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

Abstract

Implementation of higher dose (HD) thromboprophylaxis has been considered in patients infected with coronavirus disease 2019 (COVID-19). Our aim was to compare HD to standard dose (SD) thromboprophylaxis in COVID-19 patients. The protocol is registered on PROSPERO (CRD42021284808). We searched for randomised controlled studies (CENTRAL, Embase, Medline and medRxviv) that compared HD to SD anticoagulation in COVID-19 and analysed outcomes such as mortality, thrombotic events, bleedings, and disease progression. The statistical analyses were made using the random effects model. Fourteen articles were included (6253 patients). HD compared with SD showed no difference in mortality (OR 0.83 [95% CI 0.54−1.28]). The use of HD was associated with a decreased risk of thrombosis (OR 0.58 [95% CI 0.44−0.76]), although with an increased risk of major bleeding (OR 1.64 [95% CI 1.25−2.16]). The cohort with D-dimer < 1 mg/mL showed no effect (OR 1.19 [95% CI 0.67−2.11]), but in the case of D-dimer > 1 mg/mL, a tendency of lower risk in the HD group was observed (OR 0.56 [95% CI 0.31−1.00]). The need for intubation in moderately ill patients showed a nonsignificant lower likelihood in the HD group (OR 0.82 [95% CI 0.63−1.08]). We cannot advocate for HD in all COVID-19 patients, although it shows some nonsignificant benefits on disease progression in those with elevated D-dimer who do not need ICU admission.

Keywords: COVID-19; anticoagulation; disease progression; thromboinflamation.

Figure 1

PRISMA 2020 flow diagram of the updated search.

Figure 2

All-cause mortality in different dosing regimens in moderate and severe disease cohorts [19,21,22,23,24,25,50,52,53,54,55,56]. (A) All-cause mortality in severe and moderate disease cohorts; (B) all-cause mortality in cohorts where intermediate or therapeutic dose was used in the HD group.

Figure 2

All-cause mortality in different dosing regimens in moderate and severe disease cohorts [19,21,22,23,24,25,50,52,53,54,55,56]. (A) All-cause mortality in severe and moderate disease cohorts; (B) all-cause mortality in cohorts where intermediate or therapeutic dose was used in the HD group.

Figure 3

All-cause mortality in cohorts with different baseline D-dimer levels [19,21,22,23,24,25,50,52,53,54,55,56].

Figure 4

Any thrombotic events in different dosing regimens in moderate and severe disease cohorts [19,20,21,22,23,24,25,51,52,53,54,55,56]. (A) Any thrombotic events in severe and moderate disease cohorts; (B) any thrombotic events in cohorts where an intermediate or therapeutic dose was used in the HD group.

Figure 5

Major bleedings in different dosing regimens in moderate and severe disease cohorts [20,21,22,23,24,25,50,51,52,53,54,55,56]. (A) Major bleeding events in severe and moderate disease cohorts; (B) major bleeding events in cohorts where intermediate or therapeutic dose was used in the HD group.

Figure 5

Major bleedings in different dosing regimens in moderate and severe disease cohorts [20,21,22,23,24,25,50,51,52,53,54,55,56]. (A) Major bleeding events in severe and moderate disease cohorts; (B) major bleeding events in cohorts where intermediate or therapeutic dose was used in the HD group.

Figure 6

Need for invasive mechanical ventilation [19,20,21,23,25,54].

Figure 7

GRADE assessment of the included studies. ^a The included studies are open-label studies, some of them with blinded adjudication. All-cause mortality and major bleeding are objective outcomes are thus less influenced by a lack of allocation concealment. ^b Some studies included a small sample size and low number of events. The 95% confidence interval is wide and crosses the line of no effect. ^c Some of the studies included a small sample size and low number of events. ^d There were some differences in outcome measures. Need for invasive mechanical ventilation, ICU admission, progression to ARDS, and the composite outcome included a subjective clinical decision—this and the open-label design could have influenced the measurement of the outcomes. ^e There were wide differences in point estimates across studies.