Real-world Evidence of the Effects of Novel Treatments for COVID-19 on Mortality: A Nationwide Comparative Cohort Study of Hospitalized Patients in the First, Second, Third, and Fourth Waves in the Netherlands

Marleen A Slim; Brent Appelman; Hessel Peters-Sengers; Dave A Dongelmans; Nicolette F de Keizer; Rogier P Schade; Mark G J de Boer; Marcella C A Müller; Alexander P J Vlaar; W Joost Wiersinga; Lonneke A van Vught; NICE COVID-19 Research Consortium and the COVIDPredict study group

doi:10.1093/ofid/ofac632

Real-world Evidence of the Effects of Novel Treatments for COVID-19 on Mortality: A Nationwide Comparative Cohort Study of Hospitalized Patients in the First, Second, Third, and Fourth Waves in the Netherlands

Open Forum Infect Dis. 2022 Nov 22;9(12):ofac632. doi: 10.1093/ofid/ofac632. eCollection 2022 Dec.

Authors

Marleen A Slim^{1

2}, Brent Appelman¹, Hessel Peters-Sengers^{1

3}, Dave A Dongelmans^{2

4}, Nicolette F de Keizer^{4

5}, Rogier P Schade⁶, Mark G J de Boer⁷, Marcella C A Müller², Alexander P J Vlaar², W Joost Wiersinga^{1

8}, Lonneke A van Vught^{1

2}; NICE COVID-19 Research Consortium and the COVIDPredict study group

Collaborators

NICE COVID-19 Research Consortium and the COVIDPredict study group:
Brent Appelman, Michiel Schinkel, Martijn Beudel, Ronald Henry, Esther K Haspels-Hogervorst, Daisy Rusch, Niels C Gritters van den Oever, Suat Simsek, W de Ruijter, Frits H M van Osch, Joop P van den Bergh, Martijn D de Kruif, Renee Douma, Lianne R de Haan, Hazra Moeniralam, Kees Brinkman, N Bokhizzou

Affiliations

¹ Center for Experimental and Molecular Medicine, Amsterdam University Medical Centers-Location AMC, University of Amsterdam, Amsterdam Institute for Infection and Immunity, Amsterdam, the Netherlands.
² Department of Intensive Care, Amsterdam University Medical Centers-Location AMC, University of Amsterdam, Amsterdam Institute for Infection and Immunity, Amsterdam, the Netherlands.
³ Department of Epidemiology and Data Science, Amsterdam University Medical Centers-Location AMC, University of Amsterdam, Amsterdam Public Health Research Institute, Amsterdam, the Netherlands.
⁴ National Intensive Care Evaluation (NICE) Foundation, Amsterdam, the Netherlands.
⁵ Department of Medical Informatics, Amsterdam University Medical Centers, University of Amsterdam-Location AMC, Amsterdam Public Health Research Institute, Amsterdam, the Netherlands.
⁶ Department of Medical Microbiology and Infection Prevention, Amsterdam University Medical Centers-Location AMC, University of Amsterdam, Amsterdam, the Netherlands.
⁷ Department of Infectious Diseases and Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.
⁸ Division of Infectious Diseases, Department of Medicine, Amsterdam University Medical Centers-Location AMC, University of Amsterdam, Amsterdam, the Netherlands.

Abstract

Background: Large clinical trials on drugs for hospitalized coronavirus disease 2019 (COVID-19) patients have shown significant effects on mortality. There may be a discrepancy with the observed real-world effect. We describe the clinical characteristics and outcomes of hospitalized COVID-19 patients in the Netherlands during 4 pandemic waves and analyze the association of the newly introduced treatments with mortality, intensive care unit (ICU) admission, and discharge alive.

Methods: We conducted a nationwide retrospective analysis of hospitalized COVID-19 patients between February 27, 2020, and December 31, 2021. Patients were categorized into waves and into treatment groups (hydroxychloroquine, remdesivir, neutralizing severe acute respiratory syndrome coronavirus 2 monoclonal antibodies, corticosteroids, and interleukin [IL]-6 antagonists). Four types of Cox regression analyses were used: unadjusted, adjusted, propensity matched, and propensity weighted.

Results: Among 5643 patients from 11 hospitals, we observed a changing epidemiology during 4 pandemic waves, with a decrease in median age (67-64 years; P < .001), in in-hospital mortality on the ward (21%-15%; P < .001), and a trend in the ICU (24%-16%; P = .148). In ward patients, hydroxychloroquine was associated with increased mortality (1.54; 95% CI, 1.22-1.96), and remdesivir was associated with a higher rate of discharge alive within 29 days (1.16; 95% CI, 1.03-1.31). Corticosteroids were associated with a decrease in mortality (0.82; 95% CI, 0.69-0.96); the results of IL-6 antagonists were inconclusive. In patients directly admitted to the ICU, hydroxychloroquine, corticosteroids, and IL-6 antagonists were not associated with decreased mortality.

Conclusions: Both remdesivir and corticosteroids were associated with better outcomes in ward patients with COVID-19. Continuous evaluation of real-world treatment effects is needed.

Keywords: COVID-19; SARS-CoV-2; antiviral; epidemiology; immunosuppressive treatments.