Pharmacologic plaque passivation for the reduction of recurrent cardiac events in acute coronary syndromes
V. Stephen Monroe, MD*,
Richard A. Kerensky, MD, FACC*,
Enrique Rivera, MD*,
Karen M. Smith, MD, FACC* and
Carl J. Pepine, MD, MACC*,*
* Division of Cardiovascular Medicine, University of Florida College of Medicine, Gainesville, Florida, USA
Manuscript received July 26, 2002;
revised manuscript received October 17, 2002,
accepted October 31, 2002.
*
Reprint requests and correspondence: Dr. Carl J. Pepine, Division of Cardiovascular Medicine, 1600 Archer Road, Box 100277, Gainesville, Florida 32610-0277, USA.
pepincj{at}medicine.ufl.edu
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Abstract
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Acute coronary syndrome (ACS) is often associated with the rupture of vulnerable atherosclerotic plaque, coronary thrombus formation, and abrupt limitation of blood flow, leading to adverse outcomes. Passivation of vulnerable plaque represents a therapeutic concept that has the potential to prevent or limit the magnitude of a new rupture in order to reduce the recurrence or severity of events. Plaque passivation can be defined as a process by which the structure or content of the atherosclerotic plaque is changed to reduce the risk of subsequent rupture and thrombosis. This may be achieved by using strategies that address different components of the plaque or the endothelium. The following factors can affect the susceptibility of plaque to rupture: macrophage infiltration; accumulation of inflammatory cells; paracrine secretion of enzymes that may cause degradation of the fibrous cap of coronary plaque; shear stress; circadian rhythm variation in stress hormone release; and infectious agents. The use of pharmacologic agents to reduce plaque vulnerability by passivation has been explored. Clinical studies demonstrate that lipid-modifying agents (e.g., statins), antiplatelet agents (acetylsalicylic acid, thienopyridines, thianopyridines, glycoprotein IIb/IIIa inhibitors), and antithrombotic agents (unfractionated heparin and low-molecular-weight heparin) can reduce the occurrence of acute coronary events in ACS patients. In addition, angiographic studies suggest that statins may also promote regression of atherosclerosis. Angiotensin-converting enzyme inhibitors, niacin, and calcium antagonists may also contribute to plaque passivation. This article reviews atherosclerotic plaque development and vulnerability and discusses some clinical studies highlighting the role of plaque passivation in the management of ACS patients.
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Abbreviations and Acronyms
| | ACE | = angiotensin-converting enzyme | | ACS | = acute coronary syndrome(s) | | GP | = glycoprotein | | hs-CRP | = high-sensitivity C-reactive protein | | LDL | = low-density lipoprotein | | LMWH | = low-molecular-weight heparin | | NSTEMI | = non–ST-segment elevation myocardial infarction | | PCI | = percutaneous coronary intervention | | UA | = unstable angina | | UFH | = unfractionated heparin |
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Acute coronary syndrome (ACS), a major cause of hospitalization in the U.S., includes unstable angina (UA), non–ST-segment elevation myocardial infarction (NSTEMI), and ST-segment elevation MI (STEMI) (1,2). Unstable angina and NSTEMI are arbitrarily differentiated by the presence or absence of specific cardiac markers (e.g., troponin I or T, creatinine kinase–myocardial band) (2). The major cause of ACS is atherosclerotic plaque rupture or erosion (2,3). Therefore, plaque passivation and stabilization could be important strategies for reducing the risk and severity of cardiac events.
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Pathophysiology of atherosclerosis and plaque rupture
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Coronary atherosclerosis is a process characterized by the accumulation of lipids, mononuclear cells, fibrous components, and calcium in the arteries (4). It begins in early life and progresses through adulthood, exacerbated by hypertension, diabetes, hyperlipidemia, smoking, and obesity (4–6). Vascular injury, recruitment of monocyte mononuclear cells, and infiltration of foam cells (lipid-laden macrophages) which, in combination with T lymphocytes, form fatty streaks, also promote lesion formation (4,5). The lipid deposition is accompanied by smooth muscle cell migration and proliferation. Eventually, atheromas develop within the vascular wall as the intima grows outward, a process referred to as positive remodeling (4,5).
Later stages of plaque development and vessel wall modification are associated with luminal encroachment, which progressively limits blood flow (5). A phasic pattern of plaque disruption leads to the exposure of subendothelium, platelet activation and aggregation, mural thrombus formation, increased lipid accumulation within the damaged intima and mural thrombus, and lesion progression over time.
Cytokines and complement factor fragments, produced by macrophages and foam cells, contribute to monocyte mononuclear cell recruitment (4). In advanced-stage lesions, reactive oxygen species and pro-oxidant enzymes increase oxidative stress. Proteinases, including matrix metalloproteinases and elastolytic cathepsins, may alter the arterial matrix, facilitating cellular migration and contributing to plaque enlargement (Fig. 1) (4). Dying macrophages and endothelial cells in the lesions also release oxidized cholesterol phospholipids and cytokines that can increase the inflammatory response and cause further endothelial damage (4). High sensitivity C-reactive protein (hs-CRP) serum levels have been found to be independently associated with sudden death attributable to severe atherosclerotic coronary disease (7). Elevation of hs-CRP has also been associated with thin cap atheromas and immunohistochemical deposition of CRP within plaques. These results, reflected by serum hs-CRP, support the concept that inflammation is an important component of plaque instability (7).
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Figure 1 Metabolism of collagen and elastin in the plaque’s fibrous cap. The vascular smooth muscle cell synthesizes the extracellular matrix protein, collagen, and elastin from amino acids. In the unstable plaque, interferon-gamma (IFN- ) secreted by activated T cells may inhibit collagen synthesis, interfering with maintenance and repair of the collagenous framework of the fibrous cap. The activated macrophage secretes proteases that can break down both collagen and elastin to peptides and, eventually, amino acids. Breakdown of these structural molecules of the extracellular matrix can weaken the fibrous cap, rendering it more susceptible to rupture and precipitation of an acute coronary syndrome. IFN- secreted by the T lymphocytes can, in turn, activate the macrophage. Plaques also contain other activators of macrophages, including tumor necrosis factor-alpha (TNF- ), macrophage colony-stimulating factor (M-CSF), and macrophage chemoattractant protein-1 (MCP-1), among others. IL = interleukin. (Reprinted from Libby P, et al. Am J Cardiol 2000;86 Suppl:3J–9J. Copyright 2000, with permission from Excerpta Medica Inc., and reproduced with permission from the American Heart Association. Libby P, et al. Molecular bases of the acute coronary syndromes. Circulation 1995;91:2844–50.)
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Plaque passivation: a potential target for therapy
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Passivation generally refers to physical, chemical, or biological interactions that result in the stabilization of component surfaces. Atheromatous plaque passivation can be defined as a process by which the structure or content of the active atherosclerotic plaque is changed to effect a reduction in the risk of subsequent rupture and thrombosis. This may be achieved through various therapeutic strategies that address different components or processes at or near the surface of the plaque or the overlying endothelium, thereby minimizing or stabilizing vulnerable lesions that could otherwise lead to thrombotic complications. Successful treatment requires a thorough understanding of the complex processes involved in plaque formation, progression, and susceptibility to rupture. Clinical and angiographic studies have demonstrated that lipid-modifying, antiplatelet, and antithrombotic agents can reduce the occurrence of acute coronary events in ACS patients. Passivation of vulnerable plaque represents a therapeutic strategy that can potentially prevent or reduce the severity of new rupture.
The identification of future culprit lesions is uncertain with current technology. A lack of significant correlation between stenosis severity and plaque vulnerability has been repeatedly demonstrated. For example, in about two-thirds of cases studied, the plaques in the immediate proximity of the thrombotic occlusion were obstructing <70% of the lumen diameter. Also, in angiographic studies of ACS patients, the culprit coronary artery stenosis arose from the most severely occluded artery in only 34% of cases (8). Another review found only 22% of infarct-related arteries had >70% stenosis on previous angiography (9,10).
Vulnerable plaques characteristically contain a large lipid pool, thin fibrous cap, high macrophage content, and few smooth-muscle cells or collagen (6,11). Other factors that increase vulnerability include macrophage infiltration, accumulation of inflammatory cells, enzymatic degradation of the fibrous cap, hemodynamic shear stress, and circadian neurohumoral changes (6). Some infectious agents (e.g., cytomegalovirus, Chlamydia pneumoniae) are also thought to be associated with plaque rupture, but a pathophysiologic mechanism remains to be elucidated.
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Pharmacologic options for plaque, platelet, and endothelial passivation
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Lipid-modifying agents such as statins and nicotinic acid, as well as antiplatelet and antithrombotic agents, reduce the incidence of acute coronary events and have become increasingly important in ACS management (2,6,11–16). Statins and nicotinic acid are able to prevent rupture by stabilizing plaque and reducing the rate of atherosclerosis progression (17–19). Angiotensin-converting enzyme (ACE) inhibitors, and perhaps some calcium antagonists, may also play a beneficial role in plaque passivation (6).
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Statins
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The statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) effectively reduce low-density lipoprotein (LDL) cholesterol levels, modestly increase high-density lipoprotein concentrations, and reduce triglycerides (16,17). Statin-mediated lowering of lipids may stabilize vulnerable plaque by reducing levels of oxidized lipoprotein in the plaque’s core. Oxidized LDL may induce or increase enzymes such as collagenases, which are surface-bound (4,19–22). Statins may also stabilize plaques and reduce the risk of MI by improving endothelial vasodilator function, upregulating nitric oxide synthesis, and reducing intimal inflammation.
The ability of statins to improve endothelial function was tested in the REduction of Cholesterol in Ischemia and Function of the Endothelium (RECIFE) trial (20). In the RECIFE trial, 60 patients with ACS were randomly assigned to placebo (n = 30) or pravastatin 40 mg per day (n = 30) within approximately 10 days of hospital admission for a duration of six weeks. Vascular endothelial cell function was assessed by flow-mediated dilation of the brachial artery using ultrasonography. The effect of therapy on hemostatic factors and platelet activity was also evaluated.
Pravastatin significantly reduced total cholesterol by 23% (p < 0.05) and LDL by 33% (p < 0.01) (Fig. 2). Flow-mediated vasodilation of the brachial artery was unchanged with placebo but significantly improved with pravastatin (p = 0.02).
The randomized, double-blind, controlled Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) trial evaluated early use of atorvastatin in patients presenting with UA or non–Q-wave MI (23). Between 24 and 96 h after hospital admission, patients (n = 3,086) received either atorvastatin 80 mg per day or matching placebo for 16 weeks. The primary outcome (death, nonfatal acute MI, cardiac arrest with resuscitation, or recurrent symptomatic myocardial ischemia with objective evidence and requiring emergency hospitalization) was significantly reduced in the atorvastatin arm compared with placebo (14.8% vs. 17.4%; p = 0.048) (23). This corresponds to a 16% relative risk reduction with atorvastatin.
Other studies, using coronary angiography, have demonstrated a reduction in plaque progression on average of more than 30% in patients treated with a statin (24–30). These small but significant angiographic changes were accompanied by a greater reduction in clinical events than expected, indicating that statin therapy may passivate vulnerable plaques and prevent their development (17).
There are several ongoing studies evaluating statin therapy in ACS patients. The PRavastatin Or atorVastatin Evaluation and Infection Therapy (PROVE-IT) trial is designed to compare the early use of pravastatin 40 mg per day or atorvastatin 80 mg per day in 4,000 patients when therapy is initiated within 10 days after onset of an ACS (31). Patients will be followed up for a mean of two years. The Pravastatin Acute Coronary Treatment (PACT) study is evaluating early clinical outcomes in ACS patients treated with pravastatin versus placebo within the first 24 h after the beginning of an acute coronary event (32). (This trial was recently stopped and presented at XIV World Congress of Cardiology, May 15, 2002. At 30 days, there was a 12.4% [211/1698] event rate in placebo assigned patients compared with 11.6% [199/1710] in pravastatin assigned patients.) The Aggrastat to Zocor (A to Z) trial is a two-phase study. In the first phase, treatment with the glycoprotein (GP) IIb/IIIa inhibitor, tirofiban, plus unfractionated heparin (UFH) is compared with therapy with the low-molecular-weight heparin (LMWH), enoxaparin, in patients with UA or NSTEMI (33). In the second phase, stabilized patients, including those with STEMI not participating in the first phase, will be randomized to receive either simvastatin or placebo. Patients will be treated within 10 days of onset with simvastatin 40 mg per day for one month, after which the dosage will increase to 80 mg per day. After four months, patients in the placebo group will receive simvastatin 20 mg per day. Follow-up will continue until 970 primary outcome events are reached (defined as cardiac death, MI, or rehospitalization for ACS) (33).
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Antithrombotic and antiplatelet agents
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When plaque rupture occurs, the subendothelial matrix becomes exposed to circulating platelets and coagulation factors (6). Several platelet adhesion molecules are found in the subendothelial protein matrix, including von Willebrand factor and collagen. The adhesion process leads to platelet activation, platelet aggregation, calcium mobilization, and platelet degranulation (33). In the final stages of this process, circulating fibrinogen binds to upregulated GP IIb/IIIa receptors on platelet surfaces causing cross-linking of platelets (34,35). The von Willebrand factor may also bind to GP IIb/IIIa receptors, causing platelet cross-linking. During platelet activation, the lipid-laden macrophages and smooth muscle cells in the core of the disrupted plaque express tissue factor, which, when exposed to the circulation, activates the coagulation cascade (34). The GP IIb/IIIa receptor blockade with inhibition of the coagulation cascade represents an important therapeutic tool for providing protection against these processes. Aspirin combines anti-thrombotic and anti-inflammatory capabilities, reducing interleukin-6, CRP, and macrophage colony-stimulating factor, and is associated with reduced risk of cardiac events in the early weeks after an ACS.
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GP IIb/IIIa inhibitors and UFH
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Clinical trials have demonstrated that GP IIb/IIIa inhibitors yield the greatest benefit in the ACS patient population undergoing percutaneous coronary intervention (PCI) (36–40).
The Chimeric 7E3 AntiPlaTelet in Unstable angina REfractory to standard treatment (CAPTURE) trial was the first to demonstrate a clinical benefit of the GP IIb/IIIa inhibitor, abciximab, administered before percutaneous transluminal coronary angioplasty in ACS patients (36). CAPTURE was a randomized, placebo-controlled, multicenter trial enrolling 1,265 patients with refractory angina (recurrent myocardial ischemia despite intensive medical therapy) (36). Patients received either abciximab (0.25 mg/kg bolus followed by continuous infusion of 10 µg/min) 18 to 24 h before angioplasty and continued for 1 h after the coronary procedure, or matching placebo. The primary outcome was the 30-day occurrence of death from any cause, MI, or urgent intervention for recurrent ischemia (Fig. 3). Significantly fewer patients in the abciximab group experienced these events than in the placebo group (11.3% vs. 15.9%; p = 0.012). The rate of MI was lower in the abciximab group before angioplasty (0.6% vs. 2.1%; p = 0.029) as well as after the procedure (2.6% vs. 5.5%; p = 0.009) (36).
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Figure 3 Time course of the primary outcome and its major components. MI = myocardial infarction. (Reprinted with permission from Elsevier Science. Lancet 1997;349:1429–35.)
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The Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and symptoms (PRISM-PLUS) study enrolled 1,915 ACS patients who presented within 12 h of symptom onset (37). They were randomized to receive a 48-h infusion of the GP IIb/IIIa inhibitor, tirofiban, UFH, or tirofiban plus UFH. After 48 h, angiography and coronary angioplasty were performed as indicated. The primary outcome was the composite of death from any cause, MI, or refractory ischemia within seven days after randomization. Patients treated with the UFH and tirofiban combination had a lower occurrence of the composite outcome before coronary intervention, indicating an "upstream" benefit. The risk reduction for death or MI after 48 h was 34%. A prospective angiographic study from the PRISM-PLUS trial showed that the combination of tirofiban plus UFH significantly reduced the burden of intracoronary thrombus in the culprit lesion (p = 0.022), improved the perfusion grade (p = 0.002), and decreased the severity of the obstruction (p = 0.037), compared with either tirofiban or UFH alone (38).
The Platelet IIb/IIIa in Unstable angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) study evaluated the combination of eptifibatide and UFH versus UFH alone in 10,948 ACS patients (39). The primary outcome was the composite of death or MI at 30 days. Patients receiving eptifibatide derived significant benefit from treatment, with an absolute 1.5% reduction in death or MI at 30 days.
The Do Tirofiban And ReoPro Give Similar Efficacy Trial (TARGET) was a double-blind, randomized study conducted to compare the efficacy and safety of these two GP IIb/IIIa inhibitors in patients with ACS undergoing PCI with stenting (40). Patients were randomized to receive either tirofiban (n = 2,398) or abciximab (n = 2,411). The primary outcome was a composite of death, nonfatal MI, or urgent target vessel revascularization at 30 days. In the tirofiban group, there was a higher incidence of these events (7.6%) versus 6.0% in the abciximab group (p = 0.038), suggesting the clinical superiority of abciximab (40), although this difference was not as robust after six months and one year. A reduction in periprocedural enzymatically defined by defined MI appears to be the major benefit of abciximab. A lower rate of minor bleeding and thrombocytopenia was noted in the tirofiban group.
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LMWH versus UFH
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Low-molecular-weight heparin represents a class of anticoagulants with several pharmacologic and therapeutic advantages over UFH. Protein binding and incidence of thrombocytopenia are reduced with LMWHs. Also, they are not inactivated by platelet factor-4, and they do not increase platelet activation or aggregation (no "rebound" phenomenon). The LMWHs have different abilities to inhibit factor Xa versus IIa (ratios ranging from 1.9 to 3.8), corresponding to varying clinical efficacies between the different agents when used to treat ACS patients (41–44).
Two large randomized clinical trials, the Efficacy and Safety of Subcutaneous Enoxaparin in the Non–Q-wave Coronary Events (ESSENCE), and the Thrombolysis In Myocardial Infarction (TIMI) IIB, have demonstrated superiority of enoxaparin over UFH in the treatment of ACS patients (41–44). Follow-up data from the ESSENCE trial demonstrated that the superiority of enoxaparin over UFH is sustained over a one-year period, with a significant reduction in the need for diagnostic catheterization (p = 0.036) and coronary revascularization (p = 0.002) (45). Conversely, dalteparin has demonstrated only an equivalency to UFH, and nadroparin tended toward inferiority, with a higher incidence of bleeding complications associated with prolonged use (44) (Fig. 4).
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Figure 4 A clinical efficacy summary: low-molecular-weight heparin (LMWH) vs. unfractionated heparin (UFH). ESSENCE = Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q-wave Coronary Events trial; FRAXIS = FRAXiparine in Ischemic Syndromes trial; FRIC = FRagmin In unstable Coronary artery disease trial; MI = myocardial infarction; NS = not significant; RRR = relative risk reduction; TIMI = Thrombolysis In Myocardial Infarction. (Adapted [with permission from Thieme Publishers, 2002] from Semin Thromb Hemost 1999;25 Suppl 3:113–21 [Figure 3]).
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The safety of enoxaparin in combination with GP IIb/IIIa inhibitors at PCI was demonstrated in the National Investigators Collaborating on Enoxaparin (NICE) studies (46,47). The efficacy of using enoxaparin in UA/NSTEMI patients undergoing PCI has also been explored (Fig. 5). In a recent study, enoxaparin was administered for at least 48 h to 451 ACS patients, 65% of whom underwent coronary angiography within 8 h of enoxaparin treatment. When indicated, PCI (28%) was then performed without any additional administration of UFH or LMWH and without laboratory monitoring of anticoagulation (48). No abrupt closure or urgent revascularization after PCI was reported, and the incidence of death or MI at 30 days in the PCI group was low at 3%, which compares favorably with historical controls. An ongoing trial, the Superior Yield of the New strategy of Enoxaparin, Revascularization, and GlYcoprotein IIb/IIIa inhibitors (SYNERGY), is a very large (8,000 patients) randomized trial that seeks to definitively determine if enoxaparin is superior to UFH during PCI.
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Figure 5 Percutaneous coronary intervention: 30-day clinical outcome with enoxaparin. MI = myocardial infarction. (Reproduced with permission from Lippincott Williams and Wilkins. Collet JP, Montelscot G, Lisbon L, et al. Percutaneous coronary intervention after subcutaneous enoxaparin pretreatment in patients with unstable angina. Circulation 2001;103:658–62.)
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ACE inhibitors
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Angiotensin II affects several physiologic components of the vascular system that contribute to plaque instability. It may cause endothelial dysfunction, contributing to the formation of atherosclerotic lesions. It induces the expression of vascular cell adhesion molecule-1, promoting adhesion of monocytes to endothelial cells and the formation of oxygen free radicals. These all contribute to proinflammatory processes and plaque destabilization (49,50). Angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers may encourage plaque stability and reduce cardiac events. Promising animal-model studies have prompted a number of clinical trials to examine the role of these agents on surrogate outcomes in patients with coronary atherosclerosis. The outcomes include improvement of endothelial function determined by vascular response to acetylcholine, B-mode ultrasound evaluation of atherosclerotic progression in the carotid artery, and progression of coronary artery disease using quantitative coronary angiography (50).
The Study to Evaluate Carotid Ultrasound changes in patients treated with Ramipril and Vitamin E (SECURE) was a substudy of the Heart Outcomes Prevention Evaluation (HOPE) trial (51,52). This analysis examined 732 patients from the HOPE trial who had vascular disease or diabetes with at least one other risk factor. Subjects with heart failure or a low left ventricular ejection fraction were excluded. Patients receiving ramipril 10 mg per day demonstrated a significant reduction in the rate of carotid intimal medial thickening, when compared with either 2.5 mg ramipril or placebo, suggesting a beneficial negative effect on atherosclerotic progression (51).
The Trial on Reversing ENdothelial Dysfunction (TREND) was a multicenter, double-blind, randomized, placebo-controlled trial that evaluated the effect of quinapril on endothelial dysfunction in the epicardial coronary arteries (53). Subjects were normotensive with no left ventricular dysfunction, but they had one or two coronary arteries with >50% diameter stenosis and a need for coronary revascularization. Twelve hours to 72 h after successful coronary intervention, patients randomly received either placebo (n = 54) or a titrated dose of quinapril (n = 51) (10 mg on day one, increased to 20 mg per day for one week, and to 40 mg per day for six months). With quinapril, the constrictive response to acetylcholine was significantly reduced compared with placebo (p < 0.014) (Fig. 6). A substudy of the TREND trial also suggested an improvement in quantitative coronary blood flow in patients receiving quinapril (54).
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Figure 6 The Trial on Reversing Endothelial Dysfunction (TREND) investigated the effects of six months of treatment with the ACE inhibitor quinapril on a target coronary artery segment (<40% diameter stenosis) in patients who underwent nonsurgical interventions for >50% stenosis in one to two other segments. At baseline, the endothelium-dependent vasodilator acetylcholine elicited a paradoxical vasoconstriction; quinapril resulted in a significant improvement in the response to acetylcholine (p < 0.014 vs. placebo). (Reprinted from Pepine JC, et al. Improved endothelial function with angiotensin-converting enzyme inhibitors. Am J Cardiol 2002;79:29–32. Copyright 2002, with permission from Excerpta Medica Inc.)
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Calcium antagonists
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There is a significant increase in transmembrane calcium transport in atherosclerotic vessels, which suggests that calcium antagonists may delay the progression of coronary atherosclerosis. The dihydropyridine-type calcium antagonist, amlodipine, has shown an inhibitory effect on oxidative alteration to lipids associated with cellular membranes both in vitro and in vivo (55). Amlodipine may contribute to plaque passivation by interfering with lipid oxidative processes, limiting foam cell formation and other cellular mechanisms that contribute to the development of atherosclerosis (55). In the Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT), the effects of amlodipine on the development and progression of atherosclerotic lesions in coronary and carotid arteries in 825 patients with coronary artery disease were evaluated. The PREVENT study demonstrated a reduction in hospitalizations for revascularization and UA with amlodipine. By ultrasonographic analysis, amlodipine was associated with a significant delay in the progression of carotid atherosclerosis over three years (p = 0.007) (56). The Coronary Angioplasty Amlodipine Restenosis Study (CAPARES) was conducted in a similar patient population and demonstrated that amlodipine significantly reduced the occurrence of revascularization and clinical events after angioplasty without reducing luminal loss (57).
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Other agents
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Other agents that may contribute to plaque passivation include antioxidants such as vitamins C and E, which may inhibit the oxidation of LDL cholesterol and stabilize vascular reactivity. However, studies conducted so far have not shown any consistent benefit in the use of antioxidant vitamins for the treatment or prevention of coronary atherosclerosis (52,58).
The High-density lipoprotein-Atherosclerosis Treatment Study (HATS) studied the effect of niacin, a potent agent for raising high-density lipoprotein cholesterol levels, in combination with simvastatin. In patients with coronary disease and low levels of high-density lipoprotein, this combination produced a 0.4% regression in coronary stenosis (p < 0.001) (58). The primary outcome of HATS was a composite of coronary death, nonfatal MI, stroke, or revascularization for worsening ischemia. With the niacin-simvastatin therapy, the event rate was significantly lower than with placebo (3% vs. 24%; p = 0.03), corresponding to a 90% reduction in the risk for the primary outcome. These findings support those of the Familial Atherosclerosis Treatment Study (FATS), which showed that intensive lipid modification with lovastatin and niacin reduced the occurrence of clinical events by 73% and lowered the progression of coronary lesions, with some evidence of regression in existing lesions (59).
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Mechanical approaches
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Traditionally, PCI has been reserved for lesions causing luminal stenosis resulting in myocardial ischemia. Mechanical coronary intervention is also performed during or after MI or ACS to treat lesions that have already produced thrombi. The concept of using PCI for plaque passivation has not been discussed in the usual paradigm of invasive cardiology. Before the advent of coronary stenting, balloon angioplasty probably increased the instability of previously stable plaques. With the development of coronary stenting, however, plaque stabilization could be achieved by covering the eroded surface with the stent struts and mechanically creating a larger luminal area for improved blood flow.
Even with the latest technology, stents are not currently used to stabilize non-occlusive, vulnerable lesions. The reasons for this are twofold. First, the vulnerable plaque cannot be identified easily with current imaging techniques. Second, stenting with bare metal stents is inappropriate because thrombosis can occur and intimal hyperplasia will cause restenoses in some cases. Future percutaneous mechanical plaque passivation will require the development of techniques for the identification of high-risk plaque even when it is not obstructing the vessel lumen. Also, biologically neutral or coated stents with drug-delivery capabilities need to be developed. This would allow delivery of an agent that will inhibit the intimal hyperplasia associated with stent insertion. Such a concept is appealing only if stent-induced stenosis can be prevented; otherwise, this approach will lead to an exchange of vulnerable non-obstructive plaques for stenotic in-stent hyperplastic lesions. Because coronary atherosclerosis is a diffuse process, the application of local therapies such as covered, drug-eluting stents is likely to have limited application, but one can envision the use of percutaneous therapy to passivate the highest-risk plaques even before they cause an angiographic stenosis.
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Footnotes
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Please refer to the Trial Appendix at the back of this supplement for the complete list of Clinical Trials.
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Abstract
Pathophysiology of...
p = 0.01 vs. placebo; and 
p = 0.01 vs. time 0. HDL = high-density lipoprotein; LDL = low-density lipoprotein. (Reproduced with permission from Lippincott Williams and Wilkins. Dupuis J, Tardif JC, Cernacek P, et al. Cholesterol reduction rapidly improves endothelial function after acute coronary syndromes. The RECIFE trial. Circulation 1999;99:3227–33.)