European Heart Journal (1990) 11, (Supplement F), 1-4
Survival following thrombolytic therapy P.
SLEIGHT
John Radcliffe Hospital, Oxford, UK.
KEY WORDS: Myocardial infarction, thrombolysis, streptokinase, APSAC, t-PA, aspirin, mortality
Introduction The study of thrombolytic agents for the treatment of myocardial infarction (MI) has progressed beyond the stage of confirming that such drugs are effective. As reviewed by Marder and Sherry, numerous studies have established that the available thrombolytic agents are all capable of opening infarct-related coronary vessels'11. More importantly it has been demonstrated that streptokinase, APSAC (anisoylated lys-plasminogen streptokinase activator complex; anistreplase) and alteplase (t-PA) can reduce mortality rates significantly in comparison with non-thrombolytic therapy. Questions that are now being addressed include whether thrombolytic drugs are of particular benefit to some sub-groups of MI patients, whether thrombolytic drugs can be beneficial to patients for whom such agents were considered contra-indicated in earlier clinical studies, whether their efficacy can be optimized by establishing their performance in association with various adjunctive therapies and, obviously, which of these agents is best. The definitive answers to these questions will Address for correspondence: P. Sleight, Cardiac Dept., John Radcliffe Hospital, Oxford OX3 9DU, U.K. (no reprints).
0195-668X/90/OF001 + 04 $03.00/0
come from the results of studies yet to be reported. The major mortality studies that have been conducted with thrombolytic drugs to date cannot answer important questions about the pros and cons of the different agents. Major mortality studies Five major randomized studies, involving from 1000 to 17 000 patients, have investigated the effect of thrombolytic drugs on survival following myocardial infarction. Three of these, GISSI, ISAM and ISIS-2 studied streptokinase12"*1. Alteplase was studied in ASSET"1, and APSAC was studied in AIMS.'6' All have been comparisons of a thrombolytic agent with either open control (GISSI) or placebo. In earlier studies conducted to assess the effect of thrombolytic drugs on reperfusion, patency or left ventricular function, patient entry criteria were tightly defined to include only patients with pre-defined evidence of myocardial infarction, e.g. chest pain of at least 20-30 min duration not relieved by nitrates and ECG ST-segment elevation. Those studies also excluded patients in whom the expected risk/ benefit of using thrombolytic therapy was considered unfavourable, such as elderly patients, or patients presenting many hours after the © 1990 The European Society of Cardiology
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on June 6, 2016
The results of the major mortality studies of thrombolytic drugs in myocardial infarction demonstrate that streptokinase, APSAC and t-PA reduce mortality significantly. Large studies (GISSI-2 comparing Genentech t-PA with streptokinase and ISIS-3 comparing streptokinase, APSAC and Wellcome t-PA) are currently under way to identify which, if any, of the above agents is the most effective. Review of the results of the reported studies has emphasized the importance of treatment being given as soon as practical after the onset of symptoms. It has also revealed that substantial benefit is achievable in patients often not considered to be candidates for thrombolytic therapy, such as those presenting for treatment between 6 and 24 h after symptom onset, and elderly patients. It is emphasized that important benefit may be missed in clinical practice in deciding who should, or should not, receive thrombolytic drug therapy by complying too rigidly to what were investigative clinical study entry criteria.
2
P. Sleight Table 1 Comparison of entry criteria in mortality studies
Study GISSI
ISAM
Yes ST segment elevation or depression a 1 mm in any peripheral lead, and/or a 2 mm in any precordial lead. Yes ST segment elevation a 1 mm in any peripheral lead, and 2: 2 mm in any precordial lead. No No Yes ST segment elevation 2 0-1 mV in two or more standard leads, and/or 2: 0-2 mV in two or more precordial leads.
onset of symptoms of MI. Unfortunately the entry criteria used in those studies have been employed in clinical practice to establish which patients should receive thrombolytic drugs. Consequently there may be some patients currently not considered as candidates for thrombolytic therapy who may achieve benefit from such treatment. The five mortality studies mentioned above differed with regard to entry criteria (Table 1) allowing us the opportunity to assess the performance of the agents in populations of patients ranging from those with firm diagnostic evidence of MI to those in whom MI need only be suspected by the investigator and, by employing sub-set analyses, to investigate whether some of the exclusion criteria for thrombolytic therapy that have been handed down from the early investigations are valid in deciding how these drugs can be used in a normal clinical setting. Time to treatment The two largest studies were conducted with 1-5 million IU streptokinase. GISSI allowed treatment up to 12 h from the onset of chest pain in patients with ECG evidence of myocardial infarction. ISIS-2 allowed treatment up to 24 h following the onset of pain because meta-
Upper age limit (years)
Maximum time since onset of pain (h)
None
12
75
6
None 75 70
24 5 6
analysis of previous trials suggested that there was benefit in terms of improved survival for patients treated 'late''71, and did not require any definite pre-treatment ECG criteria, although these were noted. Entry into ISIS-2 was based on whether the investigator suspected on clinical grounds (including usually an ECG) that a patient had an MI. GISSI compared streptokinase with conventional management in an open fashion; ISIS-2 was double-blind, and also separately randomized to 160 mg aspirin daily or placebo in a 2 x 2 factorial fashion. In spite of these differences the major results of the two studies were very similar for the streptokinase comparison. The benefit of treating patients as early as possible was seen in both studies. The GISSI study retrospectively examined the reductions in the odds of death in-hospital for patients treated within l h , 1-3 h and 3-12 h of the onset of pain. The early benefits were more extreme than ISIS-2 and were respectively 50%, 16% and 14%. The odds ratios for the prospectively examined figures in ISIS-2 for 0-3 h, 3-6 h and after 6h since symptom onset were 34%, 24% and 17%. Combining the results of ISIS-2, the ISIS-2 pilot, GISSI and ISAM confirmed that i.v.
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on June 6, 2016
ISIS-2 ASSET AIMS
MI ECG evidence required?
Survival following thrombolysis
3
Similar findings were noted in the interim Table 2 Intravenous streptokinase (SK)—mortality by time since onset of symtoms report of the AIMS study"1. Although AIMS Mortality reductions (% ± SD) Delay before iv SK (h)
ISIS-2 only
ISIS-2 (main + pilot) + GISSI + ISAM
0-3 h 3-6h 6b
37% ± 8 24% ±8 17% ± 9
30% ±5 22% ± 6 15% ± 6
Elderly patients
Which thrombolvtic agent is best?
One of the most striking results of ISIS-2 was the benefit observed in older patients. Over 3400 people aged 70 years or more were randomized into the study. Such patients had a higher mortality rate than younger patients (Fig. 1). Thrombolytic therapy was associated with a significant reduction in mortality in such patients, and in absolute terms the improved survival observed following streptokinase was greater than that observed in younger patients ( < 6 0 years). There was also no evidence that the risk of cerebral haemorrhage was related to age. 3 251 6 h) from symptom onset (Table 2). The conclusions taken from these findings are that thrombolytic drugs should be administered as soon as is practical after the onset of symptoms of MI in order to achieve maximum benefit, but that if patients present late (6-24 h) for treatment, thrombolytic therapy may still be of benefit.
had an upper limit for entry of 70 years, comparison of the 30-day and 1-year survival for placebo- and APSAC-treated patients aged < 65 or ^ 6 5 years showed that the older group gained greater benefit in absolute terms in view of their much greater risk of death. For those 3s 65 years, the percentages of patients who had died by 30 days after treatment were 12-2% and 30-2% in the APSAC and placebo groups, respectively, compared with 5-2% and 8-5% in the younger age group. This difference was maintained in considering survival to 1 year. The difference between treatment groups of the percentages of patients who had died at one year was 17% in the older population compared with 7% in the younger ( < 65 years) group. In view of the above findings it must be concluded that the survival benefit achievable by treating elderly patients with thrombolytic drugs is substantial.
4
P. Sleight
Table 3 Reduction in the odds of death among patients treated within 6 h of the onset of symptoms Agent Streptokinase t-PA APSAC Overall: any fibrinolytic
Study
Deaths/patients Active
Control
Odds reductions (
GISSI ISIS-2 ISAM ASSET AIMS
495/4865 471/5350 50/842 182/2516 32/502
623/4878 648/5360 61/868 245/2495 61/502
23% 30% 16% 28% 50%
1230/14075
1638/14103
References
±6 ±5 ±18 ±9 ±16
27% ±3
myocardial infarction: ISIS-2. Lancet 1988; ii: 34960. [5] Wilcox RG, Von Der Uppe G, Olsson CG et al. for the ASSET Study Group. Trial of tissue plasminogen activator for mortality reduction in acute myocardial infarction. Anglo-Scandinavian Study of Early Thrombolysis (ASSET). Lancet 1988; ii: 525-30. [6] AIMS Trial Study Group. Effect of intravenous APSAC on mortality after acute myocardial infarction: preliminary report of a placebo-controlled clinical trial. Lancet 1988; i: 545-9. [7] Yusuf S, Collins R, Peto R el al. Intravenous and intracoronary fibrinolytic therapy in acute myocardial infarction: overview of results on mortality, reinfarction and side-effects from 33 randomised controlled trials. Eur Heart J 1985; 556-85.
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on June 6, 2016
[1] Marder VJ, Sherry S. Thrombolytic therapy: Current status. N Engl J Med 1988; 318: 1512-20. [2] Gruppo Italiano per lo Studio Delia Streptochinasi nell'infarcto Miocardico (GISSI). Long-term effects of intravenous thrombolysis in acute myocardial infarction: final report of the GISSI study. Lancet 1987; ii: 871-4. [3] ISAM Study Group. A prospective trial of intravenous streptokinase in acute myocardial infarction (I.S.A.M.). Mortality, morbidity and infarct size at 21 days. N Engl J Med 1986; 314: 1465-71. [4] ISIS-2 Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17187 cases of suspected acute
±sd)
Survival following thrombolytic therapy P.
SLEIGHT
John Radcliffe Hospital, Oxford, UK.
KEY WORDS: Myocardial infarction, thrombolysis, streptokinase, APSAC, t-PA, aspirin, mortality
Introduction The study of thrombolytic agents for the treatment of myocardial infarction (MI) has progressed beyond the stage of confirming that such drugs are effective. As reviewed by Marder and Sherry, numerous studies have established that the available thrombolytic agents are all capable of opening infarct-related coronary vessels'11. More importantly it has been demonstrated that streptokinase, APSAC (anisoylated lys-plasminogen streptokinase activator complex; anistreplase) and alteplase (t-PA) can reduce mortality rates significantly in comparison with non-thrombolytic therapy. Questions that are now being addressed include whether thrombolytic drugs are of particular benefit to some sub-groups of MI patients, whether thrombolytic drugs can be beneficial to patients for whom such agents were considered contra-indicated in earlier clinical studies, whether their efficacy can be optimized by establishing their performance in association with various adjunctive therapies and, obviously, which of these agents is best. The definitive answers to these questions will Address for correspondence: P. Sleight, Cardiac Dept., John Radcliffe Hospital, Oxford OX3 9DU, U.K. (no reprints).
0195-668X/90/OF001 + 04 $03.00/0
come from the results of studies yet to be reported. The major mortality studies that have been conducted with thrombolytic drugs to date cannot answer important questions about the pros and cons of the different agents. Major mortality studies Five major randomized studies, involving from 1000 to 17 000 patients, have investigated the effect of thrombolytic drugs on survival following myocardial infarction. Three of these, GISSI, ISAM and ISIS-2 studied streptokinase12"*1. Alteplase was studied in ASSET"1, and APSAC was studied in AIMS.'6' All have been comparisons of a thrombolytic agent with either open control (GISSI) or placebo. In earlier studies conducted to assess the effect of thrombolytic drugs on reperfusion, patency or left ventricular function, patient entry criteria were tightly defined to include only patients with pre-defined evidence of myocardial infarction, e.g. chest pain of at least 20-30 min duration not relieved by nitrates and ECG ST-segment elevation. Those studies also excluded patients in whom the expected risk/ benefit of using thrombolytic therapy was considered unfavourable, such as elderly patients, or patients presenting many hours after the © 1990 The European Society of Cardiology
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on June 6, 2016
The results of the major mortality studies of thrombolytic drugs in myocardial infarction demonstrate that streptokinase, APSAC and t-PA reduce mortality significantly. Large studies (GISSI-2 comparing Genentech t-PA with streptokinase and ISIS-3 comparing streptokinase, APSAC and Wellcome t-PA) are currently under way to identify which, if any, of the above agents is the most effective. Review of the results of the reported studies has emphasized the importance of treatment being given as soon as practical after the onset of symptoms. It has also revealed that substantial benefit is achievable in patients often not considered to be candidates for thrombolytic therapy, such as those presenting for treatment between 6 and 24 h after symptom onset, and elderly patients. It is emphasized that important benefit may be missed in clinical practice in deciding who should, or should not, receive thrombolytic drug therapy by complying too rigidly to what were investigative clinical study entry criteria.
2
P. Sleight Table 1 Comparison of entry criteria in mortality studies
Study GISSI
ISAM
Yes ST segment elevation or depression a 1 mm in any peripheral lead, and/or a 2 mm in any precordial lead. Yes ST segment elevation a 1 mm in any peripheral lead, and 2: 2 mm in any precordial lead. No No Yes ST segment elevation 2 0-1 mV in two or more standard leads, and/or 2: 0-2 mV in two or more precordial leads.
onset of symptoms of MI. Unfortunately the entry criteria used in those studies have been employed in clinical practice to establish which patients should receive thrombolytic drugs. Consequently there may be some patients currently not considered as candidates for thrombolytic therapy who may achieve benefit from such treatment. The five mortality studies mentioned above differed with regard to entry criteria (Table 1) allowing us the opportunity to assess the performance of the agents in populations of patients ranging from those with firm diagnostic evidence of MI to those in whom MI need only be suspected by the investigator and, by employing sub-set analyses, to investigate whether some of the exclusion criteria for thrombolytic therapy that have been handed down from the early investigations are valid in deciding how these drugs can be used in a normal clinical setting. Time to treatment The two largest studies were conducted with 1-5 million IU streptokinase. GISSI allowed treatment up to 12 h from the onset of chest pain in patients with ECG evidence of myocardial infarction. ISIS-2 allowed treatment up to 24 h following the onset of pain because meta-
Upper age limit (years)
Maximum time since onset of pain (h)
None
12
75
6
None 75 70
24 5 6
analysis of previous trials suggested that there was benefit in terms of improved survival for patients treated 'late''71, and did not require any definite pre-treatment ECG criteria, although these were noted. Entry into ISIS-2 was based on whether the investigator suspected on clinical grounds (including usually an ECG) that a patient had an MI. GISSI compared streptokinase with conventional management in an open fashion; ISIS-2 was double-blind, and also separately randomized to 160 mg aspirin daily or placebo in a 2 x 2 factorial fashion. In spite of these differences the major results of the two studies were very similar for the streptokinase comparison. The benefit of treating patients as early as possible was seen in both studies. The GISSI study retrospectively examined the reductions in the odds of death in-hospital for patients treated within l h , 1-3 h and 3-12 h of the onset of pain. The early benefits were more extreme than ISIS-2 and were respectively 50%, 16% and 14%. The odds ratios for the prospectively examined figures in ISIS-2 for 0-3 h, 3-6 h and after 6h since symptom onset were 34%, 24% and 17%. Combining the results of ISIS-2, the ISIS-2 pilot, GISSI and ISAM confirmed that i.v.
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on June 6, 2016
ISIS-2 ASSET AIMS
MI ECG evidence required?
Survival following thrombolysis
3
Similar findings were noted in the interim Table 2 Intravenous streptokinase (SK)—mortality by time since onset of symtoms report of the AIMS study"1. Although AIMS Mortality reductions (% ± SD) Delay before iv SK (h)
ISIS-2 only
ISIS-2 (main + pilot) + GISSI + ISAM
0-3 h 3-6h 6b
37% ± 8 24% ±8 17% ± 9
30% ±5 22% ± 6 15% ± 6
Elderly patients
Which thrombolvtic agent is best?
One of the most striking results of ISIS-2 was the benefit observed in older patients. Over 3400 people aged 70 years or more were randomized into the study. Such patients had a higher mortality rate than younger patients (Fig. 1). Thrombolytic therapy was associated with a significant reduction in mortality in such patients, and in absolute terms the improved survival observed following streptokinase was greater than that observed in younger patients ( < 6 0 years). There was also no evidence that the risk of cerebral haemorrhage was related to age. 3 251 6 h) from symptom onset (Table 2). The conclusions taken from these findings are that thrombolytic drugs should be administered as soon as is practical after the onset of symptoms of MI in order to achieve maximum benefit, but that if patients present late (6-24 h) for treatment, thrombolytic therapy may still be of benefit.
had an upper limit for entry of 70 years, comparison of the 30-day and 1-year survival for placebo- and APSAC-treated patients aged < 65 or ^ 6 5 years showed that the older group gained greater benefit in absolute terms in view of their much greater risk of death. For those 3s 65 years, the percentages of patients who had died by 30 days after treatment were 12-2% and 30-2% in the APSAC and placebo groups, respectively, compared with 5-2% and 8-5% in the younger age group. This difference was maintained in considering survival to 1 year. The difference between treatment groups of the percentages of patients who had died at one year was 17% in the older population compared with 7% in the younger ( < 65 years) group. In view of the above findings it must be concluded that the survival benefit achievable by treating elderly patients with thrombolytic drugs is substantial.
4
P. Sleight
Table 3 Reduction in the odds of death among patients treated within 6 h of the onset of symptoms Agent Streptokinase t-PA APSAC Overall: any fibrinolytic
Study
Deaths/patients Active
Control
Odds reductions (
GISSI ISIS-2 ISAM ASSET AIMS
495/4865 471/5350 50/842 182/2516 32/502
623/4878 648/5360 61/868 245/2495 61/502
23% 30% 16% 28% 50%
1230/14075
1638/14103
References
±6 ±5 ±18 ±9 ±16
27% ±3
myocardial infarction: ISIS-2. Lancet 1988; ii: 34960. [5] Wilcox RG, Von Der Uppe G, Olsson CG et al. for the ASSET Study Group. Trial of tissue plasminogen activator for mortality reduction in acute myocardial infarction. Anglo-Scandinavian Study of Early Thrombolysis (ASSET). Lancet 1988; ii: 525-30. [6] AIMS Trial Study Group. Effect of intravenous APSAC on mortality after acute myocardial infarction: preliminary report of a placebo-controlled clinical trial. Lancet 1988; i: 545-9. [7] Yusuf S, Collins R, Peto R el al. Intravenous and intracoronary fibrinolytic therapy in acute myocardial infarction: overview of results on mortality, reinfarction and side-effects from 33 randomised controlled trials. Eur Heart J 1985; 556-85.
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on June 6, 2016
[1] Marder VJ, Sherry S. Thrombolytic therapy: Current status. N Engl J Med 1988; 318: 1512-20. [2] Gruppo Italiano per lo Studio Delia Streptochinasi nell'infarcto Miocardico (GISSI). Long-term effects of intravenous thrombolysis in acute myocardial infarction: final report of the GISSI study. Lancet 1987; ii: 871-4. [3] ISAM Study Group. A prospective trial of intravenous streptokinase in acute myocardial infarction (I.S.A.M.). Mortality, morbidity and infarct size at 21 days. N Engl J Med 1986; 314: 1465-71. [4] ISIS-2 Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17187 cases of suspected acute
±sd)
