Azithromycin and risk of sudden cardiac death: Guilty as charged or falsely accused?
THE FDA REVISES AZITHROMYCIN’S WARNINGS AND PRECAUTIONS
The striking observations by Ray et al,10 coupled with the concerns raised by postmarketing surveillance reports, compelled the FDA to review the labels of azithromycin and other macrolide antibiotics.
Ultimately, the FDA opted to revise the “warning and precautions” section of the azithromycin drug label to include a warning about the potential risk of fatal arrhythmias, specifically QT interval prolongation and torsades de pointes. In a March 2013 safety announcement, it also urged health care professionals to use caution when prescribing azithromycin to patients known to have risk factors for drug-related arrhythmias, including congenital long QT syndrome, acquired QT interval prolongation, hypokalemia, hypomagnesia, bradycardia, and concurrent use of other medications known to prolong the QT interval, specifically the class IA (eg, quinidine and procainamide) and class III (eg, amiodarone, sotalol, and dofetilide) antiarrhythmics.
SVANSTRÖM ET AL FIND NO INCREASED RISK
However, just when the medical community appeared ready to accept that azithromycin may not be as safe as we thought it was, a large prospective study by Svanström et al, published in early May 2013, found no increased risk of cardiovascular death associated with azithromycin (Table 2).14
The patients were a representative population of young to middle-aged Danish adults at low baseline risk of underlying cardiovascular disease.
Interestingly, Svanström et al were careful to point out that their study was only powered to rule out a moderate-to-high (> 55%) increase in the relative risk of cardiovascular death. Furthermore, profound differences existed in the baseline risk of death and cardiovascular risk factors between their patients and the Tennessee Medicaid patients studied by Ray et al.14 Therefore, the authors suggested that their study complements rather than contradicts the study by Ray et al. They attributed the differences in the findings to treatment-effect heterogeneity, in which the risk of azithromycin-associated cardiovascular mortality is largely limited to high-risk patients, namely those with multiple preexisting cardiovascular risk factors.14
ACC/AHA RECOMMENDATION: IDENTIFY THOSE AT RISK
Collectively, the data reviewed above provide compelling evidence that azithromycin is not completely free of the QT-prolonging and torsadogenic effects that have long been associated with other macrolide antibiotics. However, the findings from both the study by Ray et al and that of Svanström et al suggest that preexisting cardiovascular risk factors play a prominent role in determining the incidence of azithromycin-associated cardiovascular death in a given population (Table 2).10,14
These findings should prompt physicians to carefully reassess the risks and benefits of azithromycin use in their clinical practices. They also reinforce a recent call by the American Heart Association (AHA) and American College of Cardiology (ACC) to better identify, early on, patients at risk of drug-induced ventricular arrhythmias and sudden death and to subsequently improve how these patients are monitored when the use of QT-prolonging and torsadogenic drugs is medically necessary.15
AN ELECTRONIC MEDICAL RECORD FLAGS QTc ≥ 500 MS
On the heels of these AHA/ACC suggestions, our hospital has adopted an institution-wide QT alert system. Here, the electronic medical record system (Centricity EMR; GE Healthcare) uses a proprietary algorithm to detect and electronically alert ordering physicians when a patient has a prolonged QT interval, and gives information about the potential clinical significance of this electrocardiographic finding.16 Physicians also receive a warning when ordering QT-prolonging drugs in patients at risk.
This system is still in its infancy, but it has already confirmed that a prolonged QT interval (QTc ≥ 500 ms) is a powerful predictor of death from any cause and has demonstrated that mortality rates in those with prolonged QT intervals increase in a dose-dependent fashion with the patient’s number of modifiable risk factors (eg, electrolyte disturbances or QT-prolonging medications) and nonmodifiable risk factors (eg, genetic disposition, female sex, structural heart disease, diabetes mellitus).16 We have also found evidence that modifiable risk factors may have a more pronounced effect on mortality risk than non-modifiable risk factors.16
These findings suggest that information technology-based QT alert systems may one day provide physicians with an important tool to efficiently identify and possibly even modify the risk of cardiovascular death in patients at high risk, for example, by correcting electrolyte abnormalities or reducing the burden of QT-prolonging medications.
CONSIDER RISK OF QT PROLONGATION WHEN PRESCRIBING AZITHROMYCIN
For most institutions and clinical practices, such electronic QT alert systems are still years if not decades away. However, in light of the information summarized above, all physicians should begin considering risk factors for QT prolongation and torsades de pointes (summarized in Table 3) and weighing the risks and benefits of prescribing azithromycin vs alternative antibiotics with minimal QT liability. This should be relatively simple to do. Things to keep in mind:
- Although azithromycin may increase the relative risk of a cardiovascular event, for most otherwise-healthy patients, the absolute risk is miniscule.
- In a patient at risk (eg, with baseline QT prolongation or multiple risk factors for it), if azithromycin or another QT-prolonging antibiotic such as a macrolide or fluoroquinolone is medically necessary due to preferential bacterial susceptibility or patient allergies, every effort should be made to correct modifiable risk factors (eg, electrolyte abnormalities) and, if possible, to avoid polypharmacy with multiple QT-prolonging drugs.
- For patients who have multiple risk factors for QT prolongation in whom treatment with a known QT-prolonging medication is still deemed in the patient’s best interest, strong consideration should be given to inpatient administration and monitoring until the treatment has been completed.
With careful consideration of modifiable and nonmodifiable risk factors as well as a little extra caution when prescribing potential QT-prolonging medications such as azithromycin, the clinical benefit of these often-advantageous medications can be maximized and the incidence of these tragic but rare drug-induced sudden cardiac deaths can be reduced.
