(Circulation. 2000;102:IV-2.)
© 2000 American Heart Association, Inc.
Special Anniversary Issue |
Progress in the Treatment of Acute Coronary Syndromes
A 50-Year Perspective (1950–2000)
From the University of Montreal/Montreal Heart Institute, Montreal, Quebec, Canada; the Department of Internal Medicine, University of Texas–Houston Medical School, and Texas Heart Institute; and the Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
Correspondence to James T. Willerson, MD, Circulation, SLEH/THI, 6720 Bertner, Room B524, MC 1-267, Houston, TX 77030.
Early in the past century,
skillful physicians observed that prodromal symptoms often precede
acute myocardial
infarction,1 2 3
an observation that was prospectively validated in mid-century in
cohorts of patients presenting with a changing pattern of chest
pain.4 5 6
In the 1960s, the new syndrome was in search of a semiology and a
natural history and was variously identified by symptoms (crescendo
angina, status anginosus, accelerated angina), by presumed
pathophysiology (coronary failure, acute coronary insufficiency), or by
its prognostic significance (impending myocardial infarction,
preinfarction angina). The term unstable angina proposed by Fowler was
eventually adopted.7
The modern era was introduced by an early trial by Paul Wood with an
oral antivitamin K prematurely discontinued because of excess events in
the absence of
treatment,8 and in
the 1970s and 1980s and accelerating to the present, by the definition
of risk
strata9 10
and the pioneer works on pathophysiology and treatment
(Table 1
).11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56
Constantinides described fissuring of atherosclerotic plaques leading
to coronary artery thrombosis in
1966.11 Willerson et
al, in the late 1970s, postulated that "an alteration in
atherosclerotic plaque morphology led to platelet adhesion, thromboxane
A2 accumulation, growth of thrombus and dynamic
vasoconstriction" and that this sequence of events caused the
conversion from a stable to an unstable coronary
syndrome.12 Davies
et al13 and
Falk14 showed at
postmortem studies that patients with unstable angina and myocardial
infarction almost always have atherosclerotic plaque fissuring or
ulceration. The vulnerable plaques have thin fibrous caps, an adjacent
lipid core, and a large number of inflammatory cells, primarily
monocyte-derived macrophages, activated T cells, and mast cells either
immediately beneath the cap or on its surface. The inflammatory cells
are attracted, at least in part, by oxidized LDL within the plaque.
They release metalloproteinases capable of degrading collagen in the
fibrous cap, leading to plaque fissuring or ulceration and thrombosis
(Figure 1).15 16
Other studies have shown that in addition to thromboxane
A2, serotonin, ADP, platelet-activating factor,
tissue factor, oxygen-derived free radicals, and endothelin accumulate
at sites of endothelial injury leading to thrombosis, dynamic
vasoconstriction, and fibroproliferation
(Figures 1 and 2).12 15 17 18 20 21
DeWood et al demonstrated angiographically that patients with acute
myocardial infarction usually have intracoronary
thrombi,22 and Buja
and Willerson confirmed these observations at postmortem
examination.23
Fuster et al documented that the lipid-rich core was the most
thrombogenic component of the
plaque24 and that it
also expressed intense tissue factor
activity.25 When the
thrombosis with its attendant vasoconstriction is transient or not
completely occlusive, the patient develops unstable angina, and when it
is more prolonged, myocardial infarction
occurs.16 17 18
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Recent work by Maseri and others has shown that
patients with unstable angina and non–ST-segment elevation myocardial
infarction who have elevated serum concentrations of selected
inflammatory markers, especially C-reactive protein, fibrinogen, the
serum amyloid-like protein, and interleukins 1 and 6, often have
subsequently complicated clinical
courses.26 27 28 29 30
T cells and
macrophages,31 the
complement
system,32 33
and nuclear
factor-
B34 are
also activated.
The determination of troponin T or troponin I has taken a privileged role in clinical practice during the past decade, first as a sensitive and specific marker of myocyte necrosis, and second as a useful tool for predicting prognosis and determining treatment regimens. Thirty percent to 40% of patients with unstable angina have elevated serum levels of troponin T and/or I, often with normal creatine kinase (CK)-MB values; these patients have a 5- to 15-fold increase in the risk of a future cardiac ischemic event and profit more from the new antithrombotic therapy,35 36 37 38 39 because the elevation of normal CK-MB values suggests an underlying pathophysiology related to an active plaque-shedding thrombotic material and plaque debris more distal in the coronary system that cause microinfarctions.17 40
Casscells and Willerson et al have shown that atherosclerotic plaques with the morphological characteristics that predict risk of plaque ulceration or rupture have temperature heterogeneity.41 If substantial inflammation exists in the plaque, there is an increased temperature varying from 0.8°C to 4°C.41 Stefanadis et al confirmed these findings in human coronary arteries in vivo.42 This has led to efforts to develop catheters and noninvasive imaging systems capable of detecting temperature heterogeneity within the atherosclerotic plaque itself, as well as to identify more specifically the morphology of plaques before their ulceration or fissuring, with the expectation that this will ultimately allow one to prevent the development of unstable angina and myocardial infarction. Fuster and colleagues used MRI to identify thin fibrous caps and the lipid core in vulnerable plaques for similar purposes.43 Thus, one may anticipate strong efforts in the future to use measurements of plaque temperature and characterize plaque morphology with various imaging techniques to identify the vulnerable atherosclerotic plaques before they ulcerate or fissure and lead to acute coronary syndromes (ACS) (and probably cerebrovascular accidents as well).
Determinants of progression to myocardial infarction include the duration of the thrombosis,16 17 18 variables influencing myocardial oxygen consumption,44 presence or absence of coronary collaterals, and the dynamic nature of focal coronary artery occlusion by inappropriate vasoconstriction.19 20 21 Reimer and Jennings demonstrated that ischemia and infarction begin on the inner wall of the heart and extend outward toward the epicardium.45 Necrosis in the ischemic area at risk grows exponentially within minutes and hours after coronary artery occlusion. Reperfusion halts this process but is associated with a variable amount of cell damage.46 The rapid ion shifts that follow the first few seconds and minutes of reperfusion are particularly disastrous for cell survival, precipitating contraction band necrosis.47 48 49 In the following hours and days, the inflammation process contributes further to the progression of necrosis,50 51 and a variable amount of apoptosis occurs.52 53 Subsequently, in the following weeks and months, infarct expansion and left ventricular remodeling supervene.54 Incomplete reperfusion with no-reflow at the tissue cell level caused by edema and necrosis of the small arterioles plugged with embolic material and leukocyte accumulation may compromise myocyte function at all these stages.55 55A 55B 56
The past decade has seen a new risk-stratification scheme,
based on improved insight into the cellular mechanisms of the disease,
and a new therapeutic armamentarium
(Table 1
). The previous terminology referring to the
heterogeneity of the disease has shifted toward a unifying concept
encompassing the wide spectrum of manifestations of ACS, subdivided for
the purpose of therapeutic considerations into ST-segment elevation
myocardial infarction (STEMI), or "Q-wave" myocardial infarction,
and non–ST-segment elevation ACS with or without cell necrosis, namely
unstable angina (UA) and/or non–ST-segment elevation MI (NSTEMI), or
ST-segment depression or "non–Q-wave" myocardial infarction. A
comprehensive definition of unstable angina encompassing the clinical
manifestations, the ECG changes, and the blood markers was developed by
Braunwald and was recently modified by Braunwald and
Hamm57 58
and by the guidelines for management published by the European Cardiac
Society59 and by the
American College of Cardiology and American Heart
Association.60 61
Incidence, Prognosis, and Risk Stratification
The diagnosis of UA/NSTEMI is increasingly recognized and accounts now for the majority of admissions to coronary care units. The prognosis remains serious, and improved risk stratification is associated with selective hospitalization of higher-risk patients. The cumulative risk of an ischemic event during the acute phase and the following 3 months, probably because of the prolonged time required for plaque healing, approaches 50%. This requires specific treatment algorithms to cope cost-effectively with the disease. The possibility of early risk stratification combining clinical features, ST-T changes, troponin T or I, and C-reactive protein plasma levels27 28 29 30 31 32 33 34 35 36 37 38 39 and the availability of an increasingly effective antithrombotic therapy and of safer and highly successful reperfusion procedures during the acute phase have rendered possible a fast-track approach to management of UA/NSTEMI, similar to the one developed for the management of patients with ST-segment elevation myocardial infarction.
Treatment
Management of the ACS has become multifactorial as
therapies addressing the various steps of the cascade of
pathophysiological events involved in UA/NSTEMI, from plaque activation
to ischemia and to cell necrosis, have become
available.60 61
Restoration of an optimal myocardial blood flow has also gained in
importance. In patients with STEMI, prompt reperfusion is mandatory. In
patients with UA/NSTEMI, plaque stabilization to prevent progression of
the disease and plaque passivation to prevent recurrence of thrombosis
and vasoconstriction are required. The demand side is still favorably
influenced by drugs acting on heart rate, afterload, inotropic state,
and preload to reduce myocardial oxygen consumption. Nitrates,
ß-blockers, and/or calcium antagonists titrated to the patient’s
needs are prescribed liberally for this
purpose.60 61
Antithrombotic therapy, however, has become the cornerstone of therapy
in ACS following the insights gained into the basic pathophysiological
mechanisms and documentation of the benefit of aspirin and heparin in
the mid-1980s by Théroux and others
(Figure 3).62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93
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Antithrombotic Therapy
Aspirin and Heparin
In ISIS-2, the rate of vascular death in patients with
STEMI was reduced by 21% with aspirin, a gain of similar magnitude and
additive to that of thrombolysis with
streptokinase.62
Four controlled trials in UA/NSTEMI showed nearly 50% reduction in the
rates of death or MI with very homogeneous results between trials
independently of doses of aspirin used, timing of initiation during or
after the acute phase, and duration of
administration.63 64 65 66
The important meta-analysis of the placebo-controlled trials with
aspirin by the Antiplatelet Trialists Collaboration showed a >25%
reduction in the risk of infarction, stroke, or vascular death among
70 000 high-risk
patients.67
Additional benefit was subsequently documented with the
addition of heparin to aspirin in patients with UA/NSTEMI
(Figure 3).65 66 89 90
This combination reduces the risk of death or MI by 48% compared with
aspirin alone, in harmony with the major role of tissue factor as well
as platelets and platelet-derived mediators in thrombus formation in
human coronary
arteries.17 18
The benefits of aspirin are currently explained by its
ability to irreversibly inhibit cyclooxygenase-1 activity by
acetylation of serine 516 of the enzyme, preventing thromboxane
A2 generation and thromboxane
A2–induced platelet aggregation,
vasoconstriction, and its contribution in promoting endothelial and
smooth muscle cell
proliferation.16 17 18
This inhibition is present with low doses of aspirin, 80 to 160
mg/d.68 Other
effects of aspirin, as yet not totally defined, could contribute to the
benefit provided, such as its anti-inflammation
properties.29
Aspirin, however, is a weak antiplatelet drug, and thromboxane
A2 is only one of the multiple mediators leading
to platelet
aggregation.12 16 17 18
Similarly, heparin has an imperfect pharmacokinetic profile and little
access to fibrin-bound thrombin, resulting in incomplete plaque
passivation and frequent disease reactivation after its
discontinuation.69
These limitations of aspirin and heparin and the recognition that
multiple mediators contribute to thrombosis and vasoconstriction in
injured coronary arteries
(Figure 2)16 17 18
have forced a continuous search for more effective antithrombotic
therapy that has led to the introduction in clinical practice of the
ADP receptor blockers and intravenous glycoprotein (GP) IIb/IIIa
antagonists as antiplatelet agents and of the low-molecular-weight
heparins and direct inhibitors of thrombin as alternatives to
heparin.72 75 81 82 83 84 85 90 91 92 93
Thromboxane A2 synthase inhibitors and receptor (TP) antagonists provide the theoretical advantages over aspirin of preserving production of prostacyclin, a potent vasodilator and antiplatelet agent, and of blocking the effect of cyclooxygenase-2 (COX-2)–mediated thromboxane A2 production. COX-2 is induced in activated monocytes/macrophages and in endothelial cells in inflammatory states and is poorly inhibited by low doses of aspirin.70 A new generation of agents that block the effects of thromboxane A2 and of other arachidonic acid products on the TP receptor, but not those of prostacyclin, represents promising antiplatelet therapy for the future.71 71A
ADP Receptor Blockers
The thienopyridines ticlopidine and clopidogrel
irreversibly block ADP receptors and ADP-induced platelet aggregation.
These drugs are useful for the secondary prevention of cerebral and
coronary events and of subacute stent
occlusion.72 73 74 75
Clopidogrel is now preferred over ticlopidine because of a safer
hematological side-effect profile with less leukopenia and thrombotic
thrombocytopenia
purpura.73 74
At present, it is used in the short term in combination with aspirin
after stent implantation in
patients.75 This
drug combination is now being tested in patients with UA/NSTEMI under
the hypothesis that the inhibition of 2 different pathways to platelet
aggregation will provide additive clinical
benefit.16 17 18
The recent cloning of the P2T receptor, 1 of the
3 ADP receptors identified and the one responsible for most platelet
effects, has made possible the development of more potent and specific
blockers with improved pharmacokinetic
properties.76 These
drugs directly inhibit the receptor and are active after intravenous as
well as oral administration; the inhibition is reversible and
dose-related to achieve full inhibition of the
P2T receptor, contrasting with the
thienopyridines, which are prodrugs that are active only after oral
administration, with a maximum inhibition of 40% achieved.
GP IIb/IIIa Antagonists
GP IIb/IIIa receptor antagonists are products of modern
biotechnology. From basic research on the congenital platelet defect
involved in Glanzmann thrombasthenia and the identification of the
mechanisms responsible for fibrinogen binding to GP IIb/IIIa receptors,
a chimeric monoclonal antibody was developed by
Coller,77
objectively tested in a randomized double-blind placebo-controlled
trial by Topol, Califf, et al, and subsequently approved for clinical
use.78 Shortly
thereafter, peptide and nonpeptide compounds mimicking the RGD
(arginine-glycine-aspartic acid) or KGD (lysine-glycine-aspartic acid)
chain responsible for fibrinogen binding to the receptor were
synthesized.79 80
These drugs have shown consistent benefit in the management of patients
undergoing a percutaneous intervention and in patients hospitalized
with UA/NSTEMI. In the EPIC trial, the prototype of the trials
performed with a GP IIb/IIIa antagonist, a bolus of abciximab followed
by an infusion reduced by 35% the risk of death or MI or the need for
a new revascularization in patients undergoing coronary artery
angioplasty (from 12.8% in the placebo group to 8.3%,
P=0.008).78
These benefits of abciximab have been reproduced in most subsequent
trials.81 82
In a recent placebo-controlled trial, in patients undergoing stent
implantation, the primary end point within the first 30 days occurred
in 10.8% of patients in the stent and placebo groups, in 5.3% of
patients in the stent plus abciximab group (hazard ratio 0.48,
P<0.001), and in 6.9% in the angioplasty plus
abciximab group (hazard ratio 0.63,
P=0.007).81
Trials with
abciximab,82
tirofiban (nonpeptide, nonantibody inhibitor of GP IIb/IIIa
receptors),83 and
eptifibatide (synthetic peptide inhibitor of GP IIb/IIIa
receptors)84 in
patients with UA/NSTEMI have shown a benefit and reduction in the rates
of death and MI during the initial phase of medical management and as
angioplasty or stenting was
performed.85
Ongoing trials with GP IIb/IIIa antagonists evaluate their potential as adjuncts to thrombolysis in patients with STEMI, in combination with low-molecular-weight heparin, and as part of an early routine invasive versus an early routine conservative management strategy in patients with UA/NSTEMI. The respective efficacies of tirofiban versus abciximab in patients undergoing stent implantation are also being evaluated in current trials. Trials are still ongoing with the oral GP IIb/IIIa antagonists despite the failure of 3 large-scale studies to document any benefit of the active drug over placebo.86 87 88 The unfavorable trend toward more frequent thrombotic events in these trials with the oral GP IIb/IIIa antagonists have permitted an in-depth investigation of the physiological roles of the GP IIb/IIIa receptors.
Low-Molecular-Weight Heparins and Direct
Thrombin Inhibitors
Low-molecular-weight heparins are increasingly used in
lieu of unfractionated heparin on the basis of results of
placebo-controlled trials that have documented their superiority over
placebo89 and of
similar or slightly better protection than unfractionated
heparin.90 91
The low-molecular-weight heparins have a more favorable pharmacokinetic
profile than unfractionated heparin in allowing predictable
anticoagulation with subcutaneous administration once or twice daily
without the need for routine laboratory
monitoring.92
Hirudin, a potent bipolar direct thrombin inhibitor that does not require a cofactor for its effect, has no known endogenous inhibitors, and is effective against thrombin-bound fibrin,93 has been extensively evaluated in STEMI and in UA/NSTEMI trials. The trials have, in general, shown a superiority of the drug over unfractionated heparin during the period of administration but no statistically significant advantages in the longer term in their primary end points.94 95 96 97 These results, combined with a narrow margin between efficacy and risks of bleeding, have precluded the routine clinical application of hirudin. Hirudin is now approved for the prophylaxis of deep vein thrombosis and for the management of patients with heparin-induced thrombocytopenia. Argatroban, an arginine derivative that binds thrombin at the apolar-binding site, is also approved for the latter indication, and bivalirudin (Hirulog), a small peptide modeled on the active sites of thrombin, for use with percutaneous coronary angioplasty.98
Newer Antithrombotic Drugs
The research field on antithrombotic therapy is
expanding rapidly as a result of progress in molecular biology and
genetic engineering that allows development of drugs acting on highly
specific steps of the coagulation cascade and of platelet function.
Meanwhile, the methodology of clinical trials has reached a degree of
sophistication and an international perspective that permit rapid and
objective evaluation of clinical efficacy and hypothesis generation.
Thus, drugs acting on tissue factor, factor VIIa, factor Xa, protein C,
and thrombin-activatable fibrinolysis inhibitor (TAFI), as well as
orally active heparins and antithrombins and new inhibitors of
platelets, are currently being studied.
Myocardial Cell Protection
In 1974, an editorial published in
Circulation by Braunwald and Maroko called for "the
reduction of infarct size—an idea whose time (for testing) has
come."99
Reperfusion therapy was very successfully developed in the following
decade, whereas other attempts to prevent cell necrosis
pharmacologically aimed primarily at reducing myocardial oxygen
consumption have generally failed unless reperfusion was provided. In
this era of reperfusion, however, direct cellular protection targeting
more fundamental mechanisms responsible for progression of cell
ischemia to cell necrosis and reperfusion damage and prevention and
correction of no-reflow at the cellular level are new therapeutic
targets.100
Promising interventions during ischemia and very early reperfusion are
modifiers of cell acidification and prevention of intracellular proton
and calcium accumulation by inhibiting sodium/hydrogen exchange (NHE)
with agents, such as cariporide and
enaporide,101 that
modulate the contractile state with calcium desensitizers, such as the
atrial natriuretic factor, and by uncoupling the cell gap junction to
prevent cell-to-cell progression of necrosis. Pharmacological
ische-mic preconditioning also needs to be
explored.102
Potentially useful interventions at an early stage of clinical
investigation are anti-inflammatory agents, such as monoclonal
antibodies and low-molecular-weight compounds against the terminal
fraction of the complement
system103 and
against selectins, integrins, and various cytokines, and antiapoptosis
agents. Interventions potentially capable of inhibiting and attenuating
remodeling are neurohormones, agents that modulate NHE activity, and
matrix metalloproteinase inhibitors. Favorable clinical results have
been reported with agonists of the adenosine receptors
A1 and
A3.104
The no-reflow phenomenon will most likely be influenced by
anti-inflammatory agents and agents that block platelet-leukocyte
interactions; in this regard, benefit has already been documented with
GP IIb/IIIa receptor inhibition, probably by prevention of distal
embolization of platelet aggregates and formation of platelet-leukocyte
aggregates that plug small
arterioles,105 as
well as inhibition of inappropriate vasoconstriction associated with
the platelet-derived mediators
(Figure 2).17 18
Metabolic interventions that reduce free fatty acid levels and their
oxidation and enhance glucose utilization and glycolysis, such as
glucose-insulin-potassium infusion and stimulation of pyruvate
dehydrogenase activity, may be useful in less severe ischemic
states.106 All
these interventions will most likely require reperfusion for optimal
benefit.107
Reperfusion Procedures
Reperfusion procedures have profoundly influenced the
practice of cardiology. With the help of expertise and an improved
technology, the indication of coronary artery bypass surgery and of
percutaneous intervention to relieve angina was rapidly extended to
improve prognosis of patients with UA/NSTEMI and with STEMI. The early
trials that have compared bypass surgery with medical management and
the more recent trials that have compared an early invasive and an
early noninvasive routine management strategy have provided important
insight.108 109 110 111
In the most recent trial, a routine early invasive strategy
significantly reduced the rates of death or myocardial
infarction.112
Interventions are frequently the only effective means to control
refractory angina. Judicious use of intervention and medical management
currently appears to be the optimal approach, whereas an aggressive
program for the control of risk factors is emerging as an alternative
to mechanical revascularization in stabilized
patients.113
Closing the Therapeutic Loop
The control of risk factors is associated with plaque
stabilization and with some physiological regression of the severity of
coronary artery lesions. In one study of selected patients, such
therapy was more effective than percutaneous revascularization to
prevent the need for a future revascularization
procedure.113
"Endothelial therapy" has become a therapeutic target to control
atherosclerosis and plaque activation. One can foresee new
pharmacological therapies to control and prevent the causes of the
disease and the progression of atherosclerosis and its consequences
with such agents as new anti-inflammatory and antithrombotic therapies,
as well as anti-infectious therapy and selected forms of gene therapy
(Table 1).
Fibrinolytic Therapy
In the 1950s, patients with acute myocardial infarction were admitted for a protracted period to a general medical ward without ECG or physiological monitoring. Those patients who survived received palliative therapy for their symptoms and pharmacological measures directed toward the electrical and functional hemodynamic disturbances that commonly ensued. After the introduction of specialized coronary care units in the early 1960s, anticipation of these problems became more feasible, and the advent of bedside hemodynamic monitoring in the critically ill soon followed.114 115 This development provided insight into the various physiological subsets that comprise acute myocardial infarction and not only enhanced clinical and pharmacological management but also circumvented prior detrimental practices, such as overzealous diuresis and inappropriate use of oxygen-wasting catecholamines, etc.116 By the early 1970s, the determinants of myocardial oxygen consumption were well understood, and it was appreciated that the extent of myocardial necrosis pursuant to acute myocardial infarction directly modulated clinical outcome.117 Facilitated by ECG, enzymatic, and imaging techniques to quantify both myocardial ischemia and infarction, Braunwald and others led an intense effort to reduce the extent of ischemic injury during the early hours after infarction with the goal of limiting infarct size.118 119
It has been asserted that the inauguration of clot-dissolving therapy began with Tillet and Garner’s original report in 1933 that hemolytic streptococci possess fibrinolytic activity.120 Purification efforts ensued, and further animal and human volunteer work led finally to the first human studies, in 1958, of intravenous streptokinase in patients with acute myocardial infarction.121 During this same period of time, discovery of the dynamic nature of the fibrinolytic system occurred with an appreciation of the counterbalancing stimuli for both the formation and dissolution of fibrin.122 Urokinase isolated from human urine and its precursor, prourokinase, avoided the immunogenic and pyogenic side effects of streptokinase, which affected acceptance of the latter.123 In addition, urokinase had a shorter half-life and a somewhat better balance between its clot-dissolving and systemic fibrinogenolytic activity. Despite these advances in systemic thrombolysis for myocardial infarction, the view of the Health and Public Policy Committee of the American College of Physicians in 1985 was "... considered investigational and ... it cannot yet be considered uniformly safe or effective. Until studies demonstrate that early thrombolytic therapy can significantly reduce infarct size, morbidity and mortality, widespread use of thrombolytic agents for evolving acute myocardial infarction cannot be recommended as routine therapy."124 This view was obviously influenced by continuing concern about the introduction of foreign bacterial protein, ie, streptokinase, into humans, the risk of inducing a systemic hemorrhagic state, and the lack of large-scale, well-conducted, randomized, double-blind, placebo-controlled trials on mortality.
However, enthusiasm for this form of therapy had already grown on the basis of several key developments. These included the demonstration by Chazov and colleagues as well as by Rentrop and colleagues in the late 1970s of the efficacy of intracoronary administration of streptokinase in recanalizing occluded coronary arteries in humans with acute myocardial infarction.125 126 At about this time, DeWood and coworkers were evaluating emergency coronary bypass surgery in patients presenting with acute myocardial infarction and were using urgent coronary angiography to confirm the potential of benefit.22 Their studies demonstrated the role of coronary thrombosis in the early hours in patients with acute ST-segment elevation myocardial infarction and that angiography could be accomplished expeditiously and safely in such patients. Intracoronary streptokinase soon became the subject of intense investigation, and randomized trials demonstrated its efficacy. This benefit was ultimately confirmed to enhance clinical outcome in the Western Washington study.127 This led to the FDA’s approval of streptokinase and urokinase for "intracoronary use in lysing thrombi obstructing coronary arteries in evolving transmural myocardial infarction" in 1984.128
Two randomized megatrials ushered in the current era of contemporary care for patients with acute myocardial infarction and transformed our thinking and practice forever. The GISSI study, published in 1986, was the first of these and consisted of 11 806 patients with ECG changes of either ST elevation or depression, half of whom were randomized to streptokinase within 12 hours of onset of symptoms.129 An 18% relative reduction in 21-day mortality (13% in the controls) was seen, and the benefit accrued was confined to patients with ST-segment elevation and was especially marked in those patients treated early after symptom onset. A second placebo-controlled trial (ISIS-2) also evaluated the effects of intravenous streptokinase on 35-day mortality. This trial of 17 187 patients incorporated a 2x2 factorial design to assess the effects of enteric-coated aspirin separately and together with streptokinase.62 Patients were randomized up to 24 hours after chest pain onset with ECG criteria similar to those of GISSI I. Both streptokinase and aspirin produced impressive reductions in mortality, 28% and 23%, respectively, and together were associated with a 39% reduction in mortality compared with placebo therapy.
Concurrently, a separate line of investigation, spurred by
discovery of the biochemical underpinnings of endogenous fibrinolysis,
the desire to avoid a systemic prohemorrhagic state, and the notion of
fibrin-specific clot dissolution, catalyzed the application of
recombinant DNA to technology to this area. Purification of a
plasminogen activator from the Bowes melanoma cell line and the
appreciation that it had an affinity for fibrin clot and a similarity
to the endogenous physiological plasminogen activator in blood led to
the discovery of tissue plasminogen activator (tPA). Purification of
this substance, establishment of its thrombolytic efficacy in animals
and humans, and demonstration of its relative clot-specificity occurred
at the same time as cloning and expression of the tPA gene. The
production of recombinant tPA was the next
step.122 This
subsequently spawned the design of several mutants of a deletion or
substitution character with different properties. The GUSTO trial,
which used a front-loaded rtPA infusion protocol coupled with
intravenous heparin, demonstrated that this treatment strategy had a
clear survival advantage over
streptokinase.130
Importantly, this benefit was mediated by more rapid achievement of
effective coronary patency, thereby validating the open-artery
hypothesis131
(Figure 4). The major milestones in fibrinolytic
therapy over the past 50 years are summarized in Table 2.
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Several issues still require resolution to optimize our current approach to acute myocardial infarction. Although the weight of current evidence indicates that timely percutaneous intervention coupled with appropriate pharmacological therapy may yield the best coronary patency, the broad application of this approach, even within the United States where it has been pioneered, is challenging and often impractical.132 133 Recently, the use of intracoronary stents has been demonstrated to produce better epicardial coronary reperfusion; however, data are emerging to suggest that their deployment increases the likelihood of impaired distal coronary flow.134 Primary stenting combined with platelet GP IIb/IIIa blockade may well prove to be the preferred strategy, provided that it can be delivered in a timely fashion by a skilled operator in a high-volume center.135 Clear contraindications, such as uncontrolled hypertension, prior stroke or major intracranial problems, recent major surgery, trauma or active bleeding, or concurrent use of vitamin K antagonists with significant elevation in the INR, preclude safe use of fibrinolysis.136 The increase in the frequency of older patients with myocardial infarction and their relative undertreatment, high mortality, and more frequent contraindications to fibrinolysis pose a key challenge.137 Primary coronary intervention may well become the preferred approach in elderly patients >75 years old, but this remains to be proven. Time from symptom onset constitutes a key variable at both ends of the treatment window. Delay from symptom onset to hospital arrival remains long and thus far immune to vigorous public education campaigns: hence, moving newer forms of simple-to-administer bolus fibrinolytics into the field appears to be the next most logical step.138 The longer the delay, the less thrombotic coronary occlusion is amenable to pharmacological therapy, which is presumably related to the presence of fibrin cross-linking.139 Later administration of fibrinolysis to such patients is also associated with more frequent complications, and in such circumstances, percutaneous intervention may well be preferable, especially if there is active ischemia in a substantial territory at risk. In patients who present with cardiogenic shock, mechanical intervention seems preferable, although the benefit may paradoxically be greatest in patients <75 years old.140 The global scope of acute myocardial infarction, taking into consideration the epidemic of coronary disease in Eastern Europe and Asia, coupled with a shift to a more aged population, places a high priority on simply administered, cost-effective, and safe reperfusion strategies.
Failure to achieve successful fibrinolysis pharmacologically
may reflect multiple factors, including (1) the complexity of the
culprit plaque, (2) any associated intramural hemorrhage or hematoma,
(3) the magnitude and accessibility of the thrombotic obstruction, (4)
the proportion of platelets composing the original thrombus, (5)
embolization of various components of the occlusive thrombus and plaque
with resultant small-vessel plugging, (6) associated macrovascular and
microvascular coronary spasm, and (7) finally, coronary endothelial
dysfunction modulated by the ischemic
process.141
Although even the most optimistic Phase II angiographic studies of
novel fibrinolytics report an 
60% TIMI 3 patency, Ito and
colleagues brought some sobriety to these estimates by demonstrating
impaired microcirculatory flow in as many as 23% of patients with
excellent TIMI 3
patency.56
The emergence of intravenous GP IIb/IIIa inhibitors has had
a major impact on the safety and efficacy of percutaneous coronary
interventions and the outcomes of patients presenting with acute
non–ST-segment elevation coronary
disease.56 Their use
in primary angioplasty and stenting for acute ST-segment elevation
myocardial infarction and during rescue angioplasty for failed
fibrinolysis has been a significant
advance.142
Recently, promising Phase II studies with reduced-dose fibrinolytics
combined with intravenous GP IIb/IIIa inhibitors has resulted in
earlier and improved coronary
patency143 144
(Figure 5). Whether this will be associated with
reduced intracranial hemorrhage and reinfarction is unknown and is now
being evaluated in GUSTO IV and ASSENT 3, 2 large-scale Phase III
studies. Future pathways for fibrinolysis offer both opportunity and
promise and are depicted in Table 3.
|
|
Summary
There has been enormous progress in the care of patients with acute coronary heart disease syndromes during the past 50 years. The pathogenesis of ACS has been increasingly well defined, and improved pharmacological and interventional therapies have come from the enhanced mechanistic insight. This progress will continue in the next 50 years, but the focus of future experimental efforts needs to be just as vigorously directed at identifying the genes and gene products involved in leading to premature coronary syndromes and their consequences. From this insight into genes and gene products contributing to development of ACS will come the ability to predict, prevent, and cure coronary heart disease in both its acute and chronic forms. The American Heart Association and Circulation have played major roles in contributing to these developments in the past 50 years, and their contributions will be equally important and just as dedicated in the future.
References
1.
Osler
W. The Lumleian lectures on angina pectoris. Lancet. 1910;1:697–701.
2.
Sampson
JJ, Eliaser M Jr. The diagnosis of impending acute coronary artery
occlusion. Am Heart J. 1937;13:675–686.
3.
Feil H.
Preliminary pain in coronary thrombosis. Am J Med
Sci. 1937;193:42–48.
4.
Levy H.
The natural history of changing pattern of angina pectoris. Ann
Intern Med. 1956;44:1123–1135.
5.
Vakil
RJ. Intermediate coronary syndrome. Circulation. 1961;24:557–571.
6.
Beamish
RE, Storrie VM. Impending myocardial infarction: recognition and
management. Circulation. 1960;21:1107–1115.
7.
Fowler
NO. "Preinfarctional" angina: a need for an objective definition
and for a controlled clinical trial of its management.
Circulation. 1971;44:755–758.
8.
Wood P.
Acute and subacute coronary insufficiency. BMJ. 1961;1:1779–1782.
9.
Krauss
KR, Hutter AM, De Sanctis RW. Acute coronary insufficiency: course and
follow-up. Circulation. 1972;45(suppl
I):I-66–I-71.
10.
Gazes
PCF, Mobly FM, Faris HM, et al. Pre-infarctional (unstable
angina)—a prospective study—10 year follow-up: prognostic
significance of electrocardiographic changes.
Circulation. 1973;48:331–337.
11.
Constantinides
P. Plaque fissuring in human coronary thrombosis. J Atheroscler
Res. 1966;6:1.
12.
Hirsh
PD, Hillis LD, Campbell WB, et al. Release of prostaglandins and
thromboxane into the coronary circulation in patients with ischemic
heart disease. N Engl J Med. 1981;304:685.
13.
Davies
MJ, Thomas AEC. Plaque fissuring: the cause of acute myocardial
infarction, sudden ischemic death, and crescendo angina. Br
Heart J. 1985;53:363.
14.
Falk
E. Plaque rupture with severe preexisting stenosis precipitating
coronary thrombosis: characteristics of coronary atherosclerotic
plaques underlying fatal occlusive thrombi. Br Heart
J. 1983;50:127.
15.
Libby
P. Molecular bases of the acute coronary syndromes.
Circulation. 1995;91:2844.
16.
Fuster
V, Lewis A. Mechanisms leading to myocardial infarction: insights from
studies of vascular biology. Connor Memorial Lecture.
Circulation. 1995;91:256.
17.
Willerson
JT, Golino P, Eidt JF, et al. Specific platelet mediators and unstable
coronary artery lesions: experimental evidence and potential clinical
implications. Circulation. 1989;80:198.
18.
Willerson
JT, Hillis LD, Winniford MD, et al. Speculation regarding mechanisms
responsible for acute ischemic heart disease syndromes. J
Am Coll Cardiol. 1986;8:245.
19.
Maseri
A, Mimmo R, Chierchia S. Coronary artery spasm as a cause of acute
myocardial ischemia in man. Chest. 1975;68:625.
20.
Ashton
JH, Ogletree ML, Michel IM, et al. Serotonin and thromboxane
A2/prostaglandin H2
receptor activation cooperatively mediate cyclic flow variations in
dogs with severe coronary artery stenoses.
Circulation. 1987;76:952.
21.
Golino
P, Ashton JH, Buja LM, et al. Local platelet activation causes
vasoconstriction of large epicardial canine coronary arteries in vivo:
thromboxane A2 and serotonin are possible
mediators. Circulation. 1989;79:154.
22.
DeWood
MA, Spores J, Notske R, et al. Prevalence of total coronary occlusion
during the early hours of transmural myocardial infarction.
N Engl J Med. 1980;303:897.
23.
Buja
LM, Willerson JT. Clinicopathologic correlates of acute ischemic heart
disease syndromes. Am J Cardiol. 1981;47:343.
24.
Fernandez-Ortiz
A, Badimon JJ, Falk E, et al. Characterization of the relative
thrombogenicity of atherosclerotic plaque components: implications for
consequences of plaque rupture. J Am Coll
Cardiol. 1994;23:1562–1569.
25.
Toschi
V, Gallo R, Lettino M, et al. Tissue factor modulates the
thrombogenicity of human atherosclerotic plaques.
Circulation. 1997;95:594–599.
26.
Berk
BC, Weintraub WS, Alexander RW. Elevation of C-reactive protein in
"active" coronary artery disease. Am J
Cardiol. 1990;65:168.
27.
Liuzzo
G, Biasucci LM, Gallimore JR, et al. The prognostic value of C-reactive
protein in severe angina. N Engl J Med. 1994;331:407.
28.
Kruskal
JB, Commerford PJ, Franks JJ, et al. Fibrin and fibrinogen related
antigens in patients with stable and unstable coronary artery disease.
N Engl J Med. 1987;317:1361.
29.
Ridker
PM, Cushman M, Stampfer MJ, et al. Inflammation, aspirin, and the risk
of cardiovascular disease in apparently healthy men. N
Engl J Med. 1997;336:973.
30.
Biasucci
LM, Liuzzo G, Fantuzzi G, et al. Increasing levels of interleukin
(IL)-1Ra and IL-6 during the first 2 days of hospitalization in
unstable angina are associated with increased risk of in-hospital
coronary events. Circulation. 1999;99:2079.
31.
Liuzzo
G, Kopecky SL, Frye RL, et al. Perturbation of the T-cell repertoire in
patients with unstable angina. Circulation. 1999;100:2135–2139.
32.
Langlois
PF, Gawryl MS. Detection of the terminal complement complex in patient
plasma following acute myocardial infarction.
Atherosclerosis. 1988;70:95–105.
33.
Vakeva
A, Morgan BP, Tikkanen I, et al. Time course of complement activation
and inhibitor expression after ischemic injury of rat myocardium.
Am J Pathol. 1994;144:1357–1368.
34.
Ritchie
ME. Nuclear factor-
35.
Hamm
CW, Ravkilde J, Gerhardt W, et al. The prognostic value of serum
troponin T in unstable angina. N Engl J Med. 1992;327:146–150.
36.
Hamm
CW, Goldmann BU, Heeschen C, et al. Emergency room triage of patients
with acute chest pain by means of rapid testing for cardiac troponin T
or troponin I [see comments]. N Engl J
Med. 1997;337:1648–1653.
37.
Antman
EM, Tanasijevic MJ, Thompson B, et al. Cardiac-specific troponin I
levels to predict the risk of mortality in patients with acute coronary
syndromes. N Engl J Med. 1996;335:1342.
38.
Ohman
EM, Armstrong PW, Christenson RH, et al, for the GUSTO IIA
Investigators. Cardiac troponin T levels for risk stratification in
acute myocardial ischemia [see comments]. N Engl J
Med. 1996;335:1333–1341.
39.
Hamm
CW, Heeschen C, Goldmann B, et al, for the c7E3 Fab Antiplatelet
Therapy in Unstable Refractory Angina (CAPTURE) Study Investigators.
Benefit of abciximab in patients with refractory unstable angina in
relation to serum troponin T levels. N Engl J
Med. 1999;340:1623–1629.
40.
Topol
EJ, Yadav JS. Recognition of the importance of embolization in
atherosclerotic vascular disease. Circulation. 2000;101:570–580.
41.
Casscells
W, Hathorn B, David M, et al. Thermal detection of cellular infiltrates
in living atherosclerotic plaques: possible implications for plaque
rupture and thrombosis. Lancet. 1996;347:1447.
42.
Stefanadis
C, Diamantopoulos L, Vlachopoulos C, et al. Thermal heterogeneity
within human atherosclerotic coronary arteries detected in vivo: a new
method of detection by application of a special thermography catheter.
Circulation. 1999;99:1965.
43.
Fayad
ZA, Fuster V, Fallon JT, et al. Noninvasive in vivo human coronary
artery lumen and wall imaging using black-blood magnetic resonance
imaging. Circulation. 2000;102:506.
44.
Sonnenblick
EH, Ross J Jr, Braunwald E. Oxygen consumption of the heart: newer
concepts of its multifactorial determination. Am J
Cardiol. 1968;22:328–336.
45.
Reimer
KA, Jennings RB. The "wavefront phenomenon" of myocardial ischemic
cell death, II: transmural progression of necrosis within the framework
of ischemic bed size (myocardium at risk) and collateral flow.
Lab Invest. 1979;40:633–644.
46.
Farb
A, Kolodgie FD, Jenkins M, et al. Myocardial infarct extension during
reperfusion after coronary artery occlusion: pathologic evidence.
J Am Coll Cardiol. 1993;21:1245–1253.
47.
Joseph
D, Fabiani JN, Camilleri JP. [Pathological patterns of reperfused
myocardial infarction: experimental study (author’s transl.)].
Pathol Biol (Paris). 1980;28:160–167.
48.
Avkiran
M. Rational basis for use of sodium-hydrogen exchange inhibitors in
myocardial ischemia. Am J Cardiol. 1999;83:10G–18G.
49.
Karmazyn
M, Gan XT, Humphreys RA, et al. The myocardial
Na+-H+ exchange:
structure, regulation, and its role in heart disease. Circ
Res. 1999;85:777–786.
50.
Youker
KA, Hawkins HK, Kukielka GL, et al. Molecular evidence for induction of
intracellular adhesion molecule-1 in the viable border zone associated
with ischemia-reperfusion injury of the dog heart.
Circulation. 1994;89:2736–2746.
51.
Herskowitz
A, Choi S, Ansari AA, et al. Cytokine mRNA expression in
postischemic/reperfused myocardium. Am J Pathol. 1995;146:419–428.
52.
Kajstura
J, Cheng W, Reiss K, et al. Apoptotic and necrotic myocyte cell deaths
are independent contributing variables of infarct size in rats.
Lab Invest. 1999;74:86–107.
53.
Yaoita
H, Ogawa K, Maehara K, et al. Apoptosis in relevant clinical
situations: contribution of apoptosis in myocardial infarction.
Cardiovasc Res. 2000;45:630–641.
54.
Pfeffer
MA, Braunwald E. Ventricular remodeling after myocardial infarction:
experimental observations and clinical implications.
Circulation. 1990;81:1161–1172.
55.
Kloner
RA, Ganote CE, Jennings RB. The. "no-reflow phenomenon" after
temporary coronary occlusion in the dog. J Clin
Invest. 1974;54:1496–1508.
55.
Willerson
JT, Powell WJ Jr, Guiney TE, et al. Improvement in myocardial function
and coronary blood flow in ischemic myocardium after mannitol.
J Clin Invest. 1972;51:2989–2998.
55.
Willerson
JT, Watson JT, Hutton I, et al. Reduced myocardial reflow and increased
coronary vascular resistance following prolonged myocardial ischemia in
the dog. Circ Res. 1975;36:771–781.
56.
Ito H,
Maruyama A, Iwakura K, et al. Clinical implications of the "no
reflow" phenomenon: a predictor of complications and left ventricular
remodeling in reperfused anterior wall myocardial infarction.
Circulation. 1996;93:223–228.
57.
Braunwald
E. Unstable angina: a classification. Circulation. 1989;80:410–414.
58.
Hamm
CW, Braunwald E. A classification of unstable angina revisited.
Circulation. 2000;102:118–122.
59.
Bertrand
ME, Simoons ML, Fox KAA, et al. Management of acute coronary syndromes:
acute coronary syndromes without persistent ST segment elevation.
Eur Heart J. 2000;21:1406–1432.
60.
Braunwald
E, Antman EM, Beasley JW, et al. ACC/AHA guidelines for the management
of patients with unstable angina and non–ST-segment elevation
myocardial infarction: executive summary and recommendations. A report
of the American College of Cardiology/American Heart Association Task
Force on Practice Guidelines (Committee on the Management of Patients
with Unstable Angina). Circulation. 2000;102:1193–1209.
61.
Braunwald
E, Antman EM, Beasley JW, et al. ACC/AHA guidelines for the management
of patients with unstable angina and non–ST-segment elevation MI:
executive summary and recommendations: a report of the American College
of Cardiology/American Heart Association Task Force on Practice
Guidelines (Committee on the Management of Patients with Unstable
Angina). J Am Coll Cardiol. In
press.
62.
ISIS-2
(Second International Study of Infarct Survival) Collaborative Group.
Randomised trial of intravenous streptokinase, oral aspirin, both, or
neither among 17,187 cases of suspected acute myocardial infarction:
ISIS-2. Lancet. 1988;2:349–360.
63.
Lewis
HD Jr, Davis JW, Archibald DG, et al. Protective effects of aspirin
against acute myocardial infarction and death in men with unstable
angina: results of a Veterans Administration Cooperative Study.
N Engl J Med. 1983;309:396–403.
64.
Cairns
JA, Gent M, Singer J, et al. Aspirin, sulfinpyrazone, or both in
unstable angina: results of a Canadian multicenter trial.
N Engl J Med. 1985;313:1369–1375.
65.
Théroux
P, Ouimet H, McCans J, et al. Aspirin, heparin, or both to treat acute
unstable angina. N Engl J Med. 1988;319:1105–1111.
66.
The
RISC Group. Risk of myocardial infarction and death during treatment
with low dose aspirin and intravenous heparin in men with unstable
coronary artery disease. Lancet. 1990;336:827–830.
67.
Antiplatelet
Trialists’ Collaboration. Collaborative overview of randomised trials
of antiplatelet therapy, I: prevention of death, myocardial infarction,
and stroke by prolonged antiplatelet therapy in various categories of
patients. BMJ. 1994;308:81–106.
68.
Patrono
C, Coller B, Dalen JE, et al. Platelet-active drugs: the relationships
among dose, effectiveness, and side effects. Chest. 1998;114:470S–488S.
69.
Théroux
P, Waters D, Lam J, et al. Reactivation of unstable angina after the
discontinuation of heparin [see comments]. N Engl J
Med. 1992;327:141–145.
70.
Vane
JR, Botting RM. Anti-inflammatory drugs and their mechanism of action.
Inflamm Res. 1998;47(suppl
2):S78–S87.
71.
Cayatte
AJ, Du Y, Oliver-Krasinski J, et al. The thromboxane receptor
antagonist S18886 but not aspirin inhibits atherogenesis in apo
E–deficient mice. Arterioscler Thromb Vasc Biol. 2000;20:1724–1728.
71.
Golino
P, Rosolowsky M, Yao S, et al. Endogenous prostaglandin endoperoxides
and prostacyclin modulate the thrombolytic activity of tissue
plasminogen activator. J Clin Invest. 1990;86:1095–1102.
72.
Colombo
A, Hall P, Nakamura S, et al. Intracoronary stenting without
anticoagulation accomplished with intravascular ultrasound guidance
[see comments]. Circulation. 1995;91:1676–1688.
73.
The
CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel
versus aspirin in patients at risk of ischaemic events (CAPRIE).
Lancet. 1996;348:1329–1339.
74.
Yao
SK, Ober JC, Ferguson JJ, et al. Clopidogrel is more effective than
aspirin as an adjuvant treatment to prevent reocclusion after
thrombolysis. Am J Physiol. 1994;167:H488–H493.
75.
Bertrand
ME, Rupprecht HJ, Urban P, et al, for the CLASSICS Investigators.
Double-blind study of the safety of clopidogrel with and without a
loading dose in combination with aspirin compared with ticlopidine in
combination with aspirin after coronary stenting: the Clopidogrel
Aspirin Stent International Cooperative Study (CLASSICS).
Circulation. 2000;102:624–629.
76.
Ingall
AH, Dixon J, Bailey A, et al. Antagonists of the platelet P2T receptor:
a novel approach to antithrombotic therapy. J Med
Chem. 1999;42:213–220.
77.
Coller
BS. Blockade of platelet GPIIb/IIIa receptors as an antithrombotic
strategy. Circulation. 1995;92:2373–2380.
78.
The
EPIC Investigators. Use of a monoclonal antibody directed against the
platelet glycoprotein IIb/IIIa receptor in high-risk coronary
angioplasty. N Engl J Med. 1994;330:956–961.
79.
Peerlink
K, DeLepereile I, Goldberg M, et al. MK-383 (L-700,642), a selective
non-peptide platelet glycoprotein IIb/III antagonist, is active in man.
Circulation. 1993;88:1512–1517.
80.
Phillips
DR, Scarborough RM. Clinical pharmacology of eptifibatide.
Am J Cardiol. 1997;80:11B–20B.
81.
The
EPISTENT Investigators. Randomised placebo-controlled and
balloon-angioplasty-controlled trial to assess safety of coronary
stenting with use of platelet glycoprotein-IIb/IIIa blockade.
Lancet. 1998;352:87–92.
82.
The
CAPTURE Investigators. Randomised placebo-controlled trial of abciximab
before and during coronary intervention in refractory unstable angina:
the CAPTURE Study. Lancet. 1997;349:1429–1435.
83.
Platelet
Receptor Inhibition in Ischemic Syndrome Management in Patients Limited
by Unstable Signs and Symptoms (PRISM-PLUS) Study Investigators.
Inhibition of the platelet glycoprotein IIb/IIIa receptor with
tirofiban in unstable angina and non-Q-wave myocardial infarction.
N Engl J Med. 1998;338:1488–1497.
84.
The
PURSUIT Trial Investigators. Inhibition of platelet glycoprotein
IIb/IIIa with eptifibatide in patients with acute coronary syndromes.
Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression
Using Integrilin Therapy. N Engl J Med. 1998;339:436–443.
85.
Boersma
E, Akkerhuis KM, Théroux P, et al. Platelet glycoprotein IIb/IIIa
receptor inhibition in non-ST-elevation acute coronary syndromes: early
benefit during medical treatment only, with additional protection
during percutaneous coronary intervention.
Circulation. 1999;100:2045–2048.
86.
O’Neill
WW, Serruys P, Knudtson M, et al. Long-term treatment with a platelet
glycoprotein-receptor antagonist after percutaneous coronary
revascularization. EXCITE Trial Investigators. Evaluation of
Oral Xemilofiban in Controlling Thrombotic Events. N Engl J
Med. 2000;342:1316–1324.
87.
Cannon
CP, McCabe CH, Wilcox RG, et al. Oral glycoprotein IIb/IIIa inhibition
with orbofiban in patients with unstable coronary syndromes (OPUS-TIMI
16) trial. Circulation. 2000;102:149–156.
88.
The
SYMPHONY Investigators. Comparison of sibrafiban with aspirin for
prevention of cardiovascular events after acute coronary syndromes: a
randomised trial. Sibrafiban versus Aspirin to Yield Maximum Protection
from Ischemic Heart Events Post-acute Coronary Syndromes.
Lancet. 2000;355:337–345.
89.
Fragmin
during Instability in Coronary Artery Disease (FRISC) study group.
Low-molecular-weight heparin during instability in coronary artery
disease. Lancet. 1996;347:561–568.
90.
Cohen
M, Demers C, Gurfinkel EP, et al, for the Efficacy and Safety of
Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events Study Group. A
comparison of low-molecular-weight heparin with unfractionated heparin
for unstable coronary artery disease. N Engl J
Med. 1997;337:447–452.
91.
Eikelboom
JW, Anand SS, Malmberg K, et al. Unfractionated heparin and
low-molecular-weight heparin in acute coronary syndrome without ST
elevation: a meta-analysis. Lancet. 2000;355:1936–1942.
92.
Weitz
JI. Low-molecular-weight heparins. N Engl J
Med. 1997;10:688–697.
93.
Markwardt
F. The development of hirudin as an antithrombotic drug. Thromb
Res. 1994;74:1–23.
94.
The
Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb
Investigators. A comparison of recombinant hirudin with heparin for the
treatment of acute coronary syndromes. N Engl J
Med. 1996;335:775–782.
95.
Antman
EM. Hirudin in acute myocardial infarction. Thrombolysis and Thrombin
Inhibition in Myocardial Infarction (TIMI) 9B trial.
Circulation. 1996;94:911–921.
96.
Organization
to Assess Strategies for Ischemic Syndromes (OASIS) Investigators.Comparison of the effects of two doses of recombinant hirudin
compared with heparin in patients with acute myocardial ischemia
without ST elevation: a pilot study. Circulation. 1997;96:769–777.
97.
Organisation
to Assess Strategies for Ischemic Syndromes (OASIS-2) Investigators.
Effect of recombinant hirudin (lepirudin) compared with heparin on
death, myocardial infarction, refractory angina, and revascularization
procedures in patients with acute myocardial ischaemia without ST
elevation: a randomised trial. Lancet. 1999;353:429–438.
98.
Kong
DF, Topol EJ, Bittl JA, et al. Clinical outcomes of bivalirudin for
ischemic heart disease. Circulation. 1999;100:2049–2053.
99.
Braunwald
E, Maroko PR. The reduction of infarct size: an idea whose time (for
testing) has come. Circulation. 1974;50:206–209.
100.
Théroux
P. Myocardial cell protection: a challenging time for action and a
challenging time for clinical research. Circulation. 2000;101:2874–2876.
101.
Scholz
W, Albus U, Counillon L, et al. Protective effects of HOE642, a
selective sodium-hydrogen exchange subtype 1 inhibitor, on cardiac
ischemia and reperfusion. Cardiovasc Res. 1995;29:260–268.
102.
Kloner
RA, Bolli R, Marban E, et al. Medical and cellular implications of
stunning, hibernation, and preconditioning: an NHLBI workshop.
Circulation. 1998;97:1848–1867.
103.
Fitch
JC, Rollins S, Matis L, et al. Pharmacology and biological efficacy of
a recombinant, humanized, single-chain antibody C5 complement inhibitor
in patients undergoing coronary artery bypass graft surgery with
cardiopulmonary bypass. Circulation. 1999;100:2499–2506.
104.
Mahaffey
KW, Puma JA, Barbagelata NA, et al. Adenosine as an adjunct to
thrombolytic therapy for acute myocardial infarction: results of a
multicenter, randomized, placebo-controlled trial: the Acute Myocardial
Infarction STudy of ADenosine (AMISTAD) trial. J Am Coll
Cardiol. 1999;34:1711–1720.
105.
Neumann
FJ, Blasini R, Schmitt C, et al. Effect of glycoprotein IIb/IIIa
receptor blockade on recovery of coronary flow and left ventricular
function after the placement of coronary-artery stents in acute
myocardial infarction. Circulation. 1998;98:2695–2701.
106.
Lopaschuk
GD. Treating ischemic heart disease by pharmacologically improving
cardiac energy metabolism. Am J Cardiol. 1998;82:14K–17K.
107.
Théroux
P, Chaitman BR, Danchin N, et al. Inhibition of the sodium-hydrogen
exchanger with cariporide to prevent myocardial infarction in high-risk
ischemic situations: main results of the GUARDIAN Trial.
Circulation. In
press.
108.
Russell
RO, Moraski RE, Kouchoukos N, et al. Unstable angina pectoris: National
Cooperative Study Group to compare surgical and medical therapy, II:
in-hospital experience and initial follow-up results in patients with
one, two and three vessel disease. Am J Cardiol. 1978;42:839–848.
109.
Luchi
RJ, Scott SM, Deupree RH, Principal Investigators and their Associates
of Veterans Administration Cooperative Study No. 28. Comparison of
medical and surgical treatment for unstable angina pectoris.
N Engl J Med. 1987;316:977–984.
110.
The
TIMI IIIB Investigators. Effects of tissue plasminogen activator and a
comparison of early invasive and conservative strategies in unstable
angina and non-Q-wave myocardial infarction: results of TIMI IIIB
trial. Circulation. 1994;89:1545–1556.
111.
Boden
WE, O’Rourke RA, Crawford MH, et al. Outcomes in patients with acute
non-Q-wave myocardial infarction randomly assigned to an invasive as
compared with a conservative management strategy. Veterans Affairs
Non-Q-Wave Infarction Strategies in Hospital (VANQWISH) Trial
Investigators [see comments] [published erratum appears in N
Engl J Med 1998;339:1091]. N Engl J
Med. 1998;33:1785–1792.
112.
FRagmin,
and Fast Revascularization during InStability in Coronary artery
disease Investigators. Invasive compared with non-invasive treatment in
unstable coronary-artery disease: FRISC II prospective randomised
multicentre study. Lancet. 1999;354:708–715.
113.
Pitt
B, Waters D, Brown WV, et al. Aggressive lipid-lowering therapy
compared with angioplasty in stable coronary artery disease.
N Engl J Med. 1999;341:70–76.
114.
Brown
KWG, MacMillan RL, Forbath N, et al. Coronary care unit and intensive
care centre for acute myocardial infarction. Lancet. 1963;2:349–352.
115.
Swan
HJC, Ganz W, Forrester JS, et al. Catheterization of the heart in man
with the use of a flow directed balloon tipped catheter. N
Engl J Med. 1970;283:447–451.
116.
Forrester
JS, Diamond G, Chatterjee K, et al. Medical therapy of acute myocardial
infarction by application of hemodynamic subsets (two parts).
N Engl J Med. 1976;295:1356–1362/1404–1413.
117.
Sobel
BE, Bresnahan GF, Shell WE, et al. Estimation of infarct size in man
and its relation to prognosis. Circulation. 1972;46:640–648.
118.
Maroko
PR, Libby P, Covell JW, et al. Precordial ST segment elevation mapping:
an atraumatic method for assessing alterations in the extent of
myocardial ischemic injury. Am J Cardiol. 1972;29:223–230.
119.
Rude
RE, Muller JE, Braunwald E. Efforts to limit the size of myocardial
infarcts. Ann Intern Med. 1981;95:736–761.
120.
Tillett
WS, Garner RL. The fibrinolytic activity of hemolytic streptococci.
J Exp Med. 1933;56:485–502.
121.
Fletcher
AP, Alkjaersig N, Smyrniotis FE, et al. The treatment of patients
suffering from early myocardial infarction with massive and prolonged
streptokinase therapy. Trans Assoc Am Physicians. 1958;71:287–296.
122.
Collen
D. Fibrin-selective thrombolytic therapy for acute myocardial
infarction. Circulation. 1996;93:857–865.
123.
Verstraete
M. The fibrinolytic system: from Petri dishes to genetic engineering.
Thromb Haemost. 1995;74:25–35.
124.
Health
and Public Policy Committee, American College of Physicians.
Thrombolysis for evolving myocardial infarction. Ann Intern
Med. 1985;103:463–469.
125.
Chazov
EI, Matveeva LS, Mazaev AV, et al. Intracoronary administration of
fibrinolysin in acute myocardial infarct. Ter Arkh. 1976;48:8–19.
126.
Rentrop
KP, Blanke H, Karsch KR, et al. Acute myocardial infarction:
intracoronary application of nitroglycerin and streptokinase in
combination with transluminal recanalization. Clin
Cardiol. 1979;2:354–363.
127.
Kennedy
JW, Ritchie JL, Davis KB, et al. Western Washington randomized trial of
intracoronary streptokinase in acute myocardial infarction.
N Engl J Med. 1983;309:1477–1482.
B is selectively and markedly activated in
humans with unstable angina pectoris. Circulation. 1998;98:1707–1713.