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 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, FOURIER Investigators
Lancet (London, England) · 506 citas
Cómo se estudió
- Diseño
- Ensayo controlado aleatorizado (indexado por PubMed)
- Estudiado en
- Personas
- Resultado principal
- Eventos clínicos como enfermedad o muerte
Quién lo pagó
- Financiación
- Financiación independiente
- Gobierno
- National Institute for Health and Care Research
- Gobierno
- National Institute for Health Research (NIHR)
- Subvenciones
- National Institute for Health and Care Research (NF-SI-0513-10059)
Según 2 financiadores declarados.
Publicación
- Publicado
- 2017-08-28 · Lancet · vol. 390 · número 10106 · págs. 1962–1971
- Editorial
- Elsevier BV
- Citado
- 686 citas · más que el 100% de estudios similares · 78.9× el promedio de su campo
- Impacto
- Entre el 10 % más citado de su campo
- Referencias
- 33 trabajos
- Acceso
- Acceso abierto (copia en repositorio) · CC-BY-NC-ND
- Áreas de investigación
- Lipoproteins and Cardiovascular Health · Atherosclerosis and Cardiovascular Diseases · Acute Myocardial Infarction Research
- Palabras clave
- evolocumab, PCSK9 inhibitors, LDL cholesterol lowering, very low LDL cholesterol, FOURIER trial, cardiovascular outcomes, LDL cholesterol targets, atherosclerotic cardiovascular disease, safety incidents, primary endpoint, secondary endpoints, cardiovascular mortality, myocardial infarction, stroke, coronary revascularization, unstable angina
- MeSH
- humans, hypercholesterolemia, antibodies, monoclonal, anticholesteremic agents, treatment outcome, risk assessment, follow-up studies, double-blind method, adult, aged, aged, 80 and over, middle aged, female, male, cholesterol, ldl, antibodies, monoclonal, humanized, patient safety, proprotein convertase 9, pcsk9 inhibitors
19 autores
- Robert Patrick Giugliano🇺🇸 · autor de correspondenciaBrigham and Women's Hospital; Thrombolysis in Myocardial Infarction Study Group
- Terje Rolf Pedersen🇳🇴Oslo University Hospital; University of Oslo
- Jeong‐Gun Park🇺🇸Brigham and Women's Hospital; Thrombolysis in Myocardial Infarction Study Group
- Gaetano Maria De Ferrari🇮🇹University of Pavia; Policlinico San Matteo Fondazione
- Zbigniew A. Gaciong🇵🇱Medical University of Warsaw
- R Češka🇨🇿General University Hospital in Prague
- Kálmán Tóth🇭🇺University of Pecs
- Ioanna Gouni‐Berthold🇩🇪University of Cologne
- José López‐Miranda🇪🇸Instituto Maimónides de Investigación Biomédica de Córdoba; Hospital Universitario Reina Sofía; University of Córdoba
- François Schiele🇫🇷Centre Hospitalier Universitaire de Besançon
- François Mach🇨🇭University Hospital of Geneva
- Brian R. Ott🇺🇸Brown University; Rhode Island Hospital
- Estella Kanevsky🇺🇸Brigham and Women's Hospital; Thrombolysis in Myocardial Infarction Study Group
- Armando Lira Pineda🇺🇸Amgen (United States)
- Ransi M. Somaratne🇺🇸Amgen (United States)
- Scott M. Wasserman🇺🇸Amgen (United States)
- ANTHONY C. KEECH🇦🇺The University of Sydney; National Health and Medical Research Council
- Peter S. Sever🇬🇧Imperial College London
- Marc Steven Sabatine🇺🇸Brigham and Women's Hospital; Thrombolysis in Myocardial Infarction Study Group
Resumen
El texto original del estudio, en el idioma en que se publicó.
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.
Resumen vía Europe PMC. Los derechos de autor siguen siendo de los autores o la editorial.
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