key: cord-0801120-hv9xyqw4 authors: Talasaz, Azita H.; Sadeghipour, Parham; Kakavand, Hessam; Aghakouchakzadeh, Maryam; Kordzadeh-Kermani, Elaheh; Van Tassell, Benjamin W.; Gheymati, Azin; Ariannejad, Hamid; Hosseini, Seyed Hossein; Jamalkhani, Sepehr; Sholzberg, Michelle; Monreal, Manuel; Jimenez, David; Piazza, Gregory; Parikh, Sahil A.; Kirtane, Ajay J.; Eikelboom, John W.; Connors, Jean M.; Hunt, Beverley J.; Konstantinides, Stavros V.; Cushman, Mary; Weitz, Jeffrey I.; Stone, Gregg W.; Krumholz, Harlan M.; Lip, Gregory Y.H.; Goldhaber, Samuel Z.; Bikdeli, Behnood title: Recent Randomized Trials of Antithrombotic Therapy for Patients With COVID-19: JACC State-of-the-Art Review date: 2021-03-16 journal: J Am Coll Cardiol DOI: 10.1016/j.jacc.2021.02.035 sha: 7e7160d85e2cb6ec852b45a380ff9d915559d307 doc_id: 801120 cord_uid: hv9xyqw4 Endothelial injury and microvascular/macrovascular thrombosis are common pathophysiological features of coronavirus disease-2019 (COVID-19). However, the optimal thromboprophylactic regimens remain unknown across the spectrum of illness severity of COVID-19. A variety of antithrombotic agents, doses, and durations of therapy are being assessed in ongoing randomized controlled trials (RCTs) that focus on outpatients, hospitalized patients in medical wards, and patients critically ill with COVID-19. This paper provides a perspective of the ongoing or completed RCTs related to antithrombotic strategies used in COVID-19, the opportunities and challenges for the clinical trial enterprise, and areas of existing knowledge, as well as data gaps that may motivate the design of future RCTs. in the intensive care units (ICUs) compared with non-ICU settings (28% vs. 7%) (6) . In addition, postmortem studies show frequent evidence of microvascular thrombosis in patients with COVID-19 (7, 8) . The influence of these events on mortality rates remains unknown (9) . von Willebrand factor (16) . Increased platelet reactivity, NETosis, and alterations in the aforementioned hemostatic factors result in a hypercoagulable state (17) (18) (19) (20) (21) (22) . Particularly in COVID-19, it is believed that the excessive inflammatory response plays an important role in the pathogenesis of thrombosis (thromboinflammation), including pulmonary microthrombosis and pulmonary intravascular coagulopathy (7, 8) . Antiphospholipid antibodies have been identified in some patients (23) , but their clinical significance is uncertain (24) . Finally, COVID-19 may predispose patients to venous stasis and increase the risk of (venous) thrombosis. Fatigue, hypoxemia, being connected to medical devices (for hospitalized patients), or acute illness (including pulmonary involvement, myocarditis with associated heart failure, or other forms of severe disease) can all lead to HIGHLIGHTS Venous and arterial thrombosis are prevalent in patients with COVID-19. Optimal thromboprophylaxis has not been established for patients with this disease. Numerous randomized trials are evaluating antithrombotic regimens for outpatients and inpatients with COVID-19. Ongoing experience has influenced the design, conduct, analysis, and reporting the results of these trials. 19 (27) (28) (29) (30) (31) . The concern for thrombotic risk was heightened by reports of VTE in 13% to 56% of patients despite the use of standard prophylaxis (32) (33) (34) (35) . This led some experts to recommend empirical use of escalated doses of anticoagulant agents (36) . However, the risks associated with intensified use of antithrombotic agents, such as bleeding, should be weighed against the presumptive benefits (22, 27, 31) . In addition, there have been variations in methodology and outcomes assessment for thrombotic events, including the concern about counting in situ thrombosis in small vessels (a recognized feature of acute lung injury also known as immunothrombosis) as pulmonary emboli. Due to these issues, as well as the concerns regarding excess bleeding, a number of guidance statements have not recommended empirical escalated-dose anticoagulation (27, 37) . Multiple ongoing randomized controlled trials (RCTs) are evaluating a variety of antithrombotic regimens in patients with COVID-19 ( Figure 2 ). These include trials of antiplatelet agents, anticoagulants, fibrinolytic agents, or combinations of these agents. In most trials, the intensity of antithrombotic therapy is proportional to the expected thrombotic event rates in the population under study. Less intensive therapies, including antiplatelet agents, oral anticoagulants, and standard prophylactic dose of low- After identification of 918 records and manual screening of 180 records, 75 RCTs were included in this study (Supplemental Figure 1 ). In 13 cases, a design paper and/or study protocol was available. Of all ongoing studies, 1 RCT reported the results in peer-reviewed literature (38) and 1 shared the findings on a pre-print server (39) . For 3 RCTs, final results are unknown, but patient enrollment was paused in critically ill patients due to concern for futility and potential excess of safety events (40). Categorizing the RCTs evaluating different agents in various settings, including those treated entirely as outpatients, patients in the non-ICU hospital wards, critically ill patients in the ICU, and post-hospital discharge. Others: dociparstat, nafamostat, and sulodexide. Abbreviations as in Figure 2 . Talasaz et al. Antithrombotic Therapy RCTs in COVID-19 - intensities of heparin derivatives are summarized in Supplemental Table 3 . Recognizing that heparin has an anticoagulant effect but also an antiviral and anti-inflammatory effect (47, 48) and ventilator-free days ( limited high-quality data on the horizon for these vulnerable and high-risk subgroups, decision-making for optimal management in these patients will continue to be challenging. The impact of aspirin administration on rate of MACE, disease progression, hospitalization, and death in patients with acute, symptomatic COVID-19 The safety/efficacy of sulodexide in patients with acute, symptomatic COVID-19 The safety/efficacy of intermediatedose and therapeutic-dose heparin derivatives or DOACs compared with standard prophylactic anticoagulation Proof-of-concept data of the role of inhaled antithrombotic therapy in patients with COVID-19 The impacts of antiplatelet agents on all-cause mortality The safety/efficacy of dociparstat and nafamostat in hospitalized patients with COVID-19 The safety/efficacy of intermediatedose and therapeutic-dose anticoagulation compared with prophylactic anticoagulation Effects of short-term infusion of bivalirudin on the PaO 2 /FiO 2 ratio The impacts of antiplatelet agents on thrombotic outcomes and mortality Proof-of-concept data on the role of fibrinolytic therapy in critically ill patients Proof-of-concept data on the role of inhaled antithrombotic therapy in mechanically ventilated patients with COVID-19 The safety/efficacy of extended anticoagulation with DOACs or LMWHs after hospital discharge Remaining knowledge gap PMA needed to understand the relative efficacy of antiplatelet agents, standard prophylactic dose of enoxaparin compared with DOACs The safety/efficacy of antithrombotic therapy regimens in vulnerable subgroups, including obese patients, pregnant women, and those with advanced kidney disease Anti-inflammatory properties and activity against thromboinflammation have been attributed to several antithrombotic regimens, including heparin derivatives and antiplatelet agents (30, 67, 68) , with the potential to reduce large-vessel thrombosis and improve outcomes. Another evolving concept is the role of microthrombosis and pulmonary intravascular coagulopathy (7, 8, 69) in the pathophysiology of respiratory failure in COVID-19 (70) . Results from the small HESACOVID study suggested improved arterial oxygenation (PaO 2 /FiO 2 ) with therapeutic versus standard-dose prophylaxis anticoagulation in Single specialty-based collaboration common Focused, often established study groups Specialty-based and multispecialty collaboration common Frequent ad hoc collaborations within and between institutions and countries Study design Diverse research priorities Patient enrollment over a long time period; recruitment time could be slow or fast Long-term follow-up a routine feature of many trials Distinct focus on COVID-19-related trials; some adaptations required for pre-COVID-19 trials Time-sensitive trial design (to provide rapid access to high-quality evidence). 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