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Overview of Prevention and Treatment of Atherosclerosis With Lipid-altering Therapy for Pharmacy Directors
Cardiovascular (CV) disease is the leading cause of mortality and one of the leading causes of disability worldwide. Its economic burden is enormous, and the estimated direct and indirect costs of the disease in 2006 exceeded $400 billion.
Low-density lipoprotein cholesterol is recognized as a major cause of coronary heart disease and other clinical forms of atherosclerotic disease, and an elevated low-density lipoprotein cholesterol level remains the primary target of lipidlowering therapy.
Recent retrospective evidence points to deficiencies in the management of patients with atherosclerosis in the clinical practice setting. Enhancing awareness of the need to monitor and treat dyslipidemia in atherosclerosis, and of the benefits of such treatment reported in recent studies, may help to narrow this treatment gap. This review will examine the development of atherosclerosis and the role atherosclerosis plays in the underlying pathophysiology of CV disease. Imaging methods for assessing progression of atherosclerosis and new recommendations for risk-reduction therapy in patients with established atherosclerotic vascular disease are discussed. Emphasis is on newer data regarding the effect of statins in retarding progression of atherosclerosis or even inducing regression of atherosclerosis.
(Am J Manag Care. 2007;13:S260-S269)
Cardiovascular (CV) disease is the leading cause of mortality and one of the leading causes of disability worldwide.1 In the United States, more than 70 million adults have 1 or more types of CV disease, the most prevalent of which are hypertension, coronary heart disease (CHD), stroke, heart failure, and congenital heart defects.1 The economic burden of CV disease is enormous. Estimated direct and indirect costs of CV disease in 2006 exceeded $400 billion.1 Acute coronary syndromes (ACS), characterized by ST-segment elevation myocardial infarction (MI) or unstable angina/non–ST-segment elevation MI, account for about half of deaths related to CV disease, with annual direct costs estimated to be $75 billion.2
For ischemic stroke alone, the Stroke Program at the University of Michigan Medical School projected total US direct and indirect costs will exceed $2 trillion over the period 2005-2050 (in 2005 dollars).3 Furthermore, patients at risk for CV events will significantly contribute to the future economic burden associated with CV disease, even in the short term.4
Low-density lipoprotein cholesterol (LDL-C) is recognized as the primary factor in the development and progression of atherosclerotic disease, and elevated LDL-C level remains the primary target of lipidlowering therapy.5,6 Publication of the Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III in 2001,5 and the full report in 2002,7 enhanced awareness of the importance of lipid-lowering therapy for both primary prevention of CHD and secondary prevention of CV events in patients with established CHD. In the years following publication of NCEP ATP III, results of several additional clinical trials of lipid-lowering therapy were published that addressed issues not examined in earlier studies.6,8 These new data have led to new recommendations. Newer studies have also demonstrated benefits of statins in slowing progression or even inducing regression of atherosclerosis.
However, despite the widespread availability of these recommendations and recent studies, and knowledge of the clear association of atherosclerosis and CV disease, evidence from a recent retrospective analysis of more than 10 000 patients with newly diagnosed atherosclerosis points to deficiencies in management in a real-world clinical practice setting.9 In particular, baseline LDL-C levels were not even obtained in most patients, and only one third with a baseline LDL-C level had a second lipid profile in 1-year postdiagnosis. Most patients were not prescribed lipid-lowering therapy at the time of diagnosis, or after diagnosis, regardless of baseline LDL-C level. This undertreatment was seen despite the fact that more than half of patients had an LDL-C level ≥100 mg/dL at diagnosis of atherosclerosis.
These data suggest a gap between evidencebased guidelines and their application in clinical practice. Enhancing awareness of the need to monitor and treat dyslipidemia in atherosclerosis, and of the benefits of such treatment reported in recent studies, may help to narrow this gap. This review will examine the events leading up to development of atherosclerosis and the role that atherosclerosis plays in the underlying pathophysiology of CV disease. Imaging methods for assessing progression of atherosclerosis and new recommendations for riskreduction therapy in patients with established atherosclerotic vascular disease are discussed. Emphasis is placed on newer data regarding the effect of statins in retarding progression of atherosclerosis.
Role of Atherogenesis as the Underlying Cause of CV Disease
The Atherosclerotic Plaque (Lesion). Atherosclerotic plaques consist of lipids, inflammatory cells, connective-tissue elements, smooth-muscle cells, thrombi, and calcium deposits.14,16,19,25 At the center are foam cells and extracellular lipid droplets, forming a core that is surrounded by smooth-muscle cells and a collagen matrix; lesions are infiltrated by T-cells, mast cells, and macrophages, which show signs of activation and result in cytokine production.16,19 All aspects of plaque formation and the progressive atherosclerotic process are related to inflammatory responses.
The Atherosclerotic Process. Atherosclerosis occurs preferentially at certain sites within the arterial tree, and local conditions such as shear stress and turbulent blood flow result in endothelial dysfunction.14,19 All medium-sized and large arteries are affected, including the coronary, carotid, cerebral, and major extremity arteries, and the aorta and its branches. The affected endothelium expresses surface molecules that attract circulating inflammatory cells and facilitate their migration into the subendothelial space.19 In particular, LDL-C particles infiltrate the arterial wall in hypercholesterolemic patients and are retained in the intima, with most accumulation at sites of hemodynamic strain; this initiates the inflammatory process in the arterial wall.16,26 LDL-C is modified via oxidation or enzymatic reaction, which results in release of inflammatory lipids that in turn result in expression of leukocyte adhesion molecules from endothelial cells.16
After migrating into the subendothelial space, monocytes are transformed into macrophages, which take up oxidized LDL particles to form foam cells.19,26 The earliest structural change in atherosclerosis is a subendothelial accumulation of the lipid-laden foam cells, forming a fatty streak.19 As the lesion progresses, vascular smooth-muscle cells migrate from the arterial media to the site of injury, where they proliferate and produce matrix proteins, such as collagen and elastin. Smooth-muscle cells proliferate further, and there is an increase in production of extracellular matrix, resulting in the fully formed fibrous plaque with a fibrous cap that faces the arterial lumen16,19,25 (Figure, Panel A).25 The cap separates the thrombogenic lipid core from circulating platelets and coagulation proteins, preventing thrombus formation.19
Although a coronary artery plaque large enough to cause significant stenosis can lead to myocardial ischemia, stenosis does not always occur; in fact, lumen diameter may actually increase during early atherosclerotic stages.19,25,27 Current thinking is that plaque activation rather than stenosis leads to thrombus formation and myocardial ischemia or infarction.16 The expanding plaque (even one that does not narrow the lumen) may eventually become exposed due to endothelial erosion or plaque rupture, each leading to thrombosis.19,25 Both plaque rupture and endothelial erosion are related to increased inflammatory activity within the plaque, and the main stimulus for this inflammation is the reaction of oxidized intimal LDL and macrophages.25 Erosion with thrombus around exposed subendothelial connective tissue is shown in the Figure (Panel B).
Minor episodes of endothelial erosion or plaque rupture may occur asymptomatically; however, repeated cycles of erosion or rupture, thrombosis, and repair gradually increase the size of the plaque.19,25 Major episodes, with thrombi large enough to impede blood flow, result in symptoms.25
Detection and Monitoring of Atherosclerosis Several invasive and noninvasive imaging techniques have been used to detect/diagnose atherosclerotic lesions, facilitate risk stratification, and measure atherosclerosis progression and lesion regression in response to lipid-lowering regimens. Some of these are coronary angiography, intravascular ultrasound (IVUS), IVUS-based palpography, angioscopy, intravascular thermography, optical coherence tomography, elastography, magnetic resonance imaging (MRI), computed tomography (CT), B-mode ultrasonography, electron-beam CT, immunoscintigraphy, and molecular imaging.
A detailed discussion of these techniques, many of which are mainly research-oriented, is beyond the scope of this review. The emphasis here is primarily on imaging techniques routinely used in the clinical setting to assess atherosclerosis progression and changes in response to statins. In this context, one strategy for monitoring changes in a patient’s risk of clinical events (eg, MI or death) is to use an intermediate (surrogate) end point; that is, one that can be identified before a clinical event occurs and has prognostic value.28 Trials using intermediate end points require fewer patients than clinical-outcome trials and all patients contribute to study findings.28 Typically, trials utilizing intermediate end points are also shorter in duration, which reduces the period of time that beneficial treatment is withheld from control groups, and can speed up the development of compounds, allowing an early and rapid insight into a drug’s ability to influence CV disease.28
Atherosclerosis progression/regression is widely used as an intermediate end point in clinical and observational trials of lipid-altering therapy. The 3 imaging methods used most frequently in the clinical setting for assessing atherosclerotic changes are carotid intima-media thickness (IMT) measurements using B-mode ultrasonography, IVUS, and MRI.11,28-31
Carotid IMT. B-mode ultrasound is widely used to measure carotid IMT, an early change that precedes the development of the macroscopic plaque.31 An increase in IMT is an accurate measure of subclinical atherosclerosis, and several studies have demonstrated that changes in carotid IMT are a strong predictor of future CV events.28,29,32
In the Atherosclerosis Risk in Communities (ARIC) study, the risk of a recurrent CV event was twice as high in individuals with a mean carotid IMT of ≥0.98 mm compared with those with a measurement of <0.7 mm.33 Moreover, in a metaanalysis of 8 observational studies with general population- based samples, involving 37 195 subjects with mean follow-up of 5.5 years, carotid IMT was a strong predictor of both stroke and MI.29
Carotid IMT is increasingly being used for CV risk stratification and as an intermediate end point in clinical trials.29 It has limited ability to determine extent of plaque burden and nature of plaque composition.30 However, its noninvasive nature, involving no radiation exposure, is well suited for use in longitudinal studies.28,29
IVUS. Performed during coronary angiography, IVUS can quantify the extent of atherosclerotic plaque, and has been considered the gold standard for this by some investigators.30 An ultrasound transducer at the catheter tip is used to obtain tomographic images of the arterial wall. The catheter is withdrawn, either manually or using a motorized pullback device.30,31 Motorized catheter pullback allows withdrawal at a constant rate, permitting accurate determination of plaque volume within the entire arterial segment.28,31
Although standard IVUS does not provide good characterization of plaque composition, analysis of radio frequency backscatter from the ultrasound transducer has been reported to characterize plaque components.30,31 The major disadvantage of IVUS is invasiveness, limiting use to subjects with clinical indications for coronary angiography. However, the precision and reproducibility it offers may allow for shorter-duration studies with smaller sample sizes.28
In vivo, IVUS has confirmed the observation previously made by autopsy—that the extent of atheroma is greater than that detected by angiography.28,30 It has not yet been definitively demonstrated that IVUS results correlate with clinical outcomes.30
MRI. MRI can quantify atheroma extent and distinguish its components30; it is highly sensitive to small changes in plaque size and possibly composition.28 High-resolution MRI has been shown to distinguish intact, thick fibrous caps from thin or disrupted fibrous caps, and intraplaque thrombus from extra plaque thrombus.34
Currently, use of MRI is generally limited to imaging the walls of medium to large vessels (eg, carotid, aorta); improvements are needed to obtain a clearer image and accurately assess the smaller coronary vessels.28 Advantages of MRI are its noninvasive nature and lack of ionizing radiation.
Obstacles to coronary imaging include cardiac and respiratory motion, small caliber and tortuosity of the coronary vessels, and artifacts caused by stents and sternal wires in patients who have had prior procedures. These obstacles will likely be resolved; experience in coronary imaging is still limited.34
Treatment of AtherosclerosisAtherosclerosis is a CHD/CHD risk-equivalent condition, and patients with atherosclerosis are at high risk for subsequent CV events (>20% per 10 years).5,7,8 CHD risk equivalents (Table 1) other than clinical atherosclerotic disease are diabetes and the presence of multiple (2+) risk factors with a 10-year risk of >20%.5
Available lipid-lowering therapies for patients with or without established CHD include fibrates (eg, gemfibrozil), bile acid sequestrants (eg, colesevelam), niacin, a cholesterol absorption inhibitor (ezetimibe), and statins.22,37 Statins have been shown to be the most effective agents for lowering LDL-C,22,35 and also lower triglycerides.37 They are considered the lipid-lowering agents of choice for secondary prevention in high-risk patients.9,11,37
Efficacy of Statins in Atherosclerosis
For reasons provided earlier, statins are the primary agents indicated for secondary prevention in patients with CHD and other atherosclerotic vascular disease. They can reduce the frequency of CV events and mortality in this setting. When selecting a statin or statins for the formulary, several factors must be considered, including comparative efficacy and effectiveness in lowering LDL-C (primary goal of therapy), adverse effects, pharmacokinetics/dose, drug interactions, and cost.
Statins are generally well-tolerated, and their adverse-effect profiles are similar, including more serious events.37,59 Drug–drug interactions occur most often with lovastatin and simvastatin; the lowest risk of interactions is seen with pravastatin and rosuvastatin.37 All statins can be given once daily.
In summary and considering all factors, rosuvastatin should be considered for inclusion for managing patients with an elevated risk of future CHD events due to underlying atherosclerosis.
Conclusion
Atherosclerosis is the main underlying pathology of CV disease, which is the leading cause of mortality worldwide. A recent retrospective analysis indicates there are many improvement opportunities in the management of atherosclerosis in the clinical setting, suggesting the need for enhanced awareness of newly available guidelines in regard to monitoring and managing lipids in affected patients.9 In particular, available data indicate that more aggressive lipid-lowering therapy with statins can further improve clinical outcomes relative to less intense therapy. These data are reflected in newer guidelines, which recommend reduction of LDL-C levels to <100 mg/dL in high-risk atherosclerotic patients, including those older than 65 years; a recommended option of lowering to <70 mg/dL should be considered in those at very high risk. Baseline and routine monitoring of lipid levels is essential to ensure achievement and maintenance of LDL-C goals with use of statins. Recent studies have also shown benefit of intensive statin therapy on slowing and even reversing progression of atherosclerosis, as assessed by surrogate imaging measures, such as IVUS and carotid IMT. Results of the METEOR trial have suggested that slowing of disease progression can be achieved by statins even in individuals with subclinical carotid atherosclerosis who are considered at low risk. Closer attention to instituting recent guidelines and clinical-study findings by linicians in the community can optimize therapy in the atherosclerosis patient and greatly improve long-term outcomes.
Address correspondence to: Michael H. Davidson, MD, FACC, FACP, Director of Preventive Cardiology, Rush University Medical Center, 1725 West Harrison Street, Suite 1159, Chicago, IL 60612. E-mail: michaeldavidson@radiantresearch.com.
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