TY - JOUR
T1 - Lipoprotein(a), PCSK9 inhibition, and cardiovascular risk insights from the FOURIER trial
AU - O’Donoghue, Michelle L.
AU - Fazio, Sergio
AU - Giugliano, Robert P.
AU - Stroes, Erik S.G.
AU - Kanevsky, Estella
AU - Gouni-Berthold, Ioanna
AU - Im, Kyung Ah
AU - Pineda, Armando Lira
AU - Wasserman, Scott M.
AU - Češka, Richard
AU - Ezhov, Marat V.
AU - Jukema, J. Wouter
AU - Jensen, Henrik K.
AU - Tokgözoğlu, S. Lale
AU - Mach, François
AU - Huber, Kurt
AU - Sever, Peter S.
AU - Keech, Anthony C.
AU - Pedersen, Terje R.
AU - Sabatine, Marc S.
N1 - Funding Information:
Dr O’Donoghue reports institutional research grants from Amgen, Janssen, The Medicines Company, Eisai, GlaxoSmithKline, and Astra Zeneca. Dr Fazio has served as consultant for Amgen, Amarin, Astra Zeneca, Esperion, and Novartis. Dr Ezhov reports lecture fees from Amgen, AstraZeneca, Berlin Chemie, Egis, KRKA, Pfizer, Recordati, and Sanofi; and has served as a consultant to and received grants from Amgen and Sanofi. Dr Giugliano has received grants from Amgen, honoraria from Amgen, Daiichi Sankyo, and Merck, and consultant fees from Amgen, Akcea, Amarin, Boehringer-Ingelheim, Bristol-Myers-Squibb, CVS Caremark, Daiichi Sankyo, GlaxoSmithKline, Lexicon, Merck, Portola, and Pfizer. Dr Huber reports lecture fees from Amgen, AstraZeneca, Pfizer, and Sanofi Aventis. Dr Jensen is supported by the Novo Nordisk Foundation (NN-F18OC0031258), reports lecture fees from Amgen, Pfizer, and Sanofi, and has received research grants from Amgen, Pfizer, and Sanofi. Dr Tokgozoglu has received consulting fees from MSD, Sanofi, Amgen, Bayer, Mylan, Abbott and honoraria from MSD, Actelion, Sanofi, Novartis, Amgen, Recordati, Abbott, As-traZeneca, Pfizer, Mylan, Servier, Bayer, and Novo Nordisk. Dr Mach has received research grants to the institution from Amgen, AstraZeneca, Eli Lilly, MSD, No-vartis, Sanofi, and Pfizer. Dr Češka has received consulting fees from Amgen, Sanofi, Akcea, MSD, and Boehringer Ingelheim. Dr Sever has received research grants from Amgen and honoraria for advisory boards and speaker’s bureau from Amgen. Dr Gouni-Berthold has received honoraria for consulting from Am-gen, Akcea, Sanofi, Eli Lilly, Regeneron, and Aegereon. Drs Wasserman and Lira Pineda are employees of Amgen and have stock interests in Amgen. Dr Sabatine has received research grant support through Brigham and Women’s Hospital from Abbott Laboratories, Amgen, AstraZeneca, Bayer, Critical Diagnostics, Dai-ichi-Sankyo, Eisai, Genzyme, Gilead, GlaxoSmithKline, Intarcia, Janssen Research and Development, Medicines Company, MedImmune, Merck, Novartis, Poxel, Pfizer, Quark pharmaceuticals, Roche Diagnostics, and Takeda and has received consulting fees from Alnylam, Amgen, AstraZeneca, Bristol-Myers Squibb, CVS Caremark, Dyrnamix, Esperion, IFM Pharmaceuticals, Intarcia, Ionis, Janssen Research and Development, Medicines Company, MedImmune, Merck, MyoKar-dia, and Novartis. The other authors report no conflicts.
Publisher Copyright:
© 2019 Lippincott Williams and Wilkins. All rights reserved.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
KW - Atherosclerosis
KW - Clinical trial
KW - Lipoprotein(a)
UR - http://www.scopus.com/inward/record.url?scp=85061789282&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85061789282&partnerID=8YFLogxK
U2 - 10.1161/CIRCULATIONAHA.118.037184
DO - 10.1161/CIRCULATIONAHA.118.037184
M3 - Article
C2 - 30586750
AN - SCOPUS:85061789282
SN - 0009-7322
VL - 139
SP - 1483
EP - 1492
JO - Circulation
JF - Circulation
IS - 12
ER -