HOPE: Diabetes and Cardiovascular Disease
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Transcript of HOPE: Diabetes and Cardiovascular Disease
HOPE: Diabetes and
Cardiovascular DiseaseSongsak Kiatchoosakun
Cardiology, MedicineKhon Kaen University
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
Diabetes & Cardiovascular Risks
Patients with Diabetes at Similar Risk to No Diabetes
with MI
Patients with Diabetes at Similar Risk to No Diabetes
with MI
0
10
20
30
40
50
7-ye
ar i
ncid
en
ce
of
CV
eve
nts
(%
)
No prior MI
MI
Haffner SM et al. N Engl J Med 1998;339:229-234.
p<0.001
p<0.001
No diabetes (n=1373)
Diabetes (n=1059)
ns
n=1304 n=890n=69 n=169
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 Age > 40, additional risk factors of CAD
Smoking cessation Hypertension and blood pressure
control Blood pressure goal < 130/80 mmHg
Prevention of cardiovascular disease (CVD)
Prevention of CVD
Modifying known risk factors (diabetes, dyslipidemia,hypertension, smoking) does not fully reduce CVD risk
Atherosclerosis progression - precursor of clinical CVD
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 ofCAD - Role of ACE
InhibitionANGIOTENSIN SYSTEM
Angiotensinogen
renin
Ang I
Ang II
vaso
constr
iction Potentiation of
sympathetic activity
+ACE
(enzyme)
BRADYKININ SYSTEM
kallikrein
kininogen
BradykininEndothelium
ProstaglandinNO
plateletaggregation
SMCmitogenesis
Vasodilation
Inactive peptide
++
ACEinhibitorimpact
ACEinhibitorimpact
FGFPDGF
ACE Inhibition and Anti- atherosclerotic Effect
(A) Control
Candido R et al. Circulation. 2002;106:246-253.
(B) Diabetic apoE-deficient mice
(C) Diabetic apoE-deficient mice ACE inhibition treated
ACE Inhibition forSecondary Prevention of
CADRationale
Anti-atherosclerotic effects
Improvement in vascular endothelial function
Vasodilation:reduce preload and afterload
LV hypertrophy reduction
Blood pressure lowering
Angiotensin II reduction / bradykinin increaseAngiotensin II reduction / bradykinin increase
Adapted from Dzau, Braunwald. Am Heart J 1991;121:1244–1263
Cardiovascular Death
Risk factorsDiabetes
HypertensionSmoking
Dyslipidemia
End-StageHeart Disease
Atherosclerosis
Chain of Events Leading to
End Stage Heart Disease:
CongestiveHeart Failure
Ventricular Dilation/Dysfunction
Remodelling
MyocardialInfarction
Major Clinical Outcome Trials of RAAS Manipulation
ACE inhibitionAngiotensin receptor blockade
GISSI-3ISIS-4
AIRESAVESOLVD-PreventionTRACECHARM-PreservedOPTIMAALVALIANT
SOLVD-Treat
CHARM-Added
CHARM-AlternativeELITE IIVal-HeFT
CONSENSUS
ALLHATANBP2INVESTLIFE
Survival and Ventricular Enlargement Trial
(SAVE) 19% reductionin all causes mortality
Pfeffer MA. SAVE Trial. N Engl J Med 1992;327:669
Major Clinical Outcome Trials of RAAS Manipulation
ACE inhibitionAngiotensin receptor blockade
GISSI-3ISIS-4
AIRESAVESOLVD-PreventionTRACECHARM-PreservedOPTIMAALVALIANT
SOLVD-Treat
CHARM-Added
CHARM-AlternativeELITE IIVal-HeFT
CONSENSUS
HOPEEUROPA
ALLHATANBP2INVESTLIFE
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 - microalbuminuria
Cholesterol > 5.2 - HDL<=0.9 - previous CVD
Exclusion CriteriaHeart failure or low EFDipstick + 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)
Patients were 55 years or older
CV events11% had previous
stroke80% had history of
CAD42% had history of
PVD
Diabetes39% had diabetes +
1 or more CVD risk factors
The HOPE Study Investigators. N Engl J Med. 2000;342:145-153.
HOPE: Assessment of Outcomes
Primary outcomeComposite of myocardial infarction,
stroke or cardiovascular death
Secondary outcomesUnstable angina, heart failure,
hospitalization, revascularizationMicroalbuminuria, 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
Note: Trial halted early due to the highly significant risk reductions seen with Ramipril
0.200.20
0.150.15
0.100.10
0.050.05
00
00 500500 10001000 15001500
22%22% ReductioReductionnin Eventsin EventsP=.0001P=.0001**
Days of Follow-upDays of Follow-up
% o
f P
ati
en
tsR
each
ing
En
dp
oin
tsPlaceboPlacebo
Ramipril Ramipril
15%15% ReductioReduction in n in Events at Events at 1 year1 year
Relative Risk Reduction in Cardiovascular
EndpointsCombinedcardiovascularendpoints
Cardiovascularmortality
MyocardialInfarction
Stroke
-22%, p<0.01
-26%, p<0.001
-20%, p<0.001
-32%, p<0.001
HOPE – Secondary Endpoints
16
6.2
3.3
9.2
3.7
18.6
7.4
3.8
11.7
5.3
0
5
10
15
20
25
% w
ith an
even
t
Ramipril
Placebo
RevascularizationRevascularization DMDMComplicationsComplications
New diagnosis of New diagnosis of Diabetes MellitusDiabetes Mellitus
16% Risk Reduction16% Risk ReductionPP<0.001<0.001
16% Risk Reduction16% Risk ReductionPP=0.03=0.03
23% Risk Reduction23% Risk ReductionPP<0.001<0.001
HFHFHospitalizationHospitalization
Heart FailureHeart Failure
N Engl J Med.N Engl J Med. January 20, 2000 January 20, 2000
13% Risk Reduction13% Risk ReductionPP=0.19=0.19
32% Risk Reduction32% Risk ReductionPP=0.002=0.002
The Heart Outcomes Prevention EvaluationStudy Investigators. N Engl J Med. 2000;342:145-153.
• Aspirin • Diuretics
• -blockade • Other antiplatelets
• Lipid-lowering agents • Calcium channel blockade+ Ramipril 10 mg
*P = 0.0001†P = 0.005
HOPE: Additive Risk Reduction withRamipril 10 mg
Effects beyond baseline therapy
VBWG
Ramipril
(%)
Placebo
(%)
Ramipril vs Placebo
RR 95% CI p
No. Rand 4645 4652
2 Outcomes
Unstable Angina 11.9 12.1 0.98 0.87-1.10 0.68
with ECG
changes
3.9 4.0 0.96 0.79-1.18 0.72
Heart failure 9.0 11.5 0.77 0.67-0.87 <0.001
Revascularization 16.0 18.3 0.85 0.77-0.94 0.002
Secondary Adjudicated Events
• 732 patients• Mean F/U 4.5 years
HOPE: Compliance
87.485
82.2
75.1
60
70
80
90
100
1st year 2nd year 3rd year 4th year
HOPE Study. N engl J Med 2002;342:145-153.
MicroHOPE: Outcomesin Diabetics With
Ramipril Study Parameters
Substudy of HOPE3577 Patients with diabetes + previous CV eventor 1 other CV risk factor
ExclusionProteinuriaHeart failureACE inhibitor therapyLow EF (<40%)
Duration: 4.5 years
Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Lancet. 2000;355:253-259.
MicroHOPE: CV Eventsin Diabetic Patients
Placebo Ramipril
Heart Outcomes Prevention Study Investigators. Lancet. 2000;355:253-259.
0.16
0.12
0.08
0.04
0
Total Mortality
0.16
0.12
0.08
0.04
00 500 1000 20001500
Myocardial Infarction
Stroke0.08
0.06
0.04
0.02
00 500 1000 20001500
Duration of Follow-up (Days) Duration of Follow-up (Days)
Duration of Follow-up (Days)
RR reduction: 24% RR reduction: 33%
RR reduction: 22%
500 1000 200015000
Heart Failure
0
2
4
6
8
10
12
14
Ramipril Placebo
Bosch J. European Society of Cardiology Congress 2003. Aug 30–Sep 3, 2003. Vienna,
Austria
HOPE/HOPE-TOO: Primary outcome
Hazard
Years
1 2 3 4 5 6 7
Ramipril
Placebo
0.0
0.05
0.10
0.15
0.20
0.25
0.30
1 2 3 4 5 6 7
Ramipril
Placebo
Ramipril: CV Death/MI/Stroke - Extended Follow-up
ALL: RR: 0.81, CI: (0.74-0.88)
CONT: RR: 0.83, CI: (0.75-0.91)
HOPE Study Ends
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 inhibitionAngiotensin receptor blockade
GISSI-3ISIS-4
AIRESAVESOLVD-PreventionTRACECHARM-PreservedOPTIMAALVALIANT
SOLVD-Treat
CHARM-Added
CHARM-AlternativeELITE IIVal-HeFT
CONSENSUS
HOPEEUROPA
ALLHATANBP2INVESTLIFE
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
Placebo annual event rate: 2.4%
Perindopril
Placebop = 0.0003RRR: 20%
Years0
2
4
6
8
10
12
14
0 1 2 3 4 5
EUROPA Study. Lancet 2003;362:782
HOPE, EUROPA: Treatment benefit on primary and selected secondary outcomes
Event rate (%)
ACEI Placebo 14.0 17.8
8.0 9.9
6.1 8.1 3.5 4.1
9.9 12.3 4.8 6.2
3.4 4.9 1.6 1.7
0.8 1.3
0.1 0.2
Composite outcome
CV mortality
Myocardial infarction
Stroke
Cardiac arrest
FavorsACEI
Favorsplacebo
HOPE
EUROPA
EUROPA Investigators. Lancet. 2003;362:782-8.HOPE Study Investigators. N Engl J Med. 2000;342:145-53.
EUROPA = European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery DiseaseHOPE = Heart Outcomes Prevention Evaluation
Hazard ratio 0.5 1.0 1.5
New Approach to the Classification
of Heart Failure
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)
Refractory end-stage HFD
Known structural heart disease Shortness of breath and fatigue Reduced exercise tolerance
Symptomatic HFC
Previous MI LV systolic dysfunction Asymptomatic valvular disease
Asymptomatic HFB
Hypertension CAD Diabetes mellitus Family history of cardiomyopathy
High risk for developing heart failure (HF)
APatient DescriptionStage
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 Treatment Approach for the Patient Patient
with Heart Failurewith Heart FailureStage AStage A
At high risk, no At high risk, no structural structural diseasedisease
Stage BStage B
Structural heart Structural heart disease, disease,
asymptomaticasymptomatic
Stage DStage D
Refractory HF Refractory HF requiring requiring
specialized specialized interventionsinterventions
TherapyTherapy
• Treat Treat HypertensionHypertension
• Treat lipid Treat lipid disordersdisorders
• Encourage Encourage regular exerciseregular exercise
• Discourage Discourage alcohol intakealcohol intake
• ACE inhibition for ACE inhibition for vascular disease vascular disease or diabetesor diabetes
TherapyTherapy
• All measures All measures under stage Aunder stage A
• ACE inhibitors in ACE inhibitors in appropriate appropriate patientspatients
• Beta-blockers in Beta-blockers in appropriate appropriate patientspatients
TherapyTherapy
• All measures All measures under stage Aunder stage A
Drugs:Drugs:
• DiureticsDiuretics
• ACE inhibitorsACE inhibitors
• Beta-blockersBeta-blockers
• DigitalisDigitalis
• Aldosterone Aldosterone antagonistantagonist
TherapyTherapy
• All measures All measures under stages A,B, under stages A,B, and Cand C
• Mechanical assist Mechanical assist devicesdevices
• Heart Heart transplantationtransplantation
• Continuous (not Continuous (not intermittent) IV intermittent) IV inotropic inotropic infusions for infusions for palliationpalliation
• Hospice careHospice care
Stage CStage C
Structural heart Structural heart disease with disease with prior/current prior/current
symptoms of HFsymptoms of HF
Abraham WT,et al. ACC/AHA Guidelines CHF, 2005.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.
Bosch J. European Society of Cardiology Congress 2003. Aug 30–Sep 3, 2003. Vienna, Austria
HOPE/HOPE-TOO: Development of diabetes
0.0
0.02
0.06
0.10
1 2 3 4 5 6 7
Ramipril
Placebo
Ramipril: New Diabetes - All Patients
Hazard
ALL: RR: 0.69, CI: (0.57-0.83)
HOPE Study Ends
Years
0.12
0.08
0.04
7.3%
10.3
30% reduction
HOPE: Dose-dependent effects of ramipril on LV mass and function
8.21 7.86
–3.53–6
–4
–20
2
4
6
8
10 5.31
2.9
–1.9–3
–2–10123456
Placebo (n = 151) Ramipril 2.5 mg (n = 149)Ramipril 10 mg (n = 146)
∆ LV mass
(g)
∆ LV end
systolic volume(mL)
Mean baseline LVEF 58% in all groups
Lonn E et al. J Am Coll Cardiol. 2004;43:2200-6.
P Trend = 0.03 P Trend = 0.001