key: cord-0753430-bpu9fevh authors: Talasaz, Azita H.; Sadeghipour, Parham; Aghakouchakzadeh, Maryam; Kakavand, Hessam; Ariannejad, Hamid; Connors, Jean M.; Hunt, Beverley J.; Berger, Jeffrey S.; Van Tassell, Benjamin W.; Middeldorp, Saskia; Piazza, Gregory; Weitz, Jeffrey I.; Cushman, Mary; Lip, Gregory Y. H.; Goldhaber, Samuel Z.; Bikdeli, Behnood title: Use of novel antithrombotic agents for COVID‐19: Systematic summary of ongoing randomized controlled trials date: 2021-09-30 journal: J Thromb Haemost DOI: 10.1111/jth.15533 sha: 81b74aef10b0b79041c456d31f04392ca80af83d doc_id: 753430 cord_uid: bpu9fevh BACKGROUND: Coronavirus disease 2019 (COVID‐19) is associated with macro‐ and micro‐thromboses, which are triggered by endothelial cell activation, coagulopathy, and uncontrolled inflammatory response. Conventional antithrombotic agents are under assessment in dozens of randomized controlled trials (RCTs) in patients with COVID‐19, with preliminary results not demonstrating benefit in several studies. OBJECTIVES: Given the possibility that more novel agents with antithrombotic effects may have a potential utility for management of patients with COVID‐19, we assessed ongoing RCTs including these agents with their potential mechanism of action in this population. METHODS: We searched clinicaltrials.gov and the World Health Organization International Clinical Trials Registry Platform to identify RCTs of novel antithrombotic agents in patients with COVID‐19. RESULTS: Based on a systematic literature search, 27 RCTs with 10 novel antithrombotic agents (including nafamostat, dociparstat, rNAPc2, and defibrotide) were identified. The results from these trials have not been disseminated yet. The studied drugs in the ongoing or completed RCTs include agents affecting the coagulation cascade, drugs affecting endothelial activation, and mixed acting agents. Their postulated antithrombotic mechanisms of action and their potential impact on patient management are summarized. CONCLUSION: Some novel antithrombotic agents have pleiotropic anti‐inflammatory and antiviral effects, which may help reduce the viral load or fibrosis, and improve oxygenation. Results from ongoing RCTs will elucidate their actual role in the management of patients with COVID‐19. | 3081 TALASAZ eT AL. Coronavirus disease 2019 (COVID-19) is associated with venous and arterial thrombosis. 1-3 Dozens of randomized controlled trials (RCTs) are evaluating the utility of conventional antithrombotic agents in Results from the available RCTs of the conventional antithrombotic agents have not yet led to definitive answers. In patients admitted to the intensive care unit (ICU), intermediate-dose or full-dose prophylactic anticoagulation did not lead to improvement in clinical outcomes. [5] [6] [7] [8] Among patients hospitalized in medical wards, the results for heparin-based regimens are promising, although some details are yet to be clarified. Escalated-dose prophylaxis with rivaroxaban was not associated with improvement in outcomes. 9 It is in this setting that there has been interest in novel agents with antithrombotic effects (with coexisting anti-inflammatory and/or antiviral properties) in patients with COVID-19. We summarized the ongoing RCTs of novel antithrombotic agents being tested in COVID- 19 and their potential mechanisms of action. We searched clinicaltrials.gov and the World Health Organization International Clinical Trials Registry Platform, to identify RCTs of novel antithrombotic agents (last updated on February 26, 2021) using pre-defined keywords containing COVID-19, and keyword permutations for antithrombotic agents. The search strategy and screening of the studies is described in Figure 1 . RCTs of conventional antithrombotic agents (such as heparin-based regimens, direct oral anticoagulants, fibrinolytic therapy, aspirin, and P2Y 12 inhibitors) were excluded. We identified 998 records, of which 27 RCTs met the eligibility criteria ( Figure 1 ). We did not identify registered RCTs for danaparoid, soluble thrombomodulin, or activated protein C. Objectives: Given the possibility that more novel agents with antithrombotic effects may have a potential utility for management of patients with COVID-19, we assessed ongoing RCTs including these agents with their potential mechanism of action in this population. International Clinical Trials Registry Platform to identify RCTs of novel antithrombotic agents in patients with COVID-19. Results: Based on a systematic literature search, 27 RCTs with 10 novel antithrombotic agents (including nafamostat, dociparstat, rNAPc2, and defibrotide) were identified. The results from these trials have not been disseminated yet. The studied drugs in the ongoing or completed RCTs include agents affecting the coagulation cascade, drugs affecting endothelial activation, and mixed acting agents. Their postulated antithrombotic mechanisms of action and their potential impact on patient management are summarized. Conclusion: Some novel antithrombotic agents have pleiotropic anti-inflammatory and antiviral effects, which may help reduce the viral load or fibrosis, and improve oxygenation. Results from ongoing RCTs will elucidate their actual role in the management of patients with COVID-19. • Novel antithrombotic agents with pleiotropic properties are under evaluation in 27 RCTs with 10 distinct agents. • Novel antithrombotic agents could be classified as drugs affecting the coagulation cascade, drugs affecting endothelial activation, and those with mixed mechanisms of action. • Results from these RCTs may help expand therapeutic options in COVID-19. The presumed mechanism of action relevant to COVID-19 of novel agents with antithrombotic properties is illustrated in Figure 2 . Some of these agents have anticoagulant properties, some have profibrinolytic functions, and others may impact thromboinflammation by reduction in the formation of neutrophil extracellular traps (NETs). Table 1 summarizes the ongoing RCTs of 10 novel agents and comparator arms in each RCT, and their respective clinical trial registration number. A summary of ongoing or completed trials are described in Figure 3 . These completed or ongoing RCTs have focused only on hospitalized patients with COVID-19, except one trial of quercetin, which includes outpatients. Although there may be some overlap in the putative mechanisms of action, for simplicity, these agents are grouped as those drugs affecting the coagulation cascade, drugs affecting endothelial activation, and agents with mixed mechanisms of action. 4,10 A brief discussion of these agents and their trials is provided in the following sections. The hypercoagulopathy in COVID-19 is associated with increased levels of tissue factor (TF), thrombin, von Willebrand factor (VWF), and type-1 plasminogen activator inhibitor (PAI-1), as well as reduced levels of plasminogen activators and antithrombin. 4 Drugs affecting the coagulation cascade in this review can be divided into three groups: tissue factor pathway inhibitors (recombinant nematode anticoagulant protein c2 [rNAPc2] and quercetin), serine protease inhibitors (antithrombin, nafamostat, and ulinastatin), and those that augment fibrinolysis (defibrotide). Due to multiple properties of defibrotide, it will be described in a distinct section, subsequently. 3.1.1 | Tissue factor inhibitors: rNAPc2 and quercetin rNAPc2 inhibits TF/factor VIIa complex and may decrease the interleukin-10 response and dampen the cytokine storm. 11 F I G U R E 1 PRISMA flow diagram. Keywords used for search of clinicaltrials.gov and WHO ICTRP included: COVID-19 or SARS-CoV-2 or Coronavirus disease 2019 and coagulation, thrombosis, thrombotic, thromboembolism, thromboembolic, anticoagulation, anticoagulant, antithrombotic, antiplatelet, aspirin, dipyridamole, Aggrenox, cilostazol, P2Y12 inhibitor, clopidogrel, ticagrelor, prasugrel, ticlopidine, cangrelor, vorapaxar, eptifibatide, tirofiban, abciximab, heparin, UFH, LMWH, enoxaparin, dalteparin, tinzaparin, bemiparin, nadroparin, fondaparinux, danaparoid, DTI, bivalirudin, argatroban, lepirudin, desirudin, DOAC, apixaban, rivaroxaban, edoxaban, betrixaban, dabigatran, sulodexide, thrombolytic, fibrinolytic, alteplase, reteplase, tenecteplase, dociparstat, DSTAT, nafamostat, ulinastatin, defibrotide, crizanlizumab, rNAPc2, antithrombin, recombinant antithrombin, human antithrombin, ATryn, thrombomodulin, activated protein C, drotrecogin alpha, eculizumab, ravulizumab, isoquercetin, isotrifoliin, and quercetin. COVID The presumed mechanism of action of the investigational antithrombotic agents in patients with COVID-19. Antithrombin inhibits serine proteases, coagulation factors, thrombin, and plasmin. Nafamostat affects coagulation cascade, endothelial dysfunction, and inhibits serine proteases. Also, it blocks TMPRSS2 activity-essential for spike protein (S-protein) priming of SARS-CoV-2. Blocking of TMPRSS2 activity leads to lack of S-protein priming and inhibits cell entry by angiotensin converting enzyme 2. Ulinastatin blocks serine proteases and inhibits the cytokine storm. In addition, it exerts antifibrotic effects on lung parenchyma by inhibiting the expression of inflammatory markers and fibrotic factors such as transforming growth factor β. Recombinant nematode anticoagulant protein c2 (rNAPc2) inhibits the cytokine storm and blocks TF/FVIIa by binding to activated or zymogen factor X. Quercetin derivatives inhibit protein disulfide isomerase, TF, glycoprotein IIb/IIIa activation, platelet aggregation, and decrease thrombin generation. Furthermore, quercetin can diminish reactive oxygen species and inhibit NLRP3 inflammasome. Defibrotide inhibits plasminogen activator inhibitor, induces tissue-plasminogen activator, and reduces von Willebrand factor expression and platelet aggregation. In addition, it can suppress viral attachment and viral dissemination by inhibition of syndecan-1 and heparanase. Defibrotide can also inhibit endothelial cell activation. Defibrotide, crizanlizumab, and dociparstat block P-selectin, thereby reducing platelet aggregation. Dociparstat can also inhibit cytokine storm and decreases the risk of thrombosis by reducing the formation of neutrophil extracellular traps (NETs). C5 inhibitors block C5 and cleavage into C5a and C5b, therefore they can inhibit cytokine storm and endothelial cell damage. ACE2, angiotensin-converting enzyme 2; C5, complement 5; eNOS, endothelial nitric oxide synthase; FDP, fibrin degradation products; GP IIb/IIIa, glycoprotein IIb/IIIa; HPSE, heparanase; ICU, intensive care unit; MAC, membrane attack complex; NLRP3, nod-like receptor family pyrin domain containing 3; NO, nitric oxide; PD, protein disulfide isomerase; RCT, randomized controlled trial; ROS, reactive oxygen species; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SDC-1, syndecan-1; SOC, standard of care; TF, tissue factor (factor III); TGFβ, transforming growth factor β; TNFα, tumor necrosis factorα; TMPRSS2, transmembrane protease serine 2 formation, production of ROS, and the initiation of cytokine storm. Preventing membrane attack complex formation on the vascular endothelial cells due to inhibition of C5b may protect endothelial cells from further damage leading to thrombotic microangiopathy (TMA). 20-22 Crizanlizumab is a monoclonal antibody that blocks the adhesion of leukocytes and platelets to the vessel wall. 19 The CRITICAL Defibrotide is a polydispersed oligonucleotide synthesized by depolymerization of DNA extracted from porcine intestinal mucosa. It has a complex mechanism of action with antiviral activity, antithrombotic properties, and anti-inflammatory effects via reducing TNFα and IL-6, and vascular endothelial growth factor levels. Defibrotide upregulates tissue plasminogen activator expression, decreases PAI-1 levels, and enhances plasmin activity. 24, 25 Defibrotide can inhibit viral attachment by suppression of syndecan-1 directly and indirectly via inhibiting heparanase. Also, defibrotide can diminish viral dissemination by heparanase. COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up: JACC state-of-the-art review Ethnic differences in thromboprophylaxis for COVID-19 patients: should they be considered? Clinical characteristics and risk factors for symptomatic venous thromboembolism in hospitalized COVID-19 patients: a multicenter retrospective study Recent randomized trials of antithrombotic therapy for patients with COVID-19: JACC state-of-the-art review Therapeutic anticoagulation with heparin in critically Ill patients with Covid-19 Effect of intermediatedose vs standard-dose prophylactic anticoagulation on thrombotic events, extracorporeal membrane oxygenation treatment, or mortality among patients with COVID-19 admitted to the intensive care unit: the INSPIRATION randomized clinical trial Standard prophylactic versus intermediate dose enoxaparin in adults with severe COVID-19: a multi-center, open-label, randomised controlled trial. open-label, randomised controlled trial Intermediate-dose versus standard-dose prophylactic anticoagulation in patients with COVID-19 admitted to the intensive care unit: 90-day results from the INSPIRATION randomized trial Therapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID-19 and elevated D-dimer concentration (ACTION): an open-label, multicentre, randomised, controlled trial Pulmonary embolism in COVID-19 patients: a French multicentre cohort study Recombinant nematode anticoagulant protein c2, an inhibitor of tissue factor/factor VIIa, attenuates coagulation and the interleukin-10 response in human endotoxemia New antithrombotic drugs in acute coronary syndrome Integrative considerations during the COVID-19 pandemic SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor Old drugs for a new virus: repurposed approaches for combating COVID-19 Therapeutic effect of ulinastatin on pulmonary fibrosis via downregulation of TGF-β1. TNF-α and NF-κB Lack of evidence of ACE2 expression and replicative infection by SARSCoV-2 in human endothelial cells COVID-19 is, in the end, an endothelial disease P-selectin blockade in COVID-19-related ARDS Complement-targeted therapy: development of C5-and C5a-targeted inhibition Severe COVID-19 infection and thrombotic microangiopathy: success does not come easily Is the COVID-19 thrombotic catastrophe complement-connected? Eculizumab as an emergency treatment for adult patients with severe COVID-19 in the intensive care unit: a proof-of-concept study The fibrinolytic mechanism of defibrotide: effect of defibrotide on plasmin activity Multifactorial pathogenesis of COVID-19-related coagulopathy: can defibrotide have a role in the early phases of coagulation disorders? COVID-19-induced endotheliitis: emerging evidence and possible therapeutic strategies Defibrotide in the COVID-19 coagulopathy: What is the timing? How to cite this article: Talasaz AH Use of novel antithrombotic agents for COVID-19: Systematic summary of ongoing randomized controlled trials The authors would like to express their sincere gratitude to Fatemeh Esmaeili, MS, for her kind assistance in the preparation of the figures.