid healing in group A after logistic regression analysis. Significantly more rapid healers had low grade RO (A or B) at baseline than patients with refractory RO (84% vs. 49%; P < 0.001), and significantly more refractory patients had frequent regurgitation at baseline than slow healers (80% vs. 63%; P = 0.039). Conclusions Low- (vs. high-) grade RO determines the most rapid benefit from acid suppression. Roughly two-thirds of patients healed with each time increment of potent acid suppression therapy. This suggests that some unhealed patients may still heal with continued therapy and that truly refractory RO is rare. (ClinicalTrials.gov: NCT00206245). Aliment Pharmacol Ther 2014; 40: 648–656
648
ª 2014 John Wiley & Sons Ltd doi:10.1111/apt.12877
Predictors of reflux oesophagitis healing INTRODUCTION Gastro-oesophageal reflux disease (GERD) develops when the reflux of stomach contents causes troublesome symptoms and/or complications. One manifestation of GERD, reflux oesophagitis (RO), is defined endoscopically by visible breaks of the distal oesophageal mucosa.1 Various classification systems have been used to grade the severity of RO but, most recently, the Los Angeles (LA) classification system2 has gained wide clinical acceptance.1 It is well established that healing of RO is effectively promoted by potent acid suppression and there is an association between healing rates and the degree of acid suppression3, 4 Healing rates averaging 83% have been reported after 8 weeks of proton pump inhibitor (PPI) therapy.5–7 However, with the exception of the association between more severe LA grade RO and a lower healing rate, little is known about the patient characteristics that may influence whether RO heals with acid suppression therapy, or how quickly healing occurs. AIMS The aim of this post hoc analysis of clinical trial data was to characterise patients whose RO healed rapidly (within 2 weeks) and those whose RO was unhealed after 8 weeks of potent acid suppression therapy (refractory RO). The patient characteristics assessed were age, sex, prevalence of hiatal hernia, Helicobacter pylori status, body mass index (BMI), LA grade of RO, symptom patterns and health-related quality of life (HRQoL). METHODS We performed a post hoc analysis of a large, randomised trial of AZD0865 (a potassium-competitive acid blocker) 25–75 mg/day vs. esomeprazole 40 mg/day (present as 44.5 mg/day esomeprazole magnesium trihydrate) for up to 4 or up to 8 weeks for the treatment of RO (N = 1514)8 (clinicaltrials.gov identifier: NCT00206245). Endoscopy was performed at baseline; patients included in the clinical trial had LA grade A–D RO, a minimum 6-month history of heartburn (‘burning feeling behind the breastbone’) as their main GERD symptom, and had experienced ≥4 days of at least moderate intensity heartburn in the week before randomisation, as measured by the Reflux Disease Questionnaire (RDQ)9, 10 with a 7-day recall. Most (93%) of the patients also had concomitant regurgitation of some frequency or intensity at baseline. Patients with dominant dyspeptic RDQ symptoms were excluded from the trial.8 The original trial’s primary endpoint was healing of RO at 4 weeks, although healing Aliment Pharmacol Ther 2014; 40: 648-656 ª 2014 John Wiley & Sons Ltd
rates at 2 and 8 weeks were also assessed as secondary variables. To accomplish this while minimising the number of endoscopies performed on each patient, the study population was randomly divided into groups A and B, which were of similar size. Group A patients had endoscopy planned at weeks 2 and 4 and group B at weeks 4 and 8. All patients completed the RDQ by electronic diary twice daily during the first 4 weeks of treatment and the Quality Of Life in Reflux Disease and Dyspepsia (QOLRAD) questionnaire11 at baseline, after 4 weeks (group A only), and after 8 weeks (group B only) of treatment. Higher scores on the 1–7 graded Likert scale indicate better HRQoL. Patients in group A (n = 767) were assigned treatment for up to 4 weeks. Therapy was stopped after 2 weeks in patients whose RO had healed. Patients in group B (n = 747) were assigned treatment for up to 8 weeks. Therapy was stopped after 4 weeks in patients whose RO had healed. No more endoscopies or other types of follow-up were done in patients after their RO had healed. As there was no significant difference between esomeprazole and the various doses of AZD0865 with respect to either the response of heartburn or the healing of RO, we pooled data for all treatment arms in the analysis. Healing of RO in group A was categorised as ‘rapid’ (RO had healed at 2 weeks) or unhealed at 2 weeks. Healing of RO in group B was categorised as ‘slow’ (RO not healed at 4 weeks but healed at 8 weeks) or ‘refractory’ (RO not healed at 8 weeks). Patients in group B who were healed at 4 weeks would also include unidentified ‘rapid healers’ as they did not have endoscopy at 2 weeks. Patients in group B who were healed at 4 weeks were therefore not included in the analysis.
Statistical analysis Proportions were compared by v2 tests. For age, the mean values were compared by t-tests. P-values below 0.05 were considered statistically significant. Variables with more than two categories were collapsed into two categories for comparison (e.g. the proportion of patients with LA grade A + B was compared between groups). Independent predictors of RO healing rate were evaluated by logistic regression analysis. RESULTS Baseline predictors for rapid healing vs. unhealed reflux oesophagitis (after 2 weeks of treatment) Of 767 patients in group A at baseline, 732 had an endoscopy at 2 weeks (i.e. data were missing for 649
35 patients; Figure 1) and were included in the overall analysis. Following 2 weeks of therapy, 68% of patients in group A (495/732) had healed RO (rapid healers) and 32% (n = 237) did not; 65% (153/235) of patients unhealed at 2 weeks were healed at 4 weeks, and 89% (648/730) of patients’ RO had healed by 4 weeks in group A overall since baseline. Of patients with LA grade C or D RO at baseline, 48% (81/170) were healed after 2 weeks compared with 74% (414/562) of patients with LA grade A or B. The proportion of patients with LA grade A or B RO at baseline was significantly higher among rapid healers (414/495, 84%) than among patients who were not healed at 2 weeks (148/237, 62%; P < 0.001) (Table 1, Figure 2). Of those patients who were not healed at 2 weeks, 62% had improved by at least one LA grade since baseline, whereas 38% had the same or a more severe grade. The proportion of patients who were women was also significantly higher among rapid
healers (205/495, 41%) than among patients who were not healed at 2 weeks (77/237, 32%; P = 0.020) (Table 1). The proportion of patients with hiatal hernia at baseline was significantly lower among rapid healers (316/495, 64%) than among patients who were not healed at 2 weeks (171/237, 72%; P = 0.028) (Table 1). The only factor that independently predicted rapid healing, based on logistic regression analysis, was low LA grade (A or B) RO. In the sub-group of patients who had high LA grade (C or D) RO, none of the variables assessed (hiatal hernia, sex, dyspepsia and regurgitation) was a predictor of rapid healing.
Baseline predictors for refractory reflux oesophagitis vs. slow healers Of 747 patients in group B at baseline, 698 had 4-week endoscopy data (i.e. data were missing for 49 patients; Figure 1); 127 of 141 patients unhealed after 4 weeks
Table 1 | Baseline demographics of patients with rapid healing [reflux oesophagitis (RO) healed after 2 weeks] and patients with RO that was not healed after 2 weeks of therapy. All patients were taking AZD0865 25–75 mg/day or esomeprazole 40 mg/day. Comparisons of percentages (means for age)
Baseline demographic
Rapid healers: RO healed at 2 weeks (n = 495)
Age (years) – mean 46.7 (13) (s.d.) Gender – n (%) Men 290 (59) Women 205 (41) Los Angeles grade of RO – n (%) A 192 (39) B 222 (45) C 77 (16) D 4 (1) A+B 414 (84) Hiatal hernia – n (%) 316 (64) H. pylori – n (%) 66 (13) Body mass index – n (%) Underweight 7 (1) Normal weight 96 (19) Overweight 210 (42) Obese 182 (37) Underweight 103 (21) + normal weight RDQ regurgitation – n (%) 0–3 days/week 134 (32) 4–7 days/week 289 (68) RDQ dyspepsia – n (%) 0–3 days/week 371 (81) 4–7 days/week 85 (19)
RO not healed at 2 weeks (n = 237)
P value
47.3 (12)
0.58
160 (68) 77 (32)
0.020
52 96 62 27 148 171 34
(22) (41) (26) (11) (62) (72) (14)
