Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial

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 eff...

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Veröffentlicht in:The Lancet (British edition) Jg. 390; H. 10106; S. 1962 - 1971
Hauptverfasser: 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
Format: Journal Article
Sprache:Englisch
Veröffentlicht: England Elsevier Ltd 28.10.2017
Elsevier Limited
Schlagworte:
Adult
Aged
Aged, 80 and over
Angina
Antibodies, Monoclonal - therapeutic use
Anticholesteremic Agents - therapeutic use
Arteriosclerosis
Atherosclerosis
Cardiovascular disease
Cardiovascular diseases
Cerebral infarction
Cholesterol
Cholesterol, LDL - blood
Cholesterol, LDL - drug effects
Clinical trials
Diabetes
Double-Blind Method
Drug therapy
Effectiveness
Female
Follow-Up Studies
Health risk assessment
Heart attacks
Humans
Hypercholesterolemia - blood
Hypercholesterolemia - drug therapy
Inhibitor drugs
Kexin
Laboratories
Lipids
Low density lipoprotein
Male
Middle Aged
Monoclonal antibodies
Myocardial infarction
Patient Safety
Patients
Proprotein Convertase 9 - antagonists & inhibitors
Proprotein convertases
Risk Assessment
Risk factors
Safety
Secondary analysis
Statins
Stroke
Subtilisin
Treatment Outcome
Triglycerides
ISSN:0140-6736, 1474-547X, 1474-547X
Online-Zugang:Volltext
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Abstract 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). 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. 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. 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. Amgen.
AbstractList Summary 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.
LDL cholesterol has been well established as a modifiable risk factor for atherosclerotic cardiovascular disease in epidemiological studies. In a series of landmark randomised controlled trials with statins, significant reductions in cardiovascular events were shown in patients with very high LDL-cholesterol concentrations (eg, decreasing LDL cholesterol from 5 to 3 mmol/L), average LDL-cholesterol concentrations (eg, decreasing LDL cholesterol from 3·5 to 2·5 mmol/L), and below average LDL-cholesterol concentrations (eg, decreasing LDL cholesterol from 2·5 to 1·5-2 mmol/L).1
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). 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. 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. 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. Amgen.
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).BACKGROUNDLDL 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).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.METHODSIn 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.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.FINDINGSBetween 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.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.INTERPRETATIONThere 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.Amgen.FUNDINGAmgen.
Author Giugliano, Robert P
Kanevsky, Estella
Mach, François
Sabatine, Marc S
Keech, Anthony C
Lopez-Miranda, Jose
Ott, Brian R
Sever, Peter S
De Ferrari, Gaetano M
Toth, Kalman
Gaciong, Zbigniew A
Ceska, Richard
Pineda, Armando Lira
Schiele, François
Pedersen, Terje R
Gouni-Berthold, Ioanna
Park, Jeong-Gun
Somaratne, Ransi
Wasserman, Scott M
Author_xml – sequence: 1
  givenname: Robert P
  surname: Giugliano
  fullname: Giugliano, Robert P
  email: rgiugliano@bwh.harvard.edu
  organization: TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA, USA
– sequence: 2
  givenname: Terje R
  surname: Pedersen
  fullname: Pedersen, Terje R
  organization: Oslo University Hospital, Ullevål and Medical Faculty, University of Oslo, Oslo, Norway
– sequence: 3
  givenname: Jeong-Gun
  surname: Park
  fullname: Park, Jeong-Gun
  organization: TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA, USA
– sequence: 4
  givenname: Gaetano M
  surname: De Ferrari
  fullname: De Ferrari, Gaetano M
  organization: Department of Molecular Medicine, University of Pavia and Cardiac Intensive Care Unit and Laboratories for Experimental Cardiology, IRCCS Fondazione Policlinico San Matteo, Pavia, Italy
– sequence: 5
  givenname: Zbigniew A
  surname: Gaciong
  fullname: Gaciong, Zbigniew A
  organization: Department of Internal Medicine, Hypertension and Vascular Diseases, The Medical University of Warsaw, Warsaw, Poland
– sequence: 6
  givenname: Richard
  surname: Ceska
  fullname: Ceska, Richard
  organization: Center of Preventive Cardiology, 3rd Department Internal Medicine, University General Hospital and 1st Medical Faculty, Prague, Czech Republic
– sequence: 7
  givenname: Kalman
  surname: Toth
  fullname: Toth, Kalman
  organization: 1st Department of Medicine, University of Pécs, Pécs, Hungary
– sequence: 8
  givenname: Ioanna
  surname: Gouni-Berthold
  fullname: Gouni-Berthold, Ioanna
  organization: Polyclinic for Endocrinology, Diabetes, and Preventive Medicine, University of Cologne, Cologne, Germany
– sequence: 9
  givenname: Jose
  surname: Lopez-Miranda
  fullname: Lopez-Miranda, Jose
  organization: Lipids and Atherosclerosis Unit, Maimonides Biomedical Research Institute of Cordoba, Reina Sofia University Hospital, University of Cordoba, CIBEROBN, Cordoba, Spain
– sequence: 10
  givenname: François
  surname: Schiele
  fullname: Schiele, François
  organization: University Hospital Center Besançon, Besançon, France
– sequence: 11
  givenname: François
  surname: Mach
  fullname: Mach, François
  organization: Hopital Cantonal, Hopitaux Universitaires de Geneva, Geneva, Switzerland
– sequence: 12
  givenname: Brian R
  surname: Ott
  fullname: Ott, Brian R
  organization: Rhode Island Hospital, Department of Neurology, Alpert Medical School of Brown University, Providence, RI, USA
– sequence: 13
  givenname: Estella
  surname: Kanevsky
  fullname: Kanevsky, Estella
  organization: TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA, USA
– sequence: 14
  givenname: Armando Lira
  surname: Pineda
  fullname: Pineda, Armando Lira
  organization: Amgen, Thousand Oaks, CA, USA
– sequence: 15
  givenname: Ransi
  surname: Somaratne
  fullname: Somaratne, Ransi
  organization: Amgen, Thousand Oaks, CA, USA
– sequence: 16
  givenname: Scott M
  surname: Wasserman
  fullname: Wasserman, Scott M
  organization: Amgen, Thousand Oaks, CA, USA
– sequence: 17
  givenname: Anthony C
  surname: Keech
  fullname: Keech, Anthony C
  organization: Sydney Medical School, National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia
– sequence: 18
  givenname: Peter S
  surname: Sever
  fullname: Sever, Peter S
  organization: International Centre for Circulatory Health, National Heart and Lung Institute, Imperial College London, London, UK
– sequence: 19
  givenname: Marc S
  surname: Sabatine
  fullname: Sabatine, Marc S
  organization: TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA, USA
BackLink https://www.ncbi.nlm.nih.gov/pubmed/28859947$$D View this record in MEDLINE/PubMed
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Copyright Elsevier Limited Oct 28, 2017
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Snippet LDL cholesterol is a well established risk factor for atherosclerotic cardiovascular disease. How much one should or safely can lower this risk factor remains...
LDL cholesterol has been well established as a modifiable risk factor for atherosclerotic cardiovascular disease in epidemiological studies. In a series of...
Summary Background LDL cholesterol is a well established risk factor for atherosclerotic cardiovascular disease. How much one should or safely can lower this...
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StartPage 1962
SubjectTerms Adult
Aged
Aged, 80 and over
Angina
Antibodies, Monoclonal - therapeutic use
Anticholesteremic Agents - therapeutic use
Arteriosclerosis
Atherosclerosis
Cardiovascular disease
Cardiovascular diseases
Cerebral infarction
Cholesterol
Cholesterol, LDL - blood
Cholesterol, LDL - drug effects
Clinical trials
Diabetes
Double-Blind Method
Drug therapy
Effectiveness
Female
Follow-Up Studies
Health risk assessment
Heart attacks
Humans
Hypercholesterolemia - blood
Hypercholesterolemia - drug therapy
Inhibitor drugs
Kexin
Laboratories
Lipids
Low density lipoprotein
Male
Middle Aged
Monoclonal antibodies
Myocardial infarction
Patient Safety
Patients
Proprotein Convertase 9 - antagonists & inhibitors
Proprotein convertases
Risk Assessment
Risk factors
Safety
Secondary analysis
Statins
Stroke
Subtilisin
Treatment Outcome
Triglycerides
Title Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial
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