Streptokinase: Uses. Preparations
Uses and Administration
Streptokinase is a thrombolytic drug derived from various streptococci. It rapidly activates endogenous plasminogen, indirectly by means of a streptokinase-plasminogen complex, to plasmin (see Fibrinolysin), which has fibrinolytic effects and can dissolve intravascular blood clots. The mechanisms of fibrinolysis are discussed further under Haemostasis and Fibrinolysis on site. Streptokinase affects circulating, unbound plasminogen as well as fibrin-bound plasminogen and thus may be termed a fibrin-nonspecific thrombolytic. Streptokinase is given by intravenous or sometimes intra-arterial infusion in the treatment of thromboem-bolic disorders such as myocardial infarction, peripheral arterial thromboembolism (below), and venous thromboembolism (deep-vein thrombosis and pulmonary embolism). It has also been tried in ischaemic stroke (below), although alteplase is generally preferred. Streptokinase may be used to clear cannulas and shunts and is used topically with streptodornase to clear clots and purulent matter.
In acute myocardial infarction streptokinase is usually given intravenously as a single dose of 1.5 million units infused over 1 hour as soon as possible after the onset of symptoms. Streptokinase has also been given in a suitable dose by intracoronary infusion but coronary catheterisation with the aid of angiography is required, thus restricting use to suitably equipped centres.
In the treatment of pulmonary embolism and other arteriovenous occlusions an initial loading dose of streptokinase, normally 250 000 units infused intravenously over 30 minutes, is given to overcome any resistance due to circulating antibodies. This is followed by infusion ofa maintenance dose of 100 000 units/hour for 24 to 72 hours, depending on the condition to be treated; for central retinal thrombosis, 12 hours may be adequate. Treatment should be controlled by monitoring the thrombin clotting time, which should be maintained at 2 to 4 times normal values. Since thrombolytic activity rapidly fades when the infusion stops, streptokinase treatment is generally followed after 3 to 4 hours by intravenous heparin infusion, and then oral anticoagulation, to prevent re-occlusion.
Streptokinase, as a solution containing 250 000 units in 2 mL is used to clear occluded cannulas; 1000 units/mL has been used to clear shunts of occluding thrombi.
Administration in children. There are limited data on the use of systemic thrombolytic therapy for arterial or venous thromboembolism in children and various dosage regimens have been used, based on case studies. The most widely used drugs are streptokinase and alteplase. For streptokinase, the Eighth American College of Chest Physicians (ACCP) Consensus Conference on Antithrombotic Therapy suggests a loading dose of 2000 units/kg to be given intravenously, followed by continuous infusion of 2000 units/kg per hour for 6 to 12 hours. In the UK, the BNFC suggests a loading dose of 2500 to 4000 units/kg over 30 minutes, followed by infusion of 500 to 1000 units/kg per hour, continued until reperfusion occurs, up to a maximum of 3 days.
Alteplase may be preferred because of its fibrin specificity and low immunogenicity. The dose of alteplase suggested by the ACCP is 100 to 600 micrograms/kg per hour by continuous intravenous infusion over 6 hours, while the dose recommended by the BNFC is 100 to 500 micrograms/kg per hour for 3 to 6 hours. The use of alteplase to clear occluded catheters in children is discussed on p.1208.
Empyema and pleural effusion. Thoracic empyema is treated with antibacterials and pleural drainage. Efficient removal of fluid may be impaired by fibrinous clots within the pleural cavity. Intrapleural instillation of streptokinase (100 000 to 750 000 units in up to 100 mL of sodium chloride 0.9%) has been reported to be effective in small series of patients and there have been reports of the successful use of alteplase and urokinase. However, a double-blind trial involving 454 patients found no benefit with streptokinase, and the role of thrombolytics remains unclear. A meta-analysis found no evidence of benefit, although a systematic review suggested that thrombolytics may reduce the need for surgical intervention. Intrapleural streptokinase has also been used successfully in a few patients with malignant multiloculated pleural effusion resistant to standard pleural drainage.
Intrapericardial instillation of thrombolytics has been tried in a few patients with pericardial empyema to prevent the development of constrictive pericarditis.
For reports of haemorrhage associated with intrapleural use of streptokinase, see Haemorrhage, under Adverse Effects, above.
Intracardiac thrombosis. Thrombosis of prosthetic heart valves is usually treated surgically, but thrombolytics have also been used. In a study of patients with left-sided prosthetic valve thrombosis, thrombolytic therapy was found to be more successful than surgery, especially in those who were critically ill; most patients were given streptokinase. Another retrospective study in which patients were given streptokinase, urokinase, or alteplase, concluded that thrombolytics were effective but embolic and haemorrhagic complications might limit their use.
Ischaemic heart disease. Thrombolytics such as alteplase, streptokinase, and urokinase have an established role in the early management of acute myocardial infarction. Myocardial infarction is caused by coronary artery occlusion, usually due to thrombosis, and thrombolytics are given intravenously to break up the thrombus or clot and restore the patency of the coronary artery, thereby limiting infarct size and irreversible damage to the myocardium. Reduction of ECG abnormalities and modification of ventricular remodelling may also contribute to their effect. Other antithrombotics, in particular aspirin and heparin, are given as adjunctive therapy.
Several large studies have established that thrombolytics can preserve left ventricular function and improve short-term and 1 -year mortality figures; benefit has been maintained in 5-year and 10-year follow-up studies. Benefit is greatest with early treatment. Trials such as the GISSI-1 study and the ISIS-2 study helped to establish that mortality is reduced if thrombolytics are given within 6 hours of the onset of symptoms and further studies provided evidence that patients presenting within 12 hours should receive a thrombolytic. Use after 12 hours has been associated with an increase in adverse effects, and is usually reserved for patients with evidence of ongoing ischaemia. Prehos-pital thrombolysis is feasible and reduces the time to thrombolysis and short-term mortality. Five-year follow-up of one study has suggested that there is also a beneficial effect on long-term mortality.
Choice of thrombolytic depends on factors such as cost, method of administration, and contra-indications. Although streptokinase has been the most widely used, several large studies have compared clinical benefit in terms of improved left ventricular function and mortality and have shown no difference between streptokinase and other thrombolytics, including saruplase, the tissue plasminogen activator alteplase, anistreplase, and reteplase in overall efficacy. In the GUSTO-I study, accelerated or ‘front loaded’ alteplase (that is, rapid intravenous dosage over 1 / hours rather than the conventional 3 hours) was more effective than streptokinase, although the study was criticised for not comparing like with like. On the other hand, alteplase might be associated with a greater risk of stroke than streptokinase. Studies comparing bolus injections of reteplase with accelerated alteplase (GUSTO-III) and tenecteplase with alteplase (ASSENT-2) have also found no difference in mortality rate.
The overall effectiveness of thrombolytics is limited by persistent coronary occlusion, re-occlusion, and bleeding complications. Different thrombolytic regimens, such as bolus injections of reteplase, and combinations of thrombolytics, for example alteplase with streptokinase and alteplase with saruplase, have been investigated in attempts to improve patency rates. However, there has been concern that adverse effects may be higher with bolus injection. A study comparing double-bolus alteplase with accelerated alteplase was terminated early when excess deaths were found in the group receiving bolus injections, and a subsequent meta-analysis found a higher incidence of intracranial haemorrhage associated with bolus doses of various thrombolytics. Although use of thrombolytics before percutaneous coronary intervention (PCI) does not appear to be beneficial, a small study has suggested that intracoronary streptokinase given immediately after PCI may improve microvascular reperfusion; however, there was no effect on clinical outcomes.
Thrombolytics have also been tried in other acute coronary syndromes, including unstable angina and non-ST elevation myocardial infarction. Although small-scale studies reported some benefit the results were variable, and an overview of trials in patients with suspected myocardial infarction, which included some patients with unstable angina, found that there was no mortality benefit in patients without ST elevation. In 2 studies that investigated alteplase (the TIMI-IIIB study with 1473 patients) and anistreplase (the UNASEM study involving 159 patients), thrombolysis failed to improve outcome and was associated with an excess of bleeding complications. Thrombolytic therapy is therefore not recommended for patients with unstable angina or non-ST elevation myocardial infarction.
Peripheral arterial thromboembolism. Thrombolytics including streptokinase may be used in the management of peripheral arterial thromboembolism. Streptokinase has been injected intravenously or intra-arterially directly into the clot as an alternative to surgical treatment of the occlusion. It has also been infused intra-arterially to remove distal clots during surgery. The intravenous dose generally used is 250 000 units over 30 minutes followed by 100 000 units/hour A lower dose of 5000 units/hour has been used intra-arterially directly into the clot and for removal of distal clots during surgery streptokinase has been given intra-arterially in a dose of 100 000 units over 30 minutes or as five bolus doses of 20 000 units at 5-minute intervals.
Stroke. Stroke is normally considered a contra-indica-tion to the use of thrombolytics, and clearly they would be inappropriate in acute haemorrhagic stroke. However, when stroke is associated with thrombotic occlusion there is evidence, as with myocardial infarction, that a degree of neuronal recovery is possible if the occlusion is reversed sufficiently quickly, and thrombolytics may therefore have a role in some patients with acute ischaemic stroke.
Early studies with intravenous thrombolytics in acute ischaemic stroke suggested a reduction in early death, although subsequent randomised trials produced disappointing results, with the exception of one with alteplase given within 3 hours of the onset of stroke (NINDS — National Institute of Neurological Disorders and Stroke rt-PA Stroke Trial). The studies using streptokinase — MAST-E (Multicentre Acute Stroke Trial-Europe), ASK (Australian Streptokinase Trial), and MAST-I (Multicentre Acute Stroke Trial-Italy) — were terminated before completion because of adverse outcomes (intracranial bleeding and increased mortality) in the treatment groups, particularly in those receiving therapy more than 3 hours after stroke onset. The study investigating alteplase given within 6 hours of the onset of symptoms (ECASS I — European Cooperative Acute Stroke Study) reported that, although some patients might benefit, overall alteplase was associated with higher mortality rates and an increase in some intracranial bleeding (parenchymal haemorrhage). In the NTNDS randomised study, alteplase given within 3 hours of the onset of ischaemic stroke appeared to improve clinical outcome despite an increased incidence of symptomatic intracerebral haemorrhage. Patients treated with alteplase were more likely to have minimal or no disability 3 months after stroke, and this benefit was maintained at 12 months. However, there was no difference in mortality or rate of recurrence of stroke. A second ECASS study (ECASS II) that hoped to confirm the early findings of the NTNDS study failed to confirm a statistical benefit for alteplase over placebo and found no significant differences between patients who received alteplase within 3 hours or between 3 and 6 hours. A review of several studies confirmed that alteplase needed to be given early, and preferably within 90 minutes, if it was to be effective.
On the basis of the NINDS study, alteplase given within 3 hours of the onset of ischaemic stroke is now recommended for selected patients in most guidelines on stroke management. Despite their own disappointing results, the ECASS II investigators reached a similar conclusion. However, these recommendations have been criticised. It has been pointed out that very few patients will be eligible for treatment with alteplase, since the time of onset of symptoms is often uncertain and in many patients more than 3 hours elapses before a definite diagnosis of ischaemic stroke is made. In addition, the NINDS study excluded patients with severe stroke and those taking anticoagulants. The rationale for exclusion of patients with severe stroke is that haemorrhagic transformation is more likely to occur with large areas of infarction. However, size of infarct is difficult to identify by CT scanning. Anticoagulants or antiplatelets are also contra-indicated in the first 24 hours after use of alteplase. The poor results obtained in studies using streptokinase have led to recommendations that streptokinase should be avoided in ischaemic stroke, although an overview of thrombolytic studies suggested that it may not be worse than alteplase and that the apparent hazards of streptokinase may be accounted for by differences in trial design (for example use with anticoagulants) and in patient population. Thus, while alteplase can be considered for those few patients meeting the entry criteria for the NINDS study, a systematic review concluded that further large studies are required to establish more clearly the overall role of thrombolytics in acute ischaemic stroke. Studies of the use of alteplase outside the setting of a clinical trial have had mixed results. However, an observational study found that alteplase was safe and effective when used in accordance with guidelines, while another study found that it could be used in elderly patients (80 years-of-age and older), a group normally excluded from clinical trials.
Intra-arterial thrombolytics may have advantages over intravenous use and may be used in selected patients. Studies with nasaruplase and urokinase have suggested benefit up to 6 hours after stroke due to middle cerebral artery occlusion, and use of intra-arterial thrombolytics may therefore be considered in such patients. Intra-arterial thrombolytics are also used in basilar artery occlusion, although evidence to support this is limited; intravenous alteplase may be an alternative. Combined use of intravenous and intra-arterial alteplase, as well as use of adjunctive therapies such as therapeutic ultrasound or antithrombotics, are under investigation but do not yet have an established role.
Intravenous thrombolytics have no role in the management of acute haemorrhagic stroke, but they have been given locally to facilitate the aspiration of haematomas in both intracerebral and subarachnoid haemorrhage. Small studies with urokinase have shown benefit in patients with intraventricular haemorrhage.
Preparations
British Pharmacopoeia, 2008: Streptokinase Injection.
Proprietary Preparations
Argentina: Streptase;
Australia: Streptase;
Austria; Streptase;
Belgium: Streptase;
Brazil: Kabikinase †; Solustrep; Streptase; Streptokin; Streptonase; Unitinase †;
Canada: Streptase;
Chile: Streptase †;
Czech Republic: Kabikinase †; Streptase;
Denmark: Streptase;
Finland: Streptase;
France: Streptase;
Germany; Streptase;
Greece: Streptase;
Hong Kong; Streptase;
Hungary: Streptase;
India: Fibrokinase; STpase; Streptase; Zykinase;
Indonesia: Streptase;
Ireland: Streptase †;
Israel: Ka-bikinase; Streptase;
Italy: Streptase †;
Malaysia: Streptase †;
Mexico: Streptase;
The Netherlands: Streptase;
Norway: Kabikinase †; Streptase;
New Zealand: Streptase;
Poland: Streptase;
Portugal: Streptase;
South Africa; Streptase;
Spain: Kabikinase †; Streptase;
Sweden: Streptase;
Switzerland: Streptase;
Thailand: Streptase;
United Kingdom (UK): Streptase;
United States of America (US and USA): Streptase;
Venezuela: Streptase.
Multi-ingredient
Argentina: Varidasa †;
Australia: Varidase †;
Austria: Varidase;
Denmark: Varidase;
Finland: Varidase;
Germany; Varidase;
Ireland: Varidase †;
Italy: Varidase †;
Mexico: Varidasa;
Norway: Varidase;
Poland: Distreptaza;
Portugal: Varidasa †;
Spain: Ernodasa; Varidasa;
Sweden: Varidase;
United Kingdom (UK): Varidase.
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