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| REVIEW ARTICLE |
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| Year : 2022 | Volume
: 5
| Issue : 3 | Page : 59-67 |
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Efficacy and safety of increased doses of anticoagulants in COVID-19 patients: A systematic review and meta-analysis
Evgeny Stepanov, Kirill Lobastov, Sergey Tsaplin, Ilya Schastlivtsev, Astanda Bargandzhiya, Leonid Laberko, Grigoriy Rodoman
Department of General Surgery, Pirogov Russian National Research Medical University, Moscow, Russia
| Date of Submission | 17-Feb-2022 |
| Date of Decision | 20-Apr-2022 |
| Date of Acceptance | 09-May-2022 |
| Date of Web Publication | 10-Nov-2022 |
Correspondence Address:
Dr. Kirill Lobastov
Pirogov Russian National Research Medical University, Moscow
Russia
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/2589-9686.360870
The aim of the study was to evaluate the efficacy and safety of increased doses of anticoagulants in comparison with standard doses in inpatients with COVID-19. A systematic review was carried out in October 2021 using the PubMed database. The analysis included only randomized clinical trials (RCTs) with ≥ 200 participants that reported the rate of death as the total number of cases or the percentage of patients. The primary outcome was all-cause mortality within the observational period. In addition, the risk of arterial and venous thrombotic events and major and clinically relevant nonmajor (CRNM) bleeding was assessed. Searching of Pubmed identified 8903 references. The final qualitative and quantitative analysis included the results of 6 RCTs that covered 5228 patients. Among all patients, 2660 received increased and 2568 standard doses of anticoagulants. The follow-up period varied from 21 to 30 days. The administration of increased doses did not affect the risk of death (odds ratio [OR], 0.95; 95% confidence interval [CI], 0.73–1.25; I2 = 59.5%), was associated with a reduced risk of thrombotic events (OR, 0.56; 95% CI, 0.43–0.73; I2 = 20.6%), and increased risk of major bleeding (OR, 1.86; 95% CI, 1.23–2.80; I2 = 0%) or CRNM bleeding (OR, 3.65; 95% CI, 1.65–8.09; I2 = 0%). Within the sensitivity analysis, similar results were obtained in the subgroups of critically ill or stable patients and individuals with increased D-dimer. The maximal reduction in the risk of thrombotic events was found for the subgroup of patients with increased D-dimer (OR, 0.48; 95% CI, 0.32–0.70; I2 = 36.4%). The use of increased doses of anticoagulants in inpatients with COVID-19 does not reduce the risk of death. Still, it is associated with a decrease in the risk of thrombotic events and increased risk of major bleeding.
Keywords: Anticoagulation, COVID-19, thrombosis, treatment
How to cite this article:
Stepanov E, Lobastov K, Tsaplin S, Schastlivtsev I, Bargandzhiya A, Laberko L, Rodoman G. Efficacy and safety of increased doses of anticoagulants in COVID-19 patients: A systematic review and meta-analysis. Vasc Invest Ther 2022;5:59-67 |
How to cite this URL:
Stepanov E, Lobastov K, Tsaplin S, Schastlivtsev I, Bargandzhiya A, Laberko L, Rodoman G. Efficacy and safety of increased doses of anticoagulants in COVID-19 patients: A systematic review and meta-analysis. Vasc Invest Ther [serial online] 2022 [cited 2023 Mar 22];5:59-67. Available from: https://www.vitonline.org/text.asp?2022/5/3/59/360870 |
| Introduction | |  |
According to official statistics, as of January 2022, more than 5.5 million deaths from infection caused by the novel coronavirus SARS-CoV-2 (COVID-19) have been registered worldwide.[1] Arterial and venous thrombosis appeared to be a frequent and threatening complication that increases the risk of death in inpatient settings.[2],[3],[4] The suggestion for early and active pharmacological prophylaxis for all hospitalized patients was stated in the early guidelines for COVID-19.[5] Hypotheses arose that the anticoagulants at increased doses may improve the clinical outcomes of viral pneumonia and reduce the risk of disease progression to severe forms, duration of hospital stay, and mortality rate. A paradoxical situation had arisen when, in the absence of specific antiviral therapy, anticoagulants began to be used as a treatment for infectious diseases. Antithrombotic drugs have been widely prescribed in the outpatient and inpatient management of COVID-19, despite the lack of evidence on their efficacy and safety. The ambiguous results of cohort studies did not provide an understanding of whether the implementation of anticoagulants is expedient.[6] The question about the optimal choice of drug, its dose, and duration of treatment is still pending.
The final answers should come from the results of randomized clinical trials (RCTs), which began to be published in the second half of 2021. This paper results from a systematic literature review and meta-analysis of recent RCTs assessing the benefits and risks of increased doses of anticoagulants in hospitalized patients with COVID-19.
The aim of the study was to evaluate the efficacy and safety of increased doses in comparison with standard doses of anticoagulants in patients hospitalized with COVID-19.
| Materials and Methods | | |
A systematic review and analysis of the literature was carried out in accordance with the PRISMA guidelines.[7] The protocol was developed at the beginning of October 2021 and, due to the urgency of circumstances and the threatening pace of development of the COVID-19 pandemic, was not registered in the PROSPERO register. The search for literature sources was performed in October 2021 via the PubMed database using the following keywords: “((“covid 19”[All Fields] OR “sars cov 2”[All Fields] OR “coronavirus disease”[All Fields]) AND “anticoagulation”[All Fields]) OR “anticoagulants”[All Fields]”. The search was limited by the type of publication corresponding to a RCT.
The criteria for inclusion of studies in the analysis were: (1) the design of a RCT; (2) number of participants >200; (3) comparison of increased (intermediate or therapeutic) dose of anticoagulants with standard (prophylactic or intermediate) dose; (4) results reported as the total number of patients or percentage of patients with outcomes; and (5) reported all-cause mortality within the observation period.
The exclusion criteria were: the outcome of interest is not reported; the value of outcomes could not be estimated based on published data; the publication is not in English; and inability to access the full-text version of the paper.
The primary outcome of interest was represented by the all-cause mortality over the observational period. In addition, thrombotic events were assessed, including arterial and venous thrombosis, major bleeding, and clinically relevant nonmajor (CRNM) bleeding. When assessing studies that accounted for major and minor, or symptomatic and asymptomatic thrombotic events, the analysis included the relevant outcome with the maximum number of thrombotic episodes. In addition, venous (deep-vein thrombosis, pulmonary embolism, and venous thromboses of other localizations as reported in the primary study) and arterial (myocardial infarction, stroke, major adverse limb events, systemic arterial thromboembolism, and others as reported in the primary study) thrombotic events were assessed separately. As part of the sensitivity analysis, outcomes were studied in subgroups of critically ill and noncritically ill (stable) patients, as well as in patients with increased D-dimer.
The search and selection of papers were carried out independently by two reviewers: the evaluation of full-text papers and data extraction were carried out by one author and checked by another one; the risk of bias was independently assessed by two other authors using the “Rob2Tool.”[8] All disagreements between the researcher were resolved by involving other authors. Statistical analysis was performed using the MedCalc software (MedCalc Software Ltd, Ostend, Belgium; https://www.medcalc.org; 2021). Publication bias was assessed using a funnel plot and Egger's test (significant bias at P < 0.05). The Chi-square test (significant heterogeneity at P < 0.1) and the I2 test (significant heterogeneity at >40%) were used to assess heterogeneity. Data were pooled and assessed in the intention-to-treat population (all randomized patients), which was not always compliant with the design of the original studies. For data synthesis, a random-effect model for significant heterogeneity or a fixed-effect model for nonsignificant heterogeneity was used. The results were represented as an odds ratio (OR) with 95% confidence intervals (CI).
| Results | | |
The diagram of literature search is presented in [Figure 1]. Totally, 8902 literature references were identified, and one additional reference was added from the authors' personal collection (the final results of the RAPID trial were not published at the time of the literature search; therefore, the preprint data were included in the analysis; at the time of manuscript preparation, the final paper is available).[9],[10] Based on the assessment of titles and abstracts, 8891 references were excluded from the analysis, which were found to be irrelevant. Thus, 12 full-text papers were reviewed for inclusion and exclusion criteria, of which only 6 were selected for qualitative and quantitative analysis. The general characteristics of the eligible trials are shown in [Table 1]. All trials were characterized by a low risk of bias as assessed by “Rob2Tool” [Figure 2]. | Table 1: Overall characteristics of the randomized clinical trials included in the qualitative and quantitative analysis
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The INSPIRATION trial and the multi-platform RCT (REMAP-CAP, ACTIV-4a, ATTACC) enrolled only patients with critical organ failure treated in the intensive care unit (ICU).[11],[12] The first one found no significant difference in the composite endpoint that combined venous and arterial thrombosis, need for extracorporeal membrane oxygenation, and all-cause mortality between patients treated with a standard prophylactic dose of low-molecular-weight heparin (LMWH: enoxaparin 40 mg once daily) and patients who received an intermediate dose of LMWH (enoxaparin 1 mg/kg once a day).[11] A three-platform RCT included patients requiring organ support (high-flow oxygen therapy through a nasal cannula, noninvasive or invasive mechanical ventilation, extracorporeal treatment, vasopressor, or inotropic support). The primary endpoint was represented with a mean number of days without organ support, assessed as a nominal scale (from 1 in case of death to 21 in case of discharge from the ICU before the end of the observation period). According to the results, there were no significant differences between patients who received therapeutic or standard doses of anticoagulants.[12] It is important to note that the type and dose of medications were not specified in this trial, which was of multicenter and adaptive design.
The second part of a three-platform RCT (REMAP-CAP, ACTIV-4a, and ATTACC) included noncritically ill patients who did not require similar organ support and were allocated to receive unspecified therapeutic or prophylactic anticoagulation for 21 days. When analyzing the similar endpoint, there was no significant difference in the number of days without organ support. The median value accounted for 21 days in both the groups. Meanwhile, the percentage of patients without deterioration that required organ support was significantly higher in the group of therapeutic anticoagulation.[13] The RAPID trial enrolled patients with a moderate-to-severe disease with elevated D-dimer: Any increase above the upper limit of normal (ULN) accompanied with a saturation of ≤93% or an increase >2 ULN, regardless of saturation. Patients were allocated to receive full therapeutic doses of unfractionated heparin (UFH) or weight-adjusted LMWH in comparison with standard prophylactic anticoagulation. There was no significant difference in the composite outcome of admission to ICU, need for invasive or noninvasive ventilation, and all-cause mortality.[9] The ACTION trial assessed the efficacy of therapeutic rivaroxaban (20 mg or 15 mg in case of renal impairment or co-administration with azithromycin) for 30 days (initial therapeutic doses of UFH or LMWH were accepted in critically ill patients) in comparison with standard prophylactic doses of UFH and LMWH for the inpatient period of treatment. Noncritically ill patients with elevated D-dimer were enrolled. The primary endpoint combined all-cause mortality, duration of hospital stay, and duration of oxygen support and was assessed by a hierarchical win ratio approach. The latter method involves a pairwise comparison of patients from experimental and control groups with the determination of the winner in each pair. According to the outcome hierarchy, the time to death was compared first (the winner is the one who survived longer) followed by the time to hospital discharge (the winner is the one who was discharged earlier) and the duration of oxygen support therapy (the winner is the one who received oxygen support therapy for a shorter time). As a result of comparisons of each patient from the experimental group with each patient from the control group, there were no significant differences in the number of winners.[14] The HEP-COVID trial included noncritically and critically ill patients with a significant increase in D-dimer level (>4 ULN) or signs of sepsis-induced coagulopathy (SIC score of >4 points). Therapeutic doses of enoxaparin (1 mg/kg body weight twice daily) were compared with standard prophylactic and intermediate doses of LMWH or UFH. A significant reduction of composite outcome that combined symptomatic and asymptomatic venous thromboembolism (VTE) (detected by duplex ultrasound scan performed on day 10 of hospitalization or before discharge), arterial thrombosis, and all-cause mortality was found.[15] However, therapeutic doses of heparins mainly affected the risk of thrombotic events but not the risk of death.
The final quantitative data synthesis combined treatment results of 5228 patients [Table 2]. Among all, 2660 received increased doses of anticoagulants, and other 2568 were treated with prophylactic anticoagulation. The observation period varied from 21 to 30 days. Based on the analysis of the funnel plot [Figure 3] and the Egger's test (P = 0.25), the publication bias was found to be not statistically significant. | Figure 3: Publication bias according to the funnel plot (P = 0.25 according to the Egger test)
Click here to view |
The administration of increased doses of anticoagulants had no effect on the risk of death (OR, 0.95; 95% CI, 0.73–1.25; P = 0.730; significant heterogeneity: I2 = 59.5%; P = 0.03; random-effect model used). However, it was associated with a reduced chance to develop thrombotic events (OR, 0.56; 95% CI, 0.43–0.73; P < 0.001; nonsignificant heterogeneity: I2 = 20.6%; P = 0.28; fixed-effect model used) in parallel with a significant increase in the risk of major bleeding (OR, 1.86; 95% CI, 1.23–2.80; P = 0.003; nonsignificant heterogeneity; I2 = 0%; P = 0.68; fixed-effect model used) and nonmajor clinically relevant bleeding (OR, 3.65; 95% CI, 1.65–8.09; P = 0.001; nonsignificant heterogeneity; I2 = 0%; P = 0.36; fixed-effect model) [Figure 4],[Figure 5],[Figure 6],[Figure 7]. Of overall thrombotic events, there was a significant reduction of VTE (OR, 0.48, 95% CI, 0.36–0.65; P < 0,001; nonsignificant heterogeneity: I2 = 0%; P = 0.57; fixed-effect model) but not arterial thrombosis (OR, 0.94; 95% CI, 0.63–1.43; P = 0.783; nonsignificant heterogeneity; I2 = 0%; P = 0.94; fixed-effect model). | Figure 4: All-cause mortality (significant heterogeneity: P = 0.03; I2 = 59.5%; random-effect model used; OR, 0.95; 95% CI, 0.73–1.25; P = 0.730). OR: Odds ratio, CI: Confidence interval
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 | Figure 5: Thrombotic events (nonsignificant heterogeneity: P = 0.28; I2 = 20.6%; the fixed-effects model; OR, 0.56; 95% CI, 0.43–0.73; P < 0.001). OR: Odds ratio, CI: Confidence interval
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 | Figure 6: Major bleeding (nonsignificant heterogeneity: P = 0.68; I2 = 0%; fixed-effects model used; OR, 1.86; 95% CI, 1.23–2.80; P = 0.003). OR: Odds ratio, CI: Confidence interval
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 | Figure 7: Clinically relevant nonmajor bleeding (nonsignificant heterogeneity: P = 0.36; I2 = 0%; fixed-effect model used; OR: 3.65; 95% CI, 1.65–8.09; P = 0.001). OR: Odds ratio, CI: Confidence interval
Click here to view |
Within the sensitivity analysis, similar results were obtained in the subgroups of critically ill and noncritically ill patients, as well as in individuals with elevated D-dimer [Figure 8]. The maximum reduction in the risk of thrombotic events was found for the subgroup of patients with elevated D-dimer (OR, 0.48; 95% CI, 0.32–0.70; P < 0.001; I2 = 36.4%; P = 0.19; nonsignificant heterogeneity; fixed-effect model used). | Figure 8: Analysis of the efficacy and safety of the use of high-doses of anticoagulants in comparison with standard prophylactic ones in separate subgroups of patients (A – critically ill patients; B - stable patients; C - patients with increased D-dimer)
Click here to view |
| Discussion | | |
The results of RCTs are crucial for the evaluation of the benefit–risk ratio for any kind of treatment. Conducting RCTs in the context of the ongoing COVID-19 pandemic is challenging but essential. Since the emergence of new coronavirus infection in the world, more than 100 studies have been launched to evaluate the efficacy and safety of the antithrombotic treatment in the outpatient and inpatient management of COVID-19: 11 RCTs in outpatient settings, 50 RCTs in noncritically ill patients, 33 RCTs in critically ill patients, and 8 RCTs on extended pharmacological prophylaxis after discharge.[16] A minimal portion of these studies has been completed and published. At the time of the systematic literature review in October 2021, we could only find 6 completed RCTs that enrolled more than 200 patients.
In opposite to the prevailing hypothesis about the leading role of coagulopathy and endotheliopathy in COVID-19, the use of higher doses of anticoagulants does not improve patient survival but significantly increases the risk of major and CRNM bleeding.[5] Meanwhile, increased doses of heparins can reduce the risk of thrombotic events, particularly VTE, especially in patients with elevated D-dimer. Deep-vein thrombosis and pulmonary embolism along with the thrombosis of small branches of the pulmonary artery can be detected in 17%–35% of patients with COVID-19, aggravating the underlying disease and increasing the risk of death.[2],[4],[17],[18] The protective effect of anticoagulants at higher doses may be useful in patients with individually increased risk of venous VTE, which could be assessed by Padua, Caprini, and Improve-DD scores. All of them have been validated in COVID-19 settings, demonstrating a positive correlation with the incidence of VTE and mortality.[19],[20],[21],[22],[23] However, these scores have a different sensitivity for discrimination of VTE risk groups. Furthermore, the individual thresholds that determine the increased individual VTE risk may be different in COVID-19 settings in comparison with standard values. Regarding Caprini score, the maximum increase in the VTE incidence was found in patients with a score of 11 and higher if they received intermediate doses of LMWH.[19] In such individuals, the combination of pharmacological prophylaxis with intermittent pneumatic compression shows higher efficacy in preventing VTE and may be useful.[24],[25] Finally, one should not forget about the threat of hemorrhagic complications, which occur with a mean incidence of 7.8% that may significantly increase with higher doses of anticoagulants.[2] For this reason, the protective effect of therapeutic anticoagulation may be eliminated by the development of major bleeding. That should be reflected in the all-cause mortality which was not affected by therapeutic anticoagulation according to the current meta-analysis. Thus, future research should be focused on the evaluation of efficacy and safety of anticoagulants in higher doses and/or standard doses in combination with mechanical methods (elastic compression, intermittent pneumatic compression) in selected patients with individually high VTE risk and low bleeding risk. Considering that most ICU patients are already at high or extremely high risk of VTE, the assessment of bleeding risk with modern scoring systems seems to be crucial for suggesting optimal pharmacological and mechanical prophylaxis.
While according to the current data, the routine use of therapeutic anticoagulation in hospitalized COVID-19 patients does not impact the short-term survival, someone can consider the significance of lowering VTE risk concerning the further development of the postthrombotic syndrome and chronic thromboembolic pulmonary hypertension that affect the quality of life and long-term survival. In this point of view, using increased doses of anticoagulants may be essential but need to be established in further studies with long-term follow-up.
Thus, anticoagulants did not appear to be a universal medical treatment for novel coronavirus infection, but they implement their direct action to reduce the risk of thrombosis, particularly VTE, at the cost of increasing the risk of bleeding. That requires an individual and accurate assessment of the benefits and risks.
Limitations
This systematic literature review and meta-analysis has several limitations related to primary RCTs. Most studies combined anticoagulants of different types, doses, and duration, so it was impossible to perform separate analysis according to the anticoagulation regimen. Fuethermore, included trials combined different thrombotic outcomes, such as venous and arterial, major and minor, and symptomatic and asymptomatic, so it was not always possible to extract separate results for the current thrombotic outcome. For this reason, we decided to combine all thrombotic events and use those with the highest reported incidence (e.g. minor, asymptomatic). Thus, not all thrombotic events reported in the trials may be considered clinically relevant. Finally, a minority of studies reported the incidence of CRNM bleeding, so analysis according to this outcome is limited.
| Conclusions | | |
The use of higher doses of anticoagulants in inpatients with COVID-19 does not reduce the risk of death but is associated with a reduced risk of thrombotic complications, particularly VTE, at the cost of an increased risk of major bleeding.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]
[Table 1], [Table 2]
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