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

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.

Figure 1.

Admissions, mortality, and treatments for COVID-19 in the first, second, third, and fourth waves in the Netherlands. A, Admissions, mortality, and novel antiviral and immunosuppressive treatments for COVID-19 in the first, second, third, and fourth waves in the Netherlands. Between February 27, 2020, and December 31, 2021, 89 110 patients with confirmed COVID-19 were admitted to the ward and 16 590 patients to the ICU in the Netherlands; 10 317 COVID-19 patients died on the ward and 4511 in the ICU. In this time period, 6 novel drug treatment modalities were implemented through national guidelines [10], either as standard or optional care for patients hospitalized because of COVID-19. Gray bars: included in national treatment guidelines as optional care; red bars: included as standard care. ^aDexamethasone was first only recommended for ICU patients, since September 29, 2020, also for ward patients. ^bIL-6 antagonists were first only recommended for ICU patients, since March 9, 2021, also for ward patients. ^cCasirivimab/imdevimab was recommended until December 23, 2021; sotrovimab was recommended since December 23, 2021. B, Administration of novel antiviral and immunosuppressive treatments for hospitalized COVID-19 in the first, second, third, and fourth waves in the Netherlands. The percentage of patients included in the COVIDPredict trial treated with the 6 novel drug treatment modalities implemented through national guidelines in the time period between February 27, 2020, and December 31, 2021. ^aIncluded dexamethasone, prednisolone, hydrocortisone, and methylprednisolone. Abbreviations: COVID-19, coronavirus disease 2019; ICU, intensive care unit; IL, interleukin; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Figure 2.

Hazard ratios of treatment effects per treatment group. A, Patients admitted directly to the ward. B, Patients admitted directly to the ICU. Remdesivir and SARS-CoV-2-neutralizing monoclonal antibodies were not analyzed given the small sample size. Abbreviations: ICU, intensive care unit; IL, interleukin; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Figure 3.

Effect of treatment in hospitalized COVID-19 patients of remdesivir (A), corticosteroids (B, C, F), and IL-6 antagonists (D, E, G) in patients directly admitted to the ward (A–E) and the ICU (F, G) in the propensity-weighted cohort. The treatment effect of remdesivir on discharge alive within 29 days is shown in patients directly admitted to the ward (A); the treatment effect of corticosteroids on in-hospital (B) and ICU admission (C) is shown in patients directly admitted to the ward, as well as the treatment effect of IL-6 antagonists on in-hospital (D) and ICU admission (E) in patients directly admitted to the ward. The treatment effect of corticosteroids (F) and IL-6 antagonists (G) is shown in patients directly admitted to the ICU. Abbreviations: COVID-19, coronavirus disease 2019; ICU, intensive care unit; IL, interleukin.