Therapeutic-dose heparin lowers risk for VTE, death in hospitalized patients with COVID-19
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Therapeutic-dose low-molecular-weight heparin decreased the likelihood of blood clots and death compared with standard of care among patients hospitalized with COVID-19, according to study results published in JAMA Internal Medicine.
However, researchers did not observe the protective effect among patients in the ICU, researchers noted.
“Once the COVID-19 pandemic hit — just as with other health systems across the nation — we saw an increase in thrombotic adverse events, particularly in our hospitalized patients, that unfortunately led to more intensive care and potentially death,” Alex C. Spyropoulos, MD, FACP, FCCP, FRCPC, professor at Feinstein Institutes for Medical Research at Northwell Health, told Healio. “These thrombotic events occurred in many patients despite standard doses of prophylactics to prevent blood clots and death that many guidelines had advocated for.
“We planned and initiated this study to determine whether there was benefit of therapeutic-dose heparin to prevent blood clots and death vs. standard prophylactic-dose heparin among patients who were hospitalized with COVID-19,” Spyropoulos added. “We selected high-risk patients using a new biomarker D-dimer that was elevated more than four times the normal level.”
The multicenter, randomized HEP-COVID clinical trial included 253 adults (mean age, 66.7 years; 53.8% men) receiving treatment across 12 U.S. academic centers between May 2020 and May 2021.
Researchers stratified patients according to ICU or non-ICU status. They randomly assigned 124 patients to standard prophylactic or intermediate-dose low-molecular-weight heparin or unfractionated heparin and 129 patients to therapeutic-dose enoxaparin, administered subcutaneously twice daily at a dose of 1 mg/kg for patients with creatinine clearance of 30 mL/min/1.73 m² or greater or 0.5 mg/kg for patients with creatinine clearance of 15-29 mL/min/1.73 m².
Venous thromboembolism, arterial thromboembolism or mortality due to any cause served as the primary efficacy outcome. Major bleeding at 30 ± 2 days served as the principal safety outcome.
Nearly all patients (98.4%) met inclusion criteria based on D-dimer elevation, and 32.8% were stratified as ICU-level care.
According to study results, 41.9% of patients assigned standard-dose heparin met the primary efficacy outcome, with 28.2% having experienced VTE, 3.2% arterial thromboembolism and 25% having died, compared with 28.7% of patients assigned therapeutic-dose heparin, with 11.7% having VTE, 3.2% arterial thromboembolism and 19.4% having died (RR = 0.68; 95% CI, 0.49-0.96). The difference appeared to be driven by a decrease in thromboembolism (29% vs. 10.9%; RR = 0.37; 95% CI, 0.21-0.66).
Major bleeds occurred in 1.6% of patients assigned the standard-dose compared with 4.7% among those assigned the therapeutic-dose (RR = 2.88; 95% CI, 0.59-14.02).
Non-ICU patients experienced a decrease in the primary efficacy outcome (36.1% vs. 16.7%; RR = 0.46; 95% CI, 0.27-0.81), whereas ICU patients did not (55.3% vs. 51.1%; RR = 0.92; 95% CI, 0.62-1.39).
“There appeared to be no treatment effects in critically ill patients. We knew we enrolled a high-risk, hospitalized COVID-19 population using elevated D-dimers from earlier large-scale data from Northwell, but we were surprised that elevated D-dimers were able to identify a high-risk COVID-19 population not requiring ICU-level of care whose course of disease was modifiable using therapeutic-dose heparin,” Spyropoulos said. “This was not seen in critically ill patients, whose severe course of disease was likely too far advanced for increased heparin doses to exert any benefit. We also noted greater harm from therapeutic-dose heparin, in terms of more major bleeds.”
Additional work is needed to identify the optimal approach to reducing the risk for blood clots among critically ill patients, including the use of novel or multimodal strategies, Spyropoulos added.
“More research is also needed on how to optimally reduce the risk for clotting in the immediate hospital post-discharge period,” he said. “The HEP-COVID trial, along with the multiplatform trials, provides high-quality evidence to change clinical practice guidelines to favor therapeutic-dose heparin as primary prevention of blood clots and death among high-risk patients hospitalized with COVID-19.”
The role of antiplatelet therapy remains to be determined, as well as the role of other therapies that might modulate the prothrombotic characteristics of COVID-19 in hospitalized patients, according to an accompanying editorial by Lana Wahid, MD, medical instructor in the department of medicine, and Thomas L. Ortel, MD, PhD, researcher in the departments of medicine and pathology and the division of hematology, both at Duke University Medical Center.
“The distinction between moderate and severe disease can be better defined, specifically when it comes to oxygen requirement. In addition, the transition of patients between the ICU and non-ICU settings represents a time when the intensity of anticoagulant therapy needs to be revisited,” Wahid and Ortel wrote. “Lastly, whether a course of extended anticoagulation following discharge from the hospital, particularly for patients who were hospitalized with a more severe clinical course of COVID-19 or who have persistently elevated D-dimer levels, remains to be determined.”
References:
Spyropoulos AC, et al. JAMA Intern Med. 2021;doi:10.1001/jamainternmed.2021.6203.
Wahid L and Ortel TL. JAMA Intern Med. 2021;doi:10.1001/jamainternmed.2021.6212.
For more information:
Alex C. Spyropoulos, MD, can be reached at Feinstein Institutes for Medical Research at Northwell Health at Lenox Hill Hospital, 130 E 77th St., New York, NY 10075; email: aspyropoul@northwell.edu.
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