Standards of treatment of ischemic and hemorrhagic stroke

In 1995, the results of a study of tissue plasminogen activator, published at the National Institute of Neurological Disease and Stroke (NINDS), were published. This was a historic milestone in the treatment of stroke, as it was the first undoubted proof that brain damage in stroke can be limited to therapeutic intervention. Thanks to this, stroke in the true sense of the word became an urgent neurological condition. At present, the tissue activator of plasminogen with subsequent long-term use of an antithrombotic agent is the only stroke treatment method, the effectiveness of which has been proven. However, a number of drugs with the alleged neuroprotective effect are currently undergoing clinical trials of phase II-III. It is possible that soon, as in the case of cardiac ischemia, a combination of reperfusion with cytoprotection will be used to treat stroke.

In the past, it was generally assumed that ischemic brain damage develops rapidly, as the neurological defect reaches its maximum extent shortly after the onset of the first symptoms. It was believed that even if brain tissue in the risk zone could be saved, this would not affect the final outcome, since the functional defect would not have changed. In addition, there was no information on the time necessary for the occurrence of irreversible damage to the brain, since there was no opportunity to interfere with the course of this process. Analysis of clinical data suggested that brain damage occurs rapidly and reaches maximum severity at the onset of symptoms.

This conclusion was to a certain extent reinforced by the data obtained in the study of cerebral perfusion in the event of cardiac arrest. In this case, it is easy to evaluate the time frame of cerebral ischemia. With the cessation of cardiac activity, cerebral perfusion quickly drops to zero, and reperfusion of the brain clearly corresponds to the moment of restoration of arterial pressure. The brain can tolerate the cessation of blood supply 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 with global ischemia for only a few additional minutes. Thus, massive damage to the cerebral cortex occurs if the patient resuscitates more than 15 minutes after cardiac arrest. Other organs are not much more resistant to ischemia than the brain. The kidneys, liver, heart are usually significantly damaged by cardiac arrest of such a duration, which is sufficient for the development of massive brain damage. The instant development of stroke symptoms led to the belief that brain damage quickly becomes irreversible. This until recently led to the conclusion that the treatment of stroke in the acute phase is unlikely to have any effect.

Ischemic penumbra

Fortunately, the occlusion of the artery responsible for the development of ischemic stroke does not stop the blood supply of all involved brain regions, as only in some areas the decline in perfusion falls to the level observed when cardiac arrest occurs. In this central zone of ischemia, irreversible damage probably develops within a few minutes and, at least for the time being, is not amenable to treatment. Nevertheless, most of the involved brain tissue is exposed to an intermediate level of ischemia, since the greater the distance from the central zone, the higher the perfusion - up to the area of normal perfusion provided by the other vessel. There is some threshold of perfusion, above which the brain tissue can survive indefinitely; it is only possible to temporarily turn off the function, but the infarction never develops. The boundary of the infarction zone with occlusion of the cerebral artery is determined by the threshold level of perfusion - it separates the tissue that will survive from the one that will subsequently undergo necrosis.

Decreased perfusion causes an immediate loss of function, which explains the rapid appearance of symptoms rapidly reaching maximum development. Although the symptoms manifest quickly, the development of a full heart attack takes some time. On experimental models of cerebral ischemia, it was shown that mild ischemia should be maintained for 3-6 hours in order to have a heart attack. If the infarction is not formed after 6 hours of easy reduction of cerebral perfusion, then in the future it will not develop. The area of intermediate decline in perfusion, in which the infarction can develop for several hours, is called ischemic "penumbra" (penumbra). This is the main target for emergency stroke therapy. The reality of an ischemic penumbra as a zone of the brain that can be saved after the development of stroke symptoms is difficult to prove in patients, but its existence follows from the results obtained on experimental models of ischemia. Until recently, there were no methods that would allow to study cerebral perfusion or functional status of the brain in a person during an ischemic episode. At the present time, the possibilities of new magnetic resonance techniques - diffusion-weighted and perfusion MRI - in the differentiation of reversible and irreversible ischemic lesions of the brain are being studied.

The stroke group and the concept of a "brainstorm"

Given the organizational difficulties associated with the delivery of patients to the hospital and the mobilization of doctors to perform urgent diagnostic and treatment activities, special groups specializing in the treatment of stroke should be established in medical institutions. The term "brainstorm" is suggested as an alternative to the term "stroke" in order to emphasize that cerebral ischemia is currently as curable as a heart attack.

As emergency stroke therapy becomes a standard of care, a system of timely examination of patients with signs of cerebral ischemia should be established in hospitals, in the same way as it is done 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 current possibility of specific emergency therapy for ischemic stroke is tAP, which should be administered within the first 3 hours after the onset of symptoms. Before the introduction of a tPA, a CT scan of the head should be performed to exclude cerebral hemorrhage. Thus, the minimum requirements for the resources needed to treat stroke include the possibility of rapid neurological examination, the availability of computed tomography and taps.

Therapeutic strategies for the treatment of stroke

The principles of emergency therapy for stroke are the same as in the treatment of cardiac ischemia. In cardiac ischemia, several strategies are used to minimize damage to the heart muscle, the first of which is reperfusion is of key importance. The blood flow should be restored as soon as possible in order to prevent further damage. To this end, in the most acute phase, thrombolysis is usually performed to restore perfusion, which is then often supplemented by structural restoration of the arteries either with balloon angioplasty or with aortocoronary bypass surgery. Cytoprotective therapy is also used to increase the stability of the heart muscle to ischemia, which allows it to survive longer at a low level of perfusion. So, pharmacological intervention reduces the burden 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. To this end, anticoagulants and antiaggregants are used to prevent thrombus formation.

Reperfusion and thrombolytic therapy

Given the inability to quickly and reliably measure perfusion in patients with symptoms of cerebral ischemia, little is known about the spontaneous course of ischemia. Existing data indicate that in cases of cerebral ischemia, spontaneous reperfusion often occurs. Nevertheless, such reperfusion appears to have arisen after the possibility of limiting the volume of damaged tissue has already been lost.

The first experience of thrombolytic therapy in cardiac ischemia was obtained with intra-arterial administration of thrombus-dissolving enzymes or their activators, for example, urokinase, streptokinase or tAP. After the practical value of intraarterial therapy was demonstrated, the possibility of intravenous lysis of the thrombus under the control of coronary angiography was investigated.

Initial studies of thrombolysis in stroke were also conducted with intra-arterial injection of thrombolytics. The results could often be called dramatic: after dissolving thrombus and rapidly eliminating the occlusion of a large vessel, many patients noted a significant recovery of neurological functions. Nevertheless, studies have shown that the main complication of thrombolytic therapy are hemorrhages, which are especially often developed when the thrombus was attempted to lysate many hours after the development of ischemia.

A study of tAP conducted by the National Institute of Health (USA) proved the effectiveness of intravenous thrombolysis in stroke. Improvement in the outcome of stroke after 3 months was noted according to 4 scoring scales. The study of tAP was well planned and confirmed the need to minimize the time between the development of symptoms and the initiation of treatment. One of the objectives of the study was to test a clinical protocol that could be used in any hospital where a rapid neurological examination and CT is possible. Because the purpose of the study was to evaluate the effectiveness of a tAP in a routine clinical setting, angiography was not performed. In this regard, the assumption of the presence of occlusion of the vessel and evaluation of the effectiveness of treatment were based only on clinical data. The research tasks did not include an attempt to find out whether the drug actually causes reperfusion.

The main complication of thrombolytic therapy is cerebral hemorrhage. The incidence of intracerebral hemorrhage in the tAP study was 6.4%. This indicator was much lower than in the European study of streptokinase (21%), which failed to confirm the therapeutic effect of thrombolysis. Although the administration of tAP caused several cases of intracerebral hemorrhages with a lethal outcome, there was no significant difference in the level of mortality in 3 months between the treatment group and the control group.

Protocol for the treatment of tissue plasminogen activator (tAP)

Inclusion Criteria

• Suspected acute ischemic stroke
• The possibility of introducing tAP within 3 hours after the appearance of the first symptoms
• The absence of fresh changes in CT (excluding the slightly expressed early signs of ischemia)

Exclusion criteria

• Intracerebral haemorrhage or suspicion of spontaneous subarachnoid hemorrhage
• Rapid improvement, indicative of TIA
• The minimum severity of symptoms (assessment by the National Institute of Health Stroke Scale, USA - less than 5 points)
• Stroke or severe head injury in the last 3 months
• The presence in the anamnesis of an intracerebral hemorrhage, which may increase the risk of subsequent hemorrhage in this patient
• Serious surgical intervention in the previous 14 days
• Bleeding from the gastrointestinal tract or urogenital tract in the last 3 weeks
• Uncompensated artery puncture in the preceding 7 days
• Lumbar puncture in the previous 7 days
• Systolic pressure> 185 mm Hg. Art. Or diastolic pressure> 110 mm Hg. Art. Or the need for active antihypertensive therapy (for example, with the help of nitroprusside)
• The use of warfarin or heparin in the previous 48 hours (the use of aspirin or ticlopidine is allowed)
• Coagulopathy (with increased partial thromboplastin and prothrombin time or a decrease in the number of platelets - below 100,000 in 1 μl)
• Possibility of pregnancy (fertile women should have a negative pregnancy test)
• Suspicion of pericarditis
• Signs of severe liver disease or terminal stage of kidney disease
• Epileptic seizure in the onset of stroke
• Coma at the time of receipt
• Symptomatic hypoglycaemia

Recommendations for the clinical use of taps comply with the study protocol. The dose of the drug should be 0.9 mg / kg and not exceed 90 mg. Particularly important is the requirement that the patient should undergo no more than 3 hours from the time of the onset of the first symptoms (the time that must be clearly defined) before the drug is administered. Patients with mild or rapidly regressing symptoms are not indicated. Contraindications to the use of taps are signs of intracerebral hemorrhage according to CT. The clinical trial did not include patients whose systolic pressure exceeded 185 mm Hg. Art. Or the diastolic pressure exceeded 110 mm Hg. Art. In some cases, lightweight antihypertensives were used - so that blood pressure met the inclusion criteria. Although this protocol requirement must be followed, care should be taken to avoid excessive blood pressure lowering.

Care should be taken to prescribe taps and in patients with early-onset hypodensitive foci on CT. Although such patients were not excluded from the TAP study, the results showed that the incidence of hypodensitive changes in patients with clinically significant intracranial hemorrhage reached 9% (four such patients received tAP, 2 - placebo), while in the general group this was 4%. Since the early appearance of hypotensive changes in CT can indicate an error in determining the timing of the onset of symptoms and the number of such patients is small, it is probably better to abstain from the appointment of a tAP in this group of patients.

Based on the results of the TAP test, some experts object to the use of this drug, arguing for their opinion of the relatively high risk of complications. However, even when these limitations are taken into account, it should be noted that, in general, the use of the drug resulted in a statistically significant improvement in the outcome of the stroke. It seems likely that as the experience of using the drug accumulates, its use will expand. At present, attempts are being made to optimize the protocol in order to minimize hemorrhagic complications and to determine whether the combination of taps with other drugs is effective, primarily with neuroprotective agents.

Tissue Plasminogen Activator and Reperfusion

During the test, the state of cerebral vessels was not examined. The test was divided into two parts. The first was completed by examining the patient 24 hours after the introduction of tAP - at the time when the effect of treatment could not yet be demonstrated using clinical scales. The therapeutic effect became more evident during the second stage of the study - 3 months after the administration of the drug. Some studies using intraarterial administration of taps included the identification of occluded arteries, which made it possible to correlate the patency of the artery with clinical manifestations. Since in some cases, the restoration of blood flow is accompanied by a dramatic regression of symptoms, it can be assumed that the effect of a tAP can be associated not only with a direct effect on the occluded artery, but also its effect on primary collaterals that undergo secondary occlusion due to low blood flow. On the other hand, there is no doubt that tAP promotes reperfusion of the affected area of the brain, since delay in prescribing the drug is associated with the development of hemorrhages indicative of reperfusion.

Other strategies that promote reperfusion

On the model of reversible occlusion of the middle cerebral artery in rats it was shown that blocking the adhesion of leukocytes reduces the size of the ischemic focus. After ischemia, endothelial cells in the affected area of the brain increase the expression of the molecule of adhesion of leukocytes ICAM-1. Since the size of the ischemia zone is reduced in the experimental model using monoclonal antibodies to ICAM-1, introduced during reperfusion, it can be assumed that the endothelial response to ischemia slows recovery by reperfusion. Thus, the restoration of perfusion may be more complete when inhibiting leukocyte adhesion.

Another factor capable of reducing cerebral blood flow during reperfusion is thrombosis of small collateral vessels. It is possible that the dissolution of these thrombi is an important component of the action of the tAP. Antithrombotic agents, for example, aspirin or heparin, may also be useful in these cases.

To improve perfusion after ischemia, other strategies can be implemented, the effectiveness of which has been studied both in experimental animals and in patients. Of these, arterial hypertension and hemodilution were most intensively studied. The possibilities of induction of arterial hypertension are well studied in the example of a craniocerebral trauma, in which increased intracranial pressure limits cerebral perfusion. Arterial hypertension is often used in the treatment of subarachnoid hemorrhage, in which vasospasm of cerebral vessels reduces perfusion and can lead to secondary ischemic brain damage.

The endothelium released by nitric oxide also plays an important role in the reperfusion of the brain tissue. Nitric oxide is produced in a variety of tissues, including the endothelium, where it serves as an intracellular and intercellular mediator. Nitric oxide, which has a powerful vasodilating effect, normally maintains arterial blood flow, but can also be a mediator of ischemic neuronal damage. The effect on the level of nitric oxide on the experimental models of cerebral ischemia gives conflicting results, since the outcome depends on the relationship between its effect on cerebral perfusion and neurotoxic effect.

In clinical conditions in the acute phase of a stroke, it is not always necessary to strive for strict control of blood pressure in a narrow range, except for the already mentioned situation when patients are injected with a tAP. Although in the long term, hypertension is a risk factor for stroke, in the acute phase of a stroke, it can help improve perfusion. Only when the increase in blood pressure reaches dangerous limits, appropriate intervention becomes necessary. In the acute phase of the stroke, antihypertensive drugs are often abolished, but this is contraindicated in patients taking beta-blockers, since stopping their intake can provoke myocardial ischemia, therefore, preference is given to substances that reduce symptoms of arterial vessel occlusion. Pharmacodynamic effects of such drugs should affect the contractile response of blood vessels, cerebral blood flow and rheological properties of blood.

Halidor (bcycliklan) significantly increases intravenous levels of cerebral blood flow in the ischemic region, without causing the effect of "stealing". In this connection, the data according to which bacciclan can relax sclerotically altered vessels deserve to be mentioned. With ischemia, the probability of suppressing the ability of erythrocytes to move increases. The use of bcycliklene causes two pathogenetic effects: the suppression of osmotic plasmolysis and the viscosity of the erythrocyte cytosol, and also removes the inhomogeneous distribution of the membrane protein.

The frequency of re-occlusion of stenotic vessels after the catabolic deobliteration by the Dotter method can be significantly reduced with the use of bicyclan. In a double-blind study, Zeitler (1976) found that biciclane at a dose of 600 mg per day orally reduces the frequency of re-vascular thrombosis with restoring patency to the same extent as ASA.

Individual components of the viscosity of whole blood - aggregation and elasticity of platelets, coagulability - vary with a certain pharmacological effect. Correlation analysis revealed a linear relationship between the concentration of biciclane and a decrease in spontaneous aggregation of platelets. The drug reduces the capture of adenosine by platelets, while inhibiting the serotonin-induced release of platelet content. This, in the first place, concerns the protein of beta-thromboglobulin (P-TG). According to the latest data, the content of beta-TG should correlate with AH. With the use of bicyclic, the level of beta-TG in blood plasma was significantly reduced.

Benzyclan blocks Ca channels, reduces the intracellular concentration of Ca ²⁺, activates NO-synthetase, increases NO production. Simultaneously, it inhibits phosphodiesterase, selectively blocking 5-HT serotonin receptors in erythrocytes and platelets, thus accumulating cyclic AMP, which indirectly affects the reduction of leukocyte adhesion, allowing the restoration of blood flow in microvessels.

Thus, the use of Galidor in patients with stroke becomes understandable. The recommended dosage of the drug should be at least 400 mg in a daily dose. Duration of the drug depends on the expressed vascular pathology and ranges from 3 weeks to 3 months, followed by repeated courses in six months.

At the same time, one should not forget the fact that the use of bicyclic in patients with severe cardiac pathology can cause tachyarrhythmia, but it is proved that 90% of patients do not experience side effects and complications with the use of bcycliclane.

Contraindications for the appointment of the drug are tachyarrhythmia, renal or hepatic insufficiency, age to 18 years.

Halidor is compatible with preparations of other pharmacological groups, however, when combined with cardiac glycosides and diuretics, it is necessary to monitor the potassium level in the 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 consistently show a high risk of expanding over time the ischemia zone or the occurrence of a repeated stroke in another part of the brain. This corresponds to the concept that the majority of ischemic strokes are inherently embolic in nature, with the embolism being the heart or atheromatous plaques in large vessels. Accordingly, it is believed that early initiation of treatment with antithrombotic agents can lead to a reduction in the risk of repeated ischemic episodes. Nevertheless, the effectiveness of this approach can not be considered proven, since most published studies have estimated the frequency of late relapses in patients who were included in these studies a few weeks or months after the stroke. Currently, several clinical trials are underway to evaluate the effectiveness of early therapy with antithrombotic agents in order to prevent the expansion of the ischemic zone and prevent subsequent ischemic episodes.

Formation and increase of thrombus occurs with the participation of platelets and thrombin. Although the first or second of these elements may play a more important role in a given case, both of them are likely to contribute to early recurrence of a stroke. Most of the published studies are devoted to the evaluation of the effectiveness of antiplatelet agents and are based on the long-term use of aspirin or ticlopidine in order to prevent recurrence of stroke in patients without a clearly established etiology of stroke. Such studies should be large, since the risk of stroke even in this population is relatively small. In recent years, several tests have been performed assessing the effectiveness of drugs in the intermediate post-stroke period, when the risk of recurrence of stroke is particularly high.

Aspirin

Aspirin (acetylsalicylic acid) irreversibly inhibits cyclooxygenase by acetylating the functionally significant serine residue of the enzyme. Cyclooxygenase promotes the conversion of arachidonic acid into a variety of eicosanoids, including prostaglandins and thromboxanes. Although aspirin can have a different effect, inhibition of cyclooxygenase is crucial for the prevention of thrombosis. Since platelets do not have a nucleus, they are unable to synthesize a new enzyme after the available cyclooxygenase is inhibited by aspirin. Thus, for this purpose, the drug should be taken once a day, although its half-elimination period does not exceed 3 hours, however, the duration of its effect corresponds to the life span of the platelet.

Aspirin is the drug most often used to reduce the risk of recurrence of a stroke. At least four major clinical trials have been performed demonstrating the efficacy of aspirin in patients who underwent TIA or stroke. The drawback of these tests is that, in general, the evaluation of the effectiveness of the drug included not only repeated strokes, but also other events, for example, lethal outcomes. Thus, the preventive effect of aspirin on cardiac ischemia made it difficult to interpret the results of some of these studies for recurrent stroke. Nevertheless, aspirin is recommended for all patients who do not take other antiplatelet agents or anticoagulants.

Although evidence of the ability of aspirin to reduce the risk of recurrent stroke is not in doubt, the analysis of the results of these studies need to understand the specifics of this problem. Thus, the risk of recurrent stroke is generally quite low - 5-10% per year. When treated with aspirin, this indicator decreases by approximately 25%. Sometimes the need for a large number of patients, necessary for conducting such studies, is mistakenly interpreted as a sign of low effectiveness of aspirin. Large groups of patients should be investigated even if individuals with a high risk of recurrence of stroke are selected, since in this case the likelihood of such episodes is rather small. On the other hand, sometimes there is an erroneous impression that antiaggregants completely prevent a stroke. However, drugs only reduce the risk of stroke, while the risk of recurrence of the stroke is reduced only by less than half. Therefore, people who have suffered a stroke should be informed of the continuing risk of stroke and the relative efficacy of aspirin. Patients with a high risk of recurrence of a stroke should be informed about modern treatment methods that can be used in the event of a new stroke. In recent years, it has been proven that aspirin given in the acute phase of a stroke (within 48 hours after the onset of symptoms) reduces the mortality and frequency of early recurrent stroke recurrences, but does not seem to have a significant effect on the residual defect level.

There is controversy regarding the optimal dose of aspirin in secondary prevention of stroke. Clinical evidence suggests that at a dose of 75 mg / day, aspirin can effectively reduce the risk of stroke and reduce the likelihood of death from myocardial infarction. Experimental laboratory data show that low doses of aspirin can completely inhibit cyclooxygenase. Since the gastrointestinal side effects are dose-dependent, the use of lower doses seems preferable. However, it remains an open question whether higher doses of the drug have an additional protective effect that outweighs the risk of side effects. In recent years, experts have come to a common opinion that low doses of aspirin are effective in treating cardiovascular diseases, but there is no such consensus regarding the use of aspirin in the treatment of stroke.

There are conflicting opinions about the dose of aspirin needed to reduce the risk of stroke, since there are no studies whose results would unequivocally solve this problem. It has been proven that higher doses of aspirin can be effective in some patients 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 diseases, as it acetylates a number of other proteins. Since low doses of aspirin are effective in preventing death due to coronary heart disease and there is no evidence that the mechanism of occlusion of cerebral vessels differs from occlusion of cardiac vessels, it seems likely that low doses of aspirin should be sufficiently effective in patients with stroke.

The current practice is to prescribe a low dose of aspirin (75 mg / day) to reduce the risk of vascular disease in the general population and medium doses (325 mg / day) in patients with a higher risk, and with significant side effects this dose may be reduced . High doses of aspirin (1300 mg / day) are shown only when cerebrovascular episodes occur against the background of standard therapy.

The most common side effect of aspirin is gastrointestinal disorders, occurring in 2-10% of patients taking standard analgesic doses. This percentage is significantly increased (up to 30-90%), when aspirin is prescribed to people who previously suffered peptic ulcer or gastritis. Gastrointestinal side effects include heartburn, nausea, epigastric discomfort. These effects are dose-dependent and are explained (at least in part) by the local irritant effect of the drug on the mucosa of the gastrointestinal tract. In general, preparations in a shell dissolving in the intestine are better tolerated by the majority of patients, including those who previously had peptic ulcer or gastritis. In addition, to prevent side effects, it is recommended to take aspirin during meals or along with antacids.

Aspirin should be used with caution in patients with active gastrointestinal disorders (such as gastritis or ulcer), as well as the streets that have suffered from these diseases in the past. For this category of patients, regular follow-up, low-dose aspirin, and testing for latent gastrointestinal bleeding are recommended. Caution should also be observed when prescribing aspirin to patients who consume alcohol or who take corticosteroids. The only absolute contraindication to the appointment of aspirin is a rare hypersensitivity to salicylates.

Irritation of the stomach caused by a prolonged intake of aspirin can lead to latent painless gastrointestinal bleeding. With a significant loss of blood, iron deficiency anemia may develop.

Most cases of toxic effects of aspirin are caused by the use of doses far exceeding those used for the prevention of stroke. The first symptoms of acute or chronic intoxication are often tinnitus and hearing loss. These manifestations usually occur with a decrease in the dose of aspirin. When an acute overdose of aspirin occurs metabolic acidosis, manifested by drowsiness, confusion, nausea, hyperventilation. With an overdose of aspirin, a lethal outcome is possible, associated with multiple organ dysfunction.

[1], [2], [3], [4], [5], [6]

Ticlopidine

The drug blocks the aggregation of platelets, inhibiting the adenosine diphosphate pathway. As with aspirin, the effect of ticlopidine is irreversible.

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

Diarrhea, often accompanied by spasms in the abdomen, is the most common side effect of ticlopidine. It is usually attenuated by a temporary decrease in the dose of the drug. Bruises, petechiae, nasal bleeding, microhematuria are also noted in the clinical trial, but gastrointestinal bleeding has been rare. Like aspirin, ticlopidine should be canceled one week before the planned surgery.

In a small percentage of patients, ticlopidine causes blood changes, usually in the first 3 months of treatment. In this case, neutropenia is most common (2.4%). Less commonly, agranulocytosis, even more rare complications - aplastic anemia, pancytopenia, thrombocytopenia, thrombotic thrombocytopenic purpura, immune thrombocytopenia. Every 2 weeks during the first 3 months of treatment with ticlopidine, a clinical blood test should be performed to count the platelet count and determine the leukocyte formula. Ticlopidine should be immediately withdrawn if blood changes are detected, either with infection or bleeding.

In addition, when taking ticlopidine, skin rashes and itching are possible, but they are rarely expressed. In the clinical trial of ticlopidine, rashes were detected in 5% of patients. Usually they occurred in the first 3 months of treatment. In some cases, ticlopidine may be prescribed again after a medical break-out sufficient for the disappearance of the rash - this side effect may not recur.

Like aspirin, ticlopidine should be used with caution in patients with peptic ulcer or gastritis in the phase of exacerbation. But since, unlike aspirin, ticlopidine does not have an irritant effect on the mucosa of the gastrointestinal tract, it should be preferred to aspirin in this category of patients. Ticlopidine should be used with caution in patients with increased bleeding. The safety of the drug combination with aspirin, warfarin and thrombolytics has not been studied.

Since ticlopidine is metabolized in the liver, care should be taken when administering it to patients with liver damage. With hepatic failure, it is contraindicated.

Clopidogrel

The drug, chemically close to ticlopidine, has a similar mechanism of action. The study shows 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 injury, it was found that in a group taking clopidogrel, stroke, myocardial infarction, or fatal outcome associated with vascular diseases was noted in 9.78% of patients, whereas in the group , who took aspirin, similar episodes arose in 10.64% of patients. Unlike ticlopidine, clopidogrel does not cause blood changes. Currently, the use of the drug for the purpose of secondary prevention of stroke is approved by the FDA.

[7], [8], [9], [10], [11], [12], [13], [14], [15], [16],

Dipyridamole

The ESPS2 trial showed that taking dipyridamole 200 mg twice daily (in the form of sustained-release tablets) is as effective as taking aspirin (25 mg twice daily) in patients with TIA or minor stroke with regard to prevention stroke, myocardial infarction and lethal outcome associated with vascular lesions. In comparison with placebo, the relative reduction in the risk of stroke or death was 13% for aspirin and 15% for dipyridamole. It is also shown that the combination of dipyridamole (in the form of slow release tablets) and aspirin more effectively reduces the risk of recurrence of stroke (37%) than placebo and one aspirin (22%). The dosage form containing 200 mg of dipyridamole (with sustained release) and 25 mg of aspirin has now been approved by the FDA for use as a means for secondary prevention of stroke.

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Heparin

It is a natural family of molecules found in mast cells. The drug is usually obtained from the lungs or gastrointestinal tissues of cattle. Heparin is a glycosaminoglycan. Its average molecular weight is about 12,000. Because heparin is administered intravenously and therefore is characterized by a rapid onset of action, it is used in cases where it is necessary to obtain a rapid anticoagulant effect, for example, for the purpose of urgent secondary prevention of stroke. Heparin is used in patients with the highest risk of stroke under the control of laboratory indicators. For long-term treatment use warfarin - an anticoagulant, appointed inside.

While antiaggregants block platelet aggregation and slow the formation and growth of a thrombus, heparin and warfarin directly inhibit blood clotting. When administered in sufficient doses, heparin is able to completely block the process of blood coagulation.

Heparin acts as a catalyst, accelerating the reaction, during which antithrombin III neutralizes thrombin, an enzyme that facilitates the conversion of fibrinogen into fibrin. Since fibrin is the main thrombogenic plasma protein, the blockade of its products prevents thrombus formation. In lower doses, heparin prevents the conversion of factor X to prothrombin and then to thrombin.

Although there is no direct clinical evidence supporting 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 manifests itself slowly, in urgent situations, when it is necessary to obtain a rapid effect (for example, at the risk of repeated embolic stroke in the first few days after a cerebral circulation disorder), heparin is used. Heparin is a high-speed anticoagulant that is used until the therapeutic effect of warfarin is fully manifested.

Because low doses of heparin only prevent the activation of thrombin, they are probably most useful for preventing thrombogenesis and, probably, are similar in effect to antiaggregants that prevent platelet aggregation (Internastional Stroke Trial, 1996). High doses of heparin inactivate thrombin, so they are more useful when thrombin activation has already occurred and the goal of treatment is to prevent thrombus growth. Thus, from the theoretical point of view, the main purpose of heparin is to prevent the development of complete occlusion of a partially occluded artery or to prevent the spread of a thrombus from one artery to another.

Since heparin should be particularly useful in situations where there is thrombosis, it is usually used in patients with cerebral ischemia with progressive or flickering symptoms, when only part of the basin of the affected artery is involved. So, heparin is shown if the symptoms of brain ischemia, having a transient nature, are constantly renewed or increasing ("TIA-crescendo") or, becoming persistent, tend to progress (stroke in development). If the symptoms of ischemia have stabilized and the stroke is considered complete, heparin is not used. Since at first it is difficult to predict how this or that vascular episode will develop in the future, it makes sense to prescribe heparin in the most acute phase of ischemic stroke. After the onset of symptoms, the symptom often develops, and a stroke that seems to be completed, in fact, may progress. To start treatment aimed at preventing the spread of a stroke after the sudden expansion of the ischemic zone due to the involvement of an additional part of the vascular pool may be too late.

The use of low molecular weight heparin significantly expands the therapeutic possibilities. The test of a low molecular weight fraction of heparin in patients with deep vein thrombosis of the lower limbs showed that in this state it is more effective and convenient than the standard preparation of heparin.

In a small randomized clinical trial, low-molecular-weight heparin was prescribed in patients with stroke. The results showed the possibility of improving the neurological outcome in 6 months (compared with placebo) with a low risk of hemorrhagic complications. Treatment was started in the first 48 hours after the onset of symptoms and lasted 10 days, after which aspirin was prescribed (although, as a rule, the appointment of aspirin is not usually postponed until 10-12 days). Since early therapy with aspirin is recognized as effective, it is important to compare the efficacy of low-molecular-weight heparin with aspirin in this situation.

Side effects of heparin are associated only with its anticoagulant effect. The main side effect is hemorrhages, which can vary in severity from minor bruising to major bleeding. Of particular concern is the ability of heparin to lead to the development of intracranial hemorrhages and to promote hemorrhagic transformation of the infarction. This requires caution in the conduct of anticoagulant therapy in patients with cardioembolic stroke. The risk of hemorrhagic transformation is highest in the first 3 days after a heart attack. In this regard, it is recommended to delay the appointment of anticoagulants in patients with a major cardioembolic stroke. There is no universally accepted criterion for the vastness of the stroke, but it is generally accepted that any infarct involving more than a third of the brain hemisphere should be included in this category.

Particular caution is needed when administering heparin to patients with a high risk of hemorrhagic complications. This category includes postoperative patients, patients with diseases of the gastrointestinal tract, for example, peptic ulcer, 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 can be used in place of heparin with a significant risk of bleeding.

Heparin is also capable of causing acute reversible thrombocytopenia, directly affecting platelets or stimulating the production of antibodies that promote heparin-dependent platelet aggregation. Because thrombocytopenia can be mild, even with prolonged therapy, treatment with heparin must be discontinued only if there is a significant drop in platelet count (below 100,000 / mm ³ ). Although allergic reactions are possible, they are rarely observed.

Warfarin

Several factors of blood coagulation during the activation are subjected to carboxylation - an enzymatic reaction that takes place with the participation of vitamin K. By disrupting the metabolism of vitamin K, warfarin reduces the production of these factors and, consequently, inhibits thrombus formation.

It is important to note that warfarin does not directly affect the process of blood coagulation and does not inactivate the already functioning coagulation factors, so the onset of its action depends on the time during which the metabolism of activated factors occurs. Usually, to achieve the maximum effect of warfarin, several days of its regular administration are required. Taking an increased dose in the first few days of treatment does not accelerate the onset of the effect, but may make it difficult to achieve a stable dose.

The ability of warfarin to reduce the risk of cardioembolic stroke is well established. Its effectiveness is proved by many years of experience in patients with heart defects and artificial valves, in whom the risk of stroke is highest. Until recently, atrial fibrillation, not associated with valvular heart disease, was not considered as an indication for the appointment of warfarin. However, in several recent clinical trials, it was shown that in this category of patients warfarin reduces the risk of stroke by 68%, without increasing the likelihood of major hemorrhagic complications. In two of these studies warfarin was compared with aspirin. In one study, aspirin at a dose of 75 mg / day did not have any significant positive effect, in another - aspirin at a dose of 325 mg / day reduced the risk of stroke in this category of patients, and the effect was particularly pronounced in patients with hypertension.

It was shown that warfarin is as effective as aspirin, and the risk of hemorrhagic complications in its use is not as high as it is commonly believed. Thus, warfarin can be considered a drug of choice in compliant patients with atrial fibrillation. Exception is made by younger persons who do not have other risk factors for stroke (for example, arterial 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 not associated with its anticoagulant effect. As in the case of heparin, hemorrhages from minor bruising to episodes of massive bleeding are the main side effect of warfarin.

The safety of long-term taking of warfarin is confirmed in many studies on a wide range of indications. Hemorrhagic complications are usually associated with an elevated level of anticoagulant in the plasma, which requires regular monitoring of the patient's condition. However, hemorrhagic complications can occur even with the therapeutic concentration of the drug in the blood - when a stomach ulcer or trauma occurs.

Warfarin can induce the development of necrosis, but this complication is rare. Most of these cases are noted in women and occur at the beginning of treatment, although not always after the first administration of the drug. Necrosis involves the skin and subcutaneous tissue in those regions where the subcutaneous fat is most pronounced - in the abdomen, chest, buttocks, thighs.

Occasionally, when treating warfarin, allergic reactions and dermatitis occur. Described and a number of gastrointestinal disorders (nausea, vomiting, diarrhea).

Other treatments for stroke

Surgical treatment of stroke

A North American endarterectomy study in patients with clinically manifested carotid stenosis demonstrated the effectiveness of endarterectomy in patients with carotid artery stenosis exceeding 70% on the affected side. It is important to note that the study did not differentiate the lesions associated with the involvement of large and small vessels, as well as stroke and TIA. The study showed that this group has a high risk of recurrence, especially in the first few weeks after the ischemic episode. This confirms the view that the maximum effect of endarterectomy is achieved when the operative intervention is performed as quickly as possible - within a few days after the first ischemic episode.