Plasminogen activators: a comparison.

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.

Quantification of the benefit of earlier thrombolytic therapy: five-year results of the Grampian Region Early Anistreplase Trial (GREAT).

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.

ST segment tracking for rapid determination of patency of the infarct-related artery in acute myocardial infarction.

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.

The European Myocardial Infarction Project: an assessment of pre-hospital thrombolysis.

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.

Delay times in the administration of thrombolytic therapy: the Brighton experience.

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.

Prehospital thrombolysis in rural emergency room and subsequent transport to a coronary care unit: Ravenna Myocardial Infarction (RaMI) trial.

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.

[Planar myocardial scintigraphy with technetium-99m-sestamibi in acute myocardial infarct treated with thrombolytic therapy]. / La scintigrafia miocardica planare con tecnezio-99m-sestamibi nell'infarto miocardico acuto trattato con terapia trombolitica.

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.

[A change in the prescription of thrombolytic treatment in elderly patients. The experience of the Hospital de León]. / Cambio en la prescipción de tratamiento trombolítico en pacientes ancianos. Experiencia del Hospital de León.

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.

[The safety of the treatment of an acute myocardial infarct by immediate intravenous fibrinolysis in the regional hospital environment]. / Seguridad del tratamiento del infarto agudo de miocardio mediante fibrinólisis intravenosa inmediata en el ámbito hospitalario comarcal.

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.

Pre-dosing antibody levels and efficacy of thrombolytic drugs containing streptokinase.

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.

Electrocardiographic evidence of reperfusion occurring before hospital admission. A Grampian Region Early Anistreplase Trial (GREAT) sub-study.

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.

Lipoprotein(a) levels in patients with myocardial infarction treated with anistreplase: no prediction of efficacy but inverse correlation with plasminogen activation in non-patency.

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.

[The use of myoglobin for the early diagnosis of reperfusion in acute myocardial infarct]. / Impiego della mioglobina per la diagnosi precoce di riperfusione nell'infarto miocardico acuto.

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)

Prehospital thrombolysis: beneficial effects of very early treatment on infarct size and left ventricular function.

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 randomised dose-effect trial of anisoylated plasminogen streptokinase activator complex (APSAC) in acute myocardial infarction. The APSAC Research Group.

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.