Lipoprotein(a), PCSK9 inhibition and cardiovascular risk: Insights from the FOURIER trial
File(s)
Accepted version
Author(s)
Type
Journal Article
Abstract
BACKGROUND: Lipoprotein(a) [Lp(a)] may play a causal role in atherosclerosis. Proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors have been shown to significantly reduce plasma Lp(a) concentration. However, the relationship between Lp(a) levels, PCSK9 inhibition and cardiovascular (CV) risk reduction remains undefined. METHODS: Lp(a) was measured in 25,096 patients in FOURIER, a randomized trial of evolocumab versus placebo in patients with established atherosclerotic CV disease (median follow-up 2.2 years). Cox models were used to assess the independent prognostic value of Lp(a) and the efficacy of evolocumab for coronary risk reduction by baseline Lp(a) concentration. RESULTS: The median [IQR] baseline Lp(a) concentration was 37[13-165] nmol/L. In the placebo arm, patients with baseline Lp(a) in the highest quartile had a higher risk of coronary heart disease (CHD) death, MI or urgent revascularization (UR) (adjusted HR Q4:Q1 1.22, 95% CI 1.01-1.48) independent of LDL-C. At 48 weeks, evolocumab significantly reduced Lp(a) by a median [IQR] of 26.9% [6.2-46.7%]. The percent change in Lp(a) and LDL-C at 48 weeks in evolocumab patients was moderately positively correlated (r=0.37, 95% CI 0.36-0.39, P<0.001). Evolocumab reduced the risk of CHD death, MI or UR by 23% (HR 0.77, 95% CI 0.67-0.88) in patients with a baseline Lp(a) >median, and by 7% (HR 0.93, 0.80-1.08; P interaction=0.07) in those ≤median. Coupled with the higher baseline risk, the absolute risk reductions and NNT3y were 2.49% and 40 vs. 0.95% and 105, respectively. CONCLUSIONS: Lp(a) is associated with the risk of CV events in patients with established CV disease irrespective of LDL-C. Evolocumab significantly reduced Lp(a) levels, and patients with higher baseline Lp(a) levels experienced greater absolute reductions in Lp(a) and tended to derive greater coronary benefit from PCSK9 inhibition. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov Unique Identifier: NCT01764633.
Date Issued
2019-03-19
Date Acceptance
2018-11-27
Citation
Circulation, 2019, 139 (12), pp.1483-1492
ISSN
0009-7322
Publisher
American Heart Association
Start Page
1483
End Page
1492
Journal / Book Title
Circulation
Volume
139
Issue
12
Copyright Statement
© 2018, Circulation. This is a non-final version of an article published in final form in Circulation at https://dx.doi.org/10.1161/CIRCULATIONAHA.118.037184.
Sponsor
Amgen Inc
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/30586750
Grant Number
20110118
Subjects
Lipoprotein(a)
PCSK9 inhibitor
stable atherosclerosis
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2018-11-30