Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.

Dislipemia. iPCSK9

74 views

Published on

Ponencia presentada por el Dr. Juan José Gómez Doblas en el directo online ‘Fármacos que mejoran el pronóstico cardiovascular’, realizado en la Casa del Corazón el 5 de junio de 2018

Published in: Health & Medicine
  • Be the first to comment

Dislipemia. iPCSK9

  1. 1. Inhibidores PCSK9 Dr. JJ Gómez Doblas Área del Corazón Hospital Universitario Virgen de la Victoria Málaga
  2. 2. Indice • Penetrancia de IPCSK9 en vida real en España • Beneficios en la práctica clínica diaria de nuestros pacientes más allá de la supervivencia • Reducción de mortalidad reducción de eventos de IPCSK9 • Dificultades para iniciar IPCSK9 • Y el futuro…
  3. 3. Lambert G et al. J Lipid Res. 2012;53:2515-2524 MONOCLONALES ANTI-PCSK9
  4. 4. Evolocumab – Fully human anti- PCSK9 mAb – ~60%  LDL-C – Safe & well-tolerated in Ph 2 & 3 studies – Exploratory data suggested  CV events Sever P & Mackay J. Br J Cardiol 2014;21:91-3 Giugliano RP, et al. Lancet 2012;380:2007-17 Sabatine MS, et al. NEJM 2015;372:1500-9 Background Proprotein convertase subtilisin/kexin type 9 (PCSK9) – Chaperones LDL-R to destruction   circulating LDL-C – Loss-of-fxn genetic variants   LDL-R   LDL-C &  risk of MI evolocumab An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School
  5. 5. Estudio RiCARD2 Evaluación del control glucémico en pacientes con alto riesgo cardiovascular y diabetes mellitus tipo 2 en consultas de atención primaria y cardiología
  6. 6. 2. Hipolipemiante 87,20% 12,10% 6,60% 1,10% 78,30% 5,00% 4,20% 0,80% 83,04% 8,77% 5,46% 0,97% Estatinas p=0,009 Ezetimibe p=0,005 Fibratos p=0,248 Otros Hipolipemiantes p=1 Cardiología Primaria Total Tratamientos
  7. 7. Control lípidos Cardiología Primaria N total P valor n % n % Control cLDL <70 117 43,0% 45 18,8% 162 <0,001 ≥70 155 57 % 195 81,2% 350
  8. 8. Estudios de eventos CV en IPCSK9. Fourier y Odyssey Outcome Am Heart J 2014;168:682-689.e1Am Heart J. 2016 Mar;173:94-101.
  9. 9. 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 or non–HDL-C ≥ 100 mg/dL 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 Randomization1:1 EndofStudy(EOS) Maximum approximately 15 weeks D1 W4 W12 W24 Q24W Number of key 20 endpoints achieved
  10. 10. ACC.18 6 Main Inclusion Criteria • Age ≥40 years • ACS • 1 to 12 months prior to randomization • Acute myocardial infarction (MI) or unstable angina • High-intensity statin therapy* • Atorvastatin 40 to 80 mg daily or • Rosuvastatin 20 to 40 mg daily or • Maximum tolerated dose of one of these agents for ≥2 weeks • Inadequate control of lipids • LDL-C≥70 mg/dL (1.8 mmol/L) or • Non-HDL-C≥100 mg/dL (2.6 mmol/L) or • Apolipoprotein B≥80 mg/dL *Patients not on statins were authorized to participate if tolerability issues were present and documented Schwartz GG, et al. Am Heart J 2014;168:682-689.e1.
  11. 11. An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School Endpoints • Efficacy – Primary: CV death, MI, stroke, hosp. for UA, or coronary revasc – Key secondary: CV death, MI or stroke • Safety – AEs/SAEs – Events of interest incl. muscle-related, new-onset diabetes, neurocognitive – Development of anti-evolocumab Ab (binding and neutralizing) • TIMI Clinical Events Committee (CEC) – Adjudicated all efficacy endpoints & new-onset diabetes – Members unaware of treatment assignment & lipid levels Sabatine MS et al. Am Heart J 2016;173:94-101
  12. 12. ACC.18 8 Primary Efficacy Outcome Time of first occurrence of: • Coronary heart disease (CHD) death, or • Non-fatal MI, or • Fatal or non-fatal ischemic stroke, or • Unstable angina requiring hospitalization* All outcomes adjudicated by the Clinical Events Committee, under the auspices of the Duke Clinical Research Institute (DCRI). Members were unaware of treatment assignment and lipid levels *Required all of the following: 1. Hospital admission >23 h for MI symptoms,  tempo in prior 48 hours and/or ≥20 min of chest discomfort at rest 2. New ECG findings consistent with ischemia or infarction 3. Angiographically significant obstructive coronary disease Schwartz GG, et al. Am Heart J 2014;168:682-689.e1.
  13. 13. ACC.18 9 Major Secondary Efficacy Endpoints Tested in the following hierarchical sequence: • CHD event: CHD death, non-fatal MI, unstable angina requiring hospitalization, or ischemia-driven coronary revascularization* • Major CHD event: CHD death or non-fatal MI • CV event: CV death, non-fatal CHD event, or non-fatal ischemic stroke • All-cause death, non-fatal MI, non-fatal ischemic stroke • CHD death • CV death • All-cause death *Revascularization performed because of recurrent ACS, new or progressive symptoms of myocardial ischemia or new or progressive abnormalities on functional testing, except revascularization due to restenosis at a prior coronary intervention site.
  14. 14. Acceptablerange Belowtarget ACC.18 15 Undesirably high baseline range LDL-C (mg/dL) Target range Alirocumab 705015 250 A Target Range for LDL-C Schwartz GG, et al. Am Heart J 2014;168:682-689.e1. We attempted to maximize the number of patients in the target range and minimize the number below target by blindly titrating alirocumab (75 or 150 mg SC Q2W) or blindly switching to placebo.
  15. 15. Characteristic Value Statin use(%)* High-intensity 69 Moderate-intensity 30 Ezetimibe use(%) 5 Medianlipidmeasures(IQR)–mg/dL LDL-C 92 (80-109) Totalcholesterol 168 (151-189) HDL-C 44 (37-53) Triglycerides 133 (100-182) Brigham and Women’s Hospital and Harvard Medical School Lipid Lowering Therapy & Lipid Levels at Baseline Pooled data; no differences between treatment arms *Per protocol, patients were to be on atorva ≥20 mg/d or equivalent. 1% were on low intensity or intensity data were missing. Statin intensity defined perACC/AHA2013 Cholesterol Guidelines. An Academic Research Organization of
  16. 16. Therapy,n(%) Alirocumab (N=9462) Placebo (N=9462) High-dose atorvastatin/rosuvastatin 8380(88.6) 8431(89.1) Low-/moderate-dose atorvastatin/rosuvastatin 830(8.8) 777(8.2) Other statin 19(0.2) 27(0.3) Ezetimibe, with or withoutstatin 269(2.8) 285(3.0) No lipid-lowering therapy* 87(0.9) 91(1.0) ACC.18 26 Baseline Lipid-Lowering Therapy *Patients not on statins were authorized to participate if tolerability issues were present and documented
  17. 17. Evolocumab Outcomes Trial: Resultados Placebo Median 92 mg/dL Evolocumab Median 30 mg/dL 13,251 13,151 12,954 12,596 12,311 10,812 6,926 3,352 79013,779Placebo 13,288 13,144 12,964 12,645 12,359 10,902 6,958 3,323 76813,784Evolocumab No. at risk 4 0 10 20 30 40 50 60 70 80 90 100 0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 Weeks 59% mean reduction (95%CI 58-60), P < 0.001 Absolute reduction: 56 mg/dL (95% CI 55-57) LDLCholesterol(mg/dL)
  18. 18. MeanLDL-C(mg/dL) ACC.18 29 96.4 42.3 15 0 105 90 75 60 45 30 0 4 8 12 16 20 24 28 32 36 40 44 48 93.3 55.7 mg/dL –62.7% 37.6 54.1 mg/dL –61.0% 101.4 48.1 mg/dL –54.7% 53.3 LDL-C: On-Treatment Analysis Placebo Alirocumab Months Since Randomization Excludes LDL-C values after premature treatment discontinuation or blinded switch to placebo Approximately 75% of months of active treatment were at the 75 mg dose
  19. 19. CVDeath,MI,Stroke, HospforUA,orCorRevasc An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School 10% 8% 6% 4% 2% 0% 14% 12% 16% Primary Endpoint Evolocumab Placebo Months from Randomization 0 6 12 18 24 30 36 Hazard ratio 0.85 (95% CI, 0.79-0.92) P<0.0001 14.6% 12.6%
  20. 20. CVDeath,MI,orStroke An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School 7% 6% 5% 4% 3% 2% 1% 0% 10% 9% 8% Key Secondary Endpoint Months from Randomization 0 6 12 18 24 30 36 Hazard ratio 0.80 (95% CI, 0.73-0.88) P<0.00001 Evolocumab Placebo 9.9% 7.9%
  21. 21. An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School Types of CV Outcomes Endpoint Evolocumab (N=13,784) Placebo (N=13,780) HR (95% CI) 3-yr Kaplan-Meier rate CVD, MI, stroke, UA, or revasc CV death, MI, or stroke Cardiovascular death MI Stroke Hosp for unstable angina Coronary revasc Urgent Elective Death from any cause 12.6 7.9 2.5 4.4 2.2 2.2 7.0 3.7 3.9 4.8 14.6 9.9 2.4 6.3 2.6 2.3 9.2 5.4 4.6 4.3 0.85 (0.79-0.92) 0.80 (0.73-0.88) 1.05 (0.88-1.25) 0.73 (0.65-0.82) 0.79 (0.66-0.95) 0.99 (0.82-1.18) 0.78 (0.71-0.86) 0.73 (0.64-0.83) 0.83 (0.73-0.95) 1.04 (0.91-1.19)
  22. 22. ACC.18 31 Primary Efficacy Endpoint: MACE ARR* 1.6% *Based on cumulative incidence MACE: CHD death, non-fatal MI, ischemic stroke, or unstable angina requiring hospitalization HR 0.85 (95% CI 0.78, 0.93) P=0.0003
  23. 23. Endpoint,n(%) Alirocumab (N=9462) Placebo (N=9462) HR(95%CI) Log-rank P-value MACE 903(9.5) 1052(11.1) 0.85(0.78,0.93) 0.0003 CHD death 205(2.2) 222(2.3) 0.92(0.76,1.11) 0.38 Non-fatal MI 626(6.6) 722(7.6) 0.86(0.77,0.96) 0.006 Ischemicstroke 111(1.2) 152(1.6) 0.73(0.57,0.93) 0.01 Unstable angina 37(0.4) 60(0.6) 0.61(0.41,0.92) 0.02 ACC.18 32 Primary Efficacy and Components
  24. 24. Endpoint,n(%) Alirocumab (N=9462) Placebo (N=9462) HR(95%CI) Log-rank P-value CHD event 1199(12.7) 1349(14.3) 0.88(0.81,0.95) 0.001 Major CHD event 793(8.4) 899(9.5) 0.88(0.80,0.96) 0.006 CV event 1301(13.7) 1474(15.6) 0.87(0.81,0.94) 0.0003 Death, MI, ischemic stroke 973(10.3) 1126(11.9) 0.86(0.79,0.93) 0.0003 CHD death 205(2.2) 222(2.3) 0.92(0.76,1.11) 0.38 CV death 240(2.5) 271(2.9) 0.88(0.74,1.05) 0.15 All-cause death 334(3.5) 392(4.1) 0.85(0.73,0.98) 0.026* ACC.18 33 Main Secondary Efficacy Endpoints: Hierarchical Testing *Nominal P-value
  25. 25. An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School P<0.0001 Lower LDL-C Is Better Patients divided by quartile of baseline LDL-C and by treatment arm Q4 Q3 Q2 Q1 Q4 Q3 Q2 Q1 Placebo Evolocumab
  26. 26. Safety Adverse events (%) Any Serious Allergic reaction Injection-site reaction Treatment-related and led to d/c of study drug Muscle-related Cataract Diabetes (new-onset) Neurocognitive Laboratory results (%) Binding Ab Neutralizing Ab Evolocumab (N=13,769) 77.4 24.8 3.1 2.1 1.6 5.0 1.7 8.1 1.6 0.3 none Placebo (N=13,756) 77.4 24.7 2.9 1.6 1.5 4.8 1.8 7.7 1.5 n/a n/aNew-onset diabetes assessed in patients without diabetes at baseline; adjudicated by CEC An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School
  27. 27. 0% 10% 20% 30% 40% 50% 60% No estatina Dosis baja Dosis intermedia Dosis alta 31,0% 8,1% 47,8% 10,5% 8,4% 4,6% 44,2% 42,8% 2006 2014 TRECE (2006) vs. REPAR (2014): Utilización de estatinas Cordero A, et al. Rev Esp Cardiol 2016;69:401-07
  28. 28. Pacientes de alto riesgo cardiovascular Anguita Sa ́nchez M, et al. Necesidades no cubiertas con el tratamiento hipolipemiante oral: documento de posicio ́n de la Sociedad Espan ̃ola de Cardiologı ́a. Rev Esp Cardiol. 2016.
  29. 29. A. Zamora et al. / Rev Esp Cardiol. 2017;xx(x):xxx–xxx J Am Heart Assoc. 2017 Nov; 6(11): e006537.
  30. 30. A. Zamora et al. / Rev Esp Cardiol. 2017;xx(x):xxx–xxx
  31. 31. Circulation. 2018;137:338-350
  32. 32. Circulation. 2018;137:338-350
  33. 33. BARRERAS • Kazi DS et al. Updated cost-effectiveness analysis of PCSK9 in- hibitors based on the results of the FOURIER trial. JAMA. 2017;318:748– 750. • Fonarow GC et al . Cost-effectiveness of evolocumab therapy for reducing cardiovascular events in patients with atherosclerotic cardiovascular disease. JAMA Cardiol. 2017;2:1069–1078 • Arrieta A et al Updated cost-effectiveness assessments of PCSK9 inhibitors from the perspectives of the health system and private payers: insights derived from the FOURIER Trial. JAMA Cardiol. 2017;2:1369–1374. doi:
  34. 34. @drdoblas jjgomezdoblas@gmail.com

×