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Asian Cardiovasc Thorac Ann 1998;6:03-10
© 1998 Asia Publishing EXchange Pte Ltd

INVITED REVIEW

Thrombolytic Therapy in Acute Myocardial Infarction Part II: 1997 Update

Roger L White, MD

Department of Cardiology Straub Clinic and Hospital Honolulu, Hawaii, USA
Roger L White, MD Department of Cardiology Straub Clinic and Hospital 888 South King Street Honolulu, HI 96813, USA Tel:1 808 522 4222 Fax:1 808 522 4065

   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 STUDIES ON THROMBOLYTIC THERAPY...
 STUDIES SINCE 1993 WITH...
 ROLE OF ANGIOPLASTY IN...
 ADJUNCTIVE PHARMACOLOGICAL...
 CONCLUSION
 REFERENCES
 
Thrombolytic therapy has become an established treatment for acute myocardial infarction. Streptokinase was first demonstrated in 1988 to reduce mortality rates. In 1993, tissue plasminogen activator was shown to have a slight superiority over streptokinase in reducing mortality rates (approximately 1%). Reteplase is a second generation thrombolytic agent that is given in two bolus injections intravenously over 30 minutes. Studies demonstrated slightly better and more rapid improvement in myocardial perfusion with reteplase compared to tissue plasminogen activator. However, recent studies showed 30-day mortality rates in patients treated with reteplase were similar as those treated with tissue plasminogen activator. The use of angioplasty, aspirin, beta blockers, angiotensin converting enzyme inhibitors, and lipid lowering agents also contribute to the reduction of mortality from acute myocardial infarction.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
STUDIES ON THROMBOLYTIC THERAPY...
 STUDIES SINCE 1993 WITH...
 ROLE OF ANGIOPLASTY IN...
 ADJUNCTIVE PHARMACOLOGICAL...
 CONCLUSION
 REFERENCES
 
Intravenous thrombolytic therapy has become an important therapeutic modality in treating patients with acute myocardial infarction and reducing mortality rates. In 1993, Asian Cardiovascular and Thoracic Annals published a review on thrombolytic therapy in acute myocardial infarction.1 The purpose of this update is to review important studies since then, with special emphasis on a new thrombolytic drug, reteplase (rPA), which has recently been approved for clinical use in the United States. Although thrombolytic therapy has been clearly demonstrated to reduce mortality rates it remains under-utilized and the choice of agent and dosing regimen is still controversial. In addition to mortality rates we need other clinical parameters to assess the efficacy of thrombolytic therapy in acute myocardial infarction. Adjunctive pharmacological therapy and the role of interventional angioplasty in relation to thrombolytic therapy during acute myocardial infarction is also briefly reviewed.

In the majority of cases, acute myocardial infarction is caused by an intracoronary thrombosis occurring on a ruptured atherosclerotic plaque, leading to acute obstruction of the involved vessel.2–4 Resultant hypoxia of the myocardium eventually leads to necrosis and consequent myocardial dysfunction. Complications of myocardial dysfunction include arrhythmias, congestive heart failure, hypotension, and death.5,6 Efforts to treat acute myocardial infarction have focused on restoring patency to the affected artery as soon as possible and preserving myocardial function.7–11 The body has a natural mechanism for dissolving clots by intrinsic activation of the conversion of plasminogen to plasmin by tissue plasminogen activator factor. Thrombolytic therapy accelerates clot dissolution in an attempt to restore blood flow and oxygen to the affected myocardium.12–14 It can be given intravenously and its effectiveness in reducing mortality and complications of myocardial infarction is time dependent.15–17 The greatest percentage of damage to the myocardium occurs within the first six hours of occlusion.18–21 The major complication of thrombolytic therapy has been hemorrhage, which is sometimes fatal if intracerebral or gastrointestinal.22–25 Fear of bleeding has been the major limitation on the use of thrombolytic agents.26–28

The ideal thrombolytic agent should act rapidly and effectively to dissolve a fresh intracoronary thrombus and at the same time avoid systemic side-effects and bleeding. After therapy, flow through the artery should be brisk (TIMI perfusion grade 3 [flow through coronary arteries is graded as TIMI 0 = no flow, TIMI 1 = minimal flow, TIMI 2 = adequate flow but sluggish, and TIMI 3 = brisk and near normal]).29–31 Other criteria for an ideal thrombolytic drug include minimal reocclusion of the artery, ease of administration, wide availability, and cost effectiveness. Lack of an ideal thrombolytic agent has stimulated the pharmacological industry to develop a number of thrombolytic agents and numerous studies have been carried out to evaluate their effectiveness.


   STUDIES ON THROMBOLYTIC THERAPY PRIOR TO 1993
TOP
 ABSTRACT
 INTRODUCTION
 STUDIES ON THROMBOLYTIC THERAPY...
STUDIES SINCE 1993 WITH...
 ROLE OF ANGIOPLASTY IN...
 ADJUNCTIVE PHARMACOLOGICAL...
 CONCLUSION
 REFERENCES
 
Initial studies on thrombolytic therapy in acute myocardial infarction focused on whether the treatment was effective in reducing mortality, on dosing regimens, and on the route of administration.32–34 Subsequent studies focused more on which agent was more effective with the least complications and what was appropriate adjunctive therapy.35–37 A brief review of some of the important studies follows.

GISSI I (published 1986)38 on intravenous streptokinase, clearly demonstrated reduced mortality rates (by 19% compared to placebo) and established the efficacy of thrombolytic therapy. It showed that intravenous therapy was as effective as intracoronary therapy, which made it more widely applicable, easier to use, and faster to deliver. The optimal timing was clearly established, with the greatest reduction in mortality (of 47%) obtained when therapy was given within the first hour of the onset of infarction. Benefits in reduction of mortality decrease with each subsequent hour resulting in little benefit beyond six hours. Reduced mortality was greater in anterior wall myocardial infarctions than inferior wall myocardial infarctions. Death from intracerebral hemorrhage and major bleeding occurred in approximately 1% of cases. Many other studies confirmed the results of GISSI I using streptokinase with different dosing regimens and adjunctive therapy.39–41 The AIMS study42,43 using anistreplase or APSAC, which is a synthetic inactive derivative of the plasminogen-streptokinase activator complex that can be given as a bolus over 5 minutes, showed similar reductions in mortality rates to continuously infused streptokinase given over one hour. Both streptokinase and APSAC can cause allergic reactions and hypotension.

The next major drug to be introduced was alteplase, a genetically engineered tissue plasminogen activator (rt-PA), similar to the tissue plasminogen activator that the body makes to convert plasminogen to plasmin.44 It is much more clot-specific and becomes active when it binds to fibrin. It does not deplete fibrinogen as much as streptokinase and has a short half-life. There are various dosing regimens involving a combination of bolus and continuous infusion based on body weight.33,45 Because of its short half-life, adjunctive therapy with intravenous heparin must be used.45–47 It is nonallergenic and rarely causes hypotension. Many studies such as the European Co-operative Study,49 Asset Study,50 and TIMI trials51,52 demonstrated rt-PA to be effective in reducing the mortality rates of myocardial infarction. There were slightly fewer episodes of major bleeding than with streptokinase but a slightly higher rate of intracerebral hemorrhage (1.5%) particularly in patients over 70 years of age.53 This drug was significantly more expensive than streptokinase. Subsequent studies focused on whether there were significant differences in the benefits or risks of streptokinase versus rt-PA.

ISIS-III (1991)54 did not show any significant differences in reduction of mortality rates at 35 days between streptokinase, APSAC, and rt-PA. On the basis of this study, streptokinase seemed to be the drug of choice because of its lower cost but rt-PA should be given to patients with hypotension or a history of allergy to streptokinase. However, the study was flawed because the rt-PA group received subcutaneous rather than intravenous adjunctive heparin therapy. Streptokinase became the most widely used drug in Europe as a result of this study, while rt-PA became the most widely used drug in the United States based on the TIMI studies. ISIS-III was also important in establishing that age is not a contraindication to therapy and as mortality rates increase with age, older patients may benefit the most. Patients who present with ST-segment depression generally do not benefit from thrombolytic therapy and should be treated for unstable angina rather than myocardial infarction.

GUSTO I (1993)55 was intended to be the ultimate study comparing streptokinase with rt-PA. It involved 41,021 patients to improve statistical significance. It also evaluated combination therapy using streptokinase and rt-PA together. The 30-day mortality rates for the four groups studied were: streptokinase with subcutaneous heparin, 7.2%; streptokinase with intravenous heparin, 7.4%; accelerated rt-PA with intravenous heparin, 6.3%; and the combination of rt-PA and streptokinase with intravenous heparin, 7.0%. Although the accelerated rt-PA was associated with only an approximately 1% improvement in the mortality rate, this was statistically significant given the large number of patients. This is a 14% risk reduction of mortality of rt-PA compared to all other groups. There was a slightly increased risk of intracerebral hemorrhage (in excess of 2 hemorrhagic strokes per 1000 patients treated) with rt-PA compared to streptokinase. The combined therapy group showed no advantage and had an increased risk of bleeding. Thus, GUSTO I indicated that rt-PA was slightly more effective and individuals could decide whether this justified the increased cost to the patient. Significantly, a subgroup of the GUSTO I study that had angiography 90 minutes after starting the therapy showed significantly better TIMI grade 3 and TIMI grade 2 flow rates than streptokinase. The patients that had demonstrated TIMI grade 3 flow rates at 90 minutes had the lowest mortality rate of 4.2% at 30 days, so that in addition to decreased overall mortality rates, patients who received rt-PA also demonstrated earlier and better flow.


   STUDIES SINCE 1993 WITH EMPHASIS ON RETEPLASE
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 ABSTRACT
 INTRODUCTION
 STUDIES ON THROMBOLYTIC THERAPY...
 STUDIES SINCE 1993 WITH...
ROLE OF ANGIOPLASTY IN...
 ADJUNCTIVE PHARMACOLOGICAL...
 CONCLUSION
 REFERENCES
 
The search has continued for the ideal thrombolytic therapy. The major thrust has been on modifications of rt-PA to develop a drug that restores patency faster and more effectively as well as being easier to administer (bolus injection and not weight-adjusted).

Reteplase (rPA) is a second generation genetically engineered thrombolytic drug. It was molecularly altered from alteplase (rt-PA) to enhance fibrinolytic potential.56 Its molecular structure is similar to alteplase but it has been simplified to contain only the Kingle 2 group and the protease portion of the molecule.57 This still allows the drug to be fibrin-specific. However, the fibrin affinity is five-times lower than alteplase. The potential advantage of lower fibrin-binding affinity may tend to enhance clot penetration and fibrinolysis. Because the glycosylated part of the molecule has been eliminated, the half-life of reteplase is 13 to 16 minutes, which is significantly longer than that of alteplase at 3 to 6 minutes. This allows reteplase to be given as two bolus injections of 10 mg, 30 minutes apart, making it significantly more convenient to administer than alteplase (a bolus injection followed by a weight-adjusted 90-minute infusion: reteplase does not have to be weight adjusted). In animal models in vitro, reteplase is approximately five-times more potent than alteplase, especially on platelet-rich clots that are difficult to penetrate.58–60 The question with reteplase was whether these theoretical advantages would translate into clinically significant statistical differences.

The INJECT study61 carried out in Europe, compared reteplase with streptokinase. There were 6000 patients randomly assigned to either treatment and mortality was evaluated at 35 days and at 6 months. Reteplase was demonstrated to be slightly more effective in reducing death from myocardial infarction than streptokinase (rPA 35-day mortality 8.9% versus 9.43% with streptokinase; rPA 6-month mortality 11.02% versus 12.05% with streptokinase). These results are somewhat similar to GUSTO I showing a slightly greater reduction of mortality with rt-PA compared to streptokinase. The rate of intracerebral hemorrhage was slightly higher in the reteplase group compared to the streptokinase group (rPA 0.77% versus streptokinase 0.37%). Stroke was more common (2.2%) in patients over 70 years old and with systolic blood pressure greater than 160 mm Hg. Other clinical indications such as congestive heart failure, arrhythmias, and cardiogenic shock were slightly less in the reteplase group compared to the streptokinase group. One important observation was that improvement in ST-segment elevation by 50% correlated with a significant reduction in mortality.62,63 This is probably an important clinical marker and correlates well with adequate blood flow (TIMI perfusion grade 3), which can be used to evaluate the effectiveness of therapy and whether rescue angioplasty is needed.

The RAPID I and RAPID II studies64,65 involved relatively small groups to compare the effectiveness of reteplase versus alteplase in acute myocardial infarction. Angiograms were performed immediately after thrombolytic therapy to evaluate the effectiveness of blood flow and patency. The results of these studies seemed to indicate that reteplase opened up the occluded arteries more effectively than alteplase, with better TIMI grade 3 flow and greater preservation of ventricular function.

The GUSTO III study (reported in 1997) was designed to see if the potentially better flow rates with reteplase compared to rtPA would translate into reduced mortality. The results showed that the mortality rates were very similar (rPA 7.43% versus rtPA 7.22%). Risks of bleeding complications were also similar, the incidence of intracerebral hemorrhage with rPA was 0.72% compared to 0.82% with tPA. The findings indicate that reteplase and tissue plasminogen activator are equally beneficial and the choice between these two drugs depends on individual factors because the cost is the same at this time. Although the controversy over which drug is superior continues, it should be emphasized that all thrombolytic drugs reduce mortality rates and preserve left ventricular function, so the use of any of these drugs is better than no therapy at all. As future drugs are developed to fit ideal parameters, a superior drug may not emerge because to obtain significantly statistical results many thousands of patients need to be studied. The expense of conducting large thrombolytic trials may limit future studies. It should be noted that the best thrombolytic, reteplase, is effective in restoring patency at 90 minutes in only 75% of cases approximately. With this limitation in mind, coronary angioplasty should be considered as an alternative to thrombolytic therapy or as an adjunctive therapy when available and appropriate.


   ROLE OF ANGIOPLASTY IN ACUTE MYOCARDIAL INFARCTION
TOP
 ABSTRACT
 INTRODUCTION
 STUDIES ON THROMBOLYTIC THERAPY...
 STUDIES SINCE 1993 WITH...
 ROLE OF ANGIOPLASTY IN...
ADJUNCTIVE PHARMACOLOGICAL...
 CONCLUSION
 REFERENCES
 
Acute interventional percutaneous transluminal coronary angioplasty (PTCA) has become an important therapeutic modality in treating acute myocardial infarction.67–69 The advantage is potentially more rapid and complete return of blood flow when performed by experienced interventional cardiologists. The effectiveness of therapy can be assessed immediately by angiography. The use of stents may prevent reocclusion of vessels.70 There have been many small studies demonstrating the beneficial effects of this approach.71 In addition, angioplasty can be effective when thrombolytic drugs are contraindicated or when the diagnosis is equivocal, such as stuttering myocardial infarction, extension of myocardial infarction, or unstable angina pectoris with ST-segment depression. PTCA can be used when thrombolytic therapy is considered unsuccessful (so-called rescue angioplasty) and although this is associated with a higher mortality rate it must be remembered that these patients are already in a high-risk group.73–75 The availability of acute angioplasty has limited the total number of patients receiving thrombolytic therapy. The main concern in promoting PTCA as the primary treatment for acute myocardial infarction is that skilled staff may not be readily available within one hour of the onset of symptoms. Delays in treatment or variable technical abilities of interventionists can result in no reduction or an increased rate of mortality. In general, if experienced staff are available within one hour of the onset of myocardial infarction, angioplasty is preferable to thrombolytic therapy because of the increased ability to assess the effectiveness of therapy and the decreased risk of bleeding.

Rescue angioplasty after thrombolytic therapy, although it carries a higher risk, should always be considered at 90 minutes if clinical parameters do not show significant improvement (chest pain unaltered and less than 50% reduction in ST-segment elevation).76 Reteplase may have a slight advantage over alteplase in this regard since the faster infusion time can result in an earlier decision as to whether or not rescue angioplasty is needed. Results of PTCA will probably continue to show much variability between institutions. It is important to remember that if angioplasty cannot be performed quickly, thrombolytic therapy should be strongly considered because the viability of ischemic myocardium declines with each minute of delay in therapy. The current goal in the United States is to start some form of therapy to improve perfusion within 30 minutes of the arrival at a medical facility of a patient with symptoms of acute myocardial infarction.77

Follow-up angiography a few days after successful thrombolytic therapy is advisable to evaluate the effectiveness of therapy and the risk of recurrent infarction from residual atherosclerotic plaques. Many patients will require elective angioplasty or coronary bypass surgery.77–79 If angiography is not available the patient should at least have a treadmill stress test after myocardial infarction to evaluate potential ongoing ischemia.80–82


   ADJUNCTIVE PHARMACOLOGICAL THERAPY IN ACUTE MYOCARDIAL INFARCTION
TOP
 ABSTRACT
 INTRODUCTION
 STUDIES ON THROMBOLYTIC THERAPY...
 STUDIES SINCE 1993 WITH...
 ROLE OF ANGIOPLASTY IN...
 ADJUNCTIVE PHARMACOLOGICAL...
CONCLUSION
 REFERENCES
 
In addition to thrombolytic therapy and acute angioplasty there are other established and generally inexpensive pharmacological treatments to reduce mortality rates from myocardial infarction. This is a very brief review of four important and proven effective pharmacological therapies that can supplement thrombolytic and interventional therapy.

ASPIRIN
The ISSI II trial41 and other studies83,84 found aspirin to be effective in reducing mortality by 21% during acute myocardial infarction. When combined with thrombolytic therapy the effects are an additional 37% reduction. Aspirin (325 mg) should be given as soon as possible when myocardial infarction occurs and continued on a daily basis. In spite of this inexpensive and effective therapy, one study demonstrated that 24% of patients with acute myocardial infarction eligible for aspirin therapy did not receive aspirin during their hospital stay.

Many other antiplatelet agents such as ticlopidine and glycoprotein IIb/IIIa, are currently under investigation. The PARAGON study85 investigated lamifiban (glycoprotein IIb/IIIa), an inhibitor of platelet aggregation in patients with unstable angina. Results were inconclusive. Such agents may be helpful in preserving patency following angioplasty and studies continue to assess whether they have any benefits over aspirin.

BETA BLOCKERS
The ISIS I, MIAMI and BHAT trials, and the Norwegian multicenter trial have all demonstrated significant benefits of beta-blocker use during acute myocardial infarction and for secondary prevention.86–90 An overview demonstrated a 15% reduction in mortality in the first 24 hours. Beta blockers are particularly useful in patients with poor left ventricular function and ventricular arrhythmias.91 In general, they are under-utilized because of fears of bradycardia, hypotension, and exacerbation of heart failure, yet if given carefully these rarely occur.

ANGIOTENSIN CONVERTING ENZYME INHIBITORS
The SAVE, AIRE, TRACE, SMILE, and SOLVO trials92–96 have generally shown that the early use of angiotensin converting enzyme (ACE) inhibitors reduces myocardial dysfunction and improves long-term mortality rates. They are more useful in large myocardial infarctions when greater dysfunction is present. ACE inhibitors may have antiatherogenic properties, however, the fear of hypotension has limited the usage of ACE inhibitors but if given carefully with monitoring this is rarely a serious complication.

LIPID-LOWERING AGENTS
The Scandinavian Simvastatin Survival study97 and the CARE study98 demonstrated that the use of HMG-CoA reductase inhibitors (statins) can reduce one-year mortality rates by 30% and reduce the need for angioplasty and bypass graft surgery by 37% . It is prudent to measure the high density lipoprotein-to-low density lipoprotein ratio (HDL/LDL) and cholesterol level immediately on admission if possible, to establish a baseline. Diet and exercise modification are critically important in beneficially affecting HDL/LDL and total cholesterol levels. Additional drug therapy should be considered in those patients where it is appropriate to raise HDL and lower LDL levels.


   CONCLUSION
TOP
 ABSTRACT
 INTRODUCTION
 STUDIES ON THROMBOLYTIC THERAPY...
 STUDIES SINCE 1993 WITH...
 ROLE OF ANGIOPLASTY IN...
 ADJUNCTIVE PHARMACOLOGICAL...
 CONCLUSION
REFERENCES
 
There are now many therapies available to reduce the mortality rate of myocardial infarction and preserve myocardial function. The earlier treatment is started, the more myocardium is preserved. The goal is to start some form of therapy within 30 minutes of the arrival of the patient at a medical facility. The diagnosis of acute myocardial infarction can be made quickly from history, physical examination, and routine electrocardiogram. One should not delay therapeutic intervention by waiting for the results of myocardial enzyme tests. The choice of therapy with thrombolytics or angioplasty will continue to depend on patient selection and institution. Both work well and both have advantages and disadvantages. For thrombolytic therapy, reteplase offers slightly better and more rapid patency and results in mortality studies are very similar to alteplase. An important clinical marker is a 50% reduction in ST-segment elevation. Rescue angioplasty should be considered in patients without improvement after thrombolytic therapy. Adjunctive pharmacological therapy should be considered in all patients. The ultimate goal is to restore patency to the artery as soon as possible, prevent myocardial damage, and prevent recurrent myocardial infarction.


Dr. Roger L White of Hawaii, USA, received the first place Excellence In Research Award for 1997 for Straub Clinic & Hospital in Honolulu. The article for which Dr. White won the award was "Thrombolytic Therapy For Acute Ischemic Stroke, What Cardiac Physicians Need to Know", which was published in the Asian Cardiovascular & Thoracic Annals Volume 4, Number 4 in 1996. The award is given annually to one physician from Straub Clinic based on excellence in research and contribution to the community. Straub Clinic is a multi-specialty group practice in Honolulu of approximately 250 physicians. The Straub Clinic Foundation has been a leader in medical research in Hawaii. Each year there are numerous physicians doing research and numerous papers published in prestigious journals. Dr. White has been a leader in coordinating research trials on thrombolytic therapy for acute mycardial infarction. Recently, he has used this knowledge to extend research and therapeutic protocols to acute ischemic stroke. The Asian Cardiovascular & Thoracic Annals has been proud to publish Dr. White's works and share in this recognition.

 


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 STUDIES ON THROMBOLYTIC THERAPY...
 STUDIES SINCE 1993 WITH...
 ROLE OF ANGIOPLASTY IN...
 ADJUNCTIVE PHARMACOLOGICAL...
 CONCLUSION
 REFERENCES
 

  1. White RL. Thrombolytic therapy in acute myocardial infarction: a review with current recommendations. Asian Cardiovasc Thorac Ann 1993;1:145–51.

  2. Davies MJ, Thomas AC. Plaque fissuring, the cause of acute myocardial infarction, sudden death, and crescendo angina. Br Heart J 1985;53:363–73.[Free Full Text]

  3. Ross R. The pathogenesis of atherosclerosis: an update. N Engl J Med 1986;314:488–500.[Medline]

  4. DeWood MA, Spores J, Norske R, et al. Prevalence of total coronary artery occlusion during the early hours of transmural infarction. N Engl J Med 1980;303:897–902.[Abstract]

  5. Herick J. Clinical features of sudden obstruction of coronary arteries. JAMA 1912;59:2015–20.

  6. Spann JF. Changing concepts of pathophysiology, prognosis, and therapy in acute myocardial infarction. Am J Med 1983;74:877–86.[Medline]

  7. Braunwald E. The open artery therapy is alive and well again. N Engl J Med 1993;329:1650–2.[Free Full Text]

  8. Ambrose JA. The open artery: beyond myocardial salvage. Am J Cardiol 1993;72:85G–9OG.[Medline]

  9. Rogers WJ. Contemporary management of acute myocardial infarction. Am J Med 1995;99:195–206.[Medline]

  10. Saltiss S, Mushahwar SS. The management of acute myocardial infarction. Postgrad Med J 1995;71:534–41.[Abstract/Free Full Text]

  11. Boersma E, Maas A, Deckers J, Simons M. Early thrombolytic treatment in acute myocardial infarction: reappraisal of the golden hour. Lancet 1996;348:771–5.[Medline]

  12. Murder VJ, Sherry S. Thrombolytic therapy: current status. N Engl J Med 1998;318:1520–1, 1585–95.

  13. Rentrop KP. Thrombolytic therapy in patients with acute myocardial infarction. Circulation 1985;71:627–31.[Free Full Text]

  14. Bode C, Nordt TK, Runge MS. Thrombolytic therapy in acute myocardial infarction — selected recent developments. Ann Hematol 1994;69:S35–40.[Medline]

  15. Yusaf S, Collins R, Peto R, et al. Intravenous and intracoronary fibrinolytic therapy in acute myocardial infarction: overview of results on mortality, reinfarction and side effects from 33 randomised controlled trials. Eur Heart J 1985;6: 556–85.[Abstract/Free Full Text]

  16. Spann JF, Sherry S, Carabello BA, et al. Coronary thrombolysis by intravenous streptokinase in acute myocardial infarction: acute and follow up studies. Am J Cardiol 1984; 53:655–61.[Medline]

  17. Collen D. Fibrin specific thrombolytic agents and new approaches to coronary artery thrombolysis. Thrombolysis in Cardiovascular Disease 1989;3:45–67.

  18. Grover A, Ridal CS. The importance of early patency after acute myocardial infarction. Curr Opin Cardiol 1995;10:361–6.[Medline]

  19. Reimer KA, Lowe JE, Rasmussen MM, Jennings RB. The wave front phenomenon of ischemic cell death: myocardial infarction size versus duration of coronary occlusion in dogs. Circulation 1977;56:786–94.[Abstract/Free Full Text]

  20. Reimer KA, Vander Heide RS, Richard VJ. Reperfusion in acute myocardial infarction: effect of timing and modulating factors in experimental models. Am J Cardiol 1993;72:13G–21G.[Medline]

  21. Weaver WD. Time to thrombolytic treatment: factors affecting delay and their influence on outcome. J Am Coll Cardiol 1995;25:3S–9S.

  22. Gore JM, Granger CB, Simoons ML, et al. Stroke after thrombolysis, mortality and functional outcomes in the GUSTO-I trial. Circulation 1995;92:2811–8.[Abstract/Free Full Text]

  23. Neuhaus KL. More on thrombolysis and hemorrhagic stroke. Circulation 1995;92:2794–5.[Free Full Text]

  24. Kase CS, Pessin MS, Zivin JA, et al. Intracranial hemorrhage following thrombolysis with tissue plasminogen activator. Am J Med 1992;92:384–90.[Medline]

  25. de Jaegere PP, Arnold AP, Balk AH, Simoons ML. Intracranial hemorrhage in association with thrombolytic therapy: incidence and clinical predictive factors. J Am Coll Cardiol 1992;20:289–94.

  26. Guidelines. Acute myocardial infarction: pre hospital and in hospital management. The task force on the management of acute myocardial infarction of the European Society of Cardiology. Eur Heart J 1996;17:43–63.[Free Full Text]

  27. Vermeer F, Simoons ML, Bar FW, et al. Which patients benefit most from early thrombolytic therapy with intracoronary streptokinase? Circulation 1986;74:1379–89.[Abstract/Free Full Text]

  28. Sane D, Califf R, Topol EJ, et al. Bleeding during thrombolytic therapy for acute myocardial infarction: mechanisms and management. Ann Intern Med 1989;111:1010–22.

  29. Anderson JL, Karagounis LA, Becker LC, et al. TIMI perfusion grade 3 but not grade 2. Results in improved outcome after thrombolysis for myocardial infarction: evidence from the TEAM-III study. Circulation 1993;87:1829–39.[Abstract/Free Full Text]

  30. Karagounis L, Sorensen SG, Menlove RL, et al. Does thrombolysis in myocardial infarction (TIMI) perfusion grade 2 represent a mostly patent artery or mostly occluded artery? Enzymatic and electrocardiographic evidence from TEAM-II study. J Am Coll Cardiol 1992;19:1–10.[Abstract]

  31. Dalen JE, Gore JM, Braunwald E, et al. and the TIMI Investigators. Six and twelve month follow-up of phase 1 thrombolysis in myocardial infarction (TIMI) trial. Am J Cardiol 1988;62:179–85.[Medline]

  32. Kennedy JW, Martin GV, David KB, et al. The Western Washington intravenous streptokinase in acute myocardial infarction: randomized trial. Circulation 1988;77:345–52.[Abstract/Free Full Text]

  33. Neuhaus KL, Feurrer W, Jesp Tebbe S, et al. Improved thrombolysis with modified dose regimen of recombinant tissue-type plasminogen activator. J Am Coll Cardiol 1989;14:156–89.

  34. Ganz W, Buchbonder N, Murcus H, et al. Intracoronary thrombolysis with streptokinase in acute myocardial infarction. Am Heart J 1981;101:4–13.[Medline]

  35. Fibrinolytic Therapy Trialist (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 1,000 patients. Lancet 1994;343:311–22.[Medline]

  36. Topol EJ. Which thrombolytic agent should we choose? Prog Cardiovasc Dis 1991;34:165–78.[Medline]

  37. ACC/AHA Task Force. ACC/AHA guidelines for the management of patients with acute myocardial infarction: executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 1996;94:2341–50.[Free Full Text]

  38. GISSI Study Group. Effectiveness of intravenous thrombolytic therapy in acute myocardial infarction. Gruppo Italliano per lo Studio della Streptochinase nell' Infurto Miocardico (GISSI). Lancet 1986;1:397–402.[Medline]

  39. ISAM 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;314:1465–71.[Abstract]

  40. White HD, Norris RM, Brown MA, et al. Effect of intravenous streptokinase in left ventricular function and early survival after acute myocardial infarction. N Engl J Med 1987;317:850–5.[Abstract]

  41. ISIS-II (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. Lancet 1988;2:349–60.[Medline]

  42. AIMS Trial Study Group. Effect of intravenous APSAC on mortality after acute myocardial infarction: preliminary report of a placebo controlled clinical trial. Lancet 1988;1:545–9.[Medline]

  43. AIMS Trial Study Group. Long-term effects of intravenous anistreplase in AMI: final report of the AIMS study group. Lancet 1990;335:427–31.[Medline]

  44. Brieger D, Topol EJ. Molecular biology and genetic engineering of plasminogen activators. In: Califf RM, editor. Thrombolytic therapy: new standards of cure, part 1, the science of plasminogen activators. New York: Excerpta Medica, 1996:1622. Am J Cardiol Continuing Education Series.

  45. Van de Werf F, Arnold AER. Intravenous tissue plasminogen activator and size of infarct, left ventricular function, and survival in acute myocardial infarction. Br Med J 1988;297:1374–9.

  46. Hsia J, Hamilton WP, Kleinman N, et al. A comparison between heparin and low dose aspirin as adjunctive therapy with tissue plasminogen activator for acute myocardial infarction. Heparin-aspirin reperfusion trial (HART) investigators. N Engl J Med 1990;323:1433–7.[Abstract]

  47. de Bono DP, Simoons ML, Tigssem J, et al. Effect of intravenous heparin on coronary patency, infarct size, and bleeding complications after alteplase thrombolysis: European cooperative study group trial. Br Heart J 1992;67:122–8.[Abstract/Free Full Text]

  48. Bleich SD, Nichols TC, Schumacher RR, et al. Effects of heparin on coronary artery patency after thrombolysis with tissue plasminogen activator in acute myocardial infarction. Am J Cardiol 1990;60:1412–7.

  49. Verstraete M. Randomised trial of intravenous recombinant tissue type plasminogen activator versus intravenous streptokinase in acute myocardial infarction. Report from the European Co-operative Study Group for Recombinant Tissue-Type Plasminogen Activator. Lancet 1985;1:842–7.[Medline]

  50. Wilcox RG. Trial of tissue plasminogen activator for mortality reduction in acute myocardial infarction. Anglo-Scandinavian Study of Early Thrombolysis (ASSET). Lancet 1988;2:525–30.[Medline]

  51. Chesebro JH. Thrombolysis in myocardial infarction (TIMI) trial, phase 1: a comparison between intravenous tissue plasminogen activator and intravenous streptokinase. Circulation 1987;76:142–54.[Abstract/Free Full Text]

  52. Mueller HS, Rao AK, Forman SA, and the TIMI Investigators. Thrombolysis in myocardial infarction (TIMI): comparative studies of coronary reperfusion and systemic fibrinolysis with two forms of recombinant tissue plasminogen activator. J Am Coll Cardiol 1987;10:479–90.[Abstract]

  53. Califf RM, Topol EJ, George BS, et al. Hemorrhagic complications associated with the use of intravenous tissue plasminogen activator in treatment of acute myocardial infarction. Am J Med 1988;85:353–9.[Medline]

  54. Third International Study of Infarct Survival Collaborative Group. ISIS-III: a randomized comparison of streptokinase, versus tissue plasminogen activator, versus anistreplase and aspirin plus heparin, versus aspirin alone among 41,299 cases of suspected acute myocardial infarction. Lancet 1992;339:753–70.[Medline]

  55. The GUSTO Investigators. An international randomized trial comparing four different thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993;329:673– 82.[Abstract/Free Full Text]

  56. Bode C, Kohler B, Smalling RW, Rung MS. Reteplase (r-PA), a novel recombinant plasminogen activator. Fibrinolysis 1995;9(Suppl 1):97–9.

  57. Kohnert U, Rudolph R, Verheiyan JH, et al. Biochemical properties of the Kringle 2 and protease domains are maintained in the refolded t-PA deletion variant BM06.022. Protein Eng 1992;5:93–100.[Abstract/Free Full Text]

  58. Martin U, Spona G, Strein K. Evaluation of thrombolytic and systemic effects of the novel recombinant plasminogen activator BM06.022 compared with alteplase, anistreplase, streptokinase, and urokinase in a canine model of coronary artery thrombosis. J Am Coll Cardiol 1992;19:433–40.[Abstract]

  59. Martin U, Bader R, Bohm E, et al. BM06.022: a novel recombinant plasminogen activator. Cardiovasc Drug Rev 1993;11:229–311.

  60. Tebbe U, von Essen R, Smolarz A, et al. Open non-controlled dose finding study with a novel recombinant plasminogen activator (BM06.022) given as a double bolus in patients with acute myocardial infarction. Am J Cardiol 1993;72:518–24.[Medline]

  61. International Joint Efficacy Comparison of Thrombolysis. Randomised, double-blind comparison of reteplase double-bolus administration with streptokinase in acute myocardial infarction (INJECT): trial to investigate equivalence. Lancet 1995;346:329–36.[Medline]

  62. Schroder R, Wegscheider K, Shroder K, et al. Extent of early ST-segment elevation resolution: a strong predictor of outcome in patients with acute myocardial infarction and a sensitive measure to compare thrombolytic regimens. J Am Coll Cardiol 1995;26:1657–64.[Abstract]

  63. Dissmann R, Schroder R, Busse U, et al. Early assessment of outcome by ST-segment analysis after thrombolytic therapy in acute myocardial infarction. Am Heart J 1994;128:851–7.[Medline]

  64. Smalling RW, Bode C, Kalbfleisch J, et al. More rapid, complete, and stable coronary thrombolysis with bolus administration of reteplase compared with alteplase infusion in acute myocardial infarction (RAPID-I). Circulation 1995;91:2725–32.[Abstract/Free Full Text]

  65. Bode C, Smalling RW, Berg G, et al. Randomized comparison of coronary thrombolysis achieved with double bolus reteplase (recombinant plasminogen activator) and front loaded accelerated alteplase (recombinant tissue plasminogen activator) in patients with acute myocardial infarction (RAPID II). Circulation 1996;94:891–8.[Abstract/Free Full Text]

  66. GUSTO III Study Group. A comparison of reteplase with alteplase for acute myocardial infarction. N Engl J Med 1997;337:1118–23.[Abstract/Free Full Text]

  67. Hartzler GO, Rutherford BD, McConahay DR, et al. Percutaneous transluminal coronary angioplasty with or without thrombolytic therapy for treatment of acute myocardial infarction. Am Heart J 1983;106:965–73.[Medline]

  68. Pepine CJ, Prida X, Hill JA, et al. Percutaneous transluminal coronary angioplasty in acute myocardial infarction. Am Heart J 1984;107:820–2.[Medline]

  69. Rothbaum DA, Linnemeier TJ, Landin RJ, et al. Emergency percutaneous transluminal coronary angioplasty in acute myocardial infarction, a three-year experience. J Am Coll Cardiol 1987;10:264–72.[Abstract]

  70. O'Neill W, Timmis GC, Bourdillon PD, et al. A prospective randomized clinical trial of intracoronary streptokinase versus coronary angioplasty for acute myocardial infarction. N Engl J Med 1986;314:812–18.[Abstract]

  71. Topol EJ, Califf RM, Georges BS, et al. A randomized trial of immediate versus delayed elective angioplasty after intravenous tissue plasminogen activator in acute myocardial infarction. N Engl J Med 1987;317:581–8.[Abstract]

  72. Grines CL, Browne KF, Marco J, et al. A comparison of immediate angioplasty with thrombolytic therapy for acute myocardial infarction. N Engl J Med 1993;328:673–9.[Abstract/Free Full Text]

  73. Ellis SG, Ribeiro da Silva E, Heyndrickx G, et al. Randomized comparison of rescue angioplasty with conservative management of patients with early failure of thrombolysis for acute anterior myocardial infarction. Circulation 1994;90:2280–4.[Abstract/Free Full Text]

  74. Braunwald E, Cannon P, McCabe CH. An approach to evaluating thrombolytic therapy in acute myocardial infarction. The unsatisfactory outcome end point. Circulation 1992;86: 683–7.[Free Full Text]

  75. Lee L, Bates ER, Pitt B, et al. Percutaneous transluminal coronary angioplasty improves survival in acute myocardial infarction complicated by cardiogenic shock. Circulation 1988;78:1345–51.[Abstract/Free Full Text]

  76. Epstein SE, Palmer ST, Patterson RE. Evaluating patients after myocardial infarction: indications for cardiac catheterization and surgical intervention. N Eng J Med 1982;397: 1487–91.

  77. Golding LAR, Loop FD, Hollman D, et al. Early results of emergency surgery after coronary angioplasty. Circulation 1986;74(Suppl III):III-26–9.

  78. Flameng W, Sergeant P, Van Haecke J, Suy R. Emergency coronary bypass grafting for evolving myocardial infarction: effects on infarct size and left ventricular function. J Thorac Cardiovasc Surg 1987;94:124–31.[Abstract]

  79. Ryan TJ, Faxon DP, Ganncir RF, et al. Guidelines for percutaneous transluminal angioplasty. J Am Coll Cardiol 1988;12:529–45.[Medline]

  80. Moss AJ, Bigga JT, Odoroff CL. Post infarction risk stratification. Prog Cardiovasc Dis 1987;29:389–412.[Medline]

  81. DeBusk RF, Dennis CA. Submaximal pre discharge exercise testing after acute myocardial infarction: who needs it? Am J Cardiol 1985;55:498–500.

  82. Senaratne MPJ, Hsu L, Rossall RE, Kappagoda CT. Exercise testing after myocardial infarction: relative values of low level pre discharge and post discharge exercise test. J Am Coll Cardiol 1988;12:1416–22.[Abstract]

  83. Furster V, Dyken ML, Volkanas PS, Hennekens C. Aspirin as a therapeutic agent in cardiovascular disease. Circulation 1993;87:659–75.[Free Full Text]

  84. Almany GT, Lefkovits J, Topol EJ. Antiplatelet and anticoagulation use after myocardial infarction. Clin Cardiol 1996;93:357–65.

  85. PARAGON Study Group. Use of lamifiban, a glycoprotein IIb/IIIa inhibitor to reduce reinfarction at 30 days in 2282 patients. J Am Coll Cardiol 1997;29(Suppl A):409A.

  86. Karlson BW, Herlitz J, Hjalmarson A. Impact of clinical trial in the use of beta blockers after acute myocardial infarction and its relationship to other risk indicators for death and 1-year mortality rates. Clin Cardiol 1994;17:311–6.[Medline]

  87. First International Study of Infarct Survival Collaborative Group. Randomised trial of intravenous atenolol among 16,027 cases of suspected acute myocardial infarction: ISIS-1. Lancet 1986;2:57–66.[Medline]

  88. The MIAMI Trial Research Group. Metoprolol in acute myocardial infarction (MIAMI). A randomised placebocontrolled international trial. Eur Heart J 1985;16:199– 226.

  89. BHAT Research Group. A randomized trial of propranolol in patients with acute myocardial infarction, mortality results. JAMA 1982;247:1707–14.[Abstract/Free Full Text]

  90. The Norwegian Multicenter Group. Timolol-induced reduction in mortality and reinfarction in patients surviving with acute myocardial infarction. N Engl J Med 1981;304: 801–7.[Abstract]

  91. Kendall MJ, Lynch KP, Hjelmarson A, Kiekshus J. Beta blockers and sudden cardiac death. Ann Intern Med 1995;123:358–67.[Abstract/Free Full Text]

  92. Rutherford JD, Pfeffer MA, Moye LA, et al. Effects of captopril on ischemic events after myocardial infarction. Results of the survival and ventricular enlargement trial (SAVE Investigators). Circulation 1994;90:1731–8.[Abstract/Free Full Text]

  93. 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;343:821–8.

  94. Kober L, Torp-Pederson C, Carlson JE, et al. (TRACE) Study Group. A clinical trial of angiotensin-converting enzyme inhibitor trandulapril in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 1995; 333:1670–6.[Abstract/Free Full Text]

  95. Ambrosioni E, Borghi C, Magnani B. The effects of angiotensin-converting enzyme inhibitor 39 fenopril on mortality and morbidity after anterior myocardial infarction (SMILE) study group. N Engl J Med 1995;332:80–5.[Abstract/Free Full Text]

  96. The SOLVO Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fraction. N Engl J Med 1992;327:685–91.[Abstract]

  97. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4,444 patients with coronary artery disease. Lancet 1994;344:1383–9.[Medline]

  98. Braunwald E, Paoletti L, La Rosa D, et al. Final results from CARE (Cholesterol and Recurrent Events Study): statin therapy also prevents post-MI stroke. Modern Med 1996;64: 33–8.





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