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Epidemiology of Stroke

MOrbidity and mortality after Stroke  Eprosartan compared with nitrendipine for Secondary prevention. Epidemiology of Stroke. What is stroke?. Stroke is a vascular disease Ischaemic stroke – blocked cerebral blood vessel Thrombotic infarct Cerebral infarct Lacunar infarct

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Epidemiology of Stroke

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  1. MOrbidity and mortality after Stroke  Eprosartan compared with nitrendipine for Secondary prevention

  2. Epidemiology of Stroke

  3. What is stroke? Stroke is a vascular disease • Ischaemic stroke – blocked cerebral blood vessel • Thrombotic infarct • Cerebral infarct • Lacunar infarct • Haemorrhagic stroke – ruptured cerebral blood vessel • Aneurysm • Arteriovenous malformation • Transient ischaemic attack (TIA)

  4. Incidence and impact of stroke • Third leading cause of death in developed countries1 • Incidence rates: • 1–2 per 1,000 inhabitants in the USA2 • 2–2.5 per 1,000 inhabitants in Western Europe3 • 3–3.5 per 1,000 inhabitants in Eastern Europe3 • 20 million people affected worldwide each year4,5 • 25% all-cause mortality rate in the Western world6 • 75% of strokes are non-fatal:4–6 • 33% of stroke patients become disabled5,6 • Risk of dementia is increased in stroke patients7 • Significant impact on independent living 1. Straus SE, et al. JAMA 2002;288:1388–1395; 2. American Stroke Association. Stroke. Heart Disease and Stroke Statistics2004 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.

  5. Non-modifiable risk factors in stroke1 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 orMI Indicates greater risk Existing heart disease Indicates greater risk MI=myocardial infarction 1. Straus SE, et al. JAMA 2002;288:1388–1395.

  6. Modifiable risk factors in stroke prevention 1. Bogousslavsky J, et al. Cerebrovasc Dis 2000;10:12–21; 2. Wolf P. Lancet 1998;352:1518.

  7. Primary Stroke Prevention Through Blood Pressure Control

  8. Prevention of stroke by antihypertensive treatment: SHEP1 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. SHEP Cooperative Research Group. JAMA 1991;265:3255–3264.

  9. SHEP results1 10 9 Placebo Active treatment 8 7 6 Cumulative stroke rate (per 100 participants) 5 4 3 2 1 0 0 12 24 36 48 60 Follow-up (months) 1. SHEP Cooperative Research Group. JAMA 1991;265:3255–3264.

  10. 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 1. Staessen JA, et al. Lancet 1997;350:757–764.

  11. Syst-Eur results1 6 Placebo Active treatment 5 4 Fatal or non-fatal stroke (events per 100 patients) 3 * 2 1 *P=0.003 0 0 1 2 3 4 Time since randomization (years) 1. Staesson JA, et al. Lancet 1997;350:757–764.

  12. SHEP and Syst-Eur:results and conclusions SHEP 36% total stroke reduction in patients receiving antihypertensive treatment for isolated systolic hypertension1 Syst-Eur 42% total stroke reduction in patients receiving nitrendipine for isolated systolic hypertension2 Treatment of hypertension significantly reduces the rate of primary stroke 1. SHEP Cooperative Research Group. JAMA 1991;265:3255–3264; 2. Staesson JA, et al. Lancet 1997;350:757–764.

  13. RAAS: Benefits Beyond Blood Pressure Reduction

  14. 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 vasculature1 • Agents that interact with the renin–angiotensin–aldosterone system (RAAS) could benefit those with pre-existing cardiovascular disease, in addition to blood pressure reduction1 • 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 II2 • AIIAs block the actions of angiotensin II by binding to angiotensin II receptors on the cell membrane3 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.

  15. Superior tolerability of AIIAs compared with ACE inhibitors1 • 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. Lacourcière Y. Clin Ther 2000;22:1213–1224.

  16. Additional benefits beyond blood pressure reduction: LIFE1 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.

  17. 8 7 Atenolol Losartan 6 5 Proportion of patients with stroke (%) 4 3 2 1 Stroke risk reduction (adjusted): 24.9%; P=0.0010 Stroke risk reduction (unadjusted): 25.8%; P=0.0006 0 24 48 0 12 36 60 Time (months) LIFE results1 1. Dahlöf B, et al. Lancet 2002;359:995–1003.

  18. Additional benefits beyond blood pressure reduction: SCOPE1 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 1. Lithell H, et al. J Hypertens 2003;21:875–886.

  19. SCOPE results1 Candesartan 14 12.8 Active control 12 10.3 9.7 10 7.4 8 Rate (%) 6 4 2 0 Non-fatal stroke Total stroke 1. Lithell H, et al. J Hypertens 2003;21:875–886.

  20. LIFE and SCOPE:results and conclusions LIFE 24.9% total stroke reduction with losartan in patients with hypertension1 SCOPE 27.8% non-fatal stroke reduction with candesartan in patients with mild-to-moderate hypertension2 Antihypertensive treatments that affect the RAAS provide benefits over and above blood pressure reduction 1. Dahlöf B, et al. Lancet 2002;359:995–1003; 2. Lithell H, et al. J Hypertens 2003;21:875–886.

  21. Secondary Stroke Prevention

  22. Secondary stroke prevention • After a stroke, the risk of recurrent stroke is high: • 8% of patients suffer a further stroke within 1 year1 • 17% of patients suffer a further stroke within 5 years2 • 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 recurrence3 • 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.

  23. Interventions for secondary stroke prevention1 • Lifestyle changes • Antithrombotic drugs (eg aspirin) • Anticoagulants • Surgery • Carotid endarterectomy • Angioplasty • Antihypertensive therapy 1. Straus SE, et al. JAMA 2002;288:1388–1395.

  24. Antihypertensive therapy in secondary stroke prevention: PROGRESS1 Perindopril pROtection aGainst REcurrent Stroke Study (PROGRESS) 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.

  25. 20 Placebo Active treatment P<0.0001 15 10 Cumulative stroke incidence (%) 5 0 0 1 2 3 4 Follow-up (years) PROGRESS results1 Numbers at risk Active 3051 2902 2765 2634 1595 Placebo 3054 2880 2707 2551 1533 1. PROGRESS Collaborative Group. Lancet 2001;358:1033–1041.

  26. PROGRESS: conclusions1 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 Some antihypertensive treatments reduce the risk of recurrent stroke 1. PROGRESS Collaborative Group. Lancet 2001;358:1033–1041.

  27. Eprosartan: a Safe and Effective AIIA

  28. 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.

  29. (-) (+) AII Noradrenaline 1 1 The effects of angiotensin II Sympathetic nervous system NE 2 AT1 Presynaptic AT1 receptor Postsynaptic AT1 receptor AT1 Bloodvessel AII=angiotensin II; AT1 receptor=angiotensin-II receptor type I

  30. Eprosartan AII AII 1 1 Eprosartan: mode of action Sympathetic nervous system NE 2 AT1 AT1 Bloodvessel

  31. Eprosartan reduces SNS activity 40 30 20 Eprosartan (0.3 mg/kg) 10 Losartan (0.3 mg/kg) 0 Valsartan (0.3 mg/kg) Change in DBP vs control (%) –10 Irbesartan (0.3 mg/kg) –20 Intravenously 10 min before stimulation (acute effect) –30 * –40 * P<0.05 –50 Sympathetic stimulation at 1 Hz Adapted from Ohlstein O, et al. Pharmacology, 1997;55:244251.

  32. Eprosartan effectively reduces blood pressure1 and is well tolerated2 Reduction in sitSBP (mm Hg) Reduction in sitDBP (mm Hg) -16.2 -21.2 -20.1 -29.1 Eprosartan (n=59) Enalapril (n=59) Eprosartan (n=59) Enalapril (n=59) P=0.025 P=0.136 Eprosartan has a placebo-like side-effect profile2 sitDBP=sitting DBP; sitSBP=sitting SBP 1. Sega R. Blood Press 1999;8:114121; 2. Gavras I, Gavras H. Pharmacotherapy 1999;19:102S107S.

  33. 0 2 4 6 8 10 12 Eprosartan increases post-stroke survival in animal models 100 80 60 Survival rate (%) 40 Placebo 20 Eprosartan (60 mg/kg/day) 0 Time (weeks) 1. Barone FC, et al. Cardiovasc Res 2001;50:525537.

  34. Eprosartan in Secondary Stroke Prevention: The MOSES Study

  35. 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

  36. 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 pressure1,2 • Shown to reduce SNS activity3 • Reduced secondary stroke in an experimental model4 • Why nitrendipine? • Significantly reduced the risk of a first stroke in the Syst-Eur trial5,6 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.

  37. Study design • PROBE design: • Prospective, Randomized, Open, Blinded Endpoint1 • 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 PRIND=prolonged reversible ischaemic neurologic deficit; CHF=congestive heart failure 1. Hansson L, et al. Blood Press 1992;1:113119.

  38. MOSES: treatment plan Dose increase or other additionalantihypertensive*† Add additionalantihypertensive*† Eprosartan800 mg od* Eprosartan600 mg od* Patientsrandomized (n=1,405) Nitrendipine10 mg od* Nitrendipine20 mg od* Add additionalantihypertensive*† Dose increase or other additionalantihypertensive*† Day 1 Week 3 Week 6 Week 9 Follow-up 2–4 years *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.

  39. 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

  40. 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

  41. Study profile 1,405 patients eligible for randomization 695 assigned to nitrendipine-based regimen 710 assigned to eprosartan-based regimen 29 in total: 14 withdrew consent priorto 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 681 available for intention-to-treat analyses 671 available for intention-to-treat analyses

  42. Baseline characteristics BMI=body mass index

  43. Baseline characteristics

  44. Baseline characteristics COPD=chronic obstructive pulmonary disease

  45. Eprosartan SBP Nitrendipine SBP Eprosartan DBP Nitrendipine DBP SBP and DBP reduction 160 150 140 130 Blood pressure (mm Hg) 120 110 100 90 80 70 60 0 3 6 3 6 12 18 24 36 48 Weeks Months

  46. SBP control <140 mm Hg Eprosartan Nitrendipine 79% 76.8% 80 73.3% 72.6% 70 60 50 % Controlled 40 30 20 10 0 After 3 months Study end

  47. SBP control <140 mm Hg and DBP <90 mm Hg Eprosartan Nitrendipine 77.7% 75.5% 80 72.5% 71.1% 70 60 50 % Controlled 40 30 20 10 0 After 3 months Study end

  48. Antihypertensive therapy 40 Eprosartan 34.4 33.1 Nitrendipine 31.4 29.7 30 23.5 % Patients 20 18.6 15.6 13.7 10 0 Monotherapy 2 3 >3 Number of antihypertensives prescribed

  49. Antihypertensive medication (final visit) 50 46.5 45.9 Eprosartan Nitrendipine 40 33.2 32.2 30 25.8 % Patients 20 14.4 14.4 13.8 13.0 10 7.5 0 Diuretics Beta- ACE-Is/ CCBs Other blockers AIIAs ACE-Is=ACE inhibitors; CCBs=calcium channel blockers

  50. Primary endpoint(morbidity and mortality) 300 Eprosartan Nitrendipine 250 200 Events (n) 150 Risk reduction with eprosartan: 21% (P=0.014) 100 50 0 0 200 400 600 800 1000 1200 1400 1600 Days

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