Thrombotic Events Frequent Among COVID-19 Patients in ICUs

Major arterial or venous thrombotic complications, major adverse cardiovascular events, and symptomatic venous thromboembolism (VTE) occur frequently in the first 30 days after admission to the ICU for COVID-19, and this heightened risk occurs despite the vast majority being treated with anticoagulation, a new observational study shows.

Prophylactic anticoagulation was prescribed to 89.4% of COVID-19 patients in the ICU, but roughly one-third had a major arterial or venous thrombotic complication at 30 days and more than one in four developed symptomatic VTE.

“No matter what, if you look at the data, for most patients getting thromboprophylaxis—in the ICU cohort it was around 90%—we’re still seeing quite a few thromboembolic events,” lead investigator Gregory Piazza, MD (Brigham and Women’s Hospital, Boston, MA), told TCTMD. “It makes us wonder if our standard thromboprophylaxis is enough for these patients or if we need to be doing more. That’s at the root of a number of major trials underway now, because many have also noticed that thromboembolic events continue to happen even when we give standard thromboprophylaxis.”

Since April, there have been numerous reports showing that that COVID-19 predisposes patients to venous and arterial thrombotic disease. That heightened risk has been attributed to the body’s severe inflammatory response following infection, a prothrombotic milieu, and immobility. VTE is now considered one of the biggest cardiovascular hazards for patients with COVID-19, say researchers, and this risk is highest in patients hospitalized in the ICU. The frequency of VTE in ICU patients has ranged from 25% when symptomatic disease is considered to much higher when surveillance is performed with venous ultrasonography, according to the group.

It makes us wonder if our standard thromboprophylaxis is enough for these patients or if we need to be doing more. Gregory Piazza

“We’re starting to get a better handle on all of the different factors that go into the risk of thrombosis with COVID-19,” said Piazza. “We’ve gained an appreciation of the fact that the level of inflammation in these patients with COVID-19 is so high. Other conditions that lead to a high inflammatory state are also associated with thrombosis. So that part makes sense. We’re also understanding that platelets may play a significant role in the inflammatory environment leading to thrombosis. There are also a number of other pathways where coagulation is activated.”

Risks Relegated Largely to ICU Patients

In this retrospective, observational study, published online October 26, 2020, in the Journal of the American College of Cardiology, the researchers analyzed 1,114 patients with COVID-19 diagnosed between March 13 and April 3, 2020, as part of the Mass General Brigham integrated health network. This included 170 patients admitted to the ICU, 229 admitted to hospital for nonintensive care, and 715 treated as outpatients. Overall, 22.3% of the study cohort was Hispanic/Latinx and 44.2% were nonwhite. More than half of the patients were women (54%), and the mean body mass index was approximately 30, putting patients in the category of overweight/obese.

At 30 days from COVID-19 diagnosis, 35.3% of patients in the ICU had a major arterial or venous thromboembolic event and 27.0% developed symptomatic VTE. Additionally, 39 patients (22.9%) had a symptomatic deep vein thrombosis (DVT) and 30 of these thromboses were catheter- or device-related. Pulmonary embolism was infrequent, occurring in just three ICU patients. Overall, the MACE rate in the ICU cohort was 45.9% and 30-day mortality was 23.5%.

Among the ICU patients, acute respiratory distress syndrome was associated with a sevenfold higher risk of major arterial or VTE events, a sixfold higher risk of MACE, and a 24-fold higher risk of symptomatic VTE. 

In the non-ICU cohort, prophylactic anticoagulation was prescribed to 84.7% of patients. At 30 days, rates of major arterial or venous complications, MACE, and symptomatic VTE were lower than that observed in the ICU cohort. Adverse events in the outpatient setting were extremely rare, with just two deaths due to sepsis without hospitalization. Prophylactic anticoagulation was rare among COVID-19 patients treated outside the hospital.

Thirty-Day Cardiovascular Outcomes of COVID-19 by Setting

Overall, patients with COVID-19 in the ICU who received prophylactic anticoagulation were significantly more likely to have a major venous or arterial thrombotic event (15.9% vs 0.7%), MACE (20.2% vs 1.1%), or develop symptomatic VTE (11.5% vs 0.1%; P < 0.0001 for all) than those not prescribed anticoagulation. The same trend was observed in hospitalized patients not in the ICU.

The higher rates among those treated with anticoagulation are likely the result of confounding by indication with the patients at highest risk for a thromboembolic event prescribed treatment, according to the researchers.

To TCTMD, Piazza said some of the earliest published studies from Asia and Europe reported very high rates of venous and arterial thromboembolic events in COVID-19 patients. In Asia, Piazza said, it’s not typical for hospitalized patients to be treated with prophylactic anticoagulation, which may explain the numbers. With that in mind, the group wanted to get a handle on event rates, including MACE, in their setting where anticoagulation is routinely prescribed to acutely ill patients and now to all hospitalized COVID-19-positive patients.

“Based on our data, we do see an increased rate of thrombosis, but it’s not at the level they saw in Europe or in Asia,” said Piazza.

Resist Urge to Overtreat

In an editorial, Robert McBane II, MD (Mayo Clinic, Rochester, MN), says that while patients with COVID-19 may have a thrombotic event resulting from COVID-19, the overall event rates appear to match those of patients needing hospital and ICU care outside of the pandemic. “It is therefore important to resist the urge to overprevent or overtreat patients and expose them to the serious risks of major bleeding,” he writes. “Adding major hemorrhage to the condition of a patient already severely compromised from the viral infection will undoubtedly increase the mortality risk.”

McBane notes that VTE events occurred in the first 5 to 7 days after hospital admission and the majority were related to central venous lines.

“This underscores the importance of a bundled care approach to central venous line management with daily assessment of the continued necessity of the central access,” he writes. “Whereas central venous lines are convenient, the potential for thrombotic or infectious complications requires prompt removal when no longer absolutely needed.”

Piazza agreed with that assessment, adding that if in-dwelling catheters are no longer necessary, they should be removed as soon as possible.

For physicians dealing with increased hospitalizations for COVID-19, the first step in treatment is to make sure all patients are treated with prophylactic anticoagulation, said Piazza. If the patient is at significantly higher risk for thromboembolic events or has additional risk factors that might predict failure of standard prophylaxis, they could be enrolled in one of the ongoing clinical trials testing different anticoagulation strategies, including intermediate and therapeutic doses, said Piazza.

Those randomized trials include the National Institutes of Health-sponsored ACTIV-4 trial testing different doses of unfractionated and low-molecular-weight heparin in hospitalized COVID-19 patients, as well as FREEDOM COVID-19, IMPROVE-COVID, INSPIRATION, and ATTAC, among others.