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

Christopher D Barrett, Hunter B Moore, Ernest E Moore, Janice Wang, Negin Hajizadeh, Walter L Biffl, Lawrence Lottenberg, Purvesh R Patel, Michael S Truitt, Robert C McIntyre Jr, Todd M Bull, Lee Anne Ammons, Arsen Ghasabyan, James Chandler, Ivor S Douglas, Eric P Schmidt, Peter K Moore, Franklin L Wright, Ramona Ramdeo, Robert Borrego, Mario Rueda, Achal Dhupa, D Scott McCaul, Tala Dandan, Pralay K Sarkar, Benazir Khan, Coimbatore Sreevidya, Conner McDaniel, Heather M Grossman Verner, Christopher Pearcy, Lorenzo Anez-Bustillos, Elias N Baedorf-Kassis, Rashi Jhunjhunwala, Shahzad Shaefi, Krystal Capers, Valerie Banner-Goodspeed, Daniel S Talmor, Angela Sauaia, Michael B Yaffe, Christopher D Barrett, Hunter B Moore, Ernest E Moore, Janice Wang, Negin Hajizadeh, Walter L Biffl, Lawrence Lottenberg, Purvesh R Patel, Michael S Truitt, Robert C McIntyre Jr, Todd M Bull, Lee Anne Ammons, Arsen Ghasabyan, James Chandler, Ivor S Douglas, Eric P Schmidt, Peter K Moore, Franklin L Wright, Ramona Ramdeo, Robert Borrego, Mario Rueda, Achal Dhupa, D Scott McCaul, Tala Dandan, Pralay K Sarkar, Benazir Khan, Coimbatore Sreevidya, Conner McDaniel, Heather M Grossman Verner, Christopher Pearcy, Lorenzo Anez-Bustillos, Elias N Baedorf-Kassis, Rashi Jhunjhunwala, Shahzad Shaefi, Krystal Capers, Valerie Banner-Goodspeed, Daniel S Talmor, Angela Sauaia, Michael B Yaffe

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 Pao2 to Fio2 ratio improvement from baseline at 48 h after randomization. Secondary outcomes included Pao2 to Fio2 ratio improvement of > 50% or Pao2 to Fio2 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 Pao2 to Fio2 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 Pao2 to Fio2 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).

Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

Figures

Graphical abstract
Graphical abstract
Figure 1
Figure 1
Consolidated Standards for Reporting Trials diagram for the Study of Alteplase for Respiratory Failure in SARS-CoV-2 COVID-19.
Figure 2
Figure 2
A, Graph showing Pao2 to Fio2 ratio over time in phase 1 estimates with 95% confidence bands based on the linear mixed model (interaction time × intervention; P = .14) for the tissue plasminogen activator (tPA) bolus vs control groups. Asterisks indicate significant (P < .017) differences compared with baseline. Only the tPA bolus group showed significant improvements in Pao2 to Fio2 ratio compared with baseline. No significant improvements in Pao2 to Fio2 ratio were found in the control group. B, Graph showing the Pao2 to Fio2 ratio, which is same as in (A), but further stratifying by requirement of a second tPA bolus at 24 h.
Figure 3
Figure 3
A, B, Graphs showing the role of average activated partial thromboplastin time (aPTT) in Pao2 to Fio2 ratio temporal trends in phase 1: 7-day average aPTT ≤ 40 s (n = 15) (A) and 7-day average aPTT > 40 s (n = 21) (B).
Figure 4
Figure 4
A, B, Graphs showing D-dimer temporal trends by study group in phase 1 (A) and phase 2 (B). A, In phase 1 (tissue plasminogen activator [tPA] bolus vs control), the intervention significantly changed the temporal trends of the study groups (interaction intervention × time; P < .0001). Asterisks indicate significant (P < .003, adjusted for multiple comparisons by false-discovery rate) differences compared with baseline; only the tPA bolus group showed significant changes in D-Dimer levels compared with baseline. No significant changes in D-Dimer levels were found in the control group. B, In phase 2 (tPA drip vs control), the intervention changed (albeit not significantly at P < .017) the temporal trends of the study groups (interaction intervention × time; P < .013). Asterisks indicate significant (P < .003, adjusted for multiple comparisons by false-discovery rate) differences compared with baseline. Only the tPA drip group showed significant changes in D-dimer levels compared with baseline. No significant changes in D-dimer levels were found in the control group.
Figure 5
Figure 5
A-C, Graphs showing trends in disease severity during the trial: mortality (A), Pao2 to Fio2 ratio at eligibility (B), and NEWS2 score at eligibility (C). NEWS2 = National Early Warning System 2; tPA = tissue plasminogen activator.

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Source: PubMed

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