UNA CERTEZZA CONSOLIDATA: STATINE ED EZETIMIBE Dott. Danilo Puccio U.O.C. di Cardiologia - UTIC P.O. Civico di Partinico Valderice, 3 ottobre 2015 Hotel Tonnara di Bonagia
1976: Endo et al. isolano la Mevastatina da una coltura di Penicillum 1977: Nasce il sottoscritto 1978: Brown et al. ne scoprono il meccanismo di azione
CHD EVENTS AND LDL-C IN STATIN TRIALS Opie et al. Lancet. 2006; 367: 69-78
EFFETTI PLEIOTROPICI DELLE STATINE Farmer JA. Current Atherosclerosis Reports 2000; 2: 208-17
JA. Jarcho, et al. N Engl J Med. 2015; 372: 2448-2450
Major coronary events Per ogni mmol/l di riduzione di LDL-c si ottiene una riduzione del RR del: - 23% del primo evento coronarico maggiore. - 24% dell incidenza della prima rivascolarizzazione coronarica. - 21% complessivamente dell incidenza degli eventi vascolari maggiori. - 12% di tutte le cause di mortalità (principalmente attribuibile ad un -19% delle morti coronariche). Reduction in LDL cholesterol (mmol/l) La riduzione del Rischio Relativo risulta indipendente dai livelli iniziali di LDL-C e dalle caratteristiche cliniche del paziente, è significativa già al primo anno e si mantiene altamente significativa negli anni successivi. Baigent C, et al, Cholesterol Treatment Trialists (CTT) Collaborators. Lancet 2005; 366: 1267 1278
Variazioni di C-LDL rispetto al basale C-LDL Mediano (Q1, Q3) 95 (79, 113) 21% 49% P<0.001 62 (50, 79) - 4162 pazienti (età media 58 aa, 22% femmine, 18% DM), arruolati entro 10gg da SCA - End point primario composito (morte per tutte le cause, IM, AI, rivascolarizzazione e Stroke) - Follow-up medio: 2 anni Incidenza dell End Point Primario 26.3% 22.4% Risk Reduction: 16 % CP. Cannon, et al. N Engl J Med. 2004; 350: 1495-1504
Wiviott et al. J Am Coll Cardiol. 2005; 46: 1411-6
Effects on each type of major vascular event Effects on cause-specific mortality per 1 mmol/l reduction in LDL cholesterol Baigent C, et al, Cholesterol Treatment Trialists (CTT) Collaborators. Lancet 2010; 376: 1670 81
EZETIMIBE Approvata dal 2002 negli USA Inibisce selettivamente la proteina Niemann-Pick C1-like 1 (NPC1L1) localizzata principalmente a livello dell intestino tenue dove funziona come trasportatore del colesterolo dal lume intestinale all interno degli enterociti. Riduce quindi l assorbimento del colesterolo dietetico e biliare Quando aggiunta alla statina, determina una riduzione ulteriore del 20-25% del LDL-c. Borghi C. et al. G Ital Cardiol 2015; 16: 3S - 14S
Presence of Inactivating Mutations in NPC1L1 and Plasma Lipid Levels Presence of Inactivating Mutations in NPC1L1 and the Risk of Coronary Heart Disease The Myocardial Infarction Genetics Consortium Investigators. N Engl J Med 2014; 371: 2072-82
SINERGIA TRA EZETIMIBE E STATINE L ezetimibe associata alla statina permette di: 1 Riduzione del colesterolo epatico 2 Aumentata espressione di Recettori per LDL-C 3 Aumentata clearance di LDL-C Pool Colesterolo (Micelle) Statine HMG-CoA X Colesterolo Fegato NPC1L1 X Ezetimibe 1 Pool Colesterolo Recettori Remnant 2 Espressione Recettori LDL 3 CMR LDL-C CM Sangue Ateroma Grigore L. et al. Vas Health Risk Manag. 2008; 4: 267 278
Variazione % media dal basale del C-LDL calcolato (settimana 12) 0 Ezetimibe 10 mg + atorvastatina 10 mg 10 mg 20 mg Atorvastatina 40 mg 80 mg 10 20 30 40 37* 42* 45* 50 53 54 60 *p<0,01 terapia di associazione vs. statina da sola Ballantyne CM et al. Circulation 2003; 107: 2409-2415
Stone NJ, et al. 2013 ACC/AHA Blood Cholesterol Guideline - JACC 2014; 63: 2889-934
IMPROVE-IT: STUDY DESIGN Patients stabilized post ACS 10 days: LDL-C 50 125*mg/dL (or 50 100**mg/dL if prior lipid-lowering Rx) *3.2mM **2.6mM N=18,144 Standard Medical & Interventional Therapy Simvastatin 40 mg Uptitrated to Simva 80 mg if LDL-C > 79 (adapted per FDA label 2011) Ezetimibe / Simvastatin 10 / 40 mg Follow-up Visit Day 30, every 4 months 90% power to detect ~9% difference Duration: Minimum 2 ½-year follow-up (at least 5250 events) Primary Endpoint: CV death, MI, hospital admission for UA, coronary revascularization ( 30 days after randomization), or stroke Cannon CP AHJ 2008; 156: 826-32; Califf RM NEJM 2009; 361: 712-7; Blazing MA AHJ 2014; 168: 205-12
IMPROVE-IT: BASELINE CHARACTERISTICS Simvastatin (N=9077) % EZ/Simva (N=9067) % Age (years) 64 64 Female 24 25 Diabetes 27 27 MI prior to index ACS 21 21 STEMI / NSTEMI / UA 29 / 47 / 24 29 / 47 / 24 Days post ACS to rand (IQR) 5 (3, 8) 5 (3, 8) Cath / PCI for ACS event 88 / 70 88 / 70 Prior lipid Rx 35 36 LDL-C at ACS event (mg/dl, IQR) 95 (79, 110) 95 (79,110) CP. Cannon, et al. N Engl J Med. 2015; 372: 2387-2397
IMPROVE-IT: RESULTS LDL-C and Lipid changes: Primary Composite End Point ITT approach: Cardiovascular death, MI, documented unstable angina requiring rehospitalization, coronary revascularization ( 30 days), or stroke CP. Cannon, et al. N Engl J Med. 2015; 372: 2387-2397
IMPROVE-IT: INDIVIDUAL CV END POINTS & CVD/MI/STROKE HR Simva* EZ/Simva* p-value All-cause death 0.99 15.3 15.4 0.782 CVD 1.00 6.8 6.9 0.997 CHD 0.96 5.8 5.7 0.499 MI 0.87 14.8 13.1 0.002 Stroke 0.86 4.8 4.2 0.052 Ischemic stroke 0.79 4.1 3.4 0.008 Cor revasc 30d 0.95 23.4 21.8 0.107 UA 1.06 1.9 2.1 0.618 CVD/MI/stroke 0.90 22.2 20.4 0.003 0.6 1.0 1.4 *7-year Ezetimibe/Simva Better Simva Better event rates (%) CP. Cannon, et al. N Engl J Med. 2015; 372: 2387-2397
IMPROVE-IT: SENSITIVITY ANALYSIS (WEI, LIN, WEISSFELD MODEL FOR PEP) Murphy SA, Cannon CP et al. : not published data Model HR 0.93, 95% CI 0.89, 0.99, p=0.01 First Event (n=5,314) Second Event (n=2,297) Third Event (n=972) Fourth Event (n=456) Model Average HR 0.6 Ezetimibe/Simva 1.0 Simva 1.3 Better Better
# Events Dott. Danilo Puccio IMPROVE-IT: TOTAL PEP EVENTS BY TYPE OF EVENT 506 456 Murphy SA, Cannon CP et al. : not published data 5th-14th event 972 Fourth event Third event Second event First event 5314 2297 5000 4000 4983 1442 Total NF MI RR 0.87 p=0.004 4562 1259 3000 354 Total NF Stroke RR 0.77 p=0.005 274 2000 1000 0 2481 2319 168 173 538 537 Simvastatin Alone Ezetimibe/Simvastatin NF MI NF Stroke Revascularization UA CV Death
IMPROVE-IT VS CTT: EZETIMIBE VS. STATIN BENEFIT CP. Cannon, et al. N Engl J Med. 2015; 372: 2387-2397
CHD Events (%) Dott. Danilo Puccio THE LOWER IS BETTER EVEN LOWER IS EVEN BETTER 30 25 20 15 10 5 R² = 0.9029 p < 0.0001 53 70 LIPID CARE HPS TNT PROVE IT TIMI 22 IMPROVE-IT 4S 0 30 50 70 90 110 130 150 170 190 210 LDL Cholesterol (mg/dl) Adapted and Updated from O Keefe, J. et al., J Am Coll Cardiol 2004; 43: 2142-6
C. Ip et al. International Journal of Cardiology. 2015; 191: 138 148 Effect of combination therapy vs statin monotherapy on MACEs. p=.004 (109.244) 9.70 % vs 9.92%, p=.76
Masana L. et al. Atherosclerosis.2015; 240: 161-162
European Heart Journal Advance Access published September 11, 2015
Robinson JG and Stone NJ. European Heart Journal. 2015; 36: 2110 2118
Lower is better! Even lower even better! danilo.puccio@gmail.com