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)