Statine nella cardiopatia ischemica in monoterapia: perchè?

Transcript

1 Santa Margherita Ligure 2 a Giornata Cardiologica del Tigullio 12 Febbraio, 212 Statine nella cardiopatia ischemica in monoterapia: perchè? Diego Ardissino

2 La medicina delle evidenze scientifiche Medicina delle opinioni Medicina delle evidenze Proselitismo Linee guida Caos Percorsi diagnostici terapeutici Pratica Clinica

3 Efficacy of Simvastatin in IHD Percent Change % P<,1 The 4S Study Lancet 1994;334: HPS Study Lancet 22;36: p<,1-3% p<,1 CV Death MI Stroke

4 Efficacy of Atorvastatin in IHD Percent Change 4 8 ALLIANCE Investigators JACC 24;44: % p<,1-48% p<,1-13% p<,1 CV Death MI Stroke

5 Efficacy of Pravastatin in IHD Percent Change 4-25% p<,1-29% p<,1-3 % p<,1 8 LIPID Study Group NEJM 1998;339: CARE Study NEJM 1996,335:11-19 CV Death MI Stroke

6 Efficacy of Fluvastatin in IHD Percent Change 4-22% p<,1-31% p<,1-47% p<,1 CV Death MACE CVD/MI 8 LIPS Investigators JAMA 22;

7 Efficacy of Lovastatin in IHD Percent Change 15-13% p=ns -8% p=ns -5% p=ns 3 POST-CABG Investigators NEJM 1997;336: CV Death MI Stroke

8 Efficacy of Rosuvastatin in IHD Percent Change CV Death MI Stroke

9 Efficacy of Simvastatin/Ezetimibe in IHD Percent Change CV Death MI Stroke

10 PROVE IT - TIMI 22 : Study Design 4,162 patients with an Acute Coronary Syndrome < 1 days Double-blind ASA + Standard Medical Therapy Standard Therapy Pravastatin 4 mg Intensive Therapy Atorvastatin 8 mg 2x2 Factorial: Gatifloxacin vs. placebo Duration: Mean 2 year follow-up (>925 events) Primary Endpoint: Death, MI, Documented UA requiring hospitalization, revascularization (> 3 days after randomization), or Stroke

11 Changes from (Post-ACS) Baseline in Median LDL-C 12 Median LDL-C(Q1, Q3) LDL-C (mg/dl) % 49% Pravastatin 4mg Atorvastatin 8mg 95 (79, 113) 62 (5, 79) 2 P<.1 <24h Rand. 3 Days 4 Mos. 8 Mos. 16 Mos. Final Note: Changes in LDL-C may differ from prior trials: 25% of patients on statins prior to ACS event ACS response lowers LDL-C from true baseline

12 Death or Major Cardiovascular Event percent PROVE-IT Trial Primary end-point 4 mg of pravastatin 8 mg of atorvastatin RRR 16% 95 % CI 5-26 P = Cannon CP et al N Eng J Med 24; 35: Months of Follow-up

13 PROVE-IT Trial Atorvastatin 8mg vs Pravastatin 4mg Risk Reduction Censoring Time Event Rates Risk Atorvastin Reduction percent Pravastin Hazard Ratio (95% CI) 3 Days Days Days End of follow-up High-Dose Standard-Dose Atorvastatin Better Provastatin Better Cannon CP et al N Eng J Med 24; 35:

14 A to Z Study Design Double-blind 4,497 patients with an Acute Coronary Syndrome < 5 days ASA + Standard Medical Therapy Placebo for 4 months then Simvastatin 2 mg/qd Simvastatin 4 mg/qd 1 month Simvastatin 8 mg/qd Duration follow-up : at least 6 monts to 2 year (>97 events) Primary Endpoint: Cardiovascular Death, MI, readmission for ACS, and stroke

15 Fase Z dello Studio A to Z: End-Point Primario 2 Placebo + 2 mg/d di Simvastatina Simvastatina (4/8 mg/d) Tasso cumulativo (%) HR,.89 (95% Cl, ); P = Tempo dalla Randomizzazione (mesi) De Lemos et al. JAMA 24;292:137

16 Fase Z dello Studio A to Z: End-Point Primario A Favore di Simvastatina (4/8 mg/d) A Favore di Placebo + 2 mg/d di Simvastatina Risultati complessivi Da a 4 mesi Da 4 a 24 mesi Hazard Ratio (95% CI) De Lemos et al. JAMA 24;292:137

17 Incidenza Combinata di Morte Cardiovascolare, Reinfarto, Ricovero per SCA e Ictus negli Studi PROVE-IT e A to Z Studio PROVE-IT Studio A to Z Prava 4 HR=.78 p=.7 Atorva 8 HR=.82 p= Simva 4/8 HR=1. p=1. Simva P/2 HR=.89 p=.12 (%) 1 (%) Mesi Mesi Wiviott SD et al. Circulation 26;113:146.

18 Effetti a Breve Termine del Trattamento Intensivo con Statine nella Sindrome Coronarica Acuta Riduzione degli eventi (%) C-LDL (mg/dl) 63 A to Z Miracl Prove-it

19 Effetti a Breve Termine del Trattamento Intensivo con Statine nella Sindrome Coronarica Acuta Riduzione degli eventi (%) PCR (%) A to Z Miracl Prove-it

20 ARMYDA-ACS Trial Study Design 58 pts excluded for : statin therapy - 41 emergency angiography - 43 LVEF < 3% - 3 contraindications to statins - 15 severe renal failure 771 pts with NSTE-ACS sent to early coronary angiography (48 hours) Jan 5 - Dec 6 Randomization (N=191) Atorvastatin 8 mg 12 hrs pre-angio; further 4 mg 2 hrs before N = 96 Placebo 12 hrs pre-angio; further dose 2 hrs before N = 95 2 pts excluded for indications to : - medical therapy (N=8) - bypass surgery (N=12) Coronary angiography 1 st blood smaple (pre-pci) PCI atorvastatin N = 86 PCI placebo N = 85 3 days atorvast 2 st and 3 st blood samples (8 and 24 hrs post-pci) Primary combined end point : 3-day Occurrence of Death, MI. TVR Patt G. et al JACC 27; 49: CK-MB, troponin-i, myoglobin, CRP

21 ARMYDA-ACS Trial Individual and Combined Outcome Measures of the Primary End Point at 3 days Atorvastatin Placebo 13/85 14/ Percent % P =.4 P =.1 5 1/85 5 Death MI TVR MACE 2 Patt G. et al JACC 27; 49:

22 Statin administration before PCI Impact on periprocedural myocardial infarction CK-MB rise > 5 x ULM ctni rise > 5 x ULM 18 4 Percent of case P = P = Statin Group Control Group Statin Group Control Group Brignani C. et al Eur Heart J 24; 25:

23 7 ARMYDA-3 Post-operative occurrence of AF 57% p=.3 % Occurence AF 35 35% Patti G. et al Circ 26;114: Atorvastatin 4 mg Placebo

24 Effetti delle Statine nelle Sindromi Coronariche Acute EFFETTI NON IPOLIPEMIZZANTI (effetto precoce/rapido) EFFETTI IPOLIPEMIZZANTI (effetto lento/ritardato) Disfunzione/attivazione endoteliale Statine inibitorio Infiammazione/ attivazione immunologica inibitorio Statine inibitorio Coagulazione/ attivazione piastrine Fegato Sintesi Colesterolo Epatico Rottura della placca/ occlusione trombotica Placca aterosclerotica ricca di lipidi Adapted from Ray K.K. et al J Am Coll Cardiol 25; 46:

25 Cholesterol-independent Effect of Statins TXA 2 t-pa PAI-1 MMPs TF Statins Macrophage Growth Rac1 RhoA ET-1 AT1 Receptor hs-crp Adhesion Molecule ROS NO + Platelet Activation Thrombotic Effect Plaque Stability Vascular Inflammation SMC Hypertrophy Endothelial Dysfunction SMC Proliferation Vasoconstriction Atherosclerosis Hypertension Takemoto M and Liao JK.Arterioscl Thromb Vasc Biol 21; 21: Cardiovascular Diseases

26 IMPROVE-IT TRIAL Study Design Patients stabilized post Acute Coronary Syndrome < 1 days LDL < 125 mg/dl (or < 1 mg/dl if prior statin) Double-blind ASA + Standard Medical Therapy N: 1, Simvastatin 4 mg/qd Ezetimibe/simvastatin 1/4 mg/qd Follow-up Visit Day 3, Every 4 months Duration: Minimum 2.5 year follow-up (>2955 events) Primary Endpoint: Cardiovascular Death, MI, hospital admission for UA, revascularisation (>3 days after randomization), or stroke