Transcript ONTARGET Rationale - Gastaldi Congressi

HEART FAILURE & Co.
Ninth International Symposium
Milano, 17 – 18 aprile 2009
IL BLOCCO DEL SISTEMA RAAS NEL CONTINUUM
CARDIOVASCOLARE DOPO TRENT’ANNI DI
ESPERIENZATERAPEUTICA: NON SOLO ROSE E FIORI
I sartani non sono inferiori ed insieme possono fare meglio
Pasquale Perrone Filardi
Università Federico II di Napoli
ARBs, morbidity and mortality along the
cardiovascular continuum
OPTIMAAL
VALIANT
LIFE
ONTARGET
TRANSCEND
ELITE II
Val-HeFT
CHARM
Remodeling
Ventricular
dilation
Congestive
heart failure
Myocardial
infarction
Atherosclerosis
and LVH
Risk factors
Diabetes
Hypertension
NAVIGATOR
VALUE
SCOPE
RENAAL
IDNT
IRMA-2
MARVAL
DIRECT
End-stage microvascular and
heart disease
Death
Adapted from Dzau V, Braunwald E. Am Heart J 1991; 121: 1244–1263
BIOLOGICAL EFFECTS OF RAS
 Bradykinin
Angiotensin I
Kininase II
(-)
ACE
Inhibitors
Inactive
Fragments
Angiotensin II Escape
(Chymase, Cathepsin G,
CAGE)
Angiotensin II
 t-PA
B2 Receptor
NO,
PGI2,
HPF
Natriuresis, Vasodilation
&
Anti-Inflammatory Effects
AT-II
AT-I
Dephosphorylation
Anti-Proliferative
Effects
Phosphorylation
Endothelin release
NADPH Oxidase
Vasoconstriction
Inflammation
Aldosteron
CNS
Stimulation
Proliferative
Effects
QUESTIONS
 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
The ONTARGET Trial Programme
Outcome:
Primario: mortalità CV , IMA, Ictus, ospedalizzazione per
scompenso cardiaco
Secondario: mortalità CV , IMA, Ictus (outcome HOPE)
ONTARGET
TRANSCEND
NO PLACEBO
Randomisation (n= 6,000) †
n = 7,800
Ramipril
10 mg/day +
placebo
n = 7,800
Telmisartan
80 mg/day +
Ramipril
10mg/day
5.5 Years
Randomisation (n=23,400) *
n = 7,800
Telmisartan
80 mg/day +
placebo
YES PLACEBO
Screening
n = 3,000
Telmisartan
80 mg/day
n = 3,000
Placebo
Follow-up at 6 weeks
Follow-up at 6 weeks
Follow-up at
6 months for 5.5 years
Follow-up at
6 months for 5.5 years
*planned. Actual = 25,620
†planned.
Actual = 5,926
Teo K., et al. Am Heart J 2004;148:52–61
Tempo al Primary Outcome
ONTARGET
Yr 2
7778
7832
Yr 3
7420
7473
Yr 4
7051
7095
0.05
0.10
0.15
IS RAS INHIBITION STILL USEFUL IN
CONTEMPORARY PATIENTS AT HIGH
CARDIOVASCULAR RISK?
Telmisartan
Ramipril
0.0
Cumulative Hazard Rates
0.20
0.25
# at Risk Yr 1
T 8542
8176
R 8576
8214
0
1
2
Years of Follow-up
3
4
TRANSCEND patients on
“2008 standard care, so called placebo arm”,
were almost as protected as with ramipril in HOPE
-17% absolute risk reduction
20
15
17,8%
14%
14,8%
10
13%
5
0
HOPE control
The Lancet, published on line Aug 31, 2008
N Engl J Med 2000;342:145-53
HOPE ramipril
TRANSCEND control
TRANSCEND
telmisartan
TRANSCEND
Primary 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
227 (7.7%)
223 (7.5%)
1.03 (0.85-1.24)
0.778
116 (3.9%)
147 (5.0%)
0.79 (0.62-1.01)
0.059
112 (3.8%)
136 (4.6%)
0.83 (0.64-1.06)
0.136
134 (4.5%)
129 (4.3%)
1.05 (0.82-1.34)
0.694
CV death
MI
Stroke
CHF hosp
Tempo al Primary Outcome
R
Yr 2
7832
7740
Yr 3
7473
7377
Yr 4
7095
7023
0.15
0.20
T&R
# at Risk Yr 1
8576
8214
8502
8134
0.10
Ramipril
0.05
Telmi & Ram
0.0
Cumulative Hazard Rates
0.25
ONTARGET
0
1
2
Years of Follow-up
3
4
Modifiche della PA (mmHg)
ONTARGET e HOPE
Ramipril
Telmisartan
Combinazione
Sistolica
-6.0
-6.9
-8.4
Diastolica
-4.6
-5.2
-6.0
HOPE
-3/-2
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)
VALSARTAN, CAPTOPRIL, OR BOTH IN MYOCARDIAL
INFARCTION COMPLICATED BY HEART FAILURE, LV
DYSFUNCTION OR BOTH
Pfeffer et al for the VALIANT Investigators. N Engl J Med 2003
Probability of Event
0.4
Valsartan
Valsartan and Captopril
Captopril
0.3
n=14808
f.u. 24.7 m
0.2
0.1
p = n.s. for all comparisons
0.0
No.at Risk
Valsartan
Valsartan and Captopril
Captopril
0
6
12
4909
4885
4909
4464
4414
4428
4272
4265
4241
18
24
Months
4007 2648
3994 2648
4018 2635
30
36
1437
1435
1432
357
382
364
CHARM-Overall
All-cause death
%
35
30
Placebo
25
945 (24.9%)
886 (23.3%)
20
Candesartan
15
-9%( p=0,055)
10
HR 0.91 (95% CI 0.83-1.00), p=0.055
Adjusted HR 0.90, p=0.032
5
0
0
1
2
3
3.5 years
ANNUAL MORTALITY: 8.8 % (PL) VS 8.1 %
(CANDESARTAN)
CHARM-Overall:
CV Death and non-CV Death
CV death
HR 0.88 (95% CI 0.79-0.97), p=0.012
Adjusted HR 0.87, p=0.006
30
25
Placebo
20
%
Candesartan
15
10
Non-CV death
p=0.45
Candesartan
5
Placebo
0
0
Number at risk
Candesartan
Placebo
1
3803
3796
2
3
3.5
years
Lancet. September 6, 2003
CHARM: EFFECTS ON MORTALITY IN PTS WITH
REDUCED EF
(Alternative + Added)
All-cause death (%)
40
Placebo
708 (31.0%)
35
30
Candesartan
642 (28.0%)
25
20
15
HR 0.88 (95% CI 0.79 – 0.98)
p=0.018
10
5
0
0
1
2
anni
3
3.5
Young et al Circulation 2004; 110: 2618-26
CHARM-Alternative: Primary outcome
CV death or CHF hospitalisation
50
%
406 (40.0%)
Placebo
40
334 (33.0%)
30
Candesartan
20
-23%( p=0,0004)
10
HR 0.77 (95% CI 0.67-0.89), p=0.0004
Adjusted HR 0.70, p<0.0001
0
0
1
2
3
3.5 years
MOST RECENT AND UPCOMING RANDOMIZED
CLINICAL TRIALS IN HEART FAILURE
 TRIAL













PEP-CHF
EVEREST
CORONA
ACCLAIM
Anemia
AFCHF
DSG
BEAUTIFUL
GISSI-HF
I-PRESERVE
EMPHASIS
TOPCAT
RED-HF
INTERVENTION
RESULTS
YEAR
perindopril
tolvaptan
rosuvastatin
immunomodulation
darbopoetin
rhytm vs rate control
dronaderone
ivabradine
rosuvastatin, omega-3
irbesartan
eplerenone
anti-aldosterone
darbopoetin
NEUTRAL
NEUTRAL
NEUTRAL
NEUTRAL
NEUTRAL
NEUTRAL
NEUTRAL
NEUTRAL
NEUTRAL
NEUTRAL
ongoing
ongoing
ongoing
2006
2007
2008
2008
2008
2008
2008
2008
2008
2008
ACE-Is, ARBs AND DUAL RAS
BLOCKADE IN LEFVT VENTRICULAR
DIASTOLIC DYSFUNCTION
ACE-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 Failure
and Preserved Ejection Fraction
I-PRESERVE N Engl J Med 2008;359:2456-67
Death or hospitalization for
cardiovascular causes
Angiotensin Receptor Antagonists Trials Across The Whole
Spectrum Of Type 2 Diabetic Renal Disease Progression
Prevention
Microalbuminuria
Protection
Proteinuria
ESRD
Cardiovascular morbidity and mortality
Early Stage
IRMA 2
MARVAL
IRMA 2:
MARVAL:
IDNT:
RENAAL:
ESRD:
Late Stage
End Stage
IDNT
RENAAL
Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria
Microalbuminuria Reduction with Valsartan
Irbesartan Diabetic Nephropathy Trial
Reduction of Endpoints in NIDDM with the Angiotensin II Receptor Antagonist Losartan
End-stage renal disease
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 regression
Cumulative proportion
0.4
Placebo
Candesartan
0.3
0.2
0.1
p=0.009
0.0
0
No at risk
Placebo
Candesartan
954
951
1
2
3
4
5
Time from randomisation (years)
812
811
760
755
713
692
510
492
93
100
6
1
0
CONCLUSIONS
 ARBs (telmisartan) have demonstrated to be as efficacious as ACEIs 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