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The recent establishment of a firm therapeutic role for reperfusion in acute myocardial infarction has stimulated interest in the development of more ideal thrombolytic agents. Anisoylated plasminogen streptokinase activator complex (APSAC) is a new plasminogen activator possessing properties that are promising for intravenous thrombolytic application in acute myocardial infarction. To assess the reperfusion potential of intravenous APSAC, a multi-center, angiographically controlled reperfusion trial was performed. An approved thrombolytic regimen of intracoronary streptokinase served as a control. Consenting patients with clinical and electrocardiographic signs of acute myocardial infarction were studied angiographically and 240 qualifying patients with documented coronary occlusion (flow grade 0 or 1) were randomized to treatment in less than 6 h of symptom onset (mean 3.4 h, range 0.4 to 6.0) with either intravenous APSAC (30 U in 2 to 4 min) or intracoronary streptokinase (160,000 U over 60 min). Both groups also received heparin for greater than or equal to 24 h. Reperfusion was evaluated angiographically over 90 min and success was defined as advancement of grade 0 or 1 to grade 2 or 3 flow. Rates of reperfusion for the two treatment regimens were 51% (59 of 115) at 90 min after intravenous APSAC and 60% (67 of 111) after 60 min of intracoronary streptokinase (p less than or equal to 0.18). Reperfusion at any time within the 90 min was observed in 55 and 64%, respectively (p less than or equal to 0.16). Time to reperfusion occurred at 43 +/- 23 min after intravenous and 31 +/- 17 min after intracoronary therapy. The success of intravenous therapy was dependent on the time to treatment: 60% of APSAC patients treated within 4 h exhibited reperfusion compared with 33% of those treated after 4 h (p less than or equal to 0.01). Reperfusion rates were also dependent on initial flow grade (p less than or equal to 0.0001): 48% (81 of 168) for grade 0 (APSAC = 43%, streptokinase = 54%), but 78% for grade 1 (APSAC = 78%, streptokinase = 77%). APSAC given as a rapid injection was generally well tolerated, although the median change in blood pressure at 2 to 4 min was greater after APSAC than after streptokinase (-10 versus -5 mm Hg). Mean plasma fibrogen levels fell more at 90 min after the sixfold higher dose of APSAC than after streptokinase (to 32 versus 64% of control). Reported bleeding events were more frequent after APSAC but occurred primarily at the site of catheter insertion and no event was intracranial.(ABSTRACT TRUNCATED AT 400 WORDS)
The short in vivo half-life of streptokinase limits its efficacy as an efficient blood clot-dissolving agent. During the clot-dissolving process, streptokinase is processed to smaller intermediates by plasmin. Two of the major processing sites are Lys59 and Lys386. We engineered two versions of streptokinase with either one of the lysine residues changed to glutamine and a third version with both mutations. These mutant streptokinase proteins (muteins) were produced by secretion with the protease-deficient Bacillus subtilis WB600 as the host. The purified muteins retained comparable kinetics parameters in plasminogen activation and showed different degrees of resistance to plasmin depending on the nature of the mutation. Muteins with double mutations had half-lives that were extended 21-fold when assayed in a 1:1 molar ratio with plasminogen in vitro and showed better plasminogen activation activity with time in the radial caseinolysis assay. This study indicates that plasmin-mediated processing leads to the inactivation of streptokinase and is not required to convert streptokinase to its active form. Plasmin-resistant forms of streptokinase can be engineered without affecting their activity, and blockage of the N-terminal cleavage site is essential to generate engineered streptokinase with a longer in vitro functional half-life.
OBJECTIVE: To examine the induction of antistreptokinase antibodies after giving streptokinase or anistreplase to patients with acute myocardial infarction. DESIGN: Patients were randomly allocated to receive either 1.5 x 10(6) IU, streptokinase or 30U anistreplase in a double blind study. Blood samples were collected immediately before treatment and subsequently at intervals up to 30 months; plasma samples were assayed for streptokinase resistance titre (functional assay) and streptokinase binding by IgG (microradioimmunoassay). SETTING: Cardiology department in a general hospital. PATIENTS: 128 consecutive eligible patients. Samples were collected for up to one year according to a prospective design: a subsection of 47 patients was selected for intensive study over the first 14 days. After one year, all available patients (67) were sampled on one further occasion. RESULTS: Antibody responses to streptokinase and anistreplase were similar. Streptokinase resistance titres exceeded pretreatment concentrations five days after dosing, and values peaked at 14 days. By 12 months after dosing, 92% of resistance titres (n = 84) had returned to within the pretreatment range. Antistreptokinase IgG concentrations also exceeded baseline concentrations within five days and peaked at 14 days. Half of the individual values had returned to within the pretreatment range by 12 months (n = 84) and 89% by 30 months (n = 18). CONCLUSION: Although we cannot be sure of the clinical significance, because of the increased likelihood of resistance due to antistreptokinase antibody, streptokinase and anistreplase may not be effective if administered more than five days after an earlier dose of streptokinase or anistreplase, particularly between five days and 12 months, and increased antistreptokinase antibody may increase the risk of allergic-type reactions.
The efficacy of a single intravenous bolus of anisoylated plasminogen streptokinase activator complex (APSAC 30U in 4 to 5 minutes) versus an intravenous infusion of streptokinase (1.5 X 10(6) U in 60 minutes) was assessed in 86 patients with evolving myocardial infarction of less than 6 hours duration in a cooperative randomised study. The patency of the infarct-related artery was assessed by coronary angiography at, on average, 90 minutes after therapy (mean time: APSAC 95 minutes, streptokinase 105 minutes). The treatment groups were similar with respect to sex, age, location of myocardial infarction and the delay from onset of pain to treatment. The 90-minute patency rate (grade 2 to 3) was 71.8% in the APSAC group and 55.8% in the streptokinase group; the difference was not statistically significant. There was no difference between the drop in fibrinogen concentrations in the 2 groups at 3 or 24 hours. The minimal concentration obtained at the first assessment was +/- 0.2 g/L in the streptokinase group and 0.5 g/L in the APSAC group. One patient in the APSAC group, who had a previous meningeal bleeding, had a non-fatal cerebrovascular accident. In a subgroup of 38 patients who had 3 control coronary angiograms at 90 minutes, 24 hours and 3 weeks, the patency rate was 63, 82 and 93%, respectively, in the APSAC group and 48, 88 and 92%, respectively, in the streptokinase group (the difference was not statistically significant). None of the patients in the APSAC group presented with reocclusion, whilst 3 patients in the streptokinase group had reocclusions.(ABSTRACT TRUNCATED AT 250 WORDS)
Coronary angiography was used to compare the efficacy of anisoylated plasminogen streptokinase activator complex (APSAC) administered intravenously and streptokinase given by intracoronary infusion in inducing reperfusion in patients with a proven acute myocardial infarction. Forty-two patients received 30 U of APSAC intravenously over 5 minutes and 43 patients received 250,000 IU of streptokinase given via intracoronary infusion over 90 minutes, after occlusion of the infarct-related vessel was demonstrated by angiography. Reperfusion was achieved in 23 (64%) of 36 patients (mean time to reperfusion 46 minutes) treated with APSAC and 25 (67%) of 37 patients (mean time to reperfusion 45 minutes) treated with intracoronary streptokinase, who were angiographically evaluated 90 minutes after the start of treatment. Twenty-four hours after treatment, reocclusion had occurred in 1 (5%) of 22 patients in the APSAC group and in 3 (13%) of 23 patients in the streptokinase group. No major bleeding was observed in either treatment group despite a similar systemic lytic state that lasted for up to 48 hours. Two patients treated with APSAC died after severe left ventricular failure unrelated to therapy. The results indicate that APSAC given intravenously is as effective as streptokinase given intracoronary in producing thrombolysis in acute myocardial infarction. The major advantages of APSAC are its rapid and convenient administration by a single intravenous injection, the low rate of arterial reocclusion and good patient tolerance.
Certain genotypic variants of streptokinase (ska) of beta-hemolytic streptococci group A have been associated with acute post-streptococcal glomerulonephritis (APSGN). In our earlier studies on strains isolated from Ethiopian children with various streptococcal disease manifestation, we reported an even distribution of streptokinase genotypes with no association to disease patterns. Considering the possibility that strains could differ in their ability to secrete the protein, levels of streptokinase activity in culture supernatants of these strains were determined by a plasminogen activation assay using a synthetic tripeptide, H-D-valyl-leucyl-lysin-p-nitroaniline, as a substrate. Of the 53 streptococcal group A strains, ten (19%), which belonged to genotype ska4 and ska8, did not activate human plasminogen. These strains did not activate bovine, sheep, horse, rabbit or porcine plasminogens either. They represented at least five M protein and non-typeable serotypes, and were characterized by high human plasminogen binding activity. Six of the 53 strains (11%) harbouring genotype ska3 and ska7 showed low levels of human plasminogen activation. Strains of ska1 and ska2, 37/53, activated human plasminogen at a higher level (p < 0.005). Levels of plasminogen activation were not significantly different among the ska1 and ska2 strains associated with various streptococcal disease manifestations. Antibody levels against streptokinase were higher (p < 0.05) in convalescent sera from acute rheumatic fever and APSGN patients in comparison with sera from other patient categories and healthy controls. Streptokinase genotype and in vitro streptokinase production do not correlate directly to streptococcal disease manifestation, indicating a probable significance of additional streptococcal and/or host factors in the initiation of APSGN.
To compare the reperfusion potential of anisoylated plasminogen streptokinase activator complex (APSAC), administered intravenously, and intracoronary streptokinase (the accepted standard for comparison in the United States), a randomised multicentre reperfusion trial was undertaken in the United States. A preliminary evaluation of results was made, based on the first 93 patients. Patients with acute myocardial infarction were studied angiographically, and those with coronary occlusion grade 0 or 1 were randomised and treated within 6 hours from symptom onset (mean 3 hours 25 minutes) with intracoronary streptokinase (20,000U bolus, then 2000 U/minute), or APSAC (30U over 2 to 4 minutes). Reperfusion was defined by a blinded reader as grade 2 or 3 flow after 90 minutes. Entry characteristics of patients in the 2 groups were comparable. Reperfusion rates were similar [19/39 (49%) of evaluable streptokinase patients and 19/43 (44%) of APSAC patients] and were dependent on the initial occlusion grade [38% of patients with grade 0 (streptokinase = 10/27, APSAC = 13/34), but 71% of patients with grade 1 (9/12, 6/9, respectively); p less than 0.02]. Grade 1 occlusion was present in 30% of patients treated within 4 hours, versus 16% treated at over 4 hours (p = 0.3). APSAC as a 2 to 4 minute infusion was well tolerated, and the change in mean blood pressure was minor (-6 mm Hg). Thus, APSAC and streptokinase provide similar reperfusion results, but APSAC is easier to administer, and shows excellent haemodynamic tolerance.
In a US study, anisoylated plasminogen streptokinase activator complex (APSAC), 30U intravenously over 2 minutes, was compared with streptokinase, about 150,000U by intracoronary infusion over 60 minutes. Included in the study were 106 patients with acute myocardial infarction for whom both angiographic data and coagulation study results were available. 58 of these patients received APSAC and 48 streptokinase. The degree of hypofibrinogenaemia and the percentage of patients who had a drop of greater than 10% in plasma fibrinogen was more evident with high dose intravenous APSAC treatment than with lower dosages of intracoronary streptokinase. This laboratory abnormality was not predictive of successful reperfusion in APSAC-treated patients. The dose of streptokinase administered was not correlated with the presence or absence of the lytic state or with reperfusion. However, 10 patients treated with streptokinase showed reperfusion without an apparent effect on the fibrinogen concentration and further studies are needed to determine whether treatment effects were limited to the coronary artery by regional infusion. Similarly, 2 APSAC-treated patients had groin bleeding without a decrease in plasma fibrinogen. Therefore, a final conclusion regarding the contribution of a lytic state to bleeding must await further analysis.
BACKGROUND: Streptokinase is the most widely used thrombolytic agent and can now be made using recombinant DNA technology. The present trial was initiated to assess an indigenous recombinant streptokinase (Shankinase, r-SK). AIM: To compare the efficacy and safety of indigenous recombinant streptokinase (Shankinase, r-SK) and natural streptokinase (Streptase, n-SK). SETTINGS AND DESIGN: Double blind, randomized, non-inferiority, multicentric, parallel study. MATERIALS AND METHODS: Patients of AMI < 6 hours of chest pain and 2 mm ST elevation in 2 contiguous chest leads V(1)-V(6) or 1 mm in limb leads were randomized to receive 1.5 miu of either r-SK or n-SK. CK Peaking and decrease of > or = 50% ST segment were used to assess reperfusion. STATISTICAL ANALYSIS: Difference in the groups was assessed by chi-square or paired t test as required. Probability value < 0.05 was considered significant with 95% confidence interval. RESULTS: Overall 150 patients were recruited (96 r-SK group and 54 in n-SK group) and demographic and clinical profile of the groups was comparable. Reperfusion was seen in 68.2% (58) and 69.4% (34) patients in r-SK and n-SK groups respectively. Commonly seen adverse events were fever in 7 (8.5%), hypotension in 3 (3.6%), nausea in 2 (2.4%) patients. Minor bleeding were seen in 4 (4.8%) of patients. CONCLUSION: Indigenous recombinant Streptokinase (r-SK) is as efficacious as natural streptokinase (n-SK) in establishing reperfusion as assessed by non-invasive parameters with comparable side effect profile.
OBJECTIVES: To determine whether the administration of 1.5 million units of streptokinase intravenously within 4 hours of the onset of acute ischemic stroke would reduce morbidity and mortality at 3 months and whether outcomes may be better for those receiving therapy within 3 hours of stroke onset compared with those receiving it after 3 hours. DESIGN: Randomized, double-blind, placebo-controlled trial with 3-month follow-up. PARTICIPANTS: A total of 340 patients, aged 18 to 85 years, with moderate to severe strokes were randomized from 40 centers throughout Australia from June 1992 to November 1994. INTERVENTION: Administration of 1.5 million units of streptokinase or placebo intravenously in 100 mL of normal saline over 1 hour. MAIN OUTCOME MEASURE: Combined death and disability score (Barthel index <60) 3 months after the stroke. RESULTS: Using an intention-to-treat analysis with a combined death and disability score at 3 months after stroke as the primary end point, we found a nonsignificant overall trend toward unfavorable outcomes for streptokinase vs placebo (relative risk [RR] of unfavorable outcome, 1.08; 95% confidence interval [CI], 0.74-1.58) and an excess of hematomas (13.2%[12.6% symptomatic] in the treated group, 3% [2.4% symptomatic] for placebo [P<.01]). However, poor outcomes were confined to patients receiving therapy more than 3 hours after stroke onset (RR of unfavorable outcome, 1.22; 95% CI, 0.80-1.86). In contrast, among the 70 patients who were entered into the trial within 3 hours of stroke onset, there was a trend toward improved outcomes for those who received streptokinase (RR of unfavorable outcome, 0.66; 95% CI, 0.28-1.58), and this outcome pattern was significantly better than for those receiving therapy after 3 hours (P=.04). Streptokinase administration resulted in excess deaths in the group treated after 3 hours (RR, 1.98; 95% CI, 1.18-3.35), but not among those treated within 3 hours (RR, 1.11; 95% CI, 0.38-3.21). CONCLUSION: The administration of streptokinase within 4 hours of acute ischemic stroke increased morbidity and mortality at 3 months. While treatment within 3 hours of stroke was safer and associated with significantly better outcomes than later treatment, it showed no significant benefit over placebo. The timing of thrombolytic therapy for acute stroke is critical.
OBJECTIVES: This study sought to demonstrate the equivalence of saruplase and streptokinase in terms of 30-day mortality. BACKGROUND: The use of thrombolytic agents in the treatment of acute myocardial infarction is well established and has been shown to substantially reduce post-myocardial infarction mortality. METHODS: Three thousand eighty-nine patients with symptoms compatible with those of acute myocardial infarction for < 6 h entered the study at a total of 104 centers and were randomized to receive streptokinase (1.5-MU infusion over 60 min) or saruplase (20-mg bolus and 60-mg infusion over 60 min). In the saruplase group, a bolus of heparin (5,000 IU) was administered before saruplase, and a corresponding blinded double-dummy placebo bolus was administered before streptokinase. All patients received intravenous heparin infusions for > or = 24 h starting 30 min after the end of the thrombolytic infusions; the infusions were titrated to maintain an activated partial thromboplastin time at 1.5 to 2.5 times that of normal. RESULTS: Death of any cause up to 30 days after randomization occurred in 88 (5.7%) of 1,542 patients randomized to receive saruplase and 104 (6.7%) of 1,547 patients randomized to receive streptokinase (odds ratio 0.84, p < 0.01 for equivalence). Hemorrhagic strokes occurred more often in patients receiving saruplase (0.9% vs. 0.3%), whereas thromboembolic strokes were more prevalent in the streptokinase-treated patients (0.5% vs. 1.0%). The rate of bleeding was similar in the two treatment groups (10.4% vs. 10.9%). Hypotension and cardiogenic shock occurred less frequently in the saruplase group. Reinfarction rates were similar. CONCLUSIONS: Saruplase is a clinically safe and effective thrombolytic medication. This profile ranks saruplase favorably among the currently available thrombolytic agents.
In a randomised trial the efficacy and safety of anisoylated plasminogen streptokinase activator complex (APSAC) administered intravenously and streptokinase administered by intracoronary infusion were compared in patients with proven acute myocardial infarction. Occlusion of the infarct-related vessel, reperfusion and reocclusion were all assessed angiographically. Fibrinolytic therapy was started within 4 (mean 2.4) hours of the onset of symptoms. 85 patients entered the study; 42 were treated with a single intravenous injection of APSAC (30U) given over 3 to 5 minutes and 43 with an intracoronary infusion of streptokinase (250,000U) given over 60 minutes. 12 patients were excluded because of protocol violation. Reperfusion at 90 minutes was confirmed in 23/36 patients (63.9%) in the APSAC group and 25/37 (67.6%) in the streptokinase group; at 24 (+/- 6) hours reocclusion had occurred in 1/22 (4.5%) and 4/23 (13.0%) patients in each group, respectively. These results indicate that APSAC (30U intravenously) is as effective as intracoronary streptokinase (250,000U). The major advantages of APSAC in acute myocardial infarction are its rapid, convenient administration and its low rate of arterial reocclusion.
25 patients with acute myocardial infarction pain lasting more than 20 minutes which was not relieved by nitrates, whose ECGs showed ST segment elevations of 1 mm or more in 2 or more ECG leads, and who presented less than 3 hours after onset of their symptoms were randomly assigned to one of 2 thrombolytic treatment groups: a single intravenous bolus of anisoylated plasminogen streptokinase activator complex (APSAC) 30U in 5 minutes or an intravenous infusion of streptokinase 1,500,000U over 60 minutes. 3 to 4 hours after the administration of the thrombolytic agent, all patients received intravenous heparin at full dosage for 24 hours. The patency of the infarct-related coronary vessels was assessed by angiography 1 to 4 hours after administration of the thrombolytic agent. Clinical signs, ECGs, pulse, blood pressure and temperature were monitored regularly for 24 hours after treatment or as clinically appropriate. APSAC seemed to be at least as effective as streptokinase in terms of patency of the infarct-related vessel (92% vs 63%, respectively). The adverse events were similar and none was life-threatening. APSAC and streptokinase caused similar falls in blood fibrinogen levels. APSAC, given as a bolus injection over 5 minutes, was easier to administer than streptokinase, which was given as an infusion during 60 minutes.
The systemic effects of intravenous anisoylated plasminogen streptokinase activator complex (APSAC; 30U) and intracoronary streptokinase (250,000U) were compared in 54 patients with acute myocardial infarction. In 3 patients, no signs of a systemic lytic state were observed. In all other patients, significant reductions of coagulation and fibrinolytic factors occurred: fibrinogen levels decreased by 86% in the APSAC group and 81% in the streptokinase group; for plasminogen the decreases were 68 and 66%, and for alpha 2-antiplasmin activity greater than 95 and 94%, respectively. Fibrin(ogen) degradation products were increased 68- and 38-fold, respectively. Although there was a trend for the lytic state to be more profound in the APSAC-treated patients, there was no difference between treatment groups with regard to bleeding complications or therapeutic efficacy, the latter being 79 and 73%, respectively, for APSAC and streptokinase. Total fibrinolytic activity, measured as euglobulin clot lysis time, was sustained for longer in the APSAC group, which may explain the low reocclusion rate in this group in comparison with the streptokinase group.
86 patients with a first myocardial infarction presenting within 6 hours of the onset of symptoms were randomly allocated to treatment with intravenous streptokinase or anisoylated plasminogen streptokinase activator complex (APSAC). Side effects were observed in 34.1% of patients (15 of 44) in the streptokinase group and 23.8% (10 of 42) in the APSAC group. These effects included injection related effects (in 4 patients on streptokinase versus 6 on APSAC) and neurological complications (0 vs 2 patients, respectively). Femoral haematoma accounted for the majority of bleeding events. Death occurred as a consequence of haemorrhage in 2 patients (1 receiving streptokinase and the other APSAC).