pleiotropic effects of statins rabih r. azar, md, msc, facc division of cardiology hotel dieu de...
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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
Pleiotropic Effects of StatinsPleiotropic Effects of Statins
• 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
Mechanisms of the Pleiotropic Effects of Mechanisms of the Pleiotropic Effects of StatinsStatins
• Improved endothelial functionImproved endothelial function
• Anti-thrombotic effect
• Reduced inflammation
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.
*
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
Tsunekawa, circulation 2001;104:376-379Tsunekawa, circulation 2001;104:376-379
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
Tsunekawa, circulation 2001;104:376-379Tsunekawa, circulation 2001;104:376-379
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
Mechanisms of the Pleiotropic Effects of Mechanisms of the Pleiotropic Effects of StatinsStatins
• Improved endothelial function
• Anti-thrombotic effect
• Reduced inflammation
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
Dupuis et al. Circulation. 1999;99:3227-3233.
Effects of Cerivastatin on von Willbrand FactorEffects of Cerivastatin on von Willbrand Factor
0
0.5
1
1.5
2
Controls Ceriva
Before
After
Tsunekawa, circulation 2001;104:376-379Tsunekawa, circulation 2001;104:376-379
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
Mechanisms of the Pleiotropic Effects of Mechanisms of the Pleiotropic Effects of StatinsStatins
• Improved endothelial function
• Anti-thrombotic effect
• 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
Pleiotropic Effects of StatinsPleiotropic Effects of Statins
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
Tsunekawa, circulation 2001;104:376-379Tsunekawa, circulation 2001;104:376-379
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