The COVID-19 pandemic has taken the lives of several hundred thousand people across the world. In Spain, a brief but intense outbreak took a toll of over 28,000 lives.
Hazard ratio with 95% confidence intervals and Cohen’s d for various treatments before and after propensity-score matching, for their effect on composite critical event
*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
Many different treatments have been attempted to contain the disease, including steroids and antivirals. However, evidence of their efficacy is lacking, since many therapies have been given together.
A new study published in the preprint server medRxiv* in July 2020 reports that, of the 16 drugs currently used in the treatment of COVID-19, only two have any significant benefit on the clinical outcome.
The study used the data on 1,600 patients admitted to several Madrid hospitals. The study aims to find the clinical factors that are most likely linked to positive treatment outcomes, and which may predict the prognosis.
The study: Risk factors and treatments
There were 2,307 patients originally included in the dataset, however, 679 were excluded, leaving 1,645. Of the remaining patients, 263 died and 311 died or were intubated.
The main difference between fatal and non-fatal cases was the oxygen saturation at presentation. The researchers found that age-related chronic diseases conferred a higher risk of death from COVID-19.
This includes cardiovascular disease, such as diabetes, hypertension, and ischemic heart disease; and chronic obstructive pulmonary disease. However, smoking, high blood pressure and allergies to medications were not associated with poorer outcomes at any level of population analysis.
It was concluded that sicker patients had less reserve and therefore were more likely to have a poorer outcome. However, when compared to the general population, smokers do not show different results in any measurable way.
The researchers could not find any association between any of the initial clinical features when the patient presented to the hospital and a poor outcome, except for the oxygen saturation.
On the other hand, markers of systemic inflammation, such as the lactate and lactate dehydrogenase (LDH) levels, the D-dimer, ferritin and neutrophil count, were associated with a higher death rate and greater chances of intubation.
Patients who would later die or require intubation were also found to have a lower lymphocyte count at presentation, as well as more significantly impaired renal function tests, specifically serum creatinine levels. This may indicate that such measures could help estimate the prognosis of a given patient at first presentation, but by themselves, they are unlikely to inform clinical guidelines, according to the study.
Treatment analysis for efficacy
All patients were admitted with suspected COVID-19 up to April 24 2020, with confirmed diagnoses, and either died or were discharged over the study period. Patients who died within the first 24 hours were excluded.
When they turned to treatments, they first classified the 16 therapies used into four groups, namely, steroids, antivirals, antibiotics and immunomodulators. Taking into consideration that any of these treatments were likely chosen because of the severe presentation, they adjusted the analysis.
They found small effect sizes for most medications except for prednisone, a corticosteroid, and hydroxychloroquine, an anti-inflammatory drug. These showed an associated reduction in mortality risk from COVID-19 of 15% and 16%, respectively.
The rest of the medications were found to have no measurable effect on mortality, while dexamethasone and piperacillin caused a slight increase in mortality. Three drugs, namely, hydrocortisone, linezolid and meropenem, were associated with approximately 30% increases in mortality.
Steroids not associated with mortality risk reduction
Steroids have been shown to be useful in reducing the mortality rate in seriously ill COVID-19 patients, though this is still debated.
The current study shows that, among the steroids, dexamethasone and hydrocortisone had medium to large negative effects, compared with the medium positive effect of prednisone. This is surprising given the recent reports that dexamethasone favorably impacts patient survival in severe COVID-19.
Implications and future directions
Compared with some recent results, this supports the effectiveness of hydroxychloroquine, alone or with azithromycin. Both the viral load and the clinical outcomes were found to be superior with this drug.
However, this finding was contradicted by other studies. Again, the use of antibiotics alone was not supported by any evidence; neither is the use of antivirals recommended based on currently available studies. Tocilizumab and interferon β1b may still be useful but are likely to show the most significant benefit in critical patients.
The current study shows that prednisone and hydroxychloroquine have at least a medium effect size after matching, which is seen even in patients on mechanical ventilation. The researchers consider this to be significant evidence that these drugs may help to manage COVID-19 more successfully.
Randomized, controlled trials of these medications in patients with COVID-19 are needed to avoid heavy administration of treatments with no strong evidence to support them.”
*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
SARS-CoV-2 spike protein found lingering in brain regions