Background
In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation.
Methods
This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and
ClinicalTrials.gov
(
NCT04381936
).
Findings
Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57%
vs
50%; rate ratio 1·22; 1·12–1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35%
vs
42%; risk ratio 0·84; 95% CI 0·77–0·92; p<0·0001).
Interpretation
In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids.
Funding
UK Research and Innovation (Medical Research Council) and National Institute of Health Research.
1 The possible role of the endothelium in modulating responses to human urotensin-II (U-II) was investigated using isolated segments of rat thoracic aorta, small mesenteric artery, left anterior descending coronary artery and basilar artery. 2 Human U-II was a potent vasoconstrictor of endothelium-intact isolated rat thoracic aorta (EC 50 =3.5+1.1 nM, R max =103+10% of control contraction induced by 60 mM KCl and 1 mM noradrenaline). However the contractile response was not signi®cantly altered by removal of the endothelium or inhibition of nitric oxide synthesis with L-NAME (100 mM). Human U-II did not cause relaxation of noradrenaline-precontracted, endothelium-intact rat aortae. 3 Human U-II contracted endothelium-intact rat isolated left anterior descending coronary arteries (EC 50 =1.3+0.8 nM, R max =20.1+4.9% of control contraction induced by 10 mM 5-HT). The contractile response was signi®cantly enhanced by removal of the endothelium (R max =55.4+16.1%). Moreover, human U-II caused concentration-dependent relaxation of 5-HTprecontracted arteries, which was abolished by L-NAME or removal of the endothelium. 4 No contractile eects of human U-II were found in rat small mesenteric arteries. However the peptide caused potent, concentration-and endothelium-dependent relaxations of methoxamineprecontracted vessels. The relaxant responses were potentiated by L-NAME (300 mM) but abolished in the additional presence of 25 mM KCl (which inhibits the actions of endothelium-derived hyperpolarizing factor). 5 The present study is the ®rst to show that human U-II is a potent endothelium-dependent vasodilator in some rat resistance vessels, and acts through release of EDHF as well as nitric oxide. Our ®ndings have also highlighted clear anatomical dierences in the responses of dierent vascular beds to human U-II which are likely to be important in determining the overall cardiovascular activity of this peptide.
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