Effect of Intermediate-Dose vs Standard-Dose Prophylactic Anticoagulation on Thrombotic Events, Extracorporeal Membrane Oxygenation Treatment, or Mortality Among Patients With COVID-19 Admitted to the Intensive Care Unit

Abstract

IMPORTANCE Thrombotic events are commonly reported in critically ill patients with COVID-19. Limited data exist to guide the intensity of antithrombotic prophylaxis.OBJECTIVE To evaluate the effects of intermediate-dose vs standard-dose prophylactic anticoagulation among patients with COVID-19 admitted to the intensive care unit (ICU). DESIGN, SETTING, AND PARTICIPANTSMulticenter randomized trial with a 2 × 2 factorial design performed in 10 academic centers in Iran comparing intermediate-dose vs standard-dose prophylactic anticoagulation (first hypothesis) and statin therapy vs matching placebo (second hypothesis; not reported in this article) among adult patients admitted to the ICU with COVID-19. Patients were recruited between July 29, 2020, and November 19, 2020. The final follow-up date for the 30-day primary outcome was December 19, 2020.INTERVENTIONS Intermediate-dose (enoxaparin, 1 mg/kg daily) (n = 276) vs standard prophylactic anticoagulation (enoxaparin, 40 mg daily) (n = 286), with modification according to body weight and creatinine clearance. The assigned treatments were planned to be continued until completion of 30-day follow-up. MAIN OUTCOMES AND MEASURESThe primary efficacy outcome was a composite of venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days, assessed in randomized patients who met the eligibility criteria and received at least 1 dose of the assigned treatment. Prespecified safety outcomes included major bleeding according to the Bleeding Academic Research Consortium (type 3 or 5 definition), powered for noninferiority (a noninferiority margin of 1.8 based on odds ratio), and severe thrombocytopenia (platelet count <20 ×10 3 /μL). All outcomes were blindly adjudicated. RESULTS Among 600 randomized patients, 562 (93.7%) were included in the primary analysis (median [interquartile range] age, 62 [50-71] years; 237 [42.2%] women). The primary efficacy outcome occurred in 126 patients (45.7%) in the intermediate-dose group and 126 patients (44.1%) in the standard-dose prophylaxis group (absolute risk difference, 1.5% [95% CI, −6.6% to 9.8%]; odds ratio, 1.06 [95% CI, 0.76-1.48]; P = .70). Major bleeding occurred in 7 patients (2.5%) in the intermediate-dose group and 4 patients (1.4%) in the standard-dose prophylaxis group (risk difference, 1.1% [1-sided 97.5% CI, −ϱ to 3.4%]; odds ratio, 1.83 [1-sided 97.5% CI, 0.00-5.93]), not meeting the noninferiority criteria (P for noninferiority >.99). Severe thrombocytopenia occurred only in patients assigned to the intermediate-dose group (6 vs 0 patients; risk difference, 2.2% [95% CI, 0.4%-3.8%]; P = .01).CONCLUSIONS AND RELEVANCE Among patients admitted to the ICU with COVID-19, intermediate-dose prophylactic anticoagulation, compared with standard-dose prophylactic anticoagulation, did not result in a significant difference in the primary outcome of a composite of adjudicated venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days...

COVID-19-associated coagulopathy and antithrombotic agents—lessons after 1 year

“…Research on therapeutic anticoagulation in critically ill patients with COVID-19 is still ongoing (appendix p 1; preprint). 42 Data from the INSPIRATION trial, 47 Hence, based on results from the INSPIRATION trial, there is no rationale for the current widely used intermediate dose of low-molecular-weight heparin as thrombosis prophylaxis in critically ill patients with COVID-19. Notably, this study was designed by an international committee and was done in ten centres in Iran, which might affect the generalisability to other countries and health-care systems.…”

Acute splanchnic vein thrombosis in patients with COVID-19: A systematic review

“…Previous research suggested that the incidence of thrombotic complications in ICU patients with COVID-19 infections is remarkably high despite anticoagulant therapy at standard prophylactic dose [49] . Notwithstanding this, recent evidence on patients admitted to the ICU with COVID-19 showed that intermediate-dose prophylactic anticoagulation did not result in a significant difference in the primary outcome of a composite of adjudicated venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days [50] . This might also hold true as for SVT.…”

Anti-viral treatment for SARS-CoV-2 infection: A race against time amidst the ongoing pandemic

“…Venous thromboembolism (VTE) was frequently observed in acutely ill patients with COVID-19 during the early stages of the pandemic, approaching a proportion of one-third of patients in the ICU, even when prophylactic anticoagulation was used [ 8 ]. In a recent study published in JAMA, Sadeghipour et al have reported the results of a multicenter RCT of intermediate-dose versus standard-dose heparin-based thromboprophylaxis in critically ill patients with COVID-19 [ 20 ]. Among 562 inpatients enrolled, no significant difference in the primary efficacy outcome was ascertained [a composite of venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation (ECMO)], or mortality within 30 days of enrollment) or in the main safety outcomes, such as major bleeding and severe thrombocytopenia between the two groups.…”

“…However, there are several issues worth mentioning mainly regarding the low thrombotic event rate reported in both study groups, raising the possibility of a considerable number of potentially “missed” cases. VTE rates reported in clinical studies regarding COVID-19 have substantially varied, with higher rates noted in early investigations and in studies that used VTE screening and lower rates reported in more recent investigations and in studies that did not screen for VTE [ 20 ]. Sadeghipour et al did not use universal screening for VTE.…”