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Objectives: The aim of this study was to determine whether streptokinase treatment improves long-term survival in patients with acute myocardial infarction., Background: Thrombolytic treatment for acute myocardial infarction reduces early mortality and improves the 1-year survival rate, but the long-term (3 to 8 years) survival benefits of treatment and the relation between survival and baseline clinical characteristics, infarct size and ventricular function have not been established., Methods: We assessed survival status at a minimum of 3 and a mean of 4.9 +/- 2.3 years in 618 patients randomized between 1981 and 1986 to receive conventional treatment (n = 293) or thrombolysis with streptokinase (n = 325) in the Western Washington Intracoronary (n = 250) and Intravenous (n = 368) Streptokinase in Myocardial Infarction trials. The relation between long-term survival and thrombolytic treatment, admission baseline clinical characteristics and late radionuclide tomographic thallium-201 infarct size and ejection fraction was assessed in a subset of patients., Results: Survival at 6 weeks was 94% in patients who received streptokinase versus 88% in the control group (p = 0.01). However, survival at 3 years was 84% in the streptokinase group and 82% in the control group and for the total period of follow-up, there was no significant survival benefit (p = 0.16). Analysis by infarct location showed a higher survival rate at 3 years for patients treated with anterior infarction (76% vs. 67% for the control group), but no overall survival benefit (p = 0.14). Survival at 3 years for patients with an inferior infarction was 89% in the streptokinase group and 91% in the control group (p = 0.62). By stepwise Cox regression analysis, admission clinical variables associated with decreased long-term survival were anterior infarction, advanced age, history of prior infarction and the presence of pulmonary edema or hypotension. Although streptokinase therapy was associated with improved survival, it was not an independent determinant of survival (p = 0.069). Ejection fraction and thallium-201 infarct size measured approximately 8 weeks after enrollment had a strong association with long-term survival. Univariate analysis in a subgroup of 289 patients with complete data selected infarct size, ejection fraction, age and history of prior infarction as predictors of survival. In the multivariate model, only ejection fraction (p < 0.0001), age (p = 0.008) and prior myocardial infarction (p = 0.02) remained strong predictors., Conclusions: In these early trials of thrombolytic therapy for acute myocardial infarction, streptokinase improved early survival, but there was little long-term survival benefit. This failure to show an improvement in the 3- to 8-year survival rate may also reflect the need to study a larger group of patients or to initiate treatment earlier after symptom onset.

After cardiac catheterization and coronary arteriography, 134 patients who had had an acute myocardial infarction were randomly assigned to treatment with intracoronary streptokinase (4000 U per minute, begun approximately 4 1/2 hours after the onset of symptoms, for a total of 286,000 +/- 77,800 U over 72 +/- 24 minutes); 116 control patients received standard care after they returned to the coronary care unit, immediately after angiography. Preliminary results of this trial have been published in the Journal (1983; 309:1477-81). During the first 30 days, 5 deaths occurred in the streptokinase group and 13 occurred in the control group (3.7 vs 11.2 per cent, P = 0.02); during the first year, the corresponding figures were 11 and 17 deaths (8.2 vs. 14.7 per cent, P = 0.10). However, when a minor imbalance in the ejection fraction and infarct location between the two groups was adjusted by logistic regression, the difference in one-year mortality became significant (P = 0.03). In the streptokinase group, 2 of the 80 patients in whom perfusion was reestablished (2.5 per cent) had died by one year, whereas 3 of the 13 with partial reperfusion (23.1 per cent) and 6 of the 41 with no reperfusion (14.6 per cent) had died (P = 0.008). Mortality among patients with partial reperfusion was not significantly different from that among those without reperfusion (P greater than 0.90). No base-line clinical, angiographic, or hemodynamic variable was predictive of successful reperfusion, according to univariate and multivariate analyses. We conclude that intracoronary streptokinase reduces one-year mortality among patients with acute myocardial infarction, but this improvement occurs only among those in whom thrombolysis results in coronary artery reperfusion.

Intracoronary streptokinase (STK) was given to 52 patients and 2 million U of intravenous urokinase was given to 15 patients with acute myocardial infarction less than 3 hr from onset of symptoms. Wall motion in the infarct region improved in 20 patients receiving STK alone (-2.5 +/- 1 to 2.1 +/- 1.1 SD/chord) and in 22 patients receiving STK and undergoing coronary bypass surgery within 24 hr (-2.5 +/- 1 to -1.5 +/- 1.0 SD/chord). Wall motion was unchanged in 10 patients not successfully reperfused with STK (-2.9 +/- 0.7 to -3.1 +/- 0.7 SD/chord). Regional wall motion improved at least 1.0 SD/chord in 71% of 14 patients treated within 2 hr of onset of symptoms, but in only 29% of 34 treated after 2 hr. Mean coronary artery stenosis after thrombolysis was 77 +/- 9%. Rethrombosis was associated with a stenotic cross-sectional area of less than 0.4 mm2. Ventricular function did not improve, with a residual stenosis of 0.4 mm or less in diameter. The Western Washington randomized trial reported a 1 year mortality of 2.5% in 80 successfully reperfused patients, but a mortality of 23% in 13 in whom reperfusion was partial and of 14.6% in 41 in whom reperfusion failed. The improved survival with successful reperfusion and improved ventricular performance with early and more complete reperfusion has stimulated interest in the need for angioplasty and coronary artery bypass grafting after thrombolytic therapy.

In the 3 Western Washington thrombolytic therapy trials, 54.9% of patients with acute myocardial infarction arrived at the hospital within 2 hours of symptom onset. These early arrivers were younger and more likely to be hypotensive and in cardiogenic shock than were patients arriving later. There were decreases in the time from symptom onset to hospital arrival (p = 0.0002) and in the time from hospital arrival to institution of thrombolytic therapy (p less than 0.0001) in the 8 hospitals that participated in both the Western Washington intravenous streptokinase and tissue plasminogen activator trials from 1983 to 1988. For those patients receiving thrombolysis, early arrival was associated with increased survival (p = 0.031) after adjustment by Cox regression analysis for important clinical predictors of long-term survival. These covariates included pulmonary edema, anterior wall acute myocardial infarction, hypotension and absence of chest pain at hospital arrival. Reductions in barriers to timely administration of thrombolytic therapy can be achieved and can result in improved survival.

The Western Washington Intracoronary Streptokinase In Myocardial Infarction Trial enrolled 250 patients with acute myocardial infarction. After the coronary angiographic diagnosis of thrombosis, patients were randomly assigned to receive either conventional therapy with heparin or intracoronary streptokinase followed by heparin. Of the 232 patients who survived at least 60 days, 207 (89%) underwent radionuclide ventriculographic determination of global and regional ejection fraction at a single institution at 62 +/- 35 days after infarction. In the first 100 patients, infarct size was also determined by quantitative single-photon emission tomographic imaging with thallium-201 (201Tl) and expressed as a percentage of the left ventricle with a perfusion defect. Overall, global ejection fraction did not differ between patients treated with streptokinase (45.9 +/- 13.9%; n = 115) and control patients (46.1 +/- 14.4%; n = 92, p = NS). Similarly, the regional posterolateral, inferior, and anteroseptal ejection fraction did not differ between the two groups. Infarct size as measured by 201Tl tomography was 19.4 +/- 12.8% (n = 52) of the left ventricle for the streptokinase group and 19.6 +/- 11.8% (n = 48; p = NS) for the control group. When patients were compared within groups by electrocardiographic location of infarction, time to treatment, or the presence or absence of vessel opening, there were no significant differences between streptokinase and control patients. Statistical inclusion of the 18 patients who died early and were unavailable for study also failed to modify the results, except for a possible reduction in inferior infarct size as measured by 201Tl tomography.(ABSTRACT TRUNCATED AT 250 WORDS)

The Society for Cardiac Angiography maintains a registry of intracoronary streptokinase therapy (IC-SK) in patients with acute myocardial infarction. Between July 1981 and August 1984, 1,029 patients were entered into the registry. The baseline and clinical characteristics of patients were determined, the early results of therapy were evaluated, and baseline characteristics of those in whom reperfusion was achieved were compared with those in whom it was not. Multivariate discriminant analysis was used to identify the predictors of reperfusion and hospital mortality. The overall rate of reperfusion was 71.2%. Reperfusion was positively associated with hypotension, absence of cardiogenic shock and early treatment. The hospital mortality rate for all patients was 8.2% and was higher for women and the elderly. The hospital mortality was significantly lower among patients in whom reperfusion was achieved compared with those in whom it was not (5.5% vs 14.7%, p less than 0.0001) and for several high-risk subgroups. Thus, coronary artery reperfusion induced by IC-SK significantly reduces hospital mortality in high-risk patients with acute myocardial infarction. High-risk patients in whom reperfusion fails with IC-SK therapy should be considered for early coronary angioplasty or coronary artery bypass surgery.

During the past five years percutaneous transluminal coronary angioplasty (PTCA) and intracoronary infusion of streptokinase have been introduced and rapidly accepted as new methods for the treatment of patients with ischemic heart disease. Both of these methods hold great promise for the future. PTCA is established as useful in some selected patients while intracoronary streptokinase is still investigational.

To determine whether intracoronary streptokinase improves late regional wall motion or reduces left ventricular aneurysm or thrombus formation in patients with acute myocardial infarction, two-dimensional echocardiography was performed at 8 +/- 3 weeks after infarction in 83 patients randomized to streptokinase (n = 45) or standard therapy (n = 38) in the Western Washington Intracoronary Streptokinase Trial. Among the patients treated with streptokinase, the average time to treatment was 4.7 +/- 2.5 hours after the onset of chest pain, and 67% had successful reperfusion. Regional wall motion was assessed in nine left ventricular segments on a scale of 1 to 4 (normal, hypokinetic, akinetic and dyskinetic). Left ventricular thrombus formation was interpreted as positive, equivocal or negative. All patients received anticoagulant therapy in the hospital and 52 received such therapy after hospital discharge. The mean (+/- SD) global (1.5 +/- 0.4 in both groups) and regional wall motion scores in the streptokinase-treated and control groups were not significantly different. The prevalence of aneurysm was 16% in both groups. Left ventricular thrombus was identified in only five patients (positive identification in four, and equivocal in one), all in the streptokinase-treated group (p = NS). There were also no differences between streptokinase and control treatment in any of the echocardiographic variables in subgroups of patients with anterior infarction, inferior infarction, no prior infarction or reperfusion with streptokinase. It is concluded that intracoronary streptokinase given relatively late in the course of acute myocardial infarction does not result in improved global or regional wall motion or a reduction in left ventricular thrombus or aneurysm formation in survivors studied 2 months after myocardial infarction.

A randomized trial of intracoronary thrombolysis in a multicenter, geographically limited community has been undertaken. There have been no deaths or important morbidity because of heart catheterization. Preliminary data analysis has shown that patient entry within 3 hours of the onset of infarction has been the exception rather than the rule. It is anticipated that this trial will be completed by mid 1983. It is hoped that the data obtained from this study will help clarify the role of thrombolysis in acute myocardial infarction.

This is a review of the important randomized trials of intracoronary and intravenous streptokinase therapy for treatment of acute myocardial infarction. Trials carried out before 1980 failed to recognize the relations between early coronary reperfusion and myocardial salvage and therefore have not been included in this review. Seven studies on intracoronary streptokinase have been reviewed. The two largest of these studies, the Western Washington trial and the Netherlands trial, show a similar reduction in early mortality. Two other small studies demonstrated a trend toward a reduction in mortality with streptokinase therapy and the other three did not. One small and two large intravenous streptokinase trials are reviewed. Of these, the large GISSI trial in Italy demonstrated a 23% reduction in mortality in patients treated within 3 hours from the onset of symptoms and the Intracoronary Streptokinase in Acute Myocardial Infarction (ISAM) trial showed a similar trend toward reduced mortality. The small Western Washington trial showed an even greater trend toward reduced mortality but this benefit was limited to patients with anterior myocardial infarction who received early therapy. It is concluded that intracoronary and intravenous streptokinase therapy, when initiated within the first 6 hours of acute myocardial infarction, reduces mortality. The therapy is most beneficial for those patients with anterior myocardial infarction and those who can receive therapy within the first 2 to 3 hours from the onset of symptoms.

To determine whether arteriographic dimensions of the acutely recanalized coronary lumen provide information about regional perfusion or clinical outcome, quantitative arteriography was used to measure minimum luminal diameter achieved with intracoronary streptokinase administration in 44 patients with acute myocardial infarction (AMI). Degree of coronary reperfusion was independently assessed visually using the criteria applied in the multicenter Thrombolysis in Myocardial Infarction study. Minimum diameter and qualitative reperfusion grade were both assessed from 172 coronary injections during thrombolysis. Partial perfusion (grade 1 or 2) was seen in 95 of 135 injections (70%) in which the minimum diameter was less than 0.6 mm and complete perfusion (grade 3) was seen in 35 of 37 injections (95%) in which it was 0.6 mm or more (p less than 0.001). Repeat cardiac catheterization was performed at 5.5 +/- 4.9 weeks after AMI (n = 20). When vessels were opened acutely to a minimum diameter of less than 0.6 mm, 5 of 12 vessels (42%) were reoccluded at the time of restudy and 8 of 29 patients (28%) died within 12 months. By contrast, 0 of 8 vessels (0%) were reoccluded when the artery was opened to a diameter of at least 0.6 mm (difference not significant), and only 1 of 15 patients (7%) died (p less than 0.05). Of the patients with grade 1 o r 2 perfusion at the end of the thrombolytic infusion, 7 of 19 (37%) died within 12 months and 2 of 4 vessels (50%) reoccluded; of the patients with grade 3 perfusion, 2 of 25 (8%) died (p less than 0.05) and 2 of 16 vessels (13%) reoccluded (difference not significant).(ABSTRACT TRUNCATED AT 250 WORDS)

Two hundred fifty patients were enrolled in a multicenter, community-based study of the efficacy of intracoronary streptokinase thrombolysis in acute myocardial infarction; 134 were randomly assigned to streptokinase therapy and 116 were controls. All patients underwent left ventricular angiography and coronary arteriography before the random assignment. The mean time from the onset of symptoms to hospitalization was 134 +/- 144 minutes (S.D), and the mean time to random assignment was 276 +/- 185 minutes. Coronary reperfusion was achieved in 68 per cent of the streptokinase-treated group. The overall 30-day mortality was 18 (7.2 per cent); there were five deaths in the streptokinase-treated group (3.7 per cent) and 13 in the control group (11.2 per cent, P less than 0.02). Fifteen of the 18 deaths occurred in patients with anterior infarction. Intracoronary streptokinase therapy resulted in a nearly threefold reduction in the 30-day mortality after hospitalization for acute myocardial infarction.

The Western Washington Intravenous Streptokinase in Acute Myocardial Infarction Trial randomized 368 patients with symptoms and signs of acute myocardial infarction of less than 6 h duration to either conventional care or 1.5 million units of intravenous streptokinase. The mean time to randomization was 209 min and 52% of patients were randomized within 3 h of symptom onset. Quantitative, tomographic thallium-201 infarct size and radionuclide ejection fraction were measured at 8.2 +/- 7.5 weeks in 207 survivors who lived within a 100 mile radius of a centralized laboratory. Overall, infarct size as a percent of the left ventricle was 19 +/- 13% for control subjects and 15 +/- 13% for treatment patients (p = 0.03). For anterior infarction in patients entered within 3 h of symptom onset, infarct size was 28 +/- 13% in the control group versus 19 +/- 15% for the treatment group (p = 0.09). Left ventricular ejection fraction was 47 +/- 15% in the control versus 51 +/- 15% in the treatment group (p = 0.08). For anterior infarction of less than 3 h duration, the ejection fraction was 38 +/- 16% in the control versus 48 +/- 20% in the treatment group (p = 0.13). By statistical analysis incorporating the nonsurvivors, p values for all of these variables were less than or equal to 0.08. There was no benefit for patients with inferior infarction or for anterior infarction of greater than 3 h duration. It is concluded that intravenous streptokinase, when given within 3 h of symptom onset to patients with anterior infarction, reduces infarct size and improves ventricular function.

Three hundred sixty-eight patients were randomly assigned to receive intravenous streptokinase (IVSK) (n = 191) or standard therapy (n = 177) to determine the efficacy of IVSK in the treatment of acute myocardial infarction. The mean time to treatment was 3.5 hr. At 14 days there were 12 deaths in the treatment group (6.3%) and 17 deaths in the control group (9.6%) (p = .23). Early mortality was related to infarct location. Fourteen day mortality for anterior infarctions was 10.4% for treatment with IVSK and 22.4% for control patients (p = .06) and was similar for IVSK-treated patients with inferior infarctions, 4.0% vs 1.8% (p = .32). For those randomized under 3 hr, 14 day mortality tends to be lower in treated patients, 5.2% vs 11.5% (p = .11). There was significant improvement in long-term survival for patients with anterior infarction; 2 year survival was 81% for IVSK-treated patients and 65% for control patients (p = .05). There was no improvement in survival for patients with inferior myocardial infarction (p = .27). We conclude that patients with anterior myocardial infarction have improved survival when treated within the first 6 hr of symptoms. Patients with inferior infarction do not appear to have improved survival with thrombolytic therapy. Some of this improvement in survival in patients with anterior infarction may be due to a higher frequency of revascularization procedures in the treatment group.

Thrombolytic recanalization of the obstructed coronary lumen was studied in 32 patients receiving intracoronary streptokinase for 60 to 90 min during acute myocardial infarction. The process was viewed at high arteriographic magnification and was quantified with computer-assisted measurements from repeated single-plane views. The variability of the method for this application was 0.15 to 0.18 mm on minimum diameter estimates. Structural details were seen that are not commonly appreciated at conventional magnification. The recanalized lumen appears to form along an interface between the thrombus and the vessel wall, progressively enlarging its minimum arteriographic diameter to 0.65 +/- 0.24 mm (+/- 1 SD) at the end of the short-term infusion of streptokinase reflecting a final percent stenosis of 77 +/- 10%. In nine infarct lesions found patent 5 +/- 3 weeks later, the recanalized lumen further improved an average of 0.34 mm in minimum diameter (p less than .005) and 13% stenosis (p less than .01). A thin film of contrast medium surrounding the obstructing thrombus faintly defined the boundaries of the original atherosclerotic lumen in all but two cases. The "original stenosis" measured 1.25 +/- 0.32 mm in minimum diameter and 56 +/- 14% stenosis when first visualized; it was unchanged throughout the course of infusion of streptokinase. In five patients catheterized 10 +/- 12 weeks before their infarction, the original stenosis averaged 1.15 +/- 0.22 mm in the preinfarct angiogram, as compared with 1.17 +/- 0.23 mm in its faintly defined form during thrombolytic therapy (p = NS). In 10 cases, this original lesion was less than a 50% stenosis, and in 21 cases less than 60%.(ABSTRACT TRUNCATED AT 250 WORDS)

Three trials of thrombolytic therapy in myocardial infarction (MI) up to 12 hours after symptom onset were conducted to measure the mean time from onset of chest pain to hospital arrival, and mean time to therapy. The trials, using intracoronary streptokinase, intravenous streptokinase and tissue plasminogen activator (t-PA), indicated a progressive shortening of time between symptom onset and hospital arrival. The Seattle Myocardial Infarction, Triage and Intervention (MITI) trial is evaluating the safety and efficacy of thrombolytic therapy initiated by paramedics in the prehospital setting. Phase I of the trial indicates that one-half of the patients would receive prehospital therapy in the field within the first hour of symptoms, substantially sooner than what can be achieved in the hospital. Phase II of MITI, in a nonrandomized trial, will compare the use of intravenous t-PA in the field with t-PA administered in the emergency department.

Thrombolytic therapy given within the first 4 to 6 hours to patients with evolving acute MI appears to reduce in-hospital and 1-year mortality rates. In addition, patients who receive treatment in the first few hours may also benefit through improved residual left ventricular function, resulting from the preservation of ischemic myocardium. Newer agents that are more effective in lysing intracoronary thrombi are currently under development. The most promising is tissue-type plasminogen activator (t-PA), which is being evaluated in a number of large multicenter trials, including the National Heart, Lung, and Blood Institute's Thrombolysis in Myocardial Infarction (TIMI) trial. In this study researchers are also comparing the additional value of early versus delayed coronary artery angioplasty and are evaluating a subset of patients randomly assigned to early beta-blocker therapy to assess the value of adjunctive pharmacologic therapy. In the future, it is likely that studies will be carried out to determine the usefulness of thrombolytic therapy given to patients by paramedics before hospitalization. Such a study is being planned in several communities. It is hoped that by means of prehospital therapy, it may be possible to treat a substantial group of patients with symptoms and electrocardiographic findings of acute MI before extensive left ventricular myocardial necrosis has occurred. If this goal can be realized, it may be possible to achieve a very substantial reduction in mortality resulting from acute MI. Initial experience with prehospital intravenous streptokinase therapy has already been reported from Jerusalem, Israel.(ABSTRACT TRUNCATED AT 250 WORDS)

The Western Washington Intravenous Streptokinase Trial randomized 368 patients with acute myocardial infarction to receive either intravenous streptokinase or standard therapy. The ventriculograms and coronary angiograms obtained in 170 patients 10.4 +/- 7.4 days after infarction were analyzed to evaluate the effects of thrombolytic therapy on global and regional systolic function. Streptokinase treatment resulted in a higher patency rate of the infarct-related artery (68.5%) than did standard therapy (44.8%) (p = 0.003). Ejection fraction was higher in streptokinase-treated patients (54% vs. 51%, p = 0.056), and the difference was most marked in patients with anterior myocardial infarction (53% vs. 44%, p = 0.03). Regional wall motion was measured by the centerline method and expressed in mean +/- SD motion in 52 normal subjects. There was a trend toward better function of the infarct zone in streptokinase-treated patients (SD, -2.48 vs. -2.70, p = 0.24). Additionally, streptokinase-treated patients had significantly better wall motion of noninfarct areas (SD, 0.36 vs. -0.08, p = 0.02). Treatment effects on function of noninfarct regions were most apparent in the subset of patients with multivessel disease. Thus, intravenous streptokinase preserves left ventricular function in patients with acute myocardial infarction. This benefit includes favorable effects on the function of regions remote from the site of infarction.