key: cord-0686298-f3j0qirk authors: Tholin, Birgitte; Fiskvik, Hilde; Tveita, Anders; Tsykonova, Galina; Opperud, Helene; Busterud, Kari; Mpinganzima, Clarisse; Garabet, Lamya; Ahmed, Jamal; Stavem, Knut; Ghanima, Waleed title: Thromboembolic complications during and after hospitalization for COVID-19: Incidence, risk factors and thromboprophylaxis date: 2022-01-03 journal: Thrombosis Update DOI: 10.1016/j.tru.2021.100096 sha: cd4df3154f9cc758e86573f6c3f3857252e6d981 doc_id: 686298 cord_uid: f3j0qirk Introduction The incidence of thromboembolism during COVID-19 and the use of thromboprophylaxis vary greatly between studies. Only a few studies have investigated the rate of thromboembolism post-discharge. This study determined the 90-day incidence of venous and arterial thromboembolic complications, risk factors for venous thromboembolic events and characterized the use of thromboprophylaxis during and after hospitalization. Materials and methods We retrospectively reviewed medical records for adult patients hospitalized for >24 hours for COVID-19 before May 15, 2020, in ten Norwegian hospitals. We extracted data on demographics, thromboembolic complications, thromboembolic risk factors, and the use of thromboprophylaxis. Cox proportional hazards regression was used to determine risk factors for VTE. Results 550 patients were included. The 90-day incidence of arterial and venous thromboembolism in hospitalized patients was 6.9% (95% CI: 5.1–9.3) overall and 13.8% in the ICU. Male sex (hazard ratio (HR) 7.44, 95% CI 1.73–32.02, p = 0.007) and previous VTE (HR 6.11, 95% CI: 1.74–21.39, p = 0.005) were associated with risk of VTE in multivariable analysis. Thromboprophylaxis was started in 334 patients (61%) with a median duration of 7 days (25th–75th percentile 3–13); in the VTE population 10/23 (43%) started thromboprophylaxis prior to diagnosis. After discharge 20/223 patients received extended thromboprophylaxis and 2/223 (0.7%, 95% CI: 0.3–1.9) had a thromboembolism. Conclusions The 90-day incidence of thromboembolism in COVID-19 patients was 7%, but <1% after discharge. Risk factors were male sex and previous VTE. Most patients received thromboprophylaxis during hospitalization, but only <10% after discharge. Coronavirus disease 2019 predisposes to both arterial and venous thromboembolic complications, including venous thromboembolism (VTE), ischemic stroke and myocardial infarction (MI) (1) (2) (3) (4) . The rates of thrombotic complications are higher in acute COVID-19 than in non-COVID-19 acute respiratory distress syndrome (ARDS) (5) . Autopsy studies have demonstrated microvascular thrombi, excessive activation of neutrophils and platelets, as well as neutrophil-platelet aggregates in blood (6) . Further on, endothelial injury is evident from the direct invasion of endothelial cells by SARS-CoV-2, as well as from cytokines and various acute-phase reactants (7) . Elevated circulating prothrombotic factors contribute to a hypercoagulable state (7, 8) and immobilization promotes stasis. Few studies have systematically assessed risk factors for VTE in COVID-19 patients. General VTE risk assessment models might aid in identifying high risk patients, and the IMPROVE-DD score has been externally validated for COVID-19 patients (9, 10) . Identified risk factors include active cancer, immobilization, previous VTE, ICU admission, advanced age and elevated D-dimer, amongst others. The increased risk of VTE has prompted routine institution of thromboprophylaxis in hospitalized patients with COVID-19. However, despite the use of thromboprophylaxis, the incidence of VTE during acute COVID-19 ranges from 3% to 85% in published reports (11) . Variable incidence estimates are likely explained by variations in study design, populations, and assessment methods. Only a few studies have investigated the rate of thromboembolic complications after discharge and in ambulatory patients (12, 13) . There is still a debate regarding the need for higher prophylactic dosage in this patient group (14) , and whether thromboprophylaxis after hospital discharge is warranted (15) . The main aim of our study was to determine the 90-day incidence of arterial and venous thromboembolism. Secondary aims were to assess risk factors for VTE and describe the use of thromboprophylaxis. This was a national multicenter retrospective cohort study in ten Norwegian hospitals comprising 550 patients hospitalized with COVID-19. We included subjects ≥ 18 years of age admitted for >24 hours before May 15, 2020. Patients were identified through the hospital diagnosis registries at each hospital using the ICD-10 code for polymerase chain reaction (PCR) confirmed COVID-19 (U07.1). The regional ethics committee approved the study (Helse Sør-Øst, approval no. 138629, 2020). An opt-out consent process was granted based on the distribution of study information to all participants, and consent exemption was approved for deceased patients. Investigators in the respective hospitals reviewed medical records, extracting the following data: (1) Descriptive statistics and thromboembolic complications are presented with the mean and standard deviation (SD), median (25 th -75 th percentile) or absolute number (%). Groups were compared using Mann-Whitney U test or t-test for continuous data and Fisher's exact or chisquare test for categorical variables. We calculated the incidence rates for arterial and venous thromboembolism and thromboprophylaxis practice and estimated 95% confidence intervals using the Wilson method. The cumulative incidence of VTE for males and females was presented using a Kaplan Meier curve. We used Cox proportional hazards regression to determine risk factors for VTE during 90 days after admission to hospital for COVID-19 infection. We used time to VTE (yes or no) as the dependent variable and estimated hazard ratios (HR) with 95% confidence intervals. Observations were censored at 90 days. We checked the proportional hazards assumption using log-minus-log plots and a test of non-zero slope of Schoenfeld residuals and found the assumption to be acceptable. We performed univariate analysis using age, sex (male or female), a history of previous VTE (yes or no), body mass index (BMI) ≥ 30 kg/m 2 (yes or no), D-dimer ≥ 75 percentile (1.4 mg/L) fibrinogen equivalent units (FEU) at admission to hospital (yes or no), C-reactive protein (CRP) > 75 th percentile (129 mg/L) at admission to hospital (yes or no) and Charlson comorbidity index (0-2 or >2) as independent variables. In the analysis that included D-dimer as a predictor, we excluded VTE events during the first 2 days after admission, as an elevated D-dimer could be considered the first sign of a VTE. Because of a limited number of VTE events prior to the analysis, we initially chose four independent variables (age, sex, previous VTE and BMI) for inclusion in a multivariable analysis. As a rule of thumb, a minimum of five to ten events per independent variable is recommended (17) . There were too few arterial events to conduct meaningful analysis on potential risk factors. We used Stata software version 17.0 (StataCorp, College Station, TX, USA) for all analyses, choosing a significance level of p <0.05 in two-sided tests. We included and reviewed medical records of 550 patients who were admitted for COVID-19 during the study period. Of these, 61 patients (11%) had died during hospitalization. Mean age was 61.5 years (SD 16.4), and 345 (52%) were males. The majority (64.7%) of patients had a Charlson Comorbidity Index ≥3 (range: 0-11). The median (25th to 75 th percentile) length of stay in the hospital was 7 days (4-12) overall. In total, 130 patients (23%) were admitted to the ICU, with a median length of stay in the ICU of 13 days (6-20) (Table 1 ). There was a difference in sex, BMI, inflammatory biomarkers, such as CRP and D-dimer levels, length of stay, ICU admission rate and need of mechanical ventilation between the VTE and non-VTE group (all p<0.05) ( Table 1) . Low-molecular-weight heparin (LMWH) was most often prescribed (71.4%). Anticoagulation pattern during and after hospitalization, presented as number (%) with 95% confidence intervals (CI), unless otherwise specified The cumulative incidence of VTE was higher in male than in female patients (Fig. 1) Unknown 10 29 ≤10 days 10 29 ≥2 weeks < 3 months 5 14 3 months 5 14 Indefinite 5 14 Type*** Low-molecular-weight heparin 25 71 Direct oral anticoagulation 10 28 *Intermediate intensity refers to standard prophylactic dose twice daily (enoxaparin 40mg bd or dalteparin 5000mg bd),** n=223, ***n=35 There are three main findings in this study; First, the 90-day incidence of thromboembolic events during hospitalization was about 7% in a population where 62% already had received thromboprophylaxis, mainly standard prophylactic intensity. Second, the rate of thrombotic events after discharge was very low (0.7%), despite subgroup analysis revealing that less than 10% had further prophylactic anticoagulation upon discharge from hospital. Third, male sex and a history of previous VTE were associated with an increased risk of VTE. Early reports indicated very high rates of VTE up to 85% in patients admitted for COVID-19, even in patients receiving standard thromboprophylaxis, which led to suggestions of the possible need for higher prophylactic dosage (4, 11, 18) . Some recent studies indicate a lower incidence of thromboembolic complications than earlier studies, but reports still show a large variation (19) (20) (21) (22) (23) (24) (25) . In a recent meta-analysis of more than 30 Norway has been lower than in other areas of Europe, and hospital capacity has not been overwhelmed, the threshold for admission may have been lower than in some other countries (27) . Lastly, only a small subset of fatal COVID-19 cases were autopsied, and the presence of unrecognized VTE and ATE in these patients cannot be excluded (28) . A large proportion of the patients that developed VTE had thromboprophylaxis at the time of diagnosis, however, the majority only received standard prophylactic intensity. It is possible that selected patients may benefit from higher intensity anticoagulation, although this could not be assessed in the present study. As our data did not include assessment of bleeding complications, we cannot conclude on the net benefit on mortality and morbidity. Whether the incidence of VTE in COVID-19 differs from that of other viral and bacterial pneumonia remains uncertain. In our study, thromboprophylaxis was initiated in about 2 of 3 patients during hospitalization. At the start of the pandemic, there was no national or local guidelines of thromboprophylaxis The present study has some limitations. The study period was from the early days of the pandemic; thus, it does not take into account the increased awareness around thromboembolic complications and thromboprophylaxis, mutations of the virus and the effect of vaccines. Norwegian hospitals have not been overwhelmed during the pandemic; consequently, the population admitted to hospitals in Norway might differ from that of other countries. The hospitals included in this study received more than 50% of admitted COVID-19 patients in J o u r n a l P r e -p r o o f Norway, which supports generalization to a setting without severely constrained hospital capacity. In our opinion, the retrospective study design is not a major limitation, as the same patients are likely to have been included if the study was prospective. However, it is possible that some patients are missed due to insufficient ICD-10 coding or misclassification at the time of discharge. Further on, the number of thromboembolic events were few, which limits the multivariable analysis. We did not include variables describing the severity of the infection, which could have been interesting to assess potential associations with risk of VTE. We found male sex to be a distinct risk factor of VTE during COVID-19, which could be considered a risk factor in future risk assessment models. Higher intensity thromboprophylaxis might be warranted in certain high-risk patients. Still, results from large RCTs, including both benefits of thromboprophylaxis and risk of bleeding, are needed to recommend specific dosage for different subpopulations. The incidence of thrombotic complications in patients hospitalized for COVID-19 was lower in this study compared to many other early studies. However, many patients were diagnosed with VTEs despite receiving standard thromboprophylaxis. Male sex and previous thrombosis were associated with increased risk of VTE, emphasizing the need for thorough consideration of thromboprophylaxis in these patients. J o u r n a l P r e -p r o o f All authors have contributed to drafting, revision and approval of the manuscript. BT and KS analyzed the data. The study has approval from the Norwegian Regional Ethics committee (REK). 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Research grants from Janssen None.