1) ACE inhibitors have been shown to reduce mortality in patients with heart failure, myocardial infarction, and left ventricular dysfunction based on large clinical trials from the 1980s-1990s. 2) Later trials showed that ARBs were also effective in reducing adverse outcomes in heart failure. 3) The CHARM trials in the 2000s demonstrated the benefits of ARBs like candesartan in different types of heart failure. 4) Combining an ARB with an ACE inhibitor did not provide additional benefits beyond an ACE inhibitor alone according to the ONTARGET trial.

1. Success of Neurohormonal Blockade:Success of Neurohormonal Blockade:
Looking Back – Looking ForwardLooking Back – Looking Forward
ACE InhibitorsACE Inhibitors
Marc A. Pfeffer, MD, PhDMarc A. Pfeffer, MD, PhD
Dzau Professor of Medicine, Harvard Medical SchoolDzau Professor of Medicine, Harvard Medical School
Cardiovascular Division, Brigham & Women’s HospitalCardiovascular Division, Brigham & Women’s Hospital
Boston, MassachusettsBoston, Massachusetts
Disclosures: Marc A. Pfeffer, M.D., Ph.D., reports having serves as consultant to Aastrom, Abbott Vascular, Amgen, Cleveland
Clinic, Concert, Daiichi Sankyo, Fibrogen, Genzyme, GlaxoSmithKline, Hamilton Health Sciences, Medtronic, Merck, Novartis, Novo
Nordisk, Roche, Salix, Sanderling, Sanofi Aventis, Servier, and Teva and having received grant support from Amgen, Celladon,
Novartis, and Sanofi-Aventis. The Brigham and Women’s Hospital has patents for the use of inhibitors of the renin-angiotensin
system in survivors of MI with Novartis. Dr. Pfeffer’s shares are irrevocably transferred to charity.

2. Success of Neurohormonal Blockade:Success of Neurohormonal Blockade:
Looking Back – Looking ForwardLooking Back – Looking Forward
ACE Inhibitors/ ARBsACE Inhibitors/ ARBs
Marc A. Pfeffer, MD, PhDMarc A. Pfeffer, MD, PhD
Dzau Professor of Medicine, Harvard Medical SchoolDzau Professor of Medicine, Harvard Medical School
Cardiovascular Division, Brigham & Women’s HospitalCardiovascular Division, Brigham & Women’s Hospital
Boston, MassachusettsBoston, Massachusetts
Disclosures: Marc A. Pfeffer, M.D., Ph.D., reports having serves as consultant to Aastrom, Abbott Vascular, Amgen, Cleveland
Clinic, Concert, Daiichi Sankyo, Fibrogen, Genzyme, GlaxoSmithKline, Hamilton Health Sciences, Medtronic, Merck, Novartis, Novo
Nordisk, Roche, Salix, Sanderling, Sanofi Aventis, Servier, and Teva and having received grant support from Amgen, Celladon,
Novartis, and Sanofi-Aventis. The Brigham and Women’s Hospital has patents for the use of inhibitors of the renin-angiotensin
system in survivors of MI with Novartis. Dr. Pfeffer’s shares are irrevocably transferred to charity.

3. Renin-AngiotensinRenin-Angiotensin
Aldosterone SystemAldosterone System
Angiotensinogen
· Vasoconstriction
· Cell growth
· Na/H2O retention
· Sympathetic activation
renin Angiotensin I
Angiotensin II
ACE
Cough,
Angioedema
Benefits?
 Bradykinin
Inactive
Fragments
· Vasodilation
· Antiproliferation
(kinins)
Aldosterone
66

4. Months
128
102
78
63
59
53
50
40
30
20
10
0
0 6 12 18 24 30 36 42 48
p=0.0036
Months
All-cause mortality (%)
Placebo
Enalapril
1284
1159
1085
1005
939
819NEJM 1992NEJM 1987
CONSENSUS SOLVD
0 2 4 6 8 10 12
Placebo
Enalapril
80
70
60
40
20
0
50
30
10
All-cause mortality (%)
Placebo N:
Enalapril N:
Placebo N:
Enalapril N:

5. V-HeFT II
Cumulative Mortality
0.00
0.25
0.50
0.75
0 12 24 36 48 60
Months
0.13
0.25
0.36
0.46
0.54
0.09
0.18
0.31
0.42
0.48
Isdn-hydr (n=401)
Enalapril (n=403)
1991
Deaths

6. LV DysfunctionLV Dysfunction
(Progressive)(Progressive)
MI
Asymptomatic
Remodeling
Symptomatic
CHF
Sudden Ischemic Sudden Pump failure

7. 1992
The
SAVE
Trial

8. ACE Inhibitor
MI Mortality Trials
Selective
(higher risk, long term)
SAVE
(EF £ 40%)
AIRE
(clinical HF)
TRACE
(wall motion score,
EF £ 35%)
Broad
(short term)
CONSENSUS II
GISSI-3
ISIS-4
Chinese-Cap
60 lives saved/1000
over 3 years
5 lives saved/1000
over 6 weeks
3

9. 1350g.*
ReinfarctionReinfarction
Events %
Years
Placebo
Enalapril
Events rate
Placebo
Captopril
Years
NEJM 1991 NEJM 1992
Risk reduction (95% CI) = 22% (6-35%)
P < 0.001
Risk reduction (95% CI) = 25% (5-40%)
P = 0.015
SOLVD SAVE

10. ACE-I Across
CV Disease Spectrum
DM Prevention
DREAM
VASCULAR
HOPE
DM Renal
Collab Study
ABCD
REIN
AASK
CVA
PROGRESS
HBP
CAPPP
ALLHAT
ANZ2
MI
CONSENSUS II
ISIS-4
GISSI-3
SMILE
SAVE
AIRE
TRACE
CAD
EUROPA
PEACE
IMAGINE
HF
CONSENSUS I
SOLVD
V-HeFT II
PEP-CHF
2
1987 – 2007

11. Renin-Angiotensin
Aldosterone System
Angiotensinogen
Non-ACE Pathways
(e.g., chymase)
· Vasoconstriction
· Cell growth
· Na/H2O retention
· Sympathetic activation
renin Angiotensin I
Angiotensin II
ACE
Cough,
Angioedema
Benefits?
 Bradykinin
Inactive
Fragments
· Vasodilation
· Antiproliferation
(kinins)
Aldosterone AT2
AT1
6

12. 0.00
0.80
0.85
0.90
0.95
1.00
0 100 200 300 400
Follow-up (days)
Probability of survival
Losartan n=17/352
Captopril n=32/370
Relative risk (95% CI) = 0.54 (0.31, 0.95)
p=0.035
The Lance 1997

13. Losartan metabolite
“Even in the presence
of substantial
concentrations of
captopril, angiotensin
II may be formed
locally in the heart to
enhance noradrenaline
release.”
Lancet 1998:351;644-5

14. ELITE II: Summary of Major Findings
3152 elderly CHF patients randomised to
losartan (50 mg od) or captopril (50 mg tid)
0.5 1.0 1.25
All cause Mortality
Captopril Losartan
250 (15.9%) 280 (17.7%) p=0.16
Sudden death/Resuscitated arrest
Captopril Losartan
115 (7.3%) 142 (9.0%) p=0.08
All cause Mortality/Hospitalisations
Captopril Losartan
707 (44.9%) 752 (47.7%) p=0.21
Withdrawal rate 14.5% v 9.4%: p<0.001
Favours captopril Favours losartan
odds ratio Pitt et al. Lancet 2000

15. *
Placebo
Candesartan
HR 0.84 (95% CI 0.77-0.91), p<0.0001
Adjusted HR 0.82, p<0.0001
1310 (34.5%)
1150 (30.2%)
CHARM-Overall
0
10
20
30
40
50
%
0 1 2 3 years3.5
0 1 2 3 years
0
10
20
30
40
50
Placebo
Candesartan
%
HR 0.77 (95% CI 0.67-0.89), p=0.0004
Adjusted HR 0.70, p<0.0001
3.5
406 (40%)
334 (33%)
CHARM-Alternative
CHARM-Preserved
333 (22.0%)
Placebo
Candesartan
HR 0.89 (95% CI 0.77-1.03), p=0.118
Adjusted HR 0.86, p=0.051
366 (24.3%)
0 1 2 3 years3.5
0
10
20
30
40
50
%
CHARM-Added
Placebo
Candesartan
HR 0.85 (95% CI 0.75-0.96), p=0.011
Adjusted HR 0.85, p=0.010
483 (37.9%)
538 (42.3%)
0 1 2 3 years3.5
0
10
20
30
40
50
%
2003

16. CHARM-Alternative:CHARM-Alternative:
CVCV deathdeath or CHF hospitalizationor CHF hospitalization
Number at risk
Candesartan 1013
929
831Granger et al. Lancet 2003
0 1 2 3 years
0
10
20
30
40
50
Placebo
Candesartan
%
HR 0.77 (95% CI 0.67-0.89), p=0.0004
Adjusted HR 0.70, p<0.0001
3.5
406 (40%)
334 (33%)

17. 0
5
10
15
20
25
30
35
40
45
50
0 6 12 18 24 30 36 42 48
Candesartan
(37.9%)
Placebo
(42.3%)
Relative risk reduction = 15%
HR = 0.85 (95% CI: 0.75, 0.96)
p=0.011
Median follow-up 41.0 months
%
At risk, n
Placebo 1272
1017
852
735
Time, months
Primary Endpoint
CV Death or CHF Hospitalization
CHARM-AddedCHARM-Added
McMurray et al. Lancet 2003

18. Captopril
0
0.05
0.1
0.15
0.2
0.25
0.3
0 6 12 18 24 30 36
Probability of Event
Mortality by Treatment
Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349
Months
Valsartan vs. Captopril: HR = 1.00; P = 0.982
Valsartan + Captopril vs. Captopril: HR = 0.98; P = 0.726
Valsartan
Valsartan + Captopril
18

19. Conclusion
• Combining valsartan with a proven dose of captopril
produced no further reduction in mortality—and more
adverse drug events.
In patients with MI complicated by heart failure, left
ventricular dysfunction or both:
• Valsartan is as effective as a proven dose of captopril in
reducing the risk of:
Death
CV death or nonfatal MI or heart failure admission
32
Presented at AHA 2003; N Engl J Med 2003
Mortality by Treatment
2003

20. ONTARGET Conclusions: Telmisartan plus
Ramipril vs. Ramipril
• Combination therapy does not reduce the
primary outcome to a greater extent compared
to ramipril alone
2. Higher rates of adverse events:
-hypotension related, including syncope
-renal dysfunction
N Engl J Med 2008;358:1547-59.

21. HBP Vascular MI HF
Pre Diabetes Diabetes Opht Diabetes Renal
DIRECT
LIFE
SCOPE
OPTIMAAL
CHARMVALUE
VALIANT
NAVIGATOR
ONTARGET
TRANSCEND
JIKEI
HIJ-CREATE
ELITE II
Val-Heft
RENAAL
IDNT
ROADMAP
VA NEPHRON-D)
ATAT11-Receptor Blocker (ARB)-Receptor Blocker (ARB)
Clinical Outcome StudiesClinical Outcome Studies
Atrial Fib
ACTIVE
GISSI-AF
I-PRESERVE
CVA
PRoFESS
2002 – 2014

22. The direct renin inhibitor aliskiren blocks the RAAS
proximally and may attenuate ACE or ARB induced
compensatory rise in PRA and further RAAS activation
Angiotensinogen
Non-ACE Pathways
(e.g., chymase)
· Vasoconstriction
· Cell growth
· Na/H2O retention
· Sympathetic activation
renin Angiotensin I
Angiotensin II
ACE
Cough,
Angioedema
Benefits?
Bradykinin
Inactive
Fragments
· Vasodilation
· Antiproliferation
(kinins)
Aldosterone AT2
AT1
ACE-Inhibitors
Gradman et al. Circulation, 2006; McMurray et al. Circulation, 2004
Negative Feedback
ARBs
Aliskiren

24. ASPIRE HIGHER Program
AVOID ALTITUDE n=8606
ALOFT
ATMOSPHERE n≈7000
(head to head not add on)
ASTRONAUT n≈1700
ASPIRE
ALLAY
A Post-MI trial n=zero
Albuminuria reduction in patients with
hypertension, diabetes, and nephropathy
Parving et al. N Engl J Med 2008;358:2433-6
BNP reduction in chronic heart failure
McMurray et al. Circ Heart Fail 2008;1:17-24
LV mass regression in hypertensive
patients with LVH
Solomon et al. Circulation 2009;119:530-7
Reduction in LV remodeling following MI
complicated by LV dysfunction
Solomon et al. Eur Heart J 2011;32:1227-34
In diabetic nephropathy at high risk for CV disease
In chronic heart failure
In acute heart failure
Morbidity and mortality trialsSurrogate endpoint trials
APOLLO n≈11000
BP in elderly (some add on)
X

25. Nov. 2012
Primary composite end point:
CV Death, Resuscitated Cardiac Arrest, Non-fatal MI, Nonfatal
stroke, HF hospitalization, ESRD, Renal Death, Need for RRT,
Doubling of Creatinine
Compared to placebo
Aliskiren reduced
SBP/DBP = 1.3/0.6 mmHg
albuminuria = 14%
(95%CI 11-17%)
Hans Henrik Parving MD DM Sc, Barry M. Brenner MD PhD, John JV McMurray MD, Dick de Zeeuw MD PhD, Steven M
Haffner MD, Scott D. Solomon MD, Nish Chaturvedi MD, Frederik Persson MD, Akshay S. Desai MD MPH, Maria Nicolaides
MD, Alexia Richard MSc, Zhihua Xiang PhD, Patrick Brunel MD, and Marc A Pfeffer MD PhD for the ALTITUDE Investigators
CONCLUSIONS:
The addition of aliskiren to standard therapy with renin-angiotensin system blockade
in patients with type 2 diabetes who are at high risk for cardiovascular and renal
events is not supported by these data and may even be harmful.
N = 8561

26. ASTRONAUT
Acute Heart Failure
Primary composite end point:
CV Death, HF hospitalization at 6 months
M Gheorhhiade, M Bohm, SJ Greene, G Fonarow, EF Lewis, F Zannand,
SD Solomon, F Baschiera, J Botha, TA Hua, CR Gimpelewicz, X Jaumont,
A Lesogor, AP Maggioni

27. ATMOSPHERE
Chronic Heart Failure
Population
6573 Patients with low ejection fraction heart failure
•NYHA class II – IV, LVEF < 35%
•BNP ≥ 150 pg/ml or ≥ 100 pg/ml with HF
hospitalization
Endpoints
Primary: CV death or heart failure hospitalization
Secondary: QoL / BNP / other CV / renal endpoints
Treatment
arms
Enalapril vs aliskiren vs enalapril/aliskiren combo
(on top of usual care – excluding ACEI)
Ongoing!

28. CV Death, MI, Stroke
Inhibiting RAS - 3 decades…..
ACE I or ARB (dose)
VALIANT
ONTARGET
CHARM Alt.
TRANSCEND
Combination ACE I and ARB
VALIANT
ONTARGET
? CHARM Added
ACE I – Work Horse
HF (low EF)
MI
Vascular Disease
Diabetes
Renal Disease
Population Not Improved:
DREAM
PRoFESS
I-PRESERVE
GISSI-AF
No Incremental Benefit with
Increase in Adverse Events

29. Combination of renin angiotensin inhibitors:
VALIANT
• Combining valsartan with a proven dose of captopril
produced no further reduction in mortality—and more
adverse drug events.
In patients with MI complicated by heart failure, left
ventricular dysfunction or both:
• Valsartan is as effective as a proven dose of captopril in
reducing the risk of:
Death
CV death or nonfatal MI or heart failure admission
32
Presented at AHA 2003; NEJM 2003
Historical perspective: what if ARBs and/or direct
renin inhibitors came before ACEI?

30. RAS inhibitors + Mineralocorticoid Receptor Antagonists
Angiotensinogen
Non-ACE Pathways
(e.g., chymase)
· Vasoconstriction
· Cell growth
· Na/H2O retention
· Sympathetic activation
renin Angiotensin I
Angiotensin II
ACE
Cough,
Angioedema
Benefits?
Bradykinin
Inactive
Fragments
· Vasodilation
· Antiproliferation
(kinins)
Aldosterone AT2
AT1
ACE-Inhibitors
Gradman et al. Circulation, 2006; McMurray et al. Circulation, 2004
ARBs
MRA

31. STAGES OF DISCOVERY:
Over a Quarter century of inhibiting the RAAS
u Inhibiting RAS major role in prevention and
treatment of CV diseases
u ACE-I
1975
u ARB
1995

32. Ingelfinger NEJM 2008

33. *
0 1 2 3 3.5 years
0
10
20
30
40 Placebo
Candesartan
%
HR 0.88 (95% CI 0.79-0.98)
p=0.018
Number at risk
Candesartan 2289
2105
1894
1382
708 (31.0%)
642 (28.0%)
HR 0.67
p<0.001
HR 0.80
p=0.001
Young et al. Circulation 2004
CHARM - Low EF (Alternative andCHARM - Low EF (Alternative and
Added)Added)
All-cause deathAll-cause death