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Considerations for drug interactions on QTc interval in exploratory COVID-19 treatment

      Hydroxychloroquine and azithromycin have been touted for potential prophylaxis or treatment for patients with coronavirus disease 2019 (COVID-19). Both drugs are listed as definite causes of torsade de pointes at crediblemeds.org. There are occasional case reports of hydroxychloroquine’s prolonging the QT interval and provoking torsade de pointes
      • Chen C.Y.
      • Wang F.L.
      • Lin C.C.
      Chronic hydroxychloroquine use associated with QT prolongation and refractory ventricular arrhythmia.
      • Morgan N.D.
      • Patel S.V.
      • Dvorkina O.
      Suspected hydroxychloroquine-associated QT-interval prolongation in a patient with systemic lupus erythematosus.
      • O’Laughlin J.P.
      • Mehta P.H.
      • Wong B.C.
      Life threatening severe QTc prolongation in patient with systemic lupus erythematosus due to hydroxychloroquine.
      • de Olano J.
      • Howland M.A.
      • Su M.K.
      • Hoffman R.S.
      • Biary R.
      Toxicokinetics of hydroxychloroquine following a massive overdose.
      when used to treat systemic lupus erythematosus. Antimalarial prophylactic drugs, such as hydroxychloroquine, are believed to act on the entry and post-entry stages of severe acute respiratory syndrome–associated coronavirus (SARS-CoV) and severe acute respiratory syndrome coronavirus 2 (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.
      • Giudicessi J.R.
      • Noseworthy P.A.
      • Friedman P.A.
      • Ackerman M.J.
      Urgent guidance for navigating and circumventing the QTc prolonging and torsadogenic potential of possible pharmacotherapies for COVID-19. Mayo Clin Proc.
      The widely used antibiotic azithromycin is increasingly recognized as a rare cause of QT interval prolongation,
      • Choi Y.
      • Lim H.-S.
      • Chung D.
      • Choi J.-G.
      • Yoon D.
      Risk evaluation of azithromycin-induced QT prolongation in real-world practice.
      ,
      • Sears S.P.
      • Getz T.W.
      • Austin C.O.
      • Palmer W.C.
      • Boyd E.A.
      • Stancampiano F.F.
      Incidence of sustained ventricular tachycardia in patients with prolonged QTc after the administration of azithromycin: a retrospective study.
      serious arrhythmias,
      • Huang B.H.
      • Wu C.H.
      • Hsia C.P.
      • Yin Chen C.
      Azithromycin-induced torsade de pointes.
      ,
      • Kezerashvili A.
      • Khattak H.
      • Barsky A.
      • Nazari R.
      • Fisher J.D.
      Azithromycin as a cause of QT-interval prolongation and torsade de pointes in the absence of other known precipitating factors.
      and increased risk for sudden death
      • Ray W.A.
      • Murray K.T.
      • Hall K.
      • Arbogast P.G.
      • Stein C.M.
      Azithromycin and the risk of cardiovascular death.
      ; advanced age and female sex have been implicated as risk factors. Interestingly, azithromycin can also provoke non-pause-dependent polymorphic ventricular tachycardia.
      • Kim M.H.
      • Berkowitz C.
      • Trohman R.G.
      Polymorphic ventricular tachycardia with a normal QT interval following azithromycin.
      ,
      • Yang Z.
      • Prinsen J.K.
      • Bersell K.R.
      • et al.
      Azithromycin causes a novel proarrhythmic syndrome.
      A U.S. Food and Drug Administration perspective supported the observations that azithromycin administration leaves the patient vulnerable to corrected QT (QTc) interval prolongation and torsade de pointes.
      • Mosholder A.D.
      • Mathew J.
      • Alexander J.J.
      • Smith H.
      • Nambiar S.
      Cardiovascular risks with azithromycin and other antibacterial drugs.
      Basic electrophysiological studies suggest that both drugs can provoke proarrhythmia via mechanisms beyond block of the rapidly activating delayed rectifier potassium current IKr implicated in usual cases of torsade de pointes.
      • Zhang M.
      • Xie M.
      • Li S.
      • et al.
      Electrophysiologic studies on the risks and potential mechanism underlying the proarrhythmic nature of azithromycin.
      ,
      • Capel R.A.
      • Herring N.
      • Kalla M.
      • et al.
      Hydroxychloroquine reduces heart rate by modulating the hyperpolarization-activated current If: novel electrophysiological insights and therapeutic potential.
      The effect of the combination of these agents on QT interval or arrhythmia risk has not been studied. There are very limited data evaluating the safety of combination therapy. Multiple randomized trials are currently being initiated.
      Seriously ill patients often have comorbidities that can increase the risk for serious arrhythmias. These include hypokalemia, hypomagnesemia, fever,
      • Kauthale R.R.
      • Dadarkar S.S.
      • Husain R.
      • Karande V.V.
      • Gatne M.M.
      Assessment of temperature-induced hERG channel blockade variation by drugs.
      and an inflammatory state.
      • Aromolaran A.S.
      • Srivastava U.
      • Ali A.
      • et al.
      Interleukin-6 inhibition of hERG underlies risk for acquired long QT in cardiac and systemic inflammation.
      Mechanisms to minimize arrhythmia risk include the following:
      • Electrocardiographic/QT interval monitoring
        • 1.
          Withhold the drugs in patients with baseline QT interval prolongation (e.g., QTc interval ≥500 ms) or with known congenital long-QT syndrome.
        • 2.
          Monitor cardiac rhythm and QT interval, and withdraw the drugs if QTc interval exceeds a preset threshold of 500 ms.
        • 3.
          In patients critically ill with COVID-19, frequent caregiver contact may need to be minimized, so optimal electrocardiographic interval and rhythm monitoring may not be possible.
      • Correction of hypokalemia to a level of >4 mEq/l and hypomagnesemia to a level of >2 mg/dl
      • Avoidance of other QTc interval–prolonging agents
        • Giudicessi J.R.
        • Noseworthy P.A.
        • Friedman P.A.
        • Ackerman M.J.
        Urgent guidance for navigating and circumventing the QTc prolonging and torsadogenic potential of possible pharmacotherapies for COVID-19. Mayo Clin Proc.
        whenever feasible
      Safety considerations for the use of hydroxychloroquine and azithromycin in clinical practice have been described.
      • Simpson T.F.
      • Kovacs R.J.
      • Stecker E.C.
      Some of the current COVID-19-repurposed drugs are listed in Table 1.
      Table 1Torsade de pointes potential and post-marketing adverse events associated with possible COVID-19-repurposed pharmacotherapies
      CredibleMeds classificationVT/VF/TdP/LQTS in FAERSCardiac arrest in FAERS
      Repurposed antimalarial agents
       ChloroquineKnown risk7254
       HydroxychloroquineKnown risk222105
      Repurposed antiviral agents
       Lopinavir/ritonavirPossible risk2748
      Adjunct agents
       AzithromycinKnown risk396251
      Reproduced with permission from Giudicessi et al.
      • Giudicessi J.R.
      • Noseworthy P.A.
      • Friedman P.A.
      • Ackerman M.J.
      Urgent guidance for navigating and circumventing the QTc prolonging and torsadogenic potential of possible pharmacotherapies for COVID-19. Mayo Clin Proc.
      COVID-19 = coronavirus disease 2019; FAERS = U.S. Food and Drug Administration Adverse Event Reporting System; LQTS = long-QT syndrome; TdP = torsade de pointes.

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