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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgements
  9. References

Background

Sleep disturbance is common in patients with GERD but there has been little evaluation of this problem in primary care in patients already taking therapy.

Aim

To evaluate the impact of administering a questionnaire (PASS test) to identify patients with sleep problems and evaluate the efficacy of esomeprazole to improve sleep disturbance in patients with GERD.

Methods

This was a primary care based cluster-randomised, open-label study where practices were assigned to intervention or control groups. PASS test failures continued current therapy (control) or were switched to 4 weeks' once-daily esomeprazole 20 or 40 mg (intervention). Patients were evaluated at the end of 4 weeks and the outcomes that were assessed were the sleep questions from the Quality of Life in Reflux and Dyspepsia (QOLRAD) questionnaire and the presence or absence of sleep disturbance from the PASS test questionnaire.

Results

A total of 1388 patients with evaluable data at 4 weeks were included in the analysis and 825 reported GERD-related sleep disturbance at baseline. At 4 weeks, 161 of 291 of control patients (55%) reported continued sleep disturbance compared to 120 of 534 (22.5%) of intervention patients [number needed to treat of 3: 95% confidence intervals (CI): 2.5–4]. There was a mean improvement in QOLRAD scores related to sleep in the intervention patients compared to control patients (mean improvement = 4.91; 95% CI: 3.73–6.09).

Conclusion

A PASS strategy identifies GERD patients with sleep disturbance in primary care that will benefit from a change in acid-suppressive therapy. ClinicalTrials.gov identifier: NCT00392002; study code: D9612L00096.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgements
  9. References

A good night's sleep is an important determinant of well-being and yet 20% of the population suffers sleep disturbance at least once per week.[1] Gastro-oesophageal reflux disease (GERD) has emerged as an important gastrointestinal cause of sleep disturbance with a 40% increase in reflux symptoms in those reporting insomnia.[2] Conversely two thirds of those with GERD report a problem with sleeping.[3] Reflux symptoms are common in the community with 25% complaining of heartburn at least once per month and 5% on a daily basis[4] and therefore reflux symptoms are likely to impact on sleep quality in a large proportion of individuals.

Proton pump inhibitor (PPI) therapy is very effective for controlling reflux symptoms in patients with GERD[5] and so might be expected to help sleep disorder related to this disease. Two systematic reviews[6, 7] of randomised controlled trials (RCTs) of PPI therapy have confirmed that acid suppression improves sleep quality. The most recent of these[7] identified eight RCTs that have addressed the impact of PPI therapy on sleep. Only three[8-10] of these studies had a large sample size and all trials predominantly evaluated patients in secondary care and all compared PPI with placebo.

GERD is predominantly a problem seen in primary care[11] and 13% of patients presenting with GERD state sleep disturbance is the main reason for the consultation in this setting.[12] Patients in primary care with reflux symptoms will often be prescribed acid suppression and it is not certain whether there is any value in assessing these patients to determine whether they still have sleep disturbances despite therapy. A validated 5-item questionnaire, PASS (PPI Acid Suppression Symptom – Figure 1)[13] has been developed to identify patients with continued acid-related symptoms who might benefit from a change in therapy. This test has the potential to be used in primary care to assess response to acid suppression therapy.[14, 15] This questionnaire does have one item that relates to sleep and we hypothesised that this questionnaire could identify patients with ongoing sleep disturbance despite acid suppression and that these patients would benefit from a change in their acid suppressive therapy. We addressed this hypothesis as a secondary end-point in a large open-label cluster-randomised controlled trial based in primary care.

image

Figure 1. The PASS [Proton pump inhibitor (PPI) Acid Suppression Symptom] test.[13] H2RA, H2 receptor antagonist.

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Methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgements
  9. References

Study design

This was a multicentre, cluster-randomised, open-label study (ClinicalTrials.gov identifier: NCT00392002; study code: D9612L00096). Primary care centres were randomised in a 1:1 ratio to an intervention group or a control group, stratified by Canadian province. Patients were eligible if they were adults (≥18 years) with a clinical diagnosis of GERD for which they were receiving antisecretory therapy or antacids for more than 8 weeks. These patients were given the PASS test questionnaire and those that answered at least one question in the affirmative (indicating they had ongoing acid-related symptoms) were enrolled in the study. Exclusion criteria included (i) alarm symptoms (e.g. progressive dysphagia), (ii) not eligible for private or public reimbursement of esomeprazole, (iii) dominant atypical GERD symptoms (e.g. chronic cough), (iv) currently receiving esomeprazole, (v) unable to understand or complete questionnaires in French or English.

All subjects enrolled at the same centre were included in the same treatment (intervention or control) group. At the intervention centres, patients were switched from their previous anti secretory therapy to esomeprazole 20 mg or 40 mg once daily (dosage at the discretion of the physician) for 4 weeks. At the control centres, patients continued with their previous therapy for 4 weeks. Neither arm was given specific additional lifestyle advice regarding management of GERD.

This study was conducted in full accordance with the ethical considerations outlined in the current revision of the Declaration of Helsinki and International Conference on Harmonization guidelines on Good Clinical Practice. The protocol was also approved by an independent Ethics Committee (Research Review Board Inc., Waterloo, Ontario, Canada). All patients entering the study provided written informed consent.

Assessments and outcomes

The primary variable was the change in the Global Overall Symptom score from baseline to week 4.[16] Other outcomes assessed at baseline and 4 weeks in both groups were the PASS test score,[13] Reflux Disease Questionnaire (RDQ)[17] and Quality of Life in Reflux and Dyspepsia (QOLRAD) questionnaire.[18]

The RDQ is a patient self-assessment (4-week recall) of the frequency and severity of heartburn, regurgitation, epigastric pain and overall symptoms, whereby symptom frequency and intensity are ranked according to six choices: frequency, from 1 (did not have) to 6 (daily); and intensity, from 1 (did not have) to 6 (severe). Lower scores on the RDQ therefore indicate decreased symptom burden. The 25-item QOLRAD questionnaire assesses the impact of upper gastrointestinal symptoms on patients' quality of life and daily functioning across 5 dimensions (emotional distress, food/drink problems, physical/social functioning, sleep disturbance and vitality). Each question (1-week recall) is answered on a 7-point Likert scale, scored from 1 (severe impact) to 7 (no impact); higher scores therefore indicate better quality of life. There are five questions that specifically relate to sleep problems in GERD patients (box 1) and these were summed to evaluate the impact symptoms were having on quality of life related to sleep.

Statistical analysis

The sample size calculation was based on the primary outcome of change in GOS score. A sample size of 2000 patients per group in each province involved in the study would have 80% power to detect a clinically significant between-group difference of 0.5 points (two-sample t-test, 5% significance level) in a cluster-analysis [intraclass correlation coefficient (ICC) of 0.3 with 2000 clusters], and assuming an attrition rate of at least 44%. Recruitment was lower than expected and therefore the power calculations were revised to cover the whole of Canada rather than for each province. A post hoc power calculation based on the sleep outcome was calculated. A sample size of 240 controls and 400 in the active therapy group with sleep disturbance would detect a 15 percentage point reduction in sleep disturbance with 95% power at the 5% significance level assuming an ICC <0.001 and 55% reporting sleep disturbance at the end of treatment in the control group.

A planned secondary analysis was the impact of switching to esomeprazole on GERD-related sleep disturbance in those patients that had sleep disturbance at baseline defined as a positive response to question 3 of the PASS test (Figure 1). All analyses were based on the intent-to-treat (ITT) population, which consisted of all patients who were enrolled into the study that had a sleep disturbance at baseline and where there was at least some data available at 4 weeks. For binary variables missing data were assumed to be treatment failures and for continuous variables all evaluable patient analyses were performed. Hypothesis tests were conducted using a type I error rate of 5%, with no adjustments made for multiplicity, and all tests were two-tailed.

Binary variables were analysed using Chi-squared test and the means of continuous variables were analysed using Student's independent t-test. This is a cluster-randomised trial so all analyses should take into account centre effects.[19] However, the multilevel model ICC for question 3 of the PASS test and centre was <0.0001 and for the sleep questions in QOLARD and centre was 0.006. These values are very low and indicate that the analysis can be conducted at the individual patient level. This was tested using mixed linear models with treatment as a fixed effect and centre as a random factor. Binary variables (dichotomous) were analysed using a generalised linear mixed model (distribution as binary and logit as link function). Treatment was the fixed effect and centre was included as a random factor. These analyses gave the same outcome as the individual patient analysis so the latter are reported. Analyses were performed using SPSS version 17 (IBM corporation, New York, USA).

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgements
  9. References

A total of 1758 patients were considered for the trial but 194 were excluded as they had not been prescribed antacid or anti secretory therapy at baseline and a further 176 as no data were available after baseline (Figure 2). The remaining 1388 patients were considered for the analysis and 825 [59%; 95% confidence intervals (CI): 57–62] described sleep disturbance at baseline (Figure 2). Participants that reported sleep disturbance had a lower QOLRAD score and more severe reflux symptoms (Table 1). A linear regression model evaluated gender, age, race, alcohol intake, membership of a fitness gym, primary care centre, smoking, RDQ score and sleep disturbance at baseline as independent determinants of baseline QOLRAD score. Race, alcohol intake, membership of a fitness gym and primary care centre had no statistically significant impact on QOLRAD score and were removed from the model. The remaining factors had a statistically significant (or in the case of smoking marginally statistically significant) impact on baseline QOLRAD score (Table 2). In particular sleep disturbance at baseline was an independent predictor of QOLRAD and those that reported a disturbance had on average a 13 point lower score when controlling for other confounding factors (Table 2).

Table 1. QOLRAD score and RDQ score in patients with and without sleep disturbance at baseline
CategoryQOLRAD score (mean ± s.d.)Mean difference (95% CI)RDQ score (mean ± s.d.)Mean difference (95% CI)
No sleep disturbance at baseline113.5 ± 25.0 19.5 ± 12.3 
Sleep disturbance at baseline86.9 ± 30.2−26.6 (−23.6 to −29.6)29.4 ± 14.09.9 (8.4–11.4)
Table 2. Linear regression model of determinants of GERD-related quality of life as evaluated by QOLARD score
FactorCoefficient95% CIP-value
Sleep disturbance−12.9−15.6 to −10.3<0.0001
Female−3.8−6.3 to −1.30.003
Age (per year)0.130.04–0.220.004
RDQ score (per unit)−1.3−1.4 to −1.2<0.0001
Smoker−1.5−3.0–0.0060.051
image

Figure 2. Summary of flow of the participants in the trial.

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There were 111 primary care centres randomised to deliver the intervention that enrolled at least one participant with GERD-related sleep disturbance and overall 534 subjects were recruited from these intervention practices. There were 69 primary care centres randomised to the control arm that enrolled at least one participant with GERD-related sleep disturbance and overall 291 subjects were recruited from these control practices (Figure 2). Participants were mainly recruited from three provinces, Ontario [438 (53%) subjects], Quebec [138 (17%) subjects] and Nova Scotia [114 (14%) subjects]. Overall 509 (62%) were women, 651 (79%) were Caucasian with a mean age of 53.5 years (standard deviation = 13.6). There were no major differences in baseline characteristics between the two randomised groups (Table 3).

Table 3. Baseline characteristic of randomised groups
ParameterIntervention (n = 534)Control (n = 291)
Smoker90 (17%)56 (19%)
Alcohol (≥1 drink/day)70 (13%)33 (11%)
Fitness gym membership57 (11%)29 (10%)
Female342 (64%)167 (57%)
Taking PPI at baseline368 (69%)212 (73%)
Caucasian413 (77%)238 (82%)
On a modified diet127 (24%)77 (26%)
Age (mean ± s.d.)53.2 ± 13.454.0 ± 14.1
RDQ score at baseline (mean ± s.d.)29.51 ± 13.9229.25 ± 14.06
QOLRAD sleep related scores (mean ± s.d.)19.57 ± 7.7720.61 ± 7.66

Patients in the intervention practices were randomised to esomeprazole 20–40 mg daily for 4 weeks. The dose was left to discretion of the clinician but 96% chose to prescribe esomeprazole 40 mg daily. The reflux medication of the control group was left unchanged. By definition, all patients reported GERD-related sleep disturbance at baseline whereas only 55% in the control group continued to have this problem at 4 weeks (Table 4). This reduction was statistically significantly greater in the intervention practices with only 22.5% reporting sleep disturbance (Table 4) with a number needed to treat (NNT) of 3 (95% CI: 2.5–4). Furthermore, the effect was statistically significantly greater in the subgroup that received H2 receptor antagonist (H2RA) therapy or antacid therapy compared to those that received PPI therapy (Table 4, Breslow Day homogeneity of odds ratio P = 0.048).

Table 4. Impact of esomeprazole 20–40 mg daily on PASS test sleep question at 4 weeks: ITT analysis
CategorySymptoms interfere with sleepOR of sleep disturbance in the intervention group (95% CI)
  1. CI, confidence intervals; PPI, proton pump inhibitor; H2RA, H2 receptor antagonist; OR, odds ratio.

  2. a

    Thirty-three patients had missing antisecretory baseline data and are assumed to be treatment failures.

Overall
Control group161/291 (55%)0.23 (0.17–0.32)
Intervention group120/534 (22.5%) 
PPI at baselinea
Control group114/209 (54.5%)0.11 (0.06–0.21)
Intervention group78/352 (22%) 
H2RA/antacids at baselinea
Control group39/74 (53%)0.24 (0.16–0.34)
Intervention group17/157 (11%) 

The mean QOLRAD scores related to sleep were statistically significantly higher in the intervention group indicating a better quality of life in the sleep domain (Table 5). Reflux scores were also statistically significantly lower in the intervention group (Table 6). In both cases, the effect was greater in patients in the subgroup that were prescribed H2RA or antacid therapy at baseline compared to those prescribed PPI therapy (Tables 5 and 6).

Table 5. Impact of esomeprazole 20–40 mg daily on sum of QOLRAD sleep questions at 4 weeks
CategoryQOLRAD sleep questions score (mean ± s.d.)Mean difference (95% CI)
  1. CI, confidence intervals; H2RA, H2 receptor antagonist; PPI, proton pump inhibitor; s.d., standard deviation.

Overall
Control group (n = 273)24.90 ± 6.924.91 (3.73–6.09)
Intervention group (n = 490)29.81 ± 8.49 
PPI at baseline
Control group (n = 199)24.84 ± 7.284.17 (2.81–5.53)
Intervention group (n = 339)29.01 ± 8.53 
H2RA/antacids at baseline
Control group (n = 74)25.05 ± 8.426.55 (4.68–8.42)
Intervention group (n = 151)31.60 ± 5.67 
Table 6. Impact of esomeprazole 20–40 mg daily on RDQ score at 4 weeks
CategoryRDQ score (mean ± s.d.)Mean difference (95% CI)
  1. CI, confidence intervals; PPI, proton pump inhibitor; RDQ, reflux disease questionnaire; s.d., standard deviation.

Overall
Control group (n = 275)21.19 ± 15.489.70 (7.70–11.70)
Intervention group (n = 495)11.49 ± 12.31 
PPI at baseline
Control group (n = 201)21.58 ± 15.488.30 (5.75–10.85)
Intervention group (n = 343)13.28 ± 12.89 
H2RA/antacids at baseline
Control group (n = 74)20.15 ± 15.5212.68 (8.76–16.59)
Intervention group (n = 152)7.47 ± 9.83 

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgements
  9. References

This is the first RCT to evaluate the effectiveness of the PASS test to identify GERD patients with sleep disturbance and the efficacy of increasing the intensity of PPI on improving sleep disturbance. We have shown that almost 60% of patients on medical therapy for GERD have sleep problems if their acid-related symptoms are not controlled. This sleep disturbance is more pronounced if the GERD symptoms are more severe and is associated with a reduced quality of life. Esomeprazole 40 mg daily can significantly resolve acid reflux related sleep disturbances with a NNT of 3. The PASS test therefore seems an appropriate tool to evaluate GERD patients in primary care, even those currently on medical therapy. Our data show that a significant proportion of GERD patients continue to have reflux symptoms that interfere with sleep despite therapy and these patients may benefit from more effective acid suppressive therapy.

The pathophysiology of sleep disturbance in GERD is not clear. There is an association between breathing disorders such as asthma[20] and sleep apnoea[21] and GERD. These associations may be causal but may also be due to confounding factors; for example GERD and sleep apnoea may both be more frequent with increasing obesity.[6] The possibility that these associations may be due to confounding factors is supported by polysomnography studies that show no association between GERD and sleep apnoea [22] and no significant effect of PPI therapy on the frequency of sleep apnoea events.[23] A further possibility is that GERD symptoms themselves wake the sufferer from sleep or prevent the subject getting to sleep. Nocturnal acid breakthrough is a well recognised phenomenon[24] even on PPI therapy and this can generate symptoms[25] possibly related to regurgitation, as this symptom is less well controlled on PPI therapy compared to heartburn.[26] Our data support this hypothesis as reflux symptom scores were significantly higher in patients that had sleep disturbance compared to those that did not endorse this as a problem. Others have also reported this as well as an association with greater oesophageal acid exposure.[27] The specific symptoms that are associated with sleep disturbance as well as the specific mechanisms that generate these symptoms warrants further study.

Our study has several strengths. It was conducted in primary care, where the majority of patients with GERD are seen and treated. The sample size is one of the largest reported in this area and it is the first to evaluate GERD patients already taking medical therapy. The use of a validated and simple to administer tool[13] to identify GERD patients with sleep disturbance means that this approach can simply and reliably be applied to primary care. There are also some limitations to this study. This was a planned subgroup analysis to a larger study and positive findings can occur by chance if a data set is over analysed due to multiple testing. This is unlikely, however, as this is only one of two[28, 29] planned secondary analyses. The study design was a cluster-randomised trial rather than an individual patient RCT. This design was chosen as the administration of the PASS test was felt to be the key intervention and it was appropriate to randomise this at the primary care level. A cluster-randomised design has several methodological and statistical issues that are different from individual patient randomised designs.[30] These are unlikely to have any implications for this study as the ICC between sleep disturbance and primary care centre was extremely low suggesting an individual patient trial would have similar outcomes. The study was open-label and therefore both investigators and participants were aware of the treatment being prescribed. This is likely to bias the study in favour of the intervention and the treatment effect may therefore be overestimated. It is unlikely that bias explains the positive result entirely; however, as the effect of esomeprazole was greater in those receiving H2RA or antacid therapy at baseline compared to those receiving PPIs. This is consistent with PPI therapy being more efficacious than H2RA therapy in treating reflux disease. There was a benefit of esomeprazole even in patients taking PPI therapy at baseline. This effect could be due to bias but a systematic review[31] has suggested that esomeprazole is more effective than standard doses of other PPIs used in the trial. It is possible that other PPIs used twice daily[32, 33] rather than once daily may have had a similar benefit to esomeprazole and this should be evaluated in future studies. This was a secondary outcome and therefore subjects with other reasons for sleep disturbance (e.g. sleep apnoea) were not excluded from the trial. Furthermore we used a subjective assessment of sleep disturbance whereas polysomnographic sleep measures would be more objective.[23] This approach is not feasible with such a large sample size and the use of subjective measures of sleep disturbance is likely to bias the results towards the null hypothesis. Patients had to have heartburn and other acid-related symptoms to take part in the trial and did not need to have an endoscopy to be enrolled. Surveys would suggest that only 10–40% of these patients would have oesophagitis at endoscopy[34, 35] and the rest would have non-erosive reflux disease or functional heartburn.[36] The impact of GERD on sleep is similar between erosive and non-erosive reflux disease[37] and the inclusion of some patients with functional heartburn would bias the study towards the null hypothesis.

In summary, a PASS test-based management strategy in which primary care GERD patients with persistent symptoms and sleep disturbance received more intensive acid suppressive therapy led to greater improvement in sleep disturbance than continuation of their previous therapy. This provides further support for the use of the PASS test in a management strategy to identify patients with persistent acid-related sleep disturbance that will respond to a change in acid-suppressive therapy.

Authorship

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgements
  9. References

Guarantor of the article: Paul Moayyedi.

Author contributions: Paul Moayyedi, Richard Hunt, David Armstrong, Margaret Bukoski, Robert White were involved with designing the study and writing the manuscript (Paul Moayyedi was the lead writer). Yao Lei was responsible for the database and primary analysis. Paul Moayyedi conducted secondary analyses and all authors approved the final version of the manuscript.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgements
  9. References

Declaration of personal interests: Paul Moayyedi – independent medical consultant: AstraZeneca and Janssen-Ortho; speaker's bureau: AstraZeneca, Esai, Janssen-Ortho and Nycomed; recipient of a Chair that is funded partly through an unrestricted donation from AstraZeneca Canada to McMaster University. Richard Hunt – honoraria as an investigator, consultant, or speaker: AstraZeneca, Nycomed and Takeda. David Armstrong – consultant/advisory board member: Abbott Laboratories, AstraZeneca, Axcan, Janssen-Ortho, Novartis, Nycomed (formerly Altana Pharma), Pentax Medical Canada, Proctor & Gamble, Schering-Plough and Takeda Canada; speaker's bureau: Abbott Laboratories, AstraZeneca, Axcan, Janssen-Ortho, Novartis, Nycomed, Schering-Plough and Solvay Pharmaceuticals; grants/research support: Abbott Laboratories, Allergan, AstraZeneca, Axcan, Janssen-Ortho, Negma-Gild, Nestlé Canada, Nycomed and Pentax Medical Canada; educational programme funding: Abbott Laboratories, Allergan, AstraZeneca, Axcan, Boston Scientific, ConMed, Cook Canada, Janssen-Ortho, Negma-Gild, Nestlé Canada, Nycomed, Pentax Medical Canada, Schering-Plough and Shire Pharmaceuticals. Yao Lei – former employee of AstraZeneca Canada Inc., Margaret Bukoski and Robert White – employees of AstraZeneca Canada Inc.

Declaration of funding interests: The study was funded by AstraZeneca, the manufacturer of esomeprazole. Writing and analyses of the data for this secondary analysis was by Paul Moayyedi with support from all authors.

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  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgements
  9. References
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