“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

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.

The role

of timing

in science

ACEi vs ARBs

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

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

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.

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

MI Occurence in ACE-inh trials

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

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

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

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

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

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

Endothelial cells undergo suicide (apoptosis) and regenerate

When a mismatch occurs, the endothelium loses its continuity

Atherosclerosis ACS

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

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

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

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)

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

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

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)

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

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

# ‡# ‡

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

ANGIO II TNF α

Oxygen free radicals

RAS Blockade reduces the incidence of cerebrovascular events

TrialTrial

HOPEHOPE

PROGRESSPROGRESS

MOSESMOSES

DrugDrug

RamiprilRamipril

PerindoprilPerindopril

EprosartanEprosartan

RAS Blockade reduces the incidence of diabetes

GISSI-3 Study

Effect of Lisinopril in pts with AMI

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

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

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

RAS Blockade improves renal function

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)

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 ?

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.

END

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

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

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