Thromboprophylaxis for COVID-19: Time to ask for an extension?

Commentary on: Patel L, et al. Outcomes in patients discharged with extended venous thromboembolism prophylaxis after hospitalization with COVID-19. Vasc Med 2023; 28: 331–339.

Early in the COVID-19 pandemic it became quite clear that the SARS-CoV-2 virus increases the risk for both arterial and venous thrombotic events.^1,2 Mechanisms responsible for thrombotic events associated with SARS-CoV-2 infection are not completely understood,^3–5 though platelets appear to play a smaller role in COVID-19-related thrombosis than inflammation, activation of endothelial cells, and immune-mediated mechanisms through the coagulation cascade. ⁶

Many trials were established to identify the role of anticoagulation in the various populations of patients infected with SARS-CoV-2. Current guidelines are clear, and multiple well-designed randomized controlled trials have confirmed that, in the absence of thrombosis, treatment dose anticoagulation consisting of parenteral heparin protects against adverse outcomes in hospitalized, noncritically ill patients with an increased risk for thrombosis. In critically ill patients without documented thrombosis—many of whom have hypoxemic respiratory failure—prophylactic dose anticoagulation is favored over treatment dose anticoagulation due to risk of bleeding. In patients managed as outpatients or ‘hospital-at-home’, COVID-19 is not associated with significant risk of thromboembolism, and anticoagulation is therefore not recommended.^7–9

However, 3 years into the pandemic, it remains unclear whether one should treat hospitalized patients with COVID-19 with extended thromboprophylaxis following discharge to prevent future thrombotic events. In a recent meta-analysis of eight observational studies, thromboprophylaxis decreased the composite outcome of thrombosis and postdischarge mortality without a substantial increased risk for bleeding. ¹⁰ The much-anticipated MICHELLE trial evaluated hospitalized patients with COVID-19 and an increased risk for venous thromboembolism (VTE) identified using combined risk stratification tools (IMPROVE score) and blood D-dimer concentration > 500 ng/mL. Patients were randomized 1:1 to postdischarge prophylactic anticoagulation consisting of rivaroxaban (10 mg daily) or placebo for 35 days. The primary outcome—a composite of VTE, arterial thromboembolism, and death at 35 days—was decreased in patients treated with rivaroxaban compared to placebo (3.1% vs 9.4%, p = 0.029). Rivaroxaban was protective against VTE and VTE-related mortality compared to placebo in all subgroups except asymptomatic deep vein thrombosis (DVT) detected by ultrasound. ¹¹

In this issue of Vascular Medicine, ¹² Patel and colleagues performed a retrospective cohort study among hospitalized patients with COVID-19 comparing those who received anticoagulation at discharge with those who did not. Using a discharge order set that included the IMPROVE VTE score, the IMPROVE BLEEDING score, and the patient D-dimer concentration, patients could be identified for extended duration prophylactic anticoagulation. The decision to recommend postdischarge prophylaxis and the anticoagulant choice were left to the discharging physician. Patients who were treated with extended VTE prophylaxis experienced a similar incidence of VTE at both 30 and 90 days compared to those who received standard in-hospital prophylaxis. There was no increase in major bleeding events in the extended prophylaxis group. In addition, a 65% reduction in all-cause mortality was observed at 30 days. The authors note that the decision to use extended VTE prophylaxis should be individualized based on patient risk factors and should be weighed against the potential risk of bleeding. ¹²

When available studies demonstrate different outcomes, what is a clinician to do? Overall, the available studies provide valuable insights into the use of extended VTE prophylaxis for hospitalized patients with COVID-19, emphasizing the need for personalized risk assessment and management in this population, which is consistent with most current guidelines. Both the International Society of Thrombosis and Haemostasis (ISTH) and the European guidelines do not recommend indiscriminate use of postdischarge prophylaxis but do suggest prophylaxis with rivaroxaban for approximately 1 month in select patients at high risk for VTE;^7,8 however, the current American Society of Hematology (ASH) guidelines do not share this recommendation. ASH recommend against the use of outpatient thromboprophylaxis following COVID-related hospital discharge; however, they note that an assessment of thrombosis risk, bleeding risk, and shared decision making should be employed, and the use of postdischarge prophylaxis may be reasonable when patients are judged to be at high risk of thrombosis and low risk for bleeding. ⁹

Early COVID-19 outcomes data reflect early variants in which VTE risk and anticoagulation might have been quite different, and use of COVID-19 vaccines was in its infancy. ¹³ Thus, we do not fully understand the impact of different COVID-19 strains on thromboembolic risk and mortality. Physicians who specialize in vascular medicine and others who care for patients with COVID-19 must rely on their clinical experience and available data to personalize the care of each patient according to their risk for thrombotic disease.