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  • Peter A. McCullough
    Correspondence
    Requests for reprints should be addressed to Peter A. McCullough, MD, MPH, Baylor Heart and Vascular Institute, 621 N. Hall St, H030, Dallas, TX, 75226.
    Affiliations
    Baylor University Medical Center, Dallas, Tex

    Baylor Heart and Vascular Institute, Dallas, Tex

    Baylor Jack and Jane Hamilton Heart and Vascular Hospital, Dallas, Tex
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      We are aligned with Drs Olmos and Roque that there should be comprehensive medical crisis management as shown in the 4 pillars of pandemic response in the Figure.
      • McCullough PA
      • Alexander PE
      • Armstrong R
      • et al.
      Multifaceted highly targeted sequential multidrug treatment of early ambulatory high-risk SARS-CoV-2 infection (COVID-19).
      Human severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection begins as a mild upper respiratory tract infection with a prehospital therapeutic window of opportunity, and there is an important “second pillar” of pandemic response that has the objective of reducing to the “hard outcomes” of COVID-19, hospitalization and death. For patients at high-risk of contracting coronavirus disease 2019 (COVID-19) and are acutely ill at home, contagion control is too late and the hospital is not an adequate safety net. Late-stage hospitalization as the only opportunity for initial treatment results in unacceptably high mortality.
      • Palazzuoli A
      • Ruberto F
      • De Ferrari GM
      • et al.
      Inpatient mortality according to level of respiratory support received for severe acute respiratory syndrome coronavirus 2 (Coronavirus Disease 2019) infection: a prospective multicenter study.
      Thus, in the context of a crisis, therapeutic decisions are made based on pathophysiological principles and the totality of available evidence. Because most serious viral infections require multidrug regimens, we can only expect signals of efficacy or safety with single agents from randomized and observational studies of COVID-19. Clinical judgment is required to assemble therapeutic combinations that address viral replication, cytokine storm, and thrombosis.
      • McCullough PA
      • Alexander PE
      • Armstrong R
      • et al.
      Multifaceted highly targeted sequential multidrug treatment of early ambulatory high-risk SARS-CoV-2 infection (COVID-19).
      Since the time of the original publication in The American Journal of Medicine, we are better supported from inpatient studies on the application of aspirin as well as anticoagulation that have established safety profiles.
      • McCullough PA
      • Kelly RJ
      • Ruocco G
      • et al.
      Pathophysiological basis and rationale for early outpatient treatment of SARS-CoV-2 (COVID-19) infection.
      Meizlish et al

      Meizlish ML, Goshua G, Liu Y, Fine R, et al. Intermediate-dose anticoagulation, aspirin, and in-hospital mortality in COVID-19: a propensity score-matched analysis [e-pub ahead of print]. medRxiv. Accessed December 30, 2020. doi: https://doi.org/10.1101/2021.01.12.21249577.

      found in a multicenter study (N = 2785) that aspirin administration was independently associated with a 69% reduction in mortality (P = .001). Billet et al
      • Billett HH
      • Reyes-Gil M
      • Szymanski J
      • et al.
      Anticoagulation in COVID-19: effect of enoxaparin, heparin, and apixaban on mortality.
      (N = 3625) demonstrated a significant decrease in adjusted mortality with prophylactic use of apixaban (odds ratio = 0.46, P = .001) and enoxaparin (odds ratio = 0.49, P = .001). We encourage Drs Olmos and Roque to overcome the fear of relying on clinical judgment before confirmatory large-scale multidrug, placebo-controlled, randomized trials. To our knowledge no such trials are forthcoming. Empiric regimens based on clinical judgment are not as “dangerous” as leaving patients untreated for many days only to succumb to calamitous hospitalization or death. Courageous doctors and researchers have innovated and found that sequenced, multidrug regimens are associated with ∼85% reductions in COVID-19 morbidity and mortality with no signals of harm.

      Procter BC, Ross C, Pickard V, Smith E, Hanson C, McCullough PA. Early ambulatory multidrug therapy reduces hospitalization and death in high-risk patients with SARS-CoV-2 (COVID-19) [e-pub ahead of print]. Authorea. Accessed January 25, 2021. doi: https://doi.org/10.22541/au.161000355.54720791/v1.

      ,
      • Procter BC
      • Ross C
      • Pickard V
      • Smith E
      • Hanson C
      • McCullough PA
      Clinical outcomes after early ambulatory multidrug therapy for high-risk SARS-CoV-2 (COVID-19) infection.
      ,
      • Derwand R
      • Scholz M
      • Zelenko V
      COVID-19 outpatients: early risk-stratified treatment with zinc plus low-dose hydroxychloroquine and azithromycin: a retrospective case series study.
      Figure
      FigureThe 4 pillars of pandemic response to the severe acute respiratory coronavirus 2 (SARS-CoV-2) pandemic crisis, reproduced with permission from McCullough et al.
      • McCullough PA
      • Alexander PE
      • Armstrong R
      • et al.
      Multifaceted highly targeted sequential multidrug treatment of early ambulatory high-risk SARS-CoV-2 infection (COVID-19).

      References

        • McCullough PA
        • Alexander PE
        • Armstrong R
        • et al.
        Multifaceted highly targeted sequential multidrug treatment of early ambulatory high-risk SARS-CoV-2 infection (COVID-19).
        Rev Cardiovasc Med. 2020; 21: 517-530https://doi.org/10.31083/j.rcm.2020.04.264
        • Palazzuoli A
        • Ruberto F
        • De Ferrari GM
        • et al.
        Inpatient mortality according to level of respiratory support received for severe acute respiratory syndrome coronavirus 2 (Coronavirus Disease 2019) infection: a prospective multicenter study.
        Crit Care Explor. 2020; 2: e0220https://doi.org/10.1097/CCE.0000000000000220
        • McCullough PA
        • Kelly RJ
        • Ruocco G
        • et al.
        Pathophysiological basis and rationale for early outpatient treatment of SARS-CoV-2 (COVID-19) infection.
        Am J Med. 2021; 134: 16-22https://doi.org/10.1016/j.amjmed.2020.07.003
      1. Meizlish ML, Goshua G, Liu Y, Fine R, et al. Intermediate-dose anticoagulation, aspirin, and in-hospital mortality in COVID-19: a propensity score-matched analysis [e-pub ahead of print]. medRxiv. Accessed December 30, 2020. doi: https://doi.org/10.1101/2021.01.12.21249577.

        • Billett HH
        • Reyes-Gil M
        • Szymanski J
        • et al.
        Anticoagulation in COVID-19: effect of enoxaparin, heparin, and apixaban on mortality.
        Thromb Haemost. 2020; 120: 1691-1699https://doi.org/10.1055/s-0040-1720978
      2. Procter BC, Ross C, Pickard V, Smith E, Hanson C, McCullough PA. Early ambulatory multidrug therapy reduces hospitalization and death in high-risk patients with SARS-CoV-2 (COVID-19) [e-pub ahead of print]. Authorea. Accessed January 25, 2021. doi: https://doi.org/10.22541/au.161000355.54720791/v1.

        • Procter BC
        • Ross C
        • Pickard V
        • Smith E
        • Hanson C
        • McCullough PA
        Clinical outcomes after early ambulatory multidrug therapy for high-risk SARS-CoV-2 (COVID-19) infection.
        Rev Cardiovasc Med. 2020; 21: 611-614https://doi.org/10.31083/j.rcm.2020.04.260
        • Derwand R
        • Scholz M
        • Zelenko V
        COVID-19 outpatients: early risk-stratified treatment with zinc plus low-dose hydroxychloroquine and azithromycin: a retrospective case series study.
        Int J Antimicrob Agents. 2020; 56106214https://doi.org/10.1016/j.ijantimicag.2020.106214

      Linked Article

      • Unproven Therapy Algorithms for Early SARS-CoV-2 Infection Are Dangerous
        The American Journal of MedicineVol. 134Issue 5
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          We read with interest the article by McCullough et al1 about the pathophysiological basis and rationale for early outpatient treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which results in coronavirus disease 2019 (COVID-19). Although the article discusses some significant issues, it has many important drawbacks.
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