Study of Alteplase for Respiratory Failure in SARS-CoV-2 COVID-19: A Vanguard Multicenter, Rapidly Adaptive, Pragmatic, Randomized Controlled Trial

Department of Surgery, Boston University School of Medicine, Boston, MA; Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA; Koch Institute for Integrative Cancer Research, Center for Precision Cancer Medicine, Departments of Biological Engineering and Biology, Massachusetts Institute of Technology, Cambridge, MA. Department of Surgery, University of Colorado Denver, Aurora, CO. Department of Surgery, University of Colorado Denver, Aurora, CO; Ernest E. Moore Shock Trauma Center at Denver Health, Department of Surgery, Denver, CO. Electronic address: ernest.moore@dhha.org. Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY. Division of Trauma/Acute Care Surgery, Department of Surgery, Scripps Memorial Hospital La Jolla, La Jolla, CA. Department of Surgery, St. Mary's Medical Center, Florida Atlantic University, West Palm Beach, FL. Department of Medicine, Baylor College of Medicine, Houston, Dallas, TX. Department of Surgery, Methodist Dallas Medical Center, Dallas, TX. Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado Denver, Aurora, CO. Ernest E. Moore Shock Trauma Center at Denver Health, Department of Surgery, Denver, CO. Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Denver Health Medical Center, Denver, CO. Division of Pulmonary/Critical Care Medicine, Department of Medicine, Scripps Memorial Hospital La Jolla, La Jolla, CA. Clinical Research Institute, Methodist Dallas Medical Center, Dallas, TX. Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA. Division of Pulmonary and Critical Care Medicine, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA. Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston. Ernest E. Moore Shock Trauma Center at Denver Health, Department of Surgery, Denver, CO; Colorado School of Public Health and Department of Surgery, University of Colorado Denver, Denver, CO. Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA; Koch Institute for Integrative Cancer Research, Center for Precision Cancer Medicine, Departments of Biological Engineering and Biology, Massachusetts Institute of Technology, Cambridge, MA.

Chest. 2022;161(3):710-727
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.
Study details
Language : eng
Credits : Bibliographic data from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine