Proton pump inhibitors and clopidogrel: an association to avoid?

Dual antiplatelet therapy with aspirin and clopidogrel reduces cardiovascular events following an acute coronary syndrome or stent implantation, but the associated increased risk of gastro-intestinal bleeding often leads to the co-administration of proton pump inhibitors (PPIs). PPIs have been shown to decrease antiplatelet effects of clopidogrel ex vivo, raising concerns about the cardiovascular safety of this drug combination. Clinical trials investigating PPI-clopidogrel interactions have provided conflicting results and are all subject to methodological critiques. The much desired and much needed prospective, double-bind, randomized, placebo-controlled trials with adequate follow-up and sample size have not yet been performed. Indeed, the Clopidogrel and the Optimization of GI Events Trial, which would have had such characteristics, was stopped prematurely. As a consequence, the question of the PPI-clopidogrel interaction is still unresolved, and clinical consequences cannot be excluded. At this time such combination therapy should, therefore, be provisionally advocated only for patients at high risk of bleeding (prior upper gastro-intestinal bleeding, advanced age, concomitant use of warfarin, steroidal or non-steroidal anti-inflammatory drugs and Helicobacter pylori infection) and avoiding PPIs with strong affinity for cytochrome CYP2C19, such as omeprazole and esomeprazole.