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Vecchi e nuovi farmaci in cerca di conferme Pretrattamento con alte dosi di statine nella strategia invasiva delle SCA

Vecchi e nuovi farmaci in cerca di conferme Pretrattamento con alte dosi di statine nella strategia invasiva delle SCA. Michele Galli Unità Operativa di Cardiologia Spedali Riuniti Livorno ASL6. Early statins in ACS: what evidence ?. Observational studies

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Vecchi e nuovi farmaci in cerca di conferme Pretrattamento con alte dosi di statine nella strategia invasiva delle SCA

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  1. Vecchi e nuovi farmaci in cerca di confermePretrattamento con alte dosi di statine nella strategia invasiva delle SCA Michele Galli Unità Operativa di Cardiologia Spedali Riuniti Livorno ASL6

  2. Early statins in ACS: what evidence ? • Observational studies • Stenestrand et al , 2001 (RIKS-HIA database) • Aronow et al, 2001 (GUSTO-IIB+PURSUIT) • Spencer et al, 2004 (GRACE) • Fonarow et al, 2005 (NRMI-4) • Lenderink et al, 2006 (Euro Heart Survey ACS) • Small trials and meta-analysis • ARMIDA-ACS (2007) • Large RCTs • MIRACL (2001) • A to Z (2004) • PROVE-IT TIMI 22 (2004)

  3. Statin continued/newly started All AMI STEMI Non-STEMI In-hosp mortality risk in pt who continued or newly started statin <24 h of AMI admission NRMI-4 data (300,823 patients) Fonarow et al, Am J Card 2005;96:611-616

  4. HR 0.16 (95% CI 0.08-0.37) (n=6771) HR 0.44 (95% CI 0.31-0.64) (n=1426) 7 Very early (<24 hrs) statin therapy in patients with ACS associated with reduced mortality Euro Heart Survey 2000-01 (10,484 patiens) Lenderink et al, Eur Heart J 2006;27:1799-1804

  5. Observational studiesoverestimate magnitude of an effect • Survivor treatment selection • Major limitations of propensity- and covariate-adjusted analysis: • insufficient control of confounders between groups • competing medical issues Statin therapy likely a marker of quality of care

  6. Early Treatment With Statins in ACS

  7. Briel et al, JAMA 2006

  8. Hulten et al, Arch Intern Med 2006

  9. Intensive, but not moderate, statin treatment reduces early ischemic events after ACSKaplan-Meier event curves for the primary end point MIRACL A to Z PROVE IT HR=0.8 P =0.03 Death, AMI, stroke, USA, revascularization >30 days RR=0.84 p=0.048 RR=1.01 p=NS Months of randomized treatment

  10. PROVE IT: concomitant therapies Cannon C et al, N Engl J Med 2004;350:15

  11. PROVE IT-TIMI 22: treatment effects stratified by PCI for the index ACS event Statin treatment NS p 0.01 NS p 0.07 0-4 months Trial duration Wiviott et al, Circulation 2006;113:1426

  12. 6-month mortality of patients pretreated with statins (n= 1337) vs those not statins pretreated (n=3715) at the time of PCI Statin therapy pre-PCI is an independent predictor of survival Chan et al, Circulation 2002;105:691

  13. Preprocedural Statin Reduces the Extent of Periprocedural Non-Q-Wave Myocardial Infarction CK > 3XUNL n=211 6.0% n=56 P=0.18, log-rank p<0.01 0.4% control on statin Herrmann et al, Circulation. 2002;106:2180

  14. Statin therapy, inflammation and recurrent coronary events following PCI Walter et al, J Am Coll Cardiol 2001;37:839

  15. Pre-PCI statin Rx reduces the incidence of large peri-proceduralnonQ-AMI OR 0.19 (95% CI 0.05-0.57) p = 0.02 OR 0.47 (95% CI 0.26–0.86) p = 0.01 Periprocedural AMI (%) Briguori et al, Eur Heart J2004; 25: 1822–1828 Pasceri et al, Circulation 2004;110:674

  16. atorvastatin placebo 7-day atorvastatin pretreatment decreases adhesion molecules after PCI Patti et al, J Am Coll Cardiol 2006;48:1560

  17. 5% p 0.01 17% Patti et al, J Am Coll Cardiol 2007;49:1272

  18. Atorvastatin Pretreatment Improves Outcomes inPatients With ACS Undergoing Early PCIARMYDA-ACS Randomized Trial Patti et al, J Am Coll Cardiol 2007;49:1272

  19. Atorvastatin Pretreatment Improves Outcomes inPatients With ACS Undergoing Early PCIResults of the ARMYDA-ACS Randomized Trial Patti et al, J Am Coll Cardiol 2007;49:1272

  20. High-dose statins in ACS: an intriguinghypothesis • Early benefits derived largely from the anti-inflammatoryeffects of the drug. • The delayed benefits are lipid-modulated. Nissen S, JAMA 2004;292;1365

  21. Molecular pathway of statins Cholesterol synthesis Cell signaling Ray K, Cannon C. J Am Coll Cardiol 2005;46:1425–33

  22. Acetil CoA recettori di membrana HMG CoA Mevalonato mitosi apoptosi Proteine prenilate O2- O2- O2- formazione superossido Colesterolo

  23. Pleiotropic effects ascribed to statins Reduce platelet aggregability Reduce thrombus formation  PAI-1  tF Improve endothelial function & vasomotion  NO bioavailability circ. endothelial progenitor cells Decrease matrix degradation  macrophage metalloproteinase  collagen content Reduce inflammation within plaque  CRP  monocyte adhesion Promote plaque remodeling HDL-Chol  LDL-Chol  TGL adapted from Rosensonet al. JAMA1998;279:1643–1650

  24. Potential mechanisms by which statins act rapidly and favorably in ACS • Improve endothelial integrity & vasomotion • Decrease plaque matrix degradation • Reduce plaque inflammation • Reduce platelet aggregability and thrombus formation • Decrease reperfusion injury

  25. Early statin treatment in ACSToo good to be true? 88% risk reduction of 30-day major cardiac events

  26. Severe adverse event rates for intensive vs moderate statin therapy (n. 32,279 pts) Rhabdomyolysis CPK >10 xULN AST/ALT >3 xULN mod. from Cannon et al, J Am Coll Cardiol 2006;48:438

  27. Short-term benefit by high-dose in the most vulnerable period (peri-PCIand post-ACS) Pleiotropic effects likely Proven efficacy in the long-term absence of harm Fixed doses / dose titration to achieve specific goals (lipid / anti-inflammatory) Early atorvastatin treatment in ACSConclusions

  28. Statin administration before PCI:Impact on periprocedural MI Briguori et al, Eur Heart J 2004; 25: 1822–1828

  29. 0 0 0 Statin Therapy at Carotid Angioplasty: Effect on Procedure-related Stroke, MI and Death A prospective database Preprocedural Statin Rx P <0.05 Groeschel et al, Radiology 2006;240:145

  30. *p <0.05 vs. control **p 0.001 vs. control Atorvastatin at reperfusion onset attenuates lethal myocardial injury Krebs 0 5 25 50 100 Atorvastatin mcmol/l Bell, JACC 2003; 41: 508

  31. Preprocedural statin Rx abolished the negative prognostic effect of baseline C-reactive protein elevation after PCI Chan et al, Circulation 2003;107:1750

  32. Atorvastatin reduces neointimal inflammation in atherosclerosis rabbit model Untreated Treated neointimal formation monocyte chemoattractant protein-1 Bustos et al, J Am Coll Cardiol 1998;32:2057–2064

  33. MIRACL A to Z RR=0.84 P=0.048 RR=1.01 P=NS Months of randomized treatment Intensive, but not moderate, statin treatment reduces early ischemic events after ACS mod. from Schwartz G et al, Am J Cardiol 2005;96:45F–53F

  34. Chronic pre-treatment of statins associated with reduction of no-reflow phenomenon P 0.003 P 0.04 Iwakura, Eur Heart J 2006;27: 534

  35. prenilazione statina PI3K AKt e-Nos

  36. Early statins in ACS: major effects in RCTs mod. from Nissen S, JAMA 2004;292;1365

  37. Atrial fibrillation–free survival (%) OR 0.39, 95% CI 0.18to 0.85, p 0.017 Post-operative days Atorvastatin 40 mg 7 days before CABG reduces postoperative atrial fibrillation: ARMYDA-3 results Patti G et al, Circulation 2006;114;1455-1461

  38. Statin Therapy and Outcome during Hospitalization for ACS On-statin treatment and ACS presentation in GRACE Spencer et al, Ann Intern Med 2004; 140: 857 - 866

  39. Lipid-lowering agent use at ischemic stroke onset is associated with decreased mortalityNorthern Manhattan Study population study • Taking LLAs at stroke onset • Yes No p • In hosp worsening (%) 6.3 18.2 0.04 • 90-day mortality 1.8 10.6 0.03 • Severe stroke 10.7 16.8 0.3 Elkind et al, NEUROLOGY 2005;65:253-258

  40. Statins efficacy in achieving thedual goals (LDL-Chol <70 mg/dl and C-Reactive Protein <2 mg/l) RR 0.72 (95% CI 0.52-0.99) Dual goal Dual goals not achieved Dual goals achieved Ridker P et al, N Engl J Med 2005;325:20-28

  41. Beta-blocker use OR 0.41 (95% CI 0.28-0.59) Statin use OR 0.40 (95% CI 0.24-0.68) 0.5 1.0 1.5 Beta-blockers and statins associated with reduced mortality in patients undergoing noncardiac surgery 108,593 patients undergoing noncardiac nonvascular surgery Erasmus MC 1991-2000 Adjusted Odds Ratio for perioperative mortality www.escardio.org/knowledge/congresses/abol/presentation?id=41928

  42. Efficacy of Achieving Very Low LDL-Chol With Intensive Statin Therapy PROVE IT-TIMI 22 Substudy Hazard ratio of the primary end point Wiviott S et al, J Am Coll Cardiol 2005;46:1411– 6

  43. RIKS-HIA 1995-98 (19,599 patients) GUSTO IIb & PURSUIT, 1993-98 (20,809 patients) Lipid-lowering (n=3653) No statin (n=14071) No LL (n=17156) Statin (n=5528) Relative risk 0.75 95% CI 0.63-0.89 Log-rank p<0.0001 RR 0.48 95% CI 0.37­0.63 RR 0.75 95% CI 0.63-0.89 p<0.0001 p=0.001 Stenestrand et al, JAMA 2001;285:430 Aronow et al, Lancet 2001;357:1063 Early Striking Mortality Reduction After ACS by Lipid-lowering Therapy

  44. Early statins and mortality in Euro Heart Survey Lenderink et al, Eur Heart J 2006;27:1799-1804

  45. 0.25 0.50 0.75 1.00 1.25 1.50 1.75 2.00 Atorvastatin better Placebo better RelativeRisk MIRACL: Primary end point events Death Nonfatal Acute MI Resuscitated Cardiac Arrest Worsening angina with urgent rehosp. Fatal / nonfatal stroke p=0.02 p=0.04 Schwartz et al, JAMA April 4, 2001

  46. Intensive statin Rx in ACS and all-cause mortality Meta-analysis of randomized controlled trials Study Intensive Moderate RR (95% CI) n/N n/N A to Z104/2265 130/2231 0.79 (0.61-1.1) PROVE-IT50/2099 69/2063 0.71 (0.50-1.02) Total154/4364 199/4294 0.76 (0.62-0.94) Z= 2.59 p = 0.01 0.2 0.5 1.0 2 Favours intensive Favours moderate Afilalo J et al, World Congress of Cardiology 2006, abs 5011

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