Abstract
Background: Pulmonary vascular microthrombi are a proposed mechanism of COVID-19 respiratory failure. We hypothesized that early administration of tissue plasminogen activator (tPA) followed by therapeutic heparin would improve pulmonary function in these patients.
Research question: Does tPA improve pulmonary function in severe COVID-19 respiratory failure, and is it safe?
Study design and methods: Adults with COVID-19-induced respiratory failure were randomized from May14, 2020 through March 3, 2021, in two phases. Phase 1 (n = 36) comprised a control group (standard-of-care treatment) vs a tPA bolus (50-mg tPA IV bolus followed by 7 days of heparin; goal activated partial thromboplastin time [aPTT], 60-80 s) group. Phase 2 (n = 14) comprised a control group vs a tPA drip (50-mg tPA IV bolus, followed by tPA drip 2 mg/h plus heparin 500 units/h over 24 h, then heparin to maintain aPTT of 60-80 s for 7 days) group. Patients were excluded from enrollment if they had not undergone a neurologic examination or cross-sectional brain imaging within the previous 4.5 h to rule out stroke and potential for hemorrhagic conversion. The primary outcome was Pao 2 to Fio 2 ratio improvement from baseline at 48 h after randomization. Secondary outcomes included Pao 2 to Fio 2 ratio improvement of > 50% or Pao 2 to Fio 2 ratio of ≥ 200 at 48 h (composite outcome), ventilator-free days (VFD), and mortality.
Results: Fifty patients were randomized: 17 in the control group and 19 in the tPA bolus group in phase 1 and eight in the control group and six in the tPA drip group in phase 2. No severe bleeding events occurred. In the tPA bolus group, the Pao 2 to Fio 2 ratio values were significantly (P < .017) higher than baseline at 6 through 168 h after randomization; the control group showed no significant improvements. Among patients receiving a tPA bolus, the percent change of Pao 2 to Fio 2 ratio at 48 h (16.9% control [interquartile range (IQR), -8.3% to 36.8%] vs 29.8% tPA bolus [IQR, 4.5%-88.7%]; P = .11), the composite outcome (11.8% vs 47.4%; P = .03), VFD (0.0 [IQR, 0.0-9.0] vs 12.0 [IQR, 0.0-19.0]; P = .11), and in-hospital mortality (41.2% vs 21.1%; P = .19) did not reach statistically significant differences when compared with those of control participants. The patients who received a tPA drip did not experience benefit.
Interpretation: The combination of tPA bolus plus heparin is safe in severe COVID-19 respiratory failure. A phase 3 study is warranted given the improvements in oxygenation and promising observations in VFD and mortality.
Trial registry: ClinicalTrials.gov; No.: NCT04357730 ; URL: www.
Clinicaltrials: gov.
Keywords: ARDS; COVID-19; fibrinolysis; pulmonary failure; tissue plasminogen activator (tPA).
【저자키워드】 COVID-19, ARDS, fibrinolysis, Tissue plasminogen activator (tPA)., Tissue plasminogen activator (tPA), pulmonary failure, 【초록키워드】 Treatment, Respiratory failure, Mortality, randomization, severe COVID-19, Phase 2, cross-sectional, stroke, outcome, pulmonary, Brain, Randomized, Pulmonary function, therapeutic, Patient, patients, mechanism, in-hospital mortality, Combination, Safe, microthrombi, Phase 1, observation, Hemorrhagic, Vascular, Participants, Enrollment, Primary outcome, control group, Improvements, statistically significant difference, early administration, Standard-of-care, phase 3 study, neurologic, benefit, secondary, tissue plasminogen activator, IMPROVE, occurred, significantly, eight, receiving, activated, maintain, baseline, bleeding event, improvements in oxygenation, IQR, ventilator-free day, VFD, were excluded, 【제목키워드】 SARS-CoV-2, respiratory, failure, alteplase, Controlled,