Inhaled nebulised unfractionated heparin for the treatment of hospitalised patients with COVID-19: A multicentre case series of 98 patients

Frank M.P. van Haren; Lex M. van Loon; Anne Steins; Thomas L. Smoot; Caitlin Sas; Sabrina Staas; Alicia B. Vilaseca; Ruben A. Barbera; Gustavo Vidmar; Hugo Beccari; Frida Popilevsky; Eleonora Daribayeva; Bhuvaneshwari Venkatesan; Susan Mozes; Rachel Postel; Natalie Popilevski; Andrew Webb; Quentin Nunes; John G. Laffey; Antonio Artigas; Roger Smith; Barry Dixon; Alice Richardson; Hwan Jin Yoon; Clive Page

doi:10.1111/bcp.15212

Inhaled nebulised unfractionated heparin for the treatment of hospitalised patients with COVID-19: A multicentre case series of 98 patients

Frank M.P. van Haren^*, Lex M. van Loon, Anne Steins, Thomas L. Smoot, Caitlin Sas, Sabrina Staas, Alicia B. Vilaseca, Ruben A. Barbera, Gustavo Vidmar, Hugo Beccari, Frida Popilevsky, Eleonora Daribayeva, Bhuvaneshwari Venkatesan, Susan Mozes, Rachel Postel, Natalie Popilevski, Andrew Webb, Quentin Nunes, John G. Laffey, Antonio ArtigasRoger Smith, Barry Dixon, Alice Richardson, Hwan Jin Yoon, Clive Page

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

Aims: To determine the safety and efficacy-potential of inhaled nebulised unfractionated heparin (UFH) in the treatment of hospitalised patients with COVID-19. Methods: Retrospective, uncontrolled multicentre single-arm case series of hospitalised patients with laboratory-confirmed COVID-19, treated with inhaled nebulised UFH (5000 IU q8h, 10 000 IU q4h, or 25 000 IU q6h) for 6 ± 3 (mean ± standard deviation) days. Outcomes were activated partial thromboplastin time (APTT) before treatment (baseline) and highest-level during treatment (peak), and adverse events including bleeding. Exploratory efficacy outcomes were oxygenation, assessed by ratio of oxygen saturation to fraction of inspired oxygen (FiO₂) and FiO₂, and the World Health Organisation modified ordinal clinical scale. Results: There were 98 patients included. In patients on stable prophylactic or therapeutic systemic anticoagulant therapy but not receiving therapeutic UFH infusion, APTT levels increased from baseline of 34 ± 10 seconds to a peak of 38 ± 11 seconds (P <.0001). In 3 patients on therapeutic UFH infusion, APTT levels did not significantly increase from baseline of 72 ± 20 to a peak of 84 ± 28 seconds (P =.17). Two patients had serious adverse events: bleeding gastric ulcer requiring transfusion and thigh haematoma; both were on therapeutic anticoagulation. Minor bleeding occurred in 16 patients, 13 of whom were on therapeutic anticoagulation. The oxygen saturation/FiO₂ ratio and the FiO₂ worsened before and improved after commencement of inhaled UFH (change in slope, P <.001). Conclusion: Inhaled nebulised UFH in hospitalised patients with COVID-19 was safe. Although statistically significant, inhaled nebulised UFH did not produce a clinically relevant increase in APTT (peak values in the normal range). Urgent randomised evaluation of nebulised UFH in patients with COVID-19 is warranted and several studies are currently underway.

Original language	English
Pages (from-to)	2802-2813
Number of pages	12
Journal	British Journal of Clinical Pharmacology
Volume	88
Issue number	6
DOIs	https://doi.org/10.1111/bcp.15212
Publication status	Published - Jun 2022

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van Haren, F. M. P., van Loon, L. M., Steins, A., Smoot, T. L., Sas, C., Staas, S., Vilaseca, A. B., Barbera, R. A., Vidmar, G., Beccari, H., Popilevsky, F., Daribayeva, E., Venkatesan, B., Mozes, S., Postel, R., Popilevski, N., Webb, A., Nunes, Q., Laffey, J. G., ... Page, C. (2022). Inhaled nebulised unfractionated heparin for the treatment of hospitalised patients with COVID-19: A multicentre case series of 98 patients. British Journal of Clinical Pharmacology, 88(6), 2802-2813. https://doi.org/10.1111/bcp.15212

@article{c611bd2a29b84fe8a0b0632ad370314f,

title = "Inhaled nebulised unfractionated heparin for the treatment of hospitalised patients with COVID-19: A multicentre case series of 98 patients",

abstract = "Aims: To determine the safety and efficacy-potential of inhaled nebulised unfractionated heparin (UFH) in the treatment of hospitalised patients with COVID-19. Methods: Retrospective, uncontrolled multicentre single-arm case series of hospitalised patients with laboratory-confirmed COVID-19, treated with inhaled nebulised UFH (5000 IU q8h, 10 000 IU q4h, or 25 000 IU q6h) for 6 ± 3 (mean ± standard deviation) days. Outcomes were activated partial thromboplastin time (APTT) before treatment (baseline) and highest-level during treatment (peak), and adverse events including bleeding. Exploratory efficacy outcomes were oxygenation, assessed by ratio of oxygen saturation to fraction of inspired oxygen (FiO2) and FiO2, and the World Health Organisation modified ordinal clinical scale. Results: There were 98 patients included. In patients on stable prophylactic or therapeutic systemic anticoagulant therapy but not receiving therapeutic UFH infusion, APTT levels increased from baseline of 34 ± 10 seconds to a peak of 38 ± 11 seconds (P <.0001). In 3 patients on therapeutic UFH infusion, APTT levels did not significantly increase from baseline of 72 ± 20 to a peak of 84 ± 28 seconds (P =.17). Two patients had serious adverse events: bleeding gastric ulcer requiring transfusion and thigh haematoma; both were on therapeutic anticoagulation. Minor bleeding occurred in 16 patients, 13 of whom were on therapeutic anticoagulation. The oxygen saturation/FiO2 ratio and the FiO2 worsened before and improved after commencement of inhaled UFH (change in slope, P <.001). Conclusion: Inhaled nebulised UFH in hospitalised patients with COVID-19 was safe. Although statistically significant, inhaled nebulised UFH did not produce a clinically relevant increase in APTT (peak values in the normal range). Urgent randomised evaluation of nebulised UFH in patients with COVID-19 is warranted and several studies are currently underway.",

keywords = "COVID-19, SARS-CoV-2, case series, inhaled heparin, nebulised heparin, pandemic, respiratory failure, unfractionated heparin",

author = "{van Haren}, {Frank M.P.} and {van Loon}, {Lex M.} and Anne Steins and Smoot, {Thomas L.} and Caitlin Sas and Sabrina Staas and Vilaseca, {Alicia B.} and Barbera, {Ruben A.} and Gustavo Vidmar and Hugo Beccari and Frida Popilevsky and Eleonora Daribayeva and Bhuvaneshwari Venkatesan and Susan Mozes and Rachel Postel and Natalie Popilevski and Andrew Webb and Quentin Nunes and Laffey, {John G.} and Antonio Artigas and Roger Smith and Barry Dixon and Alice Richardson and Yoon, {Hwan Jin} and Clive Page",

note = "Publisher Copyright: {\textcopyright} 2022 British Pharmacological Society.",

year = "2022",

month = jun,

doi = "10.1111/bcp.15212",

language = "English",

volume = "88",

pages = "2802--2813",

journal = "British Journal of Clinical Pharmacology",

issn = "0306-5251",

publisher = "Wiley-Blackwell Publishing Ltd",

number = "6",

}

van Haren, FMP, van Loon, LM, Steins, A, Smoot, TL, Sas, C, Staas, S, Vilaseca, AB, Barbera, RA, Vidmar, G, Beccari, H, Popilevsky, F, Daribayeva, E, Venkatesan, B, Mozes, S, Postel, R, Popilevski, N, Webb, A, Nunes, Q, Laffey, JG, Artigas, A, Smith, R, Dixon, B, Richardson, A, Yoon, HJ & Page, C 2022, 'Inhaled nebulised unfractionated heparin for the treatment of hospitalised patients with COVID-19: A multicentre case series of 98 patients', British Journal of Clinical Pharmacology, vol. 88, no. 6, pp. 2802-2813. https://doi.org/10.1111/bcp.15212

TY - JOUR

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

T2 - A multicentre case series of 98 patients

AU - van Haren, Frank M.P.

AU - van Loon, Lex M.

AU - Steins, Anne

AU - Smoot, Thomas L.

AU - Sas, Caitlin

AU - Staas, Sabrina

AU - Vilaseca, Alicia B.

AU - Barbera, Ruben A.

AU - Vidmar, Gustavo

AU - Beccari, Hugo

AU - Popilevsky, Frida

AU - Daribayeva, Eleonora

AU - Venkatesan, Bhuvaneshwari

AU - Mozes, Susan

AU - Postel, Rachel

AU - Popilevski, Natalie

AU - Webb, Andrew

AU - Nunes, Quentin

AU - Laffey, John G.

AU - Artigas, Antonio

AU - Smith, Roger

AU - Dixon, Barry

AU - Richardson, Alice

AU - Yoon, Hwan Jin

AU - Page, Clive

PY - 2022/6

Y1 - 2022/6

N2 - Aims: To determine the safety and efficacy-potential of inhaled nebulised unfractionated heparin (UFH) in the treatment of hospitalised patients with COVID-19. Methods: Retrospective, uncontrolled multicentre single-arm case series of hospitalised patients with laboratory-confirmed COVID-19, treated with inhaled nebulised UFH (5000 IU q8h, 10 000 IU q4h, or 25 000 IU q6h) for 6 ± 3 (mean ± standard deviation) days. Outcomes were activated partial thromboplastin time (APTT) before treatment (baseline) and highest-level during treatment (peak), and adverse events including bleeding. Exploratory efficacy outcomes were oxygenation, assessed by ratio of oxygen saturation to fraction of inspired oxygen (FiO2) and FiO2, and the World Health Organisation modified ordinal clinical scale. Results: There were 98 patients included. In patients on stable prophylactic or therapeutic systemic anticoagulant therapy but not receiving therapeutic UFH infusion, APTT levels increased from baseline of 34 ± 10 seconds to a peak of 38 ± 11 seconds (P <.0001). In 3 patients on therapeutic UFH infusion, APTT levels did not significantly increase from baseline of 72 ± 20 to a peak of 84 ± 28 seconds (P =.17). Two patients had serious adverse events: bleeding gastric ulcer requiring transfusion and thigh haematoma; both were on therapeutic anticoagulation. Minor bleeding occurred in 16 patients, 13 of whom were on therapeutic anticoagulation. The oxygen saturation/FiO2 ratio and the FiO2 worsened before and improved after commencement of inhaled UFH (change in slope, P <.001). Conclusion: Inhaled nebulised UFH in hospitalised patients with COVID-19 was safe. Although statistically significant, inhaled nebulised UFH did not produce a clinically relevant increase in APTT (peak values in the normal range). Urgent randomised evaluation of nebulised UFH in patients with COVID-19 is warranted and several studies are currently underway.

AB - Aims: To determine the safety and efficacy-potential of inhaled nebulised unfractionated heparin (UFH) in the treatment of hospitalised patients with COVID-19. Methods: Retrospective, uncontrolled multicentre single-arm case series of hospitalised patients with laboratory-confirmed COVID-19, treated with inhaled nebulised UFH (5000 IU q8h, 10 000 IU q4h, or 25 000 IU q6h) for 6 ± 3 (mean ± standard deviation) days. Outcomes were activated partial thromboplastin time (APTT) before treatment (baseline) and highest-level during treatment (peak), and adverse events including bleeding. Exploratory efficacy outcomes were oxygenation, assessed by ratio of oxygen saturation to fraction of inspired oxygen (FiO2) and FiO2, and the World Health Organisation modified ordinal clinical scale. Results: There were 98 patients included. In patients on stable prophylactic or therapeutic systemic anticoagulant therapy but not receiving therapeutic UFH infusion, APTT levels increased from baseline of 34 ± 10 seconds to a peak of 38 ± 11 seconds (P <.0001). In 3 patients on therapeutic UFH infusion, APTT levels did not significantly increase from baseline of 72 ± 20 to a peak of 84 ± 28 seconds (P =.17). Two patients had serious adverse events: bleeding gastric ulcer requiring transfusion and thigh haematoma; both were on therapeutic anticoagulation. Minor bleeding occurred in 16 patients, 13 of whom were on therapeutic anticoagulation. The oxygen saturation/FiO2 ratio and the FiO2 worsened before and improved after commencement of inhaled UFH (change in slope, P <.001). Conclusion: Inhaled nebulised UFH in hospitalised patients with COVID-19 was safe. Although statistically significant, inhaled nebulised UFH did not produce a clinically relevant increase in APTT (peak values in the normal range). Urgent randomised evaluation of nebulised UFH in patients with COVID-19 is warranted and several studies are currently underway.

KW - COVID-19

KW - SARS-CoV-2

KW - case series

KW - inhaled heparin

KW - nebulised heparin

KW - pandemic

KW - respiratory failure

KW - unfractionated heparin

UR - http://www.scopus.com/inward/record.url?scp=85122888935&partnerID=8YFLogxK

U2 - 10.1111/bcp.15212

DO - 10.1111/bcp.15212

M3 - Article

SN - 0306-5251

VL - 88

SP - 2802

EP - 2813

JO - British Journal of Clinical Pharmacology

JF - British Journal of Clinical Pharmacology

IS - 6

ER -

Inhaled nebulised unfractionated heparin for the treatment of hospitalised patients with COVID-19: A multicentre case series of 98 patients

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