Contemporary View of the Acute Coronary Syndromes (Part I of II)

Acute coronary syndromes (ACS) represent a clinical spectrum that extends all the way from unstable angina presenting with worsening episodes of chest pain, to non-ST segment elevation myocardial infarction (NSTEMI) with more prolonged chest pain and biochemical evidence of myocardial injury, to ST-segment elevation myocardial infarction (STEMI) with more extensive myocardial damage and usually the formation of Q-waves on the surface electrocardiogram, and finally to sudden cardiac death. Pathophysiologic correlations in ACS include minor plaque ulceration and transient thrombus formation in unstable angina, more extensive thrombosis in non-Q wave MI, and complete occlusion in STEMI and sudden death. In this review, we will limit the discussion to unstable angina and NSTEMI, and describe some recent developments and new insights into the basic mechanisms thought to underlie ACS. We will address the contemporary antithrombotic approach to treatment of this disorder, including the use of aspirin, thienopyridine agents, unfractionated and low-molecular-weight heparins, and glycoprotein (GP) IIb/IIIa receptor antagonists. In addition, we will address new therapeutic options that may target the inflammatory component of ACS (Table 1). The dilemma about the optimal approach for the treatment of ACS, whether invasive or conservative, is also briefly discussed. Pathophysiology of ACS. Atherosclerotic plaque rupture with thrombus formation is the primary pathophysiologic mechanism behind ACS.1–5 This process is complex. The thrombotic portion starts with exposure of subendothelial constituents like collagen, von Willebrand factor, fibronectin and vitronectin. These elements are recognized by platelet surface receptor GP Ib and lead to platelet activation and adhesion to the vessel wall. Activated platelets release from their alpha granules substances such as thromboxane A2, thrombin, adenosine diphosphate and serotonin, which lead to further platelet activation and aggregation. The final common pathway of platelet aggregation involves activation of the GP IIb/IIIa surface receptors, which cross-link platelets via fibrinogen bridges. Aggregated platelets facilitate the conversion of prothrombin to thrombin; this leads to increased thrombin formation, which in turn is a potent agonist for further platelet activation. Finally, the thrombus is stabilized by thrombin-mediated conversion of fibrinogen to fibrin. Inflammation and factors leading to plaque rupture. Recent studies have shown that inflammatory response to endothelial injury plays an important and possibly decisive role in the pathophysiology and vulnerability of the atherosclerotic plaque. The presence and degree of inflammation and the shift to a procoagulant state, defined by elevated C-reactive protein (CRP), fibrinogen, interleukin (IL)-1 and IL-6, and plasminogen activator inhibitor (PAI), have been strongly associated with an increased risk of future events.6–10 Histologic analysis shows that ruptured plaques exhibit an abundance of inflammatory cells, indicating a causal link. T-lymphocytes, for example, secrete gamma interferon, a cytokine that reduces collagen synthesis by smooth muscle cells.11 Macrophages, on the other hand, secrete matrix metalloproteinases, enzymes responsible for collagen degradation.12 Both T-lymphocytes and macrophages thus contribute to weakening of the collagen matrix and engender subsequent plaque rupture. Further indirect support of the role of inflammation emanates from studies showing that detecting heat released by inflammatory cells within an atherosclerotic plaque predicts future instability and rupture.13 In addition to a weak matrix and presence of inflammatory cells, other studies show that as the size of the soft lipid core increases and the fibrous cap decreases, circumferential stress will increase, particularly in the shoulder region of an atheroma, thus leading to its rupture.14 Aspirin. Aspirin exerts its antiplatelet effects by inhibition of the synthesis of thromboxane A2, a potent amplifier of platelet aggregatory response. At the pharmacological level, aspirin irreversibly acetylates and inactivates prostaglandin G/H synthase, therefore preventing the conversion of arachidonic acid to thromboxane A2. This effect is permanent for the life of the anucleate platelet. Aspirin therapy decreases the incidence of adverse cardiovascular events in patients with stable coronary artery disease, acute STEMI, and in the setting of percutaneous coronary angioplasty. In patients with ACS, four randomized trials have shown that aspirin therapy, in doses ranging from 75–1,320 mg daily, reduces the incidence of death or myocardial infarction by 30–50%.15–18 Aspirin therapy has its limitations. Platelet aggregation caused by adenosine, serotonin, catecholamines and shear stress is not completely inhibited by aspirin administration. More importantly, recent studies suggest that up to 8–12% of patients might be resistant to the antiplatelet effect of aspirin therapy,19 possibly because of its inability to completely suppress thromboxane A2 synthesis.20 Bedside platelet function tests may assist in identifying these patients, although more research is needed. Clopidogrel. Clopidogrel is a thienopyridine agent that blocks adenosine diphosphate-induced platelet aggregation and is analogous to a formerly used drug, ticlopidine. Compared to ticlopidine, however, clopidogrel has a faster onset and longer duration of action, and is associated with a better side-effect profile. In the CAPRIE trial,21 over 19,000 patients with coronary, peripheral or cerebral vascular disease were randomized to aspirin (325 mg/day) or clopidogrel (75 mg/day). Clopidogrel was shown to be modestly superior in the prevention of adverse cardiovascular events and ischemic stroke compared to aspirin (5.83% versus 5.32%; p = 0.043). More importantly, clopidogrel was not associated with an increased incidence of bone marrow suppression on gastrointestinal intolerance compared to aspirin. The CLASSICS trial,22 on the other hand, established that clopidogrel is equivalent to ticlopidine in patients who undergo stenting procedures, but with much better tolerability. The CURE trial23,24 was a randomized, double-blind trial in which 12,562 patients with ACS were randomized within 24 hours after the onset of symptoms to receive either a bolus dose of clopidogrel (300 mg) followed by 75 mg per day for 3–12 months, or matching placebo. Both groups received aspirin. The primary outcome of death from cardiovascular causes, nonfatal myocardial infarction or stroke occurred in 9.3% of the patients in the clopidogrel group and 11.4% of the patients in the placebo group (p Unfractionated heparin. Unfractionated heparin exerts its antithrombotic effects by binding to antithrombin III and inhibiting thrombin action. Data regarding the use of unfractionated heparin in patients with ACS have been conflicting. Several studies have shown that treatment with unfractionated heparin in addition to aspirin produces a trend toward a reduction in the risk of death or non fatal myocardial infarction.17,18,26,27 On the other hand, in a study by Holdright et al.,28 unfractionated heparin did not have any additional benefit over aspirin alone. In that study, however, patients received unfractionated heparin for only 2 days. In a different study by Gurfinkel et al.,29 aspirin alone or aspirin combined with unfractionated heparin were similar and both were inferior to a combination of aspirin and low-molecular-weight heparin. A recent meta-analysis30 showed that the combination of aspirin and unfractionated heparin is associated with a 33% reduction of the incidence of death and non fatal myocardial infarction compared to aspirin alone. This reduction, although not statistically significant, provides some support for the use of this combination in ACS. Low-molecular-weight heparin. Unlike unfractionated heparin, low-molecular-weight heparins exert their anticoagulant action mainly directed against factor Xa, and thus may limit rebound phenomenon by preventing thrombin regeneration after drug discontinuation. Other advantages of low-molecular-weight heparins include better bioavailability, longer duration of action, less binding to plasma proteins and endothelial cells, and resistance to inactivation by PF4. Disadvantages of low-molecular-weight heparins include lack of effective monitoring, especially in patients in the catheterization laboratory, as well as higher costs. Three low-molecular-weight heparins have been evaluated in 7 clinical trials in patients with ACS: enoxaparin,31–33 dalteparin34–37 and nadroparin.29,38 Only one low-molecular-weight heparin, enoxaparin, has been shown to be superior to unfractionated heparin in the medical phase of treatment of ACS. Both the ESSENCE trial31 and the TIMI-11B trial32 randomly assigned patients with angina at rest or non-Q wave myocardial infarction to receive either enoxaparin or continuous intravenous unfractionated heparin. The primary endpoint (death, myocardial infarction or urgent revascularization) occurred less in the enoxaparin group in both studies. A prospectively planned meta-analysis33 of the above two trials showed that enoxaparin was associated with a 20% reduction in death and serious cardiac ischemic events that appeared within the first few days of treatment, and this benefit was sustained through 43 days (Figure 2). Enoxaparin’s treatment benefit was not associated with an increase in major hemorrhage during the acute phase of therapy, but there was a slight increase in the rate of minor hemorrhage. Other low-molecular-weight heparins have also been studied, but results have not been as good as enoxaparin. Based on the FRIC34 FRISC,35 FRISC II,36,37 and FRAXIS38 trials, as well as a study by Gurfinkel at al.,29 both dalteparin and nadroparin seem to be as effective and safe as unfractionated heparin. Possible explanations for the divergent results seen among these three agents include different clinical activities among agents, different trial objectives, designs and endpoints, different patient selection criteria, and different regimens and duration of low-molecular-weight heparins. Platelet glycoprotein IIb/IIIa therapy. The GP IIb/IIIa receptor on the platelet surface membrane constitutes the final common pathway of platelet aggregation. This receptor binds circulating fibrinogen or von Willebrand factor and cross-links adjacent platelets together. Three different GP IIb/IIIa receptor antagonists are currently approved for clinical use. Abciximab is a monoclonal antibody fragment with a high binding affinity for the GP IIb/IIIa receptor, but with additional activity against the vitronectin and MAC-1 receptors. Eptifibatide and tirofiban are small-molecule agents with exclusive specificity for the GP IIb/IIIa receptor. Unlike abciximab, these agents have less binding affinity and a shorter biological half-life. Several trials have established the beneficial effects of GP IIb/IIIa receptor antagonists in patients undergoing percutaneous interventions. In patients with ACS, however, trials of GP IIb/IIIa receptor antagonists have yielded only modest benefits, and sometimes even conflicting results. These include the PRISM,39 PRISM-PLUS,40 PURSUIT,41 PARAGON,42 and GUSTO-IV43 trials (Table 2). A recent meta-analysis44 estimated that these agents reduce the composite endpoint of death or myocardial infarction at 30 days by only 12%, with a marked heterogeneity between different trials (Figure 3). Several analyses have identified certain subgroups of high-risk patients with ACS who would benefit most from GP IIb/IIIa receptor antagonist therapy. For example, when a percutaneous intervention is performed, the benefit of this therapy is more pronounced. This is shown by the 31%, 35% and 42% reductions in the 30-day incidence of death or myocardial infarction seen when a percutaneous intervention was performed in the PURSUIT,45 PARAGON-B, and PRISM-PLUS trials, respectively, as compared to only 6%, 7% and 12% reductions when a percutaneous intervention was not performed. These results are confirmed in the meta-analysis mentioned earlier,44 which revealed a 34% reduction in the incidence of the primary endpoint in patients undergoing a percutaneous intervention compared to a 7% reduction in patients who did not (Figure 3). A second group of patients with remarkable benefits from GP IIb/IIIa receptor antagonist therapy include those with elevated troponin levels. This is evidenced by the impressive reduction of death in troponin positive patients by 42%, 67% and 70% in the PARAGON-B, PRISM46 and CAPTURE47 trials, respectively. Again, the meta-analysis supports this conclusion, and shows a 58% reduction in the 30-day incidence of death or myocardial infarction in the troponin positive group compared to a 5% increase in the troponin negative group (Figure 3). One other possible way to stratify patients is to use the TIMI risk score (to be described later) and administer GP IIb/IIIa receptor antagonists only in those high-risk patients (i.e., a score of 4 or greater). This strategy is supported by a retrospective analysis of the PRISM-PLUS study, whereby tirofiban was beneficial only in those high-risk patients, and no benefit was seen in others (Figure 4).48 One question to be answered is whether the observed efficacy between different compounds is due to pharmacological differences or merely a failure to achieve adequate levels of platelet inhibition. For example, in the TARGET trial,49 abciximab was shown to be superior to tirofiban at 30 days in patients with ACS undergoing percutaneous revascularization. Recent data, however, suggest that the tirofiban used in this trial failed to achieve > 80% platelet inhibition in the early stages of the infusion. Novel therapeutic approaches. New insights into the inflammatory component of ACS are leading to novel therapeutic approaches that go beyond the thrombotic process. Recently, the MIRACL trial (Figure 5)50,51 evaluated the effect of treatment with atorvastatin, 80 mg/day, initiated 24–96 hours after an ACS. The primary endpoint event, defined as death, nonfatal acute myocardial infarction, cardiac arrest with resuscitation or recurrent symptomatic myocardial ischemia, occurred in 14.8% in the atorvastatin group and 17.4% in the placebo group (p = 0.048). It is important to note that this beneficial effect was seen irrespective of baseline lipid levels, and may be related to the statin anti-inflammatory effects.52–54 Aspirin, initially thought as mainly an antiplatelet agent, is becoming more recognized for its anti-inflammatory properties. Clinical evidence to support this role includes its beneficial effect directly related to CRP levels.55 Preliminary data suggest that matrix metalloproteinase inhibitors can delay neointimal formation in various preparations, but more extensive work is still needed.56,57 Finally, ACE inhibitors have recently been demonstrated to possess potent anti-inflammatory properties58 that may explain some of their beneficial cardiovascular effects.59 See continuation of article in Part II

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