Uchiyama S, Amarenco P, Minematsu K, Wong KSL (eds): TIA as Acute Cerebrovascular Syndrome. Front Neurol Neurosci. Basel, Karger, 2014, vol 33, pp 135–146 (DOI: 10.1159/000351914)
Stroke Subtypes and Interventional Studies for Transient Ischemic Attack Philippa Lavallée · Pierre Amarenco INSERM U-698, Department of Neurology and Stroke Center, AP-HP, Bichat-Claude Bernard Hospital, University Paris Diderot, Sorbonne Paris Cité, Paris, France
Abstract
As transient ischemic attacks (TIA) and stroke share pathophysiologic mechanisms, causes and risks, principles of secondary prevention are pretty much the same, and most randomized clinical trials of secondary stroke prevention have included TIA either alone or with cerebral infarction with no significant handicap. The main pillars of preventive treatment in TIA patients are identification and treatment of the cause
Downloaded by: Univ. of California Santa Barbara 198.143.33.34 - 6/28/2015 5:53:40 PM
Transient ischemic attack (TIA) is the most important risk factor for ischemic stroke. The risk is the highest in the first hours after symptom onset, and treatment must be initiated in emergency. In the acute phase, antithrombotic agent is probably the most important treatment, but it is not excluded that lipid-lowering agents and/or antihypertensive drugs are also important. For current guidelines, monotherapy of antiplatelet agent remains the gold standard in emergency. However, most recent data and meta-analysis support a combination therapy of clopidogrel and aspirin. Data on treatment in the very acute phase of TIA in the different etiologic stroke subtypes are also lacking especially for cardioembolic stroke and the potential benefit of anticoagulant. Long-term prevention mainly derived from large trials, in which TIA and minor stroke patients have constituted the largest part. Patients with non-cardioembolic stroke must be treated with antiplatelet agent in monotherapy, and dual antiplatelet therapy such as clopidogrel plus aspirin should be avoided, particularly in lacunar strokes, whereas anticoagulants are the treatment of choice for patients with cardioembolic stroke. Major advances concerning stroke prevention in patients with atrial fibrillation have emerged with new oral anticoagulant agents that are as effective as vitamin K antagonists and safer, especially with regard to the risk of intracranial hemorrhage. At variance with moderate and severe cerebral infarction, oral anticoagulants can be initiated without delay in TIA patients. Left atrial appendage closure seems to be a promising treatment in patients ineligible for anticoagulation. Aggressive management of vascular risk factors, including blood pressure as low as 130/80 mm Hg, intensive statin treatment, smoking cessation and diabetes control, also plays a major role in the prevention of vascular event. Copyright © 2014 S. Karger AG, Basel
and management of vascular risk factors. Prompt evaluation and adequate treatment have been shown to be highly effective and are the key factors for stroke risk reduction after a TIA [1, 2]. In the present chapter, we will discuss specific management of the main stroke causes (atherosclerosis, atrial fibrillation, AF, and small vessel disease, SVD). General principles for management of vascular risk factors are not within the scope of our topic and will be discussed in dedicated chapters. Acute secondary prevention, independent of stroke subtype, will also be shortly discussed. The etiological classification of ischemic stroke has been defined as large artery atherosclerotic (LAA) disease, which may be extracranial or intracranial; embolism from a cardiac source; SVD; other determined cause (e.g. dissection, hypercoagulable states, vasculitis), and infarcts of undetermined cause [3]. Whatever the cause of cerebral infarction, treatment still relies on the use of antithrombotic. We will see that the choice of antithrombotic depends on stroke subtypes but that in some cases further treatment is necessary.
Prospective studies have shown that stroke risk is high after a TIA: 3.1% (95% CI: 2.0–4.1) at 2 days and 5.2% (3.9–6.5) at 7 days [4]. Secondary prevention should be initiated as soon as possible, as early and intensive management (antithrombotic agent, vascular factor management, revascularization procedure if necessary) of these patients in a dedicated clinic has shown efficacy in reducing the risk of stroke by 80% in 2 studies [1, 2]. In both studies, specific details such as delay or type of antithrombotic drugs, exact delay for administration of statin or lowering blood pressure therapy are lacking. So, no conclusion concerning the relative contributions of the different aspects of their treatment to the benefit observed can be drawn. The FASTER (Fast Assessment of Stroke and Transient Ischemic Attack to prevent Early Recurrence) pilot trial [5], is the first trial dedicated to the treatment of patients in the very acute phase of minor stroke and TIA. There was no stroke subtype restriction. Patients were randomly assigned within 24 h to clopidogrel or its placebo on top of aspirin, and were separately randomly assigned to simvastatin or its placebo. The primary outcome was stroke (ischemic and hemorrhagic) at 90 days. Safety outcomes included hemorrhage related to clopidogrel and myositis related to simvastatin. Unfortunately, the study was stopped prematurely due to failure of recruitment. The risk of stroke was nonsignificantly decreased in the clopidogrel plus aspirin group in comparison with the aspirin group [7.1 vs. 10.8%, risk ratio 0.7 (95% CI: 0.3–1.2)]. Two patients on clopidogrel had intracranial hemorrhage compared with none on the placebo [absolute risk increase 1.0% (–0.4 to 2.4); p = 0.5]. No benefit was observed in the simvastatin group. Data are still too limited to recommend the combination of aspirin and clopidogrel in the acute phase of TIA. However the result of three large trials (CHANCE [6],
136
Lavallée · Amarenco Uchiyama S, Amarenco P, Minematsu K, Wong KSL (eds): TIA as Acute Cerebrovascular Syndrome. Front Neurol Neurosci. Basel, Karger, 2014, vol 33, pp 135–146 (DOI: 10.1159/000351914)
Downloaded by: Univ. of California Santa Barbara 198.143.33.34 - 6/28/2015 5:53:40 PM
Acute Management of Patients with Transient Ischemic Attack Independently of Stroke Subtype
POINT and TARDIS) testing combination of antiplatelet agents in the very acute phase of TIA or minor score are coming and could change daily practice. The results of the CHANCE trial have been recently presented at the last International Stroke Conference. 5,170 Chinese patients were randomly assigned within 24 h of symptom onset to clopidogrel (300-mg loading dose followed by 75 mg daily) plus aspirin 75 mg for the first 21 days followed by clopidogrel until 90 days or to aspirin alone. The primary outcome (ischemic and hemorrhagic stroke within the first 90 days) occurred in 11.7% of the aspirin alone group compared with 8.2% of the clopidogrel plus aspirin group (hazard ratio, HR = 0.68; 95% CI: 0.57–0.81). The risk of hemorrhagic stroke was very small (0.3%) and similar in both groups. Data on anticoagulant therapy in the acute phase of TIA are lacking. No data are available concerning blood pressure-lowering therapy or lipid-lowering agent (except in the FASTER trial [5]) in this population. Moreover, secondary prevention trials considering stroke subtypes in the acute phase of TIA do not exist, limiting the generalization of the available results.
Large Artery Atherosclerotic Disease
Antithrombotic Regimen Antiplatelet therapy has proven to be effective in reducing major vascular events (non-fatal myocardial infarction, non-fatal stroke, or vascular death) among patients with non-cardioembolic stroke or TIA. On average, antiplatelet agents reduce the risk of major vascular events by about 22% and should be administered as soon as possible after TIA [10]. Several antiplatelet drugs are available: aspirin, combination aspirin/ dipyridamole, clopidogrel, ticlopidine, cilostazol and triflusal (not all of them have been approved by all drugs agencies). All of these agents are effective in major vascular event prevention after a TIA. The choice depends on efficacy, tolerance, patient profile, price and availability. Aspirin is by far the cheapest drug. The combination of aspirin/dipyridamole is more effective than aspirin alone to prevent major vascular event or major bleeding, but tolerance such as headaches and bleeding could limit its clinical value [11, 12]. The combination of aspirin/dipyridamole has also been compared with clopidogrel alone and failed to show non-inferiority for recurrent stroke or major vascular event occurrence [13]. In this study, the combination therapy was associated with more major
Stroke Subtypes and Interventional Studies for TIA Uchiyama S, Amarenco P, Minematsu K, Wong KSL (eds): TIA as Acute Cerebrovascular Syndrome. Front Neurol Neurosci. Basel, Karger, 2014, vol 33, pp 135–146 (DOI: 10.1159/000351914)
137
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LAA is directly responsible for about 30% of TIAs. However, in 90% of cases, investigations find some form of atherosclerotic disease (regardless of the degree of stenosis) in intra- or extracranial arteries or in the thoracic aorta of coronary arteries. Importantly, the main large secondary stroke prevention trials that have tested antiplatelet agents [7–9] have also included patients with other non-cardioembolic stroke such as patients with SVD or with undetermined causes (stroke of presumed arterial origin).
Revascularization Procedures Extracranial Carotid Artery Disease Carotid endarterectomy is the gold standard for stroke prevention in patients with severe symptomatic internal carotid stenosis. Pooled analysis of data from randomized controlled trials indicates that carotid endarterectomy significantly reduces risk of stroke in patients with 50% or greater stenosis who have had a TIA or previous non-disabling stroke. Surgery was highly beneficial in patients with 70–99% stenosis and moderate in patients with 50–69% stenosis with a significant absolute risk reduc-
138
Lavallée · Amarenco Uchiyama S, Amarenco P, Minematsu K, Wong KSL (eds): TIA as Acute Cerebrovascular Syndrome. Front Neurol Neurosci. Basel, Karger, 2014, vol 33, pp 135–146 (DOI: 10.1159/000351914)
Downloaded by: Univ. of California Santa Barbara 198.143.33.34 - 6/28/2015 5:53:40 PM
hemorrhagic events including intracranial hemorrhage even though the net benefit with regard to the risk of recurrent stroke or major hemorrhagic event was similar in the two groups. Compared to aspirin, clopidogrel achieved a nonsignificant reduction of major vascular events with similar safety profile [14]. Because of safety concern, the use of ticlopidine is now limited in daily clinical practice [15]. Triflusal, which has not been approved by all drug agencies, has similar efficacy than aspirin for secondary prevention of serious vascular events and was associated with a lower risk of hemorrhagic complications [16]. In conclusion, aspirin (75–150 mg/day), the combination of aspirin (38–300 mg/ day) and dipyridamole (200 mg extended release twice daily), clopidogrel (75 mg/day) or triflusal (600 mg/day) are all good options in first-line therapy for prevention of major vascular events in patient with TIA from arterial origin. There is also some evidence that a short course of dual antiplatelet treatment could be effective in the prevention of major vascular events in the very acute period after a TIA or minor stroke especially for those related to LAA. The MATCH [17], CHARISMA [18] and FASTER [5] studies, which have compared in patients with non-cardioembolic stroke, the effectiveness of aspirin plus clopidogrel with, respectively, clopidogrel alone or aspirin alone, showed a trend in favor of the combination therapy in patients included in the acute setting. Microembolic signals are common in patients with LAA and are an independent marker of future stroke risk in patients with extracranial disease [19] or intracranial stenosis [20]. In the CARESS [21] and CLAIR [22] studies, dual therapy with clopidogrel and aspirin was more effective than aspirin alone in reducing microembolic signals in the acute phase of stroke or TIA related to intracranial and extracranial LAA. To date, these data are still too limited to recommend the combination of aspirin and clopidogrel in the acute setting of TIA due to LAA or to presume arterial origin. Recently, the CHANCE trial performed in 5,000 Chinese stroke patients found at 90 days a 32% reduction in new ischemic or hemorrhagic stroke with no increase in major hemorrhages when dual antiplatelet therapy was compared with aspirin alone during 21 days, followed by monotherapy of clopidogrel versus aspirin until 90 days [6]. One other exception could be TIA due to high grade intracranial atherosclerosis since a short course of clopidogrel plus aspirin on top of intensive management of vascular risk factors was associated with an unexpected low rate of stroke recurrence in the SAMMPRIS trial (see below) [23].
Intracranial Artery Disease Symptomatic intracranial stenosis confers a very high risk of stroke recurrence despite the use of antithrombotic treatment such as aspirin or anticoagulant [29]. The surgical option with extracranial-intracranial bypass procedures was abandoned due to the lack of benefit over medical therapy in patients with middle cerebral artery disease [30]. Recently, the SAMMPRIS trial showed that aggressive medical management alone was superior to intracranial arterial stenting in addition to aggressive medical therapy in patients with a recent TIA or stroke attributed to severe stenosis of a major intracranial artery [23]. Despite negative result for the stenting hypothesis, the SAMMPRIS study has important positive implications as it has shown that aggressive medical management (target systolic blood pressure factor
Stroke Subtypes and Interventional Studies for Transient Ischemic Attack Philippa Lavallée · Pierre Amarenco INSERM U-698, Department of Neurology and Stroke Center, AP-HP, Bichat-Claude Bernard Hospital, University Paris Diderot, Sorbonne Paris Cité, Paris, France
Abstract
As transient ischemic attacks (TIA) and stroke share pathophysiologic mechanisms, causes and risks, principles of secondary prevention are pretty much the same, and most randomized clinical trials of secondary stroke prevention have included TIA either alone or with cerebral infarction with no significant handicap. The main pillars of preventive treatment in TIA patients are identification and treatment of the cause
Downloaded by: Univ. of California Santa Barbara 198.143.33.34 - 6/28/2015 5:53:40 PM
Transient ischemic attack (TIA) is the most important risk factor for ischemic stroke. The risk is the highest in the first hours after symptom onset, and treatment must be initiated in emergency. In the acute phase, antithrombotic agent is probably the most important treatment, but it is not excluded that lipid-lowering agents and/or antihypertensive drugs are also important. For current guidelines, monotherapy of antiplatelet agent remains the gold standard in emergency. However, most recent data and meta-analysis support a combination therapy of clopidogrel and aspirin. Data on treatment in the very acute phase of TIA in the different etiologic stroke subtypes are also lacking especially for cardioembolic stroke and the potential benefit of anticoagulant. Long-term prevention mainly derived from large trials, in which TIA and minor stroke patients have constituted the largest part. Patients with non-cardioembolic stroke must be treated with antiplatelet agent in monotherapy, and dual antiplatelet therapy such as clopidogrel plus aspirin should be avoided, particularly in lacunar strokes, whereas anticoagulants are the treatment of choice for patients with cardioembolic stroke. Major advances concerning stroke prevention in patients with atrial fibrillation have emerged with new oral anticoagulant agents that are as effective as vitamin K antagonists and safer, especially with regard to the risk of intracranial hemorrhage. At variance with moderate and severe cerebral infarction, oral anticoagulants can be initiated without delay in TIA patients. Left atrial appendage closure seems to be a promising treatment in patients ineligible for anticoagulation. Aggressive management of vascular risk factors, including blood pressure as low as 130/80 mm Hg, intensive statin treatment, smoking cessation and diabetes control, also plays a major role in the prevention of vascular event. Copyright © 2014 S. Karger AG, Basel
and management of vascular risk factors. Prompt evaluation and adequate treatment have been shown to be highly effective and are the key factors for stroke risk reduction after a TIA [1, 2]. In the present chapter, we will discuss specific management of the main stroke causes (atherosclerosis, atrial fibrillation, AF, and small vessel disease, SVD). General principles for management of vascular risk factors are not within the scope of our topic and will be discussed in dedicated chapters. Acute secondary prevention, independent of stroke subtype, will also be shortly discussed. The etiological classification of ischemic stroke has been defined as large artery atherosclerotic (LAA) disease, which may be extracranial or intracranial; embolism from a cardiac source; SVD; other determined cause (e.g. dissection, hypercoagulable states, vasculitis), and infarcts of undetermined cause [3]. Whatever the cause of cerebral infarction, treatment still relies on the use of antithrombotic. We will see that the choice of antithrombotic depends on stroke subtypes but that in some cases further treatment is necessary.
Prospective studies have shown that stroke risk is high after a TIA: 3.1% (95% CI: 2.0–4.1) at 2 days and 5.2% (3.9–6.5) at 7 days [4]. Secondary prevention should be initiated as soon as possible, as early and intensive management (antithrombotic agent, vascular factor management, revascularization procedure if necessary) of these patients in a dedicated clinic has shown efficacy in reducing the risk of stroke by 80% in 2 studies [1, 2]. In both studies, specific details such as delay or type of antithrombotic drugs, exact delay for administration of statin or lowering blood pressure therapy are lacking. So, no conclusion concerning the relative contributions of the different aspects of their treatment to the benefit observed can be drawn. The FASTER (Fast Assessment of Stroke and Transient Ischemic Attack to prevent Early Recurrence) pilot trial [5], is the first trial dedicated to the treatment of patients in the very acute phase of minor stroke and TIA. There was no stroke subtype restriction. Patients were randomly assigned within 24 h to clopidogrel or its placebo on top of aspirin, and were separately randomly assigned to simvastatin or its placebo. The primary outcome was stroke (ischemic and hemorrhagic) at 90 days. Safety outcomes included hemorrhage related to clopidogrel and myositis related to simvastatin. Unfortunately, the study was stopped prematurely due to failure of recruitment. The risk of stroke was nonsignificantly decreased in the clopidogrel plus aspirin group in comparison with the aspirin group [7.1 vs. 10.8%, risk ratio 0.7 (95% CI: 0.3–1.2)]. Two patients on clopidogrel had intracranial hemorrhage compared with none on the placebo [absolute risk increase 1.0% (–0.4 to 2.4); p = 0.5]. No benefit was observed in the simvastatin group. Data are still too limited to recommend the combination of aspirin and clopidogrel in the acute phase of TIA. However the result of three large trials (CHANCE [6],
136
Lavallée · Amarenco Uchiyama S, Amarenco P, Minematsu K, Wong KSL (eds): TIA as Acute Cerebrovascular Syndrome. Front Neurol Neurosci. Basel, Karger, 2014, vol 33, pp 135–146 (DOI: 10.1159/000351914)
Downloaded by: Univ. of California Santa Barbara 198.143.33.34 - 6/28/2015 5:53:40 PM
Acute Management of Patients with Transient Ischemic Attack Independently of Stroke Subtype
POINT and TARDIS) testing combination of antiplatelet agents in the very acute phase of TIA or minor score are coming and could change daily practice. The results of the CHANCE trial have been recently presented at the last International Stroke Conference. 5,170 Chinese patients were randomly assigned within 24 h of symptom onset to clopidogrel (300-mg loading dose followed by 75 mg daily) plus aspirin 75 mg for the first 21 days followed by clopidogrel until 90 days or to aspirin alone. The primary outcome (ischemic and hemorrhagic stroke within the first 90 days) occurred in 11.7% of the aspirin alone group compared with 8.2% of the clopidogrel plus aspirin group (hazard ratio, HR = 0.68; 95% CI: 0.57–0.81). The risk of hemorrhagic stroke was very small (0.3%) and similar in both groups. Data on anticoagulant therapy in the acute phase of TIA are lacking. No data are available concerning blood pressure-lowering therapy or lipid-lowering agent (except in the FASTER trial [5]) in this population. Moreover, secondary prevention trials considering stroke subtypes in the acute phase of TIA do not exist, limiting the generalization of the available results.
Large Artery Atherosclerotic Disease
Antithrombotic Regimen Antiplatelet therapy has proven to be effective in reducing major vascular events (non-fatal myocardial infarction, non-fatal stroke, or vascular death) among patients with non-cardioembolic stroke or TIA. On average, antiplatelet agents reduce the risk of major vascular events by about 22% and should be administered as soon as possible after TIA [10]. Several antiplatelet drugs are available: aspirin, combination aspirin/ dipyridamole, clopidogrel, ticlopidine, cilostazol and triflusal (not all of them have been approved by all drugs agencies). All of these agents are effective in major vascular event prevention after a TIA. The choice depends on efficacy, tolerance, patient profile, price and availability. Aspirin is by far the cheapest drug. The combination of aspirin/dipyridamole is more effective than aspirin alone to prevent major vascular event or major bleeding, but tolerance such as headaches and bleeding could limit its clinical value [11, 12]. The combination of aspirin/dipyridamole has also been compared with clopidogrel alone and failed to show non-inferiority for recurrent stroke or major vascular event occurrence [13]. In this study, the combination therapy was associated with more major
Stroke Subtypes and Interventional Studies for TIA Uchiyama S, Amarenco P, Minematsu K, Wong KSL (eds): TIA as Acute Cerebrovascular Syndrome. Front Neurol Neurosci. Basel, Karger, 2014, vol 33, pp 135–146 (DOI: 10.1159/000351914)
137
Downloaded by: Univ. of California Santa Barbara 198.143.33.34 - 6/28/2015 5:53:40 PM
LAA is directly responsible for about 30% of TIAs. However, in 90% of cases, investigations find some form of atherosclerotic disease (regardless of the degree of stenosis) in intra- or extracranial arteries or in the thoracic aorta of coronary arteries. Importantly, the main large secondary stroke prevention trials that have tested antiplatelet agents [7–9] have also included patients with other non-cardioembolic stroke such as patients with SVD or with undetermined causes (stroke of presumed arterial origin).
Revascularization Procedures Extracranial Carotid Artery Disease Carotid endarterectomy is the gold standard for stroke prevention in patients with severe symptomatic internal carotid stenosis. Pooled analysis of data from randomized controlled trials indicates that carotid endarterectomy significantly reduces risk of stroke in patients with 50% or greater stenosis who have had a TIA or previous non-disabling stroke. Surgery was highly beneficial in patients with 70–99% stenosis and moderate in patients with 50–69% stenosis with a significant absolute risk reduc-
138
Lavallée · Amarenco Uchiyama S, Amarenco P, Minematsu K, Wong KSL (eds): TIA as Acute Cerebrovascular Syndrome. Front Neurol Neurosci. Basel, Karger, 2014, vol 33, pp 135–146 (DOI: 10.1159/000351914)
Downloaded by: Univ. of California Santa Barbara 198.143.33.34 - 6/28/2015 5:53:40 PM
hemorrhagic events including intracranial hemorrhage even though the net benefit with regard to the risk of recurrent stroke or major hemorrhagic event was similar in the two groups. Compared to aspirin, clopidogrel achieved a nonsignificant reduction of major vascular events with similar safety profile [14]. Because of safety concern, the use of ticlopidine is now limited in daily clinical practice [15]. Triflusal, which has not been approved by all drug agencies, has similar efficacy than aspirin for secondary prevention of serious vascular events and was associated with a lower risk of hemorrhagic complications [16]. In conclusion, aspirin (75–150 mg/day), the combination of aspirin (38–300 mg/ day) and dipyridamole (200 mg extended release twice daily), clopidogrel (75 mg/day) or triflusal (600 mg/day) are all good options in first-line therapy for prevention of major vascular events in patient with TIA from arterial origin. There is also some evidence that a short course of dual antiplatelet treatment could be effective in the prevention of major vascular events in the very acute period after a TIA or minor stroke especially for those related to LAA. The MATCH [17], CHARISMA [18] and FASTER [5] studies, which have compared in patients with non-cardioembolic stroke, the effectiveness of aspirin plus clopidogrel with, respectively, clopidogrel alone or aspirin alone, showed a trend in favor of the combination therapy in patients included in the acute setting. Microembolic signals are common in patients with LAA and are an independent marker of future stroke risk in patients with extracranial disease [19] or intracranial stenosis [20]. In the CARESS [21] and CLAIR [22] studies, dual therapy with clopidogrel and aspirin was more effective than aspirin alone in reducing microembolic signals in the acute phase of stroke or TIA related to intracranial and extracranial LAA. To date, these data are still too limited to recommend the combination of aspirin and clopidogrel in the acute setting of TIA due to LAA or to presume arterial origin. Recently, the CHANCE trial performed in 5,000 Chinese stroke patients found at 90 days a 32% reduction in new ischemic or hemorrhagic stroke with no increase in major hemorrhages when dual antiplatelet therapy was compared with aspirin alone during 21 days, followed by monotherapy of clopidogrel versus aspirin until 90 days [6]. One other exception could be TIA due to high grade intracranial atherosclerosis since a short course of clopidogrel plus aspirin on top of intensive management of vascular risk factors was associated with an unexpected low rate of stroke recurrence in the SAMMPRIS trial (see below) [23].
Intracranial Artery Disease Symptomatic intracranial stenosis confers a very high risk of stroke recurrence despite the use of antithrombotic treatment such as aspirin or anticoagulant [29]. The surgical option with extracranial-intracranial bypass procedures was abandoned due to the lack of benefit over medical therapy in patients with middle cerebral artery disease [30]. Recently, the SAMMPRIS trial showed that aggressive medical management alone was superior to intracranial arterial stenting in addition to aggressive medical therapy in patients with a recent TIA or stroke attributed to severe stenosis of a major intracranial artery [23]. Despite negative result for the stenting hypothesis, the SAMMPRIS study has important positive implications as it has shown that aggressive medical management (target systolic blood pressure factor
