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Background:
Systematic Review

Safety and Efficacy of Different Anticoagulant Doses for Patients with COVID-19 in the ICU: A Systematic Review and Meta-Analysis

by
Svetlana Rachina
1,*,
Yuliya Belkova
2,
Anastasia Shchendrygina
1,
Aleksandr Suvorov
3,
Denis Bourgeois
4,
Marina Karuk
5,
Violetta Sitnikova
1 and
Nikita Dyatlov
1
1
Hospital Therapy Department No. 2, I.M. Sechenov First Moscow State Medical University, 119435 Moscow, Russia
2
Department of Clinical Pharmacology, Smolensk State Medical University, 214019 Smolensk, Russia
3
Institute of Biodesign and Complex Systems Modeling, I.M. Sechenov First Moscow State Medical University, 119435 Moscow, Russia
4
Health Systemic Process (P2S), Research Unit UR4129, University Claude Bernard Lyon 1, University of Lyon, 69008 Lyon, France
5
Endovascular Surgery Department, Russian Research Center of Surgery Named after Academician B.V. Petrovsky, 119991 Moscow, Russia
*
Author to whom correspondence should be addressed.
J. Clin. Med. 2023, 12(6), 2222; https://doi.org/10.3390/jcm12062222
Submission received: 3 February 2023 / Revised: 26 February 2023 / Accepted: 6 March 2023 / Published: 13 March 2023
(This article belongs to the Section Pharmacology)
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Abstract

:
Critically ill COVID-19 patients have a high incidence of thromboembolic events, which significantly influence the risk of mortality. Anticoagulant therapy is generally recommended to these patients but the optimal dosing regimens require further investigations. The objective of this systematic review and meta-analysis was to assess the efficacy and safety of prophylactic, intermediate and therapeutic dose anticoagulation in COVID-19 patients admitted to the ICU. A systematic search for original prospective observational studies and clinical trials was performed in online databases from 2020 to 2022. A total of 13 studies (3239 patients) were included. The type of anticoagulant dosing showed no significant influence on short-term mortality (p = 0.84), deep vein thrombosis (p = 0.66), arterial thrombosis (p = 0.44), major bleeding (p = 0.35) and minor bleeding incidence (p = 0.46). An anticoagulation regimen significantly influenced pulmonary embolism occurrence (16% for prophylactic dose vs. 4% for therapeutic dose, p = 0.02), but the number of studies in the analysis was relatively low. In conclusion, the results of this meta-analysis suggest that critically ill COVID-19 patients admitted in the ICU have no benefit from therapeutic doses of anticoagulants and that all three thromboprophylaxis regimes have a comparable effect on short term mortality and venous thromboembolism incidence but for pulmonary embolism, for which the results were inconclusive.

1. Introduction

The novel coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a major health problem worldwide [1]. The infection is associated with a range of phenotypes from asymptomatic or mild to severe disease and may result in respiratory or multiple organ failure and death [2,3].
Although SARS-CoV-2 virus primarily targets the respiratory system, in a large number of patients it causes cardiovascular injuries and hypercoagulation [4,5] commonly manifesting with venous thromboembolism (VTE) including pulmonary embolism (PE) and deep vein thrombosis (DVT) [6,7]. The highest risk of thrombotic and thromboembolic events has been observed for critically ill patients admitted to the intensive care units (ICU) [8,9]. The reported incidence of VTE or PE in the patients with severe COVID-19 is about 24–28% [10,11,12] and 22–33% [13,14,15], respectively. Meanwhile, patients with thrombotic complications in the ICU have increased risk of in-hospital mortality [16].
A body of evidence shows that anticoagulant therapy, especially with low molecular weight heparin, might improve the prognosis in COVID-19 patients [17,18,19]. In accordance with these findings, a number of international societies and regulators strongly recommend the administration of thromboprophylaxis in all hospitalized patients with COVID-19 [20,21,22]. At the same time, a non-negligible risk of venous thromboses remains in critically ill individuals even despite thromboprophylaxis [23,24], and the optimal dosing regimens of anticoagulants in this subgroup of patients are still controversial. As prophylactic doses of anticoagulants may not be effective for the prevention of thromboembolic events [25], intermediate to therapeutic doses are increasingly prescribed to COVID-19 patients admitted to the ICU despite a higher risk of bleeding complications [18,26] and possible lack of influence on in-hospital mortality [27].
Several meta-analyses have been performed to clarify the matter of optimal approach to thromboprophylaxis in critically ill COVID-19 patients [12,23,28,29], but still no definitive conclusion is available probably due to shortage of reliable evidence. Thus, many studies included in the analyses were retrospective. Given that the new prospective trials addressing the issue of thromboprophylaxis in ICU COVID-19 subjects, including randomized controlled trials (RCTs), have become available, it seems reasonable to reassess the whole range of data collected prospectively regarding the thromboprophylaxis in this subset of COVID-19 patients.
The objective of this systematic review and meta-analysis was to assess the efficacy and safety of prophylactic, intermediate and therapeutic dose anticoagulation in COVID-19 patients admitted to the ICU.

2. Materials and Methods

2.1. Data Sources and Search Strategy

This systematic review and meta-analysis were designed in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines (Supplementary Table S1) [30]. The registration number is INPLASY202320033.
A systematic search for eligible trials was performed in online databases including PubMed, EMBASE, Web of Science, Cochrane Library Database and Clinicaltrials.gov, databases of international and national respiratory and infectious diseases congresses by three independent investigators (Y.B., M.K. and V.S.) from 1 January 2020 to 1 June 2022. The search terms included the combination of the following key words: coronavirus disease 2019, SARS-CoV-2, COVID-19, intensive care unit, ICU, anticoagulation, anticoagulant, thromboprophylaxis, heparin, mortality, venous thromboembolism, deep vein thrombosis, deep venous thrombosis, pulmonary embolism, bleeding. No language filter was applied. Search strategy for the databases is presented in Supplementary Table S2.

2.2. Eligibility Criteria

Any original prospective observational study or clinical trial in any format was eligible for inclusion in the review irrespective of blinding and language.
The intended outcomes of this review and meta-analysis were: (1) short-term mortality (at the end of the follow-up period but no later than 30 days); (2) deep-vein thrombosis (DVT) incidence; (3) PE incidence; (4) arterial thrombosis (AT) incidence; (5) major bleeding incidence and (6) minor bleeding incidence. All outcomes were assessed separately. The publications that had reported other outcomes or the intended outcomes as a composite one were considered ineligible for inclusion (referenced as “without outcomes of interest” in the PRISMA diagram).
The inclusion criteria were: (1) enrolment of adults (age ≥ 18 years) with severe COVID-19 disease (SARS-CoV-2 infection confirmed by positive DNA test) who were hospitalized in the ICU and received at least one anticoagulation regimen (prophylactic dose, intermediate dose, therapeutic dose of low molecular weighted or unfractionated heparin). The definition of anticoagulation regimens is listed in Supplementary Table S3. The final two inclusion criteria included: (2) reporting on the outcomes of interests and (3) design of prospective observational study or clinical trial.
The exclusion criteria were as follows: (1) other types of publications (reviews, guidelines, commentaries, case reports, expert opinions, etc.); (2) identical data used in multiple reports (e.g., duplicated studies); (3) missing or insufficient data; (4) different study population, hospital site, intervention and/or outcomes.

2.3. Data Extraction and Data Synthesis

Three researchers (Y.B., M.K. and V.S.) independently searched and evaluated the titles, abstracts, and full texts for relevant studies and extracted data from eligible ones. All duplicated search results were excluded. Any disagreement was resolved through discussion between the researchers or by the decision of a fourth researcher (S.R.). Overall risk of confounding, selection and reporting bias was assessed with ROBINS Tool [31].
Predefined variables were extracted independently from each study as follows: (1) study information (study design, first author, title, journal, publication data and country); (2) characteristics of patients (age, gender, hospital unit, number of study participants); (3) interventions (administration of anticoagulants, type and dose of anticoagulants); (4) outcomes of interest (mortality, rates and types of thrombotic or bleeding events separately).

2.4. Statistical Analyses

Analysis was carried out in R v.4.1 using meta package [32]. Because a number of studies had only one arm, the frequency of the end point was chosen as a measure of the effect size. Individual trials were considered as random effects, heterogeneity was assessed using the inverse variance method and a restricted maximum-likelihood estimator (REML) was used to estimate τ 2 . The random-effects model was adopted for all the endpoints. The overall proportion was calculated with logit transformation and the Clopper–Pearson method was used to estimate confidence intervals. Dosage type was used for subgrouping for all the endpoints, for mortality the type of trial was also considered as a moderator and for venous thrombosis endpoint the usage of routine ultrasound was considered as a moderator. The effect size was estimated in each subgroup. Differences in effect size were assessed by Q test, assuming common τ 2 in subgroups since the amount of trials is small [33]. Funnel plots were made for the overall groups and Egger’s test was performed to assess publication bias, where applicable. Sensitivity analysis was performed by the leave-one-out method.

3. Results

A comprehensive search yielded 70 records, 13 of which met the inclusion and exclusion criteria for this systematic review (Figure 1). Of the 13 studies included in the meta-analysis, 5 were RCTs [34,35,36,37,38], 3 were before-after studies [39,40,41] and the remaining 5 were observational studies [10,42,43,44,45] (Table 1).
The results of the literature search and study selection are presented on the PRISMA flowchart (Figure 1) and in Supplementary Table S4.
To estimate the role of different anticoagulation dosing on the outcome “short-term mortality” 10 studies were available, for “DVT” 11 studies, for “PE” 4 studies, for “AT” 5 studies, for “major bleeding” 8 studies and for “minor bleeding” 5 studies were available. The number of studies and patients included in the assessment for each dosing regimen are presented in Table 2.

3.1. Short-Term Mortality

Ten studies (3106 patients) were included in the analysis of short-term mortality in COVID-19 patients admitted to the ICU. The assessment of prophylactic dose anticoagulation was performed in 10 studies, of intermediate dose in 3 studies and therapeutic dose in 4 studies. A summary of studies reporting short-term mortality among COVID-19 patients in ICU receiving anticoagulation is presented in Supplementary Table S5.
The overall short-term mortality was 27% (95% CI 20; 34%) varying from study to study (range 12–42%) with high heterogeneity (I2 = 91%, p < 0.01) independent of the trial type (RCT vs. other) (p = 0.47) (Supplementary Figures S1 and S2). High heterogeneity was also observed inside each anticoagulant regimen group (Figure 2). The type of anticoagulant dosing showed no significant influence on short-term mortality (p = 0.84).

3.2. Deep Vein Thrombosis

Eleven studies (3134 patients) were included in the analysis of DVT incidence in COVID-19 patients in the ICU. The assessment of prophylactic dose anticoagulation was performed in 11 studies, of intermediate dose in 3 studies and therapeutic dose in 4 studies. A summary of studies reporting DVT incidence among COVID-19 patients in the ICU receiving anticoagulation is presented in Supplementary Table S6.
The overall DVT incidence was 13% (95% CI 5; 28%), varying from study to study (range 2–85%) with high heterogeneity (I2 = 96%, p < 0.01). High heterogeneity was also observed inside each anticoagulant regimen group. The type of anticoagulant dosing showed no significant influence on DVT incidence in COVID-19 patients (p = 0.66) (Figure 3), whereas, in contrast, routine ultrasound examinations in all patients statistically significantly increased the rate of diagnosed DVT events (p < 0.01) (Supplementary Figures S3 and S4).

3.3. Pulmonary Embolism

Four studies (414 patients) were included in the analysis of PE incidence in COVID-19 patients in the ICU. The assessment of prophylactic dose anticoagulation was performed in 4 studies and of therapeutic dose in 2 studies. No included studies assessed the influence of an intermediate dose on PE occurrence. A summary of studies reporting PE among COVID-19 patients in ICU receiving anticoagulation is presented in Supplementary Table S7.
The overall PE incidence was 13% (95% CI 10; 17%), variations range from 5 to 14%, with low heterogeneity (I2 = 0%, p < 0.76) in total (Supplementary Figure S5) and for both dosing regimens. An anticoagulation regimen significantly influenced PE occurrence (16% for prophylactic dose vs. 4% for therapeutic dose, p = 0.02) (Figure 4), but the number of studies in the analysis was relatively low.

3.4. Arterial Thrombosis

Five studies (976 patients) were included in the analysis of AT incidence in COVID-19 patients in the ICU. The assessment of prophylactic dose anticoagulation was performed in 5 studies, of intermediate dose in 1 study and of therapeutic dose in 2 studies. A summary of studies reporting AT among COVID-19 patients in the ICU receiving anticoagulation is presented in Supplementary Table S8.
The overall arterial thrombosis incidence was 2% (95% CI 1; 4%), variations range from 0 to 3%, with moderate heterogeneity (I2 = 48%, p = 0.1) in total (Supplementary Figure S6) and for different dosing regimens. No significant influence of anticoagulant dosing regimen on AT incidence was shown (p = 0.44) (Figure 5).

3.5. Major Bleeding

Eight studies (2692 patients) were included in the analysis of major bleeding incidence in COVID-19 patients in the ICU. The assessment of prophylactic dose anticoagulation was performed in 7 studies, of intermediate dose in 2 studies and of therapeutic dose in 4 studies. A summary of studies reporting major bleeding among COVID-19 patients in the ICU receiving anticoagulation is presented in Supplementary Table S9.
The overall major bleeding incidence was 4% (95% CI 2; 7%) varying from study to study (range 0–14%) with high heterogeneity (I2 = 68%, p < 0.01) in total (Supplementary Figure S7) and for different dosing regimens. Although no significant influence of anticoagulant dosing regimen on major bleeding incidence was demonstrated (p = 0.35), there was a trend towards a higher rate of major bleeding occurrence in patients who had the treatment dose of anticoagulant (Figure 6).

3.6. Minor Bleeding

Five studies (1506 patients) were included in the analysis of minor bleeding incidence in COVID-19 patients in the ICU. The assessment of prophylactic dose anticoagulation was performed in 4 studies, of intermediate dose in 2 studies and of therapeutic dose in 3 studies. A summary of studies reporting minor bleeding among COVID-19 patients in the ICU receiving anticoagulation is presented in Supplementary Table S10.
The overall major bleeding incidence was 5% (95% CI 3; 7%), varying from study to study (range 0–10%) with moderate heterogeneity (I2 = 46%, p = 0.11) in total (Supplementary Figure S8) and for different dosing regimens. No significant influence of anticoagulant dosing regimen on minor bleeding incidence was demonstrated (p = 0.46) (Figure 7).

3.7. Publication Bias and Sensitivity Analysis

ROBINS Tool was used to evaluate publication bias [31] and revealed a low-to-moderate risk of bias for both RCTs and observational studies (Supplementary Figure S9). Funnel plots for all outcomes were symmetric. Egger’s tests results evidenced a low probability of publication bias (Supplementary Figures S10–S15). A sensitivity analysis by the means of the leave-one-out method (Supplementary Figures S16–S21) showed similar results to those in the main study.

4. Discussion

In this systematic review and meta-analysis, the results from 13 high-quality studies including 3239 critically ill COVID-19 patients admitted in the ICU demonstrated comparable effect of different thromboprophylaxis regimes (prophylactic, intermediate or therapeutic) on short-term mortality and incidence of thromboembolic events, but for PE, with a similar safety profile. To our knowledge, this is the first meta-analysis which specifically focuses on a cohort of critically ill COVID-19 patients aiming to assess the efficacy and safety of different types of anticoagulant dosing in prospective studies only, including RCTs.
It is appreciated that thromboembolic events are just one of several determinates of death in these patients’ population. Nevertheless, it has been shown that the incidence of COVID-19-related thrombosis in the ICU is as high as 28% [49] and associated with significantly higher odds of mortality (OR 1.74, 95% CI, 1.01–2.98) [50]. Based on preliminary reports showing no benefit of high doses of thromboprophylaxis in critically ill COVID-19 subjects, the prophylactic dose is generally recommended [20,51]. However, the question regarding an efficient dose regimen in severe COVID-19 patients remains to be further investigated.
We found that the overall mortality rate in ICU COVID-19 individuals was 27%. Despite inclusion of high-quality studies, a heterogeneity of mortality was high and could not be explained either by the type of antithrombotic dosing or by the study design. One can assume that the heterogeneity might be a result of the difference in disease severity across the studies. Unfortunately, there is not any reliable marker to compare the severity of COVID-19 disease in the selected studies. If we consider the percentage of those that required mechanical ventilation, there is a risk of bias as we appreciate the access to this kind of treatment was limited during the pandemic and largely dependent on local settings rather than the patient’s conditions. The data on disease severity assessed by a scoring system such as APACHE [46] or SAPS scores [47,48] were reported in 6 and 3 studies, respectively. APACHE scores ranged from 8 to 16 across the studies, paradoxically demonstrating that those with the lowest APACHE score had a higher mortality rate at about 40% [37].
According to our sub-group analysis, short-term mortality did not differ significantly depending on the regimen of thromboprophylaxis: prophylactic, intermediate or therapeutic. Few meta-analyses have been highlighted on this topic when performing a sub-group analysis of critically ill individuals. Yasuda et al. [29], similarly, did not observe any significant difference in short-term mortality between groups of severe COVID-19 patients on prophylactic and treatment doses of anticoagulants. In other meta-analyses by Loffewdo et al. [52] and Elsebaie et al. [53] the finding was confirmed. Parisi et al. [54], however, reported a reduction in mortality rates in those on full-dose anticoagulation, but in this study in-hospital mortality was assessed. In addition, the conclusion was based on the analysis of 4 retrospective studies. Therefore, our results confirmed previously reported trends detected in sub-group analyses, that in critically ill COVID-19 patients therapeutic regimes cause no clear benefit over other types of anticoagulant dosing. One might find the data counterintuitive. However, the findings might confirm the assumption that thrombi formation in critically ill COVID-19 subjects has an immune mechanism due to endotelitis and, therefore, is resistant to antithrombotic treatment of any dose [55].
In our study the pooled incidence of VTE was 13% for both DVT and PE. AT occurred in 2%. Types of anticoagulant dosing did not influence the occurrence of VTE and AT. Of note, the incidence of PE was significantly higher in those on prophylactic doses compared to those on therapeutic doses. Although this finding might seem to be rational, it should be interpreted with caution as the number of studies reported PE outcomes were low (2 for therapeutic and 4 for prophylactic doses). Our findings are in line with the results of a recent meta-analysis by Valeriani et al. [12], in which the data of 4 RCTs that included critically ill COVID-19 patients were pooled. The study showed no reduction in incidence of VTE in those on full-dose anticoagulants compared to low dose. The beneficial effect of a high-dose regimen on VTE incidence in an ICU subgroup was not confirmed either in the study by Vedovati et al. [56].
Oppositely, when Yasuda et al. [29] pooled the data of 5 RCTs and observational studies they reported lower VTE incidence in those with severe COVID-19 on therapeutic doses of anticoagulant compared to a prophylactic one. However, the criteria for severity of COVID-19 were not thoroughly defined in this study, and therefore it was not clear if those individuals were critically ill patients. Previously, it has been shown that VTE was significantly reduced by full doses of anticoagulants in hospitalized non-critically ill subjects [12]. Therefore, interference could not be ruled out. The only meta-analysis reported data on AT incidence in cohorts of interest and did not demonstrate any influence of the thromboprophylaxis regime on AT occurrence [52].
The incidence of major and minor bleeding was comparable across all three types of thromboprophylaxis regimes. A trend towards the higher rate of major bleeding events in those on a therapeutic dose was observed. In those on a therapeutic dose, pooled incidence of major bleeding accounted for 6% (4 studies, 1046 patients, I2 = 0%), followed by 3% in subjects who received a prophylactic dose (7 studies, 363 patients, I2 = 70%) and 2% in patients on an intermediate dose (2 studies, 1676 patients, I2 = 95%); however, subgroup differences were not significant. Similarly, in the study by Valeriani and colleagues [12] the incidence of the risk of major bleeding did not differ between the groups of ICU COVID-19 patients on high and low doses of anticoagulants. Yasuda and colleagues [29] reported opposite findings, demonstrating the association of treatment dose with increased risk of major bleeding in a cohort of severe COVID-19 patients, but as it has been previously mentioned the criteria of disease severity were not defined clearly.
The overall results of our meta-analysis showed that all three doses of antithrombotic treatment administrated in critically ill COVID-19 individuals had a comparable effect on short-term mortality, VTE and AT incidence, as well as similar bleeding risk. We also observed a trend towards lower incidence of PE in those on therapeutic doses which, however, might occur at the cost of higher bleeding risk. Nevertheless, our study adds to the previous findings. This meta-analysis for the first time looked specifically at the cohort of critically ill COVID-19 patients in the prospective studies, while in previous publications [12,23,28,29,53] these patients were analyzed as a subgroup based on the set of prospective and retrospective data. We also incorporated recent studies not included in previous reviews [41,42]. We believe that our findings will be of value not only to improve thromboprophylaxis in the current ICU patients with SARS-CoV-2 infection but also in case of future pandemics caused by this or similar viruses.
We appreciate our study has some limitations such as variation in dosage and duration of the antithrombotic treatment across the studies, diversity in types of reported outcomes and lack of reliable criteria for disease severity assessment. Another possible limitation is the small sample size for some outcomes, particularly for intermediate doses because the occurrence outcomes had not been separately reported. For this review we have not contacted the corresponding authors of manuscripts with missing data which is also a limitation of the publication. We acknowledge that some data could have possibly been missed from the analysis. Ongoing and future studies can also bring new data and new perspectives to anticoagulant prophylaxis in critically ill COVID-19 patients. Therefore, our findings should be considered with caution.
In conclusion, the results of this meta-analysis suggest that critically ill COVID-19 patients admitted in the ICU have no benefit from therapeutic doses of anticoagulants and that all three thromboprophylaxis regimes have a comparable effect on short term mortality and VTE incidence but for PE, for which the results were inconclusive. Given the trends toward increased bleeding complications in those on full-dose anticoagulation, the results of our study do not support intermediate-to-therapeutic anticoagulant prophylaxis in the ICU COVID-19 patients. At the same time, future studies, some of which have already been published in 2023, can bring new perspectives to anticoagulant prophylaxis in critically ill COVID-19 patients.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/jcm12062222/s1.

Author Contributions

Conceptualization, S.R. and Y.B.; formal analysis, A.S. (Aleksandr Suvorov); investigation, Y.B., M.K. and V.S.; writing—original draft preparation, Y.B., D.B. and A.S. (Anastasia Shchendrygina); writing—review and editing, S.R.; supervision, S.R.; project administration, N.D.; funding acquisition, S.R. All authors have read and agreed to the published version of the manuscript.

Funding

Aleksandr Suvorov was supported by the academic leadership program Priority 2030 proposed by I.M. Sechenov of First Moscow State Medical University (Sechenov University), Moscow, Russian Federation.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Patient consent was waived because this study is a systematic review and meta-analysis of published data.

Data Availability Statement

The datasets used and/or analyzed during the current study are available from the corresponding authors on reasonable request.

Conflicts of Interest

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

References

  1. WHO Coronavirus (COVID-19) Dashboard. Available online: https://covid19.who.int/ (accessed on 15 November 2022).
  2. Wu, Z.; McGoogan, J.M. Characteristics of and important lessons from the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a report of 72314 cases from the Chinese center for disease control and prevention. JAMA 2020, 323, 1239–1242. [Google Scholar] [CrossRef] [PubMed]
  3. Zhou, F.; Yu, T.; Du, R.; Fan, G.; Liu, Y.; Liu, Z.; Xiang, J.; Wang, Y.; Song, B.; Gu, X.; et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study. Lancet 2020, 395, 1054–1062. [Google Scholar] [CrossRef] [PubMed]
  4. Gupta, A.; Madhavan, M.V.; Sehgal, K.; Nair, N.; Mahajan, S.; Sehrawat, T.S.; Bikdeli, B.; Ahluwalia, N.; Ausiello, J.C.; Wan, E.Y.; et al. Extrapulmonary manifestations of COVID-19. Nat. Med. 2020, 26, 1017–1032. [Google Scholar] [CrossRef] [PubMed]
  5. Levi, M.; Thachil, J.; Iba, T.; Levy, J.H. Coagulation abnormalities and thrombosis in patients with COVID-19. Lancet Haematol. 2020, 7, e438–e440. [Google Scholar] [CrossRef] [PubMed]
  6. Godoy, L.C.; Goligher, E.C.; Lawler, P.R.; Slutsky, A.S.; Zarychanski, R. Anticipating and managing coagulopathy and thrombotic manifestations of severe COVID-19. Can. Med. Assoc. J. 2020, 192, E1156–E1161. [Google Scholar] [CrossRef] [PubMed]
  7. Moores, L.K.; Tritschler, T.; Brosnahan, S.; Carrier, M.; Collen, J.F.; Doerschug, K.; Holley, A.B.; Jimenez, D.; Le Gal, G.; Rali, P.; et al. Prevention, Diagnosis, and Treatment of VTE in Patients with Coronavirus Disease 2019, CHEST Guideline and Expert Panel Report. Chest 2020, 158, 1143–1163. [Google Scholar] [CrossRef]
  8. Ruan, Q.; Yang, K.; Wang, W.; Jiang, L.; Song, J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020, 46, 846–848. [Google Scholar] [CrossRef] [Green Version]
  9. Shi, S.; Qin, M.; Shen, B.; Cai, Y.; Liu, T.; Yang, F.; Gong, W.; Liu, X.; Liang, J.; Zhao, Q.; et al. Association of Cardiac Injury with Mortality in Hospitalized Patients With COVID-19 in Wuhan, China. JAMA Cardiol. 2020, 5, 802–810. [Google Scholar] [CrossRef] [Green Version]
  10. Klok, F.A.; Kruip, M.J.H.A.; van der Meer, N.J.M.; Arbous, M.S.; Gommers, D.A.M.P.J.; Kant, K.M.; Kaptein, F.H.J.; van Paassen, J.; Stals, M.A.M.; Huisman, M.V.; et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb. Res. 2020, 191, 145–147. [Google Scholar] [CrossRef]
  11. Cui, S.; Chen, S.; Li, X.; Liu, S.; Wang, F. Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia. J. Thromb. Haemost. 2020, 18, 1421–1424. [Google Scholar] [CrossRef] [Green Version]
  12. Valeriani, E.; Porfidia, A.; Ageno, W.; Spoto, S.; Pola, R.; Di Nisio, M. High-dose versus low-dose venous thromboprophylaxis in hospitalized patients with COVID-19, a systematic review and meta-analysis. Intern. Emerg. Med. 2022, 17, 1817–1825. [Google Scholar] [CrossRef]
  13. Kollias, A.; Kyriakoulis, K.G.; Lagou, S.; Kontopantelis, E.; Stergiou, G.S.; Syrigos, K. Venous thromboembolism in COVID-19, A systematic review and meta-analysis. Vasc. Med. 2021, 26, 415–425. [Google Scholar] [CrossRef]
  14. Liu, Y.; Cai, J.; Wang, C.; Jin, J.; Qu, L. A systematic review and meta-analysis of incidence, prognosis, and laboratory indicators of venous thromboembolism in hospitalized patients with coronavirus disease 2019. J. Vasc. Surg. Venous Lymphat. Disord. 2021, 9, 1099–1111.e6. [Google Scholar] [CrossRef]
  15. Wichmann, D.; Sperhake, J.P.; Lütgehetmann, M.; Steurer, S.; Edler, C.; Heinemann, A.; Heinrich, F.; Mushumba, H.; Kniep, I.; Schröder, A.S.; et al. Autopsy Findings and Venous Thromboembolism in Patients With COVID-19, A Prospective Cohort Study. Ann. Intern. Med. 2020, 173, 268–277. [Google Scholar] [CrossRef]
  16. Malato, A.; Dentali, F.; Siragusa, S.; Fabbiano, F.; Kagoma, Y.; Boddi, M.; Gensini, G.F.; Peris, A.; Crowther, M.; Napolitano, M. The impact of deep vein thrombosis in critically ill patients: A meta-analysis of major clinical outcomes. Blood Transfus. 2015, 13, 559–568. [Google Scholar] [CrossRef] [Green Version]
  17. Tang, N.; Bai, H.; Chen, X.; Gong, J.; Li, D.; Sun, Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J. Thromb. Haemost. 2020, 18, 1094–1099. [Google Scholar] [CrossRef] [Green Version]
  18. Nadkarni, G.N.; Lala, A.; Bagiella, E.; Chang, H.L.; Moreno, P.R.; Pujadas, E.; Arvind, V.; Bose, S.; Charney, A.W.; Chen, M.D.; et al. Anticoagulation, Bleeding, Mortality, and Pathology in Hospitalized Patients With COVID-19. J. Am. Coll. Cardiol. 2020, 76, 1815–1826. [Google Scholar] [CrossRef]
  19. Thachil, J. The versatile heparin in COVID-19. J. Thromb. Haemost. 2020, 18, 1020–1022. [Google Scholar] [CrossRef] [Green Version]
  20. Clinical Management of COVID-19, Living Guideline, 15 September 2022. Geneva: World Health Organization. 2022. Available online: https://www.who.int/publications/i/item/WHO-2019-nCoV-Clinical-2022.2 (accessed on 10 November 2022).
  21. Kyriakoulis, K.G.; Dimakakos, E.; Kyriakoulis, I.G.; Catalano, M.; Spyropoulos, A.C.; Schulman, S.; Douketis, J.; Falanga, A.; Maraveyas, A.; Olinic, D.M.; et al. Practical Recommendations for Optimal Thromboprophylaxis in Patients with COVID-19, A Consensus Statement Based on Available Clinical Trials. J. Clin. Med. 2022, 11, 5997. [Google Scholar] [CrossRef]
  22. Spyropoulos, A.C.; Connors, J.M.; Douketis, J.D.; Goldin, M.; Hunt, B.J.; Kotila, T.R.; Lopes, R.D.; Schulman, S.; International Society on Thrombosis and Haemostasis. Good practice statements for antithrombotic therapy in the management of COVID-19, Guidance from the SSC of the ISTH. J. Thromb. Haemost. 2022, 20, 2226–2236, Does High-Dose Thromboprophylaxis Improve Outcomes in COVID-19 Patients. [Google Scholar] [CrossRef]
  23. Hasan, S.S.; Radford, S.; Kow, C.S.; Zaidi, S.T.R. Venous thromboembolism in critically ill COVID-19 patients receiving prophylactic or therapeutic anticoagulation: A systematic review and meta-analysis. J. Thromb. Thrombolysis 2020, 50, 814–821. [Google Scholar] [CrossRef] [PubMed]
  24. Santoliquido, A.; Porfidia, A.; Nesci, A.; De Matteis, G.; Marrone, G.; Porceddu, E.; Cammà, G.; Giarretta, I.; Fantoni, M.; Landi, F.; et al. Incidence of deep vein thrombosis among non-ICU patients hospitalized for COVID-19 despite pharmacological thromboprophylaxis. J. Thromb. Haemost. 2020, 18, 2358–2363. [Google Scholar] [CrossRef] [PubMed]
  25. Klok, F.A.; Kruip, M.J.H.A.; van der Meer, N.J.M.; Arbous, M.S.; Gommers, D.; Kant, K.M.; Kaptein, F.H.J.; van Paassen, J.; Stals, M.A.M.; Huisman, M.V.; et al. Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19, An updated analysis. Thromb. Res. 2020, 191, 148–150. [Google Scholar] [CrossRef] [PubMed]
  26. Patell, R.; Chiasakul, T.; Bauer, E.; Zwicker, J.I. Pharmacologic Thromboprophylaxis and Thrombosis in Hospitalized Patients with COVID-19, A Pooled Analysis. Thromb. Haemost. 2021, 121, 76–85. [Google Scholar] [CrossRef] [PubMed]
  27. Ionescu, F.; Jaiyesimi, I.; Petrescu, I.; Lawler, P.R.; Castillo, E.; Munoz-Maldonado, Y.; Imam, Z.; Narasimhan, M.; Abbas, A.E.; Konde, A.; et al. Association of anticoagulation dose and survival in hospitalized COVID-19 patients: A retrospective propensity score-weighted analysis. Eur. J. Haematol. 2021, 106, 165–174. [Google Scholar] [CrossRef]
  28. Flumignan, R.L.; Civile, V.T.; Tinôco, J.D.S.; Pascoal, P.I.; Areias, L.L.; Matar, C.F.; Tendal, B.; Trevisani, V.F.; Atallah, Á.N.; Nakano, L.C. Anticoagulants for people hospitalised with COVID-19. Cochrane Database Syst. Rev. 2022, 3, CD013739. [Google Scholar] [CrossRef]
  29. Yasuda, H.; Mayumi, T.; Okano, H. Efficacy of different anticoagulant doses for patients with COVID-19, a systematic review and network meta-analysis. Infection 2022, 50, 1453–1463. [Google Scholar] [CrossRef]
  30. Page, M.J.; McKenzie, J.E.; Bossuyt, P.M.; Boutron, I.; Hoffmann, T.C.; Mulrow, C.D.; Shamseer, L.; Tetzlaff, J.M.; Akl, E.A.; Brennan, S.E.; et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. BMJ 2021, 372, n71. [Google Scholar] [CrossRef]
  31. Risk of Bias Tools Website. Available online: https://www.riskofbias.info/ (accessed on 10 May 2022).
  32. Balduzzi, S.; Rücker, G.; Schwarzer, G. How to perform a meta-analysis with R: A practical tutorial. Evid. Based Ment. Health 2019, 22, 153–160. [Google Scholar] [CrossRef] [Green Version]
  33. Borenstein, M.; Hedges, L.V.; Higgins, J.P.T.; Rothstein, H.R. Introduction to Meta-Analysis; John Wiley & Sons: Hoboken, NJ, USA, 2021; 544p. [Google Scholar]
  34. REMAP-CAP Investigators; ACTIV-4a Investigators; ATTACC Investigators; Goligher, E.C.; Bradbury, C.A.; McVerry, B.J.; Lawler, P.R.; Berger, J.S.; Gong, M.N.; Carrier, M.; et al. Therapeutic Anticoagulation with Heparin in Critically Ill Patients with COVID-19. N. Engl. J. Med. 2021, 385, 777–789. [Google Scholar] [CrossRef]
  35. Lemos, A.C.B.; do Espírito Santo, D.A.; Salvetti, M.C.; Gilio, R.N.; Agra, L.B.; Pazin-Filho, A.; Miranda, C.H. Therapeutic versus prophylactic anticoagulation for severe COVID-19, A randomized phase II clinical trial (HESACOVID). Thromb. Res. 2020, 196, 359–366. [Google Scholar] [CrossRef]
  36. Perepu, U.S.; Chambers, I.; Wahab, A.; Ten Eyck, P.; Wu, C.; Dayal, S.; Sutamtewagul, G.; Bailey, S.R.; Rosenstein, L.J.; Lentz, S.R. Standard prophylactic versus intermediate dose enoxaparin in adults with severe COVID-19, A multi-center, open-label, randomized controlled trial. J. Thromb. Haemost. 2021, 19, 2225–2234. [Google Scholar] [CrossRef]
  37. INSPIRATION Investigators; Sadeghipour, P.; Talasaz, A.H.; Rashidi, F.; Sharif-Kashani, B.; Beigmohammadi, M.T.; Farrokhpour, M.; Sezavar, S.H.; Payandemehr, P.; Dabbagh, A.; et al. 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. JAMA 2021, 325, 1620–1630. [Google Scholar] [CrossRef]
  38. Spyropoulos, A.C.; Goldin, M.; Giannis, D.; Diab, W.; Wang, J.; Khanijo, S.; Mignatti, A.; Gianos, E.; Cohen, M.; Sharifova, G.; et al. 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. JAMA Intern. Med. 2021, 181, 1612–1620. [Google Scholar] [CrossRef]
  39. Helms, J.; Severac, F.; Merdji, H.; Schenck, M.; Clere-Jehl, R.; Baldacini, M.; Ohana, M.; Grunebaum, L.; Castelain, V.; Anglés-Cano, E.; et al. Higher anticoagulation targets and risk of thrombotic events in severe COVID-19 patients: Bi-center cohort study. Ann. Intensive Care 2021, 11, 14. [Google Scholar] [CrossRef]
  40. Stessel, B.; Vanvuchelen, C.; Bruckers, L.; Geebelen, L.; Callebaut, I.; Vandenbrande, J.; Pellens, B.; Van Tornout, M.; Ory, J.P.; van Halem, K.; et al. Impact of implementation of an individualised thromboprophylaxis protocol in critically ill ICU patients with COVID-19, A longitudinal controlled before-after study. Thromb. Res. 2020, 194, 209–215. [Google Scholar] [CrossRef]
  41. Voicu, S.; Chousterman, B.G.; Bonnin, P.; Deye, N.; Malissin, I.; Gall, A.L.; Barthélémy, R.; Sutterlin, L.; Naim, G.; Mrad, A.; et al. Increased anticoagulation reduces proximal deep vein thrombosis in mechanically ventilated COVID-19 patients: Venous thrombosis prevention & COVID-19. J. Infect. 2021, 82, 186–230. [Google Scholar] [CrossRef]
  42. Ferrandis, R.; Escontrela, B.; Ferrando, C.; Hernandez, M.; Herrera, J.; Hidalgo, F.; Librero, J.; Llau, J.V.; Martinez, A.; Pajares, A.; et al. Eficacia de la tromboprofilaxis con heparina de bajo peso molecular en pacientes críticos con COVID-19, estudio observacional, prospectivo y multicéntrico [Effectiveness of thromboprophylaxis with low molecular weight heparin in critically ill patients with COVID-19. An observational, prospective, multicenter study.]. Rev. Esp. Anestesiol. Reanim. 2022, in press. [Google Scholar] [CrossRef]
  43. Ren, B.; Yan, F.; Deng, Z.; Zhang, S.; Xiao, L.; Wu, M.; Cai, L. Extremely High Incidence of Lower Extremity Deep Venous Thrombosis in 48 Patients with Severe COVID-19 in Wuhan. Circulation 2020, 142, 181–183. [Google Scholar] [CrossRef]
  44. Stattin, K.; Lipcsey, M.; Andersson, H.; Pontén, E.; Bülow Anderberg, S.; Gradin, A.; Larsson, A.; Lubenow, N.; von Seth, M.; Rubertsson, S.; et al. Inadequate prophylactic effect of low-molecular weight heparin in critically ill COVID-19 patients. J. Crit. Care 2020, 60, 249–252. [Google Scholar] [CrossRef]
  45. Voicu, S.; Bonnin, P.; Stépanian, A.; Chousterman, B.G.; Le Gall, A.; Malissin, I.; Deye, N.; Siguret, V.; Mebazaa, A.; Mégarbane, B. High Prevalence of Deep Vein Thrombosis in Mechanically Ventilated COVID-19 Patients. J. Am. Coll. Cardiol. 2020, 76, 480–482. [Google Scholar] [CrossRef] [PubMed]
  46. Knaus, W.A.; Draper, E.A.; Wagner, D.P.; Zimmerman, J.E. APACHE II: A severity of disease classification system. Crit. Care Med. 1985, 13, 818–829. [Google Scholar] [CrossRef] [PubMed]
  47. Le Gall, J.R.; Lemeshow, S.; Saulnier, F. A new Simplified Acute Physiology Score (SAPS II) based on a European/North American multicenter study. JAMA 1993, 270, 2957–2963. [Google Scholar] [CrossRef] [PubMed]
  48. The SAPS 3 Research Group. Available online: https://www.saps3.org/ (accessed on 16 January 2023).
  49. Jiménez, D.; García-Sanchez, A.; Rali, P.; Muriel, A.; Bikdeli, B.; Ruiz-Artacho, P.; Le Mao, R.; Rodríguez, C.; Hunt, B.J.; Monreal, M. Incidence of VTE and Bleeding Among Hospitalized Patients with Coronavirus Disease 2019, A Systematic Review and Meta-analysis. Chest 2021, 159, 1182–1196. [Google Scholar] [CrossRef]
  50. Malas, M.B.; Naazie, I.N.; Elsayed, N.; Mathlouthi, A.; Marmor, R.; Clary, B. Thromboembolism risk of COVID-19 is high and associated with a higher risk of mortality: A systematic review and meta-analysis. EClinicalMedicine 2020, 29, 100639. [Google Scholar] [CrossRef]
  51. Spyropoulos, A.C.; Levy, J.H.; Ageno, W.; Connors, J.M.; Hunt, B.J.; Iba, T.; Levi, M.; Samama, C.M.; Thachil, J.; Giannis, D.; et al. Scientific and Standardization Committee communication: Clinical guidance on the diagnosis, prevention, and treatment of venous thromboembolism in hospitalized patients with COVID-19. J. Thromb. Haemost. 2020, 18, 1859–1865. [Google Scholar] [CrossRef]
  52. Loffredo, L.; Di Castelnuovo, A.; Chiariello, G.A.; Pignatelli, P.; Violi, F. Full versus prophylactic-intermediate doses of anticoagulants in COVID-19, a meta-analysis. Haematologica 2022, 107, 1933–1939. [Google Scholar] [CrossRef]
  53. Elsebaie, M.A.T.; Baral, B.; Elsebaie, M.; Shrivastava, T.; Weir, C.; Kumi, D.; Birch, N.W. Does High-Dose Thromboprophylaxis Improve Outcomes in COVID-19 Patients? A Meta-analysis of Comparative Studies. TH Open 2022, 6, e323–e334. [Google Scholar] [CrossRef]
  54. Parisi, R.; Costanzo, S.; Di Castelnuovo, A.; de Gaetano, G.; Donati, M.B.; Iacoviello, L. Different Anticoagulant Regimens, Mortality, and Bleeding in Hospitalized Patients with COVID-19, A Systematic Review and an Updated Meta-Analysis. Semin. Thromb. Hemost. 2021, 47, 372–391. [Google Scholar] [CrossRef]
  55. Sofia, R.; Carbone, M.; Landoni, G.; Zangrillo, A.; Dagna, L. Anticoagulation as secondary prevention of massive lung thromboses in hospitalized patients with COVID-19. Eur. J. Intern. Med. 2022, 100, 21–24. [Google Scholar] [CrossRef]
  56. Vedovati, M.C.; Graziani, M.; Agnelli, G.; Becattini, C. Efficacy and safety of two heparin regimens for prevention of venous thromboembolism in hospitalized patients with COVID-19, a meta-analysis. Intern. Emerg. Med. 2022, 29, 1–15. [Google Scholar] [CrossRef]
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Figure 1. Preferred reporting items for systematic review and meta-analyses (PRISMA) flow diagram of literature screening.
Figure 1. Preferred reporting items for systematic review and meta-analyses (PRISMA) flow diagram of literature screening.
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Figure 2. Forest plot of anticoagulation doses influence on short-term mortality in COVID-19 patients in the ICU [10,34,35,36,37,39,40,41,42,43].
Figure 2. Forest plot of anticoagulation doses influence on short-term mortality in COVID-19 patients in the ICU [10,34,35,36,37,39,40,41,42,43].
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Figure 3. Forest plot of anticoagulation doses influence on DVT incidence in COVID-19 patients in the ICU [10,34,35,36,37,39,40,42,43,44,45].
Figure 3. Forest plot of anticoagulation doses influence on DVT incidence in COVID-19 patients in the ICU [10,34,35,36,37,39,40,42,43,44,45].
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Figure 4. Forest plot of anticoagulation doses influence on PE incidence in COVID-19 patients in the ICU [10,35,39,44].
Figure 4. Forest plot of anticoagulation doses influence on PE incidence in COVID-19 patients in the ICU [10,35,39,44].
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Figure 5. Forest plot of anticoagulation doses influence on AT incidence in COVID-19 patients in the ICU [10,35,37,39,44].
Figure 5. Forest plot of anticoagulation doses influence on AT incidence in COVID-19 patients in the ICU [10,35,37,39,44].
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Figure 6. Forest plot of anticoagulation doses influence on major bleeding incidence in COVID-19 patients in the ICU [34,35,36,37,38,41,42,44].
Figure 6. Forest plot of anticoagulation doses influence on major bleeding incidence in COVID-19 patients in the ICU [34,35,36,37,38,41,42,44].
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Figure 7. Forest plot of anticoagulation doses influence on minor bleeding incidence in COVID-19 patients in the ICU [35,36,37,42,44].
Figure 7. Forest plot of anticoagulation doses influence on minor bleeding incidence in COVID-19 patients in the ICU [35,36,37,42,44].
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Table
Table 1. Characteristics of studies included in meta-analysis.
Table 1. Characteristics of studies included in meta-analysis.
Study
(Author, Year)		CountryStudy DesignPatients in ICU, %ComparisonsType of AnticoagulationSample,
n		Mean/Median
Age, y		Male, %Average APACHE II Score [46]Outcomes
Short-Term MortalityDVTPEATMajor BleedingMinor Bleeding
Ferrandis, 2022 [42]SpainObservational100Treatment doseUFH46263.53212++ ++
Prophylactic doseUFH258633312
Goligher, 2021 [34]Canada, multinationalOpen-label RCT100Treatment doseUFH
LMWH		53460.472.214++ +
Prophylactic doseUFH
LMWH		56461.767.913
Helms, 2021 [39]FranceBefore/after study100Treatment doseLMWH, UFH716466.247 *++++
Prophylactic doseLMWH, UFH1086176.948 *
Klok, 2020 [10]NorwayObservational100Prophylactic doseLMWH (nadroparin)1846476na++++
Lemos, 2020 [35]BrazilOpen-label RCT100Treatment doseLMWH (enoxaparin)10559056 **++++++
Prophylactic doseLMWH (enoxaparin)10587056 **
Perepu, 2021 [36]USAMulti-center, open-label RCT62Intermediate doseLMWH (enoxaparin)866554na++ ++
Prophylactic doseLMWH (enoxaparin)8763.558na
Ren, 2020 [43]ChinaCross-sectional100Prophylactic doseLMWH487054.216++
Sadeghipour, 2021 [37]IranMulticenter RCT with a 2 × 2 factorial design100Intermediate doseLMWH (enoxaparin)27662578++ +++
Prophylactic doseLMWH (enoxaparin)2866158.78
Spyropoulos, 2021 [38]USARCT100Treatment doseLMWH (enoxaparin)4565.852.7na +
Stattin, 2020 [44]SwedenObservational100Prophylactic doseLMWH (dalteparin)31658153 ** +++++
Stessel, 2020 [40]BelgiumLongitudinal controlled before/after study100Intermediate doseLMWH
(nadroparin)		266257.711++
Prophylactic doseLMWH (nadroparin)4669.573.913
Voicu, 2020 [45]FranceObservational100Prophylactic doseLMWH (enoxaparin),
UFH		56na75na +
Voicu, 2021 [41]FranceBefore/after observational exploratory study100Prophylactic doseLMWH (enoxaparin),
UFH		506272na+ +
RCT, randomized controlled trial; LMWH, low molecular weight heparin; UFH, unfractionated heparin; DVT, deep vein thrombosis; PE, pulmonary embolism; AT, arterial thrombosis; na, not available. * assessed by the SAPS II Score [47], ** assessed by the SAPS III Score [48].
Table
Table 2. The number of studies and patients included in meta-analysis for different dosing regimens.
Table 2. The number of studies and patients included in meta-analysis for different dosing regimens.
OutcomeProphylactic DoseIntermediate DoseTherapeutic DoseTotal
No. of StudiesNo. of PatientsNo. of StudiesNo. of PatientsNo. of StudiesNo. of PatientsNo. of StudiesNo. of Patients
Short-term mortality101640338941077103106
Deep vein thrombosis111672338941073113134
Pulmonary embolism4333002814414
Arterial thrombosis561912762815976
Major bleeding7128323634104682692
Minor bleeding45852363355851506
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Rachina, S.; Belkova, Y.; Shchendrygina, A.; Suvorov, A.; Bourgeois, D.; Karuk, M.; Sitnikova, V.; Dyatlov, N. Safety and Efficacy of Different Anticoagulant Doses for Patients with COVID-19 in the ICU: A Systematic Review and Meta-Analysis. J. Clin. Med. 2023, 12, 2222. https://doi.org/10.3390/jcm12062222

AMA Style

Rachina S, Belkova Y, Shchendrygina A, Suvorov A, Bourgeois D, Karuk M, Sitnikova V, Dyatlov N. Safety and Efficacy of Different Anticoagulant Doses for Patients with COVID-19 in the ICU: A Systematic Review and Meta-Analysis. Journal of Clinical Medicine. 2023; 12(6):2222. https://doi.org/10.3390/jcm12062222

Chicago/Turabian Style

Rachina, Svetlana, Yuliya Belkova, Anastasia Shchendrygina, Aleksandr Suvorov, Denis Bourgeois, Marina Karuk, Violetta Sitnikova, and Nikita Dyatlov. 2023. "Safety and Efficacy of Different Anticoagulant Doses for Patients with COVID-19 in the ICU: A Systematic Review and Meta-Analysis" Journal of Clinical Medicine 12, no. 6: 2222. https://doi.org/10.3390/jcm12062222

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