For patients who must take clopidogrel for atherosclerosis but have a history of peptic ulcer, the addition of esomeprazole to the antiplatelet therapy can prevent recurrent peptic ulcer, Dr. Ping-I Hsu and colleagues reported in the March issue of Gastroenterology.
Esomeprazole did not interfere with clopidogrel’s antiplatelet action when the two drugs were taken 14-16 hours apart every day, said Dr. Hsu of Kaohsiung (Taiwan) Veterans General Hospital and National Yang-Ming University in Taipei, Taiwan, and his associates.
Dr. Ping-I Hsu
Research has shown that a significant number of patients with atherosclerosis who have a history of peptic ulcer will develop recurrent ulcers during treatment with clopidogrel. Moreover, some data have raised concerns that proton pump inhibitors (PPIs) such as esomeprazole might inhibit the conversion of clopidogrel to its active form, interfering with its efficacy.
"Both the U.S. Food and Drug Administration and the European Medicines Agency have posted safety warnings and discourage the use of PPIs with clopidogrel unless absolutely necessary," Dr. Hsu and his colleagues noted.
They examined these issues in a 6-month, prospective, randomized clinical trial involving 165 patients who had atherosclerosis and a history of peptic ulcer confirmed by endoscopy. In the open-label study, 82 subjects were randomly assigned to take daily clopidogrel (75 mg) alone and 83 to take esomeprazole (20 mg) before breakfast and clopidogrel at bedtime every day (Gastroenterology 2011 March [doi:10.1053/j.gastro.2010.11.056]).
The study subjects were allowed to take antacids for dyspeptic symptoms but were not permitted to take anticoagulants, cyclooxygenase-2 (COX-2) inhibitors, NSAIDs, over-the-counter analgesics, corticosteroids, misoprostol, histamine H2 receptor antagonists, or sucralfate.
In the intention-to-treat analysis, there were 10 cases of recurrent peptic ulcer in patients taking clopidogrel alone, for a cumulative incidence of 11%. In contrast, only one patient taking clopidogrel plus esomeprazole developed recurrent peptic ulcer, for a cumulative incidence of only 1%.
In the per-protocol analysis of 129 patients who completed the study, the respective incidences were very similar, at 12% and 2%.
These results "confirm our hypothesis that esomeprazole can effectively prevent recurrent ulcer in clopidogrel users who have a peptic ulcer history," the investigators said.
The rates of loss to follow-up or to medication intolerance were similar between the two groups, at approximately 5% each. Also similar were rates of dyspeptic symptoms (23% with combined treatment and 28% with clopidogrel alone) and consumption of antacids (51 tablets and 66 tablets, respectively).
A subset of 42 patients (21 in each treatment group) underwent pharmacodynamic testing to examine whether esomeprazole interfered with clopidogrel’s antiplatelet action. There were no differences between the two groups in the results of platelet aggregation tests.
Moreover, the rates of cardiovascular events including unstable angina, acute MI, and ischemic stroke were not significantly different between the two groups.
"It is important to note that we widely separated the administration of esomeprazole and clopidogrel in this study," the researchers said.
The half-lives of both drugs are very short, so the 14- to 16-hour separation likely minimized any potential interactions. This study could not address potential drug interactions if the two agents are given closer together, Dr. Hsu and his associates said.
The specific reasons for recurrence of peptic ulcers in the study remain unclear. "Nonetheless, it should be noted that most of our patients had advanced age and comorbid diseases," both of which have been shown to predispose patients to the development of ulcers "even in the absence of [Helicobacter] pylori infection or the use of NSAIDs," they added.
The investigators emphasized that their results pertain only to clopidogrel monotherapy and cannot be generalized to the majority of patients who take clopidogrel in combination with low-dose aspirin (dual antiplatelet therapy).
This study was funded by the research fund of the Kaohsiung Veterans General Hospital. No financial conflicts of interest were reported.