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Risk of venous thromboembolism in patients with COVID‐19: A systematic review and meta‐analysis

Abstract Background Venous thromboembolism (VTE) is frequently observed in patients with coronavirus disease 2019 (COVID‐19). However, reported VTE rates differ substantially. Objectives We aimed at evaluating available data and estimating the prevalence of VTE in patients with COVID‐19. Methods We conducted a systematic literature search (MEDLINE, EMBASE, World Health Organization COVID‐19 database) to identify studies reporting VTE rates in patients with COVID‐19. Studies with suspected high risk of bias were excluded from quantitative synthesis. Pooled outcome rates were obtained within a random effects meta‐analysis. Subgroup analyses were performed for different settings (intensive care unit [ICU] vs non‐ICU hospitalization and screening vs no screening) and the association of d‐dimer levels and VTE risk was explored. Results Eighty‐six studies (33,970 patients) were identified and 66 (28,173 patients, mean age: 62.6 years, 60.1% men, 19.4% ICU patients) were included in quantitative analysis. The overall VTE prevalence estimate was 14.1% (95% confidence interval [CI], 11.6‐16.9), 40.3% (95% CI, 27.0‐54.3) with ultrasound screening and 9.5% (95% CI, 7.5‐11.7) without screening. Subgroup analysis revealed high heterogeneity, with a VTE prevalence of 7.9% (95% CI, 5.1‐11.2) in non‐ICU and 22.7% (95% CI, 18.1‐27.6) in ICU patients. Prevalence of pulmonary embolism (PE) in non‐ICU and ICU patients was 3.5% (95% CI, 2.2‐5.1) and 13.7% (95% CI, 10.0‐17.9). Patients developing VTE had higher d‐dimer levels (weighted mean difference, 3.26 µg/mL; 95% CI, 2.76‐3.77) than non‐VTE patients. Conclusion VTE occurs in 22.7% of patients with COVID‐19 in the ICU, but VTE risk is also increased in non‐ICU hospitalized patients. Patients developing VTE had higher d‐dimer levels. Studies evaluating thromboprophylaxis strategies in patients with COVID‐19 are needed to improve prevention of VTE.


| INTRODUCTION
The coronavirus disease 2019 , caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and formally declared a pandemic by the World Health Organization (WHO) in March 2020, is an infectious disease with a global impact on public health. It affects primarily the respiratory system; however, involvement of other organ systems may occur, especially with increasing severity of the disease. The high inflammatory burden associated with COVID-19 and inflammation in the vascular system can also result in cardiovascular complications with a variety of clinical presentations. [1][2][3] Early studies reported on coagulation abnormalities and coagulopathy with a rather prothrombotic phenotype in patients with COVID-19. 4,5 With the better understanding of COVID-19 and its clinical course, venous thromboembolism (VTE), a disease entity covering pulmonary embolism (PE) and deep vein thrombosis (DVT), has been recognized as a particular complication of the disease. Initial studies have found alarmingly high rates of PE in patients with severe COVID-19 treated at intensive care units (ICUs), reporting VTE incidences of up to 50%. 6 In response to the clinical challenges and the absence of high-quality evidence, expert groups and scientific societies have released guidance statements to address questions concerning diagnosis, prevention, and treatment of VTE in patients with COVID-19, which suggest the broad application of thromboprophylaxis in patients with severe COVID-19 in the absence of high bleeding risk. 7,8 In several studies of different design, size, and quality, rates of VTE in patients with COVID-19 have been reported. However, a definitive and robust estimate of the VTE risk in patients with COVID-19 is currently not available as of the high variability of reported rates. Therefore, the true underlying burden of VTE in patients with COVID-19 is still not fully understood. In the light of the ever-growing infection rates worldwide and the clinical challenges in patient management, understanding of the true frequency of VTE in COVID-19 is important and may help to support clinical decision making.
We conducted a systematic review of the literature and meta-analysis of available data to determine the prevalence of VTE in patients with COVID-19. Our aim was to provide an overall estimate of VTE by aggregating reported rates and to thoroughly explore differences in the VTE prevalence according to study design and the health care setting, which may account for the high degree of heterogeneity in reported rates.

| Register and protocol
We conducted a systematic review of the literature and metaanalysis of published data on the prevalence of VTE in patients with COVID-19. The study protocol was prepared before the initiation of the literature research according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) Protocols 2015 9 and submitted to PROSPERO (international prospective register of systematic reviews) on June 11, 2020 (protocol ID: CRD42020191652). The study was conducted according to the PRISMA and the guidance for reporting meta-analysis of observational studies in epidemiology. 10,11

| Eligibility criteria
Full-text articles, letters, brief reports, editorials, and correspondences published in 2019 or 2020 with available title and abstract in English were eligible for inclusion. Inclusion criteria comprised studies reporting on patients with objectively confirmed COVID-19 in combination with reporting rates of VTE as outcome of the study (DVT and/or PE). Study designs eligible for inclusion were cohort studies (prospective and retrospective), cross-sectional studies, and interventional studies with VTE reported as an outcome or adverse event. Study designs that did not allow prevalence estimates such as case reports and case series including autopsy studies were excluded. and abstract of the identified studies, and potentially eligible studies underwent full-text evaluation. The inclusion of a study was based on the consensus of its suitability by the two researchers. Where consensus opinion could not be reached, a third reviewer was consulted to make the final decision (CA). All three literature researchers are medical doctors with a thorough research background in the field of thrombosis. The most recent literature research was conducted on August 26, 2020. Figure 1 displays the process of study identification following a PRISMA flow diagram.

| Data extraction
Studies that fulfilled the predefined inclusion criteria and did not meet any exclusion criteria were subjected to data extraction. In the case of multiple studies reporting on the same patient cohort, results were merged and considered only once. Data extraction of predefined baseline and outcome variables was performed. These included methodological specifics of the studies (study design, health care setting), clinical information of the study population (demographics, comorbidities, disease severity, use of pharmacologic thromboprophylaxis, ultrasound screening, and d-dimer levels), and outcome specifics (definition, type, and rate of VTE). The full list of extracted variables is provided in the Supplementary Methods. All data were independently extracted from eligible studies by two authors (SN, FM) to ensure data reliability, with inconsistencies resolved by discussion with a third author (CA).

| Risk of bias evaluation
Methodology of identified studies was assessed independently by two researchers (FM, SN). Risk of bias of included studies was independently rated with a validated tool for assessing studies reporting prevalence data (Joanna Briggs Institute Critical Appraisal Checklist; Appendix S1). 12 This tool consists of nine categories each classifying the study as low risk of bias, high risk of bias, or unclear.
Subsequently, an overall evaluation based on these categories was derived. Studies with suspected high risk of bias were excluded from the subsequent quantitative data synthesis. Potential publication bias was assessed graphically within a funnel plot, plotting the prevalence estimate of VTE against its standard error ( Figure S1A and B).

| Outcomes, definitions, and quantitative data synthesis
The primary outcome of the present meta-analysis is VTE, defined

| Statistical methods
All statistical analyses were performed with the commercially available package STATA 15.0 (Stata Corp, Houston, TX, USA). Summary statistics were aggregated from included studies. Pooled prevalence of outcome variables was estimated by aggregating study results within a random-effects meta-analysis utilizing the STATA package metaprop. 13 The Freeman-Tukey double arcsine transformation was used to normalize variance, and 95% confidence intervals (CIs) were estimated by the score method. Heterogeneity of included studies is reported by I 2 as a measure of between-study variability beyond random variation. To explore differences in baseline d-dimer between patients with VTE and patients without VTE, mean d-dimer levels and corresponding standard deviation were calculated from reported median, interquartile range, and sample size according to Wan et al. 14 Weighted mean differences (WMDs) in baseline d-dimer levels were calculated within a pooled analysis weighted by corresponding sample sizes. Finally, differences in VTE risk according to sex and comorbidities was explored within a random-effects meta-analysis using the Mantel-Haenszel procedure.

| Selection process and general study characteristics
We identified 2018 records upon literature research after the removal of duplicates. Titles and abstracts of these identified studies were screened for conformity with our predefined inclusion and exclusion criteria, and 175 records were subsequently included in the full-text evaluation. From those, 86 studies were included in the qualitative data synthesis. Figure 1 displays the screening and selection process, and the reasons for excluding studies.
Pooled summary characteristics of the 86 eligible studies reporting on VTE in patients with COVID-19 are displayed in Table 1 A comprehensive summary of each study including the respective study design, demographics, thromboprophylaxis strategy, and outcome rates is presented in Tables S1 and S2.
Pooled patient characteristics and comorbidity data are displayed in Table 2

| Prevalence of venous thromboembolism
After excluding studies with a high risk of underlying bias, quantitative results from 66 studies were aggregated within a meta-analysis,   Table 3, and corresponding forest plots are available in Figures S3A and B.  within a random-effect meta-analysis (  (Figure 3).

| DISCUSSION
In this systematic review and meta-analysis, data from studies re- We believe that our meta-analysis is representative of patients with COVID-19 requiring hospitalization, as our systematic review confirmed the previously reported sex differences in patients with COVID-19 (higher proportion of men among more severe disease). 98 The sex differences further increased among patients admitted to the ICU, suggesting that men were more likely to suffer from greater disease severity than women. 99 Figure S2). We also provided data on thromboprophylaxis modalities for the respective studies to allow a better interpretation of differences observed in the studies. However, the generalizability of the results of our systematic review and meta-analysis still needs to be interpreted with caution because only data from patients in North America, Europe, and Asia were available and included in the meta-analysis. Upon visual inspection, VTE rates across continents and countries seem to be mainly related to between-study heterogeneity with respect to study design, clinical setting, and local clinical practice with regard to thromboprophylaxis ( Figure S4).
Given the high mortality, especially in ICU patients with COVID-19, competing risk of death might lead to an underdiagnosis of VTE.
Further, the concern of restricting the use of imaging to avoid disease exposure to health care workers might further lead to false low rates of VTE in patients with COVID-19. These uncontrollable factors in a study-level analysis should be considered upon interpreting and generalizing our findings. Also, the practice of avoiding imaging due to concerns about health care worker exposure should be critically reviewed given the risk of underdiagnosis and consequently undertreatment of patients.
Furthermore, exploratory analysis of d-dimer levels between patients who developed VTE and those who did not is limited by the lack of patient-level data and the inability to adjust for between-assay variability. Therefore, this exploration should be interpreted with appropriate caution and regarded as hypothesis generating.
Finally, there is some evidence that nonhospitalized patients with COVID-19 are at increased risk of developing VTE as well. 105 Because of the unavailability of sufficient data within our meta-analysis, we were unable to provide prevalence estimates for this population of patients, and our findings are therefore not representative for the outpatient setting of COVID-19.
In summary, we found a high prevalence of VTE in patients with COVID-19 in hospitalized non-ICU patients, and especially high VTE rates in those being critically ill and requiring intensive medical care.
There is a clinical need for further research to better understand the risk and prevent VTE in patients with COVID-19. These findings support the broad use of thromboprophylaxis, specifically in ICU patients. Future randomized clinical trials are needed to assess whether patients with COVID-19 may benefit from an intensified anticoagulation approach compared to standard thromboprophylaxis or whether a biomarker-based personalized thromboprophylaxis regimen reduces the high prevalence of VTE in patients with COVID-19.

ACKNOWLEDGEMENTS
This study was supported by research funding from the Austrian Science Fund (FWF) (Special Research Program [SFB]-54).

AUTHOR CONTRIBUTIONS
SN and FM contributed to study design, data collection, data interpretation, statistical analysis, and drafting of the manuscript. CA contributed to study design, data interpretation, and critical review of the manuscript. IP contributed to data interpretation and critical review of the manuscript. SN, FM, and CA are the guarantor of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All authors read the manuscript and approved its submission.

RELATIONSHIP DISCLOSURE
SN and FM report no potential conflict of interest. BJ has received reimbursement for scientific advice from Bayer, Octapharma, and Sanofi.