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Peut-on aller encore plus loin
avec les antagonistes de l’Angiotensine II ?
Antoine Sarkis, MDAntoine Sarkis, MD
Associate Professor of Associate Professor of CardiologyCardiology
Hotel Dieu de France HospitalHotel Dieu de France Hospital
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RAAS Blockade
Angiotensin Converting
Enzyme Inhibitors
ACE-I
Angiotensin Receptor Blockers
ARBs
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Ang II: Influence on structure, function, and atherosclerosis
Weir MR, Dzau VJ. Am J Hypertens. 1999;12:205S-213S.
Angiotensin II
Growth
Smooth musclecell growth
and migration
Plateletaggregation
Endothelialdysfunction
Thrombosis
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Ang II effect in target organ Ang II effect in target organ damagedamage
McFarlane SI et al. Am J Cardiol. 2003;91(suppl):30H-7.
Angiotensinogen
Angiotensin I
Angiotensin II
Renin
ACE
Aldosterone(Adrenal/CV tissues)
Stroke HFKidneyfailure
BP
VSMC
Fat cells
Reduced baroreceptor sensitivity
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Angiotensinogen
Ang I ACE
Bradykinin
ATn
ReninRenin Inactivepeptides
Ang II
•Vasodilator•Anti-thrombotic•Anti-atherogenic
•Vasoconstriction•Hypertrophy•Angiogenesis•Apoptosis
Endothelium
SMC
AT2AT1
NO
B2
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Angiotensinogen
Ang I ACE
Bradykinin
ATn
ACEI
ReninRenin Inactivepeptides
Ang II
•Vasodilator•Anti-thrombotic•Anti-atherogenic
•Vasoconstriction•Hypertrophy•Angiogenesis•Apoptosis
Endothelium
SMC
AT2AT1
NO
B2
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Angiotensinogen
Ang I ACE
Bradykinin
ATn
ARBs
ReninRenin Inactivepeptides
Ang II
•Vasodilator•Anti-thrombotic•Anti-atherogenic
•Vasoconstriction•Hypertrophy•Angiogenesis•Apoptosis
Endothelium
SMC
AT2AT1
NO
B2
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Angiotensin IIAngiotensin II
ReninReninReninRenin
Converting enzymeConverting enzyme
AngiotensinAngiotensinreceptorsreceptors
AngiotensinAngiotensinreceptorsreceptors
AngiotensinogenAngiotensinogen
Angiotensin IAngiotensin I
Circulating(Liver)
Local(Tissue)
Non-renin pathways• t-PA• Cathepsin G• Tonin
Non-renin pathways• t-PA• Cathepsin G• Tonin
Non-ACE pathways• Chymase• CAGE• Cathepsin G
Non-ACE pathways• Chymase• CAGE• Cathepsin G
Escape phenomena
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ANGIOTENSIN II
Vasoconstriction Proliferative Action
Vasodilatation Antiproliferative Action
AT1 AT2 ….
AT1 Receptor Blockers
RECEPTORS
Angiotensin II Receptor Blockers (ARBs)
ATn
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• ARBs more effective than ACE-I due to:
- Better RAAS Blockade
- Absence of angiotensin II escape
- Placebo like side effects
Potential advantages of ARBsPotential advantages of ARBs
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Effects of A II at ATEffects of A II at AT11 and AT and AT22 Receptors Receptors
Sensitive to blockade by ARBs
AT2AT1
VasoconstrictionAldosterone releaseOxidative stressVasopressin releaseSNS activationInhibits renin release Renal Na+ & H2O reabsorptionCell growth & proliferation
VasodilationAntiproliferationApoptosisAntidiuresis/antinatriuresisBradykinin productionNO release
Siragy H. Am J Cardiol. 1999;84:3S-8S.
?
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Postulated role of ATPostulated role of AT22R and MMP-1 in R and MMP-1 in plaque destabilizationplaque destabilization
Strauss MH, Hall AS. Circulation. 2006;114:838-54.
Destabilization Rupture ACS
Extracellularmatrix
Leukocyteactivation
Vascular smooth muscle cells
Ang II
ARB
AT1
AT2
MMP-1
Intracellular inflammation
Endothelium
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ACEIs vs ARBs: Comparative effect on stroke, HF, and CHD
Turnbull F. 15th European Meeting on Hypertension. 2005.Adapted by Strauss MH, Hall AS. Circulation. 2006;114:838-54.
CHD = MI and CV death
Blood Pressure Lowering Treatment Trialists’ Collaboration meta-analysisN = 137,356; 21 randomized clinical trials
ACEI
ARB
Stroke -1% (9% to -10%)
HF 10% (10% to 0%)
CHD 9% (14% to 3%)
Stroke 2% (33% to -3%)
HF 16% (36% to -5%)
CHD -7% (7% to -24%)
30% 0 30%Decrease Increase
StrokeP = 0.6
HFP = 0.4
CHDP = 0.001
Risk
RRR (95%)
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Similar Similar
Greater Greater with with amlodipine amlodipine (2.0/1.6 mm Hg)(2.0/1.6 mm Hg)
Losartan Losartan vs atenololvs atenolol
Valsartan Valsartan vs vs amlodipinamlodipinee
Essential HTNEssential HTN
N = 9193N = 9193
(4.8 years)(4.8 years)
Essential Essential HTN, high CV HTN, high CV riskrisk
N = 15,245N = 15,245
(4.3 years)(4.3 years)
LIFE (2002)LIFE (2002)
VALUE VALUE (2004) (2004)
BPBPTreatmeTreatmentnt
Patients Patients
(Follow-(Follow-up)up)
Trial Trial (year)(year)
HTN = hypertension
13% 13% in primary outcome in primary outcome (CV death, MI, stroke) with (CV death, MI, stroke) with ARB (P = 0.021) driven by ARB (P = 0.021) driven by 25% 25% in stroke (P = 0.001) in stroke (P = 0.001)
No difference in CV death/MINo difference in CV death/MI
Primary outcome similar Primary outcome similar at study endat study end
Trend favors amlodipine Trend favors amlodipine at 3 and 6 monthsat 3 and 6 months
Difficult to interpret due Difficult to interpret due to BP differenceto BP difference
Dahlöf B et al. Lancet. 2002;359:995-1003. Julius S et al. Lancet. 2004;363:2022-31.
CV outcomes
Clinical trials of ARBs in HTN: CV outcomes
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Algorithm for Treatment of Hypertension Algorithm for Treatment of Hypertension (JNC 7) (JNC 7) JAMA, May 2003JAMA, May 2003
Not at Goal Blood Pressure (<140/90 mmHg) (<130/80 mmHg for those with diabetes or chronic kidney disease)
Initial Drug Choices
Drug(s) for the compelling indications
With Compelling Indications
Lifestyle Modifications
Stage 2 Hypertension 2-drug combination
for most
Stage 1 Hypertension Thiazide-type diuretics
for most.
May consider ACEI, ARB, BB, CCB, or
combination
Without Compelling Indications
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2003 ESH/ESC Hypertension Guidelines2003 ESH/ESC Hypertension Guidelines
Consider:Consider:
Untreated BP levelUntreated BP level
Presence or absence of TOD and risk factorsPresence or absence of TOD and risk factors
Choose between
Single agent at Single agent at low doselow dose
Two-drug combination Two-drug combination at low-doseat low-dose
Previous agent at Previous agent at full dosefull dose
Switch to different Switch to different agent at low doseagent at low dose
Previous combination Previous combination at full doseat full dose
Add a third drug at Add a third drug at low doselow dose
Two-to three drug Two-to three drug combinationcombination
Full dose Full dose monotherapymonotherapy
Three drug combination at Three drug combination at effective doseseffective doses
If goal BP not achieved
If goal BP not achieved
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Choosing drugs for patients newly diagnosed Choosing drugs for patients newly diagnosed with hypertensionwith hypertension
BHS Guidelines (June 2006)BHS Guidelines (June 2006)
Younger than 55 years55 years or olderOr black patients of any age
A C or D
A+C or A+D
A+C+D
Add •further diuretic therapy•Or alpha blocker•Or Beta Blocker•Consider seeking specialist advice
Abbreviations:
A: ACE-I (or ARB if ACE intolerant)
C: CCB
D: thiazide type diuretic
Step 1
Step 2
Step 3
Step 4
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Hypertension and DiabetesRecommendations of the American Diabetic
Association
• Treat to BP <130/80 mmHg
• All patients with diabetes and hypertension should be treated with a regimen that includes either an ACEi or an ARB.
• If needed to achieve blood pressure targets, a thiazide diuretic should be added.
American Diabetes Association. Diabetes Care. 2005; 28 (Suppl 1): S10 – S17.
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Conditions favoring the use of ARBs
Type 2 diabetic nephropathyType 2 diabetic nephropathy Diabetic microalbuminuriaDiabetic microalbuminuria ProteinuriaProteinuria Left ventricular hypertrpphyLeft ventricular hypertrpphy ACE-I induced coughACE-I induced cough
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Specific considerations about Candesartan
Pharmacological propertiesPharmacological properties Delaying new onset of hypertension Delaying new onset of hypertension
in pre-hypertensive patientsin pre-hypertensive patients Preventing diabetesPreventing diabetes End Organ protective effects (CHF)End Organ protective effects (CHF)
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Pharmacological propertiesPharmacological properties
1. Candesartan binds unsurmountably to AT1 receptor1. Candesartan binds unsurmountably to AT1 receptor
2. Longest lasting AT1-receptor binding 2. Longest lasting AT1-receptor binding ►►T/ P Ratio almost T/ P Ratio almost 100%100%
In the latest JNC 7:In the latest JNC 7:Candesartan 8-32 mg Once dailyCandesartan 8-32 mg Once daily
Losartan 25-100 mg Once to Twice dailyLosartan 25-100 mg Once to Twice daily
Valsartan 80-320 mg Once to Twice dailyValsartan 80-320 mg Once to Twice daily
JNC 7, Hypertension, 2003JNC 7, Hypertension, 2003
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Use in pre-hypertensive Use in pre-hypertensive patients?patients?
TROPHYTROPHY hypothesis hypothesis The TRial Of Preventing HYpertension
(TROPHY) is an investigator-initiated trial.
Aim: To examine whether early treatment of high-normal blood pressure values (according to JNC VI) with 16 mg Candesartan would prevent or postpone the development of stage 1 hypertension.
Julius et al, Hypertension 2004Julius et al, Hypertension 2004
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TROPHYTROPHY – study design – study design
Two Years Two Years
Qualifying period*
Placebo
Non-pharmacological treatment
Non-pharmacological treatment
Candesartan cilexetil16 mg
n 400
n 400
Placebo
Placebo
*Clinic BP reading of 130-139/ 89 mm Hgor 139/85-89 mm Hg
Julius et al, Hypertension 2004
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40,4
63,0
13,6
53,2
0
20
40
60
80
Year 2 Year 4
Patients (%)
Placebo Candesartan 16 mg qd
TROPHY: Reduction in new-onset hypertension
66%*
16%*
Candesartan vs Placebo Placebo only
*Relative risk reduction†P < 0.001; ‡P = 0.007 Julius S et al. N Engl J Med. 2006;354:1685-97.
†
‡
N = 772
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Adipocyte and vasculature interactions
Courtesy of W. Hseuh; 2005.
IL-6
PAI-1TNF-
AdiponectinLeptin
Insulin sensitivity Insulin resistance
Vascular inflammation Endothelial dysfunction
Angiotensinogen
FFA
Visfatin
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Furuhashi M et al. Hypertension. 2003;42:76-81.
• Insulin sensitivity, BMI, and HDL-C independent determinants of adiponectin concentrations
• ACEI and ARB increased insulin sensitivity and adiponectin (P < 0.05)
• Changes in insulin sensitivity correlated with changes in adiponectin (r = 0.59, P < 0.05)
*P < 0.05
N = 16 with essential hypertension and insulin resistance
RAAS blockade increases RAAS blockade increases adiponectinadiponectin
6
4
10
Adiponectin(µg/mL)
0
8
2
Before After Before After
6
4
10
0
8
2
Temocapril 4 mg(n = 9)
Candesartan 8 mg(n = 7)
*
*
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Candesartan in preventing Candesartan in preventing Diabetes development…Diabetes development…
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ALPINE Study Design
TimeTime -4-4 00 12m12m4w4w 8w8w 12w12w 6m6m
No other antihypertensive drugs allowedNo other antihypertensive drugs allowedGoal BP: <135/<85; 65+ <140/<90 mm HgGoal BP: <135/<85; 65+ <140/<90 mm Hg
HCTZ 25 mgHCTZ 25 mg
HCTZ 25 mg + Atenolol 50 mgHCTZ 25 mg + Atenolol 50 mg
HCTZ 25 mg + Atenolol 100 mgHCTZ 25 mg + Atenolol 100 mg
Candesartan 16 mgCandesartan 16 mg
Candesartan 16 mg + Felodipine 2.5 mgCandesartan 16 mg + Felodipine 2.5 mg
Candesartan 16 mg + Felodipine 5 mgCandesartan 16 mg + Felodipine 5 mg
RRPlaceboPlacebo
Lindholm et al 2003
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ALPINE study…New onset ALPINE study…New onset of diabetesof diabetes
0
1
2
3
4
5
6
7
8
9p < 0.05
No ofpatients
HCTZ
4Candesartan
Lindholm LH J Hypertens 2003
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Development of new Development of new diabetes – CHARM studydiabetes – CHARM study
01020304050607080
No. of cases
developing new
Diabetes
Controlcandesartan
40%p=0.005
Lancet, 2003
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Possible mechanisms involved in Possible mechanisms involved in the prevention of diabetesthe prevention of diabetes
GLUCOSE ABSORPTION
MUSCLE
PANCREAS
ADIPOSE TISSUE
LIVER
INTESTINE
HYPERGLYCEMIA DECREASED PERIPHERAL
GLUCOSE UPTAKE
INCREASED GLUCOSE
PRODUCTION
DECREASED INSULIN
SECRETION
“Candesartan improved insulin sensitivity and hence reduce the development of DM in hypertensive patients ”
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Circulation, July 2005
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End Organ Protective End Organ Protective effects of Candesartaneffects of Candesartan
Congestive Heart failureCongestive Heart failure
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Renin-Angiotensin-Aldosterone System in CHF
RAASRAAS is activated early in the is activated early in the course of heart failure and course of heart failure and plays an important roleplays an important role in the in the progression of the syndromeprogression of the syndrome
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ACE-I IndicationsACE-I Indications
Symptomatic heart failure Symptomatic heart failure (stage C)(stage C) Asymptomatic ventricular dysfunction Asymptomatic ventricular dysfunction
with LVEF <35-40 % with LVEF <35-40 % (stage B)(stage B) Patients with recent or remote history of Patients with recent or remote history of
MI regardless of EF or presence of HFMI regardless of EF or presence of HF
Class I recommendation(therapy is recommended)(therapy is recommended)
Level of evidence A
AHA / ACC HF guidelines 2005AHA / ACC HF guidelines 2005
ESC HF guidelines 2005ESC HF guidelines 2005
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However: 4-year mortality remains ~40%
1. Davies MK et al. BMJ. 2000;320:428-431 (meta-analysis: 32 trials, N = 7105). 2. Gibbs CR et al. BMJ. 2000;320:495-498 (meta-analysis: 18 trials, N = 3023).
HF: Mortality Remains High
ACEIACEI Risk reduction 35% (mortality and Risk reduction 35% (mortality and
hospitalizations)hospitalizations)11
ß-blockersß-blockers Risk reduction 38% (mortality and Risk reduction 38% (mortality and
hospitalizations)hospitalizations)22
SpironolactoneSpironolactone Mortality reduction 23%Mortality reduction 23%
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Substitute or adjunctive therapy to ACE
inhibitors ?
Angiotensin Receptor Angiotensin Receptor
Blockers (ARBs) in Blockers (ARBs) in Heart FailureHeart Failure
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Pitt B, et al. Lancet. 2000;355:1582-1587.
All-cause mortality
Pro
bab
ility
o
f S
urv
ival 1.0
0.80.60.40.20.0
All-cause mortality or hospital admission
Ev
ent-
fre
e
Pro
bab
ility
Sudden death or resuscitated arrest
Ev
ent-
fre
e
Pro
bab
ility
1.00.80.60.40.2
0
1.00.80.60.40.2
0
0 100 200 400300 500 600 700
Follow-up (days)
P P = .16= .16
P P = .08= .08
P P = .18= .18
LosartanCaptopril
Comparative trial: ELITE IIComparative trial: ELITE II
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1.0
0.9
0.8
0.6
13% risk reduction p= 0.009
0
Even
t-fre
e pr
obab
ility
Placebo
Valsartan
3 6 9 12 211815 24 27Time since randomisation (months)
0.7
1.0
0.9
0.8
0.7
Time since randomisation
(months)
p = 0.80
Surv
ival
pro
babi
lity
(%)
0 3 6 9 12 211815 24 27
All-cause mortality and morbidity All-cause mortality
Cohn et al. NEJM 2001;345:1667
Add-on trial: Val-HeFT.Add-on trial: Val-HeFT.Valsartan 160 mg Bid vs placebo on Valsartan 160 mg Bid vs placebo on
top of standard therapytop of standard therapy
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CHARM Added
CHARMPreserved
CHARM ProgramCHARM ProgramCandesartan vs placebo
in patients with symptomatic heart failure
CHARMAlternative
n=2028
LVEF 40%ACE inhibitor
intolerant
n=2548
LVEF 40%ACE inhibitor
treated
n=3025
LVEF >40%ACE inhibitor
treated/not treated
Primary outcome for Overall Programme: All-cause death
Primary outcome for each trial: CV death or CHF hospitalisation
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Granger CB et al. Lancet. 2003;362:772-777
0 1 2 3Years
50
HR 0.77 p=0.00040
40
30
20
10
Candesartan
Placebo
CV
Dea
th o
f H
ospi
taliz
atio
n fo
r H
F
2,028 patients with symptomatic HF, LVSD (EF <40%), and intolerance to ACE-I randomized to candesartan (32 mg) or placebo over 34 months
CHARM Alternative trial
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0 1 2 3
0
10
20
30
40
50
3.5
HR 0.85, p=0.011
Candesartan
Placebo
CV
Dea
th o
f H
ospi
taliz
atio
n fo
r H
F
Years
McMurray JJ et al. Lancet. 2003;362:767-71
2,548 patients with symptomatic HF and LVSD (EF <40%) randomized to candesartan (32 mg) or placebo in addition
to an ACE-I over 34 months
CHARM Added Trial
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CHARM ProgramCHARM Program Mortality and morbidityMortality and morbidity
0.7 0.8 0.9 1.0 1.1 1.2 0.6 0.7 0.8 0.9 1.0 1.1 1.2
All Cause MortalityCV Death or
CHF Hospitalisation
Hazard ratio Hazard ratio
p heterogeneity=0.43
Alternative
Added
Preserved
Overall
p heterogeneity=0.37
p=0.0004
p=0.055
p=0.011
p=0.118
p<0.0001
0.77
0.85
0.89
0.840.91
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CHARM LVEF CHARM LVEF 40% 40% (CHARM-Alternative and CHARM-(CHARM-Alternative and CHARM-
AddedAdded))
All-cause death 0.88 0.79-0.98 0.018
CV death 0.84 0.75-0.95 0.005
HR CI p-value
Pfeffer et al, Lancet 2003
12%12%
ReductionReduction
16%16%
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FDA approved candesartan cilexetil on top of ACE inhibitor for HF
NYHA class II-IV heart failureNYHA class II-IV heart failure Dose: initial dose of 4 mg once daily Dose: initial dose of 4 mg once daily
to a target dose of 32 mg once daily, to a target dose of 32 mg once daily, achieved by doubling the dose at achieved by doubling the dose at approximately two-week intervals, as approximately two-week intervals, as toleratedtolerated
May 19, 2005
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ARB Indications in CHF
Patients intolerant to ACE-Inhibitors: (Class I recommendation in stage C, class IIa in stage B, class I in stage B post MI)
Use of ARB instead of ACE-I in stage C heart failure:Class IIa recommendation (reasonable, should be considered)
On top of ACE I and B Blockers in patients who remain symptomatic: optional, because of discrepancy in guidelines:Class I (ESC, CCS), IIa (HFSA), and IIb (ACC/AHA)
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CHARM-OverallNon-fatal MI
3803 3521 3206 2163 7443796 3413 3101 2088 722
0
1
3
4
5
6
7
2
0 1 2 3 3.5 yrs
Hazard ratio 0.77(95% CI 0.60 – 0.98), p=0.032
placebo
candesartan
Number at riskCandesartanPlacebo
Cumulative events%
2323 % % reduction ofreduction of Non Fatal MINon Fatal MI
Demers C et al. JAMA 2005; 294: 1794-1798.
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Clinical trials continue with ARBs…
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ONTARGET/TRANSCEND Investigators. Am Heart J. 2004;148:52-61.
ONTARGET: Study ONTARGET: Study designdesign
Ramipril 10 mg Telmisartan 80 mg
N = 25,620≥55 years with coronary, cerebrovascular, or peripheral vascular disease,
or diabetes + end-organ damage
Results anticipated in 2007
Ramipril 10 mg + telmisartan 80 mg
Primary end point:CV death, MI, stroke, hosp for HF
Secondary end point:Newly diagnosed diabetes
ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial
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Diabetic retinopathy is the most common Diabetic retinopathy is the most common cause of blindness in people aged 30-69 cause of blindness in people aged 30-69 in developed countriesin developed countries
Laser photocoagulation reduces the risk Laser photocoagulation reduces the risk of blindness, but is performed only when of blindness, but is performed only when advanced vascular damage is presentadvanced vascular damage is present
Only current established treatment Only current established treatment involves careful glycaemic controlinvolves careful glycaemic control strict glycaemic control reduces both onset and strict glycaemic control reduces both onset and
progression of retinopathyprogression of retinopathy
Diabetic retinopathy
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Beneficial effect of ACE-inhibition
3 small studies, non-significant results, positive tendency (Larsen et al 1990, Chase et al 1993, Ravid et al 1993).
EUCLID, n = 354, Lisinopril 10-20 mg or placebo, 2 year follow-upProgression reduced by 50% (p=0.02)Incidence reduced by 31% (n.s.)(Chaturvedi et al 1998)
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Study question
Does blockade of the RAS system with Candesartan cilexetil prevent incidence and progression of retinopathy in type 1 and type 2 diabetes?
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DIRECT programmeThe Diabetic REtinopathy Candesartan
Trials
3 separate studies - each sufficiently powered to establish treatment effects on retinopathy in the respective study population
Pooling of the three populations to detect effects on microalbuminuria
Results expected in 2007
JRAAS 2002;3:255-261
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DIRECT Design
I. Type 1 diabetic patients without diabetic retinopathy
Endpoint: Development of retinopathy II. Type 1 diabetic patients with diabetic
retinopathy Endpoint: Progression of retinopathy III. Type 2 diabetic patients with diabetic
retinopathy Endpoint: Progression of retinopathy Pooled populations of all three studies Endpoint: Incidence of microalbuminuria
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In conclusion The controversial dilemma between ACE-I
and ARBs is not settled ARBs have suffered from their introduction
late after ACE-I were well established However a placebo-like tolerability has
extended their indications in daily practice irrespective of guidelines
Candesartan is a potent ARB with solid data in end organ protection
Need for earlier intervention in the natural history of HTN? (targeting subclinical organ damage)