Enoxaparin for thromboprophylaxis in hospitalized COVID‐19 patients: The X‐COVID‐19 Randomized Trial
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Abstract
Background
It is uncertain whether higher doses of anticoagulants than recommended for thromboprophylaxis are necessary in COVID‐19 patients hospitalized in general wards
Methods
This is a multicentre, open‐label, randomized trial performed in 9 Italian centres, comparing 40 mg b.i.d. versus 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.
Results
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). The absence of concomitant DVT and imaging characteristics suggests that most pulmonary artery occlusions were actually caused by local thrombi rather than PE. Statistically nonsignificant differences in secondary and safety endpoints were observed, with two major bleeding events in each arm.
Conclusions
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.
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SciScore for 10.1101/2021.11.17.21266488: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: The study protocol was approved by AIFA, the Italian Medicines Agency, and by the ethics committee of Istituto Nazionale Malattie
Consent: All patients provided written informed consent.Sex as a biological variable not detected. Randomization Study Design: X-COVID 19 was an open-label, multicentre, prospective, controlled, randomized trial in patients admitted to medical wards with PCR-confirmed SARS-CoV-2 infection. Blinding Primary and secondary outcomes were adjudicated by a clinical events committee blinded to treatment assignment. Power Analysis not detected. Table 2: Resources
Software and Algorithms Sentences Resources The ASST Grande Ospedale Metropolitano Niguarda and the ASST Santi Paolo … SciScore for 10.1101/2021.11.17.21266488: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: The study protocol was approved by AIFA, the Italian Medicines Agency, and by the ethics committee of Istituto Nazionale Malattie
Consent: All patients provided written informed consent.Sex as a biological variable not detected. Randomization Study Design: X-COVID 19 was an open-label, multicentre, prospective, controlled, randomized trial in patients admitted to medical wards with PCR-confirmed SARS-CoV-2 infection. Blinding Primary and secondary outcomes were adjudicated by a clinical events committee blinded to treatment assignment. Power Analysis not detected. Table 2: Resources
Software and Algorithms Sentences Resources The ASST Grande Ospedale Metropolitano Niguarda and the ASST Santi Paolo and Carlo together with the operational staff of the Adivice Pharma Clinical Research Institute and the Center of Bioinformatics, Biostatistics and Bioimaging of School of Medicine and Surgery of the University of Milano Bicocca were responsible for data management, regulatory affairs and statistical analysis. Biostatisticssuggested: (BWH Biostatistics Center, RRID:SCR_009680)The STATA version 14 STATAsuggested: (Stata, RRID:SCR_012763)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Our trial has some limitations. It is underpowered for primary endpoint compared to the originally planned sample size. Randomisation during the COVID-19 pandemic has been really challenging in our country. Randomisation implies a clinical equipoise of the clinician participating in the study, which is defined as “the point where we are equally poised in our beliefs between the benefits and disadvantages of a certain treatment modality. … At this point we are agnostic or resting on the fulcrum of a preference”.29 Among 3550 provisionally eligible patients, clinicians excluded 3364, in many cases due to the lack of personal equipoise. Clinical and individual equipoise should always be integrated in the eligibility process to understand the generalizability of a trial; other examples have been reported in literature underlying how personal believes can significantly affect the conduct of a trial.30 Another limitation is that a minority of enrolled patients failed to undergo all the planned systematic CUS evaluations, thus some asymptomatic DVT events could have been missed. None of the non-critically ill patients with SARS-COV2 infection enrolled in our study displayed DVT within 30-day follow-up, independently of their assignment to treatment with 40 mg o.d. or 40 mg b.i.d. We think that, despite the small number of patients enrolled, our finding (together with those of recent RCTs) represents evidence that the incidence of DVT is reasonably low in these patients when they are...
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04366960 Completed Comparison of Two Doses of Enoxaparin for Thromboprophylaxis… Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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