Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab

A prespecified secondary analysis of the FOURIER trial

Robert P. Giugliano, Terje R. Pedersen, Jeong Gun Park, Gaetano M. De Ferrari, Zbigniew A. Gaciong, Richard Ceska, Kalman Toth, Ioanna Gouni-Berthold, Jose Lopez-Miranda, François Schiele, François Mach, Brian R. Ott, Estella Kanevsky, Armando Lira Pineda, Ransi Somaratne, Scott M. Wasserman, Anthony C. Keech, Peter S. Sever, Marc S. Sabatine

Research output: Contribution to journalArticle

147 Citations (Scopus)

Abstract

Background: LDL cholesterol is a well established risk factor for atherosclerotic cardiovascular disease. How much one should or safely can lower this risk factor remains debated. We aimed to explore the relationship between progressively lower LDL-cholesterol concentrations achieved at 4 weeks and clinical efficacy and safety in the FOURIER trial of evolocumab, a monoclonal antibody to proprotein convertase subtilisin-kexin type 9 (PCSK9). Methods: In this prespecified secondary analysis of 25 982 patients from the randomised FOURIER trial, the relationship between achieved LDL-cholesterol concentration at 4 weeks and subsequent cardiovascular outcomes (primary endpoint was the composite of cardiovascular death, myocardial infarction, stroke, coronary revascularisation, or unstable angina; key secondary endpoint was the composite of cardiovascular death, myocardial infarction, or stroke) and ten prespecified safety events of interest was examined over a median of 2·2 years of follow-up. We used multivariable modelling to adjust for baseline factors associated with achieved LDL cholesterol. This trial is registered with ClinicalTrials.gov, number NCT01764633. Findings: Between Feb 8, 2013, and June 5, 2015, 27 564 patients were randomly assigned a treatment in the FOURIER study. 1025 (4%) patients did not have an LDL cholesterol measured at 4 weeks and 557 (2%) had already had a primary endpoint event or one of the ten prespecified safety events before the week-4 visit. From the remaining 25 982 patients (94% of those randomly assigned) 13 013 were assigned evolocumab and 12 969 were assigned placebo. 2669 (10%) of 25 982 patients achieved LDL-cholesterol concentrations of less than 0·5 mmol/L, 8003 (31%) patients achieved concentrations between 0·5 and less than 1·3 mmol/L, 3444 (13%) patients achieved concentrations between 1·3 and less than 1·8 mmol/L, 7471 (29%) patients achieved concentrations between 1·8 to less than 2·6 mmol/L, and 4395 (17%) patients achieved concentrations of 2·6 mmol/L or higher. There was a highly significant monotonic relationship between low LDL-cholesterol concentrations and lower risk of the primary and secondary efficacy composite endpoints extending to the bottom first percentile (LDL-cholesterol concentrations of less than 0·2 mmol/L; p=0·0012 for the primary endpoint, p=0·0001 for the secondary endpoint). Conversely, no significant association was observed between achieved LDL cholesterol and safety outcomes, either for all serious adverse events or any of the other nine prespecified safety events. Interpretation: There was a monotonic relationship between achieved LDL cholesterol and major cardiovascular outcomes down to LDL-cholesterol concentrations of less than 0·2 mmol/L. Conversely, there were no safety concerns with very low LDL-cholesterol concentrations over a median of 2·2 years. These data support further LDL-cholesterol lowering in patients with cardiovascular disease to well below current recommendations. Funding: Amgen.

Original languageEnglish
Pages (from-to)1962
Number of pages10
JournalThe Lancet
DOIs
Publication statusPublished - Oct 1 2017

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LDL Cholesterol
Safety
Proprotein Convertase 9
AMG 145
Cardiovascular Diseases
Stroke
Myocardial Infarction
Unstable Angina
Monoclonal Antibodies
Placebos

ASJC Scopus subject areas

  • Medicine(all)

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Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab : A prespecified secondary analysis of the FOURIER trial. / Giugliano, Robert P.; Pedersen, Terje R.; Park, Jeong Gun; De Ferrari, Gaetano M.; Gaciong, Zbigniew A.; Ceska, Richard; Toth, Kalman; Gouni-Berthold, Ioanna; Lopez-Miranda, Jose; Schiele, François; Mach, François; Ott, Brian R.; Kanevsky, Estella; Pineda, Armando Lira; Somaratne, Ransi; Wasserman, Scott M.; Keech, Anthony C.; Sever, Peter S.; Sabatine, Marc S.

In: The Lancet, 01.10.2017, p. 1962.

Research output: Contribution to journalArticle

Giugliano, RP, Pedersen, TR, Park, JG, De Ferrari, GM, Gaciong, ZA, Ceska, R, Toth, K, Gouni-Berthold, I, Lopez-Miranda, J, Schiele, F, Mach, F, Ott, BR, Kanevsky, E, Pineda, AL, Somaratne, R, Wasserman, SM, Keech, AC, Sever, PS & Sabatine, MS 2017, 'Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: A prespecified secondary analysis of the FOURIER trial', The Lancet, pp. 1962. https://doi.org/10.1016/S0140-6736(17)32290-0
Giugliano, Robert P. ; Pedersen, Terje R. ; Park, Jeong Gun ; De Ferrari, Gaetano M. ; Gaciong, Zbigniew A. ; Ceska, Richard ; Toth, Kalman ; Gouni-Berthold, Ioanna ; Lopez-Miranda, Jose ; Schiele, François ; Mach, François ; Ott, Brian R. ; Kanevsky, Estella ; Pineda, Armando Lira ; Somaratne, Ransi ; Wasserman, Scott M. ; Keech, Anthony C. ; Sever, Peter S. ; Sabatine, Marc S. / Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab : A prespecified secondary analysis of the FOURIER trial. In: The Lancet. 2017 ; pp. 1962.
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abstract = "Background: LDL cholesterol is a well established risk factor for atherosclerotic cardiovascular disease. How much one should or safely can lower this risk factor remains debated. We aimed to explore the relationship between progressively lower LDL-cholesterol concentrations achieved at 4 weeks and clinical efficacy and safety in the FOURIER trial of evolocumab, a monoclonal antibody to proprotein convertase subtilisin-kexin type 9 (PCSK9). Methods: In this prespecified secondary analysis of 25 982 patients from the randomised FOURIER trial, the relationship between achieved LDL-cholesterol concentration at 4 weeks and subsequent cardiovascular outcomes (primary endpoint was the composite of cardiovascular death, myocardial infarction, stroke, coronary revascularisation, or unstable angina; key secondary endpoint was the composite of cardiovascular death, myocardial infarction, or stroke) and ten prespecified safety events of interest was examined over a median of 2·2 years of follow-up. We used multivariable modelling to adjust for baseline factors associated with achieved LDL cholesterol. This trial is registered with ClinicalTrials.gov, number NCT01764633. Findings: Between Feb 8, 2013, and June 5, 2015, 27 564 patients were randomly assigned a treatment in the FOURIER study. 1025 (4{\%}) patients did not have an LDL cholesterol measured at 4 weeks and 557 (2{\%}) had already had a primary endpoint event or one of the ten prespecified safety events before the week-4 visit. From the remaining 25 982 patients (94{\%} of those randomly assigned) 13 013 were assigned evolocumab and 12 969 were assigned placebo. 2669 (10{\%}) of 25 982 patients achieved LDL-cholesterol concentrations of less than 0·5 mmol/L, 8003 (31{\%}) patients achieved concentrations between 0·5 and less than 1·3 mmol/L, 3444 (13{\%}) patients achieved concentrations between 1·3 and less than 1·8 mmol/L, 7471 (29{\%}) patients achieved concentrations between 1·8 to less than 2·6 mmol/L, and 4395 (17{\%}) patients achieved concentrations of 2·6 mmol/L or higher. There was a highly significant monotonic relationship between low LDL-cholesterol concentrations and lower risk of the primary and secondary efficacy composite endpoints extending to the bottom first percentile (LDL-cholesterol concentrations of less than 0·2 mmol/L; p=0·0012 for the primary endpoint, p=0·0001 for the secondary endpoint). Conversely, no significant association was observed between achieved LDL cholesterol and safety outcomes, either for all serious adverse events or any of the other nine prespecified safety events. Interpretation: There was a monotonic relationship between achieved LDL cholesterol and major cardiovascular outcomes down to LDL-cholesterol concentrations of less than 0·2 mmol/L. Conversely, there were no safety concerns with very low LDL-cholesterol concentrations over a median of 2·2 years. These data support further LDL-cholesterol lowering in patients with cardiovascular disease to well below current recommendations. Funding: Amgen.",
author = "Giugliano, {Robert P.} and Pedersen, {Terje R.} and Park, {Jeong Gun} and {De Ferrari}, {Gaetano M.} and Gaciong, {Zbigniew A.} and Richard Ceska and Kalman Toth and Ioanna Gouni-Berthold and Jose Lopez-Miranda and Fran{\cc}ois Schiele and Fran{\cc}ois Mach and Ott, {Brian R.} and Estella Kanevsky and Pineda, {Armando Lira} and Ransi Somaratne and Wasserman, {Scott M.} and Keech, {Anthony C.} and Sever, {Peter S.} and Sabatine, {Marc S.}",
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TY - JOUR

T1 - Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab

T2 - A prespecified secondary analysis of the FOURIER trial

AU - Giugliano, Robert P.

AU - Pedersen, Terje R.

AU - Park, Jeong Gun

AU - De Ferrari, Gaetano M.

AU - Gaciong, Zbigniew A.

AU - Ceska, Richard

AU - Toth, Kalman

AU - Gouni-Berthold, Ioanna

AU - Lopez-Miranda, Jose

AU - Schiele, François

AU - Mach, François

AU - Ott, Brian R.

AU - Kanevsky, Estella

AU - Pineda, Armando Lira

AU - Somaratne, Ransi

AU - Wasserman, Scott M.

AU - Keech, Anthony C.

AU - Sever, Peter S.

AU - Sabatine, Marc S.

PY - 2017/10/1

Y1 - 2017/10/1

N2 - Background: LDL cholesterol is a well established risk factor for atherosclerotic cardiovascular disease. How much one should or safely can lower this risk factor remains debated. We aimed to explore the relationship between progressively lower LDL-cholesterol concentrations achieved at 4 weeks and clinical efficacy and safety in the FOURIER trial of evolocumab, a monoclonal antibody to proprotein convertase subtilisin-kexin type 9 (PCSK9). Methods: In this prespecified secondary analysis of 25 982 patients from the randomised FOURIER trial, the relationship between achieved LDL-cholesterol concentration at 4 weeks and subsequent cardiovascular outcomes (primary endpoint was the composite of cardiovascular death, myocardial infarction, stroke, coronary revascularisation, or unstable angina; key secondary endpoint was the composite of cardiovascular death, myocardial infarction, or stroke) and ten prespecified safety events of interest was examined over a median of 2·2 years of follow-up. We used multivariable modelling to adjust for baseline factors associated with achieved LDL cholesterol. This trial is registered with ClinicalTrials.gov, number NCT01764633. Findings: Between Feb 8, 2013, and June 5, 2015, 27 564 patients were randomly assigned a treatment in the FOURIER study. 1025 (4%) patients did not have an LDL cholesterol measured at 4 weeks and 557 (2%) had already had a primary endpoint event or one of the ten prespecified safety events before the week-4 visit. From the remaining 25 982 patients (94% of those randomly assigned) 13 013 were assigned evolocumab and 12 969 were assigned placebo. 2669 (10%) of 25 982 patients achieved LDL-cholesterol concentrations of less than 0·5 mmol/L, 8003 (31%) patients achieved concentrations between 0·5 and less than 1·3 mmol/L, 3444 (13%) patients achieved concentrations between 1·3 and less than 1·8 mmol/L, 7471 (29%) patients achieved concentrations between 1·8 to less than 2·6 mmol/L, and 4395 (17%) patients achieved concentrations of 2·6 mmol/L or higher. There was a highly significant monotonic relationship between low LDL-cholesterol concentrations and lower risk of the primary and secondary efficacy composite endpoints extending to the bottom first percentile (LDL-cholesterol concentrations of less than 0·2 mmol/L; p=0·0012 for the primary endpoint, p=0·0001 for the secondary endpoint). Conversely, no significant association was observed between achieved LDL cholesterol and safety outcomes, either for all serious adverse events or any of the other nine prespecified safety events. Interpretation: There was a monotonic relationship between achieved LDL cholesterol and major cardiovascular outcomes down to LDL-cholesterol concentrations of less than 0·2 mmol/L. Conversely, there were no safety concerns with very low LDL-cholesterol concentrations over a median of 2·2 years. These data support further LDL-cholesterol lowering in patients with cardiovascular disease to well below current recommendations. Funding: Amgen.

AB - Background: LDL cholesterol is a well established risk factor for atherosclerotic cardiovascular disease. How much one should or safely can lower this risk factor remains debated. We aimed to explore the relationship between progressively lower LDL-cholesterol concentrations achieved at 4 weeks and clinical efficacy and safety in the FOURIER trial of evolocumab, a monoclonal antibody to proprotein convertase subtilisin-kexin type 9 (PCSK9). Methods: In this prespecified secondary analysis of 25 982 patients from the randomised FOURIER trial, the relationship between achieved LDL-cholesterol concentration at 4 weeks and subsequent cardiovascular outcomes (primary endpoint was the composite of cardiovascular death, myocardial infarction, stroke, coronary revascularisation, or unstable angina; key secondary endpoint was the composite of cardiovascular death, myocardial infarction, or stroke) and ten prespecified safety events of interest was examined over a median of 2·2 years of follow-up. We used multivariable modelling to adjust for baseline factors associated with achieved LDL cholesterol. This trial is registered with ClinicalTrials.gov, number NCT01764633. Findings: Between Feb 8, 2013, and June 5, 2015, 27 564 patients were randomly assigned a treatment in the FOURIER study. 1025 (4%) patients did not have an LDL cholesterol measured at 4 weeks and 557 (2%) had already had a primary endpoint event or one of the ten prespecified safety events before the week-4 visit. From the remaining 25 982 patients (94% of those randomly assigned) 13 013 were assigned evolocumab and 12 969 were assigned placebo. 2669 (10%) of 25 982 patients achieved LDL-cholesterol concentrations of less than 0·5 mmol/L, 8003 (31%) patients achieved concentrations between 0·5 and less than 1·3 mmol/L, 3444 (13%) patients achieved concentrations between 1·3 and less than 1·8 mmol/L, 7471 (29%) patients achieved concentrations between 1·8 to less than 2·6 mmol/L, and 4395 (17%) patients achieved concentrations of 2·6 mmol/L or higher. There was a highly significant monotonic relationship between low LDL-cholesterol concentrations and lower risk of the primary and secondary efficacy composite endpoints extending to the bottom first percentile (LDL-cholesterol concentrations of less than 0·2 mmol/L; p=0·0012 for the primary endpoint, p=0·0001 for the secondary endpoint). Conversely, no significant association was observed between achieved LDL cholesterol and safety outcomes, either for all serious adverse events or any of the other nine prespecified safety events. Interpretation: There was a monotonic relationship between achieved LDL cholesterol and major cardiovascular outcomes down to LDL-cholesterol concentrations of less than 0·2 mmol/L. Conversely, there were no safety concerns with very low LDL-cholesterol concentrations over a median of 2·2 years. These data support further LDL-cholesterol lowering in patients with cardiovascular disease to well below current recommendations. Funding: Amgen.

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