Evolocumab and clinical outcomes in patients with cardiovascular disease

FOURIER Steering Committee and Investigators

Research output: Contribution to journalArticle

1401 Citations (Scopus)

Abstract

BACKGROUND Evolocumab is a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9) and lowers low-density lipoprotein (LDL) cholesterol levels by approximately 60%. Whether it prevents cardiovascular events is uncertain. METHODS We conducted a randomized, double-blind, placebo-controlled trial involving 27,564 patients with atherosclerotic cardiovascular disease and LDL cholesterol levels of 70 mg per deciliter (1.8 mmol per liter) or higher who were receiving statin therapy. Patients were randomly assigned to receive evolocumab (either 140 mg every 2 weeks or 420 mg monthly) or matching placebo as subcutaneous injections. The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke. The median duration of follow-up was 2.2 years. RESULTS At 48 weeks, the least-squares mean percentage reduction in LDL cholesterol levels with evolocumab, as compared with placebo, was 59%, from a median baseline value of 92 mg per deciliter (2.4 mmol per liter) to 30 mg per deciliter (0.78 mmol per liter) (P<0.001). Relative to placebo, evolocumab treatment significantly reduced the risk of the primary end point (1344 patients [9.8%] vs. 1563 patients [11.3%]; hazard ratio, 0.85; 95% confidence interval [CI], 0.79 to 0.92; P<0.001) and the key secondary end point (816 [5.9%] vs. 1013 [7.4%]; hazard ratio, 0.80; 95% CI, 0.73 to 0.88; P<0.001). The results were consistent across key subgroups, including the subgroup of patients in the lowest quartile for baseline LDL cholesterol levels (median, 74 mg per deciliter [1.9 mmol per liter]). There was no significant difference between the study groups with regard to adverse events (including new-onset diabetes and neurocognitive events), with the exception of injection-site reactions, which were more common with evolocumab (2.1% vs. 1.6%). CONCLUSIONS In our trial, inhibition of PCSK9 with evolocumab on a background of statin therapy lowered LDL cholesterol levels to a median of 30 mg per deciliter (0.78 mmol per liter) and reduced the risk of cardiovascular events. These findings show that patients with atherosclerotic cardiovascular disease benefit from lowering of LDL cholesterol levels below current targets.

Original languageEnglish (US)
Pages (from-to)1713-1722
Number of pages10
JournalNew England Journal of Medicine
Volume376
Issue number18
DOIs
StatePublished - May 4 2017

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LDL Cholesterol
Cardiovascular Diseases
Placebos
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Stroke
Myocardial Infarction
Confidence Intervals
Unstable Angina
Subcutaneous Injections
Least-Squares Analysis
AMG 145
Hospitalization
Therapeutics
Monoclonal Antibodies
Injections
Proprotein Convertase 9

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Evolocumab and clinical outcomes in patients with cardiovascular disease. / FOURIER Steering Committee and Investigators.

In: New England Journal of Medicine, Vol. 376, No. 18, 04.05.2017, p. 1713-1722.

Research output: Contribution to journalArticle

FOURIER Steering Committee and Investigators. / Evolocumab and clinical outcomes in patients with cardiovascular disease. In: New England Journal of Medicine. 2017 ; Vol. 376, No. 18. pp. 1713-1722.
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title = "Evolocumab and clinical outcomes in patients with cardiovascular disease",
abstract = "BACKGROUND Evolocumab is a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9) and lowers low-density lipoprotein (LDL) cholesterol levels by approximately 60{\%}. Whether it prevents cardiovascular events is uncertain. METHODS We conducted a randomized, double-blind, placebo-controlled trial involving 27,564 patients with atherosclerotic cardiovascular disease and LDL cholesterol levels of 70 mg per deciliter (1.8 mmol per liter) or higher who were receiving statin therapy. Patients were randomly assigned to receive evolocumab (either 140 mg every 2 weeks or 420 mg monthly) or matching placebo as subcutaneous injections. The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke. The median duration of follow-up was 2.2 years. RESULTS At 48 weeks, the least-squares mean percentage reduction in LDL cholesterol levels with evolocumab, as compared with placebo, was 59{\%}, from a median baseline value of 92 mg per deciliter (2.4 mmol per liter) to 30 mg per deciliter (0.78 mmol per liter) (P<0.001). Relative to placebo, evolocumab treatment significantly reduced the risk of the primary end point (1344 patients [9.8{\%}] vs. 1563 patients [11.3{\%}]; hazard ratio, 0.85; 95{\%} confidence interval [CI], 0.79 to 0.92; P<0.001) and the key secondary end point (816 [5.9{\%}] vs. 1013 [7.4{\%}]; hazard ratio, 0.80; 95{\%} CI, 0.73 to 0.88; P<0.001). The results were consistent across key subgroups, including the subgroup of patients in the lowest quartile for baseline LDL cholesterol levels (median, 74 mg per deciliter [1.9 mmol per liter]). There was no significant difference between the study groups with regard to adverse events (including new-onset diabetes and neurocognitive events), with the exception of injection-site reactions, which were more common with evolocumab (2.1{\%} vs. 1.6{\%}). CONCLUSIONS In our trial, inhibition of PCSK9 with evolocumab on a background of statin therapy lowered LDL cholesterol levels to a median of 30 mg per deciliter (0.78 mmol per liter) and reduced the risk of cardiovascular events. These findings show that patients with atherosclerotic cardiovascular disease benefit from lowering of LDL cholesterol levels below current targets.",
author = "{FOURIER Steering Committee and Investigators} and Sabatine, {Marc S.} and Giugliano, {Robert P.} and Keech, {Anthony C.} and Narimon Honarpour and Wiviott, {Stephen D.} and Murphy, {Sabina A.} and Kuder, {Julia F.} and Huei Wang and Thomas Liu and Wasserman, {Scott M.} and Sever, {Peter S.} and Pedersen, {Terje R.} and Fish, {M. P.} and Abrahamsen, {T. E.} and K. Im and E. Kanevsky and Bonaca, {M. P.} and {Lira Pineda}, A. and K. Hanlon and B. Knusel and R. Somaratne and C. Kurtz and R. Scott and {Accini Mendoza}, {J. L.} and J. Amerena and J. Badariene and L. Burgess and R. Ceska and Charng, {M. J.} and D. Choi and Cobos, {J. L.} and Dan, {G. A.} and {De Ferrari}, {G. M.} and Deedwania, {P. C.} and Chopra, {V. K.} and A. Erglis and Ezhov, {M. V.} and J. Ferreira and S. Filipov{\'a} and Gaciong, {Z. A.} and T. Pasierski and Georgiev, {B. G.} and G. Gonzalez-Galvez and I. Gouni-Berthold and T. Sch{\"a}ufele and A. Hirayama and K. Huber and M. Rammer and {Kjaerulf Jensen}, H. and Mooss, {Aryan N.}",
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TY - JOUR

T1 - Evolocumab and clinical outcomes in patients with cardiovascular disease

AU - FOURIER Steering Committee and Investigators

AU - Sabatine, Marc S.

AU - Giugliano, Robert P.

AU - Keech, Anthony C.

AU - Honarpour, Narimon

AU - Wiviott, Stephen D.

AU - Murphy, Sabina A.

AU - Kuder, Julia F.

AU - Wang, Huei

AU - Liu, Thomas

AU - Wasserman, Scott M.

AU - Sever, Peter S.

AU - Pedersen, Terje R.

AU - Fish, M. P.

AU - Abrahamsen, T. E.

AU - Im, K.

AU - Kanevsky, E.

AU - Bonaca, M. P.

AU - Lira Pineda, A.

AU - Hanlon, K.

AU - Knusel, B.

AU - Somaratne, R.

AU - Kurtz, C.

AU - Scott, R.

AU - Accini Mendoza, J. L.

AU - Amerena, J.

AU - Badariene, J.

AU - Burgess, L.

AU - Ceska, R.

AU - Charng, M. J.

AU - Choi, D.

AU - Cobos, J. L.

AU - Dan, G. A.

AU - De Ferrari, G. M.

AU - Deedwania, P. C.

AU - Chopra, V. K.

AU - Erglis, A.

AU - Ezhov, M. V.

AU - Ferreira, J.

AU - Filipová, S.

AU - Gaciong, Z. A.

AU - Pasierski, T.

AU - Georgiev, B. G.

AU - Gonzalez-Galvez, G.

AU - Gouni-Berthold, I.

AU - Schäufele, T.

AU - Hirayama, A.

AU - Huber, K.

AU - Rammer, M.

AU - Kjaerulf Jensen, H.

AU - Mooss, Aryan N.

PY - 2017/5/4

Y1 - 2017/5/4

N2 - BACKGROUND Evolocumab is a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9) and lowers low-density lipoprotein (LDL) cholesterol levels by approximately 60%. Whether it prevents cardiovascular events is uncertain. METHODS We conducted a randomized, double-blind, placebo-controlled trial involving 27,564 patients with atherosclerotic cardiovascular disease and LDL cholesterol levels of 70 mg per deciliter (1.8 mmol per liter) or higher who were receiving statin therapy. Patients were randomly assigned to receive evolocumab (either 140 mg every 2 weeks or 420 mg monthly) or matching placebo as subcutaneous injections. The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke. The median duration of follow-up was 2.2 years. RESULTS At 48 weeks, the least-squares mean percentage reduction in LDL cholesterol levels with evolocumab, as compared with placebo, was 59%, from a median baseline value of 92 mg per deciliter (2.4 mmol per liter) to 30 mg per deciliter (0.78 mmol per liter) (P<0.001). Relative to placebo, evolocumab treatment significantly reduced the risk of the primary end point (1344 patients [9.8%] vs. 1563 patients [11.3%]; hazard ratio, 0.85; 95% confidence interval [CI], 0.79 to 0.92; P<0.001) and the key secondary end point (816 [5.9%] vs. 1013 [7.4%]; hazard ratio, 0.80; 95% CI, 0.73 to 0.88; P<0.001). The results were consistent across key subgroups, including the subgroup of patients in the lowest quartile for baseline LDL cholesterol levels (median, 74 mg per deciliter [1.9 mmol per liter]). There was no significant difference between the study groups with regard to adverse events (including new-onset diabetes and neurocognitive events), with the exception of injection-site reactions, which were more common with evolocumab (2.1% vs. 1.6%). CONCLUSIONS In our trial, inhibition of PCSK9 with evolocumab on a background of statin therapy lowered LDL cholesterol levels to a median of 30 mg per deciliter (0.78 mmol per liter) and reduced the risk of cardiovascular events. These findings show that patients with atherosclerotic cardiovascular disease benefit from lowering of LDL cholesterol levels below current targets.

AB - BACKGROUND Evolocumab is a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9) and lowers low-density lipoprotein (LDL) cholesterol levels by approximately 60%. Whether it prevents cardiovascular events is uncertain. METHODS We conducted a randomized, double-blind, placebo-controlled trial involving 27,564 patients with atherosclerotic cardiovascular disease and LDL cholesterol levels of 70 mg per deciliter (1.8 mmol per liter) or higher who were receiving statin therapy. Patients were randomly assigned to receive evolocumab (either 140 mg every 2 weeks or 420 mg monthly) or matching placebo as subcutaneous injections. The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke. The median duration of follow-up was 2.2 years. RESULTS At 48 weeks, the least-squares mean percentage reduction in LDL cholesterol levels with evolocumab, as compared with placebo, was 59%, from a median baseline value of 92 mg per deciliter (2.4 mmol per liter) to 30 mg per deciliter (0.78 mmol per liter) (P<0.001). Relative to placebo, evolocumab treatment significantly reduced the risk of the primary end point (1344 patients [9.8%] vs. 1563 patients [11.3%]; hazard ratio, 0.85; 95% confidence interval [CI], 0.79 to 0.92; P<0.001) and the key secondary end point (816 [5.9%] vs. 1013 [7.4%]; hazard ratio, 0.80; 95% CI, 0.73 to 0.88; P<0.001). The results were consistent across key subgroups, including the subgroup of patients in the lowest quartile for baseline LDL cholesterol levels (median, 74 mg per deciliter [1.9 mmol per liter]). There was no significant difference between the study groups with regard to adverse events (including new-onset diabetes and neurocognitive events), with the exception of injection-site reactions, which were more common with evolocumab (2.1% vs. 1.6%). CONCLUSIONS In our trial, inhibition of PCSK9 with evolocumab on a background of statin therapy lowered LDL cholesterol levels to a median of 30 mg per deciliter (0.78 mmol per liter) and reduced the risk of cardiovascular events. These findings show that patients with atherosclerotic cardiovascular disease benefit from lowering of LDL cholesterol levels below current targets.

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U2 - 10.1056/NEJMoa1615664

DO - 10.1056/NEJMoa1615664

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JF - New England Journal of Medicine

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