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Time to reperfusion with direct coronary angioplasty and thrombolytic therapy in acute myocardial infarction
Time to Reperfusion with Direct Coronary Angioplasty and Thrombolytic Therapy in Acute Myocardial Infarction Peter B. Berger, MD, Malcolm R. Bell, MB, BS, FRACP, David R. Holmes, Jr., MD, Bernard J. Gersh, MB, DPhil, Mona Hopfenspirger, RN, and Raymond Gibbons, MD An analysis was perWmed of the Mayo Clinic transluminal domized trial of direct pe rc&mecus coronary angioplasty and tissuetype plasminogen activator (t-PA) to determine the time required to achieve repetision with direct -w ww pksty. Because patients in the Mayo trial assigned to t-PA did not undergo protowl coronary wgiogmphy, repmfusion ratesfrom the7hromb lysis in Myocardial Infarction (TIMI) I trial in which patients underwent V ~~OlgrslphY mm and 90 minutes after thrombolytic therapy were used for compahson. TIM1 perfusion grade 2 or 3 flowintheinfarctarterywasconsideredtorepresent reperkion after U~romholysis. In the 58 pa tients assigned to t-PA, the mean time from ram domization to initiation of the t+A infusion was 20 minutes. Twenty minutes were the&ore added to the previously reported 3&, 60 and minute repdusion rates to express these in terms of time from randomization (!iO,80 and 110 mire utes). In the 48 patients who had direct angb plasty, the mean time fiunl rwdom~on to m-ival in the cardiac catheterization laboratory was 45 minutes; it took a mean of 6 additional minutes for patients to be prepared and draped and art* alaccessobtained,andameanof27additional minutes to complete a@ogmphy and achieve reperhrsion. At 50,80 and 110 minutes after randomization, the reperfusion rates for direct v angioplasty were 12,54 and 83%, similar to previously reported TIM1 twperlbsion rates with t-PA (24,57 and 71%, mspectively, p q NS) but significantly greater at SO and 110 minutes than was reported for streptokinase (8,23 and s%, CB spectively, p = 0.001). tf only normalization of car~~BJv~MI perfusion grade 3 flow) represent mperfusm mperfusion rates for direct coronary a@oplasty woukl he si@iicantly #eater than fur either t-PA or streptokinase. From the Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, Rochester, Minnesota. This study was supported in part by grants from the Burroughs-Wellcome Company, E.I. duPont de Nemours and Company, Research Triangle Park, North Carolina, and C.R. Bard, Inc. (USC1 Division), Billerica, Massachusetts. Manuscript received June 1, 1993; revised manuscript received and accepted July 13, 1993. Address for reprints: Peter B. Berger, MD, Division of Cardiovascular Disease and Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905.
Thus, did coronary angIopIasty is rapid, and reperfusion rates compare favorably with those reported for thrombolytic therapy. (AmJCardiil1994,73:231-236)
I
t has been demonstratedthat rapid renerfusion is essential for salvageof myocardium and reduction of mortality in acute myocardial infarction.1-3 Numerous studies have documented delays in the evaluation and subsequenttreatment of patients with thrombolytic therapy in the early stagesof myocardial infarction.4j5To reduce these delays, protocols have been developed so that thrombolytic therapy can be administered more quickly after presentation to the hospital and in the prehospital setting.U Percutaneoustransluminal coronary angioplasty has been advocated for the treatment of acute myocardial infarction.%t2 However, a detailed analysis of the time required to achieve reperfusion with coronary angioplasty has not been reported, and whether coronary angioplasty results in more rapid reperfusion and a greater reperfusion rate than thrombolytic therapy remains unknown. Therefore, we analyzed data from the Mayo Clinic randomized trial of direct percutaneous transluminal coronary angioplasty and tissue-type plasminogen activator (t-PA) in acute myocardial infarction to determine the speed with which reperfttsion was achieved with direct coronary angioplasty and to compare the reperfusion rate with coronary angioplasty to that of thrombolytic therapy. MIVHODS lndusion
criteria: The details of the Mayo Clinic randomized trial of direct percutaneous transluminal coronary angioplasty and t-PA have been reported previously.13Patients were eligible for inclusion in the trial if they were 40 years of age, presentedwith 230 minutes of chest pain but 42 hours of onset, had either STsegmentelevation of 20.1 mV in 2 contiguous leads, or ST-segment depression of a.2 mV in 22 precordial leads between Vt and V3. Patients with contraindications to thrombolytic therapy or with cardiogenic shock were excluded. Once informed consent had been obtained, patients were randomly assigned to either t-PA or immediate angioplasty.The protocol was approvedby the Mayo Clinic Institutional Review Board. Intravenous thrombdytic therapy: An infusion of double-chain tissue plasminogen activator (duteplase, Burroughs-Wellcome Company,E.I. duPont de Nemours REPERFUSIONWITH THROMBOLYSISAND ANGIOPLASTY 231
TABLE I Baseline Characteristics Among Patients Randomized to Direct Coronary Angioplasty and Tissue-Type Plasminogen Activator (t-PA) in the Mayo Clinic Trial, and Among Those Randomized to t-PA and Streptokinase in the TIMI I Trial Mayo Clinic t-PA (n = 56) Age, years (mean)
PTCA (n = 47)
62
Men (%)
TIMI I
60
40 (71)
37 (79)
ST-segment elevation/depression
5412
46/l
Prior infarction (%)
7 (13)
2 (4)
t-PA (n = 83) 57
SK (n = 147) NA
67 (81)
118 (80)
83/O
147/o
12 (15)
19
Infarct location (%) Anterior
22 (39)
15 (32)
46 (55)
77 (52)
Inferior
30 (54)
31 (66)
36 (43)
69 (47)
Other
4 (7) 3.9
1 (2) -
l(1)
l(l) 4.8
Hours from symptom onset to initiation of thrombolytic therapy (mean)
There were no significant differences between any of the variables measured. NA = not awlable; SK = streptokinase; TIMI = Thrombolysis in Myocardlal
and Company, ResearchTriangle Park, North Carolina) was initiated as soon as possible in patients randomized to thrombolysis with a total dose of 0.6 MIU/kg administered over 4 hours, as previously described.t4Immediate heparinization was begun with an intravenous bolus of 5,000 U, followed by an intravenous infusion adjusted to maintain the partial thromboplastin time at 2.0 to 2.5 times control for the next 5 days. Each patient subsequently received 12,500 U of heparin subcutaneously every 12 hours for the remainder of the hospitalization. Direct angioplasty: Patients randomly assigned to angioplasty were immediately administered an intravenous bolus of 5,000 U of heparin. Patients presenting to the emergencyroom on weekdayswere taken to the lirst of 4 interventional catheterizationlaboratoriesto become available. For patients presenting at other times, the catheterization laboratory staff on call for emergency procedureswere notified and assembledas soon as possible (between 20 and 60 minutes in all cases). The emergencyroom is on the ground floor and the catheterization laboratories are on the sixth floor in our hospital; transport between them requires approximately 4 minutes. After angiography, patients received an additional 10,000 U of intravenous heparin before angioplasty of the infarct artery. Angioplasty was attempted whenever there was occlusion or subtotal occlusion of the infarct-related artery. An intravenous infusion of heparin was maintained for 5 days as in the group assignedto thrombolytic therapy. Concurrent therapy: All patients received 162.5mg of chewable aspirin in the emergency room and 325 m&lay for the remainder of the hospitalization. In patients without contraindications, l3 blockers were administered as soon as possible as previously described.15 The routine administration of calcium antagonists was avoided. Data analysis: The primary end point of the trial was the change in magnitude of the perfusion defect measuredbetween acute and predischargesestamibi images. For the main study, only patients with these primary nuclear end point data were included, and patients 232
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4.6
Infarction.
were analyzedon an intention-to-treat basis.In this analysis, only patients who were assignedto and underwent direct coronary angioplasty (n = 48) were included. Successful coronary angioplasty was delined as 240% improvement in luminal diameter at the dilation site. The time to reperfusion with direct coronary angioplasty was defined as the time to when the angioplasty balloon was first deflated among patients in whom angioplasty was successful. Reperfusion after thrombolytic therapy was considered to have occurred when Thrombolysis in Myocardial Infarction (TIMI) trial perfusion grade 2 or 3 flow was achieved.‘(j Comparisonuf m m Patientsassignedto t-PA did not undergo routine protocol coronary angiography; therefore, reperfusion rates among these patients could not be determined. To compare reperfusion rates achieved with coronary angioplasty in this study with those obtained with thrombolytic therapy, previously published reperfusion rates from the TIMI I trial, in which patients underwent coronary angiography at baseline and 30, 60 and 90 minutes after administration of 100mg of t-PA (alteplase)over 3 hours,17or of streptokinase 1.5 million U over 1 hour,16 were used. Although alteplase t-PA rather than duteplaset-PA was administered in the TIMI I trial, reperfusion rates from this trial were used for comparison since duteplaset-PA is no longer commercially available, and previously reported 60- and 90-minute reperfusion rates for duteplaset-PA are similar to those reported for alteplasetPA.‘* In the TIMI I trial, the time interval between randomization and initiation of thrombolytic therapy was not reported; in the current trial, the mean time from randomization to initiation of the t-PA infusion was 20 minutes. Twenty minutes were therefore added to the previously reported 30-, 60- and 9Ominute reperfusion rates in the TIMI trial to expressthese in terms of time (50, 80 and 110minutes) from randomization. RESULTS
&madmbaI . (l&Is I): The baselinecharacteristics of patients randomized to t-PA (group 1) and
FEBRUARY 1,1994
direct coronary angioplasty (group 2)i3 were similar to those of patients randomized to t-PAi and streptokinase16in the TIM1 I trial. lime intervals (Figure 1): The mean time from the onset of chest pain to arrival in the emergencyroom was <2 hours. In both groups, a history was obtained, physical examination and electrocardiography were performed, the trial was explained, informed consent was obtained and randomization was completed within 35 minutes. Treahnent intervals (Figure 2): In group 1 patients, the mean time from randomization to initiation of the tPA infusion was 20 minutes. In group 2 patients, the mean time from randomization to arrival in the cardiac catheterization laboratory was 45 minutes. It took a mean of 6 minutes for patients to be prepared, draped and arterial accessachieved, and a mean of 27 additional minutes for angiography to be completed and reperfusion achieved in patients in whom coronary angioplasty was successful. RepWu&n e In Figutc 3, previously published reperfusion rates from the TIM1 I trial for t-PAi and
streptokinasei6are compared with corresponding reperfusion rates observedwith direct coronary angioplasty in the Mayo Clinic trial. Compared with the TIM1 I reperfusion rates in 83 patients treated with t-PA, the reperfusion rate in patients who underwent direct coronary angioplasty was similar at 30 minutes (12 vs 24% vs tPA, p = 0.12), 60 minutes (54 vs 57% vs t-PA, p = 0.78) and 90 minutes (83 vs 71% vs t-PA, p = 0.12). Direct coronary angioplasty resulted in a similar 30-minute reperfusion rate to the 30-minute reperfusion rate in 119 patients in TIMI I treated with streptokinase(12 vs 8%, respectively, p = 0.42), but angioplasty had a greater reperfusion rate at 60 minutes (54 vs 23%, p = 0.001) and 90 minutes (83 vs 31%, p = 0.001). The time to reperfusion for each of the patients in whom coronary angioplasty was successful is displayed in Figure 4. Reperfusion was achieved in 88% (42 of 48) of patients between 40 and 120 minutes after randomization to direct coronary angioplasty. By 170 minutes, 45 of 48 patients (94%) in whom direct coronary angioplasty was eventually successful had achieved reperfusion.
PTCA FlGlJREl.llbsmeantimefromtheonsetof cbstpaintoafwivalintheemergencyroom forpathtsrandomizedtodirectperc&me arr-ca#lsy~(~A) and recombinant tissue-type plasminogen activator (MA).
&PA I 0
I
I
I
I
I
I
I
I
20
40
60
so
loo
120
140
160
Minutes from onset of chest pain, mean
AITII~I in Arterial cath lab access
First deflation
PTCA FlGURE2.llwmeantiifVomrandomira ttontotmatmentfor~-&edto direct percutsneous tranduminal cOcOnay a@ophty (PTCA) and mcombinzurt tissue type plasminogen activator (MA) in the Mayo Clinic trial. cath q cathetekation; bb=bboretory.
I
90-min infusion comoleted
Initiation of infusion
&PA
0
10
20
30
40
50
60
70
80
Minutes from randomization,
90
loo
110 120
mean
REPERFUSION WITHTHROMBOLYSISAND ANGIOPLASTY 233
DISCUSSION
The most important findings of this study are that reperfusion is achieved rapidly with direct coronary angioplasty, and reperfusion rates compare favorably with those reported for intravenous t-PA and streptokinasein previous studies. Thrombolytic therapy has been shown to preserve myocardial function and reduce mortality in several large, prospective, randomized trial~.~~~J~~~~ The speed with which reperfusion is achieved is a critical determinant to the amount of myocardium that can be salvaged.1-3*6It has previously been shown that the time between the onset of symptomsof myocardial infarction and arrival at an emergencyroom accountsfor the greatest delay in achieving reperfusion. However, significant delays also exist between the time a patient presentsto the emergency room with symptoms of acute myocardial infarction and the administration of thrombolytic therapy.4,5 Although much of the delay has been attributed to the time required to evaluate patients by emergencyroom physicians and to obtain an electrocardiogram, further delay exists between the time that a decision to treat with thrombolytic therapy is reached and initiation of the infusion, ranging from 23 to 63 minutes.4*5Therefore, strategieshave been developedto has-
ten the evaluation and treatment of patients presenting to the emergency room with suspectedmyocardial infarction, shortening the time from arrival in the emergency room to the administration of thrombolytic thera-
PY.l
A similar analysis of the time required for direct coronary angioplasty has not been reported. The present study suggests that attempts to shorten the delay in achieving reperfusion with direct coronary angioplasty after arrival in the emergencyroom should focus on the time required for a catheterization laboratory to become available and assemblea emergencycatheterization laboratory team. It is this time interval, 45 minutes in the present study, that results in the next greatestdelay before reperfusion is achieved. A comparison of the time to reperfusion with thrombolytic therapy and direct coronary angioplasty must include the time required to initiate each therapy, as well as the time it takes from the initiation of therapy to achieve reperfusion. Trials of intravenous thrombolytic therapy in which reperfusion rates have been reported have not included the time required to initiate thromboIn addition, the mean time to reperlytic therapy.17,21-23 fusion cannot be determined among patients in whom it was achieved,since angiography is not continuously per-
FlGURE3.Thereperfusionratefardirect percutaneous tranduminal cOtOnacy an@* plasty (PTCA) in the Mayo Clinic trial and pretiously published reperfusion rates for recombinant tissuetype plasminogen active tor (MA) and shptokinase (SK) in the lhrombolysis in Myocardiil lnfarcth trial. The tims inblvals eonespond tothetime from randomiiation to repelfusion.
Minutes from randomization
d
6
5 .5 L
4
FIGURE 4. The time to reperfusion in the 45 patients who underwent direct coronary ar@oplastya~in~coronaryW plasty was successful. Rep&us&n was achieved in most pathts between 40 and 120 minutes after randomization.
2
0 0
10
20
30
40
60
60
70
60
90
Minutes, randomization 234
100
110
120130
140 150 160-170
to reperfusion
THE AMERICANJOURNALOF CARDIOLOGY VOLUME73
FEBRUARY1, 1994
formed, and the exact moment of reperfusion in most 1. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. trial of intravenous streptokinase, oral aspirin, both or neither among patients is unknown. In contrast, analyses of the time Randomized 17,187 cases of suspected acute myoardial infarction: ISIS-2. Lancer 1988:2: required to reperfusion with direct coronary angioplasty 34F360. have included the time required to transport patients to 2. AIMS Trial Study Group. Effect of intravenous APSAC on mortality after acute infarction: preliminary report of a placebo-controlled clinical trial. Luncet the catheterization laboratory, and the mean time to re- myocardial 1988;1:545-549. perfusion has been reported.2k26These differences in 3. Califf RM, Top01 EJ, Gash BJ. From myocardial salvage to patient salvage in the methods of analysis between reperfusion rates with acute myocardial infarction: the role of repafusion therapy. J Am CON Cardiol thrombolytic therapy and direct coronary angioplasty 4.1989;14:1382-1388. Gonzalez ER, Omato JP, Jones LA, Bleecker GC, Strauss MJ, and the Virginia have introduced considerable bias, and have precluded Thrombolytic Smdy Group. Prospective multicenter assessment of critical factors an accurate comparison of reperfusion rates for these 2 delaying hospital thmmbalytic therapy (abstr). J Am Coil Cardiol 1991;17:247A. Sharkey SW, Brunette DD, Ruiz E, Hession WT, Wysham DG, Goldenberg IF, therapies. The current study includes the time required 5.Hodges M. An analysis of time delays preceding thrombolysis for acute myocxto initiate both thrombolytic therapy and coronary angi- dial infarction. JAMA 1989;262:3 171-3174. oplasty, and reports reperfusion rates from the time that 6. Weaver WD, Cerqueim M, Hallstrom AP, Litwin PE, Manin JS. Kudenchuk PJ, Eisenberg M, for the Myocaniial Infarction Triage and Intervention Pmject the decision to proceed with each of these reperfusion Group. Prehospita-initiated vs hospital-initiated thrombolytic therapy. The Myocastrategieswas made. It can thus be seen that t-PA and dial Infarction Triage and Intervention Trial. JAMA 1993;270:1211-1216. Robertson CE, Miller HC, Fox KAA. Effect of “fast-track” admisdirect coronary angioplasty have similar reperfusion 7.sionPellfor ACH, acute mycatdial infarction on delay to thrombolysis. Br Med J 1992304: rates; larger studies will be required to determine if 83-87. small differences exist between the reperfusion rates 8. European Myocardial Infarction Project (EMIP) Subcommittee. Potential time with pre-hospital intervention in acute myocardial infarction. Eur Heart J with these 2 treatments. Reperfusion rates with direct saving 1988;9:118-124. coronary angioplasty compare favorably with those re- 9. O’Keefe JH, Rutherford BD, McConahay DR, Ligon RW, Johnson WL, Giorgi LV, Crockett JE, McCallister BD, Corm RD, Gum GM, Good TH, Steinhaus ported for streptokinase. Bateman TM, Shimshak TM, Hat&r GO. Early and late results of coronary It must be rememberedthat coronary blood flow is DM, angioplasty without antecedent thmmbolytic therapy in acute myocardial infarction. nearly always restored to normal (TIMI grade 3 flow) Am J Cardiol 1989;64:1221-1230. after successful angioplasty, whereas any anterograde 10. Rothbaum DA, Linnemeier TJ, Landin RJ, Steimnetz EF, Hillis JS, Hallam Noble RJ, See MR. Emergency percutaneous tmnsluminal coronary angioplasty flow in the infarct artery beyond the occlusion (TIMI inCC,acute myocardial infarction: a 3 year experience. J Am Coil Cardiol 1987;lO: grade 2 or 3 flow) has traditionally been considered to 2W272. Ellis SG, O’Neill WW, Bates ER, Walton JA, Nabel EG, Topol EJ. Coronary represent successfulreperfusion after thrombolytic ther- 11. angioplasty as primary therapy for acute myoctiial infarction 6 to 48 hours after apy.16There is increasing evidence, however, that the symptom onset: report on an initial experience. J Am Co/l Cardiol 1989;13: outcome of patients with TIM1 2 flow 90 minutes after 1122-1126. O’Neill W, Timmis GC, Bowdillon PD, Lai P, Ganghadarhan V, Walton J Jr, thrombolytic therapy more closely resemblesthat of pa- 12. Ramos R, Laufer N, Gordon S, Schork MA, Pitt B. A prospective randomized clintients with persistent occlusion (TIMI grade 0 or 1 flow) ical trial of intracomnary streptokinase versus coronary angioplasty for acute myocwthan that of patients with normal coronary blood flow dial infarction. N Er@ J Med 1986;314:812-818. la. Gibbons RJ, Holmes DR. Bailey KR, Hopfenspirger MR, Gersh BJ, for the (TIM1 grade 3 flow).27-29If only normalization of coro- Mayo CCU and Catheterization Laboratory Groups. Randomized trial comparing nary blood flow (TIM1 grade 3 flow) was considered to immediate angioplasty with thmmbolysis followed by conservative treatment for representreperfusion, reperfusion rates would be signif- myocardial infarction. N Engl .I Med 1993;328:685-691. 14. Third International Study of Infarct Survival (ISIS-3). A randomized comicantly greater with direct coronary angioplasty than parison of streptokinase versus tissue plasminogen activator versus anistreplase and of aspirin plus heparin vel~us aspirin alone among 41,299 cases of suspected acute with both t-PA27-29and streptokinase.16 1992;339:753-770. myocxdial infarction. Lnncet Because of the convincing data 15. Study limitations: The TIM1 Study Group. Immediate versus delayed catheterization and angiofrom prospective randomized trials that immediate cor- plasty following thrombolytic therapy for acute myocardial infarction. JAMA 1988; onary angiography and coronary angioplasty after 260~2849-2858. 16. Chesebro JH, Knatterud G, Roberts R, Borer I, Cohen LS, D&n J, Dodge thrombolytic therapy is of no additional benefit,1530,31 HT, Francis CK, Hillis b, Ludebrook P, Markis JE. Mueller H, Passamani ER, patients assigned to thrombolytic therapy in the Mayo Powers ER, Rae AK, Robertson T, Ross A, Ryan TJ, Sobel BE, WilIerson J, Clinic trial did not undergo immediate coronary angiog- Williams DO, &et BL, Bmunwald E. Thrombolysis in Myocardial Infarction (TIMI) Phase I: a comparison between intravenous tissue plasminogen activator and raphy, and reperfusion rates with t-PA could not be de- Trial, intravenous streptokinase. Clinical findings through hospital discharge. Circuhtion termined in this study. Therefore, previously published 1987;76:142-154. reperfusion rates from the TIMI trial for both t-PA and 17. Mueller HS, Rae AK, Forman SA and the TIM1 Investigators. Thrombolysis Myocadial Infection (TIMI): comparative studies of coronary reperfusion and streptokinase were used for comparison.16J7The 90- insystemic tibrinogenolysis with two forms of tissue-type plasminogen activator. J minute reperfusion rate for t-PA (70%) and streptoki- Am Coil Cnrdiol 1987; 10~479490. 18. Kalbfleisch JM, Kumik PB, Thadani U, DeWocd MA, Kent R, Magorien RD. nase (55%) in the TIM1 I trial are similar to the reper- Jai” AC, Spaccavento LJ, Morris DL, Taylor GJ, Perry JM, Kutcher MA, Goriinkel fusion rates for these thrombolytic agents reported from HJ, Littlejohn JK, for the Burroughs Wellcome Study Group. Myocardial infarct several other trials of thrombolytic therapy in which 90- artery patency and reocclusion rates after treatment with duteplase at the dose used in the International Study of Infarct Survival-3. Am J Cardiol 1993;71:38&392. minute angiography was performed.21,22 It has been re- 19. Rovelli F, De Vita C, Femglio GA, Lotto A, Selvini A, Tognoni G. Effectiveported that “front-loaded” regimens of t-PA, in which ness of intravenous thrombolytic treatment in acute myocardial infarction: Gruppo more t-PA is administered in the initial 60 to 90 min- Italian0 per lo Studio della Streptochinasi nell’lnfwto Miocardico (GISSI). Lance-t 1986;1:397-%02. utes of therapy, achieve higher 60- and 90-minute re- 20. Wilcox RG, van der Lippe G, Olsson CG, Jensen G, Skew AM, Hamptom perfusion rates than were seen in the TIMI trial, in JR. Trial of tissue plasminogen activator for mortality reduction in acute myocarwhich the standard dosing regimen of t-PA was dial infarction: Anglo-Scandinavian Study of Early ‘Ihrombolysis (ASSET). Lmcet 1988: 1:525-530. used.23,32*33 Therefore, the comparison of reperfusion 21. Topal EJ, Morris DC, Smalling RW, Schumacher RR, Taylor CR, Nishikawa rates with direct coronary angioplasty and thrombolytic A, Liberman HA, Collen D, Tufte ME, Grossbard EB, O’Neill WW. A multicenter, randomized, placebo-controlled trial of a new form of intravenous recombinant therapy applies only to the dosagesand rates of admin- tissue-type plasminogen activator (activase) in acute myocardial infarction. J Am istration of the thrombolytic agents used in the TIMI Cdl Cmdiol 1987;9: 1205-12 13. 22. Smelling RW, Schumacher R, Morris D, Harder K, Fuentes F, Valentine RP, trial. REPERFUSION WITHTHROMBOLYSISAND ANGIOPLASTY 235
Batey LL Jr, Merhige M, Pins DE, Lieberman HA, Nishiiawa A, Adyanthaya A, Hopkins A, Grossbard E. Improved infarct-related arterial patency after high dose, weight-adjusted, rapid infusion of tissue-type plasminogen activator in myocardial infarction: results of a multicenter randomized trial of two dosage regimens. J Am Coil Cardiol 1990,15:915-921. 23. Camey RJ, Murphy GA, Brandt TR, D&y PJ, Pickering E, White HJ, McDonough TJ, Vennilya SK, Teichman SL, for the RAAMI Study Investigators. Randomized angiographic trial of recombinant tissue-type plasminogen activator (alteplase) in myocardial infarction. J Am Co// Cardiol 1992;20:17-23. 24. Kahn JK, Ruthefiord BD, McConahay DR. Johnson WL, Giorgi LV, Shimshak TM, Ligon R, Hartzler GO. Results of primary angioplasty for acute myocardial infarction in patients with multivessel coronary artery disease. J Am Co// Cardid 26.
1990; 16: 1089-1096.
Bmdie BR, Weintraub RA, Stuckey TD, LeBauer EJ, Katz JD, Kelly TA, Hansen CJ. Outcomes of direct coronary angioplasty for acute myocardial infarction in candidates and non-candidates for thrombolytic therapy. Am .I Cardiol 1991;
6717-12. 26. Hartzler
G, Rutherford B, McConahay DR, Johnson WL Jr, McCallister BD. Gura GM Jr, Corm RC, Crockett JE. Percutaneous transluminal coronary angioplasty with and without thrombolytic therapy of acute myocardial infarction. Am Heart J 1983:106:965-973. 27. Vogt A, van Essen R. Tebbe U, Feuerer W, Appel KF, Neuhaus KL. Impact of early perfusion status of the infarct-related artery on short-teml mortality after thmmbolysis for acute myocxdial infarction: retrospective analysis of four German multicenter studies. J Am Co// Cm-din/ 1993;21:1391-1395. 28. Kamgounis L, Sorenson SG, Menlove RL, Moreno F, Anderson JL for !he TEAM-2 Investigators. Does thmmbolysis in myocardial infarction (TIMI) perfusion
236
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grade 2 represent a mostly patent artery or a mostly occluded artery? Enzymatic and electrocardiographic evidence from the TEAM-2 study. J Am Co/l Cardiol 1992;19:1-10. 29. Anderson JL, Karagounis LA, Becker LC. Sorensen SG, Menlove RL, for the TEAM-3 Investigators. TIM1 perfusion grade 3 but not grade 2 results in improved outcome after thrombolysis for myocardial infarction: ventriculographic, enzymatic, and electrocardiographic evidence from the TEAM-3 Study. Circulation 1993; 87:182%1839. 30. Simoons M, Arnold AER, Betriu A, Bokslag M, de Bono DP, Brewer RW, Cal J, Dougherty FC, van Essen R, Lambertz H, Lubsen J, M&r B, Michel PL, Raynaud P, Rutsch W, Sanz GA, Schmidt W, Senuys PW, Uebis R, Vahanian A, Van der Werf F, Willems GM, Wood D, Verstrate M. Thrombolysis with tissue plasminogen activator in acute myocardial infarction: no additional benefit from immediate percutaneous coronary angioplasty. Lancet 1988; 1: 193-203. 31. Top01 E, Califf R, George BK, Kereiakes DJ, Abbottsmith CW, Candela RJ, Lee KL, Pitt B, Stack RS, O’Neill WW, and the TAM1 Study Group. A randomized trial of immediate V~TSUSdelayed elective angioplasty after intravenous tissue plasminogen activator in acute myocardial infarction. N En,@ J Med 1987;317: 581-588. 32. Neuhaus
K-L, van Essen R, Tebbe U, Vogt A, Roth M, Riess M, Niedenr W, Forycki F, Wirtzfeld A. Maeurer W, Limbourg P. Marx W, Haerten K. Improved thrombolysis in acute myocardial infarction with front-loaded administration of alteplase: results of the t-PA-APSAC Patency Study (TAPS). J Am CoN Cardiol 1992;19:885-891. 33. Neuhaus K-L, Feuerer W, Jeep-Tebbe S, Niederer W, Vogt A, Tebbe U. Improved thrombolysis with a modified dose regimen of recombinant tissue-type plasminogen activator. J Am Co// Cardiol 1989;14:156&1569.
FEBRUARY1, 1994
Thus, did coronary angIopIasty is rapid, and reperfusion rates compare favorably with those reported for thrombolytic therapy. (AmJCardiil1994,73:231-236)
I
t has been demonstratedthat rapid renerfusion is essential for salvageof myocardium and reduction of mortality in acute myocardial infarction.1-3 Numerous studies have documented delays in the evaluation and subsequenttreatment of patients with thrombolytic therapy in the early stagesof myocardial infarction.4j5To reduce these delays, protocols have been developed so that thrombolytic therapy can be administered more quickly after presentation to the hospital and in the prehospital setting.U Percutaneoustransluminal coronary angioplasty has been advocated for the treatment of acute myocardial infarction.%t2 However, a detailed analysis of the time required to achieve reperfusion with coronary angioplasty has not been reported, and whether coronary angioplasty results in more rapid reperfusion and a greater reperfusion rate than thrombolytic therapy remains unknown. Therefore, we analyzed data from the Mayo Clinic randomized trial of direct percutaneous transluminal coronary angioplasty and tissue-type plasminogen activator (t-PA) in acute myocardial infarction to determine the speed with which reperfttsion was achieved with direct coronary angioplasty and to compare the reperfusion rate with coronary angioplasty to that of thrombolytic therapy. MIVHODS lndusion
criteria: The details of the Mayo Clinic randomized trial of direct percutaneous transluminal coronary angioplasty and t-PA have been reported previously.13Patients were eligible for inclusion in the trial if they were 40 years of age, presentedwith 230 minutes of chest pain but 42 hours of onset, had either STsegmentelevation of 20.1 mV in 2 contiguous leads, or ST-segment depression of a.2 mV in 22 precordial leads between Vt and V3. Patients with contraindications to thrombolytic therapy or with cardiogenic shock were excluded. Once informed consent had been obtained, patients were randomly assigned to either t-PA or immediate angioplasty.The protocol was approvedby the Mayo Clinic Institutional Review Board. Intravenous thrombdytic therapy: An infusion of double-chain tissue plasminogen activator (duteplase, Burroughs-Wellcome Company,E.I. duPont de Nemours REPERFUSIONWITH THROMBOLYSISAND ANGIOPLASTY 231
TABLE I Baseline Characteristics Among Patients Randomized to Direct Coronary Angioplasty and Tissue-Type Plasminogen Activator (t-PA) in the Mayo Clinic Trial, and Among Those Randomized to t-PA and Streptokinase in the TIMI I Trial Mayo Clinic t-PA (n = 56) Age, years (mean)
PTCA (n = 47)
62
Men (%)
TIMI I
60
40 (71)
37 (79)
ST-segment elevation/depression
5412
46/l
Prior infarction (%)
7 (13)
2 (4)
t-PA (n = 83) 57
SK (n = 147) NA
67 (81)
118 (80)
83/O
147/o
12 (15)
19
Infarct location (%) Anterior
22 (39)
15 (32)
46 (55)
77 (52)
Inferior
30 (54)
31 (66)
36 (43)
69 (47)
Other
4 (7) 3.9
1 (2) -
l(1)
l(l) 4.8
Hours from symptom onset to initiation of thrombolytic therapy (mean)
There were no significant differences between any of the variables measured. NA = not awlable; SK = streptokinase; TIMI = Thrombolysis in Myocardlal
and Company, ResearchTriangle Park, North Carolina) was initiated as soon as possible in patients randomized to thrombolysis with a total dose of 0.6 MIU/kg administered over 4 hours, as previously described.t4Immediate heparinization was begun with an intravenous bolus of 5,000 U, followed by an intravenous infusion adjusted to maintain the partial thromboplastin time at 2.0 to 2.5 times control for the next 5 days. Each patient subsequently received 12,500 U of heparin subcutaneously every 12 hours for the remainder of the hospitalization. Direct angioplasty: Patients randomly assigned to angioplasty were immediately administered an intravenous bolus of 5,000 U of heparin. Patients presenting to the emergencyroom on weekdayswere taken to the lirst of 4 interventional catheterizationlaboratoriesto become available. For patients presenting at other times, the catheterization laboratory staff on call for emergency procedureswere notified and assembledas soon as possible (between 20 and 60 minutes in all cases). The emergencyroom is on the ground floor and the catheterization laboratories are on the sixth floor in our hospital; transport between them requires approximately 4 minutes. After angiography, patients received an additional 10,000 U of intravenous heparin before angioplasty of the infarct artery. Angioplasty was attempted whenever there was occlusion or subtotal occlusion of the infarct-related artery. An intravenous infusion of heparin was maintained for 5 days as in the group assignedto thrombolytic therapy. Concurrent therapy: All patients received 162.5mg of chewable aspirin in the emergency room and 325 m&lay for the remainder of the hospitalization. In patients without contraindications, l3 blockers were administered as soon as possible as previously described.15 The routine administration of calcium antagonists was avoided. Data analysis: The primary end point of the trial was the change in magnitude of the perfusion defect measuredbetween acute and predischargesestamibi images. For the main study, only patients with these primary nuclear end point data were included, and patients 232
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Infarction.
were analyzedon an intention-to-treat basis.In this analysis, only patients who were assignedto and underwent direct coronary angioplasty (n = 48) were included. Successful coronary angioplasty was delined as 240% improvement in luminal diameter at the dilation site. The time to reperfusion with direct coronary angioplasty was defined as the time to when the angioplasty balloon was first deflated among patients in whom angioplasty was successful. Reperfusion after thrombolytic therapy was considered to have occurred when Thrombolysis in Myocardial Infarction (TIMI) trial perfusion grade 2 or 3 flow was achieved.‘(j Comparisonuf m m Patientsassignedto t-PA did not undergo routine protocol coronary angiography; therefore, reperfusion rates among these patients could not be determined. To compare reperfusion rates achieved with coronary angioplasty in this study with those obtained with thrombolytic therapy, previously published reperfusion rates from the TIMI I trial, in which patients underwent coronary angiography at baseline and 30, 60 and 90 minutes after administration of 100mg of t-PA (alteplase)over 3 hours,17or of streptokinase 1.5 million U over 1 hour,16 were used. Although alteplase t-PA rather than duteplaset-PA was administered in the TIMI I trial, reperfusion rates from this trial were used for comparison since duteplaset-PA is no longer commercially available, and previously reported 60- and 90-minute reperfusion rates for duteplaset-PA are similar to those reported for alteplasetPA.‘* In the TIMI I trial, the time interval between randomization and initiation of thrombolytic therapy was not reported; in the current trial, the mean time from randomization to initiation of the t-PA infusion was 20 minutes. Twenty minutes were therefore added to the previously reported 30-, 60- and 9Ominute reperfusion rates in the TIMI trial to expressthese in terms of time (50, 80 and 110minutes) from randomization. RESULTS
&madmbaI . (l&Is I): The baselinecharacteristics of patients randomized to t-PA (group 1) and
FEBRUARY 1,1994
direct coronary angioplasty (group 2)i3 were similar to those of patients randomized to t-PAi and streptokinase16in the TIM1 I trial. lime intervals (Figure 1): The mean time from the onset of chest pain to arrival in the emergencyroom was <2 hours. In both groups, a history was obtained, physical examination and electrocardiography were performed, the trial was explained, informed consent was obtained and randomization was completed within 35 minutes. Treahnent intervals (Figure 2): In group 1 patients, the mean time from randomization to initiation of the tPA infusion was 20 minutes. In group 2 patients, the mean time from randomization to arrival in the cardiac catheterization laboratory was 45 minutes. It took a mean of 6 minutes for patients to be prepared, draped and arterial accessachieved, and a mean of 27 additional minutes for angiography to be completed and reperfusion achieved in patients in whom coronary angioplasty was successful. RepWu&n e In Figutc 3, previously published reperfusion rates from the TIM1 I trial for t-PAi and
streptokinasei6are compared with corresponding reperfusion rates observedwith direct coronary angioplasty in the Mayo Clinic trial. Compared with the TIM1 I reperfusion rates in 83 patients treated with t-PA, the reperfusion rate in patients who underwent direct coronary angioplasty was similar at 30 minutes (12 vs 24% vs tPA, p = 0.12), 60 minutes (54 vs 57% vs t-PA, p = 0.78) and 90 minutes (83 vs 71% vs t-PA, p = 0.12). Direct coronary angioplasty resulted in a similar 30-minute reperfusion rate to the 30-minute reperfusion rate in 119 patients in TIMI I treated with streptokinase(12 vs 8%, respectively, p = 0.42), but angioplasty had a greater reperfusion rate at 60 minutes (54 vs 23%, p = 0.001) and 90 minutes (83 vs 31%, p = 0.001). The time to reperfusion for each of the patients in whom coronary angioplasty was successful is displayed in Figure 4. Reperfusion was achieved in 88% (42 of 48) of patients between 40 and 120 minutes after randomization to direct coronary angioplasty. By 170 minutes, 45 of 48 patients (94%) in whom direct coronary angioplasty was eventually successful had achieved reperfusion.
PTCA FlGlJREl.llbsmeantimefromtheonsetof cbstpaintoafwivalintheemergencyroom forpathtsrandomizedtodirectperc&me arr-ca#lsy~(~A) and recombinant tissue-type plasminogen activator (MA).
&PA I 0
I
I
I
I
I
I
I
I
20
40
60
so
loo
120
140
160
Minutes from onset of chest pain, mean
AITII~I in Arterial cath lab access
First deflation
PTCA FlGURE2.llwmeantiifVomrandomira ttontotmatmentfor~-&edto direct percutsneous tranduminal cOcOnay a@ophty (PTCA) and mcombinzurt tissue type plasminogen activator (MA) in the Mayo Clinic trial. cath q cathetekation; bb=bboretory.
I
90-min infusion comoleted
Initiation of infusion
&PA
0
10
20
30
40
50
60
70
80
Minutes from randomization,
90
loo
110 120
mean
REPERFUSION WITHTHROMBOLYSISAND ANGIOPLASTY 233
DISCUSSION
The most important findings of this study are that reperfusion is achieved rapidly with direct coronary angioplasty, and reperfusion rates compare favorably with those reported for intravenous t-PA and streptokinasein previous studies. Thrombolytic therapy has been shown to preserve myocardial function and reduce mortality in several large, prospective, randomized trial~.~~~J~~~~ The speed with which reperfusion is achieved is a critical determinant to the amount of myocardium that can be salvaged.1-3*6It has previously been shown that the time between the onset of symptomsof myocardial infarction and arrival at an emergencyroom accountsfor the greatest delay in achieving reperfusion. However, significant delays also exist between the time a patient presentsto the emergency room with symptoms of acute myocardial infarction and the administration of thrombolytic therapy.4,5 Although much of the delay has been attributed to the time required to evaluate patients by emergencyroom physicians and to obtain an electrocardiogram, further delay exists between the time that a decision to treat with thrombolytic therapy is reached and initiation of the infusion, ranging from 23 to 63 minutes.4*5Therefore, strategieshave been developedto has-
ten the evaluation and treatment of patients presenting to the emergency room with suspectedmyocardial infarction, shortening the time from arrival in the emergency room to the administration of thrombolytic thera-
PY.l
A similar analysis of the time required for direct coronary angioplasty has not been reported. The present study suggests that attempts to shorten the delay in achieving reperfusion with direct coronary angioplasty after arrival in the emergencyroom should focus on the time required for a catheterization laboratory to become available and assemblea emergencycatheterization laboratory team. It is this time interval, 45 minutes in the present study, that results in the next greatestdelay before reperfusion is achieved. A comparison of the time to reperfusion with thrombolytic therapy and direct coronary angioplasty must include the time required to initiate each therapy, as well as the time it takes from the initiation of therapy to achieve reperfusion. Trials of intravenous thrombolytic therapy in which reperfusion rates have been reported have not included the time required to initiate thromboIn addition, the mean time to reperlytic therapy.17,21-23 fusion cannot be determined among patients in whom it was achieved,since angiography is not continuously per-
FlGURE3.Thereperfusionratefardirect percutaneous tranduminal cOtOnacy an@* plasty (PTCA) in the Mayo Clinic trial and pretiously published reperfusion rates for recombinant tissuetype plasminogen active tor (MA) and shptokinase (SK) in the lhrombolysis in Myocardiil lnfarcth trial. The tims inblvals eonespond tothetime from randomiiation to repelfusion.
Minutes from randomization
d
6
5 .5 L
4
FIGURE 4. The time to reperfusion in the 45 patients who underwent direct coronary ar@oplastya~in~coronaryW plasty was successful. Rep&us&n was achieved in most pathts between 40 and 120 minutes after randomization.
2
0 0
10
20
30
40
60
60
70
60
90
Minutes, randomization 234
100
110
120130
140 150 160-170
to reperfusion
THE AMERICANJOURNALOF CARDIOLOGY VOLUME73
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formed, and the exact moment of reperfusion in most 1. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. trial of intravenous streptokinase, oral aspirin, both or neither among patients is unknown. In contrast, analyses of the time Randomized 17,187 cases of suspected acute myoardial infarction: ISIS-2. Lancer 1988:2: required to reperfusion with direct coronary angioplasty 34F360. have included the time required to transport patients to 2. AIMS Trial Study Group. Effect of intravenous APSAC on mortality after acute infarction: preliminary report of a placebo-controlled clinical trial. Luncet the catheterization laboratory, and the mean time to re- myocardial 1988;1:545-549. perfusion has been reported.2k26These differences in 3. Califf RM, Top01 EJ, Gash BJ. From myocardial salvage to patient salvage in the methods of analysis between reperfusion rates with acute myocardial infarction: the role of repafusion therapy. J Am CON Cardiol thrombolytic therapy and direct coronary angioplasty 4.1989;14:1382-1388. Gonzalez ER, Omato JP, Jones LA, Bleecker GC, Strauss MJ, and the Virginia have introduced considerable bias, and have precluded Thrombolytic Smdy Group. Prospective multicenter assessment of critical factors an accurate comparison of reperfusion rates for these 2 delaying hospital thmmbalytic therapy (abstr). J Am Coil Cardiol 1991;17:247A. Sharkey SW, Brunette DD, Ruiz E, Hession WT, Wysham DG, Goldenberg IF, therapies. The current study includes the time required 5.Hodges M. An analysis of time delays preceding thrombolysis for acute myocxto initiate both thrombolytic therapy and coronary angi- dial infarction. JAMA 1989;262:3 171-3174. oplasty, and reports reperfusion rates from the time that 6. Weaver WD, Cerqueim M, Hallstrom AP, Litwin PE, Manin JS. Kudenchuk PJ, Eisenberg M, for the Myocaniial Infarction Triage and Intervention Pmject the decision to proceed with each of these reperfusion Group. Prehospita-initiated vs hospital-initiated thrombolytic therapy. The Myocastrategieswas made. It can thus be seen that t-PA and dial Infarction Triage and Intervention Trial. JAMA 1993;270:1211-1216. Robertson CE, Miller HC, Fox KAA. Effect of “fast-track” admisdirect coronary angioplasty have similar reperfusion 7.sionPellfor ACH, acute mycatdial infarction on delay to thrombolysis. Br Med J 1992304: rates; larger studies will be required to determine if 83-87. small differences exist between the reperfusion rates 8. European Myocardial Infarction Project (EMIP) Subcommittee. Potential time with pre-hospital intervention in acute myocardial infarction. Eur Heart J with these 2 treatments. Reperfusion rates with direct saving 1988;9:118-124. coronary angioplasty compare favorably with those re- 9. O’Keefe JH, Rutherford BD, McConahay DR, Ligon RW, Johnson WL, Giorgi LV, Crockett JE, McCallister BD, Corm RD, Gum GM, Good TH, Steinhaus ported for streptokinase. Bateman TM, Shimshak TM, Hat&r GO. Early and late results of coronary It must be rememberedthat coronary blood flow is DM, angioplasty without antecedent thmmbolytic therapy in acute myocardial infarction. nearly always restored to normal (TIMI grade 3 flow) Am J Cardiol 1989;64:1221-1230. after successful angioplasty, whereas any anterograde 10. Rothbaum DA, Linnemeier TJ, Landin RJ, Steimnetz EF, Hillis JS, Hallam Noble RJ, See MR. Emergency percutaneous tmnsluminal coronary angioplasty flow in the infarct artery beyond the occlusion (TIMI inCC,acute myocardial infarction: a 3 year experience. J Am Coil Cardiol 1987;lO: grade 2 or 3 flow) has traditionally been considered to 2W272. Ellis SG, O’Neill WW, Bates ER, Walton JA, Nabel EG, Topol EJ. Coronary represent successfulreperfusion after thrombolytic ther- 11. angioplasty as primary therapy for acute myoctiial infarction 6 to 48 hours after apy.16There is increasing evidence, however, that the symptom onset: report on an initial experience. J Am Co/l Cardiol 1989;13: outcome of patients with TIM1 2 flow 90 minutes after 1122-1126. O’Neill W, Timmis GC, Bowdillon PD, Lai P, Ganghadarhan V, Walton J Jr, thrombolytic therapy more closely resemblesthat of pa- 12. Ramos R, Laufer N, Gordon S, Schork MA, Pitt B. A prospective randomized clintients with persistent occlusion (TIMI grade 0 or 1 flow) ical trial of intracomnary streptokinase versus coronary angioplasty for acute myocwthan that of patients with normal coronary blood flow dial infarction. N Er@ J Med 1986;314:812-818. la. Gibbons RJ, Holmes DR. Bailey KR, Hopfenspirger MR, Gersh BJ, for the (TIM1 grade 3 flow).27-29If only normalization of coro- Mayo CCU and Catheterization Laboratory Groups. Randomized trial comparing nary blood flow (TIM1 grade 3 flow) was considered to immediate angioplasty with thmmbolysis followed by conservative treatment for representreperfusion, reperfusion rates would be signif- myocardial infarction. N Engl .I Med 1993;328:685-691. 14. Third International Study of Infarct Survival (ISIS-3). A randomized comicantly greater with direct coronary angioplasty than parison of streptokinase versus tissue plasminogen activator versus anistreplase and of aspirin plus heparin vel~us aspirin alone among 41,299 cases of suspected acute with both t-PA27-29and streptokinase.16 1992;339:753-770. myocxdial infarction. Lnncet Because of the convincing data 15. Study limitations: The TIM1 Study Group. Immediate versus delayed catheterization and angiofrom prospective randomized trials that immediate cor- plasty following thrombolytic therapy for acute myocardial infarction. JAMA 1988; onary angiography and coronary angioplasty after 260~2849-2858. 16. Chesebro JH, Knatterud G, Roberts R, Borer I, Cohen LS, D&n J, Dodge thrombolytic therapy is of no additional benefit,1530,31 HT, Francis CK, Hillis b, Ludebrook P, Markis JE. Mueller H, Passamani ER, patients assigned to thrombolytic therapy in the Mayo Powers ER, Rae AK, Robertson T, Ross A, Ryan TJ, Sobel BE, WilIerson J, Clinic trial did not undergo immediate coronary angiog- Williams DO, &et BL, Bmunwald E. Thrombolysis in Myocardial Infarction (TIMI) Phase I: a comparison between intravenous tissue plasminogen activator and raphy, and reperfusion rates with t-PA could not be de- Trial, intravenous streptokinase. Clinical findings through hospital discharge. Circuhtion termined in this study. Therefore, previously published 1987;76:142-154. reperfusion rates from the TIMI trial for both t-PA and 17. Mueller HS, Rae AK, Forman SA and the TIM1 Investigators. Thrombolysis Myocadial Infection (TIMI): comparative studies of coronary reperfusion and streptokinase were used for comparison.16J7The 90- insystemic tibrinogenolysis with two forms of tissue-type plasminogen activator. J minute reperfusion rate for t-PA (70%) and streptoki- Am Coil Cnrdiol 1987; 10~479490. 18. Kalbfleisch JM, Kumik PB, Thadani U, DeWocd MA, Kent R, Magorien RD. nase (55%) in the TIM1 I trial are similar to the reper- Jai” AC, Spaccavento LJ, Morris DL, Taylor GJ, Perry JM, Kutcher MA, Goriinkel fusion rates for these thrombolytic agents reported from HJ, Littlejohn JK, for the Burroughs Wellcome Study Group. Myocardial infarct several other trials of thrombolytic therapy in which 90- artery patency and reocclusion rates after treatment with duteplase at the dose used in the International Study of Infarct Survival-3. Am J Cardiol 1993;71:38&392. minute angiography was performed.21,22 It has been re- 19. Rovelli F, De Vita C, Femglio GA, Lotto A, Selvini A, Tognoni G. Effectiveported that “front-loaded” regimens of t-PA, in which ness of intravenous thrombolytic treatment in acute myocardial infarction: Gruppo more t-PA is administered in the initial 60 to 90 min- Italian0 per lo Studio della Streptochinasi nell’lnfwto Miocardico (GISSI). Lance-t 1986;1:397-%02. utes of therapy, achieve higher 60- and 90-minute re- 20. Wilcox RG, van der Lippe G, Olsson CG, Jensen G, Skew AM, Hamptom perfusion rates than were seen in the TIMI trial, in JR. Trial of tissue plasminogen activator for mortality reduction in acute myocarwhich the standard dosing regimen of t-PA was dial infarction: Anglo-Scandinavian Study of Early ‘Ihrombolysis (ASSET). Lmcet 1988: 1:525-530. used.23,32*33 Therefore, the comparison of reperfusion 21. Topal EJ, Morris DC, Smalling RW, Schumacher RR, Taylor CR, Nishikawa rates with direct coronary angioplasty and thrombolytic A, Liberman HA, Collen D, Tufte ME, Grossbard EB, O’Neill WW. A multicenter, randomized, placebo-controlled trial of a new form of intravenous recombinant therapy applies only to the dosagesand rates of admin- tissue-type plasminogen activator (activase) in acute myocardial infarction. J Am istration of the thrombolytic agents used in the TIMI Cdl Cmdiol 1987;9: 1205-12 13. 22. Smelling RW, Schumacher R, Morris D, Harder K, Fuentes F, Valentine RP, trial. REPERFUSION WITHTHROMBOLYSISAND ANGIOPLASTY 235
Batey LL Jr, Merhige M, Pins DE, Lieberman HA, Nishiiawa A, Adyanthaya A, Hopkins A, Grossbard E. Improved infarct-related arterial patency after high dose, weight-adjusted, rapid infusion of tissue-type plasminogen activator in myocardial infarction: results of a multicenter randomized trial of two dosage regimens. J Am Coil Cardiol 1990,15:915-921. 23. Camey RJ, Murphy GA, Brandt TR, D&y PJ, Pickering E, White HJ, McDonough TJ, Vennilya SK, Teichman SL, for the RAAMI Study Investigators. Randomized angiographic trial of recombinant tissue-type plasminogen activator (alteplase) in myocardial infarction. J Am Co// Cardiol 1992;20:17-23. 24. Kahn JK, Ruthefiord BD, McConahay DR. Johnson WL, Giorgi LV, Shimshak TM, Ligon R, Hartzler GO. Results of primary angioplasty for acute myocardial infarction in patients with multivessel coronary artery disease. J Am Co// Cardid 26.
1990; 16: 1089-1096.
Bmdie BR, Weintraub RA, Stuckey TD, LeBauer EJ, Katz JD, Kelly TA, Hansen CJ. Outcomes of direct coronary angioplasty for acute myocardial infarction in candidates and non-candidates for thrombolytic therapy. Am .I Cardiol 1991;
6717-12. 26. Hartzler
G, Rutherford B, McConahay DR, Johnson WL Jr, McCallister BD. Gura GM Jr, Corm RC, Crockett JE. Percutaneous transluminal coronary angioplasty with and without thrombolytic therapy of acute myocardial infarction. Am Heart J 1983:106:965-973. 27. Vogt A, van Essen R. Tebbe U, Feuerer W, Appel KF, Neuhaus KL. Impact of early perfusion status of the infarct-related artery on short-teml mortality after thmmbolysis for acute myocxdial infarction: retrospective analysis of four German multicenter studies. J Am Co// Cm-din/ 1993;21:1391-1395. 28. Kamgounis L, Sorenson SG, Menlove RL, Moreno F, Anderson JL for !he TEAM-2 Investigators. Does thmmbolysis in myocardial infarction (TIMI) perfusion
236
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grade 2 represent a mostly patent artery or a mostly occluded artery? Enzymatic and electrocardiographic evidence from the TEAM-2 study. J Am Co/l Cardiol 1992;19:1-10. 29. Anderson JL, Karagounis LA, Becker LC. Sorensen SG, Menlove RL, for the TEAM-3 Investigators. TIM1 perfusion grade 3 but not grade 2 results in improved outcome after thrombolysis for myocardial infarction: ventriculographic, enzymatic, and electrocardiographic evidence from the TEAM-3 Study. Circulation 1993; 87:182%1839. 30. Simoons M, Arnold AER, Betriu A, Bokslag M, de Bono DP, Brewer RW, Cal J, Dougherty FC, van Essen R, Lambertz H, Lubsen J, M&r B, Michel PL, Raynaud P, Rutsch W, Sanz GA, Schmidt W, Senuys PW, Uebis R, Vahanian A, Van der Werf F, Willems GM, Wood D, Verstrate M. Thrombolysis with tissue plasminogen activator in acute myocardial infarction: no additional benefit from immediate percutaneous coronary angioplasty. Lancet 1988; 1: 193-203. 31. Top01 E, Califf R, George BK, Kereiakes DJ, Abbottsmith CW, Candela RJ, Lee KL, Pitt B, Stack RS, O’Neill WW, and the TAM1 Study Group. A randomized trial of immediate V~TSUSdelayed elective angioplasty after intravenous tissue plasminogen activator in acute myocardial infarction. N En,@ J Med 1987;317: 581-588. 32. Neuhaus
K-L, van Essen R, Tebbe U, Vogt A, Roth M, Riess M, Niedenr W, Forycki F, Wirtzfeld A. Maeurer W, Limbourg P. Marx W, Haerten K. Improved thrombolysis in acute myocardial infarction with front-loaded administration of alteplase: results of the t-PA-APSAC Patency Study (TAPS). J Am CoN Cardiol 1992;19:885-891. 33. Neuhaus K-L, Feuerer W, Jeep-Tebbe S, Niederer W, Vogt A, Tebbe U. Improved thrombolysis with a modified dose regimen of recombinant tissue-type plasminogen activator. J Am Co// Cardiol 1989;14:156&1569.
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