D-dimer-driven versus standard prophylactic anticoagulation with fondaparinux in critically ill patients with COVID-19 and coagulopathy: an open-label, randomized controlled trial

Abstract

Abstract Background Anticoagulation with fondaparinux (FPX) has shown benefit to improve clinical outcomes in hospitalized patients with COVID-19. However, optimal thromboprophylaxis dosing in critically ill patients remains unknown. Purpose To evaluate the effects of D-dimer-driven (DDD) FPX compared with standard prophylactic-dose (SPD) FPX in critically ill patients with COVID-19 and associated coagulopathy. Methods This was a single-center, open-label, two-arms, parallel-group, randomized controlled trial conducted between April 1, 2021 and Feb 28, 2022. The eligible COVID-19 patients who were critically ill (defined as a presence of critical care-level organ support at enrollment) and presented with coagulopathy were randomly assigned (1:1 ratio) to receive pragmatically defined regimens of either DDD FPX or SPD FPX throughout hospitalization. The primary efficacy outcome was a composite of all-cause mortality (ACM), acute myocardial infarction (MI), confirmed arterial (ATE) or venous thromboembolisms (VTE), assessed up to 30 days. The secondary efficacy outcomes were 30-day ACM, composite thrombotic events, progression to invasive mechanical ventilation (IMV) or ARDS, and acute kidney injury (AKI). The safety outcomes included major bleeding and clinically relevant non-major bleeding (CRNMB). Outcomes were blindly adjudicated and analysed on a 30-day intention-to-treat basis. Results During allocated period, 270 (58%) of 465 patients were eligible and were equally assigned to DDD and SPD groups. The baseline characteristics were well-matched between groups (all p>0.05). At 30 days, the primary efficacy outcome was met in 49 of 135 patients (36.3%) with DDD FPX versus 47 of 135 patients (34.8%) with SPD FPX (hazard ratio [HR], 1.32; 95% CI, 0.89–1.98; p=0.17). DDD group compared with SPD group revealed no significant difference in 30-day ACM (22.9% vs 31.8%; HR, 0.73; p=0.17). At 30 days, DDD group demonstrated no significant reduction in thromboembolism, i.e. acute MI (14.1% vs 11.8%; HR, 1.53; p=0.21); ATE (3.0% vs 3.0%; HR, 1.27; p=0.74); and VTE (2.2% vs 4.4%; HR, 0.69; p=0.59) when compared with SPD group. Among those not on IMV at randomization, DDD group showed no significant reduction in the proportion of patients meeting the need for IMV (18.5% vs 32.6%; HR, 0.72; p=0.18) or progression to ARDS (17.8% vs 27.4%; HR, 0.81; p=0.43). Allocation to DDD FPX had no significant effect on the proportion of patients experiencing AKI within 30 days (17.8% vs 14.8%; HR, 1.36; p=0.39). There was no significant difference between DDD and SPD groups in terms of major bleeding (2.2% vs 0%; HR, 8.35; p=0.35) or CRNMB (3.0% vs 2.2%; HR, 1.70; p=0.48) at 30 days. Conclusions In critically ill patients with COVID-19 and coagulopathy, D-dimer-driven anticoagulation with fondaparinux did not significantly improve clinical outcomes at 30 days as compared to standard prophylactic-dose. The risk of bleeding was not significantly increased in this trial. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): Syarifah Ambami Rato Ebu Generał Hospital, Bangkalan, East Java, Indonesia