aggressive lipid lowering in acs: early to benefit

Aggressive Lipid Lowering in ACS:Early to Benefit

Overview

• Epidemiological Transition• Evidence based guidelines: Role of statins for Secondary

prevention of CAD.• Why do we need high dose of statin?• Why to begin early with high dose of statin?• Take home messages.

CAD: Coronary Artery Disease

1. Epidemiological Transition

“Shift in the cause of mortality from communicable diseases to CVD”

(Omran 1971).

CVD: cardiovascular diseases

CVD 30%

17.4 million

Leader in the Causes of Death

WHO; 2005

OTHERS

Total 58 million death worldwide

3.3 times than the total no. of death due to HIV,

Malaria, and Tuberculosis combined

• The problem is even worse in low-income and middle-income countries;

– four-fifths of all cardiovascular-related events occur in these parts of the world.

Nature Clinical Practice Cardiovascular Medicine sanZ and fusTer february 2009 vol 6 no 2Lancet 360;1347-1360

47%43%

10%

14%

7%

26%

IHD

Cerebrovscular disease

Other NCDs

Noncommunicable diseases (NCDs)Injuries

Communicable, maternal, perinatal, nutritional illnesses

47%43%

10%

Burden of CHD in India

Lopez A et al, 2006

Disease pattern in India

INTERHEART: 9 Modifiable factors

account for 90% of first-MI risk worldwide

Yusuf S et al. Lancet. 2004;364:937-52.

N = 15,152 patients and 14,820 controls in 52 countriesPAR = population attributable risk, adjusted for all risk factors

36

127

10

20

33

0

20

40

60

80

100

Smoking Fruits/veg

Exercise Alcohol Psycho-social

Lipids All 9 risk factors

PAR(%)

1418

90

Diabetes Abdominalobesity

Hyper-tension

Lifestyle factors

50

Conclusion: Most of the CV Risk factors are modifiable, either by lifestyle modifications or by drugs

CAD & risk factors: their association

39

59

31

1813.3

0

10

20

30

40

50

60

Fraction of Patients (with CAD) with various risk factors

LDL-C Abnormal TC/HDL ratio Smoking Hypertension DM

n= 5748 Indian patients with CAD

J Assoc Physicians India. 2004 Feb;52:103-8

2. Guidelines: Role of statin for CAD prevention.

Statin in chronic stable anginaACC/AHA

• LDL-C goal < 70 mg/dL.

• High-dose statin therapy is reasonable.

Circulation. 2007;116:2762-2772

WHO guidelines for secondary prevention of CAD

• Statin: it is recommended for all patients with established CHD. Treatment should be continued in the long-term, probably lifelong.

• Antiplatelet drugs:

• ACE-I:

• Beta-blockers:

http://www.who.int/cardiovascular_diseases; 2007

Statins in post-MI patients

NICE guidelines: Secondary prevention of CAD

• All post-MI patients should be offered combined treatment with the following:– Statin– ACE-I– Aspirin– Beta-blocker

Heart 2007;93:862-864

NICE: national institute for health and clinical excellence

AHA/ACC guidelines for secondary prevention of CAD

• Lipid lowering drug: – Reduction of LDL-C to <70mg/dL is reasonable.– If baseline LDL-C is ≥100mg/dL, initiate LDL-C lowering drug therapy.

• Antiplatelet drugs

• ACE-I

• Beta-blockers

Circulation 2006;113:2363-72

3. Why Do We Need High dose of Statins?

• Strict LDL-C goal• Benefits of high dose statin on:

• LDL-C• Progression of atherosclerosis• Cardiovascular & cerebrovascular outcome • Pleiotropic benefits

“The Lower, the Better”

RelativeRisk

for CHD (Log Scale)

3.7

2.9

2.2

1.7

1.3

1.0

LDL-C

40 70 100 130 160 190

0

1

Grundy SM et al. Circulation 2004;110:227–239.

mg/dL1.05 1.80 2.60 3.35 4.10 4.90 1.05 1.80 2.60 3.35 4.10 4.90 mmol/Lmmol/L

1% decreasein LDL-C reduces

CHD risk by1%

NCEP Report 2004

– For very high risk: • “LDL-C goal” <70 mg/dL (<1.8 mmol/L)

• “very high risk” patients defined as those with:– established CVD in addition to multiple major risk factors,

uncontrolled risk factors, or multiple risk factors of the metabolic syndrome, and patients with ACS

Circulation 2004;110:227-39.

Strict LDL-C goal

Dose of statins and LDL-C reduction

CURVES studyPercent reduction in LDL-C after 8 weeks of treatment

*†

*†

*†

*‡

*‡

*†‡

*†‡

-10

-20

-30

-40

Mea

n %

cha

nge

in L

DL -

C

-50

-6010 mg 20 mg 40 mg

Total Daily Dose (mg)

80 mg

*

*

*

AtorvastatinSimvastatin

PravastatinLovastatin

Fluvastatin

Am J Cardiol 1998; 81: 582–587

N=534; 8 wks; baseline LDL-C=192-244 mg/dl; TG<200 mg/dl*p<0.01 vs. atorvastatin at mg equivalent doses†p<0.02 vs. atorvastatin 10 mg‡p<0.01 vs. atorvastatin 20 mg

Aggressive Lipid Lowering and Progression of Atherosclerosis

ScreeningVisit*

ScreeningVisit*

Atorvastatin 80 mg/dayAtorvastatin 80 mg/day

Pravastatin 40 mg/dayPravastatin 40 mg/day

REVERSAL: Study Design

Design – Prospective, randomized, double-blind, multicenter trial

Setting – 34 community and tertiary care hospitals in the United States

Double-blind period

18-month follow-up with IVUS*Includes baseline intravascular ultrasound (IVUS)

PlaceboRun-inPhase

PlaceboRun-inPhase

Randomization

654 patients

Nissen et al JAMA 2004;291:1071-80

654 patients with symptomatic CAD with angiographic stenosis >20% and LDL-C 125–210 mg/dL; 502 with evaluable follow-up

2.7*

Pravastatin

Significant atheroscleroticprogression from baseline

-0.4†

Atorvastatin

No significant change frombaseline; atheroscleroticprogression was stopped

Primary Endpoint: Percent Change in Total Atheroma Volume

Ch

ang

e in

TA

V (

%)

-1

0

1

2

3

*Progression vs baseline (P=0.001); †No change vs baseline (P=0.98) Nissen et al JAMA 2004;291:1071-80

A, Atheroma area is calculated by subtracting the lumen area from the area of the external elastic membrane (EEM). Patient randomized to 80 mg of atorvastatin. There is substantial reduction in atheroma area (from 13.0 to 7.4 mm2). A lesser increase in lumen area is noted (from 7.7 to 9.8 mm2).

Nissen et al JAMA 2004;291:1071-80

Aggressive lipid lowering and Cardiovascular end points

High-dose better High-dose worse

Odds Reducti

on

Event RatesNo./Total (%)

High Dose

Std Dose

-17%147/2099 (7.0)

172/2063 (8.3)

-15%205/2265 (9.1)

235/2232 (10.5)

-21%334/4995 (6.7)

418/5006 (8.3)

-12%411/4439 (9.3)

463/4449 (10.4)

-16% 1097/13798 (8.0)

1288/13750 (9.4)

0.658451 1 1.51872

OR, 0.8495% CI, 0.77-0.91p=0.00003

Odds Ratio (95% CI)

Meta-Analysis of Intensive Statin Therapy Coronary Death or MI

Cannon CP, et al.

PROVE IT-TIMI 22

A-to-Z

TNT

IDEAL

Total

Myocardial Ischemia Reduction with Aggressive Cholesterol

Lowering:

MIRACL Study

Patients with UA/NSTEMI, n=2100. Randomized to high dose atorvastatin or

placebo within 1 to 4 days of hospitalization.

MIRACL: Primary Efficacy Measure

Relative risk = 0.84p=0.048

High dose High dose AtorvastatinAtorvastatin

Placebo

0

5

10

15

0 4 8 12 16Time since randomization (weeks)

Cu

mu

lativ

e In

cid

en

ce (

%)

Time to first occurrence of:• Death (any cause)• Nonfatal MI• Resuscitated cardiac arrest• Worsening angina with new objective evidence

requiring urgent rehospitalization

17.4%17.4%

14.8%14.8%

20

Schwartz et al JAMA 2001;285:1711-8

16%

MIRACL: Fatal or Non-Fatal Stroke

0

0.5

1

1.5

2

0 4 8 12 16

Time since randomization (weeks)

Cu

mu

lativ

e In

cid

en

ce (

%)

Relative risk = 0.50p=0.045

High dose High dose AtorvastatinAtorvastatin

PlaceboPlacebo 1.6%1.6%

0.8%0.8%


50%

MIRACL: Conclusions & Implications

• Early, intensive lipid-lowering treatment with atorvastatin, initiated during the acute phase of unstable angina or non–Q-wave MI, reduces early recurrent ischemic events.

• A benefit was observed in a population with low to normal baseline LDL-C levels.

• Results support consideration of treatment in the hospital, irrespective of baseline LDL-C levels.

• Treatment was safe and generally well tolerated.


4,162 patients with an Acute Coronary Syndrome < 10 days

ASA + Standard Medical Therapy

“Standard Therapy”Pravastatin 40 mg

“Intensive Therapy”With Atorvastatin

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

Double-blindDouble-blind

Cannon CP, Braunwald E, McCabe CH, et al. N Engl J Med 2004;350:1495-504.

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 40mg(26.3%)

Intensive Atorvastatin(22.4%)

16% RR

(P = 0.005)

3030

2525

2020

1515

1010

55

00

Cannon et al NEJM 2004;350:1495-504

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 F/U

Primary Endpoint Over Time

Intensive Atorvastatin Better 0.5 0.75 1.0 1.25 1.5

Pravastatin 40mg Better *2-year event rates

Cannon et al NEJM 2004;350:1495-504

Aggressive lipid lowering in patients with clinically evident CHD: previous MI, previous or

current angina, and a history of coronary revascularization.

TNT trialTreat to New Target

Atorvastatin 80 mg n=4,995


TNT Trial

Presented at ACC 2005



10,003 patients with stable coronary heart disease Age 35-75 years, LDL between 130 and 250 mg/dL, triglyceride ≤ 600 mg/dL

19% female, mean age 60.3 yearsAll received atorvastatin 10 mg during 8 week open-label run-in period

10,003 patients with stable coronary heart disease Age 35-75 years, LDL between 130 and 250 mg/dL, triglyceride ≤ 600 mg/dL

19% female, mean age 60.3 yearsAll received atorvastatin 10 mg during 8 week open-label run-in period

TNT Trial: Primary endpoint

8.7%

10.9%

0%

4%

8%

12%

High-dose Low-dose

8.7%

10.9%

0%

4%

8%

12%

High-dose Low-dose

• The primary composite endpoint of CHD death, nonfatal MI, resuscitated cardiac arrest, and fatal or nonfatal stroke was lower in the high-dose atorvastatin 80 mg group at a mean follow-up of 4.9 years.

Primary Composite of CHD death, nonfatal MI, resuscitated cardiac arrest, and fatal or nonfatal stroke

Hazard Ratio [HR]=0.78p<0.001

Presented at ACC 2005

TNT: Various subgroup analysis

• Risk of primary end points in high dose atorvastatin vs. small dose atorvastatin. – Previous PCI:

– Previous CABG:

– H/o diabetes:

– H/o of diabetes with CKD:

21% Am J Cardiol. 2008 Nov 15;102(10):1312-7

27% J Am Coll Cardiol. 2008 May 20;51(20):1938-43.

25% Diabetes Care 29:1220 –1226, 2006

35% Mayo Clin Proc. 2008;83:870-879

TNT trial and Heart Failure

Circulation. 2007;115:576-583.)

41%

Patients with stable CAD, ACS, diabetes, mild to moderate CKD,

with h/o PCI and CABG, heart failure experience marked

reduction incardiovascular events with

intensive lipid lowering,

4.8-year follow-up

8888 patients

Patient population Enrolled at 190 sites

throughout Scandinavia and the Netherlands

Diagnosed with CHD Previous hospitalization

with MI, and eligible for statin therapy

Patient population Enrolled at 190 sites

throughout Scandinavia and the Netherlands

Diagnosed with CHD Previous hospitalization

with MI, and eligible for statin therapy

Open-label period with blinded end point evaluations

Atorvastatin 80 mg/dayAtorvastatin 80 mg/day

Simvastatin 20 mg/day(titrated to 40 mg if required)Simvastatin 20 mg/day(titrated to 40 mg if required)

Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) Study

Pedersen et al. Am J Cardiol. 2004;94:720-721; Pedersen et al. JAMA. 2005;294:2437-2445.

Secondary Cardiovascular/coronary events

Cerebrovascular events

PAD

Hospitalization with primary diagnosis of CHF

All-cause mortality

Secondary Cardiovascular/coronary events

Cerebrovascular events

PAD

Hospitalization with primary diagnosis of CHF

All-cause mortality

Primary Time to occurrence of a major coronary

event− CHD death− Nonfatal MI− Resuscitated cardiac arrest

Primary Time to occurrence of a major coronary

event− CHD death− Nonfatal MI− Resuscitated cardiac arrest

Mean LDL-C = 104 mg/dL (2.7 mmol/L)

IDEAL: Effect of Treatment On LDL-C

Pedersen et al. JAMA. 2005;294:2437-2445.

0

70

80

90

100

110

120

130

Baseline Week 12 Year 1 Year 2 Year 3 Year 4 Year 5

LDL-

C (

mg/

dL)

AtorvastatinSimvastatin

0

1.8

2.0

2.3

2.6

2.8

3.1

3.4

LDL-C

(mm

ol/L)

Mean LDL-C = 81 mg/dL (2.1 mmol/L)

IDEAL: Safety

*Subset of coded myopathy.Adverse events resulting in permanent discontinuation of study drug with incidence 0.5% in either treatment group included myalgia, diarrhea, abdominal pain, and nausea.Adapted from Pedersen et al. JAMA. 2005;294:2437-2445.

No. of Patients (%)

Atorvastatin (n=4439)

Simvastatin (n=4449)

Protocol-Defined Clinically Important Lab Abnormalities

AST >3× ULN at 2 consecutive measurementsALT >3× ULN at 2 consecutive measurementsMyopathy defined as CPK >10× ULN at2 consecutive measurements with muscle symptoms

18 (0.41)43 (0.97)

0

2 (0.04)5 (0.11)

0

Investigator-Reported Adverse EventsAny adverse event resulting in permanent discontinuation of study drug

426 (9.6) 186 (4.2)

Investigator-reported myopathy 6 (0.14) 11 (0.25)Investigator-reported rhabdomyolysis* 2 (0.05) 3 (0.07)

IDEAL: Summary• IDEAL found incremental reductions in clinical end points with atorvastatin 80

mg compared to simvastatin 20-40 mg:– 17% reduction in Nonfatal MI (P=.02)– 13% reduction in MCVE (P=.02)– 16% reduction in Any CHD Event (P<.001)– 16% reduction in Any CV Event (P<.001)– 23% reduction in revascularization (P<.001)

• The results of IDEAL indicate that patients with myocardial infarction may benefit from intensive lowering of LDL-C without increase in noncardiovascular mortality or other serious adverse reactions

• IDEAL further supports the safety profile of intensive therapy with atorvastatin 80 mg

Pedersen et al. JAMA. 2005;294:2437-2445.

IDEAL study: Effects of Atorvastatin 80 mg Daily Versus Simvastatin 20 to 40 mg Daily on Any Cardiovascular Event

J Am Coll Cardiol 2009;54:2353–7)

IDEAL results indicate that intensive statin therapy continues to be more effective than

standard statin therapy, even beyond the first event, and suggest that clinicians should not

hesitate to prescribe high-dose statin therapy for patients experiencing multiple recurrent

cardiovascular events.

IDEAL study: patients with recent history of AMI within 2 months of randomization

• 999 patients who had a first acute MI <2 months before randomization.• Atorvastatin 80 mg vs. simvastatin 20 to 40 mg over approximately 5 years of

follow-up.

HR for death, MI, hospitalization for unstable angina, revascularization, and stroke at 2 and 5 years of follow up

In conclusion, our analysis provides support for the strategy of placing

patients with recent MI on intensive statin therapy and maintaining the

high dose over the long term, beyond 2 years.

Am J Cardiol 2010;106:354 –359

4. Why to begin early with high dose of statin?

Pleiotropic benefits

• Anti-inflammatory

• Anti-oxidant

• Improves endothelial function (NO).

• Plaque stabilization

• Anti-platelet

• Fibrinolytic

• Anti-proliferative ….Many more

•Pleiotropic benefits are dose dependent

•Pleiotropic benefits appears much before the lipid lowering effects

• An immediate significant effect of just a single dose of statin has been previously reported

Immediate functions of statins

Ostadal et al. demonstrated that a single dose of cerivastatin at the time of admission of patients

with unstable angina or non-ST elevation MI positively influences the inflammatory parameters

CRP and interleukin-6 at 24 hours

(Mol Cell Biochem 2003;246:45-50)

Romano et al. described that a 24-h treatment with lovastatin and simvastatin induces inhibition

of monocyte chemotactic protein-1 (MCP-1) synthesis in mononuclear and endothelial cells in

vitro

(Lab Invest 2000;80:1095-1100)

Statins indeed have beneficial effects on endothelial function by a rapid increase in nitric

oxide bioavailability; this effect has been observed as early as 3 hours following statin

administration

(Laufs et al. Circulation 1998;97:1129-1135)

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:

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)

atorvast

Subjects without on-going statin therapy

0

5

10

15

20

AtorvastatinPlacebo

ARMYDA-ACS trialComposite primary end-point (30-day death, MI, TVR)

%5

17

P=0.01

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

0

10

20

30

40


Cre

atin

e k

ina s

e-M

B (

%) P=0.002

1-3 times >3 times

0

10

20

30

40

50

60


Tro

po n

in- I

(%

)

P=0.028

ARMYDA-ACS:

Incidence (%) of post procedural Cardiac markers elevations

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


Days after PCI

MA

CE

-fre

e su

rviv

al (

%)

0

20

40

60

80

100

1 2 3 7 14 21 30

P=0.01

ARMYDA-ACS: Actuarial Survival curves

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

ARMYDA-RECAPTURE trial

793 Patients

with

stable angina

or NSTE-ACS undergoing coronary

angiography

Ra

nd

om

iza

tion

(N

=4

20

)

Atorvastatin reload: 80 mg 12 hrs before angio; further 40 mg 2 hrs before N=210 Coronary

angiography

Placebo 12 hrs before angio; further dose 2 hrs before N=210

Primary end point:30-day occurrence of cardiac death, MI, TVR

1st blood sample (before PCI)

CK-MB, Troponin-I, HS-CRP

2nd and 3rd blood samples(8 and 24 hours

after PCI)

30 days

373 patients excluded for: - 243 no chronic statin therapy (31%) - 38 emergency angiography - 82 ejection fraction <30% - 10 severe renal failure


PCI placebo N=175

68 patients excluded for indication to: - medical therapy (N=30) - bypass surgery (N=38)

N=352

J Am Coll Cardiol 2009;54:558–65

Subjects with ongoing statin therapy

ARMYDA-RECAPTURE:

PRIMARY ENDPOINT (30-day MACE)

0

3

6

9

12

3.4

9.1

P=0.045

MA

CE

(%

)

PlaceboAtorvastatin

MACE: Major Adverse Cardiac Events


Individual and Combined Outcome Measures of the Primary Endpoint at 30 days

8.69.1

P=0.045

ARMYDA-RECAPTURE

%

CompositePrimary End Point

3.4

0

3

6

9

12

Cardiac death

MI TVR MACE

Atorvastatin

Placebo

0.5 0.5

3.4


Cre

a ti n

e k i

n as e

- MB

(%

)

Tro

p oni

n-I (

%)

ARMYDA-RECAPTURE: Secondary endpoints

Proportion of patients with any post-PCI cardiac markers elevation

P=0.023P=0.032

0

10

20

30


13

23

0

10

20

30

40

50


36

47


0

20

40

60

80

100


1 2 3 7 14 21

Days after PCI

MA

CE

-fre

e s

urv

iva

l (%

)

30

P=0.045

ARMYDA-RECAPTURE trial:

Event-free survival at 30 days in the atorvastatin reload vs placebo arm


ARMYDA-RECAPTUREConclusions

ARMYDA-RECAPTURE suggests that reloading with high dose atorvastatin is associated with improved clinical outcome in patients on chronic statin therapy undergoing PCI

Acute atorvastatin bolus 80 mg + 40 mg 12 hrs pre-PCI gives a 48% relative risk reduction of 30-day MACE.

LDL-independent cardioprotective effects may be responsible of this phenomenon

These findings may support a strategy of routine reload with high dose atorvastatin early before intervention even in the background of chronic therapy


ARMYDA-CIN trial

1318 Patients

with

NSTE-ACS undergoing coronary

angiography

Ra

nd

om

iza

tion

(N

=2

70

)

Atorvastatin reload: 80 mg 12 hrs before angio; further 40 mg 2 hrs before N=135 Coronary

angiography

Placebo 12 hrs before angio; further dose 2 hrs before N=135

Primary end point:Incidence of contrast induced nephropathy

1st blood sample (before PCI)

Creatinine , HS-CRP

2nd and 3rd blood samples(24 and 48 hours

after PCI)

30 days


PCI placebo N=121

29 patients excluded for indication to: - medical therapy (N=13) - bypass surgery (N=16)

Giuseppe Patti et al., Am J Cardiol 2011;xx:xxx

CIN: contrast induced nephropathy


8.4

13.1

0

2

4

6

8

10

12

14


P= 0.01

Post-intervention peak CRP level (mg/L)

ARMYDA-CIN trial

Incidence of contrast induced nephropathy (%)

5

13.2

0

2

4

6

8

10

12

14


P= 0.046


Anti-inflammatory property may be involved

in reno-protection by atorvastatin

ARMYDA-CIN trial

NAPLES II Novel Approaches for Preventing or Limiting

Event StudyImpact of a Single High Loading Dose

of Atorvastatin 80 mg on Periprocedural Myocardial Infarction

Patients undergoing coornary angiography Jan 2005-Jan 2009 assessed for eligibility(n=1385)

Excluded (n=37)

9 withdrew consent28 did not meet the inclusion criteria

1348 patients randomized

676 allocated to Atorvastatin 80 mg group

672 allocated to Control group

338 patients included338 patients included 330 patients included

338 excluded because:155 had coronary angiography alone and not PCI98 had PCI for ISR and/or on a bypass vessel80 were referred for elective CABG5 were lost at follow-up

342 excluded because:174 had coronary angiography alone and not PCI91 had PCI for ISR and/or on a bypass vessel71 were referred for eventual CABG6 were lost at follow-up

• Non-Q wave MI:– CKMB 3X ULN

• Q wave MI:– CKMB 2X ULN with new significant Q waves in 2

contiguous leads

Definitions

Thygesen K et al. Eur Heart J 2007;28:2525-38.8

CKMB >3X ULN

0

2

4

6

8

10

12

14

16

Atorvastatin group (n= 338)

Control group (n = 330)

p = 0.014(OR = 0.56; 95% CI = 0.35-0.89)

%

9.5

15.8

cTnI >3X ULN

0

5

10

15

20

25

30

35

40

26.6

39.1



p <0.001(OR = 0.56; 95% CI = 0.40-0.78)

%%

28/252

35/23311.1

15

4/86

16/97

4.6

16.5

0

2

4

6

8

10

12

14

16

18



p = 0.18 p = 0.016

CKMB 3X ULN & CRP

Normal CRP High CRP

%%

31

39.5

15.1

38.1

0

5

10

15

20

25

30

35

40

Normal CRP High CRP



p = 0.056 p = 0.002

TnI 3X ULN & CRP

%%

78/252

92/233

13/86

37/97

In-hospital outcomeAtorvastatin

Group(N=338)

Control Group(N=330)

P value

Death 1 (0.3%) 0 NS

MI 33 (9.8%) 52 (15.8%) 0.014

Q-wave MI 1 (0.3%) 0 NS

Non Q-wave MI 32 (9.5%) 52 (15.8%) 0.014

Unplanned revasc 0 0 -

Stent thrombosis 2 (0.58%) 1 (0.30%) 0.57

Composite 34 (10%) 52 (15.7%) 0.029

Conclusions

A single, high (80 mg) loading (within 24 hours) dose of atorvastatin reduces the incidence of periprocedural non Q wave MI in elective PCI.

This cardioprotective effect seems to be more pronounced in patients with high CRP level at baseline

Possible mechanisms of the clinical benefit:

Improvement of endothelial function

Wassmann S, et al. Circ Res 2003

N=27 pts with stable angina

randomized to placebo

or

pravastatin (single dose of 40 mg).

At 24 hrs, significant attenuation of

acetylcholine-mediated vasoconstriction

* P<0.05

Circ. Res. 2003;93;e98-e103


Vasodilation of coronary microvessels

N=32 pts without CAD

randomized to placebo

or

atorvastatin (single dose of 40 mg)

transthoracic doppler

evaluation of LAD (baseline and 1 hr)

0

1

2

3

4

Placebo Atorvastatin

Before

After

Coronary flow velocity reserve (hyperemic/basal peak diastolic velocity)

P<0.01

Am J Cardiol 2005;96:89 –91


Antithrombotic effectsN=30 hypercholesterolemic pts randomized to diet or

atorvastatin (10 mg/d) for 3 days

0

1

2

3


Before

After

P<0.01

Sanguigni V, et al. Circulation 2005

0

10

20

30

40

50


Before

After

43+15 45+12 46+15

32+6

Platelet CD40L expression (AU)

2+1 2+1 2+1

1.4+0.4

P<0.05

Prothrombin fragment F1+2 (nM)

Patti G et al. JACC 2006;48:1560

ARMYDA-CAMs study

ARMYDA-CAMs RESULTS

0

20

40

60

80

100

ICAM-1 E-selectin VCAM-1


Po

st-p

roce

du

ral 2

4-h

ou

r %

incr

ease

fro

m b

asel

ine

P=0.0001

P=0.0001

P=0.20

30

59

78

42

Patti G et al. JACC 2006;48:1560

0

15

30

45

60

75

P=0.55

P=0.33

P=0.0008

No Damage Damage No Damage Damage

E-s

ele

cti

n p

ea

k l

ev

els

(n

g/m

L)


Attenuation of endothelial activation

With or without procedural myocardial damage

4. Take home messages….• CVD is the leader amongst the causes of death

worldwide.• Prevalence of CVD including CHD is increasing

rapidly in India.• Increasing burden of risk factors like:

– Hypertension– Smoking – Obesity – Diabetes– Dyslipidemia

• Statins are highly recommended for secondary prevention of CAD by all the guidelines across the globe.

• High dose of statins:– Significantly improves short term and long

term cardiovascular outcome in patients with ACS.

– Safe and well tolerated.

• Early to begin with:– Pleiotropic benefits are beyond lipid lowering effects.– Pleiotropic benefits such as anti-inflammatory property,

are responsible for very early vascular benefits.– Pleiotropic benefits appear as early as within 1 hour of

statin administration.– Evidences suggesting that even a single high dose of

atorvastatin can produce vascular benefits (outcome benefits) as early as 1st day of administration.

A healthy lifestyle strategy

PrecautionsMacrolide antibiotics like erythromycin

Azole antifungal like ketoconazole

HIV protease inhibitors like ritonavir, saquinavir

Grape fruit juice

Atorvastatin dose max. 20 mg/d

Cyclosporin Atorvastatin dose max. 10 mg/d

Statin should not be prescribed to a patients with active liver diseases, pregnancy, lactating mother

aggressive lipid lowering in acs: early to benefit

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