english.prescrire.org > Spotlight > 100 most recent > New data on the cardiac adverse effects of the combination of hydroxychloroquine (Plaquenil°) with azithromycin (Zithromax° or other brands)


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New data on the cardiac adverse effects of the combination of hydroxychloroquine (Plaquenil°) with azithromycin (Zithromax° or other brands)

 NEWS UPDATE  As of mid-April 2020, more and more clinical data are confirming that the combination of hydroxychloroquine (Plaquenil°) with azithromycin (Zithromax° or other brands) carries a risk of serious cardiac adverse effects: prolongation of the QT interval with a high risk of cardiac arrhythmia and torsade de pointes, and cardiovascular mortality, which is increased by the addition of azithromycin. Several cases of cardiac arrest have been reported.

The combination of hydroxychloroquine, an anti-malarial drug with immunosuppressant activity, and azithromycin, a macrolide antibiotic, is a treatment under evaluation for patients with covid-19. As of 15 April 2020, there is no evidence that the combination has clinical efficacy in this situation (details > HERE).

Given the adverse effect profiles of hydroxychloroquine and azithromycin, an increased risk of serious cardiac arrhythmias is predictable with this combination (details > HERE); it is being confirmed by more and more clinical data. A team in New York studied electrocardiographic data from a series of 84 patients who were hospitalised with covid-19 and treated with the hydroxychloroquine + azithromycin combination. During treatment, prolongation of the ECG QT interval exceeding 500 milliseconds was observed in 11% of patients, a threshold above which the risk of cardiac arrhythmia and torsade de pointes is particularly high (details > here).

A pharmacoepidemiological study was carried out using international databases, in order to estimate the cardiovascular risk associated with the use of the hydroxychloroquine + azithromycin combination in a setting other than covid-19 (details > here). This study involved patients with rheumatoid arthritis, which is sometimes treated with hydroxychloroquine. About 956 000 patients treated with hydroxychloroquine were compared to 310 000 patients treated with sulfasalazine (Salazopyrine°), another weak immunosuppressant used in rheumatoid arthritis. The authors analysed cardiovascular events occurring within 30 days of starting concomitant administration of an antibiotic, azithromycin or amoxicillin. There was no statistically significant difference in cardiovascular risk in patients treated with hydroxychloroquine compared to those treated with sulfasalazine. Addition of azithromycin was associated with a 2-fold greater risk of cardiovascular mortality than addition of amoxicillin.

Furthermore, the French Health Products Agency (ANSM) has commissioned two pharmacovigilance surveys of drugs used in patients with covid-19, outside of clinical trials (details > here). One of these, carried out by the Regional Pharmacovigilance Centre (CRPV) in Dijon, France, is dealing with all the adverse effects reported in France by healthcare professionals. As of 10 April 2020, 82 serious adverse effects, including 4 deaths, had been identified in connection with drugs used in covid-19 patients. The other survey, carried out by the CRPV in Nice, France, is dealing specifically with cardiovascular adverse effects linked to covid-19 treatments. 53 cases of cardiac adverse effects have been analysed, 43 of which were linked to hydroxychloroquine, alone or in combination (and in particular with azithromycin). There were 7 cases of cardiac arrest (including 3 patients who were successfully resuscitated), and around ten cases of electrocardiographic rhythm abnormalities or syncope-like cardiac symptoms, and conduction disorders including QT interval prolongation, which had a favourable outcome after treatment discontinuation. The ANSM concluded that, given the likelihood of significant under-reporting by hospital staff in such a high-pressure environment, these observed cases “constitute a significant safety signal”.

The US Institute for Safe Medication Practices reported a case of cardiac arrest due to ventricular fibrillation following QT interval prolongation when hydroxychloroquine was taken after a few days of azithromycin treatment (details > here). The female patient was successfully resuscitated.

As of 15 April 2020, there is still no treatment known to reduce the risk of progression to a severe form of covid-19 (details > HERE). Exposing patients to hydroxychloroquine and azithromycin increases the risk of serious cardiac adverse effects.

©Prescrire 16 April 2020

See also:

  • "Covid-19 and hydroxychloroquine (Plaquenil°): new data show no evidence of efficacy" 16 April 2020 > HERE
  • "Covid-19 and hydroxychloroquine (Plaquenil°): still no conclusive results" 15 April 2020 > HERE
  • "Covid-19 and hydroxychloroquine: uncertainties and unanswered questions" 2 April 2020 > HERE
  • "Covid-19 and hydroxychloroquine: caution" 30 March 2020 > HERE
  • "Covid-19 and drug trials: what to make of the initial results?" 23 March 2020 > HERE


"Des nouvelles données sur les effets indésirables cardiaques de l'association de l'hydroxychloroquine (Plaquénil°) avec l'azithromycine (Zithromax° ou autre)" Application Prescrire; 16 April 2020.

For more information (in French), see www.prescrire.org > Dans l'actualité

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