Coronavirus disease-19 (COVID-19) is a serious pandemic associated with an elevated risk of venous and arterial thrombosis.1 There is no consensus on the anticoagulant approach to be implemented to reduce the thrombotic risk; thus, most international guidelines recommend standard thromboprophylaxis with use of intermediate doses restricted to high-risk and critically ill patients.2 Therapeutic dosage superiority of anticoagulants in reducing thrombosis in moderately but not severely ill patients or uncertain cost-benefit of full-intermediate anticoagulation versus prophylactic doses were reported by previous meta-analyses.3,4 Therefore, we decided to perform a new, updated meta-analysis of randomized clinical trials comparing the effects of full anticoagulation (FA) versus prophylactic-intermediate anticoagulation (PIA) on death and thrombotic-related events in COVID-19 patients.
Eligibility criteria
Types of studies: randomized clinical trial studies that assessed the effect of therapeutic versus prophylactic anticoagulant therapy in COVID-19 hospitalized patients. No language, publication date, or publication status restrictions were imposed. We conducted all analyses according to the intention-to-treat principle. For trials with a factorial design, we based main results on 2-way analyses, that is, all trial participants receiving FA were compared with all those treated with PIA dose.
Information sources
The studies were identified by searching electronic databases. This search was applied to Pubmed, ISI Web of Science, SCOPUS and Cochrane database. The last search was run on November 14, 2021. Reference lists of all studies included in the present meta-analysis were screened for potential additional eligible studies.
Search
Two investigators independently searched in the electronic databases combining the following text terms and MeSH terms: "COVID-19"[All Fields] OR "COVID-19"[MeSH Terms] OR "SARS-CoV-2"[All Fields] OR "sars-cov-2"[MeSH Terms] OR "Severe Acute Respiratory Syndrome Coronavirus 2"[All Fields] OR "NCOV"[All Fields] OR "2019 NCOV"[All Fields] AND ("thrombosis"[MeSH Terms] OR "thrombosis"[All Fields])) AND ("anticoagulants"[Pharmacological Action] OR "anticoagulants"[MeSH Terms] OR "anticoagulants"[All Fields] OR "anticoagulant"[All Fields]) AND "humans"[MeSH Terms]Studies. We limited our search to human studies.
Study selection
Two authors independently reviewed the titles and abstracts generated by the search. Studies were excluded if the title and/or abstract showed that the papers did not meet the selection criteria of our meta-analysis. Studies not including a control group and animal studies were excluded. Case reports, editorials, commentaries, letters, review articles, guidelines were also excluded from the analysis. We defined the following exclusion criteria: (i) studies that included only the intermediate anticoagulation; (ii) studies unrelated to our topic; (iii) studies without randomization assignment of the treatment. A flowchart of the selection studies is reported in the Online Supplementary Figure S1.
Main analysis
We evaluated the effect of FA versus PIA dose in COVID-19 hospitalized patients. Our primary outcome was to compare the effect of these treatments on death and thrombotic events. Our secondary endpoints were the comparison of these treatments on death, arterial and venous thrombotic events, arterial thrombotic events and VTE; the safety endpoint was to evaluate the effect on major bleedings. This meta-analysis was conducted and reported according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) Statement issued in 2009.
Statistical analysis
We allocated the results of each trial as dichotomous frequency data. Risk ratios (RR) and 95% confidence intervals (CI) were calculated. Data were pooled and compared with a random-effect model. We calculated the number needed to treat (NNT) and the number needed to harmful (NNH) as the reciprocal of the absolute risk reduction (ARR).
Statistical heterogeneity was calculated by the I2. Presence of publication bias was explored using funnel plots of effect size against standard error and Egger's test. The software Comprehensive Meta Analysis (version 2.2.064, USA, 2011) and R (version 3.1.2, Vienna, 2014) supported the analysis.
Seven studies5-11 evaluated the effect of FA versus PIA. The relevant parameters of each study are reported in the Table 1. Antiplatelet drugs were more frequently used in patients treated with FA (11.9%) versus PIA (10.6%). A heterogeneous definition of the severity of COVID-19 infection was found among the studies. Briefly, we considered as severe patients those: hospitalized at admission in an intensive care unit (ICU), or with respiratory failure requiring mechanical ventilation or organ support as high flow oxygen, extracorporeal life support, vasopressors, or inotropes. Comparison between subgroups with severe and non-severe disease was prespecified analysis. Funnel plots are reported in the Online Supplementary Figure S2.
Table 1.Table 1. Characteristics of the studies.
No difference was observed between the rates of death and thrombotic events (as composite outcome) in patients treated with FA (16.5%) versus PIA (19.9%) in seven studies including 4,734 patients (Figure 1A). Subgroup analysis according to severity showed a lower rate of this composite outcome in patients treated with FA as compared to those treated with PIA in non-severe (RR=0.53, 95% CI: 0.30-0.94), but not in severe patients (Figure 1A). No difference was observed between the rates of death in patients treated with FA (15.4%) and PIA (14.8%) in seven studies including 4,741 patients (Figure 1B).
Figure 1.Forrest plots of death and thrombotic events. (A) Forest plots for death and thrombotic events according to the subgroups for full anticoagulation (FA) and prophylactic-intermediate anticoagulation (PIA) doses. (B) Forest plots for death according to the subgroups for FA and PIA doses. (C) Forest plots for arterial and venous and thrombotic events according to the subgroups for FA and PIA doses.
In seven studies including 4,732 patients a difference was observed between the rates of arterial and venous thrombotic events in patients treated with FA (4.0%) compared to those treated with PIA (7.2%, RR=0.58, 95% CI: 0.45-0.76), both in severe and non-severe patients (Figure 1C). In six studies (n=4,667 patients) a difference was observed between the rate of venous thrombotic events (VTE) in FA (2.7%) versus PIA patients (5.9%, RR=0.47, 95% CI: 0.35-0.63), both in severe and non-severe patients (Figure 2A). No significant difference was observed between the rates of arterial thrombotic events in three studies including 1,332 patients treated with FA or PIA (Figure 2B).
Figure 2.Forrest Plots of thrombotic events and bleeding. (A) Forest plots for venous thrombotic events according to the subgroups for full anticoagulation (FA) and prophylactic-intermediate anticoagulation (PIA) doses. (B) Forest plots for arterial thrombotic events. (C) Forest plots for major bleeding events according to the subgroups for FA and PIA doses.
Six studies, including 4,650 patients, reported major bleeding rates. Major bleeding was observed with an higher rate in FA (2.5%) versus PIA patients (1.4%, Figure 2C).
Number needed to treat (NNT) and number needed to harm (NNH) values for major bleedings and several outcomes are reported in the Online Supplementary Figure S3, in all studies and according to severity.
The study suggests a beneficial effects of FA towards venous thrombosis compared to PIA COVID-19 patients. Even if the risk of major bleeding is higher in FA-treated patients, the overall cost benefit of treatments is in favor of FA.
It is, so far, unclear whether FA is superior to lower doses of anticoagulants such as PIA on the incidence of death, arterial and venous thrombosis, and major bleeding in COVID-19 patients. The results of the present study show that, in comparison with PIA, FA did not affect the rate of death or arterial thrombosis but reduced the incidence of venous thrombosis interdependently of the clinical presentation, ie., either severe or non-severe disease. As expected, the rate of major bleeding was higher in patients on FA. Concomitant treatment with antiplatelet drugs may be an important confounder as we would expect a higher risk of bleeding in patients under full anticoagulation12 but lack of clinical information on this specific subgroup precludes definite conclusion.
The study has implications and limitations. Even if the full anticoagulation did not reduce the risk of death, the positive impact on VTE is of clinical relevance for the management and the potentially harmful long term effects of VTE; in accordance with this, for VTE and major bleeding the NTT and NNH are 31 and 90 respectively and NTT/NNH 0.34. This finding adds more to the previous meta-analyses3,4 as the bleeding risk seems to be lower and the cost-benefit in favor of full anticoagulation in either moderate or severely ill patients. Clinical outcomes were restricted to 30-day followup, thereby it is unclear the impact of several anticoagulant regimens on clinical outcomes, death included, during long term followup.
In conclusion, the results of this meta-analysis suggest the potential usefulness of FA to reduce VTE in COVID-19 patients with either severe or non-severe disease.
Further RCT with large sample size are needed to support this finding.
Footnotes
- Received January 7, 2022
- Accepted March 22, 2022
Correspondence
Disclosures
No conflicts of interest to disclose.
Contributions
FV and LL developed the study concept and design; data: PP, ADC, LL and FV analyzed and interpreted data; FV and LL wrote the initial draft; PP, ADC and GAC critically revised the manuscript for important intellectual content; ADC and LL performed the statistical analysis.
Data-sharing statement
All the data used to support the results of this study are available from the corresponding author upon request.
References
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