Concurrent Macrolide Antibiotic May Increase Statin Toxicity

Laurie Barclay, MD

June 17, 2013

Coprescription of clarithromycin or erythromycin with a statin that is metabolized by cytochrome P450 isoenzyme 3A4 (CYP3A4) increases the risk for statin toxicity in older adults, according to a population-based cohort study.

Amit M. Patel, MD, from the London Kidney Clinical Research Unit, London Health Sciences Centre, Ontario, Canada, and colleagues published their results in an article online June 17 in the Annals of Internal Medicine.

"The absolute risk increase was quite small, but providers should be careful of prescribing mycins when someone is also on a statin," Paul D. Thompson, MD, chief of cardiology at Hartford Hospital in Connecticut, told Medscape Medical News. Dr. Thompson was not involved in the study.

Statins are prescribed to millions of people each for treatment of dyslipidemia and cardiovascular disease prevention. Despite the good safety profile overall, the US Food and Drug Administration has warned of potential interactions between commonly prescribed statins and antiviral agents used to treat HIV infection and hepatitis.

Unlike azithromycin, clarithromycin and erythromycin inhibit CYP3A4, and that inhibition increases blood concentrations of statins that are metabolized by CYP3A4.

"Statins are the number one class of drugs prescribed in North America," coauthor Amit X. Garg, MD, PhD, also from the London Health Sciences Centre, said in a news release. "Co-prescription of a statin with a macrolide antibiotic is very common. Until now, the clinical and population-based consequences of this potential drug-drug interaction were unknown."

In Ontario from 2003 to 2010, the investigators examined the frequency of statin toxicity in continuous statin users older than 65 years after coprescription with clarithromycin (n = 72,591) or erythromycin (n = 3267) compared with azithromycin (n = 68,478). Hospitalization with rhabdomyolysis within 30 days of the antibiotic prescription was the main study endpoint.

The most commonly prescribed statin was atorvastatin (73%), followed by simvastatin and lovastatin. Compared with azithromycin, coprescription of a statin with clarithromycin or erythromycin was associated with a higher risk for hospitalization with rhabdomyolysis. Absolute risk increase was 0.02% (95% confidence interval [CI], 0.01% - 0.03%), with a relative risk (RR) of 2.17 (95% CI, 1.04 - 4.53). Risks were also increased for acute kidney injury (absolute risk increase, 1.26% [95% CI, 0.58% - 1.95%]; RR, 1.78 [95% CI, 1.49 - 2.14]) and for all-cause mortality (absolute risk increase, 0.25% [95% CI, 0.17% - 0.33%]; RR, 1.56 [95% CI, 1.36 - 1.80]).

Study Limitations and Implications

"The main strength is the size of the study," Dr. Thompson said. "The main limitation is that the comparison group is azithromycin, meaning that the investigators assume that the increased risk is due to CYP metabolism. There should have been a nondrug comparison group."

"Although patients with end-stage renal failure were excluded, information on the incidence of people with diabetes within the study population would have been useful, given that this population is also at greater risk of statin-induced rhabdomyolysis," Tara A. Collidge, MBChB, PhD, National Health Service Nephrologist, Renal Unit, Glasgow Royal Infirmary, United Kingdom, told Medscape Medical News after reviewing the study.

Other limitations acknowledged by the authors are the study's observational design, potential lack of generalizability beyond older adults, inability to meaningfully examine individual interactions with each CYP3A4-metabolized statin, and possible underestimation of the absolute risk increase for rhabdomyolysis because the codes used to identify it were insensitive.

"While hundreds of hospitalizations in Ontario alone are associated with this drug–drug interaction, it's preventable," said Dr. Patel in the news release. "The results provide important safety information regarding these commonly prescribed medications.... When prescribing clarithromycin or erythromycin to patients on these statins, preventative measures should be considered, such as cessation of the statin for the duration of the antibiotic therapy, increased monitoring for adverse events, or use of a different antibiotic that does not interact with these statins."

The study authors suggest use of computer software and free online drug interaction programs to increase the overall safety of polypharmacy in older adults, as well as early prevention through multidisciplinary collaboration.

"The best way to prove these things is repeat association studies, so more of the same will either prove or help disprove the present findings," Dr. Thompson added.

"While nobody would dispute the large health gains from statins, the fact that they are so commonly used within the population requires prescribers to be especially cautious when introducing new medication," Dr. Collidge concluded. "It is over a decade since the first Medicines Control Agency pharmacovigilance warning and joint [American College of Cardiology/American Heart Association/National Heart, Lung and Blood Institute] clinical advisory statement on statin use. So, while it is reassuring to see from this study that the incidence of coprescribing appears to be falling over time, it is still disappointing to see this practice is still occurring."

The Academic Medical Organization of Southwestern Ontario funded this study. Full conflict of interest information is available on the journal's Web site. Dr. Collidge has disclosed no relevant financial relationships. Dr. Thompson has reported receiving grant and research support from the National Institutes of Health, GlaxoSmithKline, Genomas, Roche, Sanofi, Regeneron, Esperion, and Amarin. He has also been a consultant for Amgen, Astra Zeneca, Regeneron, Merck, Genomas, Runners World, Sanofi, GlaxoSmithKline, Esperion, and Amarin. He has received speaking honoraria from Merck, Pfizer, Abbott, Astra Zeneca, Kowa, and Amarin and holds shares of stock in Abbvie, Abbott, General Electric, JA Wiley Publishing, and J&J Sarepta. He has performed malpractice and legal consultations on exercise complications and statin myopathy.

Ann Intern Med. Published online June 17, 2013.

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