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A Randomized Trial of Intravenous Streptokinase Versus Tissue Plasminogen Activator for the Treatment of Acute Myocardial Infarction: Results Using an Aggressive Approach

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Seventy-six patients presenting within 6 hours of the onset of an acute myocardial infarction were randomized to either treatment with 1.5 million units of Streptokinase or 100 mg of recombinant tissue plasminogen activator intravenously. Patients
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  A Randomized Trial of Intravenous Streptokinase Versus Tissue Plasminogen Activator for the Treatment of Acute Myocardial Infarction: Results Using an Aggressive Approach JOSEPH R. HARTMANN, M.D., LOUIS S. MCKEEVER, M.D., VINCENT J. BUFALINO, M.D., JOSEPH C. MAREK, M.D., ALAN S. BROWN, M.D., MARK J. GOODWIN, M.D., MICHAEL A. COLANDREA, M.D., NICHOLAS J. STAMATO, M.D., JOHN M. CAHILL, M.D., MICHAEL J. O’DONNELL, M.D., FIROUZ AMIRPARVIZ, M.D., and ELAINE L. ENGER, M.S. Froin the Midwest Cardiovuscular Institute and the Midwest Heurt Rrsrurch Foundation, Downers Grove, Illinois Seventy-six putients presenting w’ithin 6 hours ofthe ons t of an acute myocurdiul infarction were random- ized to either treatment with 1.5 million units of streptokinase or 100 mg of recombinant tissueplasminogen activator intravenously. Patients not demonstrating clinical reperfusion within I hour were taken emergently ,fbr “salvage” angioplasty or coronary bypass surgery Those patients demonstrating clinical reperjusion underwent early I 2 to 72 hours) elective angiography and either elective angioplasty or bypass surgery. The mean timefvom pain onset to treutment wus 149 minutes in the streptokinusegroup and 134 minutes in the recombinanl tissue plasminogen activator group (P = NS). There were no stutisticul differences between groups with regurd to prior myocardial infarction, infarct location, prior coronary bypass surgery and Killip classification. Clinical repevfiuion was demonstrated in 56 o the .streptokinase group and 53 of the recornbinant tissueplasminogen activator group (P = NS). Angiogruphic patcncy was demonstrated in 70 qfthc streptokinase group and 66 ofthe recombinant tissue plasminogen activator group (P = NS). Lejt ventricular ejection iuction at discharge was no diferent: 47 in the streptokinase group and 43 in the recombinant tissue plasminogen activator group (P NS). Recurrent ischemic events were ound more often in the recombinant tissueplasminogen activutor group, 18 , versus the streptokinasegroup 3 (P = 0.0.5). Treatment outcomes did not difler between groups. There was onc (3 ) death in the streptokinase group versus two (6 ) deuths in the recombinant ti.ssueplasininogen activator group (P NS). There wus a trend toward a greater need,for emergent coronurji bypass surgery ajter attempted angioplasty in the recombinant tissue plasminogen activator group, our of 18 patients (22 ) versus one qf 23 patients (4 ) in the strepto- kinuse group (P = 0.14). In summar.v, in the setting ofacute myocardiul infarction treated by thrombol-vsis, those patients treated wirh recombinunt tissue plasminogen activator experienced significantly more recur- rent ischemic events and required emergent coronary bypuss surgery more requently for failed angioplasty compared to those treated with streptokinase. The results suggest there may he agent specific increases in complications dependent upon the thrombolytic agent of choice when salvage or early coronary ungioplasty is used. J Interven Cardiol 1990:3:2) Introduction Address for reprints: Joseph R. Hartmann M.D.. Midwcst Heart Research Foundation 2340 Highland Avenue Suite 200 Lombard. IL 60148. Submitted for publication April 6. 1990; accepted with revisions May 18 1990; revisions returned June I, 1990. Restoration of myocardial perfusion in acute myocardia1 infarction is a time-dependent treat- ment goal and may be accomplished by emergent Vol. 3, No. 2 1990 Journal of Interventional Cardiology 69  HARTMANN, ET AL mechanical or surgical revascularization or by the use of thrombolytic agents. Presently, thrombo- lytic therapy has become the treatment of choice for most patients presenting with acute myocardial infarction. - However, two significant related questions remain unanswered: is there a difference in efficacy between thrombolytic agents and can the choice of a thrombolytic agent adversely affect the subsequent interventional outcome? The present study examined the choice of throm- bolytic agent in terms of efficacy, the initial com- plication rate, and the relationship of that agent to subsequent interventional strategies. This was a clinically driven protocol with a design that would best approximate general clinical practice using a plan of salvage angioplasty, early elective angio- plasty or bypass surgery. Methods Patient population. This study was conducted in five hospitals all served by the same team of cardiol- ogists. Consective patients were enrolled during a 12-month period from January 1988 to December 1988. Eligibility for randomization included those patients experiencing a chest pain syndrome of (6 hours duration compatible with myocardial infarc- tion and having ST segment elevation of 20.2 mV in at least two electrocardiographic leads that re- flected one zone of infarction. Exclusion criteria included: age > 70 years; the presence of left bun- dle branch block; prolonged cardiopulmonary re- suscitation; uncontrolled hypertension (systolic blood pressure > 190 mmHg); recent cerebrovascu- lar accident or surgery; or history of a bleeding ten- dency. Treatment protocol. All patients were treated with intravenous lidocaine and were given 5,000 units of heparin intravenously prior to thrombo- lytic therapy. Calcium channel antagonists and beta blocking agents were given routinely. The patients were randomly assigned to one of two thrombolytic regimens. Patients assigned to re- ceive streptokinase (Hoechst-Roussel Pharmaceu- ticals, Somerville, NJ, USA) were pretreated with diphenhydramine 50 mg intravenously and hydro- cortisone 200 mg intravenously. Streptokinase 1.5 million units was then administered intravenously over 30 minutes. Patients assigned to recombinant tissue plasminogen activator (Genentech Inc., South San Francisco, CA, USA) received an intra- venous bolus of 6 mg followed by 54 mg over 1 hour and 20 mg per hour for 2 hours. Randomiza- tion was accomplished using a computer generated list of random numbers available through a central desk 24 hours a day. Treatment was open label. Immediately at the completion of the strepto- kinase or the recombinant tissue plasminogen acti- vator, a continuous infusion of heparin was begun at 1,000 units per hour and adjusted to keep the partial thromboplastin time between 80 and 120 seconds. Heparin was continued for at least 48 hours in all patients except those requiring emer- gent bypass surgery. Clinical reperfusion. Clinical reperfusion was said to occur when there was resolution of the chest pain and ST segment elevation. Recurrent ischemic events. Recurrent ischemic events were said to occur when a patient met reper- fusion criteria and later experienced recurrent chest pain lasting at least 20 minutes and recurrent or new ST segment elevation. These events were tabulated until the time of discharge. Catheterization. Patients demonstrating clinical reperfusion were admitted to the coronary care unit and given intravenous heparin, which was ad- justed to maintain a partial thromboplastin time between 80- 120 seconds. Elective catheterization was scheduled for 12-72 hours after admission. Those patients in whom clinical reperfusion was not evident 1 hour after the start of thrombolytic therapy were taken directly to the catheterization laboratory. Infarct artery patency was analyzed blindly at a central laboratory using the first injec- tion of the infarct related artery, whethcr at emer- gent or elective catheterization. Coronary angioplasty. Elective angioplasty was performed when the infarct related artery con- tained a 70% or greater lesion, 12-72 hours after initial treatment. Emergent angioplasty was per- formed if the infarct related vessel remained oc- cluded (TIM1 flow 0 or 1) at the time of emergent catheterization. Aortocoronary bypass surgery. Elective coro- nary artery bypass surgery was performed in pa- tients with left main lesions > 50% or in patients whose coronary artery anatomy dictated surgery to be the better revascularization modality. Emergent coronary artery bypass surgery was performed in 70 Journal of Interventional Cardiology Vol. 3, No. 2, 1990  STREPTOKINASE VERSUS T-PA IN ACUTE MYOCARDIAL INFARCTION patients in whom the infarct related artery re- mained occluded despite angioplasty attempts pro- vided that <6 hours had elapsed since the onset of pain. Statistical analysis. Means and standard devia- tions were computed for continuous variables. Dif- ferences in means between the two treatment groups were analyzed using the Student’s t-test or Chi-square test. A P 0.05 was considered signifi- cant. Results Patients. Seventy-six patients met entry criteria and were randomized during the study period. Streptokinase wasgiven to 37 patientsand recombi- nant tissue plasminogen activator to 39 patients. Table I summarizes the clinical characteristics of the two treatment groups. For both groups, the ma- jority of patients presented with their first infarc- tion and were in Killip Class I or 11. Examination of sex, age, prior myocardial infarction, site of in- farction, incidence of hypotension, mode of trans- port to hospital, and time to treatment revealed no significant difference between groups. Treatment time characteristics are summarized in Table 11. Thrombolytic therapy. There was no significant difference between groups when clinical reperfu- sion was analyzed; 20 (56 ) for streptokinase and 20 (53 ) for recombinant tissue plasminogen acti- vator. Angiographic vessel patency rates were also similar; 25 (70%) for streptokinase and 25 (66 ) for recombinant tissue plasminogen activator. There was, however. a statistically significant dif- Table 1 Clinical Characteristics IVSKt IVr-tPA* P Number Men Age (years) Prior myocardial infarction Antcrior myocardial infarction Blood pressure < 90 mmHg Killip Class 1 111 Killip Class IV Paramcdic transport 37 29 (78%) 55 13 (8 ) 17 (47%) 9 (25%) 33 (8910) 4(11%) 11 (31%) 39 30 (77%) 57? 11 4(10 ) 16 (41%) 5 (13 ) 31 (95%) 2 (5%) 19 (49%) NS NS NS NS NS NS NS NS NS Table 11 Treatment Intervals-Onset of Symptoms to Treatment IV SKt IV r-tPA* P Mean time Range (minutes) 149 k 93 134 * 69 NS (minutes) 10-360 45-360 NS * Intravenous recombinant tissue plasrninogen activator. t lntravenous streptokinase. ference when recurrent ischemic events were exam- ined; one (3 ) in the streptokinase group versus seven ( 18 ) for the recombinant tissue plasmino- gen activator group (P = 0.05) (Table 111). There was one death in the streptokinase group (3 ) and two deaths in the recombinant tissue plasminogen activator group (6%) P = NS). Fourteen (39 ) of the streptokinase group re- quired treatment with vasopressors compared to 13 (33 ) of the recombinant tissue plasminogen activator group (P = NS). Intra-aortic balloon pumps were placed in unstable patients prior to angioplasty or surgery and were required in 12 (33 ) of the streptokinase group and 20 (5 1 ) of the recombinant tissue plasminogen activator group (P = NS . The requirements for blood transfusions and the number of units administered are summarized in Table 1V. Again, no significant differences were seen. Left ventricular function, as assessed by gated radionuclide scan, was done prior to discharge. There was no significant difference between treat- ment groups; streptokinase, 47 9 and recombi- nant tissue plasminogen activator, 43 & 12 . There has been concern about the success of emergent percutaneous transluminal coronary an- Table 111. IVSKt IVr-tPA* P Clinical reperfusion 20(56%) 20(536) NS Angiographic patency 25 (70 ) 25 (66%) NS Recurrent ischemic events I (3 ) 7 (18%) 0.05 * Intravenous recombinant tissue plasminogen activator t Intravenous streptokinase. * Intravenous recornbinant tissue plasrninogen activator Intravenous streptokinase. Vol. 3. No. 2. 1990 Journal of Interventional Cardiology 71  HARTMANN, ET AL Table IV. Transfusion Requirement SKI- r-tPA* P No ACB 0.4 1.6 0.7 1.7 NS ACB 2.0 2.3 1.8 2.8 NS Mean number of units of packed RBCs transfused per patient. ACB = aortocoronary bypass; RBC red blood cells; t SK = streptokinase; * Recombinant tissue plasminogen activator. gioplasty following the administration of intrave- nous recombinant tissue plhsminogen activator. The seventy of coronary disease, final treatment regimen, and results of angioplasty were therefore compared. Table V reveals that there were no dif- ferences between groups in the incidence of left main or three vessel disease. There were also no significant differences noted in the final form of therapy given (Table VI). Coronary angioplasty was attempted in 23 patients in the streptokinase group, one (4%) required emergent coronary by- pass surgery, four of the 18 (22 ) patients in the recombinant tissue plasminogen activator group in whom angioplasty was attempted required emer- gent surgery (P = 0.14). Discussion While comparison studies of streptokinase and recombinant tissue plasminogen activator have been performed previously, none of these have in- corporated an interventional approach incorporat- ing salvage angioplasty or surgery for unstable patients.6- Our data suggest that there is no signifi- cant difference between streptokinase and recombi- nant tissue plasminogen activator when such an Table V. Coronary Anatomy Left main 3 (10%) 3 (9%) NS 3 vessel 5 (15 ) 6 (19%) NS 2 vessel 14 (41 ) I5 (48 ) NS vessel 15 (44%) 10 (31 ) NS * Recombinant tissue plasminogen activator. 7 Streptokinase. Table VI. Final Treatment IV SKf IV r-tPA* Medical 5 (14 ) (13%) PTCA 22 (60%) 14 (36 ) Surgery 10 (26%) 20 (51%) * Intravenous recornbinant tissue plasminogen activator. t Intravenous streptokinase. PTCA = percutaneous transluminal coronary angioplasty. approach is used. However, those patients treated with recombinant tissue plasminogen activator ex- perienced significantly more recurrent ischemic events and tended to require aortocoronary bypass surgery more frequently for failed angioplasty. While there is clearly a limitation to the applica- tion of clinical variables to identify reperfusion, a clinical protocol allowing for salvage angioplasty or surgery must rely on such clinical evidences of reperfusion. This treatment protocol used early and full intravenous heparinization with 5,000 units given prior to the thrombolytic and a continu- ous infusion begun immediately after completion of the thrombolytic. Therefore, the recurrent isch- emic events seen with recombinant tissue plasmin- ogen activator cannot be attributed to a lack of postlytic anticoagulation. There has been considerable debate regarding the need for revascularization of patients who re- spond to thrombolytic therapy.'0, This clearly re- quires further study. Whether the interventional approach to the treatment of acute myocardial infarction as we have described is superior to a more conservative approach remains unclear. We feel that the in hos- pital course is less complicated in aggressively treated patients. In the present series, patients with cardiogenic shock or prior infarction were not ex- cluded and yet the mortality rate was comparable to studies where such patients were excluded. In the present study, such patients were not excluded and this may explain the relatively high rate of need for and use of vasopressors and intra-aortic counterpulsation. The mean ejection fraction for both groups may be lower than that seen in prior studies, but again, patients with prior infarctions were not excluded. This, of course, requires further study and results may be agent-dependent. 72 Journal of Interventional Cardiology Vol. 3, No. 2 1990  STREPTOKINASE VERSUS T-PA IN ACUTE MYOCARDIAL INFARCTION Summary When an interventional approach to the treat- ment of acute myocardial infarction is used, no significant differences in mortality, vessel patency, left ventricular function, or transfusion require- ments between streptokinase and recombinant tis- sue plasminogen activator could be demonstrated. Patients treated with recombinant tissue plasmino- gen activator demonstrated a higher incidence of recurrent ischemic events and tended to have a poorer outcome following percutaneous translu- mind coronary angioplasty therapy. Acknowledgments: We wish to thank the staff and nurses of the emergency room, cardiac catheterization laboratory. and coro- nary care unit at Central DuPage Hospital, Edward Hospital, Elmhurst Memorial Hospital, Good Samaritan Hospital, and Gottlieb Hospital. We also thank Karen Gustafson for prepara- tion of the manuscript. References I. Lee TH, Weisberg MC, Brand DA, et al. Candidates for thrombolysis among emergency room patients with acute chest pain: Potential true- and false-positive rates. Ann Intern Med 1989; 110:957-962. Vol. 3, No. 2. 1990 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. Murray N, Lyons J, Layton C, et al. What proportion of patients with myocardial infarction are suitable for throm- bolysis? Br Heart J 1987; 57:144-147. Doorey AJ, Michelson EL, Weber FJ, et al. Thrombolytic therapy of acute myocardial infarction: Emerging chal- lenges of implementation. J Am Coll Cardiol 1987; Hartmann JR, McKeever LS ufalino VJ, et al. Intrave- nous streptolunase in acute myocardial infarction: Experi- ence of community hospitals served by paramedics. Am Heart J 1986; 1 11:1030-1034. Hlatky MA, Cotugno H, OConnor C, et al. Adoption of thrombolytic therapy in the management of acute myo- cardial infarction. Am J Cardiol 1988; 61:510-514. The TIMI study group. The thrombolysis in myocardial infarction (TIMI) trial: Phase I findings. N Engl J Med Chesebro JH, Knatterud G, Roberts R, et al. Thromboly- sis in myocardial infarction (TIMI) trial, phase I: A com- parison between intravenous tissue plasminogen activator and intravenous streptokinase: Clinical findings through hospital discharge. Circulation 1988; 76: 142-154. Verstraete M, Bernard R, Bory M, et al. Randomised trial of intravenous recombinant tissue-type plasminogen acti- vator versus intravenous streptokinase in acute myocar- dial infarction. Lancet 1985; 1:842-847. The TIMI research group. Immediate vs delayed calheter- ization and angioplasty following thrombolytic therapy for acute myocardial infarction: TIMI I A results. J Am Topol EJ, Califf RM, George BS, et al. A randomized trial of immediate versus delayed elective angioplasty after in- travenous tissue plasminogen activator in acute myocar- dial infarction. N Engl J Med 1987; 317:581-588. The TIMI study group. Comparison of invasive and con- servative strategies after treatment with intravenous tissue plasminogen activator in acute myocardial infarction: Re- sults of the thrombolysis in myocardial infarction (TIMI) phase I1 trial. N Engl J Med 1989; 320:618-627. 10:1357-1360. 1985; 312:932-936. Med ASOC 1988; 260:2849-2858. Journal of Interventional Cardiology 73
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