Results of High Dose Intravenous Urokinase for Acute Myocardial Infarction Thomas C. Wall, MD, Harry R. Phillips, Ill, MD, Richard S. Stack, MD, Susan Mantell, RN, Lynne Aronson, BS, Jane Boswick, MPH, Kristina Sigmon, MA, Michael DiMeo, MD, Don Chaplin, MD, David Whitcomb, MD, Depak Pasi, MD, Mark Zawodniak, MD, Moosa Hajisheik, MD, Sadanaud Hegde, MD, Walter Barker, PhD, Richard Tenney, MD, and Robert M. Califf, MD
Todetenninetheoutcomeofpatkntsaftertreatment with high-dose intravenous urokinase (3 miiiienu)162pathtswere~eiYevaiuated hthesetthgofacutemyocardiaiinfaMion.The first 61 patienb received intravurokinase as
acodweusinfudenandtheiast41pa6entswere treatedwitJBtHlinitiai1.5miiiienuintraveneus bob.Sixty-twopercentotaiipatkmtshadpatent infarct-rebted arterks by the time of immediab angiography (median time 22 hours), which was pe&mnedinalpatients.TherewasnodgMcant dWrenceinpatencyratesbe4weenpatkntstreatedwithorwithoutaninitiaiintravenousboius. Twentyeight (26%) patiemts deveieped dinkai evtd8nceof-ischemnia(death,reocdudon, W-Y -9 urgent bypau rurgery)
dlaiag i8o@Mab, whereas oniy 7 (7%) deveidoamenwreocchsien.of opedangiolgclphicclry 26patimtswhofaiiedtoaddeves88cwsMreporfusionattheth8eofimmediate~,resW~~ruccercfulill~-
&B
inaiibutlpatktnt.Nos&gniiicantimprovementinmediangbMieftv~ fmction was seen bebveen immediate (48%) and foibw-qJ cathebbtion (46%). 6ignMcant bieed-
ingcutnplkaKomweretmusualexceptin1patleml whoexpedend an intraeraniai hemodmge. Eight (6%) idents died during hdtabth. Thereforo, the use of high-dose intravenous uroidnase in patied with acute myocardiai infarction is assodatedwitha62%patencyrate+aiowinddenceof reo&&onwrdbi8edingcompkaUonsandahigh tedmkaisuccessratewithrescueangbpiastyat -.nlisstudy thetimeofimmediate suppo&theneedfortvtherrandomizedcontroiied this comparing intravtinase dhCt&WithOthW -cm@-. (Am J Cardioi 1990;65:124-131)
124
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 65
uccessful reperfusion with intravenous thrombolytic therapy in acutemyocardial infarction (AMI) has been associatedwith an improvement in glob al left ventricular function, decreasedin-hospital and long-term mortality and decreasedcongestiveheart failure after infarction.1-4 Despite this apparent success,recurrent &hernia and reocclusion remain the “Achiies heel” of thrombolytic therapy.s-8Previousstudiesevaluating intravenous urokinase suggest that this problem may be substantially decreasedwhen this agent is used as monotherapyor in combination with recombinant tissue plasminogen activator.9Jo Despite this potentially important initial finding, only 2 studies have previously evaluated intravenous urokinase as monotherapy in this setting,9J1and only 1 study has used the currently recommendedintravenous dose of 3 million U. Although these studies demonstrated successfulre perfusion in a large proportion of patients and a tendency toward lower rates of recurrent ischemia and re occlusion compared with other thrombolytic agents, the combined experience representsonly 308 patients. Therefore, this study was undertaken to evaluate the effects of high-dose intravenous urokinase in establishing perfusion and sustainedpatency of infarct-related arteries in the setting of AMI, and to determine whether further comparative,controlled trials of a doseof 3 million U of intravenous uroldnase would be merited.
S
METHOD6 Patiad #action: Patients were prospectivelyidentified in North Carolina community hospitals that collab orate with Duke University Medical Center in thrombolytic trials.12 Inclusion criteria were: (1) chest pain or equivalent symptoms for 130 minutes’ duration wnsistent with wronary &hernia unresponsiveto standard sublingual nitroglycerin therapy; (2) onset of chest disFrom the Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, North Carolina. This work was sup ported in part by researchgrants H!%O4873,and -5635 from the National &ntei for Heal& Services;research grant HG17670 and HL-36587 from the National Heart. Luna and Blood Institute. Betheada, Maryland; grants from the Andrew %‘. Mellon Foundati&, New York, New York, and the Robert Wood JohnsonFoundation, Princeton, New Jersey; and a researchgrant from Abbott Labs, Chicago, Illinois. Manuscript received June 26, 1989; revised manuscript rcceivedSeptember22,1989, and acceptedSeptember 22. Addressfor reprints:Thomas C. Wail, MD, Duke University Medical Center, Box 3484,Durham, North Carolina 27710. SeeAppendix for Collaborating Centers.
comfort _ 110 mm Hg on serial measurementsin the emergencyroom; other serious advanced illnesseslikely to severely limit the patient’s life expectancy; cardiogenic shock defined as a systolic blood pressure 10 minutes) cardiopulmonary resuscitation within the previous 2 weeks; severe trauma within the past 6 months; psychologicalor physical inability to participate in the study; women known to be or suspectedof being pregnant. The protocol was approved by the institutional review board at each of the clinical sites. lhrombolytic therapy administratiom In this study, the low molecular weight form of urokinase (Abbott) was used. A total of 3 million U was infused over a 45to 6Ominute period. In the first 61 patients enrolled, urokinase was continually infused without an initial bolus. In the last 41 patients, a bolus of 1.5 million U was administered over 5 minutes with the remaining 1.5 million U infused over the subsequent45 to 60 minutes. No patient received intravenous heparin in the emergency room but aspirin, 325 mg, was administered orally at the time of thrombolytic therapy initiation. Cardiac
catheddzatiom
and -Y
w&M-W
After initiation of thrombolytic therapy, patients were transferred to the cardiac catheterization laboratory, where angiography of the infarct-related vesselwas performed as closely as possibleto 90 minutes after initiation of urokinase, but not before the 90-minute period unlessthe patient was in hemodynamicdistress.Arterial accesswas obtained via the femoral or brachial route. Five thousand units of intravenous heparin were administered once accesswas established. At 90 minutes, a minimum of 4 angiograms in various orthogonal and hemiaxial views was obtained. In addition, angiography of the noninfarct-related vesselsand the left ventricle was also performed. Coronary blood flow of the infarct-related vesselwas graded according to the Thrombolysis in Myocardial Infarction classification.13The final angiographic injection determined triage for angioplasty. Patients who re mained consistently occluded at 90 minutes (grade 0 or 1) were eligible for acute coronary angioplasty, which was performed at the discretion of the individual angiographer. In patients with grade 2 flow, acute coronary angioplasty was performed only if there was ongoing evidenceof ischemia (chest pain, presenceof collat-
erals or >O.l mV of persistent ST-segment elevation). In the absenceof these characteristics, angioplasty was deferred until predischargecatheterization or until the patient developedclinical evidenceof recurrent ischemia (emergency angioplasty). In patients who underwent angioplasty during the acute catheterization, 5,000 additional units of heparin were administered intravenously. Intracoronary urokinase in a dose of 6,000 U/min for up to 2 hours was usedin patients with angiographitally visible filling defectssuggestingthe presenceof residual thrombus after angioplasty, marked diminution of flow in the infarct-related artery with imminent reclosure or abrupt closure of the artery after angioplasty or evidenceof distal embolization as recognizedby angiographic pruning. To monitor the progressof intracoronary thrombolysis, angiographic injections were repeatedat 15-minute intervals during the urokinase infusion. Medical therapy: After immediate catheterization, patients were transferred to the coronary care unit where they received standard therapy with lidocaine, oxygen, morphine as neededfor pain and nitrates either topically or intravenously. Aspirin, 325 mg/day, was also administered along with a continuous infusion of intravenous heparin to maintain the partial thromboplastin time at 2 times the control value for our laboratory. This infusion was maintained until repeat cardiac catheterization at 7 to 10 days was accomplished.Beta blockers were not added to the medical regimen unless the patient had previously been treated with them or required such therapy for control of hypertension, supraventricular tachyarrhythmias or noncardiac disorders (e.g., migraine headache).Patients also were treated with calcium antagonistsusing either diltiazem at 60 mg orally 3 times daily or nifedipine at 20 mg orally 3 times daily. Other medications, including antiarrhythmic agents, were given at the discretion of the clinician. However, no other antiplatelet agents such as dipyridamole were used routinely. Repeat catheteriand rewasahbtbm Patients underwent repeat cardiac catheterization at 7 to 10 days after infarction even if they had an interim urgent catheterization study or if they had undergonecoronary artery bypass grafting. The follow-up study was performed to determine late patency of the infarct-related vesselas well as residual left ventricular function. Coronary angioplasty of the infarct-related vessel was performed during repeat catheterization when there was evidence of a significant residual stenosis suitable for angioplasty, especiallyif the patient had a positive exercise study. Patients with either severe multivessel diseaseor lesionsof the infarct-related vesselnot amenable to angioplasty underwent elective coronary artery bypass surgery before discharge. Emergency surgery was performed for failed angioplasty, particularly if there was evidenceof ongoing ischemia with a large amount of myocardium at risk. Bleeding and eoag&tion variables: Bleeding observed during the hospital stay was defined as follows: minor if it was of no clinical consequence,did not require a transfusion and was 4 (%)
16/29 (55) 30/54 (56)
19/29 (66) 31/54 (57)
Total (%) * Median time to first injection
11/15(73)
11/15(73)
57/98 (58)
61/98 (62)
was 2.2 hours.
64/75/91 1.9/2.8/3.6 1 32 15 50 2 53 12
* Figures shown are median (25th/SOth/75th percentile); t risk factors obtained from admission history. Definitions have been published prev~ously.~~
moderate if 250 to 500 cc of observed blood loss was noted, seuereif there was >500 cc of blood loss necessitating a transfusion; or life-threatening, which included intracranial bleeding or gastrointestinal or other internal or external bleeding causing hypotension and necessitating emergency transfusion. The site of bleeding, baselineand nadir hematocrit as well as units of packed red blood cells transfusedwere recorded for all patients. Blood sampleswere collected on 0.01 M citrate and 200 kIU/ml aprotinin at baseline,4 hours and 24 hours after initiation of thrombolytic therapy and were immediately processedand kept frozen at -2OOC until assayedby the coagulation laboratory. Fibrinogen was determined by a coagulation rate assay.Fibrinogen degradation products were analyzed by the tanned red cell agglutination inhibition technique at the core hematology laboratory at the University of Vermont. Thesetechniques have previously been described.t4 Angiographii and ventriculoggraphic analysis: All cineangiogramswere evaluatedby qualitative and quantitative methods by the angiographic laboratory. Qualitative analysis included coronary angiographic morphology, Thrombolysis in Myocardial Infarction perfusion grade and visual percent stenosisof the infarct-related vessel.This analysis was performed by at least 2 angiographers who were blinded to clinical outcome and were only aware of the designatedinfarct-related vessel. Quantitative analysis included minimum lumen diameter, percent area stenosisand percent diameter stenosis. This procedure was performed by a cardiologist and technician who were also blinded to patient outcome. The analysis was obtained from tine film using a computerized radiographic automated edge detection method.ts Details of this technique and our experiencewith its use have previously been reported.*J6 Global left ventricular function was determined by the area length method and expressedas ejection fraction.” Regional wall motion of the infarct zone and noninfarct zone was quantified as standard deviations/ cord by meansof the centerline cord method.‘* Techni126
Time to Treatment (Hours)
THE AMERICANJOURNALOF CARDIOLOGY VOLUME65
tally inadequate studies due to lack of adequate contrast or frequent ventricular extrasystoleswere not included in the analysis. Data analysis: For descriptive purposes,results are expressedas percentagesfor discrete variables and median (25th to 75th percentiles) for continuous variables. Casereport forms were completedby the clinical research nurse coordinators and reviewed by the principal investigators before submissionto the Data Coordinating Center in the Duke Cardiovascular DiseaseDatabank. The data were verified independently by study monitors from review of the clinical records. A data monitoring board met regularly during the study to review the outcomeof eachpatient and to ensurethe safety of the ongoing trial. Bleeding complications were monitored carefully by clinical research nurseswho reviewed each patient’s status on a daily basis. RESULTS Patientr: Selectedbaselineclinical and angiographic characteristics of our population are listed in Table I. Of particular note, 53% of patients had multivessel (2or 3-vessel)disease. Patency of the infarct-related vesselr The median time from treatment to the first coronary injection was 2.2 hours. Overall, 58%of patients were open at 90 minutes and 62% were open at the time of the final diagnostic injection (Table II). In patients treated >4 hours from the time of symptom onset, 73% were open at 90 minutes as opposedto 55% who were treated within 2 hours. Final infarct-related artery patency rates for patients receiving either the intravenous infusion only or the bolus and infusion were not different. At the final diagnostic injection, 62% of the infusion-only patients had patent infarct-related arteries, compared with 63% of patients treated with bolus and infusion. Of note, only 2 (2%) patients received intracoronary urokinase (750,000 U/patient) at the time of immediate catheterization. Recurrent ischetmia and reoeelusion: Twenty-eight of the 102 patients (28%) had recurrent ischemia before follow-up catheterization. Of these, 10 (10%) underwent emergency coronary angioplasty, 14 (14%) were sent to urgent (2 units Baseline fibrinogen (g/liter)* Nadir fibrinogen (g/liter)* Nadir platelets (K)* Peak FDP bg/ml)* Moderate bleeding (r-t) Genitourinary Gastrointestinal Groin Other Hematocrit drop only Severe and life-threatening bleeding (n) Gastrointestinal Intracranial Groin Brachial Other Hematocrit drop only * Figures shown are median (25th/Wth/75th FOP = fibrin(ogen) degradation products.
ww46 25/30/34 10/12/17 46%
... ..
FDp*
Fibrinogen
2.3/2.8/3.6
2.3/2.8/3.7 0.18/0.4/0.54 148/168/206 370/720/1220
1 7 2 19
1 2 4 0 12
1 1 3 1 3 5
0 1 0 0 1 2
bypass graft and 8% did not undergo follow-up catheterization. DISCUSSION
The major finding of this study is that high-dose intravenous urokinase can be administered in the community hospital setting with an efficacy profile characterized by an overall patency rate of 62% and a low reocclusionrate (
Todetenninetheoutcomeofpatkntsaftertreatment with high-dose intravenous urokinase (3 miiiienu)162pathtswere~eiYevaiuated hthesetthgofacutemyocardiaiinfaMion.The first 61 patienb received intravurokinase as
acodweusinfudenandtheiast41pa6entswere treatedwitJBtHlinitiai1.5miiiienuintraveneus bob.Sixty-twopercentotaiipatkmtshadpatent infarct-rebted arterks by the time of immediab angiography (median time 22 hours), which was pe&mnedinalpatients.TherewasnodgMcant dWrenceinpatencyratesbe4weenpatkntstreatedwithorwithoutaninitiaiintravenousboius. Twentyeight (26%) patiemts deveieped dinkai evtd8nceof-ischemnia(death,reocdudon, W-Y -9 urgent bypau rurgery)
dlaiag i8o@Mab, whereas oniy 7 (7%) deveidoamenwreocchsien.of opedangiolgclphicclry 26patimtswhofaiiedtoaddeves88cwsMreporfusionattheth8eofimmediate~,resW~~ruccercfulill~-
&B
inaiibutlpatktnt.Nos&gniiicantimprovementinmediangbMieftv~ fmction was seen bebveen immediate (48%) and foibw-qJ cathebbtion (46%). 6ignMcant bieed-
ingcutnplkaKomweretmusualexceptin1patleml whoexpedend an intraeraniai hemodmge. Eight (6%) idents died during hdtabth. Thereforo, the use of high-dose intravenous uroidnase in patied with acute myocardiai infarction is assodatedwitha62%patencyrate+aiowinddenceof reo&&onwrdbi8edingcompkaUonsandahigh tedmkaisuccessratewithrescueangbpiastyat -.nlisstudy thetimeofimmediate suppo&theneedfortvtherrandomizedcontroiied this comparing intravtinase dhCt&WithOthW -cm@-. (Am J Cardioi 1990;65:124-131)
124
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 65
uccessful reperfusion with intravenous thrombolytic therapy in acutemyocardial infarction (AMI) has been associatedwith an improvement in glob al left ventricular function, decreasedin-hospital and long-term mortality and decreasedcongestiveheart failure after infarction.1-4 Despite this apparent success,recurrent &hernia and reocclusion remain the “Achiies heel” of thrombolytic therapy.s-8Previousstudiesevaluating intravenous urokinase suggest that this problem may be substantially decreasedwhen this agent is used as monotherapyor in combination with recombinant tissue plasminogen activator.9Jo Despite this potentially important initial finding, only 2 studies have previously evaluated intravenous urokinase as monotherapy in this setting,9J1and only 1 study has used the currently recommendedintravenous dose of 3 million U. Although these studies demonstrated successfulre perfusion in a large proportion of patients and a tendency toward lower rates of recurrent ischemia and re occlusion compared with other thrombolytic agents, the combined experience representsonly 308 patients. Therefore, this study was undertaken to evaluate the effects of high-dose intravenous urokinase in establishing perfusion and sustainedpatency of infarct-related arteries in the setting of AMI, and to determine whether further comparative,controlled trials of a doseof 3 million U of intravenous uroldnase would be merited.
S
METHOD6 Patiad #action: Patients were prospectivelyidentified in North Carolina community hospitals that collab orate with Duke University Medical Center in thrombolytic trials.12 Inclusion criteria were: (1) chest pain or equivalent symptoms for 130 minutes’ duration wnsistent with wronary &hernia unresponsiveto standard sublingual nitroglycerin therapy; (2) onset of chest disFrom the Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, North Carolina. This work was sup ported in part by researchgrants H!%O4873,and -5635 from the National &ntei for Heal& Services;research grant HG17670 and HL-36587 from the National Heart. Luna and Blood Institute. Betheada, Maryland; grants from the Andrew %‘. Mellon Foundati&, New York, New York, and the Robert Wood JohnsonFoundation, Princeton, New Jersey; and a researchgrant from Abbott Labs, Chicago, Illinois. Manuscript received June 26, 1989; revised manuscript rcceivedSeptember22,1989, and acceptedSeptember 22. Addressfor reprints:Thomas C. Wail, MD, Duke University Medical Center, Box 3484,Durham, North Carolina 27710. SeeAppendix for Collaborating Centers.
comfort _ 110 mm Hg on serial measurementsin the emergencyroom; other serious advanced illnesseslikely to severely limit the patient’s life expectancy; cardiogenic shock defined as a systolic blood pressure 10 minutes) cardiopulmonary resuscitation within the previous 2 weeks; severe trauma within the past 6 months; psychologicalor physical inability to participate in the study; women known to be or suspectedof being pregnant. The protocol was approved by the institutional review board at each of the clinical sites. lhrombolytic therapy administratiom In this study, the low molecular weight form of urokinase (Abbott) was used. A total of 3 million U was infused over a 45to 6Ominute period. In the first 61 patients enrolled, urokinase was continually infused without an initial bolus. In the last 41 patients, a bolus of 1.5 million U was administered over 5 minutes with the remaining 1.5 million U infused over the subsequent45 to 60 minutes. No patient received intravenous heparin in the emergency room but aspirin, 325 mg, was administered orally at the time of thrombolytic therapy initiation. Cardiac
catheddzatiom
and -Y
w&M-W
After initiation of thrombolytic therapy, patients were transferred to the cardiac catheterization laboratory, where angiography of the infarct-related vesselwas performed as closely as possibleto 90 minutes after initiation of urokinase, but not before the 90-minute period unlessthe patient was in hemodynamicdistress.Arterial accesswas obtained via the femoral or brachial route. Five thousand units of intravenous heparin were administered once accesswas established. At 90 minutes, a minimum of 4 angiograms in various orthogonal and hemiaxial views was obtained. In addition, angiography of the noninfarct-related vesselsand the left ventricle was also performed. Coronary blood flow of the infarct-related vesselwas graded according to the Thrombolysis in Myocardial Infarction classification.13The final angiographic injection determined triage for angioplasty. Patients who re mained consistently occluded at 90 minutes (grade 0 or 1) were eligible for acute coronary angioplasty, which was performed at the discretion of the individual angiographer. In patients with grade 2 flow, acute coronary angioplasty was performed only if there was ongoing evidenceof ischemia (chest pain, presenceof collat-
erals or >O.l mV of persistent ST-segment elevation). In the absenceof these characteristics, angioplasty was deferred until predischargecatheterization or until the patient developedclinical evidenceof recurrent ischemia (emergency angioplasty). In patients who underwent angioplasty during the acute catheterization, 5,000 additional units of heparin were administered intravenously. Intracoronary urokinase in a dose of 6,000 U/min for up to 2 hours was usedin patients with angiographitally visible filling defectssuggestingthe presenceof residual thrombus after angioplasty, marked diminution of flow in the infarct-related artery with imminent reclosure or abrupt closure of the artery after angioplasty or evidenceof distal embolization as recognizedby angiographic pruning. To monitor the progressof intracoronary thrombolysis, angiographic injections were repeatedat 15-minute intervals during the urokinase infusion. Medical therapy: After immediate catheterization, patients were transferred to the coronary care unit where they received standard therapy with lidocaine, oxygen, morphine as neededfor pain and nitrates either topically or intravenously. Aspirin, 325 mg/day, was also administered along with a continuous infusion of intravenous heparin to maintain the partial thromboplastin time at 2 times the control value for our laboratory. This infusion was maintained until repeat cardiac catheterization at 7 to 10 days was accomplished.Beta blockers were not added to the medical regimen unless the patient had previously been treated with them or required such therapy for control of hypertension, supraventricular tachyarrhythmias or noncardiac disorders (e.g., migraine headache).Patients also were treated with calcium antagonistsusing either diltiazem at 60 mg orally 3 times daily or nifedipine at 20 mg orally 3 times daily. Other medications, including antiarrhythmic agents, were given at the discretion of the clinician. However, no other antiplatelet agents such as dipyridamole were used routinely. Repeat catheteriand rewasahbtbm Patients underwent repeat cardiac catheterization at 7 to 10 days after infarction even if they had an interim urgent catheterization study or if they had undergonecoronary artery bypass grafting. The follow-up study was performed to determine late patency of the infarct-related vesselas well as residual left ventricular function. Coronary angioplasty of the infarct-related vessel was performed during repeat catheterization when there was evidence of a significant residual stenosis suitable for angioplasty, especiallyif the patient had a positive exercise study. Patients with either severe multivessel diseaseor lesionsof the infarct-related vesselnot amenable to angioplasty underwent elective coronary artery bypass surgery before discharge. Emergency surgery was performed for failed angioplasty, particularly if there was evidenceof ongoing ischemia with a large amount of myocardium at risk. Bleeding and eoag&tion variables: Bleeding observed during the hospital stay was defined as follows: minor if it was of no clinical consequence,did not require a transfusion and was 4 (%)
16/29 (55) 30/54 (56)
19/29 (66) 31/54 (57)
Total (%) * Median time to first injection
11/15(73)
11/15(73)
57/98 (58)
61/98 (62)
was 2.2 hours.
64/75/91 1.9/2.8/3.6 1 32 15 50 2 53 12
* Figures shown are median (25th/SOth/75th percentile); t risk factors obtained from admission history. Definitions have been published prev~ously.~~
moderate if 250 to 500 cc of observed blood loss was noted, seuereif there was >500 cc of blood loss necessitating a transfusion; or life-threatening, which included intracranial bleeding or gastrointestinal or other internal or external bleeding causing hypotension and necessitating emergency transfusion. The site of bleeding, baselineand nadir hematocrit as well as units of packed red blood cells transfusedwere recorded for all patients. Blood sampleswere collected on 0.01 M citrate and 200 kIU/ml aprotinin at baseline,4 hours and 24 hours after initiation of thrombolytic therapy and were immediately processedand kept frozen at -2OOC until assayedby the coagulation laboratory. Fibrinogen was determined by a coagulation rate assay.Fibrinogen degradation products were analyzed by the tanned red cell agglutination inhibition technique at the core hematology laboratory at the University of Vermont. Thesetechniques have previously been described.t4 Angiographii and ventriculoggraphic analysis: All cineangiogramswere evaluatedby qualitative and quantitative methods by the angiographic laboratory. Qualitative analysis included coronary angiographic morphology, Thrombolysis in Myocardial Infarction perfusion grade and visual percent stenosisof the infarct-related vessel.This analysis was performed by at least 2 angiographers who were blinded to clinical outcome and were only aware of the designatedinfarct-related vessel. Quantitative analysis included minimum lumen diameter, percent area stenosisand percent diameter stenosis. This procedure was performed by a cardiologist and technician who were also blinded to patient outcome. The analysis was obtained from tine film using a computerized radiographic automated edge detection method.ts Details of this technique and our experiencewith its use have previously been reported.*J6 Global left ventricular function was determined by the area length method and expressedas ejection fraction.” Regional wall motion of the infarct zone and noninfarct zone was quantified as standard deviations/ cord by meansof the centerline cord method.‘* Techni126
Time to Treatment (Hours)
THE AMERICANJOURNALOF CARDIOLOGY VOLUME65
tally inadequate studies due to lack of adequate contrast or frequent ventricular extrasystoleswere not included in the analysis. Data analysis: For descriptive purposes,results are expressedas percentagesfor discrete variables and median (25th to 75th percentiles) for continuous variables. Casereport forms were completedby the clinical research nurse coordinators and reviewed by the principal investigators before submissionto the Data Coordinating Center in the Duke Cardiovascular DiseaseDatabank. The data were verified independently by study monitors from review of the clinical records. A data monitoring board met regularly during the study to review the outcomeof eachpatient and to ensurethe safety of the ongoing trial. Bleeding complications were monitored carefully by clinical research nurseswho reviewed each patient’s status on a daily basis. RESULTS Patientr: Selectedbaselineclinical and angiographic characteristics of our population are listed in Table I. Of particular note, 53% of patients had multivessel (2or 3-vessel)disease. Patency of the infarct-related vesselr The median time from treatment to the first coronary injection was 2.2 hours. Overall, 58%of patients were open at 90 minutes and 62% were open at the time of the final diagnostic injection (Table II). In patients treated >4 hours from the time of symptom onset, 73% were open at 90 minutes as opposedto 55% who were treated within 2 hours. Final infarct-related artery patency rates for patients receiving either the intravenous infusion only or the bolus and infusion were not different. At the final diagnostic injection, 62% of the infusion-only patients had patent infarct-related arteries, compared with 63% of patients treated with bolus and infusion. Of note, only 2 (2%) patients received intracoronary urokinase (750,000 U/patient) at the time of immediate catheterization. Recurrent ischetmia and reoeelusion: Twenty-eight of the 102 patients (28%) had recurrent ischemia before follow-up catheterization. Of these, 10 (10%) underwent emergency coronary angioplasty, 14 (14%) were sent to urgent (2 units Baseline fibrinogen (g/liter)* Nadir fibrinogen (g/liter)* Nadir platelets (K)* Peak FDP bg/ml)* Moderate bleeding (r-t) Genitourinary Gastrointestinal Groin Other Hematocrit drop only Severe and life-threatening bleeding (n) Gastrointestinal Intracranial Groin Brachial Other Hematocrit drop only * Figures shown are median (25th/Wth/75th FOP = fibrin(ogen) degradation products.
ww46 25/30/34 10/12/17 46%
... ..
FDp*
Fibrinogen
2.3/2.8/3.6
2.3/2.8/3.7 0.18/0.4/0.54 148/168/206 370/720/1220
1 7 2 19
1 2 4 0 12
1 1 3 1 3 5
0 1 0 0 1 2
bypass graft and 8% did not undergo follow-up catheterization. DISCUSSION
The major finding of this study is that high-dose intravenous urokinase can be administered in the community hospital setting with an efficacy profile characterized by an overall patency rate of 62% and a low reocclusionrate (
