The Effect of PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) Inhibition on the Risk of Venous Thromboembolism

Abstract

Background: The relationship between cholesterol levels and risk of venous thromboembolism (VTE) is uncertain. We set out to determine the effect of PCSK9 inhibition on the risk of VTE, explore potential mechanisms, and examine the efficacy in clinically and genetically defined risk subgroups. Methods: We performed a post-hoc analysis of the FOURIER trial testing whether evolocumab reduces the risk of VTE events (deep venous thrombosis or pulmonary embolism). Data from FOURIER and ODYSSEY OUTCOMES were then combined in a meta-analysis to assess class effect of PCSK9 inhibition on the risk of VTE. We also analyzed baseline lipids in FOURIER to investigate potential mechanisms explaining the reduction in VTE with evolocumab. Finally, an exploratory genetic analysis was performed in FOURIER to determine whether a VTE polygenic risk score could identify high-risk patients who would derive the greatest VTE reduction from evolocumab. Results: In FOURIER, the HR for VTE with evolocumab was 0.71 (95%CI 0.50-1.00, p=0.05), with no effect in the 1st year (HR 0.96, [0.57-1.62]) but a 46% reduction (HR 0.54 [0.33-0.88], p=0.014) beyond 1 year. A meta-analysis of FOURIER and ODYSSEY OUTCOMES demonstrated a 31% relative risk reduction in VTE with PCSK9 inhibition (HR 0.69 [0.53-0.90], p=0.007). There was no relation between baseline LDL-C levels and magnitude of VTE risk reduction. In contrast, in patients with higher baseline Lp(a) levels, evolocumab reduced Lp(a) by 33 nmol/L and risk of VTE by 48% (HR 0.52 [0.30-0.89], p=0.017), whereas in patients with lower baseline Lp(a) levels evolocumab reduced Lp(a) by only 7 nmol/L and had no effect on VTE risk P_interaction for HR 0.087, P_{heterogeneity} for ARR 0.037). Modeled as a continuous variable, there was a significant interaction between baseline Lp(a) concentration and magnitude of VTE risk reduction (P=0.04). A polygenic risk score identified patients who were at >2-fold increased risk for VTE and who derived greater relative (P_interaction=0.04) and absolute VTE reduction (P_{heterogeneity}=0.009) compared to those without high genetic risk. Conclusions: PCSK9 inhibition significantly reduces the risk of VTE. Lp(a) reduction may be an important mediator of this effect, a finding of particular interest given ongoing development of potent Lp(a) inhibitors.