Luana C.M.G. Bonfim,Isadora S. Guerini,Marjorie G. Zambon,Gabriela B. Pires,Amanda C.F. Silva,André L.N. Gobatto,Marcela A. Lopes,Shari B. Brosnahan
Optimal dosing of heparin for prophylactic anticoagulation in critically ill COVID-19 patients a systematic review and meta-analysis of randomized controlled trials
COVID-19,SARS-CoV2,Anticoagulants,Heparin,Hypercoagulability,Venous thromboembolism,Bleeding,Mortality,Safety,Critical care,Intensive care unit,meta-analysis
Purpose The optimal amount of anticoagulation for critically ill COVID-19 patients is controversial. Therefore, we aimed to evaluate the efficacy and safety of escalated doses of anticoagulation in critically ill patients with severe COVID-19. Materials and methods We conducted a systematic search of three major databases, including PubMed, Cochrane Library, and Embase, from inception to May 2022. Randomized controlled trials (RCTs) were included comparing therapeutic or intermediate doses to standard prophylactic doses of anticoagulants in critically ill COVID-19 patients, with heparins as the only anticoagulation therapy considered. Results Out of the six RCTs, 2130 patients were administered escalated dose anticoagulation (50.2%) and standard thromboprophylaxis therapy (49.8%). The escalated dose showed no significant impact on mortality (RR, 1.01; 95% CI, 0.90–1.13). Although there was no significant difference in DVT (RR, 0.81; 95% CI, 0.61–1.08), the risk of PE was significantly reduced in patients receiving escalated dose anticoagulation (RR, 0.35; 95% CI, 0.21–0.60), with an increased risk of bleeding events (RR, 1.65; 95% CI, 1.08–2.53). Conclusion This systematic review and meta-analysis fail to support escalated anticoagulation doses to reduce mortality in critically ill COVID-19 patients. However, higher doses of anticoagulants appear to reduce thrombotic events while increasing the risk of bleeding effectively.
Optimal dosing of heparin for prophylactic anticoagulation in critically ill COVID-19 patients a systematic review and meta-analysis of randomized controlled trials

The optimal amount of anticoagulation for critically ill COVID-19 patients is controversial. Therefore, we aimed to evaluate the efficacy and safety of escalated doses of anticoagulation in critically ill patients with severe COVID-19.

We conducted a systematic search of three major databases, including PubMed, Cochrane Library, and Embase, from inception to May 2022. Randomized controlled trials (RCTs) were included comparing therapeutic or intermediate doses to standard prophylactic doses of anticoagulants in critically ill COVID-19 patients, with heparins as the only anticoagulation therapy considered.

Out of the six RCTs, 2130 patients were administered escalated dose anticoagulation (50.2%) and standard thromboprophylaxis therapy (49.8%). The escalated dose showed no significant impact on mortality (RR, 1.01; 95% CI, 0.90–1.13). Although there was no significant difference in DVT (RR, 0.81; 95% CI, 0.61–1.08), the risk of PE was significantly reduced in patients receiving escalated dose anticoagulation (RR, 0.35; 95% CI, 0.21–0.60), with an increased risk of bleeding events (RR, 1.65; 95% CI, 1.08–2.53).

This systematic review and meta-analysis fail to support escalated anticoagulation doses to reduce mortality in critically ill COVID-19 patients. However, higher doses of anticoagulants appear to reduce thrombotic events while increasing the risk of bleeding effectively.

Early in the SARS-CoV-2 pandemic, there was an influx of thrombotic events. While these thrombotic from SARS-CoV-2 infection complications occurred in both ambulatory and hospitalized patients suffering, critically ill patients had the highest incidence of thrombosis. [1,2] As more reports emerge in the literature, COVID-19 infection likely causes a hypercoagulable state. While the mechanism is not yet described, the increased inflammation may lead to increased levels of procoagulant factors, disruption of the normal homeostasis of vascular endothelial cells resulting in microangiopathy, local thrombus formation, and extensive vessel thrombosis and major thromboembolic complications in critically ill hospitalized patients. [3] Hypercoagulopathy, with increased thrombotic events occurring both on arterial and venous sides, comprising both myocardial infarction or stroke, and venous thromboembolism – specifically, deep vein thrombosis and pulmonary thromboembolism – are much more common. [4] Given the elevation rate of thrombosis, studies set out to determine the optimal amount of anticoagulation in various COVID-19 patients based on patient location, as the rate of thrombosis at the acute level versus critically ill differed immensely. Thus, several studies have been conducted to determine the optimal amount of anticoagulation in critically ill patients, as these patients are associated with worse outcomes. Heparin-based products are the preferred agent in critically ill patients, mainly due to low cost, high availability, and known side effects. [5,6]. Besides for type of anticoagulation, the dose of anticoagulation has been explored. Extensive studies showed benefits for full dose anticoagulation in patients non critically ill in need of hospitalization but no use for patients in the ICU [[7], [8], [9], [10], [11]]. This was curious as the thrombotic risk of ICU patients is even more elevated. More studies looking at smaller augmentation of anticoagulation, increasing from prophylaxis dosing to intermediate doses, have failed to demonstrate any clinical benefit [12,13]. To answer this question, we conducted a systematic review and meta-analysis of RCTs, examining the available evidence regarding the efficacy and safety of therapeutic and intermediate doses compared to the standard prophylactic dose of anticoagulants in critically ill COVID-19 patients, focusing on both clinical outcomes and adverse events such as increased bleeding.

This systematic review and meta-analysis were performed according to the Cochrane Collaboration and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The PRISMA 2020 checklist for the present meta-analysis is presented in Supplementary File, Table 1 . The protocol was registered in the PROSPERO international prospective register of systematic reviews (CRD42022346758).

Inclusion was restricted to studies that met all the following eligibility criteria: reported critical COVID-19 patients; comparing intermediate-dose or therapeutic-dose anticoagulation with standard-dose prophylactic anticoagulation; reporting at least one of the outcomes of interest; randomized control trials (RCTs). Only full-text articles were included. We excluded studies with only laboratory outcomes (i.e., D-dimer); overlapping populations; cross-over trials; observational studies; phase II studies. The included studies were conducted in different world regions, as defined by the World Health Organization (WHO) regions [14]. Anticoagulation therapy was restricted to heparins. Standard, intermediate (doses higher than the prophylactic but lower than the therapeutic), and therapeutic-dose anticoagulation regimens used for prophylaxis were defined according to the definitions of the trials. (Table 1). • Intermediate-dose anticoagulation versus standard prophylactic anticoagulation [12,13]. • Therapeutic anticoagulation versus standard prophylactic anticoagulation [[8], [9], [10],15].  The intermediate dose was defined as administering enoxaparin at a rate of 0.5 mg/kg per day or 30 or 40 mg (4000 U) twice daily in patients with creatinine clearance (CrCl) > 30 mL/min and a body mass index (BMI) < 40 kg/m2. The therapeutic dose was defined as the administration of enoxaparin at a rate of 1.5 mg/kg once daily or 1 mg/kg twice daily in patients with CrCl >30 mL/min and BMI < 40 kg/m2, or unfractionated heparin (UFH) to achieve the therapeutic range of activated partial thromboplastin time (aPTT) based on local guidelines. For this meta-analysis, intermediate and therapeutic-dose regimens from the intervention group were combined into a single group referred to as “escalated dose,” which was compared to the standard prophylactic regimen. Combining escalated anticoagulation strategies facilitates analysis and comprehensively evaluates different dosing approaches in critically ill COVID-19 patients. Although the two systems have practical differences in administration and monitoring, pooling data from studies that use both methods can offer a complete understanding of anticoagulation's overall efficacy and safety in this patient population. Analyzing both clinical outcomes and adverse events, including bleeding, the combined data can guide the optimal therapeutic approach for critically ill COVID-19 patients, considering individual patient risk profiles and other factors that may impact treatment decisions.

A systematic search was conducted in PubMed, Cochrane Library, and Embase in May 2022 for studies published in English only. There were no date restrictions. The following medical subjects heading terms were included: ‘covid-19’, ‘critically-ill,’ ‘mechanical ventilation,’ ‘prophylactic,’ ‘standard-dose,’ ‘usual-care thromboprophylaxis,’ ‘anticoagulation,’ ‘therapeutic-dose,’ ‘intermediate-dose.’ Additionally, reference lists from previous reviews and all included studies were manually searched for any additional studies. Three authors independently conducted the search based on predefined criteria and quality assessment. Studies were screened for exclusion by title, abstract, or both. Duplicate studies were excluded. Studies of interest were selected for full manuscript review, and variables of interest and outcomes were searched in the manuscript and supplementary material. If not reported, we contacted the study's principal author. The literature search and study selection were independently performed by two reviewers (L.C.M.G.B and M.G.Z), and any discrepancies were resolved through discussion and consensus. A complete electronic search strategy is reported in Supplemental Digital Content.

The critical outcomes of interest were all-cause mortality, symptomatic or asymptomatic venous thromboembolism (VTE), and arterial thromboembolism (ATE). The safety outcomes were major, non-major, and any bleeding event. The time period for outcomes collection is mentioned in Table 1. All individual outcomes were captured per the individual studies' definitions: VTE was defined as a composite of deep vein thrombosis (DVT) or pulmonary embolism (PE). As determined by individual studies, ATE was described as a composite of myocardial infarction (MI), ischemic stroke, peripheral arterial thromboembolism, and other arterial thromboembolism diseases. A subgroup analysis on mortality was performed based on high d-dimer levels. Subanalysis for the dose of escalated dose anticoagulation (therapeutic vs. intermediate doses) was also performed for all outcomes.

The risk of bias was assessed through the Cochrane tool for assessing the risk of bias 2 (RoB 2) [16]. Two independent (L.C.M.G.B and I.S.G) completed the risk of bias assessment and documented it on a risk of bias table for every study included. The overall bias risk results were classified as low, with some concerns, or high for each domain. The certainty of the evidence was assessed according to the GRADE methodology [17,18]. An independent author (L.C.M.G.B) set the certainty of evidence and classified it as high, moderate, low, or very low, depending on factors in each domain (risk of bias, inconsistency, indirectness, imprecision, and publication bias). Disagreements were resolved through consensus and with the senior author (M.L.).

For dichotomous outcomes, the number of events and the total number of participants in both the intervention and control groups were recorded. The relative risk (RR) with a 95% confidence interval (CI) was used as a practical measure. All meta-analyses were performed by the Mantel-Haenszel test with a fixed-effect model using Review Manager (ReVMan version 5.4.1, The Cochrane Collaboration, 2020). Heterogeneity was evaluated with the Cochran Q test and I2 statistics; p values inferior to 0.05, and I2 > 25% were considered significant for heterogeneity. Random-effects meta-analyses were carried out as sensitivity analyses.

A summary of the screening process and exclusions are provided in a PRISMA flow diagram Fig. 1 . Our electronic database searches identified 506 records. There were 290 duplicates, leaving 216 to be screened by title and abstract. We identified 22 potentially relevant publications for full-text review. Of these, 6 met our prespecified criteria for inclusion [[8], [9], [10],12,13,15]. Two primary authors who were contacted provided verification and additional outcomes data.

The main characteristics of individual studies are reported in Table 1. Overall, 6 RCTs were included, comprising a total of 2374 patients who received escalated dose anticoagulation (50.2%) and standard thromboprophylaxis therapy (49.8%). Studies were from geographically diverse settings in 11 countries. The majority of participants were recruited in Europe (n = 1069), the Americas (n = 714), and the Eastern Mediterranean (n = 562). Sample sizes ranged from 126 to 1098 patients with a maximum follow-up of 30 ± 2 days. All studies recruited critically-ill patients only (n = 1959), except for the HEP-COVID [9] that stratified patients in noncritical care / non–intensive care (n = 170) and critical care (ICU) status (n = 83) and the COVID-HEP [15], which randomized acutely ill medical (n = 71) vs. critical patients hospitalized in intermediate care units or ICUs (n = 88). Data for the outcomes were available for 2064 patients. Among selected trials evaluating escalated-intensity prophylactic of low molecular weight heparin (LMWH)/UFH, two trials tested intermediate-dose anticoagulation vs. usual-care thromboprophylaxis [12,13], and four assessed practices therapeutic-dose anticoagulation vs. usual-care thromboprophylaxis [[8], [9], [10],15] The types of heparins used varied across the studies, including subcutaneous or intravenous UFH and LMWH. Eligibility based on D-dimer values for critically ill patients was required for randomization in 2 studies [9,10].

eTable 3 summarizes the baseline characteristics of study participants in the critically ill group. The average patient age per study ranged from 62 to 71 years; 54% to 72% were men; 4% to 27.6% were black, and the mean body mass index ranged from 28.6 to 31 kg/m2. Most trials included participants with an elevated baseline D-dimer varying from a median of 823 (433–1740) to 5245 (4221–5445) across studies. Five studies reported 481 (24%) patients receiving invasive mechanical ventilation. Hypertension and diabetes mellitus were documented in 562 (27%) patients and 694 (33%) patients, respectively.

All six studies reported all-cause mortality within 30 ± 2 days. A total of 1070 patients received escalated dose (therapeutic or intermediate) anticoagulation (50.2%), and 1060 received standard prophylactic dose (49.8%). The use of prophylactic anticoagulation at an escalated dose did not affect mortality (RR,1.01; 95% CI, 0.90–1.13; I2 = 10%). A subgroup analysis was conducted on 5 RCTs [9,10,12,13,15] reporting elevated D-dimer levels and involved 564 patients. The analysis revealed that administering an escalated dose was a nonsignificant reduction in mortality (RR, 0.81; 95% CI, 0.61–1.08; I2 = 0%).

Data from 5 studies [8,9,12,13,15] were pooled to evaluate VTE. The sample comprised 1995 patients, of which 982 (49.2%) were administered escalated dose anticoagulation. The findings revealed a significant reduction in VTE incidence among patients who received escalated-intensity (therapeutic or intermediate) prophylactic anticoagulation compared to standard-intensity prophylaxis (RR, 0.57; 95% CI 0.39–0.832; I2 = 10%). Although patients treated with escalated dose anticoagulation showed little to no difference in the incidence of DVT (RR, 0.98; 95% CI 0.52–1.83; I2 = 0%), they experienced a significant reduction in PE (RR, 0.35; 95% CI, 0.21–0.60; I2 = 0%).

Overall ATE events were reported in 5 studies, including MI, ischemic cerebrovascular event (i.e., ischemic stroke), and other systemic arterial thromboembolism. The findings indicate no statistically significant reduction in ATE events with escalated-intensity prophylactic anticoagulation compared to standard prophylactic anticoagulation (RR, 1.07; 95% CI 0.65–1.76; I2 = 0%). Moreover, the analysis revealed that patients treated with escalated doses did not experience a significant difference in the incidence of ischemic stroke (RR, 1.12; 95% CI 0.52, 2.41; I2 = 0%). Similarly, escalated doses showed little to no difference in the incidence of MI (RR, 0.67; 95% CI 0.30–1.50; I2 = 0%).

There was a statistically significant lower incidence of any thrombotic event in patients who received escalated dose anticoagulant therapy compared to those who received standard therapy RR 0.72; 95% 0.54–0.97; I2 = 0%).

The findings indicate that the use of escalated dose anticoagulation was associated with an increased risk of any bleeding events compared to standard prophylactic anticoagulation (RR: 1.65; 95% CI 1.08–2.53; I2 = 0%). Although the definitions of major bleeding varied between studies, the analysis suggested that the use of escalated dose anticoagulant therapy may result in a higher risk of major bleeding compared to standard therapy, although the difference was not statistically significant (RR: 1.65; 95% CI 0.97–2.81; I2 = 0%) (Fig. 4 ). Moreover, the results showed that patients who received escalated dose anticoagulant therapy had a significantly higher risk of minor bleeding events than those who received standard therapy (RR: 2.10; 95% CI 1.07–4.11; I2 = 0%).

When the studies were categorized based on varying levels of thromboprophylaxis intensity (therapeutic dose vs. standard dose and intermediate dose vs. standard dose), no differences were observed in mortality. No significant differences were observed when intermediate doses were compared to standard prophylaxis. Still, a significant reduction in VTE and PE events was observed when the therapeutic doses were used. Furthermore, pooled analysis for any thrombotic event was significantly reduced in patients receiving therapeutic doses but not those receiving intermediate doses. The increased risk of bleeding did not reach statistical significance between intermediate-dose vs. therapeutic-dose groups when they were pooled individually.

The risk of bias for each study is shown in eTable 2. Most of the studies had a low risk or some concern of bias across all five domains evaluated. The overall certainty of the evidence for the comparisons of escalated dose vs. standard dose anticoagulant groups for the outcomes is presented in Table 2 . Sensitivity analysis under fixed and random-effects models showed no difference in the overall results presented in this study. Despite this, any bleeding and major bleeding events showed a statistically non-significant difference between the escalated dose and standard dose (eTable 4).

The aim of this systematic review and meta-analysis was to evaluate the effectiveness and safety of escalated-intensity prophylactic heparins (UFH and LMWH) in critically ill COVID-19 patients. The findings indicated that escalated dose anticoagulation did not reduce all-cause mortality compared to standard prophylactic anticoagulation but significantly reduced the risk of thrombotic events, mainly driven by fewer VTEs and a decrease in PE when compared to standard prophylactic regimens. However, it is essential to note that escalated dose anticoagulation was associated with an increased risk of bleeding. The study has several strengths, including the inclusion of only RCTs that focused exclusively on critically ill COVID-19 patients or excluded non-critical patients in studies presenting both. Additionally, the study addressed an important and timely research question regarding the optimal dosing and role of heparins in critically ill COVID-19 patients. These strengths help to clarify conflicting results from previous reports and improve the evidence quality for determining optimal anticoagulation therapy for critically COVID-19 patients. While previous meta-analyses have evaluated anticoagulation regimens in COVID-19 patients, they were methodologically different, and combining their results might have led to inappropriate conclusions. The heterogeneity in studies has led to poor evidence recommendations in critically ill COVID-19 patients, including missing randomized studies, the inclusion of Phase II trials, different outcomes, and a combination of different types and doses of anticoagulants in the intervention group [[19], [20], [21]]. Critically ill COVID-19 patients may have a higher risk of thrombosis due to a hypercoagulable state, posing an increased risk of bleeding. Heparins are effective and safer, but caution must be taken due to the risk of bleeding in COVID-19 patients at risk of platelet production, destruction imbalance, and coagulation factor consumption [22]. Reports indicated a higher failure rate of anticoagulation in critically ill COVID-19 patients, and thrombus formation in severe COVID-19 is driven by an exaggerated immune response that can make surface-bound complexes and fibrin-bound thrombin resistant to inhibition by antithrombin, the essential cofactor in heparin and LMWH [23]. Therefore, when evaluating the optimal therapeutic approach for critically ill COVID-19 patients, factors such as systemic inflammation and comorbidities must also be considered, in addition to the potential risk of bleeding and the demonstrated efficacy of heparin therapy in preventing thrombotic events. The study has several limitations that should be considered when interpreting the findings. Firstly, the inclusion criteria only considered studies that exclusively reported critically ill patients or excluded non-critical patients in studies that presented both. Therefore, the findings cannot be generalized to every patient population. Secondly, excluding patients with prior use of anticoagulation therapy may have resulted in a selection bias. Additionally, the data extraction methods did not allow for the consideration of risk factors such as chronic diseases, immobilization, vasopressors, mechanical ventilation, and thrombophilias. Also, individual data was not collected. Another limitation is that the definition of standard thromboprophylaxis varied across studies, with some adjusting heparin doses based on body weight or BMI. Lastly, the open-label design of the included trials may have introduced bias in the ascertainment of outcomes, particularly for thrombotic events. Double-blind, randomized controlled trials are needed to substantiate these findings and confirm the small potential mortality benefit seen in some studies.

The results of our study suggested that therapeutic doses of anticoagulation in critically ill COVID-19 patients reduced the incidence of venous thromboembolism (VTE) but had no effect on mortality or arterial thromboembolism (ATE). The reduction in VTE risk was primarily due to a decrease in pulmonary embolism (PE). However, the use of escalated doses of anticoagulation was associated with a higher risk of bleeding events in critically ill patients. It is crucial to consider the risks and benefits of prescribing intermediate and therapeutic doses based on patient-specific factors and assessment of scoring systems.

This research received no specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Not declared.