Advance Design

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ADVANCE trial

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Advance Design

  1. 1. A factorial randomised trial of blood pressure lowering and intensive glucose control for the prevention of vascular disease among high risk patients with type 2 diabetes
  2. 2. Global distribution of diabetes 350 300 1995 2025 Projected 250 Millions 200 150 100 50 0 Developed Developing World World World
  3. 3. Risks associated with diabetes No Hazard ratio diabetes Diabetes 95% CI Coronary heart disease Asia 0.4 1.8 2.22 (1.61-3.04) ANZ 1.4 3.4 2.18 (1.71-2.78) Total 0.8 2.6 2.19 (1.81-2.66) Cerebrovascular disease Asia 0.9 1.9 1.99 (1.47-2.69) ANZ 0.5 1.0 2.09 (1.35-3.24) Total 0.7 1.5 2.02 (1.57-2.59) 1 2 3 Hazard ratio Asia Pacific Cohort Studies Collaboration
  4. 4. Blood pressure and cardiovascular death No diabetes Diabetes Coronary Heart Ischaemic Stroke Haemorrhagic 8.0 Disease Stroke Hazard ratio 4.0 2.0 1.0 0.5 120 140 160 120 140 160 120 140 160 Usual SBP (mmHg) Asia Pacific Cohort Studies Collaboration
  5. 5. Usual haemoglobin A1c and myocardial infarction myocardial infarction per 80 1000 person years (%) Adjusted incidence of 60 40 20 0 5.5 6.5 7.5 8.4 9.4 10.7 Updated mean haemoglobin A1c concentration (%) UK Prospective Diabetes Study
  6. 6. Usual haemoglobin A1c and microvascular disease microvascular disease per 80 1000 person years (%) Adjusted incidence of 60 40 20 0 5.5 6.5 7.5 8.4 9.4 10.7 Updated mean haemoglobin A1c concentration (%) UK Prospective Diabetes Study
  7. 7. Unresolved issues in 2000 1. Would benefits of BP-lowering extend to patients with diabetes across a broader range of BP? 2. Would benefits of BP-lowering with Per-Ind be manifest on top of optimal therapy with other BP-lowering drugs, including blockers of the RAS? 3. Would intensive glucose control with Gliclazide MR-based regimen decrease macrovascular disease?
  8. 8. Unresolved issues in 2000 4. Would even more intensive glucose control targeting a 6.5% level of HbA1c of further reduce microvascular disease? 5. Would the effects of BP lowering and tighter glucose control be additive?
  9. 9. Study design Registration 6-week run-in period of active BP-lowering with perindopril-indapamide Randomization N = 10,000 Optimal Therapy Optimal Therapy Optimal Therapy Optimal Therapy + + + + Perindopril- Perindopril- Placebo indapamide Placebo indapamide + combination combination + + + Intensive Standard Intensive Standard glucose control glucose control glucose control glucose control (n=2500) (n=2500) (n=2500) (n=2500) END OF FOLLOW-UP (average 4.5 years)
  10. 10. Inclusion criteria Type 2 diabetes Age 55 years or older Elevated risk of vascular disease 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
  11. 11. Primary outcomes For both treatment comparisons Macrovascular Composite of non-fatal stroke, non-fatal MI, and cardiovascular death Microvascular Composite of new of worsening nephropathy or retinopathy
  12. 12. Number of patients randomised 2000 4000 6000 8000 10000 12000 0 juil-01 août-01 sept-01 oct-01 nov-01 déc-01 janv-02 févr-02 mars-02 avr-02 mai-02 juin-02 juil-02 août-02 sept-02 oct-02 nov-02 déc-02 ADVANCE Randomisations janv-03 févr-03 mars-03 avr-03
  13. 13. Randomised participants - countries Australia 978 Italy 21 Canada 436 Lithuania 118 China 3,293 Malaysia 236 Czech Republic 209 Netherlands 630 Estonia 155 New Zealand 507 France 196 Philippines 136 Germany 327 Poland 604 Hungary 434 Russia 164 India 471 Slovakia 458 Ireland 442 United Kingdom 1,325 TOTAL = 11,140
  14. 14. Participant characteristics at baseline Number of centres 215 Number randomized 11140 Female, % 43 Mean Age, years 66 Mean SBP/DBP, mmHg 145/81 History of hypertension, % 69 Current BP lowering therapy, % 75 History of vascular disease, % 39 Current smoking, % 14 Mean BMI, kg/m2 28
  15. 15. Substudies ADVANCE Echocardiography Study This study will examine the effects of the study treatments on heart function, in about 500 patients ADVANCE Retinopathy Measurements (AdRem) Study This study will examine the effects of the study treatments on eye disease, in about 2000 patients
  16. 16. ADVANCE Echocardiography Study LV Hypertrophy Tissue Doppler 1.4cm E LV E’ 1.4cm Mitral Doppler
  17. 17. AdRem ADVANCE Retinopathy Measurements Substudy

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