Azithromycin in patients with cardiovascular disease

In a study published in the New England Journal of Medicine earlier this week, investigators observed an increased risk of sudden cardiac death associated with the macrolide antibiotic azithromycin (Zithromax^®) [1]. Azithromycin is considered a first-line option in the management of several types of upper respiratory tract infections and is one of the most widely-prescribed antibiotics in the US.  The results of the trial by Ray, et al prompted the US Food & Drug Administration (FDA) to issue a safety alert addressing the use of azithromycin in patients with cardiovascular disease and further investigation is currently underway.

Using electronic medical records and prescription-use data from patients enrolled in the Tennessee Medicaid program, investigators found a small but statistically significant increase in the risk of cardiovascular death (hazard ratio 2.88, 95% CI 1.79 - 4.63, p < 0.001) when azithromycin (5-day course) was compared to no antibiotic therapy, a result that was significant both in terms of sudden cardiac death as well as other types of cardiovascular death.  When compared to amoxicillin, the risk of cardiovascular death associated with azithromycin was similarly increased (hazard ratio 2.49; 95% CI 1.38 to 4.50; p = 0.002).

While there are some limitations with the use of any retrospective analysis, the findings do call into question the widely-held notion -- one that I believed until now -- that azithromycin is less cardiotoxic than other macrolides (clarithyomcin, erythromycin), where the risks of sudden cardiac death are fairly well-established.  Given the known association of these agents with QT prolongation and the types of deaths observed (i.e., sudden cardiac death), the most likely etiology is a disturbance in cardiac conduction that results in a fatal ventricular arrhythmia. Similar risks have been attributed to the respiratory fluoroquinolones levofloxacin and moxifloxacin, which further limits the antibiotic choices available in this patient population.

So, in light of this new evidence, how does one manage the risk of cardiovascular death associated with azithromycin?  It would be unreasonable to avoid azithromycin in all patients with cardiovascular disease; however, the results of the present study (not to mention the litigious nature of the current health care environment) should at least warrant a more careful consideration of the risks and benefits of azithromycin use.

Who is likely at risk?
The increased risk of sudden cardiac death observed in the present study likely does not apply to every patient with cardiovascular disease, especially those with milder forms (e.g., hypertension) or those who only have risk factors (e.g., dyslipidemia) for more advanced forms of cardiovascular disease.  Those at greatest risk likely include:

• Patients with a recent myocardial infarction, especially those with new-onset heart failure and those not receiving beta blockers (which  reduce the risk of ventricular arrhythmias and sudden cardiac death in this population)
• Patients with advanced heart failure, especially those who have not yet received an automatic implantable cardioverter-defibrillator (AICD)
• Patients with severe electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia), which are often associated with the use of chronic high-dose diuretic therapy
• Patients taking anti-arrhythmic medications with known risk of QT prolongation and torsade de pointes (e.g., dofetilide, flecainide); for a list of drugs associated with QT prolongation (by risk category), please see this resource developed by the Arizona Center for Education on Research and Therapeutics

Alternative strategies in high-risk patients
If the risk of sudden cardiac death is thought to outweigh the benefit of azithromycin therapy in an individual patient, alternative antibiotics should be considered.  By far, the most common indication for azithromycin is in the management of community-acquired pneumonia (CAP), where it is recommended as monotherapy in patients with no risk factors for drug-resistant Streptococcus pneumoniae, or in combination with a beta lactam in patients with comorbidities and/or risk factors for drug-resistant pathogens (e.g., chronic disease, immunosuppression, recent antibiotic use, etc) [2].  Some alternatives to consider include:

• In the lowest risk population (i.e., minimal  structural heart disease and no additional co-morbidities) for whom azithromycin monotherapy would have been considered, doxycycline alone is a reasonable alternative
• For moderate risk patients, a combination beta lactam / beta lactamase inhibitor (e.g., amoxicillin/clavulanic acid) or second to third generation cephalosporin (cefuroxime, cefpodoxime) is likely adequate; for higher risk patients (i.e., in whom the addition of a macrolide would have been considered), addition of doxycycline is a reasonable alternative
• Azithromycin is often added as adjunct therapy in patients who are at risk for atypical pathogens (e.g., Chlamydia pneumoniae, Mycoplasma pneumoniae, Legionella species), which include those with chronic pulmonary disease, long-term immunosuppression, residence in long-term care facilities, etc; in these patients, the addition of doxycycline is a reasonable alternative
• Alternatives are more limited in patients with penicillin allergies; if the allergy to penicillin is reported as "rash", "upset stomach" or similar mild reactions (i.e., not true Type I hypersensitivity reactions), use of a second or third generation cephalosporin (+/- doxycycline) is reasonable, as the reported cross-reactivity with penicillins is around 5-10% or less.  For true beta lactam allergies, options are further limited, as the respiratory fluoroquinolones (usually the first-line alternative in patients with penicillin allergies) have cardiotoxicities that are comparable to the macrolides; in these patients, monotherapy with doxycycline may be effective, but more thoughtful consideration as to risks and benefits of azithromycin or fluoroquinolone therapy is probably warranted, including whether additional monitoring (e.g., ambulatory ECG) should be performed
• When used as part of the management of CAP, some advocate the use of loading/higher doses of doxycycline (e.g., 200 mg twice daily for at least the first day) in order to achieve adequate serum concentrations early in the treatment course [3]; given the low toxicity profile of short doxycycline courses, this strategy is probably reasonable

While the increased risk of sudden cardiac death observed with azithromycin significantly limits the choice of antibiotics used for the management of CAP in the ambulatory care setting, reasonable alternatives exist for the vast majority of cases.  Also on the bright side, these findings should lead to a more careful evaluation of the risks and benefits of azithromycin therapy in this high-risk patient population, which many would argue is a step in the right direction anyway.

Acknowledgment: Thanks goes to Emily Heil, PharmD, BCPS, a clinical pharmacy specialist in infectious diseases at the University of Maryland Medical Center, who reviewed and made suggestions to the above recommendations.

References

1. Ray WA, Murray KT, Stein CM, et al. Azithromycin and the risk of cardiovascular death. N Engl J Med. 2012 May 17;366(20):1881-90.
2. Mandell LA, Wunderink RG, Whitney CG, et al; Infectious Diseases Society of America; American Thoracic Society. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007 Mar 1;44 Suppl 2:S27-72.
3. Clin Infect Dis. 2003 Sep 15;37(6):870. Doxycycline for community-acquired pneumonia. Cunha BA.