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Clinical Context

COVID-19 is known to produce significant degrees of inflammation that affects multiple organ systems, including the vasculature. From the early days of the COVID-19 pandemic, the risk for thromboembolic disease associated with infection was evident. A systematic review and meta-analysis by Suh and colleagues summarized the risk for venous thromboembolism (VTE) associated with COVID-19. Their results were summarized in the December 15, 2020 issue of Radiology.^[1]

The meta-analysis included 27 studies with a total of 3342 patients. The rates of pulmonary embolism (PE) and VTE in cases of COVID-19 were 16.5% and 14.8%, respectively. The incidence of PE increased to nearly 25% among patients admitted to the intensive care unit (ICU), but this rate was influenced by the application of routine screening with pulmonary angiography. Serum D-dimer testing, which can be helpful in the exclusion of VTE among patients at low and moderate risk, was shown to have a sensitivity for thromboembolism of 96% at a cutoff of 500 µg/L. Therefore, it was considered to be a valid tool in the diagnostic process.

This study demonstrated high rates of macrovascular thrombosis associated with COVID-19, but this infection is also associated with an increased risk for thrombosis in smaller vessels. As a result, some institutions have recommended higher doses of anticoagulation for inpatients with COVID-19 to prevent thrombosis. The current randomized trial by Labbé and colleagues compares treatment with standard-dose prophylactic anticoagulation (SD-PA), high-dose prophylactic anticoagulation (HD-PA), and therapeutic anticoagulation (TA) in the setting of COVID-19.

Study Synopsis and Perspective

High-dose prophylactic anticoagulation or TA reduced de novo thrombosis in patients with hypoxemic COVID-19 pneumonia, according to data from 334 adults.

Patients with hypoxemic COVID-19 pneumonia are at increased risk for thrombosis and anticoagulation-related bleeding, therefore data to identify the lowest effective anticoagulant dose are needed, wrote Vincent Labbé, MD, of Sorbonne University, Paris, France, and colleagues.

Previous studies of different anticoagulation strategies for noncritically ill and critically ill patients with COVID-19 pneumonia have shown contrasting results, but some institutions recommend a high-dose regimen in the wake of data showing macrovascular thrombosis in patients with COVID-19 who were treated with SD-PA, the authors wrote.

Still, no previously published studies have compared the effectiveness of the 3 anticoagulation strategies: HD-PA, SD-PA, and TA, they said.

In the open-label Anticoagulation COVID-19 (ANTICOVID) trial, published March 22 in JAMA Internal Medicine,^[2] the researchers identified consecutively hospitalized adults aged 18 years and older being treated for hypoxemic COVID-19 pneumonia in 23 centers in France between April 2021 and December 2021.The investigators randomly assigned patients to SD-PA (116 patients), HD-PA (111 patients), and TA (112 patients) using low-molecular-weight heparin (LMWH) for 14 days or until either hospital discharge or weaning from supplemental oxygen for 48 consecutive hours, whichever outcome occurred first. The patients treated with HD-PA received 2 times the SD-PA dose. The mean age of the patients was 58.3 ± 13.1 years, and approximately two-thirds were men; race and ethnicity data were not collected. Participants had no macrovascular thrombosis at the start of the study.

The primary outcomes were all-cause mortality and time to clinical improvement (defined as the time from randomization to a 2-point improvement on a 7-category respiratory function scale).

The secondary outcome was a combination of safety and efficacy at day 28 that included a composite of thrombosis (ischemic stroke, noncerebrovascular arterial thrombosis, deep venous thrombosis, pulmonary artery thrombosis, and central venous catheter-related deep venous thrombosis), major bleeding, or all-cause death.

For the primary outcome, results were similar among the groups; HD-PA had no significant benefit over SD-PA or TA. All-cause death rates for patients treated with SD-PA, HD-PA, and TA were 14%, 12%, and 13%, respectively. The time to clinical improvement for the 3 groups was approximately 8 days, 9 days, and 8 days, respectively. Results for the primary outcome were consistent across all prespecified subgroups; however, HD-PA was associated with a significant fourfold reduced risk for de novo thrombosis compared with SD-PA (5.5% vs 20.2%), with no observed increase in major bleeding. Therapeutic anticoagulation was not associated with any significant improvement in primary or secondary outcomes compared with HD-PA or SD-PA.

The current study findings of no improvement in survival or disease resolution in patients with a higher anticoagulant dose reflects data from previous studies, the researchers wrote in their discussion.

"Our study results together with those of previous RCTs support the premise that the role of microvascular thrombosis in worsening organ dysfunction may be narrower than estimated," they said.

The findings were limited by several factors, including the open-label design and the relatively small sample size, the lack of data on microvascular (vs macrovascular) thrombosis at baseline, and the predominance of the Delta variant of COVID-19 among the study participants, which may have contributed to a lower mortality rate, the researchers noted.

Nonetheless, given the significant reduction in de novo thrombosis, the results support the routine use of HD-PA in patients with severe hypoxemic COVID-19 pneumonia, they concluded.

Results Inform Current Clinical Practice

Over the course of the COVID-19 pandemic, "[p]atients hospitalized with COVID-19 manifested the highest risk for thromboembolic complications, especially patients in the intensive care setting," and early reports suggested that standard prophylactic doses of anticoagulant therapy might be insufficient to prevent thrombotic events, wrote Richard C. Becker, MD, of the University of Cincinnati, Cincinnati, Ohio, and Thomas L. Ortel, MD, of Duke University, Durham, North Carolina, in an accompanying editorial.^[3]

"Although there have been several studies that have investigated the role of anticoagulant therapy in hospitalized patients with COVID-19, this is the first study that specifically compared a standard, prophylactic dose of [LMWH] to a 'high-dose' prophylactic regimen and to a full therapeutic dose regimen," Ortel said in an interview.

"Given the concerns about an increased thrombotic risk with prophylactic dose anticoagulation, and the potential bleeding risk associated with a full therapeutic dose of anticoagulation, this approach enabled the investigators to explore the efficacy and safety of an intermediate dose between these two extremes," he said.

In the current study, "[i]t was notable that the primary driver of the improved outcomes with the 'high-dose' prophylactic regimen reflected the fourfold reduction in macrovascular thrombosis, a finding which was not observed in other studies investigating anticoagulant therapy in hospitalized patients with severe COVID-19," Ortel told Medscape. "Much initial concern about progression of disease in patients hospitalized with severe COVID-19 focused on the role of microvascular thrombosis, which appears to be less important in this process, or, alternatively, less responsive to anticoagulant therapy."

The clinical takeaway from the study, Ortel said, is the decreased risk for VTE with an HD-PA strategy compared with an SD-PA regimen for patients hospitalized with hypoxemic COVID-19 pneumonia, "leading to an improved net clinical outcome."

Looking ahead, "Additional research is needed to determine whether a higher dose of prophylactic anticoagulation would be beneficial for patients hospitalized with COVID-19 pneumonia who are not in an [ICU] setting," Ortel said. 

Studies are also needed to determine whether therapeutic interventions are equally beneficial in patients with different coronavirus variants, as most patients in the current study were infected with the Delta variant, he added.

The study was supported by LEO Pharma Inc. Lead author Labbe disclosed grants from LEO Pharma Inc. during the study and fees from AOP Health unrelated to the current study.

Becker disclosed personal fees from Basking Biosciences Scientific Advisory Board, Ionis DSMB, and Novartis Pharmaceuticals Corporation Data Safety Monitoring Board (DSMB) unrelated to the current study. Ortel disclosed grants from the US National Institutes of Health, Instrumentation Laboratory, Stago, and Siemens AG; contract fees from the Centers for Disease Control and Prevention; and honoraria from UpToDate unrelated to the current study.

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