Summary of Design Aim: Effect of Ramipril (up to 10mg/d) or Vit E (400 IU/d) vs its placebo on CV death, M I or stroke (primary) Design: Randomized double blind, 2x2 factorial, People with high CV risk, exclusion: macroalbuminuria, s-creatinine > 2.3 mg/dl Size: 9541 patients followed for 4 to 6 years: Organization: 267 hospitals from 19 countries in North & South America and Europe, Coordinated by the CCC at McMaster University, Hamilton, Canada Principal investigator: S . Yusuf, Coordinator Europe: J Mann, J Ostergren, B. Wolfenbuttel GD

G E R Gerstein, Mann, Yusuf, JAMA 2001; 286: 421 - 8

ACR and future development of clinical proteinuria / overt nephropathy Baseline microalbuminuria was associated with the development of clinical proteinuria in: Diabetes: 20.1 % / 4 years No diabetes: 4.9 % / 4 years In those with microalbuminuria, the risk was 17 - 20-fold higher than in those without (p<0.0001 after adjusting for all risk factors monitored in HOPE)

Progression of Albuminuria: MA  ON or None  MA/ON Ramipril Placebo N (%) N (%) All patients 909 (19) 1032 (22) RR (95% CI) 0.88 (0.81-0.96) p = 0.0056 MA: microalbuminuria ON: overt nephropathy

Serum creatinine (mg/dl) Serum creatinine in all diabetic patients, and in diabetics with renal insufficiency (RI) N = 333 Serum creatinine (mg/dl) Mann, Gerstein, et al, Ann Int Med 2002 N = 3,571 years