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Efficacy of inhaled nebulised unfractionated heparin to prevent intubation or death in hospitalised patients with COVID-19: an investigator-initiated international meta-trial of randomised clinical studies

van Haren et al., eClinicalMedicine, doi:10.1016/j.eclinm.2025.103339, INHALE-HEP, Oct 2025
https://c19early.org/vanharen.html
Mortality 58% improvement lower risk ← → higher risk Mortality, in hospital 71% Ventilation 47% Hospitalization 23% Inhaled Heparin  INHALE-HEP  LATE TREATMENT RCT Is late treatment with inhaled heparin beneficial for COVID-19? RCT 478 patients in multiple countries (June 2020 - December 2022) Lower mortality (p=0.012) and ventilation (p=0.015) c19early.org van Haren et al., eClinicalMedicine, Oct 2025 0 0.5 1 1.5 2+ RR
58th treatment shown to reduce risk in October 2025, now with p = 0.0077 from 3 studies.
Lower risk for mortality, ventilation, and hospitalization.
No treatment is 100% effective. Protocols combine treatments.
6,200+ studies for 180+ treatments. c19early.org
Meta-trial of 6 RCTs with 478 hospitalized COVID-19 patients showing significant benefit with inhaled nebulized unfractionated heparin (UFH). Patients receiving nebulized UFH had lower rates of intubation or death at longest follow-up (11.2% vs 22.4%, OR 0.43, p=0.001) and lower in-hospital mortality (4.3% vs 14.3%, OR 0.26, p<0.001). Authors hypothesize the benefits result from UFH's combined antiviral, anti-inflammatory, and anticoagulant properties that prevent viral entry, reduce lung injury progression, and limit pulmonary thrombosis.
Targeted administration to the respiratory tract provides treatment directly to the typical source of initial SARS-CoV-2 infection and replication, and allows for rapid onset of action, higher local drug concentration, and reduced systemic side effects (early treatment may be more beneficial).
risk of death, 57.9% lower, RR 0.42, p = 0.01, treatment 12 of 182 (6.6%), control 29 of 186 (15.6%), NNT 11, odds ratio converted to relative risk, day 28.
risk of death, 70.9% lower, RR 0.29, p < 0.001, treatment 10 of 235 (4.3%), control 34 of 238 (14.3%), NNT 10.0, odds ratio converted to relative risk, in hospital.
risk of mechanical ventilation, 47.3% lower, RR 0.53, p = 0.01, treatment 21 of 234 (9.0%), control 40 of 235 (17.0%), NNT 12, odds ratio converted to relative risk.
risk of hospitalization, 23.1% lower, HR 0.77, p = 0.02, treatment 238, control 240, inverted to make HR<1 favor treatment.
Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates
van Haren et al., 31 Oct 2025, Randomized Controlled Trial, multiple countries, peer-reviewed, 40 authors, study period June 2020 - December 2022, INHALE-HEP trial. Contact: frank.vanharen@anu.edu.au.
Efficacy of inhaled nebulised unfractionated heparin to prevent intubation or death in hospitalised patients with COVID-19: an investigator-initiated international meta-trial of randomised clinical studies
Frank M P Van Haren, Sarah J Valle, Ary Serpa Neto, Marcus J Schultz, John G Laffey, Antonio Artigas, Barry Dixon, Alicia B Vilaseca, Ruben A Barbera, Tarek I Ismail, Rabab S Mahrous, Mohamed Badr, Gilberto Denucci, Carlos Sverdloff, Marta Camprubi-Rimblas, David W Cosgrave, Bairbre Mcnicholas, Catriona Cody, Gerard Curley, Thomas L Smoot, Sabrina Staas, Khine Sann, Caitlin Sas, Anusha Belani, Christopher Hillman, Sidharta Kusuma Manggala, Dita Aditianingsih, Adhrie Sugiarto, Mira Yulianti, Herikurniawan Herikurniawan, Robert Sinto, Aino Nindya Auerkari, Septian Adi Permana, Ashley Woodcock, Mary Carroll, Tom Wilkinson, Dave Singh, Janis Kay Shute, Miles Carroll, Clive Page
eClinicalMedicine, doi:10.1016/j.eclinm.2025.103339
Background Inhaled nebulised unfractionated heparin (UFH) has a strong rationale as a treatment for severe respiratory infections, including COVID-19, due to its antiviral, anti-inflammatory, and anti-coagulant properties, which may prevent viral entry, lung injury progression, and pulmonary thrombosis. We aimed to evaluate the efficacy of inhaled nebulised UFH to prevent intubation or death in hospitalised COVID-19 patients. Methods In this prospective, a priori set up and defined, collaborative meta-trial of six randomised clinical studies, adult hospitalised but not intubated COVID-19 patients were randomly assigned to inhaled nebulised UFH on top of
Ethics and registration The Argentinian study protocol was approved by the Independent Ethics Committee for Clinical Pharmacology Trials, Buenos Aires (ID N 3183).
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Late treatment
is less effective
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