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1.
Res Pract Thromb Haemost ; 6(2): e12669, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1756641

ABSTRACT

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 PaO2/FiO2 ratio from baseline to 48 h after tPA. Linear mixed modeling was used for analysis. Results: tPA was associated with significant PaO2/FiO2 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 PaO2/FiO2 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.

2.
J Cyst Fibros ; 2022 Feb 21.
Article in English | MEDLINE | ID: covidwho-1729878

ABSTRACT

BACKGROUND: People with cystic fibrosis (pwCF) may be at risk of complications from COVID-19 but the impact of COVID-19 on pwCF remains unknown. METHODS: We conducted a multicenter retrospective cohort study to assess the impact of the COVID-19 pandemic first wave on pwCF in the New York metropolitan area (NY) from March 1, 2020 to August 31, 2020. Objectives were to determine (1) the prevalence of COVID-19 by PCR and IgG antibody testing, (2) the clinical characteristics of COVID-19, (3) delay in routine outpatient care, and (4) the effect on anxiety and depression in pwCF. RESULTS: There were 26 COVID-19 cases diagnosed by PCR or antibody testing among the study cohort of 810 pwCF. The prevalence of COVID-19 by PCR (1.6%) and IgG antibody (12.2%) testing was low. 58% of cases were asymptomatic and 82% were managed at home. 8% were hospitalized and 1 person died. 89% of pwCF experienced delay in care. The prevalence of anxiety increased from 43% baseline to 58% during the pandemic (P<0.01). In post-hoc analysis, the proportion of patients with diabetes (38% versus 16%, P<0.01) and pancreatic insufficiency (96% versus 66%, P<0.01) were higher while CFTR modulator use was lower (46% versus 65%, P = 0.05) in pwCF who tested positive for COVID-19. CONCLUSIONS: The prevalence of COVID-19 among pwCF in NY during the pandemic first wave was low and most cases were managed at home. CFTR modulators may be protective. PwCF experienced delay in routine care and increased anxiety.

3.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-306383

ABSTRACT

Background: Pulmonary vascular microthrombi have been proposed as a 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.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). The primary outcome was PaO2/FiO2 improvement 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.Findings: 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 intervention groups. In tPA-Bolus patients, PaO2/FiO2 was significantly(p<0.017) higher than baseline at 6 through 168 hours post-randomization;controls experienced no significant improvements. Compared to controls, tPA-Bolus patients showed larger, but non-significant, improvements in PaO2/FiO2 at 48hours[16.9%(-8.3–36.8) vs 29.8%(4.5–88.7),p=0.11], resulting in more patients reaching the COMPOSITE outcome (11.8% vs 47.4%,p=0.03). Controls had less VFD[0.0(0.0–9.0) vs 12.0(0.0–19.0),p=0.11] and higher mortality(41.2% vs 21.1%,p=0.19) than tPA-Bolus patients, although not significantly. tPA-Drip patients did not experience benefit compared to simultaneously enrolled controls.Interpretation: The combination tPA-Bolus+heparin is safe in severe COVID-19 respiratory failure. A Phase 3 study is warranted given promising improvements in oxygenation, VFD, and mortality.Trial Registration: The trial was performed according to the Food and Drug Administration (FDA) Investigational New Drug regulations (IND 149634) and registered with ClinicalTrials.gov (NCT04357730).Funding: This investigator-initiated trial (NCT04357730) was funded by Genentech, Inc.Declaration of Interests: CDB, HBM, EEM, and MBY have patents pending related to both coagulation/fibrinolysis diagnostics and therapeutic fibrinolytics, and are passive co-founders and holds stock options in Thrombo Therapeutics, Inc. HBM and EEM have received grant support from Haemonetics and Instrumentation Laboratories. MBY has previously received a gift of Alteplase (tPA) from Genentech, and owns stock options as a co-founder of Merrimack Pharmaceuticals. CDB, HBM, EEM, JW, NH, DST, AS, and MBY have received research grant funding from Genentech. JW receives consulting fees from Camurus A. B.. All other authors have nothing to disclose.Ethics Approval Statement: All participating trial sites had study approval and oversight from their respective Institutional Review Boards. Due to the nature of the study, which enrolled critically ill patients on mechanical ventilation, informed consent for trial participation was obtained from each patient’s Legally Authorized Representative. An independent Data Safety Monitoring Board (DSMB) oversaw the safety of the trial with mandatory reviews at each interim analysis and for all suspected serious adverse events. Data were stored in a REDCap instrument sponsored by NIH/NCATS Colorado CTSA Grant Number UL1 TR002535.

4.
Chest ; 161(3): 710-727, 2022 03.
Article in English | MEDLINE | ID: covidwho-1491838

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.


Subject(s)
COVID-19/complications , Pandemics , Respiratory Insufficiency/drug therapy , SARS-CoV-2 , Thrombosis/complications , Tissue Plasminogen Activator/administration & dosage , Adolescent , Adult , Aged , COVID-19/blood , COVID-19/epidemiology , Cross-Sectional Studies , Female , Fibrinolytic Agents/administration & dosage , Follow-Up Studies , Humans , Male , Middle Aged , Partial Thromboplastin Time , Respiratory Insufficiency/blood , Respiratory Insufficiency/etiology , Retrospective Studies , Thrombosis/blood , Thrombosis/drug therapy , Treatment Outcome , Young Adult
5.
J Cardiothorac Vasc Anesth ; 2021 Oct 16.
Article in English | MEDLINE | ID: covidwho-1467153

ABSTRACT

OBJECTIVE: To develop a practical thromboelastograph guided (TEG) anticoagulation protocol to guide the management of COVID-19 critically ill patients. DESIGN: An inter disciplinary team reviewed the current literature on hypercoagulability in critically ill COVID-19 patients, clinical management practices and challenges with high rates of thrombotic events despite anticoagulant therapies. SETTING: The largest tertiary care hospital within the Northwell Health System in New York. PATIENTS: COVID-19 invasively mechanically ventilated patients in Medical Intensive Care Unit Settings. METHODS: TEG was monitored in critically ill COVID-19 patients. Patterns were reviewed to guide the development of a treatment protocol leveraging TEG parameters to select anticoagulant therapy. Three patients are reported to highlight TEG profiles that led to the development of the algorithm. Clinical trajectory and treatment decisions were extracted retrospectively from the Electronic Health Record, with input from the intensivists. Anticoagulant use, laboratory and TEG values, and venous/arterial lower extremity (LE) ultrasound results were recorded. MAIN RESULTS: These patients demonstrated hypercoagulable TEG results despite prophylactic or therapeutic dosages of unfractionated heparin or low-molecular-weight heparin (LMHW). TEG surveillance identified functional fibrinogen and maximum amplitude in high-risk patients with hyper inflammatory markers. Anticoagulation assessment, TEG parameters, and LE ultrasound monitoring for venous and arterial thrombus were used to construct an algorithm to guide and escalate anticoagulant therapy. CONCLUSIONS: TEG provides patient-specific evidence for a hypercoagulable state in patients receiving all types of anticoagulant therapy. The proposed TEG algorithm guides anticoagulation management decisions to maintain or escalate anticoagulant dose and/or change choice of anticoagulant. A TEG algorithm may help negotiate the potential harm/benefit balance of full-dose anticoagulation in critically ill COVID-19 patients, by allowing for a more individualized approach that goes beyond the review of activated partial thromboplastin time (aPTT) levels.

6.
JAMA Intern Med ; 181(12): 1612-1620, 2021 12 01.
Article in English | MEDLINE | ID: covidwho-1453495

ABSTRACT

Importance: Hospitalized patients with COVID-19 are at risk for venous and arterial thromboembolism and death. Optimal thromboprophylaxis dosing in high-risk patients is unknown. Objective: To evaluate the effects of therapeutic-dose low-molecular-weight heparin (LMWH) vs institutional standard prophylactic or intermediate-dose heparins for thromboprophylaxis in high-risk hospitalized patients with COVID-19. Design, Setting, and Participants: The HEP-COVID multicenter randomized clinical trial recruited hospitalized adult patients with COVID-19 with D-dimer levels more than 4 times the upper limit of normal or sepsis-induced coagulopathy score of 4 or greater from May 8, 2020, through May 14, 2021, at 12 academic centers in the US. Interventions: Patients were randomized to institutional standard prophylactic or intermediate-dose LMWH or unfractionated heparin vs therapeutic-dose enoxaparin, 1 mg/kg subcutaneous, twice daily if creatinine clearance was 30 mL/min/1.73 m2 or greater (0.5 mg/kg twice daily if creatinine clearance was 15-29 mL/min/1.73 m2) throughout hospitalization. Patients were stratified at the time of randomization based on intensive care unit (ICU) or non-ICU status. Main Outcomes and Measures: The primary efficacy outcome was venous thromboembolism (VTE), arterial thromboembolism (ATE), or death from any cause, and the principal safety outcome was major bleeding at 30 ± 2 days. Data were collected and adjudicated locally by blinded investigators via imaging, laboratory, and health record data. Results: Of 257 patients randomized, 253 were included in the analysis (mean [SD] age, 66.7 [14.0] years; men, 136 [53.8%]; women, 117 [46.2%]); 249 patients (98.4%) met inclusion criteria based on D-dimer elevation and 83 patients (32.8%) were stratified as ICU-level care. There were 124 patients (49%) in the standard-dose vs 129 patients (51%) in the therapeutic-dose group. The primary efficacy outcome was met in 52 of 124 patients (41.9%) (28.2% VTE, 3.2% ATE, 25.0% death) with standard-dose heparins vs 37 of 129 patients (28.7%) (11.7% VTE, 3.2% ATE, 19.4% death) with therapeutic-dose LMWH (relative risk [RR], 0.68; 95% CI, 0.49-0.96; P = .03), including a reduction in thromboembolism (29.0% vs 10.9%; RR, 0.37; 95% CI, 0.21-0.66; P < .001). The incidence of major bleeding was 1.6% with standard-dose vs 4.7% with therapeutic-dose heparins (RR, 2.88; 95% CI, 0.59-14.02; P = .17). The primary efficacy outcome was reduced in non-ICU patients (36.1% vs 16.7%; RR, 0.46; 95% CI, 0.27-0.81; P = .004) but not ICU patients (55.3% vs 51.1%; RR, 0.92; 95% CI, 0.62-1.39; P = .71). Conclusions and Relevance: In this randomized clinical trial, therapeutic-dose LMWH reduced major thromboembolism and death compared with institutional standard heparin thromboprophylaxis among inpatients with COVID-19 with very elevated D-dimer levels. The treatment effect was not seen in ICU patients. Trial Registration: ClinicalTrials.gov Identifier: NCT04401293.


Subject(s)
Anticoagulants/administration & dosage , COVID-19/diagnosis , Enoxaparin/administration & dosage , Heparin, Low-Molecular-Weight/administration & dosage , Heparin/administration & dosage , Hospital Mortality , Inpatients , Venous Thromboembolism/prevention & control , Adult , Aged , COVID-19/blood , COVID-19/therapy , Female , Fibrin Fibrinogen Degradation Products/analysis , Hospitalization , Humans , Intensive Care Units , Male , SARS-CoV-2 , Treatment Outcome
7.
J Thromb Haemost ; 18(7): 1752-1755, 2020 07.
Article in English | MEDLINE | ID: covidwho-1317980

ABSTRACT

A prothrombotic coagulopathy is commonly found in critically ill COVID-19 patients with acute respiratory distress syndrome (ARDS). A unique feature of COVID-19 respiratory failure is a relatively preserved lung compliance and high Alveolar-arterial oxygen gradient, with pathology reports consistently demonstrating diffuse pulmonary microthrombi on autopsy, all consistent with a vascular occlusive etiology of respiratory failure rather than the more classic findings of low-compliance in ARDS. The COVID-19 pandemic is overwhelming the world's medical care capacity with unprecedented needs for mechanical ventilators and high rates of mortality once patients progress to needing mechanical ventilation, and in many environments including in parts of the United States the medical capacity is being exhausted. Fibrinolytic therapy has previously been used in a Phase 1 clinical trial that led to reduced mortality and marked improvements in oxygenation. Here we report a series of three patients with severe COVID-19 respiratory failure who were treated with tissue plasminogen activator. All three patients had a temporally related improvement in their respiratory status, with one of them being a durable response.


Subject(s)
Betacoronavirus/pathogenicity , Blood Coagulation Disorders/drug therapy , Coronavirus Infections/drug therapy , Fibrinolysis/drug effects , Fibrinolytic Agents/administration & dosage , Pneumonia, Viral/drug therapy , Thrombolytic Therapy , Tissue Plasminogen Activator/administration & dosage , Aged , Blood Coagulation Disorders/blood , Blood Coagulation Disorders/diagnosis , Blood Coagulation Disorders/virology , COVID-19 , Coronavirus Infections/blood , Coronavirus Infections/diagnosis , Coronavirus Infections/virology , Fatal Outcome , Female , Fibrinolytic Agents/adverse effects , Host-Pathogen Interactions , Humans , Male , Middle Aged , Pandemics , Pneumonia, Viral/blood , Pneumonia, Viral/diagnosis , Pneumonia, Viral/virology , Recovery of Function , SARS-CoV-2 , Thrombolytic Therapy/adverse effects , Tissue Plasminogen Activator/adverse effects , Treatment Outcome
8.
Res Pract Thromb Haemost ; 2020 May 21.
Article in English | MEDLINE | ID: covidwho-1184616

ABSTRACT

BACKGROUND: The COVID-19 pandemic has caused a large surge of acute respiratory distress syndrome (ARDS). Prior phase I trials (non COVID-19) demonstrated improvement in pulmonary function in ARDS patients using fibrinolytic therapy. A follow-up trial using the widely available tissue-plasminogen activator (alteplase) is now needed to assess optimal dosing and safety in this critically ill patient population. OBJECTIVE: To describe the design and rationale of a Phase IIa trial to evaluate the safety and efficacy of alteplase treatment for moderate/severe COVID-19-induced ARDS. PATIENTS/METHODS: A rapidly adaptive, pragmatic, open label, randomized, controlled, phase IIa clinical trial will be conducted with three groups: intravenous(IV) alteplase 50mg, IV alteplase 100mg, and control (standard-of-care). Inclusion criteria are known/suspected COVID-19 infection with PaO2/FiO2 ratio<150mmHg for >4 hours despite maximal mechanical ventilation management. Alteplase will be delivered through an initial bolus of 50mg or 100mg followed by heparin infusion for systemic anticoagulation, with alteplase re-dosing if there is a >20% PaO2/FiO2 improvement not sustained by 24 hours. RESULTS: The primary outcome is improvement in PaO2/FiO2 at 48 hours post-randomization. Other outcomes include: ventilator- and ICU-free-days, successful extubation (no reintubation ≤3 days after initial extubation), and mortality. Fifity eligible patients will be enrolled in a rapidly adaptive, modified stepped-wedge design with four looks at the data. CONCLUSION: Findings will provide timely information on the safety, efficacy and optimal dosing of tPA to treat moderate/severe COVID-19-induced ARDS, which can be rapidly adapted to a phase III trial. (NCT04357730; FDA IND 149634).

9.
Thromb Haemost ; 121(12): 1684-1695, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1171416

ABSTRACT

Coronavirus disease-2019 (COVID-19) has been associated with significant risk of venous thromboembolism (VTE), arterial thromboembolism (ATE), and mortality particularly among hospitalized patients with critical illness and elevated D-dimer (Dd) levels. Conflicting data have yet to elucidate optimal thromboprophylaxis dosing. HEP-COVID (NCT04401293) is a phase 3, multicenter, pragmatic, prospective, randomized, pseudo-blinded, active control trial to evaluate efficacy and safety of therapeutic-dose low-molecular-weight heparin (LMWH) versus prophylactic-/intermediate-dose LMWH or unfractionated heparin (UFH) for prevention of a primary efficacy composite outcome of VTE, ATE, and all-cause mortality 30 ± 2 days post-enrollment. Eligible patients have COVID-19 diagnosis by nasal swab or serologic testing, requirement for supplemental oxygen per investigator judgment, and Dd >4 × upper limit of normal (ULN) or sepsis-induced coagulopathy score ≥4. Subjects are randomized to enoxaparin 1 mg/kg subcutaneous (SQ)/two times a day (BID) (creatinine clearance [CrCl] ≥ 30 mL/min) or 0.5 mg/kg (CrCl 15-30 mL/min) versus local institutional prophylactic regimens including (1) UFH up to 22,500 IU (international unit) daily (divided BID or three times a day), (2) enoxaparin 30 and 40 mg SQ QD (once daily) or BID, or (3) dalteparin 2,500 IU or 5,000 IU QD. The principal safety outcome is major bleeding. Events are adjudicated locally. Based on expected 40% relative risk reduction with treatment-dose compared with prophylactic-dose prophylaxis, 308 subjects will be enrolled (assuming 20% drop-out) to achieve 80% power. Distinguishing design features include an enriched population for the composite endpoint anchored on Dd >4 × ULN, stratification by intensive care unit (ICU) versus non-ICU, and the ability to capture asymptomatic proximal deep venous thrombosis via screening ultrasonography prior to discharge.


Subject(s)
Anticoagulants/administration & dosage , COVID-19/drug therapy , Enoxaparin/administration & dosage , Thromboembolism/drug therapy , Anticoagulants/adverse effects , COVID-19/complications , COVID-19/diagnosis , Clinical Trials, Phase III as Topic , Enoxaparin/adverse effects , Humans , Pragmatic Clinical Trials as Topic , Prospective Studies , Risk Assessment , Risk Factors , Thromboembolism/diagnosis , Thromboembolism/etiology , Time Factors , Treatment Outcome , United States , Venous Thromboembolism/diagnosis , Venous Thromboembolism/etiology , Venous Thromboembolism/prevention & control
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