COVID-PACT Trial Supports Full-Dose Anticoagulation to Prevent Blood Clots in COVID-19 Patients

August 29, 2022—The European Society of Cardiology (ESC) announced study findings that suggest treatment of critically ill COVID-19 patients with full-dose anticoagulation lowers the risk of venous and arterial clotting complications by 44% compared with the standard dose. The addition of clopidogrel did not provide further protection.

The findings come from the COVID-PACT trial, which evaluated whether a higher intensity of anticoagulation and/or the use of antiplatelet therapy prevents arteriovenous thrombotic events with an acceptable safety profile in patients with severe COVID-19 infection. The trial was sponsored and funded by the TIMI Study Group, an academic research organization of Brigham and Women’s Hospital, an affiliate of Harvard Medical School in Boston, Massachusetts.

The late-breaking research was presented in a Hot Line session at the 2022 ESC Congress held August 26-29 in Barcelona, Spain. Erin A. Bohula, MD, et al published the study online ahead of print in Circulation.

As noted in the ESC press release, patients with COVID-19 are at high risk of developing life-threatening blood clots, and this risk is particularly high in those patients requiring intensive care.

Multiple clinical trials have assessed the benefit of anticoagulants and antiplatelets in patients with COVID-19; however, their results have varied and the optimal strategy for preventing blood clots, particularly in patients who are critically ill, has remained uncertain.

In particular, although a large trial in COVID-19 patients showed a convincing benefit of full-dose anticoagulation in hospitalized patients outside the intensive care unit (ICU), the same benefit was not seen in ICU patients and there was a question raised of potential harm.

According to ESC, COVID-PACT was a 2 x 2 factorial, randomized controlled trial in critically ill patients with COVID-19 conducted at 34 sites in the United States. Patients requiring ICU-level care (invasive mechanical ventilation, noninvasive positive pressure ventilation, high-flow nasal cannula, or vasopressors) were randomized to either full-dose or standard-dose prophylactic anticoagulation.

Use of unfractionated heparin or low-molecular-weight heparin for either regimen was at the discretion of the managing clinicians. In patients without another indication for antiplatelet therapy, there was an additional randomization to either the antiplatelet clopidogrel or no antiplatelet therapy.

Patients were assessed clinically and with lower extremity venous ultrasounds at 10 to 14 days after randomization and followed until hospital discharge or for 28 days, whichever occurred first.

ESC reported that the primary efficacy outcome was the hierarchical composite of death caused by venous or arterial thrombosis, pulmonary embolism, clinically evident deep venous thrombosis (DVT), type 1 myocardial infarction, ischemic stroke, systemic embolic event or acute limb ischemia, or clinically silent DVT, through hospital discharge or 28 days. Primary efficacy analyses included an unmatched win ratio and a time-to–first event analysis during treatment.

A total of 390 patients were randomized (390 to an anticoagulation strategy; 292 to an antiplatelet strategy).

The investigators found that in the primary efficacy analysis of anticoagulation, a greater proportion of wins occurred with the full dose (12.3%) versus standard dose (6.4%; win ratio 1.95; 95% CI, 1.08-3.55; P = .028). Results were consistent in the time-to-event analysis with 19 events on the full dose compared to 29 events on the standard dose (9.9% vs 15.2%; hazard ratio [HR], 0.56; 95% CI, 0.32-0.99; P = .046).

The primary safety outcome of fatal or life-threatening bleeding occurred in four patients on full-dose anticoagulation and one patient on standard-dose anticoagulation (2.1% vs 0.5%; P = .19); all of these were life-threatening bleeds and there were no fatal bleeding events. There was no difference in all-cause mortality between groups (HR 0.91; 95% CI, 0.56-1.48; P = .7).

In the antiplatelet analysis, there were no differences in the risks of clotting complications or of fatal or life-threatening bleeding in patients treated with clopidogrel compared with no antiplatelet therapy.

“COVID-19 treatment guidelines recommend full-dose anticoagulation for hospitalized patients outside the ICU and the standard dose for those in the ICU,” commented David Berg, MD, in the ESC press release. “This discordant advice has left many clinicians confused about what to do, particularly in COVID-19 patients at the border-zone of needing ICU-level care. The recommendation for ICU patients is largely based on a trial which found that full-dose anticoagulation, compared with the standard dose, did not decrease the number of days alive without organ support in critically ill patients with COVID-19.”

Dr. Berg, who is with Brigham and Women's Hospital, continued, “COVID-PACT shows that full-dose anticoagulation more effectively prevents the clotting complications of COVID-19, which may be a more appropriate focus for antithrombotic therapy as a preventive intervention and is the basis for anticoagulation recommendations in ICU patients without COVID-19.”