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Keywords:

  • Guideline;
  • Ischemic stroke;
  • Prevention;
  • TIA

Introduction

  1. Top of page
  2. Introduction
  3. Risk Factor Control
  4. Interventional Approaches for the Patient with Large-Artery Atherosclerosis
  5. Medical Treatment for Patients with Cardiogenic Embolism
  6. Antithrombotic Therapy for Noncardioembolic Stroke or TIA
  7. Treatment for Stroke Patients with other Specific Conditions
  8. Conflict of Interest
  9. References

Cerebrovascular disease has become the leading cause of mortality and morbidity in China, in both urban and suburb population, with 1,500,000–2,000,000 new strokes each year. After correction for age, the prevalence of stroke is 116–219/100,000/year, and mortality is 58–142/100,000/year. The prevalence of ischemic stroke has increased as the population has aged, and the lifestyle has changed. There are over 7,000,000 stroke survivors living in China, and 70% of them have suffered ischemic stroke. Many of the survivors of ischemic stroke have multiple stroke risk factors, and are at increased risk of recurrent stroke.

Many countries have stroke treatment recommendations that are based on data collected in the last decade from random controlled trials (RCTs) on stroke secondary prevention. Although the recommendations provide valuable information, there are considerable differences between Chinese and Western population in regard to genetic background of the population, health conditions, medicine tradition, cultural background, laws/regulations, and welfare systems. It is therefore necessary and urgent to establish stroke treatment guidelines that are relevant to the Chinese population. A panel of experts convened in July 2008 to develop guidelines for ischemic stroke secondary prevention that were specific for the Chinese population. It consisted of experts from neurology, cardiology, endocrinology, intensive care, respiratory, intervention, and epidemiology. The panel conducted a comprehensive review and synthesis of relevant domestic and international literature published before October 2008. When there was sufficient and reliable evidence, the evidence was used; alternatively, current best evidence and experts’ opinions were applied. After wide discussion, multiple editions, and additions of the current evidence, these guidelines have been established.

The crucial steps of secondary stroke prevention are to diagnose the causes and recognize the risk factors of stroke beginning with the acute phase of stroke. The risks of recurrent stroke are different, because the causes and the pathophysiological mechanisms of ischemic stroke/transient ischemic attack (TIA), the locations of vascular diseases, risk factors, and patients’ compliance are so variable. It is therefore important to stratify patients into high or low-risk groups based on the causes, and the numbers and severity of risk factors by using tools such as Essen stroke risk scale or the ABCD2 score. Only after stratifying correctly, is it possible to deliver individualized effective treatment and suitable prevention.

These guidelines are aimed to provide evidence-based recommendations on the secondary preventions of ischemic stroke/TIA to physicians in neurology, medicine, and other relevant departments in China. Unless specifically mentioned, the recommendations apply to both ischemic stroke and TIA. Please refer to the reference for methods used to classify the classes of evidence and the levels of certainty of the treatment effect [1].

Risk Factor Control

  1. Top of page
  2. Introduction
  3. Risk Factor Control
  4. Interventional Approaches for the Patient with Large-Artery Atherosclerosis
  5. Medical Treatment for Patients with Cardiogenic Embolism
  6. Antithrombotic Therapy for Noncardioembolic Stroke or TIA
  7. Treatment for Stroke Patients with other Specific Conditions
  8. Conflict of Interest
  9. References

Risk factors of stroke can be classified as modifiable and nonmodifiable ones. The goal is to control modifiable risk factors. Please refer to information on primary prevention regarding modifying lifestyle (such as smoking, alcohol excess, obesity, and limited physical activity) to reduce the risk of stroke. This guideline is to focus on the medical management of stroke secondary prevention.

Hypertension

Hypertension is a major risk factor for stroke/TIA. The prevalence of hypertension has been rising with the rapid socioeconomic growth and lifestyle changes in China. Studies in China suggest a logistic relationship between elevated blood pressure (BP) and the risk of stroke [2]: for every 10 mmHg elevation of systolic BP from baseline, the relative risk of stroke increases 49%; for every 5 mmHg elevation of diastolic BP, the relative risk of stroke increases 46%. The impact strength of hypertension on the risk of stroke in Chinese and Japanese populations is 1.5 times that of western population. A Chinese survey in 2002 showed the diagnose rate of hypertension was 30.2%; the treatment rate was 24.7%; and control rate was only 6.1%. During the same period, the rates of diagnosis, treatment, and control of hypertension in the United States were 70%, 59%, and 34%, respectively.

Lowering BP may benefit patients with stroke/TIA on secondary prevention. A systemic review of seven published RCT showed that lowering BP was associated with significant reductions of recurrent stroke, and total vascular events, without significant reductions in fatal stroke and vascular mortality [3]. However, the Prevention Regimen for Effectively Avoiding Second Stroke (ProFESS) trial found no difference in recurrent stroke in patients treated with telmisartan versus placebo [4].

Which antihypertensive medicines are more effective in the prevention of recurrent stroke? The Morbidity and Mortality After Stroke—Eprosartan versus Nitrendipine for Secondary Prevention (MOSES) trial suggested that an angiotensin II type I receptor antagonist (Eprosartan) could significantly lower the rate of recurrent cerebrovascular events when compared with a calcium antagonist (Nitrendipine) [5]. However, a review study on BP control in stroke prevention, which analyzed three head-to-head comparison trials consisted of total of 21,094 patients, suggested that calcium antagonist might be superior to angiotensin receptor blocker, diuretics, and β-blockers [6].

Recommendations
  • 1
    BP reduction is recommended for the prevention of recurrent stroke and other vascular events in patients with ischemic stroke/TIA. (Class I, Level of Evidence A). With consideration of age, baseline BP, routine medication, and tolerance, the target BP should be ≤140/90 mmHg, ideally 130/80 mmHg. (Class II, Level of Evidence B).
  • 2
    The effects of antihypertensive treatment on the prevention of recurrent stroke/TIA were primarily achieved by lowering BP (Class I, Level of Evidence A). Either a monotherapy or a combination of medicines can be used (Class II, Level of Evidence B). The choice should be individualized.

Diabetes

Blood glucose control is known to have protective effect on microvascular and macrovascular diseases secondary to Type II diabetes. Poor glucose control is associated with recurrence of stroke. Data on diabetic control in stroke prevention are largely based on primarily prevention. The Action Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial showed intensive control of glucose levels reduced glycated hemoglobin to 6.5%, resulting in a significant reduction in vascular events [7].

For patients with diabetes, intensive lowering BP may significantly improve the combine vascular outcome, including stroke. Epidemiological data have suggested when BP is further reduced to 120/80 mmHg there is a continuous reduction in cardiovascular events [8].

The Collaborative Atorvastatin Diabetes Study (CARDS) showed that statins are effective in reducing the risk of first incidence stroke in diabetic patients [9]. In addition, the Heart Protection Study (HPS) which included 5963 adults with diabetes, suggested add-on statins could reduce the rate of first major vascular events [10].

Recommendations
  • 1
    The goal of diabetic glycemic control is glycated hemoglobin of 6.5% or less. However hypoglycemia may be harmful, resulting in increased morbidity. (Class I, Level of Evidence A).
  • 2
    For patients with diabetes and hypertension, BP should be strictly controlled below 130/80 mmHg. Specific antihypertensive agents, such as angiotensin converting enzyme inhibitors and angiotensin receptor blockers are beneficial in the reduction of vascular events (Class I, Level of Evidence A). In combination with tight glycemic and BP control, statins may decrease the risk of stroke (Class I, Level of Evidence A).

Lipid

Evidence showed a modest association between elevated total cholesterol levels and an increased risk of ischemic stroke. Lifestyle modifying and statins are the primary lipid-lowering methods. A meta-analysis study which included statins, clofibrate, cholestyramine resin, gemfibrozil, niacin, and diet, showed that all lipid-lowering therapies significantly reduced the incidence of stroke [11]. However, the best efficacy was with statins, especially in secondary prevention, due to their higher potency.

The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial found that statin treatment may significantly reduce the recurrent rate of stroke/TIA [12]. Although the incidence of hemorrhagic stroke was higher in the statin group, there was no difference in outcome. A meta-analysis involving 121,000 patients demonstrated that prolonged statin treatment provided significant primary protection in patients at high risk of vascular diseases, without significantly elevated risk of hemorrhagic stroke [13].

For elderly patients with normal liver and renal function, the doses of lipid-lowering agents do not need to be adjusted. However, the treatment should be individualized, with lower doses initially and close monitoring [14].

Recommendations
  • 1
    Patients with ischemic stroke/TIA and elevated cholesterol should be managed with a combination of treatments including lifestyle and dietary modifications, and medications. Statins are recommended lipid-lowering agents. It is reasonable to target the low-density lipoprotein Cholesterol (LDL-C) ≤ 2.59 mmol/L or a 30–40% reduction in LDL-C (Class I, Level of Evidence A).
  • 2
    For patients with stroke/TIA and multiple risk factors (such as coronary artery disease, diabetes, current smoking, metabolic syndrome, cerebrovascular atherosclerosis without evidence of unstable plaque, arterial thrombosis or peripheral arterial disease), it is reasonable to target a LDL-C level of <2.07 mmol/L or a reduction of >40% in LDL-C (Class I, Level of Evidence A).
  • 3
    Patients with ischemic stroke/TIA and evidence of intra- and extracranial large artery atherosclerosis and unstable plaques or arterial thrombosis, are recommended early intensive statin therapy to target a LDL-C level of <2.07 mmol/L or a reduction of >40% in LDL-C (Class III, Level of Evidence C).
  • 4
    In general, long-term use of statins is safe. Before and during statin therapy, monitoring symptoms such as muscle pain, and liver enzymes (e.g., Alanine transaminase and aspartate transaminase) and muscle enzyme (creatine kinase) is required. If those markers are persistently elevated without other identifiable causes, statins should be reduced or discontinued (Discontinuation of statins was recommended when transaminases are more than three times the normal upper limits, or creatine kinease is more than five times the normal upper limit.) (Class I, Level of Evidence A). For elderly patients with multiple organ insufficiency, or taking multiple medications, drug–drug interactions and potential side effects should be closely monitored (Class III, Level of Evidence C).
  • 5
    If patients have a history or at high risk of intracranial hemorrhage, caution should be exercised with statin therapy (Class II, Level of Evidence B).

Interventional Approaches for the Patient with Large-Artery Atherosclerosis

  1. Top of page
  2. Introduction
  3. Risk Factor Control
  4. Interventional Approaches for the Patient with Large-Artery Atherosclerosis
  5. Medical Treatment for Patients with Cardiogenic Embolism
  6. Antithrombotic Therapy for Noncardioembolic Stroke or TIA
  7. Treatment for Stroke Patients with other Specific Conditions
  8. Conflict of Interest
  9. References

Carotid Endarterectomy

The North American Symptomatic Carotid Endarterectomy Trial (NASCET) and the European Carotid Surgery Trial (ECST) showed carotid endarterectomy (CEA) reduced the risk of ipsilateral stroke in patients with symptomatic high-grade stenosis (70–99%) of the internal carotid artery [15,16]. CEA is also beneficial to patients with symptomatic moderate (50–69%) ipsilateral carotid stenosis [17]. However, for patients with mild to moderate carotid stenosis (<50%), the possible benefits of CEA were outweighed by the risks of surgery. Early CEA may be associated with increased benefits, ideally within 2 weeks of their last ischemic event. Elderly patients (>75 years of age) without organ failure or severe cardiac dysfunction can also benefit from CEA. Women with severe symptomatic carotid stenosis (>70%) should consider CEA; however, women with less severe stenosis can be treated medically. It is important to prevent perioperative stroke during the procedure. The American Heart Association (AHA)/American Stroke Association Council on Stroke recommend that CEA can only be performed by a surgeon with a perioperative complication rate (combined morbidity and mortality) <6%[18]. Patients with carotid stenosis should take low-dose aspirin before and after surgery [19].

Recommendations
  • 1
    For patients with recent ischemic stroke/TIA and severe (70–99%) ipsilateral carotid artery stenosis, CEA is recommended (Class I, Level of Evidence A).
  • 2
    For patients with recent ischemic stroke/TIA and moderate (50–69%) ipsilateral carotid stenosis, CEA is recommended depending on patient-specific factors, such as age, sex, comorbidities and the severity of stroke (Class I, Level of Evidence A). CEA may benefit the most to men ≥75 years of age with their last hemispheric ischemic events within 2 weeks (Class III, Level of Evidence C).
  • 3
    CEA is recommended within 2 weeks of last ischemic event when indicated (Class II, Level of Evidence B).
  • 4
    CEA is not recommended for patients with carotid stenosis <50% (Class I, Level of Evidence A).
  • 5
    Continuation of antiplatelet therapy is recommended postoperatively (Class I, Level of Evidence A).

Endovascular Intervention for Extra and Intracranial Stenosis

Many reports suggested that Angioplasty and Stenting (CAS) can improve the outcome in patients with symptomatic carotid stenosis, but there is no evidence that CAS is superior to CEA. There is no clinical trial directly comparing the effectiveness of CAS with the best medical management. The Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS) showed CAS has comparable effectiveness as CEA on stroke secondary prevention in patients with symptomatic carotid stenosis, with less cranial neuropathy and major neck hematoma, but higher rates of restenosis [20]. A meta-analysis showed that CAS was associated with a greater 30-day risk of stroke/death when compared with CEA [21].

Intracranial angioplasty and/or stenting have been approved as safe procedures with a high degree of technical success when performed by experienced surgeons. However, the high rate of recurrent stenosis is unsolved [22].

Recommendations
  • 1
    For patients with symptomatic severe carotid stenosis (>70%), when CEA is not available, CAS may be considered, (Class IV, Level of Evidence D). For patients with symptomatic severe carotid stenosis (>70%) that are difficult to access surgically, early recurrent stenosis after CEA, and radiation-induced stenosis, CAS may be considered (Class II, Level of Evidence B). CAS may be considered in elderly patients with caution (Class II, Level of Evidence B).
  • 2
    For patients with symptomatic intracranial carotid stenosis, endovascular intervention may be effective (Class II, Level of Evidence B).
  • 3
    Combination of aspirin and clopidogrel should be given before stenting, and continued for at least 1 month after surgery. Clopidogrel alone is also recommended thereafter for at least 12 months (Class IV, Level of Evidence D).

Medical Treatment for Patients with Cardiogenic Embolism

  1. Top of page
  2. Introduction
  3. Risk Factor Control
  4. Interventional Approaches for the Patient with Large-Artery Atherosclerosis
  5. Medical Treatment for Patients with Cardiogenic Embolism
  6. Antithrombotic Therapy for Noncardioembolic Stroke or TIA
  7. Treatment for Stroke Patients with other Specific Conditions
  8. Conflict of Interest
  9. References

Atrial Fibrillation

A Cochrane review in 1995 showed that warfarin reduced the odds of recurrent stroke by two-thirds, with no reported intracranial hemorrhage [23]. In 2002, collaborative meta-analysis from Antithrombotic Trialists’ Collaboration suggested that antiplatelet agents reduced the risk of nonfatal stroke by about a quarter [24].

In 2005, the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE W) demonstrated warfarin is superior to clopidogrel plus aspirin in prevention of vascular events in patients with atrial fibrillation, with comparable risk of major bleeding [25]. Later (2009) ACTIVE A showed that in patients with atrial fibrillation who were unsuitable to warfarin, the addition of clopidogrel to aspirin significantly reduced the risk of major vascular events compared with aspirin alone [26]. However, the risks of major hemorrhage, including intracranial bleeding were increased in the dual antiplatelet group, although not significant in fatal hemorrhage.

In 2006, an RCT, comparing warfarin and aspirin in the prevention of embolic stroke in Chinese patients with atrial fibrillation without valvular diseases, showed warfarin had significantly better primary outcomes when compared with aspirin, although not significant in mortality [27].

Warfarin is effective, but it has a narrow treatment range, requiring frequent monitoring international normalized ratio (INR) and adjusting doses. Internationally, when warfarin is used for stroke prevention in patients with atrial fibrillation, the effective and safe target INR range of 2.0–3.0 is recommended. A study on the safety and the effectiveness of warfarin in Chinese patients with atrial fibrillation suggested that a target INR range of 1.5–3.0 [28]. However, this result requires further verification.

Recommendations
  • 1
    For patients with ischemic stroke/TIA and atrial fibrillation (including paroxysmal atrial fibrillation), oral anticoagulation with warfarin (target INR range of 2.0–3.0) is recommended to prevent secondary stroke (Class I, Level of Evidence A).
  • 2
    For patients unable to take oral anticoagulants, antiplatelet agents were recommended (Class I, Level of Evidence A). In addition, combination of clopidogrel and aspirin may be superior to aspirin alone (Class I, Level of Evidence A).

Acute Myocardial Infarction (MI) and Left Ventricular (LV) Thrombus

Patients with acute MI and complicated with stroke are at very high risk of recurrent vascular events. The major risk factors for stroke in the setting of acute MI are anterior MI, hypertension, atrial fibrillation, previous stroke, and advanced age.

The American College of Cardiology (ACC)/AHA guidelines for the management of patients with ST-elevation myocardial infarction (STEMI) recommended daily long-term aspirin (clopidogrel, if aspirin is contraindicated) as secondary prevention [29]. In clinically indicated patients (e.g., atrial fibrillation and LV thrombus), warfarin is recommended with a target INR range of 2.0–3.0. For patients with LV thrombus following MI and complicated with ischemic stroke/TIA, warfarin is recommended for 3 months to 1 year.

Recommendations
  • 1
    Patients with ischemic stroke/TIA in the setting of acute MI, aspirin 75– 325 mg daily is recommended (Class I, Level of Evidence A).
  • 2
    Patients with ischemic stroke/TIA in the setting of acute MI complicated with LV mural thrombus, should be treated with warfarin for at least 3 months (up to 1 year) with target INR of 2.0–3.0 (Class II, Level of Evidence B).

Valvular Heart Disease

  • 1
    Rheumatic Mitral Valve disease: Patients with rheumatic mitral valve disease and previous embolic event, have a high risk of recurrent embolism. Long-term anticoagulant therapy may effectively reduce embolic events in those patients. It has been demonstrated by transesophageal echocardiogram that long-term anticoagulant therapy may result in disappearance of left atrial thrombus [30]. ACC/AHA guidelines for the management of patients with valvular heart disease recommended anticoagulant therapy in patients with mitral stenosis and one of the following conditions: atrial fibrillation (paroxysmal, persistent or permanent), a history of embolic event (even in sinus rhythm), or left atrial thrombus [31].
  • 2
    Nonrheumatic Mitral Valve diseases: There are two nonrheumatic mitral valve diseases associated with stroke: mitral valve prolapse and mitral annular calcification. To date there have been no clinical trials addressed the efficacy of antithrombotic therapies for patients with mitral valve prolapse. Some observational studies suggested antiplatelet therapy for patients with mitral valve prolapse and a prior thrombus event; and anticoagulation or antiplatelet for patients with mitral annular calcification and prior thrombus events. ACC/AHA guidelines for the management of patients with valvular heart disease recommended aspirin (75–325 mg daily) for patients with mitral valve prolapse and prior cerebral TIA [31]. Warfarin is also recommended for stroke patients with mitral valve prolapse, and complicated with mitral regurgitation, atrial fibrillation, or left atrial thrombus.
  • 3
    Aortic Valve Disease: Although autopsy studies have reported systemic embolism in about one-third of cases with calcific aortic valves, there have been no randomized clinical trials on patients with stroke/TIA and aortic valve disease [32].
  • 4
    Cardiac Valve repair and prosthetic heart valves: There have been no random clinical trials to specifically address secondary stroke prevention in patients with cardiac valve repair or prosthetic heart valves. The European Society of Cardiology (ESC) published guidelines on the anticoagulation management of patients with valvular heart disease which suggested targeting INR should take into account patients’ risk factors and the thrombogenicity of the prosthesis [33].
Recommendations
  • 1
    For patients with ischemic stroke/TIA and rheumatic mitral valve disease, with or without atrial fibrillation, long-term anticoagulation with warfarin with a target INR range of 2.0–3.0 is recommended (Class III, Level of Evidence C). Antiplatelet agents should not be added to warfarin to avoid increasing bleeding risk (Class III, Level of Evidence C).
  • 2
    For patients with ischemic stroke/TIA and rheumatic mitral valve disease, who suffered recurrent ischemic stroke/TIA while on adequate anticoagulation, addition of antiplatelet to warfarin is reasonable (Class III, Level of Evidence C).
  • 3
    For patients with ischemic stroke/TIA and mitral valve prolapse, antiplatelet therapy may be considered (Class III, Level of Evidence C).
  • 4
    For patients with ischemic stroke/TIA and mitral valve insufficiency, atrial fibrillation or left atrial thrombus, long-term warfarin therapy is recommended (Class III, Level of Evidence C).
  • 5
    For patients with ischemic stroke/TIA and mitral annular calcification, antiplatelet or warfarin may be considered (Class IV, Level of Evidence D).
  • 6
    For patients with ischemic stroke/TIA and aortic valve disease, antiplatelet therapy is recommended (Class III, Level of Evidence C).
  • 7
    For patients with ischemic stroke/TIA who have mechanical prosthetic heart valves, anticoagulation with warfarin is recommended with a target INR range of 2.5–3.5 (Class II, Level of Evidence B).
  • 8
    For patients with ischemic stroke/TIA who have bioprosthetic heart valves or mechanic prosthetic heart valve with low thrombogenicity, anticoagulation with warfarin with a target INR range of 2.0–3.0 is recommended (Class II, Level of Evidence B).
  • 9
    For patients with ischemic stroke/TIA and treated with warfarin, who have recurrent ischemic stroke/TIA with a target INR, addition of antiplatelet may be considered (Class III, Level of Evidence C).

Cardiomyopathy and Heart Failure

Patients with dilated cardiomyopathy have a high risk of intracardial mural thrombus formation. For patients with atrial fibrillation or are at high risks of thrombus events such as deep vein thrombosis, aspirin 75–100 mg daily may be used to prevent mural thrombus. Patients with ischemic stroke/TIA and identified mural thrombi should be treated with long-term oral anticoagulation with warfarin (target INR of 2.0–3.0).

For patients with chronic heart failure, the Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) trial did not show any significant difference between warfarin and aspirin or clopidogrel at primary vascular outcome, including stroke. However, there were more bleeding events in the warfarin group [34].

Recommendations
  • 1
    For patients with ischemic stroke/TIA and dilated cardiomyopathy, antiplatelet therapy or warfarin (INR 2.0–3.0) may be considered to prevent recurrent ischemic events (Class III, Level of Evidence C).
  • 2
    For patients with ischemic stroke/TIA and chronic heart failure, antiplatelet may be considered (Class III, Level of Evidence C).

Antithrombotic Therapy for Noncardioembolic Stroke or TIA

  1. Top of page
  2. Introduction
  3. Risk Factor Control
  4. Interventional Approaches for the Patient with Large-Artery Atherosclerosis
  5. Medical Treatment for Patients with Cardiogenic Embolism
  6. Antithrombotic Therapy for Noncardioembolic Stroke or TIA
  7. Treatment for Stroke Patients with other Specific Conditions
  8. Conflict of Interest
  9. References

Noncarioembolic strokes/TIAs are ischemic events caused by atherosclerotic disease, occlusion of small arteries, or crytogenic infarcts.

Antiplatelet Agents

Antiplatelet therapy may significantly reduce the risks of vascular death, nonfatal MI, and nonfatal stroke, in patients with previous stroke/TIA [24].

  • 1
    Aspirin: Aspirin (50–1300 mg daily) provide some prevention for recurrent stroke, regardless of the dosage. However, high doses of aspirin have a higher risk of gastrointestinal bleed [18].
  • 2
    Clopidogrel: Compared with aspirin, clopidogrel may be more effective in reducing the combined risk of ischemic stroke, MI, and vascular death [35]. The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabliation, Management, and Avoidance (CHARISMA) trial suggested that clopidogrel may be more beneficial than aspirin in patients with symptomatic atherothrombosis disease [36]; however, it may not be so in patients with multiple risk factors.
  • 3
    Dipyridamole: Regardless of its formula, dipyridamole may reduce cerebrovascular events, but not death from vascular events. There is no evidence that dipyridamole is more effective than aspirin.
  • 4
    Dipyridamole and aspirin: The second European Stroke Prevention Study (ESPS2) showed that combination therapy of aspirin 25 mg twice a day and extended-release dipyridamole 200 mg twice a day significantly reduced the risk of stroke or death from vascular events when compared with aspirin alone [37].
  • 5
    The PRoFESS trial showed no difference in the recurrence rate of stroke between the clopidogrel group and the dipyridamole and aspirin combination group. However, major bleeding events (including intracranial hemorrhage) were more common in the combination group [38]. Headache is also a more common side effect in the combination group, which decreased compliance in this group.
  • 6
    Clopidogrel and aspirin: The management of Atherotherombosis with Clopidogrel in High-Risk Patients with Recent Transient Ischemic Attacks or Ischemic Stroke (MATCH) trial showed no significant benefit of clopidogrel 75 mg plus aspirin 75 mg combination therapy when compared with clopidogrel 75 mg alone in reducing major vascular events [39]. The risk of major bleeding was significantly increased in the combination therapy group. However, for patients with acute coronary syndromes or coronary artery stenting, clopidogrel and aspirin combination therapy is recommended for up to 12 months to reduce the risk of recurrent vascular event.
  • 7
    New antiplatelet agents: The randomized comparative trial of triflusal and aspirin following acute myocardial infarct showed that triflusal significantly reduced the incidence of nonfatal cerebrovascular events when compared with aspirin, with significantly lower central nervous system related bleeding [40].
  • 8
    A randomized, double-blinded study in Chinese patients with ischemic stroke/TIA, Cilostazol versus Aspirin for Secondary Ischemic Stroke Prevention (CASISP), found that cilostazol might be a more effective and safer alternative to aspirin in stroke secondary prevention [41]. However, these results require a larger phase III trial to confirm.
Recommendations
  • 1
    For patients with noncardioembolic ischemic stroke/TIA, antiplatelet agents is recommended to reduce the risk of recurrent events (Class I, Level of Evidence A)
  • 2
    Aspirin (50–325 mg daily) or Clopidogrel monotherapy are acceptable options as initial antiplatelet therapy (Class I, Level of Evidence A). Dual antiplatelet therapy is not recommended for routine secondary stroke prevention (Class I, Level of Evidence A). However, for patients with acute coronary artery diseases or recent coronary artery stenting, clopidogrel and aspirin combination therapy is recommended (Class I, Level of Evidence A)

Oral Anticoagulant

The Warfarin Aspirin Recurrent Stroke Study (WARSS) showed no significant difference in the prevention of recurrent ischemic stroke or death between aspirin (325 mg daily) and warfarin (INR 1.4–2.8) [42]. The comparison of Warfarin and Aspirin for Symptomatic Intracranial Arterial Stenosis (WASID) study showed no significant difference in stroke or vascular death in patients with stroke/TIA between aspirin (1300 mg) versus warfarin (target INR 2.0–3.0) [43]. Thus for patients with noncardioembolic ischemic stroke/TIA, anticoagulation therapy does not provide better protection when compared with aspirin; it also increases the risk of bleeding [18].

For patients with cardioembolic stroke/TIA, anticoagulation is beneficial. For patients with minor stroke/TIA, warfarin may be started immediately after ischemic event. However, for patients with neuroradiologically confirmed large infarct (greater than 1/3 of middle cerebral artery territory), warfarin should not be initiated until a few weeks later (e.g., 4 weeks). It should be individualized. Oral anticoagulation may also benefit patients with aortic atherosclerosis, basilar artery fusiform aneurysm, or carotid dissection.

Recommendations
  • 1
    For patients with noncardioebmolic ischemic stroke/TIA, oral anticoagulation is not recommended as a first line therapy for the prevention of recurrent stroke/TIA (Class I, Level of Evidence A).
  • 2
    For patients with noncardioembolic ischemic stroke/TIA, oral anticoagulation may be considered under specific conditions, e.g., aortic atherosclerosis, basilar artery fusiform aneurysm, carotid dissection, or patent foramen ovale (PFO) with deep vein thrombosis or atrial septal aneurysm (Class IV, Level of Evidence D).

Treatment for Stroke Patients with other Specific Conditions

  1. Top of page
  2. Introduction
  3. Risk Factor Control
  4. Interventional Approaches for the Patient with Large-Artery Atherosclerosis
  5. Medical Treatment for Patients with Cardiogenic Embolism
  6. Antithrombotic Therapy for Noncardioembolic Stroke or TIA
  7. Treatment for Stroke Patients with other Specific Conditions
  8. Conflict of Interest
  9. References

Arterial Dissections

Anticoagulation therapy has been used in patients with arterial dissection since the 1970s without randomized clinical trials studies. A meta-analysis showed no significant difference between anticoagulation and antiplatelet therapy in risk of death, or recurrent stroke [44]. The risks of recurrent stroke are high in the first 3–6 months of arterial dissection. Experts’ opinion is anticoagulation therapy for patients without contraindications (e.g., large infarct with severe edema or mass effect, intracranial extension of dissection, or intracranial aneurysm). Intravenous heparin may be considered in the acute phase of dissection with activated thromboplastin time at a target range of 50–70 seconds and transitioned to oral warfarin (INR 2.0–3.0) thereafter. Repeat magnetic resonance angiography or conventional angiogram 3 months after arterial dissection. If recanalization of the dissected vessel is confirms, anticoagulation can be discontinued, otherwise anticoagulation should be continued for another 3 months then repeat imaging. If recanalization is confirmed 6 months after dissection, anticoagulation can be discontinued, otherwise change to long-term antiplatelet agents.

Endovascular therapy (e.g., stenting) or vascular surgery (e.g., bypass) may be considered for patients with stroke/TIA secondary to extracranial dissection who have recurrent ischemic events despite adequate anticoagulation.

Recommendations
  • 1
    For patients with ischemic stroke/TIA and arterial dissection without contraindication for anticoagulation, intravenous heparin (activated thromboplastin time at range of 50–70 seconds) as an initial treatment is recommended. Anticoagulation can later be changed to warfarin (INR 2.0–3.0). Anticoagualtion therapy for 3–6 months is reasonable. If dissection persists at 6-month follow-up, antithrombotic treatment should be changed to long-term antiplatelet treatment (Class III, Level of Evidence C).
  • 2
    For patients with ischemic stroke/TIA and arterial dissection, and contraindication for anticoagulation therapy, antiplatelet therapy for 3–6 months is recommended. If dissection persists at 6-month follow-up, long-term antiplatelet treatment is required (Class III, Level of Evidence C).
  • 3
    For patients with stroke/TIA and arterial dissection, who fail optimal medical therapy, endovascular therapy or vascular surgery may be considered. (Class III, Level of Evidence C).

PFO

Although PFO is not an independent risk factor of ischemic stroke/TIA, PFO seems significantly associated with cryptogenic stroke. For patients with cryptogenic ischemic stroke and PFO, searching for deep vein thrombus is required. If deep vein thrombus, pulmonary emboli or atrial septal aneurysm are found, anticoagulation therapy or PFO closure is recommended. Otherwise antiplatelet is considered. For patients with asymptomatic PFO or atrial septal aneurysm, antithrombotic therapy is not recommended.

Transcatheter closure of PFO is a safe and effective technique. It can reduce the rate of recurrent thromboembolic events [45]. However, there are insufficient data to make a recommendation regarding PFO closure to prevent secondary stroke.

Recommendations
  • 1
    For young patients (<55 years of age) with cryptogenic stroke/TIA, screening for PFO is recommended (Class III, Level of Evidence C).
  • 2
    For patients with cryptogenic stroke/TIA and a PFO, antiplatelet therapy is recommended. For those patients complicated with deep vein thrombosis or atrial septal aneurysm, warfarin is recommended (INR 2.0–3.0). (Class III, Level of Evidence C).
  • 3
    For patients with cryptogenic stroke/TIA and PFO who have recurrent ischemic events despite optimal medical therapy, PFO closure may be considered (Class III, Level of Evidence C).

Hyperhomocysteinemia

Observational studies suggested hyperhomocysteinemia is associated with increased risk of stroke. Deficiencies of vitamins: folic acid, pyridoxine (B6), or cobalamin (B12) can lead to hyperhomocysteinemia.

The Heart Outcomes Prevention Evaluation (HOPE-2) study and the Norwegain Vitamin Trial (NORVIT) showed that vitamin B treatment did not lower the recurrent risk of vascular events, on the contrary there was a nonsignificant trend of worse primary outcome, especially nonfatal myocardial infarct [46,47]. The Vitamin Intervention for Stroke Prevention (VISP) study showed that high-dose B vitamin therapy reduced homocysteine levels but did not reduce vascular events [48].

Recommendation

For patients with ischemic stroke/TIA and hyperhomocysteinemia (fasting serum homocysteine level ≥16 μmol/L), daily vitamin B6, vitamin B12, and folic acid may reduce the levels of homocysteine (Class II, Level of Evidence B).

References

  1. Top of page
  2. Introduction
  3. Risk Factor Control
  4. Interventional Approaches for the Patient with Large-Artery Atherosclerosis
  5. Medical Treatment for Patients with Cardiogenic Embolism
  6. Antithrombotic Therapy for Noncardioembolic Stroke or TIA
  7. Treatment for Stroke Patients with other Specific Conditions
  8. Conflict of Interest
  9. References
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