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COVID-19 and hydroxychloroquine: Is the wonder drug failing?

  • Ugo Paliani
    Correspondence
    Corresponding author at: Division of Internal Medicine and Sport Cardiology and Director of the Umbria Covid Hospital. Media Valle del Tevere Hospital, Todi, Italy.
    Affiliations
    Division of Internal Medicine and Sport Cardiology. Media Valle del Tevere Hospital, Todi, Umbria, Italy

    Umbria Covid Hospital, Todi, Umbria, Italy
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  • Andrea Cardona
    Affiliations
    Division of Internal Medicine and Sport Cardiology. Media Valle del Tevere Hospital, Todi, Umbria, Italy

    Umbria Covid Hospital, Todi, Umbria, Italy

    Division of Cardiovascular Medicine - Department of Internal Medicine. The Ohio State University, Columbus, Ohio, USA
    Search for articles by this author
      The absence of an effective treatment against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has led clinicians to redirect drugs that are known to be effective for other medical conditions to the treatment of Covid-19. Chloroquine and hydroxychloroquine are widely used in the treatment of malaria and rheumatic diseases, and they have been suggested as effective treatments for Covid-19 on the grounds of both anti-inflammatory and antiviral effects [
      • Biot C.
      • Daher W.
      • Chavain N.
      • Fandeur T.
      • Khalife J.
      • Dive D.
      • De Clercq E
      Design and synthesis of hydroxyferroquine derivatives with antimalarial and antiviral activities.
      ,
      • Fox R.I.
      Mechanism of action of hydroxychloroquine as an antirheumatic drug.
      ,

      Devaux C.A., Rolain J.M., Colson P., Raoult D. New insights on the antiviral effects of chloroquine against coronavirus: what to expect for covid-19? Int J Antimicrob Agents. 2020:105938.

      ,
      • Fantini J.
      • Di Scala C.
      • Chahinian H.
      • Yahi N
      Structural and molecular modelling studies reveal a new mechanism of action of chloroquine and hydroxychloroquine against sars-cov-2 infection.
      ]. Mounting data suggest that Covid-19 is burdened by a higher risk of arrhythmic events, with important implications for survival [
      • Driggin E.
      • Madhavan M.V.
      • Bikdeli B.
      • Chuich T.
      • Laracy J.
      • Biondi-Zoccai G.
      • Brown T.S.
      • Der Nigoghossian C.
      • Zidar D.A.
      • Haythe J.
      • Brodie D.
      • Beckman J.A.
      • Kirtane A.J.
      • Stone G.W.
      • Krumholz H.M.
      • Parikh S.A
      Cardiovascular considerations for patients, health care workers, and health systems during the covid-19 pandemic.
      ]. Hydroxychloroquine, with or without a second-generation macrolide, has also been advocated despite limited evidence for its effectiveness and known detrimental effect of prolongation of the QT interval, which could be a mechanism that predisposes to ventricular arrhythmias [

      Gautret P., Lagier J.C., Parola P., Hoang V.T., Meddeb L., Mailhe M., Doudier B., Courjon J., Giordanengo V., Vieira V.E., Dupont H.T., Honore S., Colson P., Chabriere E., La Scola B., Rolain J.M., Brouqui P., Raoult D. Hydroxychloroquine and azithromycin as a treatment of covid-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020:105949.

      ,
      • Ray W.A.
      • Murray K.T.
      • Hall K.
      • Arbogast P.G.
      • Stein C.M
      Azithromycin and the risk of cardiovascular death.
      ,
      • 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 coronavirus disease 19 (covid-19).
      ].
      In the United States, the FDA issued an Emergency Use Authorization on March 30, 2020, that allowed the use of these drugs in patients with Covid-19 who were not enrolled in clinical trials, and to date, they have been used in many thousands of patients with acute Covid-19 around the world.
      Although several multicenter randomized controlled trials are underway, there is an urgent clinical need to provide accurate clinical guidance. Also, some countries have stockpiled these drugs, resulting in a shortage of these medications for approved clinical indications [
      • Peschken C.A.
      Possible consequences of a shortage of hydroxychloroquine for patients with systemic lupus erythematosus amid the covid-19 pandemic.
      ].
      Table 1. summarizes the most important studies published as of May 27th on the use of hydroxychloroquine for treatment of Covid-19 infection.
      Table 1Relevant studies published as of May 27th, 2020 on use of hydroxychloroquine for treatment of Covid-19 infection.
      StudyJournalPublished DateStudy PopulationTreatment RegimenOutcome
      Mercuro et al.
      • Mercuro N.J.
      • Yen C.F.
      • Shim D.J.
      • Maher T.R.
      • McCoy C.M.
      • Zimetbaum P.J.
      • Gold H.S
      Risk of QT interval prolongation associated with use of hydroxychloroquine with or without concomitant azithromycin among hospitalized patients testing positive for coronavirus disease 2019 (covid-19).
      Single center, retrospective, observational study
      JAMA CardiologyMay 1st, 202090 hospitalized subjects, mean age 60 years, 49% femaleAll patients Received HCQ, and 53 (59%) received HCQ+ AZM*QTc prolongation (ΔQTc 21 ms), and those taking HCQ+AZM had greater QT prolongation than those taking HCQ alone. One patient developed torsades de pointes
      Mahévas et al.
      • Mahevas M.
      • Tran V.T.
      • Roumier M.
      • Chabrol A.
      • Paule R.
      • Guillaud C.
      • Fois E.
      • Lepeule R.
      • Szwebel T.A.
      • Lescure F.X.
      • Schlemmer F.
      • Matignon M.
      • Khellaf M.
      • Crickx E.
      • Terrier B.
      • Morbieu C.
      • Legendre P.
      • Dang J.
      • Schoindre Y.
      • Pawlotsky J.M.
      • Michel M.
      • Perrodeau E.
      • Carlier N.
      • Roche N.
      • de Lastours V.
      • Ourghanlian C.
      • Kerneis S.
      • Menager P.
      • Mouthon L.
      • Audureau E.
      • Ravaud P.
      • Godeau B.
      • Gallien S.
      • Costedoat-Chalumeau N
      Clinical efficacy of hydroxychloroquine in patients with covid-19 pneumonia who require oxygen: observational comparative study using routine care data.
      Comparative observational study
      BMJMay 5th, 2020173 hospitalized subjects, median age 60 years, 28% female84 patients received HCQ and 89 did not (control group)**Rate of survival without transfer to the intensive care unit was not significantly different among those taking HCQ and those who did not (76 vs. 75%)
      Geleris et al.
      • Geleris J.
      • Sun Y.
      • Platt J.
      • Zucker J.
      • Baldwin M.
      • Hripcsak G.
      • Labella A.
      • Manson D.
      • Kubin C.
      • Barr R.G.
      • Sobieszczyk M.E.
      • Schluger N.W
      Observational study of hydroxychloroquine in hospitalized patients with covid-19.
      Single center, retrospective, observational study
      NEJMMay 7th, 20201376 hospitalized subjects, 60.5% age ≥ 60 years, 43% female811 (58.9%) received HCQ*** and 565 did not (control group).No significant association between HCQ use and the primary outcome of intubation or death (HR 1.04, 95%CI 0.82–1.32). Results were similar in multiple sensitivity analyses.
      Rosemberg et al.
      • Rosenberg E.S.
      • Dufort E.M.
      • Udo T.
      • Wilberschied L.A.
      • Kumar J.
      • Tesoriero J.
      • Weinberg P.
      • Kirkwood J.
      • Muse A.
      • DeHovitz J.
      • Blog D.S.
      • Hutton B.
      • Holtgrave D.R.
      • Zucker H.A
      Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with covid-19 in new york state.
      Multicenter, retrospective, cohort study
      JAMAMay 11th, 20201438 hospitalized subjects, median age, 63 years, 40.3% femaleFour groups: 1) HCQ+AZM (n = 735), 2) HCQ alone (n = 271), 3) AZM alone (n = 211), or 4) neither drug (n = 221)¥Overall in-hospital mortality rates in the four groups were 25.7% (1), 19.9% (2), 10.0% (3), and 12.7% (4), respectively, with no significant between-group differences after adjustment for potential confounders
      Mehra et al.
      • Mehra MR D.S.
      • Ruschitzka F.
      • Patel A.N
      Hydroxychloroquine or chloroquine with or without a macrolide for treatment of covid-19: a multinational registry analysis.
      Multinational registry study
      The LancetMay 22nd, 2020671 hospitals in six continents for a total of 96,032 patients, mean age 53.8 years, 46.3% female14,888 patients were in the treatment groups: 1868 received CQ, 3783 received CQ + macrolide, 3016 received HCQ, and 6221 received HCQ + macrolide§. 81,144 patients were in the control groupAfter controlling for multiple confounding factors when compared with mortality in the control group (9.3%); HCQ (18.0%; HR 1.3, 95%CI 1.2–1.5), HCQ+macrolide (23.8%; HR 1.5, 95%CI 1.4–1.5), CQ (16.4%; HR 1.4, 95%CI 1.2–1.5), and CQ+macrolide (22.2%; HR 1.4, 95%CI 1.3–1.5) were each independently associated with an increased risk of in-hospital mortality
      Note: HCQ: hydroxychloroquine, AZM: azithromycin, CQ: chloroquine. HR: hazard ratio, CI: confidence interval. Treatment regimens: * HCQ 400 mg twice on day 1, then 400 mg daily on days 2 through 5; ** HCQ 600 mg/day within 48 h of admission; ** HCQ 600 mg twice on day 1, then 400 mg daily for a median of 5 days; ¥ refer to eTable1 of the original publication; § CQ alone, 765 mg for 6.6 days; HCQ alone, 596 mg for 4.2 days; CQ+macrolide, 790 mg for 6.8 days; and HCQ+macrolide, 597 mg for 4.3 days.
      Mehra and colleagues published in the The Lancet, May 22nd, the largest observational study to date on the effects of chloroquine or hydroxychloroquine, with or without a macrolide, in 96,032 hospitalized patients (mean age 54 years, 46% women) who tested positive for SARS-CoV-2 [
      • Mehra MR D.S.
      • Ruschitzka F.
      • Patel A.N
      Hydroxychloroquine or chloroquine with or without a macrolide for treatment of covid-19: a multinational registry analysis.
      ]. Data from this international registry comprising 671 hospitals in six continents were used to compare patients with Covid-19 who received chloroquine (n = 1868), hydroxychloroquine (n = 3016), chloroquine with a macrolide (n = 3783), or hydroxychloroquine with a macrolide (n = 6221) within 48 h of Covid-19 diagnosis, with 81,144 controls who did not receive these drugs. The main outcomes of interest were in-hospital mortality and the occurrence of de-novo ventricular arrhythmias. A Cox proportional hazard model, accounting for many confounding variables, showed a significant increase in the risk of in-hospital mortality with the four treatment regimens compared with the control group (hazard ratios [HR] ranging from 1.33 [95%CI 1.22–1.46] to 1.45 [1.37–1.53]). Analyses using propensity score matching by treatment group supported this result and the risk of in-hospital mortality was similar in men and women.
      Geleris and colleagues recently published in the New England Journal of Medicine a study including 1376 consecutive patients with SARS-CoV-2 who had been admitted to a New York City medical center between March 7 and April 8, 2020 [
      • Geleris J.
      • Sun Y.
      • Platt J.
      • Zucker J.
      • Baldwin M.
      • Hripcsak G.
      • Labella A.
      • Manson D.
      • Kubin C.
      • Barr R.G.
      • Sobieszczyk M.E.
      • Schluger N.W
      Observational study of hydroxychloroquine in hospitalized patients with covid-19.
      ]. Hospital guidance suggested the use of hydroxychloroquine for patients who had a resting oxygen saturation of less than 94% on ambient air. A total of 59% of the patients were treated with hydroxychloroquine, with 60% of those treated with hydroxychloroquine also receiving azithromycin. The authors assessed the association between hydroxychloroquine use and a composite endpoint of intubation or death over a median follow-up of 22.5 days. In the adjusted analyses, there was no evidence of a substantial difference in the rate of the composite endpoint (HR 1.04; 95%CI 0.82–1.32). The findings were confirmed in the sensitivity analyses.
      In a retrospective multicenter cohort study, recently published in JAMA, the authors describe the association between use of hydroxychloroquine, with or without azithromycin, and in-hospital mortality among inpatients diagnosed with Covid-19 [
      • Rosenberg E.S.
      • Dufort E.M.
      • Udo T.
      • Wilberschied L.A.
      • Kumar J.
      • Tesoriero J.
      • Weinberg P.
      • Kirkwood J.
      • Muse A.
      • DeHovitz J.
      • Blog D.S.
      • Hutton B.
      • Holtgrave D.R.
      • Zucker H.A
      Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with covid-19 in new york state.
      ]. A random sample of all admitted patients with laboratory-confirmed Covid-19 in 25 hospitals (representing 88.2% of patients with Covid-19 in the New York metropolitan region) was selected. Among 1438 hospitalized patients with Covid-19 (median age 63 years, 40% female) overall in-hospital mortality was 20.3%. The probability of death was significantly increased for all treatment regimens compared to neither drug (Table 1). Further, in logistic models, compared with patients receiving neither drug, cardiac arrest was significantly more likely in patients receiving hydroxychloroquine+azithromycin, but not hydroxychloroquine alone or azithromycin alone.
      In one comparative observational study published in the BMJ by Mahévas and colleagues, survival at 21 days with or without acute respiratory distress syndrome did not differ between the groups treated with hydroxychloroquine (84 patients) versus the control group (89 patients) [
      • Mahevas M.
      • Tran V.T.
      • Roumier M.
      • Chabrol A.
      • Paule R.
      • Guillaud C.
      • Fois E.
      • Lepeule R.
      • Szwebel T.A.
      • Lescure F.X.
      • Schlemmer F.
      • Matignon M.
      • Khellaf M.
      • Crickx E.
      • Terrier B.
      • Morbieu C.
      • Legendre P.
      • Dang J.
      • Schoindre Y.
      • Pawlotsky J.M.
      • Michel M.
      • Perrodeau E.
      • Carlier N.
      • Roche N.
      • de Lastours V.
      • Ourghanlian C.
      • Kerneis S.
      • Menager P.
      • Mouthon L.
      • Audureau E.
      • Ravaud P.
      • Godeau B.
      • Gallien S.
      • Costedoat-Chalumeau N
      Clinical efficacy of hydroxychloroquine in patients with covid-19 pneumonia who require oxygen: observational comparative study using routine care data.
      ]. The authors concluded that hydroxychloroquine in moderately ill patients with Covid-19 was not useful, and perhaps even harmful.
      In another single center, retrospective, observational study published in JAMA Cardiology, that included 90 hospitalized subjects (mean age 60 years, 49% female) receiving hydroxychloroquine (41%) or hydroxychloroquine+azithromycin (59%), it was observed QTc prolongation (ΔQTc 21 ms), and those taking hydroxychloroquine+azithromycin had greater QT prolongation than those taking hydroxychloroquine alone [
      • Mercuro N.J.
      • Yen C.F.
      • Shim D.J.
      • Maher T.R.
      • McCoy C.M.
      • Zimetbaum P.J.
      • Gold H.S
      Risk of QT interval prolongation associated with use of hydroxychloroquine with or without concomitant azithromycin among hospitalized patients testing positive for coronavirus disease 2019 (covid-19).
      ].
      Following current scientific evidence on potential harm related to the use of hydroxychloroquine or chloroquine alone or in combination with azithromycin for the treatment or prevention of Covid-19, the European Medicines Agency (EMA) and the FDA released, on April 23rd and April 24th, respectively, drug safety announcements. The FDA stated “we are warning the public that hydroxychloroquine and chloroquine, either alone or combined with azithromycin, when used for Covid-19 should be limited to clinical trial settings or for treating certain hospitalized patients under the emergency use authorization ”. On the same line, the EMA stated: “Healthcare professionals should carefully consider the possibility of side effects, particularly with higher doses, and exercise extra caution when combining treatment with other medicines such as azithromycin that may cause similar side effects on the heart”.
      In conclusion, we strongly believe that a cardinal principle of practicing medicine is “first, do no harm” and even in situations like Covid-19 where you believe a desperate disease calls for desperate measures, good and responsible physicians should take a step back and ask themselves if they are causing harm. As physicians involved in the frontline of this unprecedented emergency, serving hundreds of patients in a dedicated Covid-Hospital, we share with colleagues around the world the burden and the responsibility of taking hard decisions on daily-basis; however, following the World Health Organization global announcement to temporarily halting any ongoing trial of hydroxychloroquine for treating Coronavirus patients, we believe that evidence-based medicine should always come first even in emergency situations like SARS-CoV-2 pandemics.

      Declaration of Competing Interest

      None.

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