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(Circulation. 1996;94:1807-1808.)
© 1996 American Heart Association, Inc.

Articles

Age and Thrombolytic Therapy

Paul M. Ridker, MD; Charles H. Hennekens, MD

the Division of Preventive Medicine (P.M.R., C.H.H.) and Cardiovascular Division (P.M.R.), Brigham and Women's Hospital, Boston, Mass.

Correspondence to Charles H. Hennekens, MD, Division of Preventive Medicine, Brigham and Women's Hospital, 900 Commonwealth Ave E, Boston, MA 02215-1204.

Key Words: Editorials • thrombolysis • aging • plasminogen activators

	Introduction

Top Introduction References

 
Among patients 75 years of age and older, mortality after acute coronary occlusion approaches 30% at 1 month and exceeds 50% at 1 year. However, despite evidence from several randomized trials that thrombolytic therapy has clear net benefits¹ and is a cost-effective² treatment in the elderly, older age is a common reason in the United States for withholding treatment among otherwise eligible patients.^{3 4} Such a clinical decision is reinforced by the fact that intracranial hemorrhage, a rare but devastating side effect of thrombolytic therapy, is more likely to occur among older patients as well as among those with hypertension or prior central nervous system disease.^{5 6} Thus, the decision to use thrombolytic therapy among appropriately selected elderly patients must involve a careful assessment of the net benefit-to-risk ratio of a given reperfusion regimen, which should include the fact that available thrombolytic regimens differ in the speed with which they open coronary arteries⁷ as well as in the rates with which they cause intracranial hemorrhage.^{8 9 10}

In this issue of Circulation, White and colleagues¹¹ provide careful and detailed analyses of the landmark GUSTO-1 trial with specific regard to the benefit-to-risk ratio of different reperfusion strategies for patients <65, 65 to 74, 75 to 84, and >85 years of age. Because GUSTO-1 is the only large-scale randomized trial that evaluated front-loaded tissue plasminogen activator (TPA) plus immediate intravenous heparin as well as standard-dose streptokinase with delayed subcutaneous heparin, these data provide the only direct comparison of the two most commonly used thrombolytic regimens used worldwide.¹² Furthermore, GUSTO-1 was performed in diverse clinical centers using state-of-the-art assessment of all end points, including stroke etiology and other major hemorrhagic complications.

The important findings presented by White and colleagues¹¹ are consistent with earlier reports indicating that regardless of the choice of thrombolytic agent, age is by far the single most important predictor of ultimate survival after acute myocardial infarction.¹³ Compared with younger patients, those over the age of 85 sustained more hemorrhagic and ischemic strokes, hypotension, cardiogenic shock, heart failure, and major hemorrhagic complications. In fact, the 24-hour mortality in GUSTO-1 for the elderly was 10 times greater than that of the youngest patients enrolled. Furthermore, overall mortality rates at 1 year were between 40% and 47% for patients >85 years of age compared with <5% for those <65 years old. Thus, these data emphasize the critical need to carefully consider thrombolytic therapy in this exceptionally high–risk group.

GUSTO-1 also provides important relevant data on the relative efficacy of different thrombolytic agents stratified by age. Overall, GUSTO-1 documented a significantly lower mortality among patients assigned to front-loaded TPA than to streptokinase.¹² However, White and colleagues¹¹ report that for patients >85 years old, 30-day mortality was nonsignificantly higher among subjects randomly assigned to front-loaded TPA with intravenous heparin (30.0%) than among those assigned to streptokinase with subcutaneous heparin (26.4%). A similar small and nonsignificant difference was present at 1 year, such that mortality among those randomly assigned to TPA plus intravenous heparin was 47.0% compared with 40.3% among those assigned to streptokinase plus delayed subcutaneous heparin.

We fully agree with the authors¹¹ that these subgroup findings may well be due to the play of chance. White and colleagues also point out, however, that the possibility of a reduced net benefit of TPA use in the elderly, if real, may be due in part to higher rates of intracranial hemorrhage associated with this agent.^{8 9} Information relating to this issue is presented in analyses detailing regimen-specific mortality rates within the first 12 hours of infarction. In contrast to younger patients in whom front-loaded TPA was generally superior in this very early time frame (as well as later), markedly lower mortality was observed among older patients treated with streptokinase than was seen in those treated with TPA during the immediate 12 hours after randomization. We concur with the authors'¹¹ note of caution that the choice of agent for elderly patients cannot be judged solely from a single data set, especially because front-loaded TPA confers lower mortality but higher risks of stroke and cerebral hemorrhage, all of which increase with age.

White and colleagues¹¹ have also provided important information for clinicians, pharmacists, and administrators charged with the task of delivering the highest quality of care possible in an increasingly competitive economic environment. The GUSTO investigators imply that the common "one size fits all" approach in many emergency departments in regard to thrombolytic therapy may require modification to optimize both the benefit for and safety of individual patients such as those >85 years of age and perhaps those with cardiogenic shock, lower body mass, or late hospital arrival.^{14 15 16}

Regardless of which specific agent a clinician chooses to use, the fundamental finding in this and other reports is that age alone is not a contraindication to thrombolysis. Through its enrollment of patients >75 years of age, GUSTO-1 provides critical information about a group of patients often excluded from clinical research. In recent registry data, such patients make up 25% to 30% of all individuals at risk.⁴ Thus, these analyses have important implications for the care of a very large number of patients.

GUSTO-1 randomized a 110-year-old man who, at last report, was doing well and was free of any drug-induced complications.¹⁷ In this important manuscript, White and colleagues¹¹ have provided new insights about age and outcome with contemporary thrombolytic therapy.

	Footnotes

 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

	References

Top Introduction References

 

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2. 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]
   
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4. Rogers WJ, Bowlby LJ, Chandra NC, French WJ, Gore JM, Lambrew CT, Rubinson 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]
   
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. Simoons ML, Maggioni AP, Knatterud G, Leimberger JD, de Jaegere P, van Domburg R, Boersma E, Franzosi MG, Califf R, Schroder R, Braunwald E. Individual risk assessment for intracranial haemorrhage during thrombolytic therapy. Lancet. 1993;342:1523-1528.[Medline] [Order article via Infotrieve]
   
7. The GUSTO Angiographic Investigators. The effects of tissue plasminogen activator, streptokinase, or both on coronary artery patency, ventricular function, and survival after acute myocardial infarction. N Engl J Med. 1993;329:1615-1622.[Abstract/Free Full Text]
   
8. de Jaegere PP, Arnold AA, Balk AH, Simoons ML. Intracranial hemorrhage in association with thrombolytic therapy: incidence and clinical predictive factors. J Am Coll Cardiol. 1992;19:289-294.[Abstract]
   
9. ISIS-3 (Third International Study of Infarct Survival Collaborative Group). ISIS-3: a randomized comparison of streptokinase vs tissue plasminogen activator vs anistreplase and of aspirin and heparin vs heparin alone among 41,299 cases of suspected acute myocardial infarction. Lancet. 1992;339:753-770.[Medline] [Order article via Infotrieve]
   
10. 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-1 Investigators. Stroke after thrombolytic therapy: mortality and functional outcomes in the GUSTO-1 trial. Circulation. 1995;92:2811-2818.[Abstract/Free Full Text]
    
11. White HD, Barbash GI, Califf RM, Simes JR, Granger CB, Weaver D, Kleiman NS, Aylward PE, Gore JM, Vahanian A, Lee KL, Ross AM, Topol EJ, for the GUSTO-1 Investigators. Age and outcome with contemporary thrombolytic therapy: results from the GUSTO-1 Trial. Circulation. 1996;94:1826-1833.[Abstract/Free Full Text]
    
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13. 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-1 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]
    
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