ABSTRACT: A host of evidence supports the treatment of high levels of low-density lipoprotein (LDL) cholesterol with HMG-CoA reductase inhibitors (statins), which are effective in both primary and secondary prevention of coronary heart disease (CHD). Studies have shown that statins prevent first cardiac events in otherwise healthy persons with elevated LDL cholesterol and low high-density lipoprotein cholesterol levels. Statins are also associated with a reduction in cardiac death, stroke, hospitalization, and the need for revascularization in patients with established CHD and hyperlipidemia. Secondary prevention trials of statin therapy that included persons aged 65 to 75 years found significant risk reduction in this age group. Among the concerns associated with statin treatment are lack of proper titration, failure to achieve LDL target goals, and underuse in patients with established CHD.
Although the cardiovascular death rate has declined in the United States, the number of hospitalizations for cardiac disease has not. The improvement in care has been offset by an increase in the number of older Americans. By 2050, more than 100 million Americans will be 60 years or older, and about 30 million will be older than 80 years.
As the number of older persons rises, clinicians will see more patients with chronic conditions-such as obesity, diabetes mellitus, and uncontrolled hypertension-that increase the risk of coronary heart disease (CHD). These risk factors have been well established by the Framingham Study1 and other epidemiologic reports. The combination of increased caloric intake and reduced physical activity that has become prevalent in our society will also contribute to a higher incidence of the metabolic syndrome-a condition whose manifestations include increased abdominal girth, low levels of high-density lipoprotein (HDL) cholesterol, hypertension, and elevated blood glucose and triglyceride levels.
All of these factors and others suggest that we must actively pursue strategies such as global risk assessment and the aggressive control of modifiable risk factors to protect our patients from CHD, which continues to be the leading cause of death in the United States. In recent years, aggressive therapy has resulted in a major improvement in the outlook for patients at risk. Yet many of these persons fail to achieve the treatment goals set forth by the National Cholesterol Education Program (NCEP).2 Moreover, many asymptomatic persons at increased risk who would benefit from treatment are not receiving it.
In this article, I highlight data from important clinical trials that demonstrate the benefits of lipid-lowering therapy. I also discuss the major causes of undertreatment.
ROLE OF STATINS IN REDUCING CHD RISK
Cardiovascular risk assessment must include intensive scrutiny of a patient's lipid profile, with particular attention to levels of low-density lipoprotein (LDL) cholesterol, the most atherogenic cholesterol (Table 1). Although very high LDL levels secondary to genetic hyperlipidemia present a significant risk, this condition is rare. In fact, initial coronary events occur much more frequently in persons with serum LDL cholesterol levels between 130 and 160 mg/dL (ie, values below those that warrant drug therapy according to the NCEP guidelines).
The rationale for lowering elevated LDL cholesterol levels is supplied by a host of double-blind placebo-controlled trials that have demonstrated a reduction in primary and secondary cardiac events in patients who are given HMG-CoA reductase inhibitors (statins).
Primary prevention. The degree of absolute risk-the likelihood that CHD will develop within a specific period-guides the intensity of primary prevention efforts. Patients are considered at high risk if the probability that they will suffer a myocardial infarction (MI) in the next 10 years is greater than 20%. According to the NCEP guidelines, risk factors in addition to elevated LDL cholesterol levels include hypertension, cigarette smoking, low HDL cholesterol levels, CHD, and CHD risk equivalents. The latter group consists of other clinical forms of atherosclerotic disease-such as peripheral arterial disease, previous abdominal aortic aneurysm, and symptomatic carotid artery disease-and diabetes. The NCEP guidelines emphasize that although persons at higher risk are candidates for drug therapy, lifestyle changes are the foundation of primary prevention. The NCEP recommendations are summarized in Table 2.
Two major randomized, double-blind, placebo-controlled trials evaluated the effectiveness of statin therapy in primary prevention. In the West of Scotland Coronary Prevention Study (WOSCOPS), pravastatin was compared with placebo in men who had elevated LDL cholesterol levels and no known heart disease.3 In the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/ TexCAPS), lovastatin was compared with placebo in adults with average total cholesterol and low levels of HDL cholesterol.4 Hospital admission for unstable angina was considered an end-point cardiac event.
Both studies demonstrated a significant reduction in first cardiac events in otherwise healthy persons treated with statins. Neither trial was powered to provide statistically significant evidence of a mortality benefit because the number of deaths was small.
Secondary prevention. A host of studies have demonstrated the value of reducing the level of LDL cholesterol in patients with established CHD and hyperlipidemia. The Scandinavian Simvastatin Survival Study (4S) examined data from 4444 patients with known CHD who were randomized to drug therapy or placebo and followed for 5 years.5 The results showed a dramatic reduction in cardiac deaths, stroke, hospitalizations, and need for revascularization in the treated group. This was the first major study to demonstrate a statin-associated reduction in all-cause mortality in patients with CHD who had high serum LDL cholesterol. Most previous trials were not powered to demonstrate a difference in an infrequent event end point.
The Cholesterol and Recurrent Events (CARE) trial followed 4159 men and women with average cholesterol levels who had had an acute MI.6 They were randomly assigned to pravastatin or placebo and followed for 5 years. There was a significant reduction in the incidence of cardiovascular events (CVEs) and stroke in the treated patients. Lowering the LDL cholesterol level below 124 mg/dL did not seem to provide additional benefits.
Both 4S and CARE recruited patients several months after they had recovered from an acute MI. These studies excluded patients in the immediate period after an acute event, when recurrent ischemia and death are most likely to occur.
Subsequently, the Myocardial Ischemia Reduction With Aggressive Cholesterol Lowering (MIRACL) study randomized 3086 patients with acute coronary syndrome (ACS) within 24 to 96 hours after hospital admission to either atorvastatin, 80 mg/d, or placebo with a 16-week follow-up.7 The treated group had a lower risk of ischemia requiring hospitalization and had fewer strokes; there were, however, no significant differences in risk of death, nonfatal MI, or cardiac arrest between the groups.
The value of statin therapy is not limited to patients with acute MI or even unstable ACS. In the Atorvastatin Versus Revascularization Treatment (AVERT) trial, 341 patients with stable coronary artery disease, relatively normal left ventricular function, asymptomatic or mild to moderate angina, and an LDL cholesterol level of at least 115 mg/dL who were referred for percutaneous transluminal coronary angioplasty (PTCA) were randomized to atorvastatin, 80 mg/d, or PTCA followed by usual care.8
After 18 months, the incidence of ischemic events-as well as PTCA and coronary artery bypass graft procedures and hospitalizations for worsening angina-was lower in the atorvastatin group. There was no mortality benefit for PTCA. After adjustment for interim analysis, the results just missed statistical significance. At the end of the study, more patients who had undergone PTCA reported improvement in angina. However, these patients were more likely to have started or increased antianginal medication. The researchers concluded that in low-risk patients with stable coronary artery disease, aggressive lipid-lowering therapy was at least as effective as PTCA and usual care in reducing the incidence of ischemic events.
More recent studies. In recent years, other studies have provided new insights into the effects of lipid-lowering therapy on atherosclero-sis.9-12 A number of trials confirmed the value of therapeutic lifestyle changes, which realistically remain the core modality or baseline upon which the effects of drugs are engrafted. In addition, it is now recognized that lipid-lowering therapy is beneficial for elderly persons; the value of this intervention was previously the subject of controversy. A major new recommendation is to have a therapeutic goal of less than or equal to 70 mg/dL for LDL cholesterol in persons known to be at highest risk for progression to or occurrence of CVEs. Following are summaries of key studies.
The Heart Protection Study (HPS) was conducted in the United Kingdom. More than 20,000 adults who were at high risk for a CVE were given either 40 mg of simvastatin or a placebo daily and followed carefully for several years.9 The group taking simvastatin experienced a reduction in all-cause mortality as well as an approximately 25% reduction in stroke, CHD, and CVE. The reduction of risk was similar for those with LDL cholesterol levels of more than 135 mg/dL and those with levels of less than 116 mg/dL.
The Prospective Study of Pravastatin in the Elderly examined the efficacy of pravastatin in older men and women.10 More than 5800 participants were randomized to either 40 mg of pravastatin or placebo. After a 3-year follow-up, there was a statistically significant reduction in nonfatal acute MI, CHD death, and transient ischemic events.
In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT-LLT), more than 19,000 hypertensive patients with at least 3 cardiovascular risk factors were randomized to atorvastatin or placebo for 5 years of treatment.11 The trial was stopped after 3 years when it became apparent that the atorvastatin group experienced a statistically significant reduction in stroke and total CVEs, and a trend toward lower total mortality.
Pravastatin or Atorvastatin Evaluation and Infection-Thrombolysis in Myocardial Infarction 22 Trial (PROVE-IT)compared atorvastatin, 80 mg, with pravastatin, 40 mg, in 4162 patients who had been hospitalized for an ACS within the preceding 10 days.12 After 2 years of therapy, the composite cardiovascular end point was reduced by 16% in the atorvastatin group, compared with the pravastatin group. The LDL cholesterol level achieved with pravastatin was 95 mg/dL, while a level of 62 mg/dL was achieved with atorvastatin.
RATIONALE FOR LOWERING THE LDL CHOLESTEROL GOAL
The HPS and PROVE-IT trials raise the following question: Is a reduction of LDL cholesterol levels to 70 mg/dL or less desirable or even obligatory? In patients at very high risk, the lower goal does seem to be worth attempting to achieve. Clinicians already have difficulty in getting all patients with known atherosclerotic heart disease to achieve a goal of less than 100 mg/dL for LDL cholesterol. To attain a lower threshold clearly would be more difficult. Nevertheless, there are settings in which the lower goal is appropriate, particularly in patients with established cardiovascular disease and any of the following characteristics:
•Multiple major risk factors.
•Uncontrolled risk factors, particularly cigarette smoking.
•The metabolic syndrome with multiple risk factors.
Although goals and position papers are all worthy efforts in the battle to control cardiovascular disease, it is important to stress the need for experienced clinical judgment. Each patient is unique and deserves specific attention directed to his or her own particular risk and behavioral identities. This is not an area where one size fits all.
TREATMENT PEARLS AND PITFALLS
Titration. The appropriate starting dose of a statin is a practical concern, primarily because of the difficulty of titration in office practice. Many primary care physicians, especially those who labor under the constraints of managed care, may not have the time for the increased number of visits required. In addition, patients-many of whom have no symptoms-may be reluctant to invest the time (and money) needed for return visits. Some clinicians are uneasy about the possibility of side effects as the dosage is increased.
The ideal is to achieve target lipid levels with the starting dose of the statin; however, this does not always occur. No single starting dose can be recommended for all patients. Each patient's needs must be taken into account and the regimen individualized accordingly. Measure lipid levels every 6 to 12 weeks, and adjust the dosage based on the patient's response to therapy.
A number of studies have compared the relative efficacy of the various statins across a typical patient cohort. The CURVES trial compared the efficacy of daily starting doses of 5 agents-atorvastatin, 10 mg; simvastatin, 10 mg; pravastatin, 20 mg; lovastatin, 20 mg; and fluvastatin, 20 mg-in patients with hypercholesterolemia for 8 weeks.13 The mean reductions in LDL cholesterol levels were, respectively, 38%, 28%, 24%, 29%, and 17%. The CURVES study also compared these drugs during titration up to 80 mg for atorvastatin and lovastatin and up to 40 mg for fluvastatin, pravastatin, and simvastatin. Atorvastatin at doses of 10, 20, and 40 mg produced greater reductions in LDL cholesterol levels than the milligram-equivalent doses of the other agents.
Since the CURVES study was published, the usual starting doses of several statins have been changed to achieve maximum lipid-lowering effects as early as possible. For example, a daily starting dose of 20 mg of simvastatin is now generally recommended, as is an 80-mg dose of long-acting fluvastatin.
Failure to achieve therapeutic goals. A number of studies have demonstrated that goal LDL cholesterol values are achieved relatively infrequently in clinical practice. For example, the Lipid Treatment Assessment Project (L-TAP), a study of the outpatient treatment of dyslipidemia, revealed that only 18% of patients with CHD had achieved the NCEP goal of 100 mg/dL.14 In the Heart and Estrogen/Progestin Replacement Study (HERS), a randomized trial of estrogen plus progesterone for secondary prevention of CHD in women, only 10% of patients achieved an LDL cholesterol goal of 100 mg/dL.15
Discharge after MI without therapy. Despite the prodigious evidence that supports the value of lipid-lowering therapy in secondary prevention, most patients who have had an acute MI leave the hospital without statin therapy. In one analysis, discharge medication data were collected for 138,000 patients with acute MI from 1470 hospitals.16 Fewer than one third (31.7%) of the patients were given a prescription for a lipid-lowering drug at discharge. The benefits of in-hospital initiation are well established (Box).17,18
An observational analysis of data from 2 major clinical trials compared mortality among 3653 patients hospitalized for symptomatic CHD who received lipid-lowering therapy at discharge with mortality among 17,156 patients discharged without such therapy.19 The results included a 50% reduction in the death rate at both 30 days and 6 months among the treated patients.
Undertreatment of elderly patients. Many patients who previously had been considered too old for pharmacologic therapy now regularly undergo cardiac revascularization at the first episode of symptomatic ischemic disease. The NCEP guidelines suggest that for primary prevention, lifestyle changes are the first line of therapy for older persons, but that LDL-lowering drugs can be considered when patients are at high risk. The results of secondary prevention trials of statin therapy that included persons aged 65 to 75 years showed that treatment was associated with significant risk reduction.20
Hazards of statin/fibric acid therapy. The use of a statin in combination with a fibric acid derivative increases the risk of rhabdomyositis and should be restricted to patients at very high risk. These patients are best referred to specialists. The withdrawal of cerivastatin from the market was prompted by an increase in the incidence of rhabdomyositis among patients treated with high doses of this agent or with a combination of cerivastatin and fibric acid derivatives.
OTHER POTENTIAL BENEFITS OF STATINS
The statins may have other benefits besides the effects of lowering LDL cholesterol levels. There is compelling in vivo evidence for direct inhibition of acute and chronic inflammatory conditions characterized by the infiltration of polymorphonuclear leukocytes.21 This is important because of the concept of "vulnerable plaque," in which disruption initiates a cascade of events leading to ACS, acute MI, or sudden death. The features of vulnerable plaque include:
•A large, predominantly acellular lipid-rich core.
•A fibrous cap with focal areas of thinning and reduced smooth muscle density and collagen content.
•Inflammatory cell infiltration at the shoulders of the lesion.
Anti-inflammatory effects. The anti-inflammatory effects of the statins may explain some of the reduction in cardiac events seen in clini- cal trials. Changes in the oxidation-sensitive mechanisms in the arterial wall, effects on nitric oxide synthesis, and modulation of intracellular signaling pathways may all play a role.
Coronary atherosclerotic disease. In a study of the effect of fluvastatin on the progression of coronary arteriosclerotic lesions measured by serial computerized angiograms, the reduction in the narrowing of coronary lumen associated with treatment occurred irrespective of baseline LDL cholesterol levels.22 Lipid effects independent of the lowering of LDL cholesterol levels include inhibition of LDL cholesterol oxidation and secretion and inhibition of scavenger receptor expression. Antiatherosclerotic effects include inhibition of migration and proliferation of arterial myocytes, inhibition of macrophage growth, inhibition of metalloproteinase secretion, inhibition of cell adhesion, and increased expression of endothelial nitric oxide synthase.
Possible prophylactic effects. A reduction in the incidence of type 2 diabetes among patients treated with statins has been reported.6 In a small study, simvastatin reduced blood pressure and 24-hour urinary albumin excretion in patients with type 2 diabetes and hypertension.23
Statin use has been associated with a reduction in the risk of dementia.24 Several studies have suggested that statin use also reduces the risk of stroke.25-27 Other reports have found that statins are associated with a reduction in C-reactive protein levels28 and a decreased risk of deep venous thrombosis.29 Some experts recommend statins as the drug of first choice for reducing cardiovascular risk in women with established CHD.30
FUTURE METHODS OF ASSESSING CHD RISK
A potentially important effect of fluvastatin on QT dispersion was reported.31 In a study of patients with hypercholesterolemia, QT interval dispersion (QTd) decreased after treatment with fluvastatin. It has been suggested that analysis of QTd might be used as a noninvasive method of evaluation of the risk of sudden death in patients with CHD.
Sophisticated techniques to help evaluate the treatment of dyslipidemia are emerging rapidly. The cholesterol ester transfer protein (CETP) has a central role in the metabolism of HDL cholesterol and may, therefore, alter susceptibility to atherosclerosis. A study designed to assess the regression of coronary atherosclerosis evaluated the polymorphisms of the B1 variant of the CETP gene.32 The 807 male participants-all of whom had angiographically documented coronary atherosclerosis-were randomly assigned to treatment with pravastatin or placebo. The B1 variant of the CETP gene was associated with both higher plasma CETP concentrations and lower HDL cholesterol levels.
The study showed that pravastatin therapy slowed the progression of atherosclerosis in B1B1 carriers but not in B2B2 carriers (who represented 16% of the patients taking pravastatin). The presence of the B1 variant appears to predict whether men with CHD will benefit from treatment with pravastatin to help delay the progression of atherosclerosis.
Other investigations have produced a single blood test that can identify 35 different cardiovascular-related gene variants. Eventually, gene testing will predict CHD risk with high accuracy.
REFERENCES:1. Kannel WB, Castelli WP, Gordon T, McNamara PM. Serum cholesterol, lipoproteins, and the risk of coronary heart disease. The Framingham study. Ann Intern Med. 1971;74:1-12.
2. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP). Bethesda, Md: NIH; 2001. NIH publication 01-3670.
3. Shepherd J, Cobbe SM, Ford I, et al, for the West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med. 1995;333:1301-1307.
4. Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. JAMA. 1998;279: 1615-1622.
5. Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344: 1383-1389.
6. Sacks FM, Pfeffer MA, Moye LA, et al, for the Cholesterol and Recurrent Events Trial Investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med. 1996;335: 1001-1009.
7. Schwartz GG, Olsson AG, Ezekowitz MD, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA. 2001; 285:1711-1718.
8. Pitt B, Waters D, Brown WV, et al. Aggressive lipid-lowering therapy compared with angioplasty in stable coronary artery disease: the Atorvastatin Ver-sus Revascularization Treatment Investigators. N Engl J Med. 1999;341:70-76.
9. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:7-22.
10. Shepherd J, Blauw GJ, Murphy MB, et al, for the PROSPER study group. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet. 2002;360: 1623-1630.
11. Sever PS, Dahlof B, Populter NR, et al, for the ASCOT Investigators. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm. (ASCOT-LLA) Lancet. 2003;361:1149-1158.
12. Cannon CP, Braunwald E, McCabe CH, et al, for the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350:1495-1504.
13. Jones P, Kafonek S, Laurora I, Hunninghake D, for the CURVES Investigators. Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study). Am J Cardiol. 1998;81:582-587.
14. Pearson TA, Laurora I, Chu H, Kafonek S. The Lipid Treatment Assessment Project (L-TAP): a multicenter survey to evaluate the percentages of dyslipidemic patients receiving lipid-lowering therapy and achieving low-density lipoprotein cholesterol goals. Arch Intern Med. 2000;160:459-467.
15. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women (HERS). JAMA. 1998;280: 605-613.
16. Fonarow GC, French WJ, Parsons LS, et al, for the National Registry of Myocardial Infarction 3 Participants. Use of lipid-lowering medications at discharge in patients with acute myocardial infarction: data from the National Registry of Myocardial Infarction 3. Circulation. 2001;103:38-44.
17. Fonarow GC, Ballantyne CM. In-hospital initiation of lipid-lowering therapy for patients with coronary heart disease: the time is now. Circulation. 2001;103:2768-2770.
18. Muhlestein JB, Horne BD, Bair TL, et al. Usefulness of in-hospital prescription of statin agents after angiographic diagnosis of coronary artery disease in improving continued compliance and reduced mortality. Am J Cardiol. 2001;87:257-261.
19. Aronow HD, Topol EJ, Roe MT, et al. Effect of lipid-lowering therapy on early mortality after acute coronary syndrome: an observational study. Lancet. 2001;357:1063-1068.
20. Kagansky N, Levy S, Berner Y, et al. Cholesterol lowering in the older population: time for reassessment? QJM. 2001;94:457-463.
21. Sparrow CP, Burton CA, Hernandez M, et al. Simvastatin has anti-inflammatory and antiatherosclerotic activities independent of plasma cholesterol lowering. Arterioscler Thromb Vasc Biol. 2001; 21:115-121.
22. Herd JA, Ballantyne CM, Farmer JA, et al. Effects of fluvastatin on coronary atherosclerosis in patients with mild to moderate cholesterol elevations (Lipoprotein and Coronary Atherosclerosis Study [LCAS]). Am J Cardiol. 1997;80:278-286.
23. Tonolo G, Melis MG, Formato M, et al. Additive effects of simvastatin beyond its effects on LDL cholesterol in hypertensive type 2 diabetic patients. Eur J Clin Invest. 2000;30:980-987.
24. Jick H, Zornberg GL, Jick SS, et al. Statins and the risk of dementia. Lancet. 2000;356:1627-1631.
25. Sirol M, Bouzamondo A, Sanchez P, Lechat P. Does statin therapy reduce incidence of stroke? A meta-analysis [in French]. Ann Med Interne (Paris). 2001;152:188-193.
26. Rackley CE. Elderly patients at risk for coronary heart disease or stroke: selecting an ideal product for lipid lowering. Am J Geriatr Cardiol. 2001;10:77-82.
27. Aronow WS. Treatment of older persons with hypercholesterolemia with and without cardiovascular disease. J Gerontol A Biol Sci Med Sci. 2001;56: M138-M145.
28. Ridker PM, Rifai N, Clearfield M, et al. Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. N Engl J Med. 2001;344:1959-1965.
29. Ray JG, Mamdani M, Tsuyuki RT, et al. Use of statins and the subsequent development of deep vein thrombosis. Arch Intern Med. 2001;161:1405-1410.
30. Welty FK. Cardiovascular disease and dyslipidemia in women. Arch Intern Med. 2001;161:514-522.
31. Mark L, Katona A. Effect of fluvastatin on QT dispersion: a new pleiotropic effect? Am J Cardiol. 2000;85:919-920.
32. Kuivenhoven JA, Jukema JW, Zwinderman AH, et al, for the Regression Growth Evaluation Statin Study Group. The role of a common variant of the cholesterol ester transfer protein gene in the progression of coronary atherosclerosis. N Engl J Med. 1998;338:86-93.