Incidence and impact of stroke Third leading cause of death in developed countries 1 Incidence rates: – 1–2 per 1,000 inhabitants in the USA 2 – 2–2.5 per 1,000 inhabitants in Western Europe 3 – 3–3.5 per 1,000 inhabitants in Eastern Europe 3 20 million people affected worldwide each year 4,5 25% all-cause mortality rate in the Western world 6 75% of strokes are non-fatal: 4–6 – 33% of stroke patients become disabled 5,6 – Risk of dementia is increased in stroke patients 7 – Significant impact on independent living 1. Straus SE, et al. JAMA 2002;288:1388–1395; 2. American Stroke Association. Stroke. Heart Disease and Stroke Statistics 2004 Update; 3. Brainin M, et al. Acute neurological stroke care in Europe: results of the European Stroke Care Inventory. Eur J Neurology 2000;7:5–10; 4. World Health Organization. World Health Report 1999. Genova: WHO 1999; 5. Bonita R. Lancet 1992;339:342–344; 6. Hankey GJ, Warlow CP. Lancet 1999;354:1457–1463; 7. Henon H. Clin Exp Hypertens 2002;24:677–686.
Non-modifiable risk factors in stroke 1 Age Elderly at greater risk Gender Males more susceptible Hereditary factors Family history indicates greater risk Race/ethnicity Non-white groups at greater risk Prior stroke or MIIndicates greater risk Existing heart diseaseIndicates greater risk 1. Straus SE, et al. JAMA 2002;288:1388–1395. MI=myocardial infarction
Modifiable risk factors in stroke prevention 1. Bogousslavsky J, et al. Cerebrovasc Dis 2000;10:12–21; 2. Wolf P. Lancet 1998;352:1518. Lifestyle 1 Pharmacotherapy 1,2 SmokingHypertension Low physical exerciseArterial disease Morbid obesityHeart disease or failure Excess alcohol consumptionRisk of thrombolic or embolic phenomena Diet (high salt and fat)Certain blood disorders High blood cholesterol Diabetes mellitus
Primary Stroke Prevention Through Blood Pressure Control
1. SHEP Cooperative Research Group. JAMA 1991;265:3255 – 3264. Prevention of stroke by antihypertensive treatment: SHEP 1 Systolic Hypertension in the Elderly Programme (SHEP) Objective: to assess the ability of antihypertensive treatment to reduce the risk of total stroke in isolated systolic hypertension Patient population: n=4,736; chlorthalidone od (± atenolol; n=2,365), placebo od (n=2,371) Primary outcome: non-fatal and fatal (total) stroke Follow-up: 4.5 years od = once daily
1. Staessen JA, et al. Lancet 1997;350:757–764. Prevention of stroke by antihypertensive treatment: Syst-Eur Systolic Hypertension in Europe (Syst-Eur) Objective: to assess the effect of the antihypertensive nitrendipine on the risk of stroke Patient population: n=4,695; nitrendipine (n=2,398), placebo (n=2,297) Primary outcome: non-fatal and fatal (total) stroke Follow-up: 4 years
Syst-Eur results 1 1. Staesson JA, et al. Lancet 1997;350:757–764. 01234 0 1 2 3 4 5 6 Placebo Active treatment Time since randomization (years) Fatal or non-fatal stroke (events per 100 patients) *P=0.003 *
1. SHEP Cooperative Research Group. JAMA 1991;265:3255 – 3264; 2. Staesson JA, et al. Lancet 1997;350:757–764. SHEP and Syst-Eur: results and conclusions SHEP 36% total stroke reduction in patients receiving antihypertensive treatment for isolated systolic hypertension 1 Syst-Eur 42% total stroke reduction in patients receiving nitrendipine for isolated systolic hypertension 2 Treatment of hypertension significantly reduces the rate of primary stroke
RAAS: additional benefits beyond blood pressure reduction Angiotensin II is a potent vasoconstrictor and growth- stimulating hormone that may have adverse structural effects on the heart and vasculature 1 Agents that interact with the renin–angiotensin–aldosterone system (RAAS) could benefit those with pre-existing cardiovascular disease, in addition to blood pressure reduction 1 Both angiotensin-converting enzyme (ACE) inhibitors and angiotensin-II receptor antagonists (AIIAs) interact with the RAAS: –ACE inhibitors block the conversion of angiotensin I to angiotensin II 2 –AIIAs block the actions of angiotensin II by binding to angiotensin II receptors on the cell membrane 3 1. Lohn EM, et al. Circulation 1994;90:2056 – 2069; 2. The Heart Outcomes Prevention Evaluation Study Investigators. New Engl J Med 2000;342:145 – 153; 3. Cohn JN, for the Valsartan Heart Failure Trial Investigators. New Engl J Med 2001;345:1667 – 1675.
1. Lacourcière Y. Clin Ther 2000;22:1213 – 1224. Superior tolerability of AIIAs compared with ACE inhibitors 1 AIIAs offer the advantage of more complete blockade of the RAAS Repeatedly shown to have excellent tolerability, with adverse event profiles similar to placebo In particular, the persistent cough that some patients develop with ACE inhibitors is not seen with AIIAs
1. Dahlöf B, et al. Lancet 2002;359:995–1003. Additional benefits beyond blood pressure reduction: LIFE 1 Losartan Intervention For Endpoint reduction in hypertension (LIFE) study Objective: to establish whether the AIIA losartan provides additional cardiovascular benefits beyond blood pressure reduction Patient population: 9,193 patients with systolic hypertension assigned either losartan (n=4,605) or atenolol (n=4,588) Primary outcome: death, MI, stroke Mean follow-up: 4.8 years
1. Dahlöf B, et al. Lancet 2002;359:995–1003. LIFE results 1 Time (months) Stroke risk reduction (adjusted): 24.9%; P=0.0010 Stroke risk reduction (unadjusted): 25.8%; P=0.0006 Proportion of patients with stroke (%) 0 1 2 3 4 5 6 7 8 Atenolol Losartan 012 24 36 48 60
1. Lithell H, et al. J Hypertens 2003;21:875–886. Additional benefits beyond blood pressure reduction: SCOPE 1 The Study on Cognition and Prognosis in the Elderly (SCOPE) Objective: to assess the effect of antihypertensive treatment with candesartan on cognition and prognosis Patient population: 4,964 patients with mild-to-moderate hypertension; candesartan (n=2,477), control (active treatment allowed; n=2,460) Primary outcome: first major cardiovascular event (including non-fatal stroke) Mean follow-up: 3.7 years
LIFE 24.9% total stroke reduction with losartan in patients with hypertension 1 SCOPE 27.8% non-fatal stroke reduction with candesartan in patients with mild-to-moderate hypertension 2 Antihypertensive treatments that affect the RAAS provide benefits over and above blood pressure reduction LIFE and SCOPE: results and conclusions 1. Dahlöf B, et al. Lancet 2002;359:995–1003; 2. Lithell H, et al. J Hypertens 2003;21:875–886.
Secondary stroke prevention After a stroke, the risk of recurrent stroke is high: – 8% of patients suffer a further stroke within 1 year 1 – 17% of patients suffer a further stroke within 5 years 2 Therefore, there is a high medical need for a safe and effective treatment for secondary stroke prevention Hypertension is an important determinant of risk of stroke recurrence 3 Most published data relate to primary prevention; little is known about secondary prevention 1. Lees KR, et al. BMJ 2000;320:991–994; 2. Hankey GJ, Warlow CP. Lancet 1999;354:1457–1463; 3. Rogers A, et al. BMJ 1996;313:147.
Interventions for secondary stroke prevention 1 Lifestyle changes Antithrombotic drugs (eg aspirin) Anticoagulants Surgery –Carotid endarterectomy –Angioplasty Antihypertensive therapy 1. Straus SE, et al. JAMA 2002;288:1388–1395.
Antihypertensive therapy in secondary stroke prevention: PROGRESS 1 Objective: to determine the effects of antihypertensive therapy with an ACE inhibitor on recurrent stroke in patients with a history of stroke or TIA, in both hypertensive and normotensive patients Patient population: n=6,105; perindopril plus indapamide (n=3,051), placebo (n=3,054) Primary outcome: total stroke (fatal or non-fatal) Follow-up: 4 years 1. PROGRESS Collaborative Group. Lancet 2001;358:1033–1041. Perindopril pROtection aGainst REcurrent Stroke Study (PROGRESS)
Some antihypertensive treatments reduce the risk of recurrent stroke 1. PROGRESS Collaborative Group. Lancet 2001;358:1033–1041. PROGRESS: conclusions 1 Active treatment (perindopril and indapamide) Reduced blood pressure by 12.3/5.0 mm Hg 43% relative risk reduction in secondary stroke Hypertensive vs normotensive Similar reduction in risk of stroke (P<0.01) No benefit from perindopril alone
Eprosartan Eprosartan is an AIIA: AIIAs have proven efficacy in blood pressure reduction AIIAs affect the RAAS, which may result in additional benefits to blood pressure reduction AIIAs have a placebo-like tolerability profile Eprosartan has been available for nearly 7 years and has an established safety record in clinical practice 1. Sega R. Blood Press 1999;8:114 121; 2. Gavras I, Gavras H. Pharmacotherapy 1999;19(4 pt 2):102S 107S.
22 Sympathetic nervous system NE (-)(+) The effects of angiotensin II AT 1 AII 11 11 Blood vessel AT 1 Postsynaptic AT 1 receptor Presynaptic AT 1 receptor Noradrenaline AII=angiotensin II; AT 1 receptor=angiotensin-II receptor type I
11 11 22 Blood vessel NE Eprosartan: mode of action AT 1 Eprosartan AII Sympathetic nervous system
Eprosartan reduces SNS activity –50 –40 –30 –20 –10 0 10 20 30 40 Change in DBP vs control (%) Eprosartan (0.3 mg/kg) Losartan (0.3 mg/kg) Valsartan (0.3 mg/kg) Irbesartan (0.3 mg/kg) Intravenously 10 min before stimulation (acute effect) Sympathetic stimulation at 1 Hz * P<0.05 * Adapted from Ohlstein O, et al. Pharmacology, 1997;55:244 251.
1. Sega R. Blood Press 1999;8:114 121; 2. Gavras I, Gavras H. Pharmacotherapy 1999;19:102S 107S. Reduction in sitDBP (mm Hg) Eprosartan (n=59) Enalapril (n=59) P=0.136 Eprosartan effectively reduces blood pressure 1 and is well tolerated 2 Eprosartan has a placebo-like side-effect profile 2 Eprosartan (n=59) Enalapril (n=59) P=0.025 Reduction in sitSBP (mm Hg) -29.1 -21.2 -20.1 -16.2 sitDBP=sitting DBP; sitSBP=sitting SBP
Eprosartan increases post-stroke survival in animal models 121086420 0 20 40 60 80 100 Eprosartan (60 mg/kg/day) Placebo Time (weeks) Survival rate (%) 1. Barone FC, et al. Cardiovasc Res 2001;50:525 537.
Eprosartan in Secondary Stroke Prevention: The MOSES Study
The MOSES study MOrbidity and mortality after Stroke Eprosartan compared with nitrendipine for Secondary prevention (MOSES) Hypothesis In hypertensive stroke patients, for the same level of blood pressure control, eprosartan will be more effective than nitrendipine in reducing cerebrovascular and cardiovascular morbidity and mortality
Rationale High risk of recurrence after stroke Need for better management of stroke patients Few comparative trials focusing on the AIIAs vs other available antihypertensives Few recurrent stroke prevention trials Additional beneficial effects of AIIAs? Why eprosartan? –Effectively lowers systolic blood pressure 1,2 –Shown to reduce SNS activity 3 –Reduced secondary stroke in an experimental model 4 Why nitrendipine? –Significantly reduced the risk of a first stroke in the Syst-Eur trial 5,6 1. Sega R. Blood Press 1999;8:114 121; 2. Gavras I, Gavras H. Pharmacotherapy 1999;19:102S 107S; 3. Ohlstein O, et al. Pharmacology 1997;55:244 251; 4. Barone FC, et al. Cardiovasc Res 2001;50:525 537; 5. Staesson JA, et al. Lancet 1997;350:757–764; 6. Forcette F, et al. Arch Intern Med 2002;162:2046 2052.
Study design PROBE design: – Prospective, Randomized, Open, Blinded Endpoint 1 Inclusion criteria: – Hypertension requiring treatment, plus one of the following within the 24 months prior to study enrolment: – Cerebral ischaemia (TIA, PRIND, complete stroke) – Cerebral haemorrhage Exclusion criteria: – Carotid artery stenosis >70% – Severe CHF, unstable angina, or valve disease – Age over 85 years – Contraindication for eprosartan or nitrendipine 1. Hansson L, et al. Blood Press 1992;1:113 119. PRIND=prolonged reversible ischaemic neurologic deficit; CHF=congestive heart failure
MOSES: treatment plan *Titration upwards if target blood pressure (sitDBP <90 mm Hg/sitSBP <140 mm Hg) not reached. † Combination therapy with antihypertensive agents, excluding ACE inhibitors, AIIAs and calcium channel blockers. Patients randomized (n=1,405) Day 1Week 3Week 6Week 9Follow-up 2–4 years Eprosartan 600 mg od* Nitrendipine 10 mg od* Eprosartan 800 mg od* Add additional antihypertensive* † Dose increase or other additional antihypertensive* † Add additional antihypertensive* † Nitrendipine 20 mg od*
Study endpoints Primary endpoint: – Total mortality plus total number of cardiovascular and cerebrovascular events Secondary endpoints: – Change in mental capacity and functional status (Barthel Index and Rankin Scale) – Individual elements of the combined primary endpoint Mean follow-up: – 2.5 years
Assessments Procedures regularly performed: –Sitting and ambulatory blood pressure measurements (ABPM) –Mini Mental State Examination (MMSE) score –Documentation of all drugs –Barthel Index and Rankin Scale –Electrocardiogram –Adverse event reporting
Study profile 29 in total: 14 withdrew consent prior to first intake of study drug 1 without known vital status 14 lost for follow-up monitoring 29 in total: 14 withdrew consent prior to first intake of study drug 1 without known vital status 14 lost for follow-up monitoring 24 in total: 10 withdrew consent prior to first intake of study drug 2 without known vital status 12 lost for follow-up monitoring 24 in total: 10 withdrew consent prior to first intake of study drug 2 without known vital status 12 lost for follow-up monitoring 1,405 patients eligible for randomization 710 assigned to eprosartan-based regimen 695 assigned to nitrendipine-based regimen 681 available for intention- to-treat analyses 671 available for intention- to-treat analyses
BMI=body mass index EprosartanNitrendipine Patient number (n) 681671 Sex (% male) 53.654.8 Age (years) 67.768.1 BMI (kg/m 2 ) 27.627.4 Mean 24 h SBP (mm Hg) 139.7140.0 Mean 24 h DBP (mm Hg) 81.781.5 Time between qualifying event and allocation (days) 347.6349.8 Baseline characteristics
EprosartanNitrendipine Qualifying disease Stroke 418 (61.4)407 (60.7) TIA 186 (27.3)184 (27.4) PRIND 36 (5.3)47 (7.0) Intracerebral haemorrhage 41 (6.0)33 (4.9) MMSE score 25.8 Barthel Index (score) 90.690.2 Patients with Barthel index 90 75.6%75.3% Modified Rankin Scale (score) 1.5 None to slight disability (0–2) 70.471.4 Moderate disability (3) 17.915.9 Severe disability (4–5) 11.712.7
MMSE, Rankin Scale, Barthel Index EprosartanNitrendipine MMSE mean score25.625.5 Modified Rankin Scale (score)1.41.5 Barthel Index (score)88.888.1
Key results Blood pressure significantly and similarly reduced in both treatment groups Eprosartan reduced the incidence of the primary composite endpoint (mortality and total cerebrovascular and cardiovascular events) by 21% Total cerebrovascular events reduced by 25% with eprosartan
Summary Eprosartan significantly and similarly lowers and maintains blood pressure over time in a high-risk patient population Compared with the calcium channel blocker nitrendipine, eprosartan affords additional benefits in terms of cerebrovascular and cardiovascular outcome These benefits are achieved above and beyond that of lowering blood pressure