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.

Cardiac arrest and drug-related cardiac toxicity in the Covid-19 era. Epidemiology, pathophysiology and management.

SARS-CoV-2 (Covid-19) infection has recently become a worldwide challenge with dramatic global economic and health consequences. As the pandemic is still spreading, new data concerning Covid-19 complications and related mechanisms become increasingly available. Accumulating data suggest that the incidence of cardiac arrest and its outcome are adversely affected during the Covid-19 period. This may be further exacerbated by drug-related cardiac toxicity of Covid-19 treatment regimens. Elucidating the underlying mechanisms that lead to Covid-19 associated cardiac arrest is imperative, not only in order to improve its effective management but also to maximize preventive measures. Herein we discuss available epidemiological data on cardiac arrest during the Covid-19 pandemic as well as possible associated causes and pathophysiological mechanisms and highlight gaps in evidence warranting further investigation. The risk of transmission during cardiopulmonary resuscitation (CPR) is also discussed in this review. Finally, we summarize currently recommended guidelines on CPR for Covid-19 patients including CPR in patients with cardiac arrest due to suspected drug-related cardiac toxicity in an effort to underscore the most important common points and discuss discrepancies proposed by established international societies.

The Cardiovascular Effects of Treatment with Hydroxychloroquine and Azithromycin.

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.

Cardiac safety of off-label COVID-19 drug therapy: a review and proposed monitoring protocol.

More than 2,000,000 individuals worldwide have had coronavirus 2019 disease infection (COVID-19), yet there is no effective medical therapy. Multiple off-label and investigational drugs, such as chloroquine and hydroxychloroquine, have gained broad interest due to positive pre-clinical data and are currently used for treatment of COVID-19. However, some of these medications have potential cardiac adverse effects. This is important because up to one-third of patients with COVID-19 have cardiac injury, which can further increase the risk of cardiomyopathy and arrhythmias. Adverse effects of chloroquine and hydroxychloroquine on cardiac function and conduction are broad and can be fatal. Both drugs have an anti-arrhythmic property and are proarrhythmic. The American Heart Association has listed chloroquine and hydroxychloroquine as agents which can cause direct myocardial toxicity. Similarly, other investigational drugs such as favipiravir and lopinavir/ritonavir can prolong QT interval and cause Torsade de Pointes. Many antibiotics commonly used for the treatment of patients with COVID-19, for instance azithromycin, can also prolong QT interval. This review summarizes evidenced-based data regarding potential cardiac adverse effects due to off-label and investigational drugs including chloroquine and hydroxychloroquine, antiviral therapy, monoclonal antibodies, as well as common antibiotics used for the treatment of COVID-19. The article focuses on practical points and offers a point-of-care protocol for providers who are taking care of patients with COVID-19 in an inpatient and outpatient setting. The proposed protocol is taking into consideration that resources during the pandemic are limited.