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Rationale, Study Design & Study Population

Rationale, Study Design & Study Population. Rationale

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Page 1: Rationale, Study Design & Study Population. Rationale

Rationale, Study Design & Study Population

Page 2: Rationale, Study Design & Study Population. Rationale

Rationale

Page 3: Rationale, Study Design & Study Population. Rationale

Global projections for diabetes (millions)2007-2025

World 2007 = 246 million 2025 = 380 million

Increase +55%

Diabetes Atlas, 3rd edition, IDF 2006

28.340.5

+43%

16.2 32.7

+102%

10.418.7

+80%

53.2 64.1+21%

24.544.5

+81%

67.099.4

+48%46.580.3

+73%

Page 4: Rationale, Study Design & Study Population. Rationale

Blood pressure and vascular risk in diabetes Best evidence: 2000

UK Prospective Diabetes Study

Page 5: Rationale, Study Design & Study Population. Rationale

SBP

UKPDS

UK Prospective Diabetes Study

Blood pressure and vascular risk in diabetes Best evidence: 2000

Page 6: Rationale, Study Design & Study Population. Rationale

Does standard treatment with fixed combination

perindopril/indapamide on top of regular BP control:

Produce additional benefits when systolic pressure is lowered

below 145 mmHg?

Produce similar benefits for hypertensive and non-

hypertensive patients?

Add to the benefits produced by other cardiovascular

preventive therapies including ACE inhibitors ?

Preventive therapy in type 2 diabetes: Unresolved issues in 2000

Page 7: Rationale, Study Design & Study Population. Rationale

ADVANCE: a factorial randomised trial of blood pressure lowering and

intensive glucose control in11,140 patients with type 2 diabetes

Effects of a fixed combination of the ACE inhibitor, perindopril, and the diuretic, indapamide, on major vascular events

Page 8: Rationale, Study Design & Study Population. Rationale

Need for type 2 DM patients

Reduction of CV events

on top of current preventive treatments

Simple, safe and well tolerated treatment

In ADVANCEFixed combination perindopril/indapamide

?

?

Simple, ?

What does ADVANCE add?

Page 9: Rationale, Study Design & Study Population. Rationale

Study design

Page 10: Rationale, Study Design & Study Population. Rationale

Main design features

Factorial, randomised trial double-blind, placebo-controlled comparison of

blood pressure lowering with a fixed combination of perindopril and indapamide

open comparison (PROBE design) of a gliclazide MR-based regimen for intensive glucose control

11,140 participants

Wide range of geographic regions

4-5 years follow-up

Page 11: Rationale, Study Design & Study Population. Rationale

ADVANCE BP hypotheses:

Major macrovascular disease including coronary disease, cerebrovascular disease or death from cardiovascular disease, and

Major microvascular disease including new or worsening nephropathy or diabetic eye disease

Among individuals with type 2 diabetes, the systematic addition of a fixed combination of perindopril and indapamide will reduce the risks of:

Irrespective of initial blood pressure or the background use of other preventive therapies, including ACE inhibitors

Page 12: Rationale, Study Design & Study Population. Rationale

Registration

Randomisation

Perindopril-indapamide

combination +

Intensive glucose control

Perindopril-indapamide combination

+Standard

glucose control

Placebo

+Intensive glucose

control

Placebo

+Standard

glucose control

End of follow-up (4-5 years)

Study design Blood pressure lowering intervention

6-week run-in phase on active perindopril and indapamide

Page 13: Rationale, Study Design & Study Population. Rationale

Registration

Randomisation

Perindopril-indapamide

combination +

Intensive glucose control

Perindopril-indapamide combination

+Standard

glucose control

Placebo

+Intensive glucose

control

Placebo

+Standard

glucose control

End of follow-up (4-5 years)

Study design Blood glucose lowering intervention

6-week run-in phase on active perindopril and indapamide

Page 14: Rationale, Study Design & Study Population. Rationale

Inclusion criteria

Type 2 diabetes mellitus Age 55 years or older Additional risk of vascular event

Age 65 years History of major macrovascular disease History of major microvascular disease First diagnosis of diabetes >10 years prior to entry Other major risk factor

Hypertensive or normotensive

Page 15: Rationale, Study Design & Study Population. Rationale

Randomised study treatments

Blood pressure lowering Double-blind perindopril-indapamide versus

matching placebo 2.0 / 0.625mg or placebo for first 3 months

4.0 / 1.25mg or placebo thereafter

Blood glucose lowering (ongoing) Open-label gliclazide MR-based intensive therapy

targeting an HbA1c of 6.5% versus usual

guideline-based care

Page 16: Rationale, Study Design & Study Population. Rationale

Randomised study treatments

Blood pressure lowering Double-blind perindopril-indapamide versus

matching placebo 2.0 / 0.625mg or placebo for first 3 months

4.0 / 1.25mg or placebo thereafter

Blood glucose lowering (ongoing) Open-label gliclazide MR-based intensive therapy

targeting an HbA1c of 6.5% versus usual

guideline-based care

Page 17: Rationale, Study Design & Study Population. Rationale

Why fixed combination of perindopril and indapamide ?

Fixed combination of perindopril and indapamide shown to be very effective in: Reducing blood pressure Reducing arterial stiffness in large arteries Enhancing micro-circulation and tissue

perfusion in the heart and the kidney

Proven CV protection in stroke/TIA patients including in diabetes subgroup (PROGRESS)

very well tolerated (PROGRESS)

Page 18: Rationale, Study Design & Study Population. Rationale

Strokes Active* Placebo

Hypertensive 163 235

Not hypertensive 144 185

Diabetes 48 65

No diabetes 259 355

Cerebral infarction 236 307

Cerebral hemorrhage 28 49

TIA/amaurosis 33 49

Total 307 420

Favorsactive

Favorsplacebo

Hazard ratio(95%CI)

0.67 (0.55-0.81)

0.73 (0.58-0.92)

0.67 (0.46-0.98)

0.72 (0.62-0.85)

0.76 (0.64-0.90)

0.52 (0.33-0.83)

0.66 (0.42-1.02)

0.72 (0.62-0.83)

0.5 2.0

Hazard ratio

1.0

* Active treatment: perindopril 4 mg +/- indapamide 2.5 mg (or 2 mg in Japan)

Reference: Lancet. 2001;358:1033-1041.

Consistent risk reduction in pre defined subgroups

Page 19: Rationale, Study Design & Study Population. Rationale

Ancillary drug treatment Blood pressure lowering therapy

At discretion of treating physician Only thiazide diuretic contraindicated

ACE inhibitor Open-label perindopril (up to 4 mg daily), if

indicated All other treatment

At discretion of treating physician Except glucose control for those assigned

intensive therapy

Page 20: Rationale, Study Design & Study Population. Rationale

What is a more effective preventive strategy in daily practice?

Aim for guideline based BP goal +

standard additition of fixed per/ind combination (like statines post MI)

What does ADVANCE add?

Aim for guideline based BP goal

OR

Page 21: Rationale, Study Design & Study Population. Rationale

Primary study outcomes Macrovascular

Non-fatal stroke, non-fatal myocardial infarction or death from any cardiovascular cause (including sudden death)

Microvascular New of worsening nephropathy or diabetic eye

disease Prespecified analyses:

Macrovascular and microvascular jointly Macrovascular and microvascular separately

Page 22: Rationale, Study Design & Study Population. Rationale

Study population

Page 23: Rationale, Study Design & Study Population. Rationale

0

2000

4000

6000

8000

10000

12000

Jul-

01

Au

g-0

1

Sep

-01

Oct

-01

No

v-01

Dec

-01

Jan

-02

Feb

-02

Mar

-02

Ap

r-02

May

-02

Jun

-02

Jul-

02

Au

g-0

2

Sep

-02

Oct

-02

No

v-02

Dec

-02

Jan

-03

Feb

-03

Mar

-03

Ap

r-03

Number of patients randomised

Cumulative randomisation Regional recruitment

Registered 12,877Randomised 11,140

ADVANCE recruitment

Region Number

ANZ / Asia 2,328

Canada 436

China 3,293

Continental Europe 2,879

Northern Europe 2,204

TOTAL 11,140

Page 24: Rationale, Study Design & Study Population. Rationale

Withdrawals during run-in

Reason for withdrawal N % of registered patients

(N=12877)

Patient ineligible 394 3.1%

Patient wishes 391 3.0%

Poor compliance with study drug 269 2.1%

Cough 238 1.8%

Hypotension 99 0.8%

Other suspected intolerance to study drug 133 1.0%

Other reasons 213 1.7%

TOTAL 1737 13.5%

Page 25: Rationale, Study Design & Study Population. Rationale

Blood pressure,other risk factors, ancillary treatment

Page 26: Rationale, Study Design & Study Population. Rationale

Randomised treatment

Active (n=5569)

Placebo (n=5571)

Age (years) 66 66

Systolic blood pressure (mmHg) 145 145

Diastolic blood pressure (mmHg) 81 81

Haemoglobin A1c (%) 7.5 7.5

History of macrovascular disease 32% 32%

History of microvascular disease 10% 10%

Microalbuminuria 26% 26%

Baseline characteristics

Page 27: Rationale, Study Design & Study Population. Rationale

Blood pressure reduction

Δ 2.2 mmHg (95% CI 2.0-2.4); p<0.001

Δ 5.6 mmHg (95% CI 5.2-6.0); p<0.001

Diastolic

Systolic

PlaceboPerindopril-Indapamide

Mea

n B

loo

d P

ress

ure

(m

mH

g)

65

75

85

95

105

115

125

135

145

155

165

Follow-up (Months)

R 6 12 18 24 30 36 42 48 54 60

140.3 mmHg134.7 mmHg

Average BP during follow-up

77.0 mmHg74.8 mmHg

145

137

81

78

Page 28: Rationale, Study Design & Study Population. Rationale

Aim for guideline based BP goal +

standard additition of fixed per/ind combination (like statines post MI)

Conclusion

Aim for guideline based BP goal

Is a more effective BP lowering strategy than

Page 29: Rationale, Study Design & Study Population. Rationale

SBP

ADVANCE BP reduction in context:UK Prospective Diabetes Study

UKPDSADV

UK Prospective Diabetes Study

Page 30: Rationale, Study Design & Study Population. Rationale

Risk factors levelsAt end of follow-up

Parameter Randomised treatment

Active (n=5569)

Placebo (n=5571)

Systolic BP (mmHg) 135.6 139.9

Diastolic BP (mmHg) 73.6 75.1

Haemoglobin A1c (%) 6.9 6.9

Total cholesterol (mmol/L) * 4.7 4.6

HDL cholesterol (mmol/L) * 1.3 1.3

LDL cholesterol (mmol/L) * 2.7 2.6

Triglycerides (mmol/L) * 1.8 1.7

* Measurements taken at month 48

Page 31: Rationale, Study Design & Study Population. Rationale

Baseline characteristicsCardiovascular and diabetes drugs

Randomised treatment

Active (n=5569)

Placebo (n=5571)

Any blood pressure lowering drug 75% 75%

ACE inhibitor*

ARB

43%

5%

43%

6%

Oral hypoglycaemic drugs 91% 91%

Statin 28% 29%

Other lipid modifying drug 9% 8%

Aspirin 44% 44%

Other antiplatelet drugs 4% 5%*By end of run-in period: 47% were receiving open label perindopril

Page 32: Rationale, Study Design & Study Population. Rationale

Randomised treatment

Active (n=5569)

Placebo (n=5571)

Any BP lowering drug 74% 83%

ACE inhibitor

ARB

50%

10%

60%

13%

Oral hypoglycaemic drugs 90% 91%

Insulin 33% 30%

Statin 44% 45%

Other lipid modifying drug 8% 7%

Aspirin 56% 55%

Other antiplatelet drugs 6% 6%

Ancillary drug therapy At end of follow-up ADVANCE results will be underestimation of real effect fixed per/ind combination

Page 33: Rationale, Study Design & Study Population. Rationale

Study population

Broad cross-section of diabetic patients: Europe, North America, Asia-Pacific With and without

history of vascular disease hypertension Other risk factors

Wide range of background treatments including ACE inhibitor/other BP lowering drugs for many

Breadth should ensure results are relevant to clinical practice worldwide