Primary and Secondary Prevention of Stroke

Apart from surgical and interventional therapy of occlusive carotid artery disease, the major approach to preventing vascular disease and subsequent stroke is to pay close attention to the control of modifiable risk factors such as hypertension, smoking, diabetes, and hypercholesterolemia. Coumadin, an anticoagulant, is effective for the primary and secondary prevention of stroke in patients with atrial fibrillation. Aspirin, clopidogrel, and the combination of aspirin and cUpyridamole have been proven to be effective for secondary stroke prevention along with the antihypertensive combination of indap-amide and perindopril. 

Many aspects of the role of inflammadon and the immune system in sdoke remain condoversial (Chamorro and Hallen-beck, 2006). However, more refined characteiizadon of immune responses after sdoke may suggest new and different therapeutic targets for acute ischemic sdoke, in addidon to novel approaches that are ongoing for the prevendon of cardiovascular disease. 

Immune cells involved in the evolution of ischemic brain lesions include  

hmnune cells involved in sti oke-i elated infla]mna.tion stroke ai e pi edominantly deiived from the cii culating blood. 

Leukocyte infiltration across the blood brain bariier after ischemic stroke is dependent on the expression of adhesion molecules on leukocytes and endothelial cells. 

Immune cells involved in stroke-related inflammation stroke are predominantly derived from the circulating blood. 

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Warfarin has not been adequately studied in non-cardioembolic stroke, but it is often recommended in patients after antiplatelet agents fail. One small retrospective study suggests that warfarin is better than aspirin.30 More recent clinical trials have not found oral anticoagulation in those patients without atrial fibrillation or carotid stenosis to be better than antiplatelet therapy. In the majority of patients without atrial fibrillation, antiplatelet therapy is recommended over warfarin. In patients with atrial fibrillation, long-term anticoagulation with warfarin is recommended and is effective in both primary and secondary prevention of stroke.12 The goal International Normalized Ratio (INR) for this indication is 2 to 3. 

Blood pressure lowering is effective in both the primary and secondary prevention of both ischemic and hemorrhagic stroke regardless of blood pressure. 

Five randomized primary and secondary prevention trials " have demonstrated the efficacy and safety of warfarin in preventing AF-related stroke. Pooled data from these trials demonstrated a 68% reduction in ischemic stroke (95% Cl 50-79) and an intracerebral hemorrhage rate of <1% per year. The data for aspirin suggested that it had a lesser effect, with a 36% risk reduction (95% Cl 4—57). 

In view of the perceived benefit of aspirin in the secondary prevention of stroke and myocardial infarction, two large trials involving physicians as subjects were initiated to study the effect of aspirin in the primary prevention of arterial thrombosis. In the American study, 22,000 volunteers (age 40 to 84 years) were randomly assigned to take 325 mg of aspirin every other day or placebo. The trial was halted early, after a mean follow-up of 5 years, when a 45% reduction in the incidence of myocardial infarction and a 72% reduction in the incidence of fatal myocardial infarction were noted with aspirin treatment. However, total mortality was reduced only 4% in the aspirin group, a difference that was not statistically significant, and there was a trend for a greater risk of hemorrhagic stroke with aspirin. Thus, the prophylactic use of aspirin in an apparently healthy population is not recommended at this time, unless there are risk factors for cardiovascular disease. 

Some of the association between atrial fibrillation and stroke must be coincidental because atrial fibrillation can be caused by coronary and hypertensive heart disease, both of which may be associated with atheromatous disease or primary intracerebral hemorrhage. Although anticoagulation markedly reduces the risk of first or recurrent stroke, this is not necessarily evidence for causality because this treatment may be working in other ways, such as by inhibiting artery-to-artery embolism, although trials of warfarin in secondary prevention of stroke in sinus rhythm have shown no benefit over aspirin (Ch. 24). 

Currently, the two antiplatelet agents with proven efficacy are aspirin, which inhibits cyclooxygenase -dependent synthesis of thromboxane Aj (TXj ), and ticlopidine, wdrich blocks the ability of ADP to inhibit stimulated adenyl cyclase. Bodi of these drags have proven prophylactic uses in reducing the risk of thrombo -occlusive and thromboembolic complications for all major arterial beds in individuals with a previous history of such episodes. Controlled trials show that both aspirin and ticlopidine are indicated in the secondary prevention of stroke, myocardial induction and peripheral vascular occlusion. However, there are limitations to their efficacy. No net changes in vascular events are seen with primary prevention. Moreover, antiplatelet drugs do not alter thrombocytopenia or impairment... 

Although there is clear evidence of benefit of acetylsalicylic acid (aspirin) in secondary prevention of strokes and heart attacks, the question of whether aspirin should also be prescribed for primary prevention in asymptomatic people is still debatable. Trials in primary prevention have given contrasting results (9,10), and aspirin can cause major harms (for example severe gastrointestinal bleeding and hemorrhagic stroke). 

Overall, single and combination HT in both primary and secondary prevention conferred no protective effects for all mortality causes, CVD death, nonfatal MI or angina. However, the study found an increased risk of stroke (relative risk, RR=1.26 95% Cf=l.ll, 1.43), venous thromboembolic events (VTEs RR=1.89 95% Cl = 1.58, 2.26), and pulmonary embolism (RR=1.84 95% Cl = 1.42,2.37) relative to placebo for both primary and secondary prevention when combination and single HT was combined. Therefore, the authors concluded that HT in postmenopausal women does not prevent CVD events, and causes an increase in the risk of stroke and VTEs [8 ]. 

Secondary prevention of death, reinfarction, and stroke is more cost effective than primary prevention of coronary heart disease events. 

The goals of treatment of acute stroke are (1) to reduce the ongoing neurologic injury and decrease mortality and long-term disabihty, (2) prevent complications secondary to immobility and neurologic dysfunction, and (3) prevent stroke recurrence. Primary prevention of stroke is reviewed elsewhere. ... 

Cardiovascular disease (CVD) remains the most important cause of morbidity and mortality in people with diabetes [1], This high-risk population is more likely to suffer a fatal event as the first manifestation of myocardial infarction (MI) or stroke, making primary prevention a priority. The pathogenesis of atherosclerosis-related disease is multifactorial but dyslipidaemia is a common and important risk predictor and is open to therapeutic intervention. Pharmacological intervention is supported by major randomised, controlled clinical trials (RCTs) of primary and secondary CVD prevention. RCTs with statin drugs have demonstrated unequivocal benefit in reducing major coronary events and stroke. 

An important further conclusion from the statin nails for both primary and secondary CVD prevention is the impact on stroke. Meta-analysis of the early... 

The goal of transfusions is to achieve and maintain an HbS concentration of less than 30% of total hemoglobin. Frequency of transfusions is adjusted to maintain the desired HbS levels and is usually every 3 to 4 weeks. After 4 years of therapy without development of complications, many clinicians give transfusions less frequently and allow the HbS concentration to rise to 50% of total hemoglobin." " The optimal duration of chronic transfusion therapy is not known. For secondary prevention, current recommendations are to continue transfusion for at least 5 years or until age 18. A study is underway to determine when transfusions can be safely stopped for primary stroke prevention. ... 

The results of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was the deciding evidence that the JNC7 used to justify thiazide diuretics as first-line therapy." It was designed to test the hypothesis that newer antihypertensive agents (an a-blocker, ACE inhibitor, and dihydropyridine CCB) would be superior to thiazide diuretic therapy. The primary objective was to compare the combined end point of fatal coronary heart disease and nonfatal myocardial infarction. Other hypertension-related complications (e.g., heart failure and stroke) were evaluated as secondary end points. This was the largest hypertension trial ever conducted and included 42,418 patients aged 55 years and older with hypertension and one additional cardiovascular risk factor. This prospective, double-blind trial randomized patients to chlorthalidone (a thiazide diuretic), amlodipine (dihydropyridine CCB), doxazosin (a-blocker), or lisinopril (ACE inhibitor) for a mean follow-up of 4.9 years. 

The doxazosin arm was terminated early when a significantly higher risk of heart failure compared with chlorthalidone was observed." The other arms were continued as scheduled, and no significant differences in the primary end point were seen between chlorthalidone and either lisinopril or amlodipine. However, chlorthalidone had statistically fewer secondary end points than amlodipine (heart failure) and lisinopril (combined cardiovascular disease, heart failure, and stroke). The study conclusions were that chlorthalidone was superior in preventing one or more major forms of cardiovascular disease and was less expensive than amlodipine and lisinopril. 

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