Drug interactions with clopidogrel

Drug interactions with clopidogrel

Drug interactions with clopidogrel: A group of investigators from France cautioned us on co-prescription of omeprazole with clopidogrel while reporting the OCLA (Omeprazole CLopidogrel Aspirin) Study [1]. As a fallout of this report, Edmund Pezalla, David Day and Indira Pulliadath [2] 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, an interaction between calcium channel blockers and clopidogrel had come into limelight through an article in the Journal of American College of Cardiology [3] with an accompanying editorial note [4].

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.

United States Food and Drug Administration (FDA) had 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.

A meta analysis evaluated the interaction between clopidogrel and proton pump inhibitors and the risk of adverse outcome among acute coronary syndrome patients treated with percutaneous coronary intervention [5]. They identified 12 studies with a total of 50,277 patients. They concluded that concomitant clopidogrel proton pump inhibitor therapy after percutaneous coronary intervention appears to be significantly associated with cardiovascular events. They suggested caution and need for further research.

References

1. Martine Gilard, Bertrand Arnaud, Jean-Christophe Cornily, Grégoire Le Gal, Karine Lacut, Geneviève Le Calvez, Jacques Mansourati, Dominique Mottier, Jean-François Abgrall, Jacques Boschat. Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomized, double-blind OCLA (Omeprazole CLopidogrel Aspirin) study. J Am Coll Cardiol. 2008 Jan 22;51(3):256-60.
2. Edmund Pezalla, David Day, Indira Pulliadath. Initial assessment of clinical impact of a drug interaction between clopidogrel and proton pump inhibitors. J Am Coll Cardiol. 2008 Sep 16;52(12):1038-9; author reply 1039.
3. Jolanta M Siller-Matula, Irene Lang, Guenter Christ, Bernd Jilma. Calcium-channel blockers reduce the antiplatelet effect of clopidogrel. J Am Coll Cardiol. 2008 Nov 4;52(19):1557-63.
4. Neal S Kleiman. Clopidogrel and calcium-channel antagonists: another drug-drug interaction for the ever-wary clinician? J Am Coll Cardiol. 2008 Nov 4;52(19):1564-6.
5. Michael A Serbin, Gregory F Guzauskas, David L Veenstra. Clopidogrel-Proton Pump Inhibitor Drug-Drug Interaction and Risk of Adverse Clinical Outcomes Among PCI-Treated ACS Patients: A Meta-analysis. J Manag Care Spec Pharm. 2016 Aug;22(8):939-47.