Circulation. 2003;108:III-6-III-13
doi: 10.1161/01.CIR.0000086950.37612.7b
(Circulation. 2003;108:III-6.)
© 2003 American Heart Association, Inc.
Current Status and Future Prospects for Acute Myocardial Infarction Therapy
Eric J. Topol, MD
From the Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio.
Correspondence to Eric J. Topol, M.D., Department of Cardiovascular Medicine, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Desk F-25, Cleveland, OH 44195. Phone: 216-445-9490, Fax: 216-445-9595, E-mail: topole{at}ccf.org
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Abstract
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Considerable new evidence has accumulated in randomized trials
of myocardial reperfusion. The trials of catheter-based reperfusion
compared with fibrinolytics have shown an advantage for angioplasty
and stenting over pharmacologic therapy, even accounting for
delays in transporting patients from facilities with intervention
capabilities. On the basis of the recent trials, it is recommended
that a regional center for infarct intervention be set up akin
to regional trauma centers in the United States. Now that we
have entered the third decade of myocardial reperfusion therapy,
we can expect iterative improvement in all aspects, and ultimately
a fused approach of pharmacology and mechanical therapies—to
achieve the optimal outcomes and continue to lower the toll
of fatality and morbidity of acute myocardial infarction (MI).
Key Words: fibrinolysis • myocardial infarction • thrombosis
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Introduction
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Since the mid-1980s, there has been steady refinement in our
approach to acute ST-elevation myocardial infarction (STEMI).
Although intravenous streptokinase was the initial pharmacologic
reperfusion therapy validated to improve survival,
1 more recent
trials have shown the superiority of tissue plasminogen activator
(t-PA), and the equivalence of t-PA with reteplase or tenecteplase.
2–4 Furthermore, catheter-based reperfusion has been assessed in
many comparative trials, and has been shown to be superior to
fibrinolytics for reduction of the composite of death, reinfarction,
or stroke.
5–7 The role of antiplatelet adjunctive therapy
has also been studied extensively, with demonstration of the
importance of aspirin in pharmacologic reperfusion and the use
of platelet glycoprotein (GP) IIb/IIIa blockade with catheter-based
reperfusion.
8–11 Catheter-based reperfusion has been increasingly
applied in preference to pharmacologic therapy in hospitals
throughout the United States, Europe, and Australasia. Yet the
practical aspects of providing continuous, 24/7 coverage for
this strategy, involving hospitals without facilities for percutaneous
coronary intervention (PCI), has only recently received attention.
Accordingly, there are many important residual and yet unsettled
questions such as whether to transport patients on an emergency
basis to primary PCI sites, the appropriate use of facilitated
and rescue PCI, combination therapy with half-dose fibrinolytic
and platelet GP IIb/IIIa blockade, incorporation of more potent
anticoagulation strategies, and the role of new devices. Beyond
these issues, there is the question of whether regeneration
of myocardium will be possible as a new means of approaching
patients who have sustained extensive myocardial necrosis. These
matters will be reviewed here to provide a contemporary perspective
of the recent progress and future directions of therapy for
acute MI.
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Transport of Patients to PCI Sites
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Three recent randomized trials have considered the dilemma of
whether patients should be preferentially sent on an emergency
basis to a site where PCI can be performed as compared with
administering fibrinolytic therapy. In the 3 trials, Danish
Multicenter Randomized Trial on Thrombolytic Therapy
versus Acute Coronary Angioplasty in Acute Myocardial Infarction (DANAMI)-2
(DANAMI-2 data were presented at the 51
st Annual Scientific
Sessions of the American College of Cardiology, Atlanta, GA,
March 2002), Primary Angioplasty in Patients Transferred from
General Community Hospitals to Specialized PTCA Units with or
without Emergency Thrombolysis (PRAGUE)-2,
12 and Air Primary
Angioplasty in Myocardial Infarction (Air PAMI),
13 there was
remarkable concordance of benefit for catheter-based reperfusion
over on-site fibrinolytic therapy for the reduction of the cluster
of death, reinfarction, or stroke (
Figure 1). Across the trials,
it is striking to note the similarity in the major adverse event
rates in the transport-PCI group, at 8–8.5%, and in the
fibrinolytic assigned patients at 13.5–15%, for a consistent
40–50% reduction of the primary event cluster.
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Figure 1. Odds ratio and 95% confidence intervals for the composite endpoint of death, reinfarction, and stroke at 30 days for the fibrinolytic (lytic) and transport plus coronary intervention arms in 3 randomized trials.12,13 (Reprinted with permission from Topol EJ, Kereiakes DJ. Regionalization of care for ischemic heart disease: A call for specialized centers. Circulation. 2003;107:1463–1466.)
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These results were not anticipated because of the intrinsic delays associated in transporting patients to specialized centers. The DANAMI-2 trial was performed in Denmark, and the 5 PCI sites had only limited experience as a regional PCI center before initiation of the trial. Similarly, the PRAGUE-2 trial was accomplished in the Czech Republic with minimal delay times from the patient entry to the door of the community hospital to the balloon inflation in the infarct vessel at the referral hospital. Although a smaller trial, the Air PAMI results were quite comparable. The delay times of only 30 minutes for transport in the DANAMI-2 and PRAGUE-2 trials are particularly noteworthy, because this rapid patient transfer and cath laboratory readiness may be difficult to replicate in many geographic locations. These 3 trials, in aggregate, highlight the advantage of a catheter-based reperfusion approach and the overriding benefit of this strategy compared with the more practical and widely available administration of intravenous fibrinolytics. Another recent trial, the Atlantic Cardiovascular Patient Outcomes Research Team (C-PORT), also provided evidence to support this tenet, but in a different matrix of hospitals.14 In this relatively small randomized trial, PCI was performed in 11 community hospital centers in Maryland and Massachusetts that had no bypass surgery backup or concurrent experience in elective PCI procedures. A significant advantage of PCI over fibrinolytic therapy for the death, MI, and stroke endpoint was confirmed. One particularly intriguing explanation is the relative time-independent benefit of angioplasty compared with fibrinolytic therapy as reflected in pooled analysis by Zijlstra et al. (Figure 2).15 Patients typically present with significant delays to the hospital, in the order of 2.5–3 h. PCI would be expected to more reliably achieve reperfusion. Alternatively, the extent of myocardial reperfusion, without a significant residual stenosis of the culprit epicardial artery lesion, may be contributing. Irrespective of the mechanism of the benefit of PCI, these results suggest the need for a revamped approach to evolving MI care in the United States.
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Figure 2. Meta-analysis from randomized trials of coronary intervention (PCI) or thrombolysis (Lysis). Major adverse event rates are lower in angioplasty patients compared with thrombolysis patients. As time from symptom onset to presentation increased, major adverse event rates increased in the thrombolysis patients but not in the angioplasty patients.
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With MI by far the most important cause of death and disability of all of the medical conditions (Figure 3),16 the recent data provide impetus to set up regional specialized centers of MI intervention. Such a system is operational for trauma centers throughout most of the states in the United States. Each regional trauma center provides particular expertise and quality assurance, and receives preferential transfers in order to fulfill the model of centers of clinical excellence. With trauma a much less prominent cause of death in the United States compared with acute MI, it seems particularly appropriate that a parallel entity of specialized centers for MI intervention be set up. This would allow an increasing number of patients to receive state-of-the-art care for acute MI and translate the evidence-based PCI advantage to routine clinical care.
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Fibrinolytic Therapy Is Validated and an Important Alternative Reperfusion Strategy
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Fibrinolytic therapy is the most intensively studied therapeutic
intervention in the history of randomized trials with clearest
survival benefit. Whereas catheter-based reperfusion has been
shown to provide incremental benefit, no comparative trial has
shown mortality reduction. The recent transport trials incorporated
minimal use of rescue PCI after fibrinolytic therapy (2.5% in
DANAMI-2 and 6.4% in PRAGUE-2), and the time of transport and
cumulative was "door-to-balloon" remarkably fast. Notwithstanding
these points, the aggregate data suggests that if PCI can be
performed rapidly by an experienced team and site, the composite
of death, reinfarction, and stroke will be favorably affected.
7
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Facilitated and Rescue PCI
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One critique of the transport trials was a very limited proportion
of patients who underwent rescue PCI if there was no ECG evidence
of reperfusion (<70% resolution of ST- segment elevation)
at 60–90 min after fibrinolytic therapy was initiated.
In the DANAMI-2 trial, for example, only 2.5% of the patients
underwent rescue PCI. A more reflective randomized trial, known
as Comparison of Angioplasty and Prehospital Thrombolysis in
Acute Myocardial infarction (CAPTIM),
17 compared PCI
versus a strategy of fibrinolytic therapy with rescue PCI in 26% of
patients. The results, as shown in
Figure 4, provide much less
compelling evidence of the superiority of the PCI approach.
There has been considerable study of ECG ST-segment resolution,
with validation that this accurately represents tissue level
perfusion by scintigraphic sestamibi myocardial perfusion study.
18 Accordingly, the appropriate use of rescue PCI needs careful
consideration, because it may provide a means of improving the
adverse outcome profile of patients receiving intravenous fibrinolytic
therapy. A major practical problem in the use of rescue PCI
is that the patients have proven resistant to a full dose of
fibrinolytic therapy, and emergency PCI is usually accompanied
by conjunctive use of intravenous platelet GP IIb/IIIa inhibitor.
This sets up a bleeding complication liability with full doses
of fibrinolytic therapy, GP IIb/IIIa blockade, aspirin, and
anticoagulation. With the recent validation of combination fibrinolytic
therapy (at half dose) and GP IIb/IIIa blockade for equivalence
in outcomes,
19,20 there may be more rationale for using this
strategy when rescue PCI can be performed.
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Figure 4. Kaplan-Meier curves for deaths and cumulative rate of composite end point of death, reinfarction, and disabling stroke in the study of patients within the 30 days after randomization, according to treatment group. (With permission from Ref. 17.)
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Importantly, it would be ideal to develop a pharmacologic "bridging" regimen that achieved myocardial reperfusion rapidly, but without the risk of significant hemorrhage, and particularly intracranial bleeding, which characterizes intravenous fibrinolytic therapy. Furthermore, such a drug strategy would support rather than undermine the PCI success, as was the case with fibrinolytic therapy. This supportive, bridging function of a pharmacologic strategy is the basis of the concept of "facilitated" PCI. Three new trials, known as ADdressing the Value of Facilitated ANgioplasty after Combination Therapy or Eptifibatide Monotherapy in Acute Myocardial Infarction (ADVANCE-MI), Facilitated Intervention with Enhanced Reperfusion Speed to Stop Events (FINESSE), and Trial of Inhibitors of Glycoprotein IIb/IIIa with Enoxaparin for Reperfusion (TIGER), are being performed to assess the role of facilitated reperfusion for MI. The study algorithms are provided in Figure 5, and each of the trials provides a distinct window into the facilitated strategy. In ADVANCE-MI, patients are assigned to either a GP IIb/IIIa inhibitor or a combination of a reduced-dose fibrinolytic and a GP IIb/IIIa inhibitor. In contrast, the FINESSE trial includes an arm that has neither drug strategy given as a bridge. The TIGER trial relies on an ECG at 60 min to determine whether reperfusion has occurred and also tests the drug strategies that are evaluated in ADVANCE-MI. ADVANCE-MI tests the use of enoxaparin versus unfractionated heparin (UFH), and TIGER also evaluates enoxaparin versus UFH based on the Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT)-3 trial results.21 Collectively, these trials will greatly enhance our understanding of how to use the pharmacologic regimens in a facilitated or rescue fashion with emergency coronary intervention.
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Figure 5. A, study algorithm for ADVANCE-MI. B, study algorithm for FINESSE. C, study algorithm for TIGER. D, study algorithm for ExTRACT-TIMI 25.
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Regional Centers for MI
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No matter the outcome of these ongoing trials, there should
be readiness for specialized centers to provide timely, high-
quality, catheter-based reperfusion. Such centers would have
a critical role whether they are providing primary, rescue,
or facilitated coronary intervention. This requires the availability,
on a continuous basis, of an on-call team with particular expertise
from having performed a high volume of emergency coronary intervention
procedures. The high volume is not only referring to the center’s
track record over the past few years, but also the experience
of the senior operator. Furthermore, the hardware of the catheterization
laboratory, consisting of high resolution cineangiographic equipment,
along with a full inventory of guide catheters, wires, balloons,
stents, and emboli protection devices, is required. Expertise
in the use of pharmacologic therapy, such as intracoronary adenosine
or nitroprusside, fibrinolytics, and parenteral antiplatelet
and anticoagulant treatment, will be imperative. Management
of the high-risk patient with hemodynamic compromise is yet
another dimension of such a center. This includes not only the
use of an intra-aortic balloon pump, but also the immediate
triage to bypass surgery, or the use of extracorporeal membrane
oxygenation or left ventricular assist devices in young patients
with a devastating MI who might be eligible for transplantation.
The unusual but important patient with intractable ventricular
arrhythmias in this setting mandates the cooperative effort
of senior electrophysiologists. Similarly, life-threatening
bleeding may require emergency consultation with hematologists
or gastroenterologists for optimal management. In aggregate,
the requirements for a regional center are extensive, and the
credentialing of hospitals and operator teams would be necessary
to ensure quality standards, and yearly review of results would
help sustain and promote the highest level of care. Outcomes
that can be tracked include time-to-treatment (e.g., door-to-balloon),
successful reperfusion of the infarct vessel, survival, congestive
heart failure, reinfarction, transfusion requirement, and use
of appropriate conjunctive medications, such as aspirin or statins.
Finally, this is a very dynamic field, and the standards continue
to be refined. Ideally, all of the regional infarct centers
would participate in clinical research projects to stay fully
abreast of the latest developments in this arena rather than
awaiting the slower process of trial publication and change
in guidelines to affect state-of-the-art clinical practice.
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Combined Fibrinolytic and Platelet GP IIb/IIIa Blockade
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Two trials have assessed the clinical outcome profile with half-dose
fibrinolytic therapy and GP IIb/IIIa blockade. In the largest
trial of 16,600 patients, Global Use of Strategies to Open Occluded
Coronary Arteries (GUSTO)-V, there was no difference in mortality
at 30 days or 1 year for combination therapy compared with reteplase
monotherapy.
19,20 There was a significant reduction in reinfarction
for combination therapy, but this was achieved with significant
excess in bleeding complications. Importantly, for younger patients,
and especially those <60 years of age, there appeared to
be a protective effect for the combination with significantly
less intracranial hemorrhage (ICH). On the other hand, those
patients >75 years of age appeared to have excessive risk
of ICH with combination therapy. Although a smaller trial of
6000 patients, ASSENT-3 had similar findings using tenecteplase
as the fibrinolytic.
21 Interestingly, the combination of tenecteplase
and enoxaparin achieved a similar outcome profile for reduction
of the death and reinfarction composite, along with less bleeding
complications, compared with the results obtained with tenecteplase
and abciximab.
High-risk subsets may derive particular benefit from combination therapy. Mukherjee et al. have shown recently that the patients with prior coronary artery bypass grafting (CABG) had a very substantial benefit of combination therapy in the GUSTO-V trial.22 Patients with large anterior MI also appeared to have a survival benefit that was nearly 1% absolute, or 14% relative,19 in keeping with the magnitude of benefit of t-PA over streptokinase in the GUSTO-I trial for the overall cohort. Accordingly, whereas combination therapy is not useful as a routine pharmacologic strategy, it may have particular value in younger patients with prior CABG or anterior MI, and the strategy for facilitated PCI is currently being assessed in ongoing trials. It is important to point out that the decision to select particular strategies for MI will be indexed not only to survival outcomes, but also to key secondary outcomes such as reinfarction and prevention of stroke or heart failure. The advantage of combined platelet GP IIb/IIIa blockade and half-dose fibrinolytics, on an individualized basis, can be supported by the composite of expected outcome effects. For a young patient with a large MI, one would anticipate reduction of intracerebral hemorrhage, less reinfarction, and at least a trend toward less mortality. The ability for a new therapy in acute MI to show an "across-the-board" striking mortality reduction at this point in the progressive refinement of treatment strategies appears unlikely, but the use of available clinical trial evidence to extrapolate an appropriate selection from a wider array of therapeutic choices for greater net benefit of a particular patient is attractive.
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More Potent Anticoagulation
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UFH has been the dominant anticoagulant used since the initiation
of reperfusion therapy in the 1980s. An indirect anticoagulant
requiring antithrombin-III as a cofactor, and readily inactivated
by platelet factor-4 and plasma proteins, the biological attributes
of heparin can be seen as suboptimal. This has led, in recent
years, to the challenge of the use of heparin using low-molecular-weight
heparins or direct thrombin inhibitors. The most favorable data
comes from ASSENT-3
21 in which enoxaparin with tenecteplase
was superior to UFH with tenecteplase for the composite of death,
MI, or recurrent ischemia. This issue is being intensively studied
in the ongoing Enoxaparin and Thrombolysis Reperfusion for Acute
Myocardial Infarction Treatment-Thrombolysis in Myocardial Infarction
study 25 (ExTRACT-TIMI 25) trial in which >20,000 patients
are being enrolled with randomization of enoxaparin or UFH with
any fibrinolytic (t-PA, reteplase, tenecteplase, or streptokinase)
selected by the physician-investigator (
Figure 5). This trial
of enoxaparin comes after not only ASSENT-3 but also the Efficacy
and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary
Events (ESSENCE) and TIMI 11B trials,
23,24 both of which validated
the benefit of enoxaparin over heparin in patients with acute
coronary syndromes (unstable angina and non-ST-elevation MI).
In addition to these completed trials in patients with acute
coronary syndromes, there is a large ongoing trial known as
Superior Yield of the New Strategy of Enoxaparin, Revascularization,
and GlYcoprotein GP IIb/IIIa Inhibitors (SYNERGY) that is currently
testing enoxaparin or heparin in acute coronary syndromes, and
the ADVANCE-MI trial, a facilitated PCI project, as depicted
in
Figure 5. The recently completed ASSENT-3 PLUS trial, in
which tenecteplase plus enoxaparin or tenecteplase plus UFH
was administered in the ambulance, confirmed the finding that
elderly patients (age >75) need to have their enoxaparin
and fibrinolytic dose adjusted down. In this trial of 1,639
patients, the ICH rate was 2.2% in the combined tenecteplase
plus enoxaparin group compared with 0.97% in the tenecteplase
plus UFH group (
P=0.047). However, almost all of the ICH events
occurred in the age >75 years group, and there was a significant
interaction between patient age and the risk of bleeding. This
was taken into account in the ExTRACT-TIMI 25, ADVANCE-MI, and
SYNERGY large-scale programs, which lowered the dose of enoxaparin
in patients
75 years of age.
There have also been studies using direct thrombin inhibitors, beginning with the GUSTO II trial that tested hirudin, and most recently, the large Hirulog Early Reperfusion/Occlusion (HERO)-2 trial that compared bivalirudin and UFH, both with streptokinase as the fibrinolytic agent. In both GUSTO II and HERO-2 there was modest evidence of reduced reinfarction but no decrease in mortality.25,26 To date, considering the totality of data available,27 there is a lack of convincing evidence from the direct thrombin inhibitor trials of an advantage compared with UFH, but ongoing trials will address this more definitively.
Other anticoagulants are in clinical development for acute MI adjunctive therapy. The pentasaccharide, a preferential factor Xa inhibitor, and selective factor Xa inhibitor agents, which have been tested in the setting of venous thrombosis, are being considered for Phase III assessment compared with UFH in acute MI. These agents have the putative advantage of blocking thrombin generation compared with direct thrombin inhibitors, which achieve thrombin activation but do not eschew the generation or accumulation of thrombin.
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New Devices
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There is considerable interest in extrapolating recent advances
in new devices from other settings in interventional cardiology
to acute MI. It is clear that most patients do not achieve TIMI
3 reflow after emergency PCI, and that the most likely explanation
for incomplete tissue level perfusion is embolization of thrombus,
with or without microparticulate atheromatous debris. Recently,
the study by Henriques et al. documented a compromised long-term
survival in patients who had suffered apparent angiographic
embolization with their PCI for acute MI (
Figure 6).
28 The Saphenous
Vein Graft Angioplasty Free of Emboli Randomized (SAFER) trial,
conducted in patients with saphenous vein graft lesions with
an emboli protection device known as the PercuSurge, served
as a key proof-of-concept. In that trial, reduction of peri-procedural
MI was substantial among patients who were assigned emboli protection.
29 It is likely that a similar extent of reinfarction or infarct
expansion can be avoided in the setting of acute MI, and ongoing
trials such as Enhanced Myocardial Efficacy and Recovery by
Aspiration of Liberalized Debris (EMERALD) are evaluating the
use of emboli protection with emergency coronary intervention.
In order for successful percutaneous intervention to be accomplished
in the infarct vessel, it is likely that embolization of clot,
with or without atheromatous debris, is obligatory. As the emboli
protection devices are better engineered and become less costly,
it is quite likely that such devices will ultimately be considered
standard of care and be used in virtually all patients undergoing
acute MI intervention. But this will take at least a few years,
given the incubation period for not only better designs, but
also validation in clinical trials.
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Figure 6. Long-term survival with and without reinfarction in patients with or without distal embolization. (With permission from Ref. 28)
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In a parallel course of development that has received considerable attention, the Randomized Study with the Sirolimus-Eluting Bx Velocity Balloon-Expandable Stent in the Treatment of Patients with de novo Native Coronary Artery Lesions (RAVEL)30 and SIrolImUS-eluting stent in de novo Native Coronary Lesions (SIRIUS) trials (SIRIUS data were presented at the 52nd Annual Scientific Sessions of the American College of Cardiology, Chicago, IL, March 2003), have demonstrated that stents coated with a rapamycin derivative, sirolimus, have a markedly lower rate of in-stent restenosis during extended follow-up. Although coated stents have not yet been specifically tested in the acute MI setting, it is likely that they will be used when commercially available given the extensive reduction in restenosis. There is an overall sense that the infarct vessel carries a higher rate of renarrowing during follow-up (compared with the coronary arteries not involved in acute MI), and that the sirolimus and other coated stents do not pose a thrombotic jeopardy of subacute stent thrombosis. However, it will be helpful and important to document these issues in the setting of acute MI.
Hypothermia to 32–34°C has been shown to ameliorate outcomes in patients who suffer cardiac arrest in a randomized trial.31 Now that there are devices that can be rapidly inserted into the central veins via percutaneous technique and achieve core hypothermia, this strategy is being tested for acute MI. There are hemodynamic effects of hypothermia including increased systemic vascular resistance and diminished cardiac output, along with metabolic effects such as hyperglycemia. We will need to have data from rigorously performed randomized trials before it is possible to suggest that hypothermia is an attractive option for patients with acute MI.
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Myocardial Regeneration
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Perhaps the most innovative and exciting approach to acute MI
lies with the potential to purposefully induce new myocyte formation.
The concept has received considerable attention in the past
couple of years, with several critical observations. First,
in a variety of species, it has been shown that myocardium can
be regenerated from hematopoietic or mesenchymal (stromal) stem
cells derived from the bone marrow. In some of these experimental
models, not only are myocytes generated but there is improved
functionality of the myocardium in the region or even amelioration
of global ventricular function (
Table 1).
32–36 Second,
the phenomena of homing of stem cells to injured myocardium
has been intensively studied, and particular factors have been
implicated in orchestrating the process that routes stem cells
to the tissue in need.
37 Third, a variety of cells can be transformed
to myocytes including embryonic stem cells, hematopoietic cells
from the bone marrow, mesenchymal or stromal cells from the
marrow, or endothelial progenitor cells.
38 Fourth, in patients
who sustain acute MI there is a natural response of recruiting
new myocytes in the weeks that follow the infarct.
39 And fifth,
early studies in humans with direct intracoronary infusion or
injection of bone marrow-derived cells have been shown to be
feasible and associated with improved ventricular function.
40,41
This series of seminal studies sets the foundation for clinical trials of stem cells for acute MI. The optimal methods for mobilization of stem cells, the precise biologic profile of particular cell lines, refinements and amplification of homing and successful transdifferentiation, and long-term function of these regenerated myocytes all need careful assessment. Whether or not the new myocardial cells can be developed in adequate quantity to acutely or ultimately restore cardiac function, and whether there will be electrical instability as a result, or oncologic potential of the cells at a future point, all stand as looming questions.42 But the excitement of this potential has captured the attention of all of the active cardiovascular investigators. The complementarity of myocardial reperfusion and myocardial regeneration seems attractive, particularly because we have been unable to find ways to get patients to present early enough for maximal myocardial salvage, and our pharmacologic approaches have not yielded a major, incremental advance in success over the past decade. But considerably more headway will be required to know whether this conceptual breakthrough will become a clinical reality at some point.
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Conclusion
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Although MI is the most important cause of death and disability
in Western society, there has been steady refinement in our
therapeutic approaches. In recent years, catheter-based reperfusion
has been shown to be clearly superior to pharmacologic therapy,
and consideration for regional centers of excellence is clearly
imperative to translate the new body of evidence into clinical
practice. It is clear that such specialized centers will require
continuous quality assurance, such as constant readiness on
a 24/7 basis, which has, until this point, not characterized
most sites for emergency coronary intervention.
43 The "facilitative"
pharmacologic approach is being extensively assessed in ongoing
trials, and, at the same time, there are trials to assess improved
adjunctive therapy, such as low-molecular-weight heparin instead
of unfractionated heparin. We clearly can do better with appropriate
triage of reperfusion therapy, since recent registry data indicate
that 30% of patients who would otherwise qualify are not getting
the therapy.
44 Moreover, systems can be re-evaluated to smooth
out the timing of therapy, as a recent British report that empowered
nurses to administer fibrinolytic therapy showed a marked reduction
in the door-to- treatment time without mistaken diagnosis.
45 In the context of improving the catheter-based approach, the
potential for routine emboli protection as a means of achieving
more complete, tissue-level reperfusion is attractive and currently
being explored. While the field of myocardial regeneration is
in a nascent phase, it clearly has enormous potential to help
us deal with the patient who has suffered quite extensive myonecrosis.
Now that we have entered the third decade of myocardial reperfusion
therapy, we can expect iterative improvement in all aspects,
and ultimately a fused approach of pharmacology and mechanical
therapies, to achieve the optimal outcomes and continue to lower
the toll of fatality and morbidity of acute MI.
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References
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- The GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med. 1993; 329: 673–682.
- The GUSTO-III Investigators. An international, multicenter, randomized comparison of reteplase with alteplase for acute myocardial infarction. N Engl J Med. 1997; 337: 1118–1123.
- ASSENT-2 (Assessment of the Safety and Efficacy of a New Thrombolytic Investigators). Single-bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: The ASSENT-2 double-blind randomized trial. Lancet. 1999; 354: 716–722.
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- Brener SJ, Barr LA, Burchenal JE, et al. Randomized, placebo-controlled trial of platelet glycoprotein IIb/IIIa blockade with primary angioplasty for acute myocardial infarction. ReoPro and Primary PTCA Organization and Randomized Trial (RAPPORT) Investigators. Circulation. 1998; 98: 734–741.
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- Widimsky P, Budesinsky T, Vorac D, et al., on behalf of the PRAGUE Study Group Investigators. Long distance transport for primary angioplasty vs immediate thrombolysis in acute myocardial infarction. Final results of the randomized national multicentre trial—The PRAGUE-2. Eur Heart J. 2003; 24: 94–104.
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Abstract
Introduction