Pharmacotherapy for Hospitalized Patients with COVID-19: Treatment Patterns by Disease Severity

Abstract

Background: Treatment decisions for Coronavirus Disease 2019 (COVID-19) depend on disease severity, but the prescribing pattern by severity and drivers of therapeutic choices remain unclear.

Objectives: The objectives of the study were to evaluate pharmacological treatment patterns by COVID-19 severity and identify the determinants of prescribing for COVID-19.

Methods: Using electronic health record data from a large Massachusetts-based healthcare system, we identified all patients aged ≥ 18 years hospitalized with laboratory-confirmed COVID-19 from 1 March to 24 May, 2020. We defined five levels of COVID-19 severity at hospital admission: (1) hospitalized but not requiring supplemental oxygen; (2-4) hospitalized and requiring oxygen ≤ 2, 3-4, and ≥ 5 L per minute, respectively; and (5) intubated or admitted to an intensive care unit. We assessed the medications used to treat COVID-19 or as supportive care during hospitalization.

Results: Among 2821 patients hospitalized for COVID-19, we found inpatient mortality increased by severity from 5% for level 1 to 23% for level 5. As compared to patients with severity level 1, those with severity level 5 were 3.53 times (95% confidence interval 2.73-4.57) more likely to receive a medication used to treat COVID-19. Other predictors of treatment were fever, low oxygen saturation, presence of co-morbidities, and elevated inflammatory biomarkers. The use of most COVID-19 relevant medications has dropped substantially while the use of remdesivir and therapeutic anticoagulants has increased over the study period.

Conclusions: Careful consideration of disease severity and other determinants of COVID-19 drug use is necessary for appropriate conduct and interpretation of non-randomized studies evaluating outcomes of COVID-19 treatments.

Fig. 1

Pharmacological treatment pattern of patients hospitalized with COVID-19 by disease severity. We defined COVID-19 disease severity as follows: severity level 1, hospitalized but not requiring supplemental oxygen; level 2, hospitalized and requiring supplemental oxygen ≤ 2 L/min; severity level 3, hospitalized and requiring oxygen therapy 3–4 L/min; level 4, hospitalized and requiring oxygen therapy ≥ 5 L/min or receiving nasal high-flow oxygen therapy, non-rebreather, or noninvasive mechanical ventilation; level 5, receiving invasive mechanical ventilation or extracorporeal membrane oxygenation, or admitted to an intensive care unit. HCQ hydroxychloroquine, others sarilumab, siltuximab, darunavir/cobicistat, interferon-beta, nitric oxide, favipiravir, canakinumab, ravulizumab, ibrutinib, anakinra, rilonacept, and umifenovir. *p-value for linear trend by COVID-19 severity

Fig. 2

Weekly time trend of pharmacological treatment for patients hospitalized for COVID-19. ACEi angiotensin-converting enzyme inhibitors, ARB angiotensin II receptor blockers, FDA US Food and Drug Administration, H2RA H₂-receptor antagonists, HCQ hydroxychloroquine, HIV human immunodeficiency virus, EUA emergency use authorization, IV intravenous, PPI proton pump inhibitors. Others: sarilumab, siltuximab, darunavir/cobicistat, interferon beta, nitric oxide, favipiravir, canakinumab, ravulizumab, ibrutinib, anakinra, rilonacept, and umifenovir. *p-value for linear time trend. The first week was excluded because of an insufficient number of patients (n = 2) and the last week was excluded because of an incomplete observation period (<1 week). ¹On 19 March, 2020, President Trump endorsed the use of hydroxychloroquine to treat COVID-19 on the television. ²On 30 March, 2020, a French study found no evidence of effective antiviral activities or clinical benefits of the combination of hydroxychloroquine and azithromycin for the treatment of hospitalized patients with severe COVID-19 [63], findings that were supported by several subsequent studies [64]. ³On 1 May, 2020, the US FDA issued an EUA of remdesivir for the treatment of hospitalized patients with COVID-19