Recent Randomized Trials of Antithrombotic Therapy for Patients With COVID-19

JACC State-of-the-Art Review

Azita H. Talasaz, PHARMD; Parham Sadeghipour, MD; Hessam Kakavand, PHARMD; Maryam Aghakouchakzadeh, PHARMD; Elaheh Kordzadeh-Kermani, PHARMD; Benjamin W. Van Tassell, PHARMD; Azin Gheymati, PHARMD; Hamid Ariannejad, MD; Seyed Hossein Hosseini, PHARMD; Sepehr Jamalkhani; Michelle Sholzberg, MDCM, MSC; Manuel Monreal, MD, PHD; David Jimenez, MD, PHD; Gregory Piazza, MD, MS; Sahil A. Parikh, MD; Ajay J. Kirtane, MD, SM; John W. Eikelboom, MBBS; Jean M. Connors, MD; Beverley J. Hunt, MD; Stavros V. Konstantinides, MD, PHD; Mary Cushman, MD, MSC; Jeffrey I. Weitz, MD; Gregg W. Stone, MD; Harlan M. Krumholz, MD, SM; Gregory Y.H. Lip, MD; Samuel Z. Goldhaber, MD; Behnood Bikdeli, MD, MS


J Am Coll Cardiol. 2021;77(15):1903-1921. 

In This Article

Antithrombotic Prophylaxis in COVID-19: Pros and Cons

Bedside observations, pathophysiological investigations, and initial epidemiological data led to enthusiasm for antithrombotic prophylaxis in COVID-19.[27–31] The concern for thrombotic risk was heightened by reports of VTE in 13% to 56% of patients despite the use of standard prophylaxis.[32–35] 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-molecular-weight heparin (LMWH), are typically studied in the outpatient or lower acuity hospital settings. In turn, more intensive therapies, including intermediate-dose or fully therapeutic doses of anticoagulants, or even fibrinolytic therapy, are under investigation in RCTs of hospitalized critically ill patients.

Figure 2.

Summary of RCTs of Antithrombotic Agents in COVID-19 Categorized Based on Pharmacological Class
Unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), direct thrombin inhibitors (DTIs), direct oral anticoagulants (DOACs), antiplatelets, fibrinolytic agents, and investigational agents are being evaluated in different settings, including outpatients, inpatients (intensive care unit [ICU] and non-ICU), and post-discharge. *Multifactorial designs or multiple interventions. COVID = coronavirus disease-2019; RCTs = randomized controlled trials.

The aims of the current paper were to systematically summarize the ongoing and completed RCTs of antithrombotic therapy in patients with COVID-19 and to evaluate the strengths and limitations of the study designs, as well as the challenges and opportunities related to conducting and interpreting RCTs during a global pandemic.