STATINE ED EZETIMIBE UNA CERTEZZA CONSOLIDATA: Dott. Danilo Puccio U.O.C. di Cardiologia - UTIC P.O. Civico di Partinico

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1 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

2 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

3 CHD EVENTS AND LDL-C IN STATIN TRIALS Opie et al. Lancet. 2006; 367: 69-78

4 EFFETTI PLEIOTROPICI DELLE STATINE Farmer JA. Current Atherosclerosis Reports 2000; 2:

5 JA. Jarcho, et al. N Engl J Med. 2015; 372:

6 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:

7 Variazioni di C-LDL rispetto al basale C-LDL Mediano (Q1, Q3) 95 (79, 113) 21% 49% P< (50, 79) 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:

8 Wiviott et al. J Am Coll Cardiol. 2005; 46:

9 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:

10 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

11 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:

12 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:

13 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 * 42* 45* *p<0,01 terapia di associazione vs. statina da sola Ballantyne CM et al. Circulation 2003; 107:

14 Stone NJ, et al ACC/AHA Blood Cholesterol Guideline - JACC 2014; 63:

15 IMPROVE-IT: STUDY DESIGN Patients stabilized post ACS 10 days: LDL-C *mg/dL (or **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: ; Califf RM NEJM 2009; 361: 712-7; Blazing MA AHJ 2014; 168:

16 IMPROVE-IT: BASELINE CHARACTERISTICS Simvastatin (N=9077) % EZ/Simva (N=9067) % Age (years) Female Diabetes MI prior to index ACS STEMI / NSTEMI / UA 29 / 47 / / 47 / 24 Days post ACS to rand (IQR) 5 (3, 8) 5 (3, 8) Cath / PCI for ACS event 88 / / 70 Prior lipid Rx LDL-C at ACS event (mg/dl, IQR) 95 (79, 110) 95 (79,110) CP. Cannon, et al. N Engl J Med. 2015; 372:

17 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:

18 IMPROVE-IT: INDIVIDUAL CV END POINTS & CVD/MI/STROKE HR Simva* EZ/Simva* p-value All-cause death CVD CHD MI Stroke Ischemic stroke Cor revasc 30d UA CVD/MI/stroke *7-year Ezetimibe/Simva Better Simva Better event rates (%) CP. Cannon, et al. N Engl J Med. 2015; 372:

19 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

20 # Events Dott. Danilo Puccio IMPROVE-IT: TOTAL PEP EVENTS BY TYPE OF EVENT Murphy SA, Cannon CP et al. : not published data 5th-14th event 972 Fourth event Third event Second event First event Total NF MI RR 0.87 p= Total NF Stroke RR 0.77 p= Simvastatin Alone Ezetimibe/Simvastatin NF MI NF Stroke Revascularization UA CV Death

21 IMPROVE-IT VS CTT: EZETIMIBE VS. STATIN BENEFIT CP. Cannon, et al. N Engl J Med. 2015; 372:

22 CHD Events (%) Dott. Danilo Puccio THE LOWER IS BETTER EVEN LOWER IS EVEN BETTER R² = p < LIPID CARE HPS TNT PROVE IT TIMI 22 IMPROVE-IT 4S LDL Cholesterol (mg/dl) Adapted and Updated from O Keefe, J. et al., J Am Coll Cardiol 2004; 43:

23 C. Ip et al. International Journal of Cardiology. 2015; 191: Effect of combination therapy vs statin monotherapy on MACEs. p=.004 ( ) 9.70 % vs 9.92%, p=.76

24 Masana L. et al. Atherosclerosis.2015; 240:

25 European Heart Journal Advance Access published September 11, 2015

26 Robinson JG and Stone NJ. European Heart Journal. 2015; 36:

27 Lower is better! Even lower even better!