Efficacy and safety of therapeutic vs. prophylactic bemiparin in noncritically ill patients with COVID-19 pneumonia

Abstract

Thrombotic and thromboembolic phenomena are one of the leading complications and causes of poor outcomes in COVID-19 patients admitted to hospital [1]. In the pathophysiology of pulmonary and endothelial damage due to SARS-CoV-2 infection, an inflammatory and prothrombotic state with microvascular thrombosis has been described [2]. Therefore, early initiation of therapeutic low molecular weight heparin (LMWH) doses could be more effective than prophylactic doses not only in preventing thrombotic/thromboembolic complications (due to its anticoagulant effect), but also in improving overall outcomes (due to its anti-inflammatory properties) in patients admitted to hospital with non-severe COVID-19 pneumonia.We conducted the BEMICOVID-19 study, a single-blind, randomized (1:1 ratio), controlled trial (NCT04420299) evaluating the efficacy and safety of therapeutic (115 IU/Kg once daily) vs. prophylactic (3.500 IU once daily) subcutaneous bemiparin for a 10-day period (after this 10day phase, thromboprophylaxis management was left at investigators' choice) in patients requiring hospital admission due to non-severe COVID-19 pneumonia (defined as CURB65≤2 points without criteria for intensive care unit [ICU] admission nor mechanical ventilation requirement) with baseline D-dimer above the upper limit of normal reference range (> 500 ng/mL), at two University Hospitals (HM-Monteprincipe/HM-Puerta-Sur) in Madrid Metropolitan Area, from August-2020 to June-2021 (the trial was prematurely stopped based on slow recruitment rate due to vaccination campaign). The primary efficacy outcome was a composite of death, ICU admission, need of mechanical ventilation support, and venous (VTE)/arterial (ATE) thromboembolism within 28±2 days of enrollment. Safety outcomes were major bleeding and non-major clinically relevant bleeding. The study involved three mandatory visits (baseline/start of treatment, 10day/end of treatment, and 28-day follow-up), including computed tomography (CT) pulmonary angiography at inclusion and at day 10±1. A full list of participating centers, investigators, statistical-analysis, and eligibility-criteria are provided in Supplementary material.Seventy-six patients (mean [SD] age: 60.6 [11.5] years; men: 60 [76.9%]) were randomized to standard thromboprophylaxis (n = 38) and therapeutic dose bemiparin (n = 38). Baseline characteristics and COVID-19 therapy are shown in Table 1a. All patients completed the follow-up period. Table 1b shows the outcomes. The primary efficacy outcome (death, ICU admission, mechanical ventilation support and VTE/ATE) was registered in 7 (18.4%) patients treated with therapeuticdose of bemiparin and in 6 (15.8%) patients receiving prophylacticdose. The relative risk (RR) was 1.17 (95%CI:0.43-3.15), the odds ratio (OR) was 1.20 (95%CI:0.38-3.83), and the absolute risk difference was 2.6% (95%CI:− 14.3-19.6;p = 0.761). Neither major bleeding event nor serious adverse event (unrelated with COVID-19 evolution) were reported in any arm of treatment. Although reductions of D-dimer levels ...

Real-world evidence with a retrospective cohort of 15,968 COVID-19 hospitalized patients suggests 21 new effective treatments

“…The drugs associated to the highest survival, bemiparin (DB09258), logarithm of Hazard ratio (LHR)= -1.62, with a 95%, confidence interval (CI) of [-1.95,-1.31], and a False Discovery Rate (FDR) adjusted pvalue = < 10 − 11 and Enoxaparin (LHR= -1.17, 95% CI [-1.36,-0.98], FDR p-value = < 10 − 11 ), are antithrombotic used, as other heparins, to prevent thrombotic and thromboembolic complications in hospitalized patients. While for bemiparin only weak evidence of its protective effect has been found in the literature [ 12 ], a lower rate mortality in COVID-19 patients was described for enoxaparin when compared to other heparins [ 13 ], in agreement with the results found here. However, this protective effect is not shared by other anticoagulants, such as tinziparin (LHR= -0.34, 95% CI[-1.38, 0.69], FDR p-value = 1), despite its use in pulmonary embolism, or Fondaparinux (LHR=-0.33, 95% CI[-1.64, 0.97], FDR p-value = 1).…”

The optimal anticoagulation strategy for COVID-19, prophylactic or therapeutic?: a meta-analysis, trial sequential analysis, and meta-regression of more than 27,000 participants

“…Enoxaparin Heparin Enoxaparin Heparin Enoxaparin, 1 mg/kg sc bid or 1.5 mg/kg sc qd or based on renal function, or higher doses titrated to antifactor Xa range of 0.6-1 IU/mL bid and 1-2 IU/mL qd Heparin, titrated to an aPTT between 70 and 110 s Enoxaparin, 30 or 40 mg sc qd Heparin, 5000 U sc tid 29 Aljuhani et al [48] Cohort study Multicenter Critical 176 176 UFH Enoxaparin UFH Enoxaparin Enoxaparin, 1 mg/kg sc bid or 1.5 mg/kg sc qd Enoxaparin, 40 mg sc qd UFH, 5000 U sc tid 30 Yu et al [49] Cohort [51] Cohort study 33 Martinelli et al [52] Cohort study [55] Cohort study [57] Cohort study [62] Cohort study…”

Therapeutic versus prophylactic heparin for thromboprophylaxis in patients with COVID-19: weighing the costs and benefits. A rapid meta-analysis of randomized controlled trials

“…However, therapeutic LMWH was associated with a significant decrease in the odds for major thrombotic events by 45% (OR = 0.55, 95% CI: 0.42–0.71, I 2 = 0%), as shown in Figure 2 , and a significant two-fold increase in the odds for major bleeding events (OR = 2.12, 95% CI: 1.29–3.49, I 2 = 23%), as depicted in Figure 3 . Exclusion of the two trials performed in the outpatient setting [ 9 , 14 ] did not have a significant impact on any of the assessed outcomes. Inspection of the corresponding funnel plot demonstrated asymmetry, generally indicative of the presence of publication bias.…”

“…Searching in clinicaltrials.gov did not yield any additional RCT for potential inclusion in our quantitative synthesis. Therefore, we finally pooled data from 8 RCTs in a total of 4817 patients with COVID-19 randomized either to therapeutic or prophylactic LMWH [7][8][9][10][11][12][13][14].…”