ACEIs vs ARBs in Congestive Heart Failure - mecire
ACEIs vs ARBs in Congestive Heart Failure - mecire
ACEIs vs ARBs in Congestive Heart Failure - mecire
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<strong>ACEIs</strong> <strong>vs</strong> <strong>ARBs</strong> <strong>in</strong> <strong>Congestive</strong><br />
<strong>Heart</strong> <strong>Failure</strong><br />
Prof. Roland KASSAB<br />
Head of Division of Cardiology<br />
Hotel-Dieu de France, Beirut<br />
Saida, 21/02/2009
Impact of <strong>Heart</strong> <strong>Failure</strong>
HF deaths<br />
<strong>Heart</strong> failure - a grow<strong>in</strong>g burden<br />
Deaths from HF 1979-1997 (USA)<br />
50000<br />
40000<br />
30000<br />
20000<br />
10000<br />
0<br />
1979 1985 1991 1997<br />
Vital Statistics of the United States, National Center for Health Statistics
<strong>Heart</strong> <strong>Failure</strong> is a Major and Grow<strong>in</strong>g<br />
Public Health Problem <strong>in</strong> the U.S.<br />
<br />
Approximately 5 million patients <strong>in</strong> this country have<br />
HF<br />
<br />
Over 550,000 patients are diagnosed with HF for the<br />
first time each year<br />
<br />
Primary reason for 12 to 15 million office visits and<br />
6.5 million hospital days each year<br />
<br />
In 2001, nearly 53,000 patients died of HF as a<br />
primary cause
<strong>Heart</strong> <strong>Failure</strong> is Primarily a<br />
Condition of the Elderly<br />
The <strong>in</strong>cidence of HF approaches 10 per 1000<br />
population after age 65<br />
<br />
HF is the most common Medicare diagnosisrelated<br />
group<br />
<br />
More dollars are spent for the diagnosis and<br />
treatment of HF than any other diagnosis by<br />
Medicare
<strong>Heart</strong> failure - an economic burden:<br />
USA (2000)<br />
Annual cost of HF estimated to be $22.5 billion (USA)<br />
Indirect Costs<br />
Healthcare<br />
providers<br />
Drugs<br />
2.2 1.5 1.1 2.2<br />
Home health/Other<br />
medical durables<br />
15.5<br />
Hospital/Nurs<strong>in</strong>g home<br />
Costs <strong>in</strong> billions of dollars<br />
American <strong>Heart</strong> Association, 2000 <strong>Heart</strong> and Stroke Statistical Update
Role of the RAAS<br />
<strong>in</strong> <strong>Heart</strong> <strong>Failure</strong>
Pathophysiology of CHF<br />
<strong>in</strong>jury to myocytes<br />
and EC matrix<br />
Neurohumoral activation<br />
Increased cytok<strong>in</strong>es<br />
Immune and<br />
<strong>in</strong>flammatory changes<br />
altered fibr<strong>in</strong>olysis<br />
Ventricular<br />
remodell<strong>in</strong>g<br />
Oxidative stress<br />
Apoptosis<br />
Altered gene<br />
Expression<br />
Electrical, vascular, renal,<br />
pulmonary,muscle effects<br />
McMurray J, Pfeffer M. Circulation. 2002.<br />
CHF
Relationship Between Neurohormone Levels<br />
and Survival (CONSENSUS)<br />
100<br />
Ang II Norep<strong>in</strong>ephr<strong>in</strong>e Aldosterone<br />
P
A II Plays a Central Role <strong>in</strong> Organ Damage<br />
Stroke<br />
Atherosclerosis*<br />
Vasoconstriction<br />
Vascular hypertrophy<br />
Hypertension<br />
A II<br />
LV hypertrophy<br />
Fibrosis<br />
Remodel<strong>in</strong>g<br />
Apoptosis<br />
<strong>Heart</strong> failure<br />
MI<br />
DEATH<br />
AT 1 receptor<br />
GFR<br />
Prote<strong>in</strong>uria<br />
Aldosterone release<br />
Glomerular sclerosis<br />
Renal failure<br />
*precl<strong>in</strong>ical data<br />
LV = left ventricular; MI = myocardial <strong>in</strong>farction; GFR = glomerular filtration rate<br />
Adapted from Willenheimer R et al Eur <strong>Heart</strong> J 1999;20(14):997-1008; Dahlöf B J Hum Hypertens 1995;9(suppl 5):S37-S44;<br />
Daugherty A et al J Cl<strong>in</strong> Invest 2000;105(11):1605-1612; Fyhrquist F et al J Hum Hypertens 1995;9(suppl 5):S19-S24;<br />
Booz GW, Baker KM <strong>Heart</strong> Fail Rev 1998;3:125-130; Beers MH, Berkow R, eds. The Merck Manual. 17th ed.<br />
Whitehouse Station, NJ: Merck Research Laboratories, 1999:1682-1704; Anderson S Exp Nephrol 1996;4(suppl 1):34-40;<br />
Fogo AB Am J Kidney Dis 2000;35(2):179-188.
Several pathways of Ang II generation<br />
Local Ang II synthesis is <strong>in</strong>dependent of ACE<br />
Bradyk<strong>in</strong><strong>in</strong><br />
Peptides<br />
Ren<strong>in</strong><br />
<strong>in</strong>hibitor<br />
ACE<br />
<strong>in</strong>hibitor<br />
<strong>ARBs</strong><br />
AT 1 receptor blocker<br />
de Gasparo et al. Pharmacol Rev 2000;<br />
52:415<br />
Angiotens<strong>in</strong>ogen<br />
(Liver)<br />
Angiotens<strong>in</strong> I<br />
Angiotens<strong>in</strong> II<br />
AT 1 AT 2<br />
Chymase
Different roles of AT 1 and AT 2 receptors<br />
Angiotens<strong>in</strong> II<br />
AT 1 AT 2<br />
Vasoconstriction<br />
Vascular proliferation<br />
Aldosterone secretion<br />
Cardiac myocyte<br />
proliferation<br />
Increased sympathetic tone<br />
de Gasparo et al. Pharmacol Rev 2000; 52:415<br />
Vasodilation<br />
Antiproliferation<br />
Apoptosis
Effects of Angiotens<strong>in</strong> II on Growth Factors/Cytok<strong>in</strong>es<br />
and LV Remodel<strong>in</strong>g<br />
Angiotens<strong>in</strong> II<br />
Myocyte hypertrophy<br />
TGF-<br />
PDGF<br />
bFGF<br />
Fibroblast<br />
proliferation<br />
Interstitial collagen<br />
LV remodell<strong>in</strong>g<br />
TGF- = transform<strong>in</strong>g growth factor beta; PDGF = platelet-derived growth factor; bFGF = basic fibroblast<br />
growth factor<br />
19
CHD<br />
ischemia<br />
Thrombus<br />
TIA<br />
Ang<strong>in</strong>a pectoris<br />
Myocardial <strong>in</strong>farction<br />
Stroke<br />
atherosclerosis<br />
LVH<br />
kidney damage<br />
endothelial dysfunction<br />
neuroendocr<strong>in</strong>e<br />
activation<br />
RAS-->AII<br />
arrhythmias<br />
dysfunction<br />
severe ischemia<br />
hypertension<br />
hyperlipemia<br />
diabetes<br />
smok<strong>in</strong>g<br />
stress<br />
.<br />
health<br />
death<br />
The CV Cont<strong>in</strong>uum:Importance of RAS<br />
CHF<br />
New other event<br />
End stage renal disease
% death at 1 year<br />
Mortality Benefit of -Blockers AND<br />
ACE-Inhibitors <strong>in</strong> CHF Trials<br />
16<br />
14<br />
12<br />
10<br />
8<br />
6<br />
4<br />
2<br />
0<br />
SOLVD (1991) CIBIS II<br />
MERIT-HF<br />
S<br />
(1999)<br />
diuretic<br />
digox<strong>in</strong><br />
diuretic<br />
digox<strong>in</strong><br />
ACE-I<br />
diuretic<br />
digox<strong>in</strong><br />
ACE-I<br />
diuretic<br />
digox<strong>in</strong><br />
ACE-I<br />
beta-blocker
CHF: Management Cascade<br />
CHF due to<br />
LVSD<br />
ACE <strong>in</strong>hibitor<br />
-blocker<br />
persist<strong>in</strong>g<br />
symptoms<br />
<strong>in</strong>tractable<br />
Spironolactone<br />
Digox<strong>in</strong><br />
CHF<br />
Transplant<br />
LVAD
HF: Mortality Rema<strong>in</strong>s High<br />
• <strong>ACEIs</strong><br />
– Risk reduction 35% (mortality and hospitalizations) 1<br />
• ß-blockers<br />
– Risk reduction 38% (mortality and hospitalizations) 2<br />
• Spironolactone<br />
– Mortality reduction 23%<br />
• Oral nitrates and hydralaz<strong>in</strong>e<br />
– Benefit <strong>vs</strong> placebo; <strong>in</strong>ferior to enalapril (mortality)<br />
However: 4-year mortality rema<strong>in</strong>s ~40%<br />
1. Davies MK et al. BMJ. 2000;320:428-431 (meta-analysis: 32 trials, N = 7105).<br />
2. Gibbs CR et al. BMJ. 2000;320:495-498 (meta-analysis: 18 trials, N = 3023).
CONSENSUS: Cooperative North Scand<strong>in</strong>avian Enalapril Survival Study<br />
- RESULTS cont<strong>in</strong>ued -<br />
Probability<br />
0.8<br />
Cumulative probability of death p = 0,001<br />
0.6<br />
0.4<br />
0.2<br />
0.0<br />
Placebo<br />
Enalapril<br />
0 2 4 6 8 10 12<br />
Months after randomization<br />
Placebo:<br />
Enalapril:<br />
126<br />
127<br />
78<br />
98<br />
59<br />
82<br />
47<br />
73<br />
34<br />
59<br />
24<br />
42<br />
17<br />
26<br />
CONSENSUS Trial Study Group. N Engl J Med 1987;316:1429–35.
V-HeFT II: Vasodilator–<strong>Heart</strong> <strong>Failure</strong> Trial<br />
- RESULTS cont<strong>in</strong>ued-<br />
Cumulative mortality<br />
Sudden death: p ~ 0,02<br />
Cumulative<br />
mortality<br />
0.75<br />
0.50<br />
0.25<br />
Hydralaz<strong>in</strong>e–<br />
isosorbide<br />
d<strong>in</strong>itrate<br />
0<br />
0<br />
12 24 36 48 60<br />
Enalapril<br />
Months after randomization<br />
Cohn et al. N Engl J Med 1991; 325:303–10.
The Evidence with ACE Inhibitors<br />
MI Mortality Trials<br />
Broad<br />
(short term)<br />
CONSENSUS II(Enalap)<br />
GISSI-3(Lis<strong>in</strong>op)<br />
ISIS-4(Captop)<br />
Ch<strong>in</strong>ese-Cap(Captop)<br />
>100,000 Patients<br />
SAVE<br />
AIRE<br />
Selective<br />
(higher risk, long term)<br />
(EF 40%) Captopril<br />
(cl<strong>in</strong>ical HF)(Ramip)<br />
SMILE (anterior MI, no lytic)<br />
TRACE (wall motion score,<br />
EF 35%)(Trandorap)
Probability of Event<br />
SAVE<br />
Radionuclide<br />
EF 40%<br />
AIRE<br />
Cl<strong>in</strong>ical and/or<br />
radiographic<br />
signs of HF<br />
TRACE<br />
Echocardiographic<br />
EF 35%<br />
0.4<br />
0.35<br />
All-Cause Mortality<br />
0.3<br />
0.25<br />
0.2<br />
Placebo<br />
ACE-I<br />
26%<br />
1500 Deaths,narrow CI<br />
0.15<br />
0.1<br />
Placebo: 866/2971 (29.1%)<br />
ACE-I: 702/2995 (23.4%)<br />
0.05<br />
OR: 0.74 (0.66–0.83)<br />
Years<br />
0<br />
0 1 2 3<br />
4<br />
ACE-I 2995 2250 1617 892 223<br />
Placebo 2971 2184 1521 853 138<br />
Flather MD, et al. Lancet. 2000;355:1575–1581
Events (%)<br />
SAVE<br />
Radionuclide<br />
EF 40%<br />
Death and Major CV Events<br />
AIRE<br />
Cl<strong>in</strong>ical and/or<br />
radiographic<br />
signs of HF<br />
TRACE<br />
Echocardiographic<br />
EF 35%<br />
0.75*<br />
ACE-I (n = 2995)<br />
Placebo (n = 2971)<br />
(0.67 – 0.83)<br />
40<br />
30<br />
20<br />
0.73*<br />
(0.63 – 0.85)<br />
0.80*<br />
(0.69 – 0.95)<br />
10<br />
0<br />
n =<br />
355<br />
n =<br />
460<br />
Readmission<br />
for HF<br />
n =<br />
324<br />
n =<br />
391<br />
Re<strong>in</strong>farction<br />
n =<br />
1049<br />
n =<br />
1244<br />
Death/MI or<br />
Readmission for HF<br />
*odds ratio (95% CI)<br />
Flather MD, et al. Lancet. 2000;355:1575–1581
ACE Inhibitors: The Gold-Standard Treatment for <strong>Heart</strong> <strong>Failure</strong><br />
Mean Duration Mortality Risk Reduction<br />
Study Patients ACE Inhibitor of Follow-Up (mo) (p value)<br />
CONSENSUS Severe heart failure (n=253) Enalapril 6 27% <strong>vs</strong>. placebo* (p=0.003)<br />
SOLVD Mild to moderate Enalapril 41 16% <strong>vs</strong>. placebo* (p=0.0036)<br />
Treatment heart failure (n=2569)<br />
V-HeFT II Mild to moderate Enalapril 30 11% <strong>vs</strong>. hyd-iso* (p=0.016)<br />
heart failure (n=804)<br />
SOLVD Asymptomatic LVD (n=4228) Enalapril 37 8% <strong>vs</strong>. placebo* (p=0.30)<br />
Prevention<br />
SAVE Post-MI with LVD (n=2331) Captopril 42 19% <strong>vs</strong>. placebo (p=0.019)<br />
AIRE Post-MI with LVD (n=2006) Ramipril 15 27% <strong>vs</strong>. placebo* (p=0.002)<br />
TRACE Post-MI with LVD (n=1749) Trandolapril 24–50 (range) 22% <strong>vs</strong>. placebo (p=0.001)<br />
CONSENSUS = Cooperative North Scand<strong>in</strong>avian Enalapril Survival Study; SOLVD = Studies of Left Ventricular Dysfunction; V-HeFT = Veterans<br />
Adm<strong>in</strong>istration Cooperative Vasodilator–<strong>Heart</strong> <strong>Failure</strong> Trial; hyd-iso = hydralaz<strong>in</strong>e–isosorbide d<strong>in</strong>itrate; LVD = left ventricular dysfunction;<br />
SAVE = Survival and Ventricular Enlargement; AIRE = Acute Infarction Ramipril Efficacy; TRACE = Trandolapril Cardiac Evaluation<br />
*Both groups also received digitalis and diuretics with or without non-ACE <strong>in</strong>hibitor vasodilators.<br />
Adapted from the CONSENSUS Trial Study Group N Engl J Med 1987;316(23):1429-1435; the SOLVD Investigators N Engl J Med<br />
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):<br />
685-691; Pfeffer MA et al N Engl J Med 1992;327(10):669-677; the Acute Infarction Ramipril Efficacy (AIRE) Study Investigators<br />
Lancet 1993;342:821-828; and Køber L et al N Engl J Med 1995;333(25):1670-1676.
CHF: Management Cascade<br />
CHF due to<br />
LVSD<br />
ACE <strong>in</strong>hibitor<br />
-blocker<br />
<strong>ARBs</strong><br />
persist<strong>in</strong>g<br />
symptoms<br />
<strong>in</strong>tractable<br />
Spironolactone<br />
Digox<strong>in</strong><br />
CHF<br />
Transplant<br />
LVAD
AT 1 -receptor blockade <strong>vs</strong> ACE-<strong>in</strong>hibition<br />
• Specific selective blockade AT 1 -receptor<br />
• Blocks also non-ACE produced AII<br />
• Stimulation of the AT 2 -receptor<br />
• Benefits beyond BP control?<br />
• No <strong>in</strong>crease <strong>in</strong> bradyk<strong>in</strong><strong>in</strong> systemically<br />
• Fewer side-effects
Balance<br />
AII<br />
AT 1 -block.<br />
AT 1<br />
•Prevention of<br />
damage/event<br />
•Reparation/<br />
regeneration<br />
AT 2
ACE escape: Ang II levels <strong>in</strong>crease over<br />
time despite ACEi<br />
Blood<br />
pressure<br />
mm Hg<br />
Plasma<br />
Ang II<br />
pg/ml<br />
180<br />
160<br />
140<br />
120<br />
100<br />
80<br />
24<br />
20<br />
16<br />
12<br />
8<br />
4<br />
0<br />
Placebo 4h 24h 1 2 3 4 5 6 Months<br />
Hospital<br />
Biollaz et al. J Cardiovasc Pharmacol 1982;4:966
Event rate (%)<br />
OPTIMAAL: Endpo<strong>in</strong>ts<br />
70<br />
60<br />
losartan<br />
captopril<br />
50<br />
40<br />
30<br />
20<br />
10<br />
0<br />
Mortality Re<strong>in</strong>farction Stroke Revasularization Hospitalisation<br />
p= 0.069 0.722 0.587 0.620 0.362<br />
Dickste<strong>in</strong> et al. Lancet 2002;360:752-760.
OPTIMAAL: Discont<strong>in</strong>uations<br />
25<br />
20<br />
p < 0.001<br />
losartan<br />
captopril<br />
% 15<br />
10<br />
p < 0.001<br />
p < 0.001<br />
5<br />
0<br />
All All due to AE Drug-related<br />
due to AE<br />
Dickste<strong>in</strong> Dickste<strong>in</strong> et al. Lancet et 2002;360:752-760. al. Lancet 2002;360:752-760.<br />
p = 0.010<br />
Serious AE<br />
p = 0.002<br />
Serious AE,<br />
drug-related
Acute MI (0.5–10 days)—SAVE, AIRE or TRACE eligible<br />
(either cl<strong>in</strong>ical/radiologic signs of HF or LV systolic dysfunction)<br />
Major Exclusion Criteria:<br />
— Serum creat<strong>in</strong><strong>in</strong>e > 2.5 mg/dL<br />
— BP < 100 mm Hg<br />
— Prior <strong>in</strong>tolerance of an ARB or ACE-I<br />
— Nonconsent<br />
Captopril 50 mg tid<br />
(n = 4909)<br />
double-bl<strong>in</strong>d active-controlled<br />
Valsartan 160 mg bid<br />
(n = 4909)<br />
Captopril 50 mg tid +<br />
Valsartan 80 mg bid<br />
(n = 4885)<br />
median duration: 24.7 months<br />
event-driven<br />
Primary Endpo<strong>in</strong>t: All-Cause Mortality<br />
Secondary Endpo<strong>in</strong>ts: CV Death, MI, or HF<br />
Other Endpo<strong>in</strong>ts: Safety and Tolerability
Probability of Event<br />
Mortality by Treatment<br />
0.3<br />
0.25<br />
Captopril<br />
Valsartan<br />
Valsartan + Captopril<br />
0.2<br />
0.15<br />
0.1<br />
Months<br />
0.05<br />
Valsartan <strong>vs</strong>. Captopril: HR = 1.00; P = 0.982<br />
Valsartan + Captopril <strong>vs</strong>. Captopril: HR = 0.98; P = 0.726<br />
0<br />
0 6 12 18 24 30 36<br />
Captopril 4909 4428 4241 4018 2635 1432 364<br />
Valsartan 4909 4464 4272 4007 2648 1437 357<br />
Valsartan + Cap 4885 4414 4265 3994 2648 1435 382<br />
Pfeffer et al. N Engl J Med 2003;349
Post – MI : The evidence so far<br />
• In light of the large amount of data, ACE<br />
<strong>in</strong>hibitors rema<strong>in</strong> the therapy of choice <strong>in</strong><br />
patients with post MI<br />
• In patients <strong>in</strong> whom ACE <strong>in</strong>hibitors are<br />
contra<strong>in</strong>dicated<br />
or not tolerated, A II antagonists may be useful<br />
alternative agents.<br />
Dickste<strong>in</strong> et al. Lancet 2002;360:752-760.
The Evidence with AII Antagonists<br />
HF Mortality Trials<br />
ELITE I<br />
Losartan (50 mg/day)<br />
ELITE II<br />
Losartan (50 mg/day)<br />
VAL-Heft<br />
Valsartan (320 mg/day)<br />
CHARM<br />
Candesartan ( 32 mg/day)<br />
HEAAL<br />
Losartan 50 <strong>vs</strong> 150 mg/day
AIIA End-Po<strong>in</strong>t Trials <strong>in</strong><br />
Patients With <strong>Heart</strong> <strong>Failure</strong><br />
Treatment groups and Patient Entry NYHA<br />
Trial dose titrations (mg) population age (y) class<br />
ELITE II Losartan 12.52550 QD ACEI naive 60 II–IV<br />
(3,152) Captopril 12.52550 TID<br />
Val-HeFT Valsartan 4080160 BID Mostly ACEI 60 II–IV<br />
(5,200) Placebo (usual care, ACEI) treated<br />
CHARM-I Candesartan 4832 + ACEI QD ACEI treated; 18 II–IV<br />
(2,300) Placebo (usual care, ACEI) depressed LV<br />
systolic function<br />
CHARM-II Candesartan 4832 QD ACEI <strong>in</strong>tolerant: 18 II–IV<br />
(1,700) Placebo (usual care) depressed LV<br />
systolic function<br />
CHARM-III Candesartan 4832 QD No ACEI treatment; 18 II–IV<br />
(2,500) Placebo (usual care) preserved LV<br />
systolic function
Probability of survival<br />
The Losartan <strong>Heart</strong> <strong>Failure</strong> Survival Study–ELITE II<br />
Primary Endpo<strong>in</strong>t: All-Cause Mortality<br />
Kaplan-Meier Estimates for Survival<br />
1.0<br />
0.8<br />
0.6<br />
0.4<br />
0.2<br />
Hazard ratio (95.7% CI):<br />
1.13 (0.95, 1.35); p=0.16)<br />
Days of follow-up<br />
Losartan (n=1578)<br />
Captopril (n=1574)<br />
0<br />
0 100 200 300 400 500 600 700<br />
• No significant<br />
difference<br />
between<br />
losartan and<br />
captopril <strong>in</strong><br />
reduc<strong>in</strong>g<br />
all-cause<br />
mortality <strong>in</strong><br />
heart failure<br />
CI = confidence <strong>in</strong>terval<br />
Adapted from Pitt B et al Lancet 2000;355:1582-1587.
The Losartan <strong>Heart</strong> <strong>Failure</strong> Survival Study–ELITE II<br />
Event-free probability<br />
Secondary Endpo<strong>in</strong>t: Sudden Death or Resuscitated<br />
Cardiac Arrest<br />
1.0<br />
0.8<br />
0.6<br />
Losartan (n=1578)<br />
Captopril (n=1574)<br />
0.4<br />
0.2<br />
Hazard ratio (95% CI):<br />
1.25 (0.98, 1.60); p=NS)<br />
0<br />
0 100 200 300 400 500 600 700<br />
Days of follow-up<br />
Adapted from Pitt B et al Lancet 2000;355:1582-1587.
% of patients<br />
The Losartan <strong>Heart</strong> <strong>Failure</strong> Survival Study–ELITE II<br />
Other Endpo<strong>in</strong>ts: Discont<strong>in</strong>uations from Study Therapy<br />
Due to Adverse Events (AEs)*<br />
16<br />
14<br />
12<br />
10<br />
8<br />
6<br />
4<br />
2<br />
0<br />
9.7<br />
p
The Losartan <strong>Heart</strong> <strong>Failure</strong> Survival Study–ELITE II<br />
Study Summary<br />
In patients with symptomatic heart failure due to systolic LVD:<br />
• No statistically significant differences were observed between<br />
losartan <strong>vs</strong>. captopril with respect to:<br />
– All-cause mortality (primary endpo<strong>in</strong>t)<br />
– Composite of sudden cardiac death/resuscitated cardiac arrest<br />
(secondary endpo<strong>in</strong>t)<br />
– Composite of all-cause mortality/all-cause hospitalization<br />
(tertiary endpo<strong>in</strong>t)<br />
– Deaths, hospitalization, discont<strong>in</strong>uations relat<strong>in</strong>g to heart failure<br />
• Losartan was better tolerated than captopril, with significantly<br />
fewer discont<strong>in</strong>uations due to adverse experiences (p
Angioedema
Val-HeFT Design<br />
5,010 HF patients<br />
>18 yr; EF
Study Overview<br />
5010 patients<br />
18 years; EF 2.9 cm/m 2<br />
ACE <strong>in</strong>hibitors (92.7%), diuretics (85.8%),<br />
digox<strong>in</strong> (67.3%), -blockers (35.6%)<br />
Randomized to<br />
Receiv<strong>in</strong>g background therapy<br />
Valsartan<br />
40 mg bid titrated to<br />
160 mg bid<br />
Placebo<br />
Cohn JN et al. Eur J <strong>Heart</strong> Fail. 2000;2:439-446.
Event-free probability<br />
Survival probability (%)<br />
Primary Endpo<strong>in</strong>ts<br />
(Overall Population)<br />
1.0<br />
0.9<br />
All-cause mortality and morbidity<br />
Valsartan<br />
1.0<br />
0.9<br />
0.8<br />
All-cause mortality<br />
p = 0.80<br />
0.8<br />
Placebo<br />
0.7<br />
0 3 6 9 12 15 18 21 24 27<br />
Time s<strong>in</strong>ce randomisation<br />
(months)<br />
0.7<br />
0.6<br />
0<br />
13% risk reduction p=<br />
0.009<br />
3 6 9 12 15 18 21 24 27<br />
Time s<strong>in</strong>ce randomisation (months)<br />
Cohn et al. NEJM 2001;345:1667
Event-free probability<br />
Secondary Endpo<strong>in</strong>ts<br />
(Overall Population)<br />
1.0<br />
0.9<br />
HF hospitalisations<br />
Valsartan<br />
27.5%<br />
risk reduction<br />
p
Proportion Survived (%)<br />
Reduction <strong>in</strong> Mortality<br />
(No ACEI)<br />
100<br />
90<br />
80<br />
Placebo<br />
(N = 181)<br />
Valsartan<br />
(N = 185)<br />
70<br />
60<br />
50<br />
Maggioni et al. J Am Coll Cardiol 2002;<br />
40:1414<br />
Risk reduction= 33.1%<br />
P value (log-rank) = 0.0171<br />
0 3 6 9 12 15 18 21 24 27 30<br />
Time S<strong>in</strong>ce Randomisation (months)
Event-Free Probability<br />
Reduction <strong>in</strong> Comb<strong>in</strong>ed Morbidity<br />
Endpo<strong>in</strong>t (No ACEI)<br />
100<br />
90<br />
80<br />
70<br />
60<br />
50<br />
40<br />
Placebo<br />
(N = 181)<br />
Risk reduction = 44.0%<br />
P value (log-rank) = 0.0002<br />
Valsartan<br />
(N = 185)<br />
0 3 6 9 12 15 18 21 24 27 30<br />
Time S<strong>in</strong>ce Randomisation (months)<br />
Maggioni et al. J Am Coll Cardiol 2002;<br />
40:1414
Background therapy: Relative risks and<br />
95% CI of morbidity and mortality endpo<strong>in</strong>ts<br />
Favors valsartan<br />
Favors placebo<br />
Morbidity<br />
ACEI+ BB– 3,034<br />
ACEI+ BB+ 1,610<br />
ACEI– BB– 226<br />
ACEI– BB+ 140<br />
Mortality<br />
ACEI+ BB– 3,034<br />
ACEI+ BB+ 1,610<br />
ACEI– BB– 226<br />
ACEI– BB+ 140<br />
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<br />
Cox regression model<br />
Cohn et al. New Engl J Med. 2001; 345: 1667
Val-HeFT - Conclusions<br />
• No difference on mortality (19.7% <strong>vs</strong> 19.4%; p=0.8)<br />
• Significant difference <strong>in</strong> favor of combo on<br />
comb<strong>in</strong>ed endpo<strong>in</strong>t of mortality and morbidity<br />
( 28.8% <strong>vs</strong> 32.1%; p=0.009) (when exclud<strong>in</strong>g pats not receiv<strong>in</strong>g an ACE-I the<br />
difference becomes non-significant)<br />
• Significant difference <strong>in</strong> favor of combo on HF<br />
hospital. (13.9% <strong>vs</strong> 18.5% ; p=0.0001)<br />
• Significantly more withdrawals due to AE’s on<br />
combo (9.9% <strong>vs</strong> 7%; p
CHARM Programme<br />
3 component trials compar<strong>in</strong>g candesartan to<br />
placebo <strong>in</strong> patients with symptomatic heart failure<br />
CHARM<br />
Alternative<br />
n=2028<br />
LVEF 40%<br />
ACE <strong>in</strong>hibitor<br />
<strong>in</strong>tolerant<br />
CHARM<br />
Added<br />
n=2548<br />
LVEF 40%<br />
ACE <strong>in</strong>hibitor<br />
treated<br />
CHARM<br />
Preserved<br />
n=3025<br />
LVEF >40%<br />
ACE <strong>in</strong>hibitor<br />
treated/not treated<br />
Primary outcome for each trial: CV death or CHF hospitalisation<br />
Primary outcome for Overall Programme: All-cause death<br />
Pfeffer et al, Lancet 2003
CHARM-Alternative<br />
Primary outcome, CV death or CHF hospitalisation<br />
%<br />
50<br />
406 (40%)<br />
Placebo<br />
40<br />
334 (33%)<br />
30<br />
Candesartan<br />
20<br />
10<br />
0<br />
Number at risk<br />
HR 0.77 (95% CI 0.67-0.89), p=0.0004<br />
Adjusted HR 0.70, p
CHARM-Alternative<br />
Conclusions<br />
• Despite prior <strong>in</strong>tolerance to another<br />
<strong>in</strong>hibitor of the ren<strong>in</strong>-angiotens<strong>in</strong>aldosterone<br />
system, candesartan was<br />
well tolerated<br />
• In patients with symptomatic CHF and<br />
ACE <strong>in</strong>hibitor <strong>in</strong>tolerance, candesartan<br />
reduces cardiovascular mortality and<br />
morbidity<br />
Granger et al, Lancet 2003
CHARM Programme<br />
3 component trials compar<strong>in</strong>g<br />
candesartan to placebo<br />
CHARM<br />
Alternative<br />
n=2028<br />
LVEF 40%<br />
ACE <strong>in</strong>hibitor<br />
<strong>in</strong>tolerant<br />
CHARM<br />
Added<br />
n=2548<br />
LVEF 40%<br />
ACE <strong>in</strong>hibitor<br />
treated<br />
CHARM<br />
Preserved<br />
n=3025<br />
LVEF >40%<br />
ACE <strong>in</strong>hibitor<br />
treated/not treated<br />
Primary outcome:<br />
CV death or CHF hospitalisation<br />
McMurray et al, Lancet 2003
CHARM-Added<br />
Primary outcome, CV death or CHF hospitalisation<br />
%<br />
50<br />
40<br />
Placebo<br />
538 (42.3%)<br />
483 (37.9%)<br />
30<br />
Candesartan<br />
20<br />
Number at risk<br />
10<br />
0<br />
HR 0.85 (95% CI 0.75-0.96), p=0.011<br />
Adjusted HR 0.85, p=0.010<br />
0 1 2 3 3.5 years<br />
Candesartan 1276 1176 1063 948 457<br />
Placebo 1272 1136 1013 906 422<br />
McMurray et al, Lancet 2003
CHARM-Added<br />
Primary and secondary outcomes<br />
Number of patients<br />
Candesartan Placebo<br />
CV death, CV hosp 483 538<br />
- CV death 302 347<br />
- CHF hosp 309 356<br />
CV death, CHF hosp, 495 550<br />
MI<br />
CV death,CHF hosp, 512 559<br />
MI, stroke<br />
CV death,CHF hosp, 548 596<br />
MI, stroke, revasc<br />
p-value<br />
0.011<br />
0.029<br />
0.014<br />
0.010<br />
0.020<br />
0.015<br />
0.6 0.8 1.0 1.2 1.4<br />
Candesartan Hazard Placebo<br />
better ratio better<br />
McMurray et al, Lancet 2003
CHARM-Added<br />
Prespecified subgroups, CV death or CHF<br />
hospitalisation<br />
Candesartan<br />
event/n<br />
Placebo<br />
event/n<br />
p-value for<br />
treatment<br />
<strong>in</strong>teraction<br />
Beta- Yes 223/702 274/711<br />
blocker No 260/574 264/561<br />
Recom. Yes 232/643 275/648<br />
dose of No 251/633 263/624<br />
ACE <strong>in</strong>hib<br />
All patients 483/1276 538/1272<br />
0.14<br />
0.26<br />
0.6 0.8 1.0 1.2 1.4<br />
Candesartan Hazard Placebo<br />
better ratio better<br />
McMurray et al, Lancet 2003
CHARM-Added<br />
Conclusions<br />
• Addition of candesartan to an ACE <strong>in</strong>hibitor<br />
(and beta-blocker) leads to a further and<br />
cl<strong>in</strong>ically important reduction <strong>in</strong> CV mortality<br />
and morbidity <strong>in</strong> patients with CHF<br />
• This benefit is obta<strong>in</strong>ed with relatively few<br />
adverse effects, although there is an<br />
<strong>in</strong>creased risk of hypotension,<br />
hyperkalaemia and renal dysfunction<br />
McMurray et al, Lancet 2003
Primary Hypothesis: HEAAL<br />
Study<br />
In patients with congestive heart failure who are<br />
<strong>in</strong>tolerant to treatment with an ACEI, treatment<br />
with losartan 150 mg daily will be superior to<br />
treatment with losartan 50 mg daily by 15% , as<br />
assessed by the effect on the composite event<br />
rate of all cause death and/or hospitalization for<br />
heart failure.
Val-HeFT impact on treatment guidel<strong>in</strong>es:<br />
Europe 2002<br />
Recommended pharmacological therapy of<br />
symptomatic chronic HF due to systolic left<br />
ventricular dysfunction:<br />
For symptoms; NYHA Class II-IV:<br />
• ARB if ACEI <strong>in</strong>tolerant<br />
• ARB+ACEI if blocker <strong>in</strong>tolerant<br />
Remme et al. Eur <strong>Heart</strong> J. 2001; 22: 1527
Val-HeFT impact on treatment<br />
guidel<strong>in</strong>es: USA 2001<br />
Recommendations for treatment of symptomatic left<br />
ventricular systolic dysfunction:<br />
Evidence class IIa<br />
• Angiotens<strong>in</strong> receptor blockade <strong>in</strong> patients who<br />
are be<strong>in</strong>g treated with digitalis, diuretics, and a <br />
blocker and who cannot be given an ACE<strong>in</strong>hibitor<br />
Evidence class IIb<br />
• Addition of an ARB to an ACE-<strong>in</strong>hibitor*<br />
(*assumes the patient is not be<strong>in</strong>g treated with a blocker)<br />
Hunt et al. Practice Guidel<strong>in</strong>es ACC/AHA 2001
<strong>Heart</strong> <strong>Failure</strong> Therapy: The evidence so far<br />
• ACE <strong>in</strong>hibitors rema<strong>in</strong> the therapy of choice <strong>in</strong><br />
patients with symptomatic heart failure due to<br />
systolic LVD.<br />
• In patients <strong>in</strong> whom ACE <strong>in</strong>hibitors are<br />
contra<strong>in</strong>dicated<br />
or not tolerated, A II antagonists at the<br />
recommended doses may be useful alternative<br />
agents.<br />
Adapted from Pitt B et al Lancet 2000;355:1582-1587.
Reduced LV<br />
SF<br />
Preserved LV<br />
SF
CHF Despite Preserved LV systolic<br />
Function<br />
• CHARM (candesartan)<br />
• PEP-CHF (per<strong>in</strong>dopril)<br />
• SENIORS (nebivolol)<br />
• I-PRESERVE (irbesartan)
CHARM-Preserved<br />
Primary outcome, CV death or CHF hospitalisation<br />
%<br />
30<br />
25<br />
20<br />
15<br />
Placebo<br />
Candesartan<br />
366 (24.3%)<br />
333 (22.0%)<br />
10<br />
Number at risk<br />
5<br />
0<br />
HR 0.89 (95% CI 0.77-1.03), p=0.118<br />
Adjusted HR 0.86, p=0.051<br />
0 1 2 3 3.5 years<br />
Candesartan 1514 1458 1377 833 182<br />
Placebo 1509 1441 1359 824 195<br />
Yusuf et al, Lancet 2003
CHARM-Preserved<br />
Investigator-reported CHF hospitalisations<br />
Patients (%)<br />
Number of<br />
episodes<br />
Placebo<br />
Candesartan<br />
25<br />
700<br />
20<br />
p=0.017<br />
600<br />
500<br />
p=0.014<br />
15<br />
400<br />
10<br />
300<br />
5<br />
200<br />
100<br />
0<br />
Patients hospitalised<br />
0<br />
Hospitalisations<br />
Yusuf et al, Lancet 2003
CHARM-Preserved<br />
Development of new diabetes<br />
Number of cases (%) HR p-value<br />
Candesartan Placebo<br />
n=1080 n=1086<br />
(CI)<br />
47 (4) 77 (7) 0.60 0.005<br />
(0.41-0.86)<br />
Yusuf et al, Lancet 2003
Cleland JGF. World Congress of Cardiology 2006;<br />
September 3, 2006; Barcelona, Spa<strong>in</strong>.<br />
One-year outcomes <strong>in</strong> PEP-CHF,<br />
per<strong>in</strong>dopril <strong>vs</strong> placebo<br />
End po<strong>in</strong>t<br />
All-cause mortality or<br />
unplanned HF<br />
hospitalization<br />
Unplanned HF<br />
hospitalization<br />
Per<strong>in</strong>dopril,<br />
n=424 (%)<br />
Placebo,<br />
n=426 (%)<br />
10.8 15.3 0.055<br />
8.0 12.4 0.033<br />
All-cause mortality 4.0 4.5 NS<br />
p
Hazard ratio for all-cause mortality or<br />
unplanned HF hospitalization at 1 year by<br />
subgroups<br />
Patient subgroups HR (95% CI) p<br />
Age 75 years 0.87 (0.53-1.42) 0.575<br />
Systolic BP 140 0.52 (0.26-1.03) 0.055<br />
History of MI 0.38 (0.19-0.75) 0.004<br />
No MI history 0.92 (0.58-1.46) 0.719<br />
Cleland JGF. World Congress of Cardiology 2006;<br />
September 3, 2006; Barcelona, Spa<strong>in</strong>.
I-PRESERVE: Entry Criteria<br />
Age 60 years<br />
Current HF symptoms<br />
LVEF 0.45<br />
NYHA class II - IV<br />
CHF hosp. 6 months<br />
NYHA Class III/IV<br />
CXR congestion<br />
ECG (LVH, LBBB)<br />
Echo (LVH, LAE)<br />
Key Exclusions: SBP >160 mm Hg; prior EF 2.5, Hb
I-PRESERVE: Study Design<br />
Randomized, double-bl<strong>in</strong>d, placebo controlled trial<br />
Irbesartan<br />
N=4,128<br />
75 mg 150 mg 300 mg<br />
Enrollment<br />
S<strong>in</strong>gle-bl<strong>in</strong>d<br />
2 weeks<br />
R<br />
Forced titration<br />
Ma<strong>in</strong>tenance<br />
Only 1/3 pts could<br />
enter on an ACEI<br />
W 2 W 4 W 8 M 6 M 10 M 14 to end<br />
Every 4 months<br />
Placebo<br />
Follow-up cont<strong>in</strong>ued until 1,440 primary endpo<strong>in</strong>ts occurred
Cumulative Incidence of<br />
Primary Events (%)<br />
I-PRESERVE: Primary Endpo<strong>in</strong>t<br />
Death or protocol specified CV hospitalization<br />
40 -<br />
HR (95% CI) = 0.95 (0.86-1.05)<br />
Log-rank p=0.35<br />
Placebo<br />
30 -<br />
Irbesartan<br />
20 -<br />
10 -<br />
0 -<br />
No. at Risk<br />
Irbesartan<br />
Placebo<br />
0 6 12 18 24 30 36 42 48 54 60<br />
Months from Randomization<br />
2067 1929 1812 1730 1640 1569 1513 1291 1088 816 497<br />
2061 1921 1808 1715 1618 1539 1466 1246 1051 776 446
Secondary Outcomes<br />
Patients with Events<br />
Outcome<br />
Placebo<br />
(n=2061)<br />
Irbesartan<br />
(n=2067)<br />
HR (95% CI)<br />
Death<br />
436<br />
445<br />
1.00 (0.88-1.14)<br />
CV death<br />
302<br />
311<br />
1.01 (0.86-1.18)<br />
HF death or HF<br />
hospitalization<br />
438<br />
428<br />
0.96 (0.84-1.09)<br />
CV death MI or stroke<br />
400<br />
402<br />
0.99 (0.86-1.13)<br />
P=NS for all
I-PRESERVE: Conclusions<br />
• In I-PRESERVE, HF-PEF patients experienced substantial<br />
mortality and cardiovascular morbidity.<br />
• Irbesartan did not reduce the primary endpo<strong>in</strong>t of death and<br />
protocol-specified CV hospitalizations, nor did it significantly<br />
benefit prespecified secondary endpo<strong>in</strong>ts.<br />
• Our results are consistent with the two previous trials <strong>in</strong> patients<br />
with HF-PEF that did not demonstrate a positive effect.<br />
• For this large group of patients constitut<strong>in</strong>g half of all heart<br />
failure patients, there cont<strong>in</strong>ues to be no specific evidencebased<br />
therapy.<br />
• In order for this field to move forward, a better understand<strong>in</strong>g of<br />
the mechanisms underly<strong>in</strong>g this syndrome and additional<br />
potential targets for treatment are required.
ACEI and/or <strong>ARBs</strong> <strong>in</strong> CHF<br />
As with any therapy, the pragmatic 4 W questions must<br />
be answered:<br />
WHY ?<br />
WHEN ?<br />
WHO ?<br />
WHAT ?
<strong>ACEIs</strong> and/or <strong>ARBs</strong> <strong>in</strong> CHF<br />
WHY?<br />
► Pivotal role of the RAAS <strong>in</strong> the<br />
pathophysiology of CHF<br />
► All Mega-trials with <strong>ACEIs</strong> or <strong>ARBs</strong> <strong>vs</strong><br />
Placebo proved that both agents:<br />
♥ Improve Survival <strong>in</strong> CHF<br />
♥ Improve Quality of Life
<strong>ACEIs</strong> and/or <strong>ARBs</strong> <strong>in</strong> CHF<br />
WHEN?<br />
► As soon as possible, once CHF diagnosed<br />
NYHA class I: <strong>ACEIs</strong>: SOLVD Prevention<br />
(Enalapril)<br />
► As soon as possible after MI, if no contra<strong>in</strong>dication<br />
► Up-titration every 2 wks for both agents<br />
→ recommended dose
<strong>ACEIs</strong> and/or <strong>ARBs</strong> <strong>in</strong> CHF<br />
WHO?<br />
Post-MI<br />
LV dysfunction<br />
Mild<br />
CHF<br />
Moderate<br />
CHF<br />
Severe<br />
CHF<br />
TRACE / AIRE / SAVE<br />
(ramipril / captopril)<br />
trandolapril<br />
ACE <strong>in</strong>tolerant:<br />
VALIANT (valsartan)<br />
SOLVD Treatment<br />
(enalapril)<br />
Val-HeFT (valsartan)<br />
CHARM (candesartan)<br />
ELITE II (losartan:dose?)<br />
CONSENSUS<br />
(enalapril)
<strong>ACEIs</strong> and/or <strong>ARBs</strong> <strong>in</strong> CHF<br />
WHAT?<br />
► Class Effect ? Evidence-based medic<strong>in</strong>e:<br />
Enalapril, Lis<strong>in</strong>opril<br />
Small trials with Per<strong>in</strong>dopril and Fos<strong>in</strong>opril<br />
Alternative Tt: Valsartan, Candesartan,<br />
Losartan (high dose?)<br />
► CHF post acute MI: Captopril, Ramipril,<br />
Trandolapril. Alternative Tt: Valsartan<br />
► Cost problems
<strong>ACEIs</strong> and <strong>ARBs</strong> <strong>in</strong> CHF<br />
♥ Rationale: complete blockade of RAAS<br />
♥ RESOLVD: Candesartan + Enalapril:<br />
↑ EF and ↓ V volumes <strong>vs</strong> Cand. or Enal.<br />
♥Val-HeFT: ACEI + ARB → Mild Benefit (morb)<br />
ACEI + ARB + B- → Harmful<br />
Valsartan + B- (+++), Valsartan + ACEI (+)<br />
♥ CHARM: Beneficial effects:<br />
Candesartan + ACEI, Candesartan + B-<br />
Candesartan + ACEI + B-
HIGH <strong>vs</strong> LOW Dose<br />
◙ <strong>ACEIs</strong> :<br />
► NETWORK: No difference between 5, 10<br />
and 20 mg Enalapril<br />
► ATLAS: High dose Lis<strong>in</strong>opril:<br />
signif. ↓ mortality + hospit. for CHF<br />
◙ <strong>ARBs</strong> : Highest tolerated dose <strong>in</strong> Val-HeFT<br />
and CHARM trials. Low dose <strong>in</strong> ELITE II<br />
→ HEAAL trial: 50 mg <strong>vs</strong> 150 mg Losartan
ATLAS compared with SOLVD<br />
Treatments Reduction <strong>in</strong> risk Reduction <strong>in</strong> risk<br />
compared of death of death or<br />
hospitalisation for HF<br />
High dose <strong>vs</strong>.<br />
placebo (SOLVD) 16% 26%<br />
Low dose <strong>vs</strong>. placebo<br />
(not studied) not known not known<br />
High dose <strong>vs</strong>.<br />
low dose (ATLAS) 8% 15%<br />
Use of low dose ACEi provides only about half<br />
of the benefit that can be achieved with high dose.
Stage A<br />
Patients at High Risk for<br />
Develop<strong>in</strong>g <strong>Heart</strong> <strong>Failure</strong>
Stage A Therapy<br />
I<br />
IIa IIb III<br />
Angiotens<strong>in</strong> Convert<strong>in</strong>g Enzyme<br />
Inhibitors (ACEI)<br />
ACEI can be useful to prevent HF <strong>in</strong> patients at<br />
high risk for develop<strong>in</strong>g HF who have a history<br />
of atherosclerotic vascular disease,<br />
diabetes mellitus, or hypertension with<br />
associated cardiovascular risk factors.
Stage A Therapy<br />
Angiotension Receptor Blockers<br />
(<strong>ARBs</strong>)<br />
I IIa IIb III<br />
<strong>ARBs</strong> can be useful to prevent HF <strong>in</strong> patients<br />
at high risk for develop<strong>in</strong>g HF who have a<br />
history of atherosclerotic vascular disease,<br />
diabetes mellitus, or hypertension with<br />
associated cardiovascular risk factors.
Stage B<br />
Patients with Asymptomatic<br />
LV Dysfunction
Stage B Therapy<br />
I<br />
IIa IIb III<br />
Angiotens<strong>in</strong> Convert<strong>in</strong>g Enzyme<br />
Inhibitors (ACEI)<br />
Beta-blockers and <strong>ACEIs</strong> should be used <strong>in</strong> all<br />
patients with a recent or remote history of MI<br />
regardless of EF or presence of HF.<br />
I<br />
IIa IIb III<br />
I IIa IIb III<br />
ACEI should be used <strong>in</strong> patients with a reduced EF<br />
and no symptoms of HF, even if they have not<br />
experienced MI.<br />
ACEI or <strong>ARBs</strong> can be beneficial <strong>in</strong> patients with<br />
hypertension and LVH and no symptoms of HF.
Stage B Therapy<br />
I IIa IIb III<br />
I IIa IIb III<br />
Angiotens<strong>in</strong> Receptor Blockers<br />
(<strong>ARBs</strong>)<br />
An ARB should be adm<strong>in</strong>istered to post-MI patients<br />
without HF who are <strong>in</strong>tolerant of <strong>ACEIs</strong> and have a<br />
low LVEF.<br />
<strong>ACEIs</strong> or <strong>ARBs</strong> can be beneficial <strong>in</strong> patients with<br />
hypertension and LVH and no symptoms of HF.<br />
I IIa IIb III<br />
<strong>ARBs</strong> can be beneficial <strong>in</strong> patients with low EF and<br />
no symptoms of HF who are <strong>in</strong>tolerant of <strong>ACEIs</strong>.
Stage C<br />
Patients with Past or Current<br />
Symptoms of <strong>Heart</strong> <strong>Failure</strong>
I<br />
IIa IIb III<br />
Stage C Therapy<br />
(Reduced LVEF with Symptoms)<br />
Angiotens<strong>in</strong> Enzyme Convert<strong>in</strong>g<br />
Inhibitors (<strong>ACEIs</strong>)<br />
<strong>ACEIs</strong> are recommended for all patients with<br />
current or prior symptoms of HF and reduced<br />
LVEF, unless contra<strong>in</strong>dicated.<br />
I<br />
IIa IIb III<br />
Rout<strong>in</strong>e comb<strong>in</strong>ed use of an ACEI, ARB, and<br />
aldosterone antagonist is not recommended for<br />
patients with current or prior symptoms of HF<br />
and reduced LVEF.
I<br />
I<br />
IIa IIb III<br />
IIa IIb III<br />
Stage C Therapy<br />
(Reduced LVEF with Symptoms)<br />
Angiotens<strong>in</strong> Receptor Blockers (<strong>ARBs</strong>)<br />
<strong>ARBs</strong> approved for the treatment of HF are<br />
recommended <strong>in</strong> patients with current or prior<br />
symptoms of HF and reduced LVEF who are ACEI<strong>in</strong>tolerant<br />
(see full text guidel<strong>in</strong>es for <strong>in</strong>formation<br />
regard<strong>in</strong>g patients with angioedema).<br />
<strong>ARBs</strong> are reasonable to use as alternatives to <strong>ACEIs</strong><br />
as first-l<strong>in</strong>e therapy for patients with mild to<br />
moderate HF and reduced LVEF, especially for<br />
patients already tak<strong>in</strong>g <strong>ARBs</strong> for other <strong>in</strong>dications.
I<br />
IIa IIb III<br />
Stage C Therapy<br />
(Reduced LVEF with Symptoms)<br />
<strong>ARBs</strong> (cont’d)<br />
The addition of an ARB may be considered <strong>in</strong><br />
persistently symptomatic patients with reduced<br />
LVEF who are already be<strong>in</strong>g treated with<br />
conventional therapy.<br />
I<br />
IIa IIb III<br />
Rout<strong>in</strong>e comb<strong>in</strong>ed use of an ACEI, ARB, and<br />
aldosterone antagonist is not recommended for<br />
Patients with current or prior symptoms of HF and<br />
reduced LVEF.
Myocardial FDG PET Before and<br />
After Myoblast Implantation<br />
before myoblast<br />
implant<br />
after myoblast implant<br />
Menasche P et al. Lancet. 2001;357:279-80.