The Cardiovascular Effects of Treatment with Hydroxychloroquine and Azithromycin

Abstract

Hydroxychloroquine combined with azithromycin has been investigated for activity against coronavirus disease 2019 (COVID‐19), but concerns about adverse cardiovascular (CV) effects have been raised. This study evaluated claims data to determine if risks for CV events were increased with hydroxychloroquine alone or combined with azithromycin. We identified data from 43,752 enrollees that qualified for analysis. The number of CV events increased by 25 (95% confidence interval [CI]: 8, 42, p=0.005) per 1000 people per year of treatment with hydroxychloroquine alone compared with pretreatment levels and by 201 (95% CI: 145, 256, p<0.001) events per 1000 people per year when individuals took hydroxychloroquine and azithromycin. These rates translate to an additional 0.34 (95% CI: 0.11, 0.58) CV events per 1000 patients placed on a 5‐day treatment with hydroxychloroquine monotherapy and 2.75 (95% CI: 1.99, 3.51) per 1000 patients on a 5‐day treatment with both hydroxychloroquine and azithromycin. The rate of adverse events increased with age following exposure to hydroxychloroquine alone and combined with azithromycin. For females aged 60 to 79 years prescribed hydroxychloroquine, the rate of adverse CV events was 0.92 per 1000 patients on 5 days of therapy, but it increased to 4.78 per 1000 patients when azithromycin was added. The rate of adverse CV events did not differ significantly from zero for patients 60 years of age or younger. These data suggest that hydroxychloroquine with or without azithromycin is likely safe in individuals under 60 years of age if they do not have additional CV risks. However, the combination of hydroxychloroquine and azithromycin should be used with extreme caution in older patients.

American College of Rheumatology White Paper on Antimalarial Cardiac Toxicity

“…Recent studies (25)(26)(27)(28), as well as earlier case reports (29,30), have shown QTc prolongation with HCQ or CQ at conventional doses used to treat rheumatic disease. In a Veterans Administration study of >800 patients with rheumatic disease (90% male and 10% female) seen between 2000 and early 2020 who were taking HCQ and had available ECG data, HCQ was associated with QTc (80) and is reflected on the surface ECG as the T wave.…”

“…A review of the World Health Organization (WHO) pharmacovigilance database from 1967 through March 1, 2020 showed increased reports of QTc prolongation with both HCQ and azithromycin, with more frequent reporting of prolonged QTc and/or TdP/ventricular tachy cardia with the combination of these 2 medications (odds ratio 2.48 [95% CI 1.28-4.79]) (27). In a commercial claims database analysis of events from 2001 through 2017, after 5 days of HCQ therapy the incidence of cardiac events (including myocardial infarction [MI], cerebrovascular accident/transient ischemic attack, sudden death, and arrhythmia) in 2001-2017 among women ages 60-79 years was 0.92 per 1,000 (28). Among those receiving both HCQ and azithromycin, the rate was 4.78 per 1,000 patients (28).…”

“…In a commercial claims database analysis of events from 2001 through 2017, after 5 days of HCQ therapy the incidence of cardiac events (including myocardial infarction [MI], cerebrovascular accident/transient ischemic attack, sudden death, and arrhythmia) in 2001-2017 among women ages 60-79 years was 0.92 per 1,000 (28). Among those receiving both HCQ and azithromycin, the rate was 4.78 per 1,000 patients (28).…”

COVID-19 and Sudden Cardiac Death in a Young Man with Myasthenia Gravis

“…In addition to MG, the proarrhythmic effects of hydroxychloroquine which is prescribed for COVID-19, should also be considered as a possible cause of SCD. QT prolongation and torsades de pointes are common cardiac adverse effects of hydroxychloroquine [18]; nevertheless, the absolute risk of hydroxychloroquine causing SCD is minor and mainly observed among patients older than 60 years of age [19]. We did not have the ECG of the patient prior to his death, however, initial EKG (electrocardiography) was normal and did not show QT prolongation and torsades de pointes.…”

Hydroxychloroquine as Therapeutic Option in COVID-19: Analysis of Suspected Cardiovascular Adverse Drug Events Reported in the VigiBase

“…Male gender and older age were closely associated with developing serious CVS events, which increased with age. A study done by Simmering et al, reported similar outcomes where patients more than 60 years were more prone to develop CVS ADEs as compared to younger ones50 . Yang et al, in their study Clinicaltrial.gov" website, only five trials had reported their results, and 257 studies were without results.…”