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, PhDDzau Professor of Medicine, Harvard Medical SchoolDzau Professor of Medicine, Harvard Medical SchoolCardiovascular 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. 

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, PhDDzau Professor of Medicine, Harvard Medical SchoolDzau Professor of Medicine, Harvard Medical SchoolCardiovascular 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. 

Renin-AngiotensinRenin-AngiotensinAldosterone SystemAldosterone System

Angiotensinogen

· Vasoconstriction· Cell growth· Na/H2O retention· Sympathetic activation

renin Angiotensin I

Angiotensin II

ACE

Cough,Angioedema

Benefits? Bradykinin

InactiveFragments

· Vasodilation· Antiproliferation

(kinins)

Aldosterone

66

Months12810278635953474234302418

17  1271119888827973645049423128

50

40

30

20

10

00 6 12 18 24 30 36 42 48

p=0.0036

Months

All-cause mortality (%)

Placebo

Enalapril

1284115910851005939819669487299

12851195112710691010891697526333

NEJM 1992NEJM 1987

CONSENSUS SOLVD

0 2 4 6 8 10 12

Placebo

Enalapril

807060

40

20

0

50

30

10

All-cause mortality (%)

Placebo N:Enalapril N:

Placebo N:Enalapril N:

V-HeFT IICumulative Mortality

0.00

0.25

0.50

0.75

0 12 24 36 48 60Months

0.13

0.25

0.360.46

0.54

0.090.18

0.31

0.420.48

Isdn-hydr (n=401)Enalapril (n=403)

1991

Deaths

LV DysfunctionLV Dysfunction(Progressive)(Progressive)

MI

Asymptomatic

Remodeling

SymptomaticCHF

Sudden Ischemic Sudden Pump failure

1992

The

SAVETrial

ACE InhibitorMI Mortality Trials

Selective(higher risk, long term)

SAVE

(EF £ 40%)AIRE

(clinical HF)TRACE

(wall motion score, 

EF £ 35%)SMILE

(anterior MI, no lytic)

Broad (short term)

CONSENSUS IIGISSI-3ISIS-4

Chinese-Cap

60 lives saved/1000over 3 years

5 lives saved/1000over 6 weeks

3

1350g.*

ReinfarctionReinfarction

Events %

Years

Placebo

Enalapril

Events ratePlacebo

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 

ACE-I AcrossCV Disease Spectrum

DM PreventionDREAM

VASCULARHOPE

DM RenalCollab Study

ABCDREINAASK

CVAPROGRESS

HBPCAPPPALLHAT

ANZ2

MICONSENSUS II

ISIS-4GISSI-3SMILESAVEAIRE

TRACE

CADEUROPAPEACE

IMAGINE

HFCONSENSUS I

SOLVDV-HeFT IIPEP-CHF

2

1987 – 2007

Renin-AngiotensinAldosterone 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

InactiveFragments

· Vasodilation· Antiproliferation

(kinins)

Aldosterone AT2

AT1

6

0.00

0.80

0.85

0.90

0.95

1.00

0 100 200 300 400Follow-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

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

ELITE II: Summary of Major Findings3152 elderly CHF patients randomised to

losartan (50 mg od) or captopril (50 mg tid)

0.5 1.0 1.25

All cause MortalityCaptopril         Losartan250 (15.9%)     280 (17.7%)   p=0.16

Sudden death/Resuscitated arrestCaptopril         Losartan115 (7.3%)       142 (9.0%)     p=0.08

All cause Mortality/HospitalisationsCaptopril         Losartan707 (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

*

Placebo

Candesartan

HR 0.84 (95% CI 0.77-0.91), p<0.0001Adjusted 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 years0

10

20

30

40

50

Placebo

Candesartan

%

HR 0.77 (95% CI 0.67-0.89), p=0.0004Adjusted HR 0.70, p<0.0001

3.5

406 (40%)

334 (33%)

CHARM-Alternative

CHARM-Preserved

333 (22.0%)Placebo

Candesartan

HR 0.89 (95% CI 0.77- 1.03), p=0.118Adjusted HR 0.86, p=0.051

366 (24.3%)

0 1 2 3 years3.50

10

20

30

40

50%

CHARM-Added

Placebo

Candesartan

HR 0.85 (95% CI 0.75-0.96), p=0.011Adjusted HR 0.85, p=0.010

483 (37.9%)538 (42.3%)

0 1 2 3 years3.50

10

20

30

40

50%

2003

CHARM-Alternative:CHARM-Alternative:CV CV deathdeath or CHF hospitalization or CHF hospitalization

Number at riskCandesartan 1013

929831434122

Placebo 1015887798427126

Granger et al. Lancet 2003

0 1 2 3 years0

10

20

30

40

50

Placebo

Candesartan

%

HR 0.77 (95% CI 0.67-0.89), p=0.0004Adjusted HR 0.70, p<0.0001

3.5

406 (40%)

334 (33%)

05

101520253035404550

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, nPlacebo 1272

1017852735338

Candesartan 12761074914793395

Time, months

Primary EndpointCV Death or CHF Hospitalization

CHARM-AddedCHARM-Added

McMurray et al. Lancet 2003

Captopril

0

0.05

0.1

0.15

0.2

0.25

0.3

0 6 12 18 24 30 36

Pro

babi

lity 

of E

vent

Mortality by Treatment

Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349

Valsartan490944644272400726481437357

Months

Valsartan vs. Captopril: HR = 1.00; P = 0.982Valsartan + Captopril vs. Captopril: HR = 0.98; P = 0.726

Captopril490944284241401826351432364

Valsartan + Cap488544144265399426481435382

Valsartan

Valsartan + Captopril

18

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, leftventricular dysfunction or both:• Valsartan is as effective as a proven dose of captopril in 

reducing the risk of:DeathCV death or nonfatal MI or heart failure admission

32

Presented at AHA 2003; N Engl J Med 2003Mortality by Treatment

2003

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.

HBP Vascular MI HF

Pre Diabetes Diabetes Opht Diabetes RenalDIRECT

LIFE SCOPE

OPTIMAAL

CHARMVALUEVALIANT

    NAVIGATOR

ONTARGETTRANSCEND

JIKEIHIJ-CREATE

ELITE IIVal-Heft

RENAALIDNT

ROADMAPVA NEPHRON-D)

ATAT11-Receptor Blocker (ARB)-Receptor Blocker (ARB)Clinical Outcome StudiesClinical Outcome Studies

Atrial FibACTIVEGISSI-AF

I-PRESERVE

CVAPRoFESS

2002 – 2014 

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

InactiveFragments

· Vasodilation· Antiproliferation

(kinins)

Aldosterone AT2

AT1

ACE-Inhibitors

Gradman et al. Circulation, 2006; McMurray et al. Circulation, 2004

Negative Feedback

ARBs

Aliskiren

ASPIRE HIGHER Program

AVOID ALTITUDE  n=8606

ALOFTATMOSPHERE 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 nephropathyParving et al. N Engl J Med 2008;358:2433-6

BNP reduction in chronic heart failureMcMurray et al. Circ Heart Fail 2008;1:17-24

LV mass regression in hypertensive patients with LVHSolomon et al. Circulation 2009;119:530-7

Reduction in LV remodeling following MI complicated by LV dysfunctionSolomon 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≈11000BP in elderly  (some add on)

X

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 CreatinineCompared to placebo

Aliskiren reducedSBP/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

ASTRONAUTAcute 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

ATMOSPHEREChronic 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!

CV Death, MI, Stroke

Inhibiting RAS - 3 decades…..

ACE I or ARB (dose)VALIANTONTARGETCHARM Alt.TRANSCEND

Combination ACE I and ARBVALIANTONTARGET? CHARM Added

ACE I – Work HorseHF (low EF)MIVascular DiseaseDiabetesRenal Disease

Population Not Improved:DREAMPRoFESSI-PRESERVEGISSI-AF

No Incremental Benefit withIncrease in Adverse Events

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, leftventricular dysfunction or both:• Valsartan is as effective as a proven dose of captopril in 

reducing the risk of:DeathCV 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?

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

InactiveFragments

· Vasodilation· Antiproliferation

(kinins)

Aldosterone AT2

AT1

ACE-Inhibitors

Gradman et al. Circulation, 2006; McMurray et al. Circulation, 2004

ARBs

MRA

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

u Mineralcorticoid

1999antagonists

u DRI

2002

u Optimal combinations still being evaluated

Ingelfinger  NEJM 2008

*

0 1   2 3 3.5 years0

10

20

30

40 Placebo

Candesartan

%

HR 0.88 (95% CI 0.79-0.98)p=0.018

Number at riskCandesartan 2289

210518941382

Placebo 2287202318111333

708 (31.0%)642 (28.0%)

HR 0.67p<0.001

HR 0.80p=0.001

Young et al. Circulation 2004

CHARM - Low EF (Alternative and CHARM - Low EF (Alternative and Added)Added)

All-cause deathAll-cause death