Post on 29-Dec-2015
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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%
Blood pressure and vascular risk in diabetes Best evidence: 2000
UK Prospective Diabetes Study
SBP
UKPDS
UK Prospective Diabetes Study
Blood pressure and vascular risk in diabetes Best evidence: 2000
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
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
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?
Study design
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
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
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
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
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
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
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
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)
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
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
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
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
Study population
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
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-02
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v-02
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-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
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%
Blood pressure,other risk factors, ancillary treatment
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
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
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
SBP
ADVANCE BP reduction in context:UK Prospective Diabetes Study
UKPDSADV
UK Prospective Diabetes Study
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
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
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
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