A Pharmacovigilance Study of Hydroxychloroquine Cardiac Safety Profile: Potential Implication in COVID-19 Mitigation

Abstract

In light of the favorable outcomes of few small, non-randomized clinical studies, the Food and Drug Administration (FDA) has issued an Emergency Use Authorization (EUA) to Hydroxychloroquine (HCQ) for hospitalized coronavirus disease 2019 (COVID-19) patients. In fact, subsequent clinical studies with COVID-19 and HCQ have reported limited efficacy and poor clinical benefits. Unfortunately, a robust clinical trial for its effectiveness is not feasible at this emergency. Additionally, HCQ was suspected of causing cardiovascular adverse reactions (CV-AEs), but it has never been directly investigated. The objective of this pharmacovigilance analysis was to determine and characterize HCQ-associated cardiovascular adverse events (CV-AEs). We performed a disproportionality analysis of HCQ-associated CV-AEs using the FDA adverse event reporting system (FAERS) database. The FAERS database, comprising more than 11,901,836 datasets and 10,668,655 patient records with drug-adverse reactions, was analyzed. The disproportionality analysis was used to calculate the reporting odds ratios (ROR) with 95% confidence intervals (CI) to predict HCQ-associated CV-AEs. HCQ was associated with higher reporting of right ventricular hypertrophy (ROR: 6.68; 95% CI: 4.02 to 11.17), left ventricular hypertrophy (ROR: 3.81; 95% CI: 2.57 to 5.66), diastolic dysfunction (ROR: 3.54; 95% CI: 2.19 to 5.71), pericarditis (ROR: 3.09; 95% CI: 2.27 to 4.23), torsades de pointes (TdP) (ROR: 3.05; 95% CI: 2.30 to 4.10), congestive cardiomyopathy (ROR: 2.98; 95% CI: 2.01 to 4.42), ejection fraction decreased (ROR: 2.41; 95% CI: 1.80 to 3.22), right ventricular failure (ROR: 2.40; 95% CI: 1.64 to 3.50), atrioventricular block complete (ROR: 2.30; 95% CI: 1.55 to 3.41) and QT prolongation (ROR: 2.09; 95% CI: 1.74 to 2.52). QT prolongation and TdP are most relevant to the COVID-19 treatment regimen of high doses for a comparatively short period and represent the most common HCQ-associated AEs. The patients receiving HCQ are at higher risk of various cardiac AEs, including QT prolongation and TdP. These findings highlight the urgent need for prospective, randomized, controlled studies to assess the risk/benefit ratio of HCQ in the COVID-19 setting before its widespread adoption as therapy.

SARS-CoV-2 Infection and COVID-19 in 5 Patients in Ecuador After Prior Treatment with Hydroxychloroquine for Systemic Lupus Erythematosus

“…Another fundamental fact that must be considered is that the FDA issued a statement against hydroxychloroquine and chloroquine for COVID-19 use outside the hospital setting due to safety concerns, especially related to heart problems. This did not include FDA-approved uses for malaria and autoimmune diseases [ 21 ].…”

COVID-19 infection and cardiac arrhythmias

“…In the setting of acute myocardial injury and acute myocarditis in patients with COVID-19 infection, various and serious ventricular arrhythmias (VAs) may occur [15] . Other important triggers include the severe respiratory insufficiency and the systemic inflammation incurred by COVID-19 infection, as well as the proarrhythmic effects of COVID therapies and other drug interactions and also the autonomic imbalance superimposed in patients afflicted by the disease [ 5 , 9 ]. Furthermore, hypoxemia which is common in these patients and electrolyte disturbances occurring for various reasons in this group of patients may aggravate arrhythmogenicity.…”

“…A recent disproportionality analysis of HCQ-associated CV adverse reactions using the FDA adverse event reporting system (FAERS) database of >11,901,836 datasets and 10,668,655 patient records indicated that HCQ was associated with higher reporting odds ratios (ROR) of TdP (ROR: 3.05; 95% CI: 2.30 to 4.10), complete atrioventricular (AV) block (ROR: 2.30; 95% CI: 1.55 to 3.41) and QT prolongation (ROR: 2.09; 95% CI: 1.74 to 2.52) [9] . QT prolongation and TdP are more frequent with high doses for a comparatively short period and represent the most common HCQ-associated side-effects…”

“…Cardiac arrhythmias, including life-threatening VAs, may be the consequence of direct effects of COVID-19 infection, but also of the deleterious effects of systemic illness and the adverse reactions to drugs employed in the treatment of this pandemic ( Table 2 , Fig. 1 ) [ 5 , [9] , [10] , [11] ]. A recent study indicated that among 700 patients with COVID-19 (mean age 50±18 years, 45% men, 71% African American, 11% receiving care in the ICU), there were 9 cardiac arrests, 25 incident atrial fibrillation (AF) episodes, 9 bradyarrhythmias, and 10 non-sustained ventricular tachycardias (NSVTs) [5] .…”

<p>Hydroxychloroquine in COVID-19: The Study Points to Premature Decisions on Efficacy While Bells Ringing for Safety</p>

“…11 Significant cardiac adverse effects associated with HCQ such as QT-prolongation, ventricular arrhythmias, torsade de pointes (TdP), and cardiomyopathy are the prime concerns that require risk-benefit judgment in COVID-19 management. [12][13][14] Apart from cardiac side effects, it has also the potential to cause bone marrow failure, hemolysis in glucose-6-phosphate dehydrogenase deficiency cases, retinopathy, gastrointestinal disorders, hepatobiliary disorders, metabolic disorders like hypoglycemia, skeletal muscle myopathy, neuromyopathy, psychiatric disorders, and exfoliative dermatitis. 15 There are variable reports from laboratory to human use in RCTs regarding the effects of such 4-aminoquinolines in some viruses like the influenza virus, Zika virus, ebola virus, dengue virus, and chikungunya virus.…”