Relation of Time to Treatment andMortality in Patients With Acute

Myocardial Infarction UndergoingPrimary Coronary Angioplasty

David Antoniucci, MD, Renato Valenti, MD, Angela Migliorini, MD, Guia Moschi, MD,Maurizio Trapani, MD, Piergiovanni Buonamici, MD, Giampaolo Cerisano, MD,

Leonardo Bolognese, MD, and Giovanni Maria Santoro, MD

The benefit of thrombolysis is dependent on time totreatment, but there is lack of evidence of this relation inpatients undergoing primary percutaneous transluminalcoronary angioplasty (PTCA). The hypothesis that therelation of time to treatment to mortality is dependent onpatient risk was tested in a series of 1,336 patients whounderwent successful primary PTCA and were stratifiedinto low-risk and not low-risk patient groups ac-cording to the Thrombolysis In Myocardial Infarctioncriteria. After stratification, 942 patients (71%) were atnot low risk, and 394 (29%) were at low risk. The6-month mortality rate was 9.3% for not low-risk pa-tients and 1.3% for low-risk patients (p

Treatment protocol: From January 1995 to March1997, our institution used provisional stenting for non-optimal angiographic results after conventionalPTCA; in April 1997, the institution began a policy ofsystematic primary infarct artery stenting in all pa-tients with AMI and a reference vessel diameter 2.5mm. Patients were routinely treated with aspirin (325mg/day indefinitely) and ticlopidine (500 mg/day for 2months). The use of abciximab was at the discretion ofthe operator; however, since 1999 its use has beenstrongly encouraged. Creatine kinase measurementswere systematically performed on admission and ev-ery 3 hours for the subsequent 24 hours, and thenevery 12 hours for 2 days. The peak value of creatinekinase and the time to peak creatine kinase wereestimated for each patient.

Angiographic analysis: Coronary flow in the infarctartery was graded according to the TIMI study groupclassification.5 Collateral flow before PTCA wasgraded using the classification developed by Rentropet al.6 Quantitative coronary angiography was per-formed with the use of an automatic edge detectionsystem (Siemens Ancor, Solna, Sweden). Coronaryocclusion was assigned a value of 0 mm for minimalluminal diameter and 100% for percent diameter ste-nosis. An optimal angiographic result was defined as

residual stenosis 30% associatedwith TIMI grade 3 flow. A subopti-mal result was defined as a TIMIgrade 2 flow or a residual stenosis30%. An unsuccessful procedurewas defined as procedure resulting inTIMI grade 0 or 1 flow, regardless ofthe residual stenosis.

Follow-up: Patients demographic,procedural, and follow-up data werecollected and stored in a prospectivedatabase. The following clinicalevents were considered: death, rein-farction, and repeat target lesion re-vascularization within 6 months ofinitial revascularization. Patientswith 1 event were assigned thehighest ranked event according to theprevious list. Recurrent ischemia wasdefined as ischemic chest pain witheither new ST-segment or T-wavechanges at rest or on exercise testing.Reinfarction was defined as recurrentchest pain with ST-segment or T-wave changes and recurrent eleva-tion of cardiac enzymes. Repeat tar-get vessel revascularization was de-fined as PTCA or coronary surgeryperformed due to restenosis or reoc-clusion of the target lesion in associ-ation with objective evidence ofischemia or viable myocardium.

Statistical analysis: Categoricaldata are presented as absolute valuesand percentages, whereas continuousdata are listed as mean value SD.

A 2-tailed Students t test or 1-way analysis of vari-ance were used to test differences among continuousvariables, whereas categorical variables were com-pared by chi-square analysis or Fishers exact test.The contribution of clinical, angiographic, and proce-dural variables to the clinical outcome was evaluatedwith multivariate analysis by the foreward stepwiseCox regression proportional hazards model. The oddsratio (OR) and 95% confidence intervals (CIs) werecalculated. The variables used for the analysis in-cluded age, gender, diabetes mellitus, previous myo-cardial infarction, anterior AMI, cardiogenic shock,multivessel disease, time to reperfusion as a continu-ous variable, infarct artery stenting, abciximab treat-ment, preprocedure TIMI grade flow 1, and collat-eral flow to the infarct artery. Survival curves weregenerated using the Kaplan-Meier method. Compari-son between survival curves was performed using thelog-rank test. A p value 0.05 was considered signif-icant. Statistical tests were performed using the SPSS7.0 software package (SPSS Inc., Chicago, Illinois).

RESULTSPatients and procedural results: Between January

1995 and October 2000, 1,362 consecutive patientswith AMI underwent primary mechanical interven-

TABLE 1 Patient Characteristics

Low RiskNot Low

Riskp Value(n 394) (n 942)

Age (yrs) 56 8 67 12 0.00170 yrs 0 465 (49%) 0.001

Women 49 (12%) 249 (26%) 0.001Systemic hypertension 121 (31%) 332 (35%) 0.110Total serum cholesterol 200 mg/dl 134 (34%) 230 (24%) 0.001Diabetes mellitus 39 (10%) 151 (16%) 0.003Anterior wall AMI 0 686 (73%) 0.001Previous MI 38 (10%) 120 (13%) 0.110Heart rate 100 beats/min 0 192 (20%) 0.001Cardiogenic shock 4 (1%) 158 (17%) 0.001Infarct artery 0.001

Left anterior descending 0 670 (71%)Right 279 (71%) 196 (21%)Circumflex 115 (29%) 60 (6%)Left main 0 16 (2%)

Collateral flow Rentrop grade 1 94 (24%) 189 (20%) 0.121Chronic occlusion 28 (7%) 139 (15%) 0.001Multivessel coronary disease 176 (45%) 482 (51%) 0.030Time from symptom onset to admission (h) 2.4 1.4 2.9 2.1 0.001

TABLE 2 Baseline Characteristics by Time to Reperfusion of Not Low-Risk Patients

Hours

p Value02 24 46 6

(n 104) (n 470) (n 272) (n 96)

Age (yrs) 65 12 66 12 68 12 68 13 0.020Women 28 (27%) 116 (25%) 74 (27%) 31 (32%) 0.469Diabetes mellitus 15 (14%) 74 (16%) 42 (15%) 20 (21%) 0.584Anterior wall AMI 81 (78%) 347 (74%) 186 (68%) 72 (75%) 0.584Previous MI 18 (17%) 47 (10%) 44 (16%) 11 (11%) 0.043Cardiogenic shock 17 (16%) 67 (14%) 60 (22%) 14 (15%) 0.048

CORONARY ARTERY DISEASE/TIME TO TREATMENT AND PRIMARY PTCA 1249

tion. Of these, 26 (2%) had an unsuccessful procedureand were excluded from the analysis, whereas 1,336patients had successful procedures. Of the 1,336 pa-tients with successful procedures, 942 (71%) were atnot low risk, and 394 (29%) were at low risk. Thebaseline characteristics of the 2 groups are listed inTable 1. The not low-risk patients were a mean age of67 12 years; 73% had an anterior AMI and 20% hadan heart rate100 beats/min on admission. Except forage, location of AMI, and heart rate at admission, the2 groups differed in several ways, with a greaterincidence of women, diabetes, multivessel disease,chronic occlusion, and cardiogenic shock in the notlow-risk group. The mean time from onset of chestpain to hospital arrival was shorter for the low-riskpatients compared with the not low-risk patients (2.4 1.4 vs 2.9 2.1 hours, respectively; p 0.001).Patients were not uniformly distributed with respect tothe different intervals from symptom onset to treat-ment. Most patients (70%) were treated between 2 and6 hours, and the higher patient concentration wasbetween 2 and 4 hours. Moreover, among not low-riskpatients, significant differences in risk profile wereassociated with increasing time to treatment (Table 2).Patients with longer time to treatment were older andhad a greater incidence of cardiogenic shock, whereaspatients with a history of myocardial infarction hadshorter time to treatment. Table 3 lists the proceduralresults. The delay from admission to the catheteriza-tion laboratory was similar for the 2 groups (21 15and 20 17 minutes, respectively; p 0.695),whereas the procedural time (from arrival at the cath-eterization laboratory to the end of the procedure) wasslightly longer in the not low-risk group (35 17 vs

32 18 minutes, respectively; p0.001). Overall, the time to reper-fusion was longer for the not low-risk group compared with the low-risk group (3.9 2.1 vs 3.3 1.7hours, respectively; p 0.001).There were no differences in the in-cidence of stenting procedures, butmore low-risk patients received ab-ciximab. As expected, peak creatinekinase values were higher in the notlow-risk group (2,741 2,400 vs1,812 1,342 U/L, respectively; p0.001).

Clinical outcome: Table 4 lists the6-month clinical outcome. The mor-tality rate was 9.3% in the not low-

risk group and 1.3% in the low-risk group (p0.001).There were no differences in reinfarction or targetvessel revascularization rates between the 2 groups.Figure 1 depicts the survival curves. The 6-monthsurvival rate was 89 1% for the not low-risk groupand 99 1% for the low-risk group (p 0.001).Unadjusted mortality of the not low-risk patients in-creased from 4.8% to 12.9% with increasing time toreperfusion (up to 6 hours) and did not increase furtherbeyond 6 hours, whereas mortality of the low-riskgroup was very low and remained constant with in-creasing time to reperfusion (Figure 2). For the notlow-risk group, the univariate analysis revealed a re-lation between time to treatment and mortality (OR1.35, 95% CI 1.06 to 1.73; p 0.017). However, timeto reperfusion was not an independent predictor ofmortality at multivariate analysis; the only indepen-dent variables were age (OR 1.05, 95% CI 1.03 to1.07, p 0.001), diabetes mellitus (OR 1.84, 95% CI1.15 to 2.94, p 0.011), and cardiogenic shock (OR8.10, 95% CI 5.29 to 12.39, p 0.001).

DISCUSSIONIn our study the relation of time to treatment with

mortality is evident for not low-risk patients, whereasit is lacking for the low-risk patient subset. Thesenumbers may be easily explained considering that thebenefit of treatment is strongly related to patient risk,and it is very difficult or even impossible to show abenefit of a reperfusive treatment for patients with avery low risk of death. For not low-risk patients,mortality increased with longer time to treatment andunivariate analysis showed that time to treatment wasrelated to mortality. However, in the multivariate anal-ysis, time to treatment did not emerge as an indepen-dent predictor of death. A potential explanation ofthese results is the worse patient risk profiles, whichwere associated with a longer delay to treatment.Late-presenting patients were older and were morelikely to be in cardiogenic shock compared with early-presenting patients. Age and cardiogenic shock arestrongest predictors of mortality and may obscure theincremental prognostic value provided by the time totreatment variable. The nonuniform distribution of thepatient risk profile by different intervals from symp-

TABLE 3 Procedural Characteristics

Low Risk(n 394)

Not Low Risk(n 942) p Value

Door-to-balloon time (min) 21 15 20 17 0.695Procedural time (min) 32 18 35 17 0.001Time from symptom onset to reperfusion (h) 3.3 1.7 3.9 2.1 0.001Infarct artery stenting 295 (75%) 730 (77%) 0.301Multiple stents 60 (20%) 185 (25%) 0.058Intra-aortic balloon counterpulsation 9 (2%) 145 (15%) 0.001Abciximab administration 110 (28%) 205 (22%) 0.016Preprocedural TIMI grade flow 01 324 (82%) 749 (80%) 0.254Postprocedure minimum lumen diameter

(mm)3.15 0.52 3.11 0.47 0.165

Peak creatine kinase (U/L) 1,812 1,342 2,741 2,400 0.001Time-to-peak creatine kinase (h) 7.9 4.4 7.3 4.2 0.019

TABLE 4 Six-Month Clinical Outcome

Low Risk(n 394)

Not LowRisk

(n 942) p Value

Death 5 (1.3%) 88 (9.3%) 0.001Reinfarction 3 (0.7%) 17 (1.7%) 0.152Target vessel revascularization 51 (13%) 134 (14%) 0.537Composite 59 (15%) 239 (25%) 0.001

1250 THE AMERICAN JOURNAL OF CARDIOLOGY VOL. 89 JUNE 1, 2002

tom onset to treatment, as revealed in this series ofpatients, and the relatively small sample populationmay explain why time to treatment did not emerge asan independent predictor of mortality. Thus, the ef-fects of other variables associated with a longer delayfrom symptom onset to admission may have a strongerimpact on mortality and overcome the power of timeto treatment as an independent variable in multivariateanalysis.

The data of our study are not consistent with thosefrom a series of 1,352 patients reported by Brodie etal.1 In this study, early mortality was significantlylower in the small group of patients reperfused within2 hours from symptom onset, whereas it was higherand fairly constant in the later reperfusion groups(4.3% and 9.0% to 9.5% respectively, p 0.04).However, the investigators did not stratify patientsaccording to the risk of death, and the overall popu-lation was younger compared with our series of pa-

tients (age ranged from 58.8 to 60.8years). Similar results were ob-tained by the the Primary Angio-plasty in Acute Myocardial Infarc-tion (PAMI) investigators in thestent cohort (American College ofCardiology, 48th Scientific Session,New Orleans, 1999). In this trial,which included 849 patients, a verylow-risk population was enrolled,and 1-month mortality was verylow and relatively constant with in-creasing time to reperfusion (from1.8% to 2.7%). A relation betweenmortality and time to treatment wasalso not observed in the Second Na-tional Registry of Myocardial In-farction, which collected data on27,080 consecutive patients withAMI who were treated with primaryPTCA.3 The median time fromsymptom onset to hospital arrivalwas 1.6 hours, and the median timefrom symptom onset to treatmentwas 3.9 hours. Thus, the Registryrevealed that in current clinicalpractice the door-to-balloon timewas longer than the delay fromsymptom onset to admission. Al-though unadjusted mortality washigher in the patients treated later,the multivariate-adjusted odds ofin-hospital mortality did not in-crease over the 24-hour period. Thislack of evidence may be explainedin several ways. It has been hypoth-esized that because it is differentfrom thrombolytic treatment, pri-mary PTCA allows successful in-farct artery flow restoration also inlate-presenting patients, and the ef-ficacy of PTCA in opening an oc-cluded infarct artery is not depen-

dent on time to treatment. Moreover, an open infarctartery, even if open too late for myocardial salvage,may result in survival benefit by preventing ventricu-lar remodeling and electrical instability.7 Another ex-planation may be based on a survivor-cohort effect,because late-presenting patients have survived the firsthigh-risk hours from AMI onset. Finally, the assess-ment of the time to treatment is not a precise mea-surement because it depends on subjective patientrecall. Beyond these hypotheses, several issues shouldbe addressed to put the results of the Registry inproper perspective. This large cohort of patients maybe considered at low risk. Overall, according to TIMIcriteria, slighty more patients who received thrombol-ysis were judged to be at high risk than those whounderwent PTCA (54% vs 46%). The incidence ofcardiogenic shock was very low (3.7%) and the over-all mortality was 6.1%. Mortality was not indepen-detly related to time to treatment, but it was related to

FIGURE 1. Kaplan-Meier curves for survival in low- and not low-risk patients.

FIGURE 2. Six-month mortality by time to reperfusion in low- and not low-risk patients.

CORONARY ARTERY DISEASE/TIME TO TREATMENT AND PRIMARY PTCA 1251

the door-to-balloon time and to the institutional vol-ume. The median door-to-balloon time was 1 hour 56minutes, and only 8% of patients had a door-to-bal-loon time of60 minutes. The door-to-balloon time isa good indicator of quality of care and is related tomortality, and it is likely that the impact on mortalityof the abnormally long door-to-balloon time in theNational Registry cohort prevailed that of the symp-tom onset-to-treatment time. Similar results were re-ported by the Global Use of Strategies to Open Oc-cluded Arteries in Acute Coronary Syndromes (GUS-TO-IIb) Investigators for the cohort of 565 patientsrandomized to primary PTCA.2 Mortality was relatedto the time from randomization to first balloon infla-tion (the median time from study enrollment to reper-fusion was 76 minutes, and only 18% of patients weretreated 60 minutes after study enrollment), but notto the time from symptom onset to PTCA. Moreover,16% of patients did not undergo PTCA. The mortalityrate was 1% in the small subset of patients treated60 minutes after study enrollment, and progres-sively increased with the increase of the delay fromrandomization to treatment. Thus, the quality of theprimary PTCA procedures, as assessed by the timefrom randomization to balloon inflation, had a preem-inent impact on mortality.

Most of the confounding effects on mortality in theNational Registry and in the GUSTO-IIb trial wereavoided in our study. This single-center experienceincluded all consecutive unselected patients who wereadmitted to our center without any restriction based onage or clinical status on presentation. The direct ad-mission from home to the catheterization laboratory,bypassing the emergency room or the coronary careunit for most patients, allowed for a very short door-to-balloon time.8,9 All patients were treated with the

same standards of care. Moreover, by stratifying pa-tients according to TIMI criteria, it was possible toshow an increased mortality based on time to treat-ment in patients at not low risk. Nevertheless, strati-fication by time categories of not low-risk patientsshowed that late-presenting patients had a worse riskprofile that prevented time to reperfusion from becom-ing an independent predictor of mortality in thisreatively small sample of patients.

1. Brodie BR, Stuckey TD, Wall TC, Kissling G, Hansen CJ, Muncy DB,Weintraub RA, Kelly TA. Importance of time to reperfusion for 30-day and latesurvival and recovery of left ventricular function after primary angioplasty foracute myocardial infarction. J Am Coll Cardiol 1998;32:13121319.2. Berger PB, Ellis SG, Holmes DR, Granger CB, Criger DA, Betriu A, Topol EJ,Califf RM. Relationship between delay in performing direct coronary angioplastyand early clinical outcome in patients with acute myocardial infarction. Resultsfrom the Global Use of Strategies to Open Occluded Arteries in Acute CoronarySyndromes (GUSTO IIb) trial. Circulation 1999;100:1420.3. Cannon CP, Gibson CM, Lambrew CT, Shoultz DA, Levy D, French WJ, GoreJM, Weaver WD, Rogers WJ, Tiefenbrunn AJ. Relationship of symptom-onset-to-balloon time and door-to-balloon time with mortality in patients undergoingangioplasty for acute myocardial infarction. JAMA 2000;283:29412947.4. The TIMI Study Group. Comparison of invasive and conservative strategiesafter treatment with intravenous tissue plasminogen activator in acute myocardialinfarction: results of the Thrombolysis in Myocardial Infarction (TIMI) Phase IITrial. N Engl J Med 1989;320:618627.5. The TIMI Study Group. The Thrombolysis in Myocardial Infarction (TIMI)Trial: phase 1 findings. N Engl J Med 1985;312:932936.6. Rentrop KP, Cohen M, Blanke H, Phillips RA. Changes in collateral fillingimmediately after controlled coronary artery occlusion by an angioplasty balloonin human subjects. J Am Coll Cardiol 1985;5:587592.7. Braunwald E. Myocardial reperfusion, limitation of infarct size, reduction ofleft ventricular dysfunction, and improved survival: should the paradigm beexpanded? Circulation 1989;79:441444.8. Antoniucci D, Valenti R, Santoro GM, Bolognese L, Trapani M, Moschi G,Fazzini PF. Systematic direct angioplasty and stent-supported direct angioplastytherapy for cardiogenic shock complicating acute myocardial infarction: in-hospital and long-term survival. J Am Coll Cardiol 1998;31:294300.9. Antoniucci D, Valenti R, Santoro GM, Bolognese L, Trapani M, Moschi G,Fazzini PF. Primary coronary infarct artery stenting in acute myocardial infarc-tion. Am J Cardiol 1999;84:505510.

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Relation of Time to Treatment and Mortality in Patients With Acute Myocardial Infarction Undergoing Primary Coronary AngioplastyMETHODSPatientsTreatment protocolAngiographic analysisFollow-upStatistical analysisRESULTSPatients and procedural resultsClinical outcomeDISCUSSION