Epidemiology of proton pump inhibitors therapy: an examination of the use and safety in general practice

Othman, Fatmah (2017) Epidemiology of proton pump inhibitors therapy: an examination of the use and safety in general practice. PhD thesis, University of Nottingham.

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Proton pump inhibitors (PPIs) have become the cornerstone of medical treatment for acid-related gastrointestinal disorders. To date, there is a distinct lack of understanding about the recent UK trends in PPI use and evidence about the association between the increased risk of these drugs and the potential adverse effects, in particular the risk of infection, remains questionable. The publication of contradictory findings in several research studies further compounds this situation.

Aim and Objectives:

This thesis aimed to examine the epidemiology of PPI use in general practices in the UK, and the side effects of PPI, mainly their proposed infective complications.

The specific objectives were:

• To determine the prevalence and pattern of PPI prescription, and to identify the practices employed to reduce PPI use in the UK general population.

• To examine the risk of community-acquired pneumonia before and after the administration of PPI and to assess whether unmeasured confounding explains this association.

• To determine whether the mechanism by which PPIs induce an increased risk of infection is supported by the same mechanism acting in another cause of achlorhydria, pernicious anaemia.


This thesis describes work conducted using the UK’s Clinical Practice Research Database (CPRD) and, for some studies in this project, a subset of the CPRD linked to the hospital records from the Hospital Episodes Statistics (HES) database. Firstly, the CPRD was used to estimate the annual prevalence of PPI use during the period 1990-2013. In this study, new users of PPI therapy who had five years of follow-up data were identified to describe patterns of cessation and duration of PPI use. Secondly, cohort (analysed using Cox regression and prior event rate ratio) and self-controlled case series studies were conducted to examine the risk of community-acquired pneumonia and PPI exposure. Thirdly, a cohort of pernicious anaemia patients was used to estimate the risk of infections (community-acquired pneumonia and Clostridium difficile infection) compared to controls to examine whether a reduction in gastric acidity might be the underlying mechanism of the increased risk of these infections.


1) There was a considerable increase in the administration of PPI prescriptions in UK general practice such that both the period and point prevalence of PPI use increased between 1990 and 2012 (period prevalence increased from 0.2% to 14.8% and point prevalence from 0.03 % to 7.7%). Of new users of PPI therapy, 27% used PPI therapy over a long-term basis (≥1 year continuously), while 4% remained on PPI therapy for five years. Clear attempts to step down the dosage were identified in 41% of long-term users.

2) Among 320, 000 patients, including 160 ,000 new PPI users, the risk of community-acquired pneumonia was 1.67 (95% confidence interval (95%CI) 1.55 to 1.79) times higher for patients exposed to PPIs than it was for the controls. Among the 48,451 PPI-exposed patients with a record of community-acquired pneumonia, the relative incidence rate ratio was 1.19 (95%CI 1.14 to 1.25) in the 30 days after a PPI prescription but was higher in the 30 days before a PPI prescription (1.92, 95%CI 1.84 to 2.00). This reduction in the increased risk in PPI users after prescription was also reflected in the prior event rate of 0.91 (95%CI 0.83 to 0.99).

3) A total of 45,467 pernicious anaemia patients were identified and matched to 449,635 controls. Patients with a pernicious anaemia diagnosis had a higher risk of developing community-acquired pneumonia than the control group (adjusted hazard ratio(HR)1.24, 95%CI 1.21 to 1.26); however, this risk decreased when a stricter definition of pernicious anaemia was applied, and the data was further restricted to incident diagnosis. The findings also suggest that pernicious anaemia patients have a 57% increased risk of Clostridium difficile infection (adjusted HR 1.57, 95% CI 1.40 -1.76) and this association persisted when we limited the analysis to a subgroup with a more restrictive definition of pernicious anaemia diagnosis, or to incident cases.


This research revealed that there was a high prevalence of PPI prescribing in the primary care setting and that there are considerable opportunities available to reduce the cost and side effects of PPI use through improving adherence to recommended withdrawal strategies. In addition, the studies investigating the proposed infective complications of PPI use on which we focussed in this thesis add important data to the development of a safety profile of PPI use.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Card, T.
Crooks, Colin
Keywords: Proton pump inhibitors, Clinical Practice Research Database, Prior event rate ratio, Infections
Subjects: QS-QZ Preclinical sciences (NLM Classification) > QU Biochemistry
Faculties/Schools: UK Campuses > Faculty of Medicine and Health Sciences > School of Medicine
Item ID: 42399
Depositing User: Othman, Fatmah
Date Deposited: 13 Oct 2017 14:17
Last Modified: 03 Jun 2018 15:53
URI: https://eprints.nottingham.ac.uk/id/eprint/42399

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