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Objective: To investigate whether there is a long-term survival benefit from receipt of thrombolysis in routine care particularly pre-hospital thrombolysis, using 20 year mortality data from the RCGP myocardial infarction (MI) cohort study., Methods: During 1991-92 the RCGP MI study assessed GP delivery of thrombolysis. Participants who received pre-hospital thrombolysis (n = 290), thrombolysis in hospital (n = 781) or no thrombolysis (n = 2021) were followed and mortality data collected to June 2012. The relationship between thrombolysis and survival time was analysed using Cox regression at 28 days, 1, 5, 10, 15 years post-AMI, and at end of follow-up (~20 years post-AMI)., Results: Compared to those who did not receive it, participants who received thrombolysis had a significant survival benefit at 28 days [adjusted hazard ratio (HR) 0.72, 95% confidence interval (CI): 0.58-0.90]; 1 year (adjusted HR 0.69, 95% CI: 0.57-0.83); 5 years (adjusted HR 0.76, 95% CI: 0.66-0.86); 10 years (adjusted HR 0.85, 95% CI: 0.77-0.95) and 15 years (adjusted HR 0.88, 95% CI: 0.80-0.96) post-AMI until end of follow-up (adjusted HR 0.92, 95% CI: 0.84-1.00). Pre versus in-hospital thrombolysis did not appear beneficial, although there was evidence among the pre-hospital group that short symptom onset-to-needle times conferred greater benefit., Conclusions: We found substantial long-term survival benefits associated with thrombolysis when used in routine care. Although primary percutaneous coronary intervention (pPCI) is now the choice treatment, thrombolysis remains an important option when pPCI cannot be delivered within 120 minutes of diagnosis., (© The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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.

Purpose: Over the past 2 decades the use of thrombolytic therapy in the management of peripheral occlusive diseases, most notably peripheral arterial occlusion (PAO) and deep venous thrombosis (DVT), has become an accepted and potentially preferable alternative to surgery. We examined the period when urokinase was in short supply and subsequently unavailable, to explore potential differences in clinical outcome and economic effect between urokinase and recombinant tissue plasminogen activator (rt-PA)., Material and Methods: Data were obtained from the Premier Perspective Database, a broad clinical database that contains information on inpatient medical practices and resource use. The study population included all patients hospitalized in 1999 and 2000 with a primary or secondary diagnosis of PAO or DVT. Incidence was calculated for common adverse events, including bleeding complications, intracranial hemorrhage, amputation, and death. Cost data were also abstracted from the database, and are expressed as mean +/- SD., Results: Demographic variables were similar in the urokinase and rt-PA groups. The rate of bleeding complications was similar in the urokinase and rt-PA groups. There were no intracranial hemorrhages in the urokinase group, compared with a rate of 1.5% in the rt-PA PAO group (P = .087) and 1.9% in the rt-PA DVT group (P = .175). The in-hospital mortality rate was lower in the urokinase-treated PAO subgroup (3.6% vs 8.5%; P = .026), but a similar finding in the DVT subgroup did not achieve statistical significance (4% vs 9.8%; P = .069). While pharmacy costs were greater in the urokinase-treated group (US 5472 dollars +/- US 5579 dollars vs US 3644 dollars +/- US 6009 dollars, P < .001; PAO subgroup, US 11,070 dollars +/- US 15,409 dollars vs US 6150 dollars +/- US 12,398 dollars, P = .003), overall hospital costs did not differ significantly between the 2 groups. This finding appears to be explained by a shorter hospital stay and reduced room and board costs in the urokinase-treated group., Conclusion: There were significant differences in outcome in patients with PAO and DVT who received treatment with urokinase and rt-PA. While pharmacy costs were significantly greater when urokinase was used, reduction in length of stay accounted for similar total hospital costs compared with rt-PA. These findings must be considered in the context of the retrospective nature of the analysis and the potential to use dosing regimens that differ from those in this study.

Background: There is evidence that the earlier a patient reaches hospital and receives thrombolysis, the better the outcome. The GREAT (Grampian Region Early Anistreplase Trial) directly addressed the issue of early thrombolysis by evaluating, in a randomised controlled trial, the efficacy of thrombolysis in the community compared with that administered in hospital., Objective: This paper aimed to model the cost and benefits of community compared with hospital thrombolysis from the UK NHS perspective, using efficacy data from the GREAT., Methods: A decision-analytic approach was used to model these two alternatives. Resource use and cost estimates were estimated for a single tertiary centre. Estimates of effectiveness in life-years were obtained from the 4-year follow-up for patients recruited to the GREAT, using declining exponential approximation of life expectancy. Costs are in pounds sterling, 2000/1 values., Results: Community thrombolysis had an average life expectancy of 12.48 years and hospital thrombolysis had an average life expectancy of 12.39 years. Costs were 361 pounds sterling for community thrombolysis and 300 pounds sterling for hospital thrombolysis. Community thrombolysis led to an additional 0.09 years of life-expectancy gained compared with hospital thrombolysis at an additional cost of 61 pounds sterling per patient. Therefore, the incremental cost per life-year gained for the community thrombolysis service over the hospital thrombolysis service was 667 pounds sterling. Sensitivity analysis showed that estimates of cost per life-year gained were most sensitive to the estimates of survival., Conclusion: This model suggests that, from the UK NHS perspective, implementing community thrombolysis may lead to extra survival but at extra cost over hospital thrombolysis. Although the incremental cost per life-year is modest, judgements still have to be made, however, as to whether the extra benefits estimated are worth the additional resources required. This requires consideration of the local context in which the service may be introduced.

The therapeutic approach to patients with acute ST-segment elevation myocardial infarction (STEMI) has advanced rapidly over the past decade. Intravenous fibrinolytic therapy remains the most common form of reperfusion therapy worldwide, since fibrinolytics are associated with a dramatic reduction in mortality rates. However, primary percutaneous coronary intervention (PCI) is associated with improved outcomes and less bleeding complications compared with fibrinolytic therapy, but it is not widely available. Adjunctive therapies with intracoronary stents, glycoprotein (GP) IIb/IIIa inhibitors, and more potent antithrombin agents have shown great promise for the initial treatment of STEMI and have stimulated further investigation of combined pharmacological/mechanical reperfusion strategies that may be synergistic. Although the optimal combination of fibrinolytics, antiplatelet agents, antithrombins, and mechanical reperfusion at hospitals with and without primary PCI facilities remains elusive, results from recent studies suggest that such a combined approach may facilitate transfer of patients with STEMI from a referral hospital to an invasive hospital for definitive primary PCI after administration of a potent pharmacologic regimen designed to enhance early infarct-related artery reperfusion. Thus, as the reperfusion era continues to evolve, the ideal treatment strategy for patients with STEMI is being redefined to integrate pharmacologic and mechanical approaches to reperfusion.

Objective: The objective of this observational study was to assess time from electrocardiogram diagnosis to treatment and time from pain onset to treatment with double bolus reteplase compared to current therapy with streptokinase or bolus anistreplase in 2 cities (Rotterdam and Nijmegen) in the Netherlands, where prehospital thrombolysis is an established way of treatment of acute myocardial infarction., Methods: Prehospital thrombolysis is performed using electrocardiogram diagnosis by the ambulance service as well as bolus anistreplase for treatment in Nijmegen, and streptokinase infusion in Rotterdam. Reteplase or anistreplase/streptokinase was assigned open label to patients according to order of presentation on a 1-to-1 basis. All patients were treated with nitrates sublingually and aspirin orally. Time intervals were recorded by the ambulance staff., Results: In total, 250 patients were treated between April 1, 1999 and August 1, 2000. Reteplase was used in 120 patients and anistreplase/streptokinase in 130 patients. Using double bolus reteplase resulted in a significantly shorter time to treatment: a median of 81 minutes compared to a median of 104 minutes with the established therapy (P <.0001). There were no differences in mortality, aborted myocardial infarction, hemorrhagic stroke or the need for rescue angioplasty between the groups., Conclusion: In prehospital thrombolysis, double bolus reteplase is associated with a shorter time to treatment than bolus anistreplase or infusion of streptokinase.

Background: Many elderly patients with an acute myocardial infarction (AMI) do not receive thrombolysis within 30 minutes of hospital arrival as recommended by the American College of Cardiology/American Heart Association Guidelines. We sought to identify factors associated with delay in administration of thrombolysis after arrival to the hospital in these patients and to determine whether this delay is associated with increased mortality rates., Methods and Results: By using the Cooperative Cardiovascular Project database, we identified patients who received thrombolysis for an AMI. The patients were stratified into groups by time to thrombolysis after hospital arrival. Among a cohort of 17,379 patients, 22.2% received thrombolysis in the first 30 minutes after hospital arrival. Patients treated after the first 30 minutes were more likely to be older, be female, be diabetic, have a history of hypertension or heart failure, and have less marked ST elevation. They were also more likely to be admitted to smaller hospitals with a lower volume of AMIs and to hospitals without a cardiac catheterization laboratory. The 30-day mortality rate was significantly lower for patients treated within the first 30 minutes. After adjustments were made for clinical and hospital characteristics, delays in therapy beyond 30 and 90 minutes were associated with an increase in 1-year mortality rates of 9% and 27%, respectively, compared with delays for patients treated within 30 minutes., Conclusions: After hospital arrival, time to treatment with thrombolytic therapy is longer than recommended in a significant proportion of patients. Clinical characteristics and institutional factors are associated with the delay in treatment. The more rapid treatment of appropriate elderly patients with an AMI probably will reduce mortality rates.

The treatment of acute myocardial infarction (MI) constitutes a significant problem in remote geographical areas of Greece. Furthermore, thrombolysis, the treatment of choice in the early phase of acute MI, requires the supervision of an expert. We have used thrombolytic treatment, using telemedicine, in remote medical centres. The Onassis Cardiac Surgery Centre was linked to six remote Aegean islands via telemedicine systems which permitted the transmission of 12-lead electrocardiograms (ECGs). The thrombolytic agent anistreplase was administered to patients with acute MI. Supervision, including consultation for treatment of complications, was achieved using the telemedicine system. One hundred and fifty-two ECGs were transmitted during 24 months, of which 108 (71%) indicated specific treatment of a cardiac condition. Ten cases were diagnosed as having acute MI and eight of these were treated with anistreplase. All patients survived acute MI and complications were treated locally. The application of thrombolytic treatment in acute MI is feasible in remote areas, with the use of a telemedicine system.

This study sought to assess the rate of acute Thrombolysis In Myocardial Infarction (TIMI) trial grade 3 patency that can be achieved with the combination of prehospital thrombolysis and standby rescue angioplasty in acute myocardial infarction. No large angiographic study has been performed after prehospital thrombolysis to determine the 90-minute TIMI 3 patency rate in the infarct-related artery. Hospital outcome and artery patency were compared to 170 matched patients treated with primary angioplasty. Prehospital thrombolysis was applied 151+/-61 minutes after the onset of pain in 170 patients (56+/-12 years, 86% men), using recombinant tissue-type plasminogen activator, streptokinase, or eminase. Emergency 90-minute angiography was performed in every case. All patients in whom thrombolysis failed underwent rescue angioplasty. After thrombolysis alone, TIMI grade 3 flow in the infarct-related artery was observed in 108 patients (64%), TIMI grade 2 in 12 (7%), and TIMI grade 0 or 1 in 50 (29%). Rescue angioplasty was successful in 47 of 50 attempts. Overall, TIMI 3 patency was achieved in 91%, and additionally TIMI 2 flow in 7% of patients, an average of 113+/-39 minutes after thrombolysis and 55+19 minutes after admission. Therefore, < 2 hours after thrombolysis, only 2% of patients had persistent occlusion (TIMI 0 or 1) of the infarct-related artery. In-hospital mortality was 4% overall (7 of 170), and 3% in the 155 patients in whom TIMI 3 was obtained during the acute phase. Severe hemorrhagic complications occurred in 14 patients (8%) with 2 fatal cerebral hemorrhages (7% of patients required transfusions). The matched comparison with primary PTCA showed no significant difference in hospital outcome. Combined prehospital thrombolysis, 90-minute angiography, and rescue angioplasty yield a high rate of acute TIMI 3 patency rate early after thrombolysis and hospital admission. A randomized, prospective comparison between these 2 reperfusion strategies may be now warranted.

Background: In an in vitro model, recombinant tissue-type plasminogen activator was significantly more effective than streptokinase in dissolving 24-hour-old human blood clots. Therefore there might be a difference in the effect of time to treatment on the efficacy of these fibrinolytics with different fibrin specificity in patients with acute myocardial infarction., Methods and Results: The effect of the interval between symptom onset and initiation of therapy on the efficacy of 6 different thrombolytic regimens was studied in a retrospective analysis of 6 angiographic trials with similar design. The patency of the infarct-related artery was assessed by angiography 90 minutes after initiation of thrombolysis in patients who were seen within 6 hours after symptom onset. Patency rates of patients with an interval of 3 hours between symptom onset and start of therapy were compared. There was no difference for Thrombolysis in Myocardial Infarction (TIMI) grade 3 perfusion after front-loaded alteplase (72.5% vs 76. 3%) and reteplase (63.6% vs 63.2% ) between the 2 groups. In contrast, in patients treated with streptokinase (36.8% vs 27.6%, P =.09), anisoylated plasminogen streptokinase activator complex (59. 5% vs 34.8%, P =.004), and urokinase (62.3% vs 41.7%, P =.03), TIMI 3 patency decreased with the increasing interval between symptom onset and initiation of therapy., Conclusions: We conclude from our data that the thrombolytic efficacy of recombinant tissue-type plasminogen activator and reteplase does not decrease with the increasing interval between symptom onset and initiation of therapy. In contrast, after anisoylated plasminogen streptokinase activator complex, streptokinase, and urokinase treatment, a decrease in patency, especially TIMI-3 patency in patients treated after >3 hours after symptom onset, was observed. These results may influence the choice of the thrombolytic agent in patients who are seen >3 hours after symptom onset.

Thrombolytic therapy in patients with acute coronary syndrome is not so widely used compared to coronary intervention, such as PTCA or stenting in Japan. This is probably because of the facts that the narrowing of the coronary artery is not completely restored after the thrombolytic therapy and that the coronary intervention is frequently necessary inspite of the administration of the thrombolytic agent. However, the thrombolytic therapy can be easily done in the peracute stage of myocardial infarction, and improvement of the prognosis of the affected patient may be possible. In this paper, the concepts as well as the effect of thrombolytic therapy and the characteristics of newly developed thrombolytic drugs are discussed.

Background: In the Grampian region early anistreplase trial (GREAT), domiciliary thrombolysis by general practitioners was associated with a halving of one year mortality compared with hospital administration. However, after completion of the trial and publication of the results, the use of this treatment by general practitioners declined sharply., Objective: To increase the proportion of eligible patients receiving timely thrombolytic treatment from their general practitioners., Setting: Practices in Grampian located > or = 30 minutes' travelling time from Aberdeen Royal Infirmary, where patients with suspected acute myocardial infarction were referred after being seen by general practitioners. AUDIT STANDARD: A call-to-needle time of 90 minutes, as proposed by the British Heart Foundation (BHF)., Methods: Findings of this audit of pre-hospital management of acute myocardial infarction were periodically fed back to the participating doctors, when practice case reviews were also conducted., Results: Of 414 administrations of thrombolytic treatment, 146 (35%) were given by general practitioners and 268 (65%) were deferred until after hospital admission. Median call-to-needle times were 45 (94% < or = 90) and 145 (7% < or = 90) minutes, respectively. Survival at one year was improved with prehospital compared with hospital thrombolysis (83% v 73%; p < 0.05). The proportion of patients receiving thrombolytic treatment from their general practitioners did not increase during the audit., Conclusions: In practices > or = 30 minutes from hospital, the BHF audit standard was readily achieved if general practitioners gave thrombolytic treatment, but not otherwise. Knowledge of the benefits of early thrombolysis, and feedback of audit results, did not lead to increased prehospital thrombolytic use. Additional incentives are required if general practitioners are to give thrombolytic treatment.

Background: QT dispersion (QTd; QT interval maximum minus minimum) has been shown to reflect regional variations in ventricular repolarization and is increased in patients with life-threatening ventricular arrhythmias., Methods: To determine correlates of QTd in patients who had had myocardial infarction (MI), 207 patients (158 men, aged 57 +/- 11 years) with acute MI who were treated with alteplase or anistreplase within 2.7 +/- 0.9 hours of symptom onset were studied. Angiograms at a median of 27 hours after thrombolysis showed reperfusion (Thrombolysis in Myocardial Infarction grade > or =2) in 184 (88%) patients. QT was measured in 10 +/- 2 leads on discharge electrocardiograms with a computerized analysis program interfaced with a digitizer. Associations of QTd with 24 variables related to patient characteristics, acute MI, angiography, interventions, and radionuclide ventriculography were evaluated by univariate and multivariate regression., Results: Univariate associations with QTd (p < or = 0.10) were Thrombolysis in Myocardial Infarction flow grade 0/1 versus 2/3 (QTd = 75 +/- 33 msec vs 53 +/- 22 msec, p < 0.0001), minimal luminal diameter (p = 0.007), left ventricular ejection fraction at discharge (p = 0.007), reinfarction (p = 0.01), number of leads with ST elevation (p = 0.05), end-systolic volume at discharge (p = 0.04), time to peak creatine kinase (p = 0.06), and YST elevation (p = 0.10). Independent associates of QTd were Thrombolysis in Myocardial Infarction grade 0/1 versus 2/3 (p < 0.0001), reinfarction (p = 0.005), and ejection fraction (p = 0.02)., Conclusions: Successful thrombolysis is associated with less QTd in patients after acute MI. Our results support the hypothesis that QTd after MI depends on reperfusion status, reinfarction, and left ventricular function. Reduction in QTd may be an additional mechanism by which the benefit of thrombolytic therapy is realized.

Objective: Our aim was to determine the relationship among the time saved by administration of thrombolytic therapy in prehospital versus hospital setting and long term mortality; number, duration of hospitalizations and their causes., Background: There is much theoretic, experimental and trial evidence to indicate that in acute myocardial infarction the earlier the thrombolytic therapy is given, the greater its efficacy. However, the clinical importance of this gain time in long term is still uncertain., Subjects: 280 patients with suspected acute myocardial infarction in perspective, controlled study with two parallel groups of consecutive patients without contraindication for thrombolysis, who were seen by general emergency physicians before hospitalization (Gr.1) or later in hospital by the attending cardiologist (Gr.2). The main outcomes measured was mortality rate at 5 years, causes, number and duration of new hospitalizations., Results: The median pain to needle time was 90' (25 degrees percentile:67'; 75 degrees percentile:165') in Gr.1 vs 165' in Gr.2 (25 degrees percentile:110'; 75 degrees percentile:225'). The median time difference was 75' (P<0.001). The 35th day total mortality rate was 7.5% and 10.6% (p:n.s.) in Gr.1 vs Gr.2 respectively, 8.6% (Gr.1) vs 19.7% (Gr.2) (P<0.015) at 1 year, and 19.2% (Gr.1) vs 47.2% (Gr.2) (P<0.015) at 5 years. The percentage of patients with a number of new hospitalizations greater than 1 during 5 years was not significantly different in Gr.1 vs Gr.2 (44.1% vs 48.35, p:n.s.). The total duration of hospitalization was 479 days in Gr.1 vs 1431 days in Gr.2 (P<0.001). The 75 Gr.1 patients alive at the end of 5 years follow up had a mean hospital stay of 3.86+/-5.92 days vs 8.05+/-16.60 days (P<0.036) of the 94 Gr.2 patients alive after 5 years. The total and mean stay for recurrence of acute MI was significantly different in Gr.1 vs Gr.2 (90 vs 425 days: P<0.001; and 13+/-6.2 days vs 25+/-5.4: P<0.003 respectively). Cardiac failure led to the 1.16% in Gr.1 vs 9.43% of new admission (P<0.028) for a total of 57 vs 243 days in Gr.1 and Gr.2 respectively (P<0.001). Cumulative mortality rate for any cause at 5 years was 19.2% and 47.2% in prehospital and in hospital treated patients (P<0.015), obtaining diverging survival curves., Conclusions: The magnitude of the benefit from earlier thrombolysis is such that giving thrombolytic treatment earlier is the main problem to reduce the time from onset of symptoms to reperfusion, to salvage myocardial muscle and obtain diverging survival curves.

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.

This randomized, double-blind trial in 311 patients with acute myocardial infarction has shown that very early therapy with anistreplase outside the hospital is not only feasible, but provides a major survival advantage. The difference in the median delay to treatment between the group treated in the hospital and those treated earlier was 2 1/4 h. After 30 months, mortality in the early group was less than half that in the later group, so that every hour of delay beyond 2 h resulted in almost 7 additional deaths per 100 patients treated. This is a greater percentage loss of life than would have resulted from a similar delay in the provision of resuscitation for the prehospital cardiac arrest. Multivariate analysis showed that age, treatment delay, and time of presentation were significant risk factors, with patients presenting at 1 h having more than twice the mortality of those presenting at 4 h; the sicker the patient, the earlier the presentation. By 5 years, prehospital administration of anistreplase, by saving 2 h, resulted in an additional 57% of a year's survival per patient. This compares favorably with the projected 14% of a year survival per patient reported with TPA versus streptokinase in GUSTO. Prehospital therapy with anistreplase was highly cost effective when compared with streptokinase given in hospital, and the marginal cost-effectiveness ratio was much lower than that for TPA versus streptokinase derived from GUSTO.

Rescue percutaneous transluminal coronary angioplasty (PTCA) has been used to establish reperfusion after failed thrombolysis, and the goal of this study was to examine the angiographic and clinical outcomes after rescue PTCA performed for an occluded artery 90 minutes after thrombolysis. Four hundred two patients with acute myocardial infarction were randomized to receive either anistreplase (APSAC), recombinant tissue plasminogen activator, or their combination in the Thrombolysis in Myocardial Infarction (TIMI) 4 trial. The angiographic and clinical outcomes of patients with a patent artery 90 minutes after thrombolysis were compared with those of patients with an occluded artery treated in a nonrandomized fashion with either rescue or no rescue PTCA. At 90 minutes, the number of frames required to opacify standard landmarks (corrected TIMI frame count) was significantly lower (i.e., flow was faster) after successful rescue PTCA (27 +/- 11) than that in patent arteries after successful thrombolysis (39 +/- 20, p < 0.001), and the incidence of TIMI grade 3 flow was correspondingly higher after successful rescue PTCA (87% vs 65%, p = 0.002). In-hospital adverse outcomes (death, recurrent acute myocardial infarction, severe congestive heart failure, cardiogenic shock or an ejection fraction <40%) occurred in 29% of successful rescue PTCAs and in 83% of failed rescue PTCAs (p = 0.01). Among all patients in whom rescue PTCA was performed (successes and failures combined), 35% of patients experienced an adverse outcome, which was the same as the 35% incidence observed in patients not undergoing rescue PTCA (p = NS) and tended to be higher than the 23% incidence observed in patients with patent arteries (p = 0.07). Although successful rescue PTCA for an occluded artery at 90 minutes results in restoration of flow that is superior to that of successful thrombolysis, the incidence of adverse events for the strategy of rescue PTCA as a whole was the same as that of undertaking no PTCA.

Early and sustained flow of grade 3 according to Thrombolysis in Myocardial infarction (TIMI) criteria and reocclusion rates are the key measures that define the physiologic efficacy of thrombolytic agents in the treatment of acute myocardial infarction. We performed a systematic overview of angiographic studies after intravenous thrombolysis with accelerated and standard-dose tissue-plasminogen activator (TPA), anisoylated plasminogen streptokinase activator complex (APSAC), and streptokinase. There were 5475 angiographic observations from 15 studies for TIMI flow analysis and 3147 angiographic observations from 27 studies for reocclusion. At 60 and 90 minutes, the rates of TIMI grade 3 flow were 57.1% and 63.2%, respectively, with accelerated TPA, 39.5% and 50.2% with standard-dose TPA, 40.2% and 50.1% with APSAC, and 31.5% at 90 minutes with streptokinase. Overall reocclusion with standard-dose TPA was 11.8% versus 6.0% for accelerated TPA, 4.2% for streptokinase, and 3.0% for APSAC. Although the incidence of TIMI grade 3 flow increased over time with all thrombolytic regimens, decreased patency was observed at 180 minutes with accelerated TPA. Still, accelerated TPA is the most effective agent to establish early (90-minute) TIMI grade 3 flow.

Objectives: To assess the cost effectiveness of community thrombolysis relative to hospital thrombolysis by investigating the extra costs and benefits of a policy of community thrombolysis, then establishing the extra cost per life saved by community thrombolysis., Design: Economic evaluation based on the results of the Grampian region early anistreplase trial., Setting: 29 rural general practices and one secondary care provider in Grampian, Scotland., Subjects: 311 patients recruited to the Grampian region early anistreplase trial., Interventions: Intravenous anistreplase given either by general practitioners or secondary care clinicians., Main Outcome Measures: Survival at 4 years and costs of administration of thrombolysis., Results: Relative to hospital thrombolysis, community thrombolysis gives an additional probability of survival at 4 years of 11% (95% confidence interval 1% to 22%) at an additional cost of 425 pounds per patient. This gives a marginal cost of life saved at 4 years of 3,890 pounds (1,990 pounds to 42,820 pounds)., Conclusions: The cost per life saved by community thrombolysis is modest compared with, for example, the cost of changing the thrombolytic drug used in hospital from streptokinase to alteplase.

Appropriate use of a thrombolytic agent may save 20 to 30 lives per 1000 treatments. Thrombolysis should be considered in all patients presenting with cardiac chest pain lasting more than 30 minutes for up to 12 hours after symptom onset. ECG criteria include ST elevation of at least 1 mm in limb leads and/or at least 2 mm in two or more adjacent chest leads or left bundle branch block. There is no upper age limit. All patients should also receive oral aspirin and subcutaneous (intravenous with rt-PA) heparin. Other adjuvant treatments have been reviewed previously in this journal. Streptokinase is the drug of choice except where there is persistent hypotension, previous streptokinase or APSAC at any time, known allergy to streptokinase, or a recent proven streptococcal infection. In these circumstances the patient should receive rt-PA. Additional indications for rt-PA, based on subset analysis by the GUSTO investigators, include patients with ALL of the following: age less than 75 years, presentation within four hours of symptom onset, and ECG evidence of anterior acute myocardial infarction. Treatment should be initiated as soon as possible. The greatest benefit is observed in patients treated early, pain to treat intervals of less than one hour make possible mortality reductions of nearly 50%. "When" matters more than "where": fast tracking to the CCU is one option but A&E initiated thrombolysis is feasible and timely. Prehospital thrombolysis is appropriate in certain geographical situations. The development of practical guidelines for thrombolysis represents the most comprehensive example of evidence based medicine. Streptokinase was first shown to influence outcome in acute myocardial infarction nearly 40 years ago. More recently alternative regimes have been evaluated in several prospective randomised controlled trials yielding pooled data on nearly 60,000 patients. However, systematic review of cumulative data reveals a statistically significant mortality gain for intravenous streptokinase over placebo which could have been identified as early as 1971-at least 15 years before it became generally used in clinical practice.

Since 1995, Onassis Cardiac Surgery Center participates in the development of Telecardiology Services in Greece. Existing connections include the islands Skiathos, Naxos, Santorini, Mykonos, Milos, Plomari and Amorgos. First hundred fifty three (153) cases have been already analysed. Eleven of them were acute myocardial infarctions and have been treated by thrombolytic medication (anistreplase). The participation of physicians and nurses was valuable for the success of the program and their further involvement in the new area of Telemedicine. The purpose of the project was to offer high quality cardiac services in remote area patients and to provide specific training in telemedicine issues to health care professionals.

Objective: To compare aspirin with anticoagulation with regard to risk of cardiac death and reinfarction in patients who received anistreplase thrombolysis for myocardial infarction., Design: A multicentre unblinded randomised clinical trial., Setting: 38 hospitals in six countries., Subjects: 1036 patients who had been treated with anistreplase for myocardial infarction were randomly assigned to either aspirin (150 mg daily) or anticoagulation (intravenous heparin followed by warfarin or other oral anticoagulant). The trial was stopped earlier than originally intended because of the slowing rate of recruitment., Main Outcome Measure: Cardiac death or recurrent myocardial infarction at 30 days., Results: After 30 days cardiac death or reinfarction, occurred in 11.0% (57/517) of the patients treated with anticoagulation and 11.2% (58/519) of the patients treated with aspirin (odds ratio 1.02, 95% confidence interval 0.69 to 1.50, P = 0.92). Corresponding findings at three months were 13.2% (68/517) and 12.1% (63/519) (0.91, 0.63 to 1.32, P = 0.67). Patients receiving anticoagulation were more likely than patients receiving aspirin to have had severe bleeding or a stroke by three months (3.9% v 1.7% (0.44, 0.20 to 0.97, P = 0.04))., Conclusion: No evidence of a difference in the incidence of cardiac events was found between the two treatment groups, though the trial is too small to claim treatment equivalence confidently. A higher incidence of severe bleeding events and strokes was detected in the group receiving anticoagulation, suggesting that aspirin may be the drug of choice for most patients in this context.

Objective: To evaluate the experience with thrombolytic therapy (TT) in the treatment of patients with the discharge diagnosis of acute myocardial infarction (AMI)., Design: Retrospective analysis of the clinical records of patients with the discharge diagnosis of AMI, between May 1988 and December 1995., Setting: Intensive Cardiac Care Unit (UCIM-Medicina IV) of Santa Maria University Hospital, Lisbon, Portugal., Patients: 1319 patients, 958 men (73%) and 361 women, mean age 64 +/- 12 years., Main Results: Thrombolytic therapy was administered in 391 patients (30%). Female patients received less thrombolytic therapy compared with male (17% vs. 34%; p < 0.001). Anterior wall infarction was more frequent (38%). Patients in Killip class I-II (77%) received more thrombolytic therapy than class III-IV (33% vs. 17%). The utilization rate of thrombolytic therapy increased from 25% in 1988 to 34% in 1995. Two major categories of patients were not treated with thrombolysis: 1) patients presented more than 12 hours after pain onset (38%); 2) patients without ST segment elevation or LBBB on the ECG presented (37%). Overall hospital mortality was 15.6%. The mortality in patients receiving thrombolytic therapy was significantly lower than in those excluded (9.4% vs. 18.2%; p < 0.001)., Conclusion: Only 30% of patients with AMI receive TT. Of those excluded from this important therapeutic intervention, 75% had no ECG criteria or were outside the standard therapeutic "window". This significant group of patients need new diagnostic and intervention strategies.

Antithrombotic and thrombolytic therapies confer clear net benefits in the treatment of acute myocardial infarction. Antithrombotic therapy with aspirin yields conclusive reductions in vascular mortality as well as reinfarction and stroke, and should be administered to all patients with suspected acute myocardial infarction. There is presently no clear evidence of net benefits from adding either delayed subcutaneous or immediate intravenous heparin to an antithrombotic regimen of aspirin. Direct thrombin inhibitors have theoretical advantages over heparin as antithrombotic agents, but further data are needed from large-scale randomized trials to determine whether these agents confer net benefits when given in conjunction with aspirin. Thrombolytic therapy yields clear reductions in mortality and should be considered for all patients with suspected acute myocardial infarction presenting within 12 h of symptom onset. The differences in the efficacy, safety or ease of administration of the various thrombolytic agents are small compared with the substantial benefits that would result from the wider use and earlier administration of any of the available agents. More widespread use of antithrombotic and thrombolytic therapies for acute myocardial infarction could prevent tens of thousands of premature deaths annually in the USA alone, and hundreds of thousands worldwide.

The number of thrombolytic drugs for the management of acute myocardial infarction is rapidly expanding. New agents, some of which are biochemically modified versions of currently available thrombolytics, will soon arrive in the marketplace. The pharmacologic differences of the new drugs are the basis for clinical differences such as enhanced clot lysis and prolonged elimination half-life. Ultimately, these features may result in improved infarct artery patency and patient survival.

Thrombolytic therapy is a practical, effective approach to the management of acute myocardial infarction that is widely used in Europe today. Early European trials demonstrated a clear reduction in mortality in patients who received thrombolytic therapy compared with those given conventional treatment. The findings of experimental studies suggest that early reperfusion of the infarct-related artery reduces myocardial damage, which results in the preservation of left ventricular function and, in turn, may improve survival. Although tissue plasminogen activator (t-PA) has been shown to produce more rapid and complete reperfusion than streptokinase, two large-scale clinical trials in which t-PA was given as a standard 3- or 4-h infusion provided no evidence of a survival advantage with this agent. However, the accelerated t-PA regimen used in the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) study was associated with a lower mortality than streptokinase or a combination of t-PA and streptokinase, thus lending support to the 'open artery' theory. Two recent studies conducted in Europe, the Grampian Region Early Anistreplase Trial (GREAT) and the European Myocardial Infarction Project (EMIP), have demonstrated the feasibility, safety, and efficacy of early thrombolytic therapy before admission to hospital. In GREAT, anistreplase (APSAC) was administered at home by general practitioners. In EMIP, this same agent was given by emergency medical personnel. In both studies, pre-hospital administration reduced the time between the onset of symptoms and initiation of thrombolysis and was associated with a lower mortality rate. Recent data from the European Cooperative Group Study show that the benefits of thrombolytic therapy are maintained for up to 5 years. Research continues in an effort to develop safer and more effective thrombolytic agents. Educational efforts to familiarize the public with the symptoms of myocardial infarction and the development of more rapid, efficient emergency response systems may also improve the outcome of thrombolytic therapy by shortening the time between symptom onset and thrombolytic drug administration.

Heart rate variability (HRV) was evaluated during the first 24 hours of hospitalization in 36 patients with acute myocardial infarction. Reperfusion was achieved by 60 minutes in 21 patients (group M1) and by 130 minutes in the remaining 15 (group M2). Mean 24-hour HRV measures were not significantly different between groups M1 and M2. Hourly spectral analysis revealed a decrease in total power (0.01 to 1.0 Hz) from 0 to 8 hours to 9 to 16 and 17 to 24 hours in groups M1 (7.04 +/- 0.27 to 6.94 +/- 0.28 and 6.52 +/- 0.18; p = 0.0006) and in group M2 (6.88 +/- 0.30 to 6.57 +/- 0.23 and 6.40 +/- 0.15; p = 0.002). Total power decreased immediately after reperfusion: in group M1 it decreased during the second hour (7.32 +/- 0.96 to 6.42 +/- 1.2; p = 0.001) and in group M2 during the third (7.47 +/- 1.2 to 6.73 +/- 1.4; p = 0.049) and fourth hours (7.47 +/- 1.2 to 6.48 +/- 1.4; p = 0.029). Mean change in total power in the second hour was -11.6% in group M1 and +3.9% in group M2 (p = 0.0001) and in the third hour, +14.5% in group M1 and -8.6% in group M2 (p = 0.006). During the remaining 21 hours, there was no significant difference in hourly change in total power between groups. Similar changes were noted in high-frequency power, but the ratio of low-frequency to high-frequency power was unchanged. In acute myocardial infarction, HRV is higher during the early phase and decreases as hours progress. Reperfusion causes an immediate, transient, and seemingly paradoxic decrease in HRV, probably because of an abrupt decrease in parasympathetic tone.

The focus of new research efforts to improve the morbidity and mortality associated with acute myocardial infarction (AMI) has turned to adjuvant agents that show promise of improving outcomes following coronary thrombolysis. We enrolled 162 patients with AMI in a randomized trial comparing front-loaded tissue-plasminogen activator (t-PA) plus weight-adjusted heparin with anisoylated plasminogen streptokinase activator complex (APSAC) without heparin as well as standard-dose (325 mg) and low-dose (81 mg) aspirin. The primary end point was an in-hospital morbidity profile; secondary end points were clinical and angiographic potency and hemorrhagic events. Selected sites performed an electrocardiographic substudy to determine the time to 50% ST-segment recovery and the time to steady state. Although the trial was terminated when the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries-I trial showed that t-PA had a significant mortality advantage over streptokinase, important trends were evident. Patients given t-PA and heparin were better anticoagulated (p = 0.001), yet AP-SAC-treated patients had more bleeding complications. The primary end point favored t-PA (25.4% vs 31.3%), and the secondary end points were similar in both groups. In the electrocardiographic substudy, the t-PA group achieved both 50% ST-segment recovery and steady-state recovery sooner than the APSAC group. Patients taking low-dose aspirin had lower in-hospital mortality and less recurrent ischemia but more strokes than the standard-dose aspirin group. Thus, this trial demonstrated trends favoring front-loaded t-PA with weight-adjusted heparin over APSAC without heparin in the treatment of AMI. The use of low-dose aspirin did not appear to impose a loss of protection from adverse events, nor did standard-dose aspirin increase serious bleeding.

Reperfusion-induced ventricular fibrillation has been demonstrated in animal models of myocardial ischaemia, but no evidence exists for this in humans. The European Myocardial Infarction Project compared the efficacy and safety of pre-hospital thrombolytic therapy with that of hospital therapy. The objective of this study was to investigate the occurrence of reperfusion-induced ventricular fibrillation in acute myocardial infarction patients following thrombolytic therapy. In a double-blind multicentre trial, eligible patients were randomized to receive anistreplase at home followed by placebo in the hospital (A/P group), or placebo followed by anistreplase (P/A group). The occurrence of ventricular fibrillation, and other adverse events were recorded on specific study forms and could be attributed to defined time intervals. The incidence of ventricular fibrillation in the A/P group was significantly higher following the pre-hospital injection than in the P/A group (2.5% vs 1.6%; P = 0.021); the situation was reversed following the hospital injection (3.6% vs 5.3%; P = 0.002). No relationship was found between this excess of ventricular fibrillation and the patients' condition, with the exception of the site of the infarct. These results suggest the existence of reperfusion-induced ventricular fibrillation in patients developing myocardial infarction who receive thrombolytic treatment.

Objective: To generalise from the results of the Grampian region early anistreplase trial (GREAT) and to express the benefit of earlier thrombolysis in terms of lives saved per hour of earlier treatment., Design: Multivariate analysis of a randomised double blind trial., Setting: 29 rural practices in Grampian region and teaching hospitals in Aberdeen., Subjects: 311 patients with suspected acute myocardial infarction and without contraindications to thrombolysis who were seen by their general practitioners within four hours of the start of symptoms., Interventions: Anisterplase 30 units given intravenously, either by general practitioners before hospitalisation or later in hospital., Main Outcome Measure: Death within 30 months of entry into trial., Results: Death within 30 months was positively related to age (P < 0.0001) and to delay between start of symptoms and thrombolytic treatment (P = 0.0004). However, the probability of dying rose exponentially with earlier presentation, so death within 30 months was negatively related to the logarithm of the time of randomisation (P = 0.0163). In patients presenting two hours after start of symptoms each hour's delay in receiving thrombolysis led to the loss of 21 lives per 1000 within 30 days (95% confidence interval 1 to 94 lives per 1000) (P = 0.03) and 69 lives per 1000 within 30 months (16 to 141 lives per 1000) (P = 0.0004)., Conclusions: The magnitude of the benefit from earlier thrombolysis is such that giving thrombolytic treatment to patients with acute myocardial infarction should be accorded the same degree of urgency as the treatment of cardiac arrest.

The present report describes a 55-year-old man who presented an anterior myocardial infarction in association with myocardial bridge of the left anterior descending artery (LAD). We discuss the pathophysiology of myocardial infarction occurring with myocardial bridge.

Unlabelled: The aim of this study was to identify post-thrombolysis stunned myocardium using low dose (10 micrograms/kg/min) dobutamine echocardiography, and to elucidate the role of the residual stenosis in the infarction artery in wall motion recovery. Forty-seven consecutive patients treated with thrombolytic agents for a first non-complicated myocardial infarction were included. An early dobutamine echocardiogram was performed 7 +/- 2 days after thrombolysis to calculate a wall motion score index at baseline and with dobutamine. A late resting echocardiogram 36 +/- 7 days and a coronariography 41 +/- 8 days after thrombolysis were also performed. In 12 patients no baseline regional dysfunction was observed in the early echocardiogram (Group I), whereas 35 patients (Group II) presented regional dysfunction which improved with dobutamine in 11 cases (Group IIA), but not in 24 (Group IIB). Maximum creatine kinase peak was smaller in Group I (458 +/- 162, P < or = 0.01) and in Group IIA (931 +/- 593, P < or = 0.05) than in Group IIB (1547 +/- 886). Late resting echocardiogram was performed in 44 patients: all 12 from Group I, 10 from Group IIA and 22 from Group IIB; all patients from Group I persisted with normal wall motion, while the baseline score index improved in seven patients (70%) from Group IIA vs. three patients (14%) from Group IIB (P < or = 0.01). Quantitative angiographic parameters in the infarction artery failed to differentiate the subgroup of patients in whom wall motion improved in the late echocardiogram. By simple regression, smaller creatine kinase peak (P < or = 0.05) and a positive response to dobutamine in the early echocardiogram (P < or = 0.001) correlated with wall motion recovery, but the minimum lumen diameter in the infarction artery did not correlate; by multiple logistic regression, only a positive response to dobutamine in the early echocardiogram independently predicted late wall motion improvement (P < or = 0.001)., Conclusions: (1) Low dose dobutamine echocardiography early after thrombolytic treatment identifies dysfunctional myocardium with potential late spontaneous improvement (stunned myocardium). (2) Myocardial stunning tends to occur in small infarctions. (3) Late wall motion improvement can occur despite severe residual stenosis in the infarction artery.

Within 1 year, 434 patients were admitted to 14 hospitals with suspected acute myocardial infarction (AMI) < or = 4 hours after the onset of symptoms. Group A consisted of 171 patients (39%) treated with thrombolysis, and group B consisted of 263 patients (61%) with contraindications. Patients in group A more likely had a "definite AMI" (92%; group A1) than patients in group B (67%; group B1). Group B1 had 277 contraindications (1.6/per patient) with increased risk for life-threatening bleeding being the most frequently recorded at admission. The in-hospital mortality in group A1 was 7% (11 of 158) and in group B1, 27% (47 of 177) (p < 0.0001). Age and type of therapy (thrombolysis or no thrombolysis) were identified as independent predictors of increased mortality (p < 0.0001 and < 0.05, respectively). Thus, although most patients with an AMI are excluded from thrombolytic therapy because of contraindications, our data suggest that their in-hospital mortality is unexpectedly high. Further evaluation of this group of patients is warranted to define the impact of contraindications as an independent factor of mortality.

The outcome of patients with Thrombolysis in Myocardial Infarction (TIMI) trial grade 2 flow is worse than that of patients with TIMI grade 3 flow after thrombolytic therapy for acute myocardial infarction. It is unclear whether TIMI grade 2 flow represents incomplete recanalization of the culprit lesion or poor distal runoff. The Thrombolytic Trial of Eminase (anistreplase) in Acute Myocardial Infarction (TEAM)-2 and TEAM-3 were randomized trials comparing anistreplase with streptokinase (TEAM-2, n = 370) or with alteplase (tissue plasminogen activator) (TEAM-3, n = 325). We compared the minimal luminal diameter of the culprit lesion in patients with TIMI grade 2 flow with that in patients with TIMI grade 3 flow both 90 minutes (TEAM-2) and 1 day (TEAM-3) after thrombolysis. Patients with TIMI grade 2 flow had a lower residual luminal diameter in the culprit lesion than patients with TIMI grade 3 flow (TEAM-2, 0.58 +/- 0.03 vs 0.79 +/- 0.02 mm, p = 0.0001; TEAM-3, 0.88 +/- 0.04 vs 1.17 +/- 0.03 mm, p = 0.0001, for patients with TIMI grades 2 and 3 flow). Residual percent stenosis was correspondingly higher in patients with TIMI grade 2 flow. At the early angiogram, 66% of patients with TIMI grade 2 flow, but only 35% of those with TIMI grade 3 flow, had a minimal luminal diameter of 0.6 mm (positive predictive value 87%, negative predictive value 35%). Incomplete recanalization of the culprit lesion may thus be an important determinant of TIMI grade 2 flow after thrombolysis. Whether more complete thrombolysis or rescue angioplasty improves outcome in these patients deserves evaluation.

Background: A double-blind, placebo-controlled study using anistreplase was performed in 159 patients with unstable angina. All patients had a history of unstable angina combined with typical ECG changes and without evidence of a previous, recent, or ongoing myocardial infarction. The purpose of the present study was to analyze the relationship between the patency of the culprit artery and the behavior of the ischemia-related regional left ventricular (LV) wall motion., Methods and Results: On entry to the study, all patients received conventional drug therapy: i.v. nitroglycerin therapy, an oral beta-blocking agent, and a calcium antagonist. Baseline angiography was carried out within 3 h after randomization, a mean of 4.2 +/- 3.0 h (range, 1 to 17 h) after the last attack of chest pain. Treatment with trial medication was withheld in 33 cases. Sixty-five patients with coronary artery disease received anistreplase (30 U/5 min)/heparin and 61 patients heparin-only therapy. Angiography was repeated 20.6 +/- 4.6 h (mean +/- SD; range, 12 to 39 h) after the baseline angiographic study. To assess changes in regional myocardial wall motion, the LV wall was divided into seven segments. The ischemia-related coronary artery stenosis was calculated quantitatively and related to the quantitatively assessed mean regional left ventricular ejection fraction (RLVEF) of the ischemia-related segments. In 118 of 126 patients who received trial medication, we found that anistreplase/heparin therapy leads to a significantly (p < 0.01) greater reduction in coronary artery diameter stenosis than heparin-only therapy (n = 63, mean +/- SD, 11 +/- 22, vs n = 55, mean +/- SD, 3 +/- 11%). Anistreplase/heparin therapy was related to a larger significant improvement of the ischemia-related RLVEF than heparin-only therapy, although the latter association was not statistically significant (n = 63, mean +/- SD, 7 +/- 15, vs n = 55, mean +/- SD, 5 +/- 14%). The effects of change of coronary artery stenosis on regional LV wall motion were also determined. A paradoxical finding was that a persistently occluded vessel or a vessel showing an increase in coronary artery stenosis was associated with a greater improvement of the ischemia-related RLVEF than a reopened vessel or a vessel with a reduction in coronary artery stenosis (n = 15, mean +/- SD, 7 +/- 11, vs n = 41, mean +/- SD, 8 +/- 13, vs n = 15, mean +/- SD, 1 +/- 12, vs n = 47, mean +/- SD, 5 +/- 16%, NS). One day after the last attack of chest pain, the regional LV wall motion was still abnormal in about 20% of patients., Conclusion: In these patients with unstable angina, the LV wall motion improved both in the treated and the control group at follow-up angiography 1 day later. Improved coronary arterial anatomy was associated with a lesser improvement of the LV contractile function than when worsening of the coronary angiographic appearance occurred. There is no rational explanation of these results. This is a beginning of an effort to elucidate the clinical significance of the stunned and hibernating myocardium in humans.

Thrombolytic therapy mimics and enhances physiological fibrinolysis. The following substances are presently available for clinical use: the nonphysiological thrombolytics streptokinase, the APSAC (acylated plasminogen-streptokinase activator complex), the physiological plasminogen activators urokinase and tissue plasminogen activator (t-PA). Whereas the first three systematically activate the fibrinolytic system, t-PA possesses relative fibrin selectivity. The fibrin-selective active pro-urokinase has not yet been officially approved for the treatment of thromboembolic diseases, but it is being clinically tested. Fibrinolytic therapy has an established place in the management of acute myocardial infarction and of massive pulmonary embolism. When an acute deep venous thrombosis is diagnosed with a proximal extension into the popliteal vein, thrombolytic therapy is clearly superior to heparin. The lysis has proven to be an effective form of treatment of peripheral occlusive arterial disease. Local thrombolytic therapy is an option for acute and chronic femoro-popliteal occlusions involving the trifurcation into the calf arteries and for embolic occlusions of the same segment in patients with contraindications to surgical therapy. First study results of thrombolytic therapy of stroke are promising.

Thrombolysis together with neuroprotective agents the two most important recent advances in the treatment of acute ischemic stroke. This update summarizes the recent randomized clinical trials and emphasizes the question of risk versus benefit of this potentially useful but dangerous treatment.

Objectives: To identify and rank the factors that currently limit the use of thrombolytic treatment in patients admitted to hospital with acute myocardial infarction., Design: Weighted sampling study with retrospective data retrieval from clinical records., Setting: All hospitals within the Trent region providing acute general medical services., Patients: Random sample of 420 patients admitted during February-April 1993 who had acute myocardial infarction as the main discharge diagnosis., Main Outcome Measures: Treatment odds ratios (and 95% confidence intervals (CI)) for the use of thrombolysis in patient groups defined by relevant clinical characteristics., Results: The patient population was older and less likely to have ST segment elevation on the initial electrocardiogram than patients entered into the randomised trials of thrombolysis. Thrombolytic treatment was given to 49% of patients (SE 2.4%). After controlling for negative associations with a history of stroke (treatment odds ratio 0.18 (95% CI 0.04 to 0.53)) and peptic ulcer (odds ratio 0.52 (95% CI 0.26 to 1.01)) use of thrombolysis decreased with increasing patient age. This was particularly noticeable for those aged > 74 years (odds ratio 0.17 (95% CI 0.05 to 0.51)) relative to those aged < 65 years. Thrombolysis was less likely to be used in patients with ST depression (odds ratio 0.22 (95% CI 0.11 to 0.41)) or bundle branch block (odds ratio 0.18 (95% CI 0.07 to 0.44)) than in those with ST elevation on the initial electrocardiogram. Delay from symptom onset to admission was more than 12 h in 15% of patients., Conclusions: The patient population admitted to hospital with acute myocardial infarction differs in several respects from the samples that have been included in the trials of thrombolysis. The main factors limiting wider use of thrombolysis are diagnostic uncertainty at admission and delayed presentation. Perceived clinical contraindications to treatment are of lesser importance. There is evident reluctance to use thrombolytic treatment in older patients, who were substantially under-represented in the clinical trials.

We report the detection of activated GP IIb-IIIa complexes on platelets of patients undergoing thrombolytic therapy after acute myocardial infarction. Protocols were established for the monoclonal antibodies (mAbs): VH10, anti-P-selectin, a marker of platelet secretion; 9F9 and F26, two anti-RIBS (receptor-induced binding sites) mAbs specific for fibrinogen (Fg) bound to the GP IIb-IIIa receptor. Of ten patients studied: two were treated with streptokinase, four with APSAC (anisoylated plasminogen-streptokinase activator complex), and three with rt-PA. Platelets were tested on at least five occasions in the week following therapy. The percentage of platelets positive with 9F9 was often high, and reached a maximum within three days. By this time, plasma Fg levels, which fell during fibrinolysis, had begun to return to normal. Levels of activated platelets had fallen to baseline after 7 days. PAC-1, a mAb which binds directly to the activated GP IIb-IIIa complex, confirmed the results with 9F9, but F26 was a less sensitive probe. Binding of the anti-P-selectin mAb (VH10) was low, showing that little secretion had occurred. A concentration-dependent inhibition of 9F9 binding by RGDW peptide, a competitive inhibitor for Fg on GP IIb-IIIa, confirmed that Fg (or epitope-containing degradation products) were being located by the antibody. The activation of GP IIb-IIIa occurred despite the patients receiving aspirin and heparin. Thus platelets of some fibrinolytic patients have an increased tendency for surface activation within the first 72 h after treatment, a finding which would be compatible with an increased thrombotic tendency.

Data are now available from three large-scale randomized trials that directly compare the risks and benefits of thrombolytic agents in acute myocardial infarction. In the interpretation of results from the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI-2) trial and its International Extension, the Third International Study of Infarct Survival (ISIS-3), and the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-1) trial, there are areas of both agreement and controversy. It is generally agreed that the agents most commonly used in the United States--tissue-type plasminogen activator (t-PA), streptokinase and anisoylated plasminogen streptokinase activator complex (APSAC)--all reduce mortality when given to patients with acute evolving myocardial infarction. Further, it is clear that thrombolytic therapy given to such patients presenting up to 12 h after onset of symptoms reduces the mortality rate by approximately 20%, that aspirin therapy for patients presenting up to 24 h reduces the mortality rate by approximately 23% and that the benefits of thrombolytic therapy and aspirin are additive. Finally, and of most importance, the earlier administration as well as the more widespread use of thrombolytic therapy and aspirin would save many more lives. The totality of evidence clearly indicates that streptokinase produces significantly fewer strokes and cerebral hemorrhages than either t-PA or APSAC. Whether or not accelerated t-PA has a small advantage for mortality is less conclusive.(ABSTRACT TRUNCATED AT 250 WORDS)

Background: Recent guidelines recommend that patients with obvious acute myocardial infarction receive thrombolysis, unless contraindicated, within 60-90 minutes of summoning assistance. If this target is to be achieved, an increasing number of general practitioners are likely to be involved in the administration of thrombolytic agents., Aim: This study aimed to assess the practicality and safety of thrombolysis with anistreplase when given by general practitioners., Method: An observational study was conducted in 805 general practices throughout the United Kingdom. Between March 1991 and September 1992, a total of 3383 patients with a clinical diagnosis of myocardial infarction were recruited--888 by 344 general practitioners who wished to include anistreplase in their management of myocardial infarction ('user' group) and 2495 by 776 general practitioners who did not wish to use anistreplase but who were willing to provide information about their cases ('comparison' group)., Results: More than half the patients were seen within two hours of onset of symptoms. A high frequency of contra-indications to thrombolysis, diagnostic uncertainty, and other, mainly practical, reasons limited the number of occasions on which anistreplase was administered. Thus, only 310 patients were given anistreplase in the community. The general practitioners in the study used anistreplase safely. Their diagnostic accuracy was high (of the 310 patients given anistreplase 69% had a definite, possible or probably myocardial infarction, 4% a definite non-cardiac diagnosis), the number of patients given anistreplase in spite of a documented contraindication was small (seven patients), and the doctors appeared to be aware of potential bleeding problems associated with thrombolysis. In all cases, the complications of acute myocardial infarction appeared to be managed appropriately., Conclusion: General practitioners can use anistreplase both appropriately and safely in the early management of acute myocardial infarction. Recognized contraindications to thrombolysis and practicalities of diagnosis and drug administration may, however, limit the number of occasions on which anistreplase is used.

Anistreplase is a thrombolytic agent comprising a complex of streptokinase, lys-plasminogen, and a p-anisoyl group, which temporarily protects the catalytic center of the enzyme complex. Streptokinase was previously shown to reduce infarct size (IS) in dogs with a fibrin-rich clot in the left anterior descending coronary artery (LAD) without necessarily producing reperfusion. Therefore, we hypothesized that IS in this model would be reduced by anistreplase. In addition, we studied the effect of tissue-type plasminogen activator (t-PA) on IS, testing our hypothesis in anesthetized dogs in which thrombin (100 U) and calcium (50 microliters, 0.05 M) were sequentially injected into the LAD to form a thrombus, anistreplase [0.01, 0.05, or 0.10 U/kg intravenous (i.v.) bolus], t-PA (0.1, 0.5, 2, or 8 micrograms/kg/min infusion for 60 min) or vehicle (VEH) was administered 55 min later. Anistreplase (0.05 or 0.10 U/kg) significantly (p < 0.05) reduced clot weight (VEH 22 +/- 3 mg; anistreplase 0.05 U/kg, 13 +/- 4 mg; anistreplase 0.10 U/kg, 0.7 +/- 0.6 mg), increased incidence of reperfusion (VEH 0%; anistreplase 0.05 U/kg, 42%; anistreplase 0.10 U/kg, 100%) and reduced IS (VEH 23 +/- 3%; anistreplase, 0.05 U/kg, 14 +/- 2%; anistreplase 0.10 U/kg, 15 +/- 2%). t-PA reduced thrombin weight (VEH 26 +/- 3 mg; 2 micrograms/kg/min t-PA 12 +/- 4; 8 micrograms/kg/min t-PA 2 +/- 2 mg) and increased incidence of reperfusion (VEH 0%; 2 micrograms/kg/min 75%; 8 micrograms/kg/min 100%), but IS was not altered (VEH 19 +/- 3%; 0.1 microgram/kg/min 18 +/- 3%; 0.5 microgram/kg/min 23 +/- 2%; 2 micrograms/kg/min 16 +/- 5%; 8 micrograms/kg/min: 19 +/- 3%).(ABSTRACT TRUNCATED AT 250 WORDS)

Our objective was to estimate the saving of life by thrombolysis and resuscitation in acute myocardial infarction (AMI) before and after hospital admission. We studied all 1516 patients admitted to a Scottish teaching hospital in 1990 and 1992 who had a final diagnosis of AMI, and 311 patients enrolled in the Grampian region early anistreplase trial (GREAT). Cardiac arrest occurred in 250/1516 (16%) hospital patients. Of these, 77 (31%) were discharged alive--a saving of 51 lives per thousand cases. 797 (53%) patients received thrombolysis, of whom 114 (14%) died. Assuming the same relative reduction in mortality as in the second international study of infarct survival (ISIS-2; 23%), 34 lives were saved by thrombolytic therapy, representing 22 lives per thousand cases. Of 311 patients in GREAT, 15 (5%) had prehospital cardiac arrest, with 7 patients surviving to discharge (48%)--a saving of 23 lives per thousand cases. Those patients given domiciliary thrombolysis had a one month mortality of 6.7% (11/163) compared with 12.2% (18/148) for those receiving hospital thrombolysis--a saving of 55 lives per thousand cases for prehospital thrombolysis. This is additional to 28 lives per thousand estimated for thrombolytic therapy in hospital, totalling 83 lives saved per thousand cases of AMI receiving thrombolytic therapy prehospital. In hospital, more lives were saved by resuscitation than by thrombolytic therapy, but this ratio was reversed in the period before hospital admission. These results emphasise the paramount importance of resuscitation in hospital, and the enhanced efficacy of thrombolysis when given at the earliest opportunity.