Postmarketing surveillance of proton pump inhibitors in perspective: the case of Lansoprazole

Abstract

The series of studies captured in this thesis have one common source, a prospective, open label, follow-up study to evaluate patterns of use, safety and effectiveness of the PPI lansoprazole in 10,008 naturally occurring patients in the Netherlands (1994-1998). Clinical record forms and medication histories of this cohort have been completed representing in total 35,000 users-months of follow-up. The study was designed and performed according to the SAMM guidelines. Briefly, this means no additional in- or exclusion criteria with respect to patient enrolment in the study, a modest remuneration for participating physicians and, most importantly, a separation in time between the moment of prescription of the study drug (i.e. lansoprazole) and the moment of inclusion of the patient in the study in order to avoid seeding prescriptions. What have we learned from all this? A primary interest of the study was to evaluate patterns of use of lansoprazole. The drug has been used for a variety of indications, frequently also beyond the official labelling of peptic ulcer and reflux oesophagitis. The study on the seeding of prescriptions revealed that in the limited number of cases when seeding was there, this occurred most likely in patients with relatively minor peptic disorders, including unlicensed indications. One out of five lansoprazole prescriptions was NSAID related. The use of corticosteroids, anticoagulants, female gender and an age between 45 and 70 years were strongly associated with NSAIDs induced PPI-use. The medley of prescribed eradication schedules and the large variety in pre- and post-testing of the existence of H. pylori confirmed the great need of guidelines and protocols to ensure treatment success. It was a peculiar finding that many patients with H. pylori eradication continued lansoprazole treatment (41.1%). Even one out of three peptic ulcer patients without GERD and treated with triple or quadruple therapies had continued PPI use after H. pylori eradication therapy. Regarding safety, we found that 17.4% of all studied patients reported adverse events. No unlabelled events were detected. The profile and frequency of occurrence were analogous to results of clinical trials and other observational studies. The reporting rates of adverse effects decreased in time. We found that certain patients had a higher risk to develop adverse events, namely women, alcohol consumers, OTC-users and patients with co-morbidity. The occurrence of headache was associated with female gender, a history of analgesics use and the tendency of reporting other adverse events as well. The onset of diarrhoea during PPI use was related with the reporting of other adverse events, alcohol use and the concomitant use of antibiotics, an important finding for ensuring treatment compliance with H. pylori eradication schemes including antibiotics. We found that indication-related complaints disappeared or improved in 90.5% of patients after 8 weeks of lansoprazole use. The effectiveness was comparable to results found in clinical trials in the registered indications for lansoprazole and high taking into account the fact that patients were only endoscopically examined in 50.3%, that 29% of the patients had not licensed indications and that patients with complex morbidity were included. We were able to gain more in depth insight in the patterns of use of a new drug launched on the Dutch market. Peptic Survey was designed as a field follow-up study bringing data from various sources together in one research database. This approach is most appealing when prescribing of a new drug is highly variable at the moment of product launch in the market place and when drug exposure is not covered sufficiently yet by automated databases. A main concern remains the costs and time burden of building such large cohorts of recipients of a new drug in the market. Industry will continue to play a major role in funding these studies. A critical appraisal of a possible conflict of interest remains necessary. The postmarketing project described in this thesis represents certainly no panacea for solving all problems, but has surely contributed to the knowledge base of conducting sound postmarketing studies of new drugs.