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International Task Force for Prevention
Of Coronary Heart Disease

Coronary heart disease and stroke:
Risk factors and global risk
Slide Kit 1
Primary prevention of stroke
International Task Force for Prevention of Coronary Heart DiseaseStrokeSlide Kit 1:Primary prevention of stroke T A B LE OF CON T E N T
Primary prevention of ischemic stroke. Recommendations for risk
factor management

Effects of ACE-inhibitors and calcium-antagonists on stroke, coronary
heart disease and total mortality

Effects of ACE-inhibitors on stroke and cardiovascular outcomes in
people with diabetes

Primary prevention of ischemic stroke in patients with atrial fibrillation
Aspirin for primary prevention of stroke and other major vascular events
Primary prevention of ischemic stroke: recommendations for management
of serum lipids

Genetic susceptibility and LDL-cholesterol in lacunar stroke
Effects of statins on stroke: Meta-analysis of CHD prevention trials
Risk reduction in major statin trials
Effects of statins on stroke type. Prospective Pravastatin Pooling Project
Effects of statins on stroke and coronary events in older patients - the CARE trial
Protective effects of statins on ischemic stroke
Statins and prevalence of Alzheimer’s disease
Statins and risk of dementia
Effects of fibrates on stroke types in men with CHD and low HDL-cholesterol
International Task Force for Prevention of Coronary Heart Disease Slide 1:
Stroke:
Primary prevention of ischemic stroke. Recommendations for risk
factor management

Primary Prevention of Ischemic Stroke
Recommendations for Risk Factor Management
Risk factor
Goal / Recommendation
Hypertension
Systolic blood pressure < 140 mm Hg
Diastolic blood pressure < 90 mm Hg

Quitting
Diabetes
Improved glucose control;treatment of hypertension
Asymptomatic carotid stenosis
Endarterectomy may be considered in selected patients
Atrial fibrillation
Antithrombotic therapy (choice depends on age and risk factors)
Serum lipids
Treatment of dyslipidemia
(choice depends on lipid profile and CHD risk factors)

Physical inactivity
30 mh of moderate- intensity activity daily
(consider individual risk profile)

Poor diet / nutrition
5 servings of fruits and vegetables per day
Moderate intake
(max. 2 drinks/day for men and 1 drink/day for women)

Drug abuse
Quitting
Source: Goldstein et al.;Stroke 2001, 32:280-299
Primary prevention of ischemic stroke. Recommendations for risk
factor management

This slide summarizes the guidelines of the Stroke Council of the American HeartAssociation for the management of modifiable risk factors for stroke.
International Task Force for Prevention of Coronary Heart DiseaseStrokeSlide Kit 1:Primary prevention of stroke Slide 2:
Stroke:
Effects of ACE-inhibitors and calcium-antagonists on stroke, coronary
heart disease and total mortality

Effect of ACE-Inhibitors and Calcium-Antagonists on
Stroke, Coronary Heart Disease and Total Mortality
ACE-inhibitors
(4 trials, 12124 patients mostly with CHD)

Coronary heart disease*
Total mortality
Calcium antagonists
(2 trials, 5520 patients mostly with hypertension)

Coronary heart disease*
Total mortality
*fatal or non-fatal
favors treatment
favors placebo
Relative risk
Source: Blood Pressure Lowering Treatment Trialists´ Collaboration;Lancet 2000, 355:1955-1964
Effects of ACE-inhibitors and calcium-antagonists on stroke, coronary
heart disease and total mortality

Effective treatment of hypertension reduces the incidence of fatal and nonfatal strokeby about 40%. By the mid 1990s, meta-analyses proved that both beta-blocker ther-apy and treatment with high-dose diuretics can prevent stroke. In 1995the BloodPressure Lowering Treatment Trialists’ Collaboration was initiated under the aegis ofthe WHO-International Society of Hypertension Liason Committee to investigate theeffects of angiotensin-converting enzyme (ACE) inhibitors, calcium antagonists andother blood-pressure-lowering drugs on mortality and major cardiovascular morbidityin several patient populations. This slide shows the benefits of ACE inhibitors andcalcium-antagonists for prevention of stroke and coronary heart disease.
International Task Force for Prevention of Coronary Heart Disease Slide 3:
Stroke:
Effects of ACE-inhibitors on stroke and cardiovascular outcomes in
people with diabetes

Effect of ACE-Inhibitors on Stroke and
Cardiovascular Outcomes
in People with Diabetes Mellitus
Myocardial infarction*
Cardiovascular death
*fatal or non-fatal
favors treatment
Relative risk (95% CI)
favors placebo
Ramipril versus placebo
Source: Heart Outcomes Prevention Evaluation (HOPE) Study Investigators;Lancet 2000, 355:253-259
Effects of ACE-inhibitors on stroke and cardiovascular outcomes in
people with diabetes

People with diabetes mellitus are at high risk of cardiovascular disease. The HeartOutcome Prevention Evaluation (HOPE) Study showed ramipril (ACE-inhibitor) on cardiovascular outcomes in people with diabetes. Therisk reduction for cardiovascular events was greater than would be expected from theobserved mean difference in blood pressures (systolic blood pressure –2.4 mmHg,diastolic blood pressure –1.0 mmHg), suggesting additional protective effects of ACEinhibitors on the arterial wall.
International Task Force for Prevention of Coronary Heart DiseaseStrokeSlide Kit 1:Primary prevention of stroke Slide 4:
Stroke:
Primary prevention of ischemic stroke in patients with atrial fibrillation

Primary Prevention of Ischemic Stroke
in Patients with Atrial Fibrillation
Antithrombotic therapy
Risk factors*
Recommendation
<65 years
Warfarin**
65-75 years
Aspirin of Warfarin**
Warfarin**
>75 years
Warfarin**
* Risk factors: hypertension, diabetes mellitus, poor left ventricular function, rheumatic mitral
valve disease, prior TIA/stroke, systemic embolism or stroke, prosthetic heart valve
** Target International Normalized Ratio (INR) 2.5;range (2.0-3.0)
Sources: W. Hacke et al.;Eur J Neurology 2000, 7:607-623;L.B. Goldstein et al.;Stroke 2001, 32:280-299
Primary prevention of ischemic stroke in patients with atrial fibrillation
Atrial fibrillation is a common arrhythmia and is responsible for about half of allthromboembolic strokes. There are a limited number of predictors of high stroke riskwithin the population of patients with atrial fibrillation. Anticoagulation therapy withwarfarin in patients with high-risk features reduces the risk of ischemic stroke by al-most 70%. The slides shows the age- and risk-feature-specific recommendations forantithrombotic treatment of patients with atrial fibrillation currently adopted by theEuropean Stroke Initiative (EUS) and the Stroke Council of the American Heart As-sociation.
International Task Force for Prevention of Coronary Heart Disease Slide 5:
Stroke:
Aspirin for primary prevention of stroke and other major vascular events

Aspirin for Primary Prevention of Stroke
and Other Major Vascular Events
Estimated effects (meta-analysis)
Number of annual events per 1.000 given Aspirin
Population
Myocardial
Major Extracranial
infarction
Middle-aged persons
No vascular risk factors
0.5 (?)
vascular risk factors
Healthy elderly persons
parenthical question mark: non-significant trend
upward arrow: increased;downward arrow: decreased

Sources: Hart et al.;Arch Neurol 2000, 57:326-332
Aspirin for primary prevention of stroke and other major vascular events
This slide summarizes data from a meta-analysis of randomized clinical trials andlarge prospective observational cohort studies examining the relation between aspirinuse and stroke in healthy male physicians and persons with diabetes mellitus, hyper-tension or with coronary risk factors. There is no scientific support for prescribingaspirin to reduce the risk of stroke. However, available data favor aspirin use for mid-dle-aged persons at special risk for myocardial infarction.
International Task Force for Prevention of Coronary Heart DiseaseStrokeSlide Kit 1:Primary prevention of stroke Slide 6:
Stroke:
Primary prevention of ischemic stroke: recommendations for management
of serum lipids

Primary Prevention of Ischemic Stroke
Recommendations for Management of Serum Lipids
Goal / Recommendation
Initial lipid evaluation (no CHD)
- TC < 200 mg/dl and HDL 35 mg/dl
General education, re-evaluation within 5 years
- TC 200-239 mg/dl and HDL 35 mg/dl
Dietary modification, re-evaluation in 1-2 years
and < 2 CHD risk factors*
- TC 240 mg/dl or HDL < 35 mg/dl
Lipoprotein analysis
or 2 CHD risk factors*
LDL-evaluation
- No CHD and < 2 CHD risk factors*
LDL < 160 mg/dl
- No CHD but 2 CHD risk factors*
LDL < 130 mg/dl
- Definite CHD or other atherosclerotic disease
LDL < 100 mg/dl
* CHD risk factors: men 45 years, women 55 years or early menopause without hormone
replacement therapy, family history of premature CHD, smoking, hypertension,
HDL < 35 mg/dl, diabetes mellitus,

Source: Goldstein et al.;Stroke 2001, 32:280-299
Primary prevention of ischemic stroke: recommendations for management
of serum lipids

This slide summarizes the recommendations for the management of serum lipids aspart of the therapeutic approach to prevent an ischemic stroke. The recommendationsgiven by the Stroke Council of the American Heart Association base on managementguidelines for patients with elevated cholesterol levels.
International Task Force for Prevention of Coronary Heart Disease Slide 7:
Stroke:
Genetic susceptibility and LDL-cholesterol in lacunar stroke

Genetic Susceptibility and LDL-Cholesterol
in Lacunar Stroke
LDL-Tertile
Controls
Odds ratio (95% CI)**
Genotype*
for lacunar stroke
1st (< 102)
1.0 (reference)
2nd (102-132)
2.8 (0.7-11.5)
3rd (>132)
3.7 (1.2-11.7)
1.6 (0.3-6.9)
8.5 (1.9-38.9)
22.2 (4.1-120.1)
* The GG Genotype of the Glu298Asp polymorphism in the ecNos gene was more frequent in
patients with lacunar stroke
** adjusted for cardiovascular history, lipid lowering drugs and blood sample delay
Sources: Elbaz et al.;Stroke 2000, 31:1634-1639
Genetic susceptibility and LDL-cholesterol in lacunar stroke
This slide provides an example of a potential synergistic relation between the geneticsusceptibility and LDL-cholesterol levels for the risk of a lacunar stroke (small, deepinfarct measuring <15mm – subtype of an ischemic stroke). In a case-control studyhomozygosity for the G allele of the Glu298Asp polymorphism in the endothelialconstitutive nitric oxide synthase as well as elevated LDL-cholesterol levels were as-sociated with lacunar stroke. The trend in lacunar stroke risk associated with LDL-cholesterol was stronger among carriers of the GG genotype.
International Task Force for Prevention of Coronary Heart DiseaseStrokeSlide Kit 1:Primary prevention of stroke Slide 8:
Stroke:
Effects of statins on stroke: Meta-analysis of CHD prevention trials

Effects of Statins on Stroke
Meta-analysis of CHD Prevention Trials
Primary prevention
(3 trials, 7961 patients)

Fatal stroke
All stroke (fatal + non-fatal)
Secondary prevention
(11 trials, 20740 patients)

Fatal stroke
All stroke (fatal + non-fatal)
favors treatment
Odds ratio (95% CI)
favors placebo
Source: Herbert et al.;JAMA 1997, 278:313-321
Effects of statins on stroke: Meta-analysis of CHD prevention trials
This slide summarizes the results of a meta-analysis of cholesterol lowering with stat-ins in stroke prevention. The meta-analysis bases on randomized trials which weredesigned to investigate the effect of statins on coronary heart disease. Despite the factthat cholesterol is not a strong risk factor for strokes, the long-term use of statins wasassociated with a significant overall reduction in risk of stroke by 29%. Risk reduc-tion was particularly pronounced in secondary prevention trials.
International Task Force for Prevention of Coronary Heart Disease Slide 9:
Stroke:
Risk reduction in major statin trials

Risk Reduction in the Major Statin Trials
Percentage of women
Age [average] (y)
35-69 [58]
21-75 [59]
31-75 [53]
45-64 [55]
CHD inclusion criteria
with acute MI
without MI
No. of patients
Average follow-up period (y) 5.4
1 p<0.05
2

Baseline lipid levels (mg/dl)
p<0.01
3 p<0.001
Total cholesterol
HDL cholesterol
LDL cholesterol
Triglyceride
Risk reduction (%)
Nonfatal MI and
death from CHD
Nonfatal and fatal stroke

Total mortality
Risk reduction in major statin trials
This slide shows the main characteristics of the major primary (WOSCOPS) and sec-ondary (4S, CARE, LIPID) coronary heart disease prevention trials that used statins.
The important point to note is that in the secondary prevention trial statins signifi-cantly reduced stroke incidence across a wide range of baseline cholesterol levels.
International Task Force for Prevention of Coronary Heart DiseaseStrokeSlide Kit 1:Primary prevention of stroke Slide 10:
Stroke:
Effects of statins on stroke type. Prospective Pravastatin Pooling Project

Effects of Statins on Stroke Type
Prospective Pravastatin Pooling Project
Non-fatal stroke (n)
Non-hemorrhagic (156)
Hemorrhagic (14)
Unknown (24)
Fatal stroke (n)
Non-hemorrhagic (18)
Hemorrhagic (5)
Unknown (8)
favors treatment
Hazard ratio (95% CI)
favors placebo
Data available from CARE + LIPID (13173 patients)
Source: Byington et al.;Circulation 2001, 103:387-392
Effects of statins on stroke type. Prospective Pravastatin Pooling Project
This slide shows that the reduced risk for stroke observed in the secondary preventiontrials CARE and LIPID was due to a reduction in nonfatal non-hemorrhagic stroke,the predominant type of stroke.
International Task Force for Prevention of Coronary Heart Disease Slide 11:
Stroke:
Effects of statins on stroke and coronary events in older patients -
the CARE trial

Effects of Statins on Stroke and Coronary
Events in Older Patients - the CARE Trial
Patients 65-75 years
Major coronary event**
Coronary death or
non-fatal myocardial infarction
Patients < 65 years
Major coronary event**
Coronary death or
non-fatal myocardial infarction0

* p<0.05 for Pravastatin vs Placebo
** death from CAD, nonfatal MI,

Number needed to treat for 5 years to prevent 1 event
CABG, or PTCA
Source: Lewis et al. for the CARE Investigators;Ann Int Med. 1998, 129:681-689
Effects of statins on stroke and coronary events in older patients -
the CARE trial

This slide shows the number of patients needed to treat for 5years to prevent onestroke or coronary event in the CARE study population. In patients aged 65-75 yearswho had had a myocardial infarction and cholesterol levels in the average range,pravastatin was associated with a clinically important reduction in risk for major coro-nary events and stroke. Given the high stroke rate in older patients, the potential forabsolute benefit in this age group is substantial.
International Task Force for Prevention of Coronary Heart DiseaseStrokeSlide Kit 1:Primary prevention of stroke Slide 12:
Stroke:
Protective effects of statins on ischemic stroke

Protective Effects of Statins on
Ischemic Stroke
Downstream effects
Stabilization of precerebral atherosclerotic plaques
Favorable hemorheological and antithrombotic effects
Upstream effects
Preserved blood flow and limited neurological loss by
simultaneous
Upregulation of endothelial nitric oxide synthase (eNOS)
Inhibition of inducible nitric oxide synthase (iNOS)
Attenuated inflammatory neuronal loss
Antioxidant properties
Sources: C.J. Vaughan and N. Delanty;Stroke 1999, 30:1969-1973
Protective effects of statins on ischemic stroke
This slide shows which mechanisms are currently thought to play a role in the preven-tion of stroke by statins. These include downstream effects and neuroprotective prop-erties of statins that likely attenuate the effects of ischemia on the brain vasculatureand parenchyma.
International Task Force for Prevention of Coronary Heart Disease Slide 13:
Stroke:
Statins and prevalence of Alzheimer’s disease

Statins and Prevalence of
Alzheimer´s Disease
Medication (n)
Lovastatin (4.180)
Ptavastatin (2.326)
Lovastatin + Pravastatin (6.506)
Simvastatin (3.580)
Captopril (4.616)
Fuxosemide (15.106)
Atenolol (5.340)
Metoprolol (3.799)
Propanolol (1.256)
β-Blocker combination (10.395)
Prevalence of Alzheimer´s Disease
* significantly different from Lovastatin + Pravastatin (p<0.01)
Source: Wolozin et al. Arch Neurol. 2000, 57:1439-1443
Statins and prevalence of Alzheimer’s disease
This slide shows that the neuroprotective properties of statins may also contribute tothe prevention of Alzheimer’s disease. In a cross-sectional analysis of patients receiv-ing different medications for treating cardiovascular disease, the prevalence of prob-able Alzheimer’s disease in those taking Lovastatin or Pravastatin was 60 to 73%lower than in the total patient population.
International Task Force for Prevention of Coronary Heart DiseaseStrokeSlide Kit 1:Primary prevention of stroke Slide 14:
Stroke:
Statins and risk of dementia

Statins and Risk of Dementia
Use of lipid-lowering agents (LLA)
None, normal lipids
Hyperlipidemia alone
(no drug treatment)

Current use of statins
Current use of other LLA
Past use of other LLA
favors treatment
Relative risk (95%) for dementia*
favors placebo
*adjusted for : body mass index, smoking, hypertension, previous history of coronary artery disease,
coronary-artery bypass, diabetes mellitus, and transient cerebral ischemia
Source: Jick et al. Lancet 2000, 356:1627-1631
Statins and risk of dementia
This slide shows results from another study indicating that statins may reduce the riskof developing dementia. This nested case-control study included data from patientsreceiving lipid-lowering agents, individuals with a clinical diagnosis of untreated hy-perlipidemia and a randomly selected group of other individuals among whom caseswith dementia were identified and matched with up to four controls. Individuals whowere prescribed statins had a substantially lowered risk of developing dementia. Theavailable data do not distinguish between Alzheimer’s disease and other forms of de-mentia.
International Task Force for Prevention of Coronary Heart Disease Slide 15:
Stroke:
Effects of fibrates on stroke types in men with CHD and low HDL-cholesterol

Effects of Fibrates on Stroke Types
in Men with CHD and Low HDL-Cholesterol
Ischemic strokes
Gemfibrozil
Atherothrombotic
Cardioembolic
Hemorrhagic strokes
Number of first strokes
Overall, relative risk reduction adjusted for baseline variables was 31% (2-52%)
Sources: Bloomfield Rubins et al. for the VA-HIT Study Group;Circulation 2001, 103:2828-2833
Effects of fibrates on stroke types in men with CHD and low HDL-cholesterol
Persons with coronary heart disease who have a low HDL-cholesterol and a low LDL-cholesterol level are commonly treated with fibrates. This slide shows that mentreated with fibrates for 5years also had a reduced incidence of ischemic stroke,namely atherothrombotic strokes.

Source: http://ww.chd-taskforce.com/pdf/sk_stroke_01.pdf

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