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Kenneth W. Mahaffey, MD Durham,NC Robert M. Califf, MD Durham,NC

Thrombolytic Therapy Kenneth W. Mahaffey, MD Robert M. Califf, MD Kenneth W. Malu1ffey, MD, is a Fellow in Cardiology; Robert M. Califf, MD, is Professor ofMedicine and Director ofthe Cardiovascular Databank, Division of Cardiology, Department ofMedicine, Duke University Medical Center. Durham, North Carolina

nly within the past decade has thrombolytic therapy revolutionized the treatment of patients with acute myocardial infarction (AMI). The ability of streptokinase to lyse clot was first recognized in the 1930s. However, thrombolytic therapy was not widely used until the landmark angiographic studies of DeWood et al. in 1980 1 demonstrated the importance of thrombosis in the pathogenesis of AMI. Following the positive results of small trials using intracoronary and intravenous throm-

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bolytic therapy, the ISIS and GISSI investigators proved the clinical benefits of thrombolysis in the first large, multicenter trials.2,3 Since then, tremendous efforts have been made to identify which patients benefit from therapy, determine which agents are most effective, minimize time-to-treatment, and develop adjunctive therapies. Thrombolytic therapy decreases mortality following AMI by 20 to 30%. However, only a minority of patients with AMI are treated with thrombolysis. An MI Registry substudy of the GUSTO trial" reviewed 618 admissions for acute myocardial infarction at 97 hospitals. Only 34% of all patients with AMI were treated with thrombolytic therapy. After excluding patients without ST elevation or bundle branch block and patients with contraindications to thrombolysis, 22% ofpatients admitted with AMI eligible for thrombolytic therapy were not treated

Interview with W. Douglas Weaver, MD W. Douglas Weaver, MD, is Professor of Medicine at the University ofWashington School ofMedicine. Seattle, Washington, and Director ofCardiovascular Critical Care at the University ofWashington Medical Center, Seattle, Washington MAHAFFEY: It is clear that the earlier thrombolytic therapy is administered the better the mortality benefit. What methods can you recommend to improve early identification of patients with acute myo-

ICANEB 3(4)1995,25-32

cardial infarction and initiation of thrombolysis? WEAVER: It is unclear what the best way to improve earlier identification of patients is. In Seattle, we have discovered that having the prehospital paramedics routinely screen patients with chest pain using a checklist and doing 12-lead electrocardiograms helps to speed the care of

with thrombolysis or primary PTCA. Physicians need to identify mechanisms to provide definitive therapy to more patients with AMI. The Fibrinolytic Therapy Trialists' (FTT) Collaboration pooled data from all trials that randomized at least 1,000 patients to thrombolytic therapy versus placebo and helped better define the patients in whom thrombolytic therapy is beneficial.' Patients presenting within 12 hours of symptom onset with ST-segment elevation or bundle branch block regardless of age, sex, blood pressure, heart rate. infarct location, or history of diabetes or infarct had significant improvement in survival if treated with thrombolytic therapy. This demonstrated that thrombolysis is beneficial in a broader range of patients than those currently receiving such treatment. continued on page 26

IN THIS ISS UE Thrombolytic Therapy

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Interview with \V. Douglas Weaver, MD 25

Thrombolytic Therapy Survey Summary

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continued on page 31

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Stump DC. Candela RI. Abbottsmith CW. Aronson 1.. Pickel A.Boswick 1M, LeeKL.O'NeillWW.CaliffRMforThe TAM! Study Group. A randomized controlled trial of intravenous tissue plasminogen activator and early intravenous heparin in acute myocardial infarction. Circulation 1989;79:281-286. 20. ISIS-3 (Third International Study of Infarct Survival) Collaborative Group. ISIS-3: a randomiscd comparison of streptokinase vstissue plasminogen activatorvs anistreplase andof aspirin plus heparin vs aspirin alone among 41,299 cases of suspected acute myocardial infarction. Lancet 1992;339:753-770. 21. Gruppo Italiano per 10 Studio dellaSopravvivenza nell'Infarto Miocardico. G1SSI-2: A factorial randomized trial of alteplase versus streptokinase andheparin versus no heparin among 12,490 pa-

Interview with Dr.W. Douglas Weaver continuedfrompage 25 patients with acute myocardialinfarction. In a small proportion (about 15%), it also leads tobetterrecognition ofpatients with ST-segment elevation. Prehospital electrocardiography and a checklist are the methods to improve the in-hospital care of patients with acute myocardial infarction. MAHAFFEY: What conclusions can you summarize about the safety and efficacy of thrombolysis initiated in the prehospital setting? WEAVER: None of the studies of prehospital-initiated thrombolytic therapy have been large enough to satisfactorily test the strategy.However,it is clear from the available data that, providing there is a remote physician to review the findings as well as the electrocardiogram,patients with acute myocardial infarction can be accurately identified. MAHAFFEY: Several investigators have shown that 30 to 40% of patients

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INTERVENTIOl'-W. CARDIOLOGY NEWSLETIER 31

tients with acute myocardial infarction. Lancet 1990;336:65-71. 22. Mahaffey KW, Granger CB, O'Connor CM, Ohman EM, Bleich SO, Col II, CaliffRM. Overview of randomized trials of intravenous heparin in patients withacute myocardial infarction treated with thrombolytic therapy. Am 1 Cardiol 1995; inpress. 23. Gore lM, Granger CB, Sloan MA, Van de Werf F, Weaver WO, Califf RM, White HO, Barbash 01, Simoons ML. Aylward PE. Topol EJ fortheGUSTO-I Investigators. Stroke after thrombolysis: mortality andfunctional outcomes in the GUSTO-! trial. Circulation 1995; in press. 24. Simoons M, Maggioni A, Knatterud G, Leimberger I, de Iaegere P, van DamburgR, Boersma E, Franzosi M, Califf R, Schroder R, Braunwald E.Individual risk assessment for intracranial hemor-

rhageduring thrombolytic therapy. lancet 1993;342:1523-1528. 25. Antman EM for the TIM! 9AInvestigators. Hirudin in acute myocardial infarction. Safety report from the Thrombolysis and Thrombin Inhibition inMyocardial Infarction (1lMI) 9Atrial. Circulation 1994;90:1624-1630. 26. TheGUSTO llAInvestigators. Randomized trial of intravenous heparin versus recombinant hirudin for acute coronary syndromes. Circulation 1994;90:16311637. 27. The GUSTO Angiographic Investigators. The effects of tissue plasminogen activator, streptokinase, or bothoncoronaryartery patency, ventricular function. and survival after acute myocardial infarction. N EnglI Med1993;329:16151622.

with acute myocardial infarction who are eligible for thrombolysis are not treated. Can this be improved and, if so. how? WEAVER: Women are more likely not to receive thrombolytictherapythan men given the equal eligibility criteria. We have found that sometimes the symptom complex in women is not simply chest pain but. instead, represents a constellation of chest and abdominal pain as well as overwhelming fatigue. This symptom complex may be confusing to the physician; less severe pain may suggest that this is angina and not acute myocardial infarction. The question will be whether serum markers of acute necrosis are sensitive enough to detect acute injury, or if the computerized interpreted electrocardiogram could improveearly recognition of patients. There is enough data in the literature suggesting that these may be helpful; however, they have not been prospectively tested. MAHAFFEY: What is the role of primary PI'CA in management of patients with acute myocardial infarction? WEAVER: The findings to date with primary angioplasty are provocative and

suggest that patients at high risk may derive greater benefit from angioplasty than with thrombolytic therapy. However. the numbers of patients randomized in trials are relatively small, and although I cannot conceive that primary angioplasty is worse than thrombolytic therapy, I am unconvinced that it is significantly better. A second question is whether the results in these trials by expert centers and physicians who concentrate on the angioplasty strategy can be replicated when done by physicians who are less familiar and less experienced with acute angioplasty. The number of procedures done by interventionalists around this country varies considerably, and it is disturbing that a large portion of our operators do far fewer than the 75 procedures recommended by the ACC guidelines. There has been some data suggesting that the caseload, at least of hospitals. is related to outcome results from elective angioplasty.Whether thisis true also for individual operators, however. is unknown at the current time and

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Interviewwith Dr.W. Douglas Weaver continuedfrom page31 needs further study. Thus. until there is adequate data showing definitive difference in outcome for primaryangioplasty and data suggesting that results in the community settingand with low volume operators are equal to those done by expertinterventionalists, thrombolytic ther-

ExecutiveEditors David P. Faxon. MD Los Angeles,CA David R. Holmes,Jr., MD Rochester,MN Tunothy A. Sanborn,MD New York, NY RichardA. Schatz, MD LaJolla,CA

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apy should be the treatment of choice where systems have not been developed to manage acuteMI by PTCA. MAHAFFEY:Tremendous emphasis in recentclinicaltrialshasbeen to studynew adjunctive therapies for patients with acute myocardial infarction treated with thrombolysis. What agents do you believeare most promising? WEAVER: The two groups of agents that are the most promising as adjunct to thrombolytic therapy are the direct an-

VOLUME 3, NUMBER 4, 1995

tithrombins and the antiplatelet agents. The question will be whether serious bleeding willbe a confounding factorthat will limit their overall utility. Soon we will have results from large trials of the antithrombins. It seems likely that sodium heparin will be replacedby alternative agents. such as the new direct antithromblns, low molecular weight heparin. or the IIb/IIIa receptor antagonists.

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