Importance of Time to Reperfusion onOutcomes With Primary CoronaryAngioplasty for Acute MyocardialInfarction (Results from the Stent

Primary Angioplasty in MyocardialInfarction Trial)

Bruce R. Brodie, MD, Gregg W. Stone, MD, Marie-Claude Morice, MD,David A. Cox, MD, Eulogio Garcia, MD, Luiz A. Mattos, MD, Judith Boura, MS,

William W. O’Neill, MD, Thomas D. Stuckey, MD, Sally Milks, RN,Alexandra J. Lansky, MD, and Cindy L. Grines, MD, for the Stent Primary Angioplasty

in Myocardial Infarction Study Group

The mortality benefit of thrombolytic therapy for acutemyocardial infarction (AMI) is strongly dependent ontime to treatment. Recent observations suggest that timeto treatment may be less important with primary percu-taneous transluminal coronary angioplasty (PTCA). Pa-tients with AMI of <12 hours duration, without cardio-genic shock, who were treated with primary PTCA fromthe Stent PAMI Trial (n � 1,232) were evaluated toassess the effect of time to reperfusion on outcomes.Thrombolysis In Myocardial Infarction grade 3 flow wasachieved in a high proportion of patients regardless oftime to treatment. Improvement in ejection fraction frombaseline to 6 months was substantial with reperfusion at<2 hours but was modest and relatively independent oftime to reperfusion after 2 hours (<2 hours, 12.3% vs

>2 hours, 4.2%, p � 0.004). There were no differencesin 1- or 6-month mortality by time to reperfusion (6-month mortality: <2 hours [5.5%], 2 to <4 hours [4.6%],4 to <6 hours [4.5%], >6 hours [4.2%], p � 0.97). Therewere also no differences in other clinical outcomes bytime to reperfusion, except that reinfarction and infarctartery reocclusion at 6 months were more frequent withlater reperfusion. The lack of correlation between time totreatment and mortality in patients without cardiogenicshock suggests that the survival benefit of primary PTCAmay be related principally to factors other than myocar-dial salvage. These data may also have implicationsregarding the triage of patients with AMI for primaryPTCA. �2001 by Excerpta Medica, Inc.

(Am J Cardiol 2001;88:1085–1090)

Reperfusion therapy for acute myocardial infarc-tion (AMI) improves short- and long-term mor-

tality and enhances recovery of left ventricular func-tion.1–4 This benefit is believed to occur when coro-nary reperfusion can be established early enough tosalvage myocardium with consequent improvement inleft ventricular function and better survival.5,6 Consis-tent with this paradigm, data from a number of ran-domized trials have shown that survival after throm-bolytic therapy is strongly dependent on time to treat-

ment.4,7,8 Recent observations suggest that time totreatment may be less important with percutaneoustransluminal coronary angioplasty (PTCA),9 althoughthis remains controversial.10,11 The purpose of thisstudy is toevaluate the importance of time to reper-fusion on 1- and 6-month outcomes after primaryPTCA for AMI from the Stent Primary Angioplasty inMyocardial Infarction (PAMI) trial.

METHODSStudy population: Stent PAMI was a multicenter,

randomized trial comparing primary PTCA with orwithout stent implantation with the Palmaz-Schatzheparin-coated stent (Cordis, Johnson & Johnson, Mi-ami, Florida) in patients with AMI.12 Patients withAMI �12 hours from symptom onset, no previousthrombolytic therapy, and no cardiogenic shock wereeligible. After catheterization, 900 patients were ran-domized to PTCA with or without stent implantation,and 558 patients, who were excluded from random-ization, were placed in a registry. After excludingregistry patients who did not undergo coronary inter-vention (n� 177) and patients with missing reperfu-

From the LeBauer Cardiovascular Research Foundation, Moses ConeHospital, Greensboro, North Carolina; Cardiovascular ResearchFoundation, New York, New York; Institut Cardiovasculaire Paris Sud,Antony, France; Mid-Carolina Cardiology, Charlotte, North Carolina;Hospital Gregorio Maranon, Madrid, Spain; Instituto Dante Pazza-nese de Cardiologia, Sao Paulo, Brazil; and the Division of Cardiol-ogy, William Beaumont Hospital, Royal Oak, Michigan. This studywas supported by Cordis, Johnson & Johnson, Miami, Florida. Manu-script received February 10, 2001; revised manuscript received andaccepted July 10, 2001.

Address for reprints: Bruce R. Brodie, MD, 520 North ElamAvenue, Greensboro, North Carolina 27403. E-mail: cvresearch@aol.com.

1085©2001 by Excerpta Medica, Inc. All rights reserved. 0002-9149/01/$–see front matterThe American Journal of Cardiology Vol. 88 November 15, 2001 PII S0002-9149(01)02039-2

sion time data (n � 49), there were 1,232 patients whowere analyzed in this study.

Treatment protocol: Patients were given heparin,chewable aspirin, and ticlopidine in the emergencydepartment and transferred directly to the catheteriza-tion laboratory. After catheterization, eligible patientswere randomized to PTCA alone or PTCA with stentplacement. Crossover to stent placement for a subop-timal PTCA result occurred in 15% of the patientswho underwent PTCA. Stents were used in 162 of 388registry patients who underwent coronary interven-tion. Abciximab was used in 5.2% of patients.

Clinical and angiographic follow-up: Clinical fol-low-up was obtained by nurse coordinators at 1 and 6months and during any interim hospitalizations. Pro-tocol angiographic follow-up was obtained in 689 of900 randomized patients (77%) at 6.5 months. Corelaboratory analysis of acute and 6-month cine angio-grams were performed by the Washington HospitalCenter, Washington, DC, and Cardialysis, Rotterdam,The Netherlands. Coronary reperfusion was gradedaccording to the Thrombolysis In Myocardial Infarc-tion (TIMI) trial classification system on a scale of 0to 3.13 Left ventricular ejection fractions were calcu-lated from tracing contours of right anterior obliquecine angiograms using the area-length method withcorrection for the right anterior oblique projection.14

Definitions: Time to reperfusion was the time fromthe onset of symptoms until initial balloon inflation.Door to balloon time was the time from arrival in theemergency department until initial balloon inflation.Reinfarction was defined as recurrent chest pain asso-ciated with any secondary increase in creatinine ki-nase and the MB fraction above the lowest value withor without diagnostic electrocardiographic changes.Ischemic-driven target vessel revascularization wasdefined as the need for repeat percutaneous coronaryintervention of the target vessel or coronary bypasssurgery in patients with recurrent ischemic symptomsor abnormal functional testing.

Statistical analysis: Statistical comparisons of base-line, angiographic, and outcome variables were per-formed using the chi-square statistic for categorical

variables and Student’s unpaired t test and analysis ofvariance for continuous variables. A step-down mul-tiple logistic regression analysis was performed toassess the relation between predictor variables and 1-and 6-month mortality.

RESULTSBaseline variables by time to reperfusion (Table 1):

Median (25th and 75th percentiles) time to reperfusionand door to balloon times were 245 (180, 376) and113 (81, 162) minutes (Figures 1 and 2), respectively.Patients with shorter reperfusion times were younger,more likely to be men, and more likely to have ananterior infarction. In contrast, patients with longerreperfusion times were older, more likely to bewomen, diabetic, and have heart rates of �100 beats/min.

Clinical outcomes by time to reperfusion (Tables 2and 3): There were no significant differences in 1- or6-month mortality, ischemic-driven target vessel re-vascularization, disabling stroke, or the composite endpoint across the 4 categories of time to reperfusion.Reinfarction at 6 months was more frequent in thelater reperfusion groups. Longer time to reperfusion(�2 hours) was not a significant predictor of mortalityafter adjusting for differences in baseline variables bymultivariate analysis. When only patients with oc-cluded arteries (TIMI 0 to 1 flow) on initial angiog-raphy were considered, there were no differences in6-month mortality across the 4 categories of time toreperfusion (�2 hours [6.0%], 2 to �4 hours [5.5%],4 to �6 hours [5.3%], and �6 hours [5.9%], p �0.99).

Door to balloon time had little effect on 1- and6-month mortality (Table 3).

Angiographic variables by time to reperfusion (Table4): TIMI 3 flow was achieved in a high proportion ofpatients (89% to 92%), regardless of time to reperfu-sion. Six-month ejection fraction was higher in theearly reperfusion groups (�2 hours and 2 to 4 hours).Improvement in ejection fraction was higher in theearly (�2 hours) versus later (�2 hours) reperfusion

TABLE 1 Baseline Variables by Time to Reperfusion

Baseline Variable

Time to Reperfusion

p Value

�2 h(n � 73)(5.9%)

2 to �4 h(n � 518)

(42%)

4 to �6(n � 311)

(25%)

�6 h(n � 330)

(27%)

Age �70 yrs 12 (16.4%) 122 (23.6%) 91 (29.2%) 96 (29.1%) 0.04Age (yrs) (mean � SD) 60.2 � 11.4 59.9 � 12.3 61.9 � 12.9 61.0 � 12.7 0.12Women 14 (19.2%) 112 (21.6%) 93 (29.9%) 96 (29.1%) 0.01Diabetes mellitus 8 (11.0%) 70 (13.5%) 52 (16.7%) 68 (20.6%) 0.03Systemic hypertension 31 (43.7%) 213 (41.5%) 146 (47.1%) 162 (49.2%) 0.14Current smoker 38 (52.1%) 242 (46.7%) 134 (43.1%) 138 (41.8%) 0.28Prior coronary bypass surgery 4 (5.6%) 9 (1.7%) 11 (3.5%) 13 (4.0%) 0.13Prior myocardial infarction 14 (19.2%) 68 (13.3%) 42 (13.6%) 31 (9.5%) 0.10Anterior wall infarction 38 (52.1%) 202 (39.0%) 116 (37.3%) 164 (49.7%) 0.001Heart rate �100 beats/min 11 (15.5%) 85 (16.5%) 39 (12.6%) 71 (21.6%) 0.02Systolic blood pressure �100 mm Hg 13 (20.3%) 128 (25.7%) 84 (27.7%) 77 (24.2%) 0.58Stent use 38 (52.1%) 283 (54.5%) 173 (55.6%) 163 (49.2%) 0.37

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groups (12.3 � 12.3% vs 4.3 � 11.2%, p � 0.004);this remained true when only patients with a patentinfarct artery at 6 months were considered. Reocclu-sion of the infarct artery was more frequent with latereperfusion, and stenting did not appear to reduce theincidence of reocclusion in the latest reperfusiongroup (�6 hours). Longer time to reperfusion re-mained a significant predictor of reocclusion afteradjusting for other variables, including stent use, finalpercent diameter stenosis, and final TIMI flow (adjust-ed odds ratio of reocclusion from one category to thenext 1.63, 95% confidence interval 1.15 to 2.31; p �0.006).

Baseline variables and outcomes inpatients excluded from the study: Pa-tients enrolled in Stent PAMI butexcluded from this analysis (be-cause of no PTCA or missing reper-fusion time, n � 226) were signifi-cantly older, more often women,and had a higher incidence of previ-ous bypass surgery, diabetes, andheart rate of �100 beats/min thanpatients included in this study. Cor-respondingly, excluded patients hada higher 6-month mortality thanstudy patients (8.8% vs 4.5%, p �0.007).

DISCUSSIONImportance of time to treatment

for survival: comparisons with previ-ous studies: Time to reperfusion isimportant for survival with throm-bolytic therapy,4,7,8 but recent stud-ies suggest that time to reperfusionmay be less important with primaryPTCA. The large Second National

Registry of Myocardial Infarction(NRMI-2) Registry11 and the GlobalUse of Strategies to Open OccludedArteries in Acute Coronary Syn-dromes (GUSTO) IIb trial10 found nosignificant relation between total timeto reperfusion and early mortality.The Moses Cone Hospital Registryfound that mortality with primaryPTCA was lower when patients werereperfused within 2 hours, but after 2hours mortality was nearly constantwith increasing time to reperfusion.9

In patients without cardiogenicshock, time to reperfusion had littleeffect on mortality.15 In our study,which excluded patients with cardio-genic shock, time to reperfusion alsoappeared to have little effect on 1-and 6-month mortality. This re-mained true after adjusting for differ-ences in baseline variables.

There are several possible reasonswhy time to treatment may be less

important with primary PTCA than with thrombolytictherapy. First, TIMI 2 to 3 flow is achieved less oftenwith increasing time to treatment with thrombolytictherapy.16,17 In contrast, in this study and other studieswith primary PTCA,9 TIMI 3 flow was achieved in ahigh percentage of patients regardless of time to treat-ment. Second, in patients treated with thrombolytictherapy, mortality rates from myocardial rupture in-creased progressively with increasing time to treat-ment.18 In contrast, mortality rates due to myocardialrupture after primary PTCA are very low.19,20 Third,for reasons that are not clear, the GUSTO-1 trial found

FIGURE 1. Cumulative frequency curves of time from symptom onset to reperfusion.The median reperfusion time was 4 hours and 5 minutes, and 5.9% of patientsachieved reperfusion in <2 hours.

FIGURE 2. Cumulative frequency curves of door to balloon time. The median door toballoon time was 113 minutes and 33% of patients achieved door to balloon timesof <90 minutes.

CORONARY ARTERY DISEASE/IMPORTANCE OF TIME TO REPERFUSION WITH PRIMARY PTCA 1087

that the incidence of intracranial hemorrhage afterthrombolytic therapy increased with increasing time totreatment.7 The occurrence of intracranial hemorrhagewith primary PTCA is rare.21

Importance of door to balloon time: comparisonswith previous studies: Both the GUSTO IIb trial10 andthe NRMI-2 Registry11 found that longer door toballoon times were associated with increased mortal-ity despite finding no correlation between total reper-fusion time and mortality. This differs from our study,

which found no correlation between door to balloontimes and 1- or 6-month mortality. The reasons forthese differences are not clear but could be related todifferences in patient populations and differences inoperator and institutional experience with primaryPTCA.

Importance of early reperfusion for myocardialsalvage: Our data and data of other results both withprimary PTCA and thrombolytic therapy22–24 showthat maximum myocardial salvage is achieved when

TABLE 2 One- and Six-month Clinical Outcomes by Time to Reperfusion

Variable

Time to Reperfusion

p Value�2 h

(n � 73)2 to �4 h(n � 518)

4 to �6 h(n � 311)

�6 h(n � 330)

1 moDeath 3 (4.1%) 17 (3.3%) 11 (3.5%) 10 (3.0%) 0.97Reinfarction 0 (0%) 2 (0.4%) 5 (1.6%) 2 (0.6%) 0.28Ischemia driven targetVessel revascularization 5 (6.9%) 12 (2.3%) 8 (2.6%) 8 (2.4%) 0.16Disabling stroke 0 (0%) 4 (0.8%) 0 (0.%) 1 (0.3%) 0.51

6 moDeath 4 (5.5%) 24 (4.6%) 14 (4.5%) 14 (4.2%) 0.97Reinfarction 0 (0%) 7 (1.4%) 13 (4.2%) 10 (3.0%) 0.03Ischemia driven targetVessel revascularization 13 (17.8%) 59 (11.4%) 32 (10.3%) 38 (11.5%) 0.35Disabling stroke 0 (0%) 4 (0.8%) 1 (0.3%) 1 (0.3%) 0.77Composite 17 (23.3%) 85 (16.4%) 50 (16.1%) 56 (17.0%) 0.50

TABLE 3 One- and Six-month Mortality by Door to Balloon Time

Mortality

Door to Balloon Time (min)

p Value0 to �60(n � 165)

60 to �90(n � 242)

90 to �120(n � 283)

120 to �180(n � 302)

�180(n � 244)

1 mo 6 (3.6%) 12 (5.0%) 5 (1.8%) 14 (4.6%) 5 (2.0%) 0.146 mo 11 (6.7%) 15 (6.2%) 8 (2.8%) 17 (5.6%) 7 (2.9%) 0.12

TABLE 4 Acute and Six-month Angiographic Variables by Time to Reperfusion*

Variable

Time to Reperfusion

p Value�2 h 2 to �4 h 4 to �6 h �6 h

Initial TIMI 2–3 flow 21 (36.8%) 115 (31.4%) 76 (34.6%) 81 (35.7%) 0.67n � 57 n � 366 n � 220 n � 227

Final TIMI 3 flow 52 (91.2%) 336 (91.8%) 194 (89.0%) 208 (91.6%) 0.69n � 57 n � 366 n � 218 n � 227

Acute ejection fraction (mean � SD) 49.8 � 12.8 55.8 � 11.4 53.9 � 12.4 52.7 � 11.1 0.15n � 38 n � 288 n � 153 n � 180

6-mo ejection fraction (mean � SD) 62.5 � 12.6 60.5 � 11.4 56.2 � 12.4 56.5 � 11.4 0.001n � 31 n � 202 n � 133 n � 132

Improvement ejection fraction (mean � SD)† 12.3 � 12.3 4.3 � 11.3 3.5 � 12.3 4.6 � 10.1 0.14n � 25 n � 173 n � 95 n � 113

6-mo infarct artery reocclusion‡

Stent 1 (4.5%) 3 (1.8%)§ 2 (1.9%)� 10 (10.0%) 0.01n � 22 n � 163 n � 104 n � 100

No Stent 0 (0.0%) 11 (9.2%) 7 (9.7%) 12 (14.6%) 0.22n � 22 n � 119 n � 72 n � 82

Total 1 (2.3%) 14 (5.0%) 9 (5.1%) 22 (12.1%) 0.01n � 44 n � 279 n � 176 n � 182

*Core laboratory analysis, randomized patients.†Improvement in ejection fraction �2 hours 12.3 � 2.3% vs �2 hours 4.3 � 11.2%; p �0.004.‡TIMI 0 to 1 flow and �90% stenosis.§p � 0.005 versus no stent; �p � 0.03 versus no stent.

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reperfusion is established at �2 hours. After 2 hours,there is some recovery of left ventricular function, butthis is modest and appears not to be very dependent ontime to reperfusion. Unfortunately, in this and previ-ous studies,9–11 only 5% to 10% of patients with AMIpresent early enough to achieve reperfusion at �2hours to obtain maximum myocardial salvage.

Study limitations: Our study has several limitations.(1) Although Stent PAMI is the largest multicenterprimary PTCA trial published to date, the number ofpatients, especially in the very early reperfusiongroup, is relatively small. Consequently, the confi-dence intervals for mortality are wide and the power todetect differences in mortality between reperfusiontime groups is limited. (2) This is an observationalstudy and there may be unrecognized differences inbaseline variables across the 4 categories of time toreperfusion that are not adjusted for by multivariateanalysis. (3) The Stent PAMI protocol excluded pa-tients with cardiogenic shock, and the results of thisstudy should not be applied to patients with shock.The Should We Emergently Revascularize OccludedCoronary arteries for Cardiogenic Shock? (SHOCK)trial25 and the Moses Cone Hospital Registry15 foundthat mortality increased with increasing time to treat-ment in patients with shock. (4) In patients with TIMI2 to 3 flow on initial angiography, reperfusion oc-curred before balloon inflation and the actual reperfu-sion time is unknown. However, when only patientswith initial TIMI 0 to 1 flow were considered in ourstudy, mortality was still independent of time to reper-fusion.

Clinical implications: The data from this and otherstudies9 indicating that time to reperfusion does notappear to have a major effect on mortality suggest thatthe survival benefit of primary PTCA may be relatedto factors other than myocardial salvage. The highrates of TIMI 3 flow after primary PTCA, regardlessof time to treatment, suggest that an open artery, ratherthan time to reperfusion, may be the primary determi-nate of survival after reperfusion therapy for AMI.

Reocclusion of the infarct artery occurred morefrequently with late reperfusion, and stents did notappear to have much impact on preventing reocclusionin the latest reperfusion group (�6 hours). The higherincidence of reocclusion and reinfarction with latereperfusion may be related to worse reperfusion at themicrovascular level,26 which may predispose to latereocclusion.

Our results could have implications regarding thetriage of patients for mechanical reperfusion. Becausetime to reperfusion does not appear to have a majorimpact on clinical outcomes, the time delay in trans-ferring patients from community hospitals to interven-tional facilities for mechanical reperfusion may not beprohibitive. Several studies suggest that this may betrue. The Zwolle Group found that patients with AMIwho transferred from community hospitals to a pri-mary PTCA center had similar clinical outcomes com-pared with patients who presented locally, despite a43-minute treatment delay.27 The randomized AIRPAMI Trial28 and the PRAGUE Trial29 found supe-

rior outcomes in patients with AMI transferred forprimary PTCA compared with patients treated withthrombolytic therapy at local hospitals. Recently,there has been a great deal of interest in the combineduse of pharmacologic therapy given acutely followedby mechanical reperfusion (facilitated percutaneouscoronary intervention) in an attempt to minimize theinherent time delay with mechanical reperfusion.Whether the potential benefits of facilitated percuta-neous coronary intervention will outweigh the in-creased bleeding risks and increased costs will need tobe determined in ongoing randomized trials.

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