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Update to the AHA/ASA Recommendations for the Prevention of Stroke in
Patients With Stroke and Transient Ischemic Attack
Robert J. Adams, Greg Albers, Mark J. Alberts, Oscar Benavente, Karen Furie, Larry B. Goldstein, Philip Gorelick, Jonathan Halperin, Robert Harbaugh, S. Claiborne Johnston, Irene Katzan, Margaret Kelly-Hayes, Edgar J. Kenton, Michael Marks, 2008;39;1647-1652; originally published online Mar 5, 2008; Stroke is published by the American Heart Association. 7272 Greenville Avenue, Dallas, TX 72514 Copyright 2008 American Heart Association. All rights reserved. Print ISSN: 0039-2499. Online The online version of this article, along with updated information and services, is Subscriptions: Information about subscribing to Stroke is online at Permissions: Permissions & Rights Desk, Lippincott Williams & Wilkins, a division of WoltersKluwer Health, 351 West Camden Street, Baltimore, MD 21202-2436. Phone: 410-528-4050. Fax:410-528-8550. E-mail: Reprints: Information about reprints can be found online at AHA/ASA Science Advisory
Update to the AHA/ASA Recommendations for the
Prevention of Stroke in Patients With Stroke and Transient
Ischemic Attack
Robert J. Adams, MS, MD, FAHA, Chair; Greg Albers, MD; Mark J. Alberts, MD, FAHA; Oscar Benavente, MD; Karen Furie, MD, MPH, FAHA; Larry B. Goldstein, MD, FAHA, FAAN; Philip Gorelick, MD, MPH, FAHA, FAAN; Jonathan Halperin, MD, FAHA; Robert Harbaugh, MD, FACS, FAHA; S. Claiborne Johnston, MD, PhD; Irene Katzan, MD, MS, FAHA; Margaret Kelly-Hayes, RN, EdD, FAHA; Edgar J. Kenton, MD, FAHA, FAAN; Michael Marks, MD; Ralph L. Sacco, MS, MD, FAHA, FAAN; Lee H. Schwamm, MD, FAHA The American Heart Association/American Stroke Asso- was a double-blinded study that randomized 15603 subjects ciation (AHA/ASA) Writing Committee for the Preven- with cardiovascular disease or multiple risk factors for tion of Stroke in Patients With Stroke and Transient Ischemic cardiovascular disease to either clopidogrel 75 mg plus Attack (TIA) has reviewed the results of recent trials that low-dose aspirin (75 to 162 mg) or placebo plus aspirin (75 to were published after our previous recommendations were 162 mg). Roughly 35% of subjects (nϭ4320) qualified on the issued.1 Our intention in the present statement is to provide a basis of the presence of cerebrovascular disease within 5 brief review of the new data, to update specific recommen- years of enrollment; approximately a third experienced TIA.
dations, and to provide the reasons for any modifications. The 2 areas in which major new clinical trials have been published No significant differences were seen in the rates of nonfatal are (1) the use of specific antiplatelet agents for stroke ischemic stroke between the 2 groups (1.7% versus 2.1%, prevention in patients with a history of noncardioembolic Pϭ0.07). The placebo plus aspirin group showed a higher ischemic stroke or TIA and (2) the use of statins in the rate of nonfatal stroke than did the clopidogrel group (1.9% versus 2.4%, Pϭ0.03). The 2 groups experienced no differ- Antithrombotic Use for Prevention of
ences in the rate of intracerebral hemorrhage (0.3%). Thecombination therapy did not significantly increase the risk of Ischemic Stroke in Patients With History of
severe or fatal bleeding; however, patients had a higher rate Noncardioembolic Ischemic Stroke
of moderate bleeding in the combination therapy arm. Pa- Recently published trials have added to the evidence of the tients in the combination therapy arm experienced a reduction benefit of the use of specific antiplatelet agents for stroke in a secondary end point, hospitalization for unstable angina, prevention in patients with a history of noncardioembolicischemic stroke or TIA. The secondary prevention guidelines TIA, or revascularization (11.1% versus 12.3%, Pϭ0.02). In have been updated to reflect this new evidence.
a prespecified subgroup analysis, the combination therapywas marginally superior to aspirin alone in symptomatic Addition of Clopidogrel to Aspirin for Prevention
patients (6.9% versus 7.9%, Pϭ0.046). In the subgroup of of Vascular Events
patients with a history of stroke, a trend was seen toward a The Clopidogrel and Aspirin Versus Aspirin Alone for the benefit from combination therapy, but it was not significant Prevention of Atherothrombotic Events (CHARISMA) trial2 (hazard ratio [HR] point estimate not provided). Subgroup The American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are requiredto complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest.
This statement was approved by the American Heart Association Science Advisory and Coordinating Committee on January 11, 2008. A single reprint is available by calling 800-242-8721 (US only) or by writing the American Heart Association, Public Information, 7272 Greenville Ave, Dallas, TX75231-4596. Ask for reprint No. 71-0442. A copy of the statement is also available at http://www.americanheart.org/presenter.jhtml?identifierϭ3003999by selecting either the “topic list” link or the “chronological list” link. To purchase additional reprints, call 843-216-2533 or [email protected]
Expert peer review of AHA Scientific Statements is conducted at the AHA National Center. For more on AHA statements and guidelines development, visit http://www.americanheart.org/presenter.jhtml?identifierϭ3023366.
Permissions: Multiple copies, modification, alteration, enhancement, and/or distribution of this document are not permitted without the express permission of the American Heart Association. Instructions for obtaining permission are located at http://www.americanheart.org/presenter.jhtml?identifierϭ4431. A link to the “Permission Request Form” appears on the right side of the page.
(Stroke. 2008;39:1647-1652.)
2008 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.107.189063
1648
Stroke
Recommendations for Antiplatelet Therapy
1. For patients with noncardioembolic ischemic stroke or TIA, antiplatelet agents rather than oral anticoagulation are recommended to reduce the risk of recurrent stroke and other cardiovascular events (Class I, Level of Evidence A).
2. Old recommendation: Aspirin (50 to 325 mg/d), the combination of aspirin and extended-release dipyridamole, and clopidogrel are all acceptable options for initial therapy (Class IIa, Level of Evidence A).
New recommendation: Aspirin (50 to 325 mg/d) monotherapy, the combination of aspirin and extended-release dipyridamole, and clopidogrel monotherapyare all acceptable options for initial therapy (Class I, Level of Evidence A).* 3. Old recommendation: Compared with aspirin alone, both the combination of aspirin and extended-release dipyridamole and clopidogrel are safe. The combination of aspirin and extended-release dipyridamole is suggested over aspirin alone (Class IIa, Level of Evidence A).
New recommendation: The combination of aspirin and extended-release dipyridamole is recommended over aspirin alone (Class I, Level of Evidence B).
1. Clopidogrel may be considered over aspirin alone on the basis of direct-comparison trials (Class IIb, Level of Evidence B).
2. For patients allergic to aspirin, clopidogrel is reasonable (Class IIa, Level of Evidence B).
The addition of aspirin to clopidogrel increases the risk of hemorrhage. Combination therapy of aspirin and clopidogrel is not routinely recommended forischemic stroke or TIA patients unless they have a specific indication for this therapy (ie, coronary stent or acute coronary syndrome) (I).
*For patients who have an ischemic cerebrovascular event while taking aspirin, there is no evidence that increasing the dose of aspirin provides additional benefit.
Although alternative antiplatelet agents are often considered for noncardioembolic patients, no single agent or combination has been well studied in patients who havehad an event while receiving aspirin.
analyses, which are subject to both type I and type II error, risk for the primary outcome was significantly lower in the dipyridamole plus aspirin arm (HR, 0.80; 95% confidence Initiation of study drug up to 5 years after the index event interval, 0.66 to 0.98). The survival curves began to diverge is significantly beyond the high-risk period for stroke recur- after the second year, which appeared to be related to rence. At this time, the Management of Atherothrombosis deceleration in the aspirin arm. The use of combined dipyr- With Clopidogrel in High-Risk Patients (MATCH) study idamole and aspirin conferred an absolute risk reduction of remains a more relevant trial of these therapies in patients 1% per year. Although there has been concern about the with cerebrovascular disease.3 The CHARISMA trial showed effect of dipyridamole on risk of myocardial infarction, no benefit for combined use of aspirin and clopidogrel for particularly with low-dose aspirin therapy, no significant stroke prevention in patients with prior history of ischemic difference in time to first cardiac event was seen between the stroke. Limited-duration combination clopidogrel and aspirin therapy is indicated in patients with recent coronary events There was a high rate of medication intolerance in the and/or prior vascular stenting, however, and the reader is aspirin plus dipyridamole arm. Thirty-four percent of subjects referred to the latest American College of Cardiology/AHA randomized to aspirin plus dipyridamole discontinued ther- guidelines for information on aspirin and clopidogrel for apy, compared with 13% of subjects in the aspirin-only group. The dose of aspirin in ESPRIT was variable andincluded 30 mg/d, which is lower than the Ն50-mg dose Aspirin With and Without Dipyridamole
recommended in consensus guidelines and conventionally The European/Australasian Stroke Prevention in Reversible used in the United States. ESPRIT, a nonblinded study, Ischemia Trial (ESPRIT) was a randomized, open-label study provided additional evidence of an incremental benefit of comparing aspirin 30 to 325 mg with or without dipyridamole combination aspirin and extended-release dipyridamole com- 200 mg bid in 2763 subjects with TIA, transient monocular pared with aspirin monotherapy for stroke prevention in blindness, or minor stroke (modified Rankin score Յ3) within patients with noncardioembolic ischemic stroke, as supported 6 months of enrollment.4 Eighty-three percent of the dipyri- by a meta-analysis that included the ESPRIT data.4 The damole used was extended release, the formulation used in impact of the study on the recommendation is lessened by the the European Stroke Prevention Study (ESPS)-2 study, and open-label design, the variable nonstandard aspirin doses, and the remainder was conventional dipyridamole. The median the divergence of significance between the on-treatment and dose of aspirin was 75 mg. Approximately 70% of patients intention-to-treat analyses. The additional evidence from were enrolled beyond a month of the index event. Patients ESPRIT, however, was considered sufficient to raise the with a cardioembolic source of embolism, high-grade stenosis previous recommendation from a Class II grade A evidence requiring intervention, or coagulation disorder were ex- to a Class I recommendation supported by grade B evidence cluded. Subjects were followed up for a mean of 3.5 years.
(Table 1). The combination of aspirin and extended-release The primary outcome was death from all vascular causes, dipyridamole is recommended over aspirin alone.
nonfatal stroke, nonfatal myocardial infarction, or major Individual patient characteristics continue to play a role in bleeding complication. Outcomes were blinded. The on- selection of antiplatelet agents for recurrent stroke preven- protocol therapy analysis of ESPRIT did not reach statistical tion. Side effects, costs, and comorbid illnesses influence significance, whereas the intention-to-treat analysis did. The decisions regarding antiplatelet therapy. Dipyridamole is not Adams et al
Stroke in Patients With Stroke and TIA
1649
tolerated by some patients because it can cause persistent low-density lipoprotein cholesterol levels were 132.7 mg/dL headache. Upward tapering of the dipyridamole dose may be (3.43 mmol/L) and 133.7 mg/dL (3.46 mmol/L) in the helpful,5,6 although this therapy requires further study. Ad- atorvastatin and placebo treatment groups, respectively. The herence to medication use is an important factor to consider net difference in use of a statin drug between the 2 treatment and is affected by costs, side effects, and frequency of groups was 78.1%. During the treatment phase of the study, dosing.7 Some patients have allergy or gastrointestinal intol- the mean low-density lipoprotein cholesterol level was 73 erance to aspirin therapy, and in these patients, clopidogrel is mg/dL (1.9 mmol/L) in the atorvastatin treatment arm and 129 mg/dL (3.3 mmol/L) in the placebo treatment arm.10 Aspirin monotherapy, clopidogrel monotherapy, and aspi- During a median follow-up of 4.9 years, 11.2% (265 patients) rin combined with extended-release dipyridamole all remain receiving atorvastatin and 13.1% (311 patients) receiving accepted options for initial therapy for patients with noncar- placebo reached the primary end point of fatal or nonfatal dioembolic ischemic stroke and TIA. Data from ongoing stroke (5-year absolute reduction in risk, 2.2%; adjusted HR, clinical trials will provide a direct comparison of the efficacy 0.84; 95% confidence interval, 0.71, 0.99; Pϭ0.03 and of clopidogrel with that of extended-release dipyridamole unadjusted Pϭ0.05). The 5-year absolute reduction in risk of plus aspirin for secondary prevention in patients with acute major cardiovascular events was 3.5% (HR, 0.80; 95% confidence interval, 0.69, 0.92; Pϭ0.002). Other secondaryoutcomes that achieved statistically significant reductions Statin Therapy in Recurrent Stroke Prevention
favoring the atorvastatin treatment arm were stroke or TIA The use of 3-hydroxy-3-methyglutaryl coenzyme A reductase (PϽ0.001), major coronary event (Pϭ0.003), acute coronary inhibitors (statins) has been approved by regulatory agencies event (Pϭ0.001), any coronary event (PϽ0.001), revascular- for prevention of ischemic stroke in patients with coronary ization (PϽ0.001), and any cardiovascular event (PϽ0.001).
heart disease (CHD).8 It is uncertain, however, whether this No statistically significant differences were seen in the rates class of drugs is indicated for recurrent stroke prevention.9 of nonfatal stroke (Pϭ0.11) or death (Pϭ0.98).
This advisory reviews new data relating to the use of The 2 treatment groups had no significant differences in the atorvastatin in recurrent stroke prevention on the basis of the incidence of serious adverse events.10 The atorvastatin treatment results of the Stroke Prevention by Aggressive Reduction in group, however, experienced 55 hemorrhagic strokes, compared with 33 in the placebo treatment group. Incidence of myalgia The SPARCL trial was a randomized, double-blind study (5.5% versus 6.0%), myopathy (0.3% versus 0.3%), and rhab- designed to determine whether atorvastatin 80 mg/d or domyolysis (0.1% versus 0.1%) did not differ between the placebo would reduce the risk of fatal or nonfatal stroke in atorvastatin or placebo treatment groups, respectively. Elevation patients with no known coronary disease who had experi- (Ͼ3 times) in liver enzymes was more common in the atorva- enced a stroke or TIA within the previous 6 months.10 statin treatment group (2.2% versus 0.5%), and elevation of Eligible patients included men and women over 18 years of creatine kinase (Ͼ10 times) was more frequent with atorvastatin age who had ischemic or hemorrhagic stroke or TIA 1 to 6 months before randomization. Patients had to be ambulatory The 16% reduction in the HR favoring atorvastatin in the with a modified Rankin score of Յ3 and a low-density SPARCL trial was less than expected; however, a prespeci- lipoprotein cholesterol level 100 mg/dL (2.6 mmol/L) to 190 fied analysis of 4162 patients according to the protocol mg/dL (4.9 mmol/L). Study exclusion criteria included atrial showed an 18% relative reduction in the risk of stroke in the fibrillation, other cardiac sources of embolism, subarachnoid atorvastatin treatment group compared with controls (HR, hemorrhage, and other criteria. The prespecified secondary 0.82; 95% confidence interval, 0.69, 0.98; Pϭ0.03). A composite outcomes were stroke or TIA; major coronary somewhat surprising finding in SPARCL was the reduction event (death from cardiac causes, nonfatal myocardial infarc- of different types of CHD events that exceeded that of stroke tion, or resuscitation after cardiac arrest); major cardiovascu- events, although study patients did not have a history of overt lar event (stroke plus any major coronary event); acute CHD. This finding supports the concept that atherosclerosis is coronary event (major coronary event or unstable angina); a systemic disease and that CHD may be an important occult any coronary event (acute coronary event plus a coronary comorbid condition in stroke patients whether or not there is revascularization procedure, unstable angina, or angina or ischemia requiring emergency hospitalization); revasculariza- The new recommendations are shown in Table 2. On the basis tion procedure (coronary, carotid, or peripheral); and any of the SPARCL trial, statin therapy with intensive lipid-lowering cardiovascular event. The study was designed to have a effects is recommended for patients with atherosclerotic ische- statistical power of 90% for the primary end point and mic stroke or TIA and without known CHD to reduce the risk of continue until 540 primary events had occurred. Intention-to- stroke and cardiovascular events10 (Class I, Level of Evidence treat analyses of primary and secondary outcomes included B).1 For those patients with atherosclerotic ischemic stroke or prespecified adjustments for geographic region, entry event TIA and a history of CHD, it is recommended that clinicians (stroke or TIA), time since entry event, sex, and baseline age.
follow the current 2006 AHA/ASA guidelines for lipid manage- Overall, 2365 patients were randomized to atorvastatin and ment, which emphasize utilization of National Cholesterol Ed- 2366 to placebo. Standard cardiovascular preventive medica- tions (eg, antiplatelet drugs, antihypertensives, and warfarin) The SPARCL trial leaves a number of important questions were used frequently in the 2 treatment groups. The baseline unanswered in relation to statin therapy in prevention of 1650
Stroke
Recommendations for Lipid Management
Ischemic stroke or TIA patients with elevated cholesterol, comorbid coronary artery disease, or evidence of an atherosclerotic origin should be managed according to NCEP III guidelines, which include lifestyle modification, dietary guidelines, andmedication recommendations.
Statin agents are recommended, and the target goal for cholesterol lowering for those with CHD or symptomatic atherosclerotic disease is an LDL-C level of Ͻ100 mg/dL. An LDL-C Ͻ70 mg/dL is recommended for very high-risk personswith multiple risk factors.
On the basis of the SPARCL trial, administration of statin therapy with intensive lipid- lowering effects is recommended for patients with atherosclerotic ischemic stroke or TIA and without known CHD to reduce the risk of stroke and cardiovascularevents.
Ischemic stroke or TIA patients with low HDL cholesterol may be considered for treatment with niacin or gemfibrozil.
NCEP indicates National Cholesterol Education Panel; LDL-C, low-density lipoprotein cholesterol; and HDL, high-density lipoprotein.
recurrent stroke. For example, in the SPARCL trial, is the recommendation conforms with AHA Guideline Develop- beneficial effect observed on recurrent stroke prevention a ment policy that assumes a class effect in the absence of data drug-class effect or an atorvastatin-specific effect? This Disclosure
Writing Group Disclosures
Adams et al
Stroke in Patients With Stroke and TIA
1651
Writing Group Disclosures Continued
This table represents the relationships of writing group members that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure Questionnaire, which all members of the writing group are required to complete and submit. A relationship is considered to be “significant” if (a) the personreceives $10 000 or more during any 12 month period, or 5% or more of the person’s gross income; or (b) the person owns 5% or more of the voting stock or shareof the entity, or owns $10 000 or more of the fair market value of the entity. A relationship is considered to be “modest” if it is less than “significant” under thepreceding definition.
1652
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1. Sacco RL, Adams R, Albers G, Alberts MJ, Benavente O, Furie K, 7. Schroeder K, Fahey T, Ebrahim S. How can we improve adherence to Goldstein LB, Gorelick P, Halperin J, Harbaugh R, Johnston SC, KatzanI, Kelly-Hayes M, Kenton EJ, Marks M, Schwamm LH, Tomsick T; blood pressure-lowering medication in ambulatory care? Systematic American Heart Association; American Stroke Association Council on review of randomized controlled trials. Arch Intern Med. 2004;164: Stroke; Council on Cardiovascular Radiology and Intervention; American Academy of Neurology. Guidelines for prevention of stroke in patients 8. Goldstein LB, Adams R, Alberts MJ, Appel LJ, Brass LM, Bushnell CD, with ischemic stroke or transient ischemic attack: a statement for Culebras A, Degraba TJ, Gorelick PB, Guyton JR, Hart RG, Howard G, healthcare professionals from the American Heart Association/American Kelly-Hayes M, Nixon JV, Sacco RL; American Heart Association/ Stroke Association Council on Stroke: co-sponsored by the Council on American Stroke Association Stroke Council; Atherosclerotic Peripheral Cardiovascular Radiology and Intervention: the American Academy of Vascular Disease Interdisciplinary Working Group; Cardiovascular Neurology affirms the value of this guideline. Stroke. 2006;37:577– 617.
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10. Amarenco P, Bogousslavsky J, Callahan A 3rd, Goldstein LB, Hennerici 4. ESPRIT Study Group, Halkes PH, van Gijn J, Kappelle LJ, Koudstaal PJ, M, Rudolph AE, Sillesen H, Simunovic L, Szarek M, Welch KM, Zivin Algra A. AAspirin plus dipyridamole versus aspirin alone after cerebral JA; Stroke Prevention by Aggressive Reduction in Cholesterol Levels ischaemia of arterial origin (ESPRIT): randomised controlled trial.
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KEY WORDS: AHA Scientific Statement Ⅲ stroke Ⅲ transient ischemic attack

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