Search results and flow of search strategies are available in the supplementary index. We identified a total of 762 articles (395 articles from Medline, 320 articles from Embase, 47 from Scopus). Grey literature search revealed 1900 articles from Google scholar, MedRxiv, and SSRN. After duplicates were removed, there were 1126 articles among which we underwent title and abstract screening. Of these, 935 articles were excluded. The remaining 191 full-text articles were assessed for eligibility criteria, and 170 articles were excluded (Suplementary index). The most common reasons for exclusion were case report or case series, which did not provide data or incidence reports and review articles. A total of 22 studies were included in the analysis. We performed a grey literature search on June 30th, 2020, and found 14 articles relevant and met the eligibility criteria.
Risk of bias assessment
All 36 studies were assessed for risk of bias using risk of bias for prevalence studies.(12) Most studies were subjected to moderate risk of bias owing to the representative of the population since they specifically reported outcomes in ICU or non-ICU settings for which were not representative of all hospitalization with COVID-19. All but seven studies were retrospective in design. All imaging studies have a high risk of bias due to selective patients who underwent imaging studies. In addition, the indications for computed tomography pulmonary angiography (CTPA) or CUS were varied between studies. We found that the criterion on national representative of the population was not applicable to the included studies since they were not population-based prevalence studies.The internal validity criterion of prevalence period was also not applicable due to, in our study, we intended to assess the prevalence of symptoms/complications (thrombotic outcomes) rather than the prevalence of the actual disease. The risk of bias assessment is presented in supplementary index.
Characteristics of the included studies
A total of 36 studies were included. Characteristics of the included studies are shown in tables 1 and 2. Twenty-nine studies were retrospective, and 7 studies were prospective studies. Twenty-seven studies were from Europe (9 from France, 6 from Italy, 3 from the Netherland, 4 from Spain, 2 from the United Kingdom (UK), one each from Belgium, Germany and Switzerland). Three studies were from the United States of America (USA). Six studies were from China. There were 28 clinical and 8 imaging studies. The diagnosis of COVID-19 in most studies required the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by real-time polymerase chain reaction (RT-PCR), but some were based on high clinical suspicion without the PCR results. In the clinical studies, 16 and 5 studies reported the incidences of outcomes only in the ICU(2, 3, 8, 14-26) or non-ICU settings (27-31), respectively. Seven studies reported the incidence of outcomes in the ICU, and non-ICU settings.(4, 9, 10, 32-35) Six studies reported on both venous and arterial thrombosis.(2, 14, 16, 18, 21, 33) Twenty-nine studies reported only venous thrombotic events, and one study reported only arterial thrombotic events.(4) Among 23 in 29 studies reported venous thrombotic outcomes, utilized anticoagulant prophylaxis. In the imaging studies, 6 studies mainly focused on CTPA in all hospitalization patients(36-41), and 2 studies focused on using compression ultrasound (CUS) in a non-ICU setting. (42, 43)
VTE in ICU setting
A total of 21 clinical studies were included. VTE occurred in 465 of 1766 patients with COVID-19 admitted in the ICU. The pooled incidence of total VTE, including DVT and PE was 28% (95% CI, 22-34%, I2=89.5) (Figure 1). The pooled incidence of PE was 3% (95% CI, 2-4%, I2 = 94.3). The pooled incidence of DVT was 15% (95% CI, 11-20%, I2=92.6) (Figures S1 and S2 in the supplementary index).
Subgroup analyses of VTE based on anticoagulant prophylaxis, eastern or western countries, and CUS screening did not reveal significant differences between subgroups (Figures S3-S5 in the supplementary index). When focusing on the incidence of DVT, subgroup analysis based on CUS screening demonstrated a significant interaction (p <0.001). In 12 studies with no CUS screening, the incidence of DVT was 6% (95% CI, 4-9%), whereas in 9 studies with CUS screening, the incidence of DVT was 32% (95% CI, 18-45%) (Figure 2).
Overall, studies from the Netherlands, France, China, Italy and UK demonstrated the pooled VTE incidence of 40% (95% CI, 29-50%), 41% (95% CI, 26-56%), 27% (95% CI, 20-34%), 16% (95% CI, 10-21%), and 12% (95% CI, 6-17%)respectively. Each study from Switzerland, USA, Belgium and Germany demonstrated the VTE incidence of 32% (95% CI, 15-54%), 22% (95% CI, 15-32%), 13% (95% CI, 4-31%), , and 10% (95% CI 3-24%), respectively (Figure 3).
VTE in non-ICU setting
A total of 10 clinical studies reported VTE events in non-ICU setting were included in the analysis. In 171 of 1662 patients with COVID-19 admitted in the general ward, the pooled incidence of total VTE was 10% (95% CI, 6-14%, I2= 96.8). The pooled incidence of PE was 0%. The pooled incidence of DVT was 1% (95% CI, 1-2%, I2=96) (Figures S6-S8 in the supplementary index).
Subgroup analysis of VTE based on anticoagulant prophylaxis was not performed since all had anticoagulant prophylaxis. There was no significant interaction on subgroup analysis based on eastern or western countries. Subgroup analyses based on CUS screening revealed a significant interaction between subgroups (p=0.007). In 8 studies of the CUS screening subgroup, the incidence of VTE was 12% (95% CI, 7-17%). In 2 studies of the no CUS screening subgroup, the incidence of VTE was 5% (95% CI, 2-6%) (Figure S9-S10 in supplementary index).
Arterial thrombosis in the ICU setting
A total of 7 clinical studies in the ICU setting reported on arterial thrombotic events, including myocardial infarction, ischemic stroke, and limb ischemia. Arterial thrombosis occurred in 30 of 713 patients with COVID-19 admitted in the ICU. The pooled incidence of total arterial thrombosis was 3% (95% CI, 2-5%, I2= 4.1) (Figure S11 in the supplementary index).
Arterial thrombosis in the non-ICU setting
Two clinical studies reported on arterial thrombotic events including ischemic stroke and myocardial infarction in the non-ICU setting. Arterial thrombosis occurred in 10 of 453 patients with COVID-19 admitted in the non-ICU. The pooled incidence of total arterial thrombosis was 2% (95%CI, 0-3%, I2=0) (Figure S12 in the supplementary index).
Six clinical studies reported the number of patients with VTE who died in the ICU setting. The overall mortality rate was 6% (3-10%, I2=63.8) (Figure S13 in the supplementary index).
A total of 8 imaging studies were included. VTE was found in 261 of 949 imaging performed in patients with COVID-19 requiring hospitalization. The pooled incidence of total VTE was 29% (95% CI, 15-42%, I2= 97.5) (Figure S14 in the supplementary index). Since each imaging study focused and reported on a specific type of imaging, we analyzed separately for imaging studies focusing on either CTPA or CUS study. In six imaging studies focusing on CTPA, the pooled incidence of PE was 26% (95% CI, 21-31%, I2 =40.8). In 2 imaging studies focusing on CUS, the pooled incidence of DVT was 0% (Figure S15-16 in supplementary index).
For the location of PE reported on imaging studies focusing on CTPA, one study did not report the location of thrombus, and one study reported sites of thrombus of subsegmental, segmental, and lobar artery together. Four imaging studies focusing on CTPA reported the location of thrombus by distal (subsegmental, segmental artery) vs. proximal (lobar and more proximal part) artery. Of 144 PE detected, distal PE was found in 81 (56%), and proximal PE was found in 36 (35%).