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Vecchi e nuovi farmaci in cerca di conferme Pretrattamento con alte dosi di statine nella strategia invasiva delle SCA. Michele Galli Unità Operativa di Cardiologia Spedali Riuniti Livorno ASL6. Early statins in ACS: what evidence ?. Observational studies

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slide1
Vecchi e nuovi farmaci in cerca di confermePretrattamento con alte dosi di statine nella strategia invasiva delle SCA

Michele Galli

Unità Operativa di Cardiologia

Spedali Riuniti Livorno ASL6

early statins in acs what evidence
Early statins in ACS: what evidence ?
  • Observational studies
    • Stenestrand et al , 2001 (RIKS-HIA database)
    • Aronow et al, 2001 (GUSTO-IIB+PURSUIT)
    • Spencer et al, 2004 (GRACE)
    • Fonarow et al, 2005 (NRMI-4)
    • Lenderink et al, 2006 (Euro Heart Survey ACS)
  • Small trials and meta-analysis
    • ARMIDA-ACS (2007)
  • Large RCTs
    • MIRACL (2001)
    • A to Z (2004)
    • PROVE-IT TIMI 22 (2004)
in hosp m ortality risk in pt who continued or newly started s tatin 24 h of ami a dmission

Statin continued/newly started

All AMI

STEMI

Non-STEMI

In-hosp mortality risk in pt who continued or newly started statin <24 h of AMI admission

NRMI-4 data (300,823 patients)

Fonarow et al, Am J Card 2005;96:611-616

very early 24 hrs statin therapy in patients with acs associated with reduced mortality

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

observational s tudies o verestimat e magnitude of an effect
Observational studiesoverestimate magnitude of an effect
  • Survivor treatment selection
  • Major limitations of propensity- and covariate-adjusted analysis:
    • insufficient control of confounders between groups
    • competing medical issues

Statin therapy likely a marker of quality of care

slide9
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

slide10

PROVE IT: concomitant therapies

Cannon C et al, N Engl J Med 2004;350:15

prove it timi 22 treatment effects stratified by pci for the index acs event
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

statin therapy pre pci is an independent predictor of survival

6-month mortality of patients pretreated with statins (n= 1337) vs those not statins pretreated (n=3715) at the time of PCI

Statin therapy pre-PCI is an independent predictor of survival

Chan et al, Circulation 2002;105:691

preprocedural statin reduces the extent of periprocedural non q wave myocardial infarction
Preprocedural Statin Reduces the Extent of Periprocedural Non-Q-Wave Myocardial Infarction

CK > 3XUNL

n=211

6.0%

n=56

P=0.18, log-rank

p<0.01

0.4%

control on statin

Herrmann et al, Circulation. 2002;106:2180

statin therapy inflammation and recurrent coronary events following pci
Statin therapy, inflammation and recurrent coronary events following PCI

Walter et al, J Am Coll Cardiol 2001;37:839

pre pci statin rx reduces the incidence of large peri procedural nonq ami
Pre-PCI statin Rx reduces the incidence of large peri-proceduralnonQ-AMI

OR 0.19 (95% CI 0.05-0.57)

p = 0.02

OR 0.47 (95% CI 0.26–0.86)

p = 0.01

Periprocedural AMI (%)

Briguori et al, Eur Heart J2004; 25: 1822–1828

Pasceri et al, Circulation 2004;110:674

7 day atorvastatin pretreatment decreases adhesion molecules after pci

atorvastatin

placebo

7-day atorvastatin pretreatment decreases adhesion molecules after PCI

Patti et al, J Am Coll Cardiol 2006;48:1560

slide17

5%

p 0.01

17%

Patti et al, J Am Coll Cardiol 2007;49:1272

slide18
Atorvastatin Pretreatment Improves Outcomes inPatients With ACS Undergoing Early PCIARMYDA-ACS Randomized Trial

Patti et al, J Am Coll Cardiol 2007;49:1272

slide19
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

high d ose s tatins in acs a n intriguing hypothesis
High-dose statins in ACS: an intriguinghypothesis
  • Early benefits derived largely from the anti-inflammatoryeffects of the drug.
  • The delayed benefits are lipid-modulated.

Nissen S, JAMA 2004;292;1365

molecular pathway of statins
Molecular pathway of statins

Cholesterol synthesis

Cell signaling

Ray K, Cannon C. J Am Coll Cardiol 2005;46:1425–33

slide22

Acetil CoA

recettori di

membrana

HMG CoA

Mevalonato

mitosi

apoptosi

Proteine

prenilate

O2-

O2-

O2-

formazione

superossido

Colesterolo

pleiotropic effects ascribed to statins
Pleiotropic effects ascribed to statins

Reduce platelet aggregability

Reduce thrombus formation

 PAI-1

 tF

Improve endothelial function & vasomotion

 NO bioavailability

circ. endothelial progenitor cells

Decrease matrix degradation

 macrophage metalloproteinase

 collagen content

Reduce inflammation within plaque

 CRP

 monocyte adhesion

Promote plaque remodeling

HDL-Chol

 LDL-Chol

 TGL

adapted from Rosensonet al. JAMA1998;279:1643–1650

p otential mechanisms by which statins act rapidly and favorably in acs
Potential mechanisms by which statins act rapidly and favorably in ACS
  • Improve endothelial integrity & vasomotion
  • Decrease plaque matrix degradation
  • Reduce plaque inflammation
  • Reduce platelet aggregability and thrombus formation
  • Decrease reperfusion injury
early statin treatment in acs too good to be true
Early statin treatment in ACSToo good to be true?

88% risk reduction of 30-day major cardiac events

severe adverse event rates for intensive vs moderate statin therapy n 32 279 pts
Severe adverse event rates for intensive vs moderate statin therapy (n. 32,279 pts)

Rhabdomyolysis CPK >10 xULN AST/ALT >3 xULN

mod. from Cannon et al, J Am Coll Cardiol 2006;48:438

early atorvastatin treatment in acs conclusions
Short-term benefit by high-dose in the most vulnerable period (peri-PCIand post-ACS)

Pleiotropic effects likely

Proven efficacy in the long-term

absence of harm

Fixed doses / dose titration to achieve specific goals (lipid / anti-inflammatory)

Early atorvastatin treatment in ACSConclusions
statin administration before pci impact on periprocedural mi
Statin administration before PCI:Impact on periprocedural MI

Briguori et al, Eur Heart J 2004; 25: 1822–1828

slide30

0

0

0

Statin Therapy at Carotid Angioplasty: Effect on Procedure-related Stroke, MI and Death A prospective database

Preprocedural Statin Rx

P <0.05

Groeschel et al, Radiology 2006;240:145

atorvastatin at reperfusion onset attenuates lethal myocardial injury

*p <0.05 vs. control

**p 0.001 vs. control

Atorvastatin at reperfusion onset attenuates lethal myocardial injury

Krebs 0 5 25 50 100

Atorvastatin mcmol/l

Bell, JACC 2003; 41: 508

slide32
Preprocedural statin Rx abolished the negative prognostic effect of baseline C-reactive protein elevation after PCI

Chan et al, Circulation 2003;107:1750

atorvastatin reduces neointimal inflammation in atherosclerosis rabbit model
Atorvastatin reduces neointimal inflammation in atherosclerosis rabbit model

Untreated

Treated

neointimal formation

monocyte chemoattractant protein-1

Bustos et al, J Am Coll Cardiol 1998;32:2057–2064

intensive but not moderate statin treatment reduces early ischemic events after acs

MIRACL A to Z

RR=0.84

P=0.048

RR=1.01

P=NS

Months of randomized treatment

Intensive, but not moderate, statin treatment reduces early ischemic events after ACS

mod. from Schwartz G et al, Am J Cardiol 2005;96:45F–53F

chronic pre treatment of statins associated with reduction of no reflow phenomenon
Chronic pre-treatment of statins associated with reduction of no-reflow phenomenon

P 0.003

P 0.04

Iwakura, Eur Heart J 2006;27: 534

slide36

prenilazione

statina

PI3K

AKt

e-Nos

early statins in acs major effects in rcts
Early statins in ACS: major effects in RCTs

mod. from Nissen S, JAMA 2004;292;1365

atorvastatin 40 mg 7 days before cabg reduces postoperative atrial f ibrillation armyda 3 r esults

Atrial fibrillation–free survival (%)

OR 0.39, 95% CI 0.18to 0.85, p 0.017

Post-operative days

Atorvastatin 40 mg 7 days before CABG reduces postoperative atrial fibrillation: ARMYDA-3 results

Patti G et al, Circulation 2006;114;1455-1461

slide40
Statin Therapy and Outcome during Hospitalization for ACS On-statin treatment and ACS presentation in GRACE

Spencer et al, Ann Intern Med 2004; 140: 857 - 866

slide42
Lipid-lowering agent use at ischemic stroke onset is associated with decreased mortalityNorthern Manhattan Study population study
  • Taking LLAs at stroke onset
  • Yes No p
  • In hosp worsening (%) 6.3 18.2 0.04
  • 90-day mortality 1.8 10.6 0.03
  • Severe stroke 10.7 16.8 0.3

Elkind et al, NEUROLOGY 2005;65:253-258

statins efficacy in achieving the dual goals ldl c hol 70 mg dl and c r eactive p rotein 2 mg l
Statins efficacy in achieving thedual goals (LDL-Chol <70 mg/dl and C-Reactive Protein <2 mg/l)

RR 0.72 (95% CI 0.52-0.99)

Dual goal

Dual goals not achieved

Dual goals achieved

Ridker P et al, N Engl J Med 2005;325:20-28

slide44

Beta-blocker use OR 0.41 (95% CI 0.28-0.59)

Statin use OR 0.40 (95% CI 0.24-0.68)

0.5

1.0

1.5

Beta-blockers and statins associated with reduced mortality in patients undergoing noncardiac surgery

108,593 patients undergoing noncardiac nonvascular surgery

Erasmus MC 1991-2000

Adjusted Odds Ratio for perioperative mortality

www.escardio.org/knowledge/congresses/abol/presentation?id=41928

efficacy of achieving very low ldl chol with intensive statin therapy prove it timi 22 substudy
Efficacy of Achieving Very Low LDL-Chol With Intensive Statin Therapy PROVE IT-TIMI 22 Substudy

Hazard ratio of the primary end point

Wiviott S et al, J Am Coll Cardiol 2005;46:1411– 6

early striking mortality reduction after acs by lipid l owering t herapy

RIKS-HIA 1995-98

(19,599 patients)

GUSTO IIb & PURSUIT, 1993-98 (20,809 patients)

Lipid-lowering (n=3653)

No statin (n=14071)

No LL (n=17156)

Statin (n=5528)

Relative risk 0.75

95% CI 0.63-0.89

Log-rank p<0.0001

RR 0.48

95% CI 0.37­0.63

RR 0.75

95% CI 0.63-0.89

p<0.0001

p=0.001

Stenestrand et al, JAMA 2001;285:430 Aronow et al, Lancet 2001;357:1063

Early Striking Mortality Reduction After ACS by Lipid-lowering Therapy
early statins and mortality in euro heart survey
Early statins and mortality in Euro Heart Survey

Lenderink et al, Eur Heart J 2006;27:1799-1804

miracl primary end point events

0.25

0.50

0.75

1.00

1.25

1.50

1.75

2.00

Atorvastatin better

Placebo better

RelativeRisk

MIRACL: Primary end point events

Death

Nonfatal Acute MI

Resuscitated

Cardiac Arrest

Worsening angina

with urgent rehosp.

Fatal / nonfatal stroke

p=0.02

p=0.04

Schwartz et al, JAMA April 4, 2001

intensive statin rx in acs and all cause mortality meta analysis of randomized controlled trials
Intensive statin Rx in ACS and all-cause mortality Meta-analysis of randomized controlled trials

Study Intensive Moderate RR (95% CI)

n/N n/N

A to Z104/2265 130/2231 0.79 (0.61-1.1)

PROVE-IT50/2099 69/2063 0.71 (0.50-1.02)

Total154/4364 199/4294 0.76 (0.62-0.94)

Z= 2.59 p = 0.01

0.2 0.5 1.0 2

Favours intensive Favours moderate

Afilalo J et al, World Congress of Cardiology 2006, abs 5011

early statin treatment reduces 1 year mortality in ami survivors
Early statin treatment reduces 1-year mortality in AMI survivors

RIKS-HIA database (19,599 patients)

RR 0.75 (95% CI 0.63-0.89)

p 0.001

Stenestrand U, Wallentin L. JAMA 2001;285:430–436

early striking mortality reduction by lipid lowering rx at hospital discharge after acs
Early striking mortality reduction by lipid-lowering RX at hospital discharge after ACS

GUSTO IIB/PURSUIT database (20,809 patients)

LLA (n=3653)

No LLA (n=17156)

RR 0.48

95% CI 0.37­0.63

Aronow et al, the Lancet April 7, 2001

early i ntensive vs a d elayed c onservative s imvastatin in p atients w ith acs the a to z trial
Early intensive vs a delayed conservativesimvastatin in patients with ACS: the AtoZ Trial

Hazard ratio0.89(95% CI0.76-1.04)

p=.14

de Lemos et al, JAMA 2004;292:1307

prove it timi 22 primary end point

HR=0.8 P =0.03

PROVE IT TIMI 22 Primary End Point

Cannon C et al, N Engl J Med 2004;350:15

miracl trial concurrent medications according to treatment group
Placebo Atorvastatin (n=1548) (n=1538)

Aspirin 91.2 91.0

Beta-blockers 77.5 77.5

Other antiplatelet agents 11.4 11.3

Oral anticoagulants 8.3 7.7

ACE inhibitors or ARBs 49.7 48.5

Nitrates 90.2 90.3

Calcium-channel blockers 48.1 47.8

MIRACL Trial: Concurrent MedicationsAccording to Treatment Group

Schwartz et al, JAMA April 4, 2001

endothelial abnormalities in acs
Endothelial abnormalities in ACS

Ray K, Cannon C. J Am Coll Cardiol 2005;46:1425–33

inflammatory changes in acs
Inflammatory changes in ACS

Ray K, Cannon C. J Am Coll Cardiol 2005;46:1425–33

pathological vascular triad implicated in acs
Pathological "vascular triad” implicated in ACS

Ray K, Cannon C. J Am Coll Cardiol 2005;46:1425–33

slide59

PCR

Local Inflammation

local reactivity

IL-6

restenosis

Risk of

persistance

Systemic Inflammation

slide60

Inibitori 2b/3a

statina

piastrina attivata

CD40L

sCD40L

attivazione

coagulazione

infiammazione

restenosi

slide61

Statine in monoterapia: elevazione CK

(Brewer, Am J Cardiol 2003)

Ceriva Prava Simva Atorva Rosuva

2.5

2.0

1.5

1.0

.05

0

CK >10X (%)

20 25 30 35 40 45 50 55 60 65 70

Riduzione LDL (%)

slide62

ARMYDA STUDY: statine e PCR post-PCI

(Pasceri V et al, Circulation 2004)

PCR Post-PCI

23%

PCR >5 (%)

10%

statina placebo

slide63
Statin Therapy at Carotid Angioplasty: Effect on Procedure-related Stroke, MI and Death A prospective database

Groeschel et al, Radiology 2006;240:145

protezione del danno da riperfusione

danno

miocardico

no-reflow

Protezione del danno da riperfusione

O2-

flogosi

Lefer, Circulation ‘99

chronic pre treatment of statins associated with reduction of no reflow phenomenon65

No statina

Pre-statina

Chronic pre-treatment of statins associated with reduction of no-reflow phenomenon

50

40

30

20

10

0

15

12

9

6

3

0

34.6%

9.4

6.7

9.1%

no-reflow wall motion score

Iwakura, Eur Heart J 2006