Earlier this year a group of investigators from France cautioned us on co-prescription of omeprazole with clopidogrel while reporting the OCLA (Omeprazole CLopidogrel Aspirin) Study (J Am Coll Cardiol, 2008; 51:256-260). As a fallout of this report, Pezella et al (J. Am. Coll. Cardiol. 2008;52;1038-1039) found a relative risk for acute myocardial infarction of 337% in those using proton pump inhibitors along with clopidogrel in a retrospective pharmacy based analysis. While further confirmation of the clinical impact of these results are awaited from well designed prospective clinical trials, a new interaction between calcium channel blockers and clopidogrel has come into limelight through an article in the Journal of American College of Cardiology (J Am Coll Cardiol, 2008; 52:1557-1563) with an accompanying editorial note (J Am Coll Cardiol, 2008; 52:1564-1566).
Cytochrome CYP3A4 involved in the activation of clopidogrel also metabolises dihydropyridine class of calcium channel blockers. Hence it was hypothesised that co-administration of calcium channel blockers and clopidogrel is likely to reduce the efficacy of clopidogrel. The Austrian group of investigators found that the platelet reactivity index was higher in patients receiving clopidogrel with calcium channel blockers than in those receiving clopidogrel alone. The evaluation was conducted in a set of 200 patients undergoing percutaneous coronary intervention. This was also associated with an adverse clinical outcome. Similar change in platelet reactivity index was not found after incubation of platelets from patients taking clopidogrel with calcium channel blockers in vitro, indicating that the interaction occurs only in vivo possibly mediated by CYP3A4.
These two interactions have to be tested for their clinical relevance by future studies as these drugs are combined very often in clinical practice. Any interaction which reduces the efficacy of clopidogrel has to be considered with great caution as dual antiplatelet therapy is the sheet anchor in preventing stent thrombosis following percutaneous coronary interventions. This is especially relevant in case of drug eluting stents which have been shown to undergo late stent thrombosis, even though in few cases.
Now United States Food and Drug Administration (FDA) has issued a safety alert on the interactions of other drugs which interfere with how the body metabolizes clopidogrel. The manufacturers have agreed to work with FDA to complete studies on the genetic aspects of effectiveness of clopidogrel as well as interactions with other drugs in a timeline. Till such data is available, FDA has suggested that health care providers should re-evaluate the need for starting or continuing treatment with proton pump inhibitors in patients taking clopidogrel. FDA also asks patients taking clopidogrel to consult with their healthcare provider if they are currently taking or considering taking a proton pump inhibitor, including the OTC form.