Lipoprotein(a), PCSK9 Inhibition, and Cardiovascular Risk

Michelle L. O'Donoghue, Sergio Fazio, Robert P. Giugliano, Erik S.G. Stroes, Estella Kanevsky, Ioanna Gouni-Berthold, Kyung Ah Im, Armando Lira Pineda, Scott M. Wasserman, Richard Češka, Marat V. Ezhov, J. Wouter Jukema, Henrik K. Jensen, S. Lale Tokgözoğlu, François Mach, Kurt Huber, Peter S. Sever, Anthony C. Keech, Terje R. Pedersen, Marc S. Sabatine

    Research output: Contribution to journalArticle

    32 Citations (Scopus)

    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. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01764633.

    Original languageEnglish (US)
    Pages (from-to)1483-1492
    Number of pages10
    JournalCirculation
    Volume139
    Issue number12
    DOIs
    StatePublished - Mar 19 2019

    Fingerprint

    Proprotein Convertases
    Subtilisin
    Lipoprotein(a)
    LDL Cholesterol
    Numbers Needed To Treat
    Risk Reduction Behavior
    Inhibition (Psychology)
    Cardiovascular Diseases
    Placebos

    Keywords

    • atherosclerosis
    • clinical trial
    • lipoprotein(a)

    ASJC Scopus subject areas

    • Cardiology and Cardiovascular Medicine
    • Physiology (medical)

    Cite this

    O'Donoghue, M. L., Fazio, S., Giugliano, R. P., Stroes, E. S. G., Kanevsky, E., Gouni-Berthold, I., ... Sabatine, M. S. (2019). Lipoprotein(a), PCSK9 Inhibition, and Cardiovascular Risk. Circulation, 139(12), 1483-1492. https://doi.org/10.1161/CIRCULATIONAHA.118.037184

    Lipoprotein(a), PCSK9 Inhibition, and Cardiovascular Risk. / O'Donoghue, Michelle L.; Fazio, Sergio; Giugliano, Robert P.; Stroes, Erik S.G.; Kanevsky, Estella; Gouni-Berthold, Ioanna; Im, Kyung Ah; Lira Pineda, Armando; Wasserman, Scott M.; Češka, Richard; Ezhov, Marat V.; Jukema, J. Wouter; Jensen, Henrik K.; Tokgözoğlu, S. Lale; Mach, François; Huber, Kurt; Sever, Peter S.; Keech, Anthony C.; Pedersen, Terje R.; Sabatine, Marc S.

    In: Circulation, Vol. 139, No. 12, 19.03.2019, p. 1483-1492.

    Research output: Contribution to journalArticle

    O'Donoghue, ML, Fazio, S, Giugliano, RP, Stroes, ESG, Kanevsky, E, Gouni-Berthold, I, Im, KA, Lira Pineda, A, Wasserman, SM, Češka, R, Ezhov, MV, Jukema, JW, Jensen, HK, Tokgözoğlu, SL, Mach, F, Huber, K, Sever, PS, Keech, AC, Pedersen, TR & Sabatine, MS 2019, 'Lipoprotein(a), PCSK9 Inhibition, and Cardiovascular Risk', Circulation, vol. 139, no. 12, pp. 1483-1492. https://doi.org/10.1161/CIRCULATIONAHA.118.037184
    O'Donoghue ML, Fazio S, Giugliano RP, Stroes ESG, Kanevsky E, Gouni-Berthold I et al. Lipoprotein(a), PCSK9 Inhibition, and Cardiovascular Risk. Circulation. 2019 Mar 19;139(12):1483-1492. https://doi.org/10.1161/CIRCULATIONAHA.118.037184
    O'Donoghue, Michelle L. ; Fazio, Sergio ; Giugliano, Robert P. ; Stroes, Erik S.G. ; Kanevsky, Estella ; Gouni-Berthold, Ioanna ; Im, Kyung Ah ; Lira Pineda, Armando ; Wasserman, Scott M. ; Češka, Richard ; Ezhov, Marat V. ; Jukema, J. Wouter ; Jensen, Henrik K. ; Tokgözoğlu, S. Lale ; Mach, François ; Huber, Kurt ; Sever, Peter S. ; Keech, Anthony C. ; Pedersen, Terje R. ; Sabatine, Marc S. / Lipoprotein(a), PCSK9 Inhibition, and Cardiovascular Risk. In: Circulation. 2019 ; Vol. 139, No. 12. pp. 1483-1492.
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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. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01764633.",
    keywords = "atherosclerosis, clinical trial, lipoprotein(a)",
    author = "O'Donoghue, {Michelle L.} and Sergio Fazio and Giugliano, {Robert P.} and Stroes, {Erik S.G.} and Estella Kanevsky and Ioanna Gouni-Berthold and Im, {Kyung Ah} and {Lira Pineda}, Armando and Wasserman, {Scott M.} and Richard Češka and Ezhov, {Marat V.} and Jukema, {J. Wouter} and Jensen, {Henrik K.} and Tokg{\"o}zoğlu, {S. Lale} and Fran{\cc}ois Mach and Kurt Huber and Sever, {Peter S.} and Keech, {Anthony C.} and Pedersen, {Terje R.} and Sabatine, {Marc S.}",
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    TY - JOUR

    T1 - Lipoprotein(a), PCSK9 Inhibition, and Cardiovascular Risk

    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 - Lira Pineda, Armando

    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.

    PY - 2019/3/19

    Y1 - 2019/3/19

    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. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01764633.

    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. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01764633.

    KW - atherosclerosis

    KW - clinical trial

    KW - lipoprotein(a)

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