HOPE: Diabetes and
Cardiovascular Disease
Songsak Kiatchoosakun
Cardiology, Medicine
Khon Kaen University
Diabetes & Cardiovascular Risks



More than 115 million people worldwide
suffered form diabetes
65% of people with diabetes die from
cardiovascular disease (CVD)
Cardiovascular mortality in type 2 diabetes
increases 2-4 fold
7 - ye a r i ncid e nce of C V e ve nts ( % )
Patients with Diabetes at Similar Risk
to No Diabetes with MI
p<0.001
50
40
30
p<0.001
N o prior M I
MI
20
10
0
ns
n=1304
n=69
No diabetes
(n=1373)
n=890
n=169
Diabetes
(n=1059)
Haffner SM et al. N Engl J Med 1998;339:229-234.
Medical Management of
Atherosclerotic in Diabetes


Treating hyperglycemic and insulin resistance
Lipid goal
Without CVD: LDL < 100 mg/dl
 With CVD LDL < 70 mg/dl


Antiplatelet therapy



Smoking cessation
Hypertension and blood pressure control


Age > 40, additional risk factors of CAD
Blood pressure goal < 130/80 mmHg
Prevention of cardiovascular disease (CVD)
Prevention of CVD
 Atherosclerosis progression - precursor of
clinical CVD
 Modifying known risk factors (diabetes,
dyslipidemia,hypertension, smoking) does not
fully reduce CVD risk
 Evidence that renin-angiotensin system
activation and lipid oxidation have important
roles in atherosclerosis progression
Angiotensin II and Progression of
Vascular Disease
LDL
DM
HT
Smoking
Oxidative Stress
Endothelial dysfunction/
Smooth muscle activation
NO
Local mediators
Tissue ACE, Angiotensin II
Platelet aggregation, VCAM/ICAM cytokines, Inflammation, Growth factor
Vasoconstriction
Thrombosis
Inflammation
Plaque rupture
Renin Angiotensin System and
Role of Angiotensin
Converting Enzyme Inhibitor
in Coronary Artery Disease
Renin Angiotensin System
Secondary Prevention of
CAD - Role of ACE Inhibition
BRADYKININ SYSTEM
ANGIOTENSIN SYSTEM
kininogen
Angiotensinogen
kallikrein
renin
Endothelium Bradykinin
+
 platelet
+
aggregation
Prostaglandin
NO
Inactive
Ang I
+
ACE
(enzyme)
Vasodilation
Ang II
Potentiation of
sympathetic
activity
peptide
 SMC
mitogenesis
ACE
inhibitor
impact
FGF
PDGF
ACE Inhibition and
Anti- atherosclerotic Effect
(A) Control
(B) Diabetic
apoE-deficient mice
(C) Diabetic
apoE-deficient mice
ACE inhibition treated
Candido R et al. Circulation. 2002;106:246-253.
ACE Inhibition for
Secondary Prevention of CAD
Rationale

Anti-atherosclerotic effects

Improvement in vascular endothelial function

Vasodilation:reduce preload and afterload

LV hypertrophy reduction
Blood
pressure lowering
Angiotensin II reduction / bradykinin increase
Chain of Events Leading to
End Stage Heart Disease:
Ventricular Dilation/
Dysfunction
Remodelling
Congestive
Heart Failure
Myocardial
Infarction
Atherosclerosis
Risk factors
Diabetes
Hypertension
Smoking
Dyslipidemia
End-Stage
Heart Disease
Cardiovascular
Death
Adapted from Dzau, Braunwald. Am Heart J 1991;121:1244–1263
Major Clinical Outcome Trials
of RAAS Manipulation
ACE inhibition
Angiotensin receptor blockade
GISSI-3
ISIS-4
AIRE
SAVE
SOLVD-Prevention
TRACE
CHARM-Preserved
OPTIMAAL
VALIANT
SOLVD-Treat
CHARM-Added
CHARM-Alternative
ELITE II
Val-HeFT
ALLHAT
ANBP2
INVEST
LIFE
CONSENSUS
Survival and Ventricular
Enlargement Trial (SAVE)
19% reduction
in all causes mortality
Pfeffer MA. SAVE Trial. N Engl J Med 1992;327:669
Major Clinical Outcome Trials
of RAAS Manipulation
ACE inhibition
Angiotensin receptor blockade
GISSI-3
ISIS-4
AIRE
SAVE
SOLVD-Prevention
TRACE
CHARM-Preserved
OPTIMAAL
VALIANT
HOPE
EUROPA
SOLVD-Treat
CHARM-Added
CHARM-Alternative
ELITE II
Val-HeFT
ALLHAT
ANBP2
INVEST
LIFE
CONSENSUS
The Heart Outcomes Prevention
Evaluation Study: HOPE Study
Aim: Effect of Ramipril (up to 10mg/d) or
Vitamin E (400 IU/d) vs its placebo on CV
death, MI or stroke (primary)
Design:Randomized double blind, 2x2 factorial,
Wide entry criteria, large, simple trial
Size: 9541 patients followed for 4 to 6 years
Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342:145.
Key Inclusion / Exclusion Criteria
Inclusion Criteria
Patients (age >55) at high risk for CV events because of:
 previous CV disease (CHD, stroke, PVD)
 DM + one other CV risk factor


BP>160/90 or on Rx- smoker
Cholesterol > 5.2
- HDL<=0.9
Exclusion Criteria
- microalbuminuria
- previous CVD
Heart failure or low EF
Dipstick + proteinuria (>=1+)
On ACE-I or Vitamin E
Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342:145.
HOPE Study Population:
“Typical” Office Practice Patients

Patients did not have
heart failure

Patients had normal or
controlled blood
pressure (53% normal)



CV events
 11% had previous stroke
 80% had history of CAD
 42% had history of PVD
Diabetes
 39% had diabetes + 1 or
more CVD risk factors
Patients were 55 years
or older
The HOPE Study Investigators. N Engl J Med. 2000;342:145-153.
HOPE: Assessment of Outcomes
Primary outcome
Composite of myocardial infarction, stroke or
cardiovascular death
Secondary outcomes
Unstable angina, heart failure, hospitalization,
revascularization
Microalbuminuria, overt nephropathy,
retinopathy, cataract
Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342:145
HOPE: Primary Outcome
Reductions in MI, Stroke, or Cardiovascular Death
% of Patients
Reaching Endpoints
0.20
Placebo
22%
Reduction
in Events
P=.0001*
0.15
Ramipril
0.10
15%
0.05
Reduction
in Events at
1 year
0
0
500
1000
1500
Days of Follow-up
Note: Trial halted early due to the highly significant risk reductions seen with Ramipril
Relative Risk Reduction in
Cardiovascular Endpoints
Combined
Cardiovascular Myocardial
cardiovascular mortality
Infarction
endpoints
Stroke
-20%, p<0.001
-22%, p<0.01
-26%, p<0.001
-32%, p<0.001
HOPE – Secondary Endpoints
25
16% Risk Reduction
P<0.001
18.6
% with an event
20
16
15
Ramipril
Placebo
23% Risk Reduction
P<0.001
16% Risk Reduction
P=0.03
11.7
10
6.2
7.4
13% Risk Reduction
P=0.19
9.2
5.3
3.3 3.8
5
Revascularization
0
N Engl J Med. January 20, 2000
DM
Complications
HF
Hospitalization
32% Risk Reduction
P=0.002
3.7
Heart Failure
New diagnosis of
Diabetes Mellitus
HOPE: Additive Risk Reduction with VBWG
Ramipril 10 mg
Effects beyond baseline therapy
• Aspirin
• b-blockade
• Lipid-lowering agents
*P = 0.0001
†P = 0.005
• Diuretics
• Other antiplatelets
• Calcium channel blockade
+ Ramipril 10 mg
The Heart Outcomes Prevention Evaluation
Study Investigators. N Engl J Med. 2000;342:145-153.
Secondary Adjudicated Events
Ramipril Placebo
(%)
(%)
Ramipril vs Placebo
RR
No. Rand
2° Outcomes
Unstable Angina
with ECG
changes
Heart failure
Revascularization
95% CI
p
4645
4652
11.9
12.1
0.98 0.87-1.10
0.68
3.9
4.0
0.96 0.79-1.18
0.72
9.0
11.5
0.77 0.67-0.87
<0.001
16.0
18.3
0.85 0.77-0.94
0.002
• 732 patients
• Mean F/U 4.5 years
HOPE: Compliance
100
90
87.4
85
80
82.2
75.1
70
60
1st year
2nd year
3rd year
4th year
HOPE Study. N engl J Med 2002;342:145-153.
MicroHOPE: Outcomes
in Diabetics With Ramipril

Study Parameters
 Substudy of HOPE
 3577 Patients with diabetes + previous CV event
or 1 other CV risk factor
 Exclusion
Proteinuria
Heart failure
ACE inhibitor therapy
Low EF (<40%)
 Duration: 4.5 years
Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Lancet. 2000;355:253-259.
MicroHOPE: CV Events
in Diabetic Patients
Placebo
Total Mortality
0.16
Ramipril
0.12
0.06
0.08
0.04
0.04
Stroke
0.08
RR reduction: 24%
0
RR reduction: 33%
0.02
0
0
Myocardial Infarction
0.16
0
500
1000
1500
2000
Duration of Follow-up (Days)
14
500
1000
1500
2000
Duration of Follow-up (Days)
Heart Failure
12
10
0.12
8
0.08
6
0.04
RR reduction: 22%
4
2
0
0
500
1000
1500
Duration of Follow-up (Days)
2000
0
Heart Outcomes Prevention Study Investigators. Lancet. 2000;355:253-259.
Ramipril
Placebo
HOPE/HOPE-TOO: Primary outcome
Ramipril: CV Death/MI/Stroke - Extended Follow-up
0.30
HOPE Study Ends
Ramipril
0.25
Placebo
0.20
Hazard
0.15
0.10
0.05
ALL: RR: 0.81, CI: (0.74-0.88)
CONT: RR: 0.83, CI: (0.75-0.91)
0.0
Years
1
2
3
4
5
6
7
Bosch J. European Society of Cardiology Congress 2003.
Aug 30–Sep 3, 2003. Vienna, Austria
HOPE:Conclusions

In people with high risk for CVD,
addition of ramipril to other effective
therapies prevents:
CV death, strokes and MI
 Total mortality
 Revascularization
 Diabetic nephropathy



The benefit is independent of the effect
on BP (3/2 mmHg)
The only adverse event is a 5% excess of
cough
HOPE: Implications for CHD



ACE-I with ramipril reduced events in most
groups
Treating 1,000 patients with ramipril for four
years prevents about 150 events in
approximately 70 patients
HOPE suggests ACE-I should be used like
aspirin, for prevention of vascular events in
high risk subjects
Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342:145.
Major Clinical Outcome Trials
of RAAS Manipulation
ACE inhibition
Angiotensin receptor blockade
GISSI-3
ISIS-4
AIRE
SAVE
SOLVD-Prevention
TRACE
CHARM-Preserved
OPTIMAAL
VALIANT
HOPE
EUROPA
SOLVD-Treat
CHARM-Added
CHARM-Alternative
ELITE II
Val-HeFT
ALLHAT
ANBP2
INVEST
LIFE
CONSENSUS
EUROPA Study Hypothesis

In selected patient groups (high CV risk or
LV dysfunction), ACE-I results in secondary
prevention of coronary disease

However, the multiple ways by which ACE
inhibition affects the atherosclerotic process,
suggest that it might occur in all patients
with coronary disease
EROPA Study. Lancet 2003;362:782
Selection Criteria

Male or female > 18 years of age

Documented coronary disease

Not scheduled for revascularisation

No clinical signs of heart failure
EUROPA Study. Lancet 2003;362:782
Primary Endpoint
% CV death, MI or cardiac arrest
14
RRR: 20%
p = 0.0003
12
10
Placebo
Perindopril
8
6
4
2
0
0
1
2
3
4
Placebo annual event rate: 2.4%
5 Years
EUROPA Study. Lancet 2003;362:78
HOPE, EUROPA: Treatment benefit on
primary and selected secondary outcomes
Favors
ACEI
Event rate (%)
ACEI
Placebo
14.0
17.8
8.0
9.9
CV mortality
6.1
3.5
8.1
4.1
Myocardial infarction
9.9
4.8
12.3
6.2
Stroke
3.4
1.6
4.9
1.7
0.8
1.3
0.1
0.2
Composite outcome
Cardiac arrest
Favors
placebo
HOPE
EUROPA
0.5
EUROPA = European Trial on Reduction of Cardiac Events
with Perindopril in Stable Coronary Artery Disease
HOPE = Heart Outcomes Prevention Evaluation
1.0
Hazard ratio
1.5
EUROPA Investigators. Lancet. 2003;362:782-8.
HOPE Study Investigators. N Engl J Med. 2000;342:145-53.
New Approach to the Classification
of Heart Failure
Stage
Patient Description
A
High risk for developing
heart failure (HF)

B
C
D
Asymptomatic HF
Symptomatic HF
Refractory
end-stage HF
Hypertension
 CAD
 Diabetes mellitus
 Family history of cardiomyopathy
 Previous MI
 LV systolic dysfunction
 Asymptomatic valvular disease
 Known structural heart disease
 Shortness of breath and fatigue
 Reduced exercise tolerance
 Marked symptoms at rest despite
maximal medical therapy (eg, those
who are recurrently hospitalized or
cannot be safely discharged from the
hospital without specialized
interventions)
Carvedilol is indicated for use in patients with mild to severe chronic HF and in patients with HTN.
Hunt SA et al. J Am Coll Cardiol. 2001;38:2101–2113.
Treatment Approach for the Patient
with Heart Failure
Stage A
Stage B
Stage C
Stage D
At high risk, no
structural
disease
Structural heart
disease,
asymptomatic
Structural heart
disease with
prior/current
symptoms of HF
Refractory HF
requiring
specialized
interventions
Therapy
Therapy
Therapy
Therapy
• Treat
Hypertension
• All measures
under stage A
• All measures
under stage A
• Treat lipid
disorders
• ACE inhibitors in
appropriate
patients
Drugs:
• Encourage
regular exercise
• Discourage
alcohol intake
• ACE inhibition for
vascular disease
or diabetes
• Beta-blockers in
appropriate
patients
• Diuretics
• ACE inhibitors
• Beta-blockers
• Digitalis
• Aldosterone
antagonist
• All measures
under stages A,B,
and C
• Mechanical assist
devices
• Heart
transplantation
• Continuous (not
intermittent) IV
inotropic
infusions for
palliation
• Hospice care
Abraham WT,et al. ACC/AHA Guidelines CHF, 2005.
Conclusions
• The relationship between RAAS and diabetic
vascular disease is well established
• Cumulative evidence supports ACE inhibitors for
a broad range of CAD patients
• Not all ACE inhibitors can be assumed to have
comparable effects on vascular protection
– Medication adherence and dosage
are important
• Evidence-based medicine should guide use ACE
inhibition (ramipril 10 mg) in patients with
diabetes and vascular disease
Pitt B. N Engl J Med. 2004;351:2115-7.
HOPE/HOPE-TOO: Development of diabetes
Ramipril: New Diabetes - All Patients
0.12
HOPE Study Ends
Ramipril
0.10
10.3
Placebo
30% reduction
0.08
Hazard
7.3%
0.06
0.04
ALL: RR: 0.69, CI: (0.57-0.83)
0.02
0.0
Years
1
2
3
4
5
6
7
Bosch J. European Society of Cardiology Congress
2003. Aug 30–Sep 3, 2003. Vienna, Austria
HOPE: Dose-dependent effects of ramipril
on LV mass and function
Mean baseline LVEF 58% in all groups
Placebo (n = 151)
Ramipril 2.5 mg (n = 149)
10
8
6
8.21
6
5
∆ LV 4
end
3
systolic 2
volume
1
(mL)
7.86
∆ LV
mass 4
(g) 2
0
–2
5.31
2.9
0
–4
–6
Ramipril 10 mg (n = 146)
–3.53
P Trend = 0.03
–1
–2
–3
–1.9
P Trend = 0.001
Lonn E et al. J Am Coll Cardiol. 2004;43:2200-6.