Table of Contents
- Risk Factors for Stroke Recurrence
- General Principles of Secondary Prevention of Stroke
- Figure 1: Algorithm for Evaluation of Stroke Patients
- Specific Guidelines for Secondary Prevention of Stroke
- Sedentary Lifestyle
- Smoking Cessation
- Substance Use
- Healthy Diet
- Medication Compliance
- Obstructive Sleep Apnea
- Antithrombotic Medications in Secondary Stroke Prevention
- Figure 2: Antiplatelet Therapy for Non-Cardioembolic Stroke and TIA
- Secondary Stroke Prevention Guidelines for Various Diseases
- Further Readings
- Stroke is the number one cause of disability worldwide
- History of stroke is the highest predictor of subsequent stroke
- Secondary stroke prevention decreases subsequent stroke and therefore disability
- Stroke constitutes a major burden of disease globally and second only to ischemic heart disease in the number of deaths according to WHO.
- High risk of recurrence of TIA requires appropriate measures of secondary prevention.
- Secondary stroke prevention refers to reducing the risk of stroke in those who have prior history of stroke or transient ischemic attack (TIA).
- Aim of secondary prevention is to avoid recurrence and evolutionary damage due to a disease process.
- Appropriate measures for secondary prevention of stroke for various risk factors can considerably reduce the recurrence rate of stroke.
Stroke Secondary Prevention 2021 Update
- Antithrombotics - Dual Antiplatelets therapy for “90 days only”
- ASA 81 and Plavix 75 Daily for most patients for 90 days
- Hypertension - Goal < 130/80 mmHg
- Diabetes - Goal HbA1c < 7%
- Physicial Activity - Goal - 20 mins twice a week
- Hyperlipidemia - LDL-C < 70 mg/dl
- BMI = or < than 25
- Risk factors for stroke can be divided into modifiable and non-modifiable risk factors.
- Modifiable risk factors constitute almost 90 percent of the global burden of stroke.
- The major modifiable risk factors for stroke include hypertension, diabetes, sedentary lifestyle, unhealthy diet, smoking, obesity, and hyperlipidemias.
- Simultaneous management of various risk factors can result in considerable reduction of these events.
- The non-modifiable risk factors cannot be changed however, controlling the risk due to modifiable risk factors significantly decrease the risk of stroke due to these.
- The major nonmodifiable risk factors for stroke includes male gender (30 percent increased risk), old age, African American race (2X increased risk), family history, previous history of stroke.
- Primary Stroke prevention refers to patients without TIA or stroke but are at high risk.
- Strategies in primary and secondary prevention of stroke overlap considerably.
- The goal of Stroke workup is to identify Etiology
- Etiology can guide secondary prevention
- Following investigations are recommended.
- ECG and Echocardiography to detect cardiac cause
- Arterial imaging to identify vascular etiology
- Prolonged cardiac rhythm monitoring to exclude atrial fibrillation
- CTA, MRA, or ultrasonography to identify cervical carotid stenosis
- HbA1c to identify undiagnosed or preclinical Diabetes
- Lipid profile to exclude risk of developing atherosclerosis
- (Increased LDL and cholesterol is associated with high risk of stroke)
- PT and APTT to identify clotting and bleeding disorders
- Prevention and treatment strategies should be modified according to need of patients and the etiology of ischemic stroke.
- Factors causing hindrance in patient compliance to medicine must be addressed and a healthy lifestyle should be encouraged.
- Recommended dose of aspirin is 81-325 mg with INR goal of 2 to 3 for warfarin.
Source: 2021 Guideline for the Prevention of Stroke in Patients with Stroke and Transient Ischemic Attack (AHA/ASA Guideline)
- Specific guidelines for each risk factor are organized according to class of recommendation (COR) and a level of evidence (LOE)
- Class of recommendation (COR) denotes the strength of recommendation and weighs the risk and benefit for a specific recommendation.
- Level of evidence (LOE) describes the authenticity and quality of evidence supported by clinical trials.
- Hypertension increases the risk of stroke by almost 50 percent in some populations.
- It is recommended to lower the blood pressure in patients with previous history of stroke.
- Use of thiazide diuretics, ACE inhibitors, and ARBs is recommended to achieve optimal blood pressure of <130/80 mmHg.
- Stroke patients with no previous history of hypertension but office BP of >130/80 mmHg should use antihypertensive to reduce the risk of stroke recurrence.
- Diabetes and prediabetes are associated with increased risk of primary stroke and stroke recurrence.
- Stroke patients should be evaluated for diabetes by HbA1c and multidimensional approach (nutritional, medical, lifestyle changes , education) should be taken to stop progression of prediabetes to diabetes and optimal control in diabetics.
- Cardio-protective antihyperglycemic drugs should be used to avoid cardiovascular events.
- The usual recommended HbA1c to avoid microvascular complications in stroke patients with diabetes is <7.0%.
- Stroke patients with prediabetes and BMI >35 and age <60 years might get benefits from using metformin to stop progression to diabetes.
- Pioglitazone can be used in patients with no history of bladder cancer and heart failure with HbA1c <7.0% , insulin resistance and stroke history of <6 months.
- Hypertriglyceridemia can be moderate or severe.
- Severe hypertriglyceridemia is associated with increased risk of ASCVD (due to VLDL) and acute pancreatitis (due to chylomicrons).
- Risk of stroke recurrence can be reduced with Icosapent ethyl (IPE) 2 g twice a day in patients having fasting triglycerides 135-499 mg/dl, LDL-C 41-100 mg/dl, HbA1c <10%, on statin therapy with no history of acute pancreatitis, atrial fibrillation, or severe heart failure.
- In severe hypertriglyceridemia, the etiology should be explored and dietary modifications should be advised e.g. reduced alcohol intake, very low fat diet, omega-3 fatty acids, avoidance of refined carbohydrates etc.
- Fibrate therapy is indicated to reduce the risk of acute pancreatitis where needed.
- Cholesterol lowering therapy has significant beneficial role in reducing the risk of stroke.
- In stroke patients with hyperlipidemia, it is important to assess the patients adherence to ‘lipid lowering drugs and life style changes.
- Fasting lipids and drug safety should be assessed 4-12 weeks after initiation and then every 3-12 months.
- Stroke patients with LDL-cholesterol >100 mg/dl with no history of CHD or cardiac source of embolism are recommended to take atorvastatin 80mg daily to reduce rate of stroke recurrence.
- The goal of LDL-cholesterol <70 mg/dl should be achieved by lipid-lowering drugs (statin and ezetimibe) that can reduce the risk of cardiovascular events in stroke patients with previous history of atherosclerotic disease.
- Stroke patients with other high risk conditions (e.g. ASCVD) whose LDL-cholesterol is >70 mg/dl despite of statin and ezetimibe should be started on PCSK9 inhibitor therapy.
- Engaging in regular physical activity reduces the risk of stroke by improving overall health and changing various risk factors (Blood pressure, cholesterol, glucose level)
- In stroke patients capable of physical activity, aerobic activity of moderate intensity minimum 10 minutes 4 times a week OR Aerobic activity of vigorous intensity at least 20 minutes 2 times a week.
- In stroke patients willing to increase physical activity, joining an exercise class with counseling to increase physical activity during leisure time.
- In patients with deficits, exercise program along with usual rehabilitation under the supervision of healthcare provider.
- Stroke patients with long sedentary periods should be asked to engage in 3 minutes of standing or exercise every 30 minutes.
- Obesity is associated with the 2X increased risk of ischemic stroke as compared to normal weight.
- Increased risk is due to the associated features mainly e.g. hypertension, increased weight, hyperglycemia, hyperlipidemia and atrial fibrillation etc.
- Stroke patient should be advised to reduce weight and behavioral life style modifications are recommended to achieve the goal and reduce ASCVD risk.
- BMI should be calculated at the time of stroke and it should be used to screen patient annually for obesity and ASCVD risk.
- Cigarette smoking doubles the risk of stroke recurrence as compared to nonsmokers.
- In stroke patients, counselling to quit smoking or at least reduce the daily consumption of smoking is recommended.
- Use drug therapy e.g. nicotine replacement where needed to aid in smoking cessation.
- Avoidance of passive smoking should be advocated.
- Ischemic stroke and alcohol consumption shows a J-shaped relation where risk initially falls but then rise above the starting point.
- Heavy alcohol consumption is associated with increased risk of stroke.
- Alcoholic drinks >2 per day in male and >1 in female must be discouraged in patients having previous history of stroke.
- Patients using drugs such as cocaine, amphetamines or IV drug abusers must be counselled regarding their risk of developing CVA and should be advised to seek help if drug-dependent.
- Mediterranean diet rich in monounsaturated fats
- DASH (Dietary Approaches to Stop Hypertension) diet
- Fish consumption
- Plant based food (fruits, vegetables and fiber) with extra virgin olive oil or nut supplementation
- Reduced dietary salt intake
- Medication adherence is cornerstone of positive outcomes for any disease therapy.
- WHO considers the medication adherence as the most important factor to improve patients’ health.
- Nonadherence can be primary i.e. not being able to initiate therapy or secondary i.e. inability to take medicine during treatment.
- Adherence to medicine is affected by following factors :
- Socioeconomic factors
- Therapy related factors
- Patient related factors
- Condition related factors
- Health system related factors
- Medication adherence can be measured by either subjective or objective method.
- Subjective Measures: These pertain to the evaluation of medication taking behavior by patient or by his healthcare provider.
- Objective Measures: These include the accessory ways to measure patient’s compliance by electronic records, pill count, or biochemical tests.
- It is important to recognize the factor affecting patient’s compliance and address those issues thus customizing the compliance enhancing strategies according to a patient’s need.
- Evaluate the patient with previous history of stroke for obstructive sleep apnea
- Diagnosis of sleep apnea can be made by polysomnography with AHI ≥5 (with symptoms) or 15 ≥15 with or without symptoms
- Patient with obstructive sleep apnea having history of transient ischemic attack or ischemic stroke, positive airway pressure like CPAP is recommend
- Ischemic stroke or transient ischemic attack (TIA) of non-cardioembolic origin:
- Recommended Antiplatelet agent over anticogualation
- Aspiring 50-325 mg/day OR Clopidogrel 75mg OR Aspiring 25 mg and extended-relaese dipyridamole 200mg BD
- Recent Ischemic stroke of non-cardioembolic origin with NIHSS score ≤3 OR high-risk Transient ischemic stroke (TIA) with ABCD score ≥4:
- Start dual antiplatelet therapy (Aspirin and clopidogrel) within 12-24 hours of symptoms onset
- Continue dual antiplatelet therapy for 90 days
- Initiate single antiplatelet therapy after that period
- Stroke within 24 hours with NIHSS Score ≤5; high-risk Transient ischemic stroke (TIA) with ABCD score ≥6; OR ≥30% stenosis of an artery:
- Dual antiplatelet therapy with ticagrelor and aspirin for 30 days
- Increased risk of bleeding and intracerebral hemorrhage
- Continuing dual or triple antiplatelet therapy beyond 90 days is associated with increased risk of hemorrhage
Source: 2021 Guideline for the Prevention of Stroke in Patients with Stroke and Transient Ischemic Attack (AHA/ASA Guideline)
Table 1: Risk Factors and Recommendations for Stroke Prevention in Various Diseases
1- 50-99% stenosis —> Aspirin 325mg/day 2- Stroke orTIA within 30 days with 70-99% stenosis of major ICA —> Add Clopidogrel 75mg/day to Aspirin upto 90 days 3- Stroke or TIA within 24 hours with stenosis 30% or more of major ICA —> Add Ticagrelor 90mg BD to Aspirin upto 30 days 4- Stroke or TIA due to stenosis of 50-99% of a major ICA —> Add Cilostazol 200 mg/day to Aspirin or Clopidogrel 5- Stroke or TIA due to 50-99% stenosis of major ICA —>Recommend moderate physical activity, systolic blood pressure below 140mmHg and statin therapy
1- Stroke or TIA within previous 6 months with 70-99% carotid artery stenosis —> Carotid endarterectomy (Perioperative risk must be <6%) 2- Stroke or TIA with carotid artery stenosis —> Control BP, Lipid lowering drugs, Antiplatelet therapy 3- Stroke or TIA recently with 50-69% carotid stenosis —> Carotid endarterectomy should be considered according to individual’s features (Perioperative risk must be <6%) 4- CEA>CAS if age of patient ≥70 years 5- CEA>CAS if revascularization is scheduled within 1 week of index stroke 6- CAS>CEA if Severe stenosis accompanied with risk factors for surgery 7- CAS is an alternative to CEA if ICA stenosis is ≥70% and there is low risk of complications with endovascular approach
If symptomatic and recent —>Intensive medical therapy that includes lipid lowering drugs, antiplatelet drugs, and control of blood pressure recommended
Stroke or TIA with aortic arch atherosclerosis —> LDL-Cholesterol must be kept <70mg/dl and antiplatelet drugs should be used
1- Stroke or TIA with atrial fibrillation —> Oral anticoagulation 2- Stroke or TIA with atrial fibrillation and no mechanical heart or moderate or sever mitral stenosis —> Apixaban, Rivaroxaban, Edoxaban, or Dabigatran > Warfarin 3- Stroke or TIA with atrial flutter —> Oral anticoagulation 4- Stroke with AF and high risk of hemorrhagic conversion —> Delay the initiation of oral anticoagulation beyond 14 days of index event 5- Stroke with AF and low risk of hemorrhagic conversion —> Initiation of oral anticoagulation 2-14 days after the index event 6- TIA with Nonvalvular AF —> Initiate oral anticoagulation immediately
1- Stroke or TIA with valvular AF —> Warfarin is recommended 2- Mechanical mitral valve —> stroke or TIA history prior to valve replacement —> Aspiring 75-100mg/day with warfarin and INR target of 3.0 3- Stroke or TIA with native aortic/nonrheumatic mitral valve disease and no AF —> Antiplatelet therapy is recommended 4- Bioprosthetic valve (Aortic or mitral) —> stroke or TIA history prior to valve replacement —> Aspirin therapy > Anticoagulation therapy
1- Stroke or TIA with left ventricle thrombus —> Give therapeutic warfarin for 3 months at least 2- Stroke or TIA with Acute Myocardial Infarction —> Cardiac Imaging to exclude LV thrombus
1- History of stroke or TIA with Moyamoya disease —> Surgical revascularization can be benificial 2- History of stroke or TIA with Moyamoya disease —> Antiplatelet therapy, specially Aspirin monotherapy may be considered
1- Stroke or TIA with LA thrombus with cardiomyopathy and LV dysfunction —> Anticoagulation therapy with warfarin for 3 months at least 2- Stroke or TIA with mechanical assisted device —> Warfarin and Aspirin may be beneficial 3- Stroke or TIA with LV noncompaction —> Warfarin may be beneficial
1- Non-lacunar stroke of undetermined origin with PFO —> Multidisciplinary decision making for PFO closure 2- Non-lacunar stroke of undetermined origin with high risk PFO in age 18-60 —> PFO closure with antiplatelet therapy
1- Stroke or TIA with Fontan palliation —> Anticoagulation with warfarin 2- Stroke or TIA or cardiac origin with cyanotic heart disease —> Warfarin therapy
Stroke or TIA with left-sided cardiac tumor —> resection of tumor may be beneficial
1- Stroke or TIA after arterial dissection of extracranial type —> Antithrombotic therapy for at least 3 months 2- Stroke or TIA in less than 3 months of extracranial arterial dissection —> Use aspirin or warfarin 3- Stroke or TIA with extracranial arterial dissection —> Recurrence despite antithrombotic therapy —> Consider endovascular therapy
1- Stroke or TIA with hematologic traits and no other identifiable cause —> Antiplatelet therapy 2- Stroke or TIA with antiphospholipid syndrome —> Warfarin with INR target 2-3 3- Stroke or TIA with antiphospholipid antibody only —> Antiplatelet therapy
1- Avoid oral contraceptive agents with exogenous estrogen 2- Preventive treatment to reduce frequency of migraine attacks
Stroke or TIA with AF and Cancer —> Anticoagulation therapy (Direct oral anticoagulants (DOACs) > Warfarin)
1- Stroke or TIA with Sickle cell disease —> Reduce HbS to <30% of total Hb by blood transfusions 2- If transfusions not possible —> Hydroxyurea may be considered
1- Stroke or TIA with symptoms of giant cell arteritis —> Start oral high-dose glucocorticoids immediately 2- Stroke or TIA with diagnosis of giant cell arteritis —> Add methotrexate and tocilizumab too 3- Stroke or TIA with CNS angiitis —> Glucocorticoids as induction therapy and/or immunosuppressants should be considered —> Maintenance therapy with steroid-sparing immunosuppressants may follow 4- Infectious vasculitis —> Treat the etiological infection; and use aspirin along with antiretroviral therapy in case of HIV
1- Stroke or TIA with Fibromuscular dysplasia and no other identifiable cause —> Antiplatelet therapy, hypertension control and lifestyle changes 2- Recurrent ischemic stroke with cervical carotid artery fibromuscular dysplasia —> Carotid angioplasty might be reasonable
Antiplatelet therapy is recommended; Carotid stenting or carotid endarterectomy may be considered in later stages
Antiplatelet therapy or anticoagulant therapy can be a reasonable choice to prevent recurrent stroke
- The mode of prevention depends upon the etiology of ischemic stroke.
- Lifestyle modifications should be considered and the role of a healthy low salt diet and physical activity must be advocated clearly.
- Various risk factors for recurrent ischemic stroke must be identified and targeted accordingly.
- Vascular risk factors are of foremost importance and special attention should be given to reduce that risk by managing them (Diabetes, hypertension, hyperlipidemias, smoking).
- Use of anti-thrombotic drugs is recommended but dual antiplatelet therapy should be given to only those with high risk of transient ischemic attacks or with severe intracranial stenosis.
- Atrial fibrillation and extracranial carotid artery disease must be excluded as a possible cause of stroke and managed either by anticoagulation use or by stenting/endarterectomy.
- Closure of patent foramen ovale should be considered in patients with high risk PFO features and no other identifiable cause of stroke.
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Secondary Stroke Prevention
Antiplatelet Therapy in the Secondary Prevention of Non-cardioembolic Ischemic Stroke and Transient Ischemic Attack: A Mini-Review
The aim of this mini-review is to discuss the main antiplatelet agents that have been successfully used in the secondary prevention of non-cardioembolic ischemic stroke and transient ischemic attacks (TIA). The methodology is based on a literature review of available peer-reviewed English studies listed in PubMed.
- Specific recommendations for prevention strategies often depend on the ischemic stroke/transient ischemic attack subtype. Therefore, new in this guideline is a section describing recommendations for the diagnostic workup after ischemic stroke, to define ischemic stroke etiology (when possible), and to identify targets for treatment in order to reduce the risk of recurrent ischemic stroke. Recommendations are now grouped by etiologic subtype.
- Management of vascular risk factors remains extremely important in secondary stroke prevention, including (but not limited to) diabetes, smoking cessation, lipids, and especially hypertension. Intensive medical management, often performed by multidisciplinary teams, is usually best, with goals of therapy tailored to the individual patient.
- Lifestyle factors, including healthy diet and physical activity, are important for preventing a second stroke. Low-salt and Mediterranean diets are recommended for stroke risk reduction. Patients with stroke are especially at risk for sedentary and prolonged sitting behaviors, and they should be encouraged to perform physical activity in a supervised and safe manner.
- Changing patient behaviors such as diet, exercise, and medication compliance requires more than just simple advice or a brochure from their physician. Programs that use theoretical models of behavior change, proven techniques, and multidisciplinary support are needed.
- Antithrombotic therapy, including antiplatelet or anticoagulant agents, is recommended for nearly all patients without contraindications. With very few exceptions, the combination of antiplatelets and anticoagulation is typically not indicated for secondary stroke prevention. Dual antiplatelet therapy is not recommended long term, and short term, dual antiplatelet therapy is recommended only in very specific patients, including those with early arriving minor stroke and high-risk transient ischemic attack or severe symptomatic intracranial stenosis.
- Atrial fibrillation remains a common and high-risk condition for second ischemic stroke. Anticoagulation is usually recommended if the patient has no contraindications. Heart rhythm monitoring for occult atrial fibrillation is usually recommended if no other cause of stroke is discovered.
- Extracranial carotid artery disease is an important and treatable cause of stroke. Patients with severe stenosis ipsilateral to a nondisabling stroke or transient ischemic attack who are candidates for intervention should have the stenosis fixed, likely relatively early after their ischemic stroke. The choice between carotid endarterectomy and carotid artery stenting should be driven by specific patient comorbidities and features of their vascular anatomy.
- Patients with severe intracranial stenosis in the vascular territory of ischemic stroke or transient ischemic attack should not receive angioplasty and stenting as a first-line therapy for preventing recurrence. Aggressive medical management of risk factors and short-term dual antiplatelet therapy are preferred.
- There have been several studies evaluating secondary stroke prevention of patent foramen ovale closure since the previous guideline in 2014. It is now considered reasonable to percutaneously close patent foramen ovale in patients who meet each of the following criteria: age 18–60 years, nonlacunar stroke, no other identified cause, and high risk patent foramen ovale features.
- Patients with embolic stroke of uncertain source should not be treated empirically with anticoagulants or ticagrelor because it was found to be of no benefit.