O'Donoghue, Michelle L., Fazio, Sergio, Giugliano, Robert P., Stroes, Erik S. G., Kanevsky, Estella, Gouni-Berthold, Ioanna, Im, KyungAh, Pineda, Armando Lira, Wasserman, Scott M., Ceska, Richard, Ezhov, Marat V., Jukema, J. Wouter, Jensen, Henrik K., Tokgozoglu, S. Lale, Mach, Francois, Huber, Kurt, Sever, Peter S., Keech, Anthony C., Pedersen, Terje R. and Sabatine, Marc S. (2019). Lipoprotein(a), PCSK9 Inhibition, and Cardiovascular Risk Insights From the FOURIER Trial. Circulation, 139 (12). S. 1483 - 1493. PHILADELPHIA: LIPPINCOTT WILLIAMS & WILKINS. ISSN 1524-4539

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Abstract

BACKGROUND: Lipoprotein(a) [Lp(a)] may play a causal role in atherosclerosis. PCSK9 (proprotein convertase subtilisin/kexin 9) inhibitors have been shown to significantly reduce plasma Lp(a) concentration. However, the relationship between Lp(a) levels, PCSK9 inhibition, and cardiovascular risk reduction remains undefined. METHODS: Lp(a) was measured in 25 096 patients in the FOURIER trial (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk), a randomized trial of evolocumab versus placebo in patients with established atherosclerotic cardiovascular 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 (interquartile range) 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 death, myocardial infarction, or urgent revascularization (adjusted hazard ratio quartile 4: quartile 1, 1.22; 95% CI, 1.01-1.48) independent of low-density lipoprotein cholesterol. At 48 weeks, evolocumab significantly reduced Lp(a) by a median (interquartile range) of 26.9% (6.2%-46.7%). The percent change in Lp(a) and low-density lipoprotein cholesterol at 48 weeks in patients taking evolocumab was moderately positively correlated (r=0.37; 95% CI, 0.36-0.39; P<0.001). Evolocumab reduced the risk of coronary heart disease death, myocardial infarction, or urgent revascularization by 23% (hazard ratio, 0.77; 95% CI, 0.67-0.88) in patients with a baseline Lp(a) >median, and by 7% (hazard ratio, 0.93; 95% CI, 0.80-1.08; P interaction=0.07) in those <= median. Coupled with the higher baseline risk, the absolute risk reductions, and number needed to treat over 3 years were 2.49% and 40 versus 0.95% and 105, respectively. CONCLUSIONS: Higher levels of Lp(a) are associated with an increased risk of cardiovascular events in patients with established cardiovascular disease irrespective of low-density lipoprotein cholesterol. 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
O'Donoghue, Michelle L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fazio, SergioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Giugliano, Robert P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stroes, Erik S. G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kanevsky, EstellaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gouni-Berthold, IoannaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Im, KyungAhUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pineda, Armando LiraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wasserman, Scott M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ceska, RichardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ezhov, Marat V.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jukema, J. WouterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jensen, Henrik K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tokgozoglu, S. LaleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mach, FrancoisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Huber, KurtUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sever, Peter S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Keech, Anthony C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pedersen, Terje R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sabatine, Marc S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-153567
DOI: 10.1161/CIRCULATIONAHA.118.037184
Journal or Publication Title: Circulation
Volume: 139
Number: 12
Page Range: S. 1483 - 1493
Date: 2019
Publisher: LIPPINCOTT WILLIAMS & WILKINS
Place of Publication: PHILADELPHIA
ISSN: 1524-4539
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
TARGETING APOLIPOPROTEIN(A); REDUCES LIPOPROTEIN(A); MONOCLONAL-ANTIBODY; DOUBLE-BLIND; HEART; THERAPY; DISEASE; STROKEMultiple languages
Cardiac & Cardiovascular Systems; Peripheral Vascular DiseaseMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/15356

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