MINI-REVIEW:

EXPERT OPINIONS

Fibrinolysis for Acute Myocardial Infarction

The Future Is Here and Now
Paul W. Armstrong, MD; Desire Collen, MD, PhD; Elliott Antman, MD
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adjusted accelerated t-PA regimen, the enhanced fibrin specificity of TNK-tPA results in a significant reduction in
systemic bleeding.4 Whereas conjunctive therapy with intravenous glycoprotein IIb/IIIa (IV GP IIb/IIIa) inhibitors enhances epicardial flow and myocardial perfusion and reduces
reinfarction, these advantages have not resulted in the expected improvement in survival.5,6 Indeed, the increase in
systemic bleeding and apparent excess of intracranial hemorrhage among STEMI patients over 75 years has led to
reassessment of the suitability of combination reperfusion
with IV GP IIb/IIIa inhibitors and reduced dose fibrinolysis.7,8 Currently, the combination of full dose fibrinolysis and
low molecular weight heparin or a direct antithrombin appears to be an attractive strategy because of reduced reinfarction and recurrent ischemia.8,9
The major goal of reperfusion therapy is to minimize the
time during which the culprit coronary artery remains occluded by rapidly achieving high quality reperfusion at both
the epicardial and microcirculatory level and preventing
reocclusion after initially successful fibrinolysis. Although
Thrombolysis In Myocardial Infarction (TIMI 3) coronary
flow has traditionally been viewed as the most reliable
surrogate of successful coronary reperfusion, it is now clear
that this is an inadequate measure of myocardial perfusion in
many patients (irrespective of how it is achieved).10,11 The
most readily available and clinically useful tool for assessing
reperfusion success is the extent of ST-segment resolution
from the baseline electrocardiogram; hence, 50% or 70%
ST resolution within the first 60 to 180 minutes after therapy

The reports of my death are greatly exaggerated.

Mark Twain, 1897,
cable from London to the Associated Press

harmacological reperfusion therapy for acute myocardial infarction was incorporated into the armamentarium of clinicians over 15 years ago and has had an
extraordinarily beneficial impact on outcome of patients with
ST-elevation myocardial infarction (STEMI). There are 3
fundamental components to pharmacological reperfusion;
these consist of the core fibrinolytic agent as well as the
accompanying antithrombotic and antiplatelet conjunctive
therapies. No contemporary therapy in cardiovascular medicine has been as carefully and critically examined in multiple
large randomized trials. These have comprehensively examined the efficacy, safety, and impact of novel therapeutic
third-generation fibrinolytics and advances in conjunctive
therapies aimed at enhancing restoration of myocardial flow
in the epicardial infarct-related coronary artery.13

Evolution of Pharmacological
Reperfusion Regimens
The tissue plasminogen activator (tPA) congeners tenecteplase (TNK-tPA) and reteplase (rPA) that possess initial
plasma half-lives of 15 to 30 minutes constitute the newest,
most conveniently administered bolus fibrinolytics. They not
only reduce the potential for medication errors but also
greatly simplify the prospects of prehospital fibrinolysis.2 4
Although these newer agents do not confer additional mortality reduction over that achieved by the 90-minute weight-

The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
From the Department of Medicine, Division of Cardiology, University of Alberta, Edmonton, Alberta, Canada (P.W.A.); Center for Molecular and
Vascular Biology, Katholieke Universiteit Leuven, Leuven, Belgium (D.C.); and Cardiovascular Division, Brigham and Womens Hospital and Harvard
Medical School, Boston, Mass (E.A.).
Correspondence to Paul W. Armstrong, MD, 2-51 Medical Sciences Building, University of Alberta, Edmonton, Alberta, Canada T6G 2H7. E-mail
paul.Armstrong@ualberta.ca
(Circulation. 2003;107:2533-2537.)
2003 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org

DOI: 10.1161/01.CIR.0000072930.64775.DC

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Figure 1. The evolution of timing and location for administration

of fibrinolytic therapy. Initially reserved for intracoronary administration in the cardiac catheterization laboratory, it then
devolved progressively to the coronary care unit (CCU), emergency department (ED), and ultimately to the prehospital arena
either in the ambulance or home. As definitive therapy moves
closer to the time of symptom onset, there is greater preservation of ischemic myocardium and enhanced clinical outcome.

provides excellent insight into the ultimate infarct size, left

ventricular function, and survival.12,13
Major evolution in both the location and timing of fibrinolysis has occurred since the initial intracoronary administration of streptokinase in the cardiac catheterization laboratory over a quarter century ago14 (Figure 1). Moving the
location of fibrinolysis earlier to the prehospital setting
results in a significant reduction in mortality over that
achieved by in-hospital fibrinolytic therapy, as demonstrated
by a meta-analysis of 6434 patients (odds ratio 0.83, 95%
confidence interval 0.70 to 0.98).15 Recognition of the fundamental importance of time on the impact of fibrinolytic
treatment on survival was underscored by the golden hour
metaphor, the time during which 65 lives per 1000 patients
treated were saved as compared with only 10 lives per 1000
patients treated between 6 and 12 hours after symptom
onset.16 Interest in moving diagnosis and therapy earlier into
the field has received additional impetus on the basis of the
disappointing outcome of the Rapid Early Action for Coronary Treatment (REACT) study. Despite an intense public
education campaign over 18 months, the time from symptom
onset to hospital presentation remained unaltered in patients
with ischemic symptoms.17 Hence, a substantial further reduction in time to treatment is likely best achieved by
enhancing prehospital diagnosis and therapy rather than by
expecting patients to seek medical attention earlier.18

Choice of Reperfusion Strategy

The debate concerning the preferred reperfusion strategy was
substantially intensified over the past year after the presentation of the much heralded but still unpublished (at the time
of this writing) DANish trial in Acute Myocardial Infarction
(DANAMI 2) study. In this trial, 1572 STEMI patients were

randomized within 12 hours of symptom onset to a fibrinolytic versus a primary percutaneous coronary intervention
(PCI) strategy in both community (n1129) and primary PCI
(n443) hospitals. 19 This study integrated an interinstitutional transfer policy for those randomized to primary
PCI if it could be achieved within 3 hours. The Data and
Safety Monitoring Board prematurely terminated DANAMI 2
because of the perception of clear benefit of primary PCI.
Although DANAMI 2 did show a substantial reduction in the
composite 30-day endpoint of death, re-MI, and disabling
stroke (13.7% versus 8.0%; P0.003) in favor of the primary
PCI strategy, this outcome was overwhelmingly influenced
by the reduction in reinfarction (from 6.3% to 1.6%;
P0.0001). Importantly, this reduction in reinfarction occurred in a clinical environment where transfer from a
community hospital was considered investigational if a
mechanical intervention after fibrinolysis was needed. Hence,
urgent PCI occurred in only 2.5% of patients, even though
28% of the patients were randomized in interventional institutions. An additional study, interpreted by some as impetus
to move to an overall primary PCI strategy, was conducted by
the Cardiovascular Patients Outcomes Research Team (CPORT) investigators who randomized 451 STEMI patients
within 12 hours of symptom onset to primary PCI versus
tPA.20 Although there was no difference in mortality, there
was a substantial reduction in the composite endpoints of
death, re-MI, and stroke with primary PCI (17.7% versus
10.7% with tPA; P0.03); this was again largely accounted
for by a reduction in an unusually high reinfarction rate
amongst fibrinolytic-treated versus PCI-treated patients
(8.8% versus 4%; P0.04). Hence, in both the aforementioned studies, which used unfractionated heparin as the
antithrombin fibrinolytic partner, the recurrent infarction rate
was by far the most important element in the composite
endpoint and seemed unusually high relative to other trials.
This is well demonstrated in Figure 2, where we compare the
incidence of recurrent infarction in a number of recent
STEMI studies that evaluated fibrinolysis and antithrombin
therapy; it is useful to evaluate them in the context of the
frequency with which mechanical cointervention with PCI
was used.
Although a recent quantitative review of 23 randomized
trials suggests that primary PCI is more effective than
fibrinolysis in STEMI, the largest component of this difference was reinfarction.21 This work failed to provide individual patient data, thereby potentially masking heterogeneity
and important treatment differences. Although the authors
propose that emergency hospital transfer is both feasible and
safe, a 1.2% complication rate amongst transported patients
was recently reported in the Primary Angioplasty in patients
transferred from General community hospitals to specialized
PTCA Units with or without Emergency thrombolysis 2
(PRAGUE 2) study, in which 2 patients died and 3 developed
ventricular fibrillation.22 In our view, this analysis is

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Figure 2. Recurrent MI rates in recent fibrinolytic trials which

utilized a conjunctive antithrombin strategy. The sample size
frequency of cointervention with urgent and non-urgent PCI and
the type of antithrombin therapy used are shown, and the trials
with their sample sizes are presented in ascending order of their
re-MI rates. ASSENT 3 indicates ASsessments of the Safety and
Efficacy of a New Thrombolytic regimen; CAPTIM, Comparison
of Angioplasty and Prehospital Thrombolysis In acute Myocardial Infarction; C-PORT, Cardiovascular Patients Outcomes
Research Team; DANAMI-2, DANish trial in Acute Myocardial
Infarction; ENTIRE, ENoxaparin as adjunctive antithrombin Therapy for ST-elevation myocardial Infarction REsults; GUSTO V,
Global Utilization of Streptokinase and Tissue plasminogen activator for Occluded coronary arteries; HERO-2, Hirulog Early
Reperfusion/Occlusion 2; TNK Enox, Tenecteplase plus enoxaparin; rPA Hep, reteplase plus heparin; tPA Hep, tissue
plasminogen activator plus heparin; and SK Bival, streptokinase plus bivalirudin.

hypothesis-generating and a signal for caution rather than

convincing evidence for practice change.
The Comparison of Angioplasty and Prehospital Thrombolysis In acute Myocardial Infarction (CAPTIM) investigators contributed important observations by comparing prehospital fibrinolysis with primary PCI.23 Although these
investigators reported a trend toward improvement in the
composite of death, reinfarction, and disabling stroke for PCI
versus fibrinolysis (6.2% versus 8.2%; P0.29), the 30-day
mortality was 3.8% for patients receiving accelerated rtPA
with unfractionated heparin versus 4.8% in those undergoing
primary PCI. Hence, the major advantage was again related
predominantly to a reduction in reinfarction in patients
undergoing PCI .18 A substudy from the Plasminogen Angioplasty Compatibility Trial (PACT) investigators underscores
the deleterious effects of delay in PCI-associated reperfusion.24 When delay to reperfusion increased from 30 through
120 minutes, there was progressively worse left ventricular
function, leading these investigators to suggest that incorporation of pharmacological reperfusion may be indicated when
door-to-balloon times exceeds 60 minutes. In our view, there
is substantial need for caution before accepting the suggestion
that widespread application of primary PCI for STEMI be
undertaken, given current knowledge and available resources.

Fibrinolysis for Acute Myocardial Infarction

2535

Indeed, the suggestion that a 3-hour delay in administering

life-saving fibrinolytic therapy is appropriate to deliver primary PCI is, in our judgment, both unwise and unsubstantiated by current data and the realities of clinical practice.25 In
this regard, it is especially noteworthy that the preponderance
of patients undergoing treatment with primary PCI in the
C-PORT study as well as the National Registry of Myocardial
Infarction (NRMI) registry did so between the hours of 0800
AM and 1600 PM. Clearly, this time window does not conform
to the temporal presentation of STEMI and biases the data
toward shorter door-to-balloon times than are likely achievable in routine clinical practice.26 A primary invasive approach is neither always feasible or successful nor without
hazard: Results are dependent on patient age, time to treatment, operator experience, and institutional volume.26,27
Rather than engaging in unnecessarily strident debate on an
either/or treatment proposition, STEMI patients can be best
served by embracing an integrated approach to management,
as depicted in Figure 3. This approach emphasizes an assessment at the earliest point of medical contact with prompt
evaluation of the elapsed time from symptom onset. Antiplatelet and antithrombin therapy should be administered as
early as possible in patients identified as having STEMI.
Simultaneously, 4 key questions need to be addressed: (1)
What is the time from symptom onset to medical contact? (2)
What is the risk of the myocardial infarction based on initial
clinical and electrocardiographic assessment? (3) What are
the risks of fibrinolytic therapy particularly as it relates to
systemic and intracranial bleeding? (4) What is the estimated
time before the affected individual could be transported to a
skilled interventional facility to access primary mechanical
intervention? We believe ideal targets should be delivery of
fibrinolysis within 60 minutes of call for medical help and
within 90 minutes for the delivery of primary PCI. In patients
receiving fibrinolysis, careful surveillance over the first 1 to
3 hours is critical to ensure that successful reperfusion occurs,
as indicated by relief of symptoms and/or any hemodynamic
or electrical instability coupled with at least 50% resolution
of the initial ST elevation.12,13 Careful subsequent observation for recurrent ischemia and ischemia brought on by
noninvasive testing should lead to prompt angiography and
appropriate revascularization. Progress in information technology that facilitates computer-assisted electrocardiographic
diagnosis, patient risk modeling, reliable transmission to a
remote facility, and triage to the most appropriate healthcare
facility is likely to serve patients best. For patients in
cardiogenic shock, those with contraindications to fibrinolysis, and others who have rapid, ie, 90 minute, access to
expert PCI facilities, primary PCI is the preferred reperfusion
strategy.
For other STEMI patients, who will likely constitute the
majority, early prehospital or emergency department administration of fibrinolysis may be best. Notwithstanding concerns about excess complications in the elderly, irrespective
of which reperfusion strategy is used, analysis from the

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Figure 3. A suggested strategy for the management of STEMI. All patients are promptly
evaluated at the earliest point of care and
should receive prompt antiplatelet and antithrombin therapy and proceed either along a
pharmacological or mechanical reperfusion
strategy. Four key questions need to be
quickly addressed: Time from symptom
onset, risk of the STEMI, potential risk of
fibrinolysis, and time required to transport
the patient to an expert PCI center. If pharmacological reperfusion is used, timely
assessment of its success and monitoring
for spontaneous or provokable ischemia
should guide the need for early angiography
and appropriate mechanical cointervention.
All patients should receive appropriate and
intense secondary prevention at an early
point in care. See text for further discussion.

Fibrinolytic Therapy Trials (FTT) overview provides compelling data that the greatest absolute benefit from fibrinolysis actually occurs in patients over the age of 75, ie, 40 lives
per 1000 patients treated versus 20 for those under 75 years
of age treated within 12 hours (Colin Baigent, Clinical Trial
Service Unit, Oxford, UK, personal communication, 2002).
In sharp contrast to the fibrinolytic-treated patients in the
DANAMI 2 trial, it should be anticipated that in approximately 1 of 4 fibrinolytic-treated patients would require
rescue PCI if clinical and/or electrocardiographic evidence of
reperfusion failure were observed.23 Emphasis should be
placed on the need to carefully evaluate patients after fibrinolytic therapy for spontaneous or provokable ischemia followed by timely in-hospital co-intervention that will minimize reinfarction (Figure 3). Risk stratification with intense
secondary prevention will optimize care. Advances in PCI
suggest that routine invasive study deserves consideration
and further study.
In addition to early bolus therapy, the future for fibrinolysis
will likely involve conjunctive therapy with a direct antithrombin or low molecular weight heparin to minimize
reinfarction.8,9,28 The optimal pharmacological approach is
still evolving. Ongoing trials are evaluating whether a combined strategy of early pharmacological therapy with further
dose modification of fibrinolytic for the elderly combined
with GP IIb/IIIa inhibitors ultimately facilitates more effective percutaneous intervention. Attempts to develop single
bolus fibrinolytics with higher fibrin specificity (eg, pegylated staphylokinase or amediplase) along with anticoagulants other than low molecular weight heparin (eg, factor Xa
inhibitors, heparin-derived pentasaccharide) and novel antiplatelet agents are underway, but the risk/benefit and costeffectiveness ratios remain to be determined.
In our opinion, fibrinolytic therapy, like Mark Twain, will
continue contributing in a vigorous and productive way long
after the premature reports of its demise.

Acknowledgments
The editorial assistance of Karen Buck is appreciated.

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Fibrinolysis for Acute Myocardial Infarction: The Future Is Here and Now
Paul W. Armstrong, Dsir Collen and Elliott Antman
Circulation. 2003;107:2533-2537
doi: 10.1161/01.CIR.0000072930.64775.DC
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