Science: Tratamientos para la COVID-19: lo que encontraron los ensayos sobre remdesivir e ivermectina

In 2020, remdesivir became the first fully approved treatment for COVID-19. It never showed that it kept patients alive. Ivermectin, an inexpensive generic tested in thousands of outpatients, did not help against the disease at all.

What The Trials Set Out To Test

Remdesivir is an intravenous antiviral, first built against other viruses and repurposed in 2020 for the one that causes COVID-19. Ivermectin is an oral antiparasitic, among the most widely used medicines in the world. Both were reasonable candidates early in the pandemic, and both were tested against placebo or standard care in large randomized trials.

What The Trials Found

Remdesivir: faster recovery, no clear survival benefit

In the ACTT-1 trial, Beigel and colleagues randomized 1,062 hospitalized patients. Remdesivir shortened median time to recovery from 15 days to 10, a recovery rate ratio of 1.29. Deaths ran 6.7% with the drug against 11.9% with placebo by day 15, but that gap did not reach statistical significance (hazard ratio 0.73, 95% CI 0.52 to 1.03).

The larger and more decisive test came from the WHO SOLIDARITY trial, run across 405 hospitals in 30 countries. Death occurred in 301 of 2,743 remdesivir patients and 303 of 2,708 controls, a rate ratio of 0.95 (95% CI 0.81 to 1.11). The trial concluded the drug had little or no effect on survival, the need for ventilation, or length of stay. Faster recovery is a separate result. On death, the largest trial found no clear benefit.

The WHO's own living-guideline panel then weighed the pooled data. On 20 November 2020, after reviewing four international trials covering more than 7,000 patients, it issued a conditional recommendation against remdesivir for hospitalized patients. A drug can win approval for shortening an illness before anyone shows it saves lives; remdesivir did.

Ivermectin: no benefit against COVID-19

Ivermectin was tested in large, careful outpatient trials. TOGETHER assigned 1,358 higher-risk outpatients to ivermectin or placebo, and found no drop in hospitalization or extended emergency-department stay (relative risk 0.90). ACTIV-6 gave 1,591 outpatients the drug or placebo, with no faster recovery (hazard ratio 1.07). Median recovery ran 12 days against 13 with placebo, and hospitalizations or deaths matched at 1.2% in each group. A Cochrane review pooling the randomized evidence reached the same result. At the doses tested, ivermectin did not help against COVID-19.

The Research & Studies

Everything here is based on the research we have collected and checked, sorted into groups and ordered with the strongest evidence first. Click any claim to open the studies behind it.

Respiratory Infection

El remdesivir aceleró la recuperación de 15 días a 10, pero no mostró beneficio de supervivencia (razón de tasas 0.95)Established

In plain terms

El remdesivir ayudó a los pacientes hospitalizados a recuperarse unos días más rápido, pero no redujo claramente las muertes. El ensayo más grande, el estudio SOLIDARITY de la OMS, no encontró ningún beneficio de supervivencia.

In detail

Beigel y colaboradores (ACTT-1) aleatorizaron a 1062 pacientes hospitalizados y encontraron que el remdesivir acortó la mediana del tiempo de recuperación de 15 días a 10 (razón de tasas de recuperación 1.29; IC del 95 % 1.12 a 1.49); la mortalidad de Kaplan-Meier fue del 6.7 % con remdesivir frente al 11.9 % con placebo (hazard ratio 0.73; IC del 95 % 0.52 a 1.03), una diferencia que no alcanzó significación estadística. Pan y colaboradores, en el ensayo SOLIDARITY de la OMS en 405 hospitales de 30 países, encontraron muerte en 301 de 2743 pacientes con remdesivir frente a 303 de 2708 controles (razón de tasas 0.95; IC del 95 % 0.81 a 1.11), y concluyeron que el remdesivir tenía poco o ningún efecto en los pacientes hospitalizados, según se juzgó por la mortalidad, la ventilación y la estancia hospitalaria. Una recuperación más rápida es un resultado aparte; en cuanto a la supervivencia, el resultado que más importa, el ensayo más sólido no encontró un beneficio claro.

Who this may not transfer to:Measured in hospitalized adults with COVID-19; these are findings about inpatient treatment, not prevention or mild illness at home.

The studies · 2

Beigel et al., remdesivir for the treatment of Covid-19: final report (ACTT-1) · N Engl J Med 2020;383(19):1813-1826

Pan et al., repurposed antiviral drugs for Covid-19: interim WHO Solidarity trial results · N Engl J Med 2021;384(6):497-511

La OMS recomendó no usar remdesivir tras combinar cuatro ensayos con más de 7000 pacientesEstablished

In plain terms

El panel de directrices de la Organización Mundial de la Salud revisó los datos combinados de los ensayos y, en noviembre de 2020, recomendó no usar remdesivir en pacientes hospitalizados.

In detail

Agarwal y colaboradores, en la directriz viva de la OMS de las Recomendaciones Rápidas del BMJ sobre fármacos para la covid-19 (BMJ 2020;370:m3379), informaron de una recomendación condicional del Grupo de Desarrollo de Directrices de la OMS en contra del remdesivir en pacientes hospitalizados con COVID-19, independientemente de la gravedad. El panel combinó evidencia de cuatro ensayos aleatorizados internacionales con más de 7000 pacientes y no encontró ningún efecto importante sobre la mortalidad, la necesidad de ventilación mecánica, el tiempo hasta la mejoría clínica u otros resultados importantes para los pacientes. Una recomendación condicional refleja evidencia de baja certeza: el panel no concluyó que el fármaco sea dañino, solo que los ensayos combinados no mostraron que mejorara los resultados que importan a los pacientes. La recomendación se publicó el 20 de noviembre de 2020; la FDA había otorgado la aprobación completa del remdesivir el 22 de octubre de 2020.

Who this may not transfer to:A guideline judgment about treating hospitalized COVID-19 patients; it does not address prevention, outpatient use, or later variants and treatments.

The study · 1

Agarwal et al., a living WHO guideline on drugs for covid-19 · BMJ 2020;370:m3379

La ivermectina no dio ningún beneficio para la COVID-19 en ensayos aleatorizados con 1358 y 1591 pacientes ambulatoriosEstablished

In plain terms

Los ensayos grandes y cuidadosos de ivermectina para la COVID-19 resultaron nulos: no redujo la hospitalización, no aceleró la recuperación ni redujo las muertes. Es un medicamento importante contra los parásitos, pero no ayudó contra la COVID-19 a las dosis estudiadas.

In detail

Reis y colaboradores, en el ensayo de plataforma aleatorizado TOGETHER, asignaron a 1358 pacientes ambulatorios de mayor riesgo con COVID-19 temprana a ivermectina (400 microgramos por kilogramo durante 3 días) o placebo y no encontraron una reducción significativa en el resultado principal de hospitalización u observación prolongada en urgencias (riesgo relativo 0.90; intervalo de credibilidad bayesiano del 95 % 0.70 a 1.16). Naggie y colaboradores, en el ensayo de plataforma ACTIV-6, administraron a 1591 pacientes ambulatorios estadounidenses la misma dosis de ivermectina o placebo y no encontraron mejoría en el tiempo hasta la recuperación sostenida (hazard ratio 1.07; intervalo de credibilidad del 95 % 0.96 a 1.17; recuperación mediana de 12 frente a 13 días), con hospitalizaciones o muertes iguales en ambos grupos (1.2 % cada uno). Popp y colaboradores, en una revisión sistemática Cochrane, combinaron la evidencia aleatorizada y concluyeron que la ivermectina tiene poco o ningún efecto sobre la mortalidad, la progresión clínica o el ingreso hospitalario en la COVID-19. La ivermectina es un antiparasitario reconocido con el Nobel, con una eficacia sólida y establecida contra las enfermedades parasitarias para las que está autorizada; para la COVID-19, la evidencia aleatorizada resolvió la cuestión en dirección nula.

Who this may not transfer to:Measured in mostly outpatient adults with early COVID-19; it says nothing about ivermectin's established use for parasitic disease.

The studies · 3

Reis et al., effect of early treatment with ivermectin among patients with Covid-19 (TOGETHER) · N Engl J Med 2022;386(18):1721-1731

Naggie et al., effect of ivermectin vs placebo on time to sustained recovery in outpatients with COVID-19 (ACTIV-6) · JAMA 2022;328(16):1595-1603

Popp et al., ivermectin for preventing and treating COVID-19 · Cochrane Database Syst Rev 2022;6:CD015017

Those rows carry different grades by design. The remdesivir survival row and the ivermectin row rest on large randomized trials, over 1,000 patients apiece, and are graded strong. The WHO guideline row is graded strong as a statement of what the pooled evidence supported. The liver and kidney signals are graded emerging, because a spontaneous-reporting database is weaker evidence than a controlled trial.

How These Drugs Were Meant To Work

As a nucleotide analogue, remdesivir blocks the enzyme the virus uses to copy its genome, slowing replication. That is why it was expected to help the hospitalized patients in the 2020 trials.

Ivermectin binds ion channels that parasites carry and mammals largely lack, the reason it clears worms and mites safely. The COVID-19 case for it came from 2020 cell-culture studies, where high concentrations suppressed the virus. Those concentrations sat far above what a standard oral dose reaches in the body, one reason the clinical trials were needed to settle the question.

Safety Once Millions Were Treated

A controlled trial follows a selected group closely, so some rarer harms surface only after a drug reaches very large numbers of ordinary patients. Global safety reporting flagged liver and kidney events more often for remdesivir than for comparable drugs, logged in the WHO safety database by 2021. Hospitalized COVID-19 patients frequently develop liver and kidney injury from the disease itself, so a report may signal the illness as well as the drug. A disproportionality signal from spontaneous reports flags a drug for investigation, but does not prove it caused any one case. The signals carry more weight because remdesivir never proved it saved lives.

A reporting signal is a reason to look harder at a drug, never proof that it harmed a given patient.

Go Deeper

The COVID-19 evidence here connects to three related pages:

• Ivermectin, the antiparasitic in full, what it treats and the doses used.
• Long COVID, the recognized post-viral condition and what helps the people living with it.
• Expectancy and belief, why a treatment can feel effective even when a trial finds no benefit.

Common Questions

Why did the WHO recommend against a drug the FDA had approved?

In 2020, the FDA and WHO reached opposite calls on the same drug. The FDA asked whether remdesivir beat placebo on a measured endpoint, and the recovery data cleared that bar. The WHO's panel asked whether the pooled trials helped patients survive, and judged that they had not. Its verdict was a conditional recommendation based on low-certainty evidence. The panel did not find that the drug harms patients.

What are the liver and kidney signals?

In medical terms these are hepatobiliary (liver) and renal (kidney) adverse events, flagged during the COVID-19 pandemic. They come from a spontaneous-reporting database, where clinicians log a suspected drug reaction after they see it. A disproportionality signal means one drug drew such reports at a higher rate than other drugs. That is how the liver and kidney reports were first flagged.

Did ivermectin work for COVID-19?

For COVID-19, no. The large 2022 outpatient trials found no benefit at those doses. Ivermectin remains a genuinely effective, Nobel-recognized medicine against parasites such as river blindness and scabies. The 2022 trials rule out ivermectin for COVID-19; they say nothing about its use against parasites, where it still works.

Cautions

Everything to be aware of is here, in one place. This practice suits most healthy people; a few situations call for real care.

Eventos adversos hepáticos (hepatobiliares) notificados de forma desproporcionada para el remdesivir una vez usado a gran escala

Kim y colaboradores analizaron notificaciones individuales de casos de seguridad en VigiBase, la base de datos internacional de farmacovigilancia de la OMS, y encontraron una señal de desproporcionalidad para las reacciones adversas hepatobiliares asociadas con el remdesivir, en comparación con la base de datos completa y con comparadores relevantes. El análisis de desproporcionalidad compara la frecuencia con la que se notifica un evento para un fármaco frente a todos los demás fármacos; una razón de posibilidades de notificación elevada señala una posible pista para seguimiento, sin establecer que el fármaco causó el evento. La señal es notable porque surgió en un fármaco cuyo beneficio de supervivencia no estaba establecido, por lo que su balance riesgo-beneficio depende precisamente de este tipo de información de seguridad del mundo real.Kim et al., hepatobiliary adverse drug reactions associated with remdesivir: the WHO international pharmacovigilance study

Insuficiencia renal notificada ~20 veces por encima de lo esperado para el remdesivir a gran escala (razón de posibilidades de notificación 20.3)

Gérard y colaboradores usaron un análisis de desproporcionalidad de la base de datos de seguridad de la OMS (VigiBase) y encontraron una señal estadísticamente significativa de insuficiencia renal aguda para el remdesivir: 138 casos observados frente a 9 esperados, una razón de posibilidades de notificación de 20.3 (IC del 95 % 15.7 a 26.3; P < 0.0001) frente a fármacos comparadores usados en situaciones similares de COVID-19 (hidroxicloroquina, tocilizumab, lopinavir/ritonavir). El análisis de desproporcionalidad compara la frecuencia con la que se notifica un evento para un fármaco frente a otros fármacos; una razón de posibilidades de notificación elevada identifica una señal para un estudio más a fondo, no un vínculo causal probado. Debido a que los pacientes hospitalizados con COVID-19 a menudo desarrollan lesión renal aguda por la propia enfermedad, los autores plantearon la señal como algo que justifica una evaluación completa, no una conclusión causal firme.Gérard et al., remdesivir and acute renal failure: a potential safety signal from disproportionality analysis of the WHO safety database

No dosing or treatment advice here

These are prescription decisions made with a clinician for a specific patient.

Read the safety signals in context

The liver and kidney reports come from patients often severely ill with COVID-19 itself. The disease damages both organs, so these reports are graded emerging.

Take any treatment decision with a professional who knows your situation.