Azithromycin associated with cardiovascular death

Azithromycin, a macrolide antibiotic, had previously been thought to be relatively free of cardiotoxic effects. In a new review of azithromycin, however, the authors cited at least 20 reports submitted to the FDA relative to azithromycin-associated prolongation of QT syndrome, torsades de pointes and ventricular tachycardia. Two other drugs in this class, erythromycin and clarithromycin, have been shown to increase the risk of life threatening arrhythmias. The azithromycin study hypothesized that patients who took azithromycin, as compared with persons who did not take antibiotics and with patients who took other selected antibiotics, would have an increased risk of cardiovascular death.

Methods of the azithromycin study

The authors analyzed data on millions of prescriptions for several antibiotics given to Tennessee Medicaid patients over a 14 year period. The study was designed to detect an increased risk of death related to short-term cardiac effects of medication, excluding patients with serious noncardiovascular illness, during and shortly after hospitalization. The cohort included patients who were prescribed azithromycin between 1992 and 2006, persons in a matched control period who took no antibiotics, and patients who took amoxicillin, ciprofloxacin, or levofloxacin.

The primary endpoints were cardiovascular death and death from any cause. The authors hypothesized that the incidence of cardiovascular death should be increased if azithromycin was proarrhythmic. They included the analysis of death from any cause to guard against differential misclassification of deaths related to use of an antibiotic.

A cardiovascular risk score was used as a measure of the risk of cardiovascular death. This risk was calculated by estimating the possibility of cardiovascular death as a function of the indicators of coexisting conditions such as diabetes, heart failure, and chronic obstructive pulmonary disease. Scores ranging from 0, indicating the lowest risk, to 19, indicating the highest risk, were established.

Results of the azithromycin study

1. The study cohort included persons with 347,795 prescriptions for azithromycin, 1,391,180 matched control periods with no study antibiotic treatment, 1,348,672 prescriptions for amoxicillin, 264,626 prescriptions for ciprofloxacin, and 193,906 prescriptions for levofloxacin.
2. There were 29 heart related deaths among those who took azithromycin during 5 days of treatment. Their risk of death while taking the drug was almost triple compared to those patients taking no antibiotic. Their risk of death while taking azithromycin was more than double that of those patients taking amoxicillin. Patients who took amoxicillin had no increase in the risk of death. For azithromycin, the highest risks of cardiovascular deaths were in those patients taking azithromycin and who had existing heart problems.
3. Calculated in another way, if a course of treatment for azithromycin was defined as one 5-day period of therapy, then there were 85 cardiovascular deaths per one million courses of treatment among azithromycin users. During the first 5 days of a course of amoxicillin therapy, there were 32 cardiovascular deaths per one million 5 day courses. During matched 5 day intervals among persons who did not take antibiotics, there were 30 cardiovascular deaths per one million periods.
4. For a 10 day period after the prescription was filled, azithromycin use was associated with about a doubling of the risk of cardiovascular death.
5. The risk of cardiovascular death was significantly greater with azithromycin than with ciprofloxacin but did not differ significantly from that with levofloxacin.
6. Azithromycin users were primarily women (77.5%), with a mean age of 49 years.
7. Azithromycin and amoxicillin were generally prescribed to treat infections of the ear, nose, or throat, or bronchitis. Ciprofloxacin was generally prescribed to treat genitourinary tract infections. Levofloxacin was prescribed to treat general respiratory or genitourinary tract infections.
8. The absolute excess risk of cardiovascular death for patients who took azithromycin, as compared with those who took amoxicillin, varied according to the baseline risk score for cardiovascular disease. In patients with the highest risk score, who accounted for 59% of the cardiovascular deaths during azithromycin therapy, there were an estimated 245 additional cardiovascular deaths per 1 million 5-day courses of azithromycin therapy.

Erythromycin, clarithromycin and azithromycin (each are macrolides) and levofloxacin (a fluoroquinolone) are antibiotics associated prolongation of the QT interval. The QT interval is measured as the time and distance between the Q point of the QRS complex and the end of the T wave in the ECG tracing. After adjustment for heart rate, the QT interval is defined as prolonged if it is more than 450 msec in men and 460 msec in women. A long QT syndrome was first described in the 1950s and 60s as a congenital syndrome involving QT interval prolongation and syncope and sudden death. Some of the congenital long QT syndromes were characterized by a peculiar electrocardiographic appearance of the QRS complex involving a premature atria beat followed by a pause, then a subsequent sinus beat showing marked QT prolongation and deformity. This type of cardiac arrhythmia was originally termed “torsade de pointes” (translated from the French as “twisting of the points”). Erythromycin, clarithromycin, azithromycin and levofloxacin are considered as having a risk of causing torsade de pointes. Since it is not known what effect vasoconstrictors in the local anesthetic regimen will have in patients with a known history of congenital prolonged QT interval or in patients taking any medication that prolongs the QT interval, a medical consult is suggested.

Azithromycin is one of the drugs now confirmed to prolong the QT interval and is accepted as having a risk of causing torsade de pointes. This was noted in the New England Journal of Medicine report. The risk of drug-induced torsade de pointes is extremely low when a single QT interval prolonging drug is prescribed. In terms of epinephrine, it is not known what effect vasoconstrictors in the local anesthetic regimen will have in patients with a known history of congenital prolonged QT interval or in patients taking any medication that prolongs the QT interval. Until more information is obtained, it is suggested that the clinician consult with the physician prior to the use of a vasoconstrictor in suspected patients, and that the vasoconstrictor (epinephrine, mepivacaine and levonordefrin [Carbocaine® 2% with Neo-Cobefrin®]) be used with caution.

Also, information can be found in the respective monographs for erythromycin, clarithromycin, azithromycin and levofloxacin in the Lexicomp Online for Dentistry database, or the Drug Information Handbook for Dentistry.