Higher-dose prophylactic anticoagulation required to prevent thrombosis in hypoxemic COVID-19
Mortality and time to improvement didn't differ with twice the standard dose of heparin versus a standard or therapeutic dose, but there was a lower rate of new thromboembolic events with no increase in major bleeding, a French trial found.
Twice the standard prophylactic heparin dose may be necessary to prevent thrombotic complications in patients with hypoxemic COVID-19 pneumonia, a recent trial found.
Researchers conducted the ANTICOVID randomized open-label trial to determine the lowest effective dose of anticoagulation in patients with COVID-19 pneumonia requiring supplemental oxygen and having no initial thrombosis on chest CT with pulmonary angiogram from April 14 to Dec. 13, 2021, at 23 centers in France. Patients received low-molecular-weight heparin (LMWH) for up to 14 days, either a standard prophylactic dose, a high dose (twice the standard dose), or a therapeutic dose. If renal failure (creatinine clearance <30 mL/min) occurred after randomization or if a patient needed an invasive procedure with high risk of bleeding, LMWH was replaced by a continuous IV infusion of unfractionated heparin (low or high prophylactic dose or therapeutic dose, guided by the anti-Xa activity). The researchers randomized 339 patients and included 334 (mean age, 58.3 years; 67.7% men) in the primary analysis: 114 in the standard-dose group, 110 in the high-dose group, and 110 in the therapeutic anticoagulation group. At randomization, 90% of patients were in the ICU. The primary efficacy outcome was a hierarchical criterion of all-cause mortality followed by time to clinical improvement at day 28. The main secondary outcome was net clinical outcome at day 28 (a composite of thrombosis, major bleeding, and all-cause death). The trial received financial support from LEO Pharma. Results were published March 22 by JAMA Internal Medicine.
Use of high-dose and standard-dose prophylactic anticoagulation had similar probabilities of favorable outcome (47.3% [95% CI, 39.9% to 54.8%] vs. 52.7% [95% CI, 45.2% to 60.1%]; P=0.48), as did therapeutic anticoagulation compared with standard-dose prophylactic anticoagulation (50.9 % [95% CI, 43.4% to 58.3%] vs. 49.1% [95% CI, 41.7% to 56.6%]; P=0.82) and with high-dose prophylactic anticoagulation (53.5% [95% CI, 45.8% to 60.9%] vs. 46.5% [95% CI, 39.1% to 54.2%]; P=0.37). The proportion of patients meeting the net clinical outcome was 29.8% in the standard-dose group (20.2% thrombosis, 2.6% bleeding, 14.0% death), 16.4% in the high-dose group (5.5% thrombosis, 3.6% bleeding, 11.8% death), and 20.0% in the therapeutic anticoagulation group (5.5% thrombosis, 3.6% bleeding, 12.7% death). Use of high-dose and therapeutic-dose heparin significantly reduced thrombosis compared with standard-dose use (absolute difference, −14.7 [95% CI, −6.2 to −23.2] and −14.7 [95% CI, −6.2 to −23.2], respectively). Compared with a standard dose, high-dose heparin significantly reduced the net clinical outcome (absolute difference, −13.5 [95% CI, −2.6 to −24.3]); therapeutic anticoagulation did not provide additional benefit compared with high dose.
The study was limited by its open-label design, the potential for detection bias (particularly related to thrombotic events), and the relatively small number of patients who were randomized, the authors noted. They added that most patients had the delta variant of SARS-CoV-2, in contrast with previous studies.
The findings of the trial align with prior observations made throughout the pandemic that patients with COVID-19 who are hypoxemic and require hospitalization have a heightened risk for venous thromboembolism and that increasing the intensity of anticoagulation reduces the risk, an accompanying editorial noted. “The ANTICOVID trial provides additional insights into the optimal dose of anticoagulant therapy for treating patients hospitalized with hypoxemic COVID-19 pneumonia: a higher dose of prophylactic LMWH (twice the standard dose) is necessary and sufficient to prevent thrombotic complications without increasing the rate of major bleeding. However, additional studies are needed to address the questions that remain unanswered,” such as why heparin-based anticoagulant therapy at any intensity does not lower mortality, the editorialists wrote.
In other COVID-19 news, a recent ACP position paper critically examined the justifications for and harms imposed by visitor restrictions during the pandemic. The paper offered ethical guidance on family caregiving, support, and visitation during public health emergencies. It was published March 20 by the Journal of General Internal Medicine.
