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Present state of the treatment of stroke
Resuscitation, 24 (1992) 1-5
Elsevier Scientific Publishers Ireland Ltd.
Editorial
Present state of the treatment of stroke A. Lowenthal Medical Research, City Hospitals, Antwerp (Belgium)
Cerebral ischemic accidents along with a persistent neurological deficiency, create a medical, a socio-economical and a serious ethic problem. It is thus useful to know in these cases, the diagnostic and therapeutic availabilities. DIAGNOSIS
Cerebrovascular accidents are classified according to their localisation and are of two types: intraparenchymatous hemorrhage, with or without subarachnoid hemorrhage and ischemic lesions of thrombo-embolic origin. The differential diagnosis between hemorrhages and ischemic lesions can only be achieved by using neuroimaging. Results of examinations made with MRI allow further information than with CT-scan alone to be obtained< This method permits the conclusion that cerebrovascular syndromes, which are not associated with anomalies visible by neuroimaging, are rare. Cerebral ischemic accidents are classified, clinically, as transient ischemic attacks (TIA), reversible ischemic neurological disease (RIND) and complete stroke. These diagnoses are not always confirmed using neuroimaging. Some confusion exists between clinical, anatomo-pathological and neuroimaging classifications. Publications in which reference to so-called lacunar lesions are made, provide good examples of this confusion. To reach a diagnosis, more research is required using all the types of imaging (functional included) available. THERAPEUTIC
CAPACITIES
In the case of hemorrhages, in particular subarachnoid hemorrhages, vascular spasms can be treated with calcium antagonists. Intracerebral hematomas have only to be operated upon should they provoke a mass reaction. An anti-edematous treatment might also be considered. There is no evidence to show that corticoids have any effect, or are of any use. Numerous treatments have been suggested during the Correspondence to: A. Lowenthal,
106 Jan Van Rijswijcklaau, Antwerp 2018, Belgium.
0300-957U9USO5.00 0 1992 Elsevier Scientific Publishers Ireland Ltd. Printed and Published in Ireland
2
acute phase of stroke: anticoagulants, prostaglandins, organic acid scavengers, vitamin E, calcium antagonists and in particular thrombolysis. The efficacy of these treatments has not yet been proven, except for thrombolysis. Discussions are still under way to discover if thrombolysis should be carried out with streptokinase or with tPA and if it has to be associated or not with anticoagulants or platelet antiaggregating substances (aspirin, ticlopidine, dipyridamole etc.). Answers to these questions require further studies with better methodology. On the one hand streptokinase raises immunological reactions, while on the other tPA provokes more cerebral hemorrhages, although they do not exceed 1%. The practical character of a treatment with thrombolysis raises many questions which are far from being solved: treatment with thrombolytics must be carried out within the first 6 h after the acute phase. Until now trials have been applied essentially to patients presenting lesions of the brainstem. One can ask oneself about the role played by thrombolysis on hemispherical lesions. The survey of the effectiveness of the treatment has also been questioned - it is difficult to carry out repetitive angiographies as formerly proposed. Non-invasive angiographies with MRI can bring an answer. An evaluation of the efficacy of the treatment during the acute phase is difficult to reach because of the variability of the lesions seen in neuroimaging and by lack of precision in the rating scales. A parallelism is not always found between the lesions identified by neuroimaging, evaluated with the help of rating scales and diagnosed by clinical observations. Among the effects of the treatment during the acute phase, one cannot discount that oxygenation of the cerebral tissue has to be secured. It is possible, when reopening occluded vessels, that toxic substances are liberated into the blood circulation. In any case, thrombolytic treatments seem to be efficient, but the technique applied for this therapy must be better defined. This explains why the preventive treatment remains to the fore. One has to designate this treatment either as primary prevention, which is not neurological, or as secondary prevention, in patients who have already had a first ischemic lesion. Primary prevention Primary prevention concerns the treatment of the risk factors. These may be divided into noncontrollable factors, like age, sex, geographical or ethnic background of the patients and controllable factors like arterial hypertension, diabetes, hyperlipidemia, tabagism and alcoholism. To these habitual risk factors we add, atria1 fibrillation and a first cerebral ischemic lesion. The frequency of cerebral ischemic lesions increases with age, in a different manner in both men and women. Men have cerebral ischemic lesions at an earlier age than women where they predominate after the age of 75. It seems certain that the control of arterial tension favors a decrease in the incidence of ischemic lesions. Having discussed hyperlipidemia, it is not proven that cerebral lesions, like coronary lesions, respond to the therapy. The treatment of diabetes probably has an influence on this, but it has not been demonstrated with certainty. Tobacco and alcohol are most likely to have harmful repercussions on the incidence of cerebral ischemic lesions but confirmation of this is needed. Anticoagulants are often prescribed to patients presenting with atria1 fibrillation with or without cerebral ischemic lesions.
3
The manner in which this treatment needs to be prolonged, such as by the use of aspirin or dipyridamole, has not yet been demonstrated conclusively.
Secondary prevention How to cope with a patient who presented a previous cerebral ischemic lesion? It is
certain that a first cerebral ischemic lesion, be it a TIA or a stroke, indicates that the risk of reoccurrence is increased. The principle of secondary prevention is to avoid the formation of new thrombi or emboli. Numerous studies have been published concerning the action of antiaggregating substances in these cases. A recent inquiry made among the participants of an international congress, has shown that secondary prevention is known and very common among neurologists. Various substances with different efficiencies on thrombi or emboli have been utilised. Their activity has been checked in the course of many studies, for some there are no studies while others give very divergent results. An overview or meta-analysis carried out by the Antiplatelet Trialists Group from Oxford showed that aspirin, ticlopidine and the combination aspirin/dipyridamole are efficient. However, if one wishes to compare the results of studies already published, one faces difficulties immediately because of the strikingly different methodologies that were applied. Diagnosis has not always been reached under the same conditions and patients with identical diagnoses are not always considered. One has to ask if the same therapy may be applied after TIA and after stroke. The criteria used to evaluate the efficiency of the therapy vary and very little information concerning the compliance of the patients to the criteria is given. The main studies are both multicentric and international and the recruitment of patients can be influenced by the decisions of the trialists and the local geographical conditions. All of these studies, have, for statistical relability, to recruit at least 1000 patients. This requires efficient coordination with strict surveillance with only those results that are statistically significant being retained. Statistical interpretations tend to be in the form of an intention to treat or as an explanatory statement. Comparisons on the other hand can be direct or indirect and the latter is not always acceptable. Which of the substances or combination (aspirin, ticlopidine or the combination aspirin/dipyria?.zmole), has to be prescribed as a daily routine? Aspirin studies show
a marked variability in their results. They never extend beyond 18-29% risk reduction. In some cases, the results are even paradoxical. It is not statistically proven that aspirin acts in some subgroups like women or patients in whom the first event was an invalidating stroke. The role of aspirin in connection with risk factors and localisations is not evident. Doses vary according to authors, between 75 mg and 5-10 g. Secondary effects, such as gastroenteric or hemorrhagic, should not be neglected. If a relapse stroke seems to recede due to aspirin, the prevention of death is still not solved - these results do not show an unequivocal reduction in the number of deaths. Ticlopidine has recently been introduced administered at a dose of 500 mg (the only per-day dose used up to now). It gives a risk reduction of less than 23% in any new cerebral ischemic accident and it acts in women and patients who have had a first stroke. The adverse effects are important and the cost of the therapy is high.
Table I. Name of study
Antiaggregating substances
Risk reduction in %
European Stroke Prevention 1 United Kingdom TIA Aspirin Study Swedish Aspirin Low-dose Trial Canadian American Ticlopidine Study
Dipyridamolel Aspirin Aspirin
35.5
Aspirin
18.0 zt 9.5
Ticlopidine
20.4 zt 7.1
??
5.0
14.3 zt 4.2
It seems that the synthesis of products with similar action but less toxicity is required. The combination aspirin/dipyridamole has given the best results so far. The role of this combination has been foreseen by FitzGerald, Sze, and Reitmanlm3. The studies which have been carried out so far, have shown that this combination can lead to a highly significant risk reduction of more than 33%. This reduction is observed in women as well as in men, in young patients and elderly, in diabetici, in patients with hypertension, after TIA and after stroke, and the combination is efficient for all localisations. This combination is not without secondary effects due to the presence of aspirin which explains why new studies are in progress in this area. It is difficult to compare the therapeutic effect of aspirin, ticlopidine and the cobmbination aspirin/dipyridamole. Looking at published results (Table I) to find similar end-points, one can see that the best results are obtained with the combination aspirin/dipyridamole. Ticlopidine is a little less active but acts better than aspirin at different doses. Surgical prevention by carotid endarterectomy should be mentioned. Resting on the first results of two large studies, NASCET4 and ECST’, one finds that for a stenosis of more than 70%, endarterectomy is recommended. More information will be available soon as studies are still in progress. In any case, surgery should be complemented with antiaggregating substances for prevention. CONCLUSIONS
In conclusion, the questions raised by stroke remain controversial. The diagnosis has to rely on neuroimaging data. The treatment of acute hemorrhagic stroke by surgery is only recommended when mass effect is observed. The treatment of acute stroke due to ischemia improves using thrombolysis. Primary prevention consists of the treatment of risk factors by internists. Secondary prevention, which is the most documented, is managed with platelet antiaggregants, sometimes after carotid surgery. In any case, regardless of the very abundant literature, new studies with a very rigorous methodology are needed. These alone will lead to clear conclusions.
5
REFERENCES FitsGerald GA. New Engl J Med 1987; 316: 1247-1287. Sze PC, Reitman D, Pincus MM, Sacks HS, Chalmers TC. Antiplatelet agents in the secondary prevention of stroke: Meta-analysis of the random&d control trials. Stroke 1988; 19: 436-442. Reitman D, Sacks HS, Chalmers TC, Sm. PC, Pincus MM. Stroke 1988; 296: 1446-1447. North American Symptomatic Carotid Endarterectomy Trial Collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med 1991; 325: 445-453. European Carotid Surgery Trialists’ Collaborative Group. MRC European Carotid Surgery Trial: interim results for symptomatic patients with severe (70~99%) or with mild (lo-29%) carotid stenosis. Lancet 1991; 337: 1235-1243.
Elsevier Scientific Publishers Ireland Ltd.
Editorial
Present state of the treatment of stroke A. Lowenthal Medical Research, City Hospitals, Antwerp (Belgium)
Cerebral ischemic accidents along with a persistent neurological deficiency, create a medical, a socio-economical and a serious ethic problem. It is thus useful to know in these cases, the diagnostic and therapeutic availabilities. DIAGNOSIS
Cerebrovascular accidents are classified according to their localisation and are of two types: intraparenchymatous hemorrhage, with or without subarachnoid hemorrhage and ischemic lesions of thrombo-embolic origin. The differential diagnosis between hemorrhages and ischemic lesions can only be achieved by using neuroimaging. Results of examinations made with MRI allow further information than with CT-scan alone to be obtained< This method permits the conclusion that cerebrovascular syndromes, which are not associated with anomalies visible by neuroimaging, are rare. Cerebral ischemic accidents are classified, clinically, as transient ischemic attacks (TIA), reversible ischemic neurological disease (RIND) and complete stroke. These diagnoses are not always confirmed using neuroimaging. Some confusion exists between clinical, anatomo-pathological and neuroimaging classifications. Publications in which reference to so-called lacunar lesions are made, provide good examples of this confusion. To reach a diagnosis, more research is required using all the types of imaging (functional included) available. THERAPEUTIC
CAPACITIES
In the case of hemorrhages, in particular subarachnoid hemorrhages, vascular spasms can be treated with calcium antagonists. Intracerebral hematomas have only to be operated upon should they provoke a mass reaction. An anti-edematous treatment might also be considered. There is no evidence to show that corticoids have any effect, or are of any use. Numerous treatments have been suggested during the Correspondence to: A. Lowenthal,
106 Jan Van Rijswijcklaau, Antwerp 2018, Belgium.
0300-957U9USO5.00 0 1992 Elsevier Scientific Publishers Ireland Ltd. Printed and Published in Ireland
2
acute phase of stroke: anticoagulants, prostaglandins, organic acid scavengers, vitamin E, calcium antagonists and in particular thrombolysis. The efficacy of these treatments has not yet been proven, except for thrombolysis. Discussions are still under way to discover if thrombolysis should be carried out with streptokinase or with tPA and if it has to be associated or not with anticoagulants or platelet antiaggregating substances (aspirin, ticlopidine, dipyridamole etc.). Answers to these questions require further studies with better methodology. On the one hand streptokinase raises immunological reactions, while on the other tPA provokes more cerebral hemorrhages, although they do not exceed 1%. The practical character of a treatment with thrombolysis raises many questions which are far from being solved: treatment with thrombolytics must be carried out within the first 6 h after the acute phase. Until now trials have been applied essentially to patients presenting lesions of the brainstem. One can ask oneself about the role played by thrombolysis on hemispherical lesions. The survey of the effectiveness of the treatment has also been questioned - it is difficult to carry out repetitive angiographies as formerly proposed. Non-invasive angiographies with MRI can bring an answer. An evaluation of the efficacy of the treatment during the acute phase is difficult to reach because of the variability of the lesions seen in neuroimaging and by lack of precision in the rating scales. A parallelism is not always found between the lesions identified by neuroimaging, evaluated with the help of rating scales and diagnosed by clinical observations. Among the effects of the treatment during the acute phase, one cannot discount that oxygenation of the cerebral tissue has to be secured. It is possible, when reopening occluded vessels, that toxic substances are liberated into the blood circulation. In any case, thrombolytic treatments seem to be efficient, but the technique applied for this therapy must be better defined. This explains why the preventive treatment remains to the fore. One has to designate this treatment either as primary prevention, which is not neurological, or as secondary prevention, in patients who have already had a first ischemic lesion. Primary prevention Primary prevention concerns the treatment of the risk factors. These may be divided into noncontrollable factors, like age, sex, geographical or ethnic background of the patients and controllable factors like arterial hypertension, diabetes, hyperlipidemia, tabagism and alcoholism. To these habitual risk factors we add, atria1 fibrillation and a first cerebral ischemic lesion. The frequency of cerebral ischemic lesions increases with age, in a different manner in both men and women. Men have cerebral ischemic lesions at an earlier age than women where they predominate after the age of 75. It seems certain that the control of arterial tension favors a decrease in the incidence of ischemic lesions. Having discussed hyperlipidemia, it is not proven that cerebral lesions, like coronary lesions, respond to the therapy. The treatment of diabetes probably has an influence on this, but it has not been demonstrated with certainty. Tobacco and alcohol are most likely to have harmful repercussions on the incidence of cerebral ischemic lesions but confirmation of this is needed. Anticoagulants are often prescribed to patients presenting with atria1 fibrillation with or without cerebral ischemic lesions.
3
The manner in which this treatment needs to be prolonged, such as by the use of aspirin or dipyridamole, has not yet been demonstrated conclusively.
Secondary prevention How to cope with a patient who presented a previous cerebral ischemic lesion? It is
certain that a first cerebral ischemic lesion, be it a TIA or a stroke, indicates that the risk of reoccurrence is increased. The principle of secondary prevention is to avoid the formation of new thrombi or emboli. Numerous studies have been published concerning the action of antiaggregating substances in these cases. A recent inquiry made among the participants of an international congress, has shown that secondary prevention is known and very common among neurologists. Various substances with different efficiencies on thrombi or emboli have been utilised. Their activity has been checked in the course of many studies, for some there are no studies while others give very divergent results. An overview or meta-analysis carried out by the Antiplatelet Trialists Group from Oxford showed that aspirin, ticlopidine and the combination aspirin/dipyridamole are efficient. However, if one wishes to compare the results of studies already published, one faces difficulties immediately because of the strikingly different methodologies that were applied. Diagnosis has not always been reached under the same conditions and patients with identical diagnoses are not always considered. One has to ask if the same therapy may be applied after TIA and after stroke. The criteria used to evaluate the efficiency of the therapy vary and very little information concerning the compliance of the patients to the criteria is given. The main studies are both multicentric and international and the recruitment of patients can be influenced by the decisions of the trialists and the local geographical conditions. All of these studies, have, for statistical relability, to recruit at least 1000 patients. This requires efficient coordination with strict surveillance with only those results that are statistically significant being retained. Statistical interpretations tend to be in the form of an intention to treat or as an explanatory statement. Comparisons on the other hand can be direct or indirect and the latter is not always acceptable. Which of the substances or combination (aspirin, ticlopidine or the combination aspirin/dipyria?.zmole), has to be prescribed as a daily routine? Aspirin studies show
a marked variability in their results. They never extend beyond 18-29% risk reduction. In some cases, the results are even paradoxical. It is not statistically proven that aspirin acts in some subgroups like women or patients in whom the first event was an invalidating stroke. The role of aspirin in connection with risk factors and localisations is not evident. Doses vary according to authors, between 75 mg and 5-10 g. Secondary effects, such as gastroenteric or hemorrhagic, should not be neglected. If a relapse stroke seems to recede due to aspirin, the prevention of death is still not solved - these results do not show an unequivocal reduction in the number of deaths. Ticlopidine has recently been introduced administered at a dose of 500 mg (the only per-day dose used up to now). It gives a risk reduction of less than 23% in any new cerebral ischemic accident and it acts in women and patients who have had a first stroke. The adverse effects are important and the cost of the therapy is high.
Table I. Name of study
Antiaggregating substances
Risk reduction in %
European Stroke Prevention 1 United Kingdom TIA Aspirin Study Swedish Aspirin Low-dose Trial Canadian American Ticlopidine Study
Dipyridamolel Aspirin Aspirin
35.5
Aspirin
18.0 zt 9.5
Ticlopidine
20.4 zt 7.1
??
5.0
14.3 zt 4.2
It seems that the synthesis of products with similar action but less toxicity is required. The combination aspirin/dipyridamole has given the best results so far. The role of this combination has been foreseen by FitzGerald, Sze, and Reitmanlm3. The studies which have been carried out so far, have shown that this combination can lead to a highly significant risk reduction of more than 33%. This reduction is observed in women as well as in men, in young patients and elderly, in diabetici, in patients with hypertension, after TIA and after stroke, and the combination is efficient for all localisations. This combination is not without secondary effects due to the presence of aspirin which explains why new studies are in progress in this area. It is difficult to compare the therapeutic effect of aspirin, ticlopidine and the cobmbination aspirin/dipyridamole. Looking at published results (Table I) to find similar end-points, one can see that the best results are obtained with the combination aspirin/dipyridamole. Ticlopidine is a little less active but acts better than aspirin at different doses. Surgical prevention by carotid endarterectomy should be mentioned. Resting on the first results of two large studies, NASCET4 and ECST’, one finds that for a stenosis of more than 70%, endarterectomy is recommended. More information will be available soon as studies are still in progress. In any case, surgery should be complemented with antiaggregating substances for prevention. CONCLUSIONS
In conclusion, the questions raised by stroke remain controversial. The diagnosis has to rely on neuroimaging data. The treatment of acute hemorrhagic stroke by surgery is only recommended when mass effect is observed. The treatment of acute stroke due to ischemia improves using thrombolysis. Primary prevention consists of the treatment of risk factors by internists. Secondary prevention, which is the most documented, is managed with platelet antiaggregants, sometimes after carotid surgery. In any case, regardless of the very abundant literature, new studies with a very rigorous methodology are needed. These alone will lead to clear conclusions.
5
REFERENCES FitsGerald GA. New Engl J Med 1987; 316: 1247-1287. Sze PC, Reitman D, Pincus MM, Sacks HS, Chalmers TC. Antiplatelet agents in the secondary prevention of stroke: Meta-analysis of the random&d control trials. Stroke 1988; 19: 436-442. Reitman D, Sacks HS, Chalmers TC, Sm. PC, Pincus MM. Stroke 1988; 296: 1446-1447. North American Symptomatic Carotid Endarterectomy Trial Collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med 1991; 325: 445-453. European Carotid Surgery Trialists’ Collaborative Group. MRC European Carotid Surgery Trial: interim results for symptomatic patients with severe (70~99%) or with mild (lo-29%) carotid stenosis. Lancet 1991; 337: 1235-1243.