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PRIORITY PRESS - 18th United European Gastroenterology Week

Barcelona, Spain / October 23-27, 2010

H. pylori Eradication and PPI Therapy

H. pylori is the most important cause of duodenal and gastric ulcers. Successful mucosal healing would appear to reduce the risk of H. pylori-related gastric cancer. In a study presented here at the UEGW, Mabe et al. (Abstract OP216) tracked the incidence of newly identified cases of gastric cancer in a cohort of 3241 patients treated for H. pylori infection. Over a mean of 5.6 years of follow-up, 31 cases were identified. The incidence rate was 0.7% in patients in whom H. pylori had been successfully eradicated vs. 1.4% in patients in whom it was not.

Eradication of H. pylori requires a PPI-based triple-therapy regimen, generally administered over the course of 1 or 2 weeks, leading to high ulcer healing rates. While most H. pylori eradication regimens are effective, regimens that can provide even higher success rates while maintaining safety continue to be explored.

In a randomized study, Aminian et al. compared eradication rates of 4 different regimens (Abstract P0307). Investigators found that the standard triple therapy consisting of omeprazole 20 mg/amoxicillin 1000 mg/clarithromycin 500 mg (all doses given b.i.d. for 10 days) was still the most effective with an eradication rate of 90.7%. The second-best regimen was quadruple therapy—with an eradication rate of 84.1%—with the addition of bismuth 240 mg and metronidazole 500 mg instead of clarithromycin. Sequential therapy was not acceptable in this patient population.

Ecabet sodium is known to have some bactericidal effect against H. pylori. To that end, Kim et al. compared the efficacy of a lansoprazole-based triple regimen vs. the same triple regimen plus ecabet sodium, all given b.i.d. for either 1 or 2 weeks (Abstract P1410). Results showed that the addition of ecabet sodium did not significantly improve the already high eradication rates achieved with standard lansoprazole-based triple therapy (86.2% vs. 80.7%, P=0.166).

Improving Pharmacology

PPIs share an impressive long-term safety record overall. Here at the UEGW, Dr. Christoph Athmann, University of Hanover, Germany, presented 15-year data of the second-generation PPI pantoprazole. No important histological changes were observed in a cohort of patients who have now received treatment for over a decade. Of 146 patients started on 40- to 160-mg doses and evaluated with endoscopy annually, 36 with severe acid-related diseases have now completed 15 years of follow-up. Dr. Athmann reported that the PPI has been effective and well-tolerated with no safety concerns identified in a carefuly monitored protocol.

According to specialized laboratory pathologist Dr. Antonio Orozco-Gámiz, Gastrolab SA, Guadalajara, Mexico, optimizing the acid dissociation constant (pKa) enhances the concentration and bactericidal effects of antibiotics. Clarithromycin is known to have a pKa of 8.9 and amoxicillin has a pKa of 2.4 and 7.4. A new magnesium formulation of pantoprazole (pantoMg) appears to improve the effect of these two antibiotics at the gastric mucus and mucosal surface by optimizing the pKa.

In the first study to report the therapeutic efficacy of pantoMg, 240 patients positive for H. pylori on both histology and urea C-14 breath tests were randomized to 1 of 2 treatment groups: amoxicillin 1 g and clarithromycin 500 mg with pantoMg 40 mg (PAC) or the same antibiotic therapy with omeprazole 20 mg (OAC). Both regimens were given b.i.d. for 14 days. One month after completing triple therapy, the C-14 breath test was repeated to assure eradication.

Both regimens were effective with per protocol eradication rates of 86.7% and 85.7% in the PAC and OAC arms, respectively. On intent-to-treat, PAC provided an 88.3% eradication rate. “The statistical difference may be related to a longer time of acid suppression to achieve optimal antibiotic activity and better pKa at an ideal pH environment,” Dr. Orozco-Gámiz noted. Overall, pantoMg offered greater efficacy in eradicating H. pylori and healing rates at 4 weeks, likely due to its longer half-life.

Dr. Orozco-Gámiz concluded that pantoMg should be considered as a first-line regimen as part of a triple H. pylori eradication regimen.

PPI and Antiplatelet Therapy

ASA is widely used for secondary cardiovascular (CV) disease prevention but it has the potential to cause peptic ulcers (PUs) and adverse upper GI symptoms, suggesting a role for concomitant PPI use in this setting as well. As presented by Dr. James Scheiman, University of Michigan Hospital, Ann Arbor, a post-hoc analysis of the OBERON study assessed the efficacy of daily esomeprazole 20 and 40 mg in PU reduction among H. pylori-negative patients at increased risk for PU taking ASA 75 to 325 mg daily. After 26 weeks, 1.4% of patients on esomeprazole 20 mg and 0.5% of patients on 40 mg had endoscopic evidence of PU compared with 7.5% of placebo controls; the PPI also reduced upper GI symptoms.

Resistance to clopidogrel has been associated with a significant increase in CV events and mortality, according to Dr. Ricardo Fontes-Carvalho, Gaia Hospital Centre Porto, Portugal. Some have now voiced concerns that the use of a PPI in the setting of antiplatelet therapy may exacerbate clopidogrel resistance. Frequently prescribed in combination with ASA, especially in acute coronary syndromes (ACS) and in acute myocardial infarction (AMI), clopidogrel is a prodrug that is highly dependent on the cytochrome P450 2C19 (CYP2C19) isoenzyme for conversion to its active metabolite.

Because both clopidogrel and ASA can induce mucosal injury in the upper GI tract, guidelines now recommend co-therapy with a PPI in patients at increased risk of GI bleeding. “All PPIs are metabolized by CYP2C19, but to varying degrees,” observed Dr. Fontes-Carvalho. These varying degrees are important, he added, because they may lead to clinically meaningful differences in antiplatelet activity.

In a study carried out at Dr. Fontes-Carvalho’s institution, the clopidogrel-PPI interaction was quantified in 34 patients receiving dual antiplatelet therapy (ASA 150 mg/clopidogrel 75 mg) 1 month after an AMI. The quantification was undertaken in 3 clinical scenarios: after a 1-month washout period, without taking any PPI; following a 4-week period of omeprazole 40 mg; and after another month washout period followed by 4 weeks of pantoprazole 40 mg. At each step, platelet function was measured in mean P2Y₁₂ reaction units (PRU). This test reflects binding at the P2Y₁₂ receptor, the target of clopidogrel’s antiplatelet effect: the higher the PRU value, the lower the antiplatelet effect. Resistance was defined as a PRU value of =240.

Results showed an important reduction in clopidogrel’s antiplatelet activity when patients received omeprazole, which is more dependent on CYP2C19 than pantoprazole, which has alternative metabolic pathways, as noted by Dr. Fontes-Carvalho. Specifically, PRU increased from an average of 202 units (±52 units) in the absence of a PPI to an average of 235 units (±58 units) on omeprazole (P<0.001), just below the predefined value for resistance, and to an average of 215 units (±54 units) on pantoprazole, which was not statistically significant (P=0.16) (Table 1). Some 26% of patients in the study were resistant to clopidogrel in the absence of a PPI; this increased to 48% with the introduction of omeprazole but remained essentially unchanged in the presence of pantoprazole.

Table 1.

“We have demonstrated that omeprazole significantly interferes with the antiplatelet effect of clopidogrel, increasing the proportion of patients resistant to this drug. To our knowledge, our study is the first to show, in an intra-individual investigation of post-MI patients, that this interaction is not a class effect,” Dr. Fontes-Carvalho concluded.

Summary

PPIs are highly effective for controlling gastric acid and as part of a triple regimen to eradicate H. pylori and reduce gastric cancer risk. However, these agents appear not to be interchangeable. New studies confirm that the pharmacodynamics of these treatments differ in ways that may be important to patient outcome, particularly among those taking concomitant therapies that depend on the CYP2C19 pathway.