“Gli ACE inibitori sono superiori”
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Transcript of “Gli ACE inibitori sono superiori”
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“Gli ACE inibitori sono superiori”
Rozzano, 17 aprile 2009
Luigi Tavazzi
GVM Hospitals of Care and Research Cotignola
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Cardiovascular disease as a sequence of related pathological
eventsCoronary thrombosis
Myocardial ischemia
Coronary artery disease
Atherosclerosis
Endothelial dysfunction
Myocardial infarction
Arrhythmia andloss of muscle
Cardiac remodeling
Ventricular dilation
Congestive heart failure
End-stage heart disease
Risk factors:HypertensionDyslipidemia
Insulin resistanceSmoking
Role of
RAS
From From CirculationCirculation 2006;114:2850-70. 2006;114:2850-70.
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The role
of timing
in science
ACEi vs ARBs
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ANGIOTENSIN ANGIOTENSIN SYSTEMSYSTEM
Angiotensinogen
renin
Ang I
Ang II
Potentiation of
sympathetic activity
ACEKyninase
(enzyme)
BRADYKININ SYSTEM
kallikrein
kininogen
Bradykinin
Endothelium
ProstaglandinNO
plateletaggregation
SMCmitogenesis
Vasodilation
Inactive peptide
++
FGFPDGF
++++
Vasoc
onst
rict
ion
aldosterone release
Angiotensin / Bradykinin Systems
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ACE INHIBITION TRIALS
SECONDARY PREVENTION
TREATMENT AFTER AMI
EF
FIC
AC
Y
BEFORE
HOPE
EUROPA
ADVANCE
QUIET
PEACE
CONS. 2
• GISSI 3
ISIS 4
AFTER
AIRE
SAVE
TRACE
CONSENSUS 1
SOLVD
AM
I
PRIMARY PREV.
ASCOT
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Cardiovascular disease as a sequence of related pathological
eventsCoronary thrombosis
Myocardial ischemia
Coronary artery disease
Atherosclerosis
Endothelial dysfunction
Myocardial infarction
Arrhythmia andloss of muscle
Cardiac remodeling
Ventricular dilation
Congestive heart failure
End-stage heart disease
Risk factors:HypertensionDyslipidemia
Insulin resistanceSmoking
Role of
RAS
From From CirculationCirculation 2006;114:2850-70. 2006;114:2850-70.
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ACE inhibition reduces the incidence of MI
Young JB. Cardiovasc Drugs Ther. 1995;9:89-102.
SOLVD combined trialsPlacebo
Enalapril
Years
P<0.001
% MI 20
15
10
5
010 2 3 4
SAVE Placebo
Captopril
Years
P=0.015
% MI 20
15
10
5
010 2 3 4
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MI Occurence in ACE-inh trials
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Rutherford et al. Circulation 1994;90:1731-1738
SAVECABG
0.2
0.1
0.00 1 2 3 4 5
Ev
ent
rate
Placebo
Captopril
PTCA
Placebo
Captopril
ACE inhibition reduces the need for revascularisation
0 1 2 3 4 5 Years
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ACE INHIBITION TRIALS
SECONDARY PREVENTION
TREATMENT AFTER AMI
EF
FIC
AC
Y
BEFORE
HOPE
EUROPA
ADVANCE
QUIET
PEACE
CONS. 2
• GISSI 3
ISIS 4
AFTER
AIRE
SAVE
TRACE
CONSENSUS 1
SOLVD
AM
I
PRIMARY PREV.
ASCOT
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HOPE Study Investigators. N Engl J Med. 2000;342:145-53. PEACE Trial Investigators. N Engl J Med. 2004;351:2058-68.EUROPA Investigators. Lancet. 2003;362:782-8. Pitt B et al. Am J Cardiol. 2001;87:1058-63.
HOPE
15
5
10
0
20
0
Placebo
Ramipril 10 mg
%Patients
2 41
22% Risk reductionRR 0.78 (0.70–0.86)
P=0.001
3
PEP: CV death, MI, strokePEP: CV death, MI, stroke
12
4
10
01 3 4
14
0
Placebo
Perindopril 8 mg
86
2
52
EUROPA
20% Risk reductionRR 0.80 (0.71–0.91)
P=0.0003
PEP: CV death, MI, cardiac arrestPEP: CV death, MI, cardiac arrest
PEACE
Time (years)
Trandolapril4 mgPlacebo
30
20
10
15
5
1 2 3 4 5
25
06
%Patients
4% Risk reductionHR 0.96 (0.88–1.06)
P=0.43
PEP: CV death, MI, revascularizationPEP: CV death, MI, revascularization
QUIET
40
20
30
0
50
0
Placebo
Quinapril 20 mg
Time(years)
1
4% Risk increaseRR 1.04 (0.89–1.22)
P=0.6
10
2 3
PEP: CV death, MI, cardiac arrest, revascularization, hospitalization for UAPEP: CV death, MI, cardiac arrest, revascularization, hospitalization for UA
Time(years)
Time(years)
Secondary prevention of CAD by ACEIs
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CV mortality 4.1% 5%CV mortality 4.1% 5%
MI 6.4% 7.7%MI 6.4% 7.7%
Death & MI 8.7% 10%Death & MI 8.7% 10%
Relative risk reduction and 95% CIRelative risk reduction and 95% CIACEI PlaceboACEI Placebo
Meta-analysis of 32 000 patientsMeta-analysis of 32 000 patients
0.850.85
0.5 0.75 1 1.25 1.5
0.820.82
0.830.83
0.850.85
0.870.87Total mortality 7.5% 8.6%Total mortality 7.5% 8.6%
ACE better Placebo betterACE better Placebo better
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Heart failure 3.8% 5%Heart failure 3.8% 5%
Revascularization 2.1% 2.7%Revascularization 2.1% 2.7%
Stroke 10.5% 11.3%Stroke 10.5% 11.3%
Relative risk reduction and 95% CIRelative risk reduction and 95% CI
ACEI PlaceboACEI Placebo
0.740.74
0.920.92
0.740.74
Meta-analysis of 32 000 patientsMeta-analysis of 32 000 patients
ACE Placebobetter better ACE Placebobetter better
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MI occurrence in ARB trials
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Incidence of AMI in ONTARGET
No statistical difference between groups,but …
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Atheroma formation and progression:a struggle between death and regeneration
Endothelial cells undergo suicide (apoptosis) and regenerate
When a mismatch occurs, the endothelium loses its continuity
Endothelial cells undergo suicide (apoptosis) and regenerate
When a mismatch occurs, the endothelium loses its continuity
Atherosclerosis ACS
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90% of ACE is a tissue enzyme present in the heart and vessel ( endothelium and smooth muscle )
CAD up-regulates tissue ACE and alters the balance between:
90% of ACE is a tissue enzyme present in the heart and vessel ( endothelium and smooth muscle )
CAD up-regulates tissue ACE and alters the balance between:
Angiotensin IIBradykinin
which, in turn, impairs endothelial function
ACE activity and endothelial function
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ENDOTHELIAL FUNCTION
eNOS activity
% of apoptosis
eNOS activity
% of apoptosis
Biologic end-points:
Clinical end-points:• Vasomotion to endothelial dependent stimulation (Ach, Bradykinine, etc)
• von Willebrand factor
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PERTINENT substudy
von Willebrand factor
p <0.01
vWf
(%/U
nit)
Normal Range
(44-158)
Placebo PlaceboPerindopril
CAD PERTINENT patients
baseline 1 year
0
100
200
300
Significant prognostic role
Years
outc
ome
outc
ome
0.7
0.8
09
1.0
00 22 33 4411
Low (142% / Unit)
High (>142% / Unit)
p<0.01
(1175 pts)
Perindopril
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Healthy subjectsHealthy subjects
Incubated (72 h) with serum from
EUROPA ptsEUROPA pts
ecNOSApoptosis
To mimic the effects of circulating blood on endothelial function
Isolation of humanendothelium
PERTINENT substudy (1175 pts)
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PERTINENT Analysis in cultured HUVECs
PP<0.05<0.05
Ap
op
tosi
s
Controls CAD PERTINENT patientsbaseline 1 year
PlaceboPlacebon=44n=44
PlaceboPlacebon=44n=44
Treatedn=43
Treatedn=43
Controlsn=45
0
10
20 PP<0.01<0.01
ApoptosisEffects of HUVEC incubation with serum from:
#P=controls vs baseline
*P=perindopril vs placebo Ceconi C et al. Cardiovasc Res. 2006
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Normal rateof apoptosis: 3%
Maintenance ofendothelial layer
Excess rate of apoptosis
Onset of atherosclerotic Protection against atherosclerosis
Endothelial apoptosis and atherosclerosis
Plaque erosion and rupture
Endothelium continuity
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WHY ?
Different tissue affinity
Different effects on the bradykinine (anti-apoptoic) angiotensin (pro-apoptoic)
Specific effects on typical apoptoic inducer: TNF-
Different tissue affinity
Different effects on the bradykinine (anti-apoptoic) angiotensin (pro-apoptoic)
Specific effects on typical apoptoic inducer: TNF-
(ANTI) bradykinine angiotensin (PRO)
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ACE Enzyme ACE activity
Bradikynin, and not Angiotensin I, is the “natural” substrate for ACE
Affinity Km~1x10-4M
Catalytic rate kcat~10 sec
Affinity Km~1x10-6M
Catalytic rate kcat~1 sec
Reaction Rate ~ 50 times faster
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Bradykinin / Angiotensin IIB
rad
ykin
in (
Pg
/mL
)
p <0.01
CAD PERTINENT
baseline 1 year
Pla
cebo
(n=4
4)P
erin
dopr
il (n
=43)
14.8
12.4
12.3
18.0
Controls
Con
trols
(n=4
5)18
.3
p<0.01
0
10
20
5
15
Pla
cebo
(n=4
4)P
erin
dopr
il (n
=43)
Bradykinin
An
gio
ten
sin
II (
Pg
/mL
)
p <0.05
CAD PERTINENT
baseline 1 year
Pla
cebo
(n=4
4)P
erin
dopr
il (n
=43)
17.1
15.8
14.4
12.5
Controls
Con
trols
(n=4
5)10
.8
p<0.01
Pla
cebo
(n=4
4)P
erin
dopr
il (n
=43)
Angiotensin II
# p=controls vs baseline‡ p=∆perindopril vs ∆placebo
0
10
20
5
15
# ‡# ‡
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0
5
10
15
20
25
30
35
40
TN
F-a
(pg
/mL
)
ControlsControlsn = 45n = 45
18.0
p<0.01 #
Controls
baseline 1 year
p <0.05 ‡
PlaceboPlacebon = 44n = 44
PlaceboPlacebon = 44n = 44
PerindoprilPerindopriln = 43n = 43
PerindoprilPerindopriln = 43n = 43
27.127.7 28.9 24.6
CAD PERTINENT patients
# p=controls vs baseline‡ p= perindopril vs placebo
TNF- PERTINENT
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ANGIO II TNF α
Oxygen free radicals
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RAS Blockade reduces the incidence of cerebrovascular events
TrialTrial
HOPEHOPE
PROGRESSPROGRESS
MOSESMOSES
DrugDrug
RamiprilRamipril
PerindoprilPerindopril
EprosartanEprosartan
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RAS Blockade reduces the incidence of diabetes
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GISSI-3 Study
Effect of Lisinopril in pts with AMI
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HOPE and PEACE: new onset diabetes
0
2
4
6
8
10
12
HOPE PEACE
ACE-i Placebo
0
2
4
6
8
10
12
HOPE PEACE
ACE-i Placebo
3.6%5.4%
9.8%
11.5%
HR 0.66 95% CI 0.51-0.85
p <0.001
HR 0.83 95% CI 0.72-0.96
p =0.014
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Incident diabetes in clinical trials of antihypertensive drugs: a network meta-analysis
Elliott WJ, et al. Lancet 2007;369(9557):201-7
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RAS blockade reduces the incidence of atrial fibrillation (?)
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Healey JS et al. JACC 2005; 45:1832-39
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Valsartan: 371/722 (51.4%)Placebo: 375/720 (52.1%)
Adjusted* HR 0.9996%CI 0.85-1.15P value 0.84
* The 96%CI was calculated by Cox proportional hazards model adjusted for ACE-I, amiodarone use, cardioversion, PAD, CAD
Time to first recurrence of AF(n. 1442)GG
IISS GISSI-AFGISSI-AF
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RAS Blockade improves renal function
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Modulatori RAS a confronto
•ACE-I hanno avuto spazi di applicazioneACE-I hanno avuto spazi di applicazione più aperti e successi più consolitatipiù aperti e successi più consolitati
•efficacia simile (bradichinina può essere un plus)efficacia simile (bradichinina può essere un plus)
•Tollerabilità simile (in qualche trial ARB in vantaggio)Tollerabilità simile (in qualche trial ARB in vantaggio)
•Associazione ACE-I + ARB non vantaggiosa Associazione ACE-I + ARB non vantaggiosa (occasionalmente dannosa)(occasionalmente dannosa)
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Evidence-based recommendations for the blockers of the RAAS
Hypertension ACE-I or ARBs
Heart failure ACE-IARBs if ACE-I not tolerated ACE-I plus ARBs
Myocardial infarction ACE-I or ARBsCombination not recommended
Renal dysfunction ACE-I or ARBsCombination???
Prevention of CV events ACE-I or ARBs Combination not recommended
Atrial fibrillation Primary prevention: ???Secondary prevention: not
recommended
Prevention of diabetes ACE-I? ARBs? Both ?
Hypertension ACE-I or ARBs
Heart failure ACE-IARBs if ACE-I not tolerated ACE-I plus ARBs
Myocardial infarction ACE-I or ARBsCombination not recommended
Renal dysfunction ACE-I or ARBsCombination???
Prevention of CV events ACE-I or ARBs Combination not recommended
Atrial fibrillation Primary prevention: ???Secondary prevention: not
recommended
Prevention of diabetes ACE-I? ARBs? Both ?
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The fallacy of surrogate end-point: Albuminuria
•In ONTARGET albuminuria was reduced In ONTARGET albuminuria was reduced by a combination of telmisartan and ramipril, by a combination of telmisartan and ramipril, but serum creatinine and dialysis rate but serum creatinine and dialysis rate doubled.doubled.
•In a diabetic subgroup (In a diabetic subgroup (~ 700 pts) with ~ 700 pts) with overt (≥ 300 mg/g creatinine) proteinuria overt (≥ 300 mg/g creatinine) proteinuria and fast loss of GFR, dual RAS blockade and fast loss of GFR, dual RAS blockade had no significant effect on renal outcome.had no significant effect on renal outcome.
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END
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Kunz R et al. Ann Intern Med 2008; 148:30-48Ratio of means (95% CI)* for change in proteinuria, by randomized therapy, over
two follow-up intervalsRandomized therapy Over 1-4 mo Over 5-12 mo
ARBs vs placebo 0.57 (0.47–0.68) 0.66 (0.63–0.69)
ARBs vs ACE-I 0.99 (0.92–1.05) 1.08 (0.96–1.22)
ARBs vs CCBs 0.69 (0.62–0.77) 0.62 (0.55–0.70)
ARB+ACE-I vs ARBs 0.76 (0.68–0.85) 0.75 (0.61–0.92)
ARB+ACE-I vs ACE-I 0.78 (0.72–0.84) 0.82 (0.67–1.01)
ACE-I=angiotensin-converting-enzyme inhibitorARB=angiotensin-receptor blockerCCB=calcium-channel blocker*Ratio of means=ratio of the average treatment effect in the intervention group (either ARBs alone or in combination with ACE-I) relative to the control group (placebo or single-drug comparator), with 95% CI
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ARBs in Secondary Prevention
Superior to placebo? YES / NO
More effective than ACEi? NO
Less effective than ACEi? NO
Equal than ACEi? YES
Should be used with ACE? NO
Superior to placebo? YES / NO
More effective than ACEi? NO
Less effective than ACEi? NO
Equal than ACEi? YES
Should be used with ACE? NO
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ARBs in Heart Failure
Superior to placebo? YES
More effective than ACEi? NO
Less effective than ACEi? NO
Equal than ACEi? YES
Should be used with ACE? NO / YES
but only to reduce hospitalisation
Superior to placebo? YES
More effective than ACEi? NO
Less effective than ACEi? NO
Equal than ACEi? YES
Should be used with ACE? NO / YES
but only to reduce hospitalisation