COVID-19: Thromboembolic Events High Despite Prophylaxis

October 26, 2020

Major thromboembolic complications and adverse cardiovascular events occurred with high frequency in patients with COVID-19, especially in the intensive care setting, despite a high use of thromboprophylaxis, in a new large observational US study.

"Despite very high rate of antithrombotic prophylaxis there were a high rate of thromboembolic events suggesting that we are probably not providing enough thromboprophylaxis," lead author Gregory Piazza, MD, Brigham and Women's Hospital, Boston, Massachusetts, told Medscape Medical News

"Standard prophylaxis as recommended in the guidelines is a low dose of low-molecular-weight heparin once daily, but these results suggest [patients] probably need higher doses," he added.

However, Piazza cautioned that this is an observational study and randomized trials are needed to make changes in treatment strategies. Several such trials are currently underway.

The current study was published online today ahead of print in the November 3 issue of the Journal of the American College of Cardiology.

Rates Similar to Other Very Sick Patients

The study showed that while thromboembolic complications were high, they were not as high as seen in some of the earlier studies from Asia and Europe, Piazza noted.

"The numbers we were seeing in early reports were so high we couldn't figure out how that was possible," he said. "Our study suggests that in a US population receiving thromboprophylaxis, the rate of thromboembolic complications [are] more in line with what we would expect to see in other very sick patients who end up in ICU."

He suggested that the very high rates of thromboembolic complications in the early studies from Asia may have been because of the lack of thromboprophylaxis, which is not routine in hospitalized patients there. "Some of the earlier studies also used routine ultrasound and so picked up asymptomatic thrombotic events, which was not the case in our study. So our results are more representative of the US population," he explained.

Piazza attributes the high rate of thromboembolic complications being reported with COVID-19 to the sheer number of very sick patients being admitted to the hospital.

"We are accustomed to seeing a rare case of thrombosis despite prophylaxis in hospitalized patients, but we are seeing more in COVID patients. This is probably just because we have more critically ill patients," he said.

"We are seeing an incredible influx of patients to the ICU that we have never experienced before, so the increase in thromboembolic complications is more obvious. In prior years we probably haven't had enough critically ill patients at any one time to raise the flag about thromboprophylaxis," he commented.

The study also found a high rate of cardiovascular complications. They are seeing an increase in the risk of myocardial infarction, which is to be expected in such sick patients, but they also see quite a bit of new atrial fibrillation, myocarditis, and heart failure in patients who don't always have underlying cardiovascular disease, he said.

"So this virus does appear to have a predilection to causing cardiovascular complications, but this is probably because it is making patients so sick,” Piazza said. "If flu was this virulent and resulted in such high rates of acute respiratory distress syndrome (ARDS), we would probably see similar cardiovascular complication rates."

For the current report, the researchers analyzed a retrospective cohort of 1114 patients with COVID-19 diagnosed through the Mass General Brigham integrated health network. Of these, 170 had been admitted to the ICU, 229 had been hospitalized but not treated in ICU, and 715 were outpatients. In terms of ethnicity, 22% were Hispanic/Latinx and 44% were non-White. 

Cardiovascular risk factors were common, with 36% of patients having hypertension, 29% hyperlipidemia, and 18% diabetes. Prophylactic anticoagulation was prescribed in 89% of patients with COVID-19 in the intensive care cohort and 85% of those in the hospitalized non-intensive care setting.

Results showed that major arterial or venous thromboembolism occurred in 35% of the intensive care cohort, 2.6% of those hospitalized but not treated in ICU, and 0% of outpatients.

Major adverse cardiovascular events occurred in 46% of the intensive care cohort, 6.1% of those hospitalized but non-ICU, and 0% of outpatients.

Symptomatic venous thromboembolism occurred in 27% of those admitted to ICU, 2.2% of those hospitalized but non-ICU, and 0% of outpatients.

"We found that outpatients had a very low rate of thromboembolic complications, with the vast majority of the risk being in hospitalized patients, especially those in ICU," Piazza said.  

"These results suggest that we don't need routine thromboprophylaxis for all outpatients with COVID-19, but there will probably be some patients who need it — those with risk factors for thromboembolism."

Catheter- and device-associated deep vein thrombosis (DVT) accounted for 76.9% of the DVTs observed in the study.

"Our finding of high frequency of catheter-associated DVT supports the judicious use of central venous catheters that have been widely implemented, especially in the ICU, to minimize recurrent health care team exposure and facilitate monitoring," the researchers say.

ARDS Biggest Risk Factor

Of all the markers of disease severity, the presence of ARDS had the strongest association with adverse outcomes, including major arterial or venous thromboembolism, major adverse cardiovascular events, symptomatic venous thromboembolism and death.

"The severe inflammatory state associated with ARDS and other complications of COVID-19 and its resultant hypercoagulability may explain, at least in part, the high frequency of thromboembolic events. Improved risk stratification, utilizing biochemical markers of inflammation and activated coagulation as well as clinical indicators, such as ARDS, may play an important role in the early identification of patients with an increased likelihood of developing symptomatic VTE or arterial thrombosis," the researchers write. "They may benefit from full- or intermediate-intensity antithrombotic therapy rather than prophylactic anticoagulation."

They point out that this study provides a cross-sectional view of the cardiovascular complications of COVID-19 in a large healthcare network, consisting of two academic medical centers serving the greater Boston area, several community hospitals, and numerous outpatient care sites.

"The study incorporates a wide scope of clinically meaningful cardiovascular endpoints and utilizes a rigorous process of event adjudication. Although data on patients with COVID-19 in the ICU have been the subject of most reports, our study provides insights into the broad spectrum of all hospitalized and outpatient populations," the authors note.

"The high frequency of arterial or venous thromboembolism in hospitalized patients despite routine thromboprophylaxis suggests the need for improved risk stratification and enhanced preventive efforts," they conclude.

The study is continuing, and the researchers expect to have data on 10,000 patients by the end of winter.

Wait for Randomized Trials

In an accompanying editorial, Robert McBane, MD, Mayo Clinic, Rochester, Minnesota, says these data provide important real-world arterial and venous thrombotic event rates across a large, integrated healthcare network and an experienced roster of clinician-scientists devoted to thrombosis research.

Noting that whether to interpret these results as alarming or reassuring requires a comparison of expected thromboembolic event rates separate from the pandemic, he points out that while the overall VTE rate among ICU patients was high, the vast majority of these events were attributable to central venous lines, and apart from these, the event rates do not appear inflated relative to prior published incidence rates from the pre–COVID-19 era.

"It is therefore important to resist the urge to overprevent or overtreat patients and expose them to the serious risks of major bleeding," McBane writes, adding that "the systematized approach to delivery of guideline-driven VTE prophylaxis across this large, integrated health network likely contributed to the relatively low rates of serious thrombotic outcomes reported."

He further notes that as the majority of VTE events were related to central venous lines in ICU patients, "this underscores the importance of a bundled care approach to central venous line management with daily assessment of the continued necessity of central access.

"A number of important clinical trials aimed at optimizing thrombo-prophylaxis during hospitalization, following hospital dismissal, and in ambulatory settings are underway. Until available, the lessons of thoughtful anticoagulant prophylaxis and treatment guidelines harvested from years of clinical research appear to apply," he concludes.

This study was funded, in part, by a research grant from Janssen Pharmaceuticals. Piazza has received research grant support from EKOS Corporation, Bayer, Bristol-Myers Squibb/Pfizer, Portola Pharmaceuticals, and Janssen Pharmaceuticals; and has received consulting fees from Amgen, Pfizer, Boston Scientific, Agile, and Thrombolex. McBane reports no relevant disclosures.

J Am Coll Cardiol. Published online October 26, 2020.  Abstract, Editorial

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