1. PROGRESS PERINDOPRIL PROTECTION AGAINST RECURRENT STROKE STUDY PROGRESS Collaborative Group Institute for International Health www.ilh.org/progress PROGRESS. Lancet 2001;358:1033-41.

2. Global burden of stroke  5 million stroke deaths each year  2 nd leading cause of death worldwide  >15 million non-fatal strokes each year  >50 million stroke/TIA survivors alive  1 in 5 survivors suffer another stroke within 5 years

3. Secondary prevention of stroke For patients with ischaemic stroke or TIA  Antiplatelet therapy  Carotid endartarectomy for patients with symptomatic carotid stenosis  Anticoagulant therapy for patients with atrial fibrillation For patients with haemorrhagic stroke  No proven treatment Lancet 2001: Randomised trial of perindopril-based blood-pressure-lowering regimen among 6105 individuals with previous stroke or transient sheamic attack Progress Collaborative Group. Lancet 2001;358:1033-41

4. PROGRESS Aim To determine the balance of benefits and risks conferred by an ACE inhibitor (perindopril) based blood pressure lowering regimen among patients with a history of cerebrovascular disease and a wide range of blood pressure at entry PROGRESS. Lancet 2001;358:1033-41.

5. Cerebral blood flow autoregulation during chronic hypertension 2001000 50 100 Hypertension Normotension Cerebral blood flow (mL/min/100 g) Mean arterial pressure (mm Hg)

6. Perindopril does not reduce cerebral blood flow after a stroke 1 Dyker AG et al. Stroke. 1997;28:580-583. Significant BP control No adverse effect on cerebral blood flow Time since administration of drug Diastolic blood pressure110100 90 80 70 mm Hg 012345678910111224 Hours Cm/sec Mean flow velocity (middle cerebral artery)0123456789101112242 Time since administration of drug 60 40 20 0 Hours Weeks Perindopril 4 mg Placebo

7. Perindopril maintains ICA flow in stroke patients with carotid occlusion Lees KR et al. Stroke. 2001;32:473-478. ICA flow maintained 24h -30 -20 -10 0 10 20 30 40 50 BS2.5h5.5h7.5h14d Change from BS (%) Perindopril 4 mg Placebo MABP reduced P=0.017 2.5h5.5h7.5h24h14dBS MABP (mm Hg)

8. Perindopril 4 mg is safe to initiate in stroke patients

9. Design  Investigator initiated and conducted  Randomised, placebo controlled  4-week open run-in phase on active perindopril before randomisation  Central, computer based randomisation  4 years double-blind treatment - Recruitment began 1996 - Follow-up ended 2001 PROGRESS. Lancet 2001;358:1033-41.

10. PROGRESS Collaborative Group Japan 33 centers Australia 16 centers New Zealand 9 centers Italy 17 centers France 24 centers Sweden 23 centers Belgium 2 centers UK and Ireland 23 centers China 26 centers 10 countries 172 centers

11. Patients  In past five years: - cerebral haemorrhage - ischaemic stroke - stroke of unknown type - TIA or amaurosis fugax  No major disability  No entry blood pressure criteria PROGRESS. Lancet 2001;358:1033-41.

12. Double blind treatments  Perindopril (4mg) plus indapamide* (2.5mg) or  Matching placebo(s)  Against a background of standard care, including other blood pressure lowering therapy * unless definite indication or contraindication to diuretic PROGRESS. Lancet 2001;358:1033-41.

13. Trial Profile 7121 patients registered 6105 patients randomised 484 ineligible 532 withdrew 3051 assigned active 3054 assigned placebo 3049 vital status known 3053 vital status known PROGRESS. Lancet 2001;358:1033-41.

14. Study outcomes  Primary - Total stroke  Secondary - Fatal or disabling stroke - Major vascular events (non-fatal stroke, non fatal MI, vascular death) - Dementia (DSM IV) & cognitive function - Disability and dependency PROGRESS. Lancet 2001;358:1033-41.

15. Baseline characteristics Demographic Female sex (%) 30 30 Age (years) 64 64 Blood pressure Systolic (mmHg)147 147 Diastolic (mmHg) 86 86 Hypertension (%) 48 48 Cerebrovascular history Cerebral haemorrhage (%) 11 11 Cerebral infarction (%) 71 71 Stroke type unknown (%) 4 5 TIA/amaurosis fugax (%) 23 23 Active (n=3051) Placebo (n=3054) PROGRESS. Lancet 2001;358:1033-41.

16. Adherence during follow-up All participants 0% 20% 40% 60% 80% 100% 0612182430364248 Follow-up (mo) Adherence Placebo Active Average adherence Active* 87% Placebo 88% P=0.07 * Active treatment: Coversyl 4 mg +/- indapamide 2.5 mg (or 2 mg in Japan) Reference: Lancet. 2001;358:1033-1041.

17. Blood pressure differences All participants active placebo PROGRESS. Lancet 2001;358:1033-41. 0 20 40 60 80 100 120 140 160 BR13691218243036424854 Month of follow up Blood pressure (mmHg) Mean BP difference 9.0/4.0 mmHg

18. Stroke All participants placebo active 0 1 2 3 4 Follow up time (years ) Proportion with event 0.2 0.15 0.1 0.05 28% risk reduction 95%CI 17-38% p<0.0001 PROGRESS. Lancet 2001;358:1033-41.

19. Stroke by medical history All participants Strokes Favours Favours Hazard ratio Active Placebo active placebo (95%CI) Hypertensive 163 235 0.67 (0.55-0.81) Not hypertensive 144 185 0.78 (0.63-0.97) Diabetes 48 65 0.67 (0.46-0.98) No diabetes 259 355 0.72 (0.62-0.85) Cerebral infarction 236 307 0.76 (0.64-0.90) Cerebral haemor. 28 49 0.52 (0.33-0.83) TIA/amaurosis 33 49 0.66 (0.42-1.02) Total 307 420 0.72 (0.62-0.83) 0.5 1.0 2.0 Hazard ratio PROGRESS. Lancet 2001;358:1033-41.

20. Stroke by Baseline Blood Pressure Active:perindopril 4mg -indapamide 2,5 mg 0.4 1.0 2.0 Hazard ratio Events active placebo Favours active Favours placebo Hazard ratio (95% CI) SBP > 160 SBP 140-159 SBP <140 57 106 54 87 39 62 DBP > 95 DBP 85-94 DBP < 85 27 68 65 99 58 88 150 255Total 0.53 (0.38-0.73) 0.59 (0.42-0.84) 0.61 (0.41-0.91) 0.38 (0.24-0.59) 0.64 (0.47-0.88) 0.63 (0.45-0.88 0.57 (0.46-0.70) PROGRESS. Lancet 2001;358:1033-41.

21. Results on cardiac outcome

22. Major vascular events PROGRESS. Lancet 2001;358:1033-41. Eur Heart J 2003: 24:475-84.

23. Major vascular events All participants Events Active Placebo Favors active Favors placebo Hazard ratio (95%CI) Vascular death Nonfatal MI Nonfatal stroke Total 0.41.02.0 Hazard Ratio 181 60 275 458 198 96 380 604 0.91 (0.75-1.12) 0.62 (0.45-0.86) 0.71 (0.61-0.83) 0.74 (0.66-0.84) PROGRESS. Lancet 2001;358:1033-41. Eur Heart J 2003: 24:475-84.

24. Major coronary events (CHD death or nonfatal myocardial infarction) Eur Heart J 2003: 24:475-84.

25. Heart failure (Death, hospitalization, or discontinuation) 0.00 0.01 0.02 0.03 0.04 0.05 0.06 0 1234 Placebo Active 26% risk reduction (95%CI 5-42%) P value = 0.01 Follow-up time (y) Proportion with event Eur Heart J 2003: 24:475-84.

26. Other anti-HT drug No anti-HT drug Aspirin or other AP No antiplatelet drug Total Events Active Placebo Favors active Favors placebo 229 347 111 458 333 271 430 174 604 33% (20 to 43%) 19% (4 to 32%) 23% (11 to 33%) 36% (19 to 50%) 26% (16 to 34%) 0.5 2.0 Hazard ratio 1.0 Risk reduction (95%CI) Major vascular events by treatment at baseline by treatment at baseline Stroke 2004; 35: 116-121

27. Results on dementia and cognitive decline outcome

28. Stroke and dementia  Stroke is the leading cause of disability in adults 1  Cerebrovascular disease is the second most common cause of dementia 2  Vascular dementia is one of the rare preventable dementias 3  One sixth of stroke patients have previous dementia 4 1. Barba R et al. Previous and incident dementia as risk factors for mortality in stroke patients. Stroke. 2002;33:1993-1998. 2. Leys D et al. Epidemiology of vascular dementia. Hemostasis. 1998;28:134-150. 3. Hachinski V. Preventable senility: a call for action against the vascular dementias. Lancet. 1992;340:654-648. 4. Barba R et al. Prestroke dementia. Cerebrosvasc Dis. 2001;11:216-224.

29. Major types of dementia  Alzheimer’s disease 53.7%  Vascular dementia 15.8% 1 – single or multiple infarcts 2 – small-vessel disease 2 – hypoperfusion 2 – hemorrhage 2 1. Lobo A et al. Neurology. 2000;54(suppl 5):S4-S9. 2. Gold G. Les démences vasculaires. Med Hyg. 2002;60:1165-1167.

30. The cumulative incidence of dementia after stroke Incidence of dementia (%) 7% 10% 15% 23% Timel (y) 13510 Incident of stroke increase the risk of dementia by 140% Lobo A et al. Neurology. 2000;54(suppl 5):S4-S9.

31. Prevalence of vascular dementia in men and women in European countries Lobo A et al. Neurology. 2000;54(suppl 5):S4-S9. Age (y) Cases/100 of population

32. Risk factors for vascular dementia Hypertension Cigarette-smoking Diabetes mellitus Atrial fibrillation Cardiac disease Carotid stenosis Hyperlipidemia

33. Antihypertensive treatment reduces the incidence of dementia 1 1. Forette F et al. Lancet. 1998;352:1347-1351. 1000 hypertensive patients treated for 5 years 19 cases of dementia prevented MSBP 173.4 MSBP 151.7 Dementia 21 cases Dementia 11 cases P<0.001 P<0.05

34. 22 ApoE4 allele carrier (%) 15 MMSE < 26 (%) 29 (27-30) Median MMSE score 39 Asian (%) 30 Female (%) 64 (10) Age, y (SD) Baseline characteristics Active Placebo (n = 3051) (n = 3054) 6105 patients with stroke or TIA FU 3.9 years MMSE / Screening for dementia each year Reference: Arch Int Med. In press.

35. Dementia 1. Screening MMSE <26 Questions about dementia MMSE missing 2. Diagnosis Specialist in each center; DSM-IV criteria Diagnosis reviewed centrally Cognitive decline = drop of 3pts or more of MMSE during FU Cognitive outcomes Reference: Arch Int Med. In press.

36. Cognitive outcomes (ctd.)  Dementia – 1580 patients screened positive during FU – Expert assessment for 98% – 410 patients demented – 108 preceded by a recurrent stroke  Cognitive decline 610 patients (25 per 1000 PY) Reference: Arch Int Med. In press.

37. Effect of treatment on dementia Dementia Post-stroke Without stroke Total Events Active* Placebo Favors active Favors placebo Risk reduction (95%CI) 43 150 193 65 152 217 34% (3 to 55%) 1% (-24 to 22%) 12% (-8 to 28%) 0.5 2.0 Odds ratio 1.0 * Active treatment: Coversyl 4 mg +/- indapamide 2.5 mg (or 2 mg in Japan) Reference: Arch Int Med. In press.

38.  With stroke  Without stroke  Total Events Active* Placebo Favors active Favors placebo Risk reduction (95%CI) 48 228 276 86 248 334 45% (21 to 61%) 9% (-10 to 84%) 19% (4 to 32%) Effect of treatment on cognitive decline Cognitive decline 0.5 2.0 Odds ratio 1.0 * Active treatment: Coversyl 4 mg +/- indapamide 2.5 mg (or 2 mg in Japan) Reference: Arch Int Med. In press.

39. Barthel scale – activities of daily living Results on Disability 4 year treatment result in avoidance of 1 case of long term disability for every 30 (95%CI, 19 to 79) patients Stroke 2003; 34: 2333-2338 Active : perindopril 4 mg ± indapamide 2,5 mg

40. PROGRESS establishes the benefits of perindopril-based therapy among patients with cerebrovascular disease for the prevention of:  Stroke  Coronary heart disease  Congestive heart failure  Total major vascular events  Cognitive decline  Disability Summary of Benefits

41. RRR CVA/TIARRR major coronary events NNT om 1 CV event te voor- komen in 5 jaar Onderzoek Aspirine 23%17%57 ATC 1 Perindopril + indapamide 43%35%11PROGRESS 2 Simvastatine 2 2% (NS ) 23%32HPS 3 1.Antithrombotic Trialist Collaboration. BMJ 2002; 324:71-86 2.PROGRESS. Lancet 2001;358:1033-41. Eur Heart J 2003: 24:475-84 3.HPS. Lancet 2004:363;757-67 Evidence based prevention in patients with history of cerebrovascular disease

42. Cardiac protection partly BP- independent Risk reduction Coronary events Expected16% 1 BP-reduction (10-12 / 5-6 mmHg) PROGRESS 35% 2 BP-reduction (10-12 / 5-6 mmHg) 1 Collins R et al. Lancet 1990;335:827-38, Expected on diuretic and beta-blocker regime 2. PROGRESS Coll. Eur Heart J (2003) 24, 475-84

43. 12.218 patients with stable coronary artery disease (no heart failure) Treated with perindopril or placebo EUROPA. Lancet 2003; 362: 782-788.

44. Primary endpoint % CV death, MI or cardiac arrest Placebo annual event rate: 2.4% Perindopril Placebo p = 0.0003 RRR: 20% Years 0 2 4 6 8 10 12140 1 2345 EUROPA. Lancet 2003; 362: 782-788.

45. Blood pressure reduction alone cannot explain perindopril’s effects in EUROPAperindoprilplacebo RRR 20% RRR 18% SBP decrease during run-in No SBP decrease during run-in 0% 2% 4% 6% 8% 10% 12% 4263 4303 1841 1804 Incidence of primary events EUROPA. Presented ESC 2004.

46. Summary of results In EUROPA, the largest and longest trial in stable documented CAD patients, perindopril 8 mg/d significantly reduced: CV mortality + non fatal MI + cardiac arrest: 20% CV mortality + non fatal MI + cardiac arrest: 20% CV mortality and non fatal MI: 19% CV mortality and non fatal MI: 19% Fatal + non fatal MI: 24% Fatal + non fatal MI: 24% Heart failure: 39% Heart failure: 39% EUROPA. Lancet 2003; 362: 782-788.

47. Summary of results Benefits with perindopril: Benefits with perindopril: occurred on top of recommended therapy (platelet inhibitors, lipid lowering drugs,  -blockers) occurred on top of recommended therapy (platelet inhibitors, lipid lowering drugs,  -blockers) consistent across predefined sub-groups consistent across predefined sub-groups “Perindopril should be considered for chronic therapy in all patients with coronary disease” EUROPA investigators: The Lancet 2003 EUROPA. Lancet 2003; 362: 782-788.

48. EUROPA and PROGRESS : Consistent results Consistent results Clear benefits for the many (hypertensive) patients with established cerebrovascular and/or coronary disease Clear benefits for the many (hypertensive) patients with established cerebrovascular and/or coronary disease EUROPA. Lancet 2003; 362: 782-788.

49. References PROGRESS. Lancet 2001;358:1033-41. Stroke 2003; 34: 2333-2338. Eur Heart J 2003: 24:475-84. Arch Intern Med 2003; 162: 1069-1075. Stroke 2004; 35: 116-211.PROGRESS. Lancet 2001;358:1033-41. Stroke 2003; 34: 2333-2338. Eur Heart J 2003: 24:475-84. Arch Intern Med 2003; 162: 1069-1075. Stroke 2004; 35: 116-211. EUROPA. Lancet 2003; 362: 782-788.EUROPA. Lancet 2003; 362: 782-788. Antithrombotic Trialist Collaboration. BMJ 2002; 324:71-86Antithrombotic Trialist Collaboration. BMJ 2002; 324:71-86 HPS. Lancet 2004:363;757-67HPS. Lancet 2004:363;757-67