Grampian Region Early Anistreplase Trial Research Articles

Part 7: The Era of Reperfusion

Part 7: The Era of Reperfusion

Extended Mortality Benefit of Early Postinfarction Reperfusion

To the Editor: Ross et al1 (April 28, 1998) report that in the GUSTO-1 angiographic substudy, successful reperfusion produced mortality benefits that were amplified beyond the first 30 days. This extended mortality benefit has been reported previously in the Grampian Region Early Anistreplase Trial (GREAT).2 In this randomized, double-blind, controlled clinical trial, 311 patients with suspected acute myocardial infarction either received anistreplase prehospital at 105 minutes (median) after symptom onset or in hospital at 240 minutes. At 30 days, there was a trend in favor of prehospital thrombolysis (≈6 lives saved per 100), but this did not reach statistical significance …

Audit of prehospital thrombolysis by general practitioners in peripheral practices in Grampian

BackgroundIn 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...

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 ∼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.

Prehospital thrombolytic therapy in acute myocardial infarction

The extent of myocardial damage occurring during acute myocardial infarction is time dependent, and there is abundant evidence from most clinical trials that mortality reduction is greatest in patients treated early with thrombolytic agents, although beneficial effects have been shown with treatment initiated up to 12 h after onset of symptoms. All studies on prehospital thrombolysis have conclusively shown the practicability and safety of patient selection and administration of the thrombolytic agent. The accuracy of diagnosis in the prehospital setting was comparable to trials of in-hospital thrombolysis, e.g., in the Myocardial Infarction Triage and Intervention Project (MITI) 98% of the patients enrolled had subsequent evidence of acute myocardial infarction. With regard to time savings, all randomized studies showed positive results. The smallest time gain was observed in the MITI trial: prehospital-treated patients received thrombolytic therapy an average of 33 min earlier than those treated in hospital. In the European Myocardial Infarction Project (EMIP) the difference in time between prehospital and hospital treatment was a median of 55 min. However, none of these trials was able to show a significant short-term mortality difference between the two groups. Only a meta analysis of five randomized studies with a combined median time gain of about 60 min showed a significant 17% reduction in short-term mortality for patients who received thrombolytic therapy in the prehospital phase. In the Grampian Region Early Anistreplase Trial (GREAT), a study performed in a more rural area than other studies, the time gain by prehospital initiation of thrombolysis was a median of 130 min. GREAT was the only study to date reporting a significant mortality benefit for prehospital-treated patients after 3 months and 1 year. In conclusion, prehospital thrombolysis is feasible and safe. Patients with acute myocardial infarction can be correctly identified and treated with thrombolytic agents in the prehospital setting with the same rate of complications as expected for in-hospital thrombolysis, provided basic resuscitation equipment including a defibrillator is available. The results of randomized studies comparing the results of prehospital and in-hospital thrombolysis seem to justify the prehospital institution of thrombolytic therapy, especially in rural areas where transport times to the hospital are long and the expected time gain is largest. The choice of the thrombolytic agent seems to be of minor importance and should follow prehospital practicability (bolus injection) and costs. Aspirin should be given to all prehospital patients with suspected myocardial infarction regardless of thrombolytic therapy.

An update on acute myocardial infarction from recent clinical trials

Exploration of new strategies and therapies to improve survival and outcomes of acute myocardial infarction (AMI) continues. Recently published large clinical trials, including the long-term results from Grampian Region Early Anistreplase Trial, Global Use of Strategies to Open Occluded Coronary Arteries, and the Global Use of Strategies to Open Occluded Arteries in Acute Coronary Syndromes (GUSTO-)IIb angioplasty substudy, have helped to clarify the relative benefits of earlier treatment, the use of third-generation thrombolytic agents, and the use of primary angioplasty. Other, smaller trials such as Evaluation of c7E3 Fab in Preventing ischemic Complications of High-risk Angioplasty and intracoronary Stenting and Antithrombotic Regimen have stimulated thoughts about new adjunctive agents and devices, including platelet glycoprotein IIb/IIIa antagonists, primary stenting, and antioxidants. Both knowledge and therapies have advanced significantly in the past year, which should improve clinical outcomes of AMI in the near future.

Thrombolytic therapy in Europe: current status.

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.

Prehospital thrombolytic therapy reduced mortality in acute MI

Source Citation Rawles J. Magnitude of benefit from earlier thrombolytic treatment in acute myocardial infarction: new evidence from Grampian region early anistreplase trial (GREAT). BMJ. 1996 Jan ...

Magnitude of benefit from earlier thrombolytic treatment in acute myocardial infarction: new evidence from Grampian region early anistreplase trial (GREAT)

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. Multivariate analysis of a randomised double blind trial. 29 rural practices in Grampian region and teaching hospitals in Aberdeen. 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. Anisterplase 30 units given intravenously, either by general practitioners before hospitalisation or later in hospital. Death within 30 months of entry into trial. 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). 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.

Impact of resuscitation and thrombolysis on mortality rate from acute myocardial infarction

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.

Prehospital thrombolysis Views of non-users ignored

EDITOR, - In his assimilation of general practitioners' views on prehospital thrombolysis John Rawles fails to look in detail at the subgroup from whom we are most likely to gain an interesting insight - namely, those general practitioners who took part in the Grampian region early anistreplase trial.1 Only 25 of the 87 doctors who took part in the study (a study which he suggests shows that the efficacy of thrombolysis is doubled when it is given before admission to hospital) identified themselves as current users of thrombolysis. Why did the remaining doctors stop using this treatment? Rawles's main conclusions are that general practitioners feel the need to be better educated and value the input of local cardiologists in establishing protocols and management guidelines. I would have thought that those general practitioners who took part in the Grampian study had been sufficiently well educated and supported by local cardiologists. Why, when these two barriers to use have been removed and the case for the effectiveness of the treatment has been well made, do large numbers of general practitioners feel unable to change their behaviour? Has it anything to do with the cost of the treatment? Given that the second international study of infarct survival suggests that aspirin is as effective as streptokinase, perhaps the role of general practice should be to ensure that this safer treatment is started as soon as possible. It is disconcerting to find that 22% of the general practitioners who gave thrombolytic drugs felt confident of doing so without recourse to electrocardiography and that 45% were happy to give them despite having no access to a defibrillator. The users also reported, on average, over 50% more cases of suspected myocardial infarction than non-users (5.27 v 3.30). …

Attitudes of general practitioners to prehospital thrombolysis

To investigate reasons for general practitioners not giving thrombolytic treatment to eligible patients with acute myocardial infarction. Postal questionnaires were sent to 424 general practitioners. 97 general practitioners who had taken part in the Grampian region early anistreplase trial, 185 whose practices in Scotland were at least 24 km from a district general hospital, and 142 who had attended postgraduate conferences at which thrombolysis had been discussed; 87, 158, and 125 respectively responded. Answers to questions about readiness to use thrombolytic treatment. Response rate was 87% (370/424). Almost all respondents (350) were convinced of benefits of thrombolysis for acute myocardial infarction, and 277 were convinced that there were additional benefits from its administration in the community at first opportunity. Most doctors working 16 km or more from hospital thought that giving treatment at home would appreciably save time (200/274). Most doctors agreed that they could make time to give thrombolytic treatment (278), and would be willing to record an electrocardiogram (284), and would be able to interpret it (280). Sixty four respondents (17%) reported using thrombolytic treatment in previous year. Among non-users, 150 (49%) were unwilling to use thrombolytic treatment without further training. While many non-users (210 (69%)) were willing to use thrombolytic treatment without encouragement from Department of Health, 184 (60%) were unwilling to use it unless encouraged to do so by their local cardiologist. The need to become better informed about thrombolysis and lack of encouragement from local cardiologists were important factors preventing wider use of thrombolytic treatment in the community by general practitioners.

Halving of mortality at 1 year by domiciliary thrombolysis in the Grampian Region Early Anistreplase Trial (GREAT): Rawles J, on behalf of the GREAT Group J Am Coll Cardiol 23:1–5 Jan 1994

Halving of mortality at 1 year by domiciliary thrombolysis in the Grampian Region Early Anistreplase Trial (GREAT): Rawles J, on behalf of the GREAT Group J Am Coll Cardiol 23:1–5 Jan 1994

Having of mortality at 1 year by domiciliary thrombolysis in the grampian region early anistreplase trial (GREAT)

Objectives. Our aim was to determine the time saved by administration of thrombolytic therapy at home rather than in the hospital and to assess whether earlier thrombolysis resulted in decreased mortality from acate myocardial infarction.Background. There is much theoretic, experimental and trial evidence to indicate that in acute myocardial infarction the earlier that thrombolytic therapy is given, the greater its efficacy. However, the clinical importance of this time effect is uncertain.Methods. In a randomized double-blind parallel-group clinical trial, 311 patients with suspected acute myocrdial infarction seen by their general practitioners within 4 h of symptom onset were given intravenous anistreplase (30 U) either at home or later, after arrival in the hospital.Results. Anistreplase was given at home or in the hospital at median times of 101 and 240 min, respectively, after symptom onset. The median time saved by domiciliary thrombolysis was 130 min. By the end of 1 year after trial entry, 17 (10.4%) of 163 patients given anistreplase at home died compared with 32 (21.6%) of 148 in those allocated anistreplase in the hospital (relative reduction 52%, 95% confidence interval 14% to 89%, p = 0.007).Conclusions. In this trial the time saved by domiciliary thrombolysis by primary care physicians was >2 h. It is likely that a similar time saving would be achieved if prehospital thrombolysis were to become established practice. Prehospital thrombolysis resulted in a halving of the mortality rate from acute myocardial infarction.

At-home thrombolysis reduced all-cause mortality and morbidity in patients with acute myocardial infarction

Source Citation GREAT Group. Feasibility, safety, and efficacy of domiciliary thrombolysis by general practitioners: Grampian region early anistreplase trial. BMJ. 1992 Sep 5;305:548-53.