Outpatient Azithromycin May Slightly Increase Risk of Cardiovascular Death

By Marilynn Larkin

June 25, 2020

NEW YORK (Reuters Health) - Taking azithromycin versus amoxicillin was linked to a small increased risk of cardiovascular death in a community-based observational study. However, the authors caution that "causality cannot be established."

A 2014 study reported an increase in cardiovascular death after azithromycin, Dr. Jonathan Zaroff of Kaiser Permanente Northern California in Oakland told Reuters Health by email. Therefore, "the US Food and Drug Administration requested additional epidemiologic investigations (from Kaiser Permanente's large databases) to evaluate the association."

The researchers analyzed data from close to three million Californians (mean age, 51; 62% women) between 1998 and 2014. Included were more than 7.8 million antibiotic exposures: 1.73 million for azithromycin (22.2%) and 6.08 million for amoxicillin.

As reported in JAMA Network Open, azithromycin was dispensed more frequently later in the study period.

Compared with those receiving amoxicillin, patients receiving azithromycin had higher rates of pneumonia (14.0% vs. 3.5%); chronic obstructive pulmonary disease (20.6% vs. 7.9%); asthma (22.6% vs. 10.4%); and beta-agonist use (40.7% vs. 19.9%) in the year prior to their prescription.

In addition, patients who took azithromycin were more likely to receive cardioprotective medications, including angiotensin-converting enzyme inhibitors (17.5% vs. 14.7%); angiotensin receptor blockers (5.8% vs. 3.4%), statins (24.9% vs. 19.6%), and beta-blockers (15.3% vs.13.8%). They also were more likely to have had a noncardiovascular-related emergency department visit within 30 days prior to the study (5.4% vs. 2.1%).

Azithromycin was associated with a significantly increased hazard of cardiovascular death (hazard ratio, 1.82) but not sudden cardiac death (HR, 1.59) within five days of exposure. No increases in risk were found six to 10 days after exposure.

Similar results were seen in patients within the top decile of cardiovascular risk (HR, 1.71).

Azithromycin also was associated with an increased risk of noncardiovascular death (HR, 2.17) and all-cause mortality (HR, 2.00) within five days of exposure.

"We do not believe azithromycin caused these (noncardiovascular) deaths," Dr. Zaroff said. "We believe it is due to underlying differences in the people receiving azithromycin compared to those receiving amoxicillin, which we were not able to control for with our statistical methods."

Further, he noted, "Though the (overall) relative increase in risk (with azithromycin) was large, the absolute increase in risk was very small, approximately 13 additional cardiovascular deaths per one million azithromycin prescriptions."

"These small risks need to be weighed against the well-established benefits of azithromycin for a broad range of infections, including serious infections such as pneumonia. Physicians should individualize their recommendations based on whether or not a patient has heart disease and the nature and severity of the infection."

Douglas Jennings, clinical pharmacist for heart transplant and mechanical circulatory support at NewYork Presbyterian Columbia University Irving Medical Center in New York City, commented in an email to Reuters Health that the two-fold increase in risk seemed higher than would be expected from QTc prolongation. "It suggests that something else is going on to cause the difference," he said.

"It's also concerning that the the risk of cardiovascular death was higher, but not sudden death," he noted. "If the patients aren't dying of sudden cardiac death, which is what's expected in the setting of QTc prolongation, then why are they dying? It suggests significant confounding."

"This study just drives home the point that we shouldn't be prescribing azithromycin unless it's truly indicated and other available antibiotics cannot be used," he said. "Azithromycin has been overprescribed for decades, and this information provided additional justification to curtail unnecessary use."

Dr. Mark Cushman, Distinguished Professor of Medicinal Chemistry at Purdue University in West Lafayette, Indiana, also commented by email, noting, "Azithromycin (was) suggested for use in combination with hydroxychloroquine for COVID-19 treatment. Both drugs are reported to have similar cardiotoxicities (arrhythmias associated with prolongation of the QT interval and cardiac arrest), and adding them together is likely to increase this risk."

"The combination was not found to be effective," he said, "and is actually detrimental."

The study was funded by Pfizer.

SOURCE: https://bit.ly/37SpZSw JAMA Network Open, online June 17, 2020.