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