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Transcript of Statine e sindromi coronariche acute : evidenze per la scelta di un trattamento appropriato Dott...
Statine e sindromi coronariche acute : evidenze per la scelta di un trattamento
appropriato
Dott Antonio GiomiEmodinamica AUSL 3 PistoiaVilla Cappugi Pistoia 16 febbraio 2008
Difendiamo il cuore
0 1 2 3 4 5 6Time (months)
0
4
8
12
16
20
% P
atie
nts
CONS
INV
O.R 0.7895% CI (0.62, 0.97)
p=0.025
19.4%
15.9%
Primary EndpointPrimary Endpoint
Death, MI, Rehosp for ACS at 6 MonthsDeath, MI, Rehosp for ACS at 6 Months
No. Pts
1o 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 MonthsCardiac 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
No. Pts
1o 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 MonthsCardiac 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
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
77Lenderink et al, Eur Heart J 2006;27:1799-1804 Lenderink et al, Eur Heart J 2006;27:1799-1804
Very early (<24 hrs) statin Very early (<24 hrs) statin therapytherapy in in patients with patients with ACS associated with reduced ACS associated with reduced
mortalitymortality
HR 0.44 HR 0.44 (95% CI 0.31-0.64)(95% CI 0.31-0.64)
77
HR 0.16 HR 0.16 (95% CI 0.08-0.37)(95% CI 0.08-0.37)
(n=1426)(n=1426)
(n=6771)(n=6771)
Euro Heart Survey 2000-01 (10,484 patiens)Euro Heart Survey 2000-01 (10,484 patiens)
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.
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 DesignPatient 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
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
Placebon=1548
Tempo dalla randomizzazione (settimane)
4 8 12 160
Inci
den
za t
ota
le(%
)
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
MIRACLRischio Relativo dei Principali End-Point
MIRACLRischio 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
0.25 0.50 0.751.001.25 1.501.752.00
A favore di AtorvastatinaA favore di Placebo
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
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
Pathological "vascular triad” implicated in ACS
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.
Simvastatin40 mg
(n=2265)
Placebo(n=2232)
1 month 4 months 24 months
Simvastatin80 mg
Simvastatin20 mg
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 inendpointcombinatoP=.14
Placebo + simvastatina (20 mg) n=2232
Simvastatina (40 mg, 80 mg)
n=2099
0 4 8 12 16 20 24Tempo dalla randomizzazione (mesi)
Tas
so t
ota
le (
%)
Occorrenza dell'endpoint principale combinato(morte cardiovascolare, IM non fatale, riammissione per SCA, e ictus)
BackgroundBackground
Statin therapy is highly effective vs. placebo in Statin therapy is highly effective vs. placebo in long-term treatment of CHD long-term treatment of CHD
Are statins effective in reducing events in Are statins effective in reducing events in patients with an acute coronary syndrome patients with an acute coronary syndrome (ACS)? (ACS)?
Does “intensive” LDL-C lowering to an Does “intensive” LDL-C lowering to an average of 65 mg/dL achieve a greater average of 65 mg/dL achieve a greater reduction in clinical events than “standard” reduction in clinical events than “standard” LDL-C lowering to an average of 95 mg/dL?LDL-C lowering to an average of 95 mg/dL?
4,162 patients with an Acute Coronary Syndrome < 10 days 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
Primary Endpoint: Death, MI, Documented UA requiring hospitalization, revascularization (> 30 days after randomization), or Stroke
PROVE IT - TIMI 22: PROVE IT - TIMI 22: Study DesignStudy Design
2x2 Factorial: Gatifloxacin vs. placebo
Double-blindDouble-blind
Changes from (Post-ACS) Changes from (Post-ACS) Baseline in Median LDL-CBaseline in Median LDL-C
Note: Changes in LDL-C may differ from prior trials: Note: Changes in LDL-C may differ from prior trials: • 25% of patients on statins prior to ACS event25% of patients on statins prior to ACS event• ACS response lowers LDL-C from true baselineACS response lowers LDL-C from true baseline
LDL-C (mg/dL)
20
40
60
80
100
120
Rand. 30 Days 4 Mos. 8 Mos. 16 Mos. Final
Pravastatin 40mg
Atorvastatin 80mg49% 49%
21%21%
P<0.001P<0.001
Median LDL-C (Q1, Q3)Median LDL-C (Q1, Q3)
95 (79, 113)95 (79, 113)
62 (50, 79) 62 (50, 79)
<24h
All-Cause Death or Major CV Events in All Randomized Subjects
00 33 1818 2121 2424 2727 303066 99 1212 1515
% with
Event
Months of Follow-up
Pravastatin 40mgPravastatin 40mg(26.3%)(26.3%)
Atorvastatin 80mgAtorvastatin 80mg(22.4%)(22.4%)
16% RR16% RR
(P = 0.005)(P = 0.005)
3030
2525
2020
1515
1010
55
00
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 Primary Endpoint Over TimeTime
Atorvastatin 80mg Better 0.5 0.75 1.0 1.2 1.5
Pravastatin 40mg Better *2-year event rates*2-year event rates
Reductions in Major Cardiac Reductions in Major Cardiac EndpointsEndpoints
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%
0.5 1.0 1.5
All-Cause Mortality
Death or MI
Death/MI/Urg.Revasc
MI
Revasc > 30 d
UA Req Hosp
0.75 1.25
Atorvastatin 80 mg Better Pravastatin 40 mg Better
CHD Death
Stroke
% % with with EvenEven
tt
00 33 1818 2121 2424 2727 303066 99 1212 1515
2020
1515
1010
55
00
Months of Follow-up
All-Cause Death, Non-Fatal MI, or Urgent Revascularization
All-Cause Death, Non-Fatal MI, or Urgent Revascularization
Pravastatin 40mgPravastatin 40mg16.7%16.7%
Atorvastatin 80mgAtorvastatin 80mg12.9%12.9%
25% RR25% RRP = 0.0004P = 0.0004
Subgroups: Reduction in All-Cause Subgroups: Reduction in All-Cause Mortality or Major CV EventsMortality or Major CV Events
All pinteraction = NS except as noted
Age > 65Age < 65
MaleFemale
0.5 0.75 1.0 1.25 1.5
DiabetesNo 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 StatinNo Prior Statin
Atorvastatin 80 mg Better Pravastatin 40 mg Better
LDL-C < 125LDL-C > 125 pi = 0.02
HDL-C < 40HDL-C > 40
% of Pts78
22
18
82
30 70
25 75
44
56
27 73
Summary Summary
In patients recently hospitalized within 10 days for an acute In patients recently hospitalized within 10 days for an acute coronary syndrome: coronary syndrome:
““Intensive” high-dose LDL-C lowering (median LDL-C 62 Intensive” high-dose LDL-C lowering (median LDL-C 62 mg/dL) compared to “moderate” standard-dose lipid-mg/dL) compared to “moderate” standard-dose lipid-lowering therapy (median LDL-C 95 mg/dL) reduced the risk lowering therapy (median LDL-C 95 mg/dL) reduced the risk of all cause mortality or major cardiac events by 16% of all cause mortality or major cardiac events by 16% (p=0.005)(p=0.005)
Benefits emerged within 30 days post ACS with continued Benefits emerged within 30 days post ACS with continued benefit observed throughout the 2.5 years of follow-upbenefit observed throughout the 2.5 years of follow-up
Benefits were consistent across all cardiovascular Benefits were consistent across all cardiovascular endpoints, except stroke, and most clinical subgroups endpoints, except stroke, and most clinical subgroups
2626
Intensive, Intensive, but not moderatebut not moderate, statin treatment , statin treatment reduces early ischemic events after reduces early ischemic events after ACSACS Kaplan-Kaplan-
Meier event curves for the primary endMeier event curves for the primary end point point
RR=0.84RR=0.84p=0.048p=0.048RR=0.84RR=0.84p=0.048p=0.048
HR=0.8HR=0.8P =0.03P =0.03HR=0.8HR=0.8P =0.03P =0.03
RR=1.01RR=1.01p=NSp=NS
RR=1.01RR=1.01p=NSp=NS
D
eath
, A
MI,
str
oke,
US
A,
revascu
lari
zati
on
>
30
days
MIRACLMIRACL A to Z A to Z PROVE IT PROVE IT
Months of randomized treatmentMonths of randomized treatment
27
IM r
ico
rren
te o
mo
rte
coro
nar
ica
(%)
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)0.0 0.5 1.0 1.5 2.0 2.5
0.00
0.04
0.02
0.06
0.08
0.10
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 <2 mg/L
LDL-C <70 mg/dL, CRP <1mg/L
2828Wiviott et al, Circulation 2006;113:1426Wiviott et al, Circulation 2006;113:1426
PROVE IT-TIMI 22: treatment effects PROVE IT-TIMI 22: treatment effects stratified by PCI for the index ACS eventstratified by PCI for the index ACS event
0-4 months0-4 months Trial duration Trial duration0-4 months0-4 months Trial duration Trial duration
Statin treatmentStatin treatment
44,7
7,1
10,910,19,9
2,83,9
0
2
4
6
8
10
12
PCI no PCI PCI no PCI
Moderate (prava 40 mg)
Intensive (atorva 80 mg)
p 0.07p 0.07
p 0.01p 0.01
NSNS
NSNS
ARMYDA-ACS Trial
771 pts with
NSTE-ACS sent to
early coronary
angiography
(<48 hours)
Jan ’05 - Dec ‘06
Ran
dom
izat
ion
(N
=19
1)
Atorvastatin 80 mg 12 hrs pre-angio;
further 40 mg 2 hrs before
N=96
Coronaryangiography
Placebo 12 hrs pre-angio;
further dose 2 hrs
before N=95
Primary combined end point:
30-day death, MI,
TVR
1st blood sample
(pre-PCI)
CK-MB, troponin-I, myoglobin, CRP
ARMYDA-ACS trial: Study design
2nd and 3rd 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)
atorvastatorvast
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
Individual and Combined Outcome Measures of the Primary End Point at 30 days
ARMYDA-ACS
0
3
6
9
12
15
18
21
Death MI TVR MACE
Atorvastatin Placebo
4/86(5%)
13/85 (15%)
1/85(2%)
14/85(17%)
4/86(5%)
P=0.04 P=0.01
%
CompositePrimary End Point
ARMYDA-ACS: Secondary end point
Post-PCI percent increase of CRP levels from baseline
0
40
80
120
160
AtorvastatinPlacebo
%%
63
147
P=0.01
0
10
20
30
40
Atorvastatin Placebo
Cre
atin
e k
ina s
e-M
B (
%) P=0.002
1-3 times >3 times
0
10
20
30
40
50
60
Atorvastatin Placebo
Tro
po n
in- I
(%
)
P=0.028
ARMYDA-ACS: Secondary end pointCardiac markers elevations
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
3737Patti et al, J Am Coll Cardiol 2007;49:1272Patti et al, J Am Coll Cardiol 2007;49:1272
Atorvastatin Pretreatment Improves Outcomes inAtorvastatin Pretreatment Improves Outcomes inPatients With ACS Undergoing Early PCIPatients With ACS Undergoing Early PCI
Results of the ARMYDA-ACS Randomized TrialResults of the ARMYDA-ACS Randomized Trial
3838Patti et al, J Am Coll Cardiol 2006;48:1560Patti et al, J Am Coll Cardiol 2006;48:1560
7-day atorvastatin pretreatment 7-day atorvastatin pretreatment decreases adhesion molecules after PCIdecreases adhesion molecules after PCI
atorvastatinatorvastatin
placeboplacebo
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
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)