It’s time to stop using ineffective Covid-19 drugs

In evidence-based medicine, physicians use the best currently available evidence on the safety and efficacy of practice to make treatment decisions for their patients. During the Covid-19 pandemic, some of the early treatment trials resulted in poorly conducted studies.1 or there were very few patients.two As a result, early evidence of the effectiveness of some Covid-19 treatments cannot be replicated.3.4 however, these drugs were common at the time, and some clinicians were reluctant to switch to proven effective alternatives. Ivermectin and fluvoxamine in particular are still widely prescribed, but evidence is steadily accumulating that both treatments are ineffective for Covid-19 at acceptable doses.3-5

In this edition A magazineBramante et al.6 Report results of the COVID-OUT randomized, controlled trial of metformin, ivermectin, and fluvoxamine for early treatment of SARS-CoV-2 infection in 1,323 outpatients. The investigators found no reduction in hypoxemia, emergency department visits, hospitalizations, or death associated with the three drugs. The strength of the trial is to select adults aged 30 to 85 who are at increased risk of severe Covid-19 due to being overweight or obese. However, as a result, the trial may not be readily generalizable to patients at low risk of severe disease. One secondary analysis, which should be interpreted with caution, suggested that metformin may reduce emergency department visits, hospitalizations, or death in this overweight or obese population, suggesting the need for further study.

When this trial began in 2020, the evidence for the three treatments was either unavailable or equivocal. Since then, data have been collected from several clinical trials, including a meta-analysis of metformin, ivermectin, and fluvoxamine. In a pooled analysis of 110 patients with diabetes and more than 3 million patients with Covid-19 in 24 observational studies and one clinical trial,7 investigators found that use of metformin before hospital admission, but not in hospital, was associated with reduced mortality. In a meta-analysis of fluvoxamine involving 2208 outpatients with non-severe cases of Covid-19 in three trials,8 The investigators found that those who received fluvoxamine had no lower rates of hospitalization, mechanical ventilation, or death than those in the control group. For ivermectin, a meta-analysis of 16 trials8 included 2,407 patients with severe and non-severe disease and showed no reliable evidence of a reduction in mechanical ventilation, hospital admissions, length of hospital stay, clinical severity, or mortality; In addition, the investigators found no effect related to the dose of ivermectin. Given 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 barometer for such decisions based on the latest evidence (interpreted by experts from many countries) to make recommendations, indicating the quality of its evidence for each candidate drug. . The latest WHO guidelines,9 They include the results of the COVID-OUT trial, clear recommendations against the use of fluvoxamine and ivemectin, but no recommendation for fluvoxamine. The guidelines also make clear recommendations about which treatments should be prescribed (Table S1 in the Supplementary Appendix , which is available with the full text of this letter at NEJM.org).

Despite this WHO guidance, some doctors continue to prescribe drugs that have not been proven effective against Covid-19. The results of the COVID-OUT trial provide compelling additional data that increase the degree of confidence and certainty that fluvoxamine and ivermectin are ineffective in preventing progression to severe disease. There is no evidence-based basis for continuing to prescribe ivermectin and fluvoxamine for patients with Covid-19 when other effective treatments are available.

Prescribing an ineffective treatment is not a neutral or harmless option. In addition to denying patients appropriate treatment, such prescribing may lead to side effects with no therapeutic benefit and drug shortages for patients who need the medication for other conditions. Therefore, it is important to have reliable evidence of effectiveness and to publish such studies in journals. As the experience of Covid-19 shows, it is important to conduct several rigorous randomized controlled trials to provide unequivocal evidence about the effectiveness of new treatments.

As the American Board of Internal Medicine10 Regarding the spread of misinformation by doctors, “There is not always a right answer, but some answers are clearly wrong.” Regarding clinical decisions regarding the treatment of Covid-19, the choice of certain drugs, especially those with negative WHO recommendations, is certainly wrong. According to evidence-based medical practice, patients with Covid-19 should be treated with effective drugs; they deserve nothing.

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