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 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.
Urgent Guidance for Navigating and Circumventing the QTc-Prolonging and Torsadogenic Potential of Possible Pharmacotherapies for Coronavirus S ince its emergence from Wuhan, China, in late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID- [bib_ref] Inhibition of hERG K currents by antimalarial drugs in stably transfected HEK293..., Traebert [/bib_ref] , has already claimed the lives of more than 70,000 individuals worldwide.With the number of COVID-19 cases and deaths increasing with each passing day, there is perhaps no more pressing need in medicine than to identify safe and efficacious therapies to prevent SARS-CoV-2 infections as well as to attenuate the severity of the resulting COVID-19 illness.Although there are no proven US Food and Drug Administration (FDA)eapproved drugs to prevent or treat COVID-19, a number of promising novel (eg, remdesivir) and repurposed (eg, hydroxychloroquine, potentially together with azithromycin) pharmacological agents, reported to inhibit the growth of SARS-CoV-2 in vitro, [bib_ref] Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in..., Wang [/bib_ref] are being evaluated in randomized clinical trials.
In advance of more definitive evidence, clinicians on the front lines of the pandemic have begun to use these medications under the auspices of "off-label," "compassionate-use," or FDA-approved Emergency Use Authorization (for chloroquine and hydroxychloroquine) with anecdotal success.In light of (1) the need for this practice to continue in the absence of viable, evidence-based therapies and (2) the proclivity of many promising COVID-19 pharmacotherapiesdspecifically antimalarial agents such as hydroxychloroquinedto prolong the QTc, thereby increasing the risk of drug-induced torsades de pointes (DI-TdP) and drug induced-sudden cardiac death (DI-SCD), this document was assembled to help health care professionals safely use these medications and minimize concomitant risks.
PHARMACODYNAMICS AND QTC-PROLONGING/TORSADOGENIC POTENTIAL OF THE ANTIMALARIAL MEDICATIONS CHLOROQUINE AND HYDROXYCHLOROQUINE Chloroquine and its analogue hydroxychloroquine have been used for nearly 80 years as prophylactic pharmacotherapies for malaria. Although still used as antimalarial agents in parts of the world with chloroquinesensitive Plasmodium falciparum protozoa, hydroxychloroquine has found new life as a disease-modifying antirheumatic drug for the management of conditions such as systemic lupus erythematosus and rheumatoid arthritis.
At the cellular level, these antimalarial drugs accumulate in intracellular vesicles such as endosomes and lysosomes where they are protonated, leading to increased vesicular pH. [bib_ref] Effects of chloroquine on viral infections: an old drug against today's diseases?, Savarino [/bib_ref] This process in turn inhibits the activity of the pH-dependent proteases involved in the intracellular processing of secretory proteins with a number of immunologic and nonimmunologic effects, including tumor necrosis factor a and interleukin 6. 7 Collectively, a reduction in these secretory proteins is believed to result in (1) the accumulation of cytotoxic heme that poisons P falciparum protozoa and (2) modulation of immune cell behavior in a manner that attenuates inflammatory processes. [bib_ref] Effects of chloroquine on viral infections: an old drug against today's diseases?, Savarino [/bib_ref] In addition, chloroquine and hydroxychloroquine possess antiviral properties in vitro. [bib_ref] Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in..., Wang [/bib_ref] [bib_ref] Effects of chloroquine on viral infections: an old drug against today's diseases?, Savarino [/bib_ref] [bib_ref] Chloroquine is a potent inhibitor of SARS coronavirus infection and spread, Vincent [/bib_ref] Both chloroquine and hydroxychloroquine are believed to act on the entry and postentry stages of severe acute respiratory syndrome coronavirus and SARS-CoV-2 infection, likely via effects on endosomal pH and the resulting underglycosylation of angiotensin-converting enzyme 2 receptors that are required for viral entry. [bib_ref] Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in..., Wang [/bib_ref] [bib_ref] Chloroquine is a potent inhibitor of SARS coronavirus infection and spread, Vincent [/bib_ref] Based on this in vitro data, it has been hypothesized that hydroxychloroquine, more so than chloroquine, may have therapeutic efficacy in the COVID-19 pandemic by (1) preventing SARS-CoV-2 infection by inhibiting angiotensin-converting enzyme 2emediated viral entry (ie, preinfection prophylaxis) and (2) attenuating the postviral cytokine storm observed in severe COVID-19 cases via a multitude of immunomodulatory mechanisms (ie, treatment of active infection/postviral sequelae). Promising in vitro data [bib_ref] Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in..., Wang [/bib_ref] as well as anecdotal in vivo evidence of therapeutic benefit 5 have led many institutions, including Mayo Clinic, to consider the use of hydroxychloroquine as a first-line COVID-19 pharmacotherapy for the time being and spurred an array of clinical trials designed to assess the efficacy of repurposed hydroxychloroquine in both the prevention and treatment of COVID-19.
Although the collective safety profiles of chloroquine and hydroxychloroquine are relatively favorable, both drugs block the KCNH2-encoded HERG/K v 11.1 potassium channel and potentially can prolong the QTc. In at-risk individuals, these so-called HERG blockers can precipitate DI-TdP or, worse, DI-SCD, especially with long-term use [fig_ref] TABLE 1: Torsadogenic Potential and Postmarketing Adverse Events Associated With Possible COVID-19 Repurposed Pharmacotherapies... [/fig_ref]. As a result, the number of DI-SCDs attributable to hydroxychloroquine in particular is not trivial [fig_ref] TABLE 1: Torsadogenic Potential and Postmarketing Adverse Events Associated With Possible COVID-19 Repurposed Pharmacotherapies... [/fig_ref]. With the theoretical possibility that a substantial proportion of the world population could receive hydroxychloroquine as first-line prophylaxis or treatment, including an estimated 3 million individuals with congenital long QT syndrome (LQTS), the number of hydroxychloroquine-mediated DI-SCDs could increase precipitously unless appropriate QTc monitoring algorithms are instituted. This risk of DI-SCD could be further amplified if multiple medications, each with their own QTc-prolonging/ torsadogenic potential (eg, chloroquine/ hydroxychloroquine plus azithromycin and/ or lopinavir/ritonavir), are used in combination [fig_ref] TABLE 1: Torsadogenic Potential and Postmarketing Adverse Events Associated With Possible COVID-19 Repurposed Pharmacotherapies... [/fig_ref].

## Mitigating the potential risk of di-tdp and di-scd associated with widespread use of chloroquine/ hydroxychloroquine in the covid-19 pandemic
Although some might argue that DI-SCDs in the setting of widespread chloroquine/ hydroxychloroquine use represents acceptable "friendly fire" in the war on SARS-CoV-2/COVID-19, we believe that with the institution of a few simple and safe precautions, the risk of DI-TdP and DI-SCD can be mitigated. Ultimately, it comes down to identifying the small subset of individuals who, either secondary to an underlying genetic predisposition (such as congenital LQTS, which is present in 1 in 2000 people) and/or by virtue of the presence of multiple modifiable and nonmodifiable QTc risk factors [fig_ref] TABLE 2: Modifiable and Nonmodifiable Risk Factors for Drug-Induced Long QT Syndrome/ Torsades de... [/fig_ref] , [bib_ref] Institution-wide QT alert system identifies patients with a high risk of mortality, Haugaa [/bib_ref] have excessive baseline QTc prolongation (QTc !500 ms) and/or have an inherent tendency for development of an exaggerated QTc response (ie, DQTc !60 ms) following exposure to medications with the adverse effect of potential QTc prolongation [fig_ref] FIGURE 1: Approach to mitigating the risk of drug-induced torsades de pointes [/fig_ref]. Although the percentage of individuals at risk is small, given the pandemic nature of COVID-19, in absolute terms the number of individuals potentially at risk for lethal adverse drug effects is large (at least 10,000 individuals of the >1,000,000 COVID-19epositive patients worldwide are expected to be at increased risk for DI-TdP/DI-SCD if treated with these medications). This issue would be especially true if these medications are adopted for postexposure prophylaxis.
Traditionally, the QTc is calculated from either lead II or V 5 of the 12-lead electrocardiogram (ECG) and corrected for heart rate using the Bazett or Fridericia formula before any intraindividual or interindividual QTc comparisons are made. Unfortunately, in the context of the COVID-19 pandemic, acquisition of the patient's QTc by the 12-lead ECG, which requires additional personnel exposure (ie, ECG technician), and a necessity for serial ECGs, which requires exposure of complex equipment (multiple ECG wires), could further strain the already limited supply of personal protective equipment (PPE) in many countries. Alternatively, some FDAapproved consumer mobile ECG devices are capable of generating accurate QTc measurements. [bib_ref] Comparison of QT interval readings in normal sinus rhythm between a smartphone..., Garabelli [/bib_ref] To this end, AliveCor, Inc, just received emergency clearance from the FDA for use of the KardiaMobile 6L device (FDAapproved for atrial fibrillation detection) for QTc monitoring of patients with COVID-19 treated with QT-prolonging medications such as chloroquine/hydroxychloroquine (March 20, 2020, 1:15 PM CST). Similarly, many telemetry systems are equipped with real-time QTc monitoring features that could be used for hospitalized patients.
For patients with COVID-19 about to be treated with medications with the increased potential for DI-TdP/DI-SCD [fig_ref] FIGURE 1: Approach to mitigating the risk of drug-induced torsades de pointes [/fig_ref] , baseline QTc status should be obtained either by a traditional 12-lead ECG or perhaps preferably with the use of a smartphoneenabled mobile QTc meter using the simple infection control measures outlined in to limit personnel exposures and conserve critical PPE. On average, the QTc values for otherwise healthy postpubertal males and females are around 410 ms and 420 ms, respectively. In contrast, a QTc value that exceeds the 99th percentile value for otherwise healthy individuals (ie, 460 ms in both sexes before puberty, 470 ms in postpubertal males, and 480 ms in postpubertal females), in the absence of any exogenous QTc-aggravating factors, may signal an individual at increased risk for QT-related ventricular arrhythmias. [bib_ref] International recommendations for electrocardiographic interpretation in athletes, Sharma [/bib_ref] [bib_ref] Determination and interpretation of the QT interval, Vink [/bib_ref] In contrast and as a frame of reference, the average QTc value was 470 ms for the more than 1400 patients with congenital LQTS who have been cared for in Mayo Clinic's Windland Smith Rice Genetic Heart Rhythm Clinic. Furthermore, with very few exceptions (amiodarone being one), patients with a resting QTc of 500 ms or more, whether secondary to congenital LQTS or acquired (QTc-prolonging drugs, QTc-prolonging electrolyte abnormalities such as hypokalemia, or QTc-prolonging disease states as detailed in [fig_ref] TABLE 2: Modifiable and Nonmodifiable Risk Factors for Drug-Induced Long QT Syndrome/ Torsades de... [/fig_ref] , have a considerably greater risk for both DI-TdP and DI-SCD. 14e16 Accordingly, the baseline QTc value can be used to roughly approximate the patient's risk of DI-TdP/DI-SCD following initiation of a medication with QTc-prolonging potential. For patients with QTc values less than the 99th percentile for age/sex (ie, 460 ms in prepubertal males/females, 470 ms in postpubertal males, and 480 ms in postpubertal females [ [fig_ref] FIGURE 1: Approach to mitigating the risk of drug-induced torsades de pointes [/fig_ref] "green light" status]), the risk of DI-TdP/DI-LQTS is low, and chloroquine/ hydroxychloroquine (or other QTcprolonging COVID-19 pharmacotherapies) should be initiated without delay as outlined in the QTc monitoring algorithm. Remember, whether by 12-lead ECG, telemetry, or smartphone-enabled acquisition of the ECG, if the noted QT interval is less than one-half the preceding RR interval, then the calculated QTc will always be less than 460 ms and the patient can be "green light go" for COVID-19 treatments that may have QTc-prolonging potential. - High-risk comorbid condition(s) (CKD, COPD, CHF, cystic fibrosis, or pulmonary fibrosis).
- Obtain pretreatment Q Tc using standard 12-lead ECG, telemetry, or mobile ECG device (see for details). - Obtain baseline expanded electrolytes (Ca 2+ , Mg 2+ , and K + ). - Determine if any home QTcprolonging medications can be discontinued (www.qtdrugs.org). - Document high-risk CV and comorbid conditions (see [fig_ref] TABLE 2: Modifiable and Nonmodifiable Risk Factors for Drug-Induced Long QT Syndrome/ Torsades de... [/fig_ref].

## Yes

## 90%
QTc 460 ms (prepuberty), 470 ms (postpubertal males), and 480 ms (postpubertal females), but <500 ms.

## 9%
- Repeat QTc using standard 12-lead ECG, telemetry, or mobile ECG device (see for details). - Obtain baseline expanded electrolytes (Ca 2+ , Mg 2+ , and K + ).

## Post-treatment checklist

## Enroll
Monitoring per trial protocol.
QTc-prolonging drug(s) under consideration?
(eg. chloroquine, hydroxychloroquine  azithromycin, and/or lopinavir/ritonavir).

## Or
Consider alternative non-QTc-prolonging therapies with in vitro activity against SARS-CoV-2  or no therapy. ) treated following a hypothetical treatment algorithm with "off-label" hydroxychloroquine alone or in combination with azithromycin. Both medications are known HERG blockers with both QTc-prolonging and torsadogenic potential. The estimated 99th percentile QTc values (derived from otherwise healthy individuals), which places a patient in the "green light" category, are less than 460 ms before puberty, less than 470 ms in men, and less than 480 ms in women. We estimate that the baseline QTc assessment will place 90% of patients in green light, 9% in yellow light, and 1% in red light status. *Severe COVID-19 cases are defined as a respiratory rate of greater than 30 breaths/min (adults) or 40 breaths/min (children), oxygen saturation of 93% or less, PaO 2 to fraction of inspired oxygen ratio less than 300, or lung infiltrates involving more than 50% of the lung field after 24 to 48 hours. U Repurposed antiviral alternatives such as lopinavir/ritonavir also have QTc-prolonging effects. CHF 14 congestive heart failure; CKD 14 chronic kidney disease; COPD 14 chronic obstructive pulmonary disease; CV 14 cardiovascular; ECG 14 electrocardiography; ICU 14 intensive care unit; NIAID 14 National Institute of Allergy and Infectious Diseases.

## Covid-19 pharmacotherapies and qtc/tdp susceptibility
In contrast, those patients with a baseline QTc of 500 ms or greater are at increased risk for DI-TdP/DI-SCD [fig_ref] FIGURE 1: Approach to mitigating the risk of drug-induced torsades de pointes [/fig_ref] "red light" status) and every effort should be made to (1) assess and correct for contributing electrolyte abnormalities (eg, replete potassium and magnesium to levels > 4 mmol/L and > 2 mg/dl, respectively), (2) review and discontinue other unnecessary QTc-prolonging medications if present or transition to alternatives with less QTc liability, and/or (3) proceed with closer monitoring (telemetry) or even consideration of more advanced countermeasures such as equipping the patient with a wearable defibrillator (eg, LifeVest [ZOLL Medical Corporation]) if the decision is made to commence therapy.
In the setting of a QTc value of 500 ms or greater, navigating and circumventing this QTc liability depends greatly on the riskbenefit calculus, and the decision rests with the treating clinician and patient. For example, in younger patients with COVID-19 (ie, <40 years) who have only mild symptoms and a QTc of 500 ms or greater, it may be reasonable to avoid treatment altogether because the arrhythmia risk may outweigh the risk of developing COVID-19erelated acute respiratory distress syndrome. However, in patients with a QTc of 500 ms or greater presenting with progressively worsening respiratory symptoms or at greater risk (eg, >65 years of age, immunosuppressed, and/or high-risk comorbid conditions) for respiratory complications, the potential benefit of QTc-prolonging COVID-19 pharmacotherapies may exceed the arrhythmia risk. Importantly, if the decision has been made to proceed with such therapies for the patient with a "red light" QTc value (ie, QTc >14 500 ms), it may be reasonable to give magnesium prophylactically, regardless of their magnesium level, as an anti-torsadogenic counter measure. Therefore, the ultimate goal of QTc surveillance in the COVID-19 pandemic should NOT be to identify those who cannot receive these medications but to identify those with FIGURE 2. Protocols for the possible inpatient and outpatient use of a smartphone-enabled mobile electrocardiogram (ECG) to assess and monitor QTc values in patients with coronavirus disease 19. A, Inpatient protocol using dedicated institutional smartphone/ tablet and mobile ECG device. Whenever possible, we strongly recommend the use of a dedicated institutional Bluetooth-enabled smartphone or tablet device that is not used for personal use (ie, phone calls or other activities) to limit the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). B, Inpatient or outpatient protocol using personal (or institutionally loaned) smartphone/tablet and mobile ECG device. *Currently, the only smartphone-enabled mobile ECG with US Food and Drug Administration approval for QTc monitoring is the AliveCor KardiaMobile 6L device. PPE 14 personal protective equipment. compromised or reduced "repolarization reserve" in whom increased QTc countermeasures can and should be taken to mitigate the risk of drug-related death from DI-TdP/DI-SCD. [bib_ref] Long QT syndrome: reduced repolarization reserve and the genetic link, Roden [/bib_ref] Ultimately, much of the risk-benefit calculus awaits determination of the therapeutic efficacy of hydroxychloroquine, with or without concomitant azithromycin. Until such information is available, if the decision has been made to treat a patient with a red light designation [fig_ref] FIGURE 1: Approach to mitigating the risk of drug-induced torsades de pointes [/fig_ref] based on their baseline QTc of 500 ms or greater, it seems prudent to start with hydroxychloroquine alone, rather than combination drug therapy with azithromycin. In addition, if combination drug therapy, with hydroxychloroquine and azithromycin, was initiated in a patient with an initial green light/yellow light QTc status and the individual transitions to red light status after self-identification as a "QTc reactor" with a DQTc of 60 ms or greater, then consideration should be given to discontinuing azithromycin, optimizing electrolyte status, or intensifying countermeasures further (placing on telemetry for continuous rhythm assessment).

## Frequency of qtc surveillance and adjustments in the setting of wide qrs complex
Ideally, following a baseline QTc assessment, therapy may be initiated with either QTc reassurance (low risk for the vast majority [90%] of patients) or varying QTc countermeasures in place for those flagged as at increased risk. The timing of on-therapy QTc surveillance will be dictated not only by the pharmacokinetics of the COVID-19 therapies used but also by the practical logistics of an institution's method of QTc monitoring. For the 12-lead ECG approach, if QTc surveillance is deemed important, then one machine should be designated for acquisition of the data and a limited number of ECG technicians/personnel should be used to minimize PPE utilization and personnel exposure. Also, the number of on-therapy QTc assessments should be constrained to minimize personnel exposure risk and PPE consumption. In this scenario, for those placed in red light status because their baseline QTc is 500 ms or greater, an initial on-therapy QTc should be obtained around 2 to 4 hours after the first dose and then again at 48 hours and 96 hours following treatment initiation. Patients receiving either green light or yellow light status can probably forego the early QTc assessment and wait until 48 hours and 96 hours for their on-drug QTc determination. If the ontherapy QTc is 500 ms or greater or the patient self-identified as a QTc reactor with a DQTc of 60 ms or greater, then the QTc countermeasures need to be reexamined or the medications stopped in an effort to neutralize the increased potential for DI-TdP and DI-SCD [fig_ref] FIGURE 1: Approach to mitigating the risk of drug-induced torsades de pointes [/fig_ref].
In contrast, for medical centers able to implement the FDA emergency-approved, smartphone-enabled approach or to determine the QTc from the telemetry strips, ECG technician exposure risk and consumption of PPE by those individuals would be eliminated and the patient's QTc could be obtained by the health care team already present, for example, with the QTc obtained per shift as another vital sign. [bib_ref] The QT interval, Giudicessi [/bib_ref] Such increased QTc surveillance would enable discovery of the QTc reactor and implementation of countermeasures sooner and hopefully would thereby circumvent the potentially preventable tragedy of DI-SCD [fig_ref] FIGURE 1: Approach to mitigating the risk of drug-induced torsades de pointes [/fig_ref].
Finally, for patients with a wide QRS complex from either ventricular pacing or right/left bundle branch block, a wide QRS complex QTc adjustment will need to be made. Otherwise, patients will receive a red light signal inappropriately, resulting in therapy delay, discontinuation, or avoidance altogether. In this setting, the simplest approach is to maintain the previously indicated QTc green, yellow, and red light thresholds and apply a simple formula to account for the wide QRS complex (wide QRS complexeadjusted QTc 14 QTc e [QRS A 120 ms]). For example, if a patient's left bundle branch block has yielded a QRS complex of 200 ms and a QTc of 520 ms, this scenario would appear to activate the red light pathway [fig_ref] FIGURE 1: Approach to mitigating the risk of drug-induced torsades de pointes [/fig_ref]. However, the wide QRS complexeadjusted QTc would be 520 ms e (200 A 120 ms) 14 520 A 80 14 440 ms, which is not red light status at all but rather "green light go" status with much QTc reassurance that the patient is at low risk for DI-SCD.

# Conclusion
As this coronavirus pandemic continues to spread and wreak havoc, economic loss, and more importantly, the tragic deaths of thousands throughout the world, we must all do our part in this war on COVID-19. Washing hands and physical distancing are core components of containment efforts to "flatten the curve." Development of a coronavirus vaccine is progressing at unprecedented speed but is still at least 12 to 18 months away. In the meantime, there is hope that a long-ago discovered antimalarial drug, hydroxychloroquine, may have lifesaving therapeutic efficacy against COVID-19. And if it does, we hope that this simple QTc surveillance strategy, enabled by innovation and the FDA's emergency approval, will help prevent altogether or at least substantially reduce the number of druginduced ventricular arrhythmias and sudden cardiac deaths, particularly if there is widespread adoption and utilization of these medications for COVID-19. Potential Competing Interests: Dr Ackerman is a consultant for Abbott, Audentes Therapeutics, BIOTRONIK SE & Co. KG, Boston Scientific Corporation, Invitae Corporation, LQT Therapeutics Inc, Medtronic, and MyoKardia. Drs Noseworthy, Friedman, and Ackerman and Mayo Clinic are involved in an equity/royalty relationship with AliveCor, Inc (not involved in this study). Dr Giudicessi reports no competing interests.
[fig] FIGURE 1: Approach to mitigating the risk of drug-induced torsades de pointes (TdP)/drug-induced sudden cardiac death in patients with coronavirus disease 19 (COVID-19 [/fig]
[table] TABLE 1: Torsadogenic Potential and Postmarketing Adverse Events Associated With Possible COVID-19 Repurposed Pharmacotherapies a COVID-19 14 coronavirus disease 2019; FAERS 14 US Food and Drug Administration Adverse Event Reporting System; LQTS 14 long QT syndrome; SARS-CoV-2 14 severe acute respiratory syndrome coronavirus 2; TdP 14 torsades de pointes; VF 14 ventricular fibrillation; VT 14 ventricular tachycardia.Adverse event reporting from postmarketing surveillance does not account for prescription volume and is often subjected to substantial bias from confounding variables, quality of reported data, duplication, and underreporting of events.Lopinavir/ritonavir has been found to inhibit other severe acute respiratory syndrome viruses in vitro. However, a recent randomized trial found no benefit in COVID-19. [/table]
[table] TABLE 2: Modifiable and Nonmodifiable Risk Factors for Drug-Induced Long QT Syndrome/ Torsades de Pointes a,b [/table]