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Comparison of Mortality Benefit of Immediate Thrombolytic Therapy VersusDelayed Primary Angioplasty for Acute Myocardial Infarction

David M. Kent, MD, MSa,*, Robin Ruthazer, MPHa, John L. Griffith, PhDa,Joni R. Beshansky, RN, MPHa, Cindy L. Grines, MDb, Thomas Aversano, MDd,

Thomas W. Concannon, PhDa, Robert J. Zalenski, MDc, and Harry P. Selker, MD, MSPHa

Primary percutaneous coronary intervention (PPCI) yields superior mortality outcomescompared with thrombolysis in ST-elevation acute myocardial infarction (STEMI) buttakes longer to administer. Previous meta-regressions have estimated that a procedure-related delay of 60 minutes would nullify the benefits of PPCI on mortality. Using acombined database from randomized clinical trials and registries (n � 2,781) and anindependently developed model of mortality risk in STEMI, we developed logistic regres-sion models predicting 30-day mortality for PPCI and thrombolysis by examining theinfluence of baseline risk on the treatment effect of PPCI and on the hazard of treatmentdelay. We used these models to solve mathematically for “time interval to mortalityequivalence,” defined as the PPCI-related delay that would nullify its expected mortalitybenefit over thrombolysis, and to explore the influence of baseline risk on this value. Asbaseline risk increases, the relative benefit of PPCI compared with thrombolytic therapysignificantly increases (p � 0.002); patients with STEMI at relatively low risk of mortalityaccrue little or no incremental mortality benefit from PPCI, but high-risk patients benefitgreatly. However, as baseline risk increases, the hazard associated with longer treatment-related delay also increases (p � 0.007). These 2 effects are compensatory and yield aroughly uniform time interval to mortality equivalence of �100 minutes in patients whohave at least a moderate degree of mortality risk (>�4%). In conclusion, the mortalitybenefits of PPCI and the hazard of PPCI-related delay depend on baseline risk. Previousmeta-regressions appear to have underestimated the PPCI-related delay that would nullifythe incremental benefits of PPCI. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol

2007;99:1384–1388)

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his study estimated the influence of primary percutaneousoronary intervention (PPCI)-related delay on PPCI-relatedortality benefit using individual patient-level data, taking

nto account the influence of baseline mortality risk on theegree of benefit and the hazard of treatment delay inatients with ST-elevation acute myocardial infarctionSTEMI). To do this, we used the multivariable thrombo-ytic predictive instrument (TPI)1 to estimate the baselineortality risk in patients in a combined database, including

hrombolysis- and PPCI-treated patients and developed aathematic model predicting mortality based on baseline

isk, mode of reperfusion (PPCI or thrombolysis), and delayo treatment.

aCenter for Cardiovascular Health Services Research, Institute for Clin-cal Research and Health Policy Studies, Tufts–New England Medicalenter, Tufts University School of Medicine, Boston, Massachusetts; bDi-ision of Cardiology, Department of Medicine, William Beaumont Hos-ital, Royal Oak, and cDepartment of Emergency Medicine, Wayne Stateniversity School of Medicine, Detroit, Michigan; and dDivision of Car-iology, Department of Medicine, Johns Hopkins Hospital, Baltimore,aryland. Manuscript received September 21, 2006; revised manuscript

eceived and accepted December 21, 2006.This research was supported by Grants R01 HS10280 from AHRQ,

ockville, Maryland, and K23 NS044929 from the National Institutes ofealth, NINDS, Bethesda, Maryland.

*Corresponding author: Tel: 617-636-3234; fax: 617-636-8023.

cE-mail address: dkent1@tufts-nemc.org (D.M. Kent).

002-9149/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved.oi:10.1016/j.amjcard.2006.12.068

ethods and Results

ased on TPI project methods,1,2 we assembled a largeombined database of patients with STEMI treated withhrombolytic therapy or PPCI from the TPI Trial,3 the Acuteardiac Ischemia Time-Insensitive Predictive Instrument

ACI-TIPI) Trial,4 the Primary Angioplasty in Myocardialnfarction (PAMI) Study,5 the PAMI-2 Study,6,7 the AirAMI Study,8 the PAMI No-Surgery On Site (No-SOS)rial,9 and the Myocardial Infarction Triage and Interven-

ion (MITI) Registry.10,11 All these included only reperfu-ion-eligible patients with STEMI except the ACI -TIPIrial and the MITI Registry, from which we included onlyatients with STEMI, all of whom received thrombolyticherapy (220 and 533, respectively). For patients in theAMI (n � 395) and Air PAMI (n � 127) databases, trialsf PPCI versus thrombolytic therapy, reperfusion type usedas by random assignment; in the TPI Trial (n � 1,193),

eperfusion type was determined by the treating physician87% received thrombolytic therapy). Databases fromAMI-2 (n � 1,100) and No-SOS (n � 401) included onlyatients treated with PPCI.

To have lead-by-lead electrocardiographic variables assed by the TPI to predict mortality risk, only patients forhom these variables were available were included in thenal database. Electronic lead-by-lead electrocardiographicariables (n � 1,526) or hard copies of presenting electro-

ardiograms (ECGs; n � 2,061), which were each subse-

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1385Coronary Artery Disease/Immediate Thrombolysis Versus Delayed PPCI

uently coded by 1 of 4 physician readers, were availableor all but 9.6% of patients (n � 382). The combinedatabase thus contained 3,587 patients with complete elec-rocardiographic information.

After excluding patients with any missing variables forge, gender, diabetes, blood pressure, type of treatmentPPCI or thrombolytic therapy), time durations for symptomnset to presentation or presentation to treatment time, theatabase contained 3,006 patients. Seventy-eight percent ofhese subjects had times for symptom onset to ECG andCG to treatment. For the remaining 22% (658 patients), forhom only symptom onset-to-door and door-to-treatment

imes were available, we imputed time of electrocardiogra-hy by using the median door-to-ECG time for their studyf origin.

During modeling, a paradoxic negative correlation withortality was seen for ECG-to-treatment times �2.5 hours;

.e., very long delays to treatment appeared to be protective,ot harmful. The small number of deaths in this group withxtreme delays was believed to be due to a selection biasreviously described in other contexts.12 Accordingly, wexcluded patients with ECG-to-treatment times �2.5 hoursn � 225). Characteristics of the 2,781 patients used forodel development are presented in Table 1.To predict mortality with thrombolysis or PPCI, we

tarted with the 30-day mortality model of the TPI. This isvalidated logistic regression equation that incorporates theariables age (truncated at 75 years), initial systolic bloodressure, history of diabetes, heart rate, number of leadsith ST-segment elevation, amount of ST-segment eleva-

ion, leads with abnormal Q waves without ST elevation,nterior wall or posterior wall acute infarction, right bundleranch block, thrombolytic therapy, and time from symp-om onset to ECG. The model, including important interac-ion terms, is described in more detail in the original report.1sing the TPI mortality risk allowed us to incorporate

able 1atient characteristics

haracteristic (unit) Development(n � 2,781)

ge (yrs) 61 � 12.0en 2,006 (72.1%)

ystolic blood pressure (mm Hg) 128 � 33iastolic blood pressure (mm Hg) 83 � 18 (1,509)eart rate (beats/min) 76 � 20ours from symptoms to ECG* 1.82 (1.12–3.13)ours from symptoms to therapy* 2.93 (2.10–4.33)ours from ECG to thrombolytic therapy(thrombolysis)*

06.0 (0.40–1.00)

ours from ECG to PCI* 1.50 (1.10–1.90)iabetes mellitus 418 (15.0%)istory of hypertension 1,216/2,749 (44.2%)istory of stroke 39/1,208 (3.2%)nterior wall acute myocardial infarction 1,146 (41.2%)ight bundle branch block 147 (5.3%)0-d mortality 109 (3.9%)ntracranial hemorrhage 21/2,609 (0.8%)reated with PCI 1,153 (41.5%)

* Values provided as medians (interquartile ranges).

ultiple prognostically important variables into a single w

ummary score for a parsimonious model and allowed us toest the influence of mortality risk on treatment effect ofPCI and on risks of treatment delay.

To ensure that mortality risk was accurately captured byhe TPI model, we tested each variable of the TPI equation.onfident that mortality risk was accurately represented, wedded a variable for PPCI treatment and a variable forCG-to-treatment time, the main subjects of the presenttudy.

In addition to these main effects, based on a priori hy-otheses, we tested for specific interactions: (1) interactionf PPCI treatment with TPI-predicted risk (to test if theelative benefit of PPCI depended on the patient’s baselineisk), (2) interaction of PPCI treatment with ECG-to-treat-ent time (to test whether treatment delay had a different

ffect depending on mode of reperfusion), (3) interaction ofymptom onset-to-ECG and ECG-to-treatment times (to testhether treatment delay had a different effect early or late

n the course of STEMI), and (4) interaction of TPI risk withCG-to-treatment time (to explore whether delays to ther-py had a different effect on patients with different levels ofisk, as suggested by a prior study13).

We checked for consistency of effects for all includedariables in the final model across each study database andvaluated for clustering within study databases using gen-ralized estimating equations.

Once the models predicting outcome with PPCI andhrombolysis were complete, we used this equation for eachatient to determine mathematically the ECG-to-balloonime for PPCI that would yield a mortality risk identical tohat patient’s predicted mortality with thrombolysis (at 30inutes). We called this ECG-to-balloon time the “time

nterval to mortality equivalence” (TIME). We then exam-ned how this value was affected by baseline mortality risk.

Because treatments were not randomized in some con-ributing studies, patients receiving PPCI may not be strictlyomparable to patients receiving thrombolytic therapy. Be-ause we assumed that the PPCI-related delay that nullifieshe mortality benefits of PPCI would be sensitive to thestimated treatment effect of PPCI, the following precau-ions were used. First, we adjusted for baseline mortalityisk using the validated TPI mortality predictions. This

igure 1. Mortality outcomes for PCI and thrombolysis in the combinedatabase are divided into equal-sized quartiles according to their TPI-redicted mortality risk. As this predicted risk increases, degree of benefitith PCI compared with thrombolytic therapy (TT) also increases.

ould ensure that PPCI-treated patients and thrombolysis-

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1386 The American Journal of Cardiology (www.AJConline.org)

reated patients of similar baseline risk were being com-ared with each another. Second, we adjusted for any otherariables that might affect mortality risk. Third, we per-ormed a sensitivity analysis by standardizing the modelsing only subjects from the randomized trials (from PAMInd Air PAMI), representing �15% of all patients. Thisdjusted the coefficients to more closely reflect outcomes inhese trials.

Outcomes in patients treated with PPCI and those withhrombolysis at different levels of TPI-predicted mortalityisk are shown in Figure 1. Only high-risk patients appearedo accrue a mortality benefit from PPCI. Unadjusted forther variables, this risk by treatment effect was significant

igure 2. Mortality with PCI with different delays to therapy comparedith immediate thrombolytic therapy. A patient’s baseline mortality risk,

ssuming treatment with thrombolytic therapy at 30 minutes (x axis), isresented. A 70-year-old patient’s expected mortality with PCI at differentCG-to-needle times for a given baseline risk (multiple solid lines) isisplayed, with prediction intervals (gray areas). Patients at low riskbaseline mortality risk �5%) have similar mortality outcomes regardlessf delay. When delay to therapy is short (e.g., ECG-to-needle time �90inutes), the degree of benefit increases with increasing baseline risk.owever, when delay to therapy is longer (e.g., ECG-to-needle time 150inutes), increasing baseline risk is associated with a higher probability of

arm. At an ECG-to-needle time of �130 minutes (representing a PCI-elated delay of �100 minutes compared with thrombolysis), mortalityutcomes are expected to be roughly similar with either form of reperfu-ion across the spectrum of baseline risk. Abbreviation as in Figure 1.

able 2redictive equation for 30-day mortality with percutaneous coronary inter

ariable

nterceptatient age (yrs)PI-computed mortality risk* (logit)eperfusion method1 if angioplasty0 if thrombolytic therapyime (h) from ECG until reperfusion (until balloon or needle)reatment-by-risk interaction: reperfusion method by TPI-computed mortime-by-risk interaction: hours from ECG until reperfusion by TPI-comp

* Logit of 30-day mortality component.1 Variables included in this risk† The p values are from coefficients before being adjusted with a slope

ubset of randomized trials in the derivation data.

t p � 0.05. p

Table 2 presents the mathematic model predicting mor-ality from STEMI if treated with PPCI or with throm-olytic therapy as derived on the entire dataset and astandardized to the randomized subset. The most impor-ant variable in the predictive model is TPI mortality risk.he only variable included in that risk score that benefitedy any further adjustment in effect was age, related at leastn part to this variable being truncated at 75 years in the TPIodel. The only additional primary variables were those

hat were the subjects of our study: the differential treatmentffect of PPCI compared with thrombolysis and ECG-to-reatment time.

There were 2 significant interaction terms. The interac-ion between PPCI treatment and TPI risk score indicatedhat as mortality risk increased, PPCI was more effective inecreasing mortality (i.e., high-risk patients received moreelative benefit from PPCI). This effect was stronger in theully adjusted model (p � 0.002) than the model shown inigure 1. In addition, there was a positive interaction be-

ween mortality risk and ECG-to-treatment time (p �.007), indicating that as risk increases, the effects of treat-ent delay increases (i.e., outcomes in higher risk patients

re more sensitive to treatment delays than lower risk pa-ients). We did not find that time from presentation toreatment influenced the relative benefits of PPCI comparedith thrombolysis or the effect of treatment delay. Resultsere unaffected when generalized estimating equationsere used to account for within-trial clustering. The goodiscrimination of the model was reflected by a receiver-perating characteristic area of 0.82.

When these 2 interaction effects were taken into account,e found that a single uniform treatment delay appeared toe justifiable in all moderate- and high-risk patients (Figure 2).ccording to our model, a PPCI-related delay of �100inutes (corresponding to an ECG-to-balloon time of 130inutes) would nullify the expected incremental mortality

enefits of PPCI compared with thrombolytic therapy. Ad-usting our predictive model using just the randomized trialubset had no effect on this estimate. In low-risk patients,ho are predicted not to benefit from PPCI in terms ofortality, effects of treatment delay approached 0. Thus, at

east for the range of treatment delays included in this study

or with thrombolysis

Coefficient Coefficient (standardized torandomized subset)

p Value†

�5.420 �4.8350.050 0.047 �0.00010.472 0.445 0.0044

�2.125 �2.004 �0.0001

1.282 1.209 0.0001k �0.608 �0.573 0.0022rtality risk 0.397 0.374 0.0069

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1387Coronary Artery Disease/Immediate Thrombolysis Versus Delayed PPCI

imilar mortality outcomes are expected in low-risk patientsith PPCI or thrombolysis, regardless of delay to therapy.Figure 2 also demonstrates that, when the PPCI-related

elays are short (e.g., when ECG-to-balloon time is 90inutes), high-risk patients are much more likely to benefit

han low-risk patients. However, when PPCI-related delaysre longer (e.g., when ECG-to-balloon time is 150 minutes),igh-risk patients are more likely to be harmed.

iscussion

his study was motivated in part by the hypothesis that theegree of mortality benefit expected from PPCI is likely toary from patient to patient based on patient risk and thathe trade-offs between the benefits of the procedure andisks of treatment delay would also differ from patient toatient. We were surprised to find that this hypothesis wasnly partly correct. Although patients at higher risk areore likely to benefit from PPCI, the delay to treatment thatould nullify these benefits (TIME) does not appear to be

specially influenced by patient risk.Our finding that the mortality benefits of PPCI are lim-

ted to patients at higher risk is consistent with the recenteanalysis of the Danish Multicenter Randomized Study onibrinolytic Therapy Versus Acute Coronary Angioplasty incute Myocardial Infarction (DANAMI) trial by Thune et

l14 and with our own previous meta-regression.15 Thesendings underscore the results of other recent studies dem-nstrating that the average summary results of clinical trialso not necessarily apply to all patients in a trial and themportance of using risk models to reveal clinically impor-ant patient variation in the likelihood of treatment bene-t.16–22

We also found that these high-risk, high-benefit patientsre more sensitive to PPCI-related treatment delays, consis-ent with a study by Antoniucci et al.13 Our model showsow these 2 independent effects lead to surprising results:1) treatment delays that would nullify the incremental ben-fits of PPCI compared with thrombolysis appear to beoughly the same for all patients not at low risk, despiteariation in the degree of benefit; and (2) although onlyigher risk patients are likely to obtain mortality benefitrom prompt PPCI compared with prompt thrombolysis, its also true that only higher risk patients are likely harmedy delayed PPCI compared with prompt thrombolysis.

Because low-risk patients are not expected to obtain anyncremental mortality benefit from PPCI and because treat-ent delay is associated with a nearly 0 additional mortality

isk in these patients (at least over the 2.5-hour range ex-mined in our data), the value of TIME is unstable/unde-ned for such patients. This reflects the clinical reality thatonsidering trade-offs between PPCI and treatment delaysing acute mortality outcomes is not likely to be useful inhese patients. Rather, unlike patients at higher mortalityisk, consideration of other outcomes, such as risks fortroke or reinfarction, and logistical concerns should guidereatment decisions more than consideration of mortalityrade-offs, which remain the over-riding concern in high-isk patients.

Previous work using meta-regression estimated that a

rocedure-related delay of �60 minutes would nullify the

otential incremental mortality benefits of PPCI.23,24 Thisnding was adopted by the American College of Cardiology/merican Heart Association guidelines as the maximal pro-

edure-related delay for which PPCI would be preferred toedical thrombolytic therapy. However, meta-regressions

se aggregate study level data. It has been shown empiri-ally that such study level analyses are not appropriate toake patient level inferences because they are extremely

ulnerable to ecologic biases.25,26 In summary, patient levelnferences require patient level, not study level, analysis.

That the previous meta-regressions underestimate thereatment delay that would nullify the potential benefit ofPCI is also suggested by the largest registry study ofutcomes in patients receiving reperfusion therapy, the Na-ional Registry of Myocardial Infarction database.27 In high-olume centers, patients treated with PPCI were still foundo have substantially better outcomes despite average pro-edure-related delays of 70 minutes. In addition, a TIME ofhour is difficult to reconcile with angiographic studies thatave demonstrated that thrombolysis with tissue plasmino-en achieves reperfusion in only �50% of patients even 60inutes after “needle time,” whereas �90% of PPCI-treated

atients will achieve reperfusion immediately after balloonnsufflation. Other recent analyses also have suggested per-istent benefit with PPCI even with longer delays.28,29 Thus,

TIME closer to 100 minutes is likely to be a betterstimate for statistical reasons and for consistency with thenderlying clinical pathophysiology.

There are several limitations to this study. Like the pre-ious meta-regressions, we had no means to control forifferences in procedural quality. If lower quality PPCIe.g., lower reperfusion Thrombolysis In Myocardial Infarc-ion grade 3 flow rates) was correlated with longer delays,hen this would exaggerate the effect of treatment delay andhe TIME might be even longer than we estimate. More-ver, not all trials in this study were randomized, and thereere more high-risk PPCI patients (Figure 1). Although theifference in risk was well controlled for, any residual riskifference might have biased our estimate of the treatmentffect of PPCI toward null, and this potential bias couldave underestimated TIME. In addition, we excluded fromnalysis patients with extremely long treatment delays (pre-entation-to-treatment times �2.5 hours). Because theseatients paradoxically had very low mortality, includinghem would have attenuated the effect of PPCI-related delaynd led to an even longer TIME. Thus, we feel that, al-hough our estimation of TIME is longer than in previoustudies, it probably represents a conservative estimate of therue TIME.

cknowledgment: The authors acknowledge James Udel-on, MD, for helpful comments on a previous version of thiseport.

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2. Selker HP, Griffith JL, Beshansky JR, Califf RM, D’Agostino RB,Laks MM, Lee KL, Maynard C, Wagner GS, Weaver WD. The

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1388 The American Journal of Cardiology (www.AJConline.org)

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