Statine e sindromi coronariche acute : evidenze per la scelta di un trattamento appropriato

1. Statine e sindromi coronariche acute : evidenze per la scelta di un trattamento appropriato Difendiamo il cuore Dott Antonio Giomi Emodinamica AUSL 3 Pistoia Villa Cappugi Pistoia 16 febbraio 2008

2. 19.4% 15.9% O.R 0.78 95% CI (0.62, 0.97) p=0.025 CONS INV Primary Endpoint Death, MI, Rehosp for ACS at 6 Months 20 16 % Patients 12 8 4 0 0 1 2 3 4 5 6 Time (months)

3. Cardiac Events at 6 Months CONS (%) INV (%) OR P value No. Pts 1o Endpoint Death/MI Death MI Rehosp ACS 1106 19.4 9.5 3.5 6.9 13.7 1114 15.9 7.3 3.3 4.8 11.0 0.78 0.74 0.93 0.67 0.78 0.025 <0.05 0.74 0.029 0.054

4. Cardiac Events at 6 Months ....tecnically succesfull treatment of an individual lesion(s) presumed responsible for an ACS event by percutaneous or surgical means does not alter the underlying pathophysiology of coronary atherosclerosis and ……..prevents approximate only 20% of recurrent ischemic events ….future plaque rupture is more likely to occur among a larger number of less obstructive lesions than among a smaller number of more obstruttive lesions…. G Schwarts Am J Cardiol 96:45F, 2005 CONS (%) INV (%) OR P value No. Pts 1o Endpoint Death/MI Death MI Rehosp ACS 1106 19.4 9.5 3.5 6.9 13.7 1114 15.9 7.3 3.3 4.8 11.0 0.78 0.74 0.93 0.67 0.78 0.025 <0.05 0.74 0.029 0.054

5. High-dose statins in ACS: an intriguinghypothesis • The early benefits of statintherapy are derived largely from the anti-inflammatoryeffects of the drugs. • The delayed benefits are lipid-modulated. S.Nissen Jama sett.2004

7. 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

8. Miracl Study :Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes Context: patients experience the highest rate of death and recurrent ischemic events during the early period after an ACS Objective: to determine whether treatment with atorvastatin 80 mg initiated 24-96 hs after ACS reduce death or nonfatal ischemic events Schwartz GG et al. JAMA. 2001;285:1711-1718.

9. Myocardial Ischemia Reduction With Aggressive Cholesterol Lowering (MIRACL): Study Design Patient population • Men and women aged 18 years • Unstable angina or acute MI • TC 270 mg/dL • Excluded if planned/anticipated coronary revascularization Atorvastatin 80 mg (n=1538) 3086 patients 24 to 96 hours (mean 63 hours) Placebo (n=1548) 16 weeks Primary efficacy end point • Composite of death, nonfatal acute MI, cardiac arrest with resuscitation, or recurrent symptomatic myocardial ischemia requiring rehospitalization Schwartz GG et al. JAMA. 2001;285:1711-1718.

10. 20 Placebo n=1548 15 Incidenza totale(%) 10 5 0 0 4 8 12 16 Tempo dalla randomizzazione (settimane) MIRACL: In pazienti con SCA Atorvastatina riduce la ricorrenza di eventi ischemici in maniera significativa Occorrenza dell'endpoint primario combinato* 16% RRR nell'endpoint triplo combinato P=.048 RR: 0.84 Atorvastatina (80 mg) n=1538 Tendenza favorevole *End poin primario combinato=morte, AMI non fatale, arresto cardiaco con rianimazione, o ischemia ricorrente sintomatica del miocardio con ricovero d'urgenza. RRR=riduzione del rischio relativo. Adapted from Schwartz GG et al. JAMA. 2001;285:1711-1718.

11. * MIRACL Rischio Relativo dei Principali End-Point Morte IMA Non-fatale Arresto Cardiaco con resuscitazione Angina ingravescente con dimostrazione di ischemia e ricoverourgente 0.25 0.50 0.75 1.00 1.25 1.50 1.75 2.00 A favore di Atorvastatina A favore di Placebo *p=0.02 Rischio relativo Schwartz et al. JAMA 2001;285:1711

12. MIRACL: La riduzione assoluta nel numero degli ictus raggiunta durante 16 settimane dello studio MIRACL è simile alla riduzione raggiunta dopo circa 5 anni negli studi CARE e LIPID Adapted from Schwartz GG et al. Am J. Cardiol. 2005; 96(Suppl.): 45F-53F

13. What Accounts for the Added Benefits of Statins? • Endothelial effects • Anti-inflammatory effects • Antioxidant effects • Reduction in plaque progression • Plaque stabilization + Reduction of lipids Wassmann S, Nickenig G. Endothelium. 2003;10:23-33.

14. Pathological "vascular triad” implicated in ACS

15. Phase Z of the A to Z Trial: Study Design Patient population 4497 patients • Men and women aged 21-80 years • ACS, MI • TC 250 mg/dL • Met stability criteria • At least 1 high-risk factor for CVD in addition to cardiac biomarker elevation Simvastatin 80 mg Simvastatin 40 mg (n=2265) Placebo (n=2232) Simvastatin 20 mg 24 months 1 month 4 months Primary efficacy end point • Composite of cardiovascular death, nonfatal MI, readmission for ACS, and stroke de Lemos JA et al. JAMA. 2004;292:1307-1316.

16. 20 Placebo + simvastatina (20 mg) n=2232 11% RRR in endpoint combinato 15 Simvastatina (40 mg, 80 mg) n=2099 P=.14 Tasso totale (%) 10 5 0 0 4 8 12 16 20 24 Tempo dalla randomizzazione (mesi) A to Z: Nessuna riduzione significativa dell'endpoint principale in pazienti con SCA trattati con Simvastatina Occorrenza dell'endpoint principale combinato(morte cardiovascolare, IM non fatale, riammissione per SCA, e ictus) Adattato da de Lemos JA et al. JAMA. 2004;292:1307-1316.

17. Statin therapy is highly effective vs. placebo in long-term treatment of CHD Are statins effective in reducing events in patients with an acute coronary syndrome (ACS)? Does “intensive” LDL-C lowering to an average of 65 mg/dL achieve a greater reduction in clinical events than “standard” LDL-C lowering to an average of 95 mg/dL? Background

18. PROVE IT - TIMI 22: Study Design 4,162 patients with an Acute Coronary Syndrome < 10 days ASA + Standard Medical Therapy Double-blind “Standard Therapy” Pravastatin 40 mg “Intensive Therapy” Atorvastatin 80 mg 2x2 Factorial: Gatifloxacin vs. placebo Duration: Mean 2 year follow-up (>925 events) Primary Endpoint: Death, MI, Documented UA requiring hospitalization, revascularization (> 30 days after randomization), or Stroke

19. Changes from (Post-ACS) Baseline in Median LDL-C Median LDL-C (Q1, Q3) 95 (79, 113) 62 (50, 79) 120 100 Pravastatin 40mg 21% 80 LDL-C (mg/dL) 60 Atorvastatin 80mg 49%  40 P<0.001 20 <24h Rand. 30 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

20. 0 30 3 6 9 12 15 18 21 24 27 All-Cause Death or Major CV Events in All Randomized Subjects 30 Pravastatin 40mg (26.3%) 25 20 % with Event Atorvastatin 80mg (22.4%) 15 10 16% RR (P = 0.005) 5 0 Months of Follow-up

21. Primary Endpoint Over Time Events Rates RRAtorva 80 Prava 40 17% 1.9% 2.2% 18% 6.3% 7.7% 14% 12.2% 14.1% 16% 22.4%* 26.3%* 30 Days 90 Days 180 Days End of Follow-up 0.5 0.75 1.0 1.2 1.5 *2-year event rates Atorvastatin 80mg Better Pravastatin 40mg Better

22. CHD Death Revasc > 30 d UA Req Hosp Reductions in Major Cardiac Endpoints 2 Year Event Rates RRAtorva 80 Prava 40 28% 2.2% 3.2% 30% 1.1% 1.4% 13% 6.6% 7.4% 18% 8.3% 10.0% 14% 16.3% 18.8% 29% 3.8% 5.1% 25% 12.9% 16.7% -9% 1% 1% All-Cause Mortality MI Death or MI Death/MI/Urg.Revasc Stroke 0.5 0.75 1.0 1.25 1.5 Atorvastatin 80 mg Better Pravastatin 40 mg Better

23. 20 % with Event 15 10 5 0 0 3 6 9 12 15 18 21 24 27 30 All-Cause Death, Non-Fatal MI, or Urgent Revascularization Pravastatin 40mg16.7% Atorvastatin 80mg12.9% 25% RRP = 0.0004 Months of Follow-up

24. Subgroups: Reduction in All-Cause Mortality or Major CV Events 2 Year Event Rates Atorva 80 Prava 40 23.0% 26.2% 20.3% 27.0% 28.8% 34.6% 21.0% 24.6% 28.1% 29.5% 20.1% 25.0% 27.5% 28.9% 20.6% 25.5% 21.7% 26.7% 23.1% 26.0% 20.1% 28.2% 23.5% 25.6% % of Pts 78 22 18 82 30 70 25 75 44 56 27 73 Male Female Diabetes No Diabetes Age > 65 Age < 65 Prior Statin No Prior Statin HDL-C > 40 HDL-C < 40 LDL-C > 125 pi = 0.02 LDL-C < 125 All pinteraction = NS except as noted 0.5 0.75 1.0 1.25 1.5 Atorvastatin 80 mg Better Pravastatin 40 mg Better

25. Summary • In patients recently hospitalized within 10 days for an acute coronary syndrome: • “Intensive” high-dose LDL-C lowering (median LDL-C 62 mg/dL) compared to “moderate” standard-dose lipid-lowering therapy (median LDL-C 95 mg/dL) reduced the risk of all cause mortality or major cardiac events by 16% (p=0.005) • Benefits emerged within 30 days post ACS with continued benefit observed throughout the 2.5 years of follow-up • Benefits were consistent across all cardiovascular endpoints, except stroke, and most clinical subgroups

26. 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

27. 0.10 LDL-C >70 mg/dL, CRP >2 mg/L 0.08 LDL-C 70 mg/dL, CRP <2 mg/L LDL-C <70 mg/dL, CRP >2 mg/L 0.06 LDL-C <70 mg/dL, CRP <2 mg/L 0.04 LDL-C <70 mg/dL, CRP <1mg/L 0.02 0.00 0.0 0.5 1.0 1.5 2.0 2.5 Follow-up (anni) Adapted from Ridker PM et al. N Engl J Med. 2005;352:20-28; Ridker PM et al. Presented at AHA Scientific Sessions; 2004. PROVE IT sottoanalisi: i pazienti con livelli più bassi di LDL-C e CRP hanno meno eventi ricorrenti IM ricorrente o morte coronarica (%)

28. 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

29. ARMYDA-ACS Trial

30. ARMYDA-ACS trial: Study design 580 pts excluded for: - 451 statin therapy - 41 emergency angiography - 43 LVEF <30% - 30 contraindications to statins - 15 severe renal failure 20 pts excluded for indication to: - medical therapy (N=8) - bypass surgery (N=12) 30 days Atorvastatin 80 mg 12 hrs pre-angio; further 40 mg 2 hrs before N=96 771 pts with NSTE-ACS sent to early coronary angiography (<48 hours) Jan ’05 - Dec ‘06 Randomization (N=191) PCI atorvastatin N=86 Primary combined end point: 30-day death, MI, TVR Coronary angiography atorvast PCI placebo N=85 Placebo 12 hrs pre-angio; further dose 2 hrs before N=95 2nd and 3rd blood samples (8 and 24 hrs post-PCI) 1st blood sample (pre-PCI) CK-MB, troponin-I, myoglobin, CRP

31. ARMYDA-ACS trial: Study end points • Primary end point: • Incidence of major adverse cardiac events (MACE: death, MI, TVR) from the procedure up to 30 days • MI definition: • - If normal baseline levels of CK-MB: post-procedural increase of CK-MB >2 times above UNL, according to the consensus statement of the Joint ESC/ACC Committee for the Redefinition of Myocardial Infarction for clinical trials on coronary intervention. • - If elevated baseline levels of CK-MB: subsequent rise of >2 times in CK-MB from baseline value • Secondary end points: • Any post-procedural increase of markers of myocardial injury above UNL (CK-MB, troponin-I, myoglobin) • Post-PCI variations from baseline of CRP levels in the 2 arms

32. ARMYDA-ACS Individual and Combined Outcome Measures of the Primary End Point at 30 days 14/85 (17%) % 13/85 (15%) P=0.01 P=0.04 4/86 (5%) 4/86 (5%) 1/85 (2%) Composite Primary End Point

33. ARMYDA-ACS: Secondary end point Post-PCI percent increase of CRP levels from baseline 147 P=0.01 % 63

34. ARMYDA-ACS: Secondary end point Cardiac markers elevations 1-3 times >3 times P=0.028 P=0.002 Creatine kinase-MB (%) Troponin-I (%)

35. ARMYDA-ACS: CONCLUSIONS • The ARMYDA-ACS trial indicates that even a short-term atorvastatin pretreatment prior to PCI may improve outcome in patients with Unstable Angina and NSTEMI. • This benefit is mostly driven by a reduction of peri-procedural MI (70% risk reduction) • Lipid-independent pleiotropic actions of atorvastatin may explain such effect • These findings may support the indication of “upstream” administration of high dose statins in patients with Acute Coronary Syndromes treated with early invasive strategy

36. 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

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

38. Conclusioni1 • La terapia “intensiva” con atorvastatina 80mg ha dimostrato vs placebo o terapia “standard” con statine, un beneficio precoce nei pazienti con SCA sottoposti o meno a rivascolarizzazione prevalentemente rappresentato da riduzione di recidiva ischemica

39. Conclusioni 2 • Dati recenti , da confermare con studi più ampi evidenziano il beneficio di un pretrattamento con atorvastatina sulla “sicurezza “ della procedura di angioplastica in pazienti con SCA (Interventional pharmacology)