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IL BLOCCO DEL SISTEMA RAAS NEL CONTINUUM IL BLOCCO DEL SISTEMA RAAS NEL CONTINUUM CARDIOVASCOLARE DOPO TRENT’ANNI DI CARDIOVASCOLARE DOPO TRENT’ANNI DI
ESPERIENZATERAPEUTICA: NON SOLO ROSE E FIORIESPERIENZATERAPEUTICA: NON SOLO ROSE E FIORI
I sartani non sono inferiori ed insieme possono fare meglioI sartani non sono inferiori ed insieme possono fare meglio
Pasquale Perrone FilardiPasquale Perrone Filardi Università Federico II di NapoliUniversità Federico II di Napoli
HEART FAILURE & Co.HEART FAILURE & Co.Ninth International SymposiumNinth International Symposium
Milano, 17 – 18 aprile 2009Milano, 17 – 18 aprile 2009
ARBs, morbidity and mortality along the cardiovascular continuum
Risk factorsDiabetes
Hypertension
Atherosclerosisand LVH
Myocardialinfarction
Remodeling Ventriculardilation
Congestiveheart failure
End-stage micro-vascular
andheart disease
Death
Adapted from Dzau V, Braunwald E. Am Heart J 1991; 121: 1244–1263
ELITE II Val-HeFTCHARM
NAVIGATOR
RENAALIDNTIRMA-2MARVAL
LIFE ONTARGETTRANSCEND
VALUESCOPE
OPTIMAAL VALIANT
DIRECT
BIOLOGICAL EFFECTS OF RASBIOLOGICAL EFFECTS OF RAS
Angiotensin IIAngiotensin II
Angiotensin IAngiotensin I
ACE ACE InhibitorsInhibitorsKininase IIKininase II
Inactive Inactive FragmentsFragments
( - )( - )
Angiotensin II Escape Angiotensin II Escape (Chymase, Cathepsin G, (Chymase, Cathepsin G,
CAGE)CAGE)
BradykininBradykinin
t-PAt-PA
BB22 Receptor Receptor
Natriuresis, VasodilationNatriuresis, Vasodilation&&
Anti-Inflammatory EffectsAnti-Inflammatory Effects
NO, NO, PGIPGI22, ,
HPFHPF AT-IIAT-II AT-IAT-I
DephosphorylationDephosphorylation
Anti-Proliferative Anti-Proliferative EffectsEffects
PhosphorylationPhosphorylation
Proliferative Proliferative EffectsEffects
CNS CNS StimulationStimulation
AldosteronAldosteronEndothelin releaseEndothelin release
VasoconstrictionVasoconstriction
NADPH OxidaseNADPH Oxidase
InflammationInflammation
ROLE OF ARBs IN CARDIOVASCUAR PROTECTION ROLE OF DUAL RAS BLOCKADE IN CARDIOVASCULAR PROTECTION
TARGET ORGANS HEART
Patients at high cardiovascular risk without LV dysfunction
Post-MI ischemic dysfunction Patients with chronic LV systolic dysfunction Patients with chronic LV diastolic dysfunction
KIDNEY EYE BRAIN
QUESTIONS
The ONTARGET Trial ProgrammeOutcome:
Primario: mortalità CV , IMA, Ictus, ospedalizzazione per scompenso cardiaco
Secondario: mortalità CV , IMA, Ictus (outcome HOPE)
Teo K., et al. Am Heart J 2004;148:52–61
Screening
n = 7,800Telmisartan80 mg/day +placebo
n = 7,800Ramipril
10 mg/day +placebo
Randomisation (n=23,400) * Randomisation (n= 6,000) †
n = 7,800Telmisartan80 mg/day +
Ramipril10mg/day
n = 3,000Placebo
Follow-up at 6 weeks
Follow-up at 6 months for 5.5 years
n = 3,000Telmisartan80 mg/day
Follow-up at 6 weeks
Follow-up at 6 months for 5.5 years
*planned. Actual = 25,620 †planned. Actual = 5,926
ONTARGET TRANSCEND
5.5
Yea
rs
NO PLACEBO YES PLACEBO
Tempo al Primary OutcomeONTARGET
Years of Follow-up
Cum
ula
tive
Haz
ard
Ra
tes
0.0
0.05
0.10
0.15
0.20
0.25
0 1 2 3 4
Telmisartan
Ramipril
# at Risk Yr 1 Yr 2 Yr 3 Yr 4T 8542 8176 7778 7420 7051R 8576 8214 7832 7473 7095
IS RAS INHIBITION STILL USEFUL IN CONTEMPORARY PATIENTS AT HIGH
CARDIOVASCULAR RISK?
TRANSCEND patients on “2008 standard care, so called placebo arm”, were almost as protected as with ramipril in HOPE
0
5
10
15
20
HOPE control HOPE ramipril TRANSCEND control TRANSCENDtelmisartan
14% 14,8%13%
17,8%
The Lancet, published on line Aug 31, 2008 N Engl J Med 2000;342:145-53
-17% absolute risk reduction
TRANSCENDPrimary and Key Secondary Outcomes
Telm Plac RR (CI) P
Primary 465 (15.7%) 504 (17.0%) 0.92 (0.81-1.05) 0.216
HOPE 384 (13.0%) 440 (14.8%) 0.87 (0.76-1.00) 0.048
CV death 227 (7.7%) 223 (7.5%) 1.03 (0.85-1.24) 0.778
MI 116 (3.9%) 147 (5.0%) 0.79 (0.62-1.01) 0.059
Stroke 112 (3.8%) 136 (4.6%) 0.83 (0.64-1.06) 0.136
CHF hosp 134 (4.5%) 129 (4.3%) 1.05 (0.82-1.34) 0.694
Tempo al Primary OutcomeONTARGET
Years of Follow-up
Cum
ulat
ive
Haz
ard
Rat
es
0.0
0.05
0.10
0.15
0.20
0.25
0 1 2 3 4
Ramipril
Telmi & Ram
# at Risk Yr 1 Yr 2 Yr 3 Yr 4R 8576 8214 7832 7473 7095T&R 8502 8134 7740 7377 7023
Modifiche della PA (mmHg)ONTARGET e HOPE
Ramipril Telmisartan Combinazione
Sistolica -6.0 -6.9 -8.4
Diastolica
HOPE
-4.6
-3/-2
-5.2 -6.0
Dogma Disputed: Can Agressively Lowering Blood Pressure in Hypertensive Patients with Coronary Artery
Disease Be Dangerous?Messerli et al Ann Intern Med 2006
ARBs AND DUAL RAS BLOCKADE IN LEFT VENTRICULAR SYSTOLIC
DYSFUNCTION
Post-ischemic (OPTIMA; VALIANT)Chronic (VAL-HeFT; CHARM)
0.0
0.1
0.2
0.3
0.4
0 6 12 18 24 30 36
VALSARTAN, CAPTOPRIL, OR BOTH IN MYOCARDIAL VALSARTAN, CAPTOPRIL, OR BOTH IN MYOCARDIAL INFARCTION COMPLICATED BY HEART FAILURE, LV INFARCTION COMPLICATED BY HEART FAILURE, LV
DYSFUNCTION OR BOTHDYSFUNCTION OR BOTHPfeffer et al for the Pfeffer et al for the VALIANTVALIANT Investigators. Investigators. N Engl J MedN Engl J Med 2003 2003
ValsartanValsartanValsartan and CaptoprilValsartan and CaptoprilCaptoprilCaptopril
Prob
abil
ity
of E
vent
MonthsNo.at RiskValsartan 4909 4464 4272 4007 2648 1437 357Valsartan and Captopril 4885 4414 4265 3994 2648 1435 382Captopril 4909 4428 4241 4018 2635 1432 364
n=14808n=14808f.u. 24.7 mf.u. 24.7 m
p = n.s. for all comparisonsp = n.s. for all comparisons
CHARM-Overall All-cause death
0 1 2 3 years3.50
10
20
30
Placebo
5
15
25
35 %
HR 0.91 (95% CI 0.83-1.00), p=0.055Adjusted HR 0.90, p=0.032
945 (24.9%)886 (23.3%)
Candesartan
-9%( p=0,055)
ANNUAL MORTALITY: 8.8 % (PL) VS 8.1 % ANNUAL MORTALITY: 8.8 % (PL) VS 8.1 % (CANDESARTAN)(CANDESARTAN)
00 11 22 33 yearsyears
55
1010
1515
2020
2525
3030
%%
00
CV deathCV deathHR 0.88 (95% CI 0.79-0.97), p=0.012HR 0.88 (95% CI 0.79-0.97), p=0.012
Adjusted HR 0.87, p=0.006Adjusted HR 0.87, p=0.006
Non-CV deathNon-CV deathp=0.45p=0.45
PlaceboPlacebo
CandesartanCandesartan
PlaceboPlacebo
CandesartanCandesartan
3.53.5
Number at riskNumber at risk
CandesartanCandesartan 3803 3803
PlaceboPlacebo 3796 3796Lancet. September 6, 2003Lancet. September 6, 2003
CHARM-Overall: CV Death and non-CV Death
CHARM: EFFECTS ON MORTALITY IN PTS WITH REDUCED EF
(Alternative + Added)
Placebo708 (31.0%)
Candesartan642 (28.0%)
anni3.50 1 2 3
0
10
20
30
All
-cau
se d
eath
(%
)
5
35
25
15
40
HR 0.88 (95% CI 0.79 – 0.98)
p=0.018
Young et al Circulation 2004; 110: 2618-26
CHARM-Alternative: Primary outcome CV death or CHF hospitalisation
0 1 2 3 years0
10
20
30
40
50
Placebo
Candesartan
%
HR 0.77 (95% CI 0.67-0.89), p=0.0004Adjusted HR 0.70, p<0.0001
3.5
406 (40.0%)
334 (33.0%)
-23%( p=0,0004)
MOST RECENT AND UPCOMING RANDOMIZED CLINICAL TRIALS IN HEART FAILURE
TRIAL INTERVENTION RESULTS YEAR
PEP-CHF perindopril NEUTRAL 2006 EVEREST tolvaptan NEUTRAL 2007 CORONA rosuvastatin NEUTRAL 2008 ACCLAIM immunomodulation NEUTRAL 2008 Anemia darbopoetin NEUTRAL 2008 AFCHF rhytm vs rate control NEUTRAL 2008 DSG dronaderone NEUTRAL
2008 BEAUTIFUL ivabradine NEUTRAL
2008 GISSI-HF rosuvastatin, omega-3 NEUTRAL 2008 I-PRESERVE irbesartan NEUTRAL
2008 EMPHASIS eplerenone ongoing TOPCAT anti-aldosterone ongoing RED-HF darbopoetin ongoing
ACE-Is, ARBs AND DUAL RAS BLOCKADE IN LEFVT VENTRICULAR
DIASTOLIC DYSFUNCTIONACE-Is (PEP-CHF)
ARBs (I-PRESERVE; CHARM PRESERVED)
Dual blockade (no studies)
Left ventricular morphology and
function in patients with heart failure with reduced or normal ejection fraction
Maeder et al. Journal of the American College of Cardiology 2009;53: 905-918
EFFECTS OF PERINDOPRIL IN ELDERLY PEOPLE WITH DIASTOLIC HEART FAILURE
Cleland et al for the PEP-CHF Investigators Eur Heart J 2006; 27: 2338–2345
Irbesartan in Patients with Heart Failureand Preserved Ejection FractionI-PRESERVE N Engl J Med 2008;359:2456-67
Death or hospitalization for cardiovascular causes
IRMA 2IRMA 2MARVALMARVAL
Prevention Protection
ESRD ESRD
Early Stage Late Stage End Stage
Microalbuminuria Microalbuminuria ProteinuriaProteinuria
IRMA 2: Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria MARVAL: Microalbuminuria Reduction with Valsartan IDNT: Irbesartan Diabetic Nephropathy TrialRENAAL: Reduction of Endpoints in NIDDM with the Angiotensin II Receptor Antagonist Losartan ESRD: End-stage renal disease
Cardiovascular morbidity and mortalityCardiovascular morbidity and mortality
Angiotensin Receptor Antagonists Trials Across The Whole Spectrum Of Type 2 Diabetic Renal Disease Progression
IDNTIDNTRENAALRENAAL
Effects of ramipril, telmisartan or both on renal outcomes (dialysis, doubling of serum creatinine, and death) in the
ONTARGET trial
Mann et al. The Lancet 2008; 372: 547-553
DIRECT-Protect 2: Retinopathy regressionC
um
ula
tive
pro
po
rtio
n
No at riskPlacebo 954 812 760 713 510 93 1Candesartan 951 811 755 692 492 100 0
0.0
0.1
0.2
0.3
0.4
p=0.009p=0.009
Time from randomisation (years)0 1 2 3 4 5 6
PlaceboPlaceboCandesartanCandesartan
CONCLUSIONS
ARBs (telmisartan) have demonstrated to be as efficacious as ACE-Is in patients at high cardiovascular risk without LV dysfunction, and in patients with post-ischemic (valsartan) and chronic LV systolic dysfunction (valsartan, candesartan)
ARBs (candesartan, irbesartan) have not demonstrated to be efficacious in patients with LV diastolic dysfunction, similarly to ACE-Is
ARBs (losartan, valsartan, irbesartan) have demonstrated to provide renal protection in patients with pre-clinical and clinical diabetic nephropathy
ARBs (candesartan) have demonstrated to induce retinopathy regression in type II diabetics (but needs confirmation)
Dual RAS blockade was ineffective and potentially harmful in patients without LV dysfunction and this association should be used with caution and strict surveillance of renal function
Dual RAS blockade (valsartan, candesartan) reduces mortality/morbidity in patients with chronic LV systolic dysfunction