Progress in the Treatment of Acute Coronary Syndromes
A 50-Year Perspective (1950–2000)
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
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-ϰB34 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.
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, β-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
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 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⇑).
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 2×2 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⇓.
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⇓.
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.
- Copyright © 2000 by American Heart Association
Osler W. The Lumleian lectures on angina pectoris. Lancet. 1910;1:697–701.
Sampson JJ, Eliaser M Jr. The diagnosis of impending acute coronary artery occlusion. Am Heart J. 1937;13:675–686.
Feil H. Preliminary pain in coronary thrombosis. Am J Med Sci. 1937;193:42–48.
Levy H. The natural history of changing pattern of angina pectoris. Ann Intern Med. 1956;44:1123–1135.
Vakil RJ. Intermediate coronary syndrome. Circulation. 1961;24:557–571.
Beamish RE, Storrie VM. Impending myocardial infarction: recognition and management. Circulation. 1960;21:1107–1115.
Fowler NO. “Preinfarctional” angina: a need for an objective definition and for a controlled clinical trial of its management. Circulation. 1971;44:755–758.
Wood P. Acute and subacute coronary insufficiency. BMJ. 1961;1:1779–1782.
Krauss KR, Hutter AM, De Sanctis RW. Acute coronary insufficiency: course and follow-up. Circulation. 1972;45(suppl I):I-66–I-71.
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.
Constantinides P. Plaque fissuring in human coronary thrombosis. J Atheroscler Res. 1966;6:1.
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.
Davies MJ, Thomas AEC. Plaque fissuring: the cause of acute myocardial infarction, sudden ischemic death, and crescendo angina. Br Heart J. 1985;53:363.
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.
Libby P. Molecular bases of the acute coronary syndromes. Circulation. 1995;91:2844.
Fuster V, Lewis A. Mechanisms leading to myocardial infarction: insights from studies of vascular biology. Connor Memorial Lecture. Circulation. 1995;91:256.
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.
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.
Maseri A, Mimmo R, Chierchia S. Coronary artery spasm as a cause of acute myocardial ischemia in man. Chest. 1975;68:625.
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.
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.
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.
Buja LM, Willerson JT. Clinicopathologic correlates of acute ischemic heart disease syndromes. Am J Cardiol. 1981;47:343.
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.
Toschi V, Gallo R, Lettino M, et al. Tissue factor modulates the thrombogenicity of human atherosclerotic plaques. Circulation. 1997;95:594–599.
Berk BC, Weintraub WS, Alexander RW. Elevation of C-reactive protein in “active” coronary artery disease. Am J Cardiol. 1990;65:168.
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.
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.
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.
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.
Liuzzo G, Kopecky SL, Frye RL, et al. Perturbation of the T-cell repertoire in patients with unstable angina. Circulation. 1999;100:2135–2139.
Langlois PF, Gawryl MS. Detection of the terminal complement complex in patient plasma following acute myocardial infarction. Atherosclerosis. 1988;70:95–105.
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.
Ritchie ME. Nuclear factor-ϰΒ is selectively and markedly activated in humans with unstable angina pectoris. Circulation. 1998;98:1707–1713.
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.
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.
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.
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.
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.
Topol EJ, Yadav JS. Recognition of the importance of embolization in atherosclerotic vascular disease. Circulation. 2000;101:570–580.
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.
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.
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.
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.
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.
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.
Joseph D, Fabiani JN, Camilleri JP. [Pathological patterns of reperfused myocardial infarction: experimental study (author’s transl.)]. Pathol Biol (Paris). 1980;28:160–167.
Avkiran M. Rational basis for use of sodium-hydrogen exchange inhibitors in myocardial ischemia. Am J Cardiol. 1999;83:10G–18G.
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.
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.
Herskowitz A, Choi S, Ansari AA, et al. Cytokine mRNA expression in postischemic/reperfused myocardium. Am J Pathol. 1995;146:419–428.
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.
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.
Pfeffer MA, Braunwald E. Ventricular remodeling after myocardial infarction: experimental observations and clinical implications. Circulation. 1990;81:1161–1172.
Kloner RA, Ganote CE, Jennings RB. The. “no-reflow phenomenon” after temporary coronary occlusion in the dog. J Clin Invest. 1974;54:1496–1508.
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.
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.
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.
Braunwald E. Unstable angina: a classification. Circulation. 1989;80:410–414.
Hamm CW, Braunwald E. A classification of unstable angina revisited. Circulation. 2000;102:118–122.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Patrono C, Coller B, Dalen JE, et al. Platelet-active drugs: the relationships among dose, effectiveness, and side effects. Chest. 1998;114:470S–488S.
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.
Vane JR, Botting RM. Anti-inflammatory drugs and their mechanism of action. Inflamm Res. 1998;47(suppl 2):S78–S87.
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.
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.
Colombo A, Hall P, Nakamura S, et al. Intracoronary stenting without anticoagulation accomplished with intravascular ultrasound guidance [see comments]. Circulation. 1995;91:1676–1688.
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.
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.
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.
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.
Coller BS. Blockade of platelet GPIIb/IIIa receptors as an antithrombotic strategy. Circulation. 1995;92:2373–2380.
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.
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.
Phillips DR, Scarborough RM. Clinical pharmacology of eptifibatide. Am J Cardiol. 1997;80:11B–20B.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Weitz JI. Low-molecular-weight heparins. N Engl J Med. 1997;10:688–697.
Markwardt F. The development of hirudin as an antithrombotic drug. Thromb Res. 1994;74:1–23.
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.
Antman EM. Hirudin in acute myocardial infarction. Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9B trial. Circulation. 1996;94:911–921.
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.
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.
Kong DF, Topol EJ, Bittl JA, et al. Clinical outcomes of bivalirudin for ischemic heart disease. Circulation. 1999;100:2049–2053.
Braunwald E, Maroko PR. The reduction of infarct size: an idea whose time (for testing) has come. Circulation. 1974;50:206–209.
Théroux P. Myocardial cell protection: a challenging time for action and a challenging time for clinical research. Circulation. 2000;101:2874–2876.
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.
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.
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.
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.
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.
Lopaschuk GD. Treating ischemic heart disease by pharmacologically improving cardiac energy metabolism. Am J Cardiol. 1998;82:14K–17K.
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.
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.
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.
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.
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.
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.
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.
Brown KWG, MacMillan RL, Forbath N, et al. Coronary care unit and intensive care centre for acute myocardial infarction. Lancet. 1963;2:349–352.
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.
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.
Sobel BE, Bresnahan GF, Shell WE, et al. Estimation of infarct size in man and its relation to prognosis. Circulation. 1972;46:640–648.
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.
Rude RE, Muller JE, Braunwald E. Efforts to limit the size of myocardial infarcts. Ann Intern Med. 1981;95:736–761.
Tillett WS, Garner RL. The fibrinolytic activity of hemolytic streptococci. J Exp Med. 1933;56:485–502.
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.
Collen D. Fibrin-selective thrombolytic therapy for acute myocardial infarction. Circulation. 1996;93:857–865.
Verstraete M. The fibrinolytic system: from Petri dishes to genetic engineering. Thromb Haemost. 1995;74:25–35.
Health and Public Policy Committee, American College of Physicians. Thrombolysis for evolving myocardial infarction. Ann Intern Med. 1985;103:463–469.
Chazov EI, Matveeva LS, Mazaev AV, et al. Intracoronary administration of fibrinolysin in acute myocardial infarct. Ter Arkh. 1976;48:8–19.
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.
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.
FDA Drug Bulletin 14(1), April, 1984.
GISSI Investigators group. Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet. 1986;1:397–401.
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 Angiographic Investigators. The comparative effects of tissue plasminogen activator, streptokinase, or both on coronary artery patency, ventricular function and survival after acute myocardial infarction. N Engl J Med. 1993;329:1615–1622.
Weaver WD, Simes RJ, Betriu A, et al. Comparison of primary coronary angioplasty and intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review. J AMA. 1997;278:2093–2098.
Danchin N, Vaur L, Genès N, et al. Treatment of acute myocardial infarction by primary coronary angioplasty or intravenous thrombolysis in the “real world.” Circulation. 1999;99:2639–2644.
Stone GW, Brodie BR, Griffin JJ, et al, on behalf of the Primary Angioplasty in Myocardial Infarction (PAMI) Investigators. Improved short term outcomes of primary coronary stenting compared to primary balloon angioplasty in acute myocardial infarction at experienced centers: the PAMI Study Group experience. J Intervent Cardiol. 1998;11:603–607.
Schömig A, Kastrati A, Dirschinger J, et al, for the Stent versus Thrombolysis for Occluded Coronary Arteries in Patients with Acute Myocardial Infarction Study Investigators. Coronary stenting for platelet glycoprotein IIb/IIIa blockade compared with tissue plasminogen activator in acute myocardial infarction. N Engl J Med. 2000;343:385–391.
White HD, Van de Werf F. Thrombolysis for acute myocardial infarction. Circulation. 1998;97:1632–1646.
Maynard C, Every NR. Thrombolysis versus primary angioplasty in older patients with acute myocardial infarction. Drugs Aging. 1999;14:427–435.
Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT-2) 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.
Chesebro JH, Knatterud G, Roberts R, et al. Thrombolysis in Myocardial Infarction (TIMI) Trial, Phase I. A comparison between intravenous tissue plasminogen activator and intravenous streptokinase: clinical findings through hospital discharge. Circulation. 1987;76:142–154.
Hochman JS, Sleeper LA, Webb JG, et al, for the SHOCK Investigators. Early revascularization in acute myocardial infarction complicated by cardiogenic shock. N Engl J Med. 1999;341:1625–1634.
Davies CH, Ormerod OJM. Failed coronary thrombolysis. Lancet. 1998;351:1191–1196.
Kong DF, Califf RM, Miller DP, et al. Clinical outcomes of therapeutic agents that block the platelet glycoprotein IIb/IIIa integrin in ischemic heart disease. Circulation. 1998;98:2829–2835.
Antman EM, Giugliano RP, Gibson CM, et al. Abciximab facilitates the rate and extent of thrombolysis: results of the Thrombolysis in Myocardial Infarction (TIMI) 14 Trial. Circulation. 1999;99:2720–2732.
Strategies for Patency Enhancement in the Emergency Department (SPEED) Group. Trial of abciximab with and without low-dose reteplase for acute myocardial infarction. Circulation.