Prevention of Ischemic Stroke or Recurrent Ischemic Stroke

Medically reviewed: 15, February 2024

Ischemic Stroke Prevention – Introduction

Strokes can have a life-altering impact on individuals and families alike. They occur when blood flow to parts of the brain gets interrupted or reduced, depriving brain tissue of oxygen and nutrients, leading to cell death. There are two main types of strokes: hemorrhagic and ischemic. This introductory article will focus on ischemic stroke prevention.

An ischemic stroke happens due to blockage caused by blood clots or narrowed arteries limiting the supply of blood to certain areas of the brain. According to the Centers for Disease Control and Prevention (CDC), ischemic strokes account for approximately 87% of all stroke cases. It is crucial to identify risk factors, symptoms, and strategies associated with preventing ischemic strokes since early intervention might significantly decrease potential damage and improve recovery outcomes.

Risk factors for ischemic stroke generally fall under modifiable and nonmodifiable categories. Nonmodifiable risks encompass age, gender, ethnicity, and genetic predisposition, whereas modifiable risk factors consist of lifestyle choices, chronic health conditions, and environmental influences.

Addressing modifiable risk factors remains vital in averting ischemic strokes. Some common controllable risk factors include:

1. High Blood Pressure: Also known as hypertension, high blood pressure is considered the most significant contributor to ischemic strokes, responsible for nearly half of all stroke incidents. Regular checkups and maintaining ideal blood pressure levels diminish the likelihood of experiencing a stroke.
2. Smoking: Nicotine constricts blood vessels, elevates heart rate, and thickens the blood, increasing chances of blood clots formation. Quitting smoking substantially decreases stroke risk over time.
3. Diabetes: Poorly controlled diabetes can cause damage to blood vessels throughout the body, escalating the probability of developing blood clots that may lead to ischemic stroke. Managing sugar levels helps prevent vascular complications.
4. Obesity & Physical Inactivity: Both contribute to plaque accumulation within the arterial walls, raising the chance of blocked arteries. Adopting healthy dietary habits combined with routine physical activity positively impacts overall wellbeing and reduces stroke incidence.
5. Poor Diet: Consuming foods rich in saturated fats, trans fats, cholesterol, and sodium raises bad cholesterol levels, triggers weight gain, hikes blood pressure, and increases stroke susceptibility. Optimal nutrition supports optimal cardiovascular function.
6. Atrial Fibrillation (AFib): AFib refers to an irregular heartbeat rhythm causing poor blood flow. Clumps of coagulated blood may form inside the atria, dislodging and traveling towards the brain, resulting in ischemic stroke. Effective treatment of AFib lowers stroke incidence considerably.

Acknowledging the warning signs of an impending stroke enhances the capacity to seek prompt medical assistance, potentially minimizing long-term consequences.

Symptoms often manifest rapidly and entail:

• sudden weakness,
• numbness,
• confusion,
• difficulty speaking,
• vision problems,
• loss of balance,
• severe headache without apparent reason,
• paralysis affecting one side of the face, arm, or leg.

Remembering the acronym FAST can facilitate recognition and action:

1. Face drooping,
2. Arm weakness,
3. Speech difficulties,
4. Time to call emergency services.

Preventing ischemic strokes involves addressing underlying causes proactively, practicing a wholesome lifestyle, managing preexisting conditions meticulously, being vigilant regarding symptomatology, and seeking timely professional healthcare interventions. Future chapters shall delve deeper into specific facets surrounding ischemic stroke prevention.

Decisions about the prescription of therapies to prevent ischemic stroke or presumed recurrent stroke are based on several factors, including:

• Presumed vascular territory and the likely cause of the ischemic symptoms
• Previous treatments
• Any contraindications for specific interventions.

How to prevent ischemic stroke?

In addition, the wishes of the patients must be respected. The options for treatment or long-term prevention of ischemic or recurrent ischemic stroke include:

• Oral anticoagulants
• Antiplatelet agents:
• Aspirin
• Ticlopidine
• Dipyridamole
• Clopidogrel
• Carotid endarterectomy (CEA)
• Other cerebrovascular operations
• Angioplasty with placement of stents.

Specific therapies that lessen the risk of thromboembolism are applied, in addition to the management to control risk factors for atherosclerosis and the treatment of co-developing heart diseases.

Decision Factors Influencing the Prevention of Recurrent Ischemic Stroke

The affected vascular territory, as reflected by the patient’s neurologic symptoms, influences decisions about the need for operations, including CEA or interventional neuroradiologic techniques. CEA is of proven value in stroke prophylaxis for patients with severe disease of the extracranial (EC) internal carotid artery.

Other operations that are aimed at reconstruction of the carotid artery and procedures aimed at the vertebrobasilar circulation are not yet established as useful.

The presumed cause of stroke greatly affects decisions about prophylaxis. An algorithm based on the cause of stroke and other clinical variables.

Patients with nonatherosclerotic vasculopathies may need specific therapies; for example, corticosteroids or cyclophosphamide may be required to treat those with inflammatory vasculopathy. Differentiating stroke due to cardioembolism from emboli of arterial origin greatly affects plans for long-term prophylaxis to prevent recurrent ischemic stroke.

Anticoagulants usually are the first choice for patients with cardioembolic stroke while antiplatelet agents are the usual primary treatment for most patients with ischemia secondary to arterial diseases.

Oral Anticoagulants against ischemic stroke

Warfarin or one of its derivatives is a suitable oral anticoagulant. As antagonists of vitamin K, these agents interfere with the gamma-carboxylation of terminal glutamic acid residues of specific coagulation factors; they also reduce plasma levels of active factors II, VII, IX, and X and proteins C and S.

Oral anticoagulants are of established utility in prevention of cardioembolic stroke. Patients with cardiac diseases associated with a high risk of thromboembolism should receive long-term anticoagulant therapy unless a specific contraindication exists.

Recent clinical trials testing the usefulness of oral anticoagulants in primary prevention of stroke among those with nonvalvular atrial fibrillation (AF) confirm the efficacy and safety of these medications.

Overall, oral anticoagulants reduce the risk of thromboembolism up to 60% among patients with AF. Recent guidelines provide additional information about the indications for and the safety and effective use of oral anticoagulants.

The role of oral anticoagulants in preventing stroke among arterial disease patients is controversial. While warfarin often is prescribed to patients with intracranial (IC) stenosis or posterior circulation disease or to patients who have had ischemic symptoms despite use of antiplatelet agents, data demonstrating the usefulness of long-term anticoagulation are not available.

At present, anticoagulants are not established as effective in prevention of stroke among patients of arterial diseases.

The level of anticoagulation is monitored by the prothrombin time (PT) but variations in laboratory activators, detection systems, and agents have led to the use of the international normalized ratio (INR) by laboratories around the world. In this way the impact of these variables has been reduced.

Nonetheless, the large number of interactions with other medications and foods adds to the complexity of the administration of warfarin. Frequent assessments of the level of anticoagulation and adjustments in doses are required. Contraindications for the use of an oral anticoagulant are few, but the factors that may limit its safety and potential efficacy are important to recognize.

In particular, physicians should review the potential interactions between warfarin and any other medication that is started, changed, or discontinued. Medications can prolong or shorten the PT. Special attention should be paid to the concomitant use of antibiotics. Patients should be instructed in the foods that contain vitamin K.

Although the consumption of these foods is not prohibited, patients should be advised to use moderation or a regular regimen so that the warfarin dose can be adjusted accordingly. Multivitamins that do not contain vitamin K are available. Because of the high teratogenic risk of the oral anticoagulants, these drugs are contraindicated during pregnancy.

Hemorrhage is the most frequent adverse experience from the use of oral anticoagulants; the leading fatal complication is IC hemorrhage. A subdural hematoma is a particularly prominent complication that may follow trivial head trauma. The “purple toe syndrome” and skin necrosis are rare complications.

Early effects of warfarin on the levels of proteins C or S may cause a transient hypercoagulable state that predisposes to ischemia in some patients. Often administration of heparin is required to ensure anticoagulation as the warfarin is started. Depending on the desired speed of achieving the optimal level of anticoagulation, higher doses of warfarin can be administered during the first few days of treatment.

Thereafter, the PT/INR is checked at regular intervals that can be expanded as the patient’s anticoagulation and treatment regimen are stabilized. The desired INR for most situations is a level of 2 to 3.5 (Table 11.3). Patients will have markedly different responses to the medication, and the treatment regimens will need to be constructed on a case-by-case basis.

Aspirin for Ischemic Stroke

Aspirin interferes with platelet function and thromboxane A2 production by irreversible acetylation and inactivation of cyclooxygenase. It has little effect on platelet adhesion or aggregation at high shear stress.

Aspirin is the most commonly prescribed medication for the primary or secondary prevention of ischemic stroke among patients with arterial diseases.

Meta-analyses show that aspirin is effective in preventing stroke, myocardial infarction, and vascular death in high-risk men and women regardless of age. The presence of hypertension or diabetes mellitus does not affect responses. Aspirin also is used as an alternative to oral anticoagulants for those with cardiac sources of thromboembolism but who cannot take warfarin. Aspirin can be started safely during the first days after stroke.

Aspirin is inexpensive and easy to administer. Its potential side effects are well known. A sizable number of people are allergic to aspirin.

Bleeding, including IC hemorrhage, is a potential complication that can occur with a wide range of doses of aspirin. The most common side effects strongly related to the dose of aspirin are gastrointestinal (GI) complications, including:

• Gastritis
• Peptic ulcer disease
• Upper GI bleeding.

Low doses (< 100 mg/day) are much less likely to be associated with major GI adverse experiences than larger doses (1000 mg or more/day). Enteric-coated aspirin preparations or the concomitant use of medications to protect the stomach (ie, histamine antagonists or antacids) may lessen the GI side effects.

Aspirin is recommended for the prevention of stroke for most patients with arterial disease. It is the usual choice for the medical prevention of arterial thromboembolism in either the carotid or vertebrobasilar circulation. Aspirin appears to be effective within a wide range of doses.

While earlier studies demonstrated efficacy of daily doses > 1000 mg, more recent data establish the usefulness of much lower daily doses. Current data support the use of aspirin in a daily dose of approximately 75 mg to 100 mg; a “baby” aspirin tablet (81 mg) is the closest dose available in the United States.

A 325 mg dose of aspirin will result in immediate and marked inhibition of platelet aggregation. The therapeutic effect can be maintained with follow-up daily doses of 81 mg. Because of its potent and prolonged effects on platelet aggregation, a once-a-day regimen is adequate. Aspirin alone, in a daily dose of 325 mg, is effective in preventing thromboembolism among people with AF.

It is recommended for treatment of those who cannot tolerate oral anticoagulants (Figure 11.1). Additional research is needed on the role of aspirin in prevention of cardioembolic stroke.

Sulfinpyrazone

Sulfinpyrazone inhibits in vitro platelet aggregation by inhibition of cyclooxygenase, and it can normalize decreased platelet survival times. It was tested against aspirin in a large clinical trial, and aspirin was found to be more effective than sulfinpyrazone. Sulfinpyrazone is not used in prophylaxis against stroke or recurrent stroke.

Ticlopidine

Ticlopidine is a potent antiplatelet agent. It blocks adenosine 5′-diphosphate (ADP)-induced platelet aggregation. Trials have demonstrated the usefulness of ticlopidine in the prevention of stroke in high-risk patients. In one trial comparing the two antiplatelet drugs in high-risk patients, ticlopidine was approximately 15% more effective than aspirin.

In the United States, ticlopidine is indicated to prevent stroke for those who are allergic to or cannot tolerate aspirin. Ticlopidine is an option for management when a patient has ischemic symptoms despite treatment with aspirin (Figure 11.1). It also is used in persons with high-risk coronary artery disease, but its utility in preventing cardioembolic stroke is unknown. The usual daily dose is 500 mg.

Ticlopidine is accompanied by bothersome side effects, including:

• Epigastric distress
• Diarrhea
• Allergic skin reactions
• Neutropenia
• Thrombocytopenia.

Approximately 0.5% of patients treated with ticlopidine develop neutropenia, which can be profound.

Thrombotic thrombocytopenia purpura also is a potential complication. The hematologic complications of ticlopidine occur during the first months after starting the medication. Because the neutropenia or thrombocytopenia can be asymptomatic, biweekly monitoring of the white blood cell and platelet counts is required during the first 3 to 4 months of treatment.

Clopidogrel

Clopidogrel is a member of the same class of antiplatelet drugs as ticlopidine. Its usual daily dose is 75 mg. The risk of major hematologic complications (neutropenia or thrombocytopenia) is lower with clopidogrel than with ticlopidine. The agent was recently tested against aspirin in a large trial that enrolled patients with:

• Ischemic heart disease
• Cerebrovascular disease
• Peripheral vascular disease.

A modest reduction in recurrent ischemic events has been noted with treatment, but the effects are not statistically significant among the patients who have had stroke or transient ischemic attack (TIA).

Dipyridamole against Ischemic Stroke

Dipyridamole has modest antiplatelet effects when used alone. Rather, it is used most frequently as an adjunct to aspirin to prevent stroke in patients with arterial diseases and as an adjunct to warfarin in those with cardiac sources of thromboembolism.

Dipyridamole has few side effects. Headaches are the most bothersome complaint. Bleeding complications are few.

A recent European trial demonstrated that the combination of a time-release formulation of dipyridamole and aspirin was superior to either drug alone.

The dosage of dipyridamole was 400 mg/day. The combination of dipyridamole and aspirin is an option for management when a patient has ischemic symptoms despite treatment with aspirin alone. The combination is an alternative to treatment with ticlopidine. Dipyridamole can be used as an adjunct to warfarin in patients with mitral valve disease.

Combinations of Medical Interventions

Because antiplatelet agents and anticoagulants affect arterial thrombosis by different mechanisms, a combination of drugs may be more effective than the use of either class of drugs alone. Similarly, the different effects of antiplatelet agents may permit combinations of treatment.

However, combinations of medications are likely to be associated with an increased risk of bleeding.

Already, dipyridamole or aspirin are added to warfarin for the prevention of thromboembolism in patients with high-risk cardiac lesions, especially those who have had symptoms despite adequate levels of anticoagulation. Also, the addition of dipyridamole to aspirin has been shown to be safe and effective. The combination of ticlopidine and aspirin is used in patients who have not responded to either medication alone, but the safety and efficacy of this approach are not known.

Other methods of Ischemic Stroke prevention

Carotid Endarterectomy

Carotid endarterectomy is of proven value in prevention of stroke among people with symptomatic or asymptomatic high-grade stenoses (> 50% to 60%) of the origin of the internal carotid artery. The role of the operation among asymptomatic patients is more controversial than among those who have had a TIA or stroke, but recent evidence suggests that CEA can be recommended to carefully selected patients.

Factors that influence the decision to recommend CEA include:

Contraindications for CEA:

• Recent (< 6 weeks) major ischemic stroke
• Recent (< 6 weeks) myocardial infarction
• Unstable angina pectoris

Neurologic factors associated with increased risk of morbidity:

• Unstable neurologically (crescendo TIA or stroke-in-evolution)
• Recent TIA or amaurosis fugax
• Asymptomatic carotid stenosis
• Medical factors associated with increased risk of morbidity:
• History of myocardial infarction or angina pectoris
• Chronic obstructive lung disease
• Diabetes mellitus
• Hypertension
• Obesity

Arteriographic factors associated with increased risk of morbidity:

• Occlusion or severe stenosis of the contralateral carotid artery
• Intracranial atherosclerotic disease
• Absence of major collateral vessels in the circle of Willis
• Severe disease of the vertebrobasilar system.

The presence of severe ulceration in addition to a high-grade stenosis increases the potential benefit from CEA. The advantage of surgical treatment increases among people with marked narrowing of the carotid artery (> 70% stenosis).

Patients with occlusions of the internal carotid artery and those with intracarotid thrombi are not usually treated by operation. Surgeons often administer heparin as a preoperative measure for persons with intracarotid thrombi.

Carotid endarterectomy can be recommended for a patient who has the following:

• Reasonable operative risk
• Appropriate vascular lesion
• Skilled surgeon available.

If these criteria cannot be met, patients should either forego a CEA or be referred to another medical institution. Overall, the surgeon should report that less than 2% to 3% symptomatic and 1% to 2% asymptomatic patients have major morbidity following CEA under his/her management.

A number of factors affect the morbidity and mortality following CEA, including:

Ischemic stroke:

• Hypoperfusion
• Carotid occlusion
• Artery-to-artery embolism
• Hemorrhagic stroke (hyperperfusion syndrome)
• Seizures
• Cranial nerve palsies
• Vagal/recurrent laryngeal nerve
• Hypoglossal nerve
• Local hematoma or infection
• Myocardial infarction.

Patients with neurologic symptoms are at a higher risk for complications than those who are asymptomatic. The neurologically unstable are at the highest risk. Surgery often is delayed for several weeks following a hemispheric stroke, but patients with mild deficits and no major stroke seen on computed tomography (CT) probably can be treated immediately.

The leading causes of death following CEA are myocardial infarction and stroke. Stroke can be the result of:

• Embolism
• Hypoperfusion
• Hemorrhage.

Techniques used to lessen the risk of complications include:

• Electroencephalographic monitoring
• Local anesthesia
• Placement of shunts.

Patients treated with CEA should receive postoperative medical management, including antiplatelet agents. These medications are often started while patients are in the operating room.

Extracranial/Intracranial Arterial Anastomoses and Other Reconstructive Operations

Extracranial/intracranial arterial anastomosis (EC-IC bypass) has not been shown to be superior to medical therapy, and it generally has been abandoned other than for exceptional cases, such as those people who have moyamoya syndrome. Occasionally patients with severe atherosclerotic lesions of the major cervical arteries (subclavian, common carotid, or vertebral) are treated with vascular reconstructive operations.

Occlusion of the proximal subclavian artery with a subclavian steal syndrome is a potential indication for such an operation, but the usefulness of surgery is not established.

Angioplasty and Placement of Arterial Stents

The use of angioplasty, with or without stent placement, in the EC or IC arteries is controversial. Preliminary studies suggest that angioplasty with placement of arterial stents is a feasible way to manage stenotic lesions of the arteries perfusing the brain.

While preliminary studies suggest these interventional techniques can be performed with success, their usefulness in the management of patients with cerebrovascular disease is not known.

Concerns about the risks of the procedure remain, and large efficacy studies will be needed to determine the utility of angioplasty with or without stent placement.