Optimal thromboprophylaxis strategies in non-critically ill patients with COVID-19 pneumonia. The PROTHROMCOVID Randomized Controlled Trial

Abstract

Background : Hospitalized patients with COVID-19 are at increased risk for thrombosis, acute respiratory distress syndrome and death. The optimal dosage of thromboprophylaxis is unknown. Objective: To evaluate the efficacy and safety of tinzaparin in prophylactic, intermediate, and therapeutic doses in non-critical patients admitted for COVID-19 pneumonia. Design, setting, and participants : Randomized controlled, multicenter trial (PROTHROMCOVID) enrolling non-critical, hospitalized adult patients with COVID-19 pneumonia. Interventions: Patients were randomized to prophylactic (4500 IU), intermediate (100 IU/kg), or therapeutic (175 IU/kg) doses of tinzaparin during hospitalization, followed by 7 days of prophylactic tinzaparin at discharge. Measurements: 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. Results : Of the 311 subjects randomized, 300 were included in the 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. Conclusions: In non-critically ill COVID-19 patients, intermediate or full-dose tinzaparin compared to standard prophylactic doses did not appear to increase benefit regarding the likelihood of thrombotic event, non-invasive ventilation or high-flow oxygen, or death. Trial Registration ClinicalTrials.gov Identifier (NCT04730856). Funding: This independent research initiative was supported by Leo-Pharma; Tinzaparin was provided by Leo Pharma.

Higher Dose Anticoagulation Cannot Prevent Disease Progression in COVID-19 Patients: A Systematic Review and Meta-Analysis

“…Our systematic search resulted in 17,114 eligible studies (8749 from the search on 18 October 2021 and 8365 from 23 May 2022). After the selection process, 14 articles were included in the meta-analysis [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 50 , 51 , 52 , 53 , 54 , 55 , 56 ] and 15 [ 57 ] articles in the systematic review. Figure 1 shows the PRISMA 2020 Flow diagram of the updated search, and the one for the initial search can be found in Supplementary material (Figure S1) [ 58 ].…”

“…The included open-label studies were conducted between April 2020 and September 2021 in 15 countries [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 50 , 51 , 52 , 53 , 54 , 55 , 56 ]. In total, they enrolled 6253 adult patients with an average age above 50 years in the cohorts.…”

“…In total, they enrolled 6253 adult patients with an average age above 50 years in the cohorts. Seven studies included patients with severe disease [ 50 , 51 , 52 , 53 , 54 , 55 , 56 ], seven with moderate disease at presentation, and one with mild disease [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 57 ]. The eligibility criteria of trials included higher than the upper limit of normal D-dimer levels or DIC score ≥3 in ten of the included studies [ 19 , 21 , 22 , 24 , 25 , 50 , 51 , 52 , 53 , 54 , 56 ].…”

“…The multiplatform trials by REMAP-cap, ATTAC, and ACTIV-4b investigators found that therapeutic dose thromboprophylaxis was associated with an increased number of organ-support-free days in moderately ill patients, which was further confirmed by the results of the RAPID trial [ 20 , 21 ]. Other trials with similar patient populations failed to show any significant advantage of the higher dose thromboprophylaxis in COVID-19 patients [ 22 , 23 , 24 , 25 ].…”

Thromboprophylaxis and anticoagulation for inpatients with COVID-19 in 2022 and beyond

“…A recently updated meta-analysis on prophylactic AC trials in noncritically ill patients with COVID-19 found that dose escalation was not associated with a reduction in all-cause death but with an increase in major bleeding and a reduction in VTE [ 10 ]. Since update of the meta-analysis, the Swiss COVID-HEP trial has been published, the PROTHROMCOVID trial is in pre-print yet to be peer-reviewed, the ASCOT trial has closed the anticoagulation domain, and all three trials indicate a lack of benefit from higher dose AC [ [11] , [12] , [13] ].…”