Salvage use of tissue plasminogen activator (tPA) in the setting of acute respiratory distress syndrome (ARDS) due to COVID-19 in the USA: a Markov decision analysis

Abstract

Background: COVID-19 threatens to quickly overwhelm our existing critical care infrastructure in the USA. Systemic tissue plasminogen activator (tPA) has been previously demonstrated to improve PaO 2 /FiO 2 (mmHg) when given to critically ill patients with acute respiratory distress syndrome (ARDS). It is unclear to what extent tPA may impact population-based survival during the current US COVID-19 pandemic. Methods: A decision analytic Markov state transition model was created to simulate the life critically ill COVID-19 patients as they transitioned to either recovery or death. Two patient groups were simulated (50,000 patients in each group); (1) Patients received tPA immediately upon diagnosis of ARDS and (2) patients received standard therapy for ARDS. Base case critically ill COVID-19 patients were defined as having a refractory PaO 2 /FiO 2 of < 60 mmHg (salvage use criteria). Transition from severe to moderate to mild ARDS, recovery, and death were estimated. Markov model parameters were extracted from existing ARDS/COVID-19 literature. Results: The use of tPA was associated with reduced mortality (47.6% [tTPA] vs. 71.0% [no tPA]) for base case patients. When extrapolated to the projected COVID-19 eligible for salvage use tPA in the USA, peak mortality (deaths/100,000 patients) was reduced for both optimal social distancing (70.5 [tPA] vs. 75.0 [no tPA]) and no social distancing (158.7 [tPA] vs. 168.8 [no tPA]) scenarios.Conclusions: Salvage use of tPA may improve recovery of ARDS patients, thereby reducing COVID-19-related mortality and ensuring sufficient resources to manage this pandemic.

Thrombosis in Coronavirus disease 2019 (COVID-19) through the prism of Virchow’s triad

“…After tPA infusion, oxygen requirements improves, allowing to avoid intubation [130]. An in silico model has also demonstrated mortality benefit with the use of tPA [131]. There is a proposal to use nebulised tPA for ADRS due to COVID-19 [132].…”

Coagulopathy, Venous Thromboembolism, and Anticoagulation in Patients with COVID‐19

“…A report using a Markov decision analysis approach to evaluate whether t-PA may improve outcomes in patients with COVID-19 demonstrated the use of fibrinolytic therapy in ARDS patients was associated with a mortality benefit, although this can be considered hypothesis generating only. 98 Given that systemic administration of fibrinolytics in the setting of PE is associated with a 10% risk of major bleeding and a 1-2% risk of intracranial hemorrhage, additional information from randomized clinical trials is needed to validate whether t-PA has any role in the management of patients with COVID-19 and ARDS. 99 Several trials are underway to address this clinical question (NCT04356833, NCT04357730).…”

Perspective on fibrinolytic therapy in COVID-19: the potential of inhalation therapy against suppressed-fibrinolytic-type DIC

“…Some articles suggest several treatment options using fibrinolytic drugs for acute respiratory distress syndrome (ARDS) in severe cases of COVID-19 [1][2][3][4]. ARDS and organ dysfunction associated with a cytokine storm have been identified as causes of death in COVID-19 [5].…”

“…Although heparin is frequently used to remedy the thrombotic pathology in COVID-19, pulmonary embolism is still seen in approximately 20% of severe cases, and there is disagreement regarding the intensity of anticoagulant therapy. Besides heparin, the thrombotic condition might be improved by using fibrinolytic drugs to degrade pre-existing fibrin in the lung [1][2][3][4]. The fibrinolytic drug, tissue-type plasminogen activator (tPA), has been systemically administered to treat ARDS in COVID-19 and appeared to be effective in some patients [2][3][4].…”

“…Besides heparin, the thrombotic condition might be improved by using fibrinolytic drugs to degrade pre-existing fibrin in the lung [1][2][3][4]. The fibrinolytic drug, tissue-type plasminogen activator (tPA), has been systemically administered to treat ARDS in COVID-19 and appeared to be effective in some patients [2][3][4]. Since tPA has been reported to show an antiinflammatory effect in addition to a fibrinolytic action, this potential of tPA would be helpful for improving the prognosis of COVID-19 patients [11,12].…”