Presentation is loading. Please wait.

Presentation is loading. Please wait.

Difendiamo il cuore Statine e sindromi coronariche acute : evidenze per la scelta di un trattamento appropriato Dott Antonio Giomi Emodinamica AUSL 3.

Similar presentations


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

1 Difendiamo il cuore 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

2 Death, MI, Rehosp for ACS at 6 Months
Primary Endpoint Death, MI, Rehosp for ACS at 6 Months CONS INV O.R 0.78 95% CI (0.62, 0.97) p=0.025 19.4% 15.9% 20 16 % Patients 12 8 4 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 0.025 <0.05 0.74 0.029 0.054 4

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 0.025 <0.05 0.74 0.029 0.054 4

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

6

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

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 hs after ACS reduce death or nonfatal ischemic events Schwartz GG et al. JAMA. 2001;285:

9 Primary efficacy end point
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 The MIRACL study was a randomized, placebo-controlled trial designed to determine if treatment with atorvastatin 80 mg, initiated 24 to 96 hours after an acute coronary event, reduced death and nonfatal ischemic events1 Men and women were included in the study if they were 18 years of age, had unstable angina or non-Q-wave acute MI, and TC levels 270 mg/dL. In both groups, the mean LDL-C at baseline was 124 mg/dL. Unstable angina was defined as chest pain or discomfort of at least 15 minutes’ duration that occurred at rest or with minimal exertion within the 24-hour period preceding hospitalization. Non-Q-wave acute MI was diagnosed on the basis of elevated serum creatine kinase or its myocardial band isozyme (MB) fraction, or increased troponin levels exceeding 2 times the upper normal limit. Patients were excluded from the study if they had plans for coronary revascularization1 Patients were monitored for 16 weeks for ischemic events defined as death, nonfatal acute MI, cardiac arrest with resuscitation, or recurrent symptomatic myocardial ischemia requiring emergency rehospitalization1 Reference: 1. Schwartz GG, Olsson AG, Ezekowitz MD, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes. JAMA. 2001;285: 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:

10 Occorrenza dell'endpoint primario combinato*
MIRACL: In pazienti con SCA Atorvastatina riduce la ricorrenza di eventi ischemici in maniera significativa 20 15 10 5 Occorrenza dell'endpoint primario combinato* 16% RRR nell'endpoint triplo combinato Incidenza totale(%) Placebo n=1548 P=.048 RR: 0.84 Atorvastatina (80 mg) n=1538 Tendenza favorevole Rispetto a placebo, atorvastatina 80 mg ha ridotto significativamente la ricorrenza di eventi ischemici in pazienti con SCA del 16% durante le 16 settimane di follow- up (P=.048)1 La riduzione maggiore del rischio si è verificata per l'ischemia sintomatica acuta con ri-ospedalizzazione (26%; P=.02)1 Reference: 1. Schwartz GG, Olsson AG, Ezekowitz MD, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes. JAMA. 2001;285: 4 8 12 16 Tempo dalla randomizzazione (settimane) *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:

11 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 New slide, please check compatibility 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 Il trattamento intensivo precoce a base di statina dopo sindrome coronarica acuta (SCA) è un mezzo efficace di riduzione dell'ictus. L'occorrenza dell'ictus fatale e non fatale sia dello studio Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL), studio di 16 settimane con atorvastatina 80 mg o placebo dopo ACS, sia del Cholesterol and Recurrent Events (CARE) e del Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID), studi di pravastatina 40 mg o placebo in pazienti con malattia aorto-coronarica stabile, è riportata sullo stesso asse. La riduzione assoluta dell'ictus raggiunta durante le 16 settimane di MIRACL è simile a quella raggiunta dopo circa 5anni di trattamento randomizzato negli ultimi due studi. Adapted from Schwartz GG et al. Am J. Cardiol ; 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 In addition to reducing LDL-C concentrations, atorvastatin may delay the development of atherosclerosis via endothelial, anti-inflammatory, or antioxidant effects, or by reducing plaque progression or promoting plaque stabilization 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 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 1 month 4 months 24 months Phase Z of the A to Z trial was a double-blind study designed to compare early initiation of an intensive statin regimen with delayed initiation of a less intensive regimen in patients with ACS1 Adults were eligible if they had either non-ST-elevation ACS or ST-elevated MI, a TC level 250 mg/dL, and had been stabilized during phase A of the trial for at least 12 consecutive hours within 5 days after symptom onset. In addition, patients had at least 1 of the following high-risk factors: age older than 70 years, diabetes mellitus, prior history of coronary artery disease (CAD), peripheral arterial disease or stroke, recurrent angina or evidence of myocardial ischemia, or elevations of serum creatine kinase-MB or troponin levels. Mean LDL-C levels at baseline were 111 mg/dL in the placebo group and 112 mg/dL in the simvastatin group1 During randomization, patients were allocated to 1 of 2 treatment regimens—simvastatin 40 mg for 1 month followed by 80 mg thereafter or placebo for 4 months followed by simvastatin 20 mg thereafter. Follow-up was from 6 to 24 months, and the primary end point was a composite of cardiovascular death, nonfatal MI, readmission for ACS, and stroke1 Reference: 1. de Lemos JA, Blazing MA, Wiviott SD, et al. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes. JAMA. 2004;292: Primary efficacy end point Composite of cardiovascular death, nonfatal MI, readmission for ACS, and stroke de Lemos JA et al. JAMA. 2004;292:

16 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) 20 Placebo + simvastatina (20 mg) n=2232 Tasso totale (%) 11% RRR in endpoint combinato 15 Simvastatina (40 mg, 80 mg) n=2099 P=.14 10 Sebbene la terapia precoce di simvastatina ad alte dosi sia associata a una riduzione dell'11% nell'endpoint principale combinato rispetto al trattamento tardivo a bassa dose, la differenza fra i due regimi non è statisticamente significativa1 La curva di sopravvivenza di Kaplan-Meier per i due regimi non diverge fino a circa 4 mesi dall'inizio della terapia, suggerendo che l'inizio precoce della terapia intensiva con simvastatina non migliora gli esiti rispetto all'inizio tardivo di un regime moderato in pazienti che hanno SCA o IM e 1 fattore di rischio CV aggiuntivo1 Reference: 1. de Lemos JA, Blazing MA, Wiviott SD, et al. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes. JAMA. 2004;292: 5 4 8 12 16 20 24 Tempo dalla randomizzazione (mesi) Adattato da de Lemos JA et al. JAMA. 2004;292:

17 Background 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?

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 PROVE IT is a double-blind, randomized trial that has enrolled 4,160 patients, at approximately 400 sites in the US, Europe, Canada, and Australia, who have experienced an acute coronary syndrome (Q wave and non-Q-wave MI or unstable angina) within the previous 10 days. Patients received either 40 mg of pravastatin or 80 mg of atorvastatin within 10 days of their event and were followed for a mean follow-up period of 2 years. To study the role of infection in ACS, one half of the patients in the trial also received gatifloxacin 400 mg in addition to either pravastatin or atorvastatin. Gatifloxacin was started on day 15 after the initial episode of ACS for a treatment period of 14 days. Gatifloxacin was subsequently given as a pulsed dose of 400mg per day for 10 days each month for a mean of 2 years. The other half of the patient population received an antibiotic placebo. 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 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 3 18 21 24 27 30 6 9 12 15 Months of Follow-up

21 Primary Endpoint Over Time
Events Rates RR Atorva 80 Prava 40 17% 1.9% 2.2% 18% 6.3% 7.7% 14% 12.2% % 16% 22.4%* %* 30 Days 90 Days 180 Days End of Follow-up *2-year event rates Atorvastatin 80mg Better Pravastatin 40mg Better 4

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

23 All-Cause Death, Non-Fatal MI, or Urgent Revascularization
% with Event 3 18 21 24 27 30 6 9 12 15 20 10 5 Pravastatin 40mg 16.7% Atorvastatin 80mg 12.9% 25% RR P = Months of Follow-up

24 Subgroups: Reduction in All-Cause Mortality or Major CV Events
2 Year Event Rates Atorva Prava 40 23.0% 26.2% 20.3% 27.0% 28.8% 34.6% 21.0% 24.6% 28.1% 29.5% % 25.0% 27.5% 28.9% % 25.5% 21.7% % % % 20.1% % % % % of Pts 78 22 18 82 30 70 25 75 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 ACS Kaplan-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 PROVE IT sottoanalisi: i pazienti con livelli più bassi di LDL-C e CRP hanno meno eventi ricorrenti
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 IM ricorrente o morte coronarica (%) 0.04 LDL-C <70 mg/dL, CRP <1mg/L I ricercatori dello studio PROVE IT hanno esaminato gli effetti di atorvastatina 80 mg e di pravastatina 40 mg e l’impatto della riduzione di LDL-C e CRP sul rischio di eventi CV ricorrenti in pazienti con ACS1 Per questa analisi, i pazienti sono stati stratificati a seconda del LDL-C (<70 mg/dL o ≥70 mg/dL) e CRP (<2 mg/L or ≥2 mg/L) per esaminare la relazione fra i livelli di LDL-C e di CRP e MI ricorrente o morte coronarica1 Meno del 3% delle variazioni nei livelli di CRP raggiunti è stata spiegato dalle variazioni raggiunte nei livelli di LDL-C. E' stata osservata una relazione lineare fra i livelli di LDL-C raggiunti dopo la terapia con statina e il rischio di MI ricorrenti o morte coronarica. Similmente, è stata osservata una relazione lineare fra i livelli di CRP raggiunti e il rischio di IM ricorrente o morte coronarica1 Questa slide mostra che, dei pazienti con livelli di LDL-C 70 mg/dL, quelli con livelli di CRP <2 mg/L avevano meno probabilità di avere Mi ricorrente o di morire per cause coronariche dei pazienti con CRP 2 mg/dL. I pazienti con LDL-C <70 mg/dL e CRP <2 mg/L erano a rischio inferiore di avere un evento ricorrente rispetto a quelli con LDL-C basso ma CRP 2 mg/L. I pazienti con LDL-C <70 mg/dL e CRP <1 mg/L avevano il rischio minore di eventi ricorrenti. In generale, i pazienti con livelli di CRP <2 mg/L avevano migliori esiti clinici di quelli che presentavano livelli più alti, indipendentemente dai livelli di LDL-C1 Reference: 1. Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med. 2005;352:20-28. 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.

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 Primary combined end point: CK-MB, troponin-I, myoglobin, CRP
ARMYDA-ACS trial: Study design 580 pts excluded for: statin therapy emergency angiography LVEF <30% contraindications to statins 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 1st blood sample (pre-PCI) 2nd and 3rd blood samples (8 and 24 hrs post-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 Composite primary end-point (30-day death, MI, TVR)
ARMYDA-ACS trial Composite primary end-point (30-day death, MI, TVR) % 17 P=0.01 5

33 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

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

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

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

38 7-day atorvastatin pretreatment decreases adhesion molecules after PCI
placebo for measurement of plasma levels of vascular cell adhesion molecule-1 (VCAM-1), intercellular cell adhesion molecule-1 (ICAM-1), and E-selectin: 38 patients belonged to atorvastatin (40 mg/day) and 38 to the placebo arm. Adhesion molecules were evaluated 7 days before intervention, immediately before PCI, and after 8 and 24 h Patti et al, J Am Coll Cardiol 2006;48:1560

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)

41


Download ppt "Difendiamo il cuore Statine e sindromi coronariche acute : evidenze per la scelta di un trattamento appropriato Dott Antonio Giomi Emodinamica AUSL 3."

Similar presentations


Ads by Google