Advancing Our Understanding of RAAS Modulation in High-Risk Patients

1
Advancing Our Understanding of RAAS Modulation
in High-Risk Patients

2
CVD has risen, accompanied by diabetes
CVD
Diabetes
7
?119
6
Discharges (millions)
Number (millions)
5
4
0
90
03
00
95
90
04
98
94
92
00
96
02
Year
Year
National Hospital Discharge Survey
National HealthInterview Survey
AHA. Circulation. 2006113e85-151. CDC.
www.cdc.gov.
3
Continued increase in CVD and diabetes is
predicted in US
By 2050, diabetes will account for an estimated
31.4 million deaths from CVD
?136
Incidence of diabetes, all ages (millions)
Year
Narayan KMV et al. Diabetes Care.
2006292114-6.NIDDK. http//diabetes.niddk.nih.g
ov.
4
Discharge ACEI post-MI remains suboptimal
Q1 2006 CRUSADE data, n 6945
Discharge medication use()

LVEF lt40, CHF, DM, HTNKnown hyperlipidemia,
?TC, ?LDL-C
CRUSADE. www.crusadeqi.com.
5
AHA/ACC secondary-prevention guidelines ACEIs
and ARBs

• ACEIs
• All patients with LVEF 40, hypertension,
  diabetes, or chronic kidney disease (IA)
• Consider for all other patients (IB)
• Optional Lower-risk, post-revascularization
  patients with normal LVEF and well-controlled
  risk factors (IIaB)
• ARBs
• ACEI-intolerant patients with HF or post-MI LVEF
  40 (IA)
• Consider in other ACEI-intolerant patients (IB)
• Consider use in combination with ACEIs in
  systolic dysfunction HF (IIbB)

Smith SC et al. Circulation. 20061132363-72.
6
Critical Role of RAAS in Vasculoprotection New
Science
7
New aspects of RAAS

• ACE homologues
• ACE2
• Soluble ACE
• ACE substrates
• Ang (17)
• Ang (19)
• N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP)
• Amyloid ß-protein
• Formation of Ang II by non-ACE peptidases
• ACE signal transduction pathway

RAAS renin-angiotensin-aldosterone system
Fleming I. Circ Res. 200698887-96.
8
RAAS Current and potential targets
Angiotensinogen
Renin
ACE2
Ang I
Ang (19)
NEP
CAGECathepsin GChymase
ACE
ACE
ACE
ACE2
Ang (17)
Ang (15)
Ang II
AT1R
AT2R
AT3R
AT4R
AT(17)R
masR
Aldosterone
Adapted from Ferrario CM, Strawn WB. Am J
Cardiol. 200698121-8.Duprez DA. J Hypertens.
200624983-91.
9
Impact of ACEI on ACE signaling pathway
ACE
ACE inhibitor
NH2
Extracellular
Clinical significance of this pathway is under
investigation
MKK7
Cytosol
CK2
JNK
COOH
cJun
P
JNK
P
cJun
P
cJun
P
P
cJun
cJun
P
cJun
P
cJun
Nucleus
AP-1
Gene expression(ACE, COX-2)
Fleming I et al. Physiology. 20052091-5.
10
ACE metabolism
Actions of ACE, kininase II
Asp-Arg-Val-Tyr-lie-His-Pro-Phe-His-Leu
Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg
Angiotensin I
Bradykinin
Angiotensin II His-Leu
Bradykinin 17 Phe-Arg
Erdös EG. FASEB J. 2006201034-8.
11
ACEI mechanism of benefit Reduction in clinical
events
Bradykinin
Angiotensin I
ACE/Kininase II
Degradation products
Angiotensin II
ACE inhibitors
?Bradykinin
?Angiotensin II
?BP ?Oxidative stress ?Endothelial
dysfunction ?Glucose metabolism ?Plaque
growth ?Fibrous cap stability ?MMP activity
?Nitric oxide
Reduction inclinical events
MMP matrix metalloprotease
Fleming I et al. Physiology. 20052091-5.
12
Renin inhibition prevents LVH in animal models
9-week-old double transgenic rats (untreated died
by week 8)
Cardiac hypertrophy index
LV wall thickness
0.40
5
0.35
4
0.30
cm
mg/g
3
0.25
2
0.20
Valsartan
Aliskiren
Valsartan
Aliskiren
10
1
0.3
3
10
1
0.3
3
mg/kg/d
mg/kg/d
P lt 0.05 vs other groups P lt 0.05 vs valsartan
10 mg/kg/d
Pilz B et al. Hypertension. 200546569-76.
13
Demonstrated benefits of AT1R blockade

• Blood pressure
• Heart failure symptoms
• Diabetic renal disease progression
• Stroke

Strauss MH, Hall AS. Circulation. 2006114838-54.
14
AT1R blockade upregulates both Ang II levels and
AT2R expression
Both physiologic and pathologic effects have been
proposed for AT2R stimulation
Ang I
Ang I
ACE
ACE
Ang II
Ang II
ARB
ARB
AT1
AT4
AT1
AT4
AT2
AT2
Vasodilation
Hypertrophy Inflammation
Strauss MH, Hall AS. Circulation. 2006114838-54.
15
Postulated role of AT2R and MMP-1 in plaque
destabilization
Ang IIARB AT1 AT2
Destabilization ? Rupture ? ACS
Endothelium
?MMP-1
Extracellularmatrix
Intracellular inflammation
Leukocyteactivation
Vascular smooth muscle cells
Strauss MH, Hall AS. Circulation. 2006114838-54.
16
AT2R mediates cardiac myocyte enlargement during
pressure overload
Agtr2/Y AT2R-deficient mice and wild-type mice
200
160
Wild-type

Left ventricular mass(mg)
120
Agtr2/Y
80
40
0
Before
2 weeks
10 weeks
Aortic-banded mice Control (sham-operated) mice

P lt 0.05
Senbonmatsu T et al. J Clin Invest.
2000106R25-9.
17
Sustained decrease in PAI-1 antigen over time
with ACEI vs ARB
N 20 obese patients with hypertension and
insulin resistance
20
10
? PAI-1antigen(ng/mL)
0
-10
-20
1
3
4
6
Weeks
ACEI (ramipril)
ARB (losartan)
BMI 33.4 ramipril, 31.2 losartanP 0.043,
drug time interaction
Brown NJ et al. Hypertension. 200240859-65.
18
ACEIs and bradykinin oppose Ang II effects
Bradykinin
ACEI
Ang I
-
-
ACE

B2R
Inactive peptides
ACEI
Ang II
Vasodilation NO Prostaglandins EDHF tPA
AT1R
Vasoconstriction Aldosterone secretion Fibrosis Pr
oliferation Oxidative stress Matrix
formation Inflammation
Adapted from Ferrario CM, Strawn WB. Am J
Cardiol. 200698121-8.Adapted from Murphey L et
al. Eur Heart J Suppl. 20035(A)A37-41.
19
Ang II effect in target organ damage
VSMC
Angiotensinogen
Fat cells
Renin
Aldosterone(Adrenal/CV tissues)
Angiotensin I
ACE
?BP
Angiotensin II
Reduced baroreceptor sensitivity
Stroke
HF
Kidneyfailure
McFarlane SI et al. Am J Cardiol.
200391(suppl)30H-7.
20
Potential role of RAAS activation in metabolic
syndrome and diabetes
Obesity
RAAS activation
Skeletal muscle
Pancreatic ß cells
?MetS
?T2DM
MetS metabolic syndrome T2DM type 2 diabetes
Adapted from Henriksen EJ, Jacob S. J Cell
Physiol. 2003196171-9.Paul M et al. Physiol
Rev. 200686747-803.
21
RAAS activation in obesity
Circulating RAAS, N 38 menopausal women

12
90

9
60
Renin(ng/l)
Aldosterone (ng/l)
6
30
3
0
0
Lean
Obese
Lean
Obese
60
0.10

45
ACE(U/l)
Ang II(nmol/l)
30
0.05
15
0
0.00
Lean
Obese
Lean
Obese
P lt 0.05
Engeli S et al. Hypertension. 200545356-62.
22
RAAS activation contributes to obesity-related
hypertension
Obesity
?Leptin
Renal medullary compression
?RAAS activation
Sodium reabsorption
Renal vasodilation
?SNS activation
Volume expansion
Arterial hypertension
SNS sympathetic nervous system
Sharma AM. Hypertension. 20044412-19.
23
ACEIs Potential mechanisms of improved glucose
metabolism
Angiotensin I
Bradykinin
ACE/Kininase II
Degradation products
Angiotensin II
ACE inhibitors
?Angiotensin II
?Bradykinin
?Nitric oxide
?Skeletal muscleblood flow ?Glucose metabolism
Henriksen EJ, Jacob S. J Cell Physiol.
2003196171-9.
24
Role of Ang II in insulin resistance Focus on
signaling pathways
BK
NO
BK2 receptor

?NO
Glucose transport
Akt1

Insulin receptor



GLUT-4 trans-location
PI3-K
IRS-1
Insulin

-
GLUT-4 biosynthesis
-
GLUT-4
AT1 receptor
Ang II
Adapted from Henriksen EJ, Jacob S. J Cell
Physiol. 2003196171-9.
25
ACEIs improve glucose uptake in peripheral tissue
KK-Ay mouse model of T2DM
500

400
Evidence for bradykinin-mediated effect
Rate constant of 2-3HDG uptake
300

200
100
0
Control
Temocapril
Temocapril HOE 140
Temocapril L-NAME
HOE 140
L-NAME
P lt 0.05 vs controlP lt 0.05 vs temocaprilHOE
140 bradykinin B2 receptor blockerL-NAME
nitric oxide synthase inhibitor
SOLEUS
Schiuchi T et al. Hypertension. 200240329-34.
26
RAAS Modulationin High-Risk Patients
27
ACEIs Evolution of benefits
BP reduction
Cardioprotection
Vascular protection
Renal protection
Improved glycemic control (?)
Lonn E et al. Eur Heart J Suppl. 20035(suppl
A)A43-8.DREAM Trial Investigators. N Engl J
Med. 20063551551-62.
28
Effect of ACEIs and ARBs on new-onset diabetes
Meta-analysis of 12 randomized controlled trials
Less likely to develop T2DM
More likely to develop T2DM
CAPPP STOP-2 HOPE LIFE ALLHAT ANBP2 SCOPE ALPINE C
HARM SOLVD VALUE PEACE All pooled ACEI
pooled ARB pooled
0.79 (0.670.94) 0.96 (0.721.27) 0.66
(0.510.85) 0.75 (0.630.88) 0.70
(0.560.86) 0.66 (0.540.85) 0.81
(0.611.02) 0.13 (0.030.99) 0.78
(0.640.96) 0.26 (0.130.53) 0.77
(0.690.86) 0.83 (0.720.96) 0.75
(0.690.82) 0.73 (0.630.84) 0.77 (0.710.83)
0.125
0.25
0.5
1
2
4
8
Relative risk (95 CI)
Abuissa H et al. J Am Coll Cardiol. 200546821-6.
29
HOPE, EUROPA, PEACE Reduction in new-onset
diabetes (placebo-controlled trials)
n 23,340 free from diabetes at baseline
Overall 14 RRR RR 0.86 (0.780.95) P 0.0023
Ramipril 10 mg
Perindopril 8 mg
Trandolapril 4 mg
(all trials)
Not a prespecified end point
Dagenais GR et al. Lancet. 2006368581-8.
30
TZDs blunt diabetes progression
Diabetes Prevention Program (DPP)
15
Placebo
Metformin 850 mg bid
Cumulative incidence of diabetes ()
10
Lifestyle
Troglitazone400 mg/d
5
0
1.5
0.5
0
1.0
Follow-up (years)
237
1568
2343
n
739
Withdrawn from study after 1.5 yr
DPP Research Group. Diabetes. 2005541150-6.
31
DPP Long-term benefit of lifestyle intervention
or metformin on diabetes prevention
N 3234 with IFG and IGT, without diabetes
40
Placebo
P
30
Metformin
lt0.001
?31
Cumulative incidence of diabetes ()
20
Lifestyle
?58
lt0.001
10
0
0
1.0
2.0
3.0
4.0
Years
vs placebo IFG impaired fasting glucose IGT
impaired glucose tolerance
DPP Research Group. N Engl J Med.
2002346393-403.

32
DREAM Background
Diabetes REduction Assessment with ramipril and
rosiglitazone Medication

• Prevalence of T2DM continues to rise
• Persons with diabetes are at ?risk for macro- and
  microvascular complications
• Current options for diabetes prevention include
• Lifestyle intervention ?50
• Acarbose, metformin ?2530
• New approaches are needed

DREAM Trial Investigators. Lancet.
20063681096-105. N Engl J Med. 20063551551-62.

33
DREAM Study design
Randomized, double-blind 2 2 factorial designN
5269 with IFG and/or IGT, free from CV disease
Ramipril 15 mg/d vs placebo AND Rosiglitazone 8
mg/d vs placebo
Primary outcomeDiabetes or death from any cause
Secondary outcomes I CV eventsCombined MI,
stroke, CV death, revascularization, HF, angina,
ventricular arrhythmia
Secondary outcomes II Renal eventsProgression
to micro- or macroalbuminuria, or ?30 CrCl
Secondary outcomes III Glycemic statusGlucose
levels,conversion to normoglycemia
Follow-up 35 years
DREAM Trial Investigators. Diabetologia.
2004471519-27.
34
DREAM 2 2 factorial design
N 5269 with IFG and/or IGT
Ramipril 5 mg 2 months 10 mg 10 months 15
mg thereafterRosiglitazone 4 mg 2 months 8
mg thereafter
DREAM Trial Investigators. Diabetologia.
2004471519-27.
35
DREAM Adjudicated HF

• Overnight (2 calendar days) hospitalization or ER
• attendance for 2 of the following criteria
• Signs/symptoms of HF
• Radiologic evidence of HF
• Need for IV/oral diuretic, vasodilator, and/or
  inotrope

DREAM Trial Investigators. N Engl J Med.
2006355suppl appendix (epub).
36
DREAM Ramipril effect on new-onset diabetes or
death
0.6
9 RRRHR 0.91 (0.811.03) P 0.15
0.5
Placebo
0.4
Cumulative hazard rate
0.3
0.2
Ramipril
0.1
0.0
0
1
2
3
4
Follow-up (years)
26462623
25102498
22772287
12401218
200194
No. at riskPlaceboRamipril
DREAM Trial Investigators. N Engl J Med.
20063551551-62.
37
DREAM Ramipril effect on glycemia
1.60
16 increaseHR 1.16 (1.071.27) P 0.001
1.20
Ramipril
Cumulative hazard rate of conversion to
normoglycemia
0.80
Placebo
0.40
0.0
1
2
3
4
0
Follow-up (years)
26462623
24942487
20902060
876791
145127
No. at riskPlaceboRamipril
FPG lt 110 mg/dL and 2-h glucose lt 140 mg/dL
DREAM Trial Investigators. N Engl J Med.
20063551551-62.
38
DREAM Rosiglitazone effect on primary end point
0.6
Placebo
60 RRR HR 0.40 (0.350.46) P lt 0.0001
0.5
0.4
Cumulative hazard rate
0.3
0.2
Rosiglitazone
0.1
0.0
0
1
2
3
4
Follow-up (years)
No. at riskPlaceboRosiglitazone
26342635
24702538
21502414
11481310
177217
DREAM Trial Investigators. Lancet.
20063681096-105.
39
DREAM Conversion to normoglycemia with
rosiglitazone
N 5269
71 increaseHR 1.71 (1.57?1.87)P lt 0.0001
FPG lt 110 mg/dL and 2-h glucose lt 140 mg/dL
DREAM Trial Investigators. Lancet.
20063681096-105.
40
DREAM Safety

• Ramipril vs placebo
• No adverse hepatic effects
• Alanine aminotransferase (ALT) levels ?1.1 U/L at
  1 year (P 0.004)
• Rosiglitazone vs placebo
• Increased incidence of HF (0.5 vs 0.1, P
  0.01)
• No cases of fatal HF
• No difference for other CV events
• Increased incidence of peripheral edema(6.8 vs
  4.9, P 0.003)
• 4.9-lb weight gain (P lt 0.0001)
• Increased hip circumference (?0.71 in, P lt
  0.0001)
• No difference in waist circumference
• Decreased waist-hip ratio (P lt 0.0001)
• No adverse hepatic effects
• ALT levels ?4.2 U/L at 1 year (P lt 0.0001)

DREAM Trial Investigators.N Engl J Med.
20063551551-62 Lancet. 20063681096-105.
Adjudicated
41
DREAM Clinical implications

• Ramipril
• No significant effect on new-onset diabetes
• Improved glucose metabolism further research is
  needed
• Routine use for diabetes prevention cannot be
  recommended
• When ACEIs are indicated, improved glucose
  metabolism may be additional benefit
• Rosiglitazone
• Provides evidence that pharmacologic intervention
  is an option for treatment of prediabetes
• Benefit/risk Of 1000 individuals treated for 3
  years, 144 cases of new-onset diabetes could be
  prevented with excess of 45 HF cases

DREAM Trial Investigators.N Engl J Med.
20063551551-62 Lancet. 20063681096-105.
42
Evolution of ACE inhibition for treating patients
with CHD

CHD without HF or LV dysfunction
Low LVEF
Severe HF
Acute MI
QUIET HOPE EUROPAPEACE
SOLVD-Prevent SOLVD-Treat SAVE AIRE
GISSI-3 ISIS-4 CCT CONSENSUS II
CONSENSUS

1987
19911993
19921995
19992004
Adapted from Yusuf S, Lonn E. Eur Heart J.
199819(suppl J)J36-44.Lonn EM et al.
Circulation. 1994902056-69.
Chinese Captopril Trial
43
Meta-analyses show consistency of ACEI benefit in
preventing CV events
Randomized, placebo-controlled trials in patients
with CAD without HF or LV dysfunction
Danchin N et al. Arch Intern Med. 2006.Al-Mallah
MH et al. J Am Coll Cardiol. 2006.Dagenais GR et
al. Lancet. 2006.
44
EUROPA, HOPE, PEACE, QUIET Treatment effect on
CV end points
EUROPA CV death/MI/cardiac arrest
HOPECV death/MI/stroke
Placebo
15
20
Placebo
22 RRR HR 0.78 (0.700.86) P lt 0.001
20 RRR HR 0.80 (0.710.91) P 0.0003
15
10
10
Ramipril 10 mg
Perindopril 8 mg
5
5
0
0
0
2
4
1
3
1
3
4
0
5
2
Patients ()
PEACECV death/MI/CABG/PCI
QUIETCV death/MI/cardiac arrest
Placebo
8
30
Placebo
5
13 RRR HR 0.87 (0.591.29)
4 RRR HR 0.96 (0.881.06) P 0.43
20
Trandolapril 4 mg
3
10
Quinapril 20 mg
1
0
0
0
1
2
3
1
2
3
4
5
6
Time (years)
Primary end pointSecondary end point
EUROPA Investigators. Lancet. 2003 HOPE Study
Investigators. N Engl J Med. 2000PEACE Trial
Investigators. N Engl J Med. 2004 Pitt B et al.
Am J Cardiol. 2001.
45
HOPE, EUROPA, PEACE Overview
HOPE Study Investigators. N Engl J Med.
2000. EUROPA Investigators. Lancet. 2003. PEACE
Trial Investigators. N Engl J Med. 2004.
or diabetes 1 CV risk factor
46
HOPE, EUROPA, PEACE Reduction in all-cause
mortality
Favors ACEI
Favors placebo
0.6
1.0
1.4
Odds ratio (95 CI)
Dagenais GR et al. Lancet. 2006368581-8.
47
HOPE, EUROPA Benefit consistent across ancillary
therapy
4-year rates in placebo groups
ACEI better
ACEI worse
Patients (n)
Subgroup
P
0.003 0.651 0.139 0.078
AntiplateletsNo antiplatelets Lipid-lowering
agentsNo lipid-lowering agents ?-blockersNo
?-blockers RevascularizationNo revascularization
18,3313184 948912,026 11,32310,192 10,39411,12
3
13.217.9 10.616.4 13.414.3 11.516.0
1.1
1.0
0.5
0.9
0.6
0.7
0.8
Odds ratio (95 CI)
For interactionCV death, nonfatal MI, or stroke
Adapted from Dagenais GR et al. Lancet.
2006368581-8.
48
HOPE, EUROPA Benefit of ACEIs consistent across
baseline combinations
ACEI better
ACEI worse
P
0.5
0.8
1.1
0.6
0.9
0.7
1.0
Odds ratio (95 CI)
For interactionCV death, nonfatal MI, or stroke
Dagenais GR et al. Lancet. 2006368581-8.
49
Benefit of ACEIs in patients with/withoutLVD or
HF
Favors ACEI
Favors placebo
1.0
0.6
1.4
Odds ratio (95 CI)
HOPE, EUROPA, PEACESAVE, AIRE, TRACE, SOLVD
Dagenais GR et al. Lancet. 2006368581-8.
50
EUROPA Consistent risk reduction regardless of
baseline risk
Relative risk reduction
12
32
17
Relative baseline risk
CV death and nonfatal MI
Deckers JW et al. Eur Heart J. 200627796-801.
51
HOPE, EUROPA, PEACE Benefit of ACEIs across
broad spectrum of risk
CV death, nonfatal MI or stroke
ACEI worse
ACEI better
-5
20
40
5
30
15
35
25
10
0
Odds reduction ()
Or total mortality in AIRE, TRACE, SOLVD, SAVE
trials
Dagenais GR et al. Lancet. 2006368581-8.
52
ACEIs in vascular disease Conclusions

• ACEIs reduce mortality, MI, HF, and stroke in
  patients with vascular disease with/without LVSD
  or HF
• Benefit in addition to antiplatelet agents,
  ß-blockers, and lipid-lowering agents
• Combining ACEIs with these agents provides
  greatest benefit
• Benefit in patients across a broad range of risk
  for CV events
• Annual rate in placebo groups of 1.422.6

• Consider ACEIs in all patients with vascular
  disease
• Assess risk/benefits and tolerability
• Use doses proven in clinical trials

Dagenais GR et al. Lancet. 2006368581-8. Fox K
et al. Eur Heart J. 2006272154-7.
53
ACEIs and elevated serum creatinine in renal
insufficiency

• Creatinine elevations are modest and
  self-limiting
• 30 above baseline
• Stabilize within 2 to 4 weeks
• If BP is controlled, elevation after 4 weeks is
  unlikely
• Causes
• ?Effective circulating volume (most common)
• Bilateral renal stenosis
• Withdraw ACEI only if creatinine is gt30 above
  baseline or K 21.9 mg/dL (5.6 mmol/L)

Bakris GL, Weir MR. Arch Intern Med.
2000160685-93.
54
HOPE CV end point by baseline creatinine
Primary end point
Myocardial infarction
80
60
60
50
Events
40
per 1000
40
30
person-
20
20
years (n)
10
0
0
lt1.4
lt1.4
1.4
1.4
Creatinine concentration
Creatinine concentration
(mg/dL)
(mg/dL)
All patients
Placebo
Ramipril 10 mg
CV death, MI, stroke
Mann JFE et al. Ann Intern Med. 2001134629-36.
55
Meta-analysis of trials comparing ARB vs placebo,
non-ACEI comparators, or ACEI
9 of 11 trials show excess MI for ARB
Favors ARB
Favors control
1.08 (1.011.16)
0.5
1.0
1.5
2.0
Odds ratio (95 Cl)
Strauss MH, Hall AS. Circulation. 2006114838-54.
56
Meta-analyses of ACEI and ARB trials
Relative risk
Strauss MH, Hall AS. Circulation. 2006. Tsuyuki
RT, McDonald MA. Circulation. 2006. Volpe M et
al. J Hypertension. 2005. Verdecchia P et al. Eur
Heart J. 2005.
57
ACEIs vs ARBs Comparative effect on stroke, HF,
and CHD
Blood Pressure Lowering Treatment Trialists
Collaboration meta-analysisN 137,356 21
randomized clinical trials
ACEI
RRR (95)
StrokeP 0.6
Stroke
-1 (9 to -10)
HF
10 (10 to 0)
HF P 0.4
CHD
9 (14 to 3)
ARB
CHD P 0.001
Stroke
2 (33 to -3)
HF
16 (36 to -5)
CHD
-7 (7 to -24)
0
30
30
Decrease
Increase
Risk
Turnbull F. 15th European Meeting on
Hypertension. 2005.Adapted by Strauss MH, Hall
AS. Circulation. 2006114838-54.
CHD MI and CV death
58
EPHESUS New subgroup analysis
N 6632 with post-MI LVSD, mean follow-up 16
months
P 0.001 0.002 0.022 0.127 0.03 0.641 0.012 0.
001 0.01
Eplerenone better
Placebo better
History of hypertension All-cause mortality CV
mortality/hospitalization Sudden cardiac
death History of diabetes All-cause
mortality CV mortality/hospitalization Sudden
cardiac death LVEF 30 All-cause mortality CV
mortality/hospitalization Sudden cardiac death
0.2
1.0
1.2
1.8
1.4
1.6
0.4
0.6
0.8
Odds ratio (95 Cl)
Eplerenone Post-Acute Myocardial Infarction Heart
Failure Efficacy and Survival Study
Pitt B et al. Am J Cardiol. 200697(suppl)26F-33F
.
59
Role of RAAS modulation continues to evolve

Vascular diseaseDiabetes
IFG/IGT
IGT
Heart failure
EMPHASIZE-HFTOPCAT
ONTARGETTRANSCEND
DREAM
NAVIGATOR

2006
2007
2011
2008
ONTARGET/TRANSCEND Investigators. Am Heart J.
2004.Skyler JS. Clin Diabetes. 2004.Greenberg B
et al. Am J Cardiol. 2006.
60
ONTARGET Study design
ONgoing Telmisartan Alone and in combination with
Ramipril Global Endpoint Trial
N 25,62055 years with coronary,
cerebrovascular, or peripheral vascular disease,
or diabetes end-organ damage
Ramipril 10 mg
Telmisartan 80 mg
Ramipril 10 mg telmisartan 80 mg
Primary end pointCV death, MI, stroke, hosp for
HF
Secondary end pointNewly diagnosed diabetes
Results anticipated in 2007
ONTARGET/TRANSCEND Investigators. Am Heart J.
200414852-61.
61
TRANSCEND Study design
Telmisartan Randomized AssessmeNt Study in aCE
iNtolerant subjects with cardiovascular Disease
N 5776 ACEI-intolerant55 years with coronary,
cerebrovascular, or peripheral vascular disease,
or diabetes end-organ damage
Telmisartan 80 mg
Placebo
Primary end pointCV death, MI, stroke, hosp for
HF
Secondary end pointNewly diagnosed diabetes
Results anticipated in 2007
ONTARGET/TRANSCEND Investigators. Am Heart J.
200414852-61.
62
ONTARGET/TRANSCEND Baseline medical conditions
vs HOPE
ONTARGET/TRANSCEND Investigators. Am Heart J.
200414852-61.
63
ONTARGET/TRANSCEND Baseline medications vs HOPE
ONTARGET/TRANSCEND Investigators. Am Heart J.
200414852-61.
64
NAVIGATOR Study design
Nateglinide and Valsartan in Impaired Glucose
Tolerance Outcomes Research
N 9150 with IGT50 years with prior CV disease
or55 years with CV risk factorsRandomized,
double-blind 2 2 factorial design
Valsartan vs placebo AND Nateglinide vs placebo
Primary end pointsCV events, new-onset diabetes
NAVIGATOR Trial Steering Committee. Diabetes.
200352(suppl 1)A505.Skyler JS. Clin Diabetes.
200422162-6.
Insulin secretagogue
65
EMPHASIZE-HF Study design
Effect of Eplerenone in Chronic Systolic Heart
Failure
N 2584 with NYHA class II chronic systolic HF
Eplerenone standard therapy
Placebo standard therapy
Primary end pointCV death, hosp for HF
Follow-up 4 years
Results anticipated 2010
Greenberg B et al. Am J Cardiol.
200697(suppl)34F-40F.
66
TOPCAT Study design
Treatment of Preserved Cardiac Function Heart
Failure with an Aldosterone Antagonist
N ? 4500 with HF and LVEF gt45
Spironolactone
Placebo
Primary end pointCV death, hosp for HF
Follow-up 2 years
Results anticipated 2011
Greenberg B et al. Am J Cardiol.
200697(suppl)34F-40F.
67
RAAS modulation in high-risk patients Summary

• Opportunity for greater use of RAAS modulation in
  patients at high risk for CV events
• ACEIs reduce CV death, MI, HF, and stroke across
  a broad range of patients with vascular disease
• With/without LVSD or HF
• With/without other proven CV therapies
• Annual event rates of 1.422.6 in untreated
  groups
• ARBs reduce HF and stroke
• ACEIs may be considered in all patients with
  vascular disease
• ARBs are an alternative in ACEI-intolerant
  patients

Dagenais GR et al. Lancet. 2006. Strauss MH, Hall
AS. Circulation. 2006. Smith SC et al.
Circulation. 2006.