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 (FiO 2 ) and FiO 2 , 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/FiO 2 ratio and the FiO 2 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 randomisedThe authors confirm that the PI for this paper is Professor Frank M.P. van Haren and that he has direct responsibility for the described case-series.

Can nebulised HepArin Reduce morTality and time to Extubation in patients with COVID‐19 Requiring invasive ventilation Meta‐Trial (CHARTER‐MT): Protocol and statistical analysis plan for an investigator‐initiated international meta‐trial of prospective randomised clinical studies

“…A recently published randomised double‐blind placebo‐controlled multi‐centre clinical trial of nebulised heparin in 256 patients with or at risk of developing ARDS, found that it reduced progression of lung injury, reduced development of ARDS and accelerated recovery with more survivors at home by Day 60 23 . We also recently reported the safety and efficacy potential of this treatment in 98 hospitalised patients with confirmed COVID‐19 24 …”

“… 23 We also recently reported the safety and efficacy potential of this treatment in 98 hospitalised patients with confirmed COVID‐19. 24 …”

Coagulopathy and Fibrinolytic Pathophysiology in COVID-19 and SARS-CoV-2 Vaccination

“…However, inhalation of fibrinolytic agents such as tPA and plasminogen [ 150 , 151 ] can reduce the risk of bleeding much more than systemic administration and may improve acute respiratory distress syndrome (ARDS) by dissolving fibrin clots in and near the alveolar spaces [ 152 ]. Inhaled heparin has also been shown to be effective in the treatment of COVID-19 patients [ 153 , 154 ]. Some problems with inhaled heparin therapy still need to be addressed, such as individual differences in blood transfer and the possibility of exposure of health care providers to droplet infection.…”

Antivirals and the Potential Benefits of Orally Inhaled Drug Administration in COVID-19 Treatment

“…130 At the end of the study, it was concluded that inhaled nebulized Heparin was safe in hospitalized COVID-19 patients and urgent randomized studies are needed to evaluate the efficacy. 131 Our study group has recently completed a clinical Phase 2b trial that proposes inhaled LMWH given via soft-mist inhaler significantly improves hypoxemia in COVID-19 patients. Soft-mist inhaled LMWH was well-tolerated and markedly decreased the need for the oxygen treatment (vs. reservoir masks, high-flow oxygen therapy) at the end of the 10-day treatment.…”