Prophylactic anticoagulation in critical COVID-19: Is full-dose or standard-dose preferred?

A full-dose prophylactic anticoagulation strategy reduced the risk of thrombosis in critically ill patients with COVID-19 who required intensive care unit (ICU)-level care compared with a standard-dose strategy, according to results of the COVID-PACT trial.  

Participants in this multicentre (34 US sites), open-label trial were 382 patients (median age 61 years, 41 percent female, 68 percent with BMI ≥30 kg/m²) with COVID-19 warranting ICU-level care*. They were randomized 1:1 to receive full-dose or standard-dose prophylactic anticoagulation with either unfractionated heparin or low-molecular-weight heparin as per clinician discretion. A total of 292 patients who were not on antiplatelet therapy in each randomized group were further randomized 1:1 to receive either clopidogrel (loading dose of 300 mg on day 1 followed by 75 mg/day) or no antiplatelet therapy. The most common comorbidities in the population were hypertension and diabetes (59 and 32 percent, respectively).

At day 28 or discharge from hospital, whichever occurred first, the risk of the primary endpoint** was reduced by 44 percent among patients who were assigned to full-dose vs standard-dose prophylactic anticoagulation (9.9 percent vs 15.2 percent; hazard ratio [HR_{on treatment}], 0.56, 95 percent confidence interval [CI], 0.32–0.99; p=0.046). The stratified win ratio for full-dose vs standard-dose anticoagulation was 1.95 (p=0.028). [ESC 2022, Hot Line Session 10]

There was a trend toward a reduced risk of the key secondary endpoint, comprising ATE- or VTE-caused death, PE, clinically evident DVT, type 1 MI, ischaemic stroke, or SEE or ALI, among patients on full-dose vs standard-dose anticoagulation (7.3 percent vs 12.0 percent; HR_{on treatment}, 0.55, 95 percent CI, 0.28–1.08). All-cause mortality incidence was comparable between groups (18.8 percent vs 16.8 percent; HR_{on treatment}, 0.91, 95 percent CI, 0.56–1.48; p=0.70).

The primary safety endpoint comprising life-threatening or fatal bleeding was not significantly different between groups (2.1 percent vs 0.5 percent; HR, 3.86; p=0.19). The outcome was driven by life-threatening bleeding in four and one patients on full-dose and standard-dose anticoagulation, respectively, while no patients in either group experienced fatal bleeding. The incidence of GUSTO moderate (requiring transfusion without haemodynamic compromise) or severe (fatal, intracranial, or causing haemodynamic compromise) bleeding occurred in more full-dose than standard-dose anticoagulation recipients (moderate: 11 vs 0 events; severe: 4 vs 1 events; 7.9 percent vs 0.5 percent; HR, 12.30; p=0.002).

Clopidogrel vs no antiplatelet

The risk of clotting complications did not differ between patients assigned to receive clopidogrel or no antiplatelet therapy (HR, 0.90, 95 percent CI, 0.48–1.69; p=0.75), with no significant stratified win ratio benefit in favour of clopidogrel (1.04; p=0.90). There were two incidents of life-threatening bleeding each in the clopidogrel and no antiplatelet therapy groups and no incidents of fatal bleeding in either group. Thirty-one percent of patients discontinued clopidogrel treatment prematurely.

Which strategy to choose?

“COVID-19 treatment guidelines recommend full-dose anticoagulation for hospitalized patients outside the ICU and the standard dose for those in the ICU,” said study author Dr David Berg from the Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, US. “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,” he added.

“Weighing clotting and bleeding risk, full-dose anticoagulation should be considered to prevent blood clots in selected critically ill patients with COVID-19. These findings may be relevant when revisiting current consensus treatment guidelines for critically ill patients with COVID-19, including those managed with advanced, non-invasive respiratory support,” Berg concluded.