1. Section I: RAS manipulation
D. Reducing stroke risk
Well-documented modifiable risk factors for stroke
Content points:
Several well-documented risk factors for stroke can be modified by treatment, among which are hypertension, smoking, diabetes, asymptomatic carotid stenosis, hyperlipidemia, and atrial fibrillation.21
Hypertension is the modifiable risk factor most strongly correlated with the incidence of stroke. People with hypertension have a risk of stroke that is four to six times higher than the risk among those without hypertension. Antihypertensive therapy decreases the risk of stroke nearly 40%.
Current smokers have a nearly 2-fold increased risk of stroke. Smoking cessation reduces the risk of stroke by 50% within a year and completely by 5 years.
Diabetes is an independent risk for ischemic stroke, with the increase in risk ranging from 1.8 to nearly 6-fold. High blood pressure is present in about 40% to 60% of adults with type 2 diabetes. Recent studies indicate that tight control of hypertension significantly reduces stroke incidence. Although current means of tight glucose control are less effective for stroke control, tight glucose control is important to reduce microvascular complications.
Asymptomatic carotid stenosis doubles the risk of stroke: treatment can reduce this risk by 50%. Carotid stenoses of >50% are probably present in ~10% of men and ~ 7% of women.
Nonvalvular atrial fibrillation increases the risk of stroke by as much as four times, depending on the patient’s age and concomitant risk factors. Combined analysis of five trials investigating the efficacy of warfarin in primary prevention of thromboembolic stroke showed the relative risk for stroke was reduced 68% in patients treated with warfarin. These studies have shown that aspirin reduces the risk of stroke by 21%.
Hyperlipidemia increases the risk of stroke by about two to three times compared with normal lipid levels. The role of cholesterol in stroke has been recognized as a result of trials that have shown significant reductions (20% to 30%) in stroke risk with statin therapy in CHD patients.

2. Influence of hypertension on carotid atherosclerosis Content points:
Extracranial carotid artery (ECCA) atherosclerosis has been associated with hypertension-related stroke. Su and colleagues studied determinants of carotid atherosclerosis in Taiwanese men with hypertension (146), borderline hypertension (n = 117), and normal blood pressure (n = 270).22
Carotid atherosclerosis was measured by high-resolution B-mode ultrasonography and expressed as maximum intima-media thickness (IMT) of the common carotid artery, ECCA plaque score, and carotid stenosis >50%.
As shown on the slide, risk factors and ECCA atherosclerosis were stratified by blood pressure status. The severity of carotid atherosclerosis, as determined by maximum carotid intima-media thickness (IMT) >75th percentile, ECCA plaque score >6, and carotid stenosis >50%, increased significantly with hypertension.
Multivariate logistic regression identified hypertension (including borderline), male gender, smoking, and age >65 years as significantly increasing the risk of thicker IMT. Hypertension, smoking, age >65, and left ventricular hypertrophy on ECG increased the risk of ECCA plaque score >6. The only determinants of >50% carotid stenosis were hypertension and smoking.
The study showed hypertension to be the most consistent and important risk factor for carotid atherosclerosis. These findings reinforce the importance of hypertension as having a major pathogenic role in atherosclerosis.

3. PROGRESS: Effect of ACEI-based BP reduction on stroke
Content points:
Blood pressure is a determinant of stroke among both hypertensive and nonhypertensive individuals with cerebrovascular disease, but there is uncertainty about the efficacy and safety of treatment to lower blood pressure for many of these patients.
The Perindopril Protection Against Recurrent Stroke Study (PROGRESS) evaluated the effects of an ACE-inhibitor-based blood pressure-lowering regimen in patients with a history of stroke or transient ischemic attack (TIA). Both hypertensive and nonhypertensive patients with a history of stroke or TIA were enrolled.23
Patients were randomly assigned to active treatment with perindopril 4 mg daily (n = 1281) or a combination of perindopril 4 mg and indapamide 2.0 to 2.5 mg (1770), or to placebo (n = 3054).
The primary outcome was total stroke (fatal or nonfatal). As shown, after more than 4 years the risk of stroke was reduced in all patients on active treatment by 28% (P < ).

4. PROGRESS: Similar reductions in events regardless of BP status
Content points:
Subgroup analysis of the PROGRESS results revealed that stoke risk and major vascular risk were reduced similarly in patients classified as nonhypertensive (mean blood pressure at entry was 136/79 mm Hg) and hypertensive (blood pressure was >160/>90 mm Hg).23
The investigators concluded that the blood-pressure–lowering treatment reduces the risk of stroke in both hypertensive and nonhypertensive patients with a history of stroke or TIA.

5. PROGRESS: Differing effects of combination and single-drug regimens
Content points:
Combination therapy with perindopril and indapamide produced larger blood pressure reduction and larger risk reductions than did single drug therapy with perindopril alone.23
Combination therapy reduced blood pressure by 12/5 mm Hg and produced stroke risk by 43%. Perindopril alone reduced blood pressure by 5/3 mm Hg and stroke risk by 5%.

6. Stroke risk reduction in HOPE and PROGRESS
Content points:
This slide shows risk reductions in comparable stroke categories in the HOPE and PROGRESS studies, including total stroke, ischemic stroke, hemorrhagic stroke, and fatal stroke.15,23
In the HOPE study, blood pressure was lowered by 3/2 mm Hg. In PROGRESS, active treatment in all patients reduced blood pressure by 9/4 mm Hg.15 Reductions in stroke in the HOPE study are not fully explained by blood pressure reductions.

7. Stroke risk reduction in clinical trials with ACE inhibitors
Content points:
The efficacy of ACE inhibitors in decreasing stroke risk as an antihypertensive has been well established in trials involving patients with high blood pressure: the Swedish Trial in Old Patients with hypertension (STOP-2), the UK Prospective Diabetes Study (UKPDS) in hypertensive diabetic patients, and recently, in PROGRESS (as discussed on the preceding slides) Recently, the HOPE study demonstrated the role of ramipril in stroke prevention that was not fully explained by blood pressure reduction.15
In the HOPE study, treatment with ramipril 10 mg significantly lowered the risk of stroke by 32% in patients at high-risk due to any type of vascular disease or diabetes and another cardiovascular risk factor. Of patients enrolled in the study, 53% did not have high blood pressure (mean entry blood pressure was 139/78 mm Hg) or their blood pressure was controlled prior to entering the study to <160/<90 mm Hg. Blood pressure in patients treated with ramipril was lowered a modest 3/2 mm Hg. Notably, the reduction in stroke with ramipril was in addition to other effective cardiovascular therapies that many patients were taking, including aspirin, diuretics, ß-blockers, and statins.

8. AHA primary stroke prevention guidelines: Lifestyle modifications
Content points:
Recent guidelines from the American Heart Association (AHA) describe appropriate interventions that can be implemented to treat, control or modify specific risk factors with the goal of reducing the risk of a first stroke.26 This slide summarizes recommendations for lifestyle modifications.
Smoking: Simply put, the AHA recommends smoking cessation. Active cigarette smoking has long been recognized as a risk factor for stroke.
Physical activity: The beneficial effects of physical activity have been documented for stroke in numerous epidemiological studies. Regular exercise of >30 minutes of moderate-intensity activity daily helps reduce comorbid conditions that can lead to stroke.
Diet: A healthy diet containing at least 5 daily servings of fruits and vegetables may reduce the risk of stroke. In the Nurses Health Study and the Health Professionals Follow-up Study that had people free of CHD at baseline, persons in the highest quintile of fruit and vegetable intake had 31% fewer strokes.26 An increment of 1 serving a day was associated with a 6% lower risk of stroke.
Alcohol: The effect of alcohol as a risk factor for ischemic stroke is controversial and likely dose dependent. There is a J-shaped dose-response curve between alcohol intake and ischemic stroke risk, with protection for those drinking up to 2 drinks a day and an increased risk for those drinking >5 drinks a day. Recommendations are for <2 drinks a day for men and <1 drink a day for women.
Drug abuse: Adjusting for other potential risk factors, some studies have found an ~7-fold increase in stroke risk among drug abusers, although another study found no significant risk.27 An in-depth history of substance abuse should be part of a complete health evaluation for all patients and the patient should be referred for appropriate counseling.

9. AHA primary stroke prevention guidelines Content points
This slide summarizes treatment recommendations for major modifiable risk factors for stroke.21
Diabetes: Careful control of hypertension to a target level of <130/80 mmHg significantly reduces stroke incidence in persons with diabetes and it is recommended. Glycemic control is less effective in reducing the risk of stroke but it is effective to reduce microvascular complications, nephropathy, and retinopathy, as well as peripheral neuropathy.
The HOPE study provides long-sought evidence for stroke prevention in diabetics.15 The ACE inhibitor ramipril 10 mg (compared with a standard medical regimen) reduced the risk of vascular outcomes, including MI, stroke, and cardiovascular death by 25%. In the MICRO-HOPE study, which included 3791 participants with diabetes and one additional risk factor, ramipril reduced the risk of stroke by 33%.28 Treatment also reduced the risk of diabetic complications including overt nephropathy, dialysis, or need for laser therapy.
Hyperlipidemia: Patients should be managed according to ATP III guidelines.20 For patients with prior CHD, LDL-C is targeted at <100 mg/dL. If LDL-C is >130 mg/dL, statin therapy should be considered along with lifestyle recommendations for smoking cessation, weight loss, diet, and exercise.
Atrial fibrillation: Antithrombotic therapy, with warfarin or aspirin, should be considered for patients with nonvalvular atrial fibrillation based on an assessment of the patient’s risk of embolism and of bleeding complications.
Asyptomatic carotid stenosis: Carotid endarterectomy may be considered in patients with high-grade asymptomatic carotid stenosis. It should be performed by a surgeon/institution with a <3% mortality/morbidity rate. Patients should be selected carefully, and the risks and benefits thoroughly discussed.