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

Br J Clin Pharmacol. 2022 Jun;88(6):2802-2813. doi: 10.1111/bcp.15212. Epub 2022 Jan 19.

Authors

Frank M P van Haren^{1

2}, Lex M van Loon¹, Anne Steins¹, Thomas L Smoot³, Caitlin Sas³, Sabrina Staas³, Alicia B Vilaseca⁴, Ruben A Barbera⁴, Gustavo Vidmar⁴, Hugo Beccari⁴, Frida Popilevsky⁵, Eleonora Daribayeva⁵, Bhuvaneshwari Venkatesan⁵, Susan Mozes⁵, Rachel Postel⁵, Natalie Popilevski⁵, Andrew Webb⁶, Quentin Nunes⁷, John G Laffey^{8

9}, Antonio Artigas¹⁰, Roger Smith¹¹, Barry Dixon¹¹, Alice Richardson¹², Hwan-Jin Yoon¹², Clive Page¹³

Affiliations

¹ Australian National University, College of Health and Medicine, Canberra, Australia.
² Intensive Care Unit, Saint George Hospital, Sydney, Australia.
³ Frederick Health Hospital, Frederick, Maryland, USA.
⁴ Service of Haematology and Haemostasis, San Camilo Clinic, Buenos Aires, Argentina.
⁵ Surgical Intensive Care Unit, Coney Island Hospital, Brooklyn, New York, USA.
⁶ Clinical Pharmacology, School of Cardiovascular Medicine & Sciences, King's College, London, United Kingdom.
⁷ Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United Kingdom.
⁸ Anaesthesia and Intensive Care Medicine, School of Medicine, and Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, Biomedical Sciences Building, National University of Ireland Galway, Galway, Ireland.
⁹ Department of Anaesthesia, University Hospital Galway, Saolta Hospital Group, Ireland.
¹⁰ Critical Center, Corporació Universitaria Sanitaria Parc Tauli, CIBER Enfermedades Respiratorias, Autonomous University of Barcelona, Sabadell, Spain.
¹¹ Department of Critical Care Medicine, St Vincent's Hospital, Melbourne, Australia.
¹² Statistical Consulting Unit, Australian National University, Canberra, Australia.
¹³ Sackler Institute of Pulmonary Pharmacology, King's College London, United Kingdom.

PMID: 34984714
DOI: 10.1111/bcp.15212

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.

Publication types

Multicenter Study

MeSH terms

Anticoagulants
COVID-19 Drug Treatment*
Hemorrhage / chemically induced
Hemorrhage / drug therapy
Heparin* / adverse effects
Humans
Partial Thromboplastin Time
Retrospective Studies

Substances

Anticoagulants
Heparin