The prevention of recurrent bleeding post-endotherapy for peptic ulcer disease (PUD) is most critical in the first 3 days. Of the 10–30% of patients who re-bleed,1,2 most do so within the first 3 days, and their prognosis is significantly worse than those who do not re-bleed.3 The current management includes i.v. infusion of proton pump inhibitors (PPI) for up to 72 h post-endotherapy. PPI improves hemostasis by raising the intragastric pH to above 4 to prevent clot lysis, and preferably above pH 6 which is necessary for hemostasis.4 The study by Javid et al. in this issue of the Journal confirms the effect of PPI in raising intragastric pH in an Indian population, and moreover concludes that different PPI can achieve the same intragastric pH levels, irrespective of p.o. or i.v. administration.5
The discovery of Helicobacter pylori by Warren and Marshall over two decades ago, and the subsequent emergence of triple therapy for PUD treatment in patients infected with H. pylori, have contributed to the decline in bleeding from PUD as a common medical emergency.6 However, this has been counterbalanced by a number of factors which increase the propensity of PUD development and its complications. These include the aging population in most developed nations,7 the utilization of non-steroidal anti-inflammatory drugs (NSAIDs) for several disorders, and the aggressive utilization of anti-platelet therapy in a variety of vascular conditions, in particular post-endovascular stenting in ischemic heart disease.8,9 Thus, bleeding PUD will remain a management challenge in the foreseeable future, and it is only prudent to understand the means by which this complication can be treated cost-effectively, whilst minimizing patient morbidity and mortality.
Published studies have suggested clear differences between ethnic groups with regard to H. pylori, PUD and responses to PPI.10 In the Asian population which encompasses the population group studied by Javid et al, the prevalence rates of H. pylori are higher in Asia at 39–49% compared to Western countries at 30–33%.11,12 However, it is important to note that over time with increased recognition and treatment of H. pylori, and improvements in hygiene and standards of living, the H. pylori prevalence rates in Asia have decreased to narrow the differences between East and West.11
On average, Asians have a smaller parietal cell mass than Europeans, which makes them more responsive to PPI.13 Moreover, there are published data that indicate there is an increased prevalence of the ‘poor metabolizer’ genotype for PPI in Asians which again would exaggerate the responsiveness to PPI.13,14 Most PPI are metabolized predominantly through the cytochrome P450 (CYP) enzymes, more specifically through CYP2C19. The majority of omeprazole metabolism occurs through his pathway, while esomeprazole > pantoprazole > lansoprazole are less metabolized through this pathway. Rabeprazole is the PPI least metabolized via CYP2C19; the majority of its metabolism is through a non-enzymatic pathway. Genetic polymorphisms of CYP2C19 expression account for the main inter-individual differences in PPI metabolism. These genetic polymorphisms result in subpopulations of patients who are PPI ‘extensive metabolizers’, ‘intermediate metabolizers’ or ‘poor metabolizers’. The issue is that a patient who is an extensive metabolizer will achieve a less consistent and likely lower pH after dosing with any PPI other than rabeprazole. The white prevalence rate for ‘poor metabolizers’ is low at 2.1%.15 However, even within Asian populations there are differences. Published data indicate that only 10% of Indians had a ‘poor metabolizer’ genotype versus 19% or higher in people of Chinese descent.15 In this context, Javid et al.'s study is surprising in that the acid suppression achieved did not vary with the different PPI used which included rabeprazole.
Published studies have also suggested clinically important differences between PPI16 and the route of delivery.17 Clearly, these are important points to clarify given that the cost of PPI vary dependent on whether they are on or off patent, and costs also vary relating to the mode of delivery (i.v. formulations are generally much more expensive than p.o. ones). In this day and age of increasingly scarce health dollars, Javid et al.'s paper suggests that among the Indian population there were no statistically significant differences between PPI and route of delivery. Therefore, in order to rationalize resources, it would be reasonable to treat their patients with the cheapest PPI available, and deliver it through the p.o. route.
Javid et al.'s paper raises much food for thought. Some limitations of the paper include the exclusion of the highest risk patients, those who re-bled in the first 3 days, the inclusion of a control arm that received a notably inferior treatment (no PPI in 72 h after endotherapy for bleeding PUD) and the comparison of pantoprazole 80 mg p.o. with other p.o. PPI of 40 mg doses. Nonetheless, the manuscript by Javid et al. remains instructive in that it raises awareness of the possible differences of PUD as a condition in different ethnic groups, and the consequential divergent responses to treatments. By addressing possible differences between PPI and delivery routes which have substantial long-term cost implications, this article may change practice or at least stimulate further research into pharmaco-economic aspects of treatment for bleeding peptic ulcer disease.