PROGRESS PERINDOPRIL PROTECTION AGAINST RECURRENT STROKE STUDY PROGRESS Collaborative Group Institute for International Health PROGRESS. Lancet 2001;358:
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
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:
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:
Cerebral blood flow autoregulation during chronic hypertension Hypertension Normotension Cerebral blood flow (mL/min/100 g) Mean arterial pressure (mm Hg)
Perindopril does not reduce cerebral blood flow after a stroke 1 Dyker AG et al. Stroke. 1997;28: Significant BP control No adverse effect on cerebral blood flow Time since administration of drug Diastolic blood pressure mm Hg Hours Cm/sec Mean flow velocity (middle cerebral artery) Time since administration of drug Hours Weeks Perindopril 4 mg Placebo
Perindopril maintains ICA flow in stroke patients with carotid occlusion Lees KR et al. Stroke. 2001;32: ICA flow maintained 24h BS2.5h5.5h7.5h14d Change from BS (%) Perindopril 4 mg Placebo MABP reduced P= h5.5h7.5h24h14dBS MABP (mm Hg)
Perindopril 4 mg is safe to initiate in stroke patients
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 Follow-up ended 2001 PROGRESS. Lancet 2001;358:
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
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:
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:
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:
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:
Baseline characteristics Demographic Female sex (%) Age (years) Blood pressure Systolic (mmHg) Diastolic (mmHg) Hypertension (%) Cerebrovascular history Cerebral haemorrhage (%) Cerebral infarction (%) Stroke type unknown (%) 4 5 TIA/amaurosis fugax (%) Active (n=3051) Placebo (n=3054) PROGRESS. Lancet 2001;358:
Adherence during follow-up All participants 0% 20% 40% 60% 80% 100% 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:
Blood pressure differences All participants active placebo PROGRESS. Lancet 2001;358: BR Month of follow up Blood pressure (mmHg) Mean BP difference 9.0/4.0 mmHg
Stroke All participants placebo active Follow up time (years ) Proportion with event % risk reduction 95%CI 17-38% p< PROGRESS. Lancet 2001;358:
Stroke by medical history All participants Strokes Favours Favours Hazard ratio Active Placebo active placebo (95%CI) Hypertensive ( ) Not hypertensive ( ) Diabetes ( ) No diabetes ( ) Cerebral infarction ( ) Cerebral haemor ( ) TIA/amaurosis ( ) Total ( ) Hazard ratio PROGRESS. Lancet 2001;358:
Stroke by Baseline Blood Pressure Active:perindopril 4mg -indapamide 2,5 mg Hazard ratio Events active placebo Favours active Favours placebo Hazard ratio (95% CI) SBP > 160 SBP SBP < DBP > 95 DBP DBP < Total 0.53 ( ) 0.59 ( ) 0.61 ( ) 0.38 ( ) 0.64 ( ) 0.63 ( ( ) PROGRESS. Lancet 2001;358:
Results on cardiac outcome
Major vascular events PROGRESS. Lancet 2001;358: Eur Heart J 2003: 24:
Major vascular events All participants Events Active Placebo Favors active Favors placebo Hazard ratio (95%CI) Vascular death Nonfatal MI Nonfatal stroke Total Hazard Ratio ( ) 0.62 ( ) 0.71 ( ) 0.74 ( ) PROGRESS. Lancet 2001;358: Eur Heart J 2003: 24:
Major coronary events (CHD death or nonfatal myocardial infarction) Eur Heart J 2003: 24:
Heart failure (Death, hospitalization, or discontinuation) 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:
Other anti-HT drug No anti-HT drug Aspirin or other AP No antiplatelet drug Total Events Active Placebo Favors active Favors placebo % (20 to 43%) 19% (4 to 32%) 23% (11 to 33%) 36% (19 to 50%) 26% (16 to 34%) Hazard ratio 1.0 Risk reduction (95%CI) Major vascular events by treatment at baseline by treatment at baseline Stroke 2004; 35:
Results on dementia and cognitive decline outcome
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: Leys D et al. Epidemiology of vascular dementia. Hemostasis. 1998;28: Hachinski V. Preventable senility: a call for action against the vascular dementias. Lancet. 1992;340: Barba R et al. Prestroke dementia. Cerebrosvasc Dis. 2001;11:
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:
The cumulative incidence of dementia after stroke Incidence of dementia (%) 7% 10% 15% 23% Timel (y) Incident of stroke increase the risk of dementia by 140% Lobo A et al. Neurology. 2000;54(suppl 5):S4-S9.
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
Risk factors for vascular dementia Hypertension Cigarette-smoking Diabetes mellitus Atrial fibrillation Cardiac disease Carotid stenosis Hyperlipidemia
Antihypertensive treatment reduces the incidence of dementia 1 1. Forette F et al. Lancet. 1998;352: hypertensive patients treated for 5 years 19 cases of dementia prevented MSBP MSBP Dementia 21 cases Dementia 11 cases P<0.001 P<0.05
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.
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.
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.
Effect of treatment on dementia Dementia Post-stroke Without stroke Total Events Active* Placebo Favors active Favors placebo Risk reduction (95%CI) % (3 to 55%) 1% (-24 to 22%) 12% (-8 to 28%) Odds ratio 1.0 * Active treatment: Coversyl 4 mg +/- indapamide 2.5 mg (or 2 mg in Japan) Reference: Arch Int Med. In press.
With stroke Without stroke Total Events Active* Placebo Favors active Favors placebo Risk reduction (95%CI) % (21 to 61%) 9% (-10 to 84%) 19% (4 to 32%) Effect of treatment on cognitive decline Cognitive decline Odds ratio 1.0 * Active treatment: Coversyl 4 mg +/- indapamide 2.5 mg (or 2 mg in Japan) Reference: Arch Int Med. In press.
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: Active : perindopril 4 mg ± indapamide 2,5 mg
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
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: PROGRESS. Lancet 2001;358: Eur Heart J 2003: 24: HPS. Lancet 2004:363; Evidence based prevention in patients with history of cerebrovascular disease
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,
patients with stable coronary artery disease (no heart failure) Treated with perindopril or placebo EUROPA. Lancet 2003; 362:
Primary endpoint % CV death, MI or cardiac arrest Placebo annual event rate: 2.4% Perindopril Placebo p = RRR: 20% Years EUROPA. Lancet 2003; 362:
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% Incidence of primary events EUROPA. Presented ESC 2004.
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:
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:
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:
References PROGRESS. Lancet 2001;358: Stroke 2003; 34: Eur Heart J 2003: 24: Arch Intern Med 2003; 162: Stroke 2004; 35: PROGRESS. Lancet 2001;358: Stroke 2003; 34: Eur Heart J 2003: 24: Arch Intern Med 2003; 162: Stroke 2004; 35: EUROPA. Lancet 2003; 362: EUROPA. Lancet 2003; 362: 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