In older patients taking a calcium-channel blocker (CCB), prescription of erythromycin or clarithromycin is associated with an increased risk of hypotension leading to hospital admission, according to an observational study.

Several macrolide antibiotics, most notably erythromycin and clarithromycin, are known inhibitors of the cytochrome P450 enzyme 3A4 (CYP3A4), and have been shown to alter the clearance of a number of drugs metabolised by this enzyme. All commonly-used CCB are metabolised at least in part via CYP3A4, however there is relatively little published information on the clinical consequences of this potential interaction. The effect would be to inhibit metabolism of the CCB, thus increasing its blood levels and consequently its cardiovascular effects: the authors therefore carried out a case-crossover study examining the risk of hypotension or shock requiring hospital admission following the simultaneous use of calcium-channel blockers and macrolide antibiotics. The study population was derived from healthcare and civil registration databases for Ontario, Canada: these were used to identify a cohort of patients aged 66 and over who were prescribed a CCB between April 1994 and March 2009 inclusive. They were followed up until hospital admission for an outcome of interest, death, discontinuation (for up to 60 days past the last recorded prescription), or switch to a different CCB, whichever came first. For each antibiotic, they estimated the risk of hypotension or shock associated with the use of a calcium blocker using a pair-matched analytic approach. This contrasted each patient's exposure to each macrolide antibiotic (erythromycin, clarithromycin or azithromycin) in a seven-day risk interval immediately before admission to hospital and in a seven-day control interval one month earlier.

During the study period, 999,234 patients (median age 71) were prescribed a single CCB, and of these, 7,100 were admitted to hospital with hypotension. In this group, 176 had received a macrolide antibiotic in either the risk or the control periods. Treatment with erythromycin or clarithromycin was associated with a significantly higher risk of admission for hypotension (i.e. if they received one of these drugs, it was much more likely to be during the risk period than the control period): greatest risk increase was associated with erythromycin (odds ratio [OR] 5.8 95% CI; 2.3 to 15.0), followed by clarithromycin (OR 3.7, 95% CI 2.3–6.1). For azithromycin, the risk did not increase significantly (OR 1.5, 95% CI 0.8 to 2.8).

The authors conclude that their analysis suggests a significant interaction between CCB and macrolides that inhibit CYP3A4, which in older patients increases their risk of hospitalisation for hypotension. They note that as an observational study, it has potential weaknesses, including the possibility of confounding by indication (hypotension due to infection); however there is a plausible biological mechanism, and the inclusion of azithromycin lessens the impact of confounding. Overall, they suggest that clinicians should be aware of this interaction, and use azithromycin preferentially in patients taking CCB.

[Editor's note: in the case-crossover design each case acts as their own control, minimising the number of confounding factors: it is suitable where a transient exposure is expected to cause a brief change in risk.]