Potential Interaction Between Heart Failure Drugs Appears Clinically Irrelevant

Patients with heart failure (HF) often receive clopidogrel and angiotensin-converting enzyme (ACE) inhibitors concurrently. Because clopidogrel inhibits the enzyme carboxylesterase 1 (CES1), and CES1 converts prodrug ACE inhibitors such as ramipril and perindopril to their active metabolites, these drugs have the potential to interact.

What is the clinical implication of this potential drug interaction that was identified in vitro? A team of researchers recently structured a study to find out.

They hypothesized that if clopidogrel inhibits CES1 in a clinically meaningful way, it would impair the bioactivation of prodrug ACE inhibitors, thus reducing their clinical benefit.

In this nested case-control study, the researchers enrolled patients aged 66 years or older who had experienced acute myocardial infarction (MI) and were treated with clopidogrel over a 10-year period. By restricting enrollment to older patients who had taken clopidogrel and an ACE inhibitor for quite some time, the investigators ensured their study population was relatively homogenous.

All participants had died from an acute MI or were hospitalized for reinfarction or HF in the subsequent year. Each patient was matched with up to 4 control subjects.

The researchers compared patients who received the prodrug ACE inhibitors ramipril or perindopril to those who received lisinopril, an active ACE inhibitor. By including only 3 ACE inhibitors, the authors minimized selection bias. They identified 45,918 post-MI patients treated with clopidogrel and 4203 active ramipril- or perindopril-treated cases, in addition to 14,964 controls.

Participants treated with ramipril or perindopril were no more likely to experience reinfarction, HF, or death than those treated with lisinopril. The researchers suggested that in vivo, drug levels and protein binding change these medications’ in vitro profile.

They concluded concurrent clopidogrel use with ACE inhibitors activated by CES1 does not increase the risk of adverse cardiovascular outcomes compared with lisinopril, suggesting recent reports about the potential for the combination to interact are not clinically relevant.

This study appeared in the May 2015 issue of the British Journal of Pharmacology.