A Comparison of Coronary Angioplasty with Fibrinolytic Therapy in Acute Myocardial Infarction
Henning R. Andersen, M.D., Torsten T. Nielsen, M.D., Klaus Rasmussen, M.D., Leif Thuesen, M.D., Henning Kelbaek, M.D., Per Thayssen, M.D., Ulrik Abildgaard, M.D., Flemming Pedersen, M.D., Jan K. Madsen, M.D., Peer Grande, M.D., Anton B. Villadsen, M.D., Lars R. Krusell, M.D., Torben Haghfelt, M.D., Preben Lomholt, M.D., Steen E. Husted, M.D., Else Vigholt, M.D., Henrik K. Kjaergard, M.D., Leif Spange Mortensen, M.Sc., for the DANAMI-2 Investigators
Background For the treatment of myocardial infarction with ST-segmentelevation, primary angioplasty is considered superior to fibrinolysisfor patients who are admitted to hospitals with angioplastyfacilities. Whether this benefit is maintained for patientswho require transportation from a community hospital to a centerwhere invasive treatment is available is uncertain.
Methods We randomly assigned 1572 patients with acute myocardialinfarction to treatment with angioplasty or accelerated treatmentwith intravenous alteplase; 1129 patients were enrolled at 24referral hospitals and 443 patients at 5 invasive-treatmentcenters. The primary study end point was a composite of death,clinical evidence of reinfarction, or disabling stroke at 30days.
Conclusions A strategy for reperfusion involving the transferof patients to an invasive-treatment center for primary angioplastyis superior to on-site fibrinolysis, provided that the transfertakes two hours or less.
Percutaneous coronary intervention has been shown to be superiorto fibrinolysis in the treatment of acute myocardial infarctionwith ST-segment elevation in patients admitted to highly experiencedangioplasty centers.1,2,3,4 In Western countries, primary angioplastyis offered only to the limited number of patients admitted directlyto hospitals with interventional services. Transportation fromthe local hospital to an angioplasty center has been consideredto represent a major limitation on the widespread use of primaryangioplasty. We conducted a community-wide trial to comparethe transfer of patients for primary angioplasty with the useof on-site fibrinolysis.
Methods
Study Design
We randomly assigned patients who had myocardial infarctionwith ST-segment elevation to fibrinolysis or primary angioplasty.From December 1997 to October 2001, we enrolled patients from24 referral hospitals without angioplasty facilities and 5 invasive-treatmenthospitals with such facilities and on-site surgical backup.The participating hospitals served 62 percent of the Danishpopulation. Patients admitted to a referral hospital underwentrandomization while they lay on the ambulance stretcher withthe crew waiting. Transfer to the nearest angioplasty centerhad to be completed within three hours. A physician accompaniedthe patient. All ambulances had resuscitation equipment. Thepatients were transported directly to the catheterization laboratory.
Treatment
Patients randomly assigned to fibrinolysis received 300 mg ofaspirin orally, a beta-blocker intravenously (up to the equivalentof 20 mg of metoprolol), accelerated treatment with tissue plasminogenactivator (alteplase, given as a 15-mg bolus and an infusionof 0.75 mg per kilogram of body weight administered over a periodof 30 minutes, followed by an infusion of 0.5 mg per kilogramfor a period of 60 minutes), and an intravenous bolus of unfractionatedheparin (5000 U), followed by a 48-hour infusion of unfractionatedheparin. The starting dose of unfractionated heparin was 1000U per hour; the dose was adjusted to maintain an activated partial-thromboplastintime of 70 to 90 seconds.
Patients randomly assigned to angioplasty received 300 mg ofaspirin intravenously, the same dose of a beta-blocker as patientsin the fibrinolysis group, and 10,000 U of unfractionated heparin.Additional heparin was given to achieve an activated clottingtime of 350 to 450 seconds during the invasive procedure. Plateletglycoprotein IIb/IIIareceptor blockers were administeredat the discretion of the physician. The infarct-related arterywas treated if it was totally occluded, if there was a culpritlesion with stenosis of more than 30 percent of the luminaldiameter, or if it had a flow grade of less than 3 accordingto the Thrombolysis in Myocardial Infarction (TIMI) classification.5Stenting of the culprit lesion was attempted in all patients,unless the vessel had a diameter of less than 2.0 mm. Angioplastyof noninfarct-related arteries was not performed. Patientswere not considered for immediate coronary-artery bypass graftingunless they had severe hemodynamic instability. Ticlopidine(500 mg) or clopidogrel (75 mg) was given daily for one monthafter stenting. The angiograms obtained before and after angioplastywere evaluated by an independent core laboratory (Cardialysis,Rotterdam, the Netherlands).
When failed reperfusion was suspected (i.e., when there wasno resolution of ST-segment elevation) or when there was reinfarctionor recurrent ischemia with ST-segment elevation after fibrinolysis,the protocol recommended repeated fibrinolysis before considerationof rescue angioplasty. An early or late reinfarction or recurrentischemia in patients with an index infarction that had beentreated by angioplasty was treated by repeated angioplasty.
The primary end point was a composite of death from any cause,clinical reinfarction, or disabling stroke at 30 days of follow-up.Procedure-related reinfarction was not included in the primaryend point. A reinfarction was diagnosed if there was an increasein the total creatine kinase and MB isoenzyme activity and eithera history of ischemic chest discomfort or electrocardiographicchanges. Clinical reinfarction was diagnosed if the creatinekinase MB level increased to above a reference limit in a patientin whom the level had normalized after the index infarctionor if there was an increase of at least 50 percent from thelast non-normalized measurement. A procedure-related reinfarctionwas diagnosed after coronary-artery bypass surgery if the creatinekinase MB level increased to five times the upper limit of normalor five times the preceding level; a procedure-related reinfarctionwas diagnosed after angioplasty if the level increased to twicethe upper limit of normal or twice the last non-normalized measurement.
Disabling stroke was defined as a fatal stroke or a stroke causinga clinically significant mental or physical handicap at 30 daysof follow-up. Clinically significant handicaps were definedas ranging from slight disability (i.e., the inability to engagein all previous activities in a patient who was still able totake care of himself or herself without assistance) to verysevere disability (i.e., a bedridden state involving a requirementfor constant nursing care and attention). Detailed definitionsof these end points are available elsewhere.6 End-point eventswere reviewed by an end-points committee that was unaware ofthe treatment-group assignments.
Criteria for Eligibility
The criteria for inclusion were an age of 18 years or more,the presence of symptoms for at least 30 minutes but less than12 hours, and cumulative ST-segment elevation of at least 4mm in at least two contiguous leads. The criteria for exclusionwere a contraindication to fibrinolysis, left bundle-branchblock, acute myocardial infarction and fibrinolytic treatmentwithin the previous 30 days, pulseless femoral arteries, previouscoronary-bypass surgery, renal failure (indicated by a serumcreatinine concentration above 2.83 mg per deciliter [250 µmolper liter]), diabetes treated with metformin, nonischemic heartdisease, and noncardiac disease associated with a life expectancyof less than 12 months. Patients who were judged to be at highrisk during transportation because of cardiogenic shock or severeheart failure (a sustained systolic blood pressure 65 mm Hg),persistent life-threatening arrhythmias, or a need for mechanicalventilation were excluded. The study was approved by the NationalEthics Committee of Denmark. All eligible patients providedwritten informed consent. The study was supervised and monitoredby an international safety and ethics committee.
At the start of the study, only two centers offered primaryangioplasty as routine treatment. Each of the five invasive-treatmentcenters had to establish a 24-hour service for angioplasty beforeit was allowed to join the study.
Statistical Analysis
The trial consisted of two simultaneously conducted substudies,one involving patients who underwent randomization at referralhospitals and the other involving patients who underwent randomizationat invasive-treatment centers. The results were analyzed bothseparately for each substudy and for the two substudies combined.Each substudy was designed with two groups, interim analyses,and stopping rules, with an overall two-sided alpha of 5 percentand a power (1 beta) of 80 percent.
The calculation of the sample size was based on the assumptionthat the combined primary end point would be reached by 30 daysin 16 percent of the patients randomly assigned to fibrinolysis,in 10 percent of the patients randomly assigned to angioplastyat referral hospitals, and in 9 percent of the patients randomlyassigned to angioplasty in invasive-treatment centers. Underthese assumptions, enrollment of 1100 patients was needed atthe referral hospitals, and enrollment of 800 patients was neededat the invasive-treatment centers. Three interim analyses wereto be performed in the referral-hospital substudy (after theenrollment of 25 percent, 50 percent, and 75 percent of thepatients), and two interim analyses were to be performed inthe invasive-treatmentcenter substudy (after the enrollmentof 33 percent and 66 percent of the patients). Thus, each interimanalysis was performed after the enrollment of approximatelythe same number of patients in both substudies.
In case of a treatment difference in favor of fibrinolysis,an alpha level of 0.05 was to be used in all interim analyses.In case of a treatment difference in favor of angioplasty, thesignificance level at the first interim analysis in each substudywas conservatively set to an alpha level of 0.001, which, togetherwith an overall alpha level of 0.05, led to significance levelsat subsequent interim analyses of 0.009 and 0.022 in the referral-hospitalsubstudy and 0.016 in the invasive-treatmentcenter substudy.The design was a hybrid of a Pocock design and an O'BrienFlemingdesign, and analyses were performed with the use of the EaStsoftware package, version 2.0 (Cytel Software).
If, in any interim analysis in the referral-hospital substudy,angioplasty was shown to be superior to fibrinolysis, both substudieswere to be stopped, since the superiority of angioplasty inthe referral-hospital substudy would imply its superiority atthe invasive-treatment centers as well. If, in any interim analysisin the referral-hospital substudy, angioplasty was shown tobe inferior to fibrinolysis, only the referral-hospital substudywas to be stopped. If, in any interim analysis in the invasive-treatmentcentersubstudy, angioplasty was shown to be superior to fibrinolysis,only the invasive-treatmentcenter substudy was to bestopped. If, in any interim analysis in the invasive-treatmentcentersubstudy, angioplasty was shown to be inferior to fibrinolysis,both substudies were to be stopped, since this would imply thesuperiority of fibrinolysis at referral hospitals as well.
Results were analyzed according to the intention-to-treat principle.For the comparison of categorical variables, Pearson's chi-squaretest was used. Values for continuous variables are reportedas medians and interquartile ranges. Groups were compared withthe use of the MannWhitney rank-sum test.
Results
Patient Population and Base-Line Characteristics
A total of 4278 patients who had myocardial infarction withST-segment elevation were screened for inclusion. Enrollmentwas stopped on October 1, 2001, after the third interim analysishad demonstrated that angioplasty was superior to fibrinolysisin the referral-hospital substudy. At that time, 1129 patientshad undergone randomization at referral hospitals, and 443 patientshad undergone randomization at invasive-treatment centers. Base-linecharacteristics of patients randomly assigned to fibrinolysiswere similar to those of patients randomly assigned to angioplasty(Table 1). Four percent of the patients screened at referralhospitals were excluded because they were judged to be unableto tolerate being transported. Detailed information on screenedand excluded patients is available elsewhere.6
Table 2. Time from Onset of Symptoms to Start of Fibrinolytic or Angioplastic Treatment.
The median distance that patients had to be transported froma referral hospital to an invasive-treatment center was 50 km,with a range of 3 to 150 km. Thirty percent of patients whowere transferred had to be transported 3 to 25 km, 34 percent26 to 50 km, 18 percent 51 to 75 km, and 18 percent 76 to 150km. The transfer time was defined as the time from randomizationat the referral hospital to arrival in the catheterization laboratory.The median transfer time was 67 minutes (interquartile range,50 to 85). Forty-three percent of patients who were transferredhad a transfer time of less than one hour, 53 percent a transfertime of one to two hours, and 4 percent a transfer time of twoto three hours.
Adverse Events during Transportation
A total of 559 of the 567 patients randomly assigned to angioplastyat referral hospitals (99 percent) were transferred. Atrialfibrillation developed in 14 patients, intermittent advancedatrioventricular block in 13 patients, and ventricular fibrillationin 8 patients. There were no deaths during transportation. Onepatient had refractory ventricular fibrillation on arrival atthe invasive-treatment center and died one hour later afteran unsuccessful attempt at resuscitation.
Immediate Treatment and Angioplasty Results
Among the 782 patients randomly assigned to fibrinolysis, 775patients (99 percent) received the assigned treatment. Of the790 patients randomly assigned to angioplasty, 777 patients(98 percent) underwent immediate angiography. Angioplasty wasattempted in 706 patients, and balloon inflation was performedin 686 patients (87 percent of the 790 who were randomly assignedto angioplasty). Stents were implanted in 638 of these patients(93 percent), and 310 patients were treated with platelet glycoproteinIIb/IIIareceptor blockers during catheterization. Theinfarct-related vessel was the left anterior descending arteryin 46 percent of the patients who underwent angiographic examination,the right coronary artery in 35 percent, and the left circumflexartery in 12 percent. The remaining infarct-related vesselswere minor side branches.
The flow of the presumed infarct-related artery was of TIMIgrade 0 or 1 on initial angiography in 68 percent of patients,grade 2 in 14 percent of patients, and grade 3 in 18 percentof patients. The postprocedural flow was of TIMI grade 0 or1 in 3 percent of patients, grade 2 in 15 percent, and grade3 in 83 percent (usable angiograms were available for 699 patients).Among the patients who underwent angioplasty, a postproceduralflow of TIMI grade 0 or 1 was achieved in 2 percent, grade 2in 16 percent, and grade 3 in 82 percent.
Of the 91 patients who underwent immediate angiography but didnot undergo balloon inflation, 31 had normal coronary arteries.Among the remaining 60 patients, medical treatment was consideredto be the best initial strategy for 36 patients, balloon inflationwas not possible for technical reasons in 17 patients, 3 patientshad chronic occlusions without a culprit lesion, and 4 patientsdied before angioplasty could be performed. Only one patientunderwent coronary surgery immediately after the angiographicexamination.
Clinical Outcome
The clinical outcomes at 30 days are shown in Table 3, Figure 1,and Figure 2. The relative reduction in the rate of the compositeoutcome was 40 percent among patients enrolled at referral hospitalsand 45 percent among those enrolled at invasive-treatment centers.The superiority of angioplasty over fibrinolysis was drivenby a 75 percent reduction in the relative risk of clinical reinfarction,whereas the reduction in the risks of death and stroke did notreach statistical significance. The number of patients who wouldneed to be treated in order to avoid one death, clinical reinfarction,or disabling stroke in a 30-day period was 17 for referral hospitalsand 18 for invasive-treatment centers. The rate of the primarycomposite end point was consistently lower with angioplastythan with fibrinolysis in a number of prespecified subgroups(Figure 2). No significant interactions between subgroups andtreatment were detected. The relative benefit of angioplastyremained constant among the 646 patients whose symptoms hadlasted less than two hours, the 549 patients whose symptomshad lasted two to four hours, and the 377 patients whose symptomshad lasted four hours or more.
Figure 1. KaplanMeier Curves Showing Cumulative Event Rates for the Primary Composite End Point of Death, Clinical Reinfarction, or Disabling Stroke during 30 Days of Follow-up.
Panel A shows the results for the 1129 patients who underwent randomization at referral hospitals, Panel B for the 443 patients who underwent randomization at invasive-treatment centers, and Panel C for all 1572 patients in the study. P values were calculated with the use of the log-rank test.
Figure 2. Odds Ratios for the Primary Composite End Point of Death, Reinfarction, or Disabling Stroke at 30 Days of Follow-up among All 790 Patients Randomly Assigned to Primary Angioplasty as Compared with All 782 Patients Randomly Assigned to Fibrinolysis, According to Base-Line Characteristics.
For analysis according to age, the median value of 63 years was used to dichotomize the variable. CI denotes confidence interval, MI myocardial infarction, and ACE angiotensin-converting enzyme.
Among the 62 patients who had clinical reinfarction during follow-up,30-day mortality was 24.2 percent, as compared with 6.5 percentamong the remaining 1510 patients (P<0.001). Procedure-relatedreinfarctions occurred in 10 patients randomly assigned to fibrinolysisand 5 patients randomly assigned to angioplasty aftercoronary-bypass surgery in 11 cases and after angioplasty in4 cases. Inclusion of these procedure-related reinfarctionsin the analysis of clinical reinfarctions did not change theresults.
The types of medication prescribed at discharge did not differbetween patients randomly assigned to angioplasty and thoseassigned to fibrinolysis. A total of 96 percent of patientsreceived aspirin, 87 percent received beta-blockers, 51 percentreceived lipid-lowering drugs, and 36 percent received angiotensin-convertingenzymeinhibitors.
Repeated Coronary Revascularization during Follow-up
In the fibrinolysis group, 26 patients underwent repeated fibrinolysiswithin 12 hours after randomization, and 15 patients underwentrescue angioplasty (P=0.22). During the 30 days of follow-up,148 patients randomly assigned to fibrinolysis underwent mechanicalrevascularization (coronary-bypass surgery in 20 patients andangioplasty in 129 patients), as did 72 patients randomly assignedto angioplasty (coronary-bypass surgery in 30 patients and angioplastyin 45 patients) (P<0.001 for the comparison between groups);some patients had more than one procedure.
The transfer of patients was found to be safe. Only 4 percentof the screened patients were considered to be unable to toleratebeing transported. Our results extend the findings of the recentPRAGUE-2 study.7
Although the rates of death, clinical reinfarction, and strokewere all reduced with angioplasty, the better overall outcomeafter angioplasty was driven primarily by the reduction in therate of reinfarction. Our finding of a higher 30-day mortalityrate among patients with reinfarction accords with recent resultsby Gibson et al.9 and indicates that clinical reinfarction inour trial was a severe event. The prognostic significance ofprocedure-related ischemic events is uncertain.10 The inclusionin the analysis of procedure-related reinfarctions strengthened,rather than weakened, the evidence of a favorable outcome afterangioplasty.
Our angiographic success rate, with the achievement of a flowof TIMI grade 3 in 83 percent of our patients, is similar tothe success rates in experienced centers.11,12,13It is welldocumented that the benefit of primary angioplasty depends onthe volume of procedures performed and the level of experienceof the physician.14,15 Although all five invasive-treatmentcenters in our study were high-volume interventional-treatmentcenters (performing 600 to 1600 angioplasty procedures per year),they had had limited experience in performing primary angioplastyat the beginning of the study. However, they were all able toadapt the training program and obtain and maintain the necessaryskills.
The frequency of rescue angioplasty was low. Although one mayargue that our approach was too conservative, there is no publishedevidence of a treatment benefit of rescue angioplasty in patientswho have been treated with fibrinolysis at referral hospitals.At 30 days of follow-up, one fifth of the patients who had beentreated with fibrinolysis had undergone ischemia-guided mechanicalrevascularization, in accordance with the protocol of our previousstudy.16
Future attempts to improve the clinical outcome associated withprimary angioplasty should focus on the logistics of transferringpatients and on adjunctive medication. One approach might beto obtain an electrocardiogram in the ambulance and then totransfer the patient directly to a center with facilities forprimary angioplasty, with or without surgical backup.17 Therehas been great interest in "facilitated" angioplasty involvingthe use of a reduced dose of a fibrinolytic drug in combinationwith more aggressive antithrombotic treatment before angioplasty.Trials dealing with such strategies have not yet provided convincingevidence of their effectiveness.18
Supported by grants from the Danish Heart Foundation, the DanishMedical Research Council, AstraZeneca, Bristol-Myers Squibb,Cordis, Pfizer, PharmaciaUpjohn, Boehringer Ingelheim,and Guerbet.
Dr. Andersen reports having received lecture fees from Eli Lilly;Dr. Nielsen lecture fees, consulting fees, or both from Bristol-MyersSquibb and Pfizer; Dr. Rasmussen lecture fees and grant supportfrom Bristol-Myers Squibb and Cordis; and Dr. Haghfelt lecturefees, grant support, or consulting fees from Merck Sharp &Dohme, Pfizer, Aventis Pharma, and AstraZeneca.
* Participants in the Danish Multicenter Randomized Study on FibrinolyticTherapy versus Acute Coronary Angioplasty in Acute MyocardialInfarction (DANAMI-2) are listed in the Appendix.
Source Information
From the Departments of Cardiology at Skejby Hospital, Aarhus University Hospital, Aarhus (H.R.A., T.T.N., L.T., L.R.K.); Aalborg University Hospital, Aalborg (K.R., A.B.V.); Rigshospitalet University Hospital, Copenhagen (H.K., J.K.M., P.G.); Odense University Hospital, Odense (P.T., T.H.); and the Gentofte Hospital, Hellerup (U.A.); the Departments of Medicine at Hilleroed Hospital, Hilleroed (F.P.); Randers Hospital, Randers (P.L.); Aarhus County Hospital and Aarhus University Hospital, Aarhus (S.E.H.); and Horsens Hospital, Horsens (E.V.); the Department of Cardiothoracic Surgery, Gentofte Hospital, Hellerup (H.K.K.); and UNI-C, Danish Information Technology Centre for Education and Research, Aarhus (L.S.M.) all in Denmark.
Address reprint requests to Dr. Andersen at the Department of Cardiology, Skejby Hospital, Aarhus University Hospital, DK-8200 Aarhus N, Denmark, or at henning.rud.andersen{at}iekf.au.dk.
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Appendix
The following are participants in DANAMI-2. Steering Committee:T.T. Nielsen (chair), H.R. Andersen, L. Thuesen, H. Kelbaek,P. Grande, J.K. Madsen, P. Thayssen, T. Haghfelt, K. Rasmussen,T. Vesterlund, O. Amtorp, U. Abildgaard, F.H. Pedersen, K. Egstrup,and H.K. Kjaergard. End Points Committee: E. Steinmetz (chair),L.R. Krusell, K.N. Hansen, P.R. Hansen, P. Clemmensen, and I.Christiansen. Audit Committee: P. Clemmensen (chair), S. Galatius,and C. Sundgreen. Safety and Ethics Committee: H. Ibsen (chair),K. Mellemgaard (chair), S. Strandgaard, J.S. Christiansen, L.S.Mortensen, M.L. Simoons, F. Zijlstra, C.L. Grines, L. Ekström,and G.W. Stone. Participating hospitals and principal investigators(the number in parenthesis is the number of patients randomized):Aalborg University Hospital, K. Rasmussen (181), Horsens Hospital,E. Vigholt (127), Randers Hospital, P. Lomholt (117), AarhusAmtssygehus, S. Husted (110), Bispebjerg Hospital, N. Gadsboell(88), Odense University Hospital, P. Thayssen (88), Skejby Sygehus,Aarhus University Hospital, H.R. Andersen (83), Viborg Hospital,O. Lederballe (71), Hjoerring Hospital, N. Falstie-Jensen (56),Gentofte Hospital, U. Abildgaard (51), Glostrup Hospital, J.R.Nielsen (47), Grenaa Hospital, H. Rickers (42), Skive Hospital,S.E. Stentebjerg (41), Silkeborg Hospital, F. Roemer (40), HerningHospital, D. Dalsgaard (40), Rigshospitalet, K. Saunamäki(40), Nykoebing Mors, A.N. Davidson (38), Kolding Hospital,M. Asklund (38), Vejle Hospital, B. Engby (37), FrederiksbergHospital, P. Hildebrandt (37), Odder Hospital, B. Jastrup (37),Amager Hospital, H. Nielsen (34), Frederikshavn Hospital, H.Sejersen (31), Hilleroed Hospital, J. Launbjerg (27), HaderslevHospital, P. Wiggers (26), Fredericia Hospital, J. Markenvard(23), Hvidovre Hospital, S.L. Rasmussen (19), Skagen Hospital,H. Sejersen (4), and Brovst Hospital, E. Steinmetz (2). Angioplastycenters (the number in parenthesis is the number of patientstreated with angioplasty): Skejby Hospital, L. Thuesen, H.R.Andersen (421), Aalborg University Hospital, K. Rasmussen, A.B.Villadsen (135), Rigshospitalet, J.K. Madsen, K. Saunamäki(108), Gentofte Hospital, U. Abildgaard, E. Kassis (63), andOdense University Hospital, P. Thayssen (55).
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