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April 14, 2020
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PCSK9 inhibitors lower VTE risk in patients with elevated Lp(a)

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Patients treated with PCSK9 inhibitors had reduced risk for venous thromboembolism, especially if they had elevated lipoprotein(a), according to findings presented at the virtual American College of Cardiology Scientific Session.

Although there appeared to be no correlation between baseline LDL and VTE risk reduction, patients with elevated Lp(a) at baseline treated with PCSK9 inhibitors experienced Lp(a) lowering in addition to decreased risk for VTE, but patients with lower baseline Lp(a) did not. The findings were simultaneously published in Circulation.

In a meta-analysis of the FOURIER trial of evolocumab (Repatha, Amgen; n = 27,564) and the ODYSSEY OUTCOMES trial of alirocumab (Praluent, Sanofi/Regeneron; n = 18,924), those assigned a PCSK9 inhibitor had a 31% risk reduction for VTE compared with those assigned placebo (HR = 0.69; 95% CI, 0.53-0.9).

In a post hoc analysis of FOURIER, evolocumab had no effect on VTE within the first year of treatment for atherosclerotic CVD (HR = 0.96; 95% CI, 0.57-1.62). However, patients experienced a 46% risk reduction beyond 1 year (HR = 0.54; 95% CI, 0.33-0.88) and the overall risk reduction was 29% (HR = 0.71; 95% CI, 0.5-1).

In FOURIER, researchers observed that among patients with elevated baseline Lp(a) levels, evolocumab reduced Lp(a) by 33 nmol/L and the risk for VTE by 48% (HR = 0.52; 95% CI, 0.3-0.89). Among patients with lower baseline Lp(a), researchers found a Lp(a) reduction of just 7 nmol/L and no effect of evolocumab on VTE risk (P for interaction = .087; P for heterogeneity = .037). This interaction led researchers to determine that when Lp(a) was modeled as a continuous variable, there was a mediating effect of baseline Lp(a) concentration on the magnitude of VTE risk reduction (P = .04).

“Although there was a substantial relative risk reduction in VTE with evolocumab, the absolute risk reduction was modest due to the low event rate,” Nicholas A. Marston, MD, clinical fellow in medicine at Brigham and Women's Hospital, and colleagues wrote in Circulation. “Therefore, given the current cost of the drug, prescribing PCSK9 inhibitors to this population for the prevention of VTE alone is likely not warranted. However, in patients with atherosclerotic cardiovascular disease being prescribed a PCSK9 inhibitor to reduce the risk of major adverse cardiovascular events, an additional benefit will be a reduction in the risk of VTE.”

Polygenic risk analysis

After an exploratory genetic analysis of the FOURIER trial, researchers found that a polygenic risk score was able to identify patients at increased genetic risk for VTE and who derived greater relative (P for interaction = .04) and absolute VTE reduction (P for heterogeneity = .009) from evolocumab compared with those without high genetic risk.

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“Of these, 273 [single nucleotide polymorphisms] were available for inclusion in the polygenic risk score following genotyping and imputation,” the researchers wrote. “The score was calculated using the genotype dosage for each allele, multiplied by its weight, and then summed across all variants. Those in the top one-third of the genetic risk score were categorized as high genetic risk for VTE.”

Possible mechanisms

“Further work is needed to confirm the mechanism for VTE reduction with PCSK9 inhibition. While these data suggest that the benefit may be associated with Lp(a), the potential pathway mediating this effect is uncertain,” the researchers wrote. “One possibility is the prothrombotic effect of Lp(a), although late divergence of the cumulative incidence curves resembles the pattern observed in atherosclerosis-mediated mechanisms. If an anti-thrombotic effect is operational, the emergence of this benefit may not follow the time course we expect from antiplatelet or anticoagulant medications with a direct effect on hemostatic/thrombotic factors and for which the effect is more immediate.” – by Scott Buzby

References:

Marston NA, et al. Highlighted Original Research: Vascular Medicine and the Year in Review. Presented at: American College of Cardiology Scientific Session; March 28-30, 2020 (virtual meeting).

Marston NA, et al. Circulation. 2020;doi:10.1161/CIRCULATIONAHA.120.046397.

Disclosures: Marston reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.