Comparative efficacy of proton pump inhibitors in the treatment of gastropathy induced by nonsteroidal anti-inflammatory drugs

The dissertation is devoted to a comparative clinical and pharmacoeconomic evaluation of three proton pump inhibitors — omeprazole, lansoprazole and rabeprazole — in patients with gastropathy induced by the use of non-steroidal anti-inflammatory drugs. The work examines the epidemiology and pathogenesis of NSAID-induced gastropathy, including the role of hydrochloric acid and Helicobacter pylori infection, and substantiates the use of antisecretory therapy. The study employs 24-hour and prolonged intragastric pH monitoring with pharmacological tests, assessment of the dynamics of the pain syndrome, the rate of epithelialisation of erosive-ulcerative defects and the morphological pattern of the gastric mucosa, taking into account H. pylori infection. On the basis of the results, recommendations are formulated for the choice of a PPI for the treatment of erosive and ulcerative lesions of the gastroduodenal zone, and a pharmacoeconomic analysis of the cost/effectiveness ratio of the investigated treatment regimens is carried out.

Relevance of the problem.

Non-steroidal anti-inflammatory drugs (NSAIDs) rank second after Helicobacter pylori (H. pylori) among the factors contributing to the development of erosive-ulcerative lesions of the mucosa of the stomach and the duodenum, and belong to the most important and frequently used «symptomatic» agents, the main indications for their prescription being inflammatory processes of various origins, pain, fever and a tendency to develop thrombosis (aspirin) [130]. As a result of their adverse action, NSAIDs can damage any part of the gastrointestinal tract (GIT), from the oesophagus to the rectum, but most frequently the stomach and the duodenum.

Such close attention to the influence of NSAIDs on the state of the GIT mucosa is due not only to their pronounced ulcerogenic effect, but also to the widespread, often uncontrolled, administration of these drugs [12, 18, 20, 26, 68, 74, 155, 174, 185]. Every day, 30 million people worldwide take NSAIDs, and annually this figure amounts to 300 million people, with only 100 million taking NSAIDs as prescribed by a physician [217]. Proceeding asymptomatically or with a minimal number of subjective sensations, which is largely due to the analgesic effect of the drugs themselves, gastropathy induced by NSAID intake is most dangerous because of its possible serious complications: GIT bleeding and perforation. The absolute risk of gastrointestinal bleeding and ulcer perforation appears low and amounts to 1–2% in patients receiving NSAIDs for less than 3 months. However, a frequency of 1% means that every year in the USA alone there are 130 thousand hospitalisations for serious gastrointestinal complications associated with NSAID intake, 7 thousand of which end fatally [30, 45, 46, 54, 67, 77, 84, 96, 100, 113, 120, 135].

The main mechanism of the formation of NSAID-induced lesions of the gastroduodenal zone, as well as the mechanism of the therapeutic action of NSAIDs, is associated with a decrease in prostaglandin (PG) synthesis, which leads to a reduction in the protective properties of the GIT mucosa. Thus the protective factors of the GIT mucosa are weakened, against the background of which the influence of aggressive factors, the main one being hydrochloric acid, becomes predominant. In this connection, in the treatment of gastropathy arising during NSAID intake, the administration of drugs reducing hydrochloric acid secretion is pathogenetically justified [48, 49, 132, 136, 142, 143, 148, 247–250]. In particular, proton pump inhibitors (PPIs), which suppress the final stage of hydrochloric acid synthesis by blocking H+, K+-ATPase, which distinguishes them favourably from other antisecretory agents that block only one of the many mechanisms of hydrochloric acid secretion [11, 31, 35, 37, 193, 257, 258, 262, 276].

In recent years, several international multicentre studies have been conducted to investigate the comparative efficacy of the well-established omeprazole and H2-blockers of histamine receptors in the treatment of gastropathy induced by NSAID intake [71, 80, 111, 115, 157]. However, no studies comparing the efficacy of several PPIs have been carried out in our country. In this regard, the study of the comparative efficacy of proton pump inhibitors — omeprazole, lansoprazole and rabeprazole — in patients with gastropathy induced by NSAID intake becomes relevant and expedient.

Aim of the study.

The aim of the work was to compare the clinical efficacy of various proton pump inhibitors in the treatment of patients with gastropathy induced by NSAID intake.

Objectives of the study:

1. To compare the speed of onset, duration and intensity of the antisecretory effect of the proton pump inhibitors omeprazole (Losec), lansoprazole (Lanzap) and rabeprazole (Pariet) according to the results of pharmacological tests during 24-hour and prolonged intragastric pH monitoring (pH-metry).

2. To perform a comparative assessment of the dynamics of the pain syndrome and the rate and frequency of epithelialisation of erosive-ulcerative defects in patients with gastropathy induced by NSAID intake during the administration of the aforementioned proton pump inhibitors.

3. To carry out a pharmacoeconomic analysis with a study of the «cost/effectiveness» ratio for the proton pump inhibitors omeprazole (Losec), lansoprazole (Lanzap) and rabeprazole (Pariet) within treatment regimens for NSAID gastropathy.

Scientific novelty of the work.

For the first time, a comparative assessment of the proton pump inhibitors lansoprazole and rabeprazole within treatment regimens for gastropathy induced by NSAID intake was carried out — their antisecretory effect and influence on the dynamics of the pain syndrome and the rate and frequency of epithelialisation of erosive and ulcerative defects. A pharmacoeconomic analysis of the investigated treatment regimens for gastropathy induced by NSAID intake was also performed.

Practical significance of the work.

The results of the study have shown that the use in patients with gastropathy induced by NSAID intake of treatment regimens based on the new-generation proton pump inhibitors omeprazole (Losec), lansoprazole (Lanzap) and rabeprazole (Pariet) makes it possible to achieve high rates of epithelialisation of erosive and ulcerative defects. With respect to the epithelialisation of erosive defects, all three investigated drugs demonstrated high clinical efficacy; however, taking into account the results of the pharmacoeconomic analysis with the evaluation of the «cost/effectiveness» parameter, from the economic point of view the use of lansoprazole (Lanzap) is more preferable. For the treatment of ulcerative defects, the regimen based on rabeprazole appears most preferable, since the use of this drug, owing to the highest clinical results, allows reducing not only the duration but also the cost of treatment for this group of patients.

Main propositions of the thesis put forward for defence:

1. Between the indicators of the antisecretory action of the studied proton pump inhibitors — omeprazole (Losec), lansoprazole (Lanzap) and rabeprazole (Pariet) — there are significant differences in favour of rabeprazole (Pariet). Nevertheless, all these drugs possess a pronounced antisecretory effect and allow maintaining an intragastric pH level >4 on average from 10 (Losec) to 15 (Pariet) hours, which is considered sufficient for achieving a high degree of epithelialisation of erosive and ulcerative defects of the stomach and the duodenum.

2. The pain syndrome in the treatment of NSAID gastropathy was relieved significantly more rapidly during the administration of rabeprazole (Pariet) (p<0.01); in comparing the healing rate of erosive defects, all three aforementioned drugs showed comparably high results without significant differences (p>0.1); in comparing the healing rate of ulcerative defects after 14 days from the start of treatment, rabeprazole (Pariet) proved to be more effective (p<0.01), while after 21 days from the start of treatment no significant differences in the efficacy of ulcer scarring between the investigated drugs were obtained (p>0.1).

3. On the basis of the pharmacoeconomic analysis with a study of the «cost/effectiveness» ratio for the proton pump inhibitors omeprazole (Losec), lansoprazole (Lanzap) and rabeprazole (Pariet), conclusions were drawn regarding the preference of treating NSAID gastropathy in the form of erosions of the gastroduodenal mucosa with lansoprazole (Lanzap), and of ulcerative defects with rabeprazole (Pariet).

Ways of implementing the results of the study.

The obtained results have been incorporated into the work of the Department of Propaedeutics of Internal Diseases and Gastroenterology of the State Educational Institution of Higher Professional Education MGMSU and are used in lectures, seminars and practical classes with students and listeners of certification courses and topical advanced training courses of the Faculty of Additional Professional Education of the State Educational Institution of Higher Professional Education MGMSU. The results of the study were reported at the conference of young scientists held on 20 April 2004, at which the second place was taken, and at the scientific and practical conference at the GKG of the Ministry of Internal Affairs of the Russian Federation held on 15 December 2004.