High-dose prophylactic anticoagulant therapy or therapeutic anticoagulant therapy reduced de novo thrombosis in patients with COVID-19 hypoxic pneumonia based on data from 334 adults.
Patients with hypoxic pneumonia caused by COVID-19 are at increased risk of thrombosis and bleeding associated with anticoagulants, so data are needed to determine the lowest effective dose of anticoagulant, write Vincent Labbé, MD, Sorbonne University, Paris, France, and colleagues .
Previous studies of different anticoagulant strategies in patients with COVID-19 pneumonia in noncritical and critically ill patients have shown conflicting results, but some institutions recommend a high-dose regimen after evidence of macrovascular thrombosis in patients with COVID-19 treated with standard therapy. anticoagulant therapy, the authors write.
However, previously published studies have not compared the efficacy of three anticoagulant strategies: high-dose prophylactic anticoagulant therapy (HD-PA), standard dose prophylactic anticoagulant therapy (SD-PA), and therapeutic anticoagulant therapy (TA).
In an open-label trial of COVID-19 anticoagulants (ANTICOVID), published last week in JAMA Internal Medicine, The researchers identified consecutively hospitalized adults aged 18 years and older who were treated for COVID-19 hypoxic pneumonia at 23 centers in France between April 2021 and December 2021.
Patients were randomized to SD-PA (116 patients), HD-PA (111 patients), and TA (112 patients) with LMWH for 14 days or until hospital discharge or weaning from supplemental oxygen for 48 consecutive hours, whichever result comes first. HD-PA patients received a double dose of SD-PA. The mean age of the patients was 58.3 years, and approximately two-thirds of them were men; data on race and ethnicity were not collected. Participants did not have macrovascular thrombosis at baseline.
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-point respiratory function scale).
The secondary outcome was a combination of safety and efficacy at day 28, which included a combination of thrombosis (ischemic stroke, non-cerebrovascular arterial thrombosis, deep vein thrombosis, pulmonary thrombosis, and deep vein thrombosis associated with a central venous catheter), major bleeding, or all cause death. .
For the primary outcome, the results were similar across the groups; HD-PA did not have a significant advantage over SD-PA or TA. All-cause mortality for patients with SD-PA, HD-PA, and TA was 14%, 12%, and 13%, respectively. The time to clinical improvement for the three groups was approximately 8 days, 9 days and 8 days, respectively. Results for the main outcome were similar across all predefined subgroups.
However, HD-PA was associated with a significant four-fold reduction in the risk of de novo thrombosis compared with SD-PA (5.5% vs. 20.2%), with no observed increase in major bleeding. TA 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 higher doses of anticoagulant reflect data from previous studies, the investigators wrote in their discussion. “The results of our study, together with those of previous RCTs, support the suggestion that the role of microvascular thrombosis in worsening organ dysfunction may be less than suggested,” they said.
The results were limited by several factors, including open design and relatively small sample size, lack of data on microvascular (versus macrovascular) thrombosis at baseline, and the prevalence of COVID-19 delta among study participants. the researchers noted that this may have contributed to the lower mortality rate.
However, given the significant reduction in de novo thrombosis, the results support the routine use of HD-PA in patients with severe COVID-19 hypoxic pneumonia, they concluded.
Results inform current clinical practice
During the COVID-19 pandemic, “patients hospitalized with COVID-19 showed the highest risk of thromboembolic complications, especially patients in intensive care settings,” and early reports suggested that standard prophylactic doses of anticoagulant therapy may not be sufficient to prevent thrombotic events. wrote Richard S. Becker, MD, of the University of Cincinnati, Ohio, and Thomas L. Ortel, MD, of Duke University, Durham, North Carolina, in an accompanying editorial.
“Although there have been several studies that have examined the role of anticoagulant therapy in hospitalized patients with COVID-19, this is the first study that specifically compared a standard prophylactic dose of low molecular weight heparin with a “high dose.” prophylactic regimen and towards a full therapeutic dosing regimen,” Ortel said in an interview.
“Given concerns about the increased thrombotic risk with prophylactic anticoagulant doses and the potential risk of bleeding associated with full therapeutic dose of anticoagulants, this approach allowed investigators to explore the efficacy and safety of an intermediate dose between these two extremes,” he said.
In the current study, “it was notable that the main factor in improving outcomes with the ‘high-dose’ prophylactic regimen was a four-fold reduction in macrovascular thrombosis, which has not been observed in other studies of anticoagulant therapy in hospitalized patients with severe COVID-19,” Ortel told Medscape. “A lot of initial concern about disease progression in patients hospitalized with severe COVID-19 has focused on the role of microvascular thrombosis, which appears to be less important in the process, or conversely less responsive to anticoagulant therapy.”
According to Ortel, the clinical conclusion from the study is a reduced risk of venous thromboembolism with a high-dose prophylactic anticoagulant strategy compared to a standard prophylactic dose regimen for patients hospitalized with COVID-19 hypoxic pneumonia, “resulting in an improved net clinical outcome.”
Looking ahead, “more research is needed to determine whether a higher dose of prophylactic anticoagulant would be beneficial for patients hospitalized with COVID-19 pneumonia who are not in the intensive care unit,” Ortel said. Research is also needed to determine whether therapeutic interventions are equally beneficial for patients with different coronavirus variants, as most of the patients in the current study were infected with the Delta variant, he added.
The study was supported by LEO Pharma. Lead author Labbe disclosed grants from LEO Pharma during the study and fees from AOP Health not related to the current study.
Becker disclosed personal fees from Novartis DSMB, Ionis DSMB, and the Basking Biosciences Scientific Advisory Board not related to the current study. Ortel announced grants from the US National Institutes of Health, Instrumentation Laboratory, Stago and Siemens; contract fees from the US Centers for Disease Control and Prevention; and fees from UpToDate not related to the current study.
JAMA Internal Med. Published online March 22, 2023. Full text, Editorial
Heidi Splete is a freelance medical journalist with 20 years of experience.
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