JMIR Publications

ABSTRACT

Background:

Background Coagulopathy associated with COVID-19 infection and venous thromboembolism (VTE) have emerged as significant contributors to morbidity in the Covid-19 pandemic. We performed a systematic review to estimate VTE incidence in hospitalized patients and to analyze characteristic factors in the VTE cohort. Methods We searched PubMed and Google Scholar using specified title search terms “SARS-Cov-2” or “COVID-19” and “Venous Thromboembolism” and “anticoagulation” among others to identify peer reviewed journal articles published from 6/22/2019 to 6/22/2020. Data was systematically extracted and synthesized using Microsoft Excel for analysis. The main outcome was VTE incidence and measures included patient characteristics, anticoagulation, and clinical outcomes with assessment for associations. Results 14 studies were included with 1677 patients. 83.3% of patients received anticoagulation, either VTE prophylaxis or treatment. VTE incidence was 26.9% (SE 3.1; 95% CI 20.8-33.1) and was correlated with systematic screening (r2 0.34, p = 0.03) and study duration (r2 -0.33, p = 0.03). D-dimer was higher for the VTE cohort (5.62 ± 0.9 vs. 1.43 ± 0.6, p = 0.00006). Odds of VTE were higher with ICU level of care (OR 6.38; 95% CI 3.67 to 11.11; p = 0.0000) but lower with anticoagulation (OR 0.58; 95% CI 0.36 to 0.92, p = 0.02). Conclusion Despite utilization of background anticoagulation, VTE incidence was historically high. Future studies will provide additional data to guide optimal VTE prophylaxis and diagnostic strategies.

Objective:

We performed a systematic review of VTE in the setting of patients hospitalized with COVID-19 infection and summarized the potential treatment effects in VTE management of VTE these patients. Our aim was to estimate the observed incidence of hospitalized VTE patients and analyze patient characteristics in the VTE cohort.

Methods:

We performed a systematic literature search in PubMed with title search terms of “COVID-19” or “SARS-CoV-2” or “Novel Coronavirus 2019” and “venous thromboembolism” or “deep vein thrombosis” or “pulmonary embolism” or “thrombosis” or “thromboembolic” or “anticoagulation” or “heparin” or “thromboprophylaxis” to identify primary research studies that report the rate of venous thromboembolism in patients hospitalized with COVID-19 infection who are treated with standard dose pharmacologic VTE prophylaxis, high dose pharmacologic VTE prophylaxis, treatment dose anticoagulation, no anticoagulation or no documentation. A supplementary search was performed with Google Scholar using the same search terms and journal article references were reviewed to identify additional studies. Studies of adult populations that were published in a PubMed peer reviewed journal from 6/22/2019 to 6/22/2020 were included for review. Data collected for each included study design, population studied, VTE event rate, VTE diagnostic strategy, VTE prophylaxis or treatment strategy, hemostatic lab abnormalities, and clinical outcomes including ICU level of care and survival. We excluded studies with arterial thrombosis, myocardial infarction or ischemic stroke, pediatric and fetal populations, and reviews, case reports, letters to the editor or any study that had not yet undergone peer review. Clinical outcomes data for the included studies were pooled, and we conducted a systematic review and meta-analysis with a random effects model to measure a single group summary for VTE incidence as our primary outcome.12 Confidence intervals were determined by the Adjusted Wald method. Secondary outcomes included a single group summary for mortality with the same methodology as the primary outcome and patient demographics with clinical characteristics using descriptive statistics with weighted mean and weighted standard deviation. Assessment of variables associated with VTE incidence was conducted using univariate linear regression and multivariate linear regression. Assessment of binary variables associated with VTE occurrence was conducted using multiple logistic regression. Estimation of differences in continuous variables between patients with VTE and patients without VTE was conducted using the z-Test (two sample for weighted means with weighted variance). Data were compiled using Google Sheets and Microsoft Excel. Cedars Sinai Hospital Institutional Review Board requirement for approval was waived as this is a systematic literature review.

Results:

The initial PubMed literature review returned 212 journal articles of which 12 studies were included in our review. The supplementary Google Scholar and journal article research identified an additional 2 studies to include in our review. In total, 14 studies were included in our review.6,9,13-24 (Figure 1). Studies included were observational (Table 1) and predominantly based on experience at a single center (Single Center N = 10, Multi-Center N = 4). The total patient sample size was 1677 patients (range 26 to 388) and represented a multinational patient population (China N = 272, France N = 206, Italy N = 415, Netherlands N = 382, Spain N = 156, United States N = 44). The weighted median study duration was 37.2 ± 17.4 days and 3 studies reported a median length of stay (LOS) (weighted mean LOS 9.5 ± 1.8 days) with patients receiving both ICU and Non-ICU level of care (Table 2). 5 studies (N = 352) did not report the patient status (eg discharged alive, expired or admitted) at completion of the study period. For the other 9 studies, there were 244 designated Non-Survivors, 717 designated Discharged Alive, 369 designated Admitted, and 20 designated Unknown. 13 studies reported utilization of VTE chemoprophylaxis or treatment anticoagulation. 83.2% of patients (N = 1306) received anticoagulation and 17.8% of patients (N = 279) did not receive anticoagulation. Of patients who received anticoagulation, standard dose VTE prophylaxis was most common (52.9%, N = 691). Patients were also prescribed high dose VTE prophylaxis (6.4%, N = 84), or treatment anticoagulation (15.1%, N = 197). In 25.6% of patients prescribed anticoagulation the dosage or intensity was not specified (N = 334). VTE diagnosis was determined by systematic screening in 7 studies, 1 of which also implemented systematic screening for PE. For 7 other studies, VTE diagnosis was made by usual practice. 3 studies exclusively screened for DVT and did not report PE. The combined estimate of VTE incidence was 26.9% (SE 3.1; 95% CI 20.8-33.1) (Figure 2). Occurrence of VTE (N = 377) was more often attributed to DVT (N = 262) and less often PE (N = 116). 10 The combined estimate of mortality incidence was 24.4% (SE 7.1, 95% CI 10.5-38.2). Absolute values were Non-Survivors N = 244, Discharged Alive N = 717, Admitted N = 369, and Unknown N = 20. Systematic screening for VTE (r2 0.34, p = 0.03) and study duration (r2 -0.33, p = 0.03) were both correlated with VTE incidence. There were no associations with VTE and mortality, percentage of patients prescribed anticoagulation, gender, age, or d-dimer. Multivariate linear regression for intensity of VTE prophylaxis and VTE incidence was not significant (r2 0.64; F = 0.25) nor was a model that included percentage of patients prescribed VTE prophylaxis or anticoagulation, percentage of patients in the ICU, gender, age, d-dimer level, study duration and implementation of systematic screening for VTE (r2 0.67; F = 0.58). 5 studies compared clinical characteristics and outcomes for patients with VTE (N = 157) to patients without VTE (N = 296). D-dimer was significantly increased in patients with VTE compared to patients without VTE (5.62 ± 0.9 vs. 1.43 ± 0.6, p = 0.00006).VTE was decreased in patients receiving anticoagulation (either VTE prophylaxis or treatment anticoagulation) (OR 0.58; 95% CI 0.36 to 0.92, p = 0.02 ) and was increased in patients receiving ICU level of care during their admission (OR 6.38; 95% CI 3.67 to 11.11; p = 0.0000). There was no difference in VTE rates for non-survivors compared to survivors (OR 2.02; 95% CI 0.98 to 4.19; p = 0.058).

Conclusions:

Coagulopathy associated with COVID-19 infection has emerged as a meaningful contributor to morbidity in the COVID-19 pandemic with early reports of a significantly increased incidence of VTE. We performed a systematic review to estimate the observed incidence of hospitalized VTE patients with COVID-19 infection. Despite utilization of background VTE prophylaxis and anticoagulation, VTE incidence is historically high. Future studies will provide additional data and generate insights to guide therapeutic decision making and optimize VTE prophylaxis and diagnostic strategies.