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(Circulation. 1995;91:2862-2864.)
© 1995 American Heart Association, Inc.

Articles

Thrombolysis for Acute Myocardial Infarction

Why Is There No Extra Benefit After Hospital Discharge?

Frans Van de Werf, MD, PhD

From the Department of Cardiology, University Hospital Gast- huisberg, Leuven, Belgium.

Correspondence to Frans Van de Werf, MD, PhD, Department of Cardiology, University Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium. E-mail cardio@uz.kuleuven.ac.be.

Key Words: Editorials • thrombolysis • myocardial infarction

	Introduction

Top Introduction Long-term Follow-up in... Possible Explanations for Lack... Validation of Concepts and... References

 
Large-scale randomized trials in patients with acute myocardial infarction have demonstrated that thrombolytic therapy when given within 12 hours after onset of symptoms reduces hospital mortality^{1 2 3 4 5 6} and that this survival benefit persists.^{7 8 9} Early and sustained coronary artery patency with infarct size reduction, preserved left ventricular function, attenuation of left ventricular dilation, and enhanced electrical stability are thought to be the responsible mechanisms of action. On the basis of these favorable effects, one would theoretically expect survival benefits not only during the hospital stay but also afterward and, therefore, diverging survival curves between patients who received thrombolytic therapy and control patients. This, however, has not been observed.

	Long-term Follow-up in Controlled Trials of Thrombolytic Therapy

Top Introduction Long-term Follow-up in... Possible Explanations for Lack... Validation of Concepts and... References

 
In all large-scale trials, the postdischarge mortality curves of treated patients and control patients run perfectly parallel for 1 to 4 years,^{7 8 9 10} even in subgroups of patients who were treated early after the onset of symptoms, as shown in GISSI-1.⁷ In the latter group, one would certainly expect substantial salvage of ischemic myocardium and significant preservation of left ventricular systolic function and therefore an extra survival benefit after hospital discharge. A meta-analysis of the long-term benefits of intravenous thrombolytic therapy in more than 40 000 patients participating in placebo-controlled trials clearly shows that the risk of death after 1 month is equal in survivors of an acute myocardial infarction whether or not thrombolytic therapy was given on admission and, surprisingly, irrespective of the time this treatment was started (Fig 1). Of 18 826 patients who received thrombolytic therapy within 12 hours after onset of symptoms and who were alive at 1 month, 726 (3.9%) died during the next 5 months versus 727 of 18 014 patients (4%) randomized to placebo. In the subgroups of patients treated within 3 hours after onset of symptoms, the mortality rates at 6 months were 3.7% (280 of 7666 patients) for those given thrombolysis versus 3.6% (265 of 7356) in control patients. Mortality rates after 6 months were also very similar whether or not thrombolytic therapy was given and irrespective of the delay between onset of symptoms and start of treatment (Fig 1) (personal communication from M. Flather, C. Baigent, and R. Collins; data from the FTT Collaborative Group⁶ ).

View larger version (33K): [in this window] [in a new window]   Figure 1. Bar graph shows mortality rates at 6 months and after 6 months in patients with an acute myocardial infarction who were alive on day 35 following the acute event. The duration of follow-up after 6 months was variable in the different trials. Time (hours) from onset of infarction to start of treatment is given below the graph. Based on data from the FTT Collaborative Group.

Considering that no differences in postdischarge mortality rates were detectable in placebo-controlled trials, it is not surprising that similar observations have been made in comparative trials of thrombolytic agents. In the GISSI-2/International,¹¹ ISIS-3,¹² and GUSTO-I¹³ trials, no significant differences in survival rates after 1 month have been observed in patients treated with different thrombolytic agents. For example, in the GUSTO-I trial, the same survival benefit (1%) of accelerated recombinant tissue-type plasminogen activator (TPA) over streptokinase observed at 30 days was also present at 1 year.¹³

	Possible Explanations for Lack of Extra Benefit After Discharge

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How can the lack of an extra late clinical benefit be explained? It can be assumed that overall survival rates after hospital discharge in a population treated with thrombolytic agents are the net result of different survival curves (Fig 2). Better survival rates than in control patients can occur because of a reduction in infarct size. However, this effect is rather limited because adequate myocardial tissue reperfusion within 1 to 3 hours after the onset of infarction occurs in only a minority of patients. Indeed, reperfusion therapy is started in few patients within the first hours after onset of symptoms. Furthermore, it has become clear that even with the best available thrombolytic regimen, the percentage of early optimal reperfusion (TIMI flow grade 3) is disappointingly low (around 50%).^{14 15} Moreover, the final aim of thrombolytic therapy is not reperfusion of an occluded epicardial coronary artery but restoration of capillary flow in jeopardized ischemic myocardium. Recent work with contrast echocardiography¹⁶ and positron emission tomography¹⁷ has shown that one fourth to one third of the patients with TIMI flow grade 3 at early angiography had inadequate tissue reperfusion ("no reflow" or "impaired reflow" phenomenon). Thus, the amount of myocardial salvage and the associated preservation of left ventricular function that is presently obtainable with thrombolysis is limited. These observations may explain the rather small effect of thrombolysis on global left ventricular ejection fraction and the lack of correlation with mortality results in controlled trials.^{18 19} Attenuation of left ventricular dilation and remodeling and greater electrical stability due to a patent infarct vessel, irrespective of myocardial salvage, also contribute to a better survival rate in patients in whom thrombolysis was successful^{18 19 20} (Fig 2). On the other hand, poorer survival rates after hospital discharge in subgroups of patients successfully treated with thrombolytic agents compared with the average survival rate in control patients are also possible (Fig 2). This may be due to a higher incidence of rethrombosis and reinfarction in patients who received thrombolytic therapy. Indeed, frequent reocclusion (30% incidence between hospital discharge and 3 months²¹ and 25% between 4 weeks and 1 year²² ) has been angiographically documented in patients who had a patent infarct-related vessel following thrombolysis. Accordingly, in all large placebo-controlled trials, a higher incidence of reinfarction has been observed very consistently in the thrombolysis group compared with control patients.^{7 8 9 10}

View larger version (15K): [in this window] [in a new window]   Figure 2. Schematic representation of mechanisms that could explain better or worse survival rates after hospital discharge in patients successfully treated with thrombolytic agents compared with control patients. Numbers indicate better survival rates because of reduction of infarct size (1), attenuation of left ventricular dilation (2), and greater electrical stability (3); worse survival rates because of excess of rethrombosis and reinfarction (4); and excess mortality rates due to heart failure or associated arrhythmias in patients with very poor residual left ventricular function who could survive the hospital phase because of effective thrombolysis on admission (5).

Poorer long-term survival after successful thrombolysis compared with the average survival in control patients may also occur in those patients with very poor residual left ventricular function, who could survive the hospital phase because of effective coronary reperfusion at the time of admission.¹⁸ Without successful thrombolysis, these patients would have had a fatal event. After discharge, a high proportion of these patients will die because of heart failure or associated arrhythmias. The high postdischarge mortality rates of these patients may partly neutralize the survival benefit observed in other successfully treated patients and contribute to the lack of an extra long-term survival benefit in the total population studied.

	Validation of Concepts and Future Treatments to Improve Long-term Clinical Benefit of Thrombolytic Therapy

Top Introduction Long-term Follow-up in... Possible Explanations for Lack... Validation of Concepts and... References

 
The long-term mortality rates reported in the different trials of thrombolytic therapy and cited above are all- cause mortality rates. While it can be assumed that the percentage of noncardiovascular deaths after myocardial infarction is small and similar whether or not thrombolytic therapy has been given, the proportions of deaths due to stroke, reinfarction, heart failure, or arrhythmias are largely unknown. For the validation of the present hypotheses, it would be of interest if follow-up data of large-scale trials would demonstrate that the salutary long-term effects of thrombolysis in specific subgroups of patients are offset by excess mortality in other subgroups, eg, due to a higher incidence of reinfarction. However, it should be noted that mortality rates after hospital discharge in patients who survived a myocardial infarction are low: around 3% at 1 year in the GUSTO-I trial¹³ and between 3.5% and 4% at 6 months in the FTT overview (see Fig 1). Therefore, the balance between the persisting, long-term, beneficial effects of thrombolysis and the disappearance of its short-term (hospital) benefit is probably very delicate and difficult to study.

Based on the observations and hypotheses mentioned above, it can also be assumed that a number of therapeutic strategies could procure an extra (long-term) clinical benefit. Greater reduction of infarct size by earlier administration of more effective thrombolytic regimens (eg, staphylokinase, mutants of TPA, bolus administration of thrombolytic agents, or direct antithrombins) and by adjunctive therapy that improves the microcirculation of the reperfused myocardium (eg, stimulation of endogenous adenosine activity, inhibition of neutrophil chemotaxis, or adhesion); better prevention of reocclusion and reinfarction by revascularization procedures in selected cases by better antiplatelets (eg, GP IIb/IIIa receptor antagonists) and perhaps also by lipid-lowering agents as recently suggested by the Scandinavian Simvastatin Survival Study²³ ; greater attenuation of left ventricular remodeling and dilation by angiotensin-converting enzyme inhibitors, as already shown by recent trials^{24 25 26 27} ; and, finally, more effective antiarrhythmic therapy may all enhance the short- or long-term beneficial effects of thrombolysis.

	Acknowledgments

 
Data from the FTT Collaborative Group were provided by M. Flather, C. Baigent, and R. Collins.

	Footnotes

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

	References

Top Introduction Long-term Follow-up in... Possible Explanations for Lack... Validation of Concepts and... References

 
1. GISSI (Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto miocardico). Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet. 1986;1:397-401. [Medline] [Order article via Infotrieve]

2. ISAM (Intravenous Streptokinase in Acute Myocardial Infarction) Study Group. A prospective trial of intravenous streptokinase in acute myocardial infarction (ISAM): mortality, morbidity, and infarct size at 21 days. N Engl J Med. 1986;314:1465-1471. [Abstract]

3. AIMS (APSAC Intervention Mortality Study) Trial Study Group. Effects 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]

4. 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]

5. Wilcox RG, von der Lippe G, Olsson CG, Jensen G, Skene AM, Hampton JR, for the ASSET (Anglo-Scandinavian Study of Early Thrombolysis) Study Group. Trial of tissue plasminogen activator for mortality reduction in acute myocardial infarction (ASSET). Lancet. 1988;2:525-530. [Medline] [Order article via Infotrieve]

6. 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]

7. 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;2:872-874.

8. 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]

9. Wilcox RG, von der Lippe G, Olsson CG, Jensen G, Skene AM, Hampton JR, for the Anglo-Scandinavian Study of Early Thrombolysis. Effects of alteplase in acute myocardial infarction: 6-month results from the ASSET study. Lancet. 1990;335:1175-1178. [Medline] [Order article via Infotrieve]

10. Baigent C, Collins R, for the ISIS Collaborative Group. ISIS-2: 4-year mortality follow-up of 17,187 patients after fibrinolytic and antiplatelet therapy in suspected acute myocardial infarction. Circulation. 1993;88(suppl I):I-291. Abstract.

11. GISSI-2 and International Study Group. Six-month survival in 20,891 patients with acute myocardial infarction randomized between alteplase and streptokinase with or without heparin. Eur Heart J. 1992;13:1692-1697. [Abstract/Free Full Text]

12. ISIS-3. A randomized comparison of streptokinase vs tissue plasminogen activator vs anistreplase and of aspirin plus heparin vs aspirin alone among 41,229 cases of suspected acute myocardial infarction. Lancet. 1992;339:753-770. [Medline] [Order article via Infotrieve]

13. Califf RM, Topol EJ, Van de Werf F, Lee KL, Woodlief L. One year follow-up from the GUSTO-I trial. Circulation. 1994;90(suppl I):I-325. Abstract.

14. 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]

15. Vogt A, von Essen R, Tebbe U, Feuerer W, Appel K-F, Neuhaus K-L. Impact of early perfusion status of the infarct-related artery on short-term mortality after thrombolysis for acute myocardial infarction: retrospective analysis of four German multicenter studies. J Am Coll Cardiol. 1993;21:1391-1395. [Abstract]

16. Ito H, Tomooka T, Sakai N, Yu H, Higashino Y, Fujii K, Masuyama T, Kitabatake A, Minamino T. Lack of myocardial perfusion immediately after successful thrombolysis. Circulation. 1992;85:1699-1705. [Abstract/Free Full Text]

17. Maes A, Mortelmans L, Nuyts JM, Verbruggen AM, Van de Werf F. Myocardial tissue perfusion measured with PET in patients with TIMI flow grade 3 after thrombolysis. Circulation. 1994;90(suppl I):I-220. Abstract.

18. Van de Werf F. Discrepancies between the effects of coronary reperfusion on survival and left ventricular function. Lancet. 1989;1:1367-1369. [Medline] [Order article via Infotrieve]

19. Califf RM, Harrelson-Woodlief L, Topol EJ. Left ventricular ejection fraction may not be useful as an end point of thrombolytic therapy comparative trials. Circulation. 1990;82:1847-1853. [Abstract/Free Full Text]

20. Braunwald E. Myocardial reperfusion, limitation of infarct size, reduction of left ventricular dysfunction, and improved survival: should the paradigm be expanded? Circulation. 1989;79:441-444. [Free Full Text]

21. Meijer A, Verheugt FWA, Werter CJPJ, Lie KI, van der Pol JMJ, van Eessige MJ. Aspirin versus Coumadin in the prevention of reocclusion and recurrent ischemia after successful thrombolysis: a prospective placebo-controlled angiographic study. Circulation. 1993;87:1524-1530. [Abstract/Free Full Text]

22. White HD, French JK, Hamer AW, Brown MA, Williams BF, Ormisten JA, Cross DB. Frequent reocclusion of patent infarct-related arteries between 4 weeks and 1 year: effects of antiplatelet therapy. J Am Coll Cardiol. 1995;25:218-223. [Abstract]

23. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383-1389. [Medline] [Order article via Infotrieve]

24. Pfeffer MA, Braunwald E, Moyé LA, Basta L, Brown EJ Jr, Cuddy TE, Davis BR, Geltman EM, Goldman S, Flaker GC. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 1992;327:669-677. [Abstract]

25. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet. 1993;342:821-828. [Medline] [Order article via Infotrieve]

26. GISSI-3. Effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after acute myocardial infarction. Lancet. 1994;343:1115-1122. [Medline] [Order article via Infotrieve]

27. ISIS-4. A randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected myocardial infarction. Lancet. 1995;345:669-685.[Medline] [Order article via Infotrieve]

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