Efficacy and Safety of Tinzaparin in Prophylactic, Intermediate and Therapeutic Doses in Non-Critically Ill Patients Hospitalized with COVID-19: The PROTHROMCOVID Randomized Controlled Trial
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Abstract
Hospitalized patients with COVID-19 are at increased risk of thrombosis, acute respiratory distress syndrome and death. The optimal dosage of thromboprophylaxis is unknown. The aim was to evaluate the efficacy and safety of tinzaparin in prophylactic, intermediate, and therapeutic doses in non-critical patients admitted for COVID-19 pneumonia. PROTHROMCOVID is a randomized, unblinded, controlled, multicenter trial enrolling non-critical, hospitalized adult patients with COVID-19 pneumonia. Patients were randomized to prophylactic (4500 IU), intermediate (100 IU/kg), or therapeutic (175 IU/kg) groups. All tinzaparin doses were administered once daily during hospitalization, followed by 7 days of prophylactic tinzaparin at discharge. The primary efficacy outcome was a composite endpoint of symptomatic systemic thrombotic events, need for invasive or non-invasive mechanical ventilation, or death within 30 days. The main safety outcome was major bleeding at 30 days. Of the 311 subjects randomized, 300 were included in the prespecified interim analysis (mean [SD] age, 56.7 [14.6] years; males, 182 [60.7%]). The composite endpoint at 30 days from randomization occurred in 58 patients (19.3%) of the total population; 19 (17.1 %) in the prophylactic group, 20 (22.1%) in the intermediate group, and 19 (18.5%) in the therapeutic dose group (p = 0.72). No major bleeding event was reported; non-major bleeding was observed in 3.7% of patients, with no intergroup differences. Due to these results and the futility analysis, the trial was stopped. In non-critically ill COVID-19 patients, intermediate or full-dose tinzaparin compared to standard prophylactic doses did not appear to affect the risk of thrombotic event, non-invasive ventilation, or mechanical ventilation or death. Trial RegistrationClinicalTrials.gov Identifier (NCT04730856). Edura-CT registration number: 2020-004279-42.
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SciScore for 10.1101/2022.05.03.22274594: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: The protocol was approved by the Ethical Committees for Drug Research at the Gregorio Marañón General University Hospital and, subsequently, by the local Drug Research Ethics Committees (18) and the Spanish Agency for Medicines and Health Products.
Consent: All patients included signed written informed consent forms.Sex as a biological variable not detected. Randomization Study Design: The PROTHROMCOVID study (NCT04730856) is a randomized, open-label, multicenter, controlled study in hospitalized patients with COVID-19 pneumonia, conducted in conventional hospital wards in 18 academic hospitals in Spain. Blinding Neither participants nor investigators were blinded as to group assignment. Powe… SciScore for 10.1101/2022.05.03.22274594: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: The protocol was approved by the Ethical Committees for Drug Research at the Gregorio Marañón General University Hospital and, subsequently, by the local Drug Research Ethics Committees (18) and the Spanish Agency for Medicines and Health Products.
Consent: All patients included signed written informed consent forms.Sex as a biological variable not detected. Randomization Study Design: The PROTHROMCOVID study (NCT04730856) is a randomized, open-label, multicenter, controlled study in hospitalized patients with COVID-19 pneumonia, conducted in conventional hospital wards in 18 academic hospitals in Spain. Blinding Neither participants nor investigators were blinded as to group assignment. Power Analysis The sample size was calculated from a proportion of a 13% reduction in thrombosis in the control group and a difference of 5% compared to treatment groups. Table 2: Resources
Software and Algorithms Sentences Resources Statistical analyses were performed using the statistical package SAS, 9.4 (Copyright © 2016 by SAS Institute Inc., Cary, NC, USA). SAS Institutesuggested: (Statistical Analysis System, RRID:SCR_008567)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 study has certain limitations; for instance, neither investigators nor patients were blinded. The main weakness of our results, however, is not having reached the estimated sample size of 600 patients, given that the researchers chose to interrupt the study on September 2021 because the results of the interim analysis. It revealed a very low absolute number of events in each arm and the futility analysis showed that it was unlikely that significant differences could have been reached with the complete sample. These results should not be extrapolated to other more severe hospitalized patients with COVID-19. The strengths of our study include the low number of withdrawals of informed consent by patients, the very early use of tinzaparin in all three arms of the study, which may have influenced the favorable efficacy and safety outcomes and the fact that the three strategies of anticoagulation have been tested with the same LMWH. Similarly, this was a multicenter study conducted in academic and general care centers. Furthermore, the study was carried out during a phase of the pandemic were the incidence of thrombosis and mortality were lower than before; thus, the findings of our study might be more applicable to future waves of the pandemic, which are expected to be milder due to generalized immunization and better treatment options. (24). In conclusion, in non-critically ill COVID-19 patients, intermediate or full-dose tinzaparin does not appear to offer any benefit over s...
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04730856 Completed Standard vs High Prophylactic Doses or Anticoagulation in Pa… 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.
- No funding statement was detected.
- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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