Inhaled nebulised unfractionated heparin (UFH) for the treatment of hospitalised patients with COVID-19: A randomised controlled pilot study

Gilberto DeNucci; Tom Wilkinson; Carlos Sverdloff; Tainah Babadopulos; Ashley Woodcock; Jan Shute; Pedro Renato Guazelli; Luis Frederico Gerbase; Paulo A.S. Mourão; Dave Singh; Frank M.P. van Haren; Clive Page

doi:10.1016/j.pupt.2023.102212

Inhaled nebulised unfractionated heparin (UFH) for the treatment of hospitalised patients with COVID-19: A randomised controlled pilot study

Gilberto DeNucci, Tom Wilkinson, Carlos Sverdloff^*, Tainah Babadopulos, Ashley Woodcock, Jan Shute, Pedro Renato Guazelli, Luis Frederico Gerbase, Paulo A.S. Mourão, Dave Singh, Frank M.P. van Haren, Clive Page

^*Corresponding author for this work

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Abstract

There is a strong scientific rationale to use nebulised unfractionated heparin (UFH) in treating patients with COVID-19. This pilot study investigated whether nebulised UFH was safe and had any impact on mortality, length of hospitalisation and clinical progression, in the treatment of hospitalised patients with COVID-19. This parallel group, open label, randomised trial included adult patients with confirmed SARS-CoV-2 infection admitted to two hospitals in Brazil. One hundred patients were planned to be randomised to either “standard of care” (SOC) or SOC plus nebulized UFH. The trial was stopped after randomisation of 75 patients due to falling COVID-19 hospitalisation rates. Significance tests were 1-sided test (10% significance level). The key analysis populations were intention to treat (ITT) and modified ITT (mITT) which excluded (from both arms) subjects admitted to ITU or who died within 24 h of randomisation. In the ITT population (n = 75), mortality was numerically lower for nebulised UFH (6 out of 38 patients; 15.8%) versus SOC (10 out of 37 patients; 27.0%), but not statistically significant; odds ratio (OR) 0.51, p = 0.24. However, in the mITT population, nebulised UFH reduced mortality (OR 0.2, p = 0.035). Length of hospital stay was similar between groups, but at day 29, there was a greater improvement in ordinal score following treatment with UFH in the ITT and mITT populations (p = 0.076 and p = 0.012 respectively), while mechanical ventilation rates were lower with UFH in the mITT population (OR 0.31; p = 0.08). Nebulised UFH did not cause any significant adverse events. In conclusion, nebulised UFH added to SOC in hospitalised patients with COVID-19 was well tolerated and showed clinical benefit, particularly in patients who received at least 6 doses of heparin. This trial was funded by The J.R. Moulton Charity Trust and registered under REBEC RBR-8r9hy8f (UTN code: U1111-1263-3136).

Original language	English
Article number	102212
Journal	Pulmonary Pharmacology and Therapeutics
Volume	80
DOIs	https://doi.org/10.1016/j.pupt.2023.102212
Publication status	Published - Jun 2023

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10.1016/j.pupt.2023.102212

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DeNucci, G., Wilkinson, T., Sverdloff, C., Babadopulos, T., Woodcock, A., Shute, J., Renato Guazelli, P., Gerbase, L. F., Mourão, P. A. S., Singh, D., van Haren, F. M. P., & Page, C. (2023). Inhaled nebulised unfractionated heparin (UFH) for the treatment of hospitalised patients with COVID-19: A randomised controlled pilot study. Pulmonary Pharmacology and Therapeutics, 80, Article 102212. https://doi.org/10.1016/j.pupt.2023.102212

@article{15b82290401d434399170dda1415203b,

title = "Inhaled nebulised unfractionated heparin (UFH) for the treatment of hospitalised patients with COVID-19: A randomised controlled pilot study",

abstract = "There is a strong scientific rationale to use nebulised unfractionated heparin (UFH) in treating patients with COVID-19. This pilot study investigated whether nebulised UFH was safe and had any impact on mortality, length of hospitalisation and clinical progression, in the treatment of hospitalised patients with COVID-19. This parallel group, open label, randomised trial included adult patients with confirmed SARS-CoV-2 infection admitted to two hospitals in Brazil. One hundred patients were planned to be randomised to either “standard of care” (SOC) or SOC plus nebulized UFH. The trial was stopped after randomisation of 75 patients due to falling COVID-19 hospitalisation rates. Significance tests were 1-sided test (10% significance level). The key analysis populations were intention to treat (ITT) and modified ITT (mITT) which excluded (from both arms) subjects admitted to ITU or who died within 24 h of randomisation. In the ITT population (n = 75), mortality was numerically lower for nebulised UFH (6 out of 38 patients; 15.8%) versus SOC (10 out of 37 patients; 27.0%), but not statistically significant; odds ratio (OR) 0.51, p = 0.24. However, in the mITT population, nebulised UFH reduced mortality (OR 0.2, p = 0.035). Length of hospital stay was similar between groups, but at day 29, there was a greater improvement in ordinal score following treatment with UFH in the ITT and mITT populations (p = 0.076 and p = 0.012 respectively), while mechanical ventilation rates were lower with UFH in the mITT population (OR 0.31; p = 0.08). Nebulised UFH did not cause any significant adverse events. In conclusion, nebulised UFH added to SOC in hospitalised patients with COVID-19 was well tolerated and showed clinical benefit, particularly in patients who received at least 6 doses of heparin. This trial was funded by The J.R. Moulton Charity Trust and registered under REBEC RBR-8r9hy8f (UTN code: U1111-1263-3136).",

keywords = "COVID-19, Inhaled heparin, Nebulised heparin, Randomised controlled trial, Respiratory failure, SARS-CoV-2, Unfractionated heparin",

author = "Gilberto DeNucci and Tom Wilkinson and Carlos Sverdloff and Tainah Babadopulos and Ashley Woodcock and Jan Shute and {Renato Guazelli}, Pedro and Gerbase, {Luis Frederico} and Mour{\~a}o, {Paulo A.S.} and Dave Singh and {van Haren}, {Frank M.P.} and Clive Page",

note = "Publisher Copyright: {\textcopyright} 2023",

year = "2023",

month = jun,

doi = "10.1016/j.pupt.2023.102212",

language = "English",

volume = "80",

journal = "Pulmonary Pharmacology and Therapeutics",

issn = "1094-5539",

publisher = "Academic Press",

}

DeNucci, G, Wilkinson, T, Sverdloff, C, Babadopulos, T, Woodcock, A, Shute, J, Renato Guazelli, P, Gerbase, LF, Mourão, PAS, Singh, D, van Haren, FMP & Page, C 2023, 'Inhaled nebulised unfractionated heparin (UFH) for the treatment of hospitalised patients with COVID-19: A randomised controlled pilot study', Pulmonary Pharmacology and Therapeutics, vol. 80, 102212. https://doi.org/10.1016/j.pupt.2023.102212

TY - JOUR

T1 - Inhaled nebulised unfractionated heparin (UFH) for the treatment of hospitalised patients with COVID-19

T2 - A randomised controlled pilot study

AU - DeNucci, Gilberto

AU - Wilkinson, Tom

AU - Sverdloff, Carlos

AU - Babadopulos, Tainah

AU - Woodcock, Ashley

AU - Shute, Jan

AU - Renato Guazelli, Pedro

AU - Gerbase, Luis Frederico

AU - Mourão, Paulo A.S.

AU - Singh, Dave

AU - van Haren, Frank M.P.

AU - Page, Clive

PY - 2023/6

Y1 - 2023/6

N2 - There is a strong scientific rationale to use nebulised unfractionated heparin (UFH) in treating patients with COVID-19. This pilot study investigated whether nebulised UFH was safe and had any impact on mortality, length of hospitalisation and clinical progression, in the treatment of hospitalised patients with COVID-19. This parallel group, open label, randomised trial included adult patients with confirmed SARS-CoV-2 infection admitted to two hospitals in Brazil. One hundred patients were planned to be randomised to either “standard of care” (SOC) or SOC plus nebulized UFH. The trial was stopped after randomisation of 75 patients due to falling COVID-19 hospitalisation rates. Significance tests were 1-sided test (10% significance level). The key analysis populations were intention to treat (ITT) and modified ITT (mITT) which excluded (from both arms) subjects admitted to ITU or who died within 24 h of randomisation. In the ITT population (n = 75), mortality was numerically lower for nebulised UFH (6 out of 38 patients; 15.8%) versus SOC (10 out of 37 patients; 27.0%), but not statistically significant; odds ratio (OR) 0.51, p = 0.24. However, in the mITT population, nebulised UFH reduced mortality (OR 0.2, p = 0.035). Length of hospital stay was similar between groups, but at day 29, there was a greater improvement in ordinal score following treatment with UFH in the ITT and mITT populations (p = 0.076 and p = 0.012 respectively), while mechanical ventilation rates were lower with UFH in the mITT population (OR 0.31; p = 0.08). Nebulised UFH did not cause any significant adverse events. In conclusion, nebulised UFH added to SOC in hospitalised patients with COVID-19 was well tolerated and showed clinical benefit, particularly in patients who received at least 6 doses of heparin. This trial was funded by The J.R. Moulton Charity Trust and registered under REBEC RBR-8r9hy8f (UTN code: U1111-1263-3136).

AB - There is a strong scientific rationale to use nebulised unfractionated heparin (UFH) in treating patients with COVID-19. This pilot study investigated whether nebulised UFH was safe and had any impact on mortality, length of hospitalisation and clinical progression, in the treatment of hospitalised patients with COVID-19. This parallel group, open label, randomised trial included adult patients with confirmed SARS-CoV-2 infection admitted to two hospitals in Brazil. One hundred patients were planned to be randomised to either “standard of care” (SOC) or SOC plus nebulized UFH. The trial was stopped after randomisation of 75 patients due to falling COVID-19 hospitalisation rates. Significance tests were 1-sided test (10% significance level). The key analysis populations were intention to treat (ITT) and modified ITT (mITT) which excluded (from both arms) subjects admitted to ITU or who died within 24 h of randomisation. In the ITT population (n = 75), mortality was numerically lower for nebulised UFH (6 out of 38 patients; 15.8%) versus SOC (10 out of 37 patients; 27.0%), but not statistically significant; odds ratio (OR) 0.51, p = 0.24. However, in the mITT population, nebulised UFH reduced mortality (OR 0.2, p = 0.035). Length of hospital stay was similar between groups, but at day 29, there was a greater improvement in ordinal score following treatment with UFH in the ITT and mITT populations (p = 0.076 and p = 0.012 respectively), while mechanical ventilation rates were lower with UFH in the mITT population (OR 0.31; p = 0.08). Nebulised UFH did not cause any significant adverse events. In conclusion, nebulised UFH added to SOC in hospitalised patients with COVID-19 was well tolerated and showed clinical benefit, particularly in patients who received at least 6 doses of heparin. This trial was funded by The J.R. Moulton Charity Trust and registered under REBEC RBR-8r9hy8f (UTN code: U1111-1263-3136).

KW - COVID-19

KW - Inhaled heparin

KW - Nebulised heparin

KW - Randomised controlled trial

KW - Respiratory failure

KW - SARS-CoV-2

KW - Unfractionated heparin

UR - http://www.scopus.com/inward/record.url?scp=85151278010&partnerID=8YFLogxK

U2 - 10.1016/j.pupt.2023.102212

DO - 10.1016/j.pupt.2023.102212

M3 - Article

SN - 1094-5539

VL - 80

JO - Pulmonary Pharmacology and Therapeutics

JF - Pulmonary Pharmacology and Therapeutics

M1 - 102212

ER -

Inhaled nebulised unfractionated heparin (UFH) for the treatment of hospitalised patients with COVID-19: A randomised controlled pilot study

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