Dosing of thromboprophylaxis and mortality in critically ill COVID-19 patients

Abstract

Background

A substantial proportion of critically ill COVID-19 patients develop thromboembolic complications, but it is unclear whether higher doses of thromboprophylaxis are associated with lower mortality rates. The purpose of the study was to evaluate the association between initial dosing strategy of thromboprophylaxis in critically ill COVID-19 patients and the risk of death, thromboembolism, and bleeding.

Method

In this retrospective study, all critically ill COVID-19 patients admitted to two intensive care units in March and April 2020 were eligible. Patients were categorized into three groups according to initial daily dose of thromboprophylaxis: low (2500–4500 IU tinzaparin or 2500–5000 IU dalteparin), medium (> 4500 IU but < 175 IU/kilogram, kg, of body weight tinzaparin or > 5000 IU but < 200 IU/kg of body weight dalteparin), and high dose (≥ 175 IU/kg of body weight tinzaparin or ≥ 200 IU/kg of body weight dalteparin). Thromboprophylaxis dosage was based on local standardized recommendations, not on degree of critical illness or risk of thrombosis. Cox proportional hazards regression was used to estimate hazard ratios with corresponding 95% confidence intervals of death within 28 days from ICU admission. Multivariable models were adjusted for sex, age, body mass index, Simplified Acute Physiology Score III, invasive respiratory support, and initial dosing strategy of thromboprophylaxis.

Results

A total of 152 patients were included: 67 received low-, 48 medium-, and 37 high-dose thromboprophylaxis. Baseline characteristics did not differ between groups. For patients who received high-dose prophylaxis, mortality was lower (13.5%) compared to those who received medium dose (25.0%) or low dose (38.8%), p = 0.02. The hazard ratio of death was 0.33 (95% confidence intervals 0.13–0.87) among those who received high dose, and 0.88 (95% confidence intervals 0.43–1.83) among those who received medium dose, as compared to those who received low-dose thromboprophylaxis. There were fewer thromboembolic events in the high (2.7%) vs medium (18.8%) and low-dose thromboprophylaxis (17.9%) groups, p = 0.04.

Conclusions

Among critically ill COVID-19 patients with respiratory failure, high-dose thromboprophylaxis was associated with a lower risk of death and a lower cumulative incidence of thromboembolic events compared with lower doses.

Trial registration

Clinicaltrials.gov NCT04412304 June 2, 2020, retrospectively registered.

SciScore for 10.1101/2020.09.17.20195867: (What is this?)

Please note, not all rigor criteria are appropriate for all manuscripts.

Table 1: Rigor

Institutional Review Board Statement	not detected.
Randomization	not detected.
Blinding	not detected.
Power Analysis	not detected.
Sex as a biological variable	not detected.

Table 2: Resources

No key resources detected.

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:

Strengths and limitations: The present study lacks the rigor of a prospective randomized design. The study groups thus reflect the progression from low to high dose thromboprophylaxis based on modifications of local clinical guidelines over time. As the study is observational, other factors might have affected outcome. During the study period the ventilation strategy was changed from a classical acute respiratory distress syndrome strategy with low tidal volumes, fluid restriction, and heavy sedation to a more liberal strategy allowing higher tidal volumes, more fluids and less sedation. However, in analysis with additional adjustment for median admission date, the risk of death was still 49% lower (although not statistically significant) among those who received high dose compared with low dose prophylaxis. Furthermore, patients were grouped according to initial dose of thromboprophylaxis at admission to the ICU, and outcomes in relation to total dose thromboprophylaxis received (including changes in dosing strategy during the ICU care) have not been analyzed. There was also a lower proportion of patients on invasive ventilation in the group with high dose, though not statistically significant, and this was adjusted for in the statistical analysis. Due to the heavy work load during the pandemic, risk of complications during intrahospital transportation of critically ill patients due to respiratory instability, and the risk of viral contamination of radiology suites, it was n...

Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

Identifier	Status	Title
NCT04412304	Completed	Anticoagulant Therapy and 28-days Mortality in Critically Il…

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:

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No protocol registration statement was detected.

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