COVID-19 patients have a higher risk of venous thromboembolism (VTE) and thromboprophylaxis after hospitalization due to COVID-19 has been linked with improved clinical outcomes, however with increased hemorrhagic events.1 We aimed to determine the prevalence of VTE after COVID-19-associated hospitalization, identify the predictors of VTE at 1 year and assess the impact of VTE on clinical outcomes.
We used data from the CV COVID-19 registry, an international, multicenter, retrospective cohort study, including 4427 consecutive patients who underwent a real-time reverse transcriptase-polymerase chain reaction for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) between February and December 2020. This registry reported no difference in cardiovascular death between COVID-19 patients and controls, but a significantly higher incidence of VTE in COVID-19 patients compared to controls.2 In this sub-analysis, we focused only on COVID-19 patients, sub-grouped according to the occurrence of VTE at 1 year, excluding patients who died or suffered VTE during the index hospitalization. The prescription of thromboprophylaxis at discharge was done at the discretion of the treating physician, as at the time the study was conducted, there were no practice guidelines for COVID-19. The primary objective was to compare the rate of all-cause mortality and major adverse cardiovascular events (a composite of cardiovascular death, any myocardial infarction, ischemic stroke, VTE, arterial thrombotic event, heart failure hospitalization, or any serious arrhythmia) at 1 year between COVID-19 patients with VTE event versus those without. Furthermore, we aimed to identify predictors of VTE after discharge at 1-year. Events were defined as in the main registry, which included independent adjudication by a clinical event committee.2 An univariable analysis was performed to compare baseline clinical characteristics, comorbidities, biomarkers, and treatment between the two groups. Subsequently, statistically significant variables (p<0.05) were included in a multivariable model to identify independent predictors of VTE. The present study was approved by the institutional ethics committee.
Of 3636 COVID-19 patients in the main registry, 743 were excluded because of in-hospital death (n=505), in-hospital VTE (n=121) or missing follow-up, with a final cohort of 2893 patients. At 1 year, 28 patients (prevalence 0.96%) experienced a VTE event. Patients who developed VTE had a significantly higher rate of all-cause death (HR 4.92, 95% CI 2.0–12.1, p=0.001) and cardiovascular death (HR 7.28, 95% CI 0.9–54.9, p=0.054) compared to those without VTE at 1 year follow-up (Fig. 1). Compared to patients without VTE, the multivariable predictors of VTE were Charlson Comorbidity Index (CCI) (3.8±2.7 vs. 2.5±2.4, p=0.004), lower mean lymphocyte count (0.7±0.3×109/L vs. 1.4±2.4×109/L, p=0.001), prior history of cancer (28.6% vs. 10.5%, p=0.002), intensive care unit admission (42.9% vs. 17.0%, p=0.001) and use of extracorporeal membrane oxygenation (ECMO) (8.3% vs. 1.1%, p=0.032). The anticoagulation regimen after discharge was not associated with a higher rate of VTE during follow-up.
Previous studies suggested that therapeutic-dose anticoagulation may improve outcomes in hospitalized, non-critically ill COVID-19 patients with elevated thrombotic risk, principally mitigating the pulmonary consequences of SARS-CoV-2 infection by preventing progressive vascular thrombosis.3 A prior placebo-controlled randomized trial showed a significant reduction of thrombotic events and a low rate of bleeding in COVID-19 patients with high risk for VTE treated with extended thromboprophylaxis with rivaroxaban compared to placebo.4 Conversely, the COVID-19 ACTIV-4 ACUTE trial, which compared pharmacologic thromboprophylaxis with apixaban versus placebo, was stopped early because of low thrombotic event rate, leading to inconclusive results.5 The use of extended thromboprophylaxis in COVID-19 patients is still being debated and the observed results are conflicting, possibly due to the selection of patients. This sub-analysis underscores the necessity of determining safe and effective VTE prophylaxis strategies in COVID-19 patients after hospital discharge, as VTE is associated with a significantly higher rate of all-cause mortality and cardiovascular death at 1 year (Fig. 1).
Notably, we identified five independent predictors of VTE after hospital discharge: (1) higher CCI; (2) prior history of cancer; (3) lower mean lymphocyte count; (4) ICU admission and (5) use of ECMO. Patients displaying these baseline clinical characteristics face the highest risk of VTE and may derive benefit from post-discharge thromboprophylaxis. Additional investigation is warranted to assess outcomes, delineate hemorrhagic risk, and ascertain whether thromboprophylaxis presents the optimal strategy for patients exhibiting this clinical profile. The present study entails the limitation of observational research, which preclude definitive determination of causality. In addition, undetected VTE during hospitalization, with a later diagnosis after discharge, cannot be ruled out.
Ethical considerationThis work has NOT involved animal testing. This work does NOT involve patients or human subjects. This work does NOT involve a clinical trial. All data shown in the figures and tables included in the manuscript are collected in the results section and the conclusions.
FundingNo financial support was received for this study.
Conflict of interestsDr. Salvatore Brugaletta has received speaker fees from General Electric.
Data availabilityIf required, all supplementary data can be uploaded.
