Document

Report
“Gli ACE inibitori sono
superiori”
Rozzano, 17 aprile 2009
Luigi Tavazzi
GVM Hospitals of Care and Research
Cotignola
Cardiovascular disease as a sequence of
related pathological events
Coronary
thrombosis
Myocardial
infarction
Myocardial
ischemia
Coronary artery
disease
Atherosclerosis
Endothelial
dysfunction
Arrhythmia and
loss of muscle
Role
of
RAS
Risk factors:
Hypertension
Dyslipidemia
Insulin resistance
Smoking
Cardiac
remodeling
Ventricular dilation
Congestive heart
failure
End-stage heart
disease
From Circulation 2006;114:2850-70.
ACEi vs ARBs
The role
of timing
in science
Angiotensin / Bradykinin Systems
BRADYKININ SYSTEM
ANGIOTENSIN SYSTEM
kininogen
Angiotensinogen
kallikrein
renin
Endothelium Bradykinin
 platelet
aggregation
+
+
ACE
Kyninase
Ang I
+
(enzyme)
Prostaglandin
NO
Inactive
peptide
 SMC
Vasodilation
mitogenesis
Ang II
Potentiation of
sympathetic
activity
FGF
PDGF
 aldosterone release
ACE INHIBITION TRIALS
SECONDARY
PREVENTION
 CONSENSUS 1
TREATMENT
AFTER AMI
EFFICACY
PRIMARY
PREV.
 SOLVD
 AIRE
 SAVE
 TRACE
 HOPE
 EUROPA
• GISSI
 ADVANCE
 ISIS 4
 QUIET
 CONS. 2
 PEACE
BEFORE
AMI
 ASCOT
3
AFTER
Cardiovascular disease as a sequence of
related pathological events
Coronary
thrombosis
Myocardial
infarction
Myocardial
ischemia
Coronary artery
disease
Atherosclerosis
Endothelial
dysfunction
Arrhythmia and
loss of muscle
Role
of
RAS
Risk factors:
Hypertension
Dyslipidemia
Insulin resistance
Smoking
Cardiac
remodeling
Ventricular dilation
Congestive heart
failure
End-stage heart
disease
From Circulation 2006;114:2850-70.
ACE inhibition reduces the incidence of MI
SOLVD combined trials
20
Placebo
15
Enalapril
10
5
P<0.001
0
0
2
1
3
4
SAVE
% MI
Years
Placebo
20
Captopril
15
10
5
P=0.015
0
0
1
Young JB. Cardiovasc Drugs Ther. 1995;9:89-102.
2
3
4 Years
MI Occurence in ACE-inh trials
ACE inhibition reduces
the need for revascularisation
SAVE
CABG
0.2
PTCA
Event rate
Placebo
Placebo
0.1
Captopril
Captopril
0.0
0
1
2
3
4
5
Rutherford et al. Circulation 1994;90:1731-1738
0
1
2
3
4
5 Years
ACE INHIBITION TRIALS
SECONDARY
PREVENTION
 CONSENSUS 1
TREATMENT
AFTER AMI
EFFICACY
PRIMARY
PREV.
 SOLVD
 AIRE
 SAVE
 TRACE
 HOPE
 EUROPA
• GISSI
 ADVANCE
 ISIS 4
 QUIET
 CONS. 2
 PEACE
BEFORE
AMI
 ASCOT
3
AFTER
Secondary prevention of CAD by ACEIs
QUIET
50
HOPE
4% Risk increase
RR 1.04 (0.89–1.22)
P=0.6
40
20
%
Patients
15
Quinapril
20 mg
30
20
Placebo
10
1
0
2
3
Ramipril
10 mg
10
PEP: CV death, MI, cardiac arrest,
revascularization, hospitalization for UA
0
Time
(years)
5
0
PEP: CV death, MI, stroke
1
0
2
EUROPA
14
12
10
8
6
20% Risk reduction
RR 0.80 (0.71–0.91)
P=0.0003
Placebo
PEP: CV death, MI, cardiac arrest
0
1
2
3
3
4
Time
(years)
PEACE
Perindopril
8 mg
4
2
0
Placebo
22% Risk reduction
RR 0.78 (0.70–0.86)
P=0.001
4
Time
5 (years)
30
4% Risk reduction
HR 0.96 (0.88–1.06)
P=0.43
%
25
Patients
20
Trandolapril
4 mg
Placebo
15
10
5
0
PEP: CV death, MI, revascularization
1
2
3
4
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.
5
Time
6 (years)
Meta-analysis of 32 000 patients
Relative risk reduction and 95% CI
ACEI Placebo
0.87
Total mortality
7.5% 8.6%
0.82
CV mortality
4.1% 5%
0.83
MI
6.4% 7.7%
0.85
0.85
Death & MI
8.7% 10%
0.5
0.75
ACE better
1
1.25
1.5
Placebo better
Meta-analysis of 32 000 patients
Relative risk reduction and 95% CI
ACEI Placebo
0.74
Heart failure
3.8% 5%
0.92
Revascularization
2.1% 2.7%
0.74
Stroke
0.5
0.75
ACE
better
10.5% 11.3%
1
1.25
Placebo
better
MI occurrence in ARB trials
Incidence of AMI in ONTARGET
No statistical difference between groups,
but …
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
Atherosclerosis
ACS
ACE activity and endothelial function

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 II
Bradykinin
which, in turn, impairs endothelial function
ENDOTHELIAL FUNCTION
Biologic end-points:
 eNOS activity
 % of apoptosis
Clinical end-points:
• Vasomotion to endothelial dependent
stimulation (Ach, Bradykinine, etc)
• von Willebrand factor
PERTINENT substudy (1175 pts)
von Willebrand factor
Significant prognostic role
CAD PERTINENT patients
baseline
300
1 year
1.0
Low (142% / Unit)
outcome
vWf (%/Unit)
p <0.01
200
Normal
Range
(44-158)
09
High (>142% / Unit)
p<0.01
0.8
100
0
0.7
Placebo Perindopril
Placebo Perindopril
0
1
2
3
Years
4
PERTINENT substudy (1175 pts)
Isolation of human
endothelium
Incubated (72 h) with serum from
Healthy subjects
EUROPA pts
ecNOS
Apoptosis
To mimic the effects of circulating blood on endothelial function
Apoptosis
PERTINENT
Analysis in cultured HUVECs
Effects of HUVEC incubation with serum from:
Controls
CAD PERTINENT patients
baseline
Apoptosis
20
1 year
P<0.01
P<0.05
10
0
Controls
n=45
Placebo Treated
n=43
n=44
Placebo Treated
n=43
n=44
#P=controls vs baseline
*P=perindopril vs placebo
Ceconi C et al. Cardiovasc Res. 2006
Endothelial apoptosis and atherosclerosis
Normal rate
of apoptosis: 3%
Excess rate of apoptosis
Maintenance of
endothelial layer
Endothelium
continuity
Protection against
atherosclerosis
Onset of atherosclerotic
Plaque erosion and rupture
WHY ?
 Different tissue affinity
 Different effects on the bradykinine
(anti-apoptoic) angiotensin (pro-apoptoic)
(ANTI) bradykinine angiotensin (PRO)
 Specific effects on typical apoptoic inducer:
TNF-
ACE Enzyme
ACE activity
Affinity Km
~1x10-4M
Catalytic rate kcat
~10 sec
Affinity Km
~1x10-6M
Catalytic rate kcat
~1 sec
Reaction Rate
~ 50 times faster
Bradikynin, and not Angiotensin I,
is the “natural” substrate for ACE
Bradykinin / Angiotensin II
Bradykinin
Controls
Angiotensin II
CAD PERTINENT
Controls
CAD PERTINENT
# p=controls vs baseline
‡ p=∆perindopril vs ∆placebo
0
baseline
20
1 year
p <0.05
p<0.01
15
0
12.5
5
14.4
10
17.1
18.0
12.3
14.8
5
12.4
10
‡
#
15.8
15
‡
10.8
1 year
p <0.01
p<0.01
18.3
Bradykinin (Pg/mL)
20
baseline
Angiotensin II (Pg/mL)
#
TNF- 
Controls
PERTINENT
CAD PERTINENT patients
40
TNF-a (pg/mL)
35
#
baseline
1 year
‡
30
p<0.01
p <0.05
25
20
27.7
15
10
27.1
28.9
24.6
18.0
5
0
#
‡
Controls
p=controls vs baseline
= 45
p= D perindopril vs Dnplacebo
Placebo Perindopril
n = 44
n = 43
Placebo Perindopril
n = 44
n = 43
ANGIO II
TNF α
Oxygen free radicals
RAS Blockade reduces
the incidence of cerebrovascular events
Trial
Drug
HOPE
Ramipril
PROGRESS
Perindopril
MOSES
Eprosartan
RAS Blockade reduces
the incidence of diabetes
Effect of Lisinopril in pts with AMI
GISSI-3 Study
HOPE and PEACE: new onset
diabetes
ACE-i
Placebo
12
10
8
11.5%
6
4
2
3.6%
5.4%
9.8%
0
HOPE
PEACE
HR 0.66 95% CI 0.51-0.85 HR 0.83 95% CI 0.72-0.96
p <0.001
p =0.014
Incident diabetes in clinical trials
of antihypertensive drugs:
a network meta-analysis
Elliott WJ, et al. Lancet 2007;369(9557):201-7
RAS blockade reduces
the incidence
of atrial fibrillation (?)
Healey JS et al. JACC 2005; 45:1832-39
Time to first recurrence of AF
G
I
S
(n. 1442)
GISSI-AF
Valsartan: 371/722 (51.4%)
Placebo: 375/720 (52.1%)
Adjusted* HR 0.99
96%CI 0.85-1.15
P value 0.84
* The 96%CI was calculated by Cox proportional hazards model adjusted for ACE-I, amiodarone use,
cardioversion, PAD, CAD
RAS Blockade
improves
renal function
Modulatori RAS a confronto
•ACE-I hanno avuto spazi di applicazione
più aperti e successi più consolitati
•efficacia simile (bradichinina può essere un plus)
•Tollerabilità simile (in qualche trial ARB in vantaggio)
•Associazione ACE-I + ARB non vantaggiosa
(occasionalmente dannosa)
Evidence-based recommendations for
the blockers of the RAAS

Hypertension
ACE-I or ARBs

Heart failure
ACE-I
ARBs if ACE-I not tolerated
ACE-I plus ARBs

Myocardial infarction

Renal dysfunction

Prevention of CV events

Atrial fibrillation

Prevention of diabetes
ACE-I or ARBs
Combination not recommended
ACE-I or ARBs
Combination???
ACE-I or ARBs
Combination not recommended
Primary prevention: ???
Secondary prevention: not recommended
ACE-I? ARBs? Both ?
The fallacy of surrogate end-point:
Albuminuria
•In ONTARGET albuminuria was reduced by
a combination of telmisartan and ramipril,
but serum creatinine and dialysis rate
doubled.
•In a diabetic subgroup (~ 700 pts) with
overt (≥ 300 mg/g creatinine) proteinuria
and fast loss of GFR, dual RAS blockade
had no significant effect on renal outcome.
END
Kunz R et al. Ann Intern Med 2008; 148:30-48
Ratio of means (95% CI)* for change in
proteinuria, by randomized therapy, over
two follow-up intervals
Randomized therapy Over 1-4 mo
Over 5-12 mo
ARBs vs placebo
0.57 (0.47–0.68)
0.66 (0.63–
0.69)
0.99 (0.92–1.05)
1.08 (0.96–
1.22)
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)
ARBs vs ACE-I
ARBs vs CCBs
ACE-I=angiotensin-converting-enzyme inhibitor
ARB=angiotensin-receptor blocker
CCB=calcium-channel blocker
*Ratio of means=ratio of the average treatment effect in the intervention group
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
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

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