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(Circulation. 1996;94:1826-1833.)
© 1996 American Heart Association, Inc.

Articles

Age and Outcome With Contemporary Thrombolytic Therapy

Results From the GUSTO-I Trial

Harvey D. White, MB, DSc; Gabriel I. Barbash, MD, MPH; Robert M. Califf, MD; R. John Simes, MD; Christopher B. Granger, MD; W. Douglas Weaver, MD; Neal S. Kleiman, MD; Philip E. Aylward, BM, BCh; Joel M. Gore, MD; Alec Vahanian, MD; Kerry L. Lee, PhD; Allan M. Ross, MD; Eric J. Topol, MD; for the GUSTO-I Investigators

Green Lane Hospital (H.D.W.), Auckland, New Zealand; Ichilov Hospital (G.I.B.), Tel Aviv, Israel; Duke University Medical Center (R.M.C., C.B.G., K.L.L.), Durham, NC; National Health Medical Research Council Clinical Trials Centre (R.J.S.), University of Sydney, Australia; University of Washington (W.D.W.), Seattle; Baylor College of Medicine/The Methodist Hospital (N.S.K.), Houston, Tex; Flinders Medical Centre (P.E.A.), Adelaide, Australia; University of Massachusetts Medical School (J.M.G.), Worcester; Hospital Tenon (A.V.), Paris, France; George Washington University Medical Center (A.M.R.), Washington, DC; and the Cleveland Clinic Foundation (E.J.T.), Cleveland, Ohio.

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

	Abstract

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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.

Key Words: thrombolysis • tissue plasminogen activator • aging • streptokinase

	Introduction

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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.^{3 4 5 6 7}

Thrombolysis with streptokinase or tissue plasminogen activator (TPA) reduces mortality in the elderly.^{8 9 10} Both agents, however, are associated with higher rates of stroke in older patients.^{5 8 11 12} 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.^{11 13 14 15 16 17 18} 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.^{20 21} Regarding the choice of thrombolytic agent, streptokinase has been advocated²² because it has been associated with less cerebral hemorrhage than TPA.^{5 23 24 25}

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

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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.^{28 29 30}

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

Top Abstract Introduction Methods Results Discussion References

 
Baseline Characteristics
Table 1 shows the higher-risk baseline clinical characteristics of the older patients and the greater use of aspirin and ß-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.

View this table: [in this window] [in a new window]   Table 1. Baseline Characteristics*

View this table: [in this window] [in a new window]   Table 2. Angiographic Characteristics

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 (²=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.

View this table: [in this window] [in a new window]   Table 3. Outcomes and Clinical Events

View larger version (13K): [in this window] [in a new window]   Figure 1. Probability of mortality at 30 days and 1 year as a function of age.

View this table: [in this window] [in a new window]   Table 4. Significant Bleeding by Age Group and Treatment Assignment*

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.

View this table: [in this window] [in a new window]   Table 5. Effects of Streptokinase and TPA on 30-Day Mortality and Stroke Rates According to Age

View larger version (25K): [in this window] [in a new window]   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.

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

View larger version (13K): [in this window] [in a new window]   Figure 3. Twenty-four hour Kaplan-Meier mortality estimates by age group.

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.

View larger version (26K): [in this window] [in a new window]   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).

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Given the evidence that thrombolytic therapy is effective in elderly patients,^{8 10 31} 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 ß-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.^{20 21}

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 ß-blockers call for more effective therapies.

	Acknowledgments

 
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

 
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).

Received May 28, 1996; revision received August 5, 1996; accepted August 6, 1996.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Stason WB, Sanders CA, Smith HC. Cardiovascular care of the elderly: economic consideration. J Am Coll Cardiol. 1987;10:18A-21A.
   
2. Roig E, Castaner A, Simmons B, Patel R, Ford E, Cooper R. In-hospital mortality rates from acute myocardial infarction by race in US hospitals: findings from the National Hospital Discharge Survey. Circulation. 1987;76:280-288.[Abstract/Free Full Text]
   
3. Norris RM, Brandt PWT, Caughey DE, Lee AJ, Scott PJ. A new coronary prognostic index. Lancet. 1969;1:274-278.[Medline] [Order article via Infotrieve]
   
4. Hillis LD, Forman S, Braunwald E, and the Thrombolysis in Myocardial Infarction (TIMI) Phase II Co-Investigators. Risk stratification before thrombolytic therapy in patients with acute myocardial infarction. J Am Coll Cardiol. 1990;16:313-315.[Abstract]
   
5. Maggioni AP, Franzosi JG, Santoro E, White H, Van de Werf F, Tognoni G, on behalf of the GISSI-2 and International Study Groups. Analysis of the risk of stroke in 20,891 patients with acute myocardial infarction following thrombolytic and antithrombotic treatment. N Engl J Med. 1992;327:1-6.[Abstract]
   
6. Stevenson R, Ranjadayalan K, Wilkinson P, Roberts R, Timmis AD. Short and long term prognosis of acute myocardial infarction since introduction of thrombolysis. Br Med J. 1993;307:349-353.
   
7. Lee KL, Woodlief LH, Topol EJ, Weaver WD, Betriu A, Col J, Simoons M, Aylward P, Van de Werf F, Califf RM, for the GUSTO-I Investigators. Predictors of 30-day mortality in the era of reperfusion for acute myocardial infarction: results from an international trial of 41 021 patients. Circulation. 1995;91:1659-1668.[Abstract/Free Full Text]
   
8. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet. 1988;2:349-360.[Medline] [Order article via Infotrieve]
   
9. Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico (GISSI). Long-term effects of intravenous thrombolysis in acute myocardial infarction: final report of the GISSI study. Lancet. 1987;2:871-874.[Medline] [Order article via Infotrieve]
   
10. Wilcox RG, von der Lippe G, Olsson CG, Jensen G, Skene AM, Hampton JR. Effects of alteplase in acute myocardial infarction: 6-month results from the ASSET study. Lancet. 1990;335:1175-1178.[Medline] [Order article via Infotrieve]
    
11. European Cooperative Study Group for Streptokinase Treatment in Acute Myocardial Infarction. Streptokinase in acute myocardial infarction. N Engl J Med. 1979;301:797-802.[Abstract]
    
12. Krumholz HM, Pasternak RC, Weinstein MC, Friesinger GC, Ridker PM, Tosteson AN, Goldman L. Cost effectiveness of thrombolytic therapy with streptokinase in elderly patients with suspected acute myocardial infarction. N Engl J Med. 1992;327:7-13.[Abstract]
    
13. Cerqueira MD, Maynard C, Ritchie JL, Davis KB, Kennedy JW. Long-term survival in 618 patients from the Western Washington Streptokinase in Myocardial Infarction Trials. J Am Coll Cardiol. 1992;20:1452-1459.[Abstract]
    
14. Topol EJ, Califf RM, George BS, Kereiakes DJ, Abbottsmith CW, Candela RJ, Lee KL, Pitt B, Stack RS, O'Neill WW, and the Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) Study Group. A randomized trial of immediate versus delayed elective angioplasty after intravenous tissue plasminogen activator in acute myocardial infarction. N Engl J Med. 1987;317:581-588.[Abstract]
    
15. The TIMI Study Group. The Thrombolysis in Myocardial Infarction (TIMI) Trial: phase 1 findings. N Engl J Med. 1985;312:932-936.[Medline] [Order article via Infotrieve]
    
16. Anderson JL, Marshall HW, Bray BE, Lutz JR, Frederick PR, Yanowitz FG, Datz FL, Klausner SC, Hagan AD. A randomized trial of intracoronary streptokinase in the treatment of acute myocardial infarction. N Engl J Med. 1983;308:1312-1318.[Abstract]
    
17. Wilcox RG, von der Lippe G, Olsson CG, Jensen G, Skene AM, Hampton JR. Trial of tissue plasminogen activation for mortality reduction in acute myocardial infarction: Anglo-Scandinavian Study of Early Thrombolysis (ASSET). Lancet. 1988;2:525-530.[Medline] [Order article via Infotrieve]
    
18. AIMS Trial Study Group. Effect of intravenous APSAC on mortality after acute myocardial infarction: preliminary report of a placebo-controlled clinical trial. Lancet. 1988;1:545-549.[Medline] [Order article via Infotrieve]
    
19. Gunnar RM, Passamani ER, Bourdillon PD, Pitt B, Dixon DW, Rapaport E, Fuster V, Reeves TJ, Karp RB, Russell RO Jr. Guidelines for the early management of patients with acute myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Assessment of Diagnostic and Therapeutic Cardiovascular Procedures (Subcommittee to Develop Guidelines for the Early Management of Patients with Acute Myocardial Infarction). J Am Coll Cardiol. 1990;16:249-292.[Medline] [Order article via Infotrieve]
    
20. Weaver WD, Litwin PE, Martin JS, Kudenchuk PJ, Maynard C, Eisenberg MS, Ho MT, Cobb LA, Kennedy JW, Wirkus MS, for the MITI Project Group. Effect of age on use of thrombolytic therapy and mortality in acute myocardial infarction. J Am Coll Cardiol. 1991;18:657-662.[Abstract]
    
21. Rogers WJ, Bowlby LJ, Chandra NC, French WJ, Gore JM, Lambrew CT, Rubison RM, Tiefenbrunn AJ, Weaver WD. Treatment of myocardial infarction in the United States (1990 to 1993): observations from the National Registry of Myocardial Infarction. Circulation. 1994;90:2103-2114.[Abstract/Free Full Text]
    
22. Fuster V. Coronary thrombolysis: a perspective for the practicing physician. N Engl J Med. 1993;329:723-725.[Free Full Text]
    
23. The GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med. 1993;329:673-682.[Abstract/Free Full Text]
    
24. ISIS-3 (Third International Study of Infarct Survival) Collaborative Group. ISIS-3: a randomised comparison of streptokinase vs. tissue plasminogen activator vs. anistreplase and of aspirin plus heparin vs. aspirin alone among 41299 cases of suspected acute myocardial infarction. Lancet. 1992;339:753-770.[Medline] [Order article via Infotrieve]
    
25. Simoons ML, Maggioni AP, Knatterud G, Leimberger JD, de Jaegere P, van Domburg R, Boersma E, Franzosi MG, Califf R, Schroder R. Individual risk assessment for intracranial haemorrhage during thrombolytic therapy. Lancet. 1993;342:1523-1528.[Medline] [Order article via Infotrieve]
    
26. Gore JM, Granger CB, Simoons ML, Sloan MA, Weaver WD, White HD, Barbash GI, Van de Werf F, Aylward PE, Topol EJ, Califf RM, for the GUSTO-I Investigators. Stroke after thrombolytic therapy: mortality and functional outcomes in the GUSTO-I trial. Circulation. 1995;92:2811-2818.[Abstract/Free Full Text]
    
27. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457-481.
    
28. Smith PL. Splines as a useful and convenient statistical tool. Am Statistician. 1979;33:57-62.
    
29. Stone CJ, Koo C. Additive splines in statistics. In: Proceedings of the Statistical Computing Section. 1985:45-48.
    
30. Devlin TF, Weeks BJ. Spline functions for logistic regression modeling. In: Proceedings of the 11th Annual SAS Users Group International Conference. 1986:646-651.
    
31. AIMS Trial Study Group. Long-term effects of intravenous anistreplase in acute myocardial infarction: final report of the AIMS study. Lancet. 1990;335:427-431.[Medline] [Order article via Infotrieve]
    
32. Fibrinolytic Therapy Trialists' (FTT) Collaborative Group. Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomised trials of more than 1000 patients. Lancet. 1994;343:311-322.[Medline] [Order article via Infotrieve]
    
33. Harrison JK, Califf RM, Woodlief LH, Kereiakes D, George BS, Stack RS, Ellis SG, Lee KL, O'Neill W, Topol EJ, for the TAMI Study Group. Systolic left ventricular function after reperfusion therapy for acute myocardial infarction: analysis of determinants of improvement. Circulation. 1993;87:1531-1541.[Abstract/Free Full Text]
    
34. Yusuf S, Collins R, Peto R. Why do we need some large, simple randomized trials? Stat Med. 1984;3:409-422.[Medline] [Order article via Infotrieve]
    
35. Mark DB, Hlatky MA, Califf RM, Naylor D, Lee KL, Armstrong PW, Barbash GI, White HD, Simoons ML, Nelson C, Clapp-Channing N, Knight D, Harrell FE Jr, Simes RJ, Topol EJ. Cost effectiveness of thrombolytic therapy with tissue plasminogen activator versus streptokinase for acute myocardial infarction: results from the GUSTO randomized trial. N Engl J Med. 1995;332:1418-1424.[Abstract/Free Full Text]
    

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				A. Jahangir, S. Sagar, and A. Terzic Aging and cardioprotection J Appl Physiol, December 1, 2007; 103(6): 2120 - 2128. [Abstract] [Full Text] [PDF]

				J. L. Anderson, C. D. Adams, E. M. Antman, C. R. Bridges, R. M. Califf, D. E. Casey Jr, W. E. Chavey II, F. M. Fesmire, J. S. Hochman, T. N. Levin, et al. ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction) Developed in Collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine J. Am. Coll. Cardiol., August 14, 2007; 50(7): e1 - e157. [Full Text] [PDF]

				K. P. Alexander, L. K. Newby, P. W. Armstrong, C. P. Cannon, W. B. Gibler, M. W. Rich, F. Van de Werf, H. D. White, W. D. Weaver, M. D. Naylor, et al. Acute Coronary Care in the Elderly, Part II: ST-Segment-Elevation Myocardial Infarction: A Scientific Statement for Healthcare Professionals From the American Heart Association Council on Clinical Cardiology: In Collaboration With the Society of Geriatric Cardiology Circulation, May 15, 2007; 115(19): 2570 - 2589. [Abstract] [Full Text] [PDF]

				S. P. Schulman and G. Gerstenblith Arginine Therapy for Acute Myocardial Infarction--Reply JAMA, May 10, 2006; 295(18): 2139 - 2140. [Full Text] [PDF]

				S. P. Schulman, L. C. Becker, D. A. Kass, H. C. Champion, M. L. Terrin, S. Forman, K. V. Ernst, M. D. Kelemen, S. N. Townsend, A. Capriotti, et al. L-Arginine Therapy in Acute Myocardial Infarction: The Vascular Interaction With Age in Myocardial Infarction (VINTAGE MI) Randomized Clinical Trial JAMA, January 4, 2006; 295(1): 58 - 64. [Abstract] [Full Text] [PDF]

				H. Bueno, M. Martinez-Selles, E. Perez-David, and R. Lopez-Palop Mechanisms of death in elderly patients with acute myocardial infarction exposed to fibrinolytic therapy: reply Eur. Heart J., January 2, 2006; 27(2): 246 - 247. [Full Text] [PDF]

				Part 8: Stabilization of the Patient With Acute Coronary Syndromes Circulation, December 13, 2005; 112(24_suppl): IV-89 - IV-110. [Full Text] [PDF]

				K. E. Szummer, S. D. Solomon, E. J. Velazquez, R. Kilaru, J. McMurray, J.-L. Rouleau, K. W. Mahaffey, A. P. Maggioni, R. M. Califf, M. A. Pfeffer, et al. Heart failure on admission and the risk of stroke following acute myocardial infarction: the VALIANT registry Eur. Heart J., October 2, 2005; 26(20): 2114 - 2119. [Abstract] [Full Text] [PDF]

				R. H. Mehta, C. B. Granger, K. P. Alexander, E. Bossone, H. D. White, and M. H. Sketch Jr Reperfusion strategies for acute myocardial infarction in the elderly: Benefits and risks J. Am. Coll. Cardiol., February 15, 2005; 45(4): 471 - 478. [Abstract] [Full Text] [PDF]

				E. G. Lakatta and S. Schulman Age-associated cardiovascular changes are the substrate for poor prognosis with myocardial infarction J. Am. Coll. Cardiol., July 7, 2004; 44(1): 35 - 37. [Full Text] [PDF]

				C.-I Cheng, K.-H. Yeh, H.-W. Chang, T.-H. Yu, Y.-H. Chen, H.-T. Chai, and H.-K. Yip Comparison of Baseline Characteristics, Clinical Features, Angiographic Results, and Early Outcomes in Men vs Women With Acute Myocardial Infarction Undergoing Primary Coronary Intervention Chest, July 1, 2004; 126(1): 47 - 53. [Abstract] [Full Text] [PDF]

				H.-K. Yip, C.-J. Wu, H.-W. Chang, C.-P. Wang, C.-I Cheng, S. Chua, and M.-C. Chen Cardiac Rupture Complicating Acute Myocardial Infarction in the Direct Percutaneous Coronary Intervention Reperfusion Era Chest, August 1, 2003; 124(2): 565 - 571. [Abstract] [Full Text] [PDF]

				U. Stenestrand and L. Wallentin Fibrinolytic Therapy in Patients 75 Years and Older With ST-Segment-Elevation Myocardial Infarction: One-Year Follow-up of a Large Prospective Cohort Arch Intern Med, April 28, 2003; 163(8): 965 - 971. [Abstract] [Full Text] [PDF]

				R. H. Mehta, K. A. Eagle, L. P. Coombs, E. D. Peterson, F. H. Edwards, F. D. Pagani, G. M. Deeb, S. F. Bolling, and R. L. Prager Influence of age on outcomes in patients undergoing mitral valve replacement Ann. Thorac. Surg., November 1, 2002; 74(5): 1459 - 1467. [Abstract] [Full Text] [PDF]

				D. R. Thiemann Primary angioplasty for elderly patients with myocardial infarction: Theory, practice and possibilities J. Am. Coll. Cardiol., June 5, 2002; 39(11): 1729 - 1732. [Full Text] [PDF]

				J M Estess and E J Topol Fibrinolytic treatment for elderly patients with acute myocardial infarction Heart, April 1, 2002; 87(4): 308 - 311. [Full Text] [PDF]

				K. E. Gould, G. E. Taffet, L. H. Michael, R. M. Christie, D. L. Konkol, J. S. Pocius, J. P. Zachariah, D. F. Chaupin, S. L. Daniel, G. E. Sandusky Jr., et al. Heart failure and greater infarct expansion in middle-aged mice: a relevant model for postinfarction failure Am J Physiol Heart Circ Physiol, February 1, 2002; 282(2): H615 - H621. [Abstract] [Full Text] [PDF]

				C. Napoli, G. Aldini, J. L. Wallace, F. de Nigris, R. Maffei, P. Abete, D. Bonaduce, G. Condorelli, F. Rengo, V. Sica, et al. Efficacy and age-related effects of nitric oxide-releasing aspirin on experimental restenosis PNAS, January 24, 2002; (2002) 22639399. [Abstract] [Full Text] [PDF]

				M. del Mar de la Torre, J. A. San Roman, J. Bermejo, G. Pastor, J. Alonso, and F. Fernandez-Aviles Prognostic Power of Dobutamine Echocardiography After Uncomplicated Acute Myocardial Infarction in the Elderly Chest, October 1, 2001; 120(4): 1200 - 1205. [Abstract] [Full Text] [PDF]

				D. Schulman, D. S. Latchman, and D. M. Yellon Effect of aging on the ability of preconditioning to protect rat hearts from ischemia-reperfusion injury Am J Physiol Heart Circ Physiol, October 1, 2001; 281(4): H1630 - H1636. [Abstract] [Full Text] [PDF]

				R. H. Mehta, S. S. Rathore, M. J. Radford, Y. Wang, Y. Wang, and H. M. Krumholz Acute myocardial infarction in the elderly: differences by age J. Am. Coll. Cardiol., September 1, 2001; 38(3): 736 - 741. [Abstract] [Full Text] [PDF]

				E. Braunwald, E. M. Antman, J. W. Beasley, R. M. Califf, M. D. Cheitlin, J. S. Hochman, R. H. Jones, D. Kereiakes, J. Kupersmith, T. N. Levin, et al. ACC/AHA guidelines for the management of patients with unstable angina and non-st-segment elevation myocardial infarction: A report of the american college of cardiology/ american heart association task force on practice guidelines (committee on the management of patients with unstable angina) J. Am. Coll. Cardiol., September 1, 2000; 36(3): 970 - 1062. [Full Text] [PDF]