A population‐based study of the drug interaction between clopidogrel and angiotensin converting enzyme inhibitors

Abstract

AimsClopidogrel and angiotensin converting enzyme (ACE) inhibitors are commonly co‐prescribed drugs. Clopidogrel inhibits carboxylesterase 1 (CES1), the enzyme responsible for converting prodrug ACE inhibitors (such as ramipril and perindopril) to their active metabolites. The clinical implications of this potential drug interaction are unknown. The clinical consequences of the potential drug interaction between clopidogrel and prodrug ACE inhibitors were examined.MethodsWe conducted a nested case–control study of Ontarians aged 66 years and older treated with clopidogrel between September 1 2003 and March 31 2013 following acute myocardial infarction. Cases were subjects who died or were hospitalized for reinfarction or heart failure in the subsequent year, and each was matched with up to four controls. The primary outcome was a composite of reinfarction, heart failure or death. The primary analysis examined whether use of the prodrug ACE inhibitors ramipril or perindopril was more common among cases than use of lisinopril, an active ACE inhibitor.ResultsAmong 45 918 patients treated with clopidogrel following myocardial infarction, we identified 4203 cases and 14 964 controls. After adjustment, we found no association between the composite outcome and use of perindopril (adjusted odds ratio (aOR) 0.94, 95% confidence interval (CI) 0.76, 1.16) or ramipril (aOR 0.97, 95% CI 0.80, 1.18), relative to lisinopril. Secondary analyses of each element of the composite outcome yielded similar findings.ConclusionsFollowing myocardial infarction, use of clopidogrel with ACE inhibitors activated by CES1 is not associated with an increased risk of adverse cardiovascular outcomes relative to lisinopril. These findings suggest that the recently described drug interaction between clopidogrel and prodrug ACE inhibitors is of little clinical relevance.

Polymorphism of CYP2C19 and ABCB1 genes associated with changes in the activity of clopidogrel in patients with ischemic stroke: clinical and ethnic aspects

“…Однако в 10-летнем ретроспективном исследовании (2003-2013 гг. ), в котором изучалось влияние ингибиторов АПФ на эффективность клопидогрела после инфаркта миокарда почти у 46 000 пациентов, не были подтверждены клиническое значение данного лекарственного взаимодействия и влияние ингибиторов АПФ на функцию тромбоцитов [29]. Другие авторы указывают на повышенный риск геморрагических осложнений при совместном применении клопидогрела и ингибиторов АПФ, так как большая часть клопидогрела, как и большинства ингибиторов АПФ, гидролизуется до неактивного метаболита печеночной карбоксилэстеразой 1 (CES1).…”

Pharmacodynamic Impact of Carboxylesterase 1 Gene Variants in Patients with Congestive Heart Failure Treated with Angiotensin-Converting Enzyme Inhibitors

“…However, these results have subsequently been challenged and the sum of current evidence would appear to indicate that although CES1 variation may account for some variability of CES1 enzymatic activity between individuals, the frequency and the effect size of the variants of CES1 are likely to be small. Hence, these variants may have limited clinical relevance [ 56 ].…”

Carboxylesterases: Pharmacological Inhibition Regulated Expression and Transcriptional Involvement of Nuclear Receptors and other Transcription Factors

“…An increased number of compounds have been shown to inhibit carboxylesterase activity including but are not limited to insecticides, natural products and therapeutic agents [23][24][25][32][33][34][35]. The inhibition is implicated in alteration of the efficacy, safety and bioavailability of drugs metabolized by these enzymes.…”