What PCPs should know about VTE in patients with COVID-19
An increased incidence of venous thromboembolism, or VTE, among patients with COVID-19 has been observed since the early days of the pandemic.
Maureen Gang, MD, professor of emergency medicine and vice chair for quality and safety at Rutgers New Jersey Medical School, told Healio Primary Care that primary care physicians “should definitely be concerned about thromboembolic events in all COVID-19 patients.”
“Although patients with acute COVID-19 are hypercoagulable, there is no evidence as to how long the risk for thrombus formation continues after the acute illness,” she said. “It seems the risks for VTE are the same as for any other non-COVID-19 patient post-discharge, and unless patients had a thromboembolic event during the hospitalization or were on anticoagulants prior to admission, they should not be discharged on anticoagulants.”
Preliminary evidence of VTE in COVID-19
There are several hypotheses about the cause of VTE in patients with COVID-19, Gang said.
“The normal immune response is inter-related with several stages of the coagulation pathway, with inflammatory mediators upsetting the usual clotting cascade,” she noted.
SARS-CoV-2 directly attacks capillary endothelial cells, which Gang said leads to the release of cytokines and other reactants and contributes to coagulation cascades.
She added that similarities have been observed between antiphospholipid syndrome and coagulation abnormalities in patients with COVID-19.
“Increased levels of autoantibodies against phospholipids and phospholipid-binding proteins have been found in COVID-19 patients and have been associated with more severe disease,” she said. “Increased levels of neutrophil extracellular traps, which are composed of cell debris, chromatin and oxidative enzymes, have been described in both COVID-19 and antiphospholipid syndrome that cause increased inflammation and clotting.”
This has been observed in other viral syndromes, as well, so the mechanisms behind the increased risk for VTE in COVID-19 are still being studied, Gang said.
Anticoagulation appears to be indicated for patients hospitalized with COVID-19, according to Gang, and prophylactic doses are currently recommended by the NIH and the American Society of Hematology.
“There are several studies underway that are looking at full dose heparinization for admitted patients compared to prophylactic dosing,” she said. “Preliminary data shows that for patients admitted to the ICU and those needing ventilatory support, there is no benefit ... whereas less-sick patients may benefit from full-dose heparin.”
In addition, there are several studies examining the role of aspirin and Eliquis (apixaban; Bristol-Myers Squibb/Pfizer) in outpatient VTE prophylaxis among patients with COVID-19.
Recently, the NIH announced that it has launched a third phase 3 clinical trial evaluating the safety and efficacy of anticoagulants among patients discharged from the hospital following a moderate-to-severe COVID-19 diagnosis. The most recent trial will investigate the use of 2.5 mg of apixaban.
Therapeutic anticoagulation
In January, a study published in the Annals of Internal Medicine concluded that early use of anticoagulation among critically ill adults did not affect patient survival.
“Our study found that increased doses of thromboprophylaxis — therapeutic-dose anticoagulation in this case — in patients with COVID-19 who were critically ill did not improve mortality,” Hanny Al-Samkari, MD, associate director of Hereditary Hemorrhagic Telangiectasia Center at Massachusetts General Hospital and an instructor of medicine at Harvard Medical School, told Healio Primary Care. “Given that many current guidance statements suggest empiric escalation of thromboprophylaxis in this population, our findings conflict with these statements.”
Al-Samkari and colleagues conducted a multicenter observational cohort study to evaluate VTE and major bleeding within 14 days of admission to the ICU and the effect of early use of therapeutic anticoagulation on patient survival.
The study included 3,239 patients admitted to ICUs at 67 U.S. hospitals from March 4, 2020, to April 11, 2020. Among all patients, 6.3% developed VTE, and 2.8% had a major bleeding event.
The researchers determined that independent predictors of VTE were being male (OR = 1.6; 95% CI, 1.13-2.27) and have higher D-dimer levels upon ICU admission (OR = 1.79; 95% CI, 1.14-2.81 for D-dimer of 1,001-2,500 ng/mL vs. 1,000 ng/mL; OR = 2.50; 95% CI, 1.40-4.50 for 2,501-10,000 ng/mL vs. 1,000 ng/mL; and OR = 4.2; 95% CI, 2.17-8.14 for > 10,000 ng/mL vs. 1,000 ng/mL).
Among 2,809 patients in the target trial emulation, 11.9% were given early therapeutic anticoagulation. During follow-up (median, 27 days), patients who were given early therapeutic anticoagulation had a risk for death similar to those who did not receive the treatment (HR = 1.12; 95% CI, 0.92-1.35).
“Critically ill patients with COVID-19 have a hypercoagulable state and are at high risk of thrombosis from COVID-19,” Al-Samkari said. “However, they also have a significant major bleeding risk, and the sum of the data as it stands suggests against empiric escalation of anticoagulant dose to therapeutic dose in these patients.”
Prophylactic anticoagulation
Another study published in BMJ suggested that prophylactic anticoagulants given within 24 hours of hospital admission were associated with a decreased risk for 30-day mortality with no increase in risk for serious bleeding events.
“Our results provide strong real-world evidence to support guidelines recommending the use of prophylactic anticoagulation as initial treatment for patients with COVID-19 on hospital admission,” Christopher T. Rentsch, PhD, MPH, assistant professor in the department of non-communicable disease epidemiology at the London School of Hygiene & Tropical Medicine, London, United Kingdom, and colleagues wrote.
Rentsch and colleagues conducted an observational cohort study of patients who received care from the U.S. Department of Veterans Affairs to compare the outcomes of patients hospitalized with COVID-19 who did or did not receive prophylactic anticoagulation.
A total of 4,297 patients who were admitted to the hospital from March 1, 2020, through July 31, 2020, were included in the study. Of these patients, 84.4% received prophylactic anticoagulation within the first day of admission, with more than 99% receiving heparin or enoxaparin.
Within 30 days of hospital admission, there were 622 deaths among patients with COVID-19, 513 of whom received prophylactic anticoagulation.
After conducting inverse probably of treatment-weighted analyses, Rentsch and colleagues determined that the cumulative incidence of 30-day mortality was 14.3% (95% CI, 13.1-15.5) in those who received prophylactic anticoagulation and 18.7% (95% CI, 15.1-22.9) in those who did not.
Further, compared with those who did not receive treatment, those who received prophylactic anticoagulation had a 27% decreased risk for death within 30 days (HR = 0.73, 95% CI, 0.66-0.81). The researchers observed similar associations for inpatient mortality with the initiation of therapeutic anticoagulation.
Additionally, they determined that there was not an increased risk for bleeding that required a transfusion associated with prophylactic anticoagulation (HR = 0.87; 95% CI, 0.71-1.05).
“Until clinical trial data are available, our results provide strong evidence for the use of prophylactic anticoagulation as initial treatment for patients with COVID-19 on hospital admission,” Renstch and colleagues wrote.
Nonadministration of prophylaxis
In a retrospective cohort analysis of patients who were discharged from Johns Hopkins Hospital from March 1, 2020, to May 12, 2020, researchers investigated whether patients with COVID-19 were missing doses of VTE prophylaxis and, if so, whether that was contributing to VTE in this population.
“We thought that patients with COVID-19 might be missing their doses of VTE prophylaxis, and that’s why we’re seeing this very high rate of VTE in COVID patients,” Elliott R. Haut, MD, PhD, vice chair of quality, safety and service in the department of surgery and an associate professor of surgery at Johns Hopkins Medicine, told Healio Primary Care.
However, Haut said they found “that is not the case.”
The study included 429 patients who tested positive for COVID-19, as well as 2,316 patients who tested negative for COVID-19 and 3,305 patents who were not tested.
Haut and colleagues found that patients with COVID-19 were more likely to be prescribed VTE prophylaxis than patients without COVID-19 (adjusted OR [aOR] = 1.51; 95% CI, 1.38–1.66) and were more likely to receive all doses of their prescribed VTE prophylaxis (aOR = 1.48; 95% CI, 1.36–1.62).
They determined that the number of patients with COVID-19 who missed a dose of VTE prophylaxis and later developed VTE was similar to the number of patients without COVID-19 who developed VTE after missing a dose of prophylaxis.
Haut noted that more research is needed to determine the best pharmacologic method of VTE prophylaxis in different COVID-19 populations, including ICU patients with severe disease who require ventilation, those hospitalized and receiving supplemental oxygen, and patients with mild disease who remain at home.
“Over the next 3 to 6 months, we’re going to have even better guidance based on some of the studies that are going to be coming out for those different patient populations,” Haut said.
References:
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Al-Samaki H, et al. Ann Intern Med. 2021;doi:10.7326/M20-6739.
Varasteh Kia M, et al. J Thromb Thrombolysis. 2021;doi:10.1007/s11239-021-02384-9.
NIH. Statement on NIH starting enrollment for third trial of blood clotting treatments for COVID-19. https://www.nih.gov/news-events/news-releases/statement-nih-starting-enrollment-third-trial-blood-clotting-treatments-covid-19. Accessed March 9, 2021.
Rentsch CT, et al. BMJ. 2021;doi:10.1136/bmj.n311.