Thrombolysis : indications, contraindications and techniques
 

CESARE FIESCHI
Dipartimento Scienze Neurologiche, Università La Sapienza, Roma, Italy

Stroke has always been considered as an unfortunate event for which there is no effective therapeutic intervention. Epidemiological studies have however demonstrated that the economic and human consequences of stroke are far too important to be ignored : third cause of mortality and the first cause of disability in industrialized countries, with a cost that accounts for about 4% of health expenses in European countries (1).
Attempting to treat ischemic stroke patients is not a choice but a necessity. The finding and treatment of the main risk factors (arterial hypertension, diabetes, embolic cardiopathy, dyslypemia)led to a reduction in stroke incidence and prevalence in the 70s and 80s. But it would be idealistic to believe that prevention can completely resolve the problem. A further step forward was, some years ago, the creation of intensive care units specialized in stroke care (stroke units). The careful management of stroke patients (prevention of stroke complications, prevention of second stroke risk, early physiotherapy,.) has not only improved the prognosis of these patients (reduction in disability and mortality) but has also reduced the length of hospital stay and the number of patients requiring stay in rehabilitation centers, thereby also cutting costs (2, 3, 4). Mortality and disability are, however, still high and the frequency of stroke seems once again rising (5). It is, therefore, now mandatory to define a specific stroke therapy.
Our improved knowledge of ischemic stroke physiopathology allows to consider some therapeutic possibilities. The physiopathological base of acute ischemic stroke therapy was put forward in the 70s and 80s in the animal studies by Hossman (6), and subsequently better outlined in PET studies on humans. Cerebral tissue tolerance to ischemia depends on the degree of blood flow reduction : the area in which it drops to 10 and 20 ml/100mg/mn, is referred as "ischemic penumbra' ; where cells can temporarily survive through compensation mechanisms (regional vascular auto-regulation, increase of oxygen extraction rate). On the other hand, under an estimated level of about 10ml/100mg/mn, cellular lesions become irreversible. However, cell death is not immediate since the irreversible lesion mechanism is gradual in all but those cases in which the blood flow is either zero or very inferior to the minimal survival rate. The Fred Plum school helped demonstrate the existence of a neuronal selective vulnerability to ischemia (7), providing data that have launched a phase of neurobiological and neuropharmacological research that have had and will continue to have repercussions on stroke patients. Baron (8) has clinically confirmed these experimental data in a patient with an ACM occlusion, one of the first cases of cerebral infarct actually studied in the acute phase with PET and oxygen 15 inhalation ; showing that ischemic tissue extracts more oxygen than the surrounding tissue. This means that if perfusion is not restored through the recanalization of the vessel or by the formation of an efficacious collateral circulation, this tissue is bound to die. These experimental and clinical data led to the concept of "therapeutic window', a term used to refer the amount of time the clinician has to initiate a therapy before lesions become irreversible. It is interesting to note that in 60% of the cases of ACM occlusion this therapeutic window lasts 5-6 hours after infarct onset (9). In order to protect ischemic penumbra cells, neuroprotective drugs capable of blocking the ischemic cascade of biochemical events have been developed. This protection is, however, temporary, as "sleeping' cells can be awakened by reperfusion alone. This is likely explanation for the failure of most of the studies conducted on humans despite the positive results obtained in animals with the same drugs. Moreover, the most recent clinical studies have demonstrated that most cases of cerebral ischemia are caused by the migration of emboli from neck vessels or from the heart (10). The presence of a fresh thrombus theoretically allows pharmaceutical fibrinolysis. Cerebral fibrinolysis was first tried in 1958. During the 1960s, a number of trials on endovenous fibrinolysis with streptokinase or urokinase revealed a high risk of intracerebral hemorrhage and few benefits for patients. But as these trials were conducted without CT scan, with patients enrolled on the basis of clinical criteria alone, hemorrhagic strokes are likely to have been included as well. Moreover, treatment was often administered a few hours after the onset of symptoms. Later, the success of myocardial infarct fibrinolysis, the development of rt-PA (recombinant tissue plasminogen activator) and advances in neuro-imaging techniques (CT scan, MRI, digitalized angiography) led to renewed interest in cerebral fibrinolysis. Thrombolytic drugs can be administered by endovenous or intra-arterial way.
 
 

The method consists in the administration of a thrombolytic drug which acts directly against the thrombus during a selective angiography of the artery involved. Intra-arterial fibrinolysis can have positive, and sometimes spectacular results, with the immediate regression of the neurological deficit, particularly in cases of vertebrobasilar occlusion. The recanalization rate after local administration of streptokinase, urokinase or rt-PA ranges in different trials from 46% to 100% and corresponds to a clinical improvement (11, 12, 13). Large controlled trials have, however, not yet been performed to confirm the validity of these results. Moreover, intra-arterial fibrinolysis requires sophisticated equipment and specialized staff, and can thus only be practised in specialized centers.
 

Recent trials have demonstrated that the success of treatment depends on the time lapse before administration: all preliminary assessments must be completed within 4-5 hours of stroke onset. It is also important to remember that, after a cerebral infarct, fibrinolysis can be dangerous. The above clinical trials seem to confirm the possibility of reperfusion lesions (cerebral edema, hemorrhagic transformation,) which may be experienced by treated patients. It is an aggressive therapy and its possible benefits must be weighed against any potential risks. In 1992, Warlow and Wardlaw published a meta-analysis on previous non-randomized trials conducted on more than 2000 patients (14). The authors found a 37% decrease in mortality and a 56% overall decrease in mortality and disability, figures which were, however, associated with a risk of hemorrhage in 11% of cases and of severe cerebral edema in 5%. In 1995, 5 randomized controlled trials versus placebo of cerebral fibrinolysis were concluded. The results are conflicting but clearly encouraging. In the MAST-I (Multicenter Acute Stroke Trial - Italy), MAST-E (Multicenter Acute Stroke Trial - Europe) and ASK (Australian Streptokinase Trial) trials, the excess of hemorrhagic transformation (MAST-E), the excess of mortality at 6 months (MAST-I) and the bad functional prognosis (ASK) in the streptokinase-treated groups led to the trials be suspended before randomization completion (15, 16, 17). By contrast, the results of the rt-PA trials are much more positive. The American NINDS (National Institute of Neurological Disorders and Stroke) trial has reported a decreased disability at 3 months after rt-PA administration at 0.9 mg/kg within 3 hours of stroke onset (18). The European ECASS (European Cooperative Acute Stroke Study) trial provided less encouraging results on patients treated within 6 hours of symptoms onset with rt-PA at 1.1 mg/kg but permitted a better definition of the patient group which can be treated without major risks (19), achieved by excluding patients who were clinically more severe and those with radiological signs of a large ischemic lesion (early hypodensity > 33% MCA territory). The observation of these strict inclusion criteria in an emergency situation within a short time span was an ambitious objective only in part accomplished. In fact, 109 of the 620 patients included (17.4%) had to be considered as protocol violators. In two thirds of these cases, the reason for exclusion was radiological. For the efficacy and safety analyses, patients were divided in two groups : "Target Population' (TP) i.e. "patients we wished to treat and "Intention To Treat " (ITT) i.e. "patients we treated'. The ITT analysis had to be considered as negative : at the cost of a slight increase in mortality, there were no reduction in disability. If, however, the analysis is limited to the TP, the treated group showed a better evolution than the placebo group, with a significant reduction in disability and length of hospital stay. The excessive mortality in the ITT group is due to the high number of cases of hemorrhagic transformation and/or severe cerebral edema in protocol violators. The ECASS trial demonstrates that cerebral fibrinolysis is efficacious but confirms that this treatment must be used with care and suggests that the main risk of hemorrhagic transformation is associated with the presence of early signs of large ischemic lesion. Limiting the use of rt-PA to selected patients (patients treatable within 3 or 6 hours of stroke onset, patients without signs of large ischemic lesion) is not satisfactory if we consider that the main aim was to significantly reduce the human and economic costs of stroke. For example, in the Italian population, 20% of ischemic stroke patients could be prescribed fibrinolysis, with 15% of them (i.e. 3% of Italian stroke patients per year) actually benefiting from the therapy. We would be able to cure about 2000 patients per year. In the USA, the Food and Drug Administration has allowed rt-PA to be used in ischemic stroke patients within 3 hours of symptom onset (20). European experts are more prudent and recommend rt-PA only in specialized centers with neurologists who are experts in vascular pathology (21). The end of 1996 saw the start of a second European trial (ECASS 2) on rt-PA at 0.9 mg/kg, the hope being that the lower dose will reduce the risks of fibrinolysis. Moreover, we are at present planning a four-arm study combining a neuroprotector and rt-PA. The early administration of a neuroprotective drug should allow the therapeutic window to be enlarged and the fibrinolytic drug to be administered after the 6 hours. The neuroprotector which is not dangerous in cases of hemorrhage, could be administered at home as a first step and then be followed by endovenous rt-PA in a hospital setting once a clinico-radiological screening has shown that there is no contraindication. This objective is within our grasp and could be reached by the year 2000.
 
 

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