Antithrombotic Therapy for COVID-19: Challenges and Lessons for the Future

Over the last year, an abundance of clinical research has been undertaken to understand common pathologies of COVID-19 illness, including the high rates of thrombosis and endothelial injury. A new state-of-the-art review notes that while an optimal antithrombotic therapy has yet to be determined and appears to be debatable, the ongoing studies provide needed clues and hope for improving outcomes.

“There is so much heterogeneity in protocols that hospitals are using for their ward patients, for their critically ill patients, and even for outpatients,” said senior author Behnood Bikdeli, MD (Brigham and Women’s Hospital, Boston, MA, and Yale University School of Medicine, New Haven, CT). “Then you have all these studies, with people feeling so strongly about one particular regimen versus the other. We thought: enough is enough. Let's systematically look to see what's out there.”

The summary, published online March 16, 2021, ahead of print in the Journal of the American College of Cardiology, takes stock of 75 ongoing or completed RCTs of antithrombotic agents for patients with COVID-19 that were registered on ClinicalTrials.gov or the WHO International Clinical Trials Registry Platform database as of December 2020.

As lead author Azita H. Talasaz, PharmD (Tehran University of Medical Sciences, Iran), and colleagues note, the agents used in the RCTs include unfractionated heparin and heparin derivatives, parenteral direct thrombin inhibitors, direct oral anticoagulants (DOACs), fibrinolytic agents, sulodexide, dociparstat, and nafamostat. In 11 trials, the focus is on antithrombotic therapy strictly for outpatients and includes enoxaparin, DOACs, aspirin, and sulodexide versus no treatment. Most are open-label, ranging from 172 to 7,000 patients, and are enrolling patients with a hyperinflammatory or procoagulant profile that includes elevated C-reactive protein.

Heparin-based regimens account for the most frequently studied of the antithrombotic agents (25 trials of hospitalized patients, 17 trials of ICU patients, and 2 outpatient trials). Six ongoing trials are looking at safety and efficacy of fibrinolytic therapy (tenecteplase or alteplase) on COVID-19-related respiratory failure, four are looking at the impact of antiplatelet agents in critically ill patients on the incidence of venous thromboembolism (VTE) or arterial thrombosis, and four are examining the synthetic serine protease inhibitor nafamostat in critically ill patients with COVID-19-related pneumonia.

Enough is enough. Let's systematically look to see what's out there. Behnood Bikdeli

Among patients who have been discharged followed hospitalization for COVID-19, the ACTIV-4c trial is evaluating the impact of apixaban on all-cause mortality and arterial/venous thromboembolism, MICHELLE is evaluating rivaroxaban on the outcomes of VTE and VTE-related death, and seven other trials, including INSPIRATION, are continuing to monitor the impact of a hospital-assigned antithrombotic therapy in the outpatient setting.

While a number of vulnerable groups have been excluded from ongoing RCTs for practical reasons, including pregnant women, those with advanced kidney disease, and obese adults, Talasaz and colleagues say the underrepresentation of these groups across hospitalized, critically ill, and outpatient categories poses problems for decision-making regarding safety and efficacy. Other knowledge gaps include the trade-offs of various investigational antithrombotic regimens depending on the patient’s condition, the best assay for low-molecular-weight heparin/unfractionated heparin monitoring in both critically ill and noncritically ill patients, the impact of antiplatelet therapy on survival, and the role antiplatelet therapy should play after discharge.

Additionally, while the ongoing trials are welcome and anticipated to inform practice, they will only provide another piece of the unwieldy COVID-19 clinical puzzle.

“The large number of antithrombotic agents under investigation, the variable dosing regimens tested, and variability in trial conduct as well as methods of outcome detection and adjudication may complicate the identification of the optimal regimens,” Talasaz and colleagues write.

Impact of Pandemic Research

To TCTMD, Bikdeli said there is no doubt that COVID-19 has taught clinical investigators new ways of working, and helped them find their way forward in terms of conducting quality studies.

“Before [COVID-19] there were large groups that would meet inside a room and try to get the records from a site, and adjudicate, and send records back, and get additional data. It was cumbersome, and it took a lot of time and resources. That was absolutely not feasible during COVID,” he said. “So, what happened was several of these trials that we included in our summary tried to use online [clinical endpoint committee] meetings where the site clinicians were coming in and presenting the cases and pieces of evidence online, in real time on a secure platform. Then people were able to sit together and have discussions and everyone had their role, but it was all virtual. In some cases, they were able to resolve issues immediately. I think that's an example of something that we hopefully can transition to and use outside of the pandemic setting.”

The time-sensitive nature of mounting COVID-19 therapy trials also meant that in many cases short study periods and small, underpowered trials became a necessity over larger, multicenter collaborations. Likewise, preprint servers saw a boon in their popularity.

“Preprint has been used for over a decade in science, mathematics, physics, et cetera, and they are very good in the sense of being able to get something out as quickly as possible, particularly if there is a public health significance,” Bikdeli said. “It also has the value of being able to save others time and effort and resources.”

The novel nature of the SARS-Cov-2 virus also has increased the willingness of patients and families to participate in clinical trials, although enrollment is affected by case numbers, Talasaz and colleagues note.

“We have to continue watching the results of these studies with an open mind,” Bikdeli concluded. “Unlike other studies in the pre-COVID era, many of these studies cannot really be looked at as positive or negative. Many of the agents that are being tested have been in common practice for years, some of them decades, and many of them are part of the routine practice of hospital protocols, but there's no evidence. So, regardless, it's a win for patients and clinicians to have [the evidence].”