Stroke Update

Educational Objectives

The goal of this program is to reduce morbidity and mortality associated with stroke through appropriate prevention and management strategies. After hearing and assimilating this program, the clinician will be better able to:

1.   Discuss the relative risks for adverse outcomes after stroke or transient ischemic attack (TIA).

2.   Detail the risk factors for stroke recurrence and the secondary prevention strategies for managing those risk factors.

3.   Identify patients likely to benefit from anticoagulation therapy, antiplatelet therapy, carotid endarterectomy, or angioplasty and stenting after stroke or TIA.

4.   Assess appropriateness of low-dose aspirin for the primary prevention of cardiovascular and cerebrovascular events, based on age, sex, and medical comorbidities.

5.   Educate patients about the risks and benefits associated with low-dose aspirin therapy.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the plan­ning committee to disclose relevant financial relationships within the past 12 months that might create any personal con­flicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Sacco is a consultant for Boehringer-Ingelheim; Dr. Stults is on the Speakers’ Bureaus for and has received honoraria from Boeh­ringer-Ingelheim, Novartis, and Pfizer; the planning committee reported nothing to disclose.

Acknowledgments

Dr. Sacco was recorded at Advances in Medicine 2009, presented by University of Miami Health System and Miller School of Medicine, and held January 25-30, 2009, in Miami Beach, FL; Dr. Stults was recorded at Advances in Internal Medicine 2009, presented by University of Utah, School of Medicine, and held February 1-6, 2009, in Park City, UT. The Audio-Di­gest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

Advances in Stroke Medicine

Ralph L. Sacco, MD, MS, Olemberg Family Chair in Neurological Diseases, Miller Professor of Neurology, Epidemiology, and Human Genetics, and Chair, Department of Neurology, University of Miami, Miller School of Medicine; Neurologist-in-Chief, Jackson Memorial Hospital; President-elect, American Heart Association (term beginning 2010); Miami, FL

Prevention curve: progression from disease-free state to preclinical to clinical disease; secondary prevention  —  patient has already had stroke or transient ischemic attack (TIA)

Acute therapy: timely recognition and management of stroke critical; recommendations  —  intravenous (IV) tissue plasminogen activator (tPA) £3 hr after onset of symptoms (treatment window may extend [eg, to 4.5 hr] in future); interventional approaches (eg, clot retrieval) within 3 to 8 hr

Outcomes after ischemic stroke: stroke recurrence  —  up to 40% by 5 yr; highest risk during first 30 days; mortality  —relatively high; commonly due to cardiovascular (CV) cause; disability  —  important morbidity; acute therapies aimed at improving function; up to 50% of patients completely or partially dependent; recurrent stroke further reduces function and quality of life; cognitive impairment  —affects up to 34% of patients by 1 yr

Stroke recurrence: prospective cohort study followed patients who suffered stroke; nonfatal and fatal stroke, most frequent event after initial stroke; myocardial infarction (MI) and fatal cardiac events occurred half as often and associated with less morbidity and mortality

Stroke after TIA: 90-day risk for stroke, 10.5% (half occur during first 48 hr); lower risk for cardiac events (2.5% at 90 days)

Etiology: hemorrhagic or ischemic; subarachnoid and intracerebral hemorrhages account for 15% to 20% of strokes; lacunar  —  (ie, small-vessel) account for »25% of ischemic strokes; cardioembolic  —  »20% of ischemic strokes; caused by, eg, atrial fibrillation, previous anterior wall MI, or significant valvular disease; associated with high rate of recurrence; large artery atherosclerosis  —  extracranial and intracranial each account for »8% of ischemic strokes (intracranial disease more common among blacks and Hispanics); cryptogenic  —etiology unknown

Risk-factor modification: important for primary and secondary intervention; lifestyle factors  —  smoking; alcohol consumption (heavy drinkers should eliminate or reduce consumption); obesity; physical inactivity

Blood pressure (BP): guidelines  —  antihypertensive agents recommended after 48 to 72 hr (lowering BP too soon may decrease perfusion and worsen ischemic infarct); evidence of benefit for patients with and without preexist­ing hypertension; lifestyle modification important for management

Perindopril Protection against Recurrent Stroke Study (PROGRESS): treatment with angiotensin converting-en­zyme (ACE) inhibitor (perindopril) and diuretic (indapamide) associated with 43% reduction in 5-yr risk; combi­nation therapy superior to monotherapy for risk reduction

Losartan Intervention for Endpoint Reduction (LIFE) trial: patients with severe hypertension (many with left ven­tricular [LV] hypertrophy) randomized to losartan (angiotensin receptor blocker [ARB]) or atenolol (b-blocker); losartan associated with »25% lower risk for stroke, despite similar control of BP

Other evidence: ACE inhibitors shown effective for patients with history of MI or stroke and those with diabetes, chronic kidney disease, heart failure, or at high risk for coronary artery disease (CAD); fewer trials using ARBs, but benefit seen

Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) Trial: in one arm, investigators looked at effect of telmisartan for prevention of stroke recurrence; no statistical difference (vs placebo), but trend toward benefit with longer (>6 mo) treatment; adherence to guidelines for BP control may have minimized differences

Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET): ARB (telmisartan) shown noninferior to ACE inhibitor (ramipril), ie, ARB as good as or better than ACE inhibitor for reducing risk; combination therapy associated with increased risk and no added benefit

Diabetes: control of BP and lipid levels important; targets often lower than for patients without diabetes; glucose control shown to improve micro-, but not macrovascular, outcomes

Dyslipidemia: follow guidelines from National Cholesterol Education Program for patients with elevated cholesterol, coronary heart disease (CHD), or atherosclerotic stroke; treat with statins (target low-density lipoprotein [LDL], <70 mL/dL or <100 mg/dL, depending on risk); Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL)  —  80 mg atorvastatin associated with decreased risk for stroke recurrence and major CV events in pa­tients with history of TIA or stroke; small increased risk for hemorrhagic stroke; after results published, guidelines added recommendation for statin therapy to lower lipid levels in patients with history of atherosclerotic ischemic stroke or TIA without known CHD

Large-artery atherosclerosis: after TIA or minor stroke, if patient has carotid stenosis >60%, assess candidacy for endarterectomy (recommended when no contraindications present); consider angioplasty if patient not candidate for endarterectomy; all patients require antiplatelet therapy

Endarterectomy: recommended for patients with ipsilateral symptomatic severe (70%-99%) carotid stenosis; con­sider for patients with moderate (50%-69%) carotid stenosis, depending on age, sex, comorbidities, and severity of symptoms; contraindicated in patients with <50% stenosis (treat medically); when indicated, endarterectomy should be performed £2 wk after minor stroke or TIA (delay >2 wk associated with increased risk for recurrence)

Angioplasty and stenting: considered (class IIb recommendation; evidence level B) when (a) stenosis difficult to access surgically, (b) comorbid medical conditions greatly increase risk associated with surgery, or (c) special circumstances (eg, radiation-induced stenosis, restenosis after endarterectomy) present; reasonable when per­formed by operators with good safety record (30-day complication rate of 4%-6%); direct comparison trials  —  French trial found carotid endarterectomy significantly better than angioplasty and stenting; German trial found no difference, but could not prove noninferiority; results of large trial in United States anticipated

Cardioembolic stroke: adjusted-dose warfarin recommended, unless contraindicated, after ischemic stroke or TIA in patients with persistent or paroxysmal atrial fibrillation; target international normalized ratio (INR), 2.5 (range 2.0-3.0); if contraindication exists, antiplatelet therapy (eg, 81-325 mg aspirin, daily) standard; other cardiac conditions  —  warfarin beneficial for patient with LV thrombus, rheumatic mitral valve disease, or prosthetic valves; trial now in progress comparing warfarin to antiplatelet therapy in patients with low ejection-fraction cardiomyopa­thy; antiplatelet therapy recommended for patients with mitral valve prolapse, mitral annular calcification, or minor aortic valve disease

Noncardioembolic stroke: eg, lacunar stroke, cryptogenic stroke, intracranial atherosclerosis, or moderate (<60% stenosis) extracranial carotid disease; antiplatelet therapy recommended; no role for oral anticoagulation agents (no benefit seen in 2 clinical trials)

Antiplatelet options: aspirin (50-325 mg/day); combination aspirin plus extended-release dipyridamole (25 mg/200 mg, bid) and clopidogrel monotherapy (75 mg/day) shown safe and more effective than aspirin alone; adding as­pirin to clopidogrel therapy increases risk for hemorrhage without improving outcomes, therefore not routinely recommended after stroke or TIA (but may be indicated, eg, if patient has unstable angina); clopidogrel recom­mended for patients with allergy to aspirin; PRoFESS trial  —  compared extended-release dipyridamole plus as­pirin to clopidogrel and found no difference in outcomes (previously, indirect evidence suggested superiority of aspirin combination); aspirin combination conferred slightly higher risk for hemorrhage, but low absolute risk; treatments considered equivalent

Future: many clinical trials in progress; goals to improve prediction of risk and detection and management of sub­clinical disease; improved imaging allows detection of small plaques, thickening of carotid artery, silent strokes, white matter hyperintensities, and aortic arch atheroma; silent stroke  —  study found »40% of men 80 yr of age had evidence of stroke on imaging but no history of symptoms; frequency increases with age and may be higher in men than in women; questions remain about management; carotid stenosis  —  plaque type may be more important than effect on blood flow; study found small plaques (£1.9 mm thick) in 25% of participants; presence associated with 70% increased risk for stroke, MI, or vascular death; most predictive in patients with low Framingham risk scores; role of genetics  —  family studies under way looking for genetic markers of risk; findings may help identify new ap­proaches for modifying risk

Interventional procedures for asymptomatic patients: 2 trials show endarterectomy has benefit over medical ther­apy for selected asymptomatic patients with >70% stenosis; factors to consider include patient age, presence of car­diac comorbidities, and surgeon experience; angioplasty and stenting not currently recommended in these patients, but trials in progress

Aspirin for Primary Prevention of Cardiovascular and Cerebrovascular Disease

Barry Stults, MD, Clinical Professor and Chief, Division of General Medicine, Department of Internal Medi­cine, and Associate Director, Internal Medicine Residency Program, University of Utah, School of Medicine, Salt Lake City

Mortality: CV disease top cause of death in men and women in United States; most commonly due to CHD or stroke; men have higher risk for CHD than women, but women have higher risk for stroke

Aspirin use: regular aspirin therapy common among adults without CV disease or diabetes; Framingham study showed 52% of men and 39% of women free of CV disease at 50 yr of age develop CV disease by 80 yr of age; cal­culated that aspirin therapy has potential to prevent »150,000 deaths each year

Meta-analysis of clinical trials: 6 primary prevention trials with >95,000 participants (median age, late 50s; no par­ticipants >70 yr of age); dose range, 100 mg every other day, up to 500 mg/day; mean follow-up, 6.4 yr; 54% women (almost all from Women’s Health Initiative [WHI])

Results in men: aspirin reduced risk for MI by 32%; no reduction in risk for stroke, CV mortality, or total mortality; risk for major bleeding increased by 72%; ie, prevents 8 MIs and causes 3 major hemorrhages when 1000 pa­tients treated for 6.4 yr; in 1 yr, aspirin prevents 1 to 2 CV events and causes 1 to 2 major hemorrhages

Risks associated with aspirin therapy: intracranial hemorrhage  —relative risk increased by 40% with aspirin therapy, but absolute risk low; warfarin therapy associated with 4000 intracranial hemorrhages each year; aspirin therapy associated with 3000 per year; upper gastrointestinal (GI) bleeding  —  among patients who do not use aspirin, risk increases with age; fre­quency of 1 per 1000 patients per year (all ages) increased 4-fold in patients >75 yr of age; with low-dose aspirin ther­apy, risk elevated 2- to 3-fold in younger patients (without high risk for bleeding) and elevated 10 times (one hemorrhage per 100 patients treated for 1 yr) in population more representative of community sample; risk associ­ated with long-term use  —  initiated in, eg, healthy man, 50 yr of age (life expectancy, additional 27 yr); over 27 yr, treatment associated with 5% risk for upper GI bleeding, 1.3% risk for major upper GI bleeding, 0.5% risk for in­tracranial hemorrhage, and 0.2% risk for death, for total increased risk of 7%; 1 of every 15 patients would have significant adverse event (number needed to harm)

Relative risk for mortality: 30-day mortality rate 40% after MI, 20% after stroke, 4% to 5% after upper GI bleeding, and >50% after intracranial hemorrhage

Aspirin for primary prevention in older adults: based on available data, in 1000 men 70 to 74 yr of age, primary prevention with low-dose aspirin would prevent 39 MIs and 19 deaths, but it would cause 58 major upper GI and/or intracranial hemorrhages and 15 deaths; more data needed before recommending aspirin for primary prevention in this population; trial in progress

Risk-benefit ratio in men: no agreement about level of risk for CHD event that warrants low-dose aspirin therapy; Framingham calculator estimates 10-yr risk for CHD event; recommendations for initiating therapy range from 10-yr risk of 6% to 10-yr risk of 15%

Aspirin therapy in women: meta-analysis showed no reduction in risk for MI, CV mortality, or total mortality; risk for stroke reduced by 17%, but risk for major bleeding increased by 68%; treating 1000 women for 6.4 yr would prevent 2 strokes and cause »2.5 hemorrhages; subgroup analysis of WHI  —among women >65 yr of age, nonsig­nificant trend toward decreased stroke risk, but significant decreases in MI (34%) and CV disease events (26%); much less benefit among women 55 to 64 yr of age; among smokers, aspirin therapy did not reduce risk for stroke and increased risk for MI and CV disease events; risk-benefit ratio  —  assess combined 10-yr risk for CHD and stroke; aspirin therapy suggested as cost effective when combined 10-yr risk ³10% (Pignone et al, 2007) or ³15% (Greving et al, 2008); published recommendations  —qualitative; based on age and risks for ischemic stroke, MI, and bleeding

Primary prevention in patients with diabetes: meta-analysis and results from 2 recent studies show no significant reduction in risk with aspirin therapy, but studies underpowered; larger studies in progress; aspirin therapy likely has lower efficacy in patients with diabetes; 2009 American Diabetes Association guidelines  —  aspirin recom­mended for primary prevention for patients >40 yr of age and for patients 30 to 40 yr of age with additional risk factors for CV disease; no evidence of benefit for patients 21 to 29 yr of age; contraindicated for patients <21 yr of age

Reducing risk for bleeding: use 81 mg/day; control systolic BP before initiating aspirin therapy in order to decrease risk for intracranial hemorrhage; avoid aspirin therapy in patients with history of upper GI bleeding (note, 12-mo risk reduced from 15% to 2% when proton pump inhibitor added; risk still considered high); avoid combining aspi­rin with warfarin (except for patients with mechanical valves); avoid combining aspirin with nonsteroidal anti-in­flammatory drugs, because risk for major bleeding increases 2- to 3-fold

Suggested Reading

Algra A, Greving JP: Aspirin in primary prevention: sex and baseline risk matter. Lancet 373:1821, 2009; Amarenco P et al: High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med 355:549, 2006; Becker RC et al: The primary and secondary prevention of coronary artery disease: American College of Chest Physicians Evidence-based Clinical Practice Guidelines (8th Edi­tion). Chest 133(6 Suppl):776S, 2008; Dahlof B et al: Cardiovascular morbidity and mortality in the Losartan Intervention For End­point reduction in hypertension study (LIFE): a randomized trial against atenolol. Lancet 359:995, 2002; Dhamoon MS et al: Recurrent stroke and cardiac risks after first ischemic stroke: the Northern Manhattan Study. Neurology 66:641, 2006; Diener HC et al: Effects of aspirin plus extended-release dipyridamole versus clopidogrel and telmisartan on disability and cognitive function after recurrent stroke in patients with ischemic stroke in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial: a double-blind, active and placebo-controlled study. Lancet Neurol 7:875, 2008; Greving JP et al: Cost-effectiveness of aspirin treat­ment in the primary prevention of cardiovascular disease events in subgroups based on age, gender, and varying cardiovascular risk. Circulation 117:2875, 2008; Murphy SA: Women’s Health Study: low dose aspirin in primary prevention. J Am Coll Cardiol 46:CS7, 2005; ONTARGET Investigators: Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 358:1547, 2008; Pignone M et al: Aspirin for the primary prevention of cardiovascular disease in women: a cost-utility analysis. Arch Intern Med 167:290, 2007; PROGRESS Collaborative Group: Randomised trial of a perindopril-based blood-pressure–low­ering regimen among 6,105 individuals with previous stroke or transient ischemic attack. Lancet 358:1033, 2001; Romero SC et al: Aspirin for primary prevention of coronary heart disease: using the Framingham Risk Score to improve utilization in a primary care clinic. South Med J 101:725, 2008; Sacco RL et al: Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack. Stroke 37:577, 2006; Selim M: Antiplatelets for stroke prevention: implications of the PRoFESS trial. Stroke 40:1936, 2009; Wolff T et al: Aspirin for the primary prevention of cardiovascular events: an update of the evidence for the U.S. Pre­ventive Services Task Force. Ann Intern Med 150:405, 2009.