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Original Articles: Gastro-oesophageal Disease

Temporal trends of Barrett’s oesophagus and gastro-oesophageal reflux and related oesophageal cancer over a 10-year period in England and Wales and associated proton pump inhibitor and H2RA prescriptions: a GPRD study

Alexandropoulou, Kalliopi; van Vlymen, Jeremy; Reid, Fiona; Poullis, Andrew; Kang, Jin-Yong

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European Journal of Gastroenterology & Hepatology: January 2013 - Volume 25 - Issue 1 - p 15-21
doi: 10.1097/MEG.0b013e3283595086
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Abstract

Introduction

The burden of gastro-oesophageal reflux disease (GORD) appears to be increasing 1,2. Ten to 20% of the population in the Western world has symptoms of heartburn or acid regurgitation at least weekly 3. Increasing BMI 4,5, the decreasing prevalence of Helicobacter pylori6–9 and an ageing population who are prone to polypharmacy, with NSAIDs, nitrates 10 predisposing to GORD, are likely to be contributing to the observed increase in GORD symptoms in the population. The presence of a hiatus hernia is well established as a cause of the symptoms and complications of GORD 11–13, whereas smoking, alcohol and comorbid conditions such as dyspepsia as well as genetic factors have also shown an association with GORD in studies 3,5,10,14. GORD symptoms are associated with impaired well-being 15, although the severity of symptoms does not relate to the presence or the severity of oesophagitis and oesophagitis can exist in the absence of symptoms 16. Complications of GORD include Barrett’s oesophagus (BO), a premalignant complication of chronic acid reflux 17,18, and oesophageal adenocarcinoma 19, the incidence of which is on the increase 20,21.

Less than a quarter of patients with gastro-oesophageal reflux consult a doctor for their symptoms 14, with consultation more likely among older individuals and those with severe symptoms 22. Consultation for symptoms of reflux accounts for a major part of the burden of gastrointestinal diseases 23 to the health services in the West both in terms of consultation time and the cost of acid suppression treatment. In the USA, in excess of $10 billion/year are spent on proton pump inhibitors (PPIs). Two PPIs are in the top five selling drugs, whereas the number of prescriptions/year has doubled since 1999 23. Similarly, in the UK, in 1995, within years of their introduction, PPIs already constituted the largest expense for any single drug group and, by 1999, PPIs were mostly prescribed in the community intermittently for relief of reflux symptoms 24.

For these reasons, epidemiological data on gastro-oesophageal reflux are of interest. However, studies are hampered by difficulties in defining the condition. GORD is used as a term to refer to a broad range of associated conditions including asymptomatic patients with endoscopic or physiological evidence of acid reflux, or reflux symptoms with normal endoscopy but positive physiology, or reflux symptoms with associated endoscopic findings from oesophageal erosions to oesophageal stricture or ulceration.

Questionnaire community studies report a high prevalence of GORD symptoms, up to 40% in Northern Europe 16,25. However, many of these patients do not seek medical consultation and as symptoms do not correlate with disease severity, these studies do not reflect the burden of GORD to the health services or the contribution towards development of complications such as Barrett’s and oesophageal cancer (OC). The increasing availability of open-access endoscopy has enabled many patients to be managed in general practice where advice in terms of lifestyle adaptations and acid antisecretory treatment can be provided. We have used the General Practice Research Database (GPRD) to investigate the incidence of GORD and BO, the incidence of OC in these two disease populations and changes in acid suppression treatment over a period of 10 years from 1996 to 2005.

Aims and methods

GPRD is the largest database of patients in the community, where approved general practitioner (GP) practices in England and Wales, following agreed guidelines, record clinical and prescribing data on all their patients. The data are recorded anonymously and in 2005 included 3 million patients from 398 GP practices. Practices are required to record a minimum of 95% of prescribing and relevant ‘patient encounter events’ 26. Data, including the diagnoses of cancer, are validated both by internal checks as well as independently carried out and reported in studies 10,27–29.

We used OXMIS and READ codes to identify all patients in the GPRD with a diagnosis of GORD and/or Barrett’s between 1996 and 2005. Gastro-oesophageal reflux codes were identified on the basis of diagnoses of oesophagitis, oesophageal ulcer, acid reflux and regurgitation. Simple heartburn was not included, as an earlier GPRD study suggested that this was a less common diagnosis, associated with occasional, nonpathological or unconfirmed gastro-oesophageal reflux diagnosis 30. BO codes included Barrett’s oesophagus, Barrett’s ulcer and columnar lined oesophagus.

OCs were identified using relevant OXMIS and READ codes, which included malignant neoplasm of the oesophagus, oesophagus carcinoma, and malignant neoplasm of the oesophagus and gastro-oesophageal junction. These codes do not distinguish between squamous OC and adenocarcinoma. PPI and histamine-2 receptor antagonist (H2RA) codes were identified using the British National Formulary classification. Age and sex of the total GPRD population over the study period was also provided, allowing incidence and prevalence calculations.

We used these data to calculate:

  • the annual sex-specific and age-specific incidence rates for GORD and BO, defined as the first ever documented GORD or BO event for a given patient between 1996 and 2005. The overall incidence in men and women was age standardized to the European Standard Population;
  • the annual period of prevalence of BO, defined as the total number of patients with a diagnosis of Barrett’s in the year of interest who were registered in a practice and not transferred out (due to having left the GP practice or death);
  • the annual period of prevalence of GORD, defined as at least a single GORD entry for a patient in the GP’s records for a given year. This was calculated instead of the overall prevalence as GORD is a relapsing and remitting condition, and patients are only likely to seek a GP consultation or prescription when symptomatic; thus, period prevalence provides a better measure of the burden of disease in the community;
  • the incidence of OC in BO per person years of BO and OC in GORD (without a record of Barrett’s) per person years of GORD. As before, OC diagnoses documented before 1996 were also used to exclude prevalent cases. Incident OCs were defined as a new diagnosis of OC if diagnosed more than 12 months after the documentation of GORD or BO. This was done to exclude any prevalent cancers, whose symptoms may have triggered consultation with the medical services. Person years were calculated initially as person days contributed within each study year by each patient to the day of development of OC or transfer out of the GP practice. The sum of person days was divided by 365.25 to obtain person years;
  • the proportion of patients prescribed PPIs or H2RA in the year of diagnosis of GORD and BO, calculated as a percentage of patients in each year. Sex-specific and age-specific prescribing rates were also obtained.

Results

Crude data

In the study period 1996–2005, there were 1 40 635 patients with GORD, of whom 1 25 519 had a new diagnosis of GORD within the study period. There were 6019 patients with BO, with 5860 patients having had the diagnosis made in the study period. Of the 6019 patients with BO, 3026 patients had no documented diagnosis of GORD or heartburn, 2395 also had a diagnosis of GORD, 325 patients with BO had a diagnosis for both GORD and heartburn and only 273 patients with BO also had a code for heartburn but not for GORD.

There were 153 OCs in patients with a diagnosis of BO, of whom only 68 (44%) occurred at least 12 months after a diagnosis of BO and 647 OCs in patients with a diagnosis of GORD, with 182 (28%) diagnosed at least 12 months after an incident diagnosis of GORD.

BO and GORD incidence and prevalence

The incidence of BO doubled from 0.11 to 0.24/1000 population in men and from 0.06 to 0.11/1000 population in women (Fig. 1). The incidence of BO in women approximated that for men with a 10-year lag (Fig. 2). Numerical results are presented in Table 1.

Fig. 1
Fig. 1:
Standardized incidence of Barrett’s oesophagus showing a two-fold increase in incidence in both men and women between 1996 and 2005.
Fig. 2
Fig. 2:
Age-specific incidence of Barrett’s oesophagus in men and women, showing a 10-year lag in incidence in women up to 45–54 years.
Table 1
Table 1:
Age-standardized incidence rates for BO and GORD and prevalence rates for BO and period prevalence rates for GORD (per 1000 population), 1996–2005

Both incidence and period prevalence of GORD diagnosed in general practice remained stable over the 10-year study period (Table 1). The mean incidence of GORD was 3.99/1000 population in men and 4.55/1000 population in women, with a higher incidence of GORD in women across the study period and age groups (Figs 3 and 4).

Fig. 3
Fig. 3:
Standardized incidence of gastro-oesophageal reflux disease over the study period.
Fig. 4
Fig. 4:
Age-specific incidence of gastro-oesophageal reflux disease in men and women.

More women than men older than 45 years of age were diagnosed with GORD. For both sexes, there was a steady increase in the incidence of GORD up to the 65–74 age group, with a slight decrease thereafter (Fig. 4).

OC incidence in BO and GORD

There were 153 OCs diagnosed in patients with BO over the 10-year study period. Of these, 68 cancers were diagnosed more that 12 months from a diagnosis of Barrett’s, 58 cases in men and 10 in women. The overall incidence of OC in BO was 3/1000 BO person years (mean age BO population 64 years).

Among patients with GORD, 647 OCs were identified, 182 (28%) of which occurred over a year from the diagnosis of GORD. Of these, 105 were reported in men and 77 in women (∼1.5 : 1). The cumulative OC incidence for the study period was 0.30/1000 GORD patient years.

The incidence of OC was higher in men than women for both BO and GORD, and increased with age (Figs 5 and 6).

Fig. 5
Fig. 5:
Oesophageal cancer incidence in men and women with Barrett’s oesophagus with increasing age.
Fig. 6
Fig. 6:
Oesophageal cancer incidence in men and women with gastro-oesophageal reflux disease (GORD) with increasing age.

Acid suppression medication prescribed in BO and GORD

Acid suppression during the year of diagnosis of BO was mostly with PPIs throughout the study period, with a slight overall increase from 81.7 to 93.6% in men and from 75 to 92.9% in women between 1996 and 2005. On average, about 90% of patients older than 35 years of age with an incident diagnosis of BO were prescribed PPIs, whereas, among those younger than 35 years of age, only 68.5% women and 84% men were given PPI during the year of diagnosis of BO. There was a progressive decrease in the use of H2RA, with 30.7% newly diagnosed patients with BO being prescribed these in 1996 down to 9.8% in 2005.

There was a more profound change in the proportion of patients with GORD with the initial prescription of PPIs from 52% in 1996 to 79% in 2005, with a reciprocal decrease in H2RA prescriptions in 39% of patients with a new diagnosis of GORD in 1996 to 14.5% in 2005 (Fig. 7). Patients older that 35 years of age were again more likely to be prescribed PPIs.

Fig. 7
Fig. 7:
Percentage of patients prescribed proton pump inhibitors (PPIs) or histamine-2 receptor antagonists (H2RAs) in the year of incident diagnosis of gastro-oesophageal reflux disease (GORD).

Interestingly, the proportion of patients with GORD on PPIs increasingly exceeded those consulting with symptoms of GORD during the study period (Fig. 8).

Fig. 8
Fig. 8:
Patients with gastro-oesophageal reflux disease (GORD) on proton pump inhibitors (PPIs) and GORD-related GP consultations.

Discussion

Our study shows a doubling in the incidence of BO in both men and women over the 10-year study period. This trend appears to plateau between 2002 and 2005 and data from subsequent years are required to assess whether the increase in incidence of BO observed in our study period is maintained. Our results may reflect a genuine increase in the incidence of Barrett’s but also increased access to endoscopy 31,32 as well as changes in the definition of BO, with short segment BO often included in the endoscopic diagnosis of BO in recent years. Data on numbers of endoscopy procedures in the overall GPRD population over the study period would have allowed a better assessment of the observed increase in the incidence of BO. Studies that considered endoscopy numbers have, however, also reported an increase in the incidence of BO, including a single-centre UK-based study looking at trends over a 20-year period, with an increase in the incidence of BO from 0.2% of all endoscopies in 1977 to 1.6% in 1996 33, whereas a recent study from the Dutch primary care database reported increasing incidence of BO in the general population despite a decrease in overall endoscopy numbers, from 0.14/1000 person years in 1997 to 0.23/1000 in 2002 34.

The incidence rate of GORD appears stable over the 10 years of the study, at 4.3/1000 population. Although this reflects the number of patients seeking medical care for symptoms of GORD and is much lower than that reported in community questionnaire surveys, the latter are prone to response bias as patients with symptoms are more likely to respond. However, GPRD data are only representative of the section of the population that seeks healthcare and will not include symptomatic individuals self-medicating with over-the-counter preparations. Our results do not suggest an increasing incidence in GORD over time, in contrast to the increasing incidence of BO over the same time.

Our results could have been skewed through the exclusion of heartburn codes. However, our calculation for the incidence of GORD in 1996, at 4.2/1000 men and 4.8/1000 women, is consistent with the results obtained by Ruigomez et al. 10 from the GPRD database, at 4.5 new diagnoses per person years for 1996. GORD is diagnosed three times more often than heartburn and comparison of patients with a diagnosis of GORD or heartburn 30 in GPRD suggests that patients labelled with heartburn are perceived by GPs as less likely to have serious disease and therefore less likely to be referred for further gastrointestinal investigations. As a result, the exclusion of patients with a heartburn code alone is unlikely to explain this apparent discrepancy between trends in BO and GORD incidence. Furthermore, it has been suggested that a symptom-based diagnosis such as heartburn may be initially recorded, to be replaced by a diagnosis of GORD once chronicity of symptoms is confirmed 30. This is a plausible pattern for the coding of GORD in GPRD and, if true, it would make the exclusion of heartburn codes an unlikely contributor to a significant underestimation of GORD incidence in our 10-year study.

Another more likely explanation for a possible underestimation in the incidence of GORD is the mislabelling of patients with GORD with the generalized term of ‘dyspepsia’. Although only 11% of patients with a first diagnosis of GORD were reported to have undergone endoscopy in 1996 27, endoscopy for patients labelled with dyspepsia rather than GORD would enable the identification of patients with BO, while underestimating the number of patients with GORD symptoms, if no endoscopic evidence of oesophagitis was reported. Guidelines for the management of dyspepsia were originally published in 1996 and were updated twice in the duration of our study in 2002 and 2004 35–37. Increasing access to endoscopy enable confirmation of oesophagitis, oesophageal ulcer or oesophageal stricture, etc., which are coded diagnoses in READ and OXMIS, resulting in high specificity for a diagnosis of GORD, as shown by validation studies in GPRD. However, patients with nonerosive reflux may have erroneously been labelled with dyspepsia. As mentioned previously, patients with symptoms of GORD who have not sought medical advice for their symptoms (e.g. because they self-medicate) are also by default excluded from the cohort because of the lack of a GP-documented GORD diagnosis.

The cumulative incidence of OC in patients with BO was 3/1000 BO person years. Interestingly, most OCs in patients with BO were already present at the time of BO diagnosis, as observed in other similar studies. The results do not distinguish oesophageal adenocarcinoma and squamous cell OC, but the former would be expected to predominate in view of the aetiological link to BO and GORD.

The cumulative incidence of OC in patients with GORD (BO excluded) was 0.3/1000 GORD patient years. This is approximately two times higher than the incidence of OC in England reported at 0.14/1000 population in 2005 20. OC rate at 0.3/1000 GORD patient years is a tenth of the magnitude of OC incidence in BO. Although the older age of BO patients compared with GORD patients (mean 64 vs. 52 years, respectively) can be a confounding factor, Solaymani-Dodaran and colleagues 39 also reported similar findings in an analysis corrected for age and sex.

In our study, the incidence rates of OC in GORD are greater than those reported in the general population by ONS, with rates in men at 0.36/1000 GORD patient years in 2005 as compared with 0.14/1000 men reported by ONS in England for the same year. In women, the respective incidence rates were 0.20/1000 GORD patient years in our study and 0.056/1000 women in the ONS report. As the GPRD population is broadly representative of the UK population in age and sex structure 26,38, comparisons of OC incidence rates between the BO and GORD population from GPRD and national rates are reasonable if not accurate. A direct comparison with overall OC rates in the total GPRD population would have been desirable.

Direct comparisons of the risk of OC in patients with GORD and controls from the GPRD population were reported by Ruigomez et al. 10 as 0.42/1000 patient years for patients with GORD but not BO, compared with 0.06/1000 person years for controls, yielding a relative risk for OC in GORD of 6.9 (1.4–32.9). Similar findings were reported by Solaymani-Dodaran et al. 39, with oesophageal incidence rate ratios of 3.1 and 4.5% in patients with reflux and oesophagitis, respectively, and a much higher rate of 29.8% in patients with BO, whereas Garcia Rodriguez et al. 40 reported an increased risk of oesophageal adenocarcinoma but not gastric adenocarcinoma in patients with a history of GORD. Solaymani-Dodaran et al. 39 reported no significant confounding effects for smoking, alcohol and BMI in the development of OC in GORD and BO.

An expected, BO predominated in men, with a 10-year lag in the incidence of BO in women up to the age of 45–54 years. Similarly, the incidence of OC in greater in men as compared with women, again likely to be related to the delayed development of oesophageal adenocarcinoma in women 41, possibly relating to protection from female sex hormones 42.

The 10-year period studied witnessed huge changes in the management of acid-related conditions. PPIs, introduced in 1988 with the release of omeprazole, became widely available in the 1990s and were prescribed as the first-line treatment in the management of acid reflux by 1999 in preference to H2RAs. This is clearly observable in our results related to acid suppression prescriptions for GORD and BO during the study period and is consistent with the results reported in the GPRD with the declining use of H2RA and increasing prescriptions for PPIs between 1994 and 1998 43. As expected, patients with BO were more likely to be prescribed a PPI, with over 80% patients being prescribed a PPI even in 1996. This increased to 93% by 2005. There was a slower switch from H2RA to PPIs in patients with GORD. The GPRD lends itself to future studies to assess the effect of the use of PPIs in patients with GORD and BO and the resulting incidence of OC.

Conclusion

This is the first study showing trends of the incidence and prevalence for GORD and Barrett’s disease from a large and well-validated database. The rate of incidence of OC in BO at 3/1000 BO person years was 10 times greater than that in patients with GORD, which was still double the reported rate in the general population. The study period from 1996 to 2005 spans a time of ongoing change in the management of acid-related conditions, including H. pylori treatment, access to endoscopy and drug prescriptions. It provides a reliable reflection of the burden of these diseases currently in the UK and a baseline for future studies to compare trends in disease epidemiology as management changes are implemented.

Acknowledgements

Conflicts of interest

There are no conflicts of interest.

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Keywords:

Barrett’s oesophagus; gastro-oesophageal reflux; General Practice Research Database; incidence; oesophageal cancer; proton pump inhibitors

© 2013 Lippincott Williams & Wilkins, Inc.