2. Aim To determine the effects of a Coversyl- based blood pressure lowering regimen on the risk of recurrent stroke among patients with a history of stroke or TIA. Reference: Neal B, MacMahon S. J Hypertens. 1995;13:1869-1873.

3. Study end points Primary outcome: stroke (fatal or non fatal) stroke (fatal or non fatal) Secondary outcomes: fatal or disabling stroke fatal or disabling stroke total major vascular events (composite of nonfatal stroke, nonfatal myocardial infarction, or death due to any vascular cause) total major vascular events (composite of nonfatal stroke, nonfatal myocardial infarction, or death due to any vascular cause) total and cause specific deaths total and cause specific deaths hospital admissions hospital admissions dementia and cognitive decline dementia and cognitive decline Reference: Neal B, MacMahon S. J Hypertens. 1995;13:1869-1873.

4. Design Eligibility Randomization Study end Coversyl run-in 2 mg od4 mg od 2 weeks 4 years Placebo Coversyl arm: Coversyl 4 mg ± diuretic (open) (double-blind) Patients with history of cerebrovascular disease Reference: Neal B, MacMahon S. J Hypertens. 1995;13:1869-1873.

5. Baseline characteristics of randomized participants Randomized treatment Characteristic Coversyl arm Placebo Demographic n=3051 n=3054 Age, years (SD) 64 (10) Female (%) 30 Asian (%) 39 Cerebrovascular disease history Stroke (%) Ischemic stroke 71 Cerebral hemorrhage 11 Unknown stroke 4 5 TIA or amaurosis fugax (%) 22 Reference: Lancet. 2001;358:1033-1041.

6. †SBP  160 mm Hg or DBP  90 mm Hg Reference: Lancet. 2001;358:1033-1041. Randomized Treatment Characteristic Coversyl armPlacebo Other medical history (%) Current smoker 20 Diabetes 13 12 Coronary heart disease 16 Blood pressure and hypertension status Mean systolic blood pressure, mm Hg (SD) 147 (19) Mean diastolic blood pressure, mm Hg (SD) 86 (11) Hypertension (%) † 48 Antihypertensive therapy (%) 50 51 Baseline characteristics of randomized participants

7. Blood pressure differences All participants 60 80 100 120 140 160 BR136912182430364248 Months of follow-up Blood pressure (mm Hg) Mean blood pressure difference 9.0/4.0 mm Hg Coversyl arm Placebo Systolic Diastolic Reference: Lancet. 2001;358:1033-1041. Placebo Coversyl arm

8. Coversyl-based regimen reduces stroke Follow-up time (y) Proportion with event 0 1234 95% CI 17 - 38% P<0.0001 28% risk reduction 0.00 0.05 0.10 0.15 0.20 Placebo Coversyl arm Reference: Lancet 2001;358:1033-1041.

9. Fatal or disabling Nonfatal or disabling Ischemic stroke Cerebral hemorrhage Stroke type unknown Total stroke Events Coversyl arm Placebo n=3051 n=3054 Favors Coversyl arm Favors placebo Risk reduction (95%CI) 33% (15 to 46) 24% (9 to 37) 24% (10 to 35) 50% (26 to 67) 18% (-24 to 45) 28% (17 to 38) Stroke subtypes 123 201 246 37 42 307 181 262 319 74 51 420 0.5 2.0 Hazard ratio 1.0 Reference: Lancet. 2001;358:1033-1041. Coversyl-based regimen reduces stroke

10. Follow-up time (y) Proportion with event 0.05 0.10 0.15 0.20 0.25 1234 26% risk reduction (95% CI 16-33%) P<0.0001 Coversyl-based regimen reduces major vascular events Placebo Coversyl arm

11. Vascular death Nonfatal MI Nonfatal stroke Total events Risk reduction (95%CI) 9% (-12 to 25) 38% (14 to 55) 29% (17 to 39) 26% (16 to 34) Major vascular events Favors Coversyl arm Favors placebo 181 60 275 458 198 96 380 604 Events Coversyl arm Placebo n=3051 n=3054 0.5 2.0 Hazard ratio 1.0 Coversyl-based regimen reduces major vascular events Reference: Lancet.2001;358:1033-1041.

12. 26% risk reduction (95%CI 6-42%) P value = 0.016 Follow-up time (y) Proportion with event 0.01 0.02 0.03 0.04 0.05 0.06 1234 Coversyl-based regimen reduces major coronary events Placebo Coversyl arm

13. 0.00 0.05 0.10 0 1234 21% risk reduction (95%CI 6-33%) P value = 0.008 Follow-up time (y) Proportion with event Coversyl-based regimen reduces total coronary events Placebo Coversyl arm

14. 0.4 Outcome Nonfatal MI Death due to CHD Coronary revascularization Unstable angina Total coronary events Events Coversyl arm placebo Favors Coversyl arm Favors placebo 60 58 63 111 233 96 62 82 134 291 38% (12 to 55%) 7% (-34 to 35%) 23% (-7 to 45%) 17% (-6 to 36%) 21% (6 to 33%) Risk Reduction (95%CI) Odds ratio 1.02.0 Coversyl-based regimen reduces total coronary events

15. Coversyl-based regimen reduces heart failure (Death, hospitalization or discontinuation) 0.00 0.01 0.02 0.03 0.04 0.05 0.06 0 1234 26% risk reduction (95%CI 5-42%) P value = 0.01 Follow-up time (y) Proportion with event Coversyl arm Placebo

16. Coversyl-based regimen reduces congestive heart failure Effects in all participants Total CHF Effects in subgroups Combination therapy Single drug therapy Hypertensive Not hypertensive CHD at baseline No CHD at baseline Events Coversyl arm placebo Favors Coversyl arm Favors placebo 113 58 55 56 57 37 76 151 69 82 75 76 59 92 26% (5 to 42%) 34% (7 to 53%) 16% (-19 to 31%) 27% (-3 to 48%) 27% (-4 to 49%) 41% (10 to 61%) 18% (-11 to 40%) Odds ratio Risk Reduction (95%CI) 0.4 1.02.0

17. 33% reduction in the risk of fatal or disabling stroke 25% reduction in the risk of less severe strokes 50% reduction in the risk of hemorrhagic stroke 25% reduction in the risk of cerebral ischemia Reference: Lancet. 2001;358:1033-1041 Coversyl-based regimen efficacy

18. 25% reduction in the risk of major cardiovascular events 22% reduction in the risk of major coronary events 33% reduction in myocardial infarction All benefits achieved against a background of standard care that included antiplatelet and antihypertensive therapy Reference: Lancet. 2001;358:1033-1041. Coversyl-based regimen efficacy

19. Recommendations for initiation Acute stroke initiate treatment with Coversyl 4 mg once daily at the time of discharge or post-discharge follow up Past history of stroke or TIA primary care physician to initiate Coversyl 4 mg once daily treatment at the patient’s next visit Reference: Lancet. 2001;358:1033-1041.