1. VBWG HOPE-TOO: Results of the HOPE Study Extension

2. VBWG HOPE-TOO: Rationale HOPE-TOO was an extension of the HOPE trial, which examined the effects of ACE inhibition in reducing major CV events in high-risk patients with vascular disease or diabetes HOPE-TOO was designed to assess whether the CV and metabolic benefits of ramipril were sustained over time and occurred in subgroups based on varying risk and concomitant treatment HOPE/HOPE-TOO Study Investigators. Circulation. 2005;112:1339-46.

3. VBWG HOPE-TOO: Study design 4528 HOPE patients at 174 centers who agreed to further follow-up Blinded treatment ended and patients were advised to use ACEI 2.6-year post-trial extension ACEI use during extension –HOPE ramipril arm (n = 2317): 72% –HOPE placebo arm (n = 2211): 68% –>90% of all HOPE-TOO patients used ramipril Heart Outcomes Prevention Evaluation–The Ongoing Outcomes HOPE/HOPE-TOO Study Investigators. Circulation. 2005;112:1339-46.

4. VBWG Major CV events and new diagnosis of diabetes for combined in-trial and post-trial periods No. of patients (%) New diagnosis of diabetes Revascularization Stroke CV death MI MI, stroke, or CV death Ramipril (n = 3393) Placebo (n = 3393) 699 (20.6) 485 (14.3) 174 (5.1) 327 (9.6) 767 (22.6) 152 (7.3) 820 (24.2) 581 (17.1) 215 (6.3) 374 (11.0) 880 (25.9) 216 (10.3) RR (95% CI) P* 0.83 (0.75–0.91) 0.81 (0.72–0.92) 0.79 (0.65–0.97) 0.86 (0.74–1.00) 0.84 (0.76–0.92) 0.69 (0.56–0.85) 0.0002 0.0007 0.023 0.045 0.0003 0.0006 *Calculated by log-rank test and data on all participants in the study extension, censored for period of observation HOPE/HOPE-TOO Study Investigators. Circulation. 2005;112: 1339-46.

5. VBWG HOPE-TOO: Primary outcome (CV death, MI, stroke) RRR = relative risk reduction HOPE/HOPE-TOO Study Investigators. Circulation. 2005;112:1339-46. 30 RRR = 17% P = 0.0002 0123 45 6 7 0 Placebo Ramipril Years Primary outcome (% HOPE-TOO patients) 25 20 15 10 5 4652 4645 4432 4456 4204 4256 3981 4079 3647 3789 2719 2819 1923 2075 1550 1731 Placebo Ramipril n HOPE-TOO begins Main HOPE study ends

6. VBWG HOPE-TOO: Effect of ACEI on major CV events and new-onset diabetes No. of HOPE patients (%) New diagnosis of diabetes Revascularization Stroke CV death MI MI, stroke, or CV death 1.31.21.11.00.90.80.70.60.50.40.3 1.4 1.5 Ramipril (n = 2317) Placebo (n = 2211) RR (95% CI) 220 (7.9) 146 (5.1) 59 (2.0) 133 (4.4) 235 (9.1) 48 (2.7) 225 (8.4) 169 (6.1) 56 (1.9) 126 (4.2) 259 (10.5) 70 (4.0) *Event rates were calculated as proportions of events in those study participants who were event-free at the end of the in-trial period. Event* HOPE/HOPE-TOO Study Investigators. Circulation. 2005;112:1339-46.

7. VBWG HOPE-TOO: Additional reduction in MI HOPE/HOPE-TOO Study Investigators. Circulation. 2005;112:1339-46. 25 RRR = 19% P = 0.0007 0 01 23 456 7 Placebo Ramipril MI (% HOPE-TOO patients) 20 15 10 5 Years 4652 4645 4474 4484 4282 4309 4088 4159 3770 3875 2814 2900 1999 2137 1612 1791 Placebo Ramipril n HOPE-TOO begins Main HOPE study ends

8. VBWG HOPE-TOO: Additional reduction in new-onset diabetes HOPE/HOPE-TOO Study Investigators. Circulation. 2005;112:1339-46. 12 6 2 4 0 1234 8 10 5 67 Placebo Ramipril Years RRR 31% P = 0.0006 HOPE-TOO begins Main HOPE study ends 2883 2837 2803 2763 2704 2672 2600 2587 2392 2431 1813 1853 1269 1324 1021 1092 New-onset diabetes (% HOPE-TOO patients) Placebo Ramipril n

9. VBWG HOPE-TOO: Sustained reduction in stroke HOPE/HOPE-TOO Study Investigators. Circulation. 2005;112:1339-46. 10 RRR = 21% P = 0.023 0 Placebo Ramipril 8 6 4 2 Years 4652 4645 4523 4539 4367 4391 4188 4263 3887 4000 2953 3011 2115 2225 1734 1876 01 23 456 7 Placebo Ramipril n Stroke (% HOPE-TOO patients) HOPE-TOO begins Main HOPE study ends

10. VBWG HOPE-TOO: Sustained reduction in CV death HOPE/HOPE-TOO Study Investigators. Circulation. 2005;112:1339-46. 15 RRR = 14% P = 0.045 0 Placebo Ramipril 10 5 Years 4652 4645 4569 4567 4453 4448 4309 4346 4027 4097 3061 3100 2203 2295 1808 1946 01 23 456 7 Placebo Ramipril n CV death (% HOPE-TOO patients) HOPE-TOO begins Main HOPE study ends

11. VBWG HOPE/HOPE-TOO: Benefits at all levels of risk and with other life-saving drugs GroupNo. of patients Lipid meds – Lipid meds + BB – BB + ASA – ASA + High Medium Low Overall9297 3083 3100 3114 6813 2484 3673 5624 2658 6639 Placebo rate 17.7 9.8 16.1 26.9 17.3 19.1 18.2 17.4 14.0 19.3 Interaction P-value 0.51 0.0019 0.89 0.68 0.60.81.01.2 Lipid meds – Lipid meds + GroupNo. of patients BB – BB + ASA – ASA + High Medium Low Overall6786 2299 2247 2240 4974 1812 2712 4074 1960 4826 Placebo rate 24.2 15.2 22.6 34.5 23.5 26.0 26.2 22.8 18.7 26.4 Interaction P-value 0.67 0.0043 0.20 0.78 0.60.81.01.2 HOPEHOPE-TOO Primary outcome = CV death/MI/stroke RR (95% CI) HOPE/HOPE-TOO Study Investigators. Circulation. 2005;112:1339-46.

12. VBWG HOPE-TOO: Study conclusions The benefits of ramipril were maintained during post-trial follow- up for CV death, stroke, and hospitalization for heart failure Additional reductions in MI, revascularization and new-onset diabetes were also observed despite similar rates of ACEI use in the randomized groups The reduction in CV outcomes demonstrated in the HOPE trial is most likely an underestimate of the full effects of long-term ramipril therapy Subgroup analyses demonstrate the benefits observed are additive to those of other life-saving therapies, and extend to all patients with vascular disease, independent of their baseline risk HOPE/HOPE-TOO Study Investigators. Circulation. 2005;112:1339-46.