Thursday, June 20, 2013

Antibiotics and Statins: A Deadly Combo? - Laino

Antibiotics and Statins: A Deadly Combo?

Prescribing clarithromycin or erythromycin to older patients taking the most commonly prescribed statins, which are metabolized by cytochrome P450 isoenzyme 3A4 (CYP3A4), raised the risk for statin toxicity, according to a population-based retrospective cohort study.

Clarithromycin and erythromycin, but not azithromycin, inhibit cytochrome CYP3A4, and that inhibition increases blood concentrations of statins that are metabolized by CYP3A4 to potentially dangerous levels, Amit M. Patel, MD, of the London Health Sciences Center in Ontario, and colleagues reported online in the Annals of Internal Medicine.

Compared with azithromycin, co-prescription of atorvastatin, simvastatin, or lovastatin with clarithromycin or erythromycin was associated with a 0.02% increase in the absolute risk of hospitalization with rhabdomyolysis within 30 days (95% CI 0.01%-0.03%). That translates to a relative risk increase 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)
  • All-cause mortality -- absolute risk increase, 0.25% (95% CI 0.17%-0.33%); RR 1.56 (95% CI 1.36-1.80)

"Statins are the No. 1 class of drugs prescribed in North America," co-author Amit Garg, MD, PhD, also from the London Health Sciences Center, said in a statement.

Coprescription 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, he said.
While the absolute risk increase is relatively small, "given the frequency at which statins are prescribed and the high rate of coprescription seen in our study and in other jurisdictions, this preventable drug-drug interaction remains clinically important. The results suggest many deaths and hospitalizations due to acute kidney injury in Ontario may have been attributable to this interaction, the researchers wrote.

For the study, the researchers examined the frequency of statin toxicity in continuous statin users older than 65 years who were prescribed clarithromycin (n=72,591) or erythromycin (n=3,267), compared with azithromycin (n=68,478) in Ontario from 2003 to 2010.

The primary outcome was rhabdomyolysis within 30 days of the antibiotic prescription.
The most commonly prescribed statin was atorvastatin (73%), followed by simvastatin (24%) and lovastatin (3%).

American Heart Association spokesperson Robert Eckel, MD, of the University of Colorado at Denver, said that although the potential for drug-drug interactions between certain antibiotics and statins was known, this study really underscores the potential for dangerous, even fatal complications.
"And while the study was only done in elderly patients, this "provides a signal" these complications could develop in younger people as well," he told "The Gupta Guide."

There's another option too, said John Higgins, MD, of the University of Texas Health Science Center at Houston. "If you have a patient on a statin and you need a mycin antibiotic, the study suggests you choose azithromycin.

"But there is also a statin that is not metabolized by the CYP3A4 system -- pravastatin. So you really have two choices here. Switch the antibiotic or switch the statin," he said.

The study has several major strengths, including its large size, Eckel said
But there are limitations, too, Higgins said. "For example they only studied people over 65, with a median age of 74, who may have a lot of comorbidities. So these patients may be more prone to some of these problems anyway," he said.

Additionally, it is an observational study and therefore subject to all the biases of such an analyses -- that is, they show associations, but cannot prove casual relationships, he said.
Finally, "coders record the health problems and we know that coders often don't note complications in all patients," Higgins said. "So, if anything, the risks may have been higher than those found in the study," he said.

Also, the researchers themselves noted that despite the large sample size, they could "not meaningfully examine interactions with each CYP3A4-metabolized statin individually. However, given the known effect on CYP3A4 statin pharmacokinetics, it remains prudent to generalize the coprescription warning to atorvastatin, simvastatin, or lovastatin with clarithromycin or erythromycin," they wrote.

Said Patel, "The results provide important safety information regarding these commonly prescribed medications. When prescribing clarithromycin or erythromycin to patients on these statins, preventive 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 authors also suggested that clinicians take advantage of free online drug interaction programs and/or software aimed at improving the overall safety of polypharmacy in older adults.
And there's always the obvious solution: Better multidisciplinary collaboration between departments, Eckel added.

Do you double-check what statins your patients are on before prescribing an antibiotic? Add Your Knowledge below. -- Sanjay Gupta, MD.
The investigators received grant support from the Academic Medical Organization of Southwestern Ontario to conduct this research. This project was conducted at the Institute for Clinical Evaluative Sciences site at Western University. The Institute for Clinical Evaluative Sciences is funded by an annual grant from the Ontario Ministry of Health and Long-term Care. The Institute for Clinical Evaluative Sciences site at Western University is funded by an operating grant from the Academic Medical Organization of Southwestern Ontario. Dr. Garg was supported by a Canadian Institutes of Health Research Clinician Scientific Award.
Eckel and Higgins have no financial conclicts of interest to disclose.

Primary source: Annals of Internal Medicine
Source reference:
Patel AM, et al "Statin toxicity from macrolide antibiotic coprescription" Ann Intern Med 2013; DOI: 10.7326/0003-4819-158-12-201306180-00004.
Read the complete article here.

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