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Remarks About Retrospective Analysis of Ivermectin Effectiveness on Coronavirus Disease 2019 (ICON Study)

      To the Editor:
      We read with interest the article in CHEST (January 2021) by Rajter et al,
      • Rajter J.C.
      • Sherman M.S.
      • Fatteh N.
      • Vogel F.
      • Sacks J.
      • Rajter J.J.
      Use of ivermectin is associated with lower mortality in hospitalized patients with coronavirus disease 2019: The Ivermectin in COVID Nineteen Study.
      a retrospective study examining 280 hospitalized patients with coronavirus disease 2019 (COVID-19), which concluded that ivermectin was associated with lower overall mortality.
      We think that the study did not report two important variables that would have influenced the outcome. The first is time of symptom onset. We cannot know what the patients’ COVID-19 infection stage was at admission. We already know that corticosteroids are effective for mortality reduction only in the second week after symptom onset.
      The RECOVERY Collaborative Group
      Dexamethasone in hospitalized patients with Covid-19.
      The second is patients’ health insurance coverage. In the American context, it is possible that uninsured patients, or those unable to afford hospitalization fees, would have delayed admission.
      • Azar K.M.J.
      • Shen Z.
      • Romanelli R.J.
      • et al.
      Disparities in outcomes among COVID-19 patients in a large health care system in California.
      An important concern is that the used dose of ivermectin (200 μg/kg) reaches a plasmatic concentration much lower than severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 50% inhibitory concentration at pulmonary tissue (<35 times inferior).
      • Schmith V.D.
      • Zhou J.J.
      • Lohmer L.R.L.
      The approved dose of ivermectin alone is not the ideal dose for the treatment of COVID-19.
      We highlight that the study considered all-cause mortality as the main outcome while evaluating only pulmonary severity. We consider that the severe pulmonary compromise category in the study is a heterogeneous one, grouping patients with different clinical statuses. The mortality trend through time was assessed as inconsistent, but a minimal variation in deaths or classification of severity would change statistical significance, so we believe it is relevant to show mortality trends over weeks.
      A caliper distance difference for propensity score matching (0.2, instead of, eg, 0.25) would risk introducing an additional selection bias. For example, a patient that received two doses of ivermectin and died was not included. If only one additional death would be included in the ivermectin treatment group, the OR for mortality would have changed from 0.47 (CI, 0.22-0.99) to 0.51 (CI, 0.25-1.05).
      Finally, in the study, the sex OR for mortality is nonstatistically significant, when there are studies that find a clear relationship between these two variables.
      • Azar K.M.J.
      • Shen Z.
      • Romanelli R.J.
      • et al.
      Disparities in outcomes among COVID-19 patients in a large health care system in California.
      ,
      • Li X.
      • Xu S.
      • Yu M.
      • et al.
      Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan.
      Taking into consideration that age and sex are powerful confounders for mortality, we would have wished deaths by age and sex to be presented.

      References

        • Rajter J.C.
        • Sherman M.S.
        • Fatteh N.
        • Vogel F.
        • Sacks J.
        • Rajter J.J.
        Use of ivermectin is associated with lower mortality in hospitalized patients with coronavirus disease 2019: The Ivermectin in COVID Nineteen Study.
        Chest. 2021; 159: 85-92
        • The RECOVERY Collaborative Group
        Dexamethasone in hospitalized patients with Covid-19.
        N Engl J Med. 2021; 384: 693-704
        • Azar K.M.J.
        • Shen Z.
        • Romanelli R.J.
        • et al.
        Disparities in outcomes among COVID-19 patients in a large health care system in California.
        Health Aff (Millwood). 2020; 39: 1253-1262
        • Schmith V.D.
        • Zhou J.J.
        • Lohmer L.R.L.
        The approved dose of ivermectin alone is not the ideal dose for the treatment of COVID-19.
        Clin Pharmacol Ther. 2020; 108: 762-765
        • Li X.
        • Xu S.
        • Yu M.
        • et al.
        Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan.
        J Allergy Clin Immunol. 2020; 146: 110-118

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