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Plaque Stabilization in the New Millenium

John A. Ambrose, MD; Eulogio E. Martinez, MD

Comprehensive Cardiovascular Center, Department of Medicine,
Saint Vincent Catholic Medical Centers of New York, USA, and The Instituto do Coração,
University of São Paulo, São Paulo, Brazil

INTRODUCTION
   The concept of plaque stabilization was developed in the 1990's in an attempt to explain the discrepancy between the small amount of plaque regression demonstrated angiographically in many randomized trials of lipid lowering and the large reduction in clinical events seen in these trials (1,2). In the 15 published angiographic lipid lowering trials, there was an approximate 22 to 34 percent reduction by pooled analysis in cardiac events which was similar to the event reduction in the large randomized secondary and primary lipid prevention trials (3-5). On the other hand, angiographic regression of atherosclerotic lesions although increased with lipid lowering versus placebo was unlikely to explain the large clinical benefit.

   Several factors were hypothesized to contribute to this reduction in clinical events. It had been generally appreciated that a majority of acute coronary events were related to disruption of a lipid-rich, "vulnerable" atherosclerotic plaque with a thinned fibrous cap lacking proper collagen and smooth muscle cell support (6). At the site of plaque disruption, the fibrous cap was infiltrated by macrophage-derived foam cells and activated lymphocytes. The acute clinical event was precipitated by the formation of an intimal, platelet-rich thrombus followed in some cases by a fibrin, red cell intraluminal thrombus which occluded the vessel in the presence of ST segment elevation myocardial infarction (7). Unstable angina and ST depression myocardial infarction were usually associated with a mural, platelet-rich thrombus without total occlusion or with a transient total occlusion (8).

   Based on several lines of evidence from human studies and regression studies in various animal models of atherosclerosis, lipid lowering over time was thought to stabilize plaques by several mechanisms which included the following: 1) depletion of plaque lipid particularly cholesterol ester. 2) a reduction in inflammatory cell activity and even the number of macrophage-rich foam cells. 3) a reduction in thrombosis risk by decreasing platelet reactivity, tissue factor expression by inflammatory cells or improving endogenous fibrinolysis. 4) overall improvements in endothelial function (9-13). All likely contributed in varying degrees to the reduction in clinical events with lipid lowering. The time course of these favorable changes in vessel wall anatomy and physiology or thrombosis risk varied. Changes in endothelial function could be demonstrated within one month of lipid lowering with use of the HmG Co A reductase inhibitors and may be immediate in cases of low-density lipoprotein apheresis in patients with elevated cholesterol. Reductions in thrombosis risk have been demonstrated at three and six months after initiation of lipid lowering therapy. Changes in the lipid and macrophage content of the plaque probably required at least six months to occur based on animal data (14). In randomized clinical trials of lipid lowering, placebo and treatment events began to diverge after 6 to 18 months of therapy suggesting a long latency between the initiation of lipid lowering and the reduction in myocardial infarction and cardiac death.

LIMITATIONS OF THE CONCEPT OF PLAQUE STABILIZATION
   Although the concept of plaque stabilization as described above was based on several lines of investigation, it is limited for several reasons.
1. The concept of a "vulnerable" atherosclerotic plaque as originally proposed would not be applicable to a significant percentage of acute coronary thrombi. At least one third of large coronary thrombi as detected by autopsy, originate from non lipid-rich plaques (15). This number may be higher in women and when clinical events are not exercise-related. Lipid lowering therapy in these individuals might not result in the same favorable changes in plaque composition as in the so-called vulnerable plaque.
2. The reduction in adverse events with lipid lowering is incomplete as adverse events are still occurring in the treated group. Thus, other factors or processes must contribute to a reduction in events.
3. The concept of plaque stabilization does not incorporate strategies directed against the plaque that has already destabilized.
4. No distinction is made between short-term (in-hospital) events, intermediate (30 day to six month) events and long-term events and plaque stabilization. The methodology used and the risk of new or recurrent events vary depending on the type of plaque and clinical presentation of the patient.
5. Angiography is an insensitive method for assessing plaque regression (16).

AN INTEGRATED APPROACH TO PLAQUE STABILIZATION
   Based on the limitations outlined above, an integrated approach to plaque stabilization is proposed incorporating plaque specific, process specific and time specific phenomena (Figure 1)

I. Plaque-Specific Considerations
   The disrupted and/or thrombosed culprit plaque in a patient with an acute coronary syndrome requires a different treatment philosophy and strategy than plaques that have not destabilized. The unstable plaque in an acute syndrome is not unlike an active volcano that must be made quiescent. The thrombotic component must dissolve or become organized, the intimal tear heal and the inflammatory activity reduced. The surrounding endothelium needs to become less dysfunctional with reduced vasoconstrictor pro inflammatory and pro coagulant activity. On the other hand, stable plaques whether or not lipid-rich must remain quiescent and atherosclerotic progression reduced or even reversed.

II. Process-Specific Considerations
   Any process or mechanism that reduces the subsequent occurrence of coronary thrombosis leading to unstable angina, myocardial infarction or sudden coronary death should be considered as possessing either plaque stabilizing properties, reducing thrombogenicity of the blood or passivating the vessel wall (reducing its propensity for vasoconstriction and thrombus formation). If the plaque is already destabilized and the clinical syndrome acute, short-term medical management will not completely eliminate thrombus or normalize vessel reactivity. In ST elevation myocardial infarction, thrombus can usually be demonstrated in the culprit lesion for at least one month after successful intravenous thrombolysis in patients on aspirin as the only antithrombotic agent (17). Furthermore, the culprit vessel in both myocardial infarction and unstable angina may be abnormally vasoreactive in comparison to normal appearing vessels or diseased vessels in patients with stable lesions (18-19).

III. Time-Specific Considerations
   Different conditions are associated with recurrent acute coronary events (unstable angina, myocardial infarction or death) that occur at different time intervals. In the medical management of acute coronary syndromes, recurrences occur during hospitalization or early after hospital discharge with the highest incidence of events within the first weeks to months following hospitalization (20). Acute recurrent events in general are related to total occlusion of the original culprit lesion (21). On the other hand, in stable clinical syndromes or in asymptomatic patients, the time frame for the appearance of adverse, acute clinical events is much longer extending over years and short-term events occur much less frequently than in patients presenting with an acute syndrome. Furthermore, in comparison to patients who present with an acute syndrome, acute events in stable or asymptomatic individuals often arise from the less severe and/or asymptomatic lesion (22).

1) Stabilization of the Culprit Plaque in an Acute Coronary Syndrome
   Stabilization of a culprit lesion in an acute syndrome whether the acute syndrome is unstable angina or myocardial infarction can be accomplished either through percutaneous intervention, with long-term antithrombotic and anticoagulant approaches or possibly with high-dose lipid lowering therapy. The prevention of total coronary occlusion at the site of obstruction in the culprit lesion is the predominant mechanism for avoiding recurrent clinical events after an acute syndrome as previously mentioned.

   A. Percutaneous Intervention
   Although not usually classified as such, percutaneous intervention is an effective method of acute plaque stabilization. Data from recent randomized trials indicate that the routine use of an invasive approach of cardiac catheterization followed by coronary intervention reduces recurrent adverse events particularly in certain high risk sub groups (for example increased troponin levels per intervention) with an acute syndrome in comparison to a more conservative approach of medical management and catheterization only for recurrent symptoms or provoked ischemia (23,24). The safest and most effective method of percutaneous intervention is probably stent placement in suitable vessels with the addition of an intravenous glycoprotein IIb/IIIa inhibitor. Whether the clinical substrate was unstable angina or non-Q or ST depression myocardial infarction, the strategy of GP IIb/IIIa inhibition and percutaneous intervention has proven efficacious in reducing subsequent events (25). Even in the Veteran Affairs Non-Q Wave Infarction Strategies in Hospital trial where a conservative approach after non-Q MI resulted in a lower in-hospital and one year mortality than the more invasive approach, percutaneous intervention in the invasive arm of that trial (but without glycoprotein IIb/IIIa receptor inhibitors) was associated with no mortality. Only when bypass surgery was employed was there an overall higher adverse event risk for the invasive therapy arm (26).

   In ST elevation MI, randomized data have also established the equivalence or superiority of intervention over thrombolytic therapy for primary management (27). Stenting in comparison to balloon angioplasty alone has been the usual approach to intervention in suitable vessels and the use of abciximab may improve coronary flow reserve and myocardial perfusion in the distal vascular bed on follow up (28). However, the preliminary results of the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications trial may appear to contradict the need for routine IIb/IIIa receptor blockade during intervention to reduce subsequent coronary events (29). In that trial, the lower 30 day and six-month event rate was related more to stent placement than administration of abciximab. Randomized data from the Evaluation of Platelet IIb/IIIa Inhibitor for Stenting (EPISTENT) trial suggest other benefits for the combination of stenting and a GP IIb/IIIa inhibitor (30). In EPISTENT, the majority of patients had an intervention after a recent bout of an acute coronary syndrome. In the diabetic subgroup from this trial, stent placement with abciximab markedly reduced the need for target vessel revascularization on follow-up compared to balloon angioplasty or stent placement without the use of abciximab,

   B. High Dose Lipid Lowering Therapy and Long-Term Antithrombotic Therapy
   In the absence of percutaneous intervention, there are other approaches to decrease subsequent events that may represent stabilization of acute culprit lesions. High dose lipid lowering therapy as given in the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering trial reduced ischemic events at the 16-week follow-up date (31). Overall, the primary endpoint of either death, myocardial infarction or recurrent ischemia requiring hospitalization was reduced from 17.4% to 14.8% in the 80 mg./day atorvastatin group, (p=0.048). The largest reduction was in the subgroup with recurrent ischemia which was reduced from 8.4 to 6.2% with high dose atorvastatin, p=0.02. These beneficial results are likely secondary to improved endothelial function and possibly to reduced thrombogenicity of the blood.

   Long-term antithrombotic and anticoagulant therapy may be another option in patients not routinely undergoing percutaneous intervention. The preliminary results of the Antithrombotics in the Prevention of Reocclusion in Coronary Thrombolysis (APRICOT)-2 and Anticoagulants in the Secondary Prevention of Events in Coronary Thrombosis (ASPECT)-2 trials suggest a role for coumadin and aspirin (APRICOT-2) or coumadin alone (ASPECT)-2 in selected patients (32-33). In APRICOT-2, patients with normal TIMI-flow after intravenous lytic therapy were randomized to either aspirin alone or aspirin plus coumadin (the INR was targeted to 2 to 3) and re-studied angiographically at 3 months. Angiographic re-occlusion was reduced from 30% to 18%, p=0.02 in the aspirin and coumadin arm and event free survival was increased from 70 to 83% respectively. These data on aspirin and coumadin complement previous angiographic data in acute myocardial infarction indicating that the percent reduction in diameter stenosis of the culprit lesion over a three month follow up was significantly greater in patients given both drugs versus aspirin alone (34). In ASPECT-2, 993 survivors of an acute syndrome were randomized to aspirin or a combination of aspirin and coumadin or to coumadin alone (INR 3-4). The use of coumadin was associated with a significant reduction in the primary endpoint of death/infarction or stroke from 9.2% with aspirin alone to 5.2% with coumadin (p<0.05). These data are similar to large scale randomized trials after myocardial infarction showing reduced adverse events on follow-up with moderate dose coumadin alone (35-36). However, in the APRICOT-1 study, the use of coumadin alone after acute myocardial infarction provided no protection against reocclusion of the culprit lesion at 3 months in comparison to placebo (37).

   At the recent American College of Cardiology Meeting in Orlando, Florida in March 2001, the results of the Clopidogrel in Unstable Angina to Prevent Recurrent Events trial were presented (38). Over 12,000 patients with either unstable angina or non-Q MI were randomized to a combination of clopridogrel and aspirin vs. aspirin alone for 12 months. There was a 20% decrease in the primary endpoint of death/myocardial infarction and stroke at 12 months with combination therapy which was highly significant (p=0.00005). Patients with or without revascularization procedures were similarly benefited. The curves began to diverge very early and were significantly different at 30 days after randomization. These data likely reflect another example of the beneficial effects of long-term antithrombotic therapy in promoting stabilization of acute lesions.

   Obviously, the approaches of intense lipid lowering, long-term antithrombotic or anticoagulant therapy and percutaneous intervention are not mutually exclusive although there are little or no data on high dose statin therapy and long-term anticoagulant therapy or other combination approaches. In addition, these approaches have not been compared in a randomized trial in patients presenting with an acute syndrome. In patients undergoing percutaneous intervention, lipid-lowering therapy should be routinely administered to decrease progression of atherosclerosis as well as reduce future coronary events in other lesions not intervened upon but not to reduce restenosis (39,40). The combination of percutaneous intervention and long-term anticoagulant therapy has also been recently reported in a new randomized trial (41). The addition of coumadin to aspirin reduced acute and follow-up events at one year versus aspirin alone, The benefit was seen in those receiving either stents or balloon angioplasty. Bleeding complications were significantly increased with coumadin although the incidence was low.

SHORT-TERM ANTITHROMBOTIC THERAPY IN THE MEDICAL MANAGEMENT OF ACUTE CORONARY LESIONS
   Several randomized trials in patients with an acute syndrome have included patients in whom medical management alone was utilized without percutaneous intervention or bypass surgery. In an overview of randomized trials with the intravenous glycoprotein IIb/IIIa receptor inhibitors, there was only an insignificant 8% reduction in recurrent events in patients treated medically with GP IIb/IIIa inhibitors but without intervention (42). In the preliminary presentation of the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO)-4 ACS trial, there was a slight but insignificant increase in adverse events with a 24 to 48 hour infusion of abciximab compared to placebo (43). It is plausible to suggest that the lack of benefit seen with abciximab in this trial was in part, related to the very low rate of acute intervention performed in that trial. These data appear similar to the results of GUSTO IIb in that the direct thrombin inhibitor, hirudin did not significantly reduce 30 day adverse events in comparison to unfractionated heparin(44). On the other hand, the universal failure of the trials with the oral glycoprotein IIb/IIIa inhibitors should not necessarily be attributed to the lack of concomitant percutaneous intervention but to other factors possibly related to their pharmacology or mode of administration (42). These adverse mechanisms include a prothrombotic tendency at low plasma drug levels or toxic effects of these agents on the myocardium. Thus, in contrast to the studies with long-term antithrombotic or antithrombotic / anticoagulant approaches, there are no data that new and more powerful antithrombotic therapy alone administered short-term, in-hospital will prevent subsequent events in patients with an acute coronary syndrome.

2) Stabilization of Non-Culprit Plaques in Acute Syndromes or Plaques in either Stable Syndromes or in Asymptomatic Patients
   Non-culprit plaques in patients with an acute syndrome and atherosclerotic plaques in stable patients or in the asymptomatic whether or not lipid-rich and potentially "vulnerable" must remain stable to reduce subsequent events. The benefits of lipid lowering in reducing coronary events and on stabilizing vulnerable plaques have been previously mentioned. Several other drug classes are routinely used in the management of coronary disease patients that reduce the incidence of subsequent acute coronary events. Angiotensin converting enzyme inhibitors, beta-blockers and standard antithrombotic agents such as aspirin may also have plaque-stabilizing effects or promote stabilization through a reduction in thrombogenicity of the blood (45-48). There are several potential mechanisms for these agents to favorably affect atherosclerotic plaques. A reduction in blood pressure and pulse at rest or with exercise may reduce the propensity for plaque disruption. ACE inhibitors have been shown to improve endothelial dysfunction. Angiotensin II within an atherosclerotic plaque induces the synthesis and release of IL-6 from macrophages (49). Theoretically, ACE inhibition may reduce inflammatory processes within the vascular wall which lead to the development of an acute coronary syndrome and/or promote thrombus formation. Aspirin will, of course, reduce platelet aggregability and its ability to reduce future myocardial infarction appears greatest in individuals with serologic evidence of increased inflammation (50). These agents have other significant effects that might also explain a reduction in adverse events. ACE inhibitors favorably influence myocardial remodeling and beta-blockers are both anti-ischemic and anti-arrhythmic (51,52). Thus, it is difficult to ascertain which effects are primarily responsible for reducing future events with the possible exception of aspirin as an antithrombotic agent. Other drug classes that might possess plaque-stabilizing properties include antioxidants and possibly macrolide antibiotics (53). Other anti-inflammatory agents such as inhibitors of the matrix metalloproteinases are likely to be studied in the near future in large clinical trials.

CONCLUSIONS
   Based on the above, we conclude the following:

1. The concept of plaque stabilization should be expanded to include stabilization of plaques that have already destabilized as well as preventing future destabilization in quiescent plaques.
2. For the unstable coronary lesion, percutaneous intervention is an effective method of acute stabilization in selected cases. As an alternative, new randomized trials with either long-term aspirin therapy in combination with coumadin to an INR of 2-3, the combination of aspirin and clopidogrel or high-dose lipid lowering therapy appear to be promising agents that, by reducing acute coronary events on follow-up, potentially possess plaque stabilizing properties. Short-term powerful antithrombotic agents alone such as GP IIb/IIIa inhibitors in this setting do not appear effective in reducing events on follow up. More studies in this area combining these different approaches are needed.
3. ACE inhibitors and beta-blockers in addition to lipid lowering agents potentially possess plaque-stabilizing properties that contribute to the reduction of subsequent acute events. Aspirin reduces future events by reducing thrombogenicity in the blood and possibly through an anti-inflammatory mechanism.
4. These concepts may require modification subsequent to the publication of new regression trials based on more sensitive methods than angiography for assessing atherosclerotic lesions such as intravascular ultrasound.

ABSTRACT
   The concept of plaque stabilization was developed to explain how lipid lowering could decrease adverse coronary events without a substantial reduction in the regression of atherosclerosis. Plaques were "stabilized" by reducing cholesterol associated with several favorable anatomic and physiologic changes in so-called "vulnerable" plaques responsible for a majority of acute coronary events. However, this concept is limited for several reasons including that it does not incorporate strategies directed against plaques that have already destabilized as well as non lipid-rich plaques which are the substrate for at least 1/3 of major coronary thrombi and may not be responsive to lipid lowering. For culprit plaques in acute syndromes, percutaneous intervention in addition to either long term anti-thrombotic or anti coagulant therapy and possibly aggressive lipid lowering appear to be able to stabilize lesions. Short term, in-hospital anti thrombotic approaches alone with agents like the GP IIb/IIIa inhibitors have not been effective. For other plaques in patients who have an acute syndrome or who are more stable, ACE inhibitors, beta-blockers and aspirin will reduce future events in part either through reduced thrombogenicity of the blood or through plaque stabilizing effects.

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2nd Virtual Congress of Cardiology

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