Advances in Interventional Cardiology
Commentary: The Role of Percutaneous Coronary
Intervention in ST-Segment–Elevation Myocardial Infarction
Eric R. Bates, MD; Brahmajee K. Nallamothu, MD, MPH
I n this issue of Circulation, Dr Gregg Stone offers a
thorough review of percutaneous coronary intervention
(PCI) strategies to treat ST-segment– elevation myocardial
infarction (STEMI).1,2 All of the major topics are ad-
dressed and comprehensively referenced, and the figures
provide a concise summary of much of the evidence base. His
ultimate vision is the establishment of STEMI systems of care
dedicated to primary PCI. Improving patient outcomes in
STEMI is a critical goal, and we agree that continued efforts
are needed to expand prehospital and hospital-based emer-
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gency medical systems for STEMI patients. However, we
also continue to believe that there are currently substantial
challenges to delivering primary PCI rapidly and reliably in
real-world settings. Given that some of the opinions offered
by Stone differ from recommendations made by professional
societies, we offer a different perspective on this controver-
sial subject and provide some of the background thinking that
led to the development of the 2004 American College of
Cardiology (ACC)/American Heart Association (AHA)
Guidelines for the Management of Patients With ST-
elevation Myocardial Infarction3 and the subsequent 2007
focused update.4 Our discussion also is informed by the ACC
Door-to-Balloon (D2B) Alliance campaign5 and the AHA
Mission: Lifeline initiative.6 Our goal is not to debate the
points made by Stone but to place PCI for STEMI in the
broader context of the patient and the healthcare system. We
do this by providing additional insights into the development
of PCI strategies in STEMI, examining the critical challenges
that remain for delivering primary PCI, highlighting the
difference between fibrinolytic therapy and a fibrinolytic
strategy, and endorsing a new paradigm for reperfusion
therapy.
Articles pp 538 and 552
PCI Strategies in STEMI
Primary PCI
Primary PCI is clearly preferred to fibrinolytic therapy when
time-to-treatment delays are short and the patient presents to
a high-volume, well-equipped center with expert interven-
tional cardiologists. Compared with fibrinolytic therapy in
randomized clinical trials, primary PCI produces higher rates
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
From the Division of Cardiovascular Diseases, Department of Internal Medicine, University of Michigan, Ann Arbor.
Reprint requests to Eric R. Bates, MD, CVC Cardiovascular Medicine, 1500 E Medical Center Dr, Ann Arbor, MI 48109 –5869. E-mail
ebates@umich.edu
(Circulation. 2008;118:567-573.)
© 2008 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org
567
of infarct artery patency, Thrombolysis in Myocardial Infarc-
tion (TIMI) grade 3 flow, and access site bleeding and lower
rates of recurrent ischemia, reinfarction, emergency repeat
revascularization procedures, intracranial hemorrhage, and
death.7 Early, successful PCI also greatly decreases the
complications of STEMI that result from longer ischemic
times or unsuccessful fibrinolytic therapy, allowing earlier
hospital discharge and resumption of daily activities. These
advantages were recognized in the 2004 ACC/AHA STEMI
guidelines3 that elevated primary PCI to the preferred strategy
for reperfusion therapy when performed in a timely fashion
(door-to-balloon time within 90 minutes) by persons skilled
in the procedure (⬎75 PCI procedures per year) in cardiac
catheterization laboratories that performed at least 200 PCI
procedures a year (including 36 primary PCI procedures a
year). In the 1999 update of the 1996 STEMI guidelines,8
primary PCI was considered an “alternative to thrombolytic
therapy” based on the limited data for superiority that existed
at that time.
Facilitated PCI
Facilitated PCI refers to a strategy of planned immediate PCI
after administration of an initial pharmacological regimen
intended to improve infarct artery patency before PCI. The
pharmacological regimens have included high-dose heparin, a
glycoprotein IIb/IIIa inhibitor, full-dose fibrinolytic therapy,
half-dose fibrinolytic therapy, or a combination of half-dose
fibrinolytic therapy and a glycoprotein IIb/IIIa inhibitor.
Potential advantages include earlier time to reperfusion,
smaller infarct size, improved patient stability, lower infarct
artery thrombus burden, greater PCI success rates, higher
TIMI flow rates, and improved survival rates. Potential risks
include increased bleeding complications, especially in older
patients. Limitations include drug contraindications and ad-
ditional cost. Unfortunately, early clinical trials of facilitated
PCI did not demonstrate any benefit in reducing infarct size
or improving outcomes compared with primary PCI.9 Never-
theless, selective use of the facilitated strategy with regimens
other than full-dose fibrinolytic therapy in subgroups of
patients at high risk (large MI or hemodynamic or electric
instability) with low risk of bleeding (younger age, absence of
poorly controlled hypertension, normal body weight) who
DOI: 10.1161/CIRCULATIONAHA.108.788620
 568 Circulation July 29, 2008
present early to hospitals without PCI capability might be
appropriate when transfer delays for primary PCI are antici-
pated.4 Early trials of facilitated PCI were limited by inade-
quate antiplatelet and anticoagulant adjunctive therapy and
the rapid performance of PCI. It would be interesting to retest
the hypothesis with clopidogrel and enoxaparin because they
have been shown to decrease ischemic complications with
fibrinolytic therapy10,11 and to limit enrollment to patients
presenting to hospitals without PCI capability.
Emergency Invasive Strategy After
Fibrinolytic Therapy
In unstable patients such as those with cardiogenic shock
(especially those ⬍75 years of age), severe congestive heart
failure/pulmonary edema, or hemodynamically compromis-
ing ventricular arrhythmias (regardless of age), a strategy of
emergency coronary angiography with intent to perform PCI
is a useful approach regardless of the time since initiation of
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fibrinolytic therapy, provided further invasive management is
not considered futile or unsuitable given the clinical
circumstances.4
In stable patients, rescue PCI may be reasonable if there is
clinical suspicion of failure of fibrinolytic therapy.12,13 His-
torically, rescue PCI was performed 90 minutes after the
initiation of fibrinolytic therapy in an infarct artery with TIMI
grade 0/1 flow. Presently, the clinical diagnosis of unsuccess-
ful reperfusion is best made when there is ⬍50% ST-segment
resolution 90 minutes after initiation of fibrinolytic therapy in
the ECG lead showing the greatest degree of ST-segment
elevation at presentation.4 Angiography is required to deter-
mine whether this is due to a persistently occluded infarct
artery or to unsuccessful microvascular reperfusion.
Given the association between bleeding events and subse-
quent ischemic events, it also might be reasonable to select
moderate- and high-risk patients for rescue PCI and to treat
low-risk patients with medical therapy. An ECG estimate of
potential infarct size in patients with persistent ST-segment
elevation and ongoing ischemic pain can be useful. Anterior
MI or inferior MI with right ventricular involvement or
precordial ST-segment depression usually predicts increased
risk.14 Conversely, patients with symptom resolution, im-
proving ST-segment elevation, or inferior MI localized to 3
ECG leads probably gain little benefit. Likewise, it is doubt-
ful that PCI of a branch artery (diagonal or obtuse marginal
branch) will change the prognosis in the absence of the
high-risk criteria noted above. The benefits of rescue PCI are
greater the earlier it is initiated after the onset of ischemic
discomfort.4
Elective Invasive Strategy After
Fibrinolytic Therapy
PCI of a hemodynamically significant stenosis in a patent
infarct artery ⬎24 hours after STEMI may be considered part
of an elective invasive strategy to maintain long-term paten-
cy.4 The presence of clinical ischemia15 or silent ischemia16
increases the chance for benefit. In contrast, the Open Artery
Trial,17,18 testing the open artery hypothesis in patients with
little myocardial ischemia and an occluded infarct artery,
demonstrated no incremental benefit with elective PCI 1 to 28
days after MI in preserving left ventricular function and
preventing subsequent cardiovascular events beyond optimal
medical therapy with aspirin, ␤-blockers, angiotensin-
converting enzyme inhibitors, and statins. Importantly, exclu-
sion criteria included New York Heart Association class III or
IV heart failure, rest angina, serum creatinine ⬎2.5 mg/dL,
left main or 3-vessel disease, clinical instability, or severe
inducible ischemia on stress testing if the infarct zone was not
akinetic or dyskinetic. Therefore, PCI for an occluded infarct
artery in asymptomatic patients with 1- or 2-vessel disease is
not recommended.4,19
Primary PCI Strategy Limitations
Access
Primary PCI is available in ⬍25% of acute care hospitals in
the United States. Although 80% of the adult population lives
within 60 minutes of a hospital with PCI capability and 95%
live within 90 minutes, timely access to primary PCI remains
a major challenge without regionalized prehospital systems of
care to rapidly direct STEMI patients to PCI hospitals.20,21
Two emergency medical service model systems have been
proposed to address this challenge. The first is the “bypass”
model in which patients with a diagnosis of STEMI on a
prehospital ECG are transported directly to a PCI center,
bypassing a closer hospital without PCI capability.22 The
second is the “transfer” model in which interhospital transfer
is accomplished rapidly through carefully established treat-
ment protocols using integrated hospital systems.23 Another
option is to establish primary PCI programs without onsite
surgery, but it is unclear whether this option really increases
access to primary PCI by skilled operators and experienced
teams.24
In the US healthcare system, political and economic
motivations, in addition to local barriers, influence the devel-
opment of regionalized STEMI systems.25 Although the
trauma system often is referenced as a model for STEMI care,
many gaps remain for regionalizing major trauma care in the
United States despite decades of effort. This serves as a
powerful reminder of the challenges that will be faced in the
implementation of STEMI systems of care within the unstruc-
tured US healthcare system. The Mission: Lifeline initiative
is a major effort sponsored by the AHA to address these
challenges. Its goals are to work within individual commu-
nities to address their unique needs, resources, and barriers to
implementing STEMI systems of care.6 The key aspect of this
effort is to help stakeholders develop local solutions for their
region, an explicit recognition that there is not a one-size-
fits-all solution. In fact, substantial barriers that facilities in
rural and underserved urban areas face remind us that even if
cooperation between hospitals can be improved, fixed re-
sources will still prevent universal access to primary PCI in
the near future. There also will be an urgent need for major
modifications in reimbursement to ensure that redistribution
of patients with suspected acute coronary syndromes will not
adversely affect referring hospital revenues or services. For
example, a recent proposition for payment reform suggested
a single prospective payment that covers care from activation
of 9-1-1 to patient transfer, which would allow emergency
 Bates and Nallamothu
medical services, non-PCI hospitals, and PCI hospitals to
share gains that would result from coordination of care and
would remove inefficiencies inherent in the current reim-
bursement system.26
Time to Treatment
It is a biological fact that ischemic time is related to MI size
and mortality rates.27–29 Although some continue to argue that
time delays are unimportant with primary PCI, there is
overwhelming evidence to the contrary, and this is acknowl-
edged in the review by Stone. However, the review then
embraces 2 reports that suggest that time delays are largely
unimportant in primary PCI.30,31 The Primary Coronary
Angioplasty Versus Thrombolysis (PCAT) analysis30 is lim-
ited by a statistical curiosity in which a U-shaped relationship
was found between PCI-related delays and death with fibrino-
lytic therapy after multivariable adjustments. It is difficult to
understand how institutional performance with time to treat-
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ment in PCI directly affected outcomes in patients receiving
fibrinolytic therapy.32 The Register of Information and
Knowledge About Swedish Heart Intensive Care Admissions
(RIKS-HIA)31 may suffer from the same selection bias that
led another Swedish registry to first conclude that drug-
eluting stents were dangerous33 and then 6 months later
conclude that they were safe.34 The RIKS-HIA registry also is
limited by the inclusion of only those patients who underwent
primary PCI. As many as 10% of patients with STEMI may
not undergo primary PCI despite emergency coronary an-
giography because of unsuitable anatomy or multivessel
disease.35 These high-risk patients may be particularly sus-
ceptible to death and other early complications.
We elicited a firestorm of protest from the interventional
cardiology community that continues to resonate by publish-
ing a meta-regression analysis of 20 randomized clinical trials
that showed an inverse relationship between PCI-related
treatment delays (door-to-balloon time minus door-to-needle
time) and mortality advantage with primary PCI versus
fibrinolytic therapy.36 The point of equipoise between reper-
fusion strategies was 60 minutes, which, when added to a
30-minute door-to-needle time, conveniently adds up to 90
minutes for door-to-balloon time. The data we abstracted
were from the same meta-analysis that has been used to show
the superiority of primary PCI and included a PCI-related
treatment delay of only 40 minutes.7 Many have suggested
that our analysis was used to formulate the ACC/AHA
guideline recommendation for the 90-minute door-to-balloon
goal or that it established a 90-minute threshold beyond
which fibrinolytic therapy would be preferable to primary
PCI. Neither concept is correct. In fact, the European Society
of Cardiology (ESC) guidelines37 had been published 9
months earlier with a first-medical-contact-to-balloon goal of
90 minutes, a more rigorous standard, and the ACC/AHA
guidelines committee had already agreed to reduce the
door-to-balloon goal from 120 minutes in the 1999 update8 to
90 minutes.3 We were simply challenging the PCI-centric
view that time to treatment did not matter with primary PCI38
and that transfer delays of up to 3 hours39 were acceptable as
an alternative to immediate fibrinolytic therapy.
Role of PCI in STEMI 569
The argument about where the point of equipoise between
therapies falls is important but misses the larger concept that
infarct size and complications from STEMI are greater with
time delays. The point of equipoise is shorter in randomized
clinical trials36 than in registries,40 in trials with alteplase41
than in trials with streptokinase,42 and in high-risk patients
than in low-risk patients.40 In addition, any analysis is
confounded by whether the patient is treated early after
symptom onset when greater myocardial salvage is possible
or treated later when infarct artery patency becomes the goal
of reperfusion therapy.29 Most important, the 90-minute
door-to-balloon time is a systems goal to drive quality
improvement programs, not a “line in the sand” to choose a
reperfusion strategy for an individual patient. Although we
interventional cardiologists like to think that we are the
reason for better outcomes compared with fibrinolytic ther-
apy, much of the advantage for the patient also may be due to
receiving specialist care instead of generalist care and being
treated in centers with better nursing staffs, more ancillary
services, and greater compliance with delivery of evidence-
based therapies, including cardiac rehabilitation
programs.43,44
Logistics of Care
The ACC/AHA guidelines state that STEMI patients pres-
enting to a hospital with PCI capability should be treated with
primary PCI within 90 minutes of first medical contact as a
systems goal, not an individual patient goal.4 The best
outcomes are achieved by offering this strategy 24 hours per
day, 7 days per week.45 The systems goal of the D2B Alliance
campaign exceeded these recommendations in nontransfer
patients by requiring at least 75% of patients to be treated
within 90 minutes of hospital presentation.5 The D2B Alli-
ance campaign promotes the use of recent evidence-based
strategies to reduce needless delays that are inherent in many
PCI hospitals in the United States.46 The 75% goal recognized
that some patients have clinically relevant non–system-based
delays that do not represent quality-of-care issues. These
include patient variables (uncertainty about diagnosis, evalu-
ation and treatment of other life-threatening conditions,
obtaining informed consent, etc) that delay the patient’s
arrival in the cardiac catheterization laboratory or anatomic
challenges (issues of arterial, coronary, or lesion access) that
prolong the PCI procedure. In the absence of such circum-
stances, however, primary PCI should be achievable within
this time frame. Indeed, many PCI hospitals with refined
systems are now approaching median door-to-balloon times
of 60 to 70 minutes and showing concomitant improvement
in mortality rates. The new focus for primary PCI is to move
toward reducing time from first medical contact because extra
time may be taken to transport patients to a PCI center in
regionalization strategies.4
Because of access issues and the critical importance of
time to treatment, fibrinolytic therapy may be generally
preferred in hospital systems that do not have the capability
of meeting the time goal for primary PCI. Transfer protocols
should be in place for arranging rescue PCI when clinically
indicated or transferring lytic-ineligible patients.4 Several
examples of regional systems now in use in Europe and the
 570 Circulation July 29, 2008
United States have incorporated these strategies into a com-
prehensive system for managing STEMI. In the Vienna
STEMI Registry,47 a citywide program was instituted that
was based largely on the implementation of the ACC/AHA
and ESC STEMI guidelines and was led by 5 high-volume
interventional cardiology departments. The system improved
not only access to primary PCI but also the appropriate use of
fibrinolytic therapy in eligible patients in whom mortality
rates equivalent to those with primary PCI were achieved. As
a consequence, overall in-hospital mortality rates in STEMI
decreased by 40% over a 2-year period. The Mayo Clinic
STEMI Protocol48 instituted a similar strategy across 28
referring hospitals in the region and found marked improve-
ments in time to treatment. Again, a strategy that targeted the
judicious use of fibrinolytic therapy appeared to be safe and
effective.
Risk Stratification and Patient Subgroups
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A strong argument can be made against the emergency
transfer of all patients with STEMI to a PCI regional center.
Studies evaluating patient risk clearly demonstrate that the
mortality advantage of primary PCI over fibrinolytic therapy
is limited to high-risk patients. There is no difference in death
between treatments in patients with nonanterior MI, age ⬍70
years, or hemodynamic stability.49,50 In contrast, patients with
cardiogenic shock, congestive heart failure, tachycardia, hy-
potension, or anterior STEMI fare better with primary PCI. In
the Danish Trial in Acute Myocardial Infarction-2
(DANAMI-2), the advantage for primary PCI was limited to
the 25% of patients with TIMI risk scores ⱖ5.51 In the
still-unpublished SENIOR-PAMI trial,52 there was no signif-
icant difference between primary PCI and fibrinolytic therapy
in death and disabling stroke in patients ⱖ70 years of age, but
there was a trend toward lower reinfarction with primary PCI.
These studies suggest that STEMI systems of care that target
use of primary PCI to a minority of the ⬇400 000 patients
with STEMI each year in the United States may improve
patient outcomes to the same extent without requiring a
fundamental restructuring of the healthcare system.
Myocardial Salvage
Claims that primary PCI produces smaller infarct size and
greater myocardial salvage than fibrinolytic therapy fail to
recognize that infarct size reduction from early, successful
reperfusion therapy is different from myocardial salvage as
measured by single-photon emission computed tomography
(SPECT) 1 to 2 weeks after STEMI.1,2 Infarct size reduction
from acute therapy would best be measured by the difference
in cumulative cardiac enzyme release, as was done earlier
with fibrinolytic therapy.53 In the Munich studies on myocar-
dial salvage, it appears that few patients were crossed over to
early revascularization, so the late SPECT measurement was
influenced by infarct artery reocclusion and reinfarction.54,55
Importantly, no data on biomarker levels or left ventricular
ejection fraction are included in the Munich reports. We know
of no evidence that suggests that primary PCI is associated with
smaller initial infarct size or better preservation of left ventric-
ular ejection fraction than fibrinolytic therapy, presumably
because of delays in reperfusion time with primary PCI. It would
be interesting to reassess this question in the current era in
which symptom-onset-to-balloon times are at least an hour
shorter than in previous studies because of the increased
emphasis focused on time to treatment.3,4,37
Fibrinolytic Therapy Versus a
Fibrinolytic Strategy
The benefit of primary PCI over fibrinolytic therapy is likely
to be smaller in real-world settings than in randomized trials.7
Patients in the trials summarized by Keeley et al7 were
selected for randomization, delays to PCI were short, and
performance of PCI was presumably excellent. Comparative
results with less experienced centers or operators are less
impressive and suggest similar in-hospital mortality rates
between treatments at low-volume PCI hospitals.56 Differ-
ences between treatments also were magnified by the inclu-
sion of studies with streptokinase compared with alteplase or
duteplase as the fibrinolytic agent.7 Moreover, bleeding and
intracerebral hemorrhage rates may have been increased by
higher anticoagulation targets than we now use, and reinfarc-
tion rates may have been higher than in the current era in
which clopidogrel10 and enoxaparin11 have shown utility with
fibrinolytic therapy. Most important, fibrinolytic therapy was
tested as monotherapy, with crossover to rescue PCI or the
early invasive strategy discouraged by most protocols. In
clinical practice, as measured by observational reports, the
emergency invasive strategy is used in 33% to 44% of
patients, and the elective invasive strategy is used in 74% to
90%.57,58 In large national registries including a broader
spectrum of patients, time delays, interventional cardiolo-
gists, and hospitals, there has been no difference in the rates
of death between primary PCI and a fibrinolytic strategy that
includes fibrinolytic therapy and rescue or elective PCI.59,60
In fact, the best treatment strategy has been prehospital
fibrinolytic therapy,60 presumably because half of the patients
contact the prehospital system within 2 hours of symptom
onset.
Time for a New Reperfusion Paradigm
The concept that primary PCI is needed for all patients is not
evidence based and is currently impractical given geograph-
ical limitations and the variability of hospital system re-
sources. Because a reduction in hospital death rates between
strategies has yet to be reliably demonstrated in real-world
settings and absent early differences in infarct size and left
ventricular function, it is more likely that the 30-day benefit
seen with primary PCI in the randomized clinical trials is due
to failure to provide rescue PCI to fibrinolytic failures and
early PCI to those after successful fibrinolysis to prevent
infarct artery reocclusion (Figure).61,62 However, primary PCI
has several important advantages that extend beyond its
impact on death. These include the ability to extend reperfu-
sion therapy to the 30% of patients with STEMI who are
frequently denied it63 and the facilitation of early hospital
discharge. Whether these advantages are worth the possible
restructuring that will be required to establish STEMI sys-
tems of care is an important question that individual commu-
nities will need to assess.
 Bates and Nallamothu
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Figure. A, In the Global Use of Strategies to Open Occluded
Arteries in Acute Coronary Syndromes (GUSTO IIb) Angioplasty
Substudy,61 arguably the best comparative randomized trial of
PCI versus fibrinolytic therapy, there was no difference in death
rates in the first several days that represent the hospital phase.
The difference in death rates between treatments occurred after
hospital discharge and could be due to differences in infarct
artery reocclusion rates. B, Incidence of infarct artery reocclu-
sion rates after fibrinolysis, balloon angioplasty, and stent
implantation.62 PTCA indicates percutaneous transluminal
coronary angiography.
Thus, the conclusion by Stone1 that “mortality could be
reduced and event-free survival enhanced by withholding
fibrinolytic therapy for the performance of primary PCI in
most patients” is off target. Instead of supporting primary PCI
for patients who present ⬎3 hours after symptom onset, the
emphasis should be on treating a greater percentage of
patients with reperfusion therapy within 3 hours of symptom
onset, preferably within 2 hours.28,29,64 This requires in-
creased educational efforts directed at early symptom recog-
nition, early activation of the emergency medical system, and
performance of prehospital ECGs. This may increase the
number of patients treated with fibrinolytic therapy, with the
small attendant risk for intracerebral hemorrhage, but the net
clinical benefit would favor treatment because of the reduc-
tion in infarct size and the rates of cardiogenic shock and
death associated with early reperfusion therapy.28,29,64 To
amplify the potential benefit of early fibrinolytic therapy,
coronary angiography should be strongly considered as soon
as necessary and clinically feasible so that PCI could be
performed both to decrease the complications of persistent
infarct artery occlusion12,13 or reocclusion,65,66 and to maxi-
Role of PCI in STEMI 571
mize the benefit of sustained infarct artery patency.3,37 Next-
day transfer for coronary angiography and same-day return of
the patient to the referring hospital could decrease some of the
logistical problems of transferring all patients emergently to
PCI centers.
The 25-year debate about primary PCI or fibrinolytic
superiority is no longer useful. The argument that longer
reperfusion delays for PCI are acceptable, usually made by
interventional cardiologists or hospitals that stand to gain by
increased procedure volumes, will not maximize the potential
patient benefit from earlier reperfusion therapy. Rather, it is
time to focus on a new reperfusion paradigm that is based on
shortening the overall time period from symptom onset to
initiation of reperfusion therapy. This will require increasing
awareness of symptoms among vulnerable populations, im-
proving access to the healthcare system, and restructuring of
the emergency medical system to improve the coordination of
care between hospitals.67 Hospitals with PCI capability, to
reproduce the results from randomized clinical trials, will
need to perform primary PCI as rapidly as possible and strive
to offer 24-hour service. Substantial gains have already been
made in this area as a result of efforts such as the ACC D2B
Alliance. Hospitals without primary PCI capability will need
to develop reperfusion therapy algorithms that may include
fibrinolytic therapy and will provide early access to coronary
angiography, perhaps for all patients. The AHA Mission:
Lifeline initiative is an excellent step in that direction.
Disclosures
None.
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KEY WORDS: cardiology 䡲 myocardial infarction 䡲 percutaneous coronary
intervention
 Commentary: The Role of Percutaneous Coronary Intervention in ST-Segment−Elevation
Myocardial Infarction
Eric R. Bates and Brahmajee K. Nallamothu

Circulation. 2008;118:567-573
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doi: 10.1161/CIRCULATIONAHA.108.788620
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