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Clinical Context

SARS-CoV2 infection increases risk for venous and arterial thrombosis, particularly in intensive care unit (ICU) patients. The inflammatory response to infection includes coagulation cascade activation, systemic endothelial dysfunction, and hyperreactive platelet response.

In critically ill patients without COVID-19, anticoagulant thromboprophylaxis is recommended because it significantly decreases venous thrombotic events. However, findings of randomized controlled trials of anticoagulant and antiplatelet treatment in patients with COVID-19 have been mixed, perhaps reflecting differing study populations, designs, and endpoints.

Study Synopsis and Perspective

BARCELONA — Hospitalized patients in the ICU because of an acute COVID-19 infection had significantly fewer thrombotic events and complications when treated with full-dose anticoagulation compared with patients who received standard-dose anticoagulation prophylaxis, but full-dose anticoagulation also triggered an excess of moderate and severe bleeding events, randomized trial results show.

The new findings from the COVID-PACT trial in an exclusively US-based cohort of 382 on-treatment patients in the ICU with COVID-19 infection may lead to a change in existing guidelines, which currently recommend standard-dose prophylaxis based on results from prior head-to-head comparisons, such as guidelines posted this past March from the American Society of Hematology.^[1]

The new findings suggest "full-dose anticoagulation should be considered to prevent thrombotic complications in selected critically ill patients with COVID-19" after weighing an individual patient's risk for both thrombotic events and bleeding, David D. Berg, MD, said at the annual congress of the European Society of Cardiology. Simultaneous with his report at the congress, the results also appeared online in Circulation.^[2]

"What the results tell us is that full-dose anticoagulation in critically ill patients with COVID-19 is highly effective for reducing thrombotic complications," said Dr Berg, a cardiologist and critical care physician at Brigham and Women's Hospital in Boston, Massachusetts.

"Need to Replace the Guidelines"

"We probably need to replace the guidelines," said Eduardo Ramacciotti, MD, PhD, MPH, a professor of vascular surgery at Santa Casa School of Medicine in São Paulo, Brazil. Dr Ramacciotti praised the study's design, the endpoints, and the fact that the design excluded patients at high risk for bleeding complications, particularly those with a fibrinogen level below 200 mg/dL (2 g/L).

But other experts questioned the significance of the COVID-PACT results, given that the outcomes did not show that full-dose anticoagulation produced incremental improvement in patient survival.

"We should abandon the thought that intensified anticoagulation should be routine because it did not overall increase the number of patients discharged from the hospital alive," commented John W. Eikelboom, MBBS, a professor of hematology and thromboembolism at McMaster University in Hamilton, Canada.

"Preventing venous thrombosis is a good thing, but the money is in saving lives and stopping need for ventilation, and we haven't been successful doing that with an antithrombotic strategy," said Dr Eikelboom. "It is useful to prevent venous thrombosis, but we need to look elsewhere to improve the outcomes of [critically ill] patients with COVID-19."

Reducing Thromboembolism Is a "Valid Goal"

Dr Berg took a different view. "It's a valid goal to try to reduce venous thromboembolism complications," the major benefit seen in his study, he said. "There is clinical significance to reducing thrombotic events in terms of how people feel, their functional status, and their complications. There are a lot of clinically relevant consequences of thrombosis beyond mortality."

COVID-PACT ran at 34 US centers from August 2020 to March 2022, but stopped short of its enrollment goal of 750 patients because of waning numbers of patients with COVID-19 admitted to ICUs. In addition to randomly assigning patients within 96 hours of their ICU admission to full-dose anticoagulation or to standard-dose antithrombotic prophylaxis, the study included a second, concurrent randomization to the antiplatelet agent clopidogrel or to no antiplatelet drug. Both randomizations used an open-label design.

The results failed to show a discernable effect from adding clopidogrel on both the primary efficacy and primary safety endpoints, adding to accumulated evidence that treatment with an antiplatelet agent, including aspirin, confers no antithrombotic benefit in patients with COVID-19.

The trial's participants averaged 61 years old, 53% had hypertension, and 30% had diabetes. The median time after ICU admission when randomized treatment began was 2.1 days, and researchers followed patients for a median of 13 days, including a median time receiving anticoagulation of 10.6 days.

The trial design allowed clinicians to use either low-molecular-weight heparin or unfractionated heparin for anticoagulation, and 82% of patients received low-molecular-weight heparin as their initial treatment. The prespecified design called for an on-treatment analysis because of an anticipated high crossover rate. During the trial, 34% of patients who started on the prophylactic dose switched to full dose and 17% had the reverse crossover.

95% Increased Win Ratio With Full Dose

The study's primary efficacy endpoint used a win-ratio analysis that included 7 different adverse outcomes that ranged from death from venous or arterial thrombosis to clinically silent deep vein thrombosis.^[3] Treatment with full-dose anticoagulation led to a significant 95% increase in win ratio.

Researchers also applied a more conventional time-to-first-event secondary efficacy analysis, which showed that full-dose anticoagulation cut the incidence of an adverse outcome by a significant 44% relative to prophylactic dosing.

The 2 study groups showed no difference in all-cause death rates. The efficacy advantage of the full-dose regimen was driven by reduced rates of venous thrombotic events, especially a reduction in clinically evident deep vein thrombotic events.

The primary safety endpoint was the rate of fatal or life-threatening bleeding episodes, and although life-threatening bleeds were numerically more common among the full-dose recipients (4 events compared with 1 event on prophylaxis dosing), the difference was not significant, and no patients died from a bleeding event.

More Secondary Safety Bleeds

The safety difference showed up in a secondary measure of bleeding severity, the rate of GUSTO moderate or severe bleeds.^[4] These occurred in 15 of the full-dose recipients compared with 1 patient receiving the prophylactic dose.

Dr Berg highlighted that several prior studies have assessed various anticoagulation regimens in critically ill (ICU-admitted and on respiratory or cardiovascular support) patients with COVID-19. For example, 2 influential reports published in 2021 by the same team of investigators in the New England Journal of Medicine had sharply divergent results.

One multicenter study, which tested full-dose heparin against prophylactic treatment in more than 1000 critically ill patients, was stopped prematurely because it had not shown a significant difference between the treatment groups.^[5] The second study, in more than 2000 multicenter patients with COVID-19 who did not require critical-level organ support, showed clear superiority of the full-dose heparin regimen.^[6]

Notably, both previous studies used a different primary efficacy endpoint than the COVID-PACT study. The earlier reports both measured efficacy in terms of patients being alive and off organ support by 21 days from randomization.

Patients to Exclude

Although Dr Berg stressed the clear positive result, he also cautioned that they should not apply to patients excluded from the study: those with severe coagulopathies, those with severe thrombocytopenia, and patients already maintained on dual antiplatelet therapy. He also cautioned against using the full-dose strategy in elderly patients because in COVID-PACT those who developed bleeding complications tended to be older.

Dr Berg also noted that heparin prophylaxis is a well-established intervention for ICU-admitted patients without COVID-19 for the purpose of preventing venous thromboembolisms without evidence that this approach reduces deaths or organ failure.

But he conceded that "the priority of treatment depends on whether it saves lives, so anticoagulation is probably not as high a priority as other effective treatments," that reduce mortality. "Preventing venous thromboembolism has rarely been shown to have a mortality benefit," Dr Berg noted.

COVID-PACT received no direct commercial funding. Dr Berg has been a consultant to AstraZeneca, Mobility Bio, and Youngene Therapeutics, and he participated in a trial sponsored by Kowa. Dr Ramacciotti has been a consultant to or speaker on behalf of Aspen, Bayer, Daiichi Sankyo, Mylan, Pfizer, and Sanofi, and he has received research support from Bayer, Esperon, Novartis, and Pfizer. Dr Eikelboom has received honoraria and research support from Bayer.

European Society of Cardiology (ESC) Congress 2022. Presented August 29, 2022.

Circulation. Published online August 29, 2022.

Clinical Implications

• In ICU patients with COVID-19, full-dose anticoagulation, but not clopidogrel, reduced thrombotic complications but with increased bleeding.
• The findings may support revisiting current consensus treatment guidelines recommending standard-dose prophylactic intensity anticoagulation in such patients.

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