PCSK9 inhibitor reduces VTE risk, especially in patients with high genetic risk

Performance of a genetic risk score to identify risk of venous thromboembolism and benefit from evolocumab therapy

Presented at ACC.20 by Nicholas Marston, MD (Boston, MA, USA)

Introduction and methods

Venous thromboembolism (VTE) has a known genetic contribution and is a major cause of CV morbidity and mortality. A 297-SNP genetic risk score has recently been developed in a general population for risk of VTE. It remains unclear whether this genetic risk score for VTE also applies to a population with cardiometabolic disease. Furthermore, it has been shown that statin therapy can reduce the risk of VTE. This reduction in VTE risk has been mediated trough pleiotropic effects of statins including antithrombotic and anti-inflammatory properties, rather than lipid lowering. It is not known whether PCSK9 inhibitors can also reduce the risk of VTE.

A patient-level meta-analysis of 31,669 patients from the FOURIER, PEGASUS-TIMI 54, and SAVOR-TIMI 53 trails was performed to evaluate the prognostic value of a genetic risk score for VTE in a population with cardiometabolic disease. Second, the effect of the PCSK9 inhibitor evolocumab was analyzed in the FOURIER trial alone, and as a summary level meta-analysis in combination with ODYSSEY OUTCOMES data to determine whether PCSK9 inhibitors reduce the risk of VTE. Third, the authors tested whether the greatest treatment benefit from PCSK9 inhibition is derived in patients with higher genetic risk for VTE.

The 297-SNP genetic risk score that was used in this study was derived from the UK biobank. The genetic risk score was calculated for each patient using the genotype dosage for each allele, multiplied by its weight, and subsequently summed across all variants. Patients were stratified into three genetic risk categories based on tertiles.

Main results

• The incidence of VTE over a 3-year follow-up period showed the highest incidence in patients at high genetic risk, followed by those with intermediate risk and lowest incidence of VTE was seen in patients with low genetic risk (P-trend <0.0001).
• A similar gradient of risk of VTE was shown in adjusted HRs across tertiles (aHR 2.36, P<0.0001 for high genetic risk; aHR 1.73, P=0.006 for intermediate genetic risk; both compared to low genetic risk).
• The HR for VTE with evolocumab was 0.71 compared to placebo in the FOURIER trial (95%CI 0.50-1.00, P=0.05). No effect of evolocumab therapy was seen in the first year (HR=0.96, 95%CI 0.57-1.62, P=0.89). However, from one year onward, a reduction in VTE risk was observed in the evolocumab group compared to the placebo group (HR=0.54, 95%CI 0.33-0.88, P=0.014).
• Effects of PCSK9 inhibitors on VTE risk found for evolocumab (HR 0.71, 95%CI 0.50-1.00, P=0.05) in the FOURIER trial were similar to those found for alirocumab (HR 0.67, 95%CI 0.44-1.01, P=0.06) in the ODYSSEY OUTCOMES trial, both compared to placebo. A meta-analysis of these two trials showed a 31% relative risk reduction of VTE with PCSK9 inhibitors (HR 0.69, 95%CI 0.53-0.90, P=0.007).
• Patients with high genetic risk (top 1/3) who received evolocumab had a 55% relative risk reduction in VTE compared to those on placebo (HR 0.45, 95%CI 0.21-0.95, ARR 0.7%). Patients without high genetic risk (bottom 2/3) had no benefit with evolocumab therapy compared to placebo (HR 1.20, 95%CI 0.66-2.2, ARR -0.1%).

Conclusion

This study showed that a genetic risk score for VTE predicts VTE risk in a population with cardiometabolic disease. A meta-analysis of FOURIER and ODYSSEY OUTCOMES data showed that PCSK9 inhibitors reduce the risk of VTE events. Treatment with evolocumab reduced the risk of VTE in patients with high genetic risk (top 1/3) compared to placebo, while no difference in treatment effect between evolocumab and placebo was observed in patients without a high genetic risk (bottom 2/3).

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The results were simultaneously published in Circulation