ACEIs vs ARBs in Congestive Heart Failure - mecire

ACEIs vs ARBs in Congestive
Heart Failure
Prof. Roland KASSAB
Head of Division of Cardiology
Hotel-Dieu de France, Beirut
Saida, 21/02/2009

Impact of Heart Failure

HF deaths
Heart failure - a growing burden
Deaths from HF 1979-1997 (USA)
50000
40000
30000
20000
10000
0
1979 1985 1991 1997
Vital Statistics of the United States, National Center for Health Statistics

Heart Failure is a Major and Growing
Public Health Problem in the U.S.
Approximately 5 million patients in this country have
HF
Over 550,000 patients are diagnosed with HF for the
first time each year
Primary reason for 12 to 15 million office visits and
6.5 million hospital days each year
In 2001, nearly 53,000 patients died of HF as a
primary cause

Heart Failure is Primarily a
Condition of the Elderly
The incidence of HF approaches 10 per 1000
population after age 65
HF is the most common Medicare diagnosisrelated
group
More dollars are spent for the diagnosis and
treatment of HF than any other diagnosis by
Medicare

Heart failure - an economic burden:
USA (2000)
Annual cost of HF estimated to be $22.5 billion (USA)
Indirect Costs
Healthcare
providers
Drugs
2.2 1.5 1.1 2.2
Home health/Other
medical durables
15.5
Hospital/Nursing home
Costs in billions of dollars
American Heart Association, 2000 Heart and Stroke Statistical Update

Role of the RAAS
in Heart Failure

Pathophysiology of CHF
injury to myocytes
and EC matrix
Neurohumoral activation
Increased cytokines
Immune and
inflammatory changes
altered fibrinolysis
Ventricular
remodelling
Oxidative stress
Apoptosis
Altered gene
Expression
Electrical, vascular, renal,
pulmonary,muscle effects
McMurray J, Pfeffer M. Circulation. 2002.
CHF

Relationship Between Neurohormone Levels
and Survival (CONSENSUS)
100
Ang II Norepinephrine Aldosterone
P

A II Plays a Central Role in Organ Damage
Stroke
Atherosclerosis*
Vasoconstriction
Vascular hypertrophy
Hypertension
A II
LV hypertrophy
Fibrosis
Remodeling
Apoptosis
Heart failure
MI
DEATH
AT 1 receptor
GFR
Proteinuria
Aldosterone release
Glomerular sclerosis
Renal failure
*preclinical data
LV = left ventricular; MI = myocardial infarction; GFR = glomerular filtration rate
Adapted from Willenheimer R et al Eur Heart J 1999;20(14):997-1008; Dahlöf B J Hum Hypertens 1995;9(suppl 5):S37-S44;
Daugherty A et al J Clin Invest 2000;105(11):1605-1612; Fyhrquist F et al J Hum Hypertens 1995;9(suppl 5):S19-S24;
Booz GW, Baker KM Heart Fail Rev 1998;3:125-130; Beers MH, Berkow R, eds. The Merck Manual. 17th ed.
Whitehouse Station, NJ: Merck Research Laboratories, 1999:1682-1704; Anderson S Exp Nephrol 1996;4(suppl 1):34-40;
Fogo AB Am J Kidney Dis 2000;35(2):179-188.

Several pathways of Ang II generation
Local Ang II synthesis is independent of ACE
Bradykinin
Peptides
Renin
inhibitor
ACE
inhibitor
ARBs
AT 1 receptor blocker
de Gasparo et al. Pharmacol Rev 2000;
52:415
Angiotensinogen
(Liver)
Angiotensin I
Angiotensin II
AT 1 AT 2
Chymase

Different roles of AT 1 and AT 2 receptors
Angiotensin II
AT 1 AT 2
Vasoconstriction
Vascular proliferation
Aldosterone secretion
Cardiac myocyte
proliferation
Increased sympathetic tone
de Gasparo et al. Pharmacol Rev 2000; 52:415
Vasodilation
Antiproliferation
Apoptosis

Effects of Angiotensin II on Growth Factors/Cytokines
and LV Remodeling
Angiotensin II
Myocyte hypertrophy
TGF-
PDGF
bFGF
Fibroblast
proliferation
Interstitial collagen
LV remodelling
TGF- = transforming growth factor beta; PDGF = platelet-derived growth factor; bFGF = basic fibroblast
growth factor
19

CHD
ischemia
Thrombus
TIA
Angina pectoris
Myocardial infarction
Stroke
atherosclerosis
LVH
kidney damage
endothelial dysfunction
neuroendocrine
activation
RAS-->AII
arrhythmias
dysfunction
severe ischemia
hypertension
hyperlipemia
diabetes
smoking
stress
.
health
death
The CV Continuum:Importance of RAS
CHF
New other event
End stage renal disease

% death at 1 year
Mortality Benefit of -Blockers AND
ACE-Inhibitors in CHF Trials
16
14
12
10
8
6
4
2
0
SOLVD (1991) CIBIS II
MERIT-HF
S
(1999)
diuretic
digoxin
diuretic
digoxin
ACE-I
diuretic
digoxin
ACE-I
diuretic
digoxin
ACE-I
beta-blocker

CHF: Management Cascade
CHF due to
LVSD
ACE inhibitor
-blocker
persisting
symptoms
intractable
Spironolactone
Digoxin
CHF
Transplant
LVAD

HF: Mortality Remains High
• ACEIs
– Risk reduction 35% (mortality and hospitalizations) 1
• ß-blockers
– Risk reduction 38% (mortality and hospitalizations) 2
• Spironolactone
– Mortality reduction 23%
• Oral nitrates and hydralazine
– Benefit vs placebo; inferior to enalapril (mortality)
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).

CONSENSUS: Cooperative North Scandinavian Enalapril Survival Study
- RESULTS continued -
Probability
0.8
Cumulative probability of death p = 0,001
0.6
0.4
0.2
0.0
Placebo
Enalapril
0 2 4 6 8 10 12
Months after randomization
Placebo:
Enalapril:
126
127
78
98
59
82
47
73
34
59
24
42
17
26
CONSENSUS Trial Study Group. N Engl J Med 1987;316:1429–35.

V-HeFT II: Vasodilator–Heart Failure Trial
- RESULTS continued-
Cumulative mortality
Sudden death: p ~ 0,02
Cumulative
mortality
0.75
0.50
0.25
Hydralazine–
isosorbide
dinitrate
0
0
12 24 36 48 60
Enalapril
Months after randomization
Cohn et al. N Engl J Med 1991; 325:303–10.

The Evidence with ACE Inhibitors
MI Mortality Trials
Broad
(short term)
CONSENSUS II(Enalap)
GISSI-3(Lisinop)
ISIS-4(Captop)
Chinese-Cap(Captop)
>100,000 Patients
SAVE
AIRE
Selective
(higher risk, long term)
(EF 40%) Captopril
(clinical HF)(Ramip)
SMILE (anterior MI, no lytic)
TRACE (wall motion score,
EF 35%)(Trandorap)

Probability of Event
SAVE
Radionuclide
EF 40%
AIRE
Clinical and/or
radiographic
signs of HF
TRACE
Echocardiographic
EF 35%
0.4
0.35
All-Cause Mortality
0.3
0.25
0.2
Placebo
ACE-I
26%
1500 Deaths,narrow CI
0.15
0.1
Placebo: 866/2971 (29.1%)
ACE-I: 702/2995 (23.4%)
0.05
OR: 0.74 (0.66–0.83)
Years
0
0 1 2 3
4
ACE-I 2995 2250 1617 892 223
Placebo 2971 2184 1521 853 138
Flather MD, et al. Lancet. 2000;355:1575–1581

Events (%)
SAVE
Radionuclide
EF 40%
Death and Major CV Events
AIRE
Clinical and/or
radiographic
signs of HF
TRACE
Echocardiographic
EF 35%
0.75*
ACE-I (n = 2995)
Placebo (n = 2971)
(0.67 – 0.83)
40
30
20
0.73*
(0.63 – 0.85)
0.80*
(0.69 – 0.95)
10
0
n =
355
n =
460
Readmission
for HF
n =
324
n =
391
Reinfarction
n =
1049
n =
1244
Death/MI or
Readmission for HF
*odds ratio (95% CI)
Flather MD, et al. Lancet. 2000;355:1575–1581

ACE Inhibitors: The Gold-Standard Treatment for Heart Failure
Mean Duration Mortality Risk Reduction
Study Patients ACE Inhibitor of Follow-Up (mo) (p value)
CONSENSUS Severe heart failure (n=253) Enalapril 6 27% vs. placebo* (p=0.003)
SOLVD Mild to moderate Enalapril 41 16% vs. placebo* (p=0.0036)
Treatment heart failure (n=2569)
V-HeFT II Mild to moderate Enalapril 30 11% vs. hyd-iso* (p=0.016)
heart failure (n=804)
SOLVD Asymptomatic LVD (n=4228) Enalapril 37 8% vs. placebo* (p=0.30)
Prevention
SAVE Post-MI with LVD (n=2331) Captopril 42 19% vs. placebo (p=0.019)
AIRE Post-MI with LVD (n=2006) Ramipril 15 27% vs. placebo* (p=0.002)
TRACE Post-MI with LVD (n=1749) Trandolapril 24–50 (range) 22% vs. placebo (p=0.001)
CONSENSUS = Cooperative North Scandinavian Enalapril Survival Study; SOLVD = Studies of Left Ventricular Dysfunction; V-HeFT = Veterans
Administration Cooperative Vasodilator–Heart Failure Trial; hyd-iso = hydralazine–isosorbide dinitrate; LVD = left ventricular dysfunction;
SAVE = Survival and Ventricular Enlargement; AIRE = Acute Infarction Ramipril Efficacy; TRACE = Trandolapril Cardiac Evaluation
*Both groups also received digitalis and diuretics with or without non-ACE inhibitor vasodilators.
Adapted from the CONSENSUS Trial Study Group N Engl J Med 1987;316(23):1429-1435; the SOLVD Investigators N Engl J Med
1991;325(5):293-302; Cohn JN et al N Engl J Med 1991;325(5):303-310; the SOLVD Investigators N Engl J Med 1992;327(10):
685-691; Pfeffer MA et al N Engl J Med 1992;327(10):669-677; the Acute Infarction Ramipril Efficacy (AIRE) Study Investigators
Lancet 1993;342:821-828; and Køber L et al N Engl J Med 1995;333(25):1670-1676.

CHF: Management Cascade
CHF due to
LVSD
ACE inhibitor
-blocker
ARBs
persisting
symptoms
intractable
Spironolactone
Digoxin
CHF
Transplant
LVAD

AT 1 -receptor blockade vs ACE-inhibition
• Specific selective blockade AT 1 -receptor
• Blocks also non-ACE produced AII
• Stimulation of the AT 2 -receptor
• Benefits beyond BP control?
• No increase in bradykinin systemically
• Fewer side-effects

Balance
AII
AT 1 -block.
AT 1
•Prevention of
damage/event
•Reparation/
regeneration
AT 2

ACE escape: Ang II levels increase over
time despite ACEi
Blood
pressure
mm Hg
Plasma
Ang II
pg/ml
180
160
140
120
100
80
24
20
16
12
8
4
0
Placebo 4h 24h 1 2 3 4 5 6 Months
Hospital
Biollaz et al. J Cardiovasc Pharmacol 1982;4:966

Event rate (%)
OPTIMAAL: Endpoints
70
60
losartan
captopril
50
40
30
20
10
0
Mortality Reinfarction Stroke Revasularization Hospitalisation
p= 0.069 0.722 0.587 0.620 0.362
Dickstein et al. Lancet 2002;360:752-760.

OPTIMAAL: Discontinuations
25
20
p < 0.001
losartan
captopril
% 15
10
p < 0.001
p < 0.001
5
0
All All due to AE Drug-related
due to AE
Dickstein Dickstein et al. Lancet et 2002;360:752-760. al. Lancet 2002;360:752-760.
p = 0.010
Serious AE
p = 0.002
Serious AE,
drug-related

Acute MI (0.5–10 days)—SAVE, AIRE or TRACE eligible
(either clinical/radiologic signs of HF or LV systolic dysfunction)
Major Exclusion Criteria:
— Serum creatinine > 2.5 mg/dL
— BP < 100 mm Hg
— Prior intolerance of an ARB or ACE-I
— Nonconsent
Captopril 50 mg tid
(n = 4909)
double-blind active-controlled
Valsartan 160 mg bid
(n = 4909)
Captopril 50 mg tid +
Valsartan 80 mg bid
(n = 4885)
median duration: 24.7 months
event-driven
Primary Endpoint: All-Cause Mortality
Secondary Endpoints: CV Death, MI, or HF
Other Endpoints: Safety and Tolerability

Probability of Event
Mortality by Treatment
0.3
0.25
Captopril
Valsartan
Valsartan + Captopril
0.2
0.15
0.1
Months
0.05
Valsartan vs. Captopril: HR = 1.00; P = 0.982
Valsartan + Captopril vs. Captopril: HR = 0.98; P = 0.726
0
0 6 12 18 24 30 36
Captopril 4909 4428 4241 4018 2635 1432 364
Valsartan 4909 4464 4272 4007 2648 1437 357
Valsartan + Cap 4885 4414 4265 3994 2648 1435 382
Pfeffer et al. N Engl J Med 2003;349

Post – MI : The evidence so far
• In light of the large amount of data, ACE
inhibitors remain the therapy of choice in
patients with post MI
• In patients in whom ACE inhibitors are
contraindicated
or not tolerated, A II antagonists may be useful
alternative agents.
Dickstein et al. Lancet 2002;360:752-760.

The Evidence with AII Antagonists
HF Mortality Trials
ELITE I
Losartan (50 mg/day)
ELITE II
Losartan (50 mg/day)
VAL-Heft
Valsartan (320 mg/day)
CHARM
Candesartan ( 32 mg/day)
HEAAL
Losartan 50 vs 150 mg/day

AIIA End-Point Trials in
Patients With Heart Failure
Treatment groups and Patient Entry NYHA
Trial dose titrations (mg) population age (y) class
ELITE II Losartan 12.52550 QD ACEI naive 60 II–IV
(3,152) Captopril 12.52550 TID
Val-HeFT Valsartan 4080160 BID Mostly ACEI 60 II–IV
(5,200) Placebo (usual care, ACEI) treated
CHARM-I Candesartan 4832 + ACEI QD ACEI treated; 18 II–IV
(2,300) Placebo (usual care, ACEI) depressed LV
systolic function
CHARM-II Candesartan 4832 QD ACEI intolerant: 18 II–IV
(1,700) Placebo (usual care) depressed LV
systolic function
CHARM-III Candesartan 4832 QD No ACEI treatment; 18 II–IV
(2,500) Placebo (usual care) preserved LV
systolic function

Probability of survival
The Losartan Heart Failure Survival Study–ELITE II
Primary Endpoint: All-Cause Mortality
Kaplan-Meier Estimates for Survival
1.0
0.8
0.6
0.4
0.2
Hazard ratio (95.7% CI):
1.13 (0.95, 1.35); p=0.16)
Days of follow-up
Losartan (n=1578)
Captopril (n=1574)
0
0 100 200 300 400 500 600 700
• No significant
difference
between
losartan and
captopril in
reducing
all-cause
mortality in
heart failure
CI = confidence interval
Adapted from Pitt B et al Lancet 2000;355:1582-1587.

The Losartan Heart Failure Survival Study–ELITE II
Event-free probability
Secondary Endpoint: Sudden Death or Resuscitated
Cardiac Arrest
1.0
0.8
0.6
Losartan (n=1578)
Captopril (n=1574)
0.4
0.2
Hazard ratio (95% CI):
1.25 (0.98, 1.60); p=NS)
0
0 100 200 300 400 500 600 700
Days of follow-up
Adapted from Pitt B et al Lancet 2000;355:1582-1587.

% of patients
The Losartan Heart Failure Survival Study–ELITE II
Other Endpoints: Discontinuations from Study Therapy
Due to Adverse Events (AEs)*
16
14
12
10
8
6
4
2
0
9.7
p

The Losartan Heart Failure Survival Study–ELITE II
Study Summary
In patients with symptomatic heart failure due to systolic LVD:
• No statistically significant differences were observed between
losartan vs. captopril with respect to:
– All-cause mortality (primary endpoint)
– Composite of sudden cardiac death/resuscitated cardiac arrest
(secondary endpoint)
– Composite of all-cause mortality/all-cause hospitalization
(tertiary endpoint)
– Deaths, hospitalization, discontinuations relating to heart failure
• Losartan was better tolerated than captopril, with significantly
fewer discontinuations due to adverse experiences (p

Angioedema

Val-HeFT Design
5,010 HF patients
>18 yr; EF

Study Overview
5010 patients
18 years; EF 2.9 cm/m 2
ACE inhibitors (92.7%), diuretics (85.8%),
digoxin (67.3%), -blockers (35.6%)
Randomized to
Receiving background therapy
Valsartan
40 mg bid titrated to
160 mg bid
Placebo
Cohn JN et al. Eur J Heart Fail. 2000;2:439-446.

Event-free probability
Survival probability (%)
Primary Endpoints
(Overall Population)
1.0
0.9
All-cause mortality and morbidity
Valsartan
1.0
0.9
0.8
All-cause mortality
p = 0.80
0.8
Placebo
0.7
0 3 6 9 12 15 18 21 24 27
Time since randomisation
(months)
0.7
0.6
0
13% risk reduction p=
0.009
3 6 9 12 15 18 21 24 27
Time since randomisation (months)
Cohn et al. NEJM 2001;345:1667

Event-free probability
Secondary Endpoints
(Overall Population)
1.0
0.9
HF hospitalisations
Valsartan
27.5%
risk reduction
p

Proportion Survived (%)
Reduction in Mortality
(No ACEI)
100
90
80
Placebo
(N = 181)
Valsartan
(N = 185)
70
60
50
Maggioni et al. J Am Coll Cardiol 2002;
40:1414
Risk reduction= 33.1%
P value (log-rank) = 0.0171
0 3 6 9 12 15 18 21 24 27 30
Time Since Randomisation (months)

Event-Free Probability
Reduction in Combined Morbidity
Endpoint (No ACEI)
100
90
80
70
60
50
40
Placebo
(N = 181)
Risk reduction = 44.0%
P value (log-rank) = 0.0002
Valsartan
(N = 185)
0 3 6 9 12 15 18 21 24 27 30
Time Since Randomisation (months)
Maggioni et al. J Am Coll Cardiol 2002;
40:1414

Background therapy: Relative risks and
95% CI of morbidity and mortality endpoints
Favors valsartan
Favors placebo
Morbidity
ACEI+ BB– 3,034
ACEI+ BB+ 1,610
ACEI– BB– 226
ACEI– BB+ 140
Mortality
ACEI+ BB– 3,034
ACEI+ BB+ 1,610
ACEI– BB– 226
ACEI– BB+ 140
0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9
Cox regression model
Cohn et al. New Engl J Med. 2001; 345: 1667

Val-HeFT - Conclusions
• No difference on mortality (19.7% vs 19.4%; p=0.8)
• Significant difference in favor of combo on
combined endpoint of mortality and morbidity
( 28.8% vs 32.1%; p=0.009) (when excluding pats not receiving an ACE-I the
difference becomes non-significant)
• Significant difference in favor of combo on HF
hospital. (13.9% vs 18.5% ; p=0.0001)
• Significantly more withdrawals due to AE’s on
combo (9.9% vs 7%; p

CHARM Programme
3 component trials comparing candesartan to
placebo in patients with symptomatic heart failure
CHARM
Alternative
n=2028
LVEF 40%
ACE inhibitor
intolerant
CHARM
Added
n=2548
LVEF 40%
ACE inhibitor
treated
CHARM
Preserved
n=3025
LVEF >40%
ACE inhibitor
treated/not treated
Primary outcome for each trial: CV death or CHF hospitalisation
Primary outcome for Overall Programme: All-cause death
Pfeffer et al, Lancet 2003

CHARM-Alternative
Primary outcome, CV death or CHF hospitalisation
%
50
406 (40%)
Placebo
40
334 (33%)
30
Candesartan
20
10
0
Number at risk
HR 0.77 (95% CI 0.67-0.89), p=0.0004
Adjusted HR 0.70, p

CHARM-Alternative
Conclusions
• Despite prior intolerance to another
inhibitor of the renin-angiotensinaldosterone
system, candesartan was
well tolerated
• In patients with symptomatic CHF and
ACE inhibitor intolerance, candesartan
reduces cardiovascular mortality and
morbidity
Granger et al, Lancet 2003

CHARM Programme
3 component trials comparing
candesartan to placebo
CHARM
Alternative
n=2028
LVEF 40%
ACE inhibitor
intolerant
CHARM
Added
n=2548
LVEF 40%
ACE inhibitor
treated
CHARM
Preserved
n=3025
LVEF >40%
ACE inhibitor
treated/not treated
Primary outcome:
CV death or CHF hospitalisation
McMurray et al, Lancet 2003

CHARM-Added
Primary outcome, CV death or CHF hospitalisation
%
50
40
Placebo
538 (42.3%)
483 (37.9%)
30
Candesartan
20
Number at risk
10
0
HR 0.85 (95% CI 0.75-0.96), p=0.011
Adjusted HR 0.85, p=0.010
0 1 2 3 3.5 years
Candesartan 1276 1176 1063 948 457
Placebo 1272 1136 1013 906 422
McMurray et al, Lancet 2003

CHARM-Added
Primary and secondary outcomes
Number of patients
Candesartan Placebo
CV death, CV hosp 483 538
- CV death 302 347
- CHF hosp 309 356
CV death, CHF hosp, 495 550
MI
CV death,CHF hosp, 512 559
MI, stroke
CV death,CHF hosp, 548 596
MI, stroke, revasc
p-value
0.011
0.029
0.014
0.010
0.020
0.015
0.6 0.8 1.0 1.2 1.4
Candesartan Hazard Placebo
better ratio better
McMurray et al, Lancet 2003

CHARM-Added
Prespecified subgroups, CV death or CHF
hospitalisation
Candesartan
event/n
Placebo
event/n
p-value for
treatment
interaction
Beta- Yes 223/702 274/711
blocker No 260/574 264/561
Recom. Yes 232/643 275/648
dose of No 251/633 263/624
ACE inhib
All patients 483/1276 538/1272
0.14
0.26
0.6 0.8 1.0 1.2 1.4
Candesartan Hazard Placebo
better ratio better
McMurray et al, Lancet 2003

CHARM-Added
Conclusions
• Addition of candesartan to an ACE inhibitor
(and beta-blocker) leads to a further and
clinically important reduction in CV mortality
and morbidity in patients with CHF
• This benefit is obtained with relatively few
adverse effects, although there is an
increased risk of hypotension,
hyperkalaemia and renal dysfunction
McMurray et al, Lancet 2003

Primary Hypothesis: HEAAL
Study
In patients with congestive heart failure who are
intolerant to treatment with an ACEI, treatment
with losartan 150 mg daily will be superior to
treatment with losartan 50 mg daily by 15% , as
assessed by the effect on the composite event
rate of all cause death and/or hospitalization for
heart failure.

Val-HeFT impact on treatment guidelines:
Europe 2002
Recommended pharmacological therapy of
symptomatic chronic HF due to systolic left
ventricular dysfunction:
For symptoms; NYHA Class II-IV:
• ARB if ACEI intolerant
• ARB+ACEI if blocker intolerant
Remme et al. Eur Heart J. 2001; 22: 1527

Val-HeFT impact on treatment
guidelines: USA 2001
Recommendations for treatment of symptomatic left
ventricular systolic dysfunction:
Evidence class IIa
• Angiotensin receptor blockade in patients who
are being treated with digitalis, diuretics, and a
blocker and who cannot be given an ACEinhibitor
Evidence class IIb
• Addition of an ARB to an ACE-inhibitor*
(*assumes the patient is not being treated with a blocker)
Hunt et al. Practice Guidelines ACC/AHA 2001

Heart Failure Therapy: The evidence so far
• ACE inhibitors remain the therapy of choice in
patients with symptomatic heart failure due to
systolic LVD.
• In patients in whom ACE inhibitors are
contraindicated
or not tolerated, A II antagonists at the
recommended doses may be useful alternative
agents.
Adapted from Pitt B et al Lancet 2000;355:1582-1587.

Reduced LV
SF
Preserved LV
SF

CHF Despite Preserved LV systolic
Function
• CHARM (candesartan)
• PEP-CHF (perindopril)
• SENIORS (nebivolol)
• I-PRESERVE (irbesartan)

CHARM-Preserved
Primary outcome, CV death or CHF hospitalisation
%
30
25
20
15
Placebo
Candesartan
366 (24.3%)
333 (22.0%)
10
Number at risk
5
0
HR 0.89 (95% CI 0.77-1.03), p=0.118
Adjusted HR 0.86, p=0.051
0 1 2 3 3.5 years
Candesartan 1514 1458 1377 833 182
Placebo 1509 1441 1359 824 195
Yusuf et al, Lancet 2003

CHARM-Preserved
Investigator-reported CHF hospitalisations
Patients (%)
Number of
episodes
Placebo
Candesartan
25
700
20
p=0.017
600
500
p=0.014
15
400
10
300
5
200
100
0
Patients hospitalised
0
Hospitalisations
Yusuf et al, Lancet 2003

CHARM-Preserved
Development of new diabetes
Number of cases (%) HR p-value
Candesartan Placebo
n=1080 n=1086
(CI)
47 (4) 77 (7) 0.60 0.005
(0.41-0.86)
Yusuf et al, Lancet 2003

Cleland JGF. World Congress of Cardiology 2006;
September 3, 2006; Barcelona, Spain.
One-year outcomes in PEP-CHF,
perindopril vs placebo
End point
All-cause mortality or
unplanned HF
hospitalization
Unplanned HF
hospitalization
Perindopril,
n=424 (%)
Placebo,
n=426 (%)
10.8 15.3 0.055
8.0 12.4 0.033
All-cause mortality 4.0 4.5 NS
p

Hazard ratio for all-cause mortality or
unplanned HF hospitalization at 1 year by
subgroups
Patient subgroups HR (95% CI) p
Age 75 years 0.87 (0.53-1.42) 0.575
Systolic BP 140 0.52 (0.26-1.03) 0.055
History of MI 0.38 (0.19-0.75) 0.004
No MI history 0.92 (0.58-1.46) 0.719
Cleland JGF. World Congress of Cardiology 2006;
September 3, 2006; Barcelona, Spain.

I-PRESERVE: Entry Criteria
Age 60 years
Current HF symptoms
LVEF 0.45
NYHA class II - IV
CHF hosp. 6 months
NYHA Class III/IV
CXR congestion
ECG (LVH, LBBB)
Echo (LVH, LAE)
Key Exclusions: SBP >160 mm Hg; prior EF 2.5, Hb

I-PRESERVE: Study Design
Randomized, double-blind, placebo controlled trial
Irbesartan
N=4,128
75 mg 150 mg 300 mg
Enrollment
Single-blind
2 weeks
R
Forced titration
Maintenance
Only 1/3 pts could
enter on an ACEI
W 2 W 4 W 8 M 6 M 10 M 14 to end
Every 4 months
Placebo
Follow-up continued until 1,440 primary endpoints occurred

Cumulative Incidence of
Primary Events (%)
I-PRESERVE: Primary Endpoint
Death or protocol specified CV hospitalization
40 -
HR (95% CI) = 0.95 (0.86-1.05)
Log-rank p=0.35
Placebo
30 -
Irbesartan
20 -
10 -
0 -
No. at Risk
Irbesartan
Placebo
0 6 12 18 24 30 36 42 48 54 60
Months from Randomization
2067 1929 1812 1730 1640 1569 1513 1291 1088 816 497
2061 1921 1808 1715 1618 1539 1466 1246 1051 776 446

Secondary Outcomes
Patients with Events
Outcome
Placebo
(n=2061)
Irbesartan
(n=2067)
HR (95% CI)
Death
436
445
1.00 (0.88-1.14)
CV death
302
311
1.01 (0.86-1.18)
HF death or HF
hospitalization
438
428
0.96 (0.84-1.09)
CV death MI or stroke
400
402
0.99 (0.86-1.13)
P=NS for all

I-PRESERVE: Conclusions
• In I-PRESERVE, HF-PEF patients experienced substantial
mortality and cardiovascular morbidity.
• Irbesartan did not reduce the primary endpoint of death and
protocol-specified CV hospitalizations, nor did it significantly
benefit prespecified secondary endpoints.
• Our results are consistent with the two previous trials in patients
with HF-PEF that did not demonstrate a positive effect.
• For this large group of patients constituting half of all heart
failure patients, there continues to be no specific evidencebased
therapy.
• In order for this field to move forward, a better understanding of
the mechanisms underlying this syndrome and additional
potential targets for treatment are required.

ACEI and/or ARBs in CHF
As with any therapy, the pragmatic 4 W questions must
be answered:
WHY ?
WHEN ?
WHO ?
WHAT ?

ACEIs and/or ARBs in CHF
WHY?
► Pivotal role of the RAAS in the
pathophysiology of CHF
► All Mega-trials with ACEIs or ARBs vs
Placebo proved that both agents:
♥ Improve Survival in CHF
♥ Improve Quality of Life

ACEIs and/or ARBs in CHF
WHEN?
► As soon as possible, once CHF diagnosed
NYHA class I: ACEIs: SOLVD Prevention
(Enalapril)
► As soon as possible after MI, if no contraindication
► Up-titration every 2 wks for both agents
→ recommended dose

ACEIs and/or ARBs in CHF
WHO?
Post-MI
LV dysfunction
Mild
CHF
Moderate
CHF
Severe
CHF
TRACE / AIRE / SAVE
(ramipril / captopril)
trandolapril
ACE intolerant:
VALIANT (valsartan)
SOLVD Treatment
(enalapril)
Val-HeFT (valsartan)
CHARM (candesartan)
ELITE II (losartan:dose?)
CONSENSUS
(enalapril)

ACEIs and/or ARBs in CHF
WHAT?
► Class Effect ? Evidence-based medicine:
Enalapril, Lisinopril
Small trials with Perindopril and Fosinopril
Alternative Tt: Valsartan, Candesartan,
Losartan (high dose?)
► CHF post acute MI: Captopril, Ramipril,
Trandolapril. Alternative Tt: Valsartan
► Cost problems

ACEIs and ARBs in CHF
♥ Rationale: complete blockade of RAAS
♥ RESOLVD: Candesartan + Enalapril:
↑ EF and ↓ V volumes vs Cand. or Enal.
♥Val-HeFT: ACEI + ARB → Mild Benefit (morb)
ACEI + ARB + B- → Harmful
Valsartan + B- (+++), Valsartan + ACEI (+)
♥ CHARM: Beneficial effects:
Candesartan + ACEI, Candesartan + B-
Candesartan + ACEI + B-

HIGH vs LOW Dose
◙ ACEIs :
► NETWORK: No difference between 5, 10
and 20 mg Enalapril
► ATLAS: High dose Lisinopril:
signif. ↓ mortality + hospit. for CHF
◙ ARBs : Highest tolerated dose in Val-HeFT
and CHARM trials. Low dose in ELITE II
→ HEAAL trial: 50 mg vs 150 mg Losartan

ATLAS compared with SOLVD
Treatments Reduction in risk Reduction in risk
compared of death of death or
hospitalisation for HF
High dose vs.
placebo (SOLVD) 16% 26%
Low dose vs. placebo
(not studied) not known not known
High dose vs.
low dose (ATLAS) 8% 15%
Use of low dose ACEi provides only about half
of the benefit that can be achieved with high dose.

Stage A
Patients at High Risk for
Developing Heart Failure

Stage A Therapy
I
IIa IIb III
Angiotensin Converting Enzyme
Inhibitors (ACEI)
ACEI can be useful to prevent HF in patients at
high risk for developing HF who have a history
of atherosclerotic vascular disease,
diabetes mellitus, or hypertension with
associated cardiovascular risk factors.

Stage A Therapy
Angiotension Receptor Blockers
(ARBs)
I IIa IIb III
ARBs can be useful to prevent HF in patients
at high risk for developing HF who have a
history of atherosclerotic vascular disease,
diabetes mellitus, or hypertension with
associated cardiovascular risk factors.

Stage B
Patients with Asymptomatic
LV Dysfunction

Stage B Therapy
I
IIa IIb III
Angiotensin Converting Enzyme
Inhibitors (ACEI)
Beta-blockers and ACEIs should be used in all
patients with a recent or remote history of MI
regardless of EF or presence of HF.
I
IIa IIb III
I IIa IIb III
ACEI should be used in patients with a reduced EF
and no symptoms of HF, even if they have not
experienced MI.
ACEI or ARBs can be beneficial in patients with
hypertension and LVH and no symptoms of HF.

Stage B Therapy
I IIa IIb III
I IIa IIb III
Angiotensin Receptor Blockers
(ARBs)
An ARB should be administered to post-MI patients
without HF who are intolerant of ACEIs and have a
low LVEF.
ACEIs or ARBs can be beneficial in patients with
hypertension and LVH and no symptoms of HF.
I IIa IIb III
ARBs can be beneficial in patients with low EF and
no symptoms of HF who are intolerant of ACEIs.

Stage C
Patients with Past or Current
Symptoms of Heart Failure

I
IIa IIb III
Stage C Therapy
(Reduced LVEF with Symptoms)
Angiotensin Enzyme Converting
Inhibitors (ACEIs)
ACEIs are recommended for all patients with
current or prior symptoms of HF and reduced
LVEF, unless contraindicated.
I
IIa IIb III
Routine combined use of an ACEI, ARB, and
aldosterone antagonist is not recommended for
patients with current or prior symptoms of HF
and reduced LVEF.

I
I
IIa IIb III
IIa IIb III
Stage C Therapy
(Reduced LVEF with Symptoms)
Angiotensin Receptor Blockers (ARBs)
ARBs approved for the treatment of HF are
recommended in patients with current or prior
symptoms of HF and reduced LVEF who are ACEIintolerant
(see full text guidelines for information
regarding patients with angioedema).
ARBs are reasonable to use as alternatives to ACEIs
as first-line therapy for patients with mild to
moderate HF and reduced LVEF, especially for
patients already taking ARBs for other indications.

I
IIa IIb III
Stage C Therapy
(Reduced LVEF with Symptoms)
ARBs (cont’d)
The addition of an ARB may be considered in
persistently symptomatic patients with reduced
LVEF who are already being treated with
conventional therapy.
I
IIa IIb III
Routine combined use of an ACEI, ARB, and
aldosterone antagonist is not recommended for
Patients with current or prior symptoms of HF and
reduced LVEF.

Myocardial FDG PET Before and
After Myoblast Implantation
before myoblast
implant
after myoblast implant
Menasche P et al. Lancet. 2001;357:279-80.