Is a Potential Drug–Drug Interaction with Clopidogrel of Concern?

Dual antiplatelet therapy (DAPT) has become a mainstay in the secondary prevention of cardiovascular (CV) events in patients with a recent history of myocardial infarction (MI) or recent percutaneous coronary intervention (PCI) with stent placement. While 3 antiplatelet agents—clopidogrel, prasugrel, and ticagrelor—are currently approved to be used in combination with aspirin, clopidogrel is the most commonly used of these agents as it has a long history of clinical utilization. Furthermore, clopidogrel is generically available, while prasugrel and ticagrelor are both branded and more expensive. 

When used together for up to 1 year following these events, the relative benefits of DAPT outweigh the potential risks in many patients. However, special attention should be given to the risks for bleeding with DAPT, especially GI bleeding and intracranial hemorrhage. In an effort to mitigate the GI bleeding risk, proton pump inhibitors (PPIs) are often utilized. However, a potential drug-drug interaction with clopidogrel is a concern that leads to uncertainty in the minds of prescribers. Does this potential interaction warrant special attention?
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A Case Study

WG is a 67-year-old male with a past medical history of hypertension and dyslipidemia, who recently suffered an MI 1 week prior. He underwent PCI and had a drug-eluting stent placed in the left circumflex artery. At discharge, the patient was prescribed atorvastatin 80 mg, clopidogrel 75 mg daily, nitroglycerin 0.4 mg sublingual as needed, and omeprazole 40 mg daily to be added to his background regimen of aspirin 81 mg daily, amlodipine 5 mg daily, and lisinopril 20 mg daily. He was given 7 days worth of medication and instructed to follow-up with his primary care practitioner within 1 week.

Follow-up. WG was seen in the clinic 5 days after discharge for a hospital follow-up visit. His blood pressure was controlled and he was not experiencing any chest pain or adverse effects from the new medications. His prescriptions were refilled and he was scheduled to return in 2 weeks. 

The next day you receive a phone call from WG’s pharmacy indicating a potential drug–drug interaction between clopidogrel and omeprazole; the pharmacist is requesting a change to an alternative PPI, such as pantoprazole. The pharmacist states that the use of omeprazole with clopidogrel will reduce the effectiveness of clopidogrel and put the patient at risk of another CV event. Does the available evidence suggest this change is warranted?

The Evidence

Clopidogrel is a prodrug that requires activation to exert its pharmacologic effects. The main pathway for activation is through the cytochrome P450 (CYP) pathway, mainly through CYP 2C19. In vitro all PPIs have been shown to inhibit CYP 2C19 to variable degrees, but omeprazole is considered to have the strongest inhibitory effects. While the PPIs may help protect against GI bleeding, there is a theoretical concern that inhibition of CYP 2C19 will decrease the activation of clopidogrel—leading to lower drug levels and increasing the risk for adverse CV events. Pharmacokinetic studies have shown this interaction leads to reduced antiplatelet activity in vitro. Due to this potential interaction, the FDA recommended against coadministration of clopidogrel with omeprazole or esomeprazole. It is noteworthy that this recommendation has not been updated by the FDA since 2012.

Despite the evidence suggesting an in vitro interaction, clinical data showing an increase in CV outcome events from this interaction has been lacking. Numerous observational studies have been conducted with conflicting results—some show an interaction while others reveal no interaction. Omeprazole has frequently been identified as the most significant offender, but other PPIs have been implicated as well.¹ 

Importantly, being that these studies are observational in nature, they cannot establish causality. As a result of this inherent limitation, the authors of these studies suggest a need for prospective randomized trials to make a definitive conclusion.

The Clopidogrel and the Optimization of Gastrointestinal Events Trial (COGENT) study was a randomized, double-blind, placebo-controlled study to evaluate the ability of a combination pill of omeprazole/clopidogrel to lower rates of GI adverse events versus clopidogrel alone.² Although the study was discontinued early due to lack of funding, the combination significantly lowered the rate of adverse GI events without showing an increase in the rate of CV events compared to clopidogrel alone. Furthermore, extra GI bleeding (bleeding outside the GI tract) was not different between groups. If the omeprazole were inhibiting the activation of clopidogrel to a clinically relevant degree, the rate of extra GI bleeding would be expected to go down due to lower concentrations of active drug. As this difference in bleeding was not seen, combined with no signal of increased CV events, it suggests that the in vitro interaction does not translate into an in vivo clinical effect.

A recent meta-analysis echoed this conclusion.¹ The authors note that inconsistent results from observational studies combined with more consistent results showing no interaction from prospective studies likely indicate this interaction is not clinically relevant. It is also possible that the increased CV risk from the observational studies was due to confounding (a major limitation of retrospective observational studies) that has been balanced in the prospective studies.

Additional Considerations

This interaction and pressure to switch to an alternative agent may be less of an issue currently than it was in 2010 simply due to the fact that multiple generic PPIs are now available. Previously, omeprazole was the only generic available and the cost concerns of an alternative agent often served as a driving factor in the clinical decision. However, as many generically available PPIs are now available, switching from omeprazole to an alternative agent likely does not increase costs. 

In all cases, the need for the PPI should be carefully evaluated and if it is not clearly indicated, it likely should not be prescribed. The newer antiplatelet agents prasugrel and ticagrelor are not susceptible to this potential drug–drug interaction and can be considered if there is any hesitation with clopidogrel. The choice in antiplatelet agent requires careful consideration and there could be additional benefits to the newer agents, but such a discussion is beyond the scope this article. 

 Finally, it is unlikely that product labeling is going to change to reflect the updated recommendation regarding the lack of a clinical interaction; as noted earlier, the last FDA statement on the matter was published online in 2012. While there is good clinical evidence in the medical literature, wording in the product labeling may also have to be considered from a medical–legal standpoint. 

Outcome of the Case

WG is taking clopidogrel and omeprazole, a combination that may result in a potential drug–drug interaction that may lower the effectiveness of the clopidogrel based on pharmacokinetic studies. However, this interaction does not seem to be clinically relevant and prospective randomized trials have failed to show a true interaction; conflicting and inconsistent results from observational studies also lend evidence suggesting that this interaction is not clinically relevant. 

Based on this evidence, we would suggest that WG could continue with omeprazole and the clopidogrel. Switching to an alternative PPI would also be acceptable, but doing so would not completely dissolve the theoretical drug–drug interaction; the observational evidence suggesting a problem with omeprazole has also implicated all PPIs. Finally, switching to prasugrel or ticagrelor and maintaining the omeprazole would also be an option, and given the favorable efficacy of the 2 agents compared to clopidogrel, may represent a better switch for the patient after careful assessment of his bleeding risks.

Eric A. Dietrich, PharmD, BCPS, graduated from the University of Florida College of Pharmacy in 2011 and completed a 2-year fellowship in family medicine where he was in charge of a Coumadin clinic. He now works for the University of Florida Colleges of Pharmacy and Medicine in Gainesville, FL. 

Kyle Davis, PharmD, BCPS, graduated from the University of Florida College of Pharmacy in 2011 and completed a PGY-1 at Jackson Memorial Hospital and a PGY-2 in internal medicine at Indiana University Health and Butler College of Pharmacy. He currently works at Jackson Memorial Hospital in Miami, FL. 

References:

1.Melloni C, Washam JB, Jones WS, et al. Conflicting results between randomized trials and observational studies on the impact of proton pump inhibitors on cardiovascular events when coadministered with dual antiplatelet therapy: a systematic review. Circ Cardiovasc Qual Outcomes. 2015;8(1):47-55.

2.Bhatt DL, Cryer BL, Contant CF, et al. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med. 2010;
363(20):1909-1917.