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Age and Outcome With Contemporary Thrombolytic Therapy

Results From the GUSTO-I Trial
and for the GUSTO-I Investigators
Originally publishedhttps://doi.org/10.1161/01.CIR.94.8.1826Circulation. 1996;94:1826–1833

    Abstract

    Background Elderly patients with acute myocardial infarction have much to gain from reperfusion with thrombolytic therapy but are also at increased risk of adverse events. We examined outcomes according to age of patients receiving thrombolysis in an international trial.

    Methods and Results Patients were randomized to streptokinase plus subcutaneous heparin, streptokinase plus intravenous heparin, accelerated tissue plasminogen activator (TPA) plus intravenous heparin, or streptokinase and TPA plus intravenous heparin. Clinical outcomes at 30 days (death, stroke, and nonfatal, disabling stroke) and 1-year mortality were summarized descriptively for patients aged <65 (n=24 708), 65 to 74 (n=11 201), 75 to 85 (n=4625), and >85 years (n=412) and assessed as continuous functions of age. Older patients had a higher-risk profile with regard to baseline clinical and angiographic characteristics. Mortality at 30 days increased markedly with age (3.0%, 9.5%, 19.6%, and 30.3% in the four groups, respectively), as did stroke, cardiogenic shock, bleeding, and reinfarction. Combined death or disabling stroke occurred less often with accelerated TPA in all but the oldest patients, who showed a weak trend toward a lower incidence with streptokinase plus subcutaneous heparin: odds ratio 1.13; 95% confidence interval 0.6, 2.1. Similarly, accelerated TPA treatment resulted in lower 1-year mortality in all but the oldest patients (47% TPA versus 40.3% streptokinase).

    Conclusions Lower mortality and greater net clinical benefit were seen with accelerated TPA in patients aged ≤85 years. Because data are limited for patients aged >85 years, the relative superiority of a given thrombolytic regimen cannot be determined. The interactions of stroke and mortality with newer thrombolytic strategies must be examined explicitly in older patients.

    Cardiovascular disease is the most common cause of death and disability in the elderly.1 Nearly 50% of patients who die after hospitalization for acute myocardial infarction are aged >75 years.2 Increasing age is the most important long-term adverse prognostic factor after an infarction.34567

    Thrombolysis with streptokinase or tissue plasminogen activator (TPA) reduces mortality in the elderly.8910 Both agents, however, are associated with higher rates of stroke in older patients.581112 Many early thrombolytic trials imposed an upper age limit of 70 to 75 years because of concern about the risks of intracerebral hemorrhage and fatal or nonfatal disabling stroke.11131415161718 Furthermore, an American College of Cardiology/American Heart Association task force stressed that physicians should be judicious in the selection of older patients for thrombolysis and suggested that treatment of patients aged >75 years was not well established by the evidence.19 Consequently, only a small proportion of patients >75 years undergoes thrombolysis.2021 Regarding the choice of thrombolytic agent, streptokinase has been advocated22 because it has been associated with less cerebral hemorrhage than TPA.5232425

    The Global Utilization of Streptokinase and TPA for Occluded coronary arteries (GUSTO-I) trial enrolled patients without age restriction, providing a unique opportunity to assess the relations between age and the risks and benefits of four thrombolytic regimens.23

    Methods

    Patient Population

    The GUSTO-I trial randomized 41 021 patients with acute myocardial infarction and ST-segment elevation within 6 hours of symptom onset to one of four thrombolytic strategies.23 Enrollment was not restricted because of age or presentation in cardiogenic shock. Patients were excluded if they had prior stroke, active or recent bleeding, recent trauma or major surgery, noncompressible vascular punctures, or previous treatment with streptokinase or anistreplase.

    Treatments

    Patients were randomized to receive streptokinase 1.5 million U infused for 1 hour and subcutaneous heparin 12 500 U twice daily beginning 4 hours after the commencement of streptokinase; streptokinase 1.5 million U for 1 hour and intravenous heparin, beginning with a 5000-U bolus and followed by an infusion of 1000 U adjusted to maintain an activated partial thromboplastin time (aPTT) of 60 to 85 seconds; accelerated TPA, bolus of 15 mg and infusions of 0.75 mg/kg for 30 minutes (up to 50 mg) and 0.5 mg/kg (up to 35 mg) for the next hour, with the same intravenous heparin regimen; or combination TPA (1 mg/kg for 1 hour, up to 90 mg, with 10% given as a bolus) and streptokinase (1 million U for 1 hour) given simultaneously through separate cannulas, with the same intravenous heparin regimen.

    End Points

    The primary end point was all-cause 30-day mortality. Inpatient mortality data were recorded on the main case report form. Postdischarge mortality data were collected by return postcard or by telephone follow-up. Mortality status at 30 days was known for 40 946 patients (99.8%). One-year follow-up data were available for 39 119 patients (95.3%). Secondary end points included stroke, death or stroke, and death or nonfatal, disabling stroke.

    Cases of neurological deficit that were fatal or persisted for 24 hours were reviewed by a blinded, independent committee.26 Events were classified as primary intracranial hemorrhage, nonhemorrhagic infarction, hemorrhagic conversion of infarction, and unknown. Anatomic or diagnostic confirmation of stroke was obtained in 93% of the cases. Bleeding complications were classified as severe or life threatening if they were intracranial or resulted in hemodynamic compromise that required intervention. Moderate bleeding was defined as bleeding that required transfusion.

    Statistical Methods

    To describe changes in baseline characteristics and clinical outcomes with age, we arbitrarily categorized patients into four groups: <65, 65 to 74, 75 to 85, and >85 years. Discrete variables are summarized with frequencies and percentages; continuous variables are described with means±SDs or medians and 25th and 75th percentiles. Clinical outcome variables were tabulated both by age category and by treatment assignment.

    Kaplan-Meier estimates27 for 24-hour, 30-day, and 1-year mortality were calculated to show the treatment effects across the different age groups. These age groups were chosen to allow ready visual inspection of trends in the data.

    Ordinary least-squares regression was used to determine the statistical significance of the relations between age and the other baseline characteristics. Logistic regression was used to evaluate the statistical significance of the relation between age and the 30-day outcomes of interest. Cox proportional hazard modeling techniques were used to determine the statistical significance of the relation between 1-year mortality and age. For both types of mortality models, the shapes of the relations were evaluated with cubic spline functions.282930

    The relation between age and 30-day mortality was also evaluated after adjustment for other baseline clinical prognostic factors.7 We assessed the joint effect of age and treatment with a logistic model that used both of these factors as predictors of outcome. We also assessed the difference in relative effect of treatment on mortality according to age by testing significance of the age-by-treatment interactions for both 30-day and 1-year mortality. We specifically avoided comparisons between individual age subgroups because of the arbitrary nature of the age categories and the limited statistical power of such comparisons.

    Results

    Baseline Characteristics

    Table 1 shows the higher-risk baseline clinical characteristics of the older patients and the greater use of aspirin and β-blockers in the younger patients. Among patients who had coronary angiography (Table 2), older patients more often had TIMI grade 0 flow15 in the infarct-related artery and less often had TIMI grade 3 flow. Older patients also had more multivessel and three-vessel disease and lower left ventricular ejection fractions.

    Clinical Outcomes

    Older patients had markedly higher 30-day mortality (Table 3). Fig 1 shows the probabilities of 30-day and 1-year mortality as a function of age. After adjustment for all other known baseline clinical prognostic factors, age remained the strongest (χ2=717, P<.00001) predictor of 30-day mortality. Total and hemorrhagic stroke also increased with age; however, the rate of nonfatal, disabling stroke was only moderately elevated as a function of age. The incidence of moderate or severe bleeding was higher in older patients, and their aPTTs were higher at both 12 and 24 hours (Tables 3 and 4). Although older patients had lower peak total creatine kinase levels, their peak creatine kinase–MB percentages were higher than those of younger patients.

    Most common postinfarction complications occurred more often in older patients, although there was no increase in ventricular arrhythmias with age. Among patients with cardiogenic shock, myocardial rupture was more common in older patients, as was the combination of asystole and tamponade in all patients. Revascularization was performed less often in older patients. The length of hospital stay was similar in all age groups.

    Comparison of Thrombolytic Strategies

    Table 5 compares clinical outcomes in patients who received TPA versus streptokinase according to age. All but the oldest patients showed lower mortality with accelerated TPA; the very elderly showed a trend toward increased survival with streptokinase plus subcutaneous heparin (Fig 2). Total and hemorrhagic stroke rates were increased in patients ≤85 years old treated with TPA, but, because of increasing overall mortality in the aged and an increased risk of stroke with streptokinase in the oldest patients, the net clinical benefit—reduction in death or nonfatal, disabling stroke—repeated the pattern observed for mortality alone.

    Fig 3 shows 24-hour mortality by age group. Mortality in the oldest patients was more than 10× higher than in the youngest group at the end of this period.

    One-year mortality as a function of age and treatment assignment is shown in Fig 4A through 4D. Although mortality increased dramatically with age, the benefit of accelerated TPA persisted in all but the oldest patients.

    Discussion

    Given the evidence that thrombolytic therapy is effective in elderly patients,81031 we evaluated the effects of age in patients randomized to different thrombolytic strategies within 6 hours of the onset of acute myocardial infarction. Older patients suffered high mortality and morbidity despite aspirin and β-blocker therapy and treatment with thrombolysis. The net clinical benefit—reduction in death or disabling stroke—was greater with accelerated TPA in patients aged ≤85 years, a dramatic example of a beneficial trade-off between lessened mortality and incremental stroke risk. Although the 95% CIs overlap unity in specific age subgroups, the magnitude of the treatment effect is consistent except in patients >85 years old. This very small population (1% of all GUSTO-I patients) derived a greater net clinical benefit from streptokinase plus subcutaneous heparin, which could have occurred by chance.

    Public policy and cost initiatives may overemphasize the risk and underemphasize the benefits of thrombolytic therapy in the elderly. Our data show that the benefits of treatment with accelerated TPA may be greater for older versus younger patients, that is, a net clinical benefit of 5 fewer deaths or disabling strokes per 1000 patients treated for those aged <65 years versus 17 events per 1000 patients treated for those aged 75 to 85 years.

    Patients in GUSTO-I were selected on the basis of thrombolytic eligibility. Patients aged >75 years composed 12% of our population, whereas Weaver et al20 reported that patients aged >75 years constituted 28% of a population with myocardial infarction. In a registry representing a sample of all myocardial infarctions at North American GUSTO-I centers, 30.1% of the patients (186/618) were older than 75, but only 17.8% of those enrolled in GUSTO-I (13/73) were older than 75. Elderly patients have more comorbid disease, and many have relative contradictions to thrombolysis, including an increased risk of intracranial hemorrhage or systemic bleeding; these factors may dissuade clinicians from using these agents in the elderly.2021

    Elderly patients present later than younger patients.32 In GUSTO-I, patients aged >65 years arrived at the hospital 20 to 40 minutes later than younger patients. The reason for this presentation delay is unclear but may relate to a higher pain threshold or a reluctance to seek help.

    Older patients have been reported to have smaller infarcts than younger patients—based on creatine kinase measurements—and, paradoxically, worse outcomes.5 We also found that older patients had lower peak creatine kinase levels; however, the peak percentage of the more cardiac-specific creatine kinase–MB isoenzyme was higher. This could indicate that the elderly have larger infarcts, which would correspond to their poorer outcomes. Not all patients had MB fractions measured, however, and the lower peak creatine kinase levels could relate to the lesser muscle mass in elderly patients or a smaller release of noncardiac creatine kinase.

    The higher prevalence of multivessel disease and lower ejection fraction were expected. The absence of compensatory hyperkinesis,33 coupled with prior infarction, could explain the higher mortality without definitive enzymatic evidence of larger infarctions. Unfortunately, we do not have direct evidence for myocardial rupture as an explanatory factor.

    Surprisingly, given their higher prevalence of multivessel coronary disease, the elderly did not have more recurrent ischemia, but they suffered more reinfarction. We could not determine whether more interventions could have resulted in less reinfarction.

    The GISSI-1 trial showed a trend toward decreased mortality with streptokinase versus control in patients aged >75 years: 28.9% versus 33.1%, respectively, at 21 days and 43.1% versus 46.1% at 1 year.9 In the placebo-controlled ISIS-2 study, 5-week mortality in patients aged >70 years was reduced with streptokinase from 21.6% to 18.2% (P<.05).8 In both trials, the number of lives saved per 1000 patients treated was greater in elderly versus younger patients. In GISSI-1, the absolute mortality reduction at 3 weeks per 1000 patients treated was 20 lives saved in patients aged ≤65 years versus 42 lives saved in patients aged >75 years.9 In ISIS-2, streptokinase treatment resulted in saving (per 1000 treated) 16 lives in patients aged <60 years, 36 lives in those aged 60 to 69 years, and 36 lives in patients aged ≥70 years.8 A recent decision-analysis model that incorporates these data suggests that streptokinase therapy is cost-effective in the elderly.12

    The accelerated TPA regimen in GUSTO-I was associated with lower 30-day mortality and higher stroke rates in patients ≤85 years old. The incidence of nonfatal, disabling stroke was only moderately elevated in the oldest patients. The comparison of the effects of streptokinase and TPA according to age, an analysis stipulated a priori in the protocol, is based on statistically underpowered cohorts. Despite randomizing 41 021 patients, we had insufficient power to detect significant variations in treatment effect with increasing age.

    The relation between cardiac and cerebrovascular effects of reperfusion deserves substantial consideration, because new treatment strategies will involve the same trade-offs. Given the increase in stroke with age, it seems logical that net clinical outcomes would be more severely compromised in the elderly with the more aggressive regimen. We observed that the hemorrhagic stroke risk in younger patients was similar with either streptokinase or TPA, and that as age increased, the risk increased more with TPA than with streptokinase. However, mortality in patients with stroke also increased dramatically with age; thus, the contribution of stroke in the elderly counted more toward the mortality component of the net clinical benefit outcome, which combines mortality and nonfatal, disabling stroke. The greater cardiac benefit of TPA in the elderly was partially offset by the effect of stroke on mortality, but so few disabled stroke survivors remained that stroke had almost no effect on treatment differences in net clinical outcome according to age.

    Compared with conservative treatment, thrombolysis is reportedly associated with an early hazard that is most pronounced in the elderly.32 Our data provide evidence that more aggressive thrombolysis is associated with an increased hazard during the first 24 hours for patients aged >75 years. Perhaps the more rapid reperfusion with accelerated TPA increases the risk of reperfusion-associated arrhythmias, myocardial stunning, or cardiac rupture in this population.

    The results in patients older than 85 years appear different from those in other age groups. Patients aged ≤85 years showed a constant relative reduction in mortality, an increasing absolute mortality reduction, and increasing relative and absolute risks of stroke, especially hemorrhagic stroke, with accelerated TPA versus streptokinase as age increased. For those aged >85 years, the risk of stroke was higher but mortality was lower in patients treated with streptokinase and subcutaneous heparin than in those treated with accelerated TPA. For the combined end point of death or nonfatal, disabling stroke, the best regimen appeared to be streptokinase and subcutaneous heparin.

    The conservative explanation for this is that the observations in patients aged >85 years (only 412 patients) are due to chance. Formal statistical testing revealed that the differences in results for both death and stroke across age categories were not statistically significant; the observed results were well within the play of chance. Previous experience has shown that variations within subgroups of large trials are more likely due to random fluctuations than to biological effects.34 A detailed analysis of statistical power showed that for the observed treatment effect, the power to detect a significant treatment difference with this sample size and event rate was only 0.20. A minimum doubling in the treatment effect difference or several thousand more elderly patients would have been required to provide adequate power. Alternatively, the mortality results in patients aged >85 years may relate to an increased early hazard with accelerated TPA or a relative reduction in benefit from accelerated TPA versus streptokinase treatment as a function of increasing age. The absence of reported stroke with accelerated TPA may also reflect the early demise of patients with intracranial hemorrhage, so that stroke could not be diagnosed.

    The policy implications of these findings are manifold. For the majority enrolled in GUSTO-I, accelerated TPA resulted in lower risks of death and the combined end point of death or disabling stroke; this result was more pronounced in absolute terms in older rather than younger patients. The recent cost-effectiveness analysis of GUSTO-I emphasized this point: the cost per year of life saved was $17 893 for patients aged >75 years with anterior infarction versus $76 417 for patients aged <40 years with anterior infarction.35 Substantial uncertainty remains about patients older than 85 years, because few data exist apart from the GUSTO-I experience. Independent of thrombolytic agent, the dramatic escalation of death and stroke with increasing age and the continued high event rates even in this population treated aggressively with thrombolysis, aspirin, and β-blockers call for more effective therapies.

    Presented in part at the 67th Scientific Sessions of the American Heart Association, Dallas, Tex, November 14-17, 1994, and published in abstract form (Circulation. 1994;90:I-563).

    
          Figure 1.

    Figure 1. Probability of mortality at 30 days and 1 year as a function of age.

    
          Figure 2.

    Figure 2. Odds ratios and 95% CIs for the risk of death, hemorrhagic stroke, and death or disabling stroke at 30 days: treatment with accelerated tissue plasminogen activator (t-PA) and intravenous heparin versus streptokinase and subcutaneous heparin.

    
          Figure 3.

    Figure 3. Twenty-four hour Kaplan-Meier mortality estimates by age group.

    
          Figure 4.

    Figure 4. One-year Kaplan-Meier mortality estimates in patients aged <65 (A), 65 to 74 (B), 75 to 85 (C), and >85 (D) years who received accelerated tissue plasminogen activator (TPA; t-PA in Figure), streptokinase with intravenous heparin (SK-IV), TPA and streptokinase with intravenous heparin (Combination), or streptokinase with subcutaneous heparin (SK-SQ).

    Table 1. Baseline Characteristics*

    Age, y
    <65 (n=24708)65 to 74 (n=11201)75 to 85 (n=4625)>85 (n=412)
    Age, y53.2±8.169.6±2.878.7±2.687.4±2.5
    Males, n (%)20386 (83)7500 (67)2569 (56)181 (44)
    Weight, kg82.6±15.876.4±1471.1±13.465.7±12.5
    Height, cm172.8±8.9169.6±9.3167.2±9.5164.6±9.3
    Diabetes, n (%)3143 (13)2017 (18)790 (17)55 (13)
    Hypertension, n (%)8318 (34)4929 (44)2099 (46)186 (45)
    Hypercholesterolemia, n (%)8993 (37)3471 (32)1049 (24)68 (17)
    Current smoking, n (%)13925 (57)2948 (27)601 (13)25 (6)
    Previous angina, n (%)8429 (34)4535 (41)1914 (42)160 (39)
    Previous myocardial infarction, n (%)3488 (14)2211 (20)927 (20)77 (19)
    Previous angioplasty, n (%)1084 (4)445 (4)113 (2)4 (1)
    Previous bypass surgery, n (%)950 (4)661 (6)167 (4)5 (1)
    Location of infarction, n (%)
     Anterior9077 (37)4533 (41)2108 (46)224 (55)
     Inferior14705 (60)6258 (56)2344 (51)174 (42)
     Other847 (3)381 (3)160 (3)12 (3)
    Killip class, n (%)
     I21882 (89)9123 (82)3486 (76)291 (71)
     II2399 (10)1707 (15)916 (20)94 (23)
     III186 (1)201 (2)144 (3)16 (4)
     IV134 (1)107 (1)63 (1)10 (2)
    Time to presentation, h1.76±1.171.96±1.22.06±1.222.06±1.23
    Time to treatment, h3.0±1.63.21±1.623.35±1.583.43±1.59
    Acute treatments, n (%)
     Aspirin24072 (98)10767 (97)4439 (96)387 (94)
     Intravenous β-blocker11922 (48)4403 (39)1718 (37)145 (35)

    Values are mean±SD.

    *All P<.001 except “other” location of infarction, comparison of age as a continuous variable with each baseline factor.

    Table 2. Angiographic Characteristics

    Age, y
    <65 (n=24708)65 to 74 (n=11201)75 to 85 (n=4625)>85 (n=412)
    TIMI flow grade, n (%)
     01600 (18)672 (20)220 (21)6 (27)
     1929 (10)402 (12)107 (10)3 (14)
     21948 (22)763 (23)239 (23)6 (27)
     34468 (50)1512 (45)486 (46)7 (32)
    No. of diseased vessels
     01368 (11)227 (5)61 (4)0
     16272 (49)1949 (41)512 (34)17 (45)
     23235 (25)1512 (31)512 (34)11 (29)
     31816 (14)1114 (23)417 (28)10 (26)
    Location of infarction, n (%)
     Left anterior descending artery5294 (35)2159 (38)698 (40)23 (51)
     Left circumflex artery1833 (12)627 (11)164 (9)2 (4)
     Right coronary artery6869 (46)2528 (44)763 (44)20 (44)
     Left main coronary artery59 (<1)23 (<1)11 (<1)0
     Bypass graft226 (2)119 (2)38 (2)0
     Unknown663 (4)237 (4)67 (4)0
     None28 (<1)2 (<1)2 (<1)0
    Angiography, n (%)15124 (61)5750 (51)1768 (37)45 (15)
    Target artery stenosis, %90 (80, 99)90 (85, 99)95 (85, 99)95 (90, 99)
    Left ventricular ejection fraction, %53 (45, 61)50 (40, 60)50 (40, 60)45 (37, 61)

    TIMI indicates Thrombolysis In Myocardial Infarction. Values are medians; where two values are given parenthetically, they represent the 25th and 75th percentiles.

    Table 3. Outcomes and Clinical Events

    Age, y
    <65 (n=24708)65 to 74 (n=11201)75 to 85 (n=4625)>85 (n=412)
    In-hospital mortality, n (%)683 (2.8)1022 (9.1)883 (19.1)115 (27.9)
    30-day mortality, n (%)742 (3.0)1064 (9.5)905 (19.6)125 (30.3)
    Stroke, n (%)184 (0.8)238 (2.1)157 (3.4)12 (2.9)
     Hemorrhagic75 (0.3)114 (1.0)72 (1.6)7 (1.7)
     Nonhemorrhagic86 (0.4)97 (0.9)62 (1.3)2 (0.5)
     Hemorrhagic conversion12 (0.1)14 (0.1)7 (0.2)1 (0.2)
     Unknown11 (0.04)13 (0.1)16 (0.4)2 (0.5)
     Nonfatal, disabling80 (0.3)82 (0.7)42 (0.9)3 (0.7)
    Death or stroke, n (%)879 (3.6)1202 (10.7)973 (21.0)130 (31.6)
    Death or hemorrhagic stroke, n (%)785 (3.2)1108 (9.9)924 (20.0)127 (30.8)
    Death or nonfatal disabling stroke, n (%)822 (3.3)1146 (10.2)947 (20.5)128 (31.1)
    Bleeding, n (%)2340 (9.5)1768 (15.8)944 (20.5)95 (23.1)
     Severe191 (0.8)181 (1.6)115 (2.5)7 (1.7)
     Moderate2149 (8.7)1587 (14.2)829 (18.0)88 (21.4)
    aPTT at 12 hours, s(n=17264)(n=7864)(n=3117)(n=250)
    78.2±44.593±49.8103.4±52108.4±52.7
    aPTT at 24 hours, s(n=16882)(n=7419)(n=2885)(n=242)
    66.5±36.975.1±40.883.5±4688.3±50.4
    Peak creatine kinase, U/L(n=23506)(n=10644)(n=4351)(n=390)
    2028±19491814±16881745±16191600±1688
    Peak creatine kinase–MB, %(n=7205)(n=3128)(n=1315)(n=114)
    18.1±44.618.9±40.517.6±29.719.7±30.1
    Anaphylaxis, n (%)128 (0.5)60 (0.5)23 (0.5)1 (0.2)
    Cardiogenic shock, n (%)960 (3.9)856 (7.7)557 (12.1)68 (16.5)
     With cardiac rupture, n (%)17 (2)25 (3)24 (4)2 (4)
    Reinfarction, n (%)795 (3.2)539 (4.8)259 (5.6)32 (7.8)
    Recurrent ischemia, n (%)4710 (19.1)2352 (21.1)981 (21.3)81 (19.8)
    Heart failure, n (%)2869 (11.6)2290 (20.5)1315 (28.4)148 (35.9)
    Sustained hypotension, n (%)2343 (9.5)1572 (14.1)879 (19.0)81 (19.7)
    Atrioventricular block,* n (%)1716 (7.0)1072 (9.6)544 (11.8)55 (13.4)
    Sustained ventricular tachycardia, n (%)1286 (5.2)815 (7.3)400 (8.7)26 (6.3)
    Ventricular fibrillation, n (%)1498 (6.1)833 (7.5)382 (8.3)30 (7.3)
    Asystole, n (%)894 (3.6)747 (6.7)620 (13.5)79 (19.2)
    Tamponade, n (%)106 (0.4)115 (1.0)87 (1.9)4 (1.0)
    Asystole and tamponade, n (%)80 (0.32)56 (0.50)51 (1.1)3 (1.0)
    Atrial fibrillation or flutter, n (%)1396 (5.7)1460 (13.1)867 (18.8)100 (24.3)
    Procedures, n (%)
     Angioplasty6077 (24.8)2205 (19.8)603 (13.1)38 (9.2)
     Bypass grafting2056 (8.4)1157 (10.4)308 (6.7)5 (1.2)
     Intra-aortic balloon pump779 (3.2)517 (4.6)179 (3.9)11 (2.7)
     Cardioversion/defibrillation2135 (8.7)1159 (10.4)510 (11.1)38 (9.2)
     Pacemaker1499 (6.1)934 (8.4)411 (8.9)26 (6.3)
     Swan-Ganz catheter2691 (10.9)1667 (14.9)660 (14.3)42 (10.2)
     Ventilator2350 (9.5)1628 (14.6)653 (14.2)42 (10.2)
    Length of hospital stay, d10.3±8.311.5±11.711.2±11.210.7±8.9

    aPTT indicates activated partial thromboplastin time; MB, myocardial band isoenzyme. Values are mean±SD.

    *Second or third degree.

    Table 4. Significant Bleeding by Age Group and Treatment Assignment*

    Age, y
    <65 (n=24708)65 to 74 (n=11201)75 to 85 (n=4625)>85 (n=412)
    Moderate or severe bleeding, n (%)
     TPA511 (8.2)382 (13.7)236 (19.4)23 (21.1)
     SK-IV heparin667 (10.6)499 (17.6)263 (22.7)19 (19.0)
     SK-SQ heparin547 (9.2)404 (14.8)189 (18.0)20 (23.0)
     Combination615 (9.9)483 (17.2)256 (21.5)33 (28.7)
    Severe bleeding, n (%)
     TPA29 (0.5)36 (1.3)26 (2.1)1 (0.9)
     SK-IV heparin59 (0.9)56 (2.0)35 (3.0)0
     SK-SQ heparin49 (0.8)42 (1.5)25 (2.4)1 (1.2)
     Combination54 (0.9)47 (1.7)29 (2.4)5 (4.4)
    Any transfusion, n (%)
     TPA378 (6.3)319 (11.9)189 (16.2)19 (17.4)
     SK-IV heparin477 (8.0)422 (15.5)225 (20.4)17 (17.7)
     SK-SQ heparin411 (7.2)334 (12.7)161 (16.0)17 (20.2)
     Combination447 (7.5)390 (14.4)205 (17.8)26 (23.2)
    Non-CABG transfusion,* n (%)
     TPA132 (2.2)147 (5.5)126 (10.8)18 (16.5)
     SK-IV heparin212 (3.5)225 (8.2)175 (15.8)15 (15.6)
     SK-SQ heparin201 (3.5)176 (6.7)110 (10.9)16 (19.1)
     Combination195 (3.3)195 (7.2)151 (13.1)24 (21.8)

    TPA indicates accelerated tissue plasminogen activator; SK, streptokinase; IV, intravenous; SQ, subcutaneous; CABG, coronary artery bypass graft; and Combination, streptokinase and TPA with intravenous heparin. Values are the number (percentage) of patients in each category.

    *Any transfusion given to a patient undergoing bypass surgery was considered bypass related.

    Table 5. Effects of Streptokinase and TPA on 30-Day Mortality and Stroke Rates According to Age

    Age, yTPASK-SQ HeparinOdds Ratio (95% CI) TPA vs SK-SQ HeparinSK-IV HeparinOdds Ratio (95% CI) TPA vs SK-IV Heparin
    <65n=6254n=5947n=6284
     Death, %2.73.20.83 (0.67, 1.03)3.40.78 (0.64, 0.96)
     Any stroke, %0.750.671.12 (0.73, 1.71)0.731.03 (0.68,1.55)
     Hemorrhagic stroke, %0.220.250.89 (0.43, 1.84)0.330.67 (0.34, 1.32)
     Disabling stroke, %0.30.221.39 (0.69, 2.82)0.241.27 (0.65, 2.51)
     Death or disabling stroke, %3.03.50.86 (0.7, 1.05)3.60.82 (0.68, 1.00)
    65 to 74n=2799n=2733n=2846
     Death, %8.310.40.77 (0.64, 0.93)10.30.79 (0.66, 0.94)
     Any stroke, %2.181.461.5 (1.00, 2.24)2.220.99 (0.69, 1.41)
     Hemorrhagic stroke, %1.140.552.1 (1.13, 3.88)0.841.36 (0.8, 2.32)
     Disabling stroke, %0.80.372.16 (1.02, 4.58)0.711.12 (0.61, 2.06)
     Death or disabling stroke, %9.110.80.83 (0.69, 0.98)11.00.8 (0.68, 0.96)
    75 to 85n=1218n=1051n=1162
     Death, %18.220.20.88 (0.71, 1.08)19.20.93 (0.76, 1.15)
     Any stroke, %4.193.241.31 (0.84, 2.03)2.51.71 (1.07, 2.71)
     Hemorrhagic stroke, %2.141.241.74 (0.89, 3.41)0.952.28 (1.12, 4.64)
     Disabling stroke, %0.930.970.96 (0.41, 2.26)0.521.78 (0.66, 4.83)
     Death or disabling stroke, %19.221.10.89 (0.72, 1.09)19.80.96 (0.79, 1.18)
    >85n=110n=87n=100
     Death, %30.026.41.19 (0.64, 2.23)32.00.91 (0.51, 1.64)
     Any stroke, %1.822.30.79 (0.11, 5.7)6.00.29 (0.06, 1.47)
     Hemorrhagic stroke, %0.912.30.39 (0.04, 4.37)3.00.3 (0.03, 2.9)
     Disabling stroke, %01.16*2.06*
     Death or disabling stroke, %30.027.61.13 (0.6, 2.1)34.00.83 (0.47, 1.49)

    SK indicates streptokinase; SQ, subcutaneous; TPA, accelerated tissue plasminogen activator; and IV, intravenous.

    *No events in the TPA group.

    This study was funded by grants from Bayer, New York, NY; CIBA-Corning, Medfield, Mass; Genentech, South San Francisco, Calif; ICI Pharmaceuticals, Wilmington, Del; and Sanofi Pharmaceuticals, Paris, France.

    Footnotes

    Correspondence to Dr Harvey White, Director of Cardiovascular Research, Green Lane Hospital, Epsom, Auckland 1003, New Zealand.

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