key: cord-0079299-ep9md9tk
authors: Fragkou, Paraskevi C.; Palaiodimou, Lina; Stefanou, Maria Ioanna; Katsanos, Aristeidis H.; Lambadiari, Vaia; Paraskevis, Dimitrios; Andreadou, Elisabeth; Dimopoulou, Dimitra; Zompola, Christina; Ferentinos, Panagiotis; Vassilakopoulos, Theodoros I.; Kotanidou, Anastasia; Sfikakis, Petros P.; Tsiodras, Sotirios; Tsivgoulis, Georgios
title: Effects of low molecular weight heparin and fondaparinux on mortality, hemorrhagic and thrombotic complications in COVID-19 patients
date: 2022-05-24
journal: Ther Adv Neurol Disord
DOI: 10.1177/17562864221099472
sha: 3c92b3bcd11dcaac5cd68d40416ee5204d7016bf
doc_id: 79299
cord_uid: ep9md9tk

BACKGROUND: Coronavirus disease 2019 (COVID-19) is associated with increased thrombosis prevalence. However, there are insufficient data supporting the appropriate anticoagulation dose in COVID-19. OBJECTIVE: We aim to systematically assess the currently available data regarding the effects of different dosing regimens of low molecular weight heparin and/or fondaparinux (LMWH/F) on mortality risk as well as the risk of arterial/venous thrombotic events and hemorrhagic complications in confirmed COVID-19 cases. DESIGN: We conducted a living systematic review and meta-analysis on the effects of different LMWH/F doses on mortality, thrombotic and hemorrhagic events in COVID-19 patients. DATA SOURCES AND METHODS: MEDLINE, Scopus, Embase, Cochrane Library, Cochrane COVID-19 study register, European Union Drug Regulating Authorities Clinical Trials Database, and ClinicalTrials.gov were searched to detect observational cohort studies and randomized-controlled clinical trials (RCTs) comparing difference doses of LMWH/F among confirmed COVID-19 cases. RESULTS: Thirty-one eligible studies (6 RCTs and 25 cohort studies) with 11,430 hospitalized patients were included. No association was found between LMWH/F and mortality during the following comparisons: (1) no LMWH/F versus any LMWH/F; (2) prophylactic versus higher than prophylactic LMWH/F; (3) prophylactic versus therapeutic LMWH/F; (4) intermediate versus therapeutic LMWH/F; and (5) lower than therapeutic versus therapeutic LMWH/F. Mortality was higher in patients receiving prophylactic versus intermediate LMWH/F (OR = 2.01; 95% CI: 1.19–3.39). However, this effect was mostly driven by observational data. No associations were detected between the intensity of LMWH/F and the risk of thrombotic and hemorrhagic events, except the lower risk for hemorrhage in patients on prophylactic compared to higher LMWH/F doses. CONCLUSION: The risk for all-cause mortality was higher in patients receiving prophylactic LMWH/F compared to those on an intermediate dose of LMWH/F, based on observational data. These results should be interpreted in light of the moderate quality and heterogeneity of the included studies. REGISTRATION: The study protocol has been registered in the International Prospective Register of Ongoing Systematic Reviews PROSPERO (Registration number: CRD42021229771).

As the coronavirus disease 2019 (COVID- 19) pandemic continues to evolve globally, our understanding of the underlying pathogenetic mechanisms still remains largely obscure. However, an increasing body of data supports Effects of low molecular weight heparin and fondaparinux on mortality, hemorrhagic and thrombotic complications in COVID-19 patients that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and-most importantly-its progression to severe and critical COVID-19 disease, may be attributed to the widespread endothelial cell damage either directly by the virus itself, or indirectly by the burst of proinflammatory cytokines, as well as the activation of complement and the development of systemic microangiopathy that leads to multi-organ damage. 1 The loss of endothelial integrity (endotheliopathy) and, consequently, the destruction of the vascular wall homeostasis are associated with a procoagulant state that activates and propagates intravascular coagulation, and leads to an increased prevalence of arterial and venous thrombotic complications in severely and critically ill COVID-19 patients. 1 The procoagulant state in COVID-19 patients is evident not only through abnormal coagulation profiles 2 -that are routinely used in most laboratories worldwidebut also through more sophisticated tests. Indeed, a study by Ranucci et al. 3 in patients with COVID-19-induced acute respiratory distress syndrome demonstrated an increased clot strength with platelet and fibrinogen contribution, using point-of-care viscoelastic tests, thus strengthening the hypothesis of activation of intravascular coagulation mechanism and verifying the hypercoagulability seen in COVID-19 infection. The prevalence of both arterial and venous thrombotic events in COVID-19 cases has been reported to range between 5.2% and 30% among different studies, [4] [5] [6] [7] although the overall risk of stroke among hospitalized patients with SARS-CoV-2 infection was found as low as 0.5% in a large multi-center observational study. 7 Taking these observations into consideration, the international stakeholders and organizations have issued guidelines on the use of antithrombotic agents in hospitalized COVID-19 patients; the National Institutes of Health of the USA and the American Society of Hematology recommend the use of prophylactic anticoagulation in all nonpregnant hospitalized adults (unless contraindicated) and suggest the administration of therapeutic doses when thrombosis is proved or highly suspected on a clinical basis. 8, 9 However, there are currently insufficient data supporting the use of intermediate or high (therapeutic) anticoagulation dose outside this context. 8 In addition, the effects of no anticoagulation versus anticoagulation and the different antithrombotic dosing schemes on mortality remain unknown.

To address these questions, we conducted a living systematic review and meta-analysis of studies comparing the mortality of patients with laboratory-confirmed COVID-19 disease not receiving any anticoagulation versus those who were anticoagulated with low molecular weight heparin or fondaparinux (LMWH/F); furthermore, we compared the mortality of patients under LMWH/F at a standard thromboprophylaxis dose versus intermediate or therapeutic dose. Finally, we explored the risk of hemorrhagic and thrombotic events among the aforementioned COVID-19 patient subgroups.

The meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines 2020. 10 The study protocol was established a priori and has been registered in the International Prospective Register of Ongoing Systematic Reviews PROSPERO (Registration number: CRD42021229771). Our study did not require an ethical board approval or written informed consent by the patients according to the study design (systematic review and meta-analysis). (3) reporting interventions not aligned with our pre-defined inclusion criteria, including treatment with classic (unfractionated) heparin, other parenteral or oral anticoagulants. Non-English publications, case reports, case series with <10 patients, commentaries, narrative and systematic reviews, non-peer reviewed studies, and pre-prints were also excluded from further analyses.

In case of overlapping data between studies, the study with the largest dataset was retained. Independent assessment of retrieved studies was performed based on the previous inclusion/exclusion criteria by three reviewers (PCF, LP, and MIS), and any disagreements were resolved by the senior author (GT).

Data extraction was performed by three independent reviewers (PCF, LP, and MIS). We extracted data regarding study details (type of study, dates of recruitment, location, publication year, etc.), baseline characteristics of each study's population (mean age, number of males, COVID-19 severity and setting of treatment, co-morbidities), and details on the outcomes of interest (type and dose of anticoagulation, mortality rate number and type of thrombotic and hemorrhagic events for each group of different treatments). Potential disagreements in data abstraction were resolved by the senior author (GT).

An aggregate data meta-analysis was performed including observational studies and RCTs reporting on rates of all-cause mortality, thrombotic or hemorrhagic events in COVID-19 patients undergoing anticoagulation with LMWH/F versus contemporary COVID-19 controls as previously defined.

We plan to update our results with emerging evidence arising from new observational studies or RCTs, by following the same search method as described in our protocol every four months. The reviewers who did the initial search (PCF, LP, and MIS) will evaluate the new evidence according to the pre-defined inclusion and exclusion criteria, and we will meta-analyze the new data according to our pre-defined methods.

Eligible studies were subjected to quality control and bias assessment employing the Cochrane Collaboration toll (RoB 2) 11 for RCTs and the Newcastle-Ottawa Scale 12 for cohort studies. The quality control and risk of bias assessment was conducted independently by three reviewers (PCF, LP, and MIS), and disagreements were resolved via consensus after discussion with the senior author (GT). We evaluated for potential differences in demographics between groups of COVID-19 patients stratified by anticoagulation status. We also assessed the previous outcomes of interest in subgroup analyses after stratification according to the treatment setting of COVID-19 (i.e., outpatient, inpatient medical ward or ICU). Finally, we performed a secondary analysis to assess for potential differences between study designs (RCTs versus observational studies).

In the current meta-analysis, the aforementioned outcomes of interest were dichotomous variables.

The random-effects model of meta-analysis (DerSimonian and Laird) 13 was used to estimate individual study effects for each association. The random-effect model, since a different underlying true effect was assumed for each study and we aimed to provide more generalizable hypotheses for the population. 13, 14 Pairwise comparisons between COVID-19 patients with LMWH/F and COVID-19 controls (according to the pre-defined between-group comparisons based on LMWH/F dose) are reported using odds ratios (ORs) and corresponding 95% confidence intervals (95% CI), as measures of effects.

As per the Cochrane Handbook for Systematic Reviews of Interventions, 15 heterogeneity between included studies was assessed using the Cochran Q and I² statistics. For the qualitative interpretation of heterogeneity, I 2 values > 50% and values >75% were considered to represent substantial and considerable heterogeneity, respectively. 15 The significance level for the Q statistic was set at 0.1.

Publication bias across individual studies was graphically assessed for the primary outcome, when more than five studies were included in each analysis, using both funnel plot inspection and the Egger's linear regression test, 16 and the equivalent z-test for each pooled estimate with a two-tailed p value < 0.05 was considered statistically significant.

All statistical analyses were performed using the Cochrane Collaboration's Review Manager (RevMan 5.3) Software Package (Copenhagen:

The Nordic Cochrane Center, The Cochrane Collaboration, 2014), the Open MetaAnalyst 17 and R software version 3.5.0 (package: metafor).

The records retrieved by the systematic search in each electronic database are shown in Figure 1 .

After excluding duplicates and out-of-scope articles based on title/abstract, 349 potentially eligible records for inclusion were selected for full-text reading. After full-text reading, 318 articles were excluded, leading to the inclusion of 31 eligible studies 18-48 (6 RCTs and 25 cohort studies) with a total of 11,430 COVID-19 patients (Table 1) .

Only hospitalized patients were included in these studies.

The risk of bias in included RCTs was assessed by the Cochrane Collaboration tool (RoB 2) 11 and is shown in Supplementary Figures S1 and S2. Overall, the included RCTs presented low risk of bias in most individual domains, with the exception of high risk of performance and detection bias, since blinding was not achieved in the majority of the studies. The risk of bias of the included observational studies was assessed by the Newcastle-Ottawa scale 12 (Supplementary  Table S2 ). The overall score was 194 of 225 (86%), which is indicative of moderate quality. Effects on mortality A summary of findings is shown in Table 2 . No association between LMHW/F administration and mortality was detected in COVID-19 patients without anticoagulation versus any LMWH/F (OR = 0.98; 95% CI: 0.42-2.28; 6 studies; I 2 = 95%; p for Cochran Q: < 0.00001; Figure 2 ), with the limitation that only 6 studies with significant heterogeneity between reported outcomes were identified. There was also no difference in mortality among patients treated with prophylactic LMWH/F versus higher than prophylactic LMWH/F (OR = 1.28; 95% CI: 0.84-1.94; 16 studies; Figure S22 ) or among patients treated with prophylactic versus therapeutic LMWH/F (OR = 0.82; 95% CI: 0.39-1.76; 9 studies; I 2 = 83%; p for Cochran Q < 0.00001; Supplementary Figure S23 ). Conversely, the risk for all-cause mortality was higher in patients receiving prophylactic versus intermediate LMWH/F (OR = 2.01; 95% CI: 1.19-3.39; 8 studies; I 2 = 68%; p for Cochran Q = 0.002; Figure 3 ). The corresponding mortality rates were comparable between patients undergoing intermediate compared with therapeutic LMWH/F (OR = 0.60; 95% CI: Figure S25 ).

Concerning thrombotic events in COVID-19 patients, no association was found between intensity of LMWH Figure S53 ).

A secondary analysis of the same outcomes of interest (mortality, thrombotic events, and hemorrhagic events) was performed stratifying by different study design (RCTs versus observational studies) to assess for potential differences. The results of this analysis are shown in Supplementary  Table S3 . Significant subgroup differences between study designs were disclosed in the analysis of mortality among patients receiving prophylactic versus intermediate LMWH/F (p for subgroup differences = 0.01; Supplementary Figure S54 ). The effect of prophylactic compared to intermediate LMWH/F on mortality was mostly driven by observational studies (OR = 2.85; Figure S55 ). No other significant differences between the two subgroups were disclosed.

Our living systematic review and meta-analysis provides an overview of the currently available data regarding the effects of different dosing regimens of LMWH/F on mortality risk as well as the risk of arterial/venous thrombotic events and hemorrhagic complications in confirmed COVID-19 cases.

The risk of all-cause mortality was higher in patients receiving prophylactic compared to intermediate doses of LMWH/F. However, this effect was mostly driven by observational data. Similar mortality rates were observed during the comparisons of (a) prophylactic versus higher than prophylactic LMWH In addition, no significant difference on mortality risk was identified when we compared populations under no anticoagulation versus any dose of LMWH/F. This paradox could be possibly explained by the fact that the majority of the eligible studies included hospitalized patients who often require anticoagulation. 8 In addition, type-II errors cannot be excluded, since in our review, only 6 studies including patients not on anticoagulation were metaanalyzed, while these studies suffered from significant heterogeneity in reported results. 26, 45 Thus, no robust conclusions can be drawn for our primary outcome given the paucity of available studies examining the benefits of LMWH/F versus no anticoagulation, especially in mild COVID-19 outpatients.

Interestingly, we demonstrated that the risk for all thrombotic events remained similar among the subgroups of different LMWH/F dosing schemes. This phenomenon may indicate that anticoagulants, and especially heparin-derived agents, avail the course of COVID-19 disease through pathophysiologic mechanisms that lie beyond their antithrombotic properties. Indeed, preclinical studies have shown that unfractionated heparin exerts both anti-inflammatory and direct antiviral effects against SARS-CoV-2. 49 Heparin binds irreversibly to the spike-protein (S-protein) as a competitive inhibitor and abrogates the viral entry into the host cells. [49] [50] [51] However, shorter-length heparins like the LMWHs have shown lower affinity to S-protein, and therefore, possibly exert little or maybe no direct antiviral effects against SARS-CoV-2, compared to unfractionated heparin. 50 Further studies are needed to explore the antiviral properties of heparin-derived antithrombotics in COVID-19 patients. Besides antiviral activity, it has been repeatedly demonstrated that unfractionated heparin dampens the inflammation in the vasculature and/or respiratory tract by (1) interacting with proinflammatory molecules, 54 in their meta-analysis reported that in-hospital anticoagulation was associated with a beneficial effect on mortality, while Wijaya et al. 55 found a tendency toward reduced mortality among mechanically ventilated patients who received therapeutic anticoagulation. Anticoagulation was also associated with lower mortality rate in the systematic review and metaanalysis conducted by Parisi et al. 56 However, the aforementioned meta-analyses had analyzed all types of antithrombotic agents, including oral anticoagulants and unfractionated heparin, while we aimed to exclusively evaluate the effectiveness TherapeuTic advances in neurological disorders Volume 15 14 journals.sagepub.com/home/tan and safety of LMWH/F. In addition, our metaanalysis included a larger number of studies.

The main strength of the current meta-analysis is the fact that it has been conducted by a multidisciplinary team, using robust methodological pipeline according to an a priori established, PRISMAbased protocol. In addition, we utilized a robust and thorough literature search that was performed by three independent reviewers. Compared to previously published meta-analyses, that included studies with any type of antithrombotic agents, our study focuses only on the effects of LMWH/F, which are the most commonly and widely applied anticoagulants in clinical practice, especially among hospitalized patients due to their ease of use (once or twice daily) and minimal monitoring (compared to unfractionated heparin). Finally, as COVID-19 research is a continuously changing landscape, the living nature of this meta-analysis will allow emerging evidence to shape new results on the effects of LMWH and fondaparinux on mortality risk, thrombotic events, and hemorrhagic complications on a regular basis.

Certain limitations of this report need to be acknowledged. First, there is a lack of a standardized definition of the 'intermediate dose' of LMWH/F; although clinicians use this term empirically for doses that are higher than prophylactic and lower than therapeutic, it is important to follow a universal definition provided by international stakeholders and specified further for each agent by the manufacturers themselves. Second, there are insufficient data on the risks and benefits of anticoagulation administration in mild COVID-19 who do not require hospitalization. As the majority of COVID-19 patients remain outpatients, it will be useful to conclude on the role of LMWH/F in this patient population, especially in the context of pleiotropic effects of unfractionated heparin and heparin-derived drugs. Furthermore, our results should be interpreted cautiously due to the moderate quality and the heterogeneity of the included studies. Pooling together data from RCTs and observational studies and recruiting diverse COVID-19 patients of different disease severity who were treated in different settings are acknowledged as potential limitations that led to further analyses exploring for potential differences between subgroups. We expect that with the emergence of data from welldesigned large-scale RCTs, these methodological limitations will soon be mitigated.

Our meta-analysis shows that the risk of all-cause mortality may be reduced in patients who receive intermediate doses of LMWH/F compared to prophylactic doses, based on observational data. Although anticoagulation constitutes a common clinical practice among patients with COVID-19 disease globally, especially among those who require hospitalization, robust evidence from ongoing RCTs defining their risks and benefits as well as the appropriate dosing scheme is warranted. We expect that our living systematic review and meta-analysis will shed light on the role and impact of LMWH/F in COVID-19 disease, as new data emerge from well-designed, high-quality trials.

Immunity, endothelial injury and complement-induced coagulopathy in COVID-19

COVID-19-related severe hypercoagulability in patients admitted to intensive care unit for acute respiratory failure

The procoagulant pattern of patients with COVID-19 acute respiratory distress syndrome

Incidence and outcomes of thrombotic events in symptomatic patients with COVID-19

Incidence of thrombotic complications in critically ill ICU patients with COVID-19

Thrombosis in hospitalized patients with COVID-19 in a New York City health system

Risk of stroke in hospitalized SARS-CoV-2 infected patients: a multinational study

Antithrombotic therapy| COVID-19 treatment guidelines

COVID-19 and VTE/anticoagulation: frequently asked questions

Updating guidance for reporting systematic reviews: development of the prisma 2020 statement

The cochrane collaboration's tool for assessing risk of bias in randomised trials

The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses

Meta-analysis in clinical trials revisited

Random-effects model for meta-analysis of clinical trials: an update

Analysing data and undertaking meta-analyses. In: Cochrane handbook for systematic reviews of interventions

Bias in meta-analysis detected by a simple, graphical test

Closing the gap between methodologists and endusers: R as a computational back-end

Therapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID-19 and elevated D-dimer concentration (ACTION): an open-label, multicentre, randomised, controlled trial

Thromboprophylaxis with enoxaparin is associated with a lower death rate in patients hospitalized with SARS-CoV-2 infection. A cohort study

COVID-19 and venous thromboembolism in intensive care or medical ward

Therapeutic versus prophylactic bemiparin in hospitalized patients with nonsevere COVID-19 pneumonia (BEMICOP Study): an openlabel, multicenter, randomized, controlled trial

Therapeutic dosing of low-molecular-weight heparin may decrease mortality in patients with severe COVID-19 infection

Comparison of standard prophylactic and preemptive therapeutic low molecular weight heparin treatments in hospitalized patients with COVID-19

Comparison between prophylactic versus therapeutic doses of low-molecular-weight heparin in severely ill coronavirus disease 2019 patients in relation to disease progression and outcome

CT imaging of pulmonary embolism in patients with COVID-19 pneumonia: a retrospective analysis

Role of low-molecular-weight heparin in hospitalized patients with severe acute respiratory syndrome coronavirus 2 pneumonia: a prospective observational study

Low molecular weight heparin is useful in adult COVID-19 inpatients. Experience during the first Spanish wave: observational study

Use of low-molecular weight heparin, transfusion and mortality in COVID-19 patients not requiring ventilation

Standard-versus intermediate-dose enoxaparin for anti-factor xa guided thromboprophylaxis in critically ill patients with COVID-19

Efficacy and safety of therapeutic-dose heparin vs standard prophylactic or intermediate-dose heparins for thromboprophylaxis in high-risk hospitalized patients with COVID-19: the HEP-COVID randomized clinical trial

Effect of intermediate-dose vs standard-dose prophylactic anticoagulation on thrombotic events, extracorporeal membrane oxygenation treatment, or mortality among patients with covid-19 admitted to the intensive care unit: the inspiration randomized clinical trial

Deep vein thrombosis in noncritically ill patients with coronavirus disease 2019 pneumonia: deep vein thrombosis in nonintensive care unit patients

The impact of different prophylactic anticoagulation doses on the outcomes of patients with COVID-19

Dosing of thromboprophylaxis and mortality in PC Fragkou, L Palaiodimou et al. COVID-19 patients

Increasing dosages of low-molecular-weight heparin in hospitalized patients with Covid-19

Clinical outcome with different doses of low-molecular-weight heparin in patients hospitalized for COVID-19

Anticoagulation, bleeding, mortality, and pathology in hospitalized patients with COVID-19

Comparison of the effect of unfractionated heparin and enoxaparin sodium at different doses on the course of COVID-19-associated coagulopathy

Preliminary experience with low molecular weight heparin strategy in COVID-19 patients

Venous thromboembolism and bleeding in critically ill COVID-19 patients treated with higher than standard low molecular weight heparin doses and aspirin: a call to action

From standard to escalated anticoagulant prophylaxis in fractured older adults with SARS-CoV-2 undergoing accelerated orthopedic surgery

Standard prophylactic versus intermediate dose enoxaparin in adults with severe COVID-19: a multi-center, open-label, randomized controlled trial

Incidence of deep vein thrombosis through an ultrasound surveillance protocol in patients with COVID-19 pneumonia in non-ICU setting: a multicenter prospective study

Low molecular weight heparin and 28-day mortality among patients with coronavirus disease 2019: a cohort study in the early epidemic era

The association of low molecular weight heparin use and in-hospital mortality among patients hospitalized with COVID-19

Impact of implementation of an individualised thromboprophylaxis protocol in critically ill ICU patients with COVID-19: a longitudinal controlled before-after study

Incidence of venous thromboembolism in critically ill coronavirus disease 2019 patients receiving prophylactic anticoagulation

Aggressive thromboprophylaxis improves clinical process and decreases the need of intensive care unit in COVID-19

Heparin as a therapy for COVID-19: current evidence and future possibilities

Characterization of heparin and severe acute respiratory syndromerelated coronavirus 2 (SARS-CoV-2) spike glycoprotein binding interactions

Inhaled and systemic heparin as a repurposed direct antiviral drug for prevention and treatment of COVID-19

Beneficial non-anticoagulant mechanisms underlying heparin treatment of COVID-19 patients

The potential role of heparin in patients with COVID-19: beyond the anticoagulant effect. A review

Anticoagulation outcomes in hospitalized Covid-19 patients: a systematic review and meta-analysis of case-control and cohort studies

The use of therapeutic-dose anticoagulation and its effect on mortality in patients with COVID-19: a systematic review

Different anticoagulant regimens, mortality, and bleeding in hospitalized patients with COVID-19: a systematic review and an updated meta-analysis

Visit SAGE journals online journals.sagepub.com/ home/tan

None.

This study did not require an ethical board approval or written informed consent by the patients according to the study design (systematic review and meta-analysis).

The authors received no financial support for the research, authorship, and/or publication of this article.

The authors declared no potential conflicts of interest.

The protocol of this systematic review and metaanalysis has been registered to the International Prospective Register of Ongoing Systematic Reviews PROSPERO (Registration number: CRD42021229771)

The data that support the findings of this study are available from the corresponding author (GT), upon reasonable request.

Supplemental material for this article is available online.