Theodor Voiosu1,2, Andrei
Voiosu1
- Colentina Clinical Hospital, Gastroenterology Department, Bucharest
- Carol Davila University of Medicine and Pharmacy, Bucharest
Corresponding author – Theodor Voiosu, Colentina Clinical Hospital,
Gastroenterology Department, 19-21 Stefan cel Mare Bvd, Bucharest,
Romania. email –
theodor.voiosu@gmail.com
Keywords – COVID-19, SARS-Cov-2, polypharmacy, drug-related adverse
events
We have read with great interest the article by Baicus et al.[1]
regarding physician practice and attitudes towards hydroxychloroquine
use during the COVID-19 pandemic and we would like to add to the context
of their findings.
For the past months the medical community has been engaged in the search
for efficient treatment and a staggering amount of conflicting primary
and secondary data has appeared in a brief period of time [2].
Fast-track pathways for peer review were put in place in order to ensure
vital data reaches the community promptly but, unfortunately, this has
also meant that standards for acceptance were sometimes lowered and,
occasionally, even leading journals published articles of low-quality
that were ultimately retracted [3]. More importantly, many
physicians rushed to embrace the use of one or several drugs with
uncertain benefits but well-documented side effects, employing them
outside the setting of rigorous clinical trials [4]. This approach
is known to cause patients significant harm, as proven in the previous
SARS-CoV 2003 pandemic with studies of ribavirin as a potential
antiviral [5].
The very essence of evidence-based medicine lies in rigorous
interpretation of quantifiable variables that ideally are recorded in an
unbiased manner. Therefore, while case series and retrospective
observational studies may provide correct information, it is generally
accepted that stringently designed, preferably multicenter,
double-blinded, prospective studies of different populations offer
better quality data. Only a handful of these studies or preliminary
reports [6,7] looking at relevant endpoints are available (and
liable to differ from their final printed form) and their results are
generally much more conservative than initial reports [8]. In the
end, in the patient-centered approach the medical professional has a
duty and responsibility to evaluate the data and, together with the
patient, decide the best option through shared decision-making.
While this is hopefully true in most settings, the exceptional
healthcare crisis we are experiencing has led to the overloading of
medical systems and the appearance of ethical dilemmas [9] which
increase the risk for physician burnout and errors. Working in a
COVID-19 dedicated unit, the authors have witnessed firsthand the price
that patients can pay when time-tested scientific approaches to
treatment are supplanted by use of unproven therapeutic agents.
At the beginning of the pandemic, Romanian authorities imposed some of
the most severe lockdown measures in Europe, including the forced
hospitalization of all COVID-19 patients with the provision that
discharge was “legal” only after two consecutive negative PCR tests
for SARS-CoV-2. The situation lasted for over 3 months [10].
Furthermore, the Health Ministry issued a series of treatment guidelines
which were written into law [11] with the aim of enforcing a uniform
approach to therapy. Although the stated aim of this two-pronged
approach was to assist hospital drug policy commissions and offer
guidance on initially promising “off-label” drugs [12], we contend
that this strategy with its’ poorly phrased documentation encouraged
doctors to abdicate from critical case-based decision-making and
resulted in polypharmacy, with unclear benefits but with confirmed and
sometimes severe drug-related adverse events.
More recently and at a time when regulatory bodies such as the Food and
Drug Administration were revoking the Emergency Use Authorization of
some drugs such as hydroxychloroquine [13], based on emerging data
suggesting a lack of efficacy and a potential for severe drug-related
adverse events, the Romanian Ministry of Health was issuing additional
national protocols encouraging the almost indiscriminate use of a wide
range of medications, including, but not limited to –
hydroxychloroquine, remdesivir, ritonavir/lopinavir, favipiravir,
tocilizumab, anakinra, corticosteroids and anticoagulants [12].
This “one-size fits all” approach to clinical practice has probably
resulted in a significant number of drug-related adverse events,
although the precise impact is impossible to assess and, very likely,
will never be comprehended fully. It is obvious that there is a high
potential risk of drug-drug interaction in the setting of COVID-19
treatment especially in frail, polymedicated patients [14]. Despite
these considerations, most severely ill patients admitted in the ICU of
our unit have likely received and continue to receive concomitant
off-label therapy with combinations of Tocilizumab, Hydroxychloroquine,
Azithromycin and Lopinavir/Ritonavir, outside of well-structured
clinical studies, in line with official recommendations which have not
been updated for several months. We strongly believe that more critical
review of the standard medical treatment in this patient group should
counterbalance the state-endorsed polypharmacy and is the responsibility
of each attending physician.
With the pandemic evolving at a rapid pace, physicians should consider
that best supportive care and avoidance of additional harm incurred
through off-label prescription of drugs with unproven efficacy could be
the best way to help our patients. Until well-conducted clinical trials
establish clear basis for antiviral prescription in COVID-19 we should
all approach this extraordinary situation with humility and equipoise,
in the best interest of our patients.
Acknowledgements: The authors would like to acknowledge the
contribution of Georgiana Stoian and Ruxandra Prusan, currently involved
in the Liver-COVID study, for contributing important insight for writing
this paper. Also, the authors would like to acknowledge the hard work
and dedication of all their fellow physicians and nursing staff involved
in caring for COVID-19 patients at Colentina Clinical Hospital.