Nuevas evidencias en el manejo de las dislipemias en pacientes con alto riesgo cardiovascular. Tenemos que tratar a todos con inhibidores de PCSK9? LUIS MASANA Unidad de Medicina Vascular y Metabolismo Hospital Universitario Sant Joan Universitat Rovira i Virgili REUS - Tarragona
Contribuciones del cambio en mortalidad a la variación de esperanza de vida al nacer. España. 1980-2009 J.M. García González. Rev Esp Cardiol. 2013;66:848 853
Ultrastructural Pathology, 37(1), 43 51, 2013 Ultrastructural Features of H uman Atherosc
Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions JAMA. 2016;316(12):1289-1297
DOI: 10.1056/NEJMoa1410489 IMPROVE IT TRIAL Kaplan Meier Curves for the Primary Efficacy End Point
Hepatic LDL-Rs and PCSK9 Play a Key Role in Regulating Plasma LDL-C Levels LDL Brown MS, Goldstein JL. Proc Natl Acad Sci U S A. 1979;76:3330-3337. Steinberg D, Witztum JL. Proc Natl Acad Sci U S A. 2009;106:9546-9547. Goldstein JL, Brown MS. Arterioscler Thromb Vasc Biol. 2009;29:431-438. Qian YW, Schmidt RJ, Zhang Y, et al. J Lipid Res. 2007;48:1488-1498. Horton JD, Cohen JC, Hobbs HH. J Lipid Res. 2009;50(suppl):S172-S177 Chan JC, Piper DE, Cao Q, et al. Proc Natl Acad Sci U S A. 2009;106:9820-9825.
LDL-C Change from Baseline (mg/dl) Percent Change in LDL-C During Treatment 20 10 0-10 -20-30 -40-50 -60-70 -80 Mean LDL-C 93.0 mg/dl Change from baseline 3.9% Mean LDL-C 36.6 mg/dl Change from baseline -59.8% 0 8 16 24 32 40 48 56 64 72 Study Week 90 mg/dl 29 mg/dl 80 88
La lesión ateromatosa puede no manifestarse con estenosis luminal SEYMOUR GLAGOV 1925-2008 Seymour Glagov et al. NEJM 1987. 316: 1371-5
PROGRESIÓN REGRESIÓN Rev Esp Cardiol. 2006;59:57-66
Nicholls S et al. JAMA. doi:10.1001/jama.2016.16951
Primary Endpoint: Percent Atheroma Volume Change in Percent Atheroma Volume (%) 0.2 0-0.2-0.4-0.6-0.8-1 0.05 P = NS P < 0.0001-0.95 P <0.0001-1.2 Statin monotherapy Statinevolocumab
Percentage of Patients (%) Percentage of Patients (%) Percent of Patients Showing Regression in PAV Statin Monotherapy 100% 100% 80% 80% Statin plus Evolocumab P <0.0001 for comparison to statin monotherapy group 64.3% 60% 47.3% 52.7% 60% 40% 40% 35.7% 20% 20% 0% 0% Regressors Progressors Regressors Progressors
Randomization 1:1 End of Study (EOS) Evolocumab Outcomes Trial: Study Design Overview Screening Age 40 85 years MI, stroke, or PAD Additional risk factors (one major or two minor) Optimal background lipid therapy (including effective dose of statin ± ezetimibe) LDL-C 70 mg/dl (1.81 mmol/l) or non HDL-C 100 mg/dl (2.59 mmol/l) Evolocumab SC 140 mg Q2W or 420 mg QM (per subject preference) n ~ 13,750 Placebo SC Q2W or QM (per subject preference) n ~ 13,750 Maximum approximately 15 weeks D1 W4 W12 W24 Q24W Number of key 2 0 endpoints achieved D, day; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction; PAD, peripheral artery disease; Q2W, every 2 weeks; Q24W, every 24 weeks; QM, every month; SC, subcutaneous; W, week. Sabatine MS, et al. Am Heart J. 2016;173:94-101.
Evolocumab Outcomes Trial: Study Endpoints Endpoint Primary* Description Composite of CV death, MI, stroke, hospitalization for unstable angina, or coronary revascularization Key secondary Composite of CV death, MI, or stroke Other Secondary All-cause death; CV death; MI; stroke; coronary revascularization; CV death or hospitalization for heart failure; ischemic stroke or transient ischemic attack Sample size based on key secondary endpoint and powered to detect a 15% risk reduction at 90% power Assuming 2% per year event rate in placebo arm, 27,500 patients followed up for a median of ~43 months should have provided 1,630 key secondary endpoints Efficacy analysis was hierarchical: If primary endpoint was significantly reduced, then key secondary endpoint was to be tested, followed in order by CV death, all-cause mortality, then additional secondary endpoints *Time to CV death, MI, stroke, hospitalization for UA, or coronary revascularization, whichever occurs first Time to CV death, MI, or stroke, whichever occurs first CV = cardiovascular; MI = myocardial infarction Sabatine MS, et al. Am Heart J. 2016;173:94-101. Sabatine MS, et al. NEJM. [published online ahead of print March 17, 2017]. doi: 10.1056/NEJMoa1615664
Evolocumab LDLc lowering effect Sabatine MC et al. NEJM.org. DOI: 10.1056/NEJMoa1615664
Evolocumab significantly reduced CV events after two years Sabatine MC et al. NEJM.org. DOI: 10.1056/NEJMoa1615664
Reduction of low density lipoprotein-cholesterol and cardiovascular events with PCSK9 inhibitors and statins: an analysis of FOURIER, SPIRE, and the Cholesterol Treatment TrialistsCollaboration European Heart Journal (2017) 0, 1 6
Evolocumab is the first LLT to induce a significant CV event reduction after the first year of treatment Key secondary endpoint: survival Landmark analysis Sabatine MC et al. NEJM.org. DOI: 10.1056/NEJMoa1615664
Excellent safety profile Sabatine MC et al. NEJM.org. DOI: 10.1056/NEJMoa1615664 0% neutralising antibodies
Indicaciones de los Inhibidores de PCSK9 CONDICIÓN CLÍNICA NIVEL DE C-LDL (mg/dl) (tras tratamiento con máxima dosis de estatina tolerada + ezetimiba) HFHe >130 COMENTARIOS HFHe bajo riesgo >160 Edad <40 años; sin factores de riesgo; Lp(a) < 50 mg/dl; no ECV isquémica familiar ) HFHe + ECV ateromatosa > 100 HFHo Al menos un alelo defectuoso. Evolocumab. ECV ateromatosa estable >130 Incluye cardíaca, cerebral y periférica oclusiva. ECV ateromatosa clínicamente inestable; progresiva y/o recidivante; síndrome coronario agudo ECV ateromatosa + diabetes o Lp(a) > 100 mg/l Diabetes + 2 factores de riesgo o albuminuria o FGe < 45 ml/min/1.73m 2 Pacientes intolerantes a estatinas >100 De cualquier localización: cardíaca, cerebral y periférica oclusiva >100 >130 No incluida en indicaciones oficiales de uso Todas las condiciones anteriores + prevención primaria con C-LDL > 190 mg/dl HFHe = Hipercolesterolemia familiar heterocigota; HFHo = Hipercolesterolemia familiar homocigota ECV = Enfermedad cardiovascular; FGe = Filtrado glomerular estimado Masana et al. Clin Investig Art, 2016
La reducción de eventos cardiovasculares mediado por agentes hipolipemiantes se debe al descenso de c-ldl La introducción de inhibidores de PCSK9 junto a los fármacos hipolipemiantes clásicos (estatinas y ezetimiba), permiten obtener descensos de LDL superiores al 80 % del valor basal Evolocumab ha proporcionado evidencia científica demostrando que su impacto en la reducción de LDL se traduce en reducción de la lesión ateromatosa y eventos cardiovasculares ya desde el primer año de su instauración. Los ensayos clínicos realizados con evolocumab han confirmado su seguridad incluso cuando se alcanzan niveles muy bajos de LDL, confirmando que el colesterol LDL como más bajo mejor