Torsade de pointes associated with chloroquine, hydroxychloroquine, and azithromycin: a retrospective analysis of individual case safety reports from VigiBase.

PURPOSE: To analyze the cases of torsade de pointes (TdP) and related symptoms reported in association with chloroquine (CQ), hydroxychloroquine (HCQ), and azithromycin (AZT) to the World Health Organization (WHO) global database of individual case safety reports (ICSRs) for drug monitoring (VigiBase) using qualitative and quantitative pharmacovigilance approaches. METHODS: The main characteristics of the ICSRs reporting TdP with CQ, HCQ, and AZT have been summarized. Co-reported drugs with risk to cause QT prolongation have been described. Reporting odds ratios (RORs) as a measure of disproportionality for reported TdP and individual drugs have been calculated. RESULTS: One hundred seventy ICSRs reporting TdP in association with the drugs of interest were identified (CQ: 11, HCQ: 31, CQ + HCQ: 1, HCQ + AZT: 27, AZT: 100). From these, 41 (24.3%) were received during the pandemic period (December 2019 to February 2021). The median age of the patients was 63, 53, and 63 years old for CQ, HCQ, and AZT, respectively. Reports included concomitant use of other QT-prolonging drugs (CQ 25.0%, HCQ 71.2%, AZT 64.6%). A proportion of the cases were fatal (CQ 25.0%, HCQ 8.6%, AZT 16.1%). Increased disproportionality has been found for the individual drugs and TdP: CQ (ROR: 7.41, 95% confidence interval (CI): 3.82, 12.96), HCQ (ROR: 8.49, 95% CI: 6.57, 10.98), azithromycin (ROR: 8.06, 95% CI: 6.76, 9.61). Disproportionality was also found for other related symptoms, Standardized MedDRA Query for torsade de pointes/QT prolongation (narrow): CQ (ROR: 11.95, 95% CI: 10.04-14.22); HCQ (ROR: 20.43, 95% CI: 19.13, 21.83), AZT (ROR: 7.78, 95% CI: 7.26, 8.34). CONCLUSIONS: The prescription of CQ, HCQ, and AZT should be restricted to therapeutic indications with established positive benefit/risk profile. Doctors and patients should be aware of this potential adverse reaction especially when several risk factors are present.

Transient Hypogonadism Is Associated With Heart Rate-Corrected QT Prolongation and Torsades de Pointes Risk During Active Systemic Inflammation in Men.

Background Systemic inflammation and male hypogonadism are 2 increasingly recognized "nonconventional" risk factors for long-QT syndrome and torsades de pointes (TdP). Specifically, inflammatory cytokines prolong, while testosterone shortens the heart rate-corrected QT interval (QTc) via direct electrophysiological effects on cardiomyocytes. Moreover, several studies demonstrated important interplays between inflammation and reduced gonad function in men. We hypothesized that, during inflammatory activation in men, testosterone levels decrease and that this enhances TdP risk by contributing to the overall prolonging effect of inflammation on QTc. Methods and Results We investigated (1) the levels of sex hormones and their relationship with inflammatory markers and QTc in male patients with different types of inflammatory diseases, during active phase and recovery; and (2) the association between inflammatory markers and sex hormones in a cohort of male patients who developed extreme QTc prolongation and TdP, consecutively collected over 10 years. In men with active inflammatory diseases, testosterone levels were significantly reduced, but promptly normalized in association with the decrease in C-reactive protein and interleukin-6 levels. Reduction of testosterone levels, which also inversely correlated with 17-ß estradiol over time, significantly contributed to inflammation-induced QTc prolongation. In men with TdP, both active systemic inflammation and hypogonadism were frequently present, with significant correlations between C-reactive protein, testosterone, and 17-ß estradiol levels; in these patients, increased C-reactive protein and reduced testosterone were associated with a worse short-term outcome of the arrhythmia. Conclusions During systemic inflammatory activation, interleukin-6 elevation is associated with reduced testosterone levels in males, possibly deriving from an enhanced androgen-to-estrogen conversion. While transient, inflammatory hypotestosteronemia is significantly associated with an increased long-QT syndrome/TdP risk in men.

Urgent Guidance for Navigating and Circumventing the QTc-Prolonging and Torsadogenic Potential of Possible Pharmacotherapies for Coronavirus Disease 19 (COVID-19).

As the coronavirus disease 19 (COVID-19) global pandemic rages across the globe, the race to prevent and treat this deadly disease has led to the "off-label" repurposing of drugs such as hydroxychloroquine and lopinavir/ritonavir, which have the potential for unwanted QT-interval prolongation and a risk of drug-induced sudden cardiac death. With the possibility that a considerable proportion of the world's population soon could receive COVID-19 pharmacotherapies with torsadogenic potential for therapy or postexposure prophylaxis, this document serves to help health care professionals mitigate the risk of drug-induced ventricular arrhythmias while minimizing risk of COVID-19 exposure to personnel and conserving the limited supply of personal protective equipment.

Drug-Induced QTc Prolongation: What We Know and Where We Are Going.

Drug-induced QTc prolongation is a concerning electrocardiogram (ECG) abnormality. This cardiac disturbance carries a 10% risk of sudden cardiac death due to the malignant arrhythmia, Torsades de Pointes. The Arizona Center for Education and Research on Therapeutics (AzCERT) has classified QTc prolonging therapeutic classes, such as antiarrhythmics, antipsychotics, anti-infectives, and others. AzCERT criteria categorize medications into three risk categories: "known," "possible," and "conditional risk" of QTc prolongation and Torsades de Pointes. The list of QTc prolonging medications continues to expand as new drug classes are approved and studied. Risk factors for QTc prolongation can be delineated into modifiable or non-modifiable. A validated risk scoring tool may be utilized to predict the likelihood of prolongation in patients receiving AzCERT classified medication. The resultant risk score may be applied to a clinical decision support system, which offers mitigation strategies. Mitigation strategies including discontinuation of possible offending agents with a selection of an alternative agent, assessment of potential drug interactions or dose adjustments through pharmacokinetic and pharmacodynamic monitoring, and initiation of both ECG and electrolyte monitoring are essential to prevent a drug-induced arrhythmia. The challenges presented by the COVID-19 pandemic have led to the development of innovative continuous monitoring technology, increasing protection for both patients and healthcare workers. Early intervention strategies may reduce adverse events and improve clinical outcomes in patients identified to be at risk of QTc prolongation.

Torsades de pointes in SARS-CoV-2 (COVID-19) pneumonia: medicine reconciliation and careful monitoring of QTc interval may help prevent cardiac complications.

Hydroxychloroquine has been widely prescribed to treat patients with COVID-19 pneumonia. A 73-year-0ld woman with COVID-19 pneumonia was treated with dexamethasone and hydroxychloroquine. Her home medications, citalopram and donepezil, were continued. The ECG prior to starting hydroxychloroquine showed normal sinus rhythm with prolonged corrected QT (QTc) of 497 ms, due to citalopram and donepezil therapy. Repeat ECG on days 3 and 4 of hydroxychloroquine therapy showed significantly prolonged QTc of 557 ms and 538 ms, respectively, despite normal serum electrolytes. All QT-prolonging medications including hydroxychloroquine were discontinued on day 4; however, she suffered a transient torsades de pointes lasting for about 15 s, which resolved before any intervention. QTc improved to 477 ms, after discontinuation of QT-prolonging medications. The patient had QTc prolongation and torsades de pointes due to therapy with multiple QT-prolonging medications. Medicine reconciliation and careful monitoring of QTc may help prevent cardiac complications in patients with COVID-19 treated with hydroxychloroquine.

Effect of COVID-19 medications on corrected QT interval and induction of torsade de pointes: Results of a multicenter national survey.

BACKGROUND: There are some data showing that repurposed drugs used for the Coronavirus disease-19 (COVID-19) have potential to increase the risk of QTc prolongation and torsade de pointes (TdP), and these arrhythmic side effects have not been adequately addressed in COVID-19 patients treated with these repurposed medications. METHODS: This is the prospective study of 2403 patients hospitalised at 13 hospitals within the COVID-19 epicentres of the Iran. These patients were treated with chloroquine, hydroxychloroquine, lopinavir/ritonavir, atazanavir/ritonavir, oseltamivir, favipiravir and remdesivir alone or in combination with azithromycin. The primary outcome of the study was incidence of critical QTc prolongation, and secondary outcomes were incidences of TdP and death. RESULTS: Of the 2403 patients, 2365 met inclusion criteria. The primary outcome of QTc ≥ 500 ms and ∆QTc ≥ 60 ms was observed in 11.2% and 17.6% of the patients, respectively. The secondary outcomes of TdP and death were reported in 0.38% and 9.8% of the patients, respectively. The risk of critical QT prolongation increased in the presence of female gender, history of heart failure, treatment with hydroxychloroquine, azithromycin combination therapy, simultaneous furosemide or beta-blocker therapy and acute renal or hepatic dysfunction. However, the risk of TdP was predicted by treatment with lopinavir-ritonavir, simultaneous amiodarone or furosemide administration and hypokalaemia during treatment. CONCLUSION: This cohort showed significant QTc prolongation with all COVID-19 medications studied, however, life-threatening arrhythmia of TdP occurred rarely. Among the repurposed drugs studied, hydroxychloroquine or lopinavir-ritonavir alone or in combination with azithromycin clearly demonstrated to increase the risk of critical QT prolongation and/or TdP.

[Panic and pandemic: Review of the literature on the links between panic disorder and the SARS-CoV-2 epidemic]. / Panique et pandémie : revue de la littérature sur les liens entre le trouble panique et l'épidémie à SARS-CoV-2.

Although the "panic" word has been abundantly linked to the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) pandemic in the press, in the scientific literature very few studies have considered whether the current epidemic could predispose to the onset or the aggravation of panic attacks or panic disorder. Indeed, most studies thus far have focused on the risk of increase and aggravation of other psychiatric disorders as a consequence of the SARS-CoV-2 epidemic, such as obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), and generalized anxiety disorder (GAD). Yet, risk of onset or aggravation of panic disorder, especially the subtype with prominent respiratory symptoms, which is characterized by a fear response conditioning to interoceptive sensations (e.g., respiratory), and hypervigilance to these interoceptive signals, could be expected in the current situation. Indeed, respiratory symptoms, such as coughs and dyspnea, are among the most commonly associated with the SARS-CoV-2 (59-82% and 31-55%, respectively), and respiratory symptoms are associated with a poor illness prognosis. Hence given that some etiological and maintenance factors associated with panic disorder - i.e., fear conditioning to abnormal breathing patterns attributable or not to the COVID-19 (coronavirus disease 2019), as well as hypervigilance towards breathing abnormalities - are supposedly more prevalent, one could expect an increased risk of panic disorder onset or aggravation following the COVID-19 epidemic in people who were affected by the virus, but also those who were not. In people with the comorbidity (i.e., panic disorder or panic attacks and the COVID-19), it is particularly important to be aware of the risk of hypokalemia in specific at-risk situations or prescriptions. For instance, in the case of salbutamol prescription, which might be overly used in patients with anxiety disorders and COVID-19, or in patients presenting with diarrhea and vomiting. Hypokalemia is associated with an increased risk of torsade de pointe, thus caution is required when prescribing specific psychotropic drugs, such as the antidepressants citalopram and escitalopram, which are first-line treatments for panic disorder, but also hydroxyzine, aiming at anxiety reduction. The results reviewed here highlight the importance of considering and further investigating the impact of the current pandemic on the diagnosis and treatment of panic disorder (alone or comorbid with the COVID-19).

Drug-drug interactions between COVID-19 treatments and antipsychotics drugs: integrated evidence from 4 databases and a systematic review.

RATIONALE: Management of anxiety, delirium, and agitation cannot be neglected in coronavirus disease (COVID-19). Antipsychotics are usually used for the pharmacological management of delirium, and confusion and behavioral disturbances. The concurrent use of treatments for COVID-19 and antipsychotics should consider eventual drug-drug interactions OBJECTIVE: To systematically review evidence-based available on drug-drug interactions between COVID-19 treatments and antipsychotics. EVIDENCE REVIEW: Three databases were consulted: Lexicomp® Drug Interactions, Micromedex® Solutions Drugs Interactions, and Liverpool© Drug Interaction Group for COVID-19 therapies. To acquire more information on QT prolongation and Torsade de Pointes (TdP), the CredibleMeds® QTDrugs List was searched. The authors made a recommendation agreed to by consensus. Additionally, a systematic review of drug-drug interactions between antipsychotics and COVID-19 treatment was conducted. RESULTS: The main interactions between COVID-19 drugs and antipsychotics are the risk of QT-prolongation and TdP, and cytochromes P450 interactions. Remdesivir, baricinitib, and anakinra can be used concomitantly with antipsychotics without risk of drug-drug interaction (except for hematological risk with clozapine and baricinitib). Favipiravir only needs caution with chlorpromazine and quetiapine. Tocilizumab is rather safe to use in combination with antipsychotics. The most demanding COVID-19 treatments for coadministration with antipsychotics are chloroquine, hydroxychloroquine, azithromycin, and lopinavir/ritonavir because of the risk of QT prolongation and TdP and cytochromes interactions. The systematic review provides highly probable drug interaction between lopinavir/ritonavir plus quetiapine and ritonavir/indinavir plus risperidone. CONCLUSIONS: Clinicians prescribing antipsychotics should be aware of the likely risk of drug-drug interaction with COVID-19 medication and may benefit from taking into account present recommendations of use to preserve patient safety.

Safely Administering Potential QTc Prolonging Therapy Across a Large Health Care System in the COVID-19 Era.

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARs-CoV-2) has resulted in a global pandemic. Hydroxychloroquine±azithromycin have been widely used to treat coronavirus disease 2019 (COVID-19) despite a paucity of evidence regarding efficacy. The incidence of torsade de pointes remains unknown. Widespread use of these medications forced overwhelmed health care systems to search for ways to effectively monitor these patients while simultaneously trying to minimize health care provider exposure and use of personal protective equipment. METHODS: Patients with COVID-19 positive who received hydroxychloroquine±azithromycin across 13 hospitals between March 1 and April 15 were included in this study. A comprehensive search of the electronic medical records was performed using a proprietary python script to identify any mention of QT prolongation, ventricular tachy-arrhythmias and cardiac arrest. RESULTS: The primary outcome of torsade de pointes was observed in 1 (0.015%) out of 6476 hospitalized patients with COVID-19 receiving hydroxychloroquine±azithromycin. Sixty-seven (1.03%) had hydroxychloroquine±azithromycin held or discontinued due to an average QT prolongation of 60.5±40.5 ms from a baseline QTc of 473.7±35.9 ms to a peak QTc of 532.6±31.6 ms. Of these patients, hydroxychloroquine±azithromycin were discontinued in 58 patients (86.6%), while one or more doses of therapy were held in the remaining nine (13.4%). A simplified approach to monitoring for QT prolongation and arrythmia was implemented on April 5. There were no deaths related to the medications with the simplified monitoring approach and health care provider exposure was reduced. CONCLUSIONS: The risk of torsade de pointes is low in hospitalized patients with COVID-19 receiving hydroxychloroquine±azithromycin therapy.

A pharmacovigilance study to quantify the strength of association between the combination of antimalarial drugs and azithromycin and cardiac arrhythmias: implications for the treatment of COVID-19.

Background: Hydroxychloroquine, an antimalarial drug, combined with azithromycin has been considered a potential treatment for COVID-19. However, these drugs may cause electrocardiogram QT prolongation (QTp) and torsade de Pointes (TdP). We examined potential safety signals for these cardiac arrhythmias. Methods: Using the OpenVigil 2.1 MedDRA platform, we mined data from the U.S. Food and Drug Administration's Adverse Event Reporting System (FAERS) from December 2019 to June 2020. We extracted individual case safety reports based on exposures of seven antimalarial drugs, azithromycin, and combinations. All other drugs in FAERS served as controls. Events of interest included QTp and TdP, with associations between drug exposures and events expressed as adjusted Reporting-Odds-Ratios (aRORs) and confidence intervals. The lower end of aROR 95% confidence interval >1 was used as the statistically significant signal detection threshold. Results: QTp safety signals were found for hydroxychloroquine[aROR:11.70 (10.40-13.16)], chloroquine[aROR:18.97 (11.30-31.87)], quinine[aROR:16.66 (10.18-27.25)], atovaquone[aROR:6.91 (4.14-11.56)], azithromycin alone [aROR:28.02 (22.87-34.32)] and hydroxychloroquine + azithromycin [aROR:75.23 (51.15-110.66)]. TdP safety signals were found for hydroxychloroquine [aROR: 5.62 (4.94-6.38)], chloroquine[aROR:49.37 (30.63-79.58)], and hydroxychloroquine + azithromycin[aROR:33.09 (21.22-51.61)]. Conclusion: Hydroxychloroquine/chloroquine and/or azithromycin was associated with QTp/TdP safety signals and their use should be monitored carefully.

Saudi Heart Rhythm Society Task Force on Management of Potential Arrhythmogenicity Associated with Pharmacotherapy for COVID-19.

Evidence of cardiovascular complications associated with the COVID-19 global pandemic continues to evolve. These include direct and indirect myocardial injury with subsequent acute myocardial ischemia, and cardiac arrhythmia. Some results from a limited number of trials of antiviral medications, along with chloroquine/hydroxychloroquine and azithromycin, have been beneficial. However, these pharmacotherapies may cause drug-induced QT prolongation leading to ventricular arrhythmias and sudden cardiac death. Mitigation of the potential risk in these susceptible patients may prove exceptionally challenging. The Saudi Heart Rhythm Society established a task force to perform a review of this subject based on has recently published reports, and studies and recommendations from major medical organizations. The objective of this review is to identify high-risk patients, and to set clear guidelines for management of patients receiving these pharmacotherapies.

Chloroquine or Hydroxychloroquine for Management of Coronavirus Disease 2019: Friend or Foe?

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to be a threat to the health of many humans across the world as they confront coronavirus disease 2019 (COVID-19). Previous promising in vitro data that emerged after the SARS-CoV outbreak in 2003, along with the emergent need for pharmacologic management strategies in the fight against COVID-19, prompted interest in the use of chloroquine and hydroxychloroquine across the globe. Unfortunately, the in vitro activity of these drugs did not necessarily correlate with most in vivo studies, which showed no consistent efficacy. Safety is also a major concern, with these agents having a known risk of QT prolongation and proarrhythmic effects. In addition, clinical practice guidelines provide no clear consensus on the role of chloroquine or hydroxychloroquine for the management of COVID-19. The United States Food and Drug Administration has declared that the potential benefits of these agents no longer outweigh the possible risks, and unless new emerging information suggests a more favorable risk:benefit ratio, neither chloroquine nor hydroxychloroquine should be recommended for COVID-19 treatment or prevention at this time.

Clinical guidance for navigating the QTc-prolonging and arrhythmogenic potential of pharmacotherapy during the COVID-19 pandemic.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for coronavirus disease 19 (COVID-19), has rapidly spread since December 2019 to become the focus of healthcare systems worldwide. Its highly contagious nature and significant mortality has led to its prioritization as a public health issue. The race to prevent and treat this disease has led to "off-label" prescribing of medications such as hydroxychloroquine, azithromycin, and Kaletra (lopinavir/ritonavir). Currently, there is no robust clinical evidence for the use of these drugs in the treatment of COVID-19, with most, if not all of these medications associated with the potential for QT interval prolongation, torsades de pointes, and resultant drug-induced sudden cardiac death. The aim of this document is to help healthcare providers mitigate the potential deleterious effects of drug-induced QTc prolongation.

QT Interval Prolongation Under Hydroxychloroquine/Azithromycin Association for Inpatients With SARS-CoV-2 Lower Respiratory Tract Infection.

Association between Hydroxychloroquine (HCQ) and Azithromycin (AZT) is under evaluation for patients with lower respiratory tract infection (LRTI) caused by the Severe Acute Respiratory Syndrome (SARS-CoV-2). Both drugs have a known torsadogenic potential, but sparse data are available concerning QT prolongation induced by this association. Our objective was to assess for COVID-19 LRTI variations of QT interval under HCQ/AZT in patients hospitalized, and to compare manual versus automated QT measurements. Before therapy initiation, a baseline 12 lead-ECG was electronically sent to our cardiology department for automated and manual QT analysis (Bazett and Fridericia's correction), repeated 2 days after initiation. According to our institutional protocol (Pasteur University Hospital), HCQ/AZT was initiated only if baseline QTc ≤ 480ms and potassium level> 4.0 mmol/L. From March 24th to April 20th 2020, 73 patients were included (mean age 62 ± 14 years, male 67%). Two patients out of 73 (2.7%) were not eligible for drug initiation (QTc ≥ 500 ms). Baseline average automated QTc was 415 ± 29 ms and lengthened to 438 ± 40 ms after 48 hours of combined therapy. The treatment had to be stopped because of significant QTc prolongation in two out of 71 patients (2.8%). No drug-induced life-threatening arrhythmia, nor death was observed. Automated QTc measurements revealed accurate in comparison with manual QTc measurements. In this specific population of inpatients with COVID-19 LRTI, HCQ/AZT could not be initiated or had to be interrupted in less than 6% of the cases.