SynopsisStreptokinase has been administered to many thousands of elderly patients with acute myocardial infarction. Results of large, randomised trials provide convincing evidence that intravenous streptokinase confers a distinct survival benefit in this population subgroup following myocardial infarction. The placebo-controlled ISIS-2 study demonstrated a 5-week absolute mortality reduction of 38 per 1000 patients aged 60 to 69 years administered streptokinase, compared with only 16 per 1000 for patients aged less than 60 years. Combining streptokinase with aspirin further reduces mortality, as shown by a 5-week absolute mortality reduction of 70 per 1000 patients aged 60 to 69 years administered this regimen in the ISIS-2 trial.While ideally patients should receive streptokinase as soon as possible after symptom onset, late benefit has been observed in patients presenting up to 12 hours after pain onset, as is often the case with the elderly. Indeed, in patients treated 6 hours after infarct in the GUSTO trial, streptokinase produced lower mortality results than accelerated recombinant tissue plasminogen activator (rt-PA). However, in contrast to the similar effects of streptokinase and conventionally administered rt-PA on overall survival demonstrated in previous large trials, the GUSTO study showed a lower mortality rate for accelerated rt-PA than for streptokinase in the elderly and in the total patient population.The most frequent adverse effects associated with streptokinase therapy are haemorrhagic complications, with an incidence of 0.4percnt; for major bleeding (requiring transfusion) and 3.6percnt; for minor bleeding among the total population in the GISSI-1 and ISIS-2 trials. An excess of stroke, particularly haemorrhagic stroke, occurring with rt-PA in GUSTO and other major mortality trials affirms the use of streptokinase as a suitable option in the elderly who are at increased risk of this complication.Significantly reduced values of end-systolic volume and regional wall motion index have been observed in elderly patients following streptokinase therapy. Overall, streptokinase and rt-PA seem to cause similar improvements in left ventricular function in this age group. Patency of occluded coronary arteries appears to be achieved in a high percentage of elderly patients following streptokinase therapy, based on a small sample.Thus, in view of the extensive clinical experience that now exists, intravenous streptokinase represents an appropriate alternative in elderly patients with acute myocardial infarction, and may be considered a first-line therapy in selected individuals, such as those with multiple risk factors for stroke or who present later than 6 hours after infarct. Furthermore, age alone should not be considered a contraindication to the use of streptokinase, as current evidence convincingly shows an increased patient survival with an acceptable risk of haemorrhagic complications in the elderly.Pharmacological PropertiesStreptokinase is a proteolytic enzyme elaborated by Lancefield Group C bgr;-haemolytic streptococci, which indirectly activates the fibrinolytic system by forming a complex with plasminogen. This plasminogen activator complex in turn converts plasminogen to plasmin which lyses insoluble fibrin, resulting in dissolution of the thrombus.As streptokinase is not specific for fibrin-bound clots, its administration results in systemic conversion of plasminogen to plasmin, reduced agr;2-antiplasmin levels, and depletion of fibrinogen and factors V and VIII. Importantly, the potential risk of increased bleeding complications with streptokinase compared with more fibrin-selective agents has not eventuated. While some studies have demonstrated a correlation between lytic state and reperfusion rate, there is as yet no conclusive evidence of a causal relationship. Streptokinase appears to exhibit a systemic fibrinolytic effect that is similar to or slightly less than that of anistreplase (anisoylated plasminogen streptokinase activator complex; APSAC), but significantly greater than that of fibrin-selective recombinant tissue plasminogen activator (rt-PA).Decreases in plasma viscosity (correlating with reduced plasma fibrinogen levels) and in erythrocyte aggregation observed following streptokinase therapy may contribute towards limiting infarct size via improving microcirculation to the affected area. In addition, streptokinase has been shown to inhibit both neutrophil and platelet aggregation in patients with acute myocardial infarction.In patients successfully reperfused following intracoronary streptokinase, peak levels of the cardiac enzymes creatine phosphokinase and creatine phosphokinase isoenzyme MB are achieved earlier, but generally are not higher, than those in nonreperfused patients. Similar trends were also observed for aspartate aminotransferase and lactate dehydrogenase.Inhibition of thrombin activity by streptokinase appears to be associated with the success of reperfusion, although paradoxical increases in thrombotic activity have also been demonstrated in patients with recanalised arteries. In the TIMI trial, comparable maximal increases in plasma fibrinopeptide A levels and reocclusion rates were reported in patients receiving intravenous streptokinase or rt-PA.Streptokinase, like other foreign proteins, is antigenic and therefore is capable of provoking allergic reactions. Circulating antibodies to streptokinase are widespread, presumably as a consequence of previous exposure to streptococcal infections. Following an initial fall in antibody titres within 24 hours of therapy, levels increase by the fourth or fifth day and remain elevated in the majority of patients for at least 4 years.Because of difficulties in developing a suitable assay, the pharmacokinetics of streptokinase are not clearly defined. While no formal studies have been performed to investigate the pharmacokinetics of streptokinase exclusively in elderly patients, studies that included subjects aged 65 years or more have demonstrated apparently similar pharmacokinetic properties in older and younger patients. Discrepancies in assay specificity and pharmacokinetic analysis may explain the wide variations observed in some pharmacokinetic parameters. A peak plasma streptokinase activity of 175 unitssol;ml was demonstrated following a dose of 1.5 million units, while mean apparent volumes of distribution ranging from 1.10 to 5.68L and total clearances of 0.65 to 7.08 Lsol;h have been reported. Rapid clearance of streptokinase from the circulation occurs mainly via combination with plasma antibodies. Estimates of elimination half-life vary considerably and values of 18 to 37 minutes have been reported in some studies, while others have demonstrated a half-life of up to 83 minutes, particularly for the streptokinase-plasminogen activator complex.Therapeutic EfficacyThe therapeutic efficacy of intravenous streptokinase has been investigated in thousands of elderly patients examined in distinct subsets of large trials. While some earlier evaluations imposed upper age limits, large randomised trials using mortality as the primary end-point (GISSI-1, GISSI-2, ISIS-2, ISIS-3 and GUSTO) have been conducted with no age limit for exclusion.The GISSI-1 and ISIS-2 trials included a total of more than 13 500 patients aged 60 years or over and evaluated the efficacy of intravenous streptokinase 1.5 million units compared with standard therapy. The ISIS-2 study clearly demonstrated that 5-week mortality was significantly reduced by streptokinase compared with placebo in patients aged 60 to 69 years (10.6vs14.4percnt;, p 0.05), with a similar trend being observed in patients aged 70 years and over (18.2vs21.6percnt;, p 0.05). A tendency towards a reduction in 3-week mortality with streptokinase (28.9percnt;) compared with control patients aged over 75 years (33.1percnt;) was evident in the GISSI-1 trial with this trend persisting at the 1-year follow-up (43.1vs46.1percnt;). While this difference failed to reach statistical significance, the absolute mortality benefit was much greater in older as opposed to younger patients because of the high mortality in elderly patients in the control groups of these trials.Combining aspirin with streptokinase therapy produces an even greater reduction in mortality than streptokinase alone, particularly in patients aged 60 years or more. In the ISIS-2 study, the combination resulted in 25, 70 and 80 lives saved per 1000 patients treated aged less than 60 years, 60 to 69 years, and 70 years or more, respectively. Data from the ISIS-2 and EMERAS trials, while not specific for the elderly, indicate a survival advantage with ldquo;laterdquo; streptokinase, i.e. when infused up to 12 hours after symptom onset.A decision-analytical model utilising pooled data from both the GISSI-1 and ISIS-2 studies and the multicentre Chest Pain Study suggested that streptokinase therapy is cost-effective and has a survival benefit in elderly patients over a wide range of estimates of the risks and benefits of thrombolytic therapy. Therefore, age alone should not be considered a contraindication to thrombolytic therapy. These findings support those of the ISIS Collaborative Group, which also pooled results from the GISSI-1 and ISIS-2 trials, and those of the multicentre European Cooperative Study Group which found a significant reduction in mortality in elderly patients administered streptokinase compared with those in the control group.Results of the GUSTO trial differ from those of previous mortality trials using conventional rt-PA regimens and indicate a greater mortality reduction with an accelerated rt-PA regimen compared with streptokinase in the elderly, as in the total population studied. In the elderly, an increased rate of any or haemorrhagic stroke for rt-PA offsets this benefit. However, absolute net benefit for the combined endpoint of death plus nonfatal stroke was similar between young and older groups, and greater in the rt-PA group.Available data confirm the ability of streptokinase to salvage left ventricular function in older patients. Significantly reduced values of end-systolic volume and regional wall motion index have been reported in elderly patients following streptokinase therapy compared with placebo or conventional therapy. Overall, streptokinase and rt-PA appear to have similar effects on left ventricular function in the elderly, as assessed by increases in ejection fraction. Because increased age is independently associated with a lower ejection fraction following acute myocardial infarction, streptokinase may confer a greater improvement in older as opposed to younger patients.Patency of occluded coronary arteries appears to occur in a high percentage of elderly patients following streptokinase. An overall reperfusion rate of 77percnt; was demonstrated in patients aged 65 to 80 years who received either intracoronary streptokinase or intracoronary or intravenous anistreplase, although no direct comparison was made between active treatments. Patency rates (for patients with TIMI grades IIsol;III) in the GUSTO trial were higher at 90 minutes with accelerated rt-PA (ap;80percnt;) than with streptokinase (ap;55 to 60percnt;) for the total population, but reocclusion rates were similar. Reocclusion rates with intravenous streptokinase have not been specifically evaluated in the elderly when assessed by serial coronary angiography, but clinical events suggestive of coronary reocclusion were evident in 30percnt; of elderly patients enrolled in one relatively small study.TolerabilityThe most common adverse effect associated with streptokinase therapy is haemorrhage, with an incidence of 0.4 and 3.6percnt; for major (requiring transfusion) and minor bleeding, respectively, as demonstrated in the GISSI and ISIS-2 trials. However, neither of these studies demonstrated a significant difference in haemorrhagic complications in older as opposed to younger patients administered streptokinase. Indeed, according to the results of large placebo-controlled trials, there does not appear to be a clinically significant increased risk of stroke during streptokinase therapy in the elderly. While in the GISSI-2 study the incidence of major bleeding episodes appeared higher with streptokinase than rt-PA, in this and other large trials treatment with rt-PA was associated with a significant excess of total stroke mainly related to cerebral haemorrhage, which was most pronounced in the elderly. The excess of nonfatal reinfarction reported in streptokinasetreated patients in the ISIS-2 study was avoided in patients also receiving aspirin and while an increase in major bleeding was associated with the combination, there was an overall reduction in the incidence of stroke.Allergic reactions are possible with streptokinase. Of these, most are minor and consist of shivering, pyrexia or rashes, although approximately one-tenth of these reactions (0.3percnt;) caused persistent symptoms in the ISIS-3 trial. While there were no confirmed cases of anaphylaxis in the ISIS-2 trial, 7 cases of nonfatal anaphylactic reactions were reported in the GISSI-1 study, with 1.7percnt; of patients who experienced allergic reactions being withdrawn from streptokinase therapy. As evidenced by the GUSTO and ISIS-3 studies, anaphylaxis is more frequent with streptokinase than with rt-PA.Transient hypotension and bradycardia have been observed during, or shortly following, intravenous streptokinase, occurring in 10percnt; of patients compared with 2percnt; for placebo in the ISIS-2 study.Dosage and AdministrationThe most widely used and currently recommended dosage of intravenously administered streptokinase in elderly patients with acute myocardial infarction is 1.5 million units infused over 30 to 60 minutes. Therapy should be commenced as soon as possible after the onset of symptoms, although a significant reduction in mortality has been demonstrated with streptokinase administration up to 12 hours after symptom onset.As with other thrombolytic agents, contraindications to streptokinase therapy include active internal bleeding, intracranial neoplasm, severe uncontrolled hypertension, and recent cerebrovascular accident or intraspinal or intracranial surgery. Furthermore, because the elderly generally have a higher frequency of major co-existing illnesses, the risk to benefit ratio of streptokinase therapy should be carefully considered when other conditions are present, particularly other life-threatening diseases.Patients should be closely monitored for possible bleeding complications. Elevated titres of streptococcal antibodies resulting from recent streptococcal infections or previous exposure to the drug may cause resistance to therapy, and it is recommended that readministration of streptokinase should be avoided between 3 days and at least 4 years after initial therapy.
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