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As the COVID-19 pandemic continues and evidence evolves, clinical judgment is the bottom line for clinical care, according to Adarsh Bhimraj, MD, of the Cleveland Clinic, and James Walter, MD, of Northwestern Medicine, Chicago.
In a debate/discussion presented at SHM Converge, the annual conference of the Society of Hospital Medicine, Bhimraj and Walter took sides in a friendly debate on the value of remdesivir and tocilizumab for hospitalized COVID-19 patients.
Bhimraj argued for the use of remdesivir or tocilizumab in patients hospitalized with COVID-19 pneumonia, and Walter presented the case against their use.
Referendum on Remdesivir
The main sources referenced by the presenters regarding remdesivir were the WHO Solidarity Trial (N Engl J Med. 2021 Feb 11. doi: 10.1056/NEJMoa2023184) and the Adaptive Covid-19 Treatment Trial (ACCT) final report (N Engl J Med. 2020 Nov 5. doi: 10.1056/NEJMoa2007764).
“The ‘debate’ is partly artificial,” and meant to illustrate how clinicians can use their own clinical faculties and reasoning to make an informed decision when treating COVID-19 patients, Bhimraj said.
The ACCT trial compared remdesivir with placebo in patients with severe enough COVID-19 to require supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation. The primary outcome in the study was time to recovery, and “the devil is in the details,” Bhimraj said. The outcomes clinicians should look for in studies are those that matter to patients, such as death, disability, and discomfort, he noted. Disease-oriented endpoints are easier to measure, but not always meaningful for patients, he said. The study showed an average 5-day decrease in illness, “but the fact is that it did not show a mortality benefit,” he noted.
Another large, open-label study of remdesivir across 30 countries showed no survival benefit associated with the drug, compared with standard of care, said Bhimraj. Patients treated with remdesivir remained in the hospital longer, but Bhimraj said he believed that was a bias. “I think the physicians kept the patients in the hospital longer to give the treatment rather than the treatments themselves prolonging the treatment duration,” he said.
In conclusion for remdesivir, “the solid data show that there is an early recovery,” he said. “At least for severe disease, even if there is no mortality benefit, there is a role. I argue that, if someone asks if you want to use remdesivir in severe COVID-19 patients, say yes, especially if you value people getting out of the hospital sooner. In a crisis situation, there is a role for remdesivir.”
Walter discussed the “con” side of using remdesivir. “We can start with a predata hypothesis, but integrate new data about the efficacy into a postdata hypothesis,” he said.
Walter made several points against the use of remdesivir in hospitalized COVID-19 patients. First, it has not shown any improvement in mortality and may increase the length of hospital stay, he noted.
Data from the ACCT-1 trial and the WHO solidarity trial, showed “no signal of mortality benefit at all,” he said. In addition, the World Health Organization, American College of Physicians, and National Institutes of Health all recommend against remdesivir for patients who require mechanical ventilation or extracorporeal membrane oxygenation, he said. The efficacy when used with steroids remains unclear, and long-term safety data are lacking, he added.
Taking on Tocilizumab
Tocilizumab, an anti-inflammatory agent, has demonstrated an impact on several surrogate markers, notably C-reactive protein, temperature, and oxygenation. Bhimraj said. He reviewed data from eight published studies on the use of tocilizumab in COVID-19 patients.
Arguably, some trials may not have been powered adequately, and in combination, some trials show an effect on clinical deterioration, if not a mortality benefit, he said.
Consequently, in the context of COVID-19, tocilizumab “should be used early in the disease process, especially if steroids are not working,” said Bhimraj. Despite the limited evidence, “there is a niche population where this might be beneficial,” he said.
By contrast, Walter took the position of skepticism about the value of tocilizumab for COVID-19 patients.
Notably, decades of research show that tocilizumab has shown no benefit in patients with sepsis or septic shock, or those with acute respiratory distress syndrome, which have similarities to COVID-19 (JAMA. 2020 Sep 3. doi: 10.1001/jama.2020.17052).
He cited a research letter published in JAMA in September 2020, which showed that cytokine levels were in fact lower in critically ill patients with COVID-19, compared with those who had conditions including sepsis with and without ARDS.
Walter also cited data on the questionable benefit of tocilizumab when used with steroids and the negligible impact on mortality in hospitalized COVID-19 patients seen in the RECOVERY trial.
Limited data mean that therapeutic decisions related to COVID-19 are more nuanced, but they can be made, the presenters agreed.
Ultimately, when trying to decide whether a drug is efficacious, futile, or harmful, “What we have to do is consider the grand totality of the evidence,” Bhimraj emphasized.
Bhimraj and Walter had no relevant financial conflicts to disclose.
This article originally appeared on MDedge.com, part of the Medscape Professional Network.
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