Supportive Care Is "Doing Something"

As I write this column, the worst of the cornoavirus diesease 2019 (COVID-19) illness in our community has passed, at least for now. It has been a remarkable journey of learning and observation, and we can hopefully use this knowledge going forward to make good decisions both administratively and clinically, as we deal with other crises or possibly subsequent waves of severe acute respiratory syndrome coronavirus 2 infections and we learn more about the natural history of this organism and our response to it. One of the most striking things that I observed related to how so many presumably evidence-based and well-educated clinicians were making patient care decisions that were anything but evidence-based and rational. There seemed to be a pervasive attitude that we must “do something” in the face of the devastating consequences of this viral infection, despite the fact that at the time there were no proven effective treatment options. Almost every major medical and scientific organization was recommending that experimental treatments only be considered within the context of a clinical trial. Despite the lack of meaningful evidence of effectiveness and safety, there were overnight shortages of azithromycin and hydroxychloroquine, because of widespread prescribing for everything from preventative therapy to treatment. This stampede was based on questionable anecdotal data involving very small numbers of patients from China and Europe that did not include clinical outcome end points or safety data. Hydroxychloroquine is a reasonably toxic drug and when combined with azithromycin may have life-threatening effects on cardiac conduction. Why did any well-trained clinician think this was a good idea outside of a clinical trial?

To make things worse, the FDA issued an emergency use authorization for the use of hydroxychloroquine and chloroquine, which is even more toxic, for hospitalized patients with COVID-19. The day that was announced, our conversation was, “based on what, political motivations?” certainly not the scientific standards we expect from the FDA. Then the federal government doubled down by releasing hydroxychloroquine from the “strategic stockpile” and shipping it to hospitals that neither requested or wanted it. Meanwhile, the evidence began to increase that hydroxychloroquine may not be effective and more concerning, that it might be contributing to increased patient mortality. An observational study from a Veterans Administration hospital in South Carolina reported a significantly higher mortality in the cohorts receiving hydroxychloroquine,¹ and though not a definitive answer on the question of safety, it was a sobering observation and reminder that unproven therapies have no place in wide clinical adoption. If this observation does turn out to accurately reflect the risk to benefit of hydroxychloroquine for treatment of COVID-19, there will likely be a reckoning at multiple levels for how this could be allowed and even encouraged by those who should have known better. Most recently, as of the date of this writing, the RECOVERY study in Europe and the National Institutes of Health clinical trial in the United States have suspended enrollment in the hydroxychloroquine arms of their multi-interventional trials, because of a lack of effectiveness relative to placebo, and fortunately no evidence of significant mortality or toxicity.^2,3 Hydroxychloroquine also failed to show benefit for prevention of COVID as post-exposure prophylaxis.⁴ So, what am I going to do with all that “free” hydroxychloroquine the federal government sent that went unused? I am thinking maybe I can salt my driveway with it this winter. This rush to uncontrolled clinical application of unproven therapies has not been limited to hydroxychloroquine but has involved a number of different theoretically beneficial treatments, including antiretroviral drug combinations, convalescent plasma, interferon, intravenous immunoglobulin, systemic anticoagulation, tocilizumab, and many other immunosuppressive drugs. All these treatments have a substantial risk of toxicity and very thin to no evidence of benefit in the treatment of COVID-19.

Andre Kalil, MD, MPH, professor in the Department of Internal Medicine and director of transplant infectious diseases at Nebraska Medical Center in Omaha, wrote a thoughtful commentary early during the COVID pandemic that summarized the concerns with uncontrolled use of unproven therapies during a health care crisis.5 He wrote that when a patient condition worsens, we tend to blame the disease, while if a patient improves, we tend to give credit to the experimental therapy being used, reinforcing a bias that “doing something” is beneficial. Or, as has been said in the past, anecdotal experience can be the single most dangerous thing in medicine. Kalil further reminded us that unless a disease process is 100% fatal, it is not possible to know if a drug is harmful or helpful without the inclusion of a control, and from a safety perspective a patient randomized to a placebo is safer, because he or she is assured of receiving the current standard of care. An experimental drug given in an uncontrolled setting “may be less safe, and moreover, will not lead to the discovery of any new therapy,” he wrote.5 Or otherwise stated, broad therapeutic application getting out ahead of the clinical data is irresponsible. So, where does pharmacy fit into all of this? In my opinion, pharmacists should be vocal in their objection to unproven therapies being widely used primarily based on wishful thinking. We should be holding our colleagues to a high standard when developing treatment guidelines for emerging and news diseases, such as COVID-19, and should not be facilitating false hope. As a good friend once told me, faith-based medicine should not prevail over evidencebased medicine. I recently attended (via Zoom, of course) an excellent medical grand rounds presented by Ann R. Falsey, MD, a noted infectious disease and virology expert at the University of Rochester Medical Center, during which she reminded the audience that supportive care is “doing something.” curtis e. haas, pharmd, fccp, is the director of pharmacy for the University of Rochester health care system in New York.

Curtis E. Hass, PharmD, FCCP, is the director of pharmacy for the University of Rochester health care system in New York.

REFERENCES

• Magagnoli J, Narendran S, Pereira F, et al. Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19. medRxiv. 2020;2020.04.16.20065920. doi: 10.1101/2020.04.16.20065920
• University of Oxford. Statement from the chief investigators of the Randomised Evaluation of COVid-19 thERapY (RECOVERY) Trial on hydroxychloroquine. No clinical benefit from use of hydroxychloroquine in hospitalised patients with COVID-19. Published June 5, 2020. Accessed June 29, 2020. https://www.recoverytrial.net/news/ statement-from-the-chief-investigators-of-the-randomised-evaluation-of-covid-19-therapyrecovery- trial-on-hydroxychloroquine-5-june-2020-no-clinical-benefit-from-use-of-hydroxychloroquine- in-hospitalised-patients-with-covid-19
• National Institutes of Health. NIH halts clinical trial of hydroxychloroquine. Study shows treatment does no harm, but provides no benefit. News release. June 20, 2020: US Department of Health & Human Services. Accessed June 29, 2020. https://www.nih.gov/news-events/ news-releases/nih-halts-clinical-trial-hydroxychloroquine
• Boulware DR, Pullen MF, Bangdiwala AS, et al. A randomized trial of hydroxychloroquine as postexposure prophylaxis for Covid-19. N Engl J Med. 2020;NEJMoa2016638. doi: 10.1056/ NEJMoa2016638 5. 5. Kalil AC. Treating COVID-19-off-label drug use, compassionate use, and randomized clinical trials during pandemics. JAMA. 2020. doi: 10.1001/jama.2020.4742