Comparative study of the adverse event profile of hydroxychloroquine before and during the Sars-CoV2 pandemic.

AIMS: At the beginning of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, there were no clinically-tested medications for the effective treatment of coronavirus disease. In this context, on 5 March 2020, the French Public Health Council issued several recommendations for the therapeutic management of this new disease, including the use of hydroxychloroquine (HCQ). An unexpected cardiovascular safety signal was quickly identified as being more frequent than expected thanks to the reports of adverse drug reactions (ADRs) submitted to French regional pharmacovigilance centres (RPVC). The objective of this study was to compare all ADRs reported with HCQ used in its usual indication, collected before the pandemic period (1985 to 31 December, 2019) with those reported with the coronavirus disease 2019 (COVID-19) indication (1 January to 21 July, 2020). METHODS: For this purpose, reports were extracted from the French pharmacovigilance database and analysed for these two periods. RESULTS: Our study showed a different safety profile in COVID-19 patients with more cardiac disorders (57% of ADRs versus 5% before the pandemic period), especially QT interval prolongation, resulting from an interaction with azithromycin in more than 20% of cases. Hepatobiliary disorders were also significantly more frequent. CONCLUSIONS: These observations could be associated with the effect of the virus itself on the various organs, the profile of the patients treated, and concomitant drug treatments.

Spontaneous reported cardiotoxicity induced by lopinavir/ritonavir in COVID-19. An alleged past-resolved problem.

The antiretroviral drug lopinavir/ritonavir has been recently repurposed for the treatment of COVID-19. Its empirical use has been associated with multiple cardiac adverse reactions pertaining to its ancillary multi-channel blocking properties, vaguely characterized until now. We aimed to characterize qualitatively the cardiotoxicity associated with lopinavir/ritonavir in the setting of COVID-19. Spontaneous notifications of cardiac adverse drug reactions reported to the national Pharmacovigilance Network were collected for 8 weeks since March 1st 2020. The Nice Regional Center of Pharmacovigilance, whose scope of expertise is drug-induced long QT syndrome, analyzed the cases, including the reassessment of all available ECGs. QTc ≥ 500 ms and delta QTc > 60 ms from baseline were deemed serious. Twenty-two cases presented with 28 cardiac adverse reactions associated with the empirical use of lopinavir/ritonavir in a hospital setting. Most adverse reactions reflected lopinavir/ritonavir potency to block voltage-gated potassium channels with 5 ventricular arrhythmias and 17 QTc prolongations. An average QTc augmentation of 97 ± 69 ms was reported. Twelve QTc prolongations were deemed serious. Other cases were likely related to lopinavir/ritonavir potency to block sodium channels: 1 case of bundle branch block and 5 recurrent bradycardias. The incidence of cardiac adverse reactions of lopinavir/ritonavir was estimated between 0.3% and 0.4%. These cardiac adverse drug reactions offer a new insight in its ancillary multi-channel blocking functions. Lopinavir/ritonavir cardiotoxicity may be of concern for its empirical use during the COVID-19 pandemic. Caution should be exerted relative to this risk where lopinavir/ritonavir summary of product characteristics should be implemented accordingly.

Insights on the Evidence of Cardiotoxicity of Hydroxychloroquine Prior and During COVID-19 Epidemic.

The recent empirical use of hydroxychloroquine (HCQ) in coronavirus disease 2019 (COVID-19) revived the interest in its cardiac toxicity, increasingly sidelined over time. We aimed to assess and compare the profile of cardiac adverse drug reactions (CADRs) associated with HCQ before and during COVID-19. We performed a retrospective comparative observational study using the French Pharmacovigilance network database between 1985 and May 2020 to assess all postmarketing CADRs associated with HCQ notified before COVID-19 in its approved indications for lupus and rheumatoid arthritis (preCOV), and those concerning its empirical use in COVID-19 (COV). Eighty-five CADR in preCOV were compared with 141 CADRs in COV. The most common CADR of preCOV were cardiomyopathies (42.4%) and conduction disorders (28.2%), both statistically more frequent than in COV (P < 0.001). COV notifications significantly highlighted repolarization and ventricular rhythm disorders (78.0%, P < 0.001) as well as sinus bradycardias (14.9%, P = 0.01) as compared with preCOV. Estimated incidence of CADR was significantly higher among patients exposed to off-label use of HCQ in COVID-19 (2.9%) than before COVID-19 in its approved indications (0.01%, P < 0.001). The use of HCQ in COVID-19 sheds a new light on the spectrum of its cardiac toxicity. This fosters the value of a closer monitoring of all patients treated with HCQ, regardless of its indication, and the importance of an update of its summary of product characteristics.

“Off-label” use of hydroxychloroquine, azithromycin, lopinavir-ritonavir and chloroquine in COVID-19: a survey of cardiac adverse drug reactions by the French Network of Pharmacovigilance Centers

Summary Introduction: COVID-19 is an unprecedented challenge for physicians and scientists. Several publicized drugs are being used with not much evidence of their efficacy such as hydroxychloroquine, azithromycin or lopinavir-ritonavir. Yet, the cardiac safety of these drugs in COVID-19 deserves scrutiny as they are known to foster cardiac adverse ADRs, notably QTc interval prolongation on the electrocardiogram and its arrhythmogenic consequences. Methods: Since March 27th, 2020, the French Pharmacovigilance Network directed all cardiac adverse drug reactions associated with “off-label” use of hydroxychloroquine, azithromycin and lopinavir-ritonavir in COVID-19 to the Nice Regional Center of Pharmacovigilance. Each Regional Center of Pharmacovigilance first assessed causality of drugs. We performed a specific analysis of these cardiac adverse drug reactions amidst an array of risk factors, reassessed the electrocardiograms and estimated their incidence in coronavirus-disease-2019. Results: In one month, 120 reports of cardiac adverse drug reactions have been notified, 102 of which associated with hydroxychloroquine alone (85%), or associated with azithromycin (60%). Their estimated incidence is 0.77% to 1.54% of all patients, notwithstanding strong underreporting. Lopinavir-ritonavir came third with 17 reports (14%) and chloroquine fourth with 3 reports (2.5%). There were 8 sudden, unexplained or aborted deaths (7%), 8 ventricular arrhythmias (7 %), 90 reports of prolonged QTc (75%) most of them “serious” (64%), 48 of which proved ≥ 500 ms, 20 reports of severe conduction disorders (17%) and 5 reports of other cardiac causes (4%). Six reports derived from automedication. Discussion and conclusion: “Off-label” use of treatments in COVID-19 increases the risk of cardiac ADRs, some of them avoidable. Even if these drugs are perceived as familiar, they are used in patients with added risk factors caused by infection. Precautions should be taken to mitigate the risk, even if they will be proven efficacious.