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, according to research presented at ESC Congress 2022.1 The study also found that the addition of clopidogrel did not provide further protection.

Patients with COVID-19 are at high risk of developing life-threatening blood clots, and this risk is particularly high in those requiring intensive care.2-4 Multiple clinical trials have assessed the benefit of anticoagulants and anti-platelets in patients with COVID-19;5-12 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, while 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.

The COVID-PACT trial evaluated whether a higher intensity of anticoagulation and/or the use of anti-platelet therapy prevents blood clots with an acceptable safety profile in patients with severe COVID-19 infection. COVID-PACT was a 2×2 factorial, randomized controlled trial in critically ill patients with COVID-19 conducted at 34 sites in the US. Patients requiring ICU-level care (invasive mechanical ventilation, non-invasive positive pressure ventilation, high-flow nasal cannula, or vasopressors) were randomized to either full-dose or standard-dose prophylactic anticoagulation. Use of unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) for either regimen was at the discretion of the managing clinicians. In patients without another indication for anti-platelet therapy, there was an additional randomization to either the anti-platelet clopidogrel or no anti-platelet therapy. Patients were assessed clinically and with lower extremity venous ultrasounds 10 to 14 days after randomization and followed until hospital discharge or for 28 days, whichever occurred first.

The primary efficacy outcome was the hierarchical composite of death due to 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 and 292 to an anti-platelet strategy). 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% confidence interval [CI] 1.08–3.55, p=0.028). Results were consistent in the time-to-event analysis (19 [9.9%] events on the full dose vs. 29 [15.2%] on the standard dose; HR 0.56, 95% CI 0.32–0.99, p=0.046).

The primary safety outcome of fatal or life-threatening bleeding occurred in four patients (2.1%) on full-dose anticoagulation and one patient (0.5%) on standard-dose anticoagulation (p=0.19); 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=0.70).

In the anti-platelet 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 anti-platelet therapy.

Dr. David Berg of Brigham and Women’s Hospital, Harvard Medical School, US said: “COVID-19 treatment guidelines recommend full-dose anticoagulation for hospitalized patients outside the ICU and the standard dose for those in the ICU.13,14 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. 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.”

References / Notes

1COVID-PACT will be discussed during Hot Line Session 10 on Monday 29 August at 16:30 to 17:30 CEST in the Barcelona auditorium.

2Connors JM, Levy JH. Thromboinflammation and the hypercoagulability of COVID-19. J Thromb Haemost. 2020;18:1559–1561.

3Piazza G, Campia U, Hurwitz S, et al. Registry of arterial and venous thromboembolic complications in patients with COVID-19. J Am Coll Cardiol. 2020;76:2060–2072.

4Bikdeli B, Madhavan MV, Jimenez D, et al. COVID-19 and thrombotic or thromboembolic disease: Implications for prevention, antithrombotic therapy, and follow-up: JACC state-of-the-art review. J Am Coll Cardiol. 2020;75:2950–2973.

5Berger JS, Kornblith LZ, Gong MN, et al. Effect of P2Y12 inhibitors on survival free of organ support among non-critically ill hospitalizedpPatients with COVID-19: A randomized clinical trial. JAMA. 2022;327:227–236.

6REMAP-CAP Writing Committee for the REMAP-CAP Investigators, Bradbury CA, Lawler PR, et al. Effect of antiplatelet therapy on survival and organ support-free days in critically ill patients with COVID-19: A randomized clinical trial. JAMA. 2022;327:1247–1259.

7RECOVERY Collaborative Group. Aspirin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2022;399:143–151.

8ATTACC Investigators; ACTIV-4a Investigators; REMAP-CAP Investigators, et al. Therapeutic anticoagulation with heparin in noncritically ill patients with Covid-19. N Engl J Med. 2021;385:790–802.

9REMAP-CAP Investigators; ACTIV-4a Investigators; ATTACC Investigators, et al. Therapeutic anticoagulation with heparin in critically ill patients with Covid-19. N Engl J Med. 2021;385:777–789.

10Lemos ACB, do Espirito Santo DA, Salvetti MC, et al. Therapeutic versus prophylactic anticoagulation for severe COVID-19: A randomized phase II clinical trial (HESACOVID). Thromb Res. 2020;196:359–366.

11Lopes RD, de Barros E Silva PGM, Furtado RHM, et al. Therapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID-19 and elevated D-dimer concentration (ACTION): an open-label, multicentre, randomised, controlled trial. Lancet. 2021;397:2253–2263.

12Spyropoulos AC, Goldin M, Giannis D, et al. Efficacy and safety of therapeutic-dose heparin vs standard prophylactic or intermediate-dose heparins for thromboprophylaxis in high-risk hospitalized patients with COVID-19: The HEP-COVID randomized clinical trial. JAMA Intern Med. 2021;181:1612–1620.

13Coronavirus disease 2019 (COVID-19) treatment guidelines. National Institutes of Health.

14ASH guidelines on use of anticoagulation in patients with COVID-19. American Society of Hematology.