scholarly journals 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

2021 ◽  
Vol 5 (2) ◽  
pp. 103-108
Author(s):  
Gilson Soares Feitosa-Filho ◽  
Gabriella S. Sodré ◽  
Juliane Penalva C. Serra ◽  
Rhanniel Theodorus-Villar ◽  
Tatiana Otero Mendelez ◽  
...  
Keyword(s):  
Controlled Trial ◽  
Primary Efficacy ◽  
Therapeutic Group ◽  
Open Label ◽  
Safety Outcome ◽  
Therapeutic Anticoagulation ◽  
Efficacy Outcome ◽  
Randomised Controlled ◽  
Prophylactic Anticoagulation ◽  
D Dimer

Background. COVID-19 is associated with a prothrombotic state leading to adverse clinical outcomes. Whether therapeutic anticoagulation improves outcomes in patients hospitalised with COVID-19 is unknown. We aimed to compare the efficacy and safety of therapeutic versus prophylactic anticoagulation in this population. Methods. We did a pragmatic, open-label (with blinded adjudication), multicentre, randomised, controlled trial, at 31 sites in Brazil. Patients (aged ≥18 years) hospitalised with COVID-19 and elevated D-dimer concentration, and who had COVID-19 symptoms for up to 14 days before randomisation, were randomly assigned (1:1) to receive either therapeutic or prophylactic anticoagulation. Therapeutic anticoagulation was in-hospital oral rivaroxaban (20 mg or 15 mg daily) for stable patients, or initial subcutaneous enoxaparin (1 mg/kg twice per day) or intravenous unfractionated heparin (to achieve a 0·3–0·7 IU/mL anti-Xa concentration) for clinically unstable patients, followed by rivaroxaban to day 30. Prophylactic anticoagulation was standard in-hospital enoxaparin or unfractionated heparin. The primary efficacy outcome was a hierarchical analysis of time to death, duration of hospitalisation, or duration of supplemental oxygen to day 30, analysed with the win ratio method (a ratio >1 reflects a better outcome in the therapeutic anticoagulation group) in the intention-to-treat population. The primary safety outcome was major or clinically relevant non-major bleeding through 30 days. This study is registered with ClinicalTrials.gov (NCT04394377) and is completed. Findings. From June 24, 2020, to Feb 26, 2021, 3331 patients were screened and 615 were randomly allocated (311 [50%] to the therapeutic anticoagulation group and 304 [50%] to the prophylactic anticoagulation group). 576 (94%) were clinically stable and 39 (6%) clinically unstable. One patient, in the therapeutic group, was lost to follow-up because of withdrawal of consent and was not included in the primary analysis. The primary efficacy outcome was not different between patients assigned therapeutic or prophylactic anticoagulation, with 28.899 (34.8%) wins in the therapeutic group and 34.288 (41.3%) in the prophylactic group (win ratio 0.86 [95% CI 0.59–1.22], p=0·40). Consistent results were seen in clinically stable and clinically unstable patients. The primary safety outcome of major or clinically relevant non-major bleeding occurred in 26 (8%) patients assigned therapeutic anticoagulation and seven (2%) assigned prophylactic anticoagulation (relative risk 3.64 [95% CI 1.61–8.27], p=0.0010). Allergic reaction to the study medication occurred in two (1%) patients in the therapeutic anticoagulation group and three (1%) in the prophylactic anticoagulation group. Interpretation. In patients hospitalised with COVID-19 and elevated D-dimer concentration, in-hospital therapeutic anticoagulation with rivaroxaban or enoxaparin followed by rivaroxaban to day 30 did not improve clinical outcomes and increased bleeding compared with prophylactic anticoagulation. Therefore, use of therapeutic-dose rivaroxaban, and other direct oral anticoagulants, should be avoided in these patients in the absence of an evidence-based indication for oral anticoagulation.

scholarly journals Therapeutic vs. prophylactic bemiparin in hospitalized patients with non-severe COVID-19 (BEMICOP): an open-label, multicenter, randomized trial

2021 ◽  
Author(s):  
María Marcos ◽  
Francisco Carmona-Torre ◽  
Rosa Vidal Laso ◽  
PEDRO RUIZ-ARTACHO ◽  
David Filella ◽  
...  
Keyword(s):  
Major Bleeding ◽  
Therapeutic Dose ◽  
Hospitalized Patients ◽  
Primary Efficacy ◽  
Open Label ◽  
Primary Efficacy Outcome ◽  
Prophylactic Dose ◽  
Efficacy Outcome ◽  
Multicenter Randomized Controlled Trial ◽  
D Dimer

Thrombophylaxis with low molecular weight heparin (LMWH) in hospitalized patients with COVID-19 is mandatory, unless contraindicated. Given the links between inflammation and thrombosis, the use of higher doses of anticoagulants could improve outcomes. We conducted an open-label, multicenter, randomized, controlled trial in adult patients hospitalized with non-severe COVID-19 pneumonia and elevated D-dimer. Patients were randomized to therapeutic-dose bemiparin (115 IU/Kg daily) vs. standard prophylaxis (bemiparin 3,500 IU daily), for 10 days. The primary efficacy outcome was a composite of death, intensive care unit admission, need of mechanical ventilation support, development of moderate/severe acute respiratory distress and venous or arterial thrombosis within 10 days of enrollment. The primary safety outcome was major bleeding (ISTH criteria). A prespecified interim analysis was performed when 40% of the planned study population was reached. From October 2020 to May 2021, 70 patients were randomized at 5 sites and 65 were included in the primary analysis; 32 patients allocated to therapeutic-dose and 33 to standard prophylactic-dose. The primary efficacy outcome occurred in 7 patients (21.9%) in the therapeutic-dose group and 6 patients (18.2%) in the prophylactic-dose (absolute risk difference 3.6% [95% CI, -16%- 24%]; odds ratio 1.26 [95% CI, 0.37-4.26]; p=0.95). Discharge in the first 10 days was possible in 66% and 79% of patients, respectively. No major bleeding event was registered. Therefore, in patients with COVID-19 hospitalized with non-severe pneumonia but elevated D-dimer, the use of a short course of therapeutic-dose bemiparin did not improve clinical outcomes compared to standard prophylactic doses.

Low-Dose Heparin in Critically Ill Patients Undergoing Extracorporeal Membrane Oxygenation - the Help-ECMO Pilot Randomised Controlled Trial

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3822-3822 ◽  
Author(s):  
Zoe McQuilten ◽  
Cecile Aubron ◽  
Michael Bailey ◽  
Jasmin Board ◽  
Heidi Buhr ◽  
...  
Keyword(s):  
Low Dose ◽  
Controlled Trial ◽  
Therapeutic Group ◽  
Heparin Dose ◽  
Bleeding Events ◽  
Dose Heparin ◽  
Therapeutic Anticoagulation ◽  
Significant Difference ◽  
Randomised Controlled ◽  
Low Dose Heparin

Abstract Extra corporeal membrane oxygenation (ECMO) is a rescue therapy for reversible cardiac and/or respiratory failure. Despite improvement in management of patients undergoing ECMO, mortality remains high. Due to thrombosis risk, which includes arterial and venous thrombosis as well as in the extracorporeal circuit and components, variable intensity systemic anticoagulation with unfractionated heparin is routinely used. However, bleeding is one of the most frequent complications, can be severe and is independently associated with worse outcomes. Optimal anticoagulation to prevent thrombosis whilst minimising bleeding in adults on ECMO remains unknown. Before conducting a large randomised controlled trial to determine whether lower anticoagulation intensity is safe and effective compared with therapeutic anticoagulation, we aimed to determine the feasibility of randomising ECMO patients to these anticoagulation protocols. Methods: The HELP-ECMO pilot study (ACTRN12613001324707) is a randomised, controlled, unblinded trial at two Australian intensive care units (ICUs). Inclusion criteria were ICU patients who required ECMO (venous-venous [VV] or venous-arterial [VA]). Patients who did not meet any exclusion criteria were randomised to receive either therapeutic anticoagulation with heparin (target activated partial thromboplastin time [aPTT] between 50 and 70 seconds) or low dose heparin (12000 units/24 hours aiming for aPTT <45 seconds). Paired aPTT and anti-Xa assays were taken according to protocol, and at a minimum once a day. The primary endpoints for feasibility were difference in mean heparin dose, aPTT and anti-Xa levels between both study groups. Secondary endpoints included incidence of thromboembolic events, ECMO circuit thrombosis and bleeding events. All primary outcomes were log-transformed prior to analysis and reported as geometric means (95%CI) with overall differences determined using Repeat measures ANOVA. Results: Between May 2014 and March 2016, 31 patients who underwent ECMO (9 (29%) VA and 22 (71%) VV) were enrolled; 16 were randomised to low dose and 15 to therapeutic dose heparin. The groups were similar in age (mean 41 years [SD 16.8] vs 43 [SD 17.6] p=0.75), gender (68% vs 80% male, p=0.47), type of ECMO (31% vs 27% VA, p=0.78) and Acute Physiology and Chronic Health Evaluation III illness severity score (mean 65.4 [SD 23.5] vs 61.8 [SD 30.1], p=0.72) and sepsis-related organ failure assessment score (mean 10 [SD 3.6] vs 10 [SD 3.3], p=1.0). The mean duration of ECMO support was 9.33 days (SD 5.97) in the low dose and 9.79 days (SD 4.77) in the therapeutic dose group (p=0.82). For the primary outcomes, there was a significant difference in the daily mean aPTT (48.1 [95% CI 43.5-53.3] vs 56.2 [95% CI 50.7-62.3], p=0.03), daily mean anti-Xa (0.11 [95% CI 0.07-0.18] vs 0.30 [IQR 0.19-0.46], p=0.003) and daily mean heparin dose (11784 units [95% CI 8693-15972] vs 22050 [IQR 16262-29899], p=0.004) in the low dose compared to therapeutic group. There was no difference in thrombotic complications with regard to DVT (2 [12.5%] vs 3 [20%], p=0.57), PE (1 [6.3%] vs 0 [0%], p=0.33), stroke (no events), intracardiac thrombus (1 [6.3%] vs 2 [13.3%], p=0.51), acute pump (1 [6.3%] vs 1[6.7%], p=0.96) and distal perfusion cannula thrombosis (2 [12.5%] vs 0 [0%], p=0.16) in low dose compared with therapeutic group, respectively. With regard to bleeding, there was no difference in intracranial haemorrhage (ICH) (0 [0%] vs 1 [6.7%], p=0.29), retroperitoneal bleeding (1 [6.3%] vs 1 [6.7%], p=0.96), gastrointestinal bleeding (0 [0%] vs 2 [13.3%] , p=0.13), or haemoptysis (1 [6.5%] vs 1 [6.7%], p=0.96) in low dose compared with therapeutic group, respectively. Conclusion: In this pilot trial, administration of a low dose heparin protocol was feasible, and resulted in a significant difference in mean heparin dose administered and daily aPTT and anti-Xa levels between groups. Low dose heparin was not associated with an increase in thrombotic events nor a decrease in bleeding events; however the study was not powered for these outcomes. Our findings support the feasibility of a larger phase III study to evaluate the safety and efficacy of low-dose anticoagulation compared with therapeutic heparin with regard to thrombotic and bleeding events in patients receiving ECMO. Disclosures No relevant conflicts of interest to declare.

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