Enoxaparin for thromboprophylaxis in hospitalized COVID-19 patients: comparison of 40 mg o.d.vs40 mg b.i.d. The X-COVID19 Randomized Clinical Trial

Abstract

SummaryIt is uncertain whether higher doses of anticoagulants than recommended for thromboprophylaxis are necessary in COVID-19 patients hospitalized in general wards. This is a multicentre, open-label, randomized trial performed in 9 Italian centres, comparing 40 mg b.i.d. vs 40 mg o.d. enoxaparin in COVID-19 patients, between April 30, 2020 and April 25, 2021. Primary efficacy outcome was in-hospital incidence of venous thromboembolism (VTE): asymptomatic or symptomatic proximal deep vein thrombosis (DVT) diagnosed by serial compression ultrasonography (CUS), and/or symptomatic pulmonary embolism (PE) diagnosed by computed tomography angiography (CTA). Secondary endpoints included each individual component of the primary efficacy outcome and a composite of death, VTE, mechanical ventilation, stroke, myocardial infarction, admission to ICU. Safety outcomes included major bleeding. The study was interrupted prematurely due to slow recruitment. We included 183 (96%) of the 189 enrolled patients in the primary analysis (91 in b.i.d., 92 in o.d.). Primary efficacy outcome occurred in 6 patients (6·5%, 0 DVT, 6 PE) in the o.d. group and 0 in the b.id. group (ARR 6·5, 95% CI, 1·5-11·6). Absence of concomitant DVT and imaging characteristics suggest that most pulmonary artery occlusions were actually caused by local thrombi rather than PE. Statistically non-significant differences in secondary and safety endpoints were observed, with two major bleeding events in each arm. In conclusion, no DVT developed in COVID-19 patients hospitalized in general wards, independently of enoxaparin dosing used for thromboprophylaxis. Pulmonary artery occlusions developed only in the o.d. group. Our trial is underpowered and with few events.REGISTRATIONClinicalTrials.gov Identifier: NCT04366960Ethics Commettee approvation number75/2020

Anticoagulant Treatment Regimens in Patients With Covid‐19: A Meta‐Analysis

“…Seventh, we included one study in our analysis that did not yet undergo the peer‐review process. 30 However, sensitivity analyses confirmed that this trial had no significant impact on our main findings.…”

“…Ten studies with a total of 5,753 patients with COVID‐19 were included in the final analysis. 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 More information on the literature search is provided in the flow diagram ( Figure S2 ). Table 1 summarizes the study design of the 10 included trials (further information in Table S3 and S4 ).…”

“…One trial (XCOVID‐19) was not peer‐reviewed at the time of the literature search and was retrieved from the preprint server medRxiv. 30 Of note, the ACTION trial used rivaroxaban instead of an LMWH as the preferred anticoagulant agent. Dual antiplatelet therapy was an exclusion criterion in four trials (ATTACC, RAPID, HEP‐COVID, and REMAP‐CAP trials).…”

Comparison of Preprint Postings of Randomized Clinical Trials on COVID-19 and Corresponding Published Journal Articles

“…After abstract screening and full-text reading, 152 RCTs were included in the analysis. All 152 RCTs were posted on the medRxiv server …”

Updated meta-analysis of randomized controlled trials on the safety and efficacy of different prophylactic anticoagulation dosing regimens in non-critically ill hospitalized patients with COVID-19

“…Our updated analyses included a total of 3808 patients, 3306 patients from the previous report; 253 from HEP-COVID 4 using low-molecular-weight heparin or unfractionated heparin; 66 from the BEMICOP study 5 using bemiparin; and 183 from X-COVID 6 using enoxaparin. Among non-critically ill hospitalized patients, the incidence of all-cause death was 8.0% (157/1962) in the escalated-dose and 8.7% (160/1838) in the standard-dose prophylactic anticoagulation group.…”