VTE Risk Higher With COVID-19 Than With Flu

Among hospitalized patients, COVID-19 carries a greater risk of venous thromboembolic (VTE) events than does influenza, data from the US Food and Drug Administration’s Sentinel System show.

Compared with patients hospitalized with flu during the 2018-2019 season, those who landed in the hospital with COVID-19 were more likely to develop deep vein thrombosis or pulmonary embolism within 90 days, both before and after vaccines against SARS-CoV-2 were available, according to researchers led by Vincent Lo Re III, MD (University of Pennsylvania, Philadelphia).

The risk of arterial thrombotic events (acute MI or ischemic stroke) did not, however, differ between the COVID-19 and flu cohorts, they report in a study published in the August 16, 2022, issue of JAMA.

After the pandemic got underway, it became apparent that COVID-19 carried an increased risk of both arterial and venous thrombosis, a link confirmed in multiple studies. But it had been less clear how that risk compared with other respiratory viruses, like influenza, which also has been associated with thrombotic events, has caused pandemics, and can result in hospitalization and death.

The most-important implication of this new analysis is that “clinicians should be aware that there is a sizable risk of venous thrombotic events” in patients hospitalized with COVID-19, Lo Re told TCTMD. “It particularly occurs within the initial 30 days of hospitalization, and it was associated with a higher risk of mortality. And I think when one examines the risk factors that we studied, clinicians potentially could identify subgroups that are at higher risk in whom you’d want to monitor more closely and potentially ensure that there was prophylactic anticoagulation initiated to prevent the development of those events over time.”

Risks Hold Steady

For the study, Lo Re and colleagues examined data from the FDA’s Sentinel System, which contains administrative claims from two national health insurers and electronic health records from four regional integrated health systems. The analysis focused on three groups of patients:

• 8,269 hospitalized with influenza between October 2018 and April 2019
• 41,443 hospitalized with COVID-19 between April and November 2020 (before vaccine availability)
• 44,194 hospitalized with COVID-19 between December 2020 and May 2021 (during vaccine availability)

Mean patient age was 72 in both the COVID-19 and influenza cohorts. The proportion of men was higher in the COVID-19 group (50.5% vs 45.0%).

Through 90 days of follow-up, the absolute risk of arterial thrombotic events was 14.4% in the flu cohort, 15.8% in the pre-vaccine COVID-19 cohort, and 16.3% in the vaccine-era COVID-19 cohort. After adjustment using propensity scores, risk was not significantly higher in patients with COVID-19, either before vaccines became available (adjusted HR 1.04; 95% CI 0.97-1.11) or after vaccines started rolling out (adjusted HR 1.07; 95% CI 1.00-1.14).

It’s pretty obvious that there is a preponderance of venous thromboembolic outcomes for COVID patients compared to influenza. Menno Huisman

For VTE events, 90-day rates were 5.3% in the flu cohort, 9.5% in the pre-vaccine COVID-19 cohort, and 10.9% in the vaccine-era COVID-19 cohort. Risks were significantly greater with COVID-19 before vaccines were available (adjusted HR 1.60; 95% CI 1.43-1.79) and after (adjusted HR 1.89; 95% CI 1.68-2.12).

The hazard of all-cause mortality within 30 days of having an arterial or VTE event was greater in patients who had been hospitalized with COVID-19 versus influenza (adjusted HRs 2.96 to 3.80). That might be explained, the researchers suggest, by a higher likelihood of clots that contributed to organ failure, multisystem injury, and death in patients with COVID-19, although there was no information on the severity of the thrombotic events available for the analysis.

By covering a 14-month span of the COVID-19 pandemic, the study enabled the researchers to look at how risks of thrombotic events potentially changed over time and differed based on which variant was dominant at any given time, and they found that rates of both arterial and venous events remained relatively steady.

As for why COVID-19 was more tightly linked than influenza to venous events, Lo Re and colleagues speculate that “SARS-CoV-2 infection of endothelial cells incites inflammation and abnormalities in coagulation, such as an increased abundance of antiphospholipid antibodies and enhanced platelet activity. These abnormalities might be more marked in patients with COVID-19 versus in patients with influenza infections.”

In addition, it could be that “heightened awareness of thrombosis with COVID-19 might have led to a greater ascertainment of events in patients with COVID-19 after case series published early in the pandemic reported high rates of these complications,” they say, noting, however, that a similar phenomenon would have been expected with arterial events but wasn’t seen.

Earlier Rules ‘Not Valid Anymore’

The findings provide confirmation of a study published last year in Research and Practice in Thrombosis and Haemostasis, which also showed a higher risk of VTE events in patients hospitalized with COVID-19 versus influenza, according to Menno Huisman, MD, PhD (Leiden University Medical Center, the Netherlands), senior author of that analysis. “It’s pretty obvious that there is a preponderance of venous thromboembolic outcomes for COVID patients compared to influenza,” he commented to TCTMD. He speculated that that could be related to a greater likelihood of a patient with COVID-19 requiring mechanical ventilation, which predisposes to the formation of clots in the legs, than one with flu.

Huisman cautioned, however, that the findings might not be applicable to the current COVID-19 situation, as the study period ended when the Delta variant was predominant. It’s likely that patients requiring hospitalization for COVID-19 in the current Omicron era, during which most of the population has been vaccinated, differ from those admitted earlier in the pandemic, and they probably have a risk of thrombotic complications that is not much different from what is seen in a hospitalized influenza cohort, Huisman said.

What that means, he said, is that the many randomized trials that have been conducted throughout the pandemic to evaluate ways to prevent thrombosis probably don’t apply to the current era, when changes to the virus and extensive vaccination together have helped lessen the risk of clotting. “In a way, vaccination has been the best medicine to prevent thrombosis from occurring, indirectly,” Huisman said, who added, “The rules of 2020 are not valid anymore for 2022.”

Huisman said he has been a strict adherent to the belief that hospitalized COVID-19 patients should be anticoagulated to prevent thrombosis at standard prophylactic doses and not therapeutic doses, although he acknowledged that not all international societies are in agreement. “Thrombotic burden is so much less, so prophylaxis is more than enough for hospitalized patients with Omicron COVID,” he said, pointing out that he and his colleague Erik Klok, MD, PhD (Leiden University Medical Center), lay out that same argument in an editorial published earlier this year.