The Effects of Proton Pump Inhibition on Patient-reported Severity of Dyspepsia When Receiving Dual Anti-platelet Therapy With Clopidogrel and Low-dose Aspirin

Analysis From the Clopidogrel and the Optimization of Gastrointestinal Events Trial

M. Vardi; B. L. Cryer; M. Cohen; A. Lanas; T. J. Schnitzer; P. Lapuerta; M. A. Goldsmith; L. Laine; G. Doros; Y. Liu; A. I. McIntosh; C. P. Cannon; D. L. Bhatt


Aliment Pharmacol Ther. 2015;42(3):365-374. 

In This Article

Abstract and Introduction


Background Dual anti-platelet therapy with clopidogrel and low-dose aspirin increases the risk for gastrointestinal clinical events. Omeprazole has been shown to significantly reduce these events without compromising cardiovascular safety in patients treated with dual anti-platelet therapy. Whether or not omeprazole improves patient-reported outcomes is undetermined.

Aim To assess the impact of prophylactic omeprazole with background dual anti-platelet therapy on patient-reported symptoms of dyspepsia compared to placebo.

Methods We analysed results of the Severity of Dyspepsia Assessment questionnaires collected in the Clopidogrel and the Optimization of Gastrointestinal Events Trial.

Results Patient-reported outcome data from 3759 subjects were available for analysis. At 4 weeks, the mean scores of pain intensity and nonpain symptoms were lower in the omeprazole group (5.61 ± 0.17 vs. 6.40 ± 0.17, P = 0.001, and 10.61 ± 0.07 vs. 11.00 ± 0.07, P < 0.001 respectively). These differences were maintained at 24 weeks (5.91 ± 0.35 vs. 7.10 ± 0.37, P = 0.020 for pain intensity; 10.36 ± 0.12 vs. 10.93 ± 0.13, P = 0.001 for nonpain symptoms). After adjusting for covariates there were no statistically significant differences between the groups in the percent of patients with dyspepsia during follow-up.

Conclusions In addition to reducing the risk of gastrointestinal bleeding, statistically significant benefits with prophylactic omeprazole use on both pain and nonpain symptoms were evident at 4 weeks and sustained through 24 weeks. The clinical significance of these overall results is unclear, but greater in patients with pain at baseline.


Dyspepsia is a common condition, affecting approximately 25% of the population,[1,2] and causing significant impairment of quality of life.[3,4] Dyspepsia can represent conditions such as peptic ulcer, gastroesopagheal reflux disease (GERD) or stomach tumours, but the most common aetiology is functional dyspepsia in which no evidence of structural disease is present.[4–6] The Severity of Dyspepsia Assessment (SODA) questionnaire is a patient-reported outcome tool which assesses dyspepsia symptoms. The tool has been reported to have good internal consistency, including in patients taking nonsteroidal anti-inflammatory drugs (NSAIDs).[7,8]

Low-dose aspirin may cause dyspepsia, ulcers and gastrointestinal (GI) complications such as bleeding.[9]An estimated 50 million Americans are taking low-dose aspirin (≤325 mg) daily. Pooled data estimate the absolute increase in risk per year of symptomatic or complicated ulcers with aspirin to be 0.12% when compared with placebo (number needed to harm 833), and the use of enteric-coated or buffered formulations does not appear to reduce this risk.[10,11] The use of dual anti-platelet therapy (DAPT) with clopidogrel and low-dose aspirin further increases the risk for serious clinical gastrointestinal events, and use of more potent anti-platelet agents results in even greater bleeding risk.[12,13] Aspirin therapy may lead to dyspepsia in 20–40% of chronic users,[14,15] and dyspepsia is associated with reduced compliance,[16,17] increased healthcare costs[18] and reduced health-related quality of life.[19] The magnitude of dyspepsia and the effect of proton pump inhibitors in reducing it have not been thoroughly evaluated to date.

Despite its early termination, the Clopidogrel and the Optimization of Gastrointestinal Events Trial (COGENT, NCT00557921) is the only large scale randomised controlled study in which omeprazole was compared with placebo in-patients receiving DAPT. No significant difference in CV events was shown between the study groups [Hazard ratio (HR): 0.99; 95% confidence interval (CI): 0.68–1.44], while a significant reduction in GI events occurred (HR: 0.34; 95% CI: 0.18–0.63).[20] The purpose of the current analysis of the COGENT data is to evaluate further the impact of omeprazole on dyspepsia in patients treated with DAPT, as assessed by the SODA questionnaire. We also evaluated predictors of dyspepsia and for GI events in this population.