Intensive Lipid-lowering Therapy Research Articles

A Randomized Trial of Intensive Lipid-Lowering Therapy in Calcific Aortic Stenosis

Calcific aortic stenosis has many characteristics in common with atherosclerosis, including hypercholesterolemia. We hypothesized that intensive lipid-lowering therapy would halt the progression of calcific aortic stenosis or induce its regression. In this double-blind, placebo-controlled trial, patients with calcific aortic stenosis were randomly assigned to receive either 80 mg of atorvastatin daily or a matched placebo. Aortic-valve stenosis and calcification were assessed with the use of Doppler echocardiography and helical computed tomography, respectively. The primary end points were change in aortic-jet velocity and aortic-valve calcium score. Seventy-seven patients were assigned to atorvastatin and 78 to placebo, with a median follow-up of 25 months (range, 7 to 36). Serum low-density lipoprotein cholesterol concentrations remained at 130+/-30 mg per deciliter in the placebo group and fell to 63+/-23 mg per deciliter in the atorvastatin group (P<0.001). Increases in aortic-jet velocity were 0.199+/-0.210 m per second per year in the atorvastatin group and 0.203+/-0.208 m per second per year in the placebo group (P=0.95; adjusted mean difference, 0.002; 95 percent confidence interval, -0.066 to 0.070 m per second per year). Progression in valvular calcification was 22.3+/-21.0 percent per year in the atorvastatin group, and 21.7+/-19.8 percent per year in the placebo group (P=0.93; ratio of post-treatment aortic-valve calcium score, 0.998; 95 percent confidence interval, 0.947 to 1.050). Intensive lipid-lowering therapy does not halt the progression of calcific aortic stenosis or induce its regression. This study cannot exclude a small reduction in the rate of disease progression or a significant reduction in major clinical end points. Long-term, large-scale, randomized, controlled trials are needed to establish the role of statin therapy in patients with calcific aortic stenosis.

Modulation du HDL-C et régression des plaques

High-density lipoproteins are distinct in exerting a wide range of anti-atherogenic actions at the arterial wall and in peripheral tissues. These actions include the capacity of HDL to facilitate efflux of cellular cholesterol in the process of reverse cholesterol transport and to mediate anti-inflammatory, antioxidative and anti-thrombotic effects. By contrast, atherogenic, cholesterol-rich lipoproteins containing apoB 100 (VLDL, VLDL remnants, IDL and LDL) penetrate the arterial intima and undergo retention, thus favoring cholesterol accumulation and atherosclerotic plaque formation. Despite the success of statin therapy in lowering atherogenic lipoprotein levels and thereby reducing cardiovascular morbi-mortality by up to 35% across a broad range of dyslipidaemic phenotypes in both primary and secondary prevention trials, demonstration of significant regression of atherosclerotic plaques in coronary arteries has been infrequent. Indeed, even in recent intervention trials involving intensive lipid lowering therapy in patients with coronary atherosclerosis, reduced atheroma progression -rather than significant plaque regression — was predominantly observed. What key mechanistic features might account for these findings? Potent statins act primarily to reduce circulating concentrations of atherogenic, apoB-containing lipoproteins (VLDL, VLDL remnants, IDL and LDL) by up to 50% or more. By contrast, statins fail to induce elevation in HDL to a similar degree, and indeed statin-induced raising of HDL cholesterol levels is typically in the range of 5-10%. Clearly then, statins are efficacious in reducing cholesterol influx into the arterial wall in the form of atherogenic lipoproteins, but do not appear to induce elevation of HDL to levels facilitating maximal efflux of cholesterol from cholesterol-rich atherosclerotic plaques. Indeed maximal rates of arterial cholesterol efflux to HDL concomitant with marked reduction in cholesterol influx and accumulation would be predicted to lead to significant plaque regression. In this context, it is especially relevant that recent in vivo findings in patients with acute coronary syndromes clearly suggest that infusion of HDL mimetic particles containing apoAI and phospholipids can lead to significant and rapid reduction of coronary atheroma plaque volume consistent with lesion regression. Such reduction in disease burden is suggestive of significant improvement in long term clinical outcome. Considered together, these findings clearly indicate that marked elevation of HDL-C may be a critical component of atherosclerosis regression. HDL therefore represents a key therapeutic target in atherogenic dyslipidaemia, a proposal consistent with epidemiological data (Framingham, PROCAM, ARIC) which have revealed that there is a potent and progressive reduction of coronary artery disease risk with increasing HDL-C levels.

Apolipoprotein L-I is positively associated with hyperglycemia and plasma triglycerides in CAD patients with low HDL

Apolipoprotein L-I (apoL-I) is present on a subset of HDL particles and is positively correlated with plasma triglycerides (TGs). We measured plasma apoL-I levels in coronary artery disease (CAD) subjects with low HDL who were enrolled in an angiographic CAD prevention trial. At baseline, apoL-I levels (n = 136; range, 2.2-64.1 mug/ml) were right skewed with a large degree of variability. Multivariate analysis for biological determinants of apoL-I revealed that the log of VLDL-TG (+0.17; P < 0.05) and hyperglycemia (HG; +0.26; P < 0.005) independently predicted apoL-I level. Hyperglycemic patients (n = 24) had mean apoL-I levels >50% higher than normoglycemic subjects (n = 112; 13.2 vs. 8.3 mug/ml, respectively; P < 0.001). No relationship between apoL-I level and change in CAD was found (r = 0.06, P = 0.49). Simvastatin-niacin therapy did not alter apoL-I levels (n = 34; P = 0.27), whereas antioxidant vitamins alone increased apoL-I by >50% (n = 36; P < 0.01). Genotyping of a known apoL-I polymorphism (Lys166Glu) did not independently account for any of the variability in apoL-I levels. In conclusion, we found TG and HG to be the strongest predictors of apoL-I within a dyslipidemic CAD population. These data provide further characterization of the novel HDL-associated apoL-I.

Intensive Lipid-Lowering Therapy in Patients with Coronary Heart Disease

To describe current data evaluating the use of intensive lipid-lowering therapy in patients with coronary heart disease. A literature search using MEDLINE (1966-September 2004) was conducted using the search terms lipoproteins, low-density lipoprotein cholesterol (LDL-C), hydroxymethylglutaryl-coenzyme A reductase inhibitors, coronary arteriosclerosis, and coronary disease to identify published trials comparing the effects of intensive and conventional lipid-lowering therapy. Intensive lipid-lowering therapy reduces LDL-C levels significantly more than conventional treatment and appears to reduce cardiovascular morbidity and mortality in patients who have recently experienced acute coronary syndrome (ACS). However, evidence suggesting clinical benefits in patients with stable coronary heart disease is currently lacking. Although data are limited, patients with ACS may benefit from intensive lipid-lowering therapy. Several studies are underway to determine the appropriate role of intensive lipid-lowering therapy.

Effects of ezetimibe on plasma lipoproteins in severely hypercholesterolemic patients treated with regular LDL-apheresis and statins

Ezetimibe, a cholesterol absorption inhibitor, can be combined with statins to lower LDL-cholesterol. We evaluated additional ezetimibe (10 mg/day) in a placebo-controlled, double blind, randomized cross-over study in 20 patients (age 56 ± 9 years, m:f 10:10, BMI 27.5 ± 4.0 kg/m 2) suffering from severe hypercholesterolemia and CHD who were treated by statins and regular LDL-apheresis. Lipoproteins (cholesterol, triglycerides, LDL-cholesterol, HDL-cholesterol, VLDL-cholesterol, VLDL-triglycerides, lipoprotein(a)) were determined twice (before and during ezetimibe/placebo, each given for 5 weeks), dietary behaviour was analyzed once (3-days-protocol) during each treatment period. During ezetimibe the mean (±S.D.) preapheresis LDL-cholesterol concentration decreased from 159 ± 26 mg/dl (4.11 ± 0.67 mmol/l) to 133 ± 28 mg/dl (3.44 ± 0.72 mmol/l) (−16 ± 11%, P < 0.0001, Wilcoxon test) and the postapheresis LDL-cholesterol from 51 ± 9 mg/dl (1.32 ± 0.23 mmol/l) to 43 ± 8 mg/dl (1.11 ± 0.21 mmol/l) (−14 ± 25%, P < 0.05), while there was no significant change during placebo. Mean VLDL-cholesterol fell by 18 ± 71% ( P < 0.05) during ezetimibe and was not significantly changed by placebo (+19 ± 70%). Furthermore, during ezetimibe less plasma volume was treated (3725 ± 1560 versus 3870 ± 1549 ml, P < 0.05). Ezetimibe had no effect on pre- and postapheresis triglyceride, HDL-cholesterol and lipoprotein(a) levels. The effect of ezetimibe was independent of the statin dose. Dietary behaviour did not change and no side effects were observed. Thus, in patients with severe LDL-hypercholesterolemia and CHD the addition of ezetimibe to intensive lipid lowering therapy (statins and LDL-apheresis) resulted in a further, clinically significant decrease of LDL-cholesterol.

Treatment of lipids and type 2 diabetes.

The development of type 2 diabetes is increasing in epidemic proportions. There is a significant risk for cardiovascular disease, which is the most prevalent and detrimental complication for the diabetic population. Serum lipid abnormalities are common in patients with diabetes, and due to this increased vascular risk, it is recommended to aggressively treat the hyperlipidemia. Therefore, intensive lipid-lowering therapy should be used for primary and secondary prevention against macrovascular complications for patients with type 2 diabetes. In this article some of the key studies justifying the need for lipid reduction in patients with type 2 diabetes are reviewed and practical guidelines for management of the dyslipidemia are suggested.

Intensive lipid lowering with atorvastatin reduces progression of coronary atherosclerosis, as measured by intravascular ultrasound

Summary Question Is intensive lipid lowering more effective than moderate lipid lowering in reducing progression of coronary atherosclerosis in people with coronary heart disease? Study design Double-blind randomised controlled trial. Main results Atorvastatin significantly lowered the progression rate of coronary atherosclerosis compared with pravastatin at 18 months (see Results table). Coronary atherosclerosis progressed in people treated with pravastatin but not those treated with atorvastatin (pravastatin: 2.7%, 95%CI 0.2% to 4.7%; atorvastatin: −0.4%, 95%CI −2.4% to 1.5%). LDL-cholesterol and C-reactive protein levels were lower in the atorvastatin group at baseline (pravastatin ν atorvastatin LDL cholesterol: 110 mg/dL ν 79 mg/dL, p p Authors’ conclusions Intensive lipid-lowering therapy with atorvastatin reduces progression of coronary atherosclerosis in people with coronary heart disease. Moderate lipid-lowering therapy with pravastatin did not reduce progression of coronary atherosclerosis. This study indicates that target LDL-cholesterol levels lower than those recommended in current guidelines help prevent progression of coronary atherosclerosis.

A pharmacoeconomic evaluation of the effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes in Spain

To determine the 16-week health economic outcomes of short-term, intensive lipid-lowering therapy with atorvastatin in patients with acute coronary syndrome (ACS) using unit costs from Spain. The total expected cost per patient and the cost per inpatient event avoided were compared for patients on atorvastatin 80 mg daily versus placebo. The analysis was based on clinical outcome data from the MIRACL study. Clinical outcomes measured in this analysis included: death, cardiac arrest, nonfatal myocardial infarction (MI), fatal MI, angina pectoris, stroke, congestive heart failure (CHF), and surgical or percutaneous coronary revascularizations. Unit costs for outcomes were values using 2001 Diagnosis Related Group (DRG) costs in Spain. The cost of a follow-up visit was added to the cost of each outcome in both groups. In the atorvastatin group, monitoring costs were also added. All direct medical costs were taken from the perspective of the Spanish National Health System during a 16-week period. The hospital cost in the atorvastatin group was <euro> 1,921 per patient, compared to <euro> 1,853 in the placebo group. The incremental cost per patient in the atorvastatin group was <euro> 67.47, corresponding to a cost per inpatient event avoided of <euro> 1,760. The cost of atorvastatin for 16 weeks was <euro> 128. Forty-seven percent of this cost of atorvastatin was offset by the cost savings obtained through the reduction of number of events in the atorvastatin group. In Spain, the intensive short-term use of atorvastatin in patients with ACS has a favorable cost-effectiveness. The direct cost of the drug was largely offset by the associated reduction in costs for treating fewer cardiovascular events.

High-resolution magnetic resonance imaging of carotid atherosclerosis

High-resolution imaging techniques that permit serial, in vivo examination of the atherosclerotic plaque are needed to better understand the mechanisms involved in the progression of stable, early lesions into high-risk plaques in humans. Such an imaging tool would serve as a bridge between what is learned in the laboratory and the clinical setting. Furthermore, it would permit direct assessment of the efficacy of phamacological interventions.Magnetic resonance imaging (MRI) is ideally suited for serial examination of the diseased arterial wall. Studies have shown that MRI is capable of measuring plaque burden, identifying fibrous cap characteristics and lesion types using American Heart Association (AHA) criteria, and quantifying neovasculature within the plaque. Case-control studies have shown an association between thin/ruptured fibrous caps, as identified by MRI, and recent transient ischemic attack (TIA) and stroke, and have shown that prolonged intensive lipid-lowering therapy is associated with decreased plaque lipid content.Thus, MRI is a promising tool for direct, serial assessment of carotid atherosclerosis in vivo. This article will briefly review our previously published work validating the technique.

Low-density lipoprotein cholesterol reduction and cardiovascular disease prevention: the search for superior treatment

Current US lipid-lowering guidelines indicate that optimal plasma levels of low-density lipoprotein cholesterol (LDL-C) are <100 mg/dL, and targeting global risk assessment has significantly increased the number of individuals who are candidates for intensive plasma lipid-lowering therapy. There is accumulating evidence that reduction of plasma LDL-C concentrations to targets even lower than those currently recommended may provide additional benefit in coronary heart disease (CHD) prevention. For example, the Heart Protection Study (HPS) found that statin treatment initiated at a baseline LDL-C plasma level of <100 mg/dL in patients at high risk provided a relative benefit in reducing the incidence of cardiovascular events that was similar to when it was initiated at higher LDL-C plasma levels. In addition, it is becoming clear that CHD risk, and the need for intensive lipid-lowering treatment, may be underestimated in some populations, including individuals with the metabolic syndrome. In the overall primary prevention population, high-sensitivity C-reactive protein measurement has been shown to identify individuals at high risk of cardiovascular events who would not be considered at high risk on the basis of current systems of risk assessment. The increasing focus on intensive plasma lipid lowering to reduce CHD risk has placed a premium on the development of therapies with improved ability to reduce plasma levels of LDL-C.

Hepatic lipase: a marker for cardiovascular disease risk and response to therapy.

Hepatic lipase plays a key role in the metabolism of pro-atherogenic and anti-atherogenic lipoproteins affecting their plasma level as well as their physico-chemical properties. However, controversial evidence exists concerning whether hepatic lipase is pro or anti-atherogenic. The goal of this review is to summarize recent evidence that connects the enzyme to cardiovascular disease. The potential impact of genetic determinants of hepatic lipase activity in modulating both the development of coronary and carotid atherosclerosis will be discussed based on hepatic lipase proposed roles in lipoprotein metabolism. Twenty to 30% of individual variation of hepatic lipase activity is accounted for by the presence of a common polymorphism in the promoter region (-514 C to T) of the hepatic lipase gene (LIPC). This polymorphism, via its impact on hepatic lipase synthesis and activity, appears to contribute to (1) individual susceptibility to cardiovascular disease: the presence of the T allele (low hepatic lipase activity) may carry a marginally increased risk of atherosclerosis; (2) carotid plaque composition and individual susceptibility to cerebrovascular events: the presence of the C allele (high hepatic lipase activity) is associated with increased carotid intima-media thickness and abundance of macrophages in the carotid plaque (unstable plaque); and (3) response of cardiovascular disease patients to lipid-lowering therapy: patients with the CC genotype have the greatest clinical benefit from intensive lipid-lowering therapy. Convincing evidence shows that hepatic lipase plays a key role in remnant lipoprotein catabolism as well as in remodeling of LDL and HDL particles. The anti or pro-atherogenic role of hepatic lipase is likely to be modulated by the concurrent presence of other lipid abnormalities (i.e. increased LDL cholesterol levels) as well as by the genetic regulation of other enzymes involved in lipoprotein metabolism. Characterization of patients by their LIPC genotype will contribute to a better definition of individual risk of coronary and cerebrovascular events, specifically in patients with qualitative (small, atherogenic LDL and low HDL2 cholesterol) rather than quantitative lipid abnormalities for whom the routine lipid profile may underestimate the risk of coronary and cerebrovascular disease.

Resolution of typical lipoprotein glomerulopathy by intensive lipid-lowering therapy

Lipoprotein glomerulopathy (LPG), characterized by glomerular lipoprotein thrombi, presumably composed of abnormal apolipoprotein E (apoE), leads to a progressive decline in renal function and eventually results in end-stage renal failure. A successful treatment for LPG has not yet been established. The authors treated a 36-year-old woman with LPG and exhibiting a nephrotic syndrome using an intensive lipid-lowering therapy consisting of fenofibrate (300 mg), niceritrol (750 mg), ethyl-icosapentate (1,800 mg), and probucol (500 mg). After the start of treatment, a remarkable decrease in urinary protein excretion and improvement in the hyperlipidemia were obtained; proteinuria was no longer detected 11 months after the initiation of treatment. A second biopsy performed 11 months after the initiation of treatment showed the complete disappearance of the lipoprotein thrombi that had been observed in a diffuse and global manner in the first renal biopsy. These findings suggest that typical LPG could be regressed if the abnormal lipoproteinemia is controlled sufficiently. Am J Kidney Dis 41:244-249. © 2003 by the National Kidney Foundation, Inc.

Exploiting the Vascular Protective Effects of High-Density Lipoprotein and Its Apolipoproteins

“ An invasion of armies can be resisted but not an idea whose time has come.” —Victor Hugo. Vaso-occlusive disease resulting from atherosclerosis and thrombosis is the leading cause of death and morbidity in the United States and other industrialized nations. Although the precise cause of atherosclerosis is unclear, an emerging paradigm suggests that atherosclerosis involves multiple pathways in which lipoprotein entry and retention, injury to the vessel wall from diverse stimuli, and an associated long-term inflammatory and immune response seem to play a key role.1–4 Dyslipidemia characterized predominantly by elevated levels of one or more circulating non-HDL cholesterol lipoproteins [LDL, VLDL, lipoprotein(a), triglycerides] and/or reduced HDL cholesterol is one of the key risk factors for atherosclerosis and cardiovascular disease.5–16 Over the past several years, a number of large, prospective, randomized, controlled clinical trials have demonstrated both angiographic and clinical benefits of lipid-lowering therapy, with a significant reduction in fatal and nonfatal cardiovascular events.17–23 These studies have primarily targeted LDL cholesterol through pharmacotherapy (mostly statins), with or without dietary counseling, lifestyle modification, or surgery (intestinal bypass in Program on the Surgical Control of the Hyperlipidemias [POSCH] trial). Overall, a significant and clinically worthwhile relative risk reduction ranging from 20% to 40% in major cardiovascular events has been achieved with these strategies, without significant adverse effects or increased noncardiovascular mortality. These remarkable results prompted Brown and Goldstein24 to predict that heart attacks will be gone with the century. This clearly reflects an overoptimistic point of view, because 60% to 70% of adverse cardiovascular events continue to occur despite LDL-lowering therapy. Potential reasons why cardiovascular events may continue to occur despite low LDL levels or despite LDL-lowering therapy include the following: (1) we may not be lowering LDL cholesterol to optimal levels, because optimal levels are not clearly …

Lp A-I and Niacin

Increasing evidence from epidemiological, clinical, and basic mechanistic studies supports the importance of HDL in preventing or even reversing atherosclerosis. The well-known structural and compositional diversity of HDL subfractions seems to be an important, if still somewhat unclear, factor in the atheroprotective potential of a given HDL particle. Perhaps as important as the parameter of particle size is that of apolipoprotein content of HDL. HDL particles which lack apo A-II (Lp A-I) appear to associate with reduced atherosclerosis risk1 and are reported to be better cholesterol acceptors in some2,3 although not all studies4 as compared with HDL with apo A-II (Lp A-I/A-II). See page 1783 Niacin generally is considered the most effective agent for raising HDL levels, typically increasing HDL-C by 30%.5 The mechanism of this effect has been shown, by in vivo human turnover studies, to be a decrease in its fractional catabolic rate6,7 Interestingly, despite the clinical importance of both niacin and Lp A-I levels, the impact of the former on the latter has been little studied. One earlier intensive study of a small number of subjects showed that niacin selectively raised Lp A-I levels while Lp A-I/A-II declined somewhat,8 but this question appears not to have been further tested in almost two decades since. Gemfibrozil also is effective in raising HDL levels, although generally less than half as much as niacin.9 The major HDL-raising mechanism of gemfibrozil appears to be an increase in production of apo A-I, as demonstrated by Saku et al10 in vivo and by Jin et al11 in vitro. Surprisingly, the effect of gemfibrozil on levels of Lp A-I and Lp A-I/A-II has not been reported, to our knowledge. Sakai and coworkers12 have now addressed some of the gaps in our understanding of the …

Preventing Cardiovascular Complications of Type 2 Diabetes: Focus on Lipid Management

IN BRIEF Because type 2 diabetes can be considered a cardiovascular disease in its own right, current American Diabetes Association and National Cholesterol Education Program guidelines recommend aggressive treatment of dyslipidemia in people with diabetes, particularly for elevated LDL cholesterol levels. Use of appropriate treatment as determined by the pattern of lipid abnormalities can substantially reduce the risk of macrovascular disease. Institution of tight glycemic control will be beneficial to most patients, but the majority of people with diabetes will also require diet therapy, weight reduction when necessary, and intensive lipid-lowering therapy, which commonly involves one of the statins or fibric acid derivatives.

Common hepatic lipase gene promoter variant determines clinical response to intensive lipid lowering therapy

Common hepatic lipase gene promoter variant determines clinical response to intensive lipid lowering therapy

Evidence for a New Pathophysiological Mechanism for Coronary Artery Disease Regression

Small, dense LDL particles are associated with coronary artery disease (CAD) and predict angiographic changes in response to lipid-lowering therapy. Intensive lipid-lowering therapy in the Familial Atherosclerosis Treatment Study (FATS) resulted in significant improvement in CAD. This study examines the relationship among LDL density, hepatic lipase (HL), and CAD progression, identifying a new biological mechanism for the favorable effects of lipid-altering therapy. Eighty-eight of the subjects in FATS with documented coronary disease, apolipoprotein B levels >/=125 mg/dL, and family history of CAD were selected for this study. They were randomly assigned to receive lovastatin (40 mg/d) and colestipol (30 g/d), niacin (4 g/d) and colestipol, or conventional therapy with placebo alone or with colestipol in those with elevated LDL cholesterol levels. Plasma hepatic lipase (HL), lipoprotein lipase, and LDL density were measured when subjects were and were not receiving lipid-lowering therapy. LDL buoyancy increased with lovastatin-colestipol therapy (7.7%; P<0.01) and niacin-colestipol therapy (10.3%; P<0.01), whereas HL decreased in both groups (-14% [P<0.01] and -17% [P<0.01] with lovastatin-colestipol and niacin-colestipol, respectively). Changes in LDL buoyancy and HL activity were associated with changes in disease severity (P<0.001). In a multivariate analysis, an increase in LDL buoyancy was most strongly associated with CAD regression, accounting for 37% of the variance of change in coronary stenosis (P<0.01), followed by reduction in apolipoprotein Bl (5% of variance; P<0.05). These studies support the hypothesis that therapy-associated changes in HL alter LDL density, which favorably influences CAD progression. This is a new and potentially clinically relevant mechanism linking lipid-altering therapy to CAD improvement.

GENETICS OF LIPOPROTEIN DISORDERS

The study of lipoprotein metabolism has led to major breakthroughs in the fields of cellular physiology, molecular genetics, and protein chemistry. These advances in basic science are reflected in medicine in the form of improved diagnostic methods and better therapeutic tools. Perhaps the greatest benefit is the improved ability to identify at an early stage patients who are at high risk for atherosclerosis, providing clinicians the opportunity to proceed swiftly with intensive lipid-lowering therapy for the prevention of cardiovascular complications. Recent clinical trials have shown that such an approach is not only cost-effective but saves lives while improving the quality of life. They also emphasize the important role physicians can have in prevention. More than half of patients with premature CAD have a familial form of dyslipoproteinemia. This review of the genetics of atherogenic lipoprotein disorders underscores the importance of identifying major genetic defects. It also stresses the need to take into account multifactorial etiologies and clustering of risk factors, as well as gene-gene and gene-environment interactions in assessing the atherogenic potential of a lipid transport disorder. Table 2 summarizes the key points in the diagnosis, clinical implications, and treatment of the major inherited atherogenic dyslipidemias.

Treatment challenges in hypercholesterolemia.

Primary and secondary prevention trials in individuals with high plasma cholesterol levels have proven that cholesterol-lowering drug treatment significantly reduces the risk of coronary heart disease (CHD) morbidity and mortality, and prolongs life. The degree of clinical benefit derived from such treatment appears to be proportional to the percentage reduction in plasma cholesterol. Regression and reduced progression of atherosclerosis may partially account for the clinical gains derived from lipid-lowering drug therapy; however, other direct mechanisms may be operative, including reduced atherogenicity of macrophages, improved vascular vasodilation, and reduced thrombogenesis. Specific treatment is determined on the basis of LDL cholesterol levels and overall global risk for CHD, that is, the presence of CHD and/or other CHD risk factors. Angiographic and clinical data support intensive lipid-lowering therapy in all hypercholesterolemic patients with CHD and those with high CHD risk, particularly those with ultrasonographic evidence (but no symptoms) or clinical signs of extracoronary atherosclerosis. Selection criteria for monotherapy include LDL-cholesterol lowering efficacy, CHD morbidity/mortality and overall survival benefits, no adverse effect on concomitant metabolic diseases (e.g., diabetes), tolerability, long-term safety, simple dose schedule, and cost effectiveness. However, in refractory hypercholesterolemia combination therapy may be required. Secondary prevention and primary prevention in individuals at high CHD risk are cost effective.

Performance Assessment Model for Guideline-Recommended Pharmacotherapy in the Secondary Prevention of Coronary Artery Disease and Treatment of Left Ventricular Dysfunction

The Agency for Health Care Policy and Research, the National Heart Lung and Blood Institute of the National Institutes of Health, the American Heart Association, and the American College of Cardiology have all developed guidelines for improving the care of patients with cardiovascular disease. The guidelines include recommendations for intensive lipid-lowering therapy in patients with coronary artery disease (CAD) and angiotensin-converting enzyme (ACE) inhibitors in those patients with symptomatic heart failure and asymptomatic left ventricular dysfunction. Despite clinical trial evidence and consensus that these therapies improve survival in high-risk patients, data suggest that there is wide variation in the delivery of guideline-based care. To investigate whether evidence-based assessment of provider practice patterns can impact the delivery of quality cost-effective care, Merck and Company, in conjunction with leading cardiology group practices, the University of North Carolina at Chapel Hill, and Medical Review of North Carolina developed an ambulatory medical record abstraction study. This quality assurance initiative was conducted at practices beginning in the spring of 1996 and continues. Medical records and administrative claims of patients with ischemic heart disease or heart failure were abstracted by a healthcare consulting organization to maintain patient and physician confidentiality. As of mid-July 1997, 626 group practices had completed the medical record abstraction process, with >1,136 practices participating at some stage of the project; >6,000 physicians participated in the project and >270,000 patients charts were abstracted. Analysis of these data will provide insight and benchmark patterns of care in the pharmacologic management of heart failure and CAD. This project represents a unique collaboration between a pharmaceutical company, an academic institution, a Peer Review Organization, and practicing physicians, to support evidence-based best medical practices.