Pleiotropic Effects of Statins Rabih R. Azar, MD, MSc, FACC Division of Cardiology Hotel Dieu de France Hospital

Pleiotropic Effects of StatinsPleiotropic Effects of Statins

Rabih R. Azar, MD, MSc, FACCRabih R. Azar, MD, MSc, FACC

Division of CardiologyDivision of Cardiology

Hotel Dieu de France HospitalHotel Dieu de France Hospital


• Statins block the biosynthesis of cholesterol

• This mechanism explains theid main benefit

• However, they are also beneficial in patients with normal

cholesterol

• In addition, a substantial quantity of data show that statins

exert various effects on multiple targets and which are

INDEPENDENT of their cholesterol lowering properties

• These are called the PLEOTROPIC EFFECTS of statins

Mechanisms of the Pleiotropic Effects of Mechanisms of the Pleiotropic Effects of StatinsStatins

• Improved endothelial function

• Anti-thrombotic effect

• Reduced inflammation


• Improved endothelial functionImproved endothelial function



Normal Endothelial FunctionNormal Endothelial Function

• 60 pts with acute coronary syndromes and hypercholesterolemia randomized to placebo or pravastatin 40 mg/d for 6 weeks

• Flow-mediated dilatation measured by brachial artery ultrasound at baseline and 6 weeks

• Total C decreased by 14% and LDL-C by 26% in pravastatin group during treatment

Cholesterol Reduction Improves Endothelial Cholesterol Reduction Improves Endothelial Function After ACS: The RECIFE TrialFunction After ACS: The RECIFE Trial

Dupuis et al. Circulation. 1999;99:3227-3233.

*


Cholesterol Lowering Improves Flow-Mediated Cholesterol Lowering Improves Flow-Mediated Dilatation After ACS: The RECIFE TrialDilatation After ACS: The RECIFE Trial

%

Placebo

Pravastatin

Time 0 6 Weeks

12

10

8

6

4

2

0Time 0 6 Weeks

8

7

6

5

4

3

2

Flow-mediated Dilatation Nitroglycerin Dilatation

*p<0.05

Effect of Cerivastatin on Endothelial FunctionEffect of Cerivastatin on Endothelial Function

• 27 elderly diabetic patients

• With or without mild hypercholesterolemia

• 3 days treatment with low dose cerivastatin (0.15 mg/day)

• Levels of plasma lipids were not changed

Tsunekawa, circulation 2001;104:376-379Tsunekawa, circulation 2001;104:376-379

Effects of Cerivastatin on Brachial Artery FlowEffects of Cerivastatin on Brachial Artery Flow

01

23

456

78

910

Before After

P < 0.05

0

1

2

3

4

5

6

7

8

9

10

Before After

Endothelial dependent dilation NTG dependent dilation

Controls

Ceriva 3 days

Ceriva 3 months


P = NSP = NS P = NS P = NS

Effects of Cerivastatin on Plasma cGMP LevelsEffects of Cerivastatin on Plasma cGMP Levels

0

1

2

3

4

5

6

Ceriva Controls

Before

After

P < 0.05P < 0.05P = NSP = NS


Activation of eNos by StatinsActivation of eNos by StatinsN

O C

on

cen

trat

ion

(n

M)

NO

Co

nce

ntr

atio

n (

nM

)180180

150150

120120

9090

6060

3030

00

** ++

**

++

ACETYLCHOLINEACETYLCHOLINE

**

++++

**

PRAVASTATINPRAVASTATIN

** **

SIMVASTATINSIMVASTATIN

****

Basal ReleaseBasal Release

0.1 µM Agent0.1 µM Agent

1 µM Agent1 µM Agent

10 µM Agent10 µM Agent

* Indicates difference form basal release (control); + indicates difference for response * Indicates difference form basal release (control); + indicates difference for response at 0.1 µmol/liter, p < 0.05.at 0.1 µmol/liter, p < 0.05.Kaesemeyer, et al JACC Kaesemeyer, et al JACC

1999;33:234-41.1999;33:234-41.

• Improved capacity for vasodilatation– improved regional blood flow and O2 delivery

• An increase in NO decreases thrombogenicity– inhibits platelet adhesion and deposition– favorably affects the balance between PA

and PAI

• NO inhibits inflammation within the vessel wall

Potential Benefits of Improved Endothelial Potential Benefits of Improved Endothelial Function in Acute Coronary SyndromesFunction in Acute Coronary Syndromes





Pravastatin Reduces Markers of Thrombosis in Pravastatin Reduces Markers of Thrombosis in Hypercholesterolemic PatientsHypercholesterolemic Patients

0

20

40

60

placebo prava

Before

After0

1

2

3

placebo prava

Before

After

• Hypercholesterolemic patients (mean cholesterol 258 mg/dL, mean LDL 170 mg/dL)

• Pravastatin 40mg/day vs. placebo for 8 weeks

P < 0.02P < 0.02 P < 0.02P < 0.02F VIIa, mU/mLF VIIa, mU/mL F1+2 nmol/LF1+2 nmol/L

Cipollone et al. Circulation 2002;106:399-402Cipollone et al. Circulation 2002;106:399-402

Effects of Pravastatin on Markers of Thrombosis in Effects of Pravastatin on Markers of Thrombosis in the RECIFE Trialthe RECIFE Trial

Marker Effect

• Thrombin anti-thrombin No change

• PAI-1 No change

• Von Willbrand factor No change

• Tissue Factor No change

• TFPI No change

• Total GP IIb/IIIa No change

• Factor VII No change


Effects of Cerivastatin on von Willbrand FactorEffects of Cerivastatin on von Willbrand Factor

0

0.5

1

1.5

2

Controls Ceriva

Before

After


P = NSP = NSP = NSP = NS

% Change in Fibrinogen from Baseline% Change in Fibrinogen from Baseline-20 -10 0 10 20 30 40 50

Pravastatin (n = 3510)

Simvastatin (n = 364)

Atorvastatin (n = 1083)

60

Lovastatin (n = 615)

Variable Effects of Statins on Fibrinogen Variable Effects of Statins on Fibrinogen

Atorvastatin: Marais AD 1997; Davidson M 1997; Wierzicki AS 1998; Nair 1998; Stein 1998; Lovastatin: Sinzinger H 1995; Koenig W 1992; Beigel Y 1991 (2); Koppensteiner R 1990; Illingworth DR 1992; Stein 1998; Simvastatin: McDowell IF 1991; Steinmetz A 1996; Kehely A 1995; Farnier M 1994; Illingworth DR 1992; Branchi 1993; Stein 1998; Pravastatin: Lowe G 1998 (personal communication); Salonen 1995; Fogari R 1997; Tsuda Y 1996; Avellone G 1994; Tsuda Y 1993; Branchi A 1993; Wada H 1992; Jay RH 1990; Stein 1998;

• 16 hypercholesterolemic coronary pts and 16 coronary pts with normal cholesterol levels (<200 mg/dL)

• Thrombus formation assessed by exposing porcine aortic media (simulating plaque rupture) to the pt’s flowing venous blood x 3 mins at low and high shear rates, using an ex vivo superfusion chamber

• Tests repeated in hypercholesterolemic pts after 1 week and 2.4 months of pravastatin 40 mg/d

Cholesterol Levels and Platelet Thrombus Cholesterol Levels and Platelet Thrombus DepositionDeposition

Lacoste L et al. Circulation. 1995;92:3172-3177.

Cholesterol Levels and Platelet Thrombus Cholesterol Levels and Platelet Thrombus DepositionDeposition

*p<0.05 normocholesterolemic vs hypercholesterolemic (basal) at both shear rates.†p<0.05 basal vs after pravastatin at both shear rates.Lacoste L et al. Circulation. 1995;92:3172-3177.

Platelet

deposition

(µm2/mm)

6

5

4

3

2

1

0Normochol Basal After prava

Hypercholesterolemic

6

5

4

3

2

1

0Normochol Basal After prava

Hypercholesterolemic

Shear Rate 754 S-1Shear Rate 2346 S-1

*

*

†

†

The shedding of sCD40L during platelets The shedding of sCD40L during platelets stimulationstimulation

Effects of sCD40LEffects of sCD40L

• Initiation of the inflammatory response– Expression of ICAM, VICAM, E-selectin

– Expression of chemokines (IL-6, IL-6, MCP-1)

• Prothrombotic effect– Expression of tissue factor

– Interaction with the GP IIb/IIIa receptor

• Progression of atherosclerosis

Levels of sCD40L are increased in unstable angina suggesting that it may have a role in Levels of sCD40L are increased in unstable angina suggesting that it may have a role in plaque destabilizationplaque destabilization (Circulation 1999;100:614-620)(Circulation 1999;100:614-620)

sCD40L levels in different clinical conditionssCD40L levels in different clinical conditions

Cerivastatin and Pravastatin Reduce soluble CD40 ligand Cerivastatin and Pravastatin Reduce soluble CD40 ligand Levels in Hypercholesterolemic PatientsLevels in Hypercholesterolemic Patients

0

2

4

6

8

10

12

placebo prava

Before

After

0

1

2

3

4

5

6

7

placebo ceriva

Before

After

P = NSP = NS

P < 0.05P < 0.05

P = NSP = NSP < 0.02P < 0.02

sCD40l, ng/mLsCD40l, ng/mL sCD40l, ng/mLsCD40l, ng/mL

Cipollone et al. Circulation 2002;106:399-402Cipollone et al. Circulation 2002;106:399-402




• Reduced inflammationReduced inflammation

Unstable Plaques are Hot. CRP probably identifies Unstable Plaques are Hot. CRP probably identifies vulnerable plaquesvulnerable plaques

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

S. Angina U.Angina MI

Difference of temp from Difference of temp from background tempbackground temp

Stefanadis. Circ 99;99:1965Stefanadis. Circ 99;99:1965

Sources of Inflammatory MarkersSources of Inflammatory Markers

Risk of MI According to CRP LevelsRisk of MI According to CRP Levels

Atorvastatin Enhances the Decline in CRP in Atorvastatin Enhances the Decline in CRP in Patients with Acute Coronary Syndromes (MIRACL)Patients with Acute Coronary Syndromes (MIRACL)

11.5

1.9

11

2.9

0

2

4

6

8

10

12

14

Baseline 16 weeks

Atorva

Placebo

P < 0.01P < 0.01

P = NSP = NS

-83

-74

-84

-82

-80

-78

-76

-74

-72

-70

-68

Atorva Placebo

P < 0.001P < 0.001

Mean hs-CRP ValuesMean hs-CRP Values Mean Change in hs-CRP Mean Change in hs-CRP

Kinlay et al. Circulation 2003;108:1560-1566Kinlay et al. Circulation 2003;108:1560-1566

Simvastatin lowers CRP within 14 daysSimvastatin lowers CRP within 14 daysAn effect independent of LDL cholesterol reductionAn effect independent of LDL cholesterol reduction

2.55

2

1.6

2.2

0

0.5

1

1.5

2

2.5

3

simva placebo

• day 0day 0

• day 14day 14

Median Median CRPCRP

Plenge et al. Circ 2002;106:1447-52Plenge et al. Circ 2002;106:1447-52

P = NSP = NSP = 0.01P = 0.01

Coronary Angioplasty Induces a Systemic Coronary Angioplasty Induces a Systemic Inflammatory ResponseInflammatory Response

0

5

10

15

20

25

30

Angioplasty Controls

Baseline

48 hours

Mean CRP Mean CRP mg/Lmg/L

P < 0.001P < 0.001

P = NSP = NS

Azar et al. Am J Cardiol 1997;80:1476-8Azar et al. Am J Cardiol 1997;80:1476-8

Effects of Statin Therapy on the Rise of Markers of Effects of Statin Therapy on the Rise of Markers of Inflammation and on Platelets Activation Following Inflammation and on Platelets Activation Following

AngioplastyAngioplasty

P = 0.008P = 0.008

Azar et al. Submitted to circulation 2004Azar et al. Submitted to circulation 2004

Statin therapy at the time of PCI confers an early Statin therapy at the time of PCI confers an early and sustained survival benefitand sustained survival benefit

Chan et al. Circulation 2002;105:691-696Chan et al. Circulation 2002;105:691-696

Mortality according to baseline CRP and statins use Mortality according to baseline CRP and statins use following PCIfollowing PCI

3.1

14.8

1.2 1.8

5.6 5.76.3

2.8

0

2

4

6

8

10

12

14

16

1st quartile 2nd quartile 3rd quartile 4th quartile

placebo

statin

1-ye

ar m

ort

alit

y (%

)1-

year

mo

rtal

ity

(%)

P = NSP = NS P = NSP = NS

P = NSP = NS

P < 0.009P < 0.009

Preprocedural CRPPreprocedural CRPChen et al. Circulation 2003;107:1750-1756Chen et al. Circulation 2003;107:1750-1756

Statins suppress elevation of hs-CRP following angioplasty Statins suppress elevation of hs-CRP following angioplasty in patients with high levels of hs-CRP at baselinein patients with high levels of hs-CRP at baseline

Azar et al. Submitted to circulation 2004Azar et al. Submitted to circulation 2004


ARE THEY CLINICALLY RELEVANT?ARE THEY CLINICALLY RELEVANT?

0

2

4

6

8

10

12

14

1 2 3 4 50

2

4

6

8

10

12

14

1 2 3 4 5

WOSCOPS: Framingham Predicted vs Observed Event Rates: Placebo and Pravastatin Group

4.4

Yea

r C

HD

Ev

ent

Rat

e (%

)*4.

4 Y

ear

CH

D E

ven

t R

ate

(%)*

Quintiles of RiskQuintiles of Risk

* Predicted on the basis of on-treatment lipid levels* Predicted on the basis of on-treatment lipid levels* Predicted on the basis of on-treatment lipid levels* Predicted on the basis of on-treatment lipid levels

PLACEBO PRAVASTATINPRAVASTATIN

-- predicted 5.6%-- predicted 5.6%

observed 4.5%observed 4.5%

p = 0.026p = 0.026

-- predicted 7.4%-- predicted 7.4%

observed 7%observed 7%

p = 0.58p = 0.58

Withdrawal of statins increases event rates in Withdrawal of statins increases event rates in patients with acute coronary syndromespatients with acute coronary syndromes

Heeschen et al. Circulation 2002;105:1446-1452Heeschen et al. Circulation 2002;105:1446-1452

• Cholesterol lowering with atorvastatin 80 mg/d will reduce the incidence of ischemic events as compared to placebo in patients hospitalized with unstable angina or non-Q wave MI

MIRACL HypothesisMIRACL Hypothesis

• Double-blind, randomized, placebo-controlled trial in 3000 pts with unstable angina or non-Q MI

• Atorvastatin 80 mg/d or placebo begun 1-4 days after hospital admission and continued for 4 months

• Primary end point is a composite of death, nonfatal MI, resuscitated cardiac arrest, and recurrent, symptomatic myocardial ischemia with objective evidence requiring emergency hospitalization

Myocardial Ischemia Reduction With Aggressive Myocardial Ischemia Reduction With Aggressive Cholesterol Lowering (MIRACL) StudyCholesterol Lowering (MIRACL) Study

Schwartz et al. Am J Cardiol. 1998;81:578.

MIRACL: Primary Efficacy MeasureMIRACL: Primary Efficacy Measure

Relative risk = 0.84P=0.04895% CI 0.701-0.999

Atorvastatin

Placebo

0

5

10

15

0 4 8 12 16Time since randomization (weeks)

Cu

mu

lati

ve I

nci

den

ce (

%)

• Time to first occurrence of:• Death (any cause)• Non-fatal MI• Resuscitated cardiac arrest• Worsening angina with new

objective evidence and urgent rehospitalization

17.4%

14.8%

MIRACL: Fatal or non-fatal strokeMIRACL: Fatal or non-fatal stroke

0

0.5

1

1.5

2

0 4 8 12 16

Time since randomization (weeks)

Cu

mu

lati

ve I

nci

den

ce (

%)

Relative risk = 0.50P=0.04595% CI 0.26-0.99

Atorvastatin

Placebo 1.6%

0.8%

Pleiotropic Effects of Statins: ConclusionsPleiotropic Effects of Statins: Conclusions

• Yes, 2 of 3 are proved and may explain the benefits of Yes, 2 of 3 are proved and may explain the benefits of

statins beyond lipid loweringstatins beyond lipid lowering

• Improvement in endothelial function: PROVEDImprovement in endothelial function: PROVED

• Anti-platelets and anti-thrombotic: ?Anti-platelets and anti-thrombotic: ?

• Anti-inflammatory: PROVEDAnti-inflammatory: PROVED

Statin therapy reduced the Statin therapy reduced the number and volume of number and volume of inflammatory lesions in inflammatory lesions in

multiple-sclerosis patientsmultiple-sclerosis patients

Vollmer et al. Lancet 2004;363:1607-08

Normal Endothelial FunctionNormal Endothelial Function

Effects of Cerivastatin on Plasma Nitrite/Nitrate Effects of Cerivastatin on Plasma Nitrite/Nitrate (Nox)(Nox)

0

5

10

15

20

25

Ceriva Controls

Before

After

Co

nc

e ntr

ati

on

(μ

M)

P < 0.05P < 0.05


P = NSP = NS

CRP and Cholesterol in the Prediction of CRP and Cholesterol in the Prediction of Cardiovascular EventsCardiovascular Events

CRP Is a Risk Factor in Unstable AnginaCRP Is a Risk Factor in Unstable Angina

Liuzzo et al. N Engl J Med. 1994;331:417.

CRP<0.3 mg/dL

(n=11)

CRP≥0.3 mg/dL

(n=20) p-value

Ischemic episodes 1.8±2.4 4.8±2.5 0.004

In-hospital events:

Death 0 2

MI 0 5

Revascularization 2 12

Total 2 (18%) 18 (90%) <0.001

Event Reduction in CARE According to Event Reduction in CARE According to Presence or Absence of Inflammatory MarkersPresence or Absence of Inflammatory Markers

Ridker et al. Circulation. 1998;98:839.

Relativerisk

3

2

1

0

p trend = 0.005

Inflammation absent

Pravastatin

Inflammation absent

Placebo

Inflammation present

Pravastatin

Inflammation present

Placebo

Inflammation defined as CRP and SAA ≥90th percentile

Documents

Pleiotropic Effects of Statins Rabih R. Azar, MD, MSc, FACC Division of Cardiology Hotel Dieu de France Hospital