ࡱ> QSNOP` Z(bjbjss .,2,,,,,,,"NgNgNgNgdg$zjhiiiiiNi4jKzMzMzMzMzMzMz$Z|h~qz9,8jii8j8jqz,,iizjjj8j^,i,iKzj8jKzjjrtT,,uih l|zJmNgjtGuz0zujuu,#u$8j8jj8j8j8j8j8jqzqzj8j8j8jz8j8j8j8j&@&@@4,,,,,, Stroke: Effective Strategies for Secondary Prevention Louis Caplan, MD and Howard Kirshner, MD Louis Caplan, MD, is Chief of the Division of Cerebrovascular Diseases at Beth Israel Deaconess Medical Center, and Professor of Neurology at Harvard Medical School, Boston. Howard Kirshner, MD, is Professor and Vice Chair of Neurology at Vanderbilt University Medical Center, Nashville. Stroke remains the third leading cause of death in the United States, and evidence suggests that available and proven effective methods for its diagnosis, prevention, and treatment are underused. Most strokes are preventable and primary prevention strategies aimed at reducing modifiable risk factors and identifying treatable conditions, such as atrial fibrillation, remain paramount. Education of high-risk patients with respect to stroke warning signs is also essential. Urgency is the focus in acute ischemic stroke and adequate treatment of the first ischemic insult may have a significant impact on reducing recurrence risk. Nevertheless, patients who have experienced an ischemic stroke or transient ischemic attack remain at the highest risk of stroke. Recent studies have revealed that the incidence of short-term stroke recurrence is substantially higher than previously realized in these patients. Thus, secondary prevention measures should be implemented as early and aggressively as possible after the index event. In-hospital initiation of secondary prevention strategies should be considered. Drugs such as statins, antihypertensives, antithrombotic agents, and methods such as endarterectomy or stenting, can prevent a second stroke. In particular, all patients who have experienced noncardioembolic stroke should be placed on a regimen of antiplatelet agents, such as aspirin plus extended-release dipyridamole. INTRODUCTION Stroke is the third leading cause of death in the United States and a major cause of disability.1,2 Over 700,000 strokes occur each year, or slightly more than one per minute, and 70% of these are first strokes.1,3,4 The financial burden created by stroke is high; direct (eg, hospital and physician care) and indirect costs (eg, lost productivity) are estimated at $57 billion in 2005.1 Enormous progress has been made in diagnostic technology and new therapeutic options for prevention and treatment of stroke over the past 20 years, such as newer magnetic resonance imaging (MRI) techniques, helical computed tomography (CT), duplex extracranial ultrasound, and newer and more effective antiplatelet agents and antihypertensives. Despite this progress, recent evidence suggests that mortality from stroke is no longer on the decline and the incidence of stroke is again on the rise.3,5 These data suggest shortcomings in present methods for preventing and treating stroke or suboptimal application of available treatments.6 Stroke prevention is not like a cure for cancer, awaiting a scientific breakthrough but rather a matter of applying readily available, proven therapies to patients at risk. Updating knowledge about recent diagnostic/therapeutic advances and appropriate use of these advances may facilitate a more favorable prognosis for the future. While the main focus of this review is on secondary stroke prevention, key considerations pertaining to primary stroke prevention will also be addressed. PRIMARY PREVENTION Most strokes are preventable. The essence of primary prevention is reduction of as many modifiable risk factors as possible and evaluation of potentially treatable lesions/conditions, such as carotid artery disease and atrial fibrillation (AF).  HYPERLINK "http://www.jobsoneducation.com/clinicianscme/print.asp?page=courses/105162/lesson.htm" \l "Table1" Table 1 presents risk factors for ischemic stroke, stratified by strength of evidence and modifiability. Patients who have had a prior transient ischemic attack (TIA) or ischemic stroke are at the highest risk for stroke. In a relatively large cohort study, Johnston et al7 reported that 180 of 1,707 patients (10.5%) diagnosed with TIA in an emergency department returned with a stroke within a 90-day period. Stroke occurred in 91 of these patients (5%) within 48 hours of the index TIA. For this reason, TIA should be considered a medical emergency and immediate testing for preventable causes of stroke is advised. PRIMARY PREVENTION GUIDELINES A menu for risk factor modification in primary prevention is: Treat hypertension. Correct dyslipidemia (diet, drug therapy). Eliminate smoking. Eliminate heavy alcohol use (moderate alcohol use may be protective against total and ischemic stroke).8 Engage in an exercise program. Detect and treat cardiac disease, including AF, which accounts for 15% of all strokes in the US.9 Detect and treat asymptomatic carotid artery stenosis (consider endarterectomy).3 Control diabetes mellitus. Use aspirin to prevent a first MI in men10 and stroke in women.11 Recommendations of the American Heart Association (AHA) for primary prevention are available.3 Effective management of hypertension alone can reduce stroke incidence by as much as 70%.12 No specific antihypertensive agent of choice has emerged, however, and ensuring control of blood pressure may be more important than the specific class of antihypertensive agent used. Table 1 Stroke Risk Factors and Their Modifiability*1-3,7,12 Nonmodifiable Age: Advancing; doubles in each decade after age 55 Gender: More prevalent in men; however, rate of stroke-related case fatality higher in women Race/Ethnicity: African-Americans/Hispanics have higher risk/mortality rates than do whites Heredity: Maternal and paternal history may increase risk; fivefold increase in stroke prevalence in monozygotic vs dizygotic twins Modifiable, well-documented Prior TIA/stroke Cardiac disease Hypertension Atrial fibrillation Diabetes mellitus Asymptomatic carotid stenosis Cigarette smoking Sickle cell disease Dyslipidemia Potentially modifiable/Less well-documented Alcohol abuse Hypercoagulability Drug abuse HRT/Oral contraceptives Obesity Inflammatory processes Poor nutrition Stress (?) Physical inactivity Sleep apnea (?) Hyperhomocysteinemia TIA, transient ischemic attack; HRT, hormone replacement therapy. * Well-documented and modifiable risk factors are supported by good epidemiologic data and modifiability in randomized clinical trials. Modifiable and/or less well-documented risk factors likely increase stroke risk but usually apply to small groups in the population; in some cases, modifiability has not been clearly demonstrated. Recent studies have demonstrated reduction in ischemic stroke/TIA risk in survivors of MI with HMG-CoA reductase inhibitors (statins).3,13,14 Pravastatin and simvastatin are approved for stroke reduction after MI. In general, statins are indicated for primary stroke prevention in selected patients with high low-density lipoprotein cholesterol (LDL-C) levels following MI and in patients in whom vascular studies identify atherosclerotic plaques within large arteries.2,15,16 New guidelines proposed by the National Cholesterol Education Program (NCEP) are that LDL-C levels be reduced to less than 100 mg/dL (2.6 mmol/L) in high-risk patients; in very high-risk patients less than 70 mg/dL (1.8 mmol/L) should be considered.15,16 Aggressive LDL-C reduction has been shown to decrease atherosclerosis progression in both carotid and coronary arteries.16 In patients with asymptomatic carotid artery stenosis, carotid endarterectomy is generally recommended if there is greater than 60% and less than 100% carotid stenosis. The Asymptomatic Carotid Atherosclerosis Study (ACAS) compared carotid endarterectomy plus medical therapy with medical therapy alone in patients with high-grade stenosis (> 60% diameter reduction). The study was stopped after median follow-up of 2.7 years because of the benefit of surgery. The estimated five-year aggregate risk for ipsilateral stroke, any perioperative stroke, or death was 5% in surgical patients and 11% in medical patients (53% relative risk reduction [RRR]).17 This amounts to an absolute risk reduction of approximately one case per 100 cases operated per year, and the operative morbidity and mortality of 2.4% should be taken into account before recommending surgery to asymptomatic patients. Carotid artery stenting with an embolus protection device has recently been used effectively as a less invasive approach for patients with asymptomatic or symptomatic carotid artery stenosis (see Secondary Prevention of Ischemic Stroke). Ischemic stroke in patients with AF is mainly due to cardiac (cardiogenic) embolism, and patients with AF have at least a four- to fivefold higher risk of stroke.9,18,19 Nonvalvular AF is the most common cause of cardiac emboli.19 AF is one of the few indications for warfarin in stroke patients. Five placebo-controlled primary prevention trials have evaluated the efficacy of warfarin to prevent acute ischemic stroke (AIS) in AF.3,9 Collectively, these trials showed that warfarin reduced annual ischemic stroke rates from 3.0% to 7.4% (control) to 0.4% to 3.4%; the relative risk of thromboembolic stroke was reduced by 68%. Although either aspirin or warfarin is recommended in AF by the AHA, based on risk factors and age, warfarin is more effective and preferred. Studies comparing aspirin with control groups indicated an RRR of 21% with aspirin. Comparisons of aspirin and warfarin demonstrated a significantly greater RRR with warfarin.9 CHADS2 risk scores represent an alternative to AHA recommendations for evaluating AF patients.20-22 An acronym derived from the risk factors of Congestive heart failure, Hypertension, Age greater than 75, Diabetes mellitus, and prior Stroke or transient ischemic attack, CHADS2 can reliably estimate the risk of stroke at the bedside and may assist in the selection of antithrombotic therapy. Two points are assigned for prior stroke or TIA, with one point given to the other risk factors ( HYPERLINK "http://www.jobsoneducation.com/clinicianscme/print.asp?page=courses/105162/lesson.htm" \l "Fig1" Figure 1). Patients with no points can be managed with aspirin, those with more than three points should receive warfarin, and those with one to two points can be managed at the clinicians discretion. The CHADS2 scheme has been validated in 1,733 Medicare beneficiaries with nonvalvular AF who were not receiving warfarin upon hospital discharge.20 These guidelines bear similarity to those provided in AHA guidelines.3 For secondary prevention, warfarin is indicated over aspirin in AF patients.23 INCLUDEPICTURE "CE%20Lesson_files/fig1.gif" \* MERGEFORMAT  Figure 1: CHADS2 Score Risk Stratification Scheme for AF 20,21 Relationship between CHADS2 score and annual risk of stroke. ASA, aspirin. Post-MI: Aspirin is recommended to prevent a second MI but is not routinely recommended for primary stroke prevention following MI.2 Warfarin is recommended after MI if other conditions are also present, such as AF, left ventricular thrombi, or significant left ventricular dysfunction.2 STROKE WARNING SIGNSAN OVERLOOKED PROBLEM Most patients who are having a stroke, and most bystanders witnessing the event, are unaware of initial stroke symptoms.24 Studies have also shown that those at highest risk of stroke, including African-Americans, the elderly (older than 75), and men, have the least knowledge about stroke warning signs and risk factors.1 Time is paramount for stroke victims, and lack of awareness of warning signs can delay potentially life-saving treatment. Greater education of the general public is needed; most importantly, clinicians must inform high-risk patients and their families of warning signs and risk factors. A warning sign refresher is found in the sidebar.25 URGENCY In the setting of AIS, catchphrases time is brain and stroke is a brain attack should be on the minds of all clinicians and should be conveyed to patients. Patients at high risk or who have had prior TIA or stroke and their immediate family members should be urged to call 911 and not their doctor or HMO. Reminders for clinicians in the emergency setting of AIS include: triage to hospital with stroke team; ABCs (airway, breathing, circulation); early consultation with a neurologist or stroke team; emergency CT or MRI of the brain; and thrombolytic therapy.23,24,26 The only thrombolytic currently approved by the FDA for acute stroke is rt-PA (alteplase). Early and effective treatment of an acute stroke may significantly reduce the risk of recurrence. Standard management of the AIS patient should incorporate: For IV fluids, use of normal saline, not dextrose 5% in water. Avoidance of hyperthermia; treatment of fever. Swallowing assessment. Oxygen saturation (pulse oximetry). Electrolytes, renal and liver function tests, coagulation tests, blood glucose, complete blood count. Additional diagnostic imaging. Secondary stroke prevention. Deep vein thrombosis prophylaxis. SECONDARY PREVENTION OF ISCHEMIC STROKE Many essential ingredients of secondary prevention are similar to those of primary prevention. A therapeutic checklist for secondary prevention is: Treat hypertension. Treat dyslipidemia with HMG-CoA reductase inhibitors (statins). Antithrombotic agents ( HYPERLINK "http://www.jobsoneducation.com/clinicianscme/print.asp?page=courses/105162/lesson.htm" \l "Table2" Table 2). Endarterectomy or stenting for symptomatic carotid artery stenosis. Modify all other known risk factors (eg, screen for diabetes mellitus). Encourage smoking cessation. In the study by Johnston et al mentioned earlier, 5% of patients diagnosed with TIA in an emergency department returned within 48 hours with a stroke.7 Data from this study and another study in patients with minor stroke27 suggest that the early risk of a subsequent stroke is much higher than previously thought. Patients who have already had stroke or TIA also represent the group that is at highest risk of a recurrent cerebrovascular event. These combined data emphasize the need for early and aggressive secondary prevention strategies. The stroke Preventing Recurrence of Thromboembolic Events through Coordinated Treatment (PROTECT) program implements eight evidence-based drug/behavioral secondary prevention measures during the hospitalization of patients who have had an ischemic stroke or TIA. High adherence rates have been observed posthospital discharge for all measures, including therapy with statins, antithrombotics, and antihypertensives.25 The inpatient setting is ideal for initiation of secondary prevention and should be considered. Not taking advantage of this opportunity may significantly delay implementation of secondary prevention measures during the early postevent period, where they are needed most. In-hospital immediate secondary prevention appears safe and at least potentially capable of improving 90-day adherence rates. It might also enhance compliance with national guidelines for treating patients at high-risk for vascular events.25 Stroke warning-sign education or re-education should be an important component of a secondary prevention program (sidebar). Patient Education Refresher: Early Warning Signs of Stroke25 Sudden numbness/weakness of face or extremities Sudden confusion or trouble speaking Sudden trouble seeing Sudden trouble walking or dizziness Sudden severe headache ANTIHYPERTENSIVES Data on the use of antihypertensives in patients following stroke or TIA are limited compared with primary prevention, in part because potential deleterious effects of acute blood pressure lowering in ischemic stroke have raised concerns about the use of antihypertensive agents at all in these patients.28,29 However, results of the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) assured that reducing blood pressure in ischemic-stroke patients is beneficial and that benefits were actually greater with more aggressive blood pressure lowering.29,30 PROGRESS (N = 6,105) evaluated the angiotensin-converting enzyme (ACE) inhibitor perindopril 4 mg per day with or without indapamide versus placebo in hypertensive and nonhypertensive patients with a history of recent stroke or TIA. Stroke occurred in 10% and 14% of those given active treatment and placebo, respectively, a significant difference (RRR 28%). The risk of total major vascular events was also significantly reduced by active treatment (26%). Patients receiving the combination of perindopril plus indapamide experienced greater risk reductions for stroke and major vascular events than those given perindopril alone.30 Table 2 Recommendations for Use of Antithrombotic Agents in the Secondary Prevention of Stroke. From the Seventh American College of Chest Physicians (ACCP) Conference on Antithrombotic and Thrombolytic Therapy23* Prevention of: Recommendations/Evidence-Based Guideline Rating: Cerebral ischemic events in patients with noncardioembolic stroke or TIA (atherothrombotic, lacunar, or cryptogenic): antiplatelet agents 1. Antiplatelet therapy recommended for all patients (1A) 2. Aspirin 50325 mg/day, clopidogrel 75 mg/day, or the combination of aspirin 25 mg and ER dipyridamole 200 mg bid are all acceptable options for initial therapy 3. Aspirin plus ER dipyridamole 25200 mg bid suggested over aspirin alone (2A); clopidogrel suggested over aspirin (2B) 4. Low-dose aspirin (50100 mg/day) suggested in patients at moderate to high risk of bleeding (1C+) 5. Clopidogrel recommended in patients allergic to aspirin (1C+) Cerebral ischemic events in patients with noncardioembolic stroke or TIA: oral anticoagulants 1. Antiplatelet agents recommended over oral anticoagulation for most patients (1A) 2. For well-documented prothrombotic disorders, oral anticoagulation recommended over antiplatelet agents (2C) Cerebral ischemic events in patients undergoing carotid en- darterectomy: antiplatelet agents Aspirin 81325 mg/day recommended before and following the procedure (1A) Cardioembolic cerebral ischemic events in patients with prior stroke or TIA and underlying atrial fibrillation 1. Long-term anticoagulation recommended (target INR 2.5) (1A) Aspirin 81325 mg/day recommended before and following the procedure (1A) 2. Aspirin is recommended in patients with contraindications to oral anticoagulants (1A) Cardioembolic cerebral ischemic events in patients with stroke associated with aortic atherosclerotic lesions Antiplatelet therapy is recommended over no therapy (1C+) Cardioembolic cerebral ischemic events Either oral anticoagulants or antiplatelet agents recommended (2C) Cardioembolic cerebral ischemic events in patients with cryptogenic ischemic stroke and a patent foramen ovale Antiplatelet therapy recommended over no therapy (1C+) and antiplatelet agents suggested over anticoagulation (2A) Cardioembolic cerebral ischemic events in patients with mitral valve strands or prolapse who have history of TIA or stroke Antiplatelet therapy recommended (1C+) * Copyright Lippincott Williams & Wilkins 2001. Used with permission. For a review of this specific grading system, see Guyatt G, Schunemann HJ, Cook D, et al. Applying the grades of recommendation for antithrombotic and thrombolytic therapy: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(3 suppl):179S-187S. The Morbidity and Mortality After Stroke Eprosartan Versus Nitrendipine for Secondary Prevention (MOSES) study recently announced initial results in patients with a history of ischemic stroke and hypertension (N = 1,400). Anti-hypertensive efficacy was similar with the calcium-channel blocking agent and the angiotensin receptor blocker (ARB) eprosartan. However, eprosartan protected against cerebrovascular and cardiovascular events, suggesting benefits above protection via blood pressure control.31 In evaluation of Acute Candesartan Cilexetil Evaluation in Stroke Survivors (ACCESS), a phase II study, patients with ischemic stroke were randomized to the ARB candesartan or placebo as soon as possible after recognition of symptoms (average 30 hours). Blood pressure was similar in the two groups throughout one year of follow-up. There was also no difference in outcome at three months of treatment, but a significant benefit of candesartan was seen at one year, as evidenced by reduced mortality (2.9% vs 7.2%) and vascular events (9.8% vs 18.7%), including recurrent stroke.32 These benefits were not seen when candesartan was initiated seven days after stroke onset, underscoring the need for early and aggressive secondary prevention. Findings similar to the above studies were observed in some primary prevention trials, such as the Losartan Intervention For Endpoint (LIFE) reduction study33 and the Heart Outcomes Prevention Evaluation (HOPE) trial.34 Although mainly a primary prevention study, the HOPE trial (N = 9,297) included a broad range of high-risk patients; about 11% had had a prior TIA or stroke. The ACE inhibitor ramipril reduced the rates of MI, stroke, and vascular death; stroke was reduced from 4.9% to 3.4%. Other studies and clinical data also suggest that beneficial effects of ACE inhibitors or ARBs in secondary and primary stroke prevention are independent of blood pressure reduction; ie, effects on the renin-angiotensin-aldosterone system.28,31,35 Evidence is somewhat stronger for ARBs.31 The specific efficacy of these agents in secondary prevention remains to be confirmed by ongoing clinical trials, such as the Prevention Regimen For Effectively avoiding Second Strokes (PRoFESS) trial.31 In the meantime, use of an ACE inhibitor or ARB, with or without a diuretic, would seem to be a rational choice in the secondary prevention setting. However, effective blood pressure control should be the primary goal for all patients with prior cerebrovascular events,29 regardless of the specific class of antihypertensive agent used. STATINS Statins have not been evaluated extensively for secondary prevention and specific guidelines are unavailable. However, statins are justified and indicated in patients with atherosclerotic ischemic stroke.36,37 The NCEP Adult Treatment Panel III (ATP III) recommends optimal LDL-C lowering in coronary heart disease risk equivalents (< 100 mg/dL or 2.6 mmol/L) and atherosclerotic symptomatic carotid artery disease is considered a coronary heart disease risk equivalent by ATP III.15 Aggressive LDL-C reduction has been shown to decrease atherosclerosis progression in both carotid and coronary arteries.16 In the Heart Protection Study,38 simvastatin 40 mg per day was compared with placebo in high-risk patients, which included those with coronary disease, other occlusive arterial disease, or diabetes mellitus (N = 20,536). Approximately 9% of the initial population had suffered TIA or stroke. Simvastatin was shown to reduce the occurrence of first stroke (fatal, nonfatal), from 5.7% to 4.3% (RRR 25%), regardless of initial LDL-C level. The subgroup of patients with prior TIA or stroke also benefited from simvastatin therapy. The FDA has approved simvastatin 40 mg per day for secondary stroke prevention. More definitive guidelines regarding statins for secondary stroke prevention will emerge from the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study, which is assessing the efficacy of atorvastatin versus placebo in patients with prior stroke or TIA. The primary endpoint is fatal or nonfatal stroke.36 ANTITHROMBOTIC AGENTS Refresher: Vascular Pathology39,40 The goals of antithrombotic therapy are to prevent formation of new thrombi and to prevent propagation and embolization of thrombi already present. Thrombus formation is dependent upon the interplay of many factors, including the number of circulating platelets and their activation and local vascular injury or roughening. White clots (platelets and fibrin) can form on abnormal or roughened surface areas of systemic arteries, characteristically in fast-moving bloodstreams, whereas red clots (erythrocyte-fibrin thrombi) tend to form in areas of low flow or stagnation. Antithrombotic agents for secondary prevention may be classified as antiplatelet agents and anticoagulants. In general terms, antiplatelet agents prevent adhesion, activation, and/or aggregation of white platelet clots. Anticoagulant agents, such as warfarin, heparin, and heparinoids, and direct thrombin inhibitors (eg, hirudin, ximelagatran) prevent formation of red clots. ACCP guidelines for the use of antithrombotic agents for secondary prevention are found in  HYPERLINK "http://www.jobsoneducation.com/clinicianscme/print.asp?page=courses/105162/lesson.htm" \l "Table2" Table 2. Antiplatelet Agents Aspirin inhibits platelet aggregation via irreversible inhibition of platelet cyclooxygenase; however, it has minimal effect on other pathways of platelet activation.26 Noncardioembolic stroke prevention: Aspirin is moderately effective for preventing stroke after noncardioembolic ischemic stroke or TIA (RRR 20% to 25%).23,41,42 In large controlled studies such as the Dutch TIA Trial, the UK-TIA trial, and Swedish Aspirin Low-dose Trial (SALT), low doses (30325 mg/day) were about as effective as high doses (up to 1,300 mg/day).23 The UK-TIA trial, for example, found similar efficacy with 325 mg and 1,300 mg. Cardioembolic stroke prevention: In stroke or TIA patients with high-risk sources of cardiac embolism (mainly AF), aspirin has been evaluated in only one secondary prevention trial, European Atrial Fibrillation Trial (EAFT).43 In this study, 1,007 nonvalvular AF patients with recent TIA or stroke were assigned to either open oral anticoagulation (international normalized ratio [INR] 2.54.0) or double-blind treatment with aspirin 300 mg per day or placebo. With a mean follow-up of 2.3 years, the RRR was 16% for stroke with aspirin 300 mg per day relative to placebo but this difference failed to reach statistical significance. In contrast, oral anticoagulation was highly effective and more effective than aspirin, reducing stroke incidence from 12% to 4% per year. Based on aspirin data from primary prevention trials (RRR 21%), the ACCP recommends aspirin in patients with contraindications to warfarin.23 Cilostazol: This quinoline derivative is somewhat unique in that it has putative platelet anti-adhesion, vasodilator, antimitogenic, and cardiotonic activity; beneficial effects on serum lipids have been observed.26 In a secondary prevention trial in patients with stroke within the prior one to six months (N = 1,052), cilostazol 100 mg bid was significantly more effective than placebo in reducing the risk of recurrent stroke (RRR 41.7%). Similar results were achieved on intention-to-treat analysis (RRR 42.3%). No significant adverse effects were reported.44 Cilostazol is not generally recognized for its antiplatelet activity in the US but it is used for symptomatic relief of peripheral vascular disease. Clopidogrel: This thienopyridine derivative inhibits adenosine diphosphate-induced binding of fibrinogen to platelets.26 It has been slightly but significantly more effective than aspirin for secondary prevention. Clopidogrel versus aspirin: In the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) study (N = 19,185),45 patients with prior ischemic stroke, MI, or peripheral arterial disease were randomized to clopidogrel 75 mg per day or aspirin 325 mg per day for one to three years. The endpoint was stroke, MI, or vascular death, and the annual endpoint risk was 5.32% in the clopidogrel group and 5.83% in the aspirin group (RRR 8.7% for clopidogrel). Safety was similar. Clopidogrel plus aspirin: In the Management of Atherothrombosis with Clopidogrel in High-risk patients (MATCH) study (N = 7,599),46 aspirin 75 mg per day or placebo was added to clopidogrel 75 mg per day for 1.5 years in high-risk patients with recent ischemic stroke or TIA plus one additional vascular risk factor ( HYPERLINK "http://www.jobsoneducation.com/clinicianscme/print.asp?page=courses/105162/lesson.htm" \l "Table3" Table 3). The primary endpoint was a composite of ischemic stroke, MI, vascular death, or rehospitalization for an ischemic event, and analysis was by intention to treat. The endpoint was reached in 16.7% on clopidogrel alone and 15.7% on clopidogrel plus aspirin (nonsignificant). Life-threatening/major bleeding was greater with the combination (3% vs 1%). Mortality did not differ between groups. Clopidogrel plus aspirin versus warfarin: The large Atrial fibrillation Clopidogrel Trials with Irbesartan for prevention of Vascular Events (ACTIVE) are designed to compare aspirin plus clopidogrel versus warfarin, clopidogrel plus aspirin versus aspirin, and irbesartan versus placebo for prevention of stroke, MI, or vascular death in high-risk AF patients.47 However, the aspirin plus clopidogrel versus warfarin portion of this trial was recently halted due to the high incidence of stroke in the clopidogrel/aspirin group. The other studies are ongoing. Dipyridamole: This coronary vasodilator inhibits platelet aggregation and also has effects on the vascular endothelium. In placebo-controlled studies, the combination of dipyridamole plus aspirin reduced composite stroke, MI, or vascular death by about 30%; extended-release (ER) dipyridamole plus aspirin reduced recurrent stroke by about 37%.23,42 The second European Stroke Prevention Study (ESPS-2) (N = 6,602),42 involving patients with prior stroke or TIA, found that the combination of aspirin and ER dipyridamole was superior to either agent given singly. Stroke was reduced by 37% with aspirin 25 mg plus ER dipyridamole 200 mg bid, 18% with aspirin alone 25 mg bid, and 16% with ER dipyridamole alone 200 mg bid ( HYPERLINK "http://www.jobsoneducation.com/clinicianscme/print.asp?page=courses/105162/lesson.htm" \l "Fig2" Figure 2). The comparison between ER dipyridamole plus aspirin versus aspirin alone showed a RRR of 23%. Ticlopidine: The mechanism of action of ticlopi-dine is similar to that of clopidogrel. In secondary prevention studies, such as the Ticlopidine Aspirin Stroke Study (TASS), the drug has shown efficacy in reducing the risk of stroke and other vascular outcomes.23,26 However, adverse effects of ticlopidine, including severe neutropenia and thrombotic thrombocytopenic purpura, have limited its use. Table 3 MATCH Outcomes Number (%) With Event Risk Reduction P Aspirin + Clopidogrel (N = 3,797) Placebo + Clopidogrel (N = 3,802) Absolute (95% CI) Relative (95% CI) (Log-Rank Test) Primary Outcome 596 (16%) 636 (17%) 1.0% (-0.6 2.7) 6.4% (-4.6 16.3) 0.244 Ischemic Stroke (All) 309 (8%) 333 (9%) 0.62% (-0.6 1.9) 7.1% (-8.5 20.4) 0.353 Life-Threatening Bleeding 96 (3%) 49 (1%) Difference between groups = 1.26 (CI 0.64 1.88); Pearsons ?2 test: P <.001 All-Cause Mortality 201 (5%) 201 (5%) -0.01% (-1.0 1.0) 0.1% (-21.5 17.8) 0.992 Summary of antiplatelet efficacy and recommendations: According to ACCP guidelines, aspirin, clopidogrel, or aspirin plus ER dipyridamole are all acceptable options for initial therapy of noncardioembolic stroke or TIA. Aspirin/ER dipyridamole and clopidogrel are more efficacious than aspirin alone. The use of aspirin with clopidogrel offers no benefit over clopidogrel alone and causes more bleeding. For secondary prevention of stroke in patients with AF, warfarin is indicated (below), with aspirin reserved for patients with contraindications to anticoagulant therapy. Anticoagulants Warfarin has limited application in stroke. It is highly effective for both primary and secondary prevention in patients with AF.23,43 Warfarin is also favored in patients with prosthetic heart valves, low ejection fraction cardiomyopathy, and hypercoagulable states, though most of these indications have not been confirmed by randomized clinical trials. Warfarin is indicated for three to six months in cerebral venous sinus thrombosis following initial heparin therapy.23 Warfarin may also be indicated in patients with dissections of the vertebral or carotid arteries, though no randomized trials have been carried out. In the Warfarin-Aspirin Recurrent Stroke Study (WARSS) (N = 2,206), patients with previous noncardioembolic stroke were randomized to warfarin (INR 1.42.8) or aspirin 325 mg per day. No significant difference in the incidence of recurrent ischemic stroke was observed over a two-year period, although there was a slight trend favoring aspirin ( HYPERLINK "http://www.jobsoneducation.com/clinicianscme/print.asp?page=courses/105162/lesson.htm" \l "Fig3" Figure 3). Overall, the primary combined endpoint of death from any cause or recurrent stroke occurred in 16% and 17.8% of patients in the aspirin and warfarin groups, respectively. The incidence of major hemorrhage was similar in each group; however, minor hemorrhages were significantly more frequent in those receiving warfarin.48 Warfarin is not indicated for patients with ischemic stroke, without the above mechanisms. INCLUDEPICTURE "CE%20Lesson_files/fig2.gif" \* MERGEFORMAT  Figure 2: ESPS-2: Effects on Stroke ESPS-2: second European Stroke Prevention Study; RRR, relative risk reduction; ASA, aspirin; ER-DP, extended-release dipyridamole. The Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) trial included patients with TIA or stroke caused by 50% to 99% intracranial artery stenosis. There was no benefit of warfarin (INR 2.03.0) over aspirin 1.3 g per day. A significantly higher rate of adverse events was seen with warfarin.49 Aspirin is preferred in this setting, although combination antiplatelet regimens have not been evaluated. INCLUDEPICTURE "CE%20Lesson_files/fig3.gif" \* MERGEFORMAT  Figure 3: Warfarin-Aspirin Recurrent Stroke Study (WARSS) Direct thrombin inhibitors include parenteral hirudin and argatroban (indicated for heparin-induced thrombocytopenia) and parenteral bivalirudin (indicated as a heparin substitute during coronary angioplasty).26 Ximelagatran is an orally administered direct thrombin inhibitor that gained attention for stroke prevention because of the simplicity of its use. Unfortunately, the drug has not been approved because of hepatotoxicity. Other direct thrombin inhibitors are under development. CAROTID ENDARTERECTOMY/STENTING Results of the North American Symptomatic Carotid Endarterectomy Trial (NASCET)50,51 showed that carotid endarterectomy significantly reduced stroke in patients with symptomatic carotid stenosis of greater than 70%, whereas lesser benefit was seen in patients with moderate stenosis of 50% to 69%; there was no benefit in those with stenosis of less than 50%. The European Carotid Surgery Trial (ECST)52 showed similar benefit with greater than 70% stenosis but no benefit in moderate stenosis. In patients with prior TIA or nondisabling stroke, endarterectomy is generally recommended only for those with high-grade stenosis (70% to 99%).12 In NASCET, cumulative risks of ipsilateral stroke after two years in patients with high-grade stenosis were 9% in patients who underwent endarterectomy and 26% in those receiving medical care only. The absolute risk reduction with endarterectomy was 17%.50 Patients 75 or older in NASCET with 70% to 99% stenosis benefited more from carotid endarterectomy than did younger patients (risk reduction 29% vs 15% in those 65 to 74 and 10% in youngest group).53 Carotid-artery stenting using an embolus-protection device is an effective alternative in patients with either asymptomatic or symptomatic carotid artery stenosis who are deemed unsafe for endarterectomy due to coexistent cardiac or cerebrovascular high risk conditions. The Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial found that stenting (nitinol stents) with an embolus-protection device (AngioGuard"!) in such patients was not inferior to carotid endarterectomy. The study included patients with asymptomatic stenosis of 80% or greater and those with symptomatic stenosis of at least 50%. The primary composite endpoint of death, stroke, or MI within one month postintervention was 39% less frequent in the stenting group.54 Protected stenting should be considered over endarterectomy in symptomatic, high-risk surgical patients. The ongoing Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) is comparing carotid endarterectomy and carotid artery stenting in patients with symptomatic stenosis of 50% or greater.55 CONCLUSION Prevention still trumps treatment and modification of risk factors remains paramount in the prevention of a first stroke, including control of hypertension, dyslipidemia, AF, and asymptomatic carotid artery stenosis, and cessation of smoking. In hypertension, control of blood pressure may be more important than the class of agent used. Secondary prevention after stroke or TIA has occurred should be initiated as early as possible and should incorporate the use of statins, antihypertensives, anticoagulants or antiplatelet therapy, carotid endarterectomy/stenting in selected patients, and continued modification of other known risk factors. All noncardioembolic stroke patients should be placed on antiplatelet agents, such as aspirin, aspirin plus ER dipyridamole, or clopidogrel. There is no benefit from adding aspirin to clopidogrel in high-risk patients post-TIA or ischemic stroke. Warfarin is indicated for both primary and secondary prevention in patients with AF. TS REFERENCES American Heart Association. Heart Disease and Stroke Statistics 2005 Update. Dallas, Texas: American Heart Association; 2005. Available at: www.cdc.gov/nccdphp/factsheets/prevention/cvh.htm. Accessed October 30, 2005. Gorelick PB, Sacco RL, Smith DB, et al. Prevention of a first stroke. A review of guidelines and multidisciplinary consensus statement from the National Stroke Association. JAMA. 1999;281:1112-1120. Goldstein LB, Adams R, Becker K, et al. Primary prevention of ischemic stroke: A statement for healthcare professionals from the Stroke Council of the American Heart Association. Circulation. 2001;103:163-182. Broderick J, Brott T, Kothari R, et al. The Greater Cincinnati/Northern Kentucky Stroke Study: preliminary first-ever and total incidence rates of stroke among blacks. Stroke. 1998;29:415-421. Howard G, Howard VJ, Katholi C, et al. Decline in US stroke mortality: an analysis of temporal patterns by sex, race, and geographic region. Stroke. 2001;32:2213-2220. Caplan LR. Treatment of acute stroke: still struggling. JAMA. 2004;292:1883-1885. Johnston SC, Gress DR, Browner WS, Sydney S. Short-term prognosis after emergency department diagnosis of TIA. JAMA. 2000;284:2901-2906. Reynolds K, Lewis B, Nolen JD, et al. Alcohol consumption and risk of stroke: a meta-analysis. JAMA. 2003;289:579-588. Singer DE, Albers GW, Dalen JE, et al. Antithrombotic therapy in atrial fibrillation: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(3 suppl):429S-456S. Steering Committee of the Physicians Health Study Research Group. Final report on the aspirin component of the ongoing Physicians Health Study. N Engl J Med. 1989;321:129-135. Ridker PM, Cook NR, Lee IM, et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med. 2005;352:1293-1304. Gorelick PB. Stroke prevention. Arch Neurol. 1995;52:347-355. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med. 1996;335:1001-1009. The Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998;339:1349-1357. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA. 2001;285:2486-2497. Drugs for lipids. Treatment Guidelines from The Medical Letter. 2005;3:15-22. Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. Endarterectomy for asymptomatic carotid artery stenosis. JAMA. 1995;273:1421-1428. Fuster V, Ryden LE, Asinger RW, et al. ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation: executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the North American Society of Pacing and Electrophysiology. J Am Coll Cardiol. 2001;38:1231-1266. Cerebral Embolism Task Force. Cardiogenic brain embolism. Arch Neurol. 1986;43:71-84. Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA. 2001;285:2864-2870. Gage BF, van Walraven C, Pearce L, et al. Selecting patients with atrial fibrillation for anticoagulation: stroke risk stratification in patients taking aspirin. Circulation. 2004;110:2287-2292. Hersi A, Wyse DG. Management of atrial fibrillation. Curr Probl Cardiol. 2005;30:175-234. Albers GW, Amarenco P, Easton JD, et al. Antithrombotic and thrombolytic therapy for ischemic stroke. Chest. 2004;126(suppl):483S-512S. Brott T, Bogousslavsky J. Treatment of acute ischemic stroke. N Engl J Med. 2000;343:710-722. Ovbiagele B, Saver JL, Fredieu A, et al. In-hospital initiation of secondary stroke prevention therapies yields high rates of adherence at follow-up. Stroke. 2004;35:2879-2883. Connors JJ III. Pharmacologic agents in stroke prevention, acute stroke therapy, and interventional procedures. J Vasc Interv Radiol. 2004;15:S87-S101. Coull AJ, Lovett JK, Rothwell PM. Oxford Vascular Study. Population based study of early risk of stroke after transient ischaemic attack or minor stroke: implications for public education and organisation of services. BMJ. 2004;328:326. (Epub 2004 Jan. 26). Hilleman DE, Lucas BD Jr. Angiotensin-converting enzyme inhibitors and stroke risk: benefit beyond blood pressure reduction? Pharmacotherapy. 2004;24:1064-1076. Chapman N, Huxley R, Anderson C, et al. Effects of a perindopril-based blood pressure-lowering regimen on the risk of recurrent stroke according to stroke subtype and medical history: the PROGRESS trial. Stroke. 2004;35:116-121. PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood pressure-lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack. Lancet. 2001;358:1033-1041. Weber MA. Managing the patient at risk for a second stroke. J Hypertens. 2005;23(suppl 1):S41-S47. Schrader J, Luders S, Kulschewski A, et al. The ACCESS Study: evaluation of acute candesartan cilexetil therapy in stroke survivors. Stroke. 2003;34:1699-1703. Dahlof B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002;359:995-1003. Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342:145-153. Julius S, Kjeldsen SE, Weber M, et al. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet. 2004;363:2022-2031. Gorelick PB. Stroke prevention therapy beyond antithrombotics: unifying mechanisms in ischemic stroke pathogenesis and implications for therapy: an invited review. Stroke. 2002;33:862-875. Shaltoni HM, Yatsu FM, Hess DC. Statins and stroke prevention. Curr Atheroscler Rep. 2005;7:313-318. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:7-22. Caplan LR. Caplans Stroke: a Clinical Approach, 3rd ed. Boston: Butterworth-Heinemann; 2000. Caplan LR. Antiplatelet therapy in stroke prevention: present and future. Cerebrovasc Dis. 2006. Submitted for publication. Antithrombotic Trialists Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocar-dial infarction, and stroke in high-risk patients. BMJ. 2002;324:71-86. Diener HC, Cunha L, Forbes C, et al. European Stroke Prevention Study 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci. 1996;143:1-13. EAFT (European Atrial Fibrillation Trial) Study Group. Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke. Lancet. 1993;342:1255-1262. Gotoh F, Tohgi H, Hirai S, et al. Cilostazol Stroke Prevention Study: a placebo-controlled double-blind trial for secondary prevention of cerebral infarction. J Stroke Cerebrovasc Dis. 2000;9:147-157. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet. 1996;348:1329-1339. Diener HC, Bogousslavsky J, Brass LM, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet. 2004;364:331-337. Hankey GJ. Ongoing and planned trials of antiplatelet therapy in the acute and long-term management of patients with ischaemic brain syndromes: setting a new standard of care. Cerebrovasc Dis. 2004;17(suppl 3):11-16. Mohr JP, Thompson JL, Lazar RM, et al. A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. N Engl J Med. 2001;345:1444-1451. Chimowitz MI, Lynn MJ, Howlett-Smith H, et al. Comparison of warfarin and aspirin for symptomatic intracranial arterial stenosis. N Engl J Med. 2005;352:1305-1316. North American Symptomatic Carotid Endarterectomy Trial Collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med. 1991;325:445-453. Barnett HJ, Taylor DW, Eliasziw M, et al. Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. North American Symptomatic Carotid Endarterectomy Trial Collaborators. N Engl J Med. 1998;339:1415-1425. European Carotid Surgery Trialists Collaborative Group. Randomised trial of endarterectomy for recently symptomatic carotid stenosis: final results of the MRC European Carotid Surgery Trial (ECST). Lancet. 1998;351:1379-1387. Alamowitch S, Eliasziw M, Algra A, et al. Risk, causes, and prevention of ischaemic stroke in elderly patients with symptomatic internal-carotid-artery stenosis. Lancet. 2001;357:1154-1160. Yadav JS, Wholey MH, Kuntz RE, et al. Protected carotid-artery stenting versus endarterectomy in high-risk patients. 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