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Thrombolytic drugs play a crucial role in the management of patients with acute myocardial infarction, pulmonary embolism, deep vein thrombosis, arterial thrombosis, acute thrombosis of retinal vessel, extensive coronary emboli, and peripheral vascular thromboembolism. Recognition of the importance of fibrinolytic system in thrombus resolution has resulted in the development of different fibrinolytic agents. Now a days several newer plasminogen activators with different pharmacokinetic and pharmacodynamic properties have been developed to treat thrombotic disease, which are fibrin specific with prolonged half-life and can be administered as a single bolus.

Objectives: This report presents the 5-year results of the Grampian Region Early Anistreplase Trial (GREAT) and quantifies the benefit of earlier thrombolysis in terms that are generally applicable., Background: Although it is accepted that the earlier thrombolytic therapy is given for acute myocardial infarction the greater the benefit, there are widely differing estimates of the magnitude of the time-related benefit of thrombolysis because of inappropriate trial design and analysis., Methods: In a previously reported randomized trial, anistreplase (30 U) was given intravenously either before hospital admission or in the hospital, at a median time of 105 and 240 min, respectively, after onset of symptoms. Intention to treat and multivariate analyses of the 5-year results were performed., Results: By 5 years, 41 (25%) of 163 patients had died in the prehospital treatment group compared with 53 (36%) of 148 in the hospital treatment group (log-rank test, p < 0.025). Delaying thrombolytic treatment by 1 h increases the hazard ratio of death by 20%, equivalent to the loss of 43/1,000 lives within the next 5 years (95% confidence interval 7 to 88, p = 0.012). Delaying thrombolytic treatment by 30 min reduces the average expectation of life by approximately 1 year., Conclusions: The magnitude of the benefit from earlier thrombolysis is such that giving thrombolytic therapy to patients with acute myocardial infarction should be accorded the same degree of urgency as treatment of cardiac arrest. Policies should be developed for giving thrombolytic therapy on-site if practicable and by the first qualified person to see the patient.

Objectives: This study was designed to test the hypothesis that monitoring the ST segment on a single electrocardiographic (ECG) lead reflecting activity in the infarct zone provides sensitive and specific recognition of reperfusion within 60 min of initiation of therapy in acute myocardial infarction., Background: Infarct-related arteries that fail to recanalize early may benefit from immediate rescue angioplasty. Hence, detection of reperfusion has important practical clinical implications., Methods: Of 41 patients with acute myocardial infarction who had ambulatory ECG (Holter) monitors placed, 38 had adequate ST segment monitoring for 3 h; 35 of the 38 were treated with thrombolytic agents and 3 with primary angioplasty. All patients underwent early coronary angiography and were classified into two groups: Group P (22 patients) had angiographic patency (Thrombolysis in Myocardial Infarction [TIMI] grade 2 or 3 flow), the Group O (16 patients) had persistent occlusion (TIMI grade 0 or 1 flow) of the infarct-related vessel at 60 min from initiation of therapy. The initial ST segment level was defined as the first ST segment level recorded; the peak ST segment level was defined as the highest ST segment level measured during the 1st 60 min. To assess the optimal ST segment recovery criteria for reperfusion, the presence or absence of a > or = 75%, > or = 50% and > or = 25% decrement from initial and peak ST segment levels, sampled and analyzed at 2.5-, 5-, 10-, 15-and 20-min intervals, was correlated with patency of the infarct-related artery at 60 min., Results: ST segment recovery of > or = 50% reduction from peak ST segment levels with sampling rates at < or = 10-min intervals provided the optimal criterion for recognizing coronary artery patency at 60 min (sensitivity 96%, 95% confidence interval [CI] 77% to 99%; specificity 94%, 95% CI 69% to 99%, p < 0.0001). The subgroup of 13 patients in Group P with TIMI grade 3 reperfusion flow all met this criterion (sensitivity 100%, 95% CI 75% to 100%). The use of the initial ST segment level as the baseline for determining the presence of a > or = 50% reduction in ST segment levels within 60 min was less sensitive. Prediction of coronary reperfusion within 60 min of therapy on the basis of a > or = 75% decrement from peak ST segment levels was less sensitive, and the use of a > or = 25% decrement was less specific., Conclusions: ST segment monitoring of a single lead reflecting the infarct zone provides a reliable method for assessing reperfusion within 60 min of acute myocardial infarction. Optimal criteria for ECG reperfusion include a > or = 50% decrease from peak ST segment levels, with ST segment measurements recorded continuously or at least every 10 min.

Objective: To assess the feasibility, safety and efficacy of thrombolysis in the Emergency Room of a Rural Hospital with no Coronary Care Unit, and subsequent transfer to the Coronary Care Unit of a City Hospital., Design: Prospective study, controlled with two parallel groups of consecutive patients (Group 1: Rural Hospital, Group 2: CCU Ravenna) and administration of Anistreplase 30 intravenous unit., Setting: Rural Emergency Rooms which transmitted the electrocardiogram by cardiotelephone to the Ravenna Coronary Care Unit (average distance 35 km; range: 17-50 km)., Patients: 280 (Group 1: 102 patients, Group 2: 178 patients) with suspected acute myocardial infarction and with no contra-indications to fibrinolysis, within 6 h of onset of symptoms., Main Outcome Measures: time saving, accuracy of diagnosis, adverse events, left ventricular function and survival., Results: the median pain to needle time was 90' in Group 1 and 165' in Group 2 (P < 0.001). Accuracy of diagnosis for acute myocardial infarction was 91% and 100%, respectively. Complications were rare and none occurred during transfer. The creatine phosphokinase peak of Group 1 was lower than Group 2 (1389 vs. 2186 IU/l; P < 0.001). The echocardiographic Wall Motion Abnormality Score Index of Group 1 was lower than Group 2 (3.571 vs. 5.589; P < 0.001). Mortality at 35 days in Group 1 was 7.5% vs. 10.7% in Group 2 (-30%; P = n.s.)., Conclusions: The Emergency Room physician, in close collaboration with the cardiologist, supplied a very high standard of pre-Coronary Care Unit diagnosis and therapy. Administration of Anistreplase in the rural Emergency Room brought about a significant reduction of pain to needle time, a significant improvement in left ventricular function and a reduction in mortality.

We reviewed the effectiveness of a strategy involving paramedic ambulances and community education to reduce the delay to thrombolytic therapy in patients admitted with acute myocardial infarction, by analysing delay times recorded during routine treatment. Rapid identification and treatment of patients with acute myocardial infarction who were eligible for thrombolysis was carried out in the Accident and Emergency and Cardiac Care Units. Two hundred seventy-four patients were admitted with acute myocardial infarction over an 18-month period and treated with anistreplase (168) or streptokinase (106). The following median times were recorded: symptom onset to administration of thrombolytic therapy, 142 min (range 43-980 min); symptom onset to ambulance arrival, 60 min; ambulance with patient to arrival in hospital, 35 min; time to treatment in hospital ('door to needle time'), 25 min; in-hospital delays were notably shorter for patients given anistreplase as opposed to streptokinase. Shortened delays for the delivery of thrombolytic therapy can be achieved by a strategy involving public education, the availability of resuscitation ambulances, and close liaison with the Accident and Emergency Department.

Background: Nuclear cardiology permits the estimation of the myocardial infarction size and the result of the thrombolytic therapy. The aim of the study was to demonstrate the feasibility of the planar myocardial scintigraphy with Technetium-99-m-sestamibi in the coronary intensive care unit for the early identification of the infarct size and the result of the thrombolytic therapy., Materials and Methods: We considered 10 patients affected by a first myocardial infarction (5 anterior and 5 inferior wall) then treated with thrombolytic therapy (APSAC 30 U. iv) within an interval of 3 hours from the onset of the symptoms. Technetium-99-m-sestamibi was injected before the thrombolytic therapy and the planar imaging was registered after 2-3 hours with a mobile gamma-camera. After 24 hours and before patient discharge we repeated the scintigraphic evaluation. Within 24 hours from the thrombolytic therapy the coronary angiography was performed for the demonstration of patency of the infarct-related artery. The left ventricle myocardial perfusion was divided in the 3 planar projections into 13 segments. The perfusion in each segment was evaluated with a perfusion score: 0 = normal perfusion, 1 = moderately reduced, 2 = severely reduced, 3 = absent. The sum of the hypoperfused segments represented the infarct size. A perfusion score improvement greater than 40% was considered a marker of reperfusion., Results: The infarct size involved 4.4 +/- 1.4 segments in the anterior and 2 +/- 0.6 segments in the inferior wall infarctions (p < 0.05). The scintigraphic imaging made 24 hours after the myocardial infarction allowed the diagnosis of coronary reperfusion in 7 patients. The coronary angiography demonstrated the infarct related artery patency in 9 patients (all with TIMI perfusion score = 3). The nuclear imaging at patient discharge provided the diagnosis or reperfusion in 8 cases and demonstrated an improvement of the myocardial perfusion score in 5 cases., Conclusion: The scintigraphic imaging with Technetium-99-m-sestamibi in the patients with a myocardial infarction treated with thrombolytic therapy is feasible with a mobile gamma-camera in the intensive coronary care unit. The quality of planar imaging is good and allows the evaluation of myocardial infarct size and efficiency of thrombolytic therapy. An earlier scintigraphic imaging should be taken into consideration for a more timely non-invasive evaluation of patients who need coronary angiography and, if necessary, a rescue PTCA.

The use of thrombolytic agents in patients with suspected myocardial infarction has been shown to reduce early and long-term mortality by about 20%, and it has been suggested that since time is an important factor, pre-hospital treatment would give better results. However, health deciders need reliable data on which to base future policies concerning this. The European Myocardial Infarction Project was a European Economic Community-supported double-blind study designed to evaluate the efficacy and safety of pre-hospital early thrombolytic treatment in patients with suspected myocardial infarction compared with the same treatment given later in a hospital setting. A total of 5469 patients in 16 countries were randomised by 198 mobile emergency units to receive either pre-hospital treatment with anistreplase, the thrombolytic agent used, followed by placebo after hospital admission (pre-hospital group; 2750 patients), or placebo followed by anistreplase (hospital group; 2719 patients). The median time delay between the injections was 55 min. A non-significant decrease in 30-day mortality was observed in favour of the pre-hospital group (13%: P = 0.08), whereas the decrease in cardiac death observed, also in favour of the pre-hospital group, was on the borderline of significance (16%; P = 0.049). Although some complications occurred more frequently in the pre-hospital group in the pre-hospital period, the overall incidence for serious complications was similar for both groups. These results show that the pre-hospital thrombolytic strategy in patients with suspected myocardial infarction is both effective and safe when performed by well-equipped well-staffed mobile emergency units.

Introduction and Objectives: Most deaths caused from AMI occur in elderly patients, and it is know that these patients way also benefit from the type treatment normally offered to younger patients. We proposed to analyse how our therapeutic strategy has evolved for patients of advanced age related to the admission in the CCU and the prescription of thrombolytic treatment., Methods: In order to carry our investigation, we compared the clinical profile, the treatment and the results of patients over the age of 70 who were hospitalized in our Service with suspected AMI during last 3 years. A total number of 366 which were divided into two consecutive periods of 18 months; 176 patients from January'91 to June'92 (Period I--former--) and 190 patients from July'92 to December'93 (Period II--latter--)., Results: In both periods, nearly all patients with suspected AMI and < 48 hours of since symptoms began were hospitalized in the CCU irrespective of their age. In both periods, over 40% of the total number of patients admitted to CCU were > 70 years (I: 45.2% vs II: 42.6%). We observed that in the latter group a major part of patients had complicated AMI at the moment of admittance (I: 15.3% vs II: 24.2%; p < 0.05). This is probably related to a less favorable clinical profile. Despite this, a parallel increase in hospital death rate was not observed (I: 21% vs II: 17%; p: NS). Over time, the ratio of patients prescribed with thrombolysis > 70 was nearly doubled (I: 13.7% vs II: 24.7%; p < 0.01), without a detected increase in complications of hemorrhages., Conclusions: For a variety of factors, the number of elderly patients admitted with complicated AMI has increased. In our experience the simple modification in the way thrombolysis is prescribed is capable of restraining the hospital death rate ratio.

Introduction and Objectives: Our aim was to evaluate the utility of thrombolytic therapy administered outside tertiary hospital., Methods: We analyzed 80 consecutive patients with acute myocardial infarction admitted to the emergency area of primary hospital within 24 hours after the onset of symptoms and lastly transported to a coronary care unit (CCU) of a reference hospital. The thrombolytic protocol was performed by medicine department of primary hospital and the CCU of reference hospital., Results: 23 patients without (group A) and 57 with (group B) fibrinolytic therapy (APSAC 50 patients and streptokinase 7 patients) were analyzed. Group A patient were older (mean: 67 +/- 11 vs mean: 62 +/- 10 years; p = 0.01), and arrived later to emergency area (mean 254 +/- 284 vs mean 163 SD 161 min; p = 0.04) and to the coronary care unit (mean 561 +/- 371 vs mean 334 +/- 177 min; p = 0.0002). The guard physician decision to start or not the fibrinolytic therapy, was adequate in 86% of the patients (sensitivity 87%, predictive positive value 95%, specificity 83%). Complications on emergency area or during transport in group B were ventricular fibrillation in 9%, AV block (2-3 degree) in 9%, severe nonsustained ventricular arrhythmia in 11% and transitory hypotension in 23%. No death occurred before CCU admission. In group B, 35% patients was treated within the first 2 hours. The average time gain was 124 min (thrombolysis administration--CCU admission)., Conclusion: On emergency area of primary hospital, thrombolytic therapy is feasible and safe when administered by well-equipped and well-trained medical emergence area and ambulance staff.

Objective: To evaluate the influence of pretreatment streptokinase resistance titre and the concentration of IgG antibodies to streptokinase on the efficacy of thrombolytic drugs containing streptokinase in restoring coronary patency in acute myocardial infarction., Design: Comparative observational study., Setting: City general hospital., Patients: One hundred and twenty four previously unexposed patients presenting within six hours of onset of acute myocardial infarction., Interventions: Streptokinase, 1.5 MIU as intravenous infusion over 60 minutes (60 patients), or anistreplase, 30 units as intravenous injection over five minutes (64 patients)., Main Outcome Measures: Pretreatment streptokinase resistance titre and concentration of IgG antibodies to streptokinase were measured in 96 and 124 patients respectively and coronary patency assessed angiographically at 90 minutes and 24 hours., Results: Pretreatment streptokinase resistance titre and concentrations of IgG antibodies to streptokinase were low and skewed towards higher values. Those patients with coronary occlusion at 24 hours had a significantly higher median streptokinase resistance titre (100 v 50 streptokinase IU ml-1, P = 0.02). There were trends towards a higher streptokinase resistance titre in those patients with coronary occlusion at 90 minutes (50 v 20 streptokinase IU ml-1, P = 0.06) and higher concentrations of IgG antibodies to streptokinase in those with coronary occlusion at both 90 minutes and 24 hours (1.53 v 0.925, P = 0.03; 1.65 v 1.04 micrograms streptokinase binding ml-1, P = 0.06). Coronary patency rates were similar in the two treatment groups., Conclusions: In the range measured in previously unexposed patients the streptokinase resistance titre has a small, but significant, negative influence on the efficacy of streptokinase and anistreplase. This effect should be considered if retreatment with streptokinase or anistreplase is proposed.

The benefits of thrombolysis are believed to be related to the speed of reperfusion of the infarct-related artery. In this sub-study, evidence for the occurrence of reperfusion before admission to hospital has been sought. In a randomized double-blind controlled trial, 311 patients with suspected acute myocardial infarction were given anistreplase 30 units i.v., either at home at a median 101 min (early group, n = 163), or in hospital at a median 240 min after symptom onset (large group, n = 148). Paired electrocardiograms recorded at home and on admission to hospital were available for study in 143 and 137 patients in early and late groups. Reduction in ST elevation between home and hospital electrocardiograms of > 25% in a single lead was taken as evidence of reperfusion. Patients with significant ST elevation in either electrocardiogram comprised the sub-study groups, and numbered 63/143 (44%) and 68/137 (50%) in early and late groups respectively. A reduction of > 25% in the single lead demonstrating greatest ST elevation on the presenting electrocardiogram was observed in 37/63 (59%) and 23/68 (34%) patients in the early and late sub-study groups (difference 25%, 95% confidence interval 8% to 42%, P = 0.003). It was found that domiciliary thrombolysis was associated with electrocardiographic evidence of an increased rate of reperfusion occurring before admission to hospital. Evidence of reperfusion occurring pre-hospital, whether spontaneous or following thrombolytic therapy, was associated with a better outcome.

The aim of this study was to investigate whether failure of thrombolytic treatment might be due to inhibition of fibrinolysis by high lipoprotein(a) levels. Fifty-eight patients with acute myocardial infarction were treated intravenously within 4 h after onset of symptoms with anistreplase (30 units) and heparin (30,000 IU/24 h). Blood samples for measurement of coagulation parameters were taken before and 1.5 h after treatment. Coronary angiography was performed after 48 h. Levels of lipoprotein(a) were measured 6 months after discharge from hospital. The patency rate was 74% (43/58). Median lipoprotein(a) levels were not different between the patients with a patent and those with a non-patent vessel (10 and 8 mg/dl, respectively), however, in patients with a non-patent infarct-related vessel, a significant inverse correlation was found between the lipoprotein(a) level and the decrease of plasminogen in the first 1.5 h after treatment. It is concluded that high lipoprotein(a) levels, although not directly associated with a poor outcome of anistreplase therapy, might contribute to insufficient fibrinolysis in patients with a non-patent infarct-related vessel.

Myoglobin (Mb) is an intracardiac protein known to be rapidly released after onset of reperfusion. The new automated latex-enhanced nephelometric immunoassay is an interesting fast alternative to the other methods. Therefore we sought to assess the accuracy of rapid rise of Mb concentration to predict the success of reperfusion. Thirty consecutive patients, admitted to the coronary care unit for first acute Q-wave myocardial infarction, were prospectively studied. They underwent thrombolysis 126 +/- 45 min (range 30-180) after onset of symptoms. Mb determinations were obtained before starting therapy and, thereafter, hourly for 5 hours, and after 8 and 12 hours. The usual non invasive markers of reperfusion were considered, and coronary arteriography was performed in all patients at 5.5 +/- 0.9 days (range 1-6). In 23 patients (77%) patent infarct-related artery (IRA) (TIMI II-III) and in 7 (23%) occluded IRA (TIMI 0-I) was observed at coronary arteriography. We modified the judgment in 3 cases (10%) with occluded IRA. All reperfused patients (Group A) showed a rapid rise of Mb concentration with a mean time to peak occurring 133 +/- 80 min (range 60-180) after therapy. Mean value of unreperfused patients (Group B) was 330 +/- 173 min (range 180-420). We retrospectively stated a time to peak of Mb concentration within 180 min as diagnostic threshold for reperfusion. Sensitivity was 100%, specificity 50%, positive predictive value 93%, negative predictive value 100%. The results of this study confirm that Mb release kinetics may play an interesting role in the early prediction of patency of IRA in acute myocardial infarction after thrombolysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Objectives: The purpose of this study was to compare the effects of very early (< or = 1.5 h after symptom onset) and later (> 1.5 up to 4 h) thrombolytic therapy on infarct size, left ventricular function and early mortality in patients with acute myocardial infarction. To start thrombolysis at the earliest possible moment, it was performed in the prehospital setting. A cutoff time of 1.5 h was prospectively stipulated., Background: Shortening of ischemic time is crucial within the 1st 2 h. Prehospital thrombolysis can reduce time to treatment and enables very early initiation of therapy for many patients., Methods: One hundred seventy patients received 30 mg of anistreplase up to 4 h from symptom onset by a mobile intensive care unit physician. Infarct size was measured from cumulative release of alpha-hydroxybutyrate dehydrogenase, and left ventricular function was assessed by contrast angiograms 10 days after the infarction., Results: The decision to treat on scene was correct in 98% of patients. There were no bleeding complications or deaths outside the hospital setting. In 28 patients (17%) the ischemic process was interrupted. Findings with thrombolytic therapy initiated < or = 1.5 (96 patients) versus > 1.5 h (74 patients) were the following: initial extent of epicardial injury, 1.6 +/- 0.9 versus 1.4 +/- 0.7 mV, p = NS; infarct size by cardiac enzyme release 646 +/- 634 versus 886 +/- 712 IU/liter, p < 0.05; ejection fraction 57 +/- 14% versus 51 +/- 13%, p < 0.05; regional dyssynergic area 24 +/- 22 versus 33 +/- 24 U, p < 0.05; 21-day mortality 1 of 96 versus 5 of 74 patients (1% vs. 7%, p < 0.05)., Conclusions: The data suggest that in evolving myocardial infarction up to 4 h in duration, the start of thrombolytic therapy at < or = 1.5 h compared with > 1.5 h limits infarct size, preserves left ventricular function and may save lives.

A double-blind controlled trial was performed to evaluate the dose-effect relationship of APSAC on coronary reperfusion in patients with acute myocardial infarction. A total of 103 patients were recruited in 14 centres and randomly allocated to receive 3.75, 7.5, 15.0 or 30.0 U of anisoylated plasminogen streptokinase activator complex (APSAC), a thrombolytic. Angiograms were taken at baseline to assess eligibility and at six times after administration at 15-min intervals (up to 90 min). A control angiogram was performed at 24 h for patients with a patent artery at 90 min. Angiograms were read centrally by independent readers. There was a non-significant difference between the four groups for the main outcome, reperfusion of an initially occluded artery: 5/20 (25%; 3.75 U); 13/22 (59%; 7.5 U); 11/22 (50%; 15.0 U); 14/25 (56%; 30.0 U); p = 0.11. There was no apparent difference between group 7.5 U, 15.0 U and 30.0 U (mean recanalisation rate: 55%), but the reperfusion rate in the 3.75 U group was significantly lower (p = 0.02). No apparent differences were observed for the delay of recanalisation between the four groups. The mean values of minimum fibrinogen concentration were different in the four groups, with a clear dose-effect relationship (p = 0.0004). The side effects were not found to be dose-dependent.

Within 4 hours from the onset of symptoms in 61 patients with myocardial infarction and intravenous thrombolysis, ST segment elevation and creatine phosphokinase (CK) were measured every 15 minutes. Because of a premature enzyme rise, 42 patients (69%) were reperfused early (group 1). Immediately following reperfusion, eight of them (13%, group 1a) showed a marked increase of the ST elevation, in six of whom it was associated with clearly intensified chest pain. These patients exhibited a much steeper enzyme release and developed a larger enzymatic infarct size than patients (group 1b) without an additional transient ST elevation at reperfusion (CK peak 5.1 +/- 1.6 vs 9.8 +/- 4.2 hours after the start of thrombolysis; CK release 48 +/- 22 vs 19 +/- 18 IU/ml x hours, both p < 0.005). At angiography 11 days later, left ventricular function was significantly worse in group 1a than in group 1b (regional dyssynergic area 51 +/- 24 vs 21 +/- 18, global ejection fraction 39 +/- 14 vs 58 +/- 11; both p < 0.0005). During intravenous thrombolysis in acute myocardial infarction, some patients show a marked transient increase of the ST segment elevation at reperfusion. Their enzyme rise is very rapid and suggests a special reperfusion pattern. Most of these patients suffered large infarcts.

In 60 patients with acute myocardial infarction (pain < or = 4 h), we examined the value of ST segment monitoring in predicting early reperfusion, resulting left ventricular damage, and complications during hospitalization. Two criteria were determined by observation of the ST segment elevation during the first 4 h following initiation of thrombolysis. Early reperfusion was assessed by an early increase of the creatine phosphokinase (CK) with measurements taken in 15-min intervals. Cardiac catheterization was performed on days 11 +/- 5. According to the CK measurements, a reduction of the ST elevation > or = 50% within 1 h of serial ECG follow-up (ST criterion A) was the best indicator of early reperfusion (sensitivity 84%, specificity 80%, positive predictive value 93%, negative predictive value 67%). Simple comparison of the ST segment in the initial ECG and an ECG recorded 3 h later (ST criterion B) was less accurate according to the detection of early reperfusion (sensitivity 68%, specitivity 93%, positive predictive value 97%, negative predictive value 50%). However, contrary to ST criterion A, criterion B was useful in predicting subsequent left ventricular damage. Patients with a resolution of the initial ST elevation > or = 70%/3 h showed smaller regional wall motion abnormalities (dyssynergic area 21.3 +/- 20.3 vs 33.8 +/- 18.4, p < 0.01) and a better left ventricular ejection fraction (57.7 +/- 11.6 vs 50.2 +/- 12.6, p < 0.05). Patients with early reduction of the ST elevation following either criterion experienced fewer critical events (reinfarction, reischemia, death). In conclusion, the investigated criteria are useful in assessing reperfusion of the infarcted artery following thrombolysis.(ABSTRACT TRUNCATED AT 250 WORDS)

The properties and physiological effects of three currently FDA-approved thrombolytic agents, streptokinase (SK), tissue plasminogen activator (tPA), and anisoylated plasminogen activator complex (APSAC) are reviewed. All thrombolytic agents have been shown to reduce mortality postmyocardial infarction (MI). Comparative trials have failed to demonstrate a difference between the effects of tPA, SK, and APSAC on mortality. In addition, no consistent difference between the three agents on ejection fraction (EF) has been found despite a superior reperfusion rate with tPA at 90 min. Furthermore, reinfarction and interventional procedure rates were significantly higher after thrombolytic treatment, and the incidence of total strokes was higher with tPA than SK in some comparative studies. Based on analysis of the published megatrials, SK is a more cost-effective thrombolytic agent for patients with acute MI than tPA or APSAC.

The results of an overview of early (90-240 min) and late (24 hours or more) patency and of stroke rates for each of the three commercially available thrombolytic agents, streptokinase, alteplase, and anistreplase are presented. Studies included in this analysis are all those published between 1985 and March 1992 and focus on the licensed dosage regimens of each agent. The rates of early and late patency for streptokinase were 64.7% and 80.8%; for alteplase, 66.6% and 73.7%; and for anistreplase, 72.1% and 84.5%. The rates of total and hemorrhagic stroke for streptokinase were 0.69% and 0.17%; for alteplase, 1.27% and 0.50%; and for anistreplase 0.91% and 0.38%. These results provided evidence that the rates of early and late patency appeared to be greatest for anistreplase and that the rates of stroke are within "acceptable" ranges for all three thrombolytic agents with streptokinase affording the lowest rate.

This randomized study compares the coronary perfusion rate in patients with acute myocardial infarction (AMI) treated with 2 different intravenous thrombolytic agents: streptokinase 1.5 million U given over 60 minutes and anisoylated human plasminogen streptokinase activator complex (anistreplase) administrated as a bolus of 30 U over 5 minutes. One hundred seventy-five patients (149 men and 26 women, mean age 54 years) have been included in this study. Eighty-nine patients were treated with anistreplase and 86 patients with streptokinase. AMI was inferior in 54 patients (61%) in the anistreplase group and in 54 patients (63%) in the streptokinase group. It was anterior in 35 (40%) and 32 (37%) patients, respectively. Coronary angiography and ventriculography were performed at a mean time (+/- SEM) of 207 +/- 11 minutes after the beginning of thrombolysis in 170 patients. A perfusion score grade of 2 or 3 according to the Thrombolysis in Myocardial Infarction trial was found in 63 patients (72%) in the anistreplase group and in 56 patients (68%) in the streptokinase group (p = NS). Severe bleeding occurred in 7 patients (8%) after anistreplase and in 6 patients (7%) after streptokinase. No cerebral hemorrhage occurred. Nine patients (5%) died during their hospital stay: 6 after anistreplase and 3 after streptokinase. It is concluded that intravenous administration of anistreplase or streptokinase is efficient and safe. Coronary patency 207 minutes after fibrinolysis, incidence of adverse events and mortality are similar in both groups.

Two hundred and seventy patients, under 71 years of age and suffering from a less than 4 h infarction diagnosed according to clinical and electrocardiographic criteria, were included: two 90-patient groups were randomized and then treated with either anistreplase (30 mg iv over 5 min) or alteplase (10 mg bolus injection + 5000 IU heparin bolus injection, followed by 90 mg alteplase over 3 h), and compared with a consecutive control series of 90 patients treated with streptokinase (1.5 million U over 1 h). Intravenous heparin and aspirin (250 mg day-1) were then prescribed routinely. The three groups were comparable as regards age (55.2 +/- 10 years), male/female ratio (10.4), the site of the infarction (42% anterior, 55% inferior) and initial clinical seriousness (Killip I = 90%, II = 8%, III = 2%). The patients were thrombolysed in 17 community hospitals, and then referred to a university hospital with catheterization facilities. An efficacy score was determined, based on four parameters: two obtained from coronary angiography and left ventriculography performed on day 6 +/- 2 (N = 252) (asynergic score and patency of the infarct-related artery), one from Tl-tomography performed at rest (infarct size) and one from radionuclide angiography (global left ventricular ejection fraction) performed between day 15 and day 21 (N = 242). The score (range: 0-24 per patient) was 17.8 +/- 6.4 for alteplase, 17.7 +/- 6.0 for anistreplase and 18.1 +/- 6.0 for streptokinase respectively (NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Streptokinase and anistreplase are antigenic and their administration often leads to antibody formation. These can cause allergic reactions and/or neutralization of streptokinase with resulting suboptimal treatment. Currently, streptokinase re-administration is considered appropriate for up to 5 days and from 1 year after a previous dose. Antistreptokinase antibody and neutralization titres (NT) were measured in three groups of patients to determine if this practice is appropriate: 1. (early)--36 patients whose titres were measured for at least 5 days after thrombolysis; 2. (late)--57 patients who received thrombolysis 12-54 months previously; 3. (controls)--182 consecutive suspected myocardial infarction patients (without previous exposure to thrombolysis). Results were as follows (mean +/- SEM): 1. (early)--the antibody and/or NT were raised by day 4 in 19.4% of the patients. One patient could have neutralized 1.97 million units (MU) of streptokinase by day 4. (Day 4--antibody 1:39 +/- 11, NT 0.19 +/- 0.05 MU; day 5--1:136 +/- 41 and NT 0.7 +/- 0.43 MU respectively.) 2. (late)--23 patients (40%) had either antibody titres > or = 1:160 and/or NT > 1.5 MU. (12-23 months--antibody 1:243 +/- 43, NT 0.63 +/- 0.15 MU; 24-35 months--1:98 +/- 31 and 0.69 +/- 0.22 MU; 36-54 months--1:87 +/- 14 and 0.54 +/- 0.12 MU.) All titres were significantly higher than the controls (antibody 1:25 +/- 3, NT 0.14 +/- 0.01 MU, P < 0.01). After streptokinase or antistreplase, antibodies are raised from 4 days to at least 54 months. It would seem prudent to avoid their re-administration during this time interval.

167 patients suffering from acute myocardial infarction (AMI) were recruited from 12 cardiology centres and given thrombolytic treatment. Cost-utility analyses were performed and a cost-utility ratio was computed according to time of initiation of thrombolysis after the AMI and the location of the infarct. Early thrombolysis ( less than 3 hours) proved to cost about the same per QALY ($US3734 vs $US3577) as late thrombolysis ( greater than 3 hours), although posterior infarcts cost slightly more per QALY ($3433 vs $2996) than anterior infarcts. Quality of life coefficients for all patients after the AMI were judged to be about 40% less than before the AMI. Thus, in terms of resources consumed and patient well-being, time of treatment initiation or location of the infarct were less significant than the fact of having an AMI. In terms of quality of life, the best strategy is that which seeks to prevent AMI occurring.

A prospective, open, multicentre post-marketing surveillance on the efficacy and safety of intravenous APSAC in the treatment of acute myocardial infarction was performed in 2436 patients. Reperfusion suggested by non-invasive parameters was achieved in 77.3% of patients. In-hospital mortality was low (7.1%). After exclusion from analysis of patients greater than 70 years of age and those reported to be in cardiogenic shock, mortality rate was 2.9%. More importantly, non-invasive evidence for successful thrombolysis resulted in a significantly lower mortality (3.3%) compared with patients without evidence of successful reperfusion (17.2%). The incidence of serious adverse events was low (132 in 2436 patients, 8/2436 = 0.3% fatal). The data from this post-marketing surveillance conducted under every-day clinical conditions confirm the efficacy and safety of APSAC as a thrombolytic agent in acute myocardial infarction, as demonstrated previously in controlled clinical trials.

1. Intracarotid (i.c.) administration of thrombin induced a marked accumulation of 111indium-labelled platelets and 125I-labelled fibrinogen within the cranial vasculature of anaesthetized rabbits. 2. Thrombin (100 iu kg-1, i.c.) - induced platelet accumulation was completely abolished by pretreatment with desulphatohirudin (CGP 39393; 1 mg kg-1 i.c., 1 min prior to thrombin). Administration of CGP 39393 1 or 20 min after thrombin produced a significant reduction in platelet accumulation. 3. Intravenous (i.v.) administration of the platelet activating factor (PAF) receptor antagonist BN 52021 (10 mg kg-1) 5 min prior to thrombin (100 iu kg-1, i.c.) had no effect on platelet accumulation. 4. An inhibitor of NO biosynthesis, L-NG-nitro arginine methyl ester (L-NAME; 100 mg kg-1, i.c.), had no significant effect on the cranial platelet accumulation response to thrombin (10 iu kg-1, i.c.) when administered 5 min prior to thrombin. 5. Defibrotide (32 or 64 mg kg-1 bolus i.c. followed by 32 or 64 mg kg-1 h-1, i.c., infusion for 45 min) treatment begun 20 min after thrombin (100 iu kg-1, i.c.) did not significantly modify the cranial platelet accumulation response. 6. Cranial platelet accumulation induced by thrombin (100 iu kg-1, i.c.) was significantly reversed by the fibrinolytic drugs urokinase (20 iu kg-1, i.c., infusion for 45 min), anisoylated plasminogen streptokinase activator complex (APSAC) (200 micrograms kg-1, i.v. bolus) or recombinant tissue plasminogen activator (rt-PA; 100 micrograms kg-1, i.c. bolus followed by 20 micrograms kg-1 min-1, i.c., infusion for 45 min) administered 20 min after thrombin.8. These results suggest that neither endogenous PAF nor NO modulate thrombin-induced intracranial platelet accumulation in the rabbit. However, fibrin deposition appears to play an important role as shown by the ability of fibrinolytic agents to reverse platelet and fibrinogen accumulation induced by i.c. thrombin.

Pulmonary embolism (PE) is an important cause of morbidity and mortality in the Western World. Systemic heparinization is usually applied as the treatment of first choice. However, a subgroup of patients presenting with massive PE and haemodynamic deterioration die in the acute phase or remain severely disabled. Several studies have demonstrated the beneficial effects of thrombolytic agents in the treatment of massive PE. This communication presents two patients with clinically massive PE of recent onset (confirmed by lung perfusion scans) who were successfully treated with a single i.v. dose of 30 mg of anisoylated lys-plasminogen streptokinase activator complex (APSAC, comparable to 1,500,000 U of streptokinase) followed by systemic heparinization for 7 days. Both patients showed a considerable improvement in their clinical condition shortly after APSAC administration. Control perfusion scans made after two days revealed marked reduction of perfusion defects.

The effects of thrombolytic therapy on enzymatic and electrocardiographic indexes of myocardial infarction were examined in 370 patients who were enrolled within 4 hours of onset of symptoms and were randomized to blinded therapy with intravenous anistreplase (30 U/5 min, n = 188) or streptokinase (1.5 million IU/1 hour, n = 182). Creatine kinase and its MB isoenzyme were initially measured every 4 to 6 hours, and lactic dehydrogenase (LDH) and its cardiac isoenzyme (LDH-1) every 8 to 12 hours. Electrocardiograms were obtained before, and at 90 minutes and 8 hours after starting thrombolysis, and on discharge. Enzymatic and electrocardiographic measures of infarction were compared between drug treatment and patency groups. Early patency was associated with significant reductions in peak values for each of 4 cardiac enzymes (averaging 21 to 25%, p less than 0.01 to 0.001), even though later rescue procedures were often used in the nonpatient group; times to peaks were also reduced for 3 of the enzymes. Treatment with anistreplase was associated with enzymatic peaks that tended to be lower than with streptokinase (6 to 16%), approaching or reaching significance for LDH (p less than or equal to 0.07) and LDH-1 (p less than or equal to 0.04); times to peaks were similar. Early patency favorably affected electrocardiographic indexes. Summed ST-segment elevations resolved more rapidly (p less than or equal to 0.04), summed Q-wave amplitude was reduced by 32% (p less than or equal to 0.01), and total QRS infarct score on discharge was 22% less (p less than or equal to 0.006) in those achieving early patency. Small differences in electrocardiographic indexes between the 2 drug treatment groups were not significant. These results support use of early reperfusion to reduce infarct size in acute myocardial infarction with administration of streptokinase and anistreplase.

Three agents approved for the lysis of thrombi in coronary arteries--alteplase, anistreplase and streptokinase--have undergone critical clinical experimental trials in Europe and the United States. Global comparison of their efficacy shows that alteplase is slightly more effective (71 percent) in restoring patency than anistreplase (60 percent) and streptokinase (58 percent). Streptokinase and anistreplase are allergenic, and repeat administration is not feasible in the short-term, a distinct advantage for alteplase. More accurate dosing of thrombolytic agents and skillful use of aspirin and heparin improve the efficacy of thrombolytic therapy but can also increase the risk of bleeding. A recanalization rate of 90 percent or more could be achieved if the thrombolytic agent is administered within the first hour after thrombosis. Administration this soon after the development of thrombosis may be possible if the agent is given outside the hospital by practicing physicians or, perhaps, paramedics.

Purpose: Analysis of the first 20 patients with acute myocardial infarction (AMI) who were treated with intravenous APSAC., Methods: Twenty patients with AMI less than 6 hours of duration of symptoms were treated with IV APSAC bolus of 30 mg. Seventeen were males, ages ranging between 40 and 73 (mean 54) years. The first angiographic study was performed in 90 minutes and 5-7 days after drug administration., Results: In the angiographic study performed at 90 minutes the infarct--related artery were left anterior descending (LAD) in 7 patients (35%), right coronary artery (RCA) in 9 (45%) and left circumflex (LCX) in 4 (20%). In 14 (70%) of the patients had patent infarct-related artery and the mean of left ventricular ejection fraction (LVEF) was 0.49 +/- 0.15. In six non recanalized patients the mean LVEF was 0.40 +/- 0.14. No complications were observed, and in the second angiographic study one patient showed reocclusion of the infarct-related artery., Conclusion: Because of easy application (IV bolus), no complication and high rate of early recanalization, IV APSAC seems to be an efficient thrombolytic agent in the treatment of patients with AMI.

Between 1986 and 1988, 239 consecutive patients with acute myocardial infarction received thrombolytic therapy up to 285 minutes after onset of symptoms; in 39 (17 with anterior infarction, 21 inferior, one lateral infarction) recombinant tissue plasminogen activator or anistreplase was administered a mean of 51 minutes (range 20-60 minutes) after the onset of symptoms. The patency rates (26 of 30; 87 per cent), rapid ST segment resolution (36 of 38; 95 per cent) and QRS score of less than or equal to 3 (28 of 38; 74 per cent) were statistically significantly higher for those seen and treated in the first hour in comparison with those seen and treated later. For those treated within the first hour mean peak creatine kinase was 1264 U/l for those with TIMI grade 2 or 3 (partial or complete perfusion) compared with 3005 U/l for those with TIMI grade 0 or 1 (no perfusion or penetration without perfusion) (p = 0.02): mean peak creatine kinase-MB for those with TIMI grade 2 or 3 perfusion was 115 U/l compared with 312 U/l for those with TIMI grade 0 or 1 (p = 0.01). Four of the 39 patients developed ventricular fibrillation following thrombolytic therapy, three within 24 hours of infarction and one following reinfarction on day 15. There were no significant bleeding complications. One patient died. Thrombolytic therapy within 1 hour of the onset of symptoms led to a very high angiographic patency rate, rapid ST segment resolution with preservation of left ventricular function. This therapy is without significant complications.

Of consecutive patients seen with first myocardial infarction (88 of whom were treated out-of-hospital by mobile coronary care staff), 139 received 30 units of intravenous anistreplase at a mean of 101 minutes (range 35-180) from onset of symptoms. Thrombolysis in myocardial infarction patency grade 2 or 3 was found in 76/91 (83.5%) patients. At 3-4 months after hospital discharge, the mean global left ventricular ejection fraction and mean infarct-related regional third ejection fraction declined with increasing delay to anistreplase. For the first, second and third hour administrations, global ejection fraction was 54%, 50% and 45% (P = 0.002) and for regional third ejection fractions 49%, 43% and 41% (P = 0.02) respectively. Of the patients, 130 were reviewed at approximately 1 year: reinfarction had occurred in 9, 6 had undergone coronary angioplasty and 1 had coronary arterial bypass grafting performed since discharge. Mean global left ventricular ejection fraction was 52% and mean infarct-related regional third ejection fraction was 51%. Thus, intravenous anistreplase induces high rates of arterial patency. Global and regional third ejection fractions decline with increasing delay in the time of administration of anistreplase. Mortality and morbidity is low in the first year.

1. The pharmacokinetics of streptokinase (SK) and anistreplase in conventional dosage regimens of 1.5 x 10(6) i.u. of SK infused over 60 min and 30 units of anistreplase over 5 min were studied in 24 consecutive patients presenting with acute myocardial infarction, using a functional bioassay to assess concentrations. 2. The two agents were found to have similar volumes of distribution (5.68 and 5.90 l), but SK was cleared significantly more rapidly than anistreplase, resulting in a shorter terminal phase half-life (0.61 vs 1.16 h) and a shorter mean residence time (0.76 vs 1.55 h).

IRS II (Invasive reperfusion study II) was a multicentre randomized trial comparing the efficacy of a 2-5-min 30 U anistreplase intravenous injection with a 1,500,000 U 60-min streptokinase (SK) intravenous infusion in acute myocardial infarction. 116 patients were randomized within 6 h of onset of symptoms. Early coronary patency was assessable in 107 patients by coronary angiogram performed 102 min after thrombolytic treatment (range: 30-297 min) in the anistreplase group and 93 min (range: 22-330 min) in the SK group. The early coronary patency rate was significantly higher in the anistreplase group than in the SK group: respectively, 70% (38/54) and 51% (27/53), P less than 0.05). Fifty patients had assessable coronary angiograms at 90 min and 24 h. The 24-h patency rate was 92.3% (24/26) in the anistreplase group vs 87.5% (21/24) in the SK group. No early reocclusion occurred in the anistreplase group vs 15.4% (2/13) in the SK group (NS). Fibrinogen fell to 13.2 +/- 19.8% on anistreplase vs 9.4 +/- 10.3% on SK (NS). Bleeding complications occurred in 12% (7/58) of treated patients in the anistreplase group vs 20.7% (13/58) in the SK group (NS). Two cerebrovascular accidents occurred after thrombolytic treatment with anistreplase (3.4%) vs one after SK (1.7%) (NS). Thus, anistreplase is more effective than intravenous SK and easier to administer.

The underlying cause of acute myocardial infarction can now be effectively treated with thrombolytic agents, thereby increasing myocardial salvage and reducing mortality. Clinicians should always be aware of the risk-to-benefit ratio in treating patients with thrombolytic agents and treat each patient on an individual basis.