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Stroke is a major public health burden

Third leading cause of death: >150,000/year in US
> 750,000 symptomatic strokes per year in US, >11 million silent strokes/year
The leading cause of serious disability in the United States
> 4 million stroke survivors alive in the US today
Economic impact: estimated 1998 cost in US $43.3 billion
Aging population: Risk of stroke ~ doubles with each decade of life

Overview of stroke risk factors and impact on prevention
The best approach to reducing the burden of stroke remains prevention. Unfavorable trends in stroke risk factor profile, lack of prevention programs, lack of awareness of stroke risk factors and warning signs by the public, and misapplication or underutilization of stroke prevention therapies have contributed to persistently high stroke rates and served to widen the stroke trial - practice prevention gap. Secondary prevention medical therapies are underutilized in patients with established stroke and transient ischemic attack receiving standard medical care. There are several modifiable stroke risk factors, the control of which would result in significant decreases in recurrent stroke rates. It is now quite clear that high-risk or stroke-prone individuals can be selectively identified and targeted for specific medication and behavioral interventions. Medical treatments and behavioral therapies that target the underlying atherosclerosis disease process can markedly lower the risk of recurrent cerebrovascular ischemic events and death.

1. Traditional interventions
These interventions have proven efficacy in the prevention of recurrent stroke but optimal application of these measures in primary stroke and transient ischemic attack patients remains a challenge thus placing large numbers of patients at unnecessarily high risk.

Antithrombotics: Antiplatelet agents are the treatment of choice for prevention of future stroke in patients who have experienced a primary stroke or transient ischemic attack of atherothrombotic origin. Atherosclerosis produces cerebral ischemia through large vessel disease and intracranial branch (lacunar) disease. There are four antiplatelet agents which based on various trials have shown efficacy in preventing stroke in patients with cerebrovascular disease. Current guidelines recognize aspirin, clopidogrel, and aspirin/dipyridamole as first-line agents, and suggest ticlopidine as only a second line agent due to neutropenic and TTP side effects. In head to head trials, both clopidogrel and aspirin/dipyridamole reduced vascular events to a greater degree than aspirin alone. Practice studies suggest that only 70-90% of TIA and ischemic stroke patients with indications for antiplatelet therapy are discharged on antiplatelet agents. Clinical trial data and national guidelines suggest that all patients with an atherothrombotic stroke or TIA should receive daily therapy with an antiplatelet agent to reduce the risk of recurrent stroke.

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The annual risk of stroke in patients with nonvalvular atrial fibrillation is 3%-5% with the condition being responsible for 50% of cardioembolic strokes. Adjusted-dose oral anticoagulation with warfarin is the therapy of choice for stroke prevention in patients with atrial fibrillation who have had a stroke or transient ischemic attack. The superior efficacy of anticoagulation over aspirin for prevention of stroke in patients with atrial fibrillation and a recent TIA or minor stroke was shown in the European Atrial Fibrillation Trial. The relative risk of thromboembolic strokes for patients treated with warfarin was reduced by 68% in a combined analysis of 5 placebo-controlled trials investigating the efficacy of warfarin. National guidelines suggest that warfarin with a target INR of 2.0 to 3.0 is indicated in all patients with atrial fibrillation and TIA or ischemic stroke without strong contraindications to anticoagulation. However, only 40-60% of patients with atrial fibrillation and indications for warfarin are placed on anticoagulation in routine clinical practice.

· Smoking: Approximately 18% of strokes are attributable to active cigarette smoking. Smoking causes reduced blood vessel distensibility and compliance by leading to increased wall stiffness. In addition it is associated with increased fibrinogen levels, increased platelet aggregation, decreased high density lipoprotein cholesterol levels and increased hematocrit. The stroke risk associated with former smoking has been shown to substantially decrease with increasing time since cessation. The Framingham study found stroke risk to be at the level of nonsmokers at 5 years from cessation. Based on these and other cohort and epidemiological studies, a consensus committee of healthcare professionals from the Stroke Council of the American Heart Association have recommended immediate smoking cessation advice to be given to all current smokers.

· Exercise: There are well established benefits of regular physical activity in stroke prevention. The protective effect of physical activity may be mediated in part through its role in controlling known stroke risk factors like hypertension, cardiovascular disease, diabetes and body weight. Other possible mechanisms including reductions in fibrinogen and platelet activity as well as elevations in plasma tissue plasminogen activator activity and HDL concentrations play a role. Guidelines endorsed by the Centers for Disease Control and Prevention and the National Institutes of Health recommend that Americans should exercise moderately for at least 30 minutes on most and preferably all days of the week. For stroke the benefits are apparent even for light to moderate activities such as walking and increasing the level and duration of one's recreational activity.

· Diet: There may be a protective relationship between stroke and the consumption of fruits and vegetables, especially cruciferous and green leafy vegetables and citrus fruit and juice. Analysis of data from the Nurses Health Study and Health Professionals Follow up Study found that an increment of 1 serving of fruit and vegetables was associated with a 6% lower risk of stroke. The American Heart Association recommends a diet emphasizing low cholesterol, low fat diet in conjunction with anticholesterol medications.

2. Emerging strategies
The realization that atherosclerosis is, in part, an inflammatory disease has led to a search for new stroke risk factors and treatments. Destabilization of the atheromatous plaque is a forerunner of ischemic stroke. This vulnerable plaque has become the main focus for new directions in prevention and treatment of cerebrovascular atherosclerosis.

Statins: Recent studies have shown that the risk of stroke and amount of carotid atheroma can be reduced with cholesterol lowering medications. Other recent studies utilizing ultrasound technology have established an association between lipid levels and extracranial carotid atherosclerosis and intimal-media thickness. Also clinical trials using serial ultrasound measurements showed that the reductions of elevations in LDL with B-hydroxy-B-methylglutaryl-CoA reductase inhibitors "statins" can modestly retard the progression of asymptomatic carotid atherosclerosis.

Trials using these agents have demonstrated consistent benefits in the reduction of stroke risk among individuals with coronary heart disease and elevated cholesterol levels, as well as those with only mild to borderline and normal cholesterol levels. Evidence from individual statin trials in patients with CHD and meta-analyses of these trials show that stroke risk is reduced by statin agents. The mechanism by which statins confer protection from stroke is uncertain and likely multifactorial, including lipoprotein alterations (upregulation of LDL receptor activity and reducing the entry of LDL into the circulation), improved endothelial function (upgrade endothelial nitric oxide synthase, inhibit inductible nitric oxide synthase), plaque stabilization, antithrombotic, attenuate the inflammatory cytokine reponses that accompany cerebral ischemia and possess antioxidant properties that ameliorate ischemic oxidative stress on the brain. In addition, statins may also have neuroprotective properties. The statins are generally well tolerated. Updated guidelines from the National Cholesterol Evaluation Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) includes a target goal of <100 mg/dl in persons with coronary heart disease or coronary heart disease risk equivalents. The latter include other clinical forms of atherosclerotic disease such as symptomatic carotid artery disease; diabetes mellitus; and multiple risk factors that confer a 10-year risk for CHD > 20%. Therefore patients with symptomatic atherosclerotic strokes are candidates for this level of lipid-lowering therapy.

Results of the Heart Protection Study suggest that around a third of all heart attacks and strokes can be avoided in people at risk of vascular disease by using statin drugs to lower blood cholesterol levels - irrespective of the person's age or sex, and even if their cholesterol levels do not seem high. It revealed that about 5 years of statin treatment typically prevents heart attacks, strokes or other major vascular events in 70 of every 1000 patients who've previously had a stroke. The benefits increased throughout the study treatment period (so a more prolonged therapy might be expected to produce even bigger benefits). The trial provided uniquely reliable evidence about the safety of a statin regimen, with no support for previous concerns about possible adverse effects of lowering cholesterol on particular non-vascular causes of death, on cancers or on strokes due to bleeding.

Hypertension: Hypertension is the most important modifiable risk factor for stroke. Patients with high-normal blood pressure or mild hypertension are at risk for stroke. Despite extensive education efforts, a significant proportion of the population has undiagnosed or inadequately treated hypertension. Stroke incidence rates increase in proportion to both systolic and diastolic blood pressures in a "direct, continuous, and apparently independent" manner. Elevated systolic blood pressure with or without an accompanying rise in diastolic pressure has also been shown to increase stroke risk. Compelling evidence has revealed that control of high blood pressure contributes significantly to the prevention of stroke. Recent clinical trials have confirmed that blood pressure reduction following first stroke substantially reduces the risk of recurrent stroke, and have further suggested that even high normotensive stroke patients benefit from additional treatment with ACE inhibitors and diuretics.

· Ace Inhibitors: Hypertension may predispose to stroke by facilitating atherosclerosis of the aorta and large cerebral arteries, causing arteriosclerosis and lipohyalinosis of small-diameter penetrating arteries and promoting heart disease. Angiotensin converting enzyme inhibitors (ACE-I) act on the renin-angiotensin-aldosterone system by blocking the conversion of angiotensin I to angiotensin II by inhibiting the angiotensin converting enzyme. Physiological and pathological studies in hypertensives receiving ACE-I have shown that vascular compliance increases after therapy as well as regression of periarteriolar collagen area, total interstitial collagen volume density and slight reduction in the arteriolar wall area in coronary arterioles with improvement in coronary reserve. There is also normalization of resistance artery structure.

The HOPE trial showed that ACE inhibition with ramipril significantly reduced the relative risk of stroke by 30%. It also revealed that the blood pressure difference in the ramipril treatment group of about 3 mm Hg systolic and 2 mm Hg diastolic accounted for only 40% of the benefit in reducing stroke, suggesting that the stroke prevention effects of ACE inhibitors may not be ascribed solely to blood pressure reduction. The PROGRESS trial showed that the use of the ACE inhibitor perindopril and the diuretic indapamide yielded a relative reduction in the primary outcome endpoint of total recurrent stroke of 43%. The most impressive benefits for stroke reduction occurred amongst those taking perindopril plus indapamide combination therapy. In both HOPE and PROGRESS non hypertensives benefited from ACE-I therapy. The LIFE trial compared treatment with an angiotensin receptor blocker and a beta-blocker. Both reduced blood pressure to a roughly equal degree, but the ARB reduced stroke rates by 25% more, providing further evidence that renin-angiotensin-aldosterone agents are distinctively beneficial in stroke prevention.

Diuretics: The PROGRESS trial showed that the use of the ACE inhibitor perindopril and the diuretic indapamide yielded a relative reduction in the primary outcome endpoint of total recurrent stroke of 43%. The most impressive benefits for stroke reduction occurred amongst those taking perindopril plus indapamide combination therapy. In addition, the findings of the Post-stroke Antihypertensive Treatment Study (PATS) showed that in patients with a history of stroke or TIA, blood pressure reduction of 5/2 mmHg with 2.5 mg indapamide reduced the first incidence of fatal and nonfatal stroke by 29%, with a three-year absolute benefit of 29 events per 1000 participants.

· Patient Education: The American Heart Association, the National Stroke Association, the National Institute of Neurological Disorders and Stroke, and other major health organizations have emphasized educating the public regarding the signs, symptoms, and risk factors for stroke. Despite current educational campaigns, public knowledge remains inadequate. Previous surveys of the general public suggest that up to 27% of the adult population do not know a single sign or symptom of a stroke and up to 25% do not know a single risk factor. This number is even larger in those patients who have actually had a stroke. Immediately after having an acute stroke, 43% of acute stroke patients in one study did not know a single sign or symptom of a stroke. It is clear from all these studies that to improve the outcomes of stroke patients, patient education is crucial.