In the practice of evidence-based medicine, clinicians use the best currently available evidence about safety and efficacy in making decisions about treatment options for their patients. During the Covid-19 pandemic, some early treatment trials were rushed, resulting in poor studies1 Or she had very few patients.2 As a result, preliminary evidence of the effectiveness of some Covid-19 treatments cannot be replicated.3,4 But these drugs were already in widespread use by then, and some doctors were reluctant to change to alternatives that had proven effective. Ivermectin and fluvoxamine in particular are still widely prescribed, although evidence is steadily accumulating to indicate that both treatments at acceptable doses are ineffective for Covid-19.3-5
In this issue of magazineBramante et al.6 Reporting the results of the COVID-OUT randomized controlled trial of oral metformin, ivermectin and fluvoxamine for the early treatment of SARS-CoV-2 infection in 1323 outpatients. The investigators found no reduction in hypoxia, emergency department visits, hospitalization, or death associated with any of the three drugs. One of the trial’s strengths was the selection of adults aged 30 to 85 who were at high risk of severe Covid-19 infection due to being overweight or obese. However, as a result, the trial may not be easily generalizable to patients at lower risk of severe disease. One secondary analysis, which should be interpreted with caution, suggested that metformin may reduce a composite number of emergency department visits, hospitalizations, or death in this overweight or obese population, a finding that indicates no more than a need for further From the investigation at this time.
When this trial began in 2020, evidence for all three treatments was either unavailable or equivocal. Since then, data from several clinical trials, including meta-analyses of metformin, ivermectin, and fluvoxamine, have accumulated. In a combined analysis of antidiabetic agents involving more than 3 million patients with diabetes and Covid-19 in 24 observational studies and 110 patients in one clinical trial,7 The researchers found that pre-hospital use of metformin, but not in-hospital use, was associated with lower mortality. In a meta-analysis of fluvoxamine of 2,208 outpatients with non-serious cases of Covid-19 in three trials,8 The investigators found that those who received fluvoxamine had no lower rate of hospitalization, mechanical ventilation, or death than those in the control groups. For ivermectin, a meta-analysis of 16 trials8 2407 patients with severe, non-serious illness showed no reliable evidence of decreased mechanical ventilation, hospitalization, duration of hospitalization, clinical severity, or mortality; Additionally, the researchers found no effect related to the dose of ivermectin. In light of this available evidence of ineffectiveness of ivermectin and fluvoxamine, how much evidence of ineffectiveness is sufficient?
The World Health Organization (WHO) treatment guidelines provide a scale for such decisions based on the most recent evidence (as interpreted by experts from many countries) to make recommendations for each candidate drug, noting its quality of evidence. The latest WHO guidance,9 which does not include the results of the COVID-OUT trial, states explicit recommendations against the use of fluvoxamine and ivermectin but makes no recommendation regarding metformin. The guidelines also provide explicit recommendations on which treatments to prescribe (Table S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org).
Despite these WHO guidelines, some doctors still prescribe drugs with unproven efficacy against Covid-19. The results of the COVID-OUT trial provide compelling additional data that increase confidence and degree of certainty that fluvoxamine and ivermectin are ineffective in preventing progression to severe disease. There are no evidence-based reasons for continuing to prescribe ivermectin and fluvoxamine when other effective treatments are available for patients with non-severe Covid-19.
Prescribing ineffective treatments is not a neutral or harmless option. In addition to depriving patients of appropriate treatment, such prescriptions can lead to side effects without any therapeutic benefit and drug shortages for patients who need medication for other conditions. Thus, it is important to have reliable evidence of ineffectiveness and for journals to publish such studies. It is also important to conduct several rigorous randomized controlled trials to provide unequivocal evidence of the effectiveness of new treatments, as the Covid-19 experience has shown.
As the American Board of Internal Medicine10 He noted regarding the promotion of misinformation by clinicians, “There are not always right answers, but some of the answers are clearly wrong.” In terms of clinical decisions regarding the treatment of Covid-19, some drug choices, especially those with negative recommendations from the World Health Organization, are clearly wrong. In line with evidence-based medical practice, COVID-19 patients should be treated with effective medications; They deserve no less.
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