Upload
gisselle-myers
View
223
Download
2
Tags:
Embed Size (px)
Citation preview
MOrbidity and mortality after Stroke
Eprosartan compared with nitrendipine for
Secondary prevention
MOrbidity and mortality after Stroke
Eprosartan compared with nitrendipine for
Secondary prevention
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: 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 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
1. PROGRESS Collaborative Group. Lancet 2001;358:1033–1041.
Some antihypertensive treatments reduce the risk of recurrent stroke
1. PROGRESS Collaborative Group. Lancet 2001;358:1033–1041.
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
• 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
antihypertensive*†
Dose increase or other additional
antihypertensive*†
Add additional
antihypertensive*†
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
681 available for intention-to-treat analyses
671 available for intention-to-treat analyses
671 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
Baseline characteristics
Eprosartan Nitrendipine
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
Baseline characteristics
Eprosartan Nitrendipine
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
Eprosartan Nitrendipine
% 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
Eprosartan Nitrendipine
% 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
Eprosartan Nitrendipine
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
Eprosartan Nitrendipine
Secondary endpoint(cerebrovascular events)
Days
Eve
nts
(n
)
Risk reduction with eprosartan: 25% (P=0.02)
0
20
40
60
80
100
120
140
160
0 200 400 600 800 1000 1200 1400 1600 1800
Eprosartan Nitrendipine
Days
Eve
nts
(n
)
Secondary endpoint(cardiovascular events)
Risk reduction with eprosartan: 25% (P=0.06)
MMSE, Rankin Scale,Barthel Index
Eprosartan Nitrendipine
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