William Virgil Brown

Aggressive lipid-lowering therapy compared with angioplasty in stable coronary artery disease

BACKGROUND Percutaneous coronary revascularization is widely used in improving symptoms and exercise performance in patients with ischemic heart disease and stable angina pectoris. In this study, we compared percutaneous coronary revascularization with lipid-lowering treatment for reducing the incidence of ischemic events. METHODS We studied 341 patients with stable coronary artery disease, relatively normal left ventricular function, asymptomatic or mild-to-moderate angina, and a serum level of low-density lipoprotein (LDL) cholesterol of at least 115 mg per deciliter (3.0 mmol per liter) who were referred for percutaneous revascularization. We randomly assigned the patients either to receive medical treatment with atorvastatin, at 80 mg per day (164 patients), or to undergo the recommended percutaneous revascularization procedure (angioplasty) followed by usual care, which could include lipid-lowering treatment (177 patients). The follow-up period was 18 months. RESULTS Twenty-two (13 percent) of the patients who received aggressive lipid-lowering treatment with atorvastatin (resulting in a 46 percent reduction in the mean serum LDL cholesterol level, to 77 mg per deciliter [2.0 mmol per liter]) had ischemic events, as compared with 37 (21 percent) of the patients who underwent angioplasty (who had an 18 percent reduction in the mean serum LDL cholesterol level, to 119 mg per deciliter [3.0 mmol per liter]). The incidence of ischemic events was thus 36 percent lower in the atorvastatin group over an 18-month period (P=0.048, which was not statistically significant after adjustment for interim analyses). This reduction in events was due to a smaller number of angioplasty procedures, coronary-artery bypass operations, and hospitalizations for worsening angina. As compared with the patients who were treated with angioplasty and usual care, the patients who received atorvastatin had a significantly longer time to the first ischemic event (P=0.03). CONCLUSIONS In low-risk patients with stable coronary artery disease, aggressive lipid-lowering therapy is at least as effective as angioplasty and usual care in reducing the incidence of ischemic events.

High-density lipoprotein and transport of cholesterol and triglyceride in blood

High-density lipoproteins (HDL) contain approximately 25% of the cholesterol and <5% of the triglyceride in the plasma of human blood. However, the dynamic exchange of lipids and lipid-binding proteins is not revealed by simply considering the mass of material at any point in time. HDL are the most complex of lipoprotein species with multiple protein constituents, which facilitate cholesterol secretion from cells, cholesterol esterification in plasma, and transfer of cholesterol to other lipoproteins and to the liver for excretion. They also play a major role in triglyceride transport by providing for activation of lipoprotein lipase, exchange of triglyceride among the lipoproteins, and removal of triglyceride rich remnants of chylomicrons and very-low-density lipoproteins after lipase action. In addition, antioxidative enzymes and phospholipid transfer proteins are important components of HDL. Many of the proteins of HDL are exchangeable with other lipoproteins, including chylomicrons and very-low-density lipoproteins. The constantly changing content of lipids and apolipoproteins in HDL particles generate a series of structures that can be analyzed by using separation techniques that depend on size or charge of the particles. Interaction of these various structures can be very different with cell surfaces depending on the size or apolipoprotein content. A series of different transport proteins preferentially exchange lipids with specific structures among the HDL but interact poorly or not at all with others. The role of these differing forms of HDL and their interactions with cells and other lipoprotein species in plasma is the subject of intense study stimulated by the potential for reducing atherogenesis. The strength of this is only partially indicated by the correlation of higher total levels of the HDL particles with reduced incidence of vascular disease in various clinical trials and epidemiological studies.

Metabolic syndrome and risk of stroke

Stroke is one of the leading causes of death in the United States and worldwide. Metabolic syndrome, comprising abdominal obesity, elevated triglyceride levels, low levels of high-density lipoprotein cholesterol, elevated blood pressure, and impaired glucose metabolism, greatly increases the risk of cardiovascular disease, including stroke. The high prevalence of metabolic syndrome among individuals who experience stroke makes the metabolic syndrome a target for aggressive intervention and therapy. In addition to lifestyle changes, therapy with statins, angiotensin-converting enzyme inhibitors, insulin sensitizers, and antithrombotic agents to aggressively treat elements of metabolic syndrome is warranted. Statins favorably affect both lipid and nonlipid risk factors for stroke, making them a useful tool for stroke prevention.

JCL roundtable: Diagnosis and clinical management of lipodystrophy

Lipodystrophy comes in several forms, some involving the complete failure to develop adipose tissue and others with a partial absence in various bodily distributions. All appear to have a major genetic basis, and all involve a high frequency of lipoprotein disorders. High triglycerides and low high-density lipoprotein cholesterol are the usual findings that raise interesting questions as to how such abnormalities characteristic of obesity can be caused by genetic variants that produce a paucity of adiposity. We are learning to link some specific genetic variants that seem causal and to manage these disorders in more effective ways. We are joined by 3 experts who have been leaders in the study of the clinical presentation, genetics, abnormal physiology, and the management of lipodystrophy in recent years. They are Drs Abhimanyu Garg from the University of Texas Southwestern, Phillip Gorden of the National Institute of Diabetes, Digestive and Kidney Diseases, and Robert Shamburek of the National Heart, Lung and Blood Institute.

Clinical Lipidology and the Prevention of Vascular Disease: Time for Personalized Therapy

Genetic, metabolic, and lifestyle modifications can cause elevations of lipoproteins that contribute to atherosclerotic lesions over time. In the modern world with life extension from many improvements in medicine and public health, most humans live long enough to develop atherosclerosis with concentrations of blood plasma lipoproteins that are very common. Familial abnormalities are prevalent and provide additional challenges in identifying unhealthy but treatable values of low‐density (LDL) and very low‐density lipoproteins (VLDL). Multiple community studies and clinical trials have provided guidance on selecting targets and new tools that make possible effective goals of treatment. Lipid‐lowering drugs are making it possible to achieve those goals and place responsibility on physicians to master the art of preventing atherosclerotic events. Lipoprotein management remains a very focused effort and requires an artful individualized approach for each patient. Few skills are more important for healthcare providers in primary care and cardiovascular medicine.

Genetics and Valve Calcification

SEE PAGE 2941 C alcification of vascular structures is poorly understood, but genetic studies are offering important clues as to mechanisms. Calcification of the aortic valve has been found to result from a single nuclear polymorphism (SNP) (rs10455872) in the lipoprotein “little a” [Lp(a)] gene locus by Clarke et al. (1). This variant is associated with higher plasma concentrations of Lp(a) and is consistent with earlier reports of aortic stenosis correlating with measures of Lp(a) in cohort studies (2–4). The binding of the little protein to low-density lipoprotein (LDL) particles, thus creating Lp(a), changes the metabolism of the lipoprotein (5) in that it carries much of the oxidized phospholipid in plasma (6) and more readily accumulates after mechanical injury to arteries in animal models (7). These alterations may explain a greater propensity than LDL for localization in the high stress tissue of the aortic valve. Thanassoulis et al. (8) found that this SNP in the LPA gene was strongly associated with both Lp(a) plasma concentrations and prevalence of aortic calcification in white European, AfricanAmerican, and Hispanic cohorts. These investigators also documented the increased incidence of aortic valve calcification in a Swedish and a Danish cohort in association with the same Lp(a) SNP. In this report, an increased incidence ofmitral annular calciumdeposition was found to be related to a SNP on chromosome 2 near the proinflammatory gene for ILF1F9, but this was not replicated consistently. These findings are

JCL roundtable: Cardiovascular disease risk reduction in menopausal women

Ovarian failure occurs in most women during the late fifth decade or early sixth decade of life. This causes a number of changes in physiology as estrogen and progestin concentrations decline. These involve lipoprotein metabolism and the vasculature. The risk factors for large vessel disease increase, and dysfunction of the small resistance vessels responds with changes in blood flow to the skin causing unpleasant symptoms. These and other changes result in visits to the physician. A reassessment of risk factors and symptoms is needed to develop a new plan for effective management, both short term and long term.

What is sufficient drug therapy for lipoprotein elevations

It has become clear that after statin therapy, there is residual risk related to lipoprotein concentrations.Most trials even with very high doses of the most effective statin preparations have failed to produce a reduction in event rates exceeding 50%. Large trials testing the addition of niacin, fibrates, and inhibitors of cholesteryl ester transfer protein failed to reach their objectives. The addition of ezetimibe to moderate-intense statin therapy, which produced an additional reduction of low-density lipoprotein cholesterol (LDL-C) by 16%, required a very large and prolonged study to demonstrate a small but statistically significant effect on arteriosclerotic vascular events. However, the mean LDL-C in these patients was 69.5 mg/dL while taking high doses of a statin. Although proof of principle can be claimed by this study, it leaves open many questions. Are there much lower values of LDL-C that if achieved can produce more impressive effects even when patients are at values ,70 mg/dL? Recently, the completion of a trial of humanized monoclonal antibodies against proprotein convertase subtilisin/ kexin type 9 (PCSK9) demonstrated that significant reductions in major cardiovascular (CV) events can be achieved by reductions in LDL-C beyond the statin effects. Called ‘‘Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk’’ (FOURIER), this trial added evolocumab to maximally tolerated statin (simvastatin up to 80 mg/d) therapy reducing LDL-

From the Editor: Using PCSK9 inhibitors in practice

60 61 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 94 95 96 97 98 99 100 101 102 For almost 20 years, there has been general agreement that discoveryofpersonswithveryhigh riskof experiencing amajor vascular event calls for our attempts to reduce low-density lipoprotein cholesterol (LDL-C) to values , 70 mg/dL. More recently, the goal of also reducing non-high density lipoprotein cholesterol (non-HDL-C) , 100 mg/dL has been recommended as appropriate as well. Statin trials and combinations of statin and ezetimibe have been successful in demonstrating the value of achieving such reductions in the apolipoprotein B–containing lipoproteins that carry this cholesterol. Trials with clinical endpoints and those evaluating the artery wall with ultrasound have shown a clear relationship between very low values of these lipoproteins and the incidence of vascular events and of reduction of atheroma volume in the coronary arteries. To date, we have seen no evidence of significant adverse events related specifically to the achievement of such reduced concentrations of LDL-C or non-HDL-C. The conclusion has been that the ‘‘lower the better’’ is a valid conceptwhen using a therapeutic program that produces LDL-C well below 50 mg/dL. The major problem is that the LDL-C values commonly observed in surveys of patients in primary care or cardiology practices are not achieving such values. It is commonly found that less than 25% of patients on statin therapy have LDL-C concentrations, 70 mg/dL. The fear of well-studied dosages of the most effective statins is an impediment to achieving the maximum benefit possible. It is now fully documented that LDL-C and non-HDL-C can be reduced significantly more with the new inhibitors of proprotein convertase subtilisin/Kexin type 9 (PCSK9). These drugs allow prolonged survival of LDL receptors and their recycling to the cell membranes providing for a much greater capacity for the liver to take up LDL-C from the plasma and thereby produce mean reductions of approximately 60% greater than highly effective statins. The benefit of these drugs is now convincingly demonstrated in several clinical trials including thousands of patients. The evidence for this benefit in specific studies of carefully characterized patient populations is summarized in this issue of the Journal by Orringer et al with a panel representing the National Lipid Association. In the Fourier trial, a doubleblind randomized study of 27,564 high-risk patients, LDL-C was maintained at an average value of 30 mg/dL in those

From the Editor: New guidelines are coming

3 58 59 60 61 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 94 95 96 97 98 99 100 101 102 As a revision of the guidelines for lipid management are being considered by the American College of Cardiology and American Heart Association, I am prompted to think about the basis of our approach to preventing death and disability from cardiovascular disease. Currently, this is built on a ‘‘risk factor’’ model, not on the diagnosis of the disease itself. The current clarion call is to use evidencebased attacks on the total risk of any given patient. This means that if you have done something in the past and there has been an effect on the incidence of measurable clinical events then that can be recommended in the future. This of course has been refined to mean a measurable effect demonstrated by interventions with a new therapy randomly assigned to one group or to a contemporaneous control group with all receiving the accepted therapy of the time. The hypothesis tested is that the new treatment will reduce clinical endpoints in addition to the old method. This evidence-based approach allows one the comfort of knowing that the specific intervention (ie, drug and dose) have been tested in terms of efficacy and safety. However, this leaves several hurdles to its application in practice. Interpretation of the mean responses tends to ignore the actual distribution of the treatment target response to the drug in individual patients. How do you effectively manage patients who are on the low end of the response curve with any particular therapy? The composite data from many trials clearly demonstrate that those who have below average reduction in blood pressure or atherogenic lipoprotein reduction are not fully or even adequately addressed as a group. Usually, such trials provide data on patients selected to meet strict inclusion and exclusion criteria. Many if not most patients referred to a clinical lipidologist would not have been included in trials due to a series of other diseases present or due to excluding risk elements. Focusing on a theory of the disease process and managing instigating factors as targets of therapy is much more consistent with our scientific approach to disease management. Evidence from clinical trials is not science, it is simply evidence. Just as evidence is not the law, evidence is not the art of medicine. Considering evidence provides for inductive reasoning, but this requires deductive considerations to actually apply evidence in the most effective ways. I hope that the new committee will consider the fact that we have very strong evidence regarding the causation of