2018 Section 6 - Laryngology, Voice Disorders, and Bronchoesophalogy

Long-term safety of PPI therapy

INTRODUCTION Gastro-oesophageal re fl ux disease (GERD) is common in Western adult populations and treatment of GERD has been studied extensively in clinical trials. Proton pump inhibitors (PPIs) have become a cornerstone of short- and long-term therapy for GERD to control disease manifestations and normalise quality of life. The safety pro fi les of omeprazole and esomeprazole have been well established through clinical trials and over 25 years (omeprazole) and 13 years (esomeprazole) of market exposure. Indeed, worldwide exposure to esomeprazole now exceeds 90 million patient-years (data from the sponsor). The most commonly reported adverse drug reactions are headache, abdominal pain, diarrhoea, fl atulence, nausea/vomiting and constipation (included in the product label). These adverse drug reactions are often mild and reversible and both drugs are generally well tolerated. Nevertheless, as with any drug used to treat chronic disease, the extensive use of PPIs requires that their long-term safety is continuously scrutinised. Potential safety concerns for long-term PPI use that have been reported in the literature include an increased risk of pneumonia and enteric infections, such as Clos- tridium dif fi cile , 1 – 3 nutritional de fi ciencies owing to the requirement of acid for the effective absorption of many nutrients (e.g. vitamin B 12 and iron), 1, 2 increased risk for osteoporotic fractures and neoplasms, 1, 2 and more recently the potential for PPIs to interact with the anti- platelet agent clopidogrel and reduce its clinical ef fi - cacy. 1, 4, 5 It has also been suggested that increases in gastrin levels seen with prolonged acid suppression may drive proliferation of gastric enterochromaf fi n-like (ECL) cells and also the development of atrophic gastritis, although histopathological data do not so far support these concerns. 6, 7 Indeed, this topic was discussed at a US Food and Drug Administration (FDA) Advisory Committee meeting in 1994, the ultimate outcome of which was support for the long-term use of omeprazole. The SOPRAN (Safety of Omeprazole in Peptic Re fl ux Esophagitis: A Nordic Open Study) 8 and LOTUS (Long- Term Usage of Esomeprazole vs. Surgery for Treatment of Chronic GERD) 9, 10 studies included assessments of the safety of long-term PPI therapy vs. anti-re fl ux sur- gery (ARS) among their secondary objectives, as well as laboratory measurements of potential relevance to long- term PPI safety. Long-term PPI safety has been explored in at least one large study, 11 but we are not aware of any studies as large as SOPRAN and LOTUS that have been conducted in a randomised setting. This is an important

consideration when SAEs are investigated over a signi fi - cant period of time, incorporating by necessity an ageing and heterogeneous patient cohort in which there may be confounding factors that cannot be fully identi fi ed and adjusted for. Our objective was thus to compare PPI data to those seen in the ARS control groups within the SOP- RAN and LOTUS studies, with the aim of gaining bal- anced insights into questions of long-term PPI safety highlighted in the literature. Logistics The clinical study protocol in the SOPRAN study was developed through close collaboration between the spon- sor and the principal investigator, and the investigators participating in the study met regularly to follow and evaluate data. In the LOTUS study, the clinical study protocol was developed and fi nalised by a Steering Com- mittee, which then met annually to review data, with additional meetings held as necessary. The LOTUS study was classi fi ed as a post-authorisation safety study [PASS, de fi ned in Directive 2001/83/EC (DIR) Art 1 (15)] with regular reporting to and evaluation by the European Medicines Agency. Both studies were performed in accordance with the Declaration of Helsinki and with International Confer- ence on Harmonisation/Good Clinical Practice and applicable regulatory requirements. The study protocols were approved by the relevant local institutional review boards or independent ethics committees according to local regulations. All patients provided written, informed consent before enrolment in the trials. Study designs The SOPRAN and LOTUS studies were multicentre, open-label, parallel-group studies that compared the ef fi - cacy and safety of maintenance therapy with a PPI with that of ARS, in patients with chronic GERD who were suitable candidates for either treatment. Both studies included only patients who were responsive to initial PPI therapy and excluded patients with signi fi cant comorbid- ities and those considered likely to be poorly compliant (e.g. patients with a history of alcohol abuse). The surgi- cal procedure used in the SOPRAN study (open ARS) differed to that used in the LOTUS study (laparoscopic ARS) because laparoscopic ARS replaced open ARS as the standard surgical procedure between 1991 (SOPRAN start date) and 2001 (LOTUS start date). METHODS

Aliment Pharmacol Ther 2015; 41: 1162 – 1174 ª 2015 John Wiley & Sons Ltd

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