v. gerc clinic for heart disease and rheumatism sarajevo advantages of renin-angiotensin system...
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V. GercClinic for Heart Disease and
RheumatismSarajevo
Advantages of renin-angiotensin system blockade in the treatment
of cardiovascular disease
The cardiovascular continua in cardiovascular disease
The pathophysiological continua incardiovascular disease
Angiotensin II is central to atherosclerotic mechanisms
Oxidative Stress Inflammation
Endothelial dysfunction Tissue remodelling
Vascular permeability ↑ Leucocyte infiltration ↑
Activation of signalling pathways
Production of inflammatory mediators
Proliferation of VSMCs
Matrix deposition
MMP activationPlatelet aggregationPAI-1 activation
Vasoconstriction
Nitric oxide ↓
LDL peroxidation ↓
LDL peroxidation ↑
Reactive oxygen species ↑
NAD(P)H oxidase activity ↑
Angiotensin II
Schmieder et al. Lancet 2007;369:1208−1219
Vascular Risk Factors and Endothelial Dysfunction
Role of oxidative stress:
Hypertension
Angiotensin II Smoking
Diabetes
Homocysteine
oxLDL
Endothelial Dysfunction
-Bradykinin/NO
mod. from Gibbons GH, Clin Cardiol 20 (1997)
- Antioxidants (?)
oxidative stress
Long-term cardiovascular effects of angiotensin II
Metabolism of the Renin-Angiotensin System
Component Half-life in circulation Degrading enzyme(s)
Renin 15–20 min —
Angiotensinogen 4–16 h Renin
Angiotensin I 1–2 min Angiotensin-converting enzyme
Angiotensin II Seconds Aminopeptidase A, endopeptidase,
Prolylcarboxy-peptidase
Mechanism of action of angiotensin-converting enzyme inhibitors
EFFECTS OF ANGITENSIN II
vasoconstriction (”afterload” ) reabsorption of Na+ and water (“preload” ) coronary constriction
syntesis of cellular proteins (HLV)
fibroblastic hyperplasia (myocardial fibrosis)
apoptosis of myocites
diastolic dysfunction of the heart
EFFECTS OF ANGIOTENSIN II
endothelial dysfunction
PAI-1 ( fibrinolysis)
tissue factor
proliferation and migration of smooth
muscles
sympathetic, vagal activity
adrenocortex ( catecholamine, aldosterone)
Potential pathogenic propertiesof Angiotensin II
• Heart• Myocardial hypertrophy• Interstitial fibrosis
Potential pathogenic propertiesof Angiotensin II
• Coronary Arteries
• Endothelial dysfunction with decreased release of nitric oxide
• Coronary constriction via release of noradrelanine
• Increased oxidative stress; oxygen derived free radicals formed via NADH
• Promotion of inflamatory response and atheroma
Potential pathogenic propertiesof Angiotensin II
• Kidneys• Increased intraglomerular pressure• Increased protein leak• Glomerular growth and fibrosis• Increased sodium reabsorption
Potential pathogenic propertiesof Angiotensin II
• Adrenals• Increased formation of aldosterone
Potential pathogenic propertiesof Angiotensin II
• Coagulation system• Increased fibrinogen• Increased PAI-1
Inhibition of the RAS
• Inhibition of the RAS is established for the treatment and now prevention of a wide range of cardiovascular disease. The basic concept hinges on the adverse effects of excess angiotensin II and increase protective bradykinin.
Renin – Angiotensin - Aldosterone system:where inhibitors act
Dual role of ACE inhibitors, both preventing and treating cardiovascular disease
Pharmacodynamic effects of ACEI
Hemodynamic: vasodilation (AII, BK, PGI, NO)Sympatholytic: Ach NAEndothel: PGI, NO, AII, endothelinAntiproliferative: AII, aldo, c-fos, c-mycAntithrombotic: PAI-1Antiatherogenic: the above + antioxidants
Indications for ACEI, based on trial data
• 1.Heart failure, all stages• 2. Hypertension• 3.AMI, postinfarct LV dysfunction• 4.Nephropathy, nondiabetic and diabetic• 5. Diabetes type 2, lessens new
microalbuminuria and LV hypertrophy
ACE
Blood pressure
Oxidative stress
Inflammation
Endothelian dysf.
Nitric oxide
Growth of the plaque
Fibrinolysis
tPA
PAI-1
Re
du
ction
of
card
iov
asc
ula
r eve
nts
Antiatherosclerotic effect of LISINOPRIL
Pleiotropic effects of renin-angiotensin system blockers
Pleiotropic effects
Statins ACEI
Early effects(hours, days)
LDL,TG;HDLNOS, O-
AII, BK, PGO-
Intermediaryeffects (weeks)
Viscosity Tr aggregation
PAI-1
Fibrinolysis Tr activation
BMP-2
Late effects(months)
Cell migration, proliferation;
stabilisation of the plaque
Cell migration, proliferation;
stabilisation of the plaque
Angiotensin-converting enzyme inhibitors in hypertensive patients at high cardiovascular risk
ACEI
ACE inhibitors in hypertension
• ACEI are effective as monotherapy in BP reduction in most patients. There are few side effects and contraindication
ACE inhibitors in hypertension
• A particulary attractive combination is that with diuretics, because diuretics increase circulating renin activity and angiotensin II levels, wich ACEI counterregulate by inhibiting the conversion of angiotensin I to angiotensin II.
RAAS, ACEIs, and ARBs: Summary
• RAAS is a major regulator of CV and renal function
• RAAS blockade – Reduces BP– Exerts antiatherosclerotic effects– Delays or avoids onset of T2DM
• ACEIs and ARBs are the major RAAS blockers in use
• ACEIs do not inhibit Ang II formation by non-ACE pathways
• ACEIs block AT1 and AT2 receptors, whereas ARBs inhibit AT1 receptors and leave AT2 receptors open for stimulation
Schmieder RE et al. Lancet. 2007;369:1208-19.
Role of ARB in the treatment of cardiovascular diseases, with a
special reference to LOSARTAN
Arguments favoring development of ARBs
• ACE inhibitors are not specific
• ACE inhibitors do not provide
complete blockade of RAS
• Alternative pathways for angiotensin
II formation
• Significant incidence of cough
Arguments favoring development of ARBs
• ACE inhibitors are not specific
• ACE inhibitors do not provide
complete blockade of RAS
• Alternative pathways for angiotensin
II formation
• Significant incidence of cough
Angiotensin II formation in the heart mediated by chymase v.s. formation mediated by angiotensin
converting enzyme
Balcells E, et al. Am J Physiol. 1997;273:H1769–H1774.
A II fo
rmati
on, %
Mouse
Rabbit
Rat Dog Human
0
40
60
80
100
20
ACE mediatedChymase mediated
“Escape” of angiotensin II despite ACE inhibition
Biollaz J, et al. J Cardiovasc Pharmacol. 1982;4(6):966-972.
Plasma Ang II(pg/mL)
Plasma ACE(nmoL/mL/min)
*
********
0
10
20
30
Placebo 4 h 24 h 1 2 3 4 5 6
Hospital Months
020406080
100
*P <.001 vs placebo
Inhibition of the RAS
• ARBs directly block the angiotensin II receptor (AT1), thereby largely avoiding the side effects of excess bradykinin such as cough and angioedema.
Mechanism of action of angiotensin receptor blockers
Effects of Angiotensin II upon AT1 i AT2 receptors
AT2AT1
VasoconstrictionAldosteron releaseOxidative stressVasopresin release Activation of SNS Inhibition of renin release Renal reabsorption of Na+ i H2OCell growth and proliferation
VasodilationAntiproliferative effectApoptosisAntidiuresis/antinatriuresisBradykinin formationRelease of NO
Siragy H. Am J Cardiol. 1999;84:3S-8S.
ARBs currently available for clinical use
Generic name Trade name Drug company
LosartanLosartan H
TenlopTenlop H
Bosnalijek
Valsartan Diovan, Tareg, Nisis
Novartis
Irbesartan Aprovel, Avapro, Karvea
Bristol-Myers, Squibb, Sanofi
Candesartan Atacand, Kenzen, Blopress
AstraZeneca/ Takeda
Telmisartan Micardis, Pritor Glaxo Smith Kline
Eprosartan Teveten Glaxo Smith Kline
Olmesartan Benycar, Daiichi Sankyo
Pharmacology of Angiotensin Receptor Blockers
Drug Half-life, h
Bioavailabili
ty %
Volume of distributio
n
Renal/hepatic
clearance, %
Candesartan 9 15 0.13 L/kg 60/40
Eprosartan 5 13 13 L 30/70
Irbesartan 11–15 60–80 53–93 L 1/99
Losartan 2 33 34 L 10/90
E-3174 6–9 − 12 L 50/50
Olmesartan 10–15 28 17 L 45/55
Telmisartan 24 42–58 500 L 1/99
Valsartan 6 ∼25 17 L 30/70
ARBs currently available for clinical use
Drug Recommended initial dosage
Dosage range Tablet/capsule
Losartan,Tenlop
50 mg once daily 25-50 mg, once daily, or 100 mg once daily
tablet12,5, 50, 100 mg
Valsartan 80 mg once daily 80-320 mg once or twice daily
capsule80,160 mg .
Irbesartan 150 mg once daily 150-300mg once daily
tablet75,150, 300 mg
Candesartan 8 mg once daily 8-16 mg once or twice daily;32 mg once daily
tablet4,8,16,32 mg
Eprosartan 400 mg once daily 400-800 mg once daily
tablet200, 400 mg
Telmisartan 40 mg once daily 40-80 mg once daily
tablet 40,80 mg
Olmesartan 20 mg once daily 20-40 mg once daily tablet 20,40 mg
ARBsIndications
• Hypertension• Heart failure• Secondary prevention following
myocardial infarction• Diabetic nephropathy• Proteinuria/microalbuminuria• Left ventricle hypertrophy• Atrial fibrilation• Cough caused by ACEI
Losartan and hypertension
Studies with Losartan
The Losartan Heart Failure n=722
Study (ELITE)
The Losartan Hypertension n=9194
Survival Study (LIFE)
The Losartan Heart Failuren=3152
Survival Study (ELITE II)
The Losartan Post-MI Survival n=5000
Study (OPTIMAAL)
The Losartan Renal Protectionn=1520
Study (RENAAL)
19,588
Comparison of efficacy of candesartan and losartan in the
treatment of hypertension : results at trough
-20
-16
-12
-8
-4
0
4
SPmmHg
Plac Los CC CC 50 8 16
*
**
* p<0.001 vs plac ; # p>0.05 vs Los-20
-16
-12
-8
-4
0
4
DPmmHg
Plac Los CC CC 50 8 16
**
* #
85 83 82 84n
Andersson, 1998
Comparison of efficacy of candesartan and losartan in the treatment of hypertension : results at peak
Andersson, 1998
-20
-16
-12
-8
-4
0
4
-20
-16
-12
-8
-4
0
4
DPmmHg
SPmmHg
Plac Los CC CC 50 8 16
Plac Los CC CC 50 8 16
**
*
*
*
*
* p<0.001 vs plac 85 83 82 84n
Comparison of efficacy of ARBs and amlodipine in the treatment of mild and
moderate hypertension
mmHg
mmHg
-16
-12
-8
-4
0
-16
-12
-8
-4
0
-16
-12
-8
-4
0
-16
-12
-8
-4
0
Los 50 Amlo 10 Vals 80 Amlo 5
Irbe 75 - 300 Amlo 2.5 - 10 CC 8 Amlo 10 Plac
SP
DP
Comparison of efficacy of ARBs and enalapril in the treatment of mild and moderate
hypertension
mmHg
-16
-12
-8
-4
0
-16
-12
-8
-4
0
mmHg
-16
-12
-8
-4
0
-16
-12
-8
-4
0Los 50 Enal 20 Vals 80 Enal 20
Irbe 75-300 Enal 10- 40 CC 4- 8 Enal 10-20
SP
DP
Comparison of efficacy of ARBs and hydrochlorothiazide in the treatment of
hypertension
-16
-12
-8
-4
0
-16
-12
-8
-4
0
0
-16
-12
-8
-4
Los 50 HCTZ 12.5 Vals 80 HCTZ 25
CC 8 HCTZ 25
mmHg
mmHg
SP
DP
Comparison of efficacy of ARBs and atenolol in the treatment of mild and moderate
hypertension
mmHg
-14
-12
-10
-8
-6
-4
-2
0
Los 50 Atenolol 50
SP
DP
-14
-12
-10
-8
-6
-4
-2
0
Irbes75-150
Atenolol50-100
Dijastolni P.
Angiotensin receptor blockers and hypertension: meta-analysis
Meta-analysis of CV events with ARBsvs comparators
BPLTTC. Lancet. 2003;362:1527-35.
Blood Pressure Lowering Treatment Trialists’ Collaboration4 trials; N = 16,791
Relative risk of event with ARB vs comparator
Stroke CHD Heart failure Major CV event
1.2
1.0
0.8
0.6
Efficacy vs. Tolerability
AT1- Receptor Antagonists
DOSETherapeuticWindow
Tolerability
Efficacy
excellent
low
50 %
Compliance With Antihypertensive
Treatment at 1 Year
38
43
50
58
*64
Co
mp
lian
ce a
t 1
Yea
r (%
)
ThiazideDiuretics
BetaBlockers
CCBs ACEInhibitors
ARBs
35
40
45
50
55
60
65
0
ARBs: Evolution of protective benefits
↓BP
↓Stroke
↑Glycemic control
↓Heart failure
↓Renal dysfunction
↓CHD (?)
ARBs: Evolution of protective benefits
↓BP
↓Stroke
↑Glycemic control
↓Heart failure
↓Renal dysfunction
↓CHD (?)
Combination antihypertensive therapy and cardiovascular event rate: amlodipine and
renin-angiotensin system blockade
Baseline Control Rates37.2 37.9
ACCOMPLISH: Exceptional Control Rates with Initial Combination Therapy
ACEI / HCTZN=5733
Co
ntr
ol
rate
(%
)
CCB / ACEIN=5713
10
20
30
40
50
60
70
80
9078.5
81.7
P<0.001 at 30 months follow-up Control defined as <140/90 mmHg
Kaplan Meier for Primary Endpoint
Cum
ulat
ive
even
t ra
te
HR (95% CI): 0.80 (0.72, 0.90)
20% Risk Reduction
Time to 1st CV morbidity/mortality (days)
p = 0
ACEI / HCTZ
CCB / ACEI650
526
.0002
I
0.5 1.0 2.0
Primary Endpoint and Components
Composite CV mortality/morbidity
Cardiovascular mortality
Non-fatal MI
Non-fatal stroke
Hospitalization for unstable angina
Coronary revascularization procedure
Resuscitated sudden death
Risk Ratio(95%)
Favors CCB / ACEI
Favors ACEI / HCTZ
0.80 (0.72–0.90)
0.81 (0.62-1.06)
0.81 (0.63-1.05)
0.87 (0.67-1.13)
0.74 (0.49-1.11)
0.85 (0.74-0.99)
1.75 (0.73-4.17)
Clinical trials of RAAS manipulation with ARBs
CAD/MI
VALIANTOPTIMAALVal-PREST
Hypertension
VALUESCOPETROPHYLIFE
CHF
ELITE 1 and 2Val-HEFTCHARM
Stroke
SCOPEMOSES
Dzau V. J Hypertens. 2005.Dahlof B. Am J Cardiol. 2007.
Barnett AH et al. N Engl J Med. 2004.Bakris G et al. ASH 2007 Scientific Sessions.
Diabetes and/or renal disease
RENAAL ABCD-2V AMADEOIDNT DETAILIRMA-2 MARVAL
LIFE study• The Losartan Intervention For Endpoint reduction in
hypertension study
• Prospective, multinational, double-blind, controlled, random study, intention-to-treat study
• 9.193 patients with hypertension and ecg signes of LVH
• Losartan compared to atenololom
Dahlöf B. et al, Lancet 2002.; 359:995-1003.
LIFE: Losartan and atenolol reduced comparably blood pressure
Systolic
Diastolic
Mean arterial pressuremm
Hg
180
160
140
120
100
40
80
60
Duration (months)
423624 3012 1860 48 54
Dahlöf B et al Lancet 2002;359:995–1003.
AtenololLosartan
Composite of CV Death, Stroke and MI
Pro
port
ion
of P
atie
nts
with
Fir
st E
vent
(%
)0
2
4
6
8
10
12
14
16
0 6 12 18 24 30 3642 48 5460 66
Adjusted Risk Reduction: 13.0%, P = 0.021
Months
LIFE: LVH Regression and Primary Endpoint
Ch
ang
e fr
om
Ba
selin
e (
%)
-18
-16
-14
-12
-10
-8
-6
-4
-2
0
P < 0.0001
P < 0.0001
4.4%
10.2%
15.3%
9.0%
LosartanAtenolol
Dahlöf B et al. Lancet. 2002;359:995-1003.
Cornell Voltage-Duration Product
Sokolow-LyonVoltage
LIFE – significant regression of LVH in
comparison to baseline values
-18
-16
-14
-12
-10
-8
-6
-4
-2
0
Cornell Product Sokolow-Lyon
Mea
n ch
ange
s in
the
bas
elin
e va
lues
(%
)
losartan
atenolol
p<0.0001
10.2 %
9.0 %
15.3 %
4.4 %
p<0.0001
Reduction of left ventricular mass stratified according to various antihypertensive regimens
Klingbeil et al Am J Med 2003
reduction in left ventricular mass LV (%)
Diuretics Beta-blockers
Calciumantagonist
*
ACEinhibitors
**
ARBs
*
*p<0.05; **p<0.001 vs beta-blocker
0
5
10
15
20
0
2
4
6
8
10
12
14
16
% o
f p
ati
en
ts w
ith
th
e f
irs
t s
ign
es
of
hy
pe
rte
ns
ive
co
mp
lic
ati
on
sCardiovascula death, stroke and myocardial
infarction miokarda
Losartan
Atenolol
Months 0 6 12 18 24 30 36 42 48 54 60 66
Losartan (n) 4605 4524 4460 4392 4312 4247 4189 4112 4047 3897 1889 901Atenolol (n) 4588 4494 4414 4349 4289 4205 4135 4066 3992 3821 1854 876
Adjusted risk reduction 13.0%, p=0.021Non-adjusted risk reduction 14.6%, p=0.009
Dahlöf B i sur. Lancet 2002;359:995-1003.
No. of patients with risk
13%
Losartan reduces CV complications with equal antihypertensive efficacy
Losartan
Atenolol
Adjusted risk reduction 24.9%, p=0.001Non-adjusted risk reduction 25.8%, p=0.0006
Months 0 6 12 18 24 30 36 42 48 54 60 660
1
2
3
4
5
6
7
8
Dahlöf B i sur. Lancet 2002;359:995-1003.
Losartan 4605 4528 4469 4408 4332 4273 4224 4166 4117 3974 1928 925Atenolol 4588 4490 4424 4372 4317 4245 4180 4119 4055 3894 1901 897
Stroke with and without death
% o
f p
ati
en
ts w
ith
th
e f
irs
t s
tro
ke
25%
Losartan reduces more efectively stroke with equal antihypertensive efficacy
Angiotensin receptor blockers and stroke risk
MOSES: ARB surpasses CCB for secondary stroke prevention
Schrader J et al. Stroke. 2005;36:1218-26.
N = 1405 with HTN and prior cerebral event
-21
-25 -25-30
-25
-20
-15
-10
-5
0
Primary compositeoutcome*
*Cerebrovascular, CV events, and all-cause death †Events per 100 person-years, including recurrent events
Fatal/nonfatalCV events
Fatal/nonfatalstroke
RRR Eprosartan vs nitrendipine†
(%)
P = 0.014
P = 0.061 P = 0.026
Meta-analysis of CV events with ARBsvs comparators
BPLTTC. Lancet. 2003;362:1527-35.
Blood Pressure Lowering Treatment Trialists’ Collaboration4 trials; N = 16,791
Relative risk of event with ARB vs comparator
Stroke CHD Heart failure Major CV event
1.2
1.0
0.8
0.6
Intention-to-Treat
LIFE: New Onset Diabetes
Losartan
Atenolol
En
dp
oin
t R
ate
Study Day 0 180 360 540 720 900 1080 1260 1440 1620 1800 19800.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.10
Adjusted Risk Reduction 25%, p<0.001Unadjusted Risk Reduction 25%, p<0.001
B Dahlof et al. Lancet 2002;359:995-1003
Months 0 6 12 18 24 30 36 42 48 54 60 66Losartan (n) 586 569 558 548 532 520 513 501 484 459 237 127Atenolol (n) 609 588 562 552 540 527 507 486 472 434 204 99
24
20
16
12
8
4
0
LH Lindholm, et al Lancet 2002; 359:1004-1010
Atenolol n= 139 (23%)
Losartann= 103 (18%)
Cardiovascular death, stroke and myocardial infarction in diabetics
25%
Adjusted risk reduction = 24,5%; p=0,031Non- adjusted risk reduction = 26,7%; p=0,017
% o
f p
ati
en
ts w
ith
th
e
firs
t o
ns
et
of
co
mp
lic
ati
on
s
0 6 12 18 24 30 36 42 48 54 60 66
Study Month
Pro
po
rtio
n o
f p
atie
nts
, %
24
20
16
12
8
4
0
RRR 39%
p = 0.002
LIFE: Diabetes Subgroup (n = 1195) Total Mortality
(secondary endpoint)
Losartan
Atenolol
(from Lindholm LH et al., Lancet 359: 1004-1010, 2002)
The role and importance of Losartan in the treatment of diabetic nephropathy with
proteinuria
Lewis EJ et al. N Engl J Med 1993;329:1456-1462.
Progression to death,
dialysis or transplant
(%)
Captopril
Placebo
Follow-up (y)0 1 2 3 4
0
10
20
30
40
*
Effect of ACE Inhibition on Nephropathy in Patients with Type 1 Diabetes
Collaborative Study Group* p = 0.006 vs placebo.
M e ta - re g re s s io n a n a ly s is o f 1 0 0 s tu d ie s to ta l in g 2 ,4 9 4 p a t ie n tsw ith ty p e 1 a n d t y p e 2 d ia b e te s .* p < 0 .0 5 v s c a lc iu m c h a n n e l b lo c k e rs .† p < 0 .0 5 v s c o n tro l.
E ffe c t o f B P R e d u c t io n v s A C E In h ib it io n o n P ro te in u r ia a n d R e n a l F u n c t io n in P a t ie n ts w ith D ia b e te s
K a s is k e B L e t a l. A n n In te rn M e d 1 9 9 3 ;1 1 8 :1 2 9 -1 3 8 .
Renal protection beyond RR ?
RR
Risk ESRF
Other drugs
ACEIor
ARB
DHP- Ca Antag.
Intraglomerular pressure may stay unchanged
DHP- CaAntag
Ang II
Dilation ofafferentarteriole
RR
Reduction of intraglomerular pressure
ACEI or ARB
Ang II
RR
Dilation of efferent
artheriole
Studies with ARBs in diabetics
RENAAL (Reduction in Endpoints in NIDDM with Angiotensin II Antagonist Losartan)
IDNT (Irbesartan in Diabetic Nephropathy Trial)
IRMA2 (Irbesartan Micro-Albuminuria type 2 diabetes mellitus in hypertensive patients
RENAAL study
The Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan Study
Brenner BM et al. N Engl J Med 2001; 345(12):861-869.
Brenner BM et al J Renin-Angio-Aldo System 2000;1(4):328-335.
RENAALProgression of renal disease
Losartan Placebo0
-.02
-.04
-.06
-.08
dl/m
g/ye
ar -0.056
-0.069
p=0.0118% reduction
Brenner BM et al New Engl J Med 2001 ;345(12):861-869.
RENALL – Results
Patients in the losartan group had a reduction in proteinuria of 35%, while the patients in the placebo group had an increase in proteinuria (P=<0.001)
Brenner et al. NEJM. 2001.
RENALL – Conclusions
• Losartan has renoprotective effects by reducing risk of doubling creatinine AND by reducing progression to ESRD
• Losartan reduces episodes of CHF
• Effects reported as independent of blood pressure
ARBs decrease renal complications in T2DM
ESRD/Cr 2/all deaths:16% vs placebo (P = 0.02)
Losartan/ placebo
Nephropathy(1513)
RENAAL
UAER at 24 weeks: 44% valsartan vs 8% amlodipine (P < 0.001)
Valsartan/amlodipine
Microalbuminuria(332)
MARVAL
ESRD/ Cr 2/mortality: 20% vs placebo (P = 0.02) 23% vs amlodipine (P = 0.006)
Irbesartan/amlodipine/placebo
Nephropathy(1715)
IDNT
Time to nephropathy: 39% (150 mg, P = 0.08) 70% (300 mg, P < 0.001)
Irbesartan150/300 mg vs placebo
Microalbuminuria(590)
IRMA-2
Primary outcomeTreatmentT2DM (N)
Adapted from Sharma AM. Hypertension. 2004;44:12-19.Cr = creatinineUAER = urinary albumin excretion rate
Combination treatment
• ACEI+ARB: different mechanisms of action make combination treatment useful owing to complete RAS blockade,
CALM
Objectives: To assess and compare the effects of candesartan or lisinopril, or both, on blood pressure and urinary albumin excretion in patients with microalbuminuria, hypertension, and type 2 diabetes
Design: 12 weeks' monotherapy with candesartan or lisinopril followed by 12 weeks' monotherapy or combination treatment199 patients aged 30-75 yearsCandesartan 16 mg od or lisinopril 20 mg
Outcome: Blood pressure and urinary albumin:creatinine ratio
(Candesartan And Lisinopril Microalbuminuria study)
CALM Mean difference at week 24
Candesartan Lisinopril Combination
Sitting DBP (mm Hg) 10.4 10.7 16.3
Sitting SBP (mm Hg) 14.1 16.7 25.3
Urinary albumin/creatinine ratio (%) 24 39 50
Mogensen et al. BMJ 321; 1440
p=0.005p=0.003
p=0.002p=0.02
p=0.04p>0.20
CALM
• Conclusions– Candesartan 16 mg od has similar effect to
lisinopril on BP and microalbuminuria in hypertensive patients with type 2 diabetes
– Combination treatment ACEI+ARB is more effective than either monotherapy at reducing BP and urinary albumin/creatinine ratio
Mogensen et al. BMJ 321; 1440
Pharmacokinetic differences between angiotensin-converting enzyme inhibitors and angiotensin
receptor blockers in renal failure Parameter ACE
inhibitorsAngiotensin receptor
antagonists
Proteinuria ↓↓ ↓↓
Uric acid ↓ ↓↓
Glomerular filtration rate ↓↓ ↓↓
Hyperkalemia ↑↑ ↑
Blood pressure reduction ↓↓ ↓↓
Systemic accumulation Yes No
AT2-receptor stimulation
Possibly ↑↑
Renal and Pharmacokinetic Aspects of ACE Inhibitor and Angiotensin Receptor Antagonist
Therapy in End-stage Renal Disease Parameter ACE
inhibitorsAngiotensin receptor
antagonists
Angioneurotic edema Yes Yes, but much less frequently
Dialyzer reactions Yes No
Residual renal function ↓↓ ↓↓
Dialyzability Yes No
Hyperkalemia ↑↑ ↑↑
Blood pressure reduction ↓↓ ↓↓
Systemic accumulation Yes No
AT2-receptor stimulation
Possibly ↑↑
Landmark studies with ACEI and ARBs and clinical significance of RAAS blockade in hypertension, coronary disease, MI and heart failure
Reduction of mortality (%)
7
12
29
1922
27
0
5
10
15
20
25
30
35
GISSI-3 SMILE SAVE TRACE AIREISIS-4
ACEI in post-MI
> 100 000 patients !
ACEI in early phase AMI
• ACE inhibitors achieve a modest but statistically significant reduction in mortality ( 6% to 11%). Best results are obtained in higher risk patients treated long term, such as those with large infarcts, in whom ACEI give a striking reduction of 26% in mortality
ACE Inhibitors• ACEI in patients with heart failure
reduce– morbidity– mortality
• ACEI in sedondary prevention of MI reduce
– morbidity– mortality
– - development of HF
Studies: CONSENSUS, SOLVD, SAVE, AIRE, ISSIS-4
ARBs and chronic heart failure
®
Studies of ARBs in chronic heart failure
ELITE
ELITE II
Val-HeFT
CHARM
ELITE study
• Application of 50 mg losartan, in comparison with captopril, in patients with heart failure reduced mortality by 46% and sudden cardiac death by 64%
ARBs and heart failure
• ARBs have been tested in an era when ACE inhibitors were already the established therapy of choise for heart failure. Had the ARBs come earlier, they would probably have been first choise.
Combination therapy with ACE inhibitors and
ARB• Adding the ARB to the ACEI gave better
results in more severe heart failure with the mean ejection fraction about 25% (Val-HeFT and CHARM trials). In diabetes and diabetic renal disease, the combination is advised when monotherapy fails to reduce proteinuria sufficiently.
Indication and evidence forcombining ACEI and ARB
Indication Indication for dual RAS inhibition
Hypertension Not standard, possibly in LVH, microalbuminuria, DM
Systolic heart failure Yes, when symptoms persist despite diuretic, beta blocker, and ACEI
Post myocardial infarction No
Nephroprotection (diabetics) Yes
Nephroprotection (non -diabetics) Da
ONgoing Telmisartan Alone and in combination
with Ramipril Global Endpoint Trial
The telmisartan trial in cardiovascular protection
Sponsored by Boehringer Ingelheim
ONgoing Telmisartan Alone and in combination
with Ramipril Global Endpoint Trial
The telmisartan trial in cardiovascular protection
Sponsored by Boehringer Ingelheim
Indication and evidence forcombining ACEI and ARB
Indication Indication for dual RAS inhibition
Hypertension Not standard, possibly in LVH, microalbuminuria, DM
Systolic heart failure Yes, when symptoms persist despite diuretic, beta blocker, and ACEI
Post myocardial infarction No
Nephroprotection (diabetics) Yes
Nephroprotection (non -diabetics) Yes
Less new diabetes
• An important finding with ACE inhibitors and ARBs, especially when compared with beta blockers or diuretics, is the decreased developement of new diabetes.
Effect of ACEIs and ARBs on new-onset diabetes
Abuissa H et al. J Am Coll Cardiol. 2005;46:821-6.
Meta-analysis: 12 randomized controlled trials; N = 72,333 patients without 72,333 patients without T2DM at baselineT2DM at baseline
CAPPPSTOP-2
HOPELIFE
ALLHATANBP2SCOPEALPINECHARMSOLVDVALUEPEACE
All pooledACEI pooledARB pooled
0.125 0.25 0.5 1 2
Less likely to develop T2DM
Relative risk (95% CI)
More likely to develop T2DM
New-onset diabetes rate reduced by renin-angiotensin-aldosterone system modulation
Risk of new-onset diabetes in hypertension: comparison of antihypertensive drug classes
Drug related new diabetes
Inhibitors of renin-angiotensin-aldosterone system
• Several analyses of retrospective clinical trials suggest benefit of ACE inhibitors or AT1 blockers in prevention of atrial fibrillation, especially in patients with left ventricular hypertrophy or dysfunction.
Atrial Fibrillation (AF) - Primary Prevention
• In 2007 ESH / ESC guidelines recommendation to preferentially use ARBs / ACEIs
• Evidence mainly from post-hoc analyses
Atrial Fibrillation
• In a meta-analysis on almost 12.000 patients with systolic HF BBs were found to reduce (-27%) AF
• In patients with an AF history and systolic HF BBs are a specific indication
Angiotensin receptor blockers in atrial fibrillation: losartan versus atenolol
Pleiotropic effects of renin-angiotensin system blockers
Inhibitors of renin-angiotensin-aldosterone system
• Plasma aldosterone concentracions increase in patients with atrial fibrillation and atrial expression of the aldosterone receptor is higher in these patients than in those without the disorder.
Inhibitors of renin-angiotensin-aldosterone system
• Patients with primary hyperaldosteronism have a 12-fold greater risk of atrial fibrillation than do controls matched for blood pressure.
Inhibitors of renin-angiotensin-aldosterone system
• Hence blockade of aldosterone receptors could be a therapeutic option for patients with atrial fibrillation, but data from trials are not available.