Azithromycin in combination may increase risk for cardiac events

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While azithromycin by itself is not associated with an increase in cardiac events, if the taken with certain other drugs cardiac events increased, found a University of Illinois study.

Debates over whether hydroxychloroquine should be taken to help lessen the duration and impact of COVID-19 have revolved around the drug’s reputation for causing cardiac events such as abnormal heart rhythms or beats and cardiac arrest. Because of this, the US Food and Drug Administration has revoked emergency use authorisation for the drug in treating COVID-19.

Another drug, azithromycin – a commonly-prescribed antibiotic – also is being investigated as a potential treatment for COVID-19. Azithromycin’s association with cardiac events also has been debated. In 2012, the FDA issued a warning for azithromycin stating that it had been linked to cardiac events, but subsequent studies have yielded mixed results.

Now, researchers from the University of Illinois Chicago have found that azithromycin by itself is not associated with an increase in cardiac events; however, if the drug is taken with certain other drugs that affect the electrical functioning of the heart, then cardiac events increased.

“Our findings should give researchers and clinicians looking at azithromycin as a potential treatment for COVID-19 pause,” said Haridarshan Patel, a researcher in the department of pharmacy systems, outcomes and policy at the UIC College of Pharmacy and corresponding author on the paper. “We found that if taken together with drugs that affect the electrical impulses of the heart, the combination is linked with a 40% increase in cardiac events, including fainting, heart palpitations and even cardiac arrest.”

Drugs that affect the electrical impulses of the heart, specifically the interval in the electrical rhythm called the QT interval, are called QT-prolonging drugs. These drugs include blood pressure medications such as ACE inhibitors and beta-blockers, some antidepressants, anti-malaria drugs such as hydroxychloroquine and chloroquine, opioid medications and even muscle relaxers.

“Because QT-prolonging drugs are used so commonly, our findings suggest that doctors prescribing azithromycin should be sure that patients are not also taking a QT-prolonging drug,” Patel said.

In a previous study, Patel and colleagues found that one in five people prescribed azithromycin also were taking a QT-prolonging drug.

Previous studies looking at azithromycin and cardiac events examined specific populations that tend to be older and have more health issues, including Medicaid patients and veterans. But in this study, Patel and colleagues used a large database containing medical data on millions of patients in the US with a mean age of 36 years old.

The risk of cardiac events with azithromycin was evaluated against amoxicillin, another antibiotic that has never been linked to cardiac events and which has no impact on the QT-interval. The researchers looked at data from more than 4m patients enrolled in private health insurance plans who were hospitalized or visited an emergency department for a cardiac event between 2009 and 2015 who started taking either amoxicillin or azithromycin within five days of their hospital visit. There were approximately 2m episodes in each group. Cardiac events included ventricular arrhythmias, fainting, palpitations and cardiac arrest, and death.

“Drugs often prolong QT-interval but may not necessarily result in cardiac events that self-resolve over time,” Patel said. “We looked at events that led to emergency department visits or hospitalisations in this study.”

The researchers found that the likelihood of cardiac events with azithromycin compared with amoxicillin were not significantly higher, and these events actually were quite low or rare in both groups, with the most common cardiac events being fainting and palpitations. However, among patients taking both a QT-prolonging medication and azithromycin together, the risk of cardiac events was 40% higher compared with the amoxicillin group.

“Because both QT-prolonging drugs and azithromycin are so commonly prescribed, the risk for cardiac events due to the combination, while still rare, is serious,” Patel said. “Studies looking at using azithromycin to treat COVID-19 or other diseases should very carefully consider its use among patients who are also taking QT-prolonging medications.”

Gregory Calip, Robert DiDomenico, Glen Schumock and Todd Lee of the UIC College of Pharmacy and Katie Suda of the University of Pittsburgh are co-authors on the study.

Abstract 1
Importance: Conflicting evidence exists on the association between azithromycin use and cardiac events.
Objective: To compare the odds of cardiac events among new users of azithromycin relative to new users of amoxicillin using real-world data.
Design, Setting, and Participants: This retrospective cohort study used data from Truven Health Analytics MarketScan database from January 1, 2009, to June 30, 2015. Patients receiving either amoxicillin or azithromycin and enrolled in a health care plan 365 days before (baseline period) the dispensing date (index date) were included in the study. Patients were matched 1:1 on high-dimensional propensity scores. Data were analyzed from October 1, 2018, to December 31, 2019.
Exposures: New use of azithromycin compared with new use of amoxicillin.
Main Outcomes and Measures: The primary outcome consisted of cardiac events, including syncope, palpitations, ventricular arrhythmias, cardiac arrest, or death as a primary diagnosis for hospitalization at 5, 10, and 30 days from the index date. Logistic regression models were used to estimate odds ratios (ORs) with 95% CIs.
Results: After matching, the final cohort included 2 141 285 episodes of each index therapy (N = 4 282 570) (mean [SD] age of patients, 35.7 [22.3] years; 52.6% female). Within 5 days after therapy initiation, 1474 cardiac events (0.03%) occurred (708 in the amoxicillin cohort and 766 in the azithromycin cohort). The 2 most frequent events were syncope (1032 [70.0%]) and palpitations (331 [22.5%]). The odds of cardiac events with azithromycin compared with amoxicillin were not significantly higher at 5 days (OR, 1.08; 95% CI, 0.98-1.20), 10 days (OR, 1.05; 95% CI, 0.97-1.15), and 30 days (OR, 0.98; 95% CI, 0.92-1.04). Among patients receiving any concurrent QT-prolonging drug, the odds of cardiac events with azithromycin were 1.40 (95% CI, 1.04-1.87) greater compared with amoxicillin. Among patients 65 years or older and those with a history of cardiovascular disease and other risk factors, no increased risk of cardiac events with azithromycin was noted.
Conclusions and Relevance: This study found no association of cardiac events with azithromycin compared with amoxicillin except among patients using other QT-prolonging drugs concurrently. Although azithromycin is a safe therapy, clinicians should carefully consider its use among patients concurrently using other QT-prolonging drugs.

Authors
Haridarshan Patel, Gregory S Calip, Robert J DiDomenico, Glen T Schumock, Katie J Suda, Todd A Lee

Abstract 2
Study Objective: To measure the prevalence of cardiac risk factors among patients prescribed azithromycin before and after the United States Food and Drug Administration (FDA) issued a warning on May 17, 2012, on the risk of potentially fatal heart rhythms associated with the drug.
Design: Retrospective cohort study using administrative claims data.
Data Source: Truven Health Analytics MarketScan database.
Patients: A total of 12,971,078 unique patients with 23,749,652 azithromycin prescriptions dispensed between January 2009 and June 2015 were included. Patients had to be continuously enrolled in a health plan for at least 365 days (baseline) before the date of azithromycin dispensing (index date). Cohorts were assigned based on the index dates of the azithromycin prescriptions, either before (January 1, 2009–May 1, 2012) or after (June 1, 2012–June 30, 2015) the FDA warning was issued.
Measurements and Main Results: A cardiac risk factor included either a cardiac condition (heart failure or dysrhythmias) or concurrent use of drugs that prolong the QT interval. The unit of analysis was each prescription of azithromycin. Multivariable logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the prevalence of cardiac risk factors. Mean age of the patients was 40.1 ± 21.3 years old, with 60.8% females. Prior to the FDA warning, 11,596,022 (48.8%) azithromycin prescriptions were identified, and 12,153,630 (51.2%) were identified after the warning. The prevalence of a preexisting cardiac condition was 7.3% versus 7.9% (p<0.0001) before and after the FDA warning, respectively. Concurrent use of a QT‐interval–prolonging drug was 23.3% versus 24.2% (p<0.0001) before and after the FDA warning, respectively. After controlling for confounders, the odds of having a cardiac risk factor after the FDA warning were significantly lower (odds ratio 0.938, 95% CI 0.936–0.940) compared with before the FDA warning.
Conclusion: Despite the 2012 FDA warning, a nontrivial number of azithromycin prescriptions was prescribed concurrently in patients with preexisting a cardiac condition (1 of 12 azithromycin prescriptions) and in those using a QT‐interval–prolonging drug (1 of 5 azithromycin prescriptions). After adjusting for confounders, the odds of cardiac risk factors being present in patients prescribed azithromycin were modestly lower after the warning; however, the prevalence remained essentially unchanged before and after the FDA warning was issued.

Authors
Haridarshan Patel, Gregory Sampang Calip, Robert J DiDomenico, Glen T Schumock, Katie J Suda, Todd A Lee

 

University of Illinois at Chicago

 

JAMA Network Open abstract

 

Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy abstract

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