key: cord-0751575-0geej1e0 authors: Barrett, Christopher D.; Moore, Hunter B.; Moore, Ernest E.; Benjamin Christie, Dudley; Orfanos, Sarah; Anez‐Bustillos, Lorenzo; Jhunjhunwala, Rashi; Hussain, Sabiha; Shaefi, Shahzad; Wang, Janice; Hajizadeh, Negin; Baedorf‐Kassis, Elias N.; Al‐Shammaa, Ammar; Capers, Krystal; Banner‐Goodspeed, Valerie; Wright, Franklin L.; Bull, Todd; Moore, Peter K.; Nemec, Hannah; Thomas Buchanan, John; Nonnemacher, Cory; Rajcooar, Natalie; Ramdeo, Ramona; Yacoub, Mena; Guevara, Ana; Espinal, Aileen; Hattar, Laith; Moraco, Andrew; McIntyre, Robert; Talmor, Daniel S.; Sauaia, Angela; Yaffe, Michael B. title: MUlticenter STudy of tissue plasminogen activator (alteplase) use in COVID‐19 severe respiratory failure (MUST COVID): A retrospective cohort study date: 2022-03-21 journal: Res Pract Thromb Haemost DOI: 10.1002/rth2.12669 sha: c038cf6320799e71c69724377c76f5937c820114 doc_id: 751575 cord_uid: 0geej1e0 BACKGROUND: Few therapies exist to treat severe COVID‐19 respiratory failure once it develops. Given known diffuse pulmonary microthrombi on autopsy studies of COVID‐19 patients, we hypothesized that tissue plasminogen activator (tPA) may improve pulmonary function in COVID‐19 respiratory failure. METHODS: A multicenter, retrospective, observational study of patients with confirmed COVID‐19 and severe respiratory failure who received systemic tPA (alteplase) was performed. Seventy‐nine adults from seven medical centers were included in the final analysis after institutional review boards' approval; 23 were excluded from analysis because tPA was administered for pulmonary macroembolism or deep venous thrombosis. The primary outcome was improvement in the PaO(2)/FiO(2) ratio from baseline to 48 h after tPA. Linear mixed modeling was used for analysis. RESULTS: tPA was associated with significant PaO(2)/FiO(2) improvement at 48 h (estimated paired difference = 23.1 ± 6.7), which was sustained at 72 h (interaction term p < 0.00). tPA administration was also associated with improved National Early Warning Score 2 scores at 24, 48, and 72 h after receiving tPA (interaction term p = 0.00). D‐dimer was significantly elevated immediately after tPA, consistent with lysis of formed clot. Patients with declining respiratory status preceding tPA administration had more marked improvement in PaO(2)/FiO(2) ratios than those who had poor but stable (not declining) respiratory status. There was one intracranial hemorrhage, which occurred within 24 h following tPA administration. CONCLUSIONS: These data suggest tPA is associated with significant improvement in pulmonary function in severe COVID‐19 respiratory failure, especially in patients whose pulmonary function is in decline, and has an acceptable safety profile in this patient population. • Few effective therapies exist for critically ill COVID-19 respiratory failure patients. • A retrospective study of 79 severe COVID-19 respiratory failure patients was performed. • Systemic alteplase is associated with improved oxygenation in severe COVID-19. • We found a low risk (1.3%) of intracranial hemorrhage with alteplase use in COVID-19 patients. The SARS-CoV-2 (COVID- 19) global pandemic overwhelmed the capacity of many medical infrastructures to accommodate a large surge of patients with acute respiratory distress syndrome (ARDS), particularly those requiring mechanical ventilation. ARDS currently has little evidence-based treatment other than low tidal volume ventilation to limit mechanical stress on the lung 1 and prone positioning, 2 with additional evidence for benefit of steroids in COVIDrelated ARDS. 3 Although vaccination and public health measures remain the mainstay of reducing COVID-19 disease burden, new viral variants, inadequate access, and skepticism of vaccines in the broader public exist. Thus, an ongoing effort to develop new therapeutic approaches capable of rapidly treating and attenuating ARDS secondary to COVID-19 is essential. The dominant pathologic feature of viral-induced ARDS is fibrin accumulation in the microvasculature and airspaces, and multiple autopsy studies have now confirmed that nearly all patients who die of COVID-19 have diffuse pulmonary microthrombi as a prominent feature. [4] [5] [6] The high physiologic dead space and relatively preserved lung compliance early in the course of respiratory failure from COVID-19 suggests this histopathologic finding is not incidental, but rather that pulmonary vascular microthrombosis is a significant contributor to the development of these patients' respiratory compromise, 7 particularly early in their course before the fibroproliferative phase predominates. Therapeutic anticoagulation initiated before precipitous respiratory decline has now been shown to improve clinical outcomes in the large, multicenter ACTIV-4 trial which was halted early for efficacy in the "moderate group". 8 However, in the "severe group" within ACTIV-4 who had severe respiratory failure before initiation of therapeutic anticoagulation, the study was halted early for futility. 9 This is consistent with the concept that anticoagulation before the development of an overwhelming microthrombotic burden is beneficial, but once a significant microthrombotic burden exists it is too late to benefit from anticoagulation because the thrombotic phenomena has already occurred. At this point, when all less aggressive clinical options have been exhausted, our group hypothesized that there may be a role for fibrinolytic therapy with tissue plasminogen activator (tPA) to salvage pulmonary microvascular patency and improve oxygenation in patients who would otherwise die of hypoxemic respiratory failure. 10 -12 The notion that fibrinolytic therapy may have a role in ARDS is not new, with substantial preclinical work suggesting that fibrinolytic therapy can attenuate ARDS provoked from diverse insults (reviewed in Liu et al. 13 and Barrett et al. 10 ). Further, in 2001 a small phase 1 clinical trial 14 indicated that urokinase and streptokinase were effective in patients with terminal ARDS, markedly improving oxygenation and reducing an expected mortality from 100% to 70%. A more contemporary approach to thrombolytic therapy uses tPA rather than urokinase or streptokinase because of its higher efficacy of clot lysis with comparable bleeding risk. 15 Several case series and a small retrospective observational study have now been published suggesting a potential benefit of tPA therapy in COVID-19 respiratory failure. [16] [17] [18] [19] [20] [21] To investigate the respiratory changes associated with tPA use in COVID-19 respiratory failure, a retrospective analysis of existing data from multiple centers with experience using tPA in COVID-19 respiratory failure was proposed. To accomplish this, we established a registry of retrospectively collected deidentified clinical data from COVID-19 patients who were treated with tPA for severe acute respiratory failure across multiple centers. We hypothesized that tPA administered to patients with COVID-19associated acute respiratory failure would be associated with improved pulmonary function within 48 h with a low risk for severe bleeding. The MUST COVID study is a multicenter, retrospective, observational study of patients with confirmed COVID-19 severe respiratory failure (i.e., requiring mechanical ventilation) who received tPA (alteplase, sold under tradename Activase by Genentech, Inc.). Baseline characteristics, comorbidities, and rationale for tPA administration were collected along with tPA dosing information, concomitant anticoagulation, and use of remdesivir and/or dexamethasone. Clinical and laboratory data were obtained at 6-h intervals for the 72 h preceding and the 72 h following administration of tPA in addition to adverse events and hospital mortality data. Seven academic tertiary care hospitals agreed to participate: Beth The primary outcome was improvement in PaO 2 /FiO 2 from pre-tPA baseline (i.e., 3-6 h before tPA administration) to up to 48 h (within 42-54 h) after the first dose of tPA. Secondary outcomes included improvement in dead-space ventilation, 20 estimated by the ventilatory ratio (calculated as proposed by Sinha et al. 22 and National Early Warning System-2 score [NEWS2] 23 ),bleeding (defined as any bleeding requiring therapy such as blood product transfusion, operative procedure, tranexamic acid, or resulting in prolonged hospitalization, death, or disability) or thrombotic complications, complications, in-hospital mortality, ventilator-free days, and intensive care unit free days (both up to 28 days since admission). All complications occurring within 72 h of tPA administration were deemed potentially related to tPA. The reported study outcomes were predefined in the institutional review board application before any data collection or analysis (Appendix S1). We collected data on demographic characteristics shown in previous studies to affect the prognosis of COVID-19 pulmonary failure such as age, sex, body mass index, comorbidities and complications present before tPA administration, as well as administration of two medications shown in previous studies to improve survival in these patients (dexamethasone and remdesivir). This is a retrospective cohort of patients known to have been treated with tPA, and thus is inherently affected by selection bias because the decision to give tPA was not standardized but instead made by the local health care providers (except for the participants of the STARS randomized controlled trial, 24 We included all patients who were admitted since the beginning of the US COVID-19 pandemic and who received tPA for respiratory failure up to March 2021, as described previously. As no comparator was selected, we did not calculate power/sample size. Analysis was conducted using linear mixed models for the outcomes with pairwise comparisons with the time immediately before tPA was administered. The models allow for missing observations, adjustment for confounders, repeated measures data by subject, and account for the clustering effects by institution. Confounders were chosen based on their univariate association with mortality with p < 0.25 or because they were shown to be clinically relevant in COVID-19. Effect modification by trends in outcomes before tPA administration was assessed by testing interactions in the model. A qualitative analysis of nonsurvivors was also conducted to better understand the cause of death and potential association with tPA. Overall significance was set at p < 0.05 for the time trends effect, followed by pairwise comparisons between the time right before tPA (baseline) and other times adjusted by false-discovery rate to minimize type I error. All quantitative analyses were carried out with SAS vs 9.4 (SAS Institute, Cary, NC). Overall, there were 102 patients admitted from March 1, 2020, through March 3, 2021, at the seven participating centers with laboratory confirmed COVID-19 infection resulting in severe acute respiratory failure requiring mechanical ventilation who received tPA. Twenty-three (22.5%) patients were excluded because their principal reason for tPA therapy was an imaging-confirmed diagnosis of PE or deep venous thrombosis/suspected PE. Table 1 shows the demographics and medical history of the 79 patients included in the analysis, whereas Table 2 shows the pre- Dosing strategies and amounts for therapeutic heparin regimens were highly variable between institutions and patients to achieve therapeutic partial thromboplastin time levels or anti-Xa levels. Inhospital mortality for the cohort was high at 58%. Evaluation of the primary endpoint demonstrated that at 48 and 72 h post-tPA, there was a statistically significant increase in PaO 2 /FiO 2 ratio relative to pre-tPA dosing ( Figure 1A ). in Figure 1B There were significant decreases in ventilatory ratio (a correlate of dead space ventilation) at 2, 6, 24, 48, and 72 h (Figure 2A ). However, these improvements did not persist after adjustment for confounders ( Figure 2B ). The pre-tPA trends in ventilatory ratios did not significantly modify the temporal trends of this outcome. It should be noted that, distinct from other outcomes, there was a large proportion of missing data for ventilatory ratio (>30%), which may have affected these results. Abbreviations: aPTT, activated partial thromboplastin time; IFD, intensive care unit-free days; INR, international normalized ratio of prothrombin time; NEWS2, National Early Warning Score-2; tPA, tissue plasminogen activator; VFD, ventilation-free days. Complications are described in Table 3 There was one intracranial hemorrhage (ICH; 1.27%), which resulted in death. Of note, this patient received tPA on hospital day 47, much later than all other patients, and had no head imaging before the administration of tPA, raising concern that this event was a hemorrhagic conversion of an undiagnosed thrombotic stroke. Fibrinolytic therapy for COVID-19 respiratory failure has been hypothesized to improve respiratory function in critically ill patients with tenuous respiratory status and a poor prognosis. 10, 25 The results of this study provide evidence that fibrinolytic therapy (1) improves respiratory function and oxygenation in COVID-19 patients, F I G U R E 1 PaO 2 /FiO 2 estimates over time. The value "-4" in the x-axis indicates the baseline PaO 2 /FiO 2 , collected 3-6 h before tPA was administered. The red bar marks the administration of tPA. (A) Unadjusted PaO 2 /FiO 2 ; overall time effect p = 0.02, asterisks indicate significant differences compared with baseline. (B) PaO 2 /FiO 2 estimates, adjusted for significant covariates (see text), stratified by the trend in pre-tPA PaO 2 /FiO 2 (significant effect modifier interaction time × pre-tPA trend p < 0.00). Colorconcordant asterisks indicate significant differences compared with baseline. Only the group with declining PaO 2 / FiO 2 showed significant differences compared with baseline. tPA, tissue plasminogen activator particularly those with rapidly declining respiratory status; and (2) that the safety profile is acceptable, particularly when considering the potential benefit in such a critically ill cohort with high mortality. The risk of ICH in this multi-institutional series was 1.3%, much smaller than those reported in recent reviews of the ICH risk associated with extracorporeal membrane oxygenation (ECMO), the next likely treatment intervention for these patients if the hospital has such extensive resources. Recent reports of ICH in ECMO for the treatment of COVID-19-associated respiratory failure varied from 6% in the Extracorporeal Life Support Organization registry (36 countries) to 9% in a New York, US, institution, and 12% in the report of the ECMO network for Greater Paris (17 intensive care units) to 33% in two US academic centers. [26] [27] [28] [29] Further, it is unclear whether this complication could have been mitigated with pre-tPA neurologic examination or cross-sectional imaging of the brain (e.g., computed tomography; Table 4 ). cluded 59 patients and found no benefit. 30 The latter study, the largest to date until the present report, assembled arterial blood gas data from patients by chronologic order (arterial blood gas 1, 2, 3) post-tPA rather than by synchronous times after tPA (e.g., 12, 24, 48 h), introducing substantial heterogeneity and margins of error that rendered to results difficult to interpret given the time dependency of thrombolysis and its results. Additionally, the Douin et al. study included patients who were being treated for known macroscopic PE and patients in the peri-arrest setting, which was not the study question. Our study was larger, contained highly granular data in 6-h increments for 72 h before and after tPA administration F I G U R E 2 Ventilatory ratio (correlate of dead space) estimates over time. The value "-4" in the x-axis indicates the baseline ventilatory ratio, collected 3-6 h before tPA was administered. The red bar marks the administration of tPA. (A) Unadjusted ventilatory ratio; overall time effect p = 0.00, asterisks indicate significant differences compared with baseline. (B) Ventilatory ratio estimates after adjustment for significant covariates (see text) did not significantly change over time (p = 0.16) and the temporal trend was not modified by the pre-tPA trend in ventilatory ratio (interaction time × pre-tPA trend p = 0.15). tPA, tissue plasminogen activator collected with the explicit intent of testing our hypothesis, and used prespecified outcomes defined before data collection. 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