morbidity and mortality after stroke eprosartan compared with nitrendipine for secondary prevention

MOrbidity and mortality after Stroke

Eprosartan compared with nitrendipine for

Secondary prevention

MOrbidity and mortality after Stroke

Eprosartan compared with nitrendipine for

Secondary prevention

Epidemiology of StrokeEpidemiology of Stroke

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)

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 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 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 or MI Indicates greater risk

Existing heart disease Indicates 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.

Lifestyle1 Pharmacotherapy1,2

Smoking Hypertension

Low physical exercise Arterial disease

Morbid obesity Heart disease or failure

Excess alcohol consumption Risk 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

Primary Stroke Prevention Through Blood Pressure Control

1. SHEP Cooperative Research Group. JAMA 1991;265:3255–3264.

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.

0 12 24 36 48 60

0

1

2

3

4

5

6

7

8

9

10

Follow-up (months)

Cu

mu

lati

ve s

tro

ke r

ate

(per

100

par

tici

pan

ts) Placebo

Active treatment

SHEP results1

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 results1

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

0 1 2 3 4

0

1

2

3

4

5

6PlaceboActive treatment

Time since randomization (years)

Fat

al o

r n

on

-fat

al s

tro

ke(e

ven

ts p

er 1

00 p

atie

nts

)

*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

SHEP36% total stroke reduction in patients receiving antihypertensive treatment for isolated systolic

hypertension1

Syst-Eur42% total stroke reduction in patients receiving nitrendipine for isolated systolic hypertension2

Treatment of hypertension significantly reduces the rate of primary stroke

RAAS: Benefits Beyond Blood Pressure Reduction

RAAS: Benefits Beyond Blood Pressure Reduction

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.

1. Lacourcière Y. Clin Ther 2000;22:1213–1224.

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. Dahlöf B, et al. Lancet 2002;359:995–1003.

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.

LIFE results1

Time (months)

Stroke risk reduction (adjusted): 24.9%; P=0.0010Stroke risk reduction (unadjusted): 25.8%; P=0.0006

Pro

po

rtio

n o

f p

atie

nts

w

ith

str

oke

(%

)

0

1

2

3

4

5

6

7

8

AtenololLosartan

0 12 24 36 48 60

1. Lithell H, et al. J Hypertens 2003;21:875–886.

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

7.4

9.710.3

12.8

0

2

4

6

8

10

12

14

Non-fatal stroke Total stroke

Candesartan

Active control

Rat

e (%

)SCOPE results1

1. Lithell H, et al. J Hypertens 2003;21:875–886.

LIFE24.9% total stroke reduction with losartan in patients

with hypertension1

SCOPE27.8% 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

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 PreventionSecondary Stroke Prevention

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.

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.

Antihypertensive therapy in secondary stroke prevention: PROGRESS1

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)

PROGRESS results1

Numbers at riskActive 3051 2902 2765 2634 1595Placebo 3054 2880 2707 2551 1533

PlaceboActive treatment

P<0.0001

Follow-up (years)

Cu

mu

lati

ve s

tro

ke i

nci

den

ce (

%)

0 1 2 3 4

0

5

10

15

20


Some antihypertensive treatments reduce the risk of recurrent stroke


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

Eprosartan: a Safe and Effective AIIA

Eprosartan: a Safe and Effective AIIA

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;8:114121; 2. Gavras I, Gavras H. Pharmacotherapy 1999;19(4 pt 2):102S107S.

2

Sympathetic nervous system

NE

(-) (+)

The effects of angiotensin II

AT1

AII

11

Bloodvessel

AT1Postsynaptic AT1 receptor

Presynaptic AT1 receptor

Noradrenaline

AII=angiotensin II; AT1 receptor=angiotensin-II receptor type I

11

2

Bloodvessel

NE

Eprosartan: mode of action

AT1

AT1

Eprosartan

AII

AII

Sympathetic nervous system

Eprosartan reduces SNS activity

–50

–40

–30

–20

–10

0

10

20

30

40

Ch

ang

e in

DB

P v

s co

ntr

ol

(%)

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;55:244251.

1. Sega R. Blood Press 1999;8:114121; 2. Gavras I, Gavras H. Pharmacotherapy 1999;19:102S107S.

Red

uct

ion

in s

itD

BP

(m

m H

g)

Eprosartan(n=59)

Enalapril(n=59)

P=0.136

Eprosartan effectively reduces blood pressure1 and is well tolerated2

-30

-25

-20

-15

-10

-5

0

Eprosartan has a placebo-like side-effect profile2

Eprosartan(n=59)

Enalapril(n=59)

P=0.025

Red

uct

ion

in s

itS

BP

(m

m H

g)

-25

-20

-15

-10

-5

0

-29.1

-21.2-20.1

-16.2

sitDBP=sitting DBP; sitSBP=sitting SBP

Eprosartan increases post-stroke survival in animal models

1210864200

20

40

60

80

100

Eprosartan(60 mg/kg/day)

Placebo

Time (weeks)

Su

rviv

al r

ate

(%

)

1. Barone FC, et al. Cardiovasc Res 2001;50:525537.

Eprosartan in Secondary Stroke Prevention: The MOSES Study

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 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;8:114121; 2. Gavras I, Gavras H. Pharmacotherapy 1999;19:102S107S; 3. Ohlstein O, et al. Pharmacology 1997;55:244251; 4. Barone FC, et al. Cardiovasc Res 2001;50:525537; 5. Staesson JA, et al. Lancet 1997;350:757–764; 6. Forcette F, et al. Arch Intern Med 2002;162:20462052.

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

1. Hansson L, et al. Blood Press 1992;1:113119.

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.

Patientsrandomized (n=1,405)

Day 1 Week 3 Week 6 Week 9 Follow-up 2–4 years

Eprosartan600 mg od*

Nitrendipine10 mg od*

Eprosartan800 mg od*

Add additional

antihypertensive*†

Dose increase or other additional


Dose increase or other additional


Add additional


Nitrendipine20 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 priorto first intake of study drug

1 without known vital status14 lost for follow-up monitoring

29 in total:14 withdrew consent priorto first intake of study drug

1 without known vital status14 lost for follow-up monitoring

24 in total:10 withdrew consent prior to first intake of study drug2 without known vital status12 lost for follow-up monitoring

24 in total:10 withdrew consent prior to first intake of study drug2 without known vital status12 lost for follow-up monitoring

1,405 patients eligible for randomization1,405 patients eligible for randomization

710 assigned to eprosartan-based

regimen

710 assigned to eprosartan-based

regimen

695 assigned to nitrendipine-based

regimen

695 assigned to nitrendipine-based

regimen

681 available for intention-to-treat analyses




BMI=body mass index

Eprosartan Nitrendipine

Patient number (n) 681 671

Sex (% male) 53.6 54.8

Age (years) 67.7 68.1

BMI (kg/m2) 27.6 27.4

Mean 24 h SBP (mm Hg) 139.7 140.0

Mean 24 h DBP (mm Hg) 81.7 81.5

Time between qualifying event and allocation (days)

347.6 349.8

Baseline characteristics



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 25.8

Barthel Index (score) 90.6 90.2Patients with Barthel index 90 75.6% 75.3%

Modified Rankin Scale (score) 1.5 1.5None to slight disability (0–2) 70.4 71.4

Moderate disability (3) 17.9 15.9

Severe disability (4–5) 11.7 12.7



Diabetes mellitus 36.0 37.7

Hyperlipidaemia 54.3 51.9

Hyperuricaemia 17.6 18.5

MI 8.5 7.7

Renal insufficiency 4.7 6.0

Coronary heart disease 27.2 25.3

COPD 4.4 3.6

No concomitant diseases 24.4 23.0

COPD=chronic obstructive pulmonary disease

60

70

80

90

100

110

120

130

140

150

160

0 3 6 3 6 12 18 24 36 48

Eprosartan SBP Nitrendipine SBP Eprosartan DBP Nitrendipine DBP

MonthsWeeks

Blo

od

pre

ssu

re (

mm

Hg

)

SBP and DBP reduction

SBP control <140 mm Hg

76.8% 79%72.6% 73.3%

010

2030

4050

6070

80

After 3 months Study end


% C

on

tro

lled

SBP control <140 mm Hg and DBP <90 mm Hg

75.5% 77.7%71.1% 72.5%

010

2030

4050

6070

80

After 3 months Study end


% C

on

tro

lled

Antihypertensive therapy

34.4 33.131.4

29.7

18.6

23.5

15.613.7

0

10

20

30

40

Monotherapy 2 3 >3

Eprosartan

Nitrendipine

Number of antihypertensives prescribed

% P

atie

nts

46.5 45.9

33.2 32.2

13.8

25.8

14.4

7.5

14.4 13.0

0

10

20

30

40

50

Diuretics Beta-blockers

ACE-Is/AIIAs

CCBs Other

Eprosartan

Nitrendipine

Antihypertensive medication (final visit)

% P

atie

nts

ACE-Is=ACE inhibitors; CCBs=calcium channel blockers

Primary endpoint(morbidity and mortality)

Eve

nts

(n

)

Days

0

50

100

150

200

250

300

0 200 400 600 800 1000 1200 1400 1600


Risk reduction with eprosartan: 21% (P=0.014)

0

20

40

60

80

100

120

140

160

0 200 400 600 800 1000 1200 1400 1600


Secondary endpoint(cerebrovascular events)

Days

Eve

nts

(n

)


0

20

40

60

80

100

120

140

160

0 200 400 600 800 1000 1200 1400 1600 1800


Days

Eve

nts

(n

)

Secondary endpoint(cardiovascular events)


MMSE, Rankin Scale,Barthel Index


MMSE mean score 25.6 25.5

Modified Rankin Scale (score) 1.4 1.5

Barthel Index (score) 88.8 88.1

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

morbidity and mortality after stroke eprosartan compared with nitrendipine for secondary prevention

Documents

prevention of stroke

impact of stroke

stroke patients

stroke eprosartan

stroke statistics

risk of total stroke

epidemiology of stroke

primary stroke prevention