Study of Alteplase for Respiratory Failure in SARS-CoV-2 COVID-19

Abstract

Background Pulmonary vascular microthrombi are a proposed mechanism of COVID19 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 May14,2020-March 3,2021 in two phases: Phase-1(n=36): control (standard-of-care) vs tPA-Bolus (50mg tPA IV-bolus followed by 7 days of heparin (goal aPTT=60-80s); Phase-2(n=14): control vs tPA-Drip (50 mg of tPA IV-bolus, followed by tPA drip 2mg/hr plus heparin 500U/hour over 24 hours, then heparin to maintain aPTT 60-80s/7 days). Patients were excluded from enrollment if they did not have a neurologic exam or cross-sectional brain imaging within the previous 4.5 hours to rule out stroke and potential for hemorrhagic conversion. The primary outcome was PaO2/FiO2 improvement from baseline at 48 hours post-randomization. Secondary outcomes included: PaO2/FiO2 improvement>50% or PaO2/FiO2>=200 at 48hrs(COMPOSITE), ventilator-free days(VFD) and mortality. Results Fifty patients were randomized: Phase 1: 17 control, 19 tPA-Bolus ; Phase 2: 8 control, 6 tPA-Drip . There were no severe bleeding events. In tPA-Bolus patients, the PaO2/FiO2 ratio was significantly(p<0.017) higher than baseline at 6 through 168 hours post-randomization; controls experienced no significant improvements. When compared to controls, tPA-Bolus patients’ PaO2/FiO2 ratio at 48hours[16.9%(-8.3–36.8) vs 29.8%(4.5–88.7),p=0.11], COMPOSITE outcome (11.8% vs 47.4%,p=0.03), VFD[0.0(0.0–9.0) vs 12.0(0.0–19.0),p=0.11] and in-hospital mortality(41.2% vs 21.1%,p=0.19) did not reach statistically significant differences. tPA-Drip patients did not experience benefit. Interpretation The combination tPA-Bolus +heparin is safe in severe COVID-19 respiratory failure. A Phase 3 study is warranted given improvements in oxygenation and promising observations in VFD and mortality.

The temporal changes of hemostatic activity in hospitalized patients with COVID-19: a prospective observational study

“…Described hemostatic abnormalities in patients with COVID-19 made appropriate thromboprophylaxis one of the cornerstones of COVID-19 management. There are also some promising reports showing a potential benefit of fibrinolytic therapy in patients with severe COVID-19 [30][31][32].…”

Fibrinolytic therapy in patients with COVID-19 and ARDS: protocol for a systematic review and meta-analysis

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Fibrinolytic system and COVID-19: From an innovative view of epithelial ion transport

“…Hence, except for giving tPA alone, systemic thrombolytic therapy is necessary for patients who have developed into severe progression. The combination administration of tPA and heparin can accelerate dead‐space ventilation and gas exchange significantly and immediately, so as to improve lung function in patients with severe COVID-19-induced respiratory failure [70] , [71] .…”