In a recent study published in JAMA Network, researchers assessed the long-term outcomes of critically ill coronavirus disease 2019 (COVID-19) patients.
The Randomized Embedded Multifactorial Adaptive Platform for Community-Acquired Pneumonia (REMAP-CAP) experiment is a multicenter and randomized platform trial testing numerous treatments for patients suffering from severe pneumonia, taking into account pandemic as well as non-pandemic contexts. Results have been reported for six therapeutic domains for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients, including antiviral therapy, anticoagulation, corticosteroids, immune modulators, immunoglobulin, and antiplatelet treatment.
The trial’s primary endpoint for COVID-19 patients is the combination of hospital survival and provision of organ support for up to 21 days. Interleukin (IL)-6 receptor antagonists demonstrated efficacy in this primary outcome. However, it is yet unknown if these initial therapeutic results translate to a significant impact on long-term survival, health-related quality of life (HRQoL), and disability.
About the study
In the present study, researchers determined the effect of different therapies on longer-term outcomes for adults having critical COVID-19.
Patients were evaluated for eligibility and randomly assigned to receive one or more therapies across various treatment domains. These domains include therapeutic domains and at least two interventions. Both critically sick and non-critically ill patients in varied severity states were enrolled in the study, and group-specific effects were noted. Adults who were aged 18 years or more, were hospitalized in an intensive care unit (ICU) with either suspected or confirmed SARS-CoV-2 infection, and were receiving cardiovascular or respiratory organ support were eligible for participation. Patients were required to be recruited within 48 hours after ICU admission. Patients from 197 sites across 14 countries were enrolled.
In the corticosteroid domain, patients were randomized to be treated with a fixed seven-day course of either intravenous (IV) hydrocortisone, a shock-dependent schedule, or no corticosteroid. On the other hand, in the immune modulation domain, patients were randomized to be treated with IL-6 receptor antagonists, namely tocilizumab, and sarilumab, an IL-1 receptor antagonist named anakinra, interferon-ꞵ1a, or no immune modulator. The antiviral domain participants received either hydroxychloroquine, lopinavir-ritonavir, the combination of the two therapies, or no antiviral. The immunoglobulin domain participants were randomized to be treated with delayed convalescent plasma, ABO-compatible convalescent plasma, or no convalescent plasma. Furthermore, the anticoagulation domain patients were randomized to be treated with pharmacologic thromboprophylaxis or heparin. Lastly, antiplatelet domain participants received a P2Y12 inhibitor like prasugrel, clopidogrel, or ticagrelor; aspirin; or no antiplatelet treatment.
The primary outcome of this prespecified secondary study of longer-term impact was all-cause death within six months. Additional secondary outcomes included 90-day mortality along with HRQoL observed at 180 days as estimated by the 5-level EuroQol-5 Dimension (EQ-5D-5L) utility score as well as the visual analog scale (VAS) score, and disability noted at 180 days as measured by the 12-item World Health Organization Disability Assessment Schedule (WHODAS) 2.0.
For 4107 of the 4318 patients who were randomized at sites participating in 180-day follow-up, mortality status at 180 days was available. Patients having a known 180-day mortality status varied from those whose status was unknown. Patients having an unknown status were younger, displayed higher frequencies corresponding to the receipt of noninvasive ventilation at baseline, reported lower frequencies with respect to vasopressor usage and invasive mechanical ventilation at baseline, scored lower on the Acute Physiology and Chronic Health Evaluation II, and had a lower chance of reporting prevalent chronic obstructive pulmonary disease, asthma, immunosuppressive disease, or be treated with chronic immunosuppressive medications.
A total of 1517 patients who had a known 180-day death rate succumbed. Almost 91 out of 1516 patients died by day 180 and passed away between discharge from the hospital and day 180. Compared to their respective control groups, the antiplatelet therapy and IL-6 receptor antagonists groups demonstrated a high chance of benefit. Compared to no corticosteroids, the likelihood of benefit for shock-dependent as well as fixed-dose corticosteroids was 57.1% and 61.6%, respectively. For therapeutic anticoagulation, lopinavir-ritonavir, and convalescent plasma, the likelihood of statistical futility was considerably high. Notably, the combination of hydroxychloroquine with lopinavir-ritonavir posed a significant risk of adverse effects.
Patients who did not have WHODAS and EQ-5D-5L utility scores were younger, required less high-flow nasal oxygen, needed more invasive and non-invasive ventilation, and had a lower chance of having an immunosuppressive disease or being treated with prolonged immunosuppressive medications. The median EQ-5D-5L utility score for the survivors was 0.74, while the median score on the EQ-VAS was 75. The survivors also reported an adjusted mean difference in EQ-5D-5L utility score that was 0.08 units higher among the pooled antiplatelet cohort than in the control group.
The study findings showed that among patients having critical COVID-19, IL-6 receptor antagonist therapy was associated with a probability of over 99.9% of improved 180-day mortality, while antiplatelet treatment was associated with a 95.0% likelihood of improved 180-day mortality in comparison to the control group. When compared to previously reported short-term results, the data indicated that the initial effects of in-hospital treatment were consistent for the majority of therapies up to six months.
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