key: cord-0721080-w8egoqc6 authors: Srivastava, Rashmi; Parveen, Rizwana; Mishra, Pinki; Saha, Nilanjan; Bajpai, Ram; Agarwal, Nidhi Bharal title: Venous thromboembolism is linked to severity of disease in COVID‐19 patients: A systematic literature review and exploratory meta‐analysis date: 2021-09-28 journal: Int J Clin Pract DOI: 10.1111/ijcp.14910 sha: 5d99840a4d143c61642d6753640874a187020ffb doc_id: 721080 cord_uid: w8egoqc6 PURPOSE: Coronavirus disease‐2019 (COVID‐19) may predispose to venous thromboembolism (VTE) and arterial thromboembolism because of excessive inflammation, hypoxia, immobilisation and diffuse intravascular coagulation. The understanding of the association might be helpful in early vigilant monitoring and better management of COVID‐19 patients at high risk. Thus, in this meta‐analysis, we aim to assess the association of VTE with the severity of COVID‐19 disease. METHODS: A literature search was conducted on PubMed and Cochrane Central Register of Controlled Trials using the keywords “COVID‐19 and thromboembolism” and “COVID‐19 and embolism,” till 20 February 2021. Thirteen studies including 6648 COVID‐19 patients were incorporated in this systematic review and exploratory meta‐analysis. RESULTS: The analysis revealed nearly three times more risk than intensive care unit (ICU) care in patients with VTE compared to non‐VTE patients (RR: 2.78; 95% CI: 1.75‐4.39; P < .001; I (2): 65.1%). Patients with pulmonary embolism and deep vein thrombosis are at increased risk of being admitted to ICU (RR: 2.21; 95% CI: 1.86‐2.61; P < .001; I (2): 41.2%) and (RR: 2.69; 95% CI: 2.37‐3.06; P < .001; I (2): 0.0%), respectively. The quality assessment indicated that the included studies were of fair quality. CONCLUSIONS: Our findings suggest that VTE either deep vein thrombosis or pulmonary embolism may have a negative effect on the health status of COVID‐19 patients. This study highlights the need to consider measures for reducing thromboembolism risk amongst COVID‐19 patients. patients has been reported in various studies. 1, [12] [13] [14] A retrospective study reported a high prevalence of deep vein thrombosis and associated adverse outcomes in COVID-19 patients. 15 Another prospective study demonstrated a very high incidence of deep vein thrombosis in COVID-19 patients requiring ICU admission. 16 A cohort study observed a high risk for VTE in COVID-19 patients requiring ICU care. 14 Several studies have demonstrated a higher incidence of VTE in COVID-19 patients, 1, 14, 17, 18 however, the effect of the incidence of VTE on the prognosis of the disease needs further exploration. Precise knowledge of the incidence of thrombotic complications in COVID-19 patients is important for decision-making with regards to the intensity of thromboprophylaxis. 13 The understanding of the association might be helpful for clinicians in early vigilant monitoring and better management of COVID-19 patients at high risk. Thus, in the present exploratory meta-analysis, we aimed to assess the association of VTE with the severity of disease in COVID-19 patients. Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines extension for scoping reviews 19 was followed for designing and reporting this systematic literature review. We searched PubMed and Cochrane Central Register of Controlled Trials until 20 February 2021 using the keywords "COVID-19 and thromboembolism" and "COVID-19 and embolism." Grey literature was searched on Clinical Trial Registry of India, Clinicaltrials.gov, Google Scholar and reference list of eligible articles. Studies describing the incidence of thromboembolism according to disease severity were included. We excluded duplicate publications, reviews, editorials, case reports, letters, meta-analyses, protocols, studies in a language other than English and studies not reporting the required data. The first author (RS) searched data and screened articles for eligibility. Senior author (RP) double checked all the included articles and any dispute was resolved by consensus. Two reviewers (RS and RP) assessed the quality of data included in this study using the National Institute of Health (NIH) quality assessment tools developed by the National Heart, Lung, and Blood Institute. 20 We preferred the NIH tool because it is comprehensive and widely accepted for an exhaustive assessment of data quality. We rated the general quality of included studies nearly as good, fair and poor and incorporated them within the result of the meta-analysis. Data were inputted into a standardised data extraction table (Excel) and independently checked by a second reviewer (RP) for accuracy. The following variables were extracted: name of the first author, year of publication, study design, age, gender, number of patients in ICU and non-ICU care with comorbidities as well as prognosis. The disease was considered severe if the patient with COVID-19 required ICU care. We performed an exploratory meta-analysis to understand the magnitude and direction of the effect estimate. Relative risk (RR) was calculated and presented with respective 95% confidence intervals (CIs). Mantel-Haenszel random effects meta-analysis using DerSimonian and Laird method was used to pool RR. 21 Heterogeneity between studies was assessed using the χ 2 -based Cochran's Q statistic (P < .1 • We conducted a systematic review and meta-analysis of the studies describing the incidence of venous thromboembolism in COVID-19 patients requiring intensive care unit care. • We searched PUBMED and Cochrane Central Register of Controlled Trials using the keywords "COVID-19 and thromboembolism" and "COVID-19 and embolism" till 20 February 2021. • We pooled dichotomous outcomes as risk ratios and continuous outcomes as mean differences with 95% confidence intervals, both under the random or fixed effects model. • This study highlights the need to consider measures for reducing thromboembolism risk amongst COVID-19 patients. • Precise knowledge of the incidence of thrombotic complications in COVID-19 patients is important for decision-making with regards to the intensity of thromboprophylaxis. • The understanding of the association might be helpful in early vigilant monitoring and better management of COVID-19 patients at high risk. considered as the presence of heterogeneity) and I 2 statistics (>50% representing moderate heterogeneity). 21 Forest plot was produced, and subgroup analysis was conducted according to the study design. The 95% prediction interval (PI) was calculated, which estimates the uncertainty bounds for a new study evaluating that the same association by considering between-study heterogeneity. Publication bias was not assessed as a total number of studies were <10 for a given outcome. 21 P value < .05 was set as statistical significance for comparing study level effects. The systematic search yielded a total of 1607 publications. Out of 1607 studies, 920 studies were found using the keywords "COVID-19 and thromboembolism," and 686 studies with keywords "COVID-19 and embolism." One study was found from another source. After removing duplicates, 1200 articles were found to be potential publications for screening. After the application of predefined inclusion and exclusion criteria, a total of 13 studies were included for the meta-analysis ( Figure 1 ). The incidence of VTE either deep vein thrombosis or pulmonary embolism was reported in ICU care and non-ICU care in 12 studies, 12,14-17,22-28 and one study reported the incidence of VTE either deep vein thrombosis or pulmonary embolism in survivors and non-survivors group. 1 Among the 13 included studies, a total of 6648 patients were enrolled, including 3973 males and 2675 females. The baseline characteristics of the subjects included in these studies are provided in Table 1 . We assessed the quality of data in the included studies using the NIH quality assessment tools. The quality assessment indicated that most of the included studies were of fair quality. All the studies clearly stated the research question or the objective, the study population was clearly specified and defined, all the subjects were selected from similar populations. The detailed result of the quality assessment is provided in Supplementary File 1. In order to assess the association between VTE and disease severity, four cohort studies qualified for inclusion in quantitative analysis. To assess the association between pulmonary embolism and disease I 2 : 37.8%) ( Figure S2 ). For the outcome, in order to assess the association between deep patients and revealed that the overall proportion of patients with pulmonary embolism was 5.4%, increasing to 16.2% in ICU patients. Pulmonary embolism was diagnosed in 3.5% patients receiving ward-based care. The higher incidence of pulmonary embolism in ICU patients is consistent with previous studies (16.7%-47%). 28 A cohort study reported a high incidence of pulmonary embolism in the critically ill COVID-19 patients, also it was found to be one of the major thrombotic complications in this study. 13 Therefore, pulmonary thromboembolism may be considered in COVID-19 patients with sudden onset of oxygenation deterioration, respiratory distress and reduced blood pressure as these patients are often immobile and present with an acute inflammatory state. 29 The present meta-analysis demonstrated the positive associa- No potential conflict of interest to declare in relation to this publication. Rashmi and Nidhi. Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia Venous thromboembolism complicated with COVID-19: what do we know so far? 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