SynopsisStreptokinase, the first of the thrombolytic agents to be used in acute myocardial infarction, has now been administered to many thousands of patients with this condition. Since early intervention and accessibility of care is paramount in these patients, intravenous infusion of streptokinase has largely replaced intracoronary use.Results of major trials (GISSI, ISIS-2 and ISAM) comparing streptokinase with standard treatment in more than 30000 patients prove convincingly that intravenous streptokinase increases patient survival after myocardial infarction. The largest trial, ISIS-2, demonstrated a 23% reduction in 5-week vascular mortality after streptokinase use. The greatest benefits occur where streptokinase infusion is initiated early after symptom onset, although late benefit has been observed in patients treated up to 24 hours after pain onset. Importantly, mortality is further decreased by combining streptokinase with aspirin, as shown by a 53% reduction in mortality using the combination in the ISIS-2 trial. Mortality has also been reduced in trials investigating the use of the thrombolytic agents rt-PA and anistreplase. Streptokinase and rt-PA produced similar reductions in mortality in the recent GISSI-2 and International t-PA/Streptokinase Mortality trials, findings which may be further clarified by ongoing comparative trials such as ISIS-3.Reperfusion of about 50 to 60% of occluded coronary arteries occurs with intravenous streptokinase, and left ventricular function is improved. Direct comparisons with rt-PA show a superior effect for the newer agent on early reperfusion, but a similar ability to salvage myocardial function. The complexities of the relationship between reperfusion, left ventricular function and mortality constitute an area of considerable clinical interest requiring further study to clearly differentiate between the drugs available to the physician.The most common adverse events observed during intravenous streptokinase infusion are bleeding complications. An incidence of 3.6% for minor bleeding and 0.4% for major haemorrhage (requiring transfusion) is derived from the combined results of the GISSI and ISIS-2 studies. Bleeding does not appear to be more frequent or severe with intravenous streptokinase than with the more fibrin-selective agent, rt-PA. While the risk to benefit ratio of sequential heparin following streptokinase therapy remains equivocal, the adjuvant use of aspirin confers a clinical advantage over streptokinase alone.In conclusion, streptokinase has now been proven to reduce mortality in patients with acute myocardial infarction, with an acceptable risk of bleeding complications. Given the substantial data that have now accumulated with extensive clinical experience, intravenous streptokinase should be considered a first-line agent in suitable patients. While current evidence suggests there is little difference among various thrombolytics in reducing mortality, this remains to be established definitively in large ongoing or planned comparative trials.Pharmacological PropertiesStreptokinase is a streptococcal protein of Lancefield group C &bgr;-haemolytic streptococci. It activates the fibrinolytic system by combining with plasminogen to form a plasminogen activator complex that is rapidly converted to a streptokinase-plasmin complex capable of converting plasminogen to plasmin. Insoluble fibrin within the thrombus is lysed by plasmin, resulting in dissolution of the thrombus. Streptokinase thus causes thrombolysis by indirect means or in 2 steps.Because of its low fibrin selectivity, streptokinase results in a systemic fibrinolytic state. However, decreased levels of plasma fibrinogen and plasminogen return to baseline within 48 hours after stopping streptokinase infusion, and the theoretical risk of increased bleeding complications relative to more fibrin-selective agents has not been seen (see Adverse Effects, below). A correlation has been observed in some instances between the extent of systemic fibrinolysis, as assessed by the decrease in fibrinogen, and the success of reperfusion; however, there is no conclusive evidence supporting a causal relationship between lytic state and reperfusion rate. The extent of systemic fibrinolysis with streptokinase appears to be similar to or marginally less than that which occurs with anistreplase, but is more extensive than with urokinase or fibrin-selective rt-PA.Reductions in plasma viscosity correlating with decreased plasma fibrinogen levels are apparentin vitroand in patients treated with streptokinase. Streptokinase, urokinase and rt-PA inhibited platelet aggregation in plasma from healthy volunteers.Levels of the cardiac enzymes creatine phosphokinase (CK) and creatine phosphokinase isoenzyme MB (CK-MB) achieve a peak earlier, but in general are not higher, in successfully reperfused patients compared with those who fail treatment. Similar patterns are seen with aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) levels. Levels of CK-MB peaked earlier with streptokinase treatment than with conventional treatment or placebo.Plasma levels of fibrinopeptide A, an indicator of thrombin activity, have decreased in some patients successfully reperfused with streptokinase, but have paradoxically increased in others. This latter effect may have been due to an insufficient dosage of streptokinase being administered. In the TIMI trial the magnitude rises in plasma fibrinopeptide A levels were similar in patients administered streptokinase or rt-PA.Like other foreign proteins streptokinase is antigenic. Antibody titres rise within several days after streptokinase infusion and may remain high for 6 months or longer. Streptokinase infusion may cause transient but significant hypotension through an unknown mechanism postulated to involve bradykinin production (see Adverse Effects, below).Little has been published regarding the pharmacokinetics of streptokinase. Peak plasma streptokinase activity has been reported as 175 U/ml after infusion of 1.5 million U. Mean apparent volume of distribution is reported as 1.10L, and total clearance as 0.65 L/h. Clearance of streptokinase occurs primarily via rapid combination with antibodies in the plasma. Differences in assay methods confound the determination of elimination half-life values for streptokinase; most reports indicate a value of 23 to 29 minutes, while in others the half-life is 83 minutes. The drug does not cross the placenta.Therapeutic UsePractical difficulties of widespread use of intracoronary streptokinase have resulted in a number of studies involving intravenous administration. This has the main advantages of decreasing the delay between onset of symptoms and infusion of streptokinase, and increased availability to patients with acute myocardial infarction. Initial comparative studies between intracoronary and intravenous streptokinase tended to show a slightly higher reperfusion rate with the intracoronary route, but low intravenous doses (≤ 750 000U) were used. The advantages of intravenous administration outweigh any differences, and intracoronary administration is not considered further in this review.Large randomised mortality trials - GISSI, ISIS-2 and ISAM - conducted in more than 30,000 patients in total have evaluated streptokinase as an intravenous infusion of 1.5 million U compared with standard treatment. These studies demonstrate a distinct benefit in reducing mortality with an intravenous infusion of streptokinase. The GISSI study showed that mortality was significantly reduced by streptokinase versus conventional treatment at 21 days (10.7vs13%) and one year (17.2vs19%). Similar results were found in the ISIS-2 trial, which demonstrated mortality rates of 9.2% for streptokinase compared with 12% for placebo at 5 weeks, and a significant (p < 0.01) reduction at a median follow-up of 15 months. The smaller ISAM study showed lower 21-day and 21-month mortality rates for streptokinase than for placebo (6.3vs7.1% and 14.4vs16.1%, respectively), although these differences were not statistically significant.At 21 days after therapy, the incidence of nonfatal reinfarction in the streptokinase group was twice that observed in the control groups of the GISSI and ISAM studies (about 4 to 6%vs2 to 4%). However, the incidence was 2.8% for streptokinase versus 2.4% for placebo in the ISIS-2 study. Ventricular arrhythmias and other rhythm disturbances were monitored in the ISAM trial and were not more frequent with streptokinase than with placebo.The GISSI study confirms that the sooner the intravenous infusion of streptokinase can be initiated after symptom onset then the greater is the overall benefit in reducing mortality. Overall reductions in 21-day mortality were 47% in patients treated with streptokinase within 1 hour of symptom onset, 23% in those treated within 3 hours and 18% in patients treated within 12 hours. The ISIS-2 results showed no distinct advantage of administering streptokinase within 3 hours of infarct compared with between 3 and 6 hours, but there was a trend to greater benefit with earlier treatment. Although the GISSI study did not show a mortality reduction in patients treated 6 or more hours after pain onset, a significant reduction was found in the ISIS-2 trial in patients treated between 6 and 24 hours after symptom onset. This suggests that thrombolytic therapy should not necessarily be restricted to patients presenting early.Addition of aspirin to streptokinase therapy provides an even greater reduction in mortality than streptokinase alone, as demonstrated by a 53% reduction in the odds of death for patients treated within 4 hours in the ISIS-2 trial, and negates the increased rate of reinfarction seen with streptokinase alone.On present evidence it appears that the various thrombolytic agents produce similar decreases in mortality. Streptokinase and rt-PA were comparable in the GISSI-2 study, and in the International t-PA/Streptokinase Mortality Trial (which included GISSI-2 patients). Mortality rates with streptokinase, anistreplase and rt-PA appear similar in comparative trials not designed to assess mortality as a primary endpoint. However, the question of whether differences do indeed exist among the thrombolytics is being addressed further in the ISIS-3, TEAM-3 and other planned comparative trials.Reperfusion rates of occluded coronary vessels are about 50 to 60% for intravenous streptokinase in comparative trials including angiography to confirm vessel occlusion. A tendency for a lower patency rate with streptokinase than with anistreplase in 2 trials not including pretreatment angiography reached statistical significance in 1 study, but patency rates were similar in a third trial. Analysis of combined data from 2 directly comparative trials shows a greater early reperfusion rate (90 minutes after initiating infusion) with rt-PA than with streptokinase. The thrombolytic effect of either drug lessens as the time interval from onset of symptoms to treatment increases. Importantly, it is unclear whether differences in reperfusion rates among thrombolytic agents will translate into comparable reductions in mortality.Streptokinase improves left ventricular function, and increases of 3 to 6% in ejection fraction are seen relative to placebo or conventional therapy. On the whole, streptokinase and rt-PA appear to have similar effects on left ventricular function as assessed by directly comparative trials. The complexities of the relationship between reperfusion, left ventricular function and mortality remain to be elucidated.Reocclusion rates with intravenous streptokinase have not been specifically investigated using serial coronary angiography, but averaged 18% in an overview of several trials and 16% for both streptokinase and rt-PA in a more recent overview. The TIMI-I study reported reocclusion rates of 30% with streptokinase and 29% with rt-PA at hospital discharge, but these values appear to overestimate the reocclusion rates for both drugs. At present, neither coronary artery bypass surgery nor coronary angioplasty can be recommended as routine adjuvant treatment following streptokinase therapy. Immediate angioplasty after thrombolysis offers no advantage over thrombolysis plus conservative strategies, although selected patients may benefit.The benefit to risk ratio of sequential heparin following streptokinase infusion has not been satisfactorily established. In the SCATI trial heparin prevented the development of mural thrombi, but the use of streptokinase plus heparin in the GISSI-2 trial was not more effective than streptokinase alone. Streptokinase plus aspirin 160 mg/day confers significant clinical advantages over streptokinase alone, as discussed above.Adverse EffectsBoth intravenous and intracoronary streptokinase cause a peripheral lytic state which theoretically carries an increased risk of bleeding complications. The most common adverse effect is haemorrhage, with an incidence of 3.6% and 0.4% for minor (not requiring transfusion) and major bleeding episodes, respectively, as reported in the GISSI and ISIS-2 trials. In the ISIS-2 study the overall incidence for intracranial bleeding in the streptokinase group was 0.1%, and for stroke was 0.8% in patients who were scanned. Compared with placebo, streptokinase was associated with a higher number of ‘early’ haemorrhagic or other strokes on the first 2 days of treatment, but thereafter the rate was significantly lower with streptokinase. There does not appear to be an appreciable difference between streptokinase or rt-PA in producing bleeding.Transient hypotension and bradycardia are observed during or after intravenous streptokinase infusion, with an incidence of 10% versus 2% with placebo in the ISIS-2 study. As streptokinase is a streptococcal protein, allergic reactions are possible. Shivering, pyrexia or rashes were noted in 4.4% of ISIS-2 patients administered streptokinase versus 0.9% of placebo recipients, and 99 patients (1.7%) who experienced allergic reactions were withdrawn from streptokinase therapy in the GISSI study. Nonfatal anaphylactic reactions occurred in 7 patients in the GISSI study but none were reported in the ISIS-2 study.Dosage and AdministrationThe currently recommended dosage of intravenously administered streptokinase in patients with acute myocardial infarction is 1.5 million U infused over 30 to 60 minutes, although an optimum dosage has not yet been established. The infusion should be started as soon as possible after onset of symptoms, preferably within 6 hours, but patients presenting up to 24 hours should not necessarily be excluded.Contraindications to streptokinase include active internal bleeding, intracranial neoplasm, severe uncontrolled hypertension, and recent cerebrovascular accident or intraspinal or intracranial surgery. The risk to benefit ratio of streptokinase should be carefully considered when other conditions are present, including: recent major surgery; serious gastrointestinal bleeding; organ biopsy; obstetrical delivery or previous puncture of noncompressible vessels; sustained hypertension; recent trauma; infectious endocarditis; pregnancy; cerebrovascular disease; diabetic haemorrhagic retinopathy and haemostatic defects.Patients should be monitored for possible bleeding complications, particularly when anticoagulant or antiplatelet drugs are also administered. Patients with elevated levels of streptococcal antibodies because of recent streptococcal infections or previous exposure to streptokinase may be resistant to therapy.