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(Circulation. 1997;96:4424-4430.)
© 1997 American Heart Association, Inc.

Articles

Cholesterol Management in Theory and Practice

Antonio M. Gotto, Jr, MD, DPhil

From Cornell University Medical College, New York, NY.

Correspondence to Antonio M. Gotto, Jr, MD, DPhil, Cornell University Medical College, 1300 York Avenue, F-105, New York, NY 10021. E-mail dean{at}mail.med.cornell.edu

	Abstract

Top Abstract Introduction Benefits of Lipid Lowering:... Mechanisms Leading to Event... Lipid Management: Awareness... Statin Therapy New Perspectives in Patient... Cost-Effectiveness of LDL-C... References

 
Abstract The preponderance of evidence confirms the importance of aggressive lipid modification in patients at risk for coronary heart disease (CHD). However, data suggest that this information is underimplemented in the clinical setting, even in patients with existing CHD, in whom the greatest benefit of such treatment has been shown. The fact that many practitioners do not pursue a proven treatment strategy in patients who qualify must be redressed through education and reinforcement of existing recommendations. In the present review, the current clinical and mechanistic understanding of the benefit of aggressive lipid management is summarized, with a focus on the clinical implications of recent findings. These include growing public awareness of cholesterol as a modifiable CHD risk factor, recommendations for earlier and more aggressive intervention in patients with existing disease, and discussion of the cost-effectiveness of lipid-regulating therapy. Despite the secular trend of declining CHD morbidity and mortality rates in recent years, CHD remains the leading cause of death in both men and women in the United States. It is imperative to prevent any reduction in public focus on primary and secondary prevention.

Key Words: cholesterol • lipids • atherosclerosis • heart diseases • epidemiology

	Introduction

Top Abstract Introduction Benefits of Lipid Lowering:... Mechanisms Leading to Event... Lipid Management: Awareness... Statin Therapy New Perspectives in Patient... Cost-Effectiveness of LDL-C... References

 
The clinical benefit of serum cholesterol management is supported by extensive clinical and laboratory research spanning more than 20 years. Despite this wealth of evidence, however, 97 million US adults have TC concentrations of 5.2 mmol/L (200 mg/dL), and 38 million have concentrations of 6.2 mmol/L (240 mg/dL),¹ which are elevated and high concentrations according to NCEP action limits for the general adult population.² CHD remains the leading cause of death of US men and women.¹ What has become apparent in recent years is that clinical interventions that have been proved to reduce coronary morbidity and mortality rates have not been fully implemented. Although progress has been made in reducing the toll of CHD, including a 28.6% reduction in CHD death rate between 1984 and 1994,¹ it is imperative to prevent any reduction in public focus on the primary and secondary prevention of CHD. This review highlights recent advances in clinical thinking about lipid lowering and CHD risk reduction. Although there is increasing evidence to support roles for additional factors, such as elevated plasma triglyceride and insulin resistance syndrome (or metabolic syndrome X),^3–5 in the development of CHD, the focus of this article is blood cholesterol.

	Benefits of Lipid Lowering: Clinical Experience

Top Abstract Introduction Benefits of Lipid Lowering:... Mechanisms Leading to Event... Lipid Management: Awareness... Statin Therapy New Perspectives in Patient... Cost-Effectiveness of LDL-C... References

 
More than 50 clinical trials have provided strong evidence that lowering serum or plasma concentrations of TC or LDL-C results in decreased rates of CHD events, including coronary death. Although a variety of interventions have been used—diet and other lifestyle measures, pharmacotherapy, and even ileal bypass surgery—the results of the trials have been remarkably consistent. In a meta-analysis of 28 trials that assessed effects on clinical events or vascular end points, Law et al⁶ found that in men, each 10% reduction in TC yielded a 22% reduction in CHD incidence at 2.1 to 5 years (P<.001) and a 25% reduction after 5 years (P<.001). Intervention needed to last at least 2 years to obtain significant benefit. During the first 2 years, CHD risk was reduced only 7% (P=.06), although the data indicated that if intervention were continued for 20 years, a 3:1 reduction in CHD incidence might occur. On the basis of more limited data, the authors found similar results in women.⁶ The 2:1 reduction in CHD incidence accords with the results of the early Lipid Research Clinics Coronary Primary Prevention Trial, a test of the bile acid–sequestering agent cholestyramine, which showed a 19% reduction in the rate of MI or CHD death for each 8% reduction in TC after an average of 7.4 years.⁷ It is important to note that nearly all the trials analyzed by Law et al were conducted before the advent of the HMG-CoA reductase inhibitors, or statins, which provide the greatest cholesterol lowering of all available agents. In another recent meta-analysis of preponderantly prestatin trials, Gould and colleagues⁸ found a 13% reduction in the CHD death rate for each 10% reduction in cholesterol (P<.002). The reduction of all-cause mortality rate in this analysis of 35 trials of >2 years' duration was 10% for each 10% reduction in cholesterol.

Recently, three landmark trials with clinical end points, each testing a statin with background dietary therapy, have been able to extend this body of evidence to demonstrate that cholesterol lowering can also increase overall survival in secondary and primary prevention and can reduce CHD risk in patients without high cholesterol concentrations. These three trials—the 4S,^9–11 the WOSCOPS,¹² and the CARE trial¹³—together enrolled more than 15 000 patients, and each lasted 5 years.

The 4S results provided the first unequivocal evidence that aggressive cholesterol lowering can significantly reduce all-cause mortality rate, which was the sole end point of the trial. This double-blind, placebo-controlled, secondary-prevention trial enrolled 4444 men and women 35 to 70 years old with a history of angina pectoris or MI and hypercholesterolemia (mean TC, 6.7 mmol/L [261 mg/dL]; TC enrollment criterion, 5.5 to 8.0 mmol/L [212 to 310 mg/dL], with triglyceride 2.5 mmol/L [220 mg/dL]). Simvastatin was initially given at 20 mg daily; dosage was titrated to 10 or 40 mg daily as needed to achieve TC of 3.0 to 5.2 mmol/L (115 to 200 mg/dL). Over the median follow-up of 5.4 years, treatment lowered TC by 25%, LDL-C by 35%, and triglyceride by 10% and raised HDL-C by 8% (all mean changes from baseline) with few adverse effects. Treatment reduced the all-cause mortality rate by 30% (P=.0003), the major coronary event rate by 34% (P<.00001), the coronary death rate by 42% (95% CI, 0.46 to 0.73), and the need for revascularization by 37% (P<.00001).⁹ The significant reduction in major CHD events applied to all quartiles of baseline TC, LDL-C, and HDL-C.¹⁰ The impact of simvastatin on CHD appeared to occur near the end of the first year.⁹ Prospective subgroup analyses showed that the risk for a major CHD event was significantly reduced in women as well as men and in younger and older patients (<60 or 60 years old). Post hoc analyses showed a 30% reduction in the rate of stroke (P=.024),⁹ and CHD and mortality benefits in patients with diabetes mellitus were similar to reductions in nondiabetic patients.¹¹

Risk for all-cause death was also reduced, by 22%, in WOSCOPS, a double-blind, placebo-controlled, primary-prevention trial of pravastatin at 40 mg daily, although the reduction was not statistically significant (P=.051).¹² This double-blind trial enrolled 6595 men 45 to 64 years old who had hypercholesterolemia (mean TC, 7.0 mmol/L [272 mg/dL]) and no history of MI; 5% had evidence of angina according to the Rose questionnaire. At an average follow-up of 4.9 years, mean lipid changes with treatment were TC, -20%; LDL-C, -26%; triglyceride, -12%; and HDL-C, +5% from baseline. In addition to the reduction in the secondary end point of total mortality (including no significant differences in the numbers of deaths from cancer, suicide, or trauma), pravastatin therapy, which was well tolerated, was associated with significant reductions in nonfatal MI plus CHD death (-31%, P<.001) and nonfatal MI (-31%, P<.001), which were principal end points. The need for revascularization procedures was reduced by 37% (P=.009). Beneficial effects on nonfatal MI plus CHD death applied to all predefined subgroups, among them patients 55 and <55 years old, patients with and without multiple risk factors, and those with LDL-C >4.9 and <4.9 mmol/L (189 mg/dL).¹² The investigators noted that a divergence in CHD effect between drug and placebo began to emerge 6 months after the beginning of the trial,¹² although the difference was not significant at that early date.

CARE was a double-blind, placebo-controlled, secondary-prevention trial of pravastatin at 40 mg daily in MI survivors without high cholesterol concentrations. Subjects were 4159 men and women 21 to 75 years old who had an acute MI 3 to 20 months before randomization and TC <6.2 mmol/L (240 mg/dL), LDL-C of 3.0 to 4.5 mmol/L (115 to 174 mg/dL), and triglyceride <4.0 mmol/L (350 mg/dL).¹³ It was required that the left ventricular ejection fraction be 25%. During the 5 years of the trial, pravastatin reduced TC by 20%, LDL-C by 28%, and triglyceride by 14% and increased HDL-C by 5% compared with placebo. The primary end point of CHD death or nonfatal MI was reduced by 24% (P=.003), with divergence between the drug and placebo arms beginning near the second year. Among other specified end points, treatment lowered the rate of revascularization procedures by 27% (P<.001) and the rate of stroke by 31% (P=.03). There was no increase in noncardiovascular deaths.

Women in the CARE trial benefited from aggressive lipid-lowering treatment substantially more than men (46% versus 20% reduction in the rate of major coronary events; P=.05 for interaction of sex and treatment). The effect of pravastatin on major coronary events was not substantially altered by age (including 60 years), presence of diabetes, or an ejection fraction >40%, among other factors. An interesting finding in a subanalysis of CARE data was that patients whose baseline LDL-C was <3.2 mmol/L (125 mg/dL) did not benefit from treatment.¹³ This finding supports the use of a target goal in treating hyperlipidemia but has been widely debated because of its post hoc nature. In the CARE treatment group as a whole, LDL-C was reduced from a mean of 3.6 to a mean of 2.5 mmol/L [139 to 97 mg/dL]), consistent with the NCEP LDL-C goal of 2.6 mmol/L (100 mg/dL) in secondary prevention.² Whereas the post hoc CARE analysis suggests that pretreatment LDL-C concentration is a major determinant of outcome, a view supported by at least one meta-analysis of vascular results in angiographic trials,¹⁴ other meta-analyses have indicated that percentage change rather than prevailing concentration of LDL-C determines therapeutic response.^15,16

The important message from CARE is that cholesterol lowering can reduce coronary morbidity and mortality rates in CHD patients without high serum cholesterol, a description applicable to many survivors of an acute coronary event. In fact, the mean baseline TC of the CARE participants was 5.4 mmol/L (209 mg/dL), which is about the same as the mean TC concentration of 5.3 mmol/L (206 mg/dL) in the US adult population, according to 1988 to 1991 data from NHANES III.¹⁷

The results of the Post-CABG trial, which used lovastatin (with or without cholestyramine) and had an angiographic primary end point,¹⁸ provide an interesting addition to the treat-to-target versus percentage reduction debate. This trial assessed the effects of aggressive versus moderate lipid-lowering therapy on atherosclerotic progression in saphenous vein grafts in 1351 patients (92% male) who had undergone bypass surgery 1 to 11 years earlier. Eligible patients were 21 to 74 years old, had LDL-C of 3.4 to 4.5 mmol/L (130 to 175 mg/dL), and had at least one patent saphenous graft visible on angiography. Lipid-lowering therapy was lovastatin titrated to achieve LDL-C of <2.2 mmol/L (85 mg/dL) in the aggressive-treatment group and <3.6 mmol/L (140 mg/dL) in the moderate-treatment group; after two consecutive visits, cholestyramine was added if LDL-C remained >2.5 or 4.1 mmol/L (95 or 160 mg/dL). Patients were also randomized, within the two lipid-lowering groups, to placebo or to the anticoagulant warfarin. Across the average 4.3-year follow-up, mean LDL-C ranged from 2.4 to 2.5 mmol/L (93 to 97 mg/dL) in the aggressive-treatment group and from 3.4 to 3.5 mmol/L (132 to 136 mg/dL) in the moderate-treatment group. At the end of the study, the mean percentage of grafts with progression was 27% for patients in the aggressive-treatment group and 39% with the moderate-treatment group (P<.001). There was no significant difference between the warfarin and placebo groups. Thus, treatment to below the NCEP recommended LDL-C target of 2.6 mmol/L (100 mg/dL) resulted in significantly greater angiographic benefit. In addition, the rate of revascularization over the 4.3 years was 29% lower with aggressive lipid reduction (P=.03).

The results of 4S, WOSCOPS, and CARE (Fig 1) impressively demonstrate the benefits of LDL-C lowering. Yet only a fraction of the participants in the three trials achieved LDL-C reductions sufficient to meet recommended cholesterol goals set by the ATP II of the NCEP in 1993.² The results of the Post-CABG trial indicate that greater angiographic benefit can be achieved by treating to the NCEP target for patients with evidence of atherosclerotic disease.

View larger version (38K): [in this window] [in a new window]   Figure 1. Summary of effects of lipid lowering on coronary events in recent statin trials (adapted from Scandinavian Simvastatin Survival Study Group,9,10 Shepherd et al,12 and Sacks et al13,50).

	Mechanisms Leading to Event Benefits

Top Abstract Introduction Benefits of Lipid Lowering:... Mechanisms Leading to Event... Lipid Management: Awareness... Statin Therapy New Perspectives in Patient... Cost-Effectiveness of LDL-C... References

 
The exact molecular mechanisms by which lipid-lowering therapy reduces CHD event rates are not yet known. Numerous angiographically monitored trials have shown the benefit of lipid reduction in slowing the rate of progression of atherosclerotic disease, and regression of atherosclerotic lesions was achieved in some studies.^19,20 The modest anatomic changes have been associated with disproportionately large reductions in clinical event rates in several studies.^19,20 Recent data have also shown that the atherosclerotic lesions most likely to lead to an event are mildly to moderately stenotic, lipid-rich "culprit" lesions with few smooth muscle cells and a thin fibrous cap. These findings have suggested that the clinical benefit of treatment may depend on the stabilization of these rupture-prone lesions and have spurred further investigation into the functional state of the atheroma. The reduction in coronary events is probably related to favorable effects on the influx and efflux of lipoproteins in the lipid-rich lesions.²¹ It is also possible that effects of drug or lifestyle therapy independent of lipid-lowering effects contribute to lesion stabilization.^19,20

A number of investigators have examined the question of which types of lesions lead to MI.^19,22–25 Although severely stenotic lesions are more likely to progress to complete occlusion, mild-to-moderate lesions are more common and hence cause MI more frequently. Furthermore, occlusion of severely stenosed vessels may be clinically less harmful than thrombogenic rupture of smaller lesions, because larger lesions may be associated with the development of collateral vessels, allowing continued blood supply.

Libby described vulnerable (unstable) and stable atherosclerotic plaque morphology (Fig 2).²⁶ Vulnerable plaques often have a well-preserved lumen and a substantial lipid core with a thin, friable fibrous cap that is subject to rupture or disruption. A stable plaque has a relatively thick fibrous cap that separates arterial blood from the thrombogenic lipid core and is not easily ruptured. Evidence suggests that macrophage activity plays a key role in rendering the plaque vulnerable to rupture through the production of degradative enzymes (such as metalloproteinases) that weaken the connective tissue of the fibrous cap. Thus, one mechanism by which lipid lowering mediates clinical benefit may be a reduction in the inflammatory response associated with lipid-laden macrophages (foam cells). The unpredictable progression of unstable lesions is most likely a result of plaque disruption followed by thrombus formation, which alters plaque geometry and leads to intermittent plaque growth and the acute coronary syndromes.²¹ Therefore, effects of lipid modification on thrombogenicity are also being investigated.

View larger version (57K): [in this window] [in a new window]   Figure 2. Characteristics of plaques prone to rupture (from Libby26).

In addition, it is possible that improvement of endothelial function plays a role in the clinical success of lipid lowering, and clinical trials have now begun to address this question. Atherosclerosis and hypercholesterolemia impair endothelium-mediated vasodilator responses, an impairment that may be involved in the development of myocardial ischemia. Treasure et al²⁷ used quantitative angiography to assess endothelium-mediated vasodilatation in a double-blind trial in which 23 patients undergoing coronary angioplasty were randomly assigned to dietary counseling plus lovastatin at 40 mg twice daily or placebo (enrollment TC, 4.1 to 7.8 mmol/L [160 to 300 mg/dL]). At 12 days and at 6 months, patients were given serial intracoronary infusions of acetylcholine in an artery not affected by angioplasty. After 12 days of therapy, there was no difference in vasodilatation according to treatment group despite significant reductions in cholesterol with drug therapy. After 6 months, however, cholesterol lowering significantly improved endothelium-mediated responses in the coronary arteries. Treatment with a statin for 6 months has also been shown to reduce the number of silent ischemic episodes.^28,29 Anderson et al³⁰ angiographically assessed endothelium-dependent coronary artery vasomotion in response to acetylcholine infusion at baseline and after 1 year in 49 patients (TC eligibility, 4.7 to 7.2 mmol/L [180 to 280 mg/dL]; mean, 5.4 mmol/L [209 mg/dL]) randomly assigned to diet alone, diet plus lovastatin and cholestyramine, or diet plus lovastatin and the antioxidant probucol. Coronary artery vasomotor response was improved in both drug-treated groups compared with the group receiving only diet, with greater improvement in the lovastatin plus antioxidant group.

	Lipid Management: Awareness Versus Treatment Realities

Top Abstract Introduction Benefits of Lipid Lowering:... Mechanisms Leading to Event... Lipid Management: Awareness... Statin Therapy New Perspectives in Patient... Cost-Effectiveness of LDL-C... References

 
Clinical guidelines were first issued by the NCEP in 1987. An NHLBI survey conducted in 1990 showed substantial improvements in cholesterol awareness since an initial survey in 1986. Knowledge among the public that high blood cholesterol has a major role in heart disease risk increased from 64% to 74%. The proportion of adults who had their cholesterol concentration checked increased from 35% to 65%. Public awareness of the definition of a desirable cholesterol concentration increased by fourfold.³¹

Improvement was seen again in 1995 with the completion of the NHLBI's fourth national survey to assess attitudes, knowledge, and practices concerning high blood cholesterol and CHD.³¹ Among the public, 79% of adults were aware of "good" and "bad" cholesterol and 66% acknowledged the importance of avoiding high cholesterol levels, which they believed to be defined at 5.2 mmol/L (200 mg/dL). Among physicians, diet modification was recommended for patients without CHD beginning at an average TC concentration of 5.6 mmol/L (216 mg/dL) for men and women. Use of drug therapy after diet in these patients was considered appropriate beginning at an average TC of 6.4 mmol/L (249 mg/dL) for men and 6.5 mmol/L (252 mg/dL) for women. Treatment thresholds used were lower for patients with CHD or multiple risk factors for CHD. Surprisingly, however, among patients without CHD, only 7% were receiving dietary therapy and 3% were receiving drug therapy³¹; NHANES III data indicate that 29% and 7% of all US adults would be candidates for lipid-lowering dietary and drug therapy, respectively,³² by current NCEP guidelines.² Among patients with CHD in the NHLBI survey, only 27% had been prescribed dietary therapy and 29% drug therapy. About two thirds of individuals with CHD were receiving no treatment whatsoever to lower LDL-C. These findings accord with other studies; for example, Bairey Merz et al³³ found that although 72% of 379 men and women with established CHD were aware of their cholesterol concentration, only 26% had been prescribed lipid-lowering drug therapy. Despite the convincing evidence for the benefit of LDL-C lowering in primary and secondary prevention, a great gap exists between knowledge and practice.

Roberts notes that 50% of patients prescribed a lipid-lowering drug stop taking the drug in the first year; after 2 years, compliance is only 25%.³⁴ Yet in a 1-year retrospective study of 90 patients prescribed statin monotherapy at a Veterans Administration Medical Center, Marcelino and Feingold³⁵ attributed failure to reach NCEP LDL-C goals in large measure to inadequate treatment by physicians. Only 24% of the secondary-prevention patients reached the goal of 2.6 mmol/L (100 mg/dL), and only 33% of all the patients reached the goal of 2.6, <3.4, or <4.1 mmol/L [100, 130, or 160 mg/dL]). Nearly all the patients were given the drug at a low dosage, and fewer than half were adequately monitored for hepatotoxicity. Data from HERS similarly suggest inadequate implementation of current lipid management guidelines. HERS is a multicenter, placebo-controlled study of the effects of hormone replacement in 2763 postmenopausal women with documented CHD, <80 years old, and with an intact uterus. In a cross-sectional analysis of the cohort at baseline, of the 47% of these patients who were on lipid-lowering medications, 91% did not reach LDL-C 2.6 mmol/L (100 mg/dL), as specified by the ATP II.³⁶ However, at the time the HERS investigators began enrolling patients, the LDL-C goal for secondary prevention was 3.4 mmol/L (130 mg/dL), as specified by the ATP I.³⁷ Of patients taking lipid-lowering medication, 63% did not reach this less rigorous target. It is important to remember, however, that any reduction in elevated cholesterol appears to be associated with some benefit.

	Statin Therapy

Top Abstract Introduction Benefits of Lipid Lowering:... Mechanisms Leading to Event... Lipid Management: Awareness... Statin Therapy New Perspectives in Patient... Cost-Effectiveness of LDL-C... References

 
HMG-CoA reductase inhibitors, or statins, are the most effective class of medications available for lowering LDL-C. They are competitive inhibitors of HMG-CoA reductase, the enzyme whose action is the rate-limiting step in the cholesterol biosynthetic pathway; they block the formation of mevalonic acid and decrease intracellular cholesterol synthesis. As a consequence of decreased intracellular concentration of cholesterol in the liver, LDL receptor activity is regulated upward, leading to increased clearance of plasma LDL.^38,39 Approved statins are lovastatin, pravastatin, simvastatin, fluvastatin, and the recently approved atorvastatin. Data available for atorvastatin show that it is well tolerated and effective in lowering LDL-C in daily doses ranging from 10 to 80 mg. At that dosing range, atorvastatin reduces LDL-C by 39% to 60% and triglyceride by 19% to 37%.^40,41 Cerivastatin is in clinical trials and has been reported to be effective and well tolerated in daily doses of 50 to 200 µg.⁴²

The statins are considered by many authorities to be an excellent choice for reducing elevated LDL-C. Statin therapy may also be a particularly good choice in patients who have increased LDL-C and mildly elevated triglyceride, a common finding in patients with non–insulin-dependent diabetes mellitus or patients who have hyperlipidemia due to nephrotic syndrome or renal failure. This class of lipid-lowering agent also has proved to be well tolerated by most patients, with the side effects being mild gastrointestinal complaints and rare instances of myopathy that usually resolve on discontinuation of the drug. The risk for myopathy with these drugs, defined as myalgia (muscle aches, soreness, or weakness) and creatine kinase values >10 times the upper limit of normal,² may be increased by concomitant administration of cyclosporine, gemfibrozil, or perhaps nicotinic acid.

	New Perspectives in Patient Management

Top Abstract Introduction Benefits of Lipid Lowering:... Mechanisms Leading to Event... Lipid Management: Awareness... Statin Therapy New Perspectives in Patient... Cost-Effectiveness of LDL-C... References

 
The NCEP recommends that, in general, at least a 3-month trial of dietary and other lifestyle changes be instituted before the addition of lipid-lowering drug therapy in secondary prevention, with earlier initiation left to clinical judgment.² However, because of the impressive outcomes of the recent large clinical trials using statins, a number of clinical experts, including the American College of Cardiology/American Heart Association Task Force on Practice Guidelines,⁴³ have recommended considering lipid-lowering drug therapy when LDL-C is 3.4 mmol/L (130 mg/dL) after a briefer trial of dietary therapy. The American Heart Association Task Force on Risk Reduction, chaired by Scott Grundy, MD, chairman of the NCEP–ATP II,² recently concluded that withholding drug therapy in an effort to reach target LDL-C with lifestyle changes is not necessary when LDL-C exceeds 3.4 mmol/L (130 mg/dL) in patients with CHD, and a 6-week trial of lifestyle therapy is recommended when LDL-C is between 2.6 and 3.4 mmol/L (100 and 130 mg/dL).⁴⁴ The addition of drug therapy before hospital release may be advantageous in terms of compliance, adding to the benefit of greater LDL-C reduction. It should be remembered that in an infarct patient, lipid determinations need to be made at the time of admission or no later than 24 hours after the event; otherwise, at least a 4-week waiting period should be observed to enable lipoprotein concentrations to stabilize and to ensure accuracy.⁴³ The recommendations to begin drug therapy without delay accord with the experience of Ballantyne and colleagues⁴⁵ in the secondary-prevention Lipoprotein and Coronary Atherosclerosis Study, a regression trial of fluvastatin, in which <2% of the subset of enrollees with LDL-C of 3.4 mmol/L (130 mg/dL) achieved LDL-C of 2.6 mmol/L (100 mg/dL) after 8 weeks of a diet containing less fat and cholesterol and only slightly higher saturated fat than the Step II diet. Only 15% of the enrollees with LDL-C of 3.4 mmol/L (130 mg/dL) achieved LDL-C lowering of 0.8 mmol/L (30 mg/dL) during this dietary lead-in/stabilization period of the trial.

	Cost-Effectiveness of LDL-C Lowering

Top Abstract Introduction Benefits of Lipid Lowering:... Mechanisms Leading to Event... Lipid Management: Awareness... Statin Therapy New Perspectives in Patient... Cost-Effectiveness of LDL-C... References

 
The American Heart Association reports that CHD will cost the nation an estimated $90.9 billion in 1997, comprising $47.5 billion in direct costs and $43.4 in lost productivity.¹ Of these costs, medications account for $2.7 billion, or only 6% of direct costs and 3% of all costs.¹ Adding congestive heart failure and other heart diseases swells the figure to $167.2 billion, with medication costs remaining at 3% of the total. Review of cost-effectiveness analyses of cholesterol lowering supports population-wide educational endeavors and aggressive risk reduction in secondary prevention, but drug therapy in primary prevention tends to be cost-effective only in high-risk groups.^2,46–48 Targeting by factors such as age, coexisting risk factors, and sex will improve the cost-effectiveness profile in primary prevention.^47,48 In 4S, in which patients had a history of MI or angina, cost-effectiveness was analyzed prospectively, and the investigators found that simvastatin therapy markedly reduced use of hospital services, thereby offsetting most of its cost.⁴⁹ Cost-effectiveness analysis of the pooled results of two regression trials using pravastatin showed favorable outcome compared with other widely accepted medical interventions.⁵⁰ Gains in life expectancy with strict control of cholesterol concentrations are similar to those achieved with smoking cessation, control of diastolic blood pressure, or weight.⁴⁹ Given the crucial role of cholesterol lowering in reducing CHD incidence, high priority should be given to validating its cost-effectiveness.⁴⁶

Despite the impressive body of evidence supporting the management of hyperlipidemia in CHD prevention, there is a discouraging lack of implementation of lipid-lowering interventions in the clinical setting. Awareness of cholesterol as a CHD risk factor has increased, and there has been a secular trend toward a reduction in CHD morbidity and mortality rates as a result of aggressive public education campaigns and improved treatment options. Furthermore, basic scientific research has continued to elucidate the roles of cholesterol lowering in slowing or preventing the development of symptomatic heart disease. However, drug therapy has not been as widely used as the NCEP guidelines recommend, in part because of the need for evidence of reduction of total mortality rate. The evidence is now available, and it is critical that lipid management, a proven method for CHD risk reduction, be emphasized to cardiologists and other physicians who treat at-risk patients.

	Selected Abbreviations and Acronyms

 

ATP II = Adult Treatment Panel CARE = Cholesterol and Recurrent Events CHD = coronary heart disease HERS = Heart and Estrogen/Progestin Replacement Study HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A MI = myocardial infarction NCEP = National Cholesterol Education Program NHANES III = National Health and Nutrition Examination Surveys Post-CABG = Post Coronary Artery Bypass Graft 4S = Simvastatin Survival Study TC = total cholesterol WOSCOPS = West of Scotland Coronary Prevention Study

	Footnotes

 

	References

Top Abstract Introduction Benefits of Lipid Lowering:... Mechanisms Leading to Event... Lipid Management: Awareness... Statin Therapy New Perspectives in Patient... Cost-Effectiveness of LDL-C... References

 

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