Introduction

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Dyspeptic symptoms are a common presenting complaint to general practitioners, and there is continuing debate about management.¹ Acid suppressant drugs, the most potent of which are proton pump inhibitors, are often prescribed, and it has been suggested that proton pump inhibitors are "probably too widely prescribed for minor symptoms, and the cost implications of this are clear."² The first proton pump inhibitor, omeprazole, was introduced in 1989, since when two further drugs in the class have been marketed, lansoprazole and pantoprazole. There has been a substantial, continuing, and unexplained rise in prescribing of proton pump inhibitors, which now account for over 6% (£23m) of primary care expenditure on drugs in the West Midlands region. It is unknown whether their use in practice has corresponded to their licensed indications.

General practitioners, health authorities, and their advisers use prescribing analysis and cost (PACT) data to monitor prescribing in primary care and interpret trends. A recognised disadvantage of PACT data is the inability to link prescribing directly with morbidity or individual patients. ^{3 4} The General Practitioner Research Database, previously known as VAMP Research, is a UK database recording morbidity, prescribing data, and referrals and provides a resource for monitoring drug use and appropriate prescribing.^5-7 Anonymised records of individual patients are allocated a unique patient number. Data on medical events, patient problems, and other doctor-patient interventions are captured in the database by means of codes from the Oxford Medical Information System (OXMIS) dictionary. The dictionary was based initially on an amalgamation of the eighth revision of the International Classification of Diseases (ICD-8) and surgical operation codes of the Office for National Statistics. General practitioners who provide data have agreed to record information in a standard manner, which can be used for research purposes. The General Practitioner Research Database for the former West Midlands region contains 33 million records for prescribing or diagnosis for a population of 612 700 patients. The age-sex profile of the patients matches that for the West Midlands region and England and Wales.⁸

Using the General Practitioner Research Database for the years 1991-5, we identified new prescriptions for proton pump inhibitors and analysed the associated clinical data, comparing the results with the licensed indications. The licensed indications for lansoprazole, introduced in 1994, were more restricted than those for omeprazole (table 1). Pantoprazole, available since 1996, falls outside the years that we investigated. To establish whether the results could be applied to the interpretation of PACT data for proton pump inhibitors, we determined that the prescribing trends for the General Practitioner Research Database and PACT data matched.

	Methods

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We extracted all records of prescribing of a proton pump inhibitor within the General Practitioner Research Database and analysed them using Microsoft Access software. For individual patient records, two of us (a general practitioner and a medical adviser) reviewed OXMIS diagnosis codes that were linked to prescribing of proton pump inhibitors. We grouped 205 codes that could be reasonably linked to gastrointestinal disease or presenting complaints into eight categories (table 2). A consultant gastroenterologist verified this categorisation, which is available on request.

All records for patients who had been prescribed a proton pump inhibitor were divided into calendar years from 1991 to 1995. From 1991, we identified the first prescription of a proton pump inhibitor for each patient and extracted the record with the OXMIS code and data to calculate defined daily doses. Subsequent years' data were similarly analysed, and patients from preceding years excluded, thus separating patients newly prescribed proton pump inhibitors from those given repeat or recurrent prescriptions. Patients with a relevant OXMIS code were then placed into one of the eight categories.

Two of us reviewed the relevant data fields and developed an algorithm to convert the data on the drug's quantity, strength, and duration into defined daily doses. The defined daily dose is the assumed average dose per day for a drug used for its main indication in adults, as defined by the World Health Organisation, and is an internationally recognised comparator for research into drug use.⁹ Thirty three records (0.05%) lacked the necessary data for conversion to defined daily doses and were discarded with negligible effect on the final calculation. We analysed quarterly PACT data from June 1991 to December 1995 for proton pump inhibitors for the former West Midlands region and similarly converted these to defined daily doses.

Statistical analysis
For both sets of data, we plotted the trend over time and performed regression analyses to test the linearity of the trends. We used Wilcoxon's matched pairs signed ranks test to compare the rate of change in defined daily doses between two consecutive quarters for both trends, and to test for a difference in the median rate of changes between the two sets. Finally, for each year, we calculated the defined daily doses for first prescriptions for all new patients and subtracted these from the total to quantify repeat prescribing.

	Results

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Table 3 shows the numbers of new prescriptions of proton pump inhibitors and their clinical indications. During the study period the largest absolute increases in recorded clinical indications for starting proton pump inhibitors were duodenal disease (780%), non-ulcer dyspepsia (690%), gastric disease (450%), and non-specific abdominal pain (390%). The smallest increase was for oesophagitis (75%).

There were significant changes in prescribing for different disease categories over time. In 1991 oesophagitis was the largest category (31% of the total), but in 1995 it was only the third largest (14%) after non-ulcer dyspepsia (32%) and hiatus hernia and reflux (17%). Prescribing for duodenal disease increased at the time omeprazole was licensed for long term treatment of this condition, whereas prescribing for non-ulcer dyspepsia increased steadily throughout the study period despite the drugs not being licensed for this condition until April 1997. Most of the data relate to omeprazole: the proportion of defined daily doses accounted for by lansoprazole was 2.5% in 1994, rising to 6.4% in 1995 (table 4).

During the study, the total volume of prescribing increased 10-fold. The percentage contribution from new prescriptions decreased yearly from 29% in 1992 to 23% in 1995 (fig 1). The proportion attributable to repeat prescribing (77%) accords with previous work, which established that repeat prescriptions generally account for 75% of the volume and 81% of the cost of prescribing.¹⁰

View larger version (18K): [in this window] [in a new window]   Fig 1.   Proportions of new and repeat prescriptions for proton pump inhibitors during 1991-5 (data from General Practitioner Research Database)

Figure 2 shows that the prescribing of proton pump inhibitors, as measured by defined daily doses, increased linearly for both the data from the General Practitioner Research Database and from PACT (regression analysis slope=2727.3 for PACT data, 157.4 for General Practitioner Research Database). Both data sets had the same coefficient of determination (98.5%), indicating a high degree of fit. The P value (0.913) for Wilcoxon's matched pairs signed ranks test (z=0.109) was not significant at the 1% level of significance, indicating that the two data sets had the same rate of change. The median (interquartile range) values were 0.524 (0.471-0.566) for PACT and 0.521 (0.356-0.632) for the General Practitioner Research Database, indicating that the rates of change also had the same distribution.

View larger version (23K): [in this window] [in a new window]   Fig 2.   Total prescriptions for proton pump inhibitors during 1991-5 according to General Practitioner Research Database (GPRD) and prescribing analysis and cost (PACT) data

	Discussion

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The purpose of this study was to examine the clinical reasons recorded by general practitioners when prescribing proton pump inhibitors to patients for the first time. Diversity of diagnostic labelling between doctors is inevitable, and we are aware that the recorded indication could, as Marinker stated, be "not so much the basis for the choice of drug but rather the alibi for it."¹¹ Also, the diagnosis could change from that initially entered. Despite these limitations, the coding entered when a patient is first prescribed a proton pump inhibitor is deemed to reflect the perceived clinical reason at that time.

Prescribing patterns
The first licensed indication for which proton pump inhibitors represented a major advance in treatment was reflux oesophagitis, so this might reasonably be expected to be a major driver in the increase in new prescribing. This was not the case: the proportion of new prescriptions for this condition fell steadily between 1991 and 1995 and accounted for only 8% of the total increase in new prescriptions. This decrease is explained in part by the expansion of the licensed indications, with appropriate increases in new prescribing for duodenal and gastric disease.

Limitations of study
We may have underestimated unlicensed use of proton pump inhibitors for several reasons. In some categories such as duodenal disease there is a mixture of codes reflecting licensed and unlicensed indications, but the category as a whole was designated as licensed. The inclusion of lansoprazole, which at the time of introduction had more restrictive licensing than omeprazole, will also have underestimated the proportion of new prescriptions for unlicensed indications.

Implications of study
We have demonstrated that the General Practitioner Research Database and PACT show similar trends for prescribing of proton pump inhibitors and that the proportion of repeat prescribing is close to that reported in other studies. We infer that both the subset of West Midland general practitioners providing data for the General Practitioner Research Database and general practitioners throughout the region have responded in a similar manner to the influences that have produced this change in prescribing. It is therefore reasonable to assume that the number of different diagnoses contributing to this rise is similar for both the General Practitioner Research Database and PACT populations.

Conclusions
In 1991, 54% of patients newly prescribed proton pump inhibitors were recorded as having gastro-oesophageal reflux disease, followed by 32% with non-specific indications, and 14% with "ulcer" disease. These proportions had changed in 1995 to 31%, 46%, and 23% respectively, and do not necessarily reflect changes in licensed indications. Although general practitioners seemed to have responded to changes in licensing, particularly for duodenal and gastric disease, we found there had also been increasing use of proton pump inhibitors for non-ulcer dyspepsia and non-specific abdominal pain.