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AHA Scientific Statement
Supplement to the Guidelines for the Management of
Transient Ischemic Attacks
A Statement From the Ad Hoc Committee on Guidelines for the
Management of Transient Ischemic Attacks, Stroke Council,
American Heart Association
Gregory W. Albers, MD, Chair; Robert G. Hart, MD; Helmi L. Lutsep, MD; In 1994, a panel of the American Heart Association Stroke of these conditions, although few of these studies were Council published guidelines for the management of tran- sient ischemic attacks (TIAs).1 Over the last 5 years, many Reduction of both systolic and diastolic pressure in hyper- significant advances in medical and surgical therapy for tensive subjects substantially reduces stroke risk.4,5 Reduc- patients with TIAs have occurred. In addition, new data tion of isolated systolic hypertension to Ͻ140 mm Hg in the regarding risk factors for cerebral ischemic events have elderly, for example, in the recently completed Syst-Eur trial6 become available. These scientific advances have prompted demonstrated that treatment of older patients with isolated this supplement to the 1994 guidelines, which provides systolic hypertension led to a 42% reduction in stroke risk updated recommendations for management of patients with with no significant decline in overall mortality. Current guidelines for the treatment of hypertension have been Specific stroke-prevention strategies after a TIA are tai- published by the Joint National Committee on Prevention, lored to the most likely cause of the event and the patient’s Detection, Evaluation, and Treatment of High Blood underlying risk factors as determined by a focused, expedient diagnostic evaluation. For more information about epidemi- Diabetes mellitus is a well-established stroke risk factor.8,9 ology, etiology, and diagnostic evaluation of TIAs, see the Death due to cerebrovascular disease is substantially in- original guidelines.1 For the current report, panel members creased in patients with 2-hour blood glucose values above followed the rules of evidence used by the 1998 American the 97.5 percentile compared with those with values below College of Chest Physicians Conference on Antithrombotic the 80th percentile.10 Intensive treatment of both type 1 and type 2 diabetes, aimed at obtaining near-normal levels ofblood glucose, can substantially reduce the risk of microvas- Risk Factor Modification
cular complications such as retinopathy, nephropathy, and The approach to stroke prevention among patients who have neuropathy but has not been conclusively shown to reduce already had their first TIA includes identification and modi- macrovascular complications, including stroke.11–14 One re- fication of stroke risk factors. Nonmodifiable risk markers for cent study13 demonstrated that aggressive treatment of blood stroke include age, sex, race-ethnicity, and heredity.3 Al- pressure in persons with type 2 diabetes reduced the risk of though these risk markers cannot be changed, they nonethe- stroke by 44% (Pϭ0.01). Recent guidelines for management less serve as important identifiers of patients at risk of stroke, of diabetes have been published by the American Diabetes for whom an aggressive search for other modifiable risk factors might be particularly important. Modifiable strokerisk factors include hypertension, cardiac disease (particularly Lifestyle factors, including cigarette smoking, heavy use of atrial fibrillation), diabetes, hypercholesterolemia, cigarette alcohol, and physical inactivity, have all been associated with smoking, excessive use of alcohol, and physical inactivity.
an increased risk of stroke.16–19 Modification of these behav- Numerous prospective studies and clinical trials have consis- iors can lead to a decrease in risk of stroke, which may be tently shown a decreased risk of stroke with control of most mediated by reductions in other stroke risk factors, such ashypertension, diabetes, hypercholesterolemia, and coronaryartery disease.
This statement was approved by the American Heart Association Science Advisory and Coordinating Committee in July 1999. A single Clinical trials analyzing the relationship of lipid-lowering reprint is available by calling 800-242-8721 (US only) or writing the strategies and stroke have yet to confirm a reduction in risk American Heart Association, Public Information, 7272 Greenville Ave, for patients who have already had a TIA or stroke. Data Dallas, TX 75231-4596. Ask for reprint No. 71-0179. To purchaseadditional reprints: up to 999 copies, call 800-611-6083 (US only) or fax addressing the impact of treatment with statins on the 413-665-2671; 1000 or more copies, call 214-706-1466, fax 214-691- incidence of stroke are derived exclusively from trials of 6342, or e-mail pubauth@heart.org. To make photocopies for personal or primary and secondary prevention of coronary disease. In educational use, call the Copyright Clearance Center, 978-750-8400.
(Stroke. 1999;30:2502-2511.)
these studies, stroke was either a secondary end point or a 1999 American Heart Association, Inc.
nonspecified end point determined on the basis of post hoc Stroke is available at http://www.strokeaha.org
analyses. Meta-analyses of the lipid-lowering trials with the 2502
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new statin agents have found significant reductions in stroke dose selection. Recent clinical trials have addressed this risk.20 A 29% reduced risk of stroke and a 22% reduction in overall mortality were found. Secondary prevention trialsshowed a 32% reduction in stroke risk, and primary trials Optimal Dose of Aspirin to Prevent Stroke
demonstrated a 20% reduction. Two large trials21,22 in which After TIA
stroke was prespecified as a secondary end point have also Aspirin doses ranging from 25 mg 2 times per day29 to 325 shown significant reductions with pravastatin among subjects mg 4 times per day30 have been shown to be efficacious for with coronary artery disease and normal to only modest prevention of stroke after TIA. Controversy continues to elevations of cholesterol. Some clinical trials23,24 have also surround the question of whether aspirin doses in the higher demonstrated carotid plaque regression with statins. Although end of this range (ie, Ն650 mg/d) offer more protection statins have not been tested in patients with stroke or TIA, against stroke than lower doses.31–34 Two well-executed clinical trials in patients with cerebrovascular disease are randomized trials directly compared different aspirin doses in under way. TIA patients with cardiovascular risk factors and patients with TIAs and minor ischemic stroke (1200 versus cholesterol levels Ͼ200 mg/dL should have a complete lipid 300 mg/d35 and 283 versus 30 mg/d36) and found no statisti- analysis (total cholesterol, LDL, HDL, and triglycerides) and cally significant differences. Some have criticized these most likely will benefit from cholesterol-lowering regimens results because patients recruited into these trials were younger and had a relatively lower risk of stroke than most There are no data available from randomized clinical trials TIA patients, and because modest differences favoring high- to address the risks or benefits of postmenopausal hormone dose aspirin were not excluded with statistical confi- replacement therapy after a TIA. Ongoing trials, such as the dence.31,34 Nevertheless, available data from these direct Women’s Estrogen Stroke Trial and the Postmenopausal comparisons in TIA patients suggest that the efficacy of Estrogen and Progestin Intervention trial, may help provide aspirin for prevention of stroke is similar for all doses in the more evidence-based recommendations regarding the use of ranges tested. Indirect comparisons and results of in vitrostudies have been marshaled to support the possible addi- postmenopausal hormone replacement therapy. Data from tional efficacy of high-dose aspirin,31,34 but their clinical observational studies suggest that hormone replacement ther- apy may be associated with a reduction in myocardial A recently completed randomized trial, the Aspirin Carotid infarction and death. Data suggesting an increased risk of Endarterectomy (ACE) study, also directly compared differ- stroke from oral contraceptive use cannot be extrapolated to ent doses of aspirin in 2849 patients after carotid endarterec- postmenopausal hormone replacement therapy (for which the tomy. The rate of the event constellation of stroke, myocar- goal is to obtain physiological levels of estrogen).
dial infarction, or death within 3 months of surgery was Studies25,26 are continuing regarding the importance of modestly (6.2% versus 8.4%) but significantly lower in those other risk factors, including elevation of homocysteine, li- assigned lower doses of aspirin (81 or 325 mg/d) versus poprotein fractions [including lipoprotein (a)], and hyperco- higher doses (650 or 1300 mg/d) (PϽ0.03).37 The effect on agulable states from antiphospholipid antibodies, factor V, stroke as a separate end point was similar: 64 versus 85 protein C, and protein S deficiencies.
(PϭNS) among those receiving lower versus higher doses, Despite the wealth of data on the importance of stroke risk respectively. These findings contrast with the nonrandomized factors, control of these conditions is still inadequate because post hoc analysis of long-term follow-up data from the North of poor patient compliance and adherence to behavior mod- ifications as well as decreased detection and treatment by (NASCET),38 which suggested that high doses of aspirin healthcare providers.27,28 Further reductions in the risk of might be more effective than low doses. Although the stroke among patients with TIA will require enhancements in relevance of these findings to patients with TIA who have not our ability to detect, modify, and treat cerebrovascular risk had surgery is open to question, the results of the ACE study lend support to the use of lower doses of aspirin in patientswith cerebrovascular atherosclerosis.
Medical Therapy for TIAs
The gastrointestinal toxicity of aspirin is dose related, but Antiplatelet Agents
even low-dose aspirin (ie, 50 to 75 mg/d) slightly increases Antiplatelet agents are typically the treatment of choice for the risk of major bleeding, particularly gastrointestinal hem- prevention of future stroke in patients who have experienced orrhage.39 Enteric coating reduces gastrointestinal toxicity a TIA of presumed atherothrombotic origin. Four different and appears to inhibit thromboxane synthetase similarly to antiplatelet agents have shown efficacy for preventing stroke equal doses of uncoated preparations despite altered pharma- and/or other vascular events in patients with cerebrovascular cokinetics and dynamics, although this has not been thor- disease. The selection of a specific agent is typically based on oughly studied in elderly stroke-prone patients.
interpretation of the results of randomized clinical trials that Recently, the US Food and Drug Administration advocated have tested these agents in populations of patients who have the use of aspirin in doses of 50 to 325 mg/d for prevention had a recent TIA or stroke. Aspirin continues to be the most of stroke. There appears to be an emerging consensus in economical and frequently chosen antiplatelet agent for North America, irrespective of specialty, favoring the use of treatment of patients after a TIA. The greatest controversy aspirin 325 mg/d for prevention of stroke.40 For those unable regarding the use of aspirin for stroke prevention involves to tolerate aspirin 325 mg/d because of minor dyspepsia, the 2504
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options include taking aspirin with meals, using an enteric- ticlopidine patients; it was severe in 0.8% of patients (none of coated formulation, or taking a lower dose. It is the view of the patients in the aspirin group of TASS had severe neutro- this writing group that reasonable management of patients penia) but was reversible in all. Because severe neutropenia with TIA includes aspirin in doses of 50 to 1300 mg/d. With occurred within 90 days of initiation of therapy, a recommen- respect to the lack of established benefit of higher doses dation was made to screen for this potential side effect by coupled with modest dose-related toxicity, the writing group obtaining a complete blood count with differential every 2 recommends a dosage range of 50 to 325 mg of aspirin per weeks. Since the release of this drug, reports have described another hematologic problem, thrombotic thrombocytopenic For patients who experience an initial or recurrent TIA while taking aspirin (“aspirin failures”), there is no good Although ticlopidine is efficacious in stroke prevention, its evidence that altering the dose of aspirin instead of continu- usefulness is limited by its side effects. Ticlopidine is ing the original dose will reduce the risk of subsequent typically used in patients who are intolerant to aspirin or who stroke.41 Those who experience TIA or minor ischemic stroke have had an ischemic event despite taking aspirin. Because while taking aspirin appear to have a particularly high risk for the majority of side effects occur within the first 3 months, subsequent stroke. Most clinicians empirically replace aspirin patients who have tolerated these early months of therapy can with another antiplatelet agent in this circumstance. Although such an approach seems sensible, it is not evidencebased.41–43 Clopidogrel
Clopidogrel is chemically related to ticlopidine and also
Alternative Antiplatelet Agents
works by inhibiting platelet aggregation induced by ADP. Apotentially better side-effect profile than that of ticlopidine Ticlopidine
generated interest in this antiplatelet agent.
Ticlopidine hydrochloride prevents platelet aggregation in- The Clopidogrel versus Aspirin in Patients at Risk of duced by adenosine diphosphate (ADP). It is approved in theUnited States for prevention of stroke in patients with TIA or Ischemic Events (CAPRIE) trial47 assessed the relative effi- minor stroke. Two large, multicenter, randomized trials have cacy of clopidogrel and aspirin in reducing the risk of a evaluated the efficacy of ticlopidine in patients with cerebro- composite outcome cluster of ischemic stroke, myocardial infarction, or vascular death. Stroke by itself was not a The Canadian American Ticlopidine Study (CATS)44 as- prespecified end point in this trial. A 75 mg/d dose of sessed the efficacy of ticlopidine in patients who had a recent clopidogrel was compared with a 325 mg/d dose of aspirin in moderate to severe atherothrombotic (74%) or lacunar (26%) patients with recent ischemic stroke or myocardial infarction stroke for reducing the incidence of important vascular or patients who had symptomatic atherosclerotic peripheral events: stroke, myocardial infarction, or vascular death.
arterial disease. Patients in the stroke subgroup had had a Patients with strokes occurring from 1 week to 4 months stroke within 6 months of randomization and exhibited earlier were randomized to 250 mg of ticlopidine 2 times per persistent neurological signs for Ն1 week. TIA patients were day or placebo. A total of 1053 patients at 25 centers in not eligible for this study. In the entire group of 19 185 Canada and the United States were enrolled in the study.
patients enrolled in the study, intention-to-treat analysis According to an intention-to-treat analysis, the relative risk showed a statistically significant but quite small relative risk reduction for the cluster of important vascular events was reduction of 8.7% for the event cluster in favor of clopidogrel.
For the 6431 patients in the stroke subgroup, the relative risk In the Ticlopidine Aspirin Stroke Study (TASS),45 the reduction was a nonsignificant 7.3% in favor of clopidogrel efficacy of ticlopidine was compared with aspirin in reducing (Pϭ0.26). The majority of these stroke subgroup patients the incidence of stroke and death from all causes in 3069 developed a stroke as their first outcome event.
patients with a recent TIA (50%), reversible ischemic neuro- The safety profile of the drug appeared to be at least as logical deficit (12%), minor stroke (23%), or Ͼ1 of these good as that of aspirin. Although diarrhea and rash occurred events (15%). Patients with ischemic symptoms that occurred more commonly in the clopidogrel group than in the aspirin within 3 months of randomization were assigned to receive group, gastrointestinal distress and hemorrhage were reported either 250 mg of ticlopidine twice a day or 650 mg of aspirin more often in the aspirin cohort. Because the clopidogrel- twice a day. According to an intention-to-treat analysis, the treated patients showed no excess myelotoxicity, routine overall risk reduction of fatal and nonfatal stroke by ticlopi- blood count monitoring is not recommended as it is for dine at 3 years was 21%. Ticlopidine also reduced the risk of stroke and all causes of death by 12% compared with aspirin.
Although clopidogrel had a slightly greater efficacy than In a subgroup analysis of the TASS study, ticlopidine was aspirin in reducing the combined end point of myocardial noted to be particularly effective in patients who had been infarction, stroke, and vascular death in patients with athero- taking aspirin or anticoagulant therapy at the time of their sclerotic vascular diseases, the absolute benefit was small (0.5% absolute annual risk reduction), and there was no Diarrhea was the most frequent side effect of ticlopidine, significant benefit in patients with a recent stroke. Compared occurring in 12.5% of patients. Neutropenia was more com- with aspirin, clopidogrel had a smaller relative risk reduction mon in the ticlopidine groups in the TASS and CATS studies for stroke than ticlopidine. No direct comparisons between than in the comparison groups and occurred in 2.4% of all clopidogrel and ticlopidine are available (see Figure 1).
Albers et al
Supplement to Guidelines for TIA Management
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A second European Stroke Prevention Study (ESPS-2)29 was designed to ascertain the efficacy of aspirin and anextended-release formulation of dipyridamole for preventionof stroke or death and to determine whether the combinationof the 2 agents was superior to each agent given alone.
ESPS-2 was larger than previous trials investigating thedipyridamole and aspirin combination; it included 6602patients with stroke (76.3%) or TIA (23.7%) within 3 monthsof enrollment. The study had a 2ϫ2 factorial design, whichallowed comparisons between 4 treatment groups: aspirin 25 Figure 1. Comparison of the efficacy of alternative antiplatelet
mg BID; extended-release dipyridamole 200 mg BID; the agents with aspirin in patients with cerebrovascular disease: combination of aspirin 25 mg BID and extended-release major outcome events (relative risk reductions and 95% confi-dence intervals) in 3 large trials that compared an alternative dipyridamole 200 mg BID; and matched placebo. Com- antiplatelet agent with aspirin therapy alone. These data suggest pared with placebo, stroke risk was significantly reduced by that each of the 3 alternative agents is more effective than aspi- 18% with aspirin alone, 16% with dipyridamole alone, and rin alone for prevention of major vascular events. Data fromESPS-2 for the combined vascular end point reflect stroke 37% with combination therapy. The risk of the combination and/or MI and/or sudden death. Data taken from: Albers GW, of stroke or death was also reduced by each active treatment, Easton JD, Sacco RL, Teal P. Antithrombotic and thrombolytic although no effect was seen on death alone. When combina- therapy for ischemic stroke. Chest. 1998;114:683S– 698S.
tion therapy with aspirin and dipyridamole was comparedwith aspirin alone, there was a statistically significant 23.1% However, clopidogrel clearly has an advantage over ticlopi- reduction in stroke risk, whereas combination therapy com- dine in its side-effect profile. Clopidogrel offers another pared with dipyridamole alone reduced stroke risk by 24.7%.
alternative to aspirin that is particularly useful for patients Nearly twice as many events were avoided with combination with intolerance to aspirin. It is also likely to be useful for therapy as with aspirin or dipyridamole alone. The narrow patients who have an ischemic event despite aspirin therapy.
confidence interval of the ESPS-2 trial overlapped the wide Dipyridamole and Aspirin
confidence intervals of the earlier, smaller trials, which was The combination of aspirin, a cyclo-oxygenase inhibitor, and compatible with a consistent beneficial treatment effect of the dipyridamole, a cyclic nucleotide phosphodiesterase inhibi- dipyridamole and aspirin combination.
tor, theoretically offers a pharmacological advantage over The most common side effects of extended-release dipyr- each of these agents alone. This combination was evaluated in idamole-containing preparations were headache and gastro- 5 trials of cerebral ischemia, 4 of which included a compar- intestinal events. The aspirin-containing regimens produced ison with aspirin. The first 3 trials were relatively small. The more frequent and severe bleeding episodes.
French Toulouse Study enrolled 440 patients with TIAs.48 In comparison with aspirin, reductions in stroke risk with There was no statistically significant difference in outcome the combination therapy of extended-release dipyridamole measures among groups receiving aspirin 900 mg/d, aspirin and aspirin were greater than those reported for clopidogrel plus dihydroergotamine, aspirin plus dipyridamole and dihy- (see Figure 1); however, these agents have not been compared droergotamine, or dihydroergotamine alone. A study by directly. The aspirin and extended-release dipyridamole com- Bousser et al,49 the Accidents Ischemiques Cerebraux Lies a bination was well tolerated and provides another useful l’Atherosclerose (AICLA) study, included 604 patients with alternative to aspirin for prevention of stroke. Combinations TIAs (16%) or small strokes (84%). Patients were randomly of aspirin and ticlopidine or clopidogrel have not been tested assigned to receive aspirin 1000 mg/d, aspirin combined with in TIA or stroke patients. Therefore, the efficacy and safety of dipyridamole 225 mg/d, or placebo. There was a 42% these combinations in patients at risk of stroke are unknown.
reduction in risk of stroke with aspirin compared withplacebo. No added benefit was derived with dipyridamole. In Anticoagulants
the American-Canadian Cooperative Study,50 890 patients Cardioembolic Stroke
with carotid-distribution TIAs were evaluated. Brain or reti- Adjusted-dose oral anticoagulation with warfarin continues to nal infarction occurred in 60 (14%) of 442 patients taking be the therapy of choice for stroke prevention in patients with aspirin and in 53 (12%) of 448 patients taking aspirin plus atrial fibrillation who have had a TIA. The superior efficacy dipyridamole, which was not a significant difference.
of anticoagulation over aspirin for prevention of stroke in The European Stroke Prevention Study (ESPS)51 compared patients with atrial fibrillation and a recent TIA or minor placebo with aspirin 975 mg/d plus dipyridamole 225 mg/d in stroke was shown in the European Atrial Fibrillation Trial.52 2500 patients with TIAs (33%), reversible ischemic neuro- In addition, considerable data from multiple randomized trials logical deficits (7%), or stroke (60%). Because no patients have shown that oral anticoagulation is the treatment of were given aspirin alone, this study did not permit compari- choice for primary stroke prevention in high-risk atrial son of the combination with aspirin therapy. However, there fibrillation patients. Patients with atrial fibrillation who are at was an overall reduction of 33% in the risk of stroke and high risk of stroke include persons with a history of hyper- death and a reduction of 38% in the risk of stroke alone for tension, poor left ventricular function, rheumatic mitral valve those assigned to the combination treatment compared with disease, prosthetic heart valves, a prior stroke, TIA, systemic 2506
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The efficacy of aspirin for prevention of cardioembolic study). Some experts also recommend anticoagulation ther- stroke is considerably less than warfarin. Aspirin is recom- apy for patients who experienced a TIA while taking an mended for patients at high risk of cardioembolism who have antiplatelet agent or for persons with crescendo TIAs. Some contraindications to oral anticoagulation. Anticoagulant ther- clinicians use short-term anticoagulation after a TIA while an apy is appropriate for patients with several other high-risk urgent evaluation is being performed. No adequate data are sources of cardiogenic emboli who have a TIA; however, available to support or refute this practice. TIA patients with randomized clinical trials have not been performed in these extracranial cervical artery dissections, severe carotid steno- specific patient populations. These high-risk sources for sis before endarterectomy, antiphospholipid antibody syn- recurrent cardiac embolization include mechanical prosthetic drome, or cerebral venous sinus thrombosis may respond heart valves, recent myocardial infarction, left ventricular favorably to anticoagulation therapy; however, randomized thrombus, dilated cardiomyopathies, and marantic endocardi- clinical trial data are not available for these specific disorders.
tis. The role of anticoagulation for patients with TIA whohave a patent foramen ovale or an atrial septal aneurysm is Surgical Management
not clear. An ongoing study is comparing the efficacy of Carotid Artery Disease
aspirin with oral anticoagulation in patients with patent Atherosclerotic narrowing of the internal carotid artery at the foramen ovale who suffered a recent cryptogenic stroke.
carotid bifurcation in the neck is a common cause of TIA and Mitral valve prolapse, a common valvular abnormality, was stroke. During the late 1980s and 1990s, the value of carotid formerly thought to cause stroke, but more recent population- endarterectomy for stroke prevention was assessed by pro- based and case-control studies have not demonstrated an spective randomized trials. Three major prospective random- ized trials—NASCET, the European Carotid Surgery Trial(ECST), and the Veterans Affairs Cooperative Study Program Optimal Intensity of Anticoagulation
Recent studies have addressed the optimal intensity of oral
309 (VACSP 309)— evaluated the efficacy of carotid endar- anticoagulation for prevention of stroke in patients with atrial terectomy in symptomatic patients (patients with TIAs or fibrillation. Results from a large case-control study56 and 2 small strokes) with high-grade carotid stenosis. The results of randomized clinical trials52,57 suggest that the efficacy of oral these trials were reported in 1991 and showed a clear benefit anticoagulation declines significantly below an International of carotid endarterectomy.62–64 Endarterectomy was not ben- Normalized Ratio (INR) of 2.0. Recent surveys indicate that eficial for patients with mild stenosis (Ͻ30%) in the ECST.63 a high percentage of atrial fibrillation patients who are taking Recent Results for Moderate Carotid Stenosis
warfarin have subtherapeutic levels of anticoagulation.58 The results of NASCET and ECST, which compared surgical Current recommendations suggest a target INR of 2.5 (range and medical therapy in patients with recently symptomatic 2.0 to 3.0) for most indications for oral anticoagulation.59 moderate carotid stenosis, were reported in 1998.39,65 The Anticoagulation for Atherothrombotic Stroke
long-term (up to 8 years) outcome in patients with high-grade The relative efficacy of oral anticoagulation compared with stenosis who were entered in the trials was also reported.
antiplatelet therapy has not been adequately studied in pa- NASCET reported the results for symptomatic patients tients with atherothrombotic stroke or TIA. At present, the with moderate carotid stenosis who were randomly assigned only large randomized trial available compared very-high- to receive medical care (1108 patients) or surgery (1118 intensity oral anticoagulation (INR 3.0 to 4.5) with aspirin patients). Entry criteria included moderate carotid stenosis (30 mg/d) in patients with a recent TIA or minor stroke.60 and a nondisabling stroke or TIA referable to the stenosis This study was terminated prematurely because of a high rate within 180 days. Patients were stratified into 2 groups (either of major hemorrhage in the anticoagulation group. These a 50% to 69% or 30% to 49% stenosis of the internal carotid results demonstrate that an INR range of 3.0 to 4.5 is not safe artery measured angiographically). Average follow-up was 5 for patients with a recent TIA or atherothrombotic stroke. The years, and primary outcome measures were fatal or nonfatal Warfarin Aspirin Recurrent Stroke Study is a large ongoing stroke ipsilateral to carotid stenosis. For patients with 50% to trial comparing a lower target INR (1.4 to 2.8) with aspirin 69% stenosis, the rate of ipsilateral stroke over the 5-year (325 mg/d) in patients with a recent atherothrombotic stroke.
period was 22.2% in the medically treated group and 15.7% A European study (European and Australian Stroke Preven- in the surgically treated group (6.5% absolute risk reduction tion in Reversible Ischemia Trial) is also comparing the over 5 years, Pϭ0.045).39 In patients with Ͻ50% stenosis, the efficacy of oral anticoagulation with antiplatelet therapy for ipsilateral stroke rate was slightly lower (14.9%) in those secondary stroke prevention. The results of these trials are treated with endarterectomy than in those who were medi- expected to significantly clarify the role of oral anticoagula- cally treated (18.7%), but this was not significantly different tion after a noncardioembolic cerebral ischemic event.
(Pϭ0.16). The benefit achieved by surgery was greatest It is possible that specific atherothrombotic stroke subtypes among men, in patients with recent stroke (rather than TIA) may respond favorably to oral anticoagulation. For example, as the qualifying event, and in patients with hemispheric a nonrandomized retrospective study61 found that patients with symptomatic intracranial stenosis had a lower stroke rate The final results of ECST were also reported in 1998.65 when they took warfarin rather than aspirin. A randomized This report contained long-term follow-up data on patients trial based on these preliminary results is currently under way with a moderate degree of stenosis randomly assigned to (the Warfarin-Aspirin Symptomatic Intracranial Disease surgery or medical treatment as well as additional follow-up Albers et al
Supplement to Guidelines for TIA Management
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symptomatic patients with Ͼ70% stenosis as measured by theNASCET method can expect a far greater benefit fromcarotid endarterectomy. Surgical benefits appear to be partic-ularly robust for men, patients with hemispheric symptomsand without diabetes, and for persons with significant ulcersas demonstrated by angiography. The benefit of carotidendarterectomy is highly dependent on surgical risk.
NASCET had strict criteria for qualifying surgeons and usedongoing quality assessments to ensure acceptable levels ofperioperative complications.
Angioplasty and Stent Placement
Transluminal angioplasty with intravascular placement of
Figure 2. Differences in measurement techniques used by
NASCET and ECST. Comparisons of differences in stenosis
stents for treatment of carotid stenosis is currently being severity by the 2 methods are also illustrated. Reprinted with evaluated as an alternative to carotid endarterectomy. Some permission from: Donnan GA, Davis SM, Chambers BR, Gates initial case series have reported relatively low complication PC. Commentary: surgery for prevention of stroke. Lancet.
1998;351:1372–1373.
rates, and some investigators advocate this method of treat-ment for patients who are at high risk for surgery because of in patients with severe carotid stenosis and mild carotid heart disease or other comorbid factors. However, other stenosis. This multicenter, prospective, randomized, con- recent reports have suggested that the complication rate from trolled trial enrolled a total of 3024 patients. Entry criteria this procedure may be higher than initially reported.68 Early included Ն1 transient or mild symptomatic ischemic vascular results have demonstrated high rates of restoration of the event in the distribution of a carotid artery with some degree luminal diameter in the internal carotid artery.69 Case series have included patients with asymptomatic as well as symp- Like the results of NASCET, the results of ECST revealed tomatic carotid stenosis and mixtures of patients with various that surgery was most effective in patients with more severe degrees of comorbidity. The long-term effects of stenting and degrees of carotid stenosis. In the entire group (all degrees of rate of restenosis are unknown. Prospective randomized trials stenosis), 669 (37%) of the patients in the surgery group and comparing angioplasty and stenting with carotid endarterec- 440 (36.5%) of the patients in the control group sustained a tomy are ongoing.70,71 Until the results of these studies are major stroke or death (not significantly different). There was available, this procedure should be considered investiga- a 7% chance of major stroke or death complicating surgery.
tional. Recent case series have also provided preliminary data The risk of major ischemic strokes was much higher ipsilat- regarding the safety and efficacy of angioplasty for treatment eral to an unoperated symptomatic carotid artery with a of symptomatic intracranial stenosis.72,73 A high degree of stenosis Ͼ80% for 2 to 3 years after randomization. The technical success and low complication rates have been long-term risk of major stroke or death in medically treated patients with carotid stenosis Ͼ80% of the original lumendiameter at 3 years was 26.5% versus 14.9% in the surgically Extracranial-Intracranial Bypass
treated group for an absolute benefit of 11.6% over 3 years Extracranial-intracranial bypass is a procedure designed to (Pϭ0.001). As in the NASCET findings, women benefited improve blood flow to the brain by direct vascular conduits from the external carotid circulation to the intracranial circu- It is important to consider that the degree of carotid lation.74 The effects of superficial temporal to middle cerebral stenosis in ECST was measured differently than that in artery bypass were evaluated for patients with TIAs or mild NASCET.66,67 The degree of carotid stenosis is significantly strokes in a large, prospective, randomized trial funded by the higher if calculated by the NASCET rather than the ECST National Institutes of Health and conducted in 71 North method66 (see Figure 2). Stroke rates in medically treated American, European, and Asian centers.75 Entry criteria patients with carotid stenosis increase dramatically with included recent cerebral ischemic symptoms combined with stenosis Ͼ80% as measured by the ECST method. This carotid occlusion, carotid artery narrowing distal to the corresponds roughly to a 60% stenosis measured by the carotid bifurcation, or intracranial stenosis. Although a high patency rate of the bypass was demonstrated, the study found In summary, it appears that patients with a recent TIA or that superficial temporal artery–middle cerebral artery bypass nondisabling stroke with ipsilateral carotid stenosis benefit had no advantage over medical therapy.
from surgery if the stenosis is Ͼ50% as measured by the Because this trial included patients without hemodynamic NASCET method; however, this benefit appears to be less insufficiency, it is possible that patients selected on a hemo- pronounced in women. Sex and age differences, as well as dynamic basis may benefit from the procedure.76–79 New comorbidity, must be considered when treatment options are imaging techniques such as positron emission tomography, evaluated in patients with stenosis of 50% to 69%, because xenon computed tomography, and transcranial Doppler with the absolute benefit of surgery is relatively small for these vasoreactivity testing have been shown to identify patients patients. Women or patients with retinal TIAs with carotid with extracranial occlusive disease who are at high risk for stenosis Ͻ70% may not benefit from surgery. Recently subsequent stroke.80–82 Randomized clinical trials will be 2508
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Use of Antithrombotic Agents in Patients With TIAs
TIA (atherothrombotic) and aspirin-intolerant* or if ASA 50–325 mg/d (if contraindications to warfarin) ASA indicates acetylsalicylic acid (aspirin); ER-DP, extended-release dipyridamole.
*Neither ER-DPϩASA or ASA alone is recommended for patients who are allergic to aspirin or unable to take low-dose aspirin.
†The recommended antithrombotic agents have not been specifically tested in patients who have experienced a TIA during ASA therapy.
required to establish whether extracranial-intracranial bypass 2. Cigarette smoking should be discontinued. Counseling, surgery can benefit a specific subgroup of patients. Patients nicotine replacement therapies, bupropion, and formal with moyamoya disease who have had TIAs or recent strokes smoking cessation programs may all be helpful.
may benefit from extracranial-intracranial bypass or encepha- 3. Coronary artery disease, cardiac arrhythmias, conges- tive heart failure, and valvular heart disease should be lodural synangiosis procedures; however, results of well- controlled trials are not available.83–86 4. Excessive use of alcohol should be eliminated. Formal alcohol cessation programs are recommended. Mild to Surgery for Vertebrobasilar Disease
moderate use of alcohol (1 to 2 drinks per day) has been TIAs referable to the posterior circulation can result from associated with a reduction in stroke rates.
occlusive disease of the vertebrobasilar system. The 2 most 5. Treatment of hyperlipidemia is recommended. The common sites for vertebral artery atheroma are the origin of the AHA Step II diet (Յ30% of calories derived from fat, vertebral artery and slightly distal to the transition from the Ͻ7% from saturated fat, and Ͻ200 mg/d cholesterol extracranial to the intracranial portion.87–89 Surgical and endo- consumed) is recommended along with maintenance ofideal body weight and engagement in regular physical vascular treatments have been performed for patients with TIAs activity. If lipid levels remain elevated (LDL Ͼ130 or small strokes referable to atheromatous disease of the verte- mg/dL), use of a lipid-lowering agent, preferably a brobasilar system.90–92 Small case series have reported favorable statin, is recommended. The goal of therapy should be results. Vertebral artery transposition to the common carotid artery is increasingly used for vertebral origin stenosis.87,92–95 6. Fasting blood glucose levels Ͻ126 mg/dL are recom- Angioplasty can also be performed at this site. Either direct mended. Diet and oral hypoglycemics or insulin should endarterectomy or angioplasty with or without stenting has also be prescribed as needed to control diabetes.
been performed for patients with symptomatic intracranial ver- 7. Physical activity (30 to 60 minutes of exercise Ն3 to 4 tebral artery stenosis.88,90,96 For mid-vertebral lesions with fixed 8. Discontinuation of postmenopausal estrogen replace- stenosis or positional obstruction with ischemic symptoms, surgical reconstruction or decompression can be effective inrelieving symptoms.92,97 Bypass procedures have also been used Medical Therapy (Table)
in patients with vertebrobasilar ischemia.91 Comparisons ofsurgery and endovascular therapy are lacking, and there are no Atherothrombotic TIAs
Patients who have had an atherothrombotic TIA should
randomized controlled trials comparing these procedures with receive daily therapy with an antiplatelet agent to reduce the risk of recurrent stroke (grade A-1). Aspirin, clopidogrel,ticlopidine, and the combination of aspirin and extended- Recommendations
release dipyridamole are all acceptable options for initial Risk Factor Management
Risk factor guidelines are grade C because randomized trials In general, aspirin at a dosage range of 50 to 325 mg/d is have not been completed in TIA patients.
recommended as initial therapy for patients who are not allergicor intolerant to aspirin. For patients who have an atherothrom- 1. After thorough evaluation to determine the cause of the botic TIA while taking aspirin, there is no compelling evidence TIA, hypertension should be treated to maintain systolic that increasing the dose of aspirin provides additional benefit.
blood pressure below 140 mm Hg and diastolic blood Alternative antiplatelet agents are typically considered for these pressure below 90 mm Hg. For persons with diabetes, patients, although they have not been specifically evaluated in blood pressure levels Ͻ130/85 mm Hg are recommended.
patients who have “failed aspirin.” Although ticlopidine may be Albers et al
Supplement to Guidelines for TIA Management
2509
more effective for preventing stroke (on the basis of indirect Bypass Surgery
comparisons), clopidogrel (75 mg/d) is generally recommended Extracranial-intracranial bypass is not recommended for patients in favor of ticlopidine (250 mg BID) (grade C-2) because of its with TIAs (grade A-1). A subgroup of patients with anterior superior safety profile. The combination of extended-release circulation ischemia unresponsive to medical therapy with he- dipyridamole and aspirin may also be more effective than modynamic disturbances may benefit from bypass surgery.
clopidogrel (on the basis of indirect comparisons; grade C-2), Additional studies are required to determine the role of surgery and both have a favorable safety profile.
in these patients. Patients with moyamoya disease may benefit Anticoagulant therapy is not routinely recommended for from extracranial-intracranial bypass (grade C-2).
patients with atherothrombotic TIAs, as either short- or Therapy for Vertebrobasilar Ischemia
long-term therapy (grade B-2). Anticoagulant therapy is an Surgical or endovascular therapy may be appropriate for option for patients with a TIA who continue to have symp- patients with significant vertebrobasilar stenosis who have toms despite antiplatelet therapy (grade C-2). At anticoagu- continued symptoms referable to the posterior circulation lation intensities of INR 3.0 to 4.5, the risk of brain hemor- despite medical therapy. For significant stenosis at the origin rhage outweighs the potential benefits (grade A-1).
of the vertebral artery, vertebral artery transposition to the Therefore, if oral anticoagulants are used for atherothrom- common carotid artery or angioplasty and stenting are treat- botic TIA patients, a target INR Ͻ3.0 should be chosen.
ment options (grade C-2). For significant stenosis at the distal Cardioembolic TIAs
vertebral artery, endarterectomy, bypass, or endovascular Long-term oral anticoagulation is recommended for patients procedures are treatment options. For midvertebral lesions with atrial fibrillation who have a TIA (grade A-1). For these with fixed stenosis or positional obstruction with ischemic patients, a target INR of 2.5 (range 2.0 to 3.0) is recom- symptoms, surgical reconstruction or decompression can be mended. Oral anticoagulation is also beneficial for prevention effective in relieving symptoms (grade C-2).
of stroke in patients with other high-risk cardiac sources ofembolism (see section on Anticoagulants, Cardioembolic References
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