Standards of care for ischemic and hemorrhagic stroke

In 1995, the results of the NINDS study on tissue plasminogen activator were published. This was a landmark in stroke treatment because it provided the first definitive evidence that brain damage from stroke could be limited by therapeutic intervention. This made stroke a true neurological emergency. Currently, tissue plasminogen activator followed by long-term administration of an antithrombotic agent is the only proven treatment for stroke. However, a number of agents with putative neuroprotective effects are currently undergoing phase II and III clinical trials. It is possible that, as in the case of cardiac ischemia, a combination of reperfusion and cytoprotection will soon be used in stroke treatment.

In the past, it was generally accepted that ischemic brain injury developed rapidly, since the neurological deficit reached its maximum severity soon after the onset of symptoms. It was believed that even if the brain tissue at risk could be saved, this would not affect the final outcome, since the functional deficit would not change. In addition, there was no information on the time required for irreversible brain damage to occur, since there was no way to intervene in this process. Analysis of clinical data has led to the assumption that brain damage occurs rapidly and reaches its maximum severity at the time of symptom onset.

This conclusion was supported to some extent by data obtained in the study of cerebral perfusion in the case of cardiac arrest. In this case, the time frame of cerebral ischemia can be easily estimated. When cardiac activity ceases, cerebral perfusion quickly drops to zero, and brain reperfusion clearly corresponds to the moment of restoration of arterial pressure. The brain can tolerate the cessation of blood supply for no more than 10 minutes, after which irreversible damage occurs to the most sensitive areas of the brain. Less sensitive areas of the brain are able to survive global ischemia only for a few additional minutes. Thus, massive damage to the cerebral cortex occurs if the patient is resuscitated more than 15 minutes after cardiac arrest. Other organs are not much more resistant to ischemia than the brain. The kidneys, liver, and heart are usually significantly damaged during cardiac arrest of such duration that it is sufficient for the development of massive brain damage. The sudden onset of stroke symptoms has led to the belief that brain damage quickly becomes irreversible. This has led, until recently, to the conclusion that treatment of stroke in the acute phase is unlikely to have any effect.

Ischemic penumbra

Fortunately, the arterial occlusion responsible for ischemic stroke does not cut off the blood supply to all involved areas of the brain, since only in some areas does the perfusion decline to the level seen in cardiac arrest. In this central zone of ischemia, irreversible damage probably develops within minutes and, at least at present, is not treatable. However, most of the involved brain tissue is subject to intermediate levels of ischemia, since the greater the distance from the central zone, the higher the perfusion, up to the area of normal perfusion provided by another vessel. There is some threshold of perfusion above which brain tissue can survive indefinitely; only temporary loss of function is possible, but infarction never develops. The boundary of the infarction zone in cerebral artery occlusion is defined by the perfusion threshold line, which separates the tissue that will survive from that which will subsequently undergo necrosis.

Reduced perfusion causes immediate loss of function, which explains the rapid onset of symptoms that rapidly reach their maximum development. Although symptoms appear rapidly, full infarction takes some time to develop. Experimental models of cerebral ischemia have shown that mild ischemia must be maintained for 3–6 h to initiate infarction. If an infarction has not developed after 6 h of mildly reduced cerebral perfusion, it will not develop further. The region of intermediate perfusion reduction in which infarction can develop within a few hours is called the ischemic penumbra. It is the primary target for acute stroke therapy. The reality of the ischemic penumbra as a brain region that can be salvaged after the development of stroke symptoms is difficult to prove in patients, but its existence follows from results obtained in experimental models of ischemia. Until recently, there were no methods that could study cerebral perfusion or the functional status of the human brain during an ischemic episode. Currently, the capabilities of new magnetic resonance techniques - diffusion-weighted and perfusion MRI - in differentiating reversible and irreversible ischemic brain lesions are being studied.

Stroke group and the concept of "brain attack"

Given the organizational difficulties associated with delivering a patient to a hospital and mobilizing doctors to perform emergency diagnostic and therapeutic measures, special groups specializing in the treatment of stroke should be organized in medical institutions. The term "cerebral attack" is proposed as an alternative to the term "stroke" in order to emphasize that cerebral ischemia is currently as treatable a condition as a heart attack.

As emergency stroke therapy becomes the standard of care, hospitals should establish a system for promptly examining patients with signs of cerebral ischemia, just as they do for cardiac ischemia. As with acute cardiac ischemia, patients with acute cerebral ischemia should be hospitalized only in those hospitals where it is possible to quickly examine and begin treatment.

The only currently available specific acute therapy for ischemic stroke is tPA, which should be administered within 3 hours of symptom onset. Before tPA is administered, a head CT scan should be performed to rule out intracerebral hemorrhage. Thus, the minimum resource requirements for stroke management include the ability to perform a rapid neurological examination, CT scanning, and tPA.

Therapeutic strategies for stroke treatment

The principles of emergency treatment of stroke are the same as those used in the treatment of cardiac ischemia. In cardiac ischemia, several strategies are used to minimize damage to the heart muscle, the first of which, reperfusion, is of key importance. Blood flow must be restored as quickly as possible to prevent further damage. To this end, thrombolysis is usually performed in the acute phase to restore perfusion, which is then often supplemented by structural restoration of the arteries, either by balloon angioplasty or by coronary artery bypass grafting. Cytoprotective therapy is also used to increase the resistance of the heart muscle to ischemia, allowing it to survive longer at a low perfusion level. Thus, pharmacological intervention reduces the load on the heart, allowing ischemic tissue to survive a period of low perfusion. In addition, patients with cardiac ischemia are prescribed drugs to prevent subsequent ischemic episodes. Anticoagulants and antiplatelet agents are used for this purpose, preventing thrombus formation.

Reperfusion and thrombolytic therapy

Given the inability to rapidly and reliably measure perfusion in patients with symptomatic cerebral ischemia, little is known about the spontaneous course of ischemia. Existing data indicate that spontaneous reperfusion often occurs in cerebral ischemia. However, such reperfusion appears to occur after the opportunity to limit the volume of damaged tissue has been lost.

The first experience with thrombolytic therapy in cardiac ischemia was obtained with intra-arterial administration of thrombus-dissolving enzymes or their activators, such as urokinase, streptokinase, or tPA. After the practical value of intra-arterial therapy was demonstrated, the possibilities of intravenous thrombolysis under coronary angiography control were investigated.

Initial studies of thrombolysis in stroke also involved intra-arterial administration of thrombolytics. The results were often dramatic: after thrombus dissolution and rapid clearance of the large vessel occlusion, many patients experienced significant recovery of neurological function. However, studies have shown that the major complication of thrombolytic therapy is hemorrhage, which is particularly common when attempts were made to lyse the thrombus many hours after the onset of ischemia.

The tPA trial conducted by the National Institutes of Health (USA) demonstrated the effectiveness of intravenous thrombolysis in stroke. Improvement in stroke outcome was noted at 3 months, as measured by 4 grading scales. The tPA trial was well designed and confirmed the need to minimize the time between symptom onset and treatment. One of the goals of the trial was to test a clinical protocol that could be used in any hospital where rapid neurological examination and CT scanning are available. Since the purpose of the trial was to evaluate the effectiveness of tPA in a routine clinical setting, angiography was not performed. Therefore, the assumption of vessel occlusion and assessment of treatment effectiveness were based only on clinical data. It was not the purpose of the trial to determine whether the drug actually causes reperfusion.

The major complication of thrombolytic therapy is cerebral hemorrhage. The incidence of intracerebral hemorrhage in the tPA study was 6.4%. This rate was much lower than in the European Streptokinase Study (21%), which failed to demonstrate a therapeutic effect of thrombolysis. Although tPA administration caused a few cases of fatal intracerebral hemorrhage, there was no significant difference in the mortality rate at 3 months between the treatment and control groups.

Tissue Plasminogen Activator (tPA) Treatment Protocol

Inclusion Criteria

• Suspected acute ischemic stroke
• Possibility of tPA administration within 3 hours after the onset of the first symptoms
• No recent changes on CT (excluding mild early signs of ischemia)

Exclusion criteria

• Intracerebral hemorrhage or suspected spontaneous subarachnoid hemorrhage
• Rapid improvement suggestive of TIA
• Minimal symptom severity (National Institutes of Health Stroke Scale score, USA - less than 5 points)
• Stroke or major head injury in the last 3 months
• A history of intracerebral hemorrhage that may increase the patient's risk of subsequent hemorrhage
• Major surgery in the previous 14 days
• Gastrointestinal or genitourinary tract bleeding in the last 3 weeks
• Uncompressed arterial puncture in the previous 7 days
• Lumbar puncture in the previous 7 days
• Systolic pressure >185 mmHg or diastolic pressure >110 mmHg or need for active antihypertensive therapy (eg, with nitroprusside)
• Use of warfarin or heparin in the previous 48 hours (use of aspirin or ticlopidine is allowed)
• Coagulopathy (with an increase in partial thromboplastin and prothrombin time or a decrease in the platelet count - below 100,000 in 1 μl)
• Possibility of pregnancy (fertile women must have a negative pregnancy test)
• Suspicion of pericarditis
• Signs of advanced liver disease or end-stage renal disease
• Epileptic seizure at the onset of stroke
• Coma on admission
• Symptomatic hypoglycemia

Recommendations for the clinical use of tPA are in accordance with the study protocol. The dose should be 0.9 mg/kg and should not exceed 90 mg. Of particular importance is the requirement that no more than 3 hours should pass from the onset of symptoms (the time of which should be clearly defined) to the administration of the drug. The drug is not indicated for patients with mild or rapidly regressing symptoms. A contraindication to the use of tPA is evidence of intracerebral hemorrhage on CT. The clinical trial did not include patients with systolic pressure exceeding 185 mm Hg or diastolic pressure exceeding 110 mm Hg. In some cases, mild antihypertensive agents were used to ensure that blood pressure met the inclusion criteria. Although this requirement of the protocol should be followed, caution should be exercised to avoid excessive reduction in blood pressure.

Caution should also be exercised in administering tPA to patients with early hypodense lesions on CT. Although such patients were not excluded from the tPA trial, the results showed that the incidence of hypodense lesions in patients with symptomatic intracranial hemorrhage was 9% (4 patients received tPA, 2 received placebo), compared with 4% in the overall group. Because early hypodense lesions on CT may indicate an error in the timing of symptom onset and the number of such patients is small, it is probably best to withhold tPA in this group of patients.

Based on the results of the tPA trial, some experts object to the use of this drug, citing a relatively high risk of complications. However, even taking these limitations into account, it should be noted that overall the use of the drug led to a statistically significant improvement in stroke outcome. It seems likely that as experience with the drug accumulates, its use will expand. Attempts are currently underway to optimize the protocol to minimize hemorrhagic complications and to determine whether the combination of tPA with other drugs, especially neuroprotective agents, is effective.

Tissue plasminogen activator and reperfusion

The cerebral vasculature was not examined during the tPA trial. The trial was divided into two parts. The first ended with the patient being examined 24 hours after tPA administration, at a time when the treatment effect could not yet be demonstrated using clinical scales. The therapeutic effect became more evident during the second part of the study, 3 months after the drug was administered. Some studies using intra-arterial tPA included identification of occluded arteries, which allowed arterial patency to be correlated with clinical manifestations. Since restoration of blood flow is accompanied by dramatic regression of symptoms in some cases, it can be assumed that the effect of tPA may be associated not only with a direct effect on the occluded artery, but also with its effect on primary collaterals, which are subject to secondary occlusion due to low blood flow. On the other hand, there is no doubt that tPA promotes reperfusion of the affected area of the brain, since a delay in administering the drug is associated with the development of hemorrhages indicating reperfusion.

Other strategies to promote reperfusion

In a model of reversible middle cerebral artery occlusion in rats, blocking leukocyte adhesion reduced the size of the ischemic lesion. After ischemia, endothelial cells in the affected brain region increased expression of the leukocyte adhesion molecule ICAM-1. Since the size of the ischemic zone was reduced in the experimental model using monoclonal antibodies to ICAM-1 administered during reperfusion, it can be assumed that the endothelial response to ischemia slows recovery during reperfusion. Thus, perfusion recovery may be more complete with inhibition of leukocyte adhesion.

Another factor that may reduce cerebral blood flow during reperfusion is thrombosis of small collateral vessels. It is possible that dissolution of these thrombi is an important component of the action of tPA. Antithrombotic agents such as aspirin or heparin may also be useful in these cases.

Other strategies may be used to improve perfusion after ischemia and their effectiveness has been studied in both animal models and patients. Of these, hypertension and hemodilution have been studied most intensively. The potential for inducing hypertension has been well studied in traumatic brain injury, where increased intracranial pressure limits cerebral perfusion. Hypertension is often used in the treatment of subarachnoid hemorrhage, where cerebral vasospasm reduces perfusion and may lead to secondary ischemic brain injury.

Endothelial nitric oxide also plays an important role in brain tissue reperfusion. Nitric oxide is produced in various tissues, including the endothelium, where it serves as an intracellular and intercellular mediator. Nitric oxide, a powerful vasodilator, normally maintains arterial blood flow, but can also be a mediator of ischemic neuronal injury. Effects on nitric oxide levels in experimental models of cerebral ischemia have yielded conflicting results, since the outcome depends on the relationship between its effect on cerebral perfusion and its neurotoxic effect.

In the clinical setting, it is not always necessary to aim for strict control of blood pressure within a narrow range in the acute phase of stroke, with the exception of the situation already mentioned when patients are receiving tPA. Although hypertension is a risk factor for stroke in the long term, it may improve perfusion in the acute phase of stroke. Only when blood pressure increases to dangerous levels does intervention become necessary. Antihypertensive drugs are often discontinued in the acute phase of stroke, but this is contraindicated in patients taking beta-blockers, since their discontinuation may provoke myocardial ischemia, so preference is given to agents that reduce the symptoms of arterial occlusion. The pharmacodynamic effects of such drugs should influence the contractile response of blood vessels, cerebral blood flow, and the rheological properties of blood.

Halidor (bencyclane) reliably increases the level of cerebral blood flow in the ischemic area when administered intravenously, without causing the "stealing" effect. In this regard, it is worth mentioning the data according to which bencyclane can relax sclerotically altered vessels. During ischemia, the probability of suppression of the ability of erythrocytes to move increases. The use of bencyclane causes two pathogenetic effects: suppression of osmotic plasmolysis and viscosity of the erythrocyte cytosol, and also eliminates the inhomogeneous distribution of membrane protein.

The frequency of reocclusion of stenosed vessels after catheterization deobliteration by the Dotter method can be significantly reduced by the use of bencyclane. In a double-blind study, Zeitler (1976) found that bencyclane at a dose of 600 mg per day orally reduces the frequency of re-thrombosis of vessels with restoration of patency to the same extent as ASA.

Individual components of whole blood viscosity - platelet aggregation and elasticity, coagulability - change with a certain pharmacological effect. Correlation analysis revealed a linear relationship between the concentration of bencyclane and a decrease in spontaneous platelet aggregation. The drug reduces the uptake of adenosine by platelets, while simultaneously inhibiting the serotonin-induced reaction of platelet content release. This primarily concerns the beta-thromboglobulin protein (P-TG). According to the latest data, the beta-TG content should correlate with AG. When using bencyclane, the beta-TG level in blood plasma decreased significantly.

Bencyclane blocks Ca channels, reduces intracellular concentration of Ca ²⁺, activates NO synthase, increases NO production. At the same time, it inhibits phosphodiesterase, selectively blocking 5-HT serotonin receptors in erythrocytes and platelets, which leads to accumulation of cyclic AMP, which indirectly affects the reduction of leukocyte adhesion, allowing to restore blood flow in microvessels.

Thus, the fact of using Galidor in patients with stroke becomes understandable. The recommended dosage of the drug should be at least 400 mg per day. The duration of use of the drug depends on the severity of vascular pathology and ranges from 3 weeks to 3 months, with subsequent repeat courses after six months.

At the same time, one should not forget the fact that the use of bencyclane in patients with severe cardiac pathology can cause an increase in tachyarrhythmia, but it has been proven that 90% of patients do not experience side effects and complications when using bencyclane.

Contraindications for prescribing the drug are tachyarrhythmia, renal or hepatic insufficiency, age under 18 years.

Halidor is compatible with drugs of other pharmacological groups, however, when combined with cardiac glycosides and diuretics, it is necessary to monitor the level of potassium in the blood serum due to the possible development of hypokalemia. When combined with these drugs and drugs that depress the myocardium, the dose of Halidor is reduced to 200 mg per day.

Prevention of recurrent ischemic episodes

Studies have consistently demonstrated a high risk of ischemic enlargement over time or of recurrent stroke in another part of the brain. This is consistent with the concept that most ischemic strokes are embolic in nature, with the embolism originating in the heart or atheromatous plaques in large vessels. Accordingly, early treatment with antithrombotic agents is thought to reduce the risk of recurrent ischemic events. However, the effectiveness of this approach is not proven because most published studies have assessed the incidence of late recurrence in patients enrolled weeks or months after the stroke. Several clinical trials are currently underway to evaluate the effectiveness of early antithrombotic therapy in preventing ischemic enlargement and preventing subsequent ischemic events.

The formation and enlargement of a thrombus involves platelets and thrombin. Although one or the other may be more important in one setting, both are likely to contribute to early stroke recurrence. Most published studies have evaluated the efficacy of antiplatelet agents and have been based on long-term use of aspirin or ticlopidine to prevent stroke recurrence in patients with no clear etiology for stroke. Such studies must be large because the risk of stroke even in this population is relatively low. In recent years, several trials have evaluated the efficacy of drugs in the intermediate post-stroke period, when the risk of stroke recurrence is particularly high.

Aspirin

Aspirin (acetylsalicylic acid) irreversibly inhibits cyclooxygenase by acetylating the functionally important serine residue of the enzyme. Cyclooxygenase promotes the conversion of arachidonic acid into many eicosanoids, including prostaglandins and thromboxanes. Although aspirin may have other effects, inhibition of cyclooxygenase is critical for preventing thrombosis. Since platelets do not have a nucleus, they are unable to synthesize new enzyme after the existing cyclooxygenase is inhibited by aspirin. Thus, for this purpose, the drug only needs to be taken once a day, although its half-life does not exceed 3 hours, but the duration of its effect corresponds to the lifespan of the platelet.

Aspirin is the drug most often used to reduce the risk of recurrent stroke. At least four large clinical trials have demonstrated the effectiveness of aspirin in patients who have had a TIA or stroke. A limitation of these trials is that, in general, the assessment of the drug's effectiveness included not only recurrent strokes but also other events, such as death. Thus, the preventive effect of aspirin on cardiac ischemia has complicated the interpretation of the results of some of these studies on recurrent stroke. Nevertheless, aspirin is recommended for all patients who are not taking other antiplatelet or anticoagulant drugs.

Although the evidence for aspirin's ability to reduce the risk of recurrent stroke is clear, it is important to understand the context in which these studies are conducted. The risk of recurrent stroke is generally low, at 5-10% per year. With aspirin, this risk is reduced by about 25%. The large number of patients needed for such studies is sometimes mistakenly interpreted as a sign of aspirin's low effectiveness. Large groups of patients should be studied even if the subjects are at high risk of recurrent stroke, since the likelihood of such events is still low. On the other hand, there is sometimes a misconception that antiplatelet drugs prevent stroke completely. However, these drugs only reduce the risk of stroke, and the likelihood of recurrent stroke is reduced by less than half. Therefore, stroke survivors should be informed of the continuing risk of stroke and the relative effectiveness of aspirin. Patients at high risk of recurrent stroke should be informed about current treatment options that may be used if a new stroke occurs. In recent years, aspirin given in the acute phase of stroke (within 48 hours of symptom onset) has been shown to reduce mortality and early recurrent stroke, but does not appear to have a significant effect on residual defect levels.

There is some debate about the optimal dose of aspirin for secondary prevention of stroke. Clinical data suggest that aspirin 75 mg/day can effectively reduce the risk of stroke and decrease the risk of death from myocardial infarction. Experimental laboratory data show that low doses of aspirin can completely inhibit cyclooxygenase. Because gastrointestinal side effects are dose-dependent, lower doses seem preferable. However, the question remains whether higher doses provide additional protection that outweighs the risk of side effects. In recent years, there has been a consensus among experts that low doses of aspirin are effective in the treatment of cardiovascular disease, but there is no such consensus regarding the use of aspirin in the treatment of stroke.

There is controversy about the dose of aspirin needed to reduce the risk of stroke, because there are no studies that have definitively resolved this issue. It has been shown that higher doses of aspirin may be effective in some patients who are resistant to the antiplatelet effect of low doses of aspirin. It is possible that inhibition of cyclooxygenase activity is not the only mechanism of action of aspirin in cerebrovascular disease, since aspirin also acetylates a number of other proteins. Since low doses of aspirin are effective in preventing death due to coronary heart disease and there are no data confirming that cerebral vascular occlusion differs in mechanism from cardiac vascular occlusion, it seems likely that low doses of aspirin should be quite effective in patients with stroke.

Current practice is to prescribe low-dose aspirin (75 mg/day) to reduce the risk of vascular disease in the general population and intermediate doses (325 mg/day) in patients at higher risk, with the dose being reduced if significant side effects occur. High-dose aspirin (1300 mg/day) is indicated only when cerebrovascular events occur during standard therapy.

The most common side effect of aspirin is gastrointestinal disorders, occurring in 2-10% of patients taking standard analgesic doses. This percentage increases significantly (up to 30-90%) when aspirin is prescribed to individuals with a history of peptic ulcer disease or gastritis. Gastrointestinal side effects include heartburn, nausea, and epigastric discomfort. These effects are dose-dependent and are explained (at least in part) by the local irritant effect of the drug on the gastrointestinal mucosa. In general, enteric-coated drugs are better tolerated by most patients, including those with a history of peptic ulcer disease or gastritis. In addition, to prevent side effects, it is recommended to take aspirin with food or with antacids.

Aspirin should be used with caution in patients with active gastrointestinal disorders (such as gastritis or ulcers) or with a history of these disorders. In these patients, regular monitoring, low-dose aspirin, and testing for occult gastrointestinal bleeding are recommended. Caution should also be exercised when prescribing aspirin to patients who consume alcohol or take corticosteroids. The only absolute contraindication to aspirin is rare hypersensitivity to salicylates.

Gastric irritation caused by long-term use of aspirin may lead to hidden, painless gastrointestinal bleeding. If significant blood loss occurs, iron deficiency anemia may develop.

Most cases of aspirin toxicity are caused by doses significantly higher than those used to prevent stroke. The first symptoms of acute or chronic intoxication are often tinnitus and hearing loss. These symptoms usually resolve when the aspirin dose is reduced. Acute aspirin overdose causes metabolic acidosis, which includes drowsiness, confusion, nausea, and hyperventilation. Aspirin overdose can be fatal due to multiple organ failure.

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Ticlopidine

The drug blocks platelet aggregation by inhibiting the adenosine diphosphate pathway. Like aspirin, the effect of ticlopidine is irreversible.

The Ticlopidine Aspirin Stroke Study (TASS) compared the efficacy of aspirin and ticlopidine in preventing recurrent stroke. The results showed that ticlopidine was superior to aspirin in its efficacy. The study included 3,069 patients - the rate of recurrent stroke with or without fatal outcome after 3 years of treatment was 10% for ticlopidine and 13% for aspirin, thus the protective effect of ticlopidine was 21% higher. The advantage of ticlopidine was maintained throughout the 5-year study period.

Diarrhea, often accompanied by abdominal cramps, is the most common side effect of ticlopidine. It usually improves with a temporary reduction in the dose. Bruising, petechiae, epistaxis, and microscopic hematuria were also reported in the clinical trial, but gastrointestinal bleeding was rare. Like aspirin, ticlopidine should be discontinued one week before elective surgery.

In a small percentage of patients, ticlopidine causes blood changes, usually in the first 3 months of treatment. Neutropenia is most common (2.4%). Agranulocytosis is observed less frequently, and even rarer complications include aplastic anemia, pancytopenia, thrombocytopenia, thrombotic thrombocytopenic purpura, and immune thrombocytopenia. A clinical blood test with platelet count and white blood cell count should be performed every 2 weeks during the first 3 months of treatment with ticlopidine. Ticlopidine should be discontinued immediately if blood changes are detected or if infection or bleeding develops.

In addition, skin rashes and itching are possible when taking ticlopidine, but they are rarely severe. In a clinical trial of ticlopidine, rashes were detected in 5% of patients. They usually occurred in the first 3 months of treatment. In some cases, ticlopidine may be prescribed again after a drug holiday sufficient for the rash to disappear - this side effect may not develop again.

Like aspirin, ticlopidine should be used with caution in patients with peptic ulcer disease or gastritis in the acute phase. However, since, unlike aspirin, ticlopidine does not irritate the gastrointestinal mucosa, it should be preferred to aspirin in this category of patients. Ticlopidine should also be used with caution in patients with increased bleeding. The safety of the combination of the drug with aspirin, warfarin and thrombolytics has not been studied.

Since ticlopidine is metabolized in the liver, caution should be exercised when prescribing it to patients with liver disease. It is contraindicated in liver failure.

Clopidogrel

The drug, chemically related to ticlopidine, has a similar mechanism of action. The study showed its effectiveness as a means of secondary prevention of ischemic episodes. When comparing the results of studies in patients with stroke, myocardial infarction and peripheral vascular disease, it was shown that in the group taking clopidogrel, stroke, myocardial infarction or death associated with vascular diseases was noted in 9.78% of patients, while in the group taking aspirin, similar episodes occurred in 10.64% of patients. Unlike ticlopidine, clopidogrel does not cause blood changes. Currently, the use of the drug for secondary prevention of stroke is approved by the FDA.

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Dipyridamole

The ESPS2 trial showed that dipyridamole 200 mg twice daily (as extended-release tablets) was as effective as aspirin (25 mg twice daily) in preventing stroke, myocardial infarction, and vascular death in patients with TIA or minor stroke. Compared with placebo, the relative risk reduction for stroke or death was 13% for aspirin and 15% for dipyridamole. The combination of dipyridamole (as extended-release tablets) and aspirin was also shown to be more effective in reducing the risk of recurrent stroke (37%) than placebo and aspirin alone (22%). A dosage form containing 200 mg dipyridamole (extended release) and 25 mg aspirin is currently FDA approved for use in secondary stroke prevention.

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Heparin

It is a naturally occurring family of molecules found in mast cells. The drug is usually obtained from the lung or gastrointestinal tissue of cattle. Heparin is a glycosaminoglycan. Its average molecular weight is about 12,000. Because heparin is administered intravenously and therefore has a rapid onset of action, it is used when a rapid anticoagulant effect is needed, such as for the immediate secondary prevention of stroke. Heparin is used in patients with the highest risk of stroke under laboratory monitoring. Warfarin, an oral anticoagulant, is used for long-term treatment.

While antiplatelet agents block platelet aggregation and slow thrombus formation and growth, heparin and warfarin directly inhibit blood clotting. When administered in sufficient doses, heparin can completely block the blood clotting process.

Heparin acts as a catalyst, speeding up the reaction by which antithrombin III neutralizes thrombin, the enzyme that helps convert fibrinogen into fibrin. Since fibrin is the main clot-forming protein in plasma, blocking its production prevents thrombus formation. At lower doses, heparin prevents the conversion of factor X to prothrombin and then to thrombin.

Although there is no direct clinical evidence to support the efficacy of heparin in the acute phase of stroke, its use is supported by data indicating the therapeutic efficacy of warfarin, since both drugs inhibit coagulation, albeit through different mechanisms. Since the anticoagulant effect of warfarin is slow to manifest, heparin is used in emergency situations when a rapid effect is needed (for example, when there is a risk of recurrent embolic stroke in the first few days after a cerebrovascular accident). Heparin is a fast-acting anticoagulant that is used until the full therapeutic effect of warfarin has manifested itself.

Because low-dose heparin merely prevents thrombin activation, it is probably most useful in preventing thrombus formation and may be analogous in action to antiplatelet agents in preventing platelet aggregation (Internastional Stroke Trial, 1996). High-dose heparin inactivates thrombin and is therefore more useful in cases where thrombin activation has already occurred and the goal of treatment is to prevent thrombus growth. Thus, from a theoretical point of view, the main purpose of heparin is to prevent the development of complete occlusion of a partially thrombosed artery or to prevent the spread of a thrombus from one artery to another.

Since heparin should be especially useful in situations where thrombus formation occurs, it is usually used in patients with cerebral ischemia with progressive or flickering symptoms, when only part of the affected artery basin is involved. Thus, heparin is indicated if the symptoms of cerebral ischemia, being transient, constantly recur or increase ("TIA crescendo") or, having become persistent, tend to progress (stroke in progress). If the symptoms of ischemia have stabilized and the stroke is considered complete, heparin is not used. Since it is difficult to predict how a particular vascular episode will develop in the future, it makes sense to prescribe heparin in the acute phase of ischemic stroke. After the onset of symptoms, symptoms often increase, and the stroke, which seems to have ended, may in fact progress. It may be too late to begin treatment aimed at preventing the spread of stroke after a sudden expansion of the ischemic zone due to the involvement of an additional part of the vascular bed.

The use of low-molecular heparin significantly expands therapeutic options. A trial of a low-molecular heparin fraction in patients with deep vein thrombosis of the lower extremities showed that in this condition it is a more effective and convenient remedy than the standard heparin preparation.

In a small randomized clinical trial, low-molecular-weight heparin was given to patients with stroke. Results showed that it could improve neurologic outcome at 6 months (compared with placebo) with a low risk of bleeding complications. Treatment was started within 48 hours of symptom onset and continued for 10 days, after which aspirin was given (although aspirin is not usually delayed until days 10–12). Because early aspirin therapy is recognized as effective, it is important to compare the efficacy of low-molecular-weight heparin with aspirin in this situation.

The side effects of heparin are related only to its anticoagulant action. The main side effect is hemorrhage, which can vary in severity from minor bruising to major bleeding. Of particular concern is the ability of heparin to cause intracranial hemorrhage and promote hemorrhagic transformation of infarction. This requires caution when administering anticoagulant therapy to patients with cardioembolic stroke. The risk of hemorrhagic transformation is highest in the first 3 days after infarction. In this regard, it is recommended to delay the administration of anticoagulants in patients with major cardioembolic stroke. There is no generally accepted criterion for the extent of stroke, but it is generally accepted that any infarction involving more than a third of the cerebral hemisphere should be included in this category.

Particular caution is required when prescribing heparin to patients with a high risk of hemorrhagic complications. This category includes postoperative patients, patients with gastrointestinal diseases, such as peptic ulcer disease, diverticulitis, or colitis. The lack of reliable information on the therapeutic efficacy of heparin in patients with stroke makes it difficult to assess the risk-benefit ratio of heparin. It is suggested that antiplatelet agents or low doses of warfarin may be used instead of heparin if the risk of bleeding is significant.

Heparin can also cause acute reversible thrombocytopenia by directly affecting platelets or by stimulating the production of antibodies that promote heparin-dependent platelet aggregation. Because thrombocytopenia may be mild, even with long-term therapy, heparin therapy should be discontinued only if the platelet count drops significantly (below 100,000/mm ³ ). Although allergic reactions are possible, they are rare.

Warfarin

Several blood coagulation factors undergo carboxylation during activation, an enzymatic reaction involving vitamin K. By disrupting vitamin K metabolism, warfarin reduces the production of these factors and, therefore, inhibits thrombus formation.

It is important to note that warfarin does not directly affect the blood clotting process and does not inactivate already functioning clotting factors, so its onset of action depends on the time it takes for the activated factors to be metabolized. It usually takes several days of regular use to achieve the maximum effect of warfarin. Taking a higher dose in the first few days of treatment does not speed up the onset of effect, but may make it more difficult to achieve a stable dose.

The ability of warfarin to reduce the risk of cardioembolic stroke is well established. Its efficacy has been demonstrated over many years in patients with valvular heart disease and artificial valves, who have the highest risk of stroke. Until recently, atrial fibrillation not associated with valvular heart disease was not considered an indication for warfarin. However, several recent clinical trials have shown that in this category of patients, warfarin reduces the risk of stroke by 68% without increasing the likelihood of major hemorrhagic complications. Two of these studies compared warfarin with aspirin. In one study, aspirin at a dose of 75 mg/day had no significant beneficial effect, while in the other, aspirin at a dose of 325 mg/day reduced the risk of stroke in this category of patients, with the effect being particularly pronounced in patients with arterial hypertension.

Warfarin has been shown to be more effective than aspirin, and the risk of hemorrhagic complications with its use is not as high as is commonly believed. Thus, warfarin can be considered the drug of choice in compliant patients with atrial fibrillation. The exception is younger individuals who do not have other risk factors for stroke (e.g., hypertension, diabetes, smoking, heart disease). The risk of stroke in these patients with isolated atrial fibrillation is not so high as to justify the use of warfarin.

Warfarin rarely causes any significant side effects unrelated to its anticoagulant action. As with heparin, hemorrhage, ranging from minor bruising to episodes of massive bleeding, is the main side effect of warfarin.

The safety of long-term use of warfarin has been confirmed in many studies across a wide range of indications. Hemorrhagic complications are usually associated with elevated levels of the anticoagulant in the plasma, which requires regular monitoring of the patient's condition. However, hemorrhagic complications may occur even with therapeutic concentrations of the drug in the blood - in the event of a stomach ulcer or injury.

Warfarin may induce necrosis, but this complication is rare. Most cases occur in women and occur early in treatment, although not always after the first dose. Necrosis involves the skin and subcutaneous tissues in areas where subcutaneous fat is most abundant - the abdomen, chest, buttocks, and thighs.

Rarely, allergic reactions and dermatitis occur during treatment with warfarin. A number of gastrointestinal disorders (nausea, vomiting, diarrhea) have also been described.

Other Stroke Treatments

Surgical treatment of stroke

The North American Symptomatic Carotid Endarterectomy Trial (NASCET) demonstrated the efficacy of endarterectomy in patients with carotid stenosis greater than 70% on the affected side. Importantly, the study did not differentiate between large-vessel and small-vessel lesions, or between stroke and TIA. The study showed that this group has a high risk of recurrent stroke, especially in the first few weeks after the ischemic episode. This supports the idea that the maximum benefit of endarterectomy is achieved when the surgery is performed as soon as possible - within a few days after the first ischemic episode.