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Statine e sindromi coronariche acute : evidenze per la scelta di un trattamento appropriato Dott Antonio Giomi Emodinamica AUSL 3 Pistoia Villa Cappugi.

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Presentation on theme: "Statine e sindromi coronariche acute : evidenze per la scelta di un trattamento appropriato Dott Antonio Giomi Emodinamica AUSL 3 Pistoia Villa Cappugi."— Presentation transcript:

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

2 0123456 Time (months) 0 4 8 12 16 20 % Patients CONS INV O.R 0.78 95% CI (0.62, 0.97) p=0.025 19.4% 15.9% Primary Endpoint Death, MI, Rehosp for ACS at 6 Months

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

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

5 5 High-dose statins in ACS: an intriguing hypothesis The early benefits of statin therapy are derived largely from the anti- inflammatory effects of the drugs. The delayed benefits are lipid- modulated. S.Nissen Jama sett.2004

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

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 3086 patients 24 to 96 hours (mean 63 hours) 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) Placebo (n=1548) 16 weeks Myocardial Ischemia Reduction With Aggressive Cholesterol Lowering (MIRACL): Study Design Patient population Composite of death, nonfatal acute MI, cardiac arrest with resuscitation, or recurrent symptomatic myocardial ischemia requiring rehospitalization Primary efficacy end point Schwartz GG et al. JAMA. 2001;285:1711-1718.

10 10 MIRACL: In pazienti con SCA Atorvastatina riduce la ricorrenza di eventi ischemici in maniera significativa P=.048 RR: 0.84 20 15 10 5 0 Placebo n=1548 Tempo dalla randomizzazione (settimane) 48 1216 0 Incidenza totale(%) Atorvastatina (80 mg) n=1538 16% RRR nell'endpoint triplo combinato Adapted from Schwartz GG et al. JAMA. 2001;285:1711-1718. *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. Occorrenza dell'endpoint primario combinato* Tendenza favorevole

11 MIRACL Rischio Relativo dei Principali End-Point MIRACL Rischio Relativo dei Principali End-Point Morte IMA Non-fatale Arresto Cardiaco con resuscitazione Angina ingravescente con dimostrazione di ischemia e ricovero urgente *p=0.02 0.250.500.751.001.251.501.752.00 A favore di AtorvastatinaA favore di Placebo Rischio relativo * Schwartz et al. JAMA 2001;285:1711

12 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? Reduction of lipids + Endothelial effects Anti-inflammatory effects Antioxidant effects Reduction in plaque progression Plaque stabilization Wassmann S, Nickenig G. Endothelium. 2003;10:23-33.

14 14 Pathological "vascular triad implicated in ACS

15 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 Phase Z of the A to Z Trial: Study Design Patient population Composite of cardiovascular death, nonfatal MI, readmission for ACS, and stroke Primary efficacy end point de Lemos JA et al. JAMA. 2004;292:1307-1316. Simvastatin 40 mg (n=2265) Placebo (n=2232) 1 month 4 months 24 months Simvastatin 80 mg Simvastatin 20 mg

16 16 A to Z: Nessuna riduzione significativa dell'endpoint principale in pazienti con SCA trattati con Simvastatina Adattato da de Lemos JA et al. JAMA. 2004;292:1307-1316. 0 5 10 15 20 11% RRR in endpoint combinato P=.14 Placebo + simvastatina (20 mg) n=2232 Simvastatina (40 mg, 80 mg) n=2099 048121620 24 Tempo dalla randomizzazione (mesi) Tasso totale (%) Occorrenza dell'endpoint principale combinato (morte cardiovascolare, IM non fatale, riammissione per SCA, e ictus)

17 Background Statin therapy is highly effective vs. placebo in long-term treatment of CHD l Are statins effective in reducing events in patients with an acute coronary syndrome (ACS)? l 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?

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

19 Changes from (Post-ACS) Baseline in Median LDL-C Note: Changes in LDL-C may differ from prior trials: 25% of patients on statins prior to ACS event 25% of patients on statins prior to ACS event ACS response lowers LDL-C from true baseline ACS response lowers LDL-C from true baseline LDL-C (mg/dL) 20 40 60 80 100 120 Rand.30 Days4 Mos.8 Mos.16 Mos.Final Pravastatin 40mg Atorvastatin 80mg 49% 49% 21% 21% P<0.001 Median LDL-C (Q1, Q3) 95 (79, 113) 62 (50, 79) <24h

20 All-Cause Death or Major CV Events in All Randomized Subjects031821242730691215 % with Event Months of Follow-up Pravastatin 40mg (26.3%) Atorvastatin 80mg (22.4%) 16% RR (P = 0.005) 30 25 20 15 10 5 0

21 Events Rates RR Atorva 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 Primary Endpoint Over Time Atorvastatin 80mg Better 0.5 0.751.0 1.2 1.5 Pravastatin 40mg Better *2-year event rates

22 Reductions in Major Cardiac Endpoints 2 Year Event Rates RR Atorva 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% 0.51.01.5 All-Cause Mortality Death or MI Death/MI/Urg.Revasc MI Revasc > 30 d UA Req Hosp 0.751.25 Atorvastatin 80 mg BetterPravastatin 40 mg Better CHD Death Stroke

23 % with Even t 031821242730691215 20 15 10 5 0 Months of Follow-up All-Cause Death, Non-Fatal MI, or Urgent Revascularization Pravastatin 40mg 16.7% Atorvastatin 80mg 12.9% 25% RR P = 0.0004

24 Subgroups: Reduction in All-Cause Mortality or Major CV Events All p interaction = NS except as noted Age > 65 Age < 65 Male Female 0.50.751.01.251.5 Diabetes No Diabetes 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% Prior Statin No Prior Statin Atorvastatin 80 mg BetterPravastatin 40 mg Better LDL-C < 125 LDL-C > 125 p i = 0.02 HDL-C < 40 HDL-C > 40 % of Pts 78 22 18 82 30 70 25 75 44 56 27 73

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) 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 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 Benefits were consistent across all cardiovascular endpoints, except stroke, and most clinical subgroups

26 26 Intensive, but not moderate, statin treatment reduces early ischemic events after ACS Kaplan-Meier event curves for the primary end point RR=0.84p=0.048 HR=0.8 P =0.03 RR=1.01p=NS Death, AMI, stroke, USA, revascularization >30 days MIRACLA to Z PROVE IT Months of randomized treatment

27 27 IM ricorrente o morte coronarica (%) PROVE IT sottoanalisi: i pazienti con livelli più bassi di LDL-C e CRP hanno meno eventi ricorrenti Adapted from Ridker PM et al. N Engl J Med. 2005;352:20-28; Ridker PM et al. Presented at AHA Scientific Sessions; 2004. Follow-up (anni) 0.00.51.01.52.02.5 0.00 0.04 0.02 0.06 0.08 0.10 LDL-C 2 mg/L LDL-C >70 mg/dL, CRP >2 mg/L LDL-C 70 mg/dL, CRP <2 mg/L LDL-C <70 mg/dL, CRP <2 mg/L LDL-C <70 mg/dL, CRP <1mg/L

28 28 Wiviott et al, Circulation 2006;113:1426 PROVE IT-TIMI 22: treatment effects stratified by PCI for the index ACS event 0-4 months Trial duration Statin treatment p 0.07 p 0.01 NS NS

29 ARMYDA-ACS Trial

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

31 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 ARMYDA-ACS trial: Study end points

32 ARMYDA-ACS trial Composite primary end-point (30-day death, MI, TVR) % 5 17 P=0.01

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

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

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

36 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

37 37 Patti et al, J Am Coll Cardiol 2007;49:1272 Atorvastatin Pretreatment Improves Outcomes in Patients With ACS Undergoing Early PCI Results of the ARMYDA-ACS Randomized Trial

38 38 Patti et al, J Am Coll Cardiol 2006;48:1560 7-day atorvastatin pretreatment decreases adhesion molecules after PCI atorvastatinplacebo

39 Conclusioni 1 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

40 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)

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