Therapy with hydroxymethylglutaryl coenzyme a reductase inhibitors (statins) and associated risk of incident cardiovascular events in older adults: evidence from the Cardiovascular Health Study

BACKGROUND: Recommendations to treat older adults with hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) for the primary prevention of coronary heart disease events are supported by a single clinical trial restricted to adults 73 years or younger with low levels of high-density lipoprotein cholesterol. METHODS: We investigated the association of statin use with incident cardiovascular disease and all-cause mortality during up to 7.3 years' follow-up of 1250 women and 664 men from the Cardiovascular Health Study. Study participants were 65 years and older and free of cardiovascular disease at baseline. They received drug therapy to lower cholesterol levels at baseline or no treatment with a recommendation for therapy according to the National Cholesterol Education Program guidelines. Use of these drugs was assessed annually. We used proportional-hazards models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs), adjusted for confounding variables. RESULTS: We found 382 incident cardiovascular events (159 myocardial infarctions, 159 strokes, and 64 deaths due to coronary heart disease) and 362 total deaths from June 1, 1989, to May 31, 1997. Compared with no use of drugs to lower cholesterol levels, statin use was associated with decreased risk of cardiovascular events (multivariate HR, 0.44; 95% CI, 0.27-0.71) and all-cause mortality (HR, 0.56; 95% CI, 0.36-0.88). Similar associations were observed among participants 74 years or older at baseline. CONCLUSIONS: Use of statins was associated with decreased risk of incident cardiovascular events among elderly adults. These findings lend support to the National Cholesterol Education Program guidelines, which recommend therapy for the lowering of cholesterol levels for older adults with hypercholesterolemia.     

The Role of Statin Therapy for Primary Prevention: What is the Evidence?

Almost one third of annual worldwide mortality is attributed to cardiovascular disease (CVD), making it the leading cause of global death. Dyslipidemia is a well-established risk factor for CVD and plays a pivotal role in the pathogenesis of atherosclerosis. Statins, which inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and lower low-density lipoprotein cholesterol, have emerged as the most effective therapy to date against atherothrombotic CVD. Although their role in secondary prevention of CVD is undisputed, it remains a topic for debate as to how widely they should be used for primary prevention. The Framingham Risk Score and the National Cholesterol Education Program Adult Treatment Panel III guidelines are the cornerstones for the current guidelines for primary prevention statin therapy. Although these guidelines serve as help to evaluate cardiovascular risk and effectively identify many patients who will benefit from statin therapy, there is a growing population of “intermediate-risk” patients who may be undertreated. Additional noninvasive tests may complement the traditional risk scores, potentially expanding the indications for statins.     

Women do benefit from lipid lowering: latest clinical trial data

Cardiovascular disease is the leading cause of morbidity and mortality among women in industrialized nations. Optimizing cardiovascular risk reduction is therefore of paramount importance, particularly among postmenopausal women, in whom the incidence of cardiovascular disease is highest. Accumulated data from a series of landmark trials unequivocally demonstrate the efficacy of statin therapy in the primary and secondary prevention of cardiovascular outcomes in both men and women. Moreover, the recently released Heart Protection Study provides substantive evidence that lowering low-density lipoprotein cholesterol below levels currently defined as optimal by National Cholesterol Educational Program guidelines is strongly associated with further cardiovascular risk reduction, and that this benefit accrues in all subgroups of patients, including women and the elderly. Despite the ability of hormone replacement therapy to improve serum lipid profiles, randomized trials of hormone therapy have demonstrated no benefit in reducing coronary outcomes among postmenopausal women. In contrast, data from over 8,000 women enrolled in the statin trials demonstrate that lipid lowering with statins is as effective at reducing cardiovascular outcomes in women as it is in men and suggest that statins should be considered standard of care for the prevention of adverse cardiovascular events in women at risk for coronary heart disease.     

Therapy to reduce risk of coronary heart disease

Recent primary and secondary intervention studies have shown that reduction of low-density lipoprotein cholesterol (LDL-C) with statins significantly reduced coronary heart disease (CHD) morbidity and mortality. However, many patients with dyslipidemia who have or are at risk for CHD do not reach target LDL-C goals. The recently updated National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III guidelines identify a group of patients at very high risk for CHD for more aggressive LDL-C reduction and reaffirm the importance of high-density lipoprotein cholesterol (HDL-C) by raising the categorical threshold to 40 mg/dl. Lipid-lowering therapy needs to be more aggressive in both primary and secondary prevention settings, and therapy should be considered to increase HDL-C as well as lower LDL-C in order to improve patient outcomes. Both combination therapy and the next generation of statins may provide improved efficacy across the dyslipidemia spectrum.     

Statins and stroke prevention

Data from studies on the benefits of statins in coronary artery disease patients in preventing recurrent primary and secondary cardiac endpoints, as well as ischemic strokes, imply the potential value of statins in recurrent ischemic stroke prevention without coronary artery disease symptoms or, by extension, primary ischemic stroke prevention. However, data on the latter are lacking, although the ongoing Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study is designed to answer that question. Until these data become available, clinicians are justified in using statins to avert recurrent ischemic strokes due to atherosclerosis, especially if elevated total cholesterol, increased low-density lipoprotein cholesterol, and/or reduced high-density lipoprotein cholesterol, as specified in the National Cholesterol Education Program Third Adult Treatment Panel, are present. This article reviews the pathophysiology of atherosclerosis, particularly the major components of atheromas of cholesterol, smooth muscle cells, inflammation, “foam cells,” and connective tissue elements. Emphasis is placed on the first three and the results of statin trials in coronary artery disease, as well as the beneficial pleiotrophic effects of statins in ischemic strokes.     

Genetic polymorphisms in emerging cardiovascular risk factors and response to statin therapy

Current strategies for both the primary and secondary prevention of coronary heart disease (CHD) focus on the traditional risk factors, such as hypertension, smoking cessation, and cholesterol, as the primary determinants of the cardiac risk profile, with particular emphasis on the reduction of low-density lipoprotein cholesterol (LDL-C) to targeted goal levels as endorsed by the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATPIII). Large primary and secondary prevention trials with the hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have demonstrated varying reductions in cardiovascular events associated with similar changes in LDL-C levels, suggesting statins may possess additional beneficial effects on other risk factors.Retrospective analyses of many statin trials have evaluated the association between several polymorphic candidate genes (apolipoprotein E, stromelysin-1, -fibrinogen, cholesteryl ester transfer protein, lipoprotein lipase, hepatic lipase, and platelet glycoprotein III) which have been identified as predictors of disease severity and both metabolic and clinical response to statin therapy. These results suggest that statin therapy improves plasma lipid profiles in all patients, but preferentially benefits individuals who carry a high risk, variant genotype for these risk factors as compared to individuals with the wild-type genotype. These observations suggest that determining individual patient genotype may be useful in optimizing the benefits of statin therapy. These hypothesis-generating data need to be prospectively evaluated in genotyped patients.     

Cost-effectiveness of cholesterol-lowering therapies according to selected patient characteristics

BACKGROUND: The National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II) recommends treatment guidelines based on cholesterol level and number of risk factors. OBJECTIVE: To evaluate how the cost-effectiveness ratios of cholesterol-lowering therapies vary according to different risk factors. DESIGN: Cost-effectiveness analysis. DATA SOURCES: Published data. TARGET POPULATION: Women and men 35 to 84 years of age with low-density lipoprotein cholesterol levels of 4.1 mmol/L or greater (> or =160 mg/dL), divided into 240 risk subgroups according to age, sex, and the presence or absence of four coronary heart disease risk factors (smoking status, blood pressure, low-density lipoprotein cholesterol level, and high-density lipoprotein cholesterol level). TIME HORIZON: 30 years. PERSPECTIVE: Societal. INTERVENTIONS: Step I diet, statin therapy, and no preventive treatment for primary and secondary prevention. OUTCOME MEASURES: Incremental cost-effectiveness ratios. RESULTS OF BASE-CASE ANALYSIS: Incremental cost-effectiveness ratios for primary prevention with step I diet ranged from $1900 per quality-adjusted life-year (QALY) gained to $500000 per QALY depending on risk subgroup characteristics. Primary prevention with a statin compared with diet therapy was $54000 per QALY to $1400000 per QALY. Secondary prevention with a statin cost less than $50000 per QALY for all risk subgroups. RESULTS OF SENSITIVITY ANALYSIS: The inclusion of niacin as a primary prevention option resulted in much less favorable incremental cost-effectiveness ratios for primary prevention with a statin (>$500000 per QALY). CONCLUSIONS: Cost-effectiveness of treatment strategies varies significantly when adjusted for age, sex, and the presence or absence of additional risk factors. Primary prevention with a step I diet seems to be cost-effective for most risk subgroups but may not be cost-effective for otherwise healthy young women. Primary prevention with a statin may not be cost-effective for younger men and women with few risk factors, given the option of secondary prevention and of primary prevention in older age ranges. Secondary prevention with a statin seems to be cost-effective for all risk subgroups and is cost-saving in some high-risk subgroups.     

Low-density lipoprotein cholesterol lowering in the prevention of CHD: How low should we go?

Opinion statement The past 12 years have seen the publication of numerous randomized placebo-controlled studies using statins to lower low-density lipoprotein cholesterol (LDLC) to assess the efficacy of cholesterol lowering on cardiovascular events. Initial studies predominantly evaluated mortality or nonfatal myocardial infarctions and coronary heart disease (CHD) death in patients with known or presumed established coronary disease and moderately elevated to very elevated serum cholesterol concentrations. Subsequent investigations studied a broader spectrum of cardiovascular events as a composite primary end point in both primary and secondary prevention strategies in subjects with lower mean entry serum LDLC concentrations. These studies have generally shown a reduction in a composite end point of cardiovascular events, although not necessarily the more restricted end points used in previous studies. Although the LDLC mantra "lower is better" has been popularized in advertising and continuing medical education and suggested as an option in "very high risk" patients by the National Cholesterol Education Program Adult Treatment Panel, the precise target level for LDLC for optimal treatment has not been rigorously defined. Serum LDLC less than 100 mg/dL seems reasonable for patients with known atherosclerosis or at high risk for atherosclerosis (diabetes or presence of multiple risk factors). Serum LDLC less than 70 mg/dL may be a reasonable goal in the setting of acute coronary syndromes, but there are many problems with the data on which this recommendation is made. Furthermore, many advocates of "lower is better" seem oblivious to the potential downsides of more aggressive lipid-lowering therapy. The LDLC target in lower risk primary prevention is less clear. What is obvious is that moderate-dose statin therapy can lower CHD risk in primary prevention and secondary prevention with minimal side effects, and with the imminent availability of several generic statins, with great costeffectiveness.     

Evidence-based use of statins for primary prevention of cardiovascular disease

Three-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, commonly known as statins, are widely available, inexpensive, and represent a potent therapy for treating elevated cholesterol. Current national guidelines put forth by the Adult Treatment Panel III recommend statins as part of a comprehensive primary prevention strategy for patients with elevated low-density lipoprotein cholesterol at increased risk for developing coronary heart disease within 10 years. Lack of a clear-cut mortality benefit in primary prevention has caused some to question the use of statins for patients without known coronary heart disease. On review of the literature, we conclude that current data support only a modest mortality benefit for statin primary prevention when assessed in the short term (<5 years). Of note, statin primary prevention results in a significant decrease in cardiovascular morbidity over the short and long term and a trend toward increased reduction in mortality over the long term. When appraised together, these data provide compelling evidence to support the use of statins for primary prevention in patients with risk factors for developing coronary heart disease over the next 10 years.     

Evaluation of the National Cholesterol Education Program Adult Treatment Panel III algorithm for selecting candidates for statin therapy: insights from the A to Z trial

The National Cholesterol Education Program Adult Treatment Panel III recommends an algorithm to integrate iterative risk-stratification information with low-density lipoprotein (LDL) cholesterol levels to identify candidates for statin therapy. We used the Aggrastat to Zocor (A to Z) trial, in which all patients presented with an acute coronary syndrome (ACS) event in the absence of previous statin therapy, to evaluate the performance of this algorithm. Of 1,750 patients with ACS included in this analysis, 1,126 (64%) had an indication for statin therapy before enrollment and 624 (36%) did not have a statin indication before enrollment. We estimate that initiating statin therapy at moderate dosages (decreasing LDL by 1 mmol/L) according to the National Cholesterol Education Program Adult Treatment Panel III guidelines would have prevented approximately 15% of the ACS events leading to enrollment in the A to Z trial, whereas more intensive statin therapy (decreasing LDL by 1.5 mmol/L) would have prevented >21% of events. Aspirin use before enrollment was reported in only 38% of subjects with a statin indication. In conclusion, these observations represent missed opportunities for primary and secondary prevention and highlight the need for assessment of patient risk and better adherence to existing prevention guidelines.     

Gap between guidelines and practice: attainment of treatment targets in patients with primary hypercholesterolemia starting statin therapy. Results of the 4E-Registry (Efficacy Calculation and Measurement of Cardiovascular and Cerebrovascular Events Including Physicians' Experience and Evaluation).

BACKGROUND: The aim of this study was to determine the achievement of National Cholesterol Education Program Adult Treatment Panel III goals in patients with primary hypercholesterolemia starting statin therapy in clinical practice. METHODS AND RESULTS: Data were collected by 4401 physicians in private practice on 52 848 patients aged 35-65 years (46.3% women, 53.7% men). 56.1% of patients had no manifested atherosclerosis (primary prevention) among whom 34.9% of men and 0.5% of women had a 10-year coronary heart disease risk over 20% (high-risk) as calculated using the Prospective Cardiovascular Münster study (PROCAM) algorithm. After 6 weeks of statins, only 6.9% of these high-risk men and 4.6% of these high-risk women reached their low-density lipoprotein (LDL) cholesterol target of 2.6 mmol/l or below (100 mg/dl). Even after 9 months, only 8.0% of these men and 6.2% of these women achieved their LDL target. No fewer than 57.3% of treated women had a coronary risk below 10%, and 18.8% of women were already at target before statins were prescribed. Of patients 43.9% had manifest atherosclerosis (secondary prevention). After 6 weeks of therapy, only 12.9% of the women and 16.3% of the men in this secondary prevention group reached LDL target levels of 2.6 mmol/l or below. Even after 9 months, only 21.3% of men and 17.3% of women with manifest atherosclerosis reached target LDL. CONCLUSIONS: Most high-risk patients do not achieve LDL targets. Overtreatment of low-risk groups is also very common.     

The importance of lipid evaluation and management in the prevention and treatment of acute myocardial infarction

There is an obvious need to measure low-density lipoprotein cholesterol in all patients with acute myocardial infarction and coronary artery disease. The recent guidelines of the National Cholesterol Education Program have established the desired level for low-density lipoprotein cholesterol for such patients at <100 mg/dL. However, several studies have demonstrated a lack of low-density lipoprotein cholesterol measurement and lipid-lowering therapy with statins in patients with acute myocardial infarction and coronary artery disease. These findings point to a need for quality of care improvement efforts to foster both lipid measurement and statin use in such patients. Many studies have demonstrated the numerous beneficial effects of statin use. In addition to lipid lowering, these include plaque stability and antiplatelet, antimacrophage, and antiatherothrombotic activities as well as enhanced endothelial activity. As a class of drugs, the statins have been shown to offer significant benefits with little in the way of associated risks.     

Diabetic dyslipidaemia: effective management reduces cardiovascular risk

Patients with diabetes are at significantly increased risk for coronary heart disease (CHD); even those patients without a history of a previous myocardial infarction (MI) have as high a risk of a fatal or nonfatal MI as nondiabetic patients with a history of previous MI. As a result it is now generally recommended that cardiovascular risk factors be treated as aggressively in patients with diabetes as in nondiabetic patients with a history of CHD. Results from the recently published Collaborative Atorvastatin Diabetes Study (CARDS) and meta-analysis of primary and secondary interventions trials confirm that there is a uniform relative risk reduction across a wide range of high-risk patients including diabetes patients without established CHD. A highly significant 22-24% reduction in risk of future vascular events is evident when patients with diabetes are treated with statins in trials. Current guidelines, including the recently updated National Cholesterol Education Program (NCEP) guidelines, endorse aggressive, early intervention in very-high-risk patients, such as those with diabetes plus cardiovascular disease (CVD), regardless of baseline low-density lipoprotein cholesterol (LDL-C) level in order to achieve an LDL-C goal of 70 mg/dL (1.8 mmol/L). However, despite increasing evidence and knowledge of the value of lipid lowering, a recent survey of diabetes specialists indicates that many patients with diabetes remain untreated or undertreated. The availability of more effective statins should help to close this "action gap", in concert with other measures such as initiatives to improve patient compliance.     

Relative atherogenicity and predictive value of non-high-density lipoprotein cholesterol for coronary heart disease

Although low-density lipoprotein cholesterol (LDL-C) is a well-established atherogenic factor for coronary heart disease, it does not completely represent the risk associated with atherogenic lipoproteins in the presence of high triglyceride (TG) levels. Constituent lipoproteins constituting non-high-density lipoprotein cholesterol (non-HDL-C) include atherogenic TG-rich lipoproteins, cholesteryl ester-enriched remnants of TG-rich lipoproteins, and lipoprotein(a). Recent observational and intervention studies suggest that the predictive value of non-HDL-C for cardiovascular risk and mortality is better than low-density lipoprotein cholesterol and that non-HDL-C correlates highly with plasma apolipoprotein B levels. Currently, the National Cholesterol Education Program Adult Treatment Panel III guidelines identify non-HDL-C as a secondary target of therapy in patients with TG elevation (> or =200 mg/dl) after the attainment of LDL-C target goals. In patients with coronary heart disease or coronary heart disease risk equivalents, an optional non-HDL-C goal is <100 mg/dl. To achieve the non-HDL-C goal, statin therapy may be intensified or combined with ezetimibe, niacin, a fibrate, or omega-3 fatty acids. In conclusion, non-HDL-C remains an important target of therapy for patients with elevated TGs, although its widespread adoption has yet to gain a foothold among health care professionals treating patients with dyslipidemia.     

The relative influence of secondary versus primary prevention using the National Cholesterol Education Program Adult Treatment Panel II guidelines.

OBJECTIVES: This study was undertaken to project the population-wide effect of full implementation of the Adult Treatment Panel (ATP) II guidelines of the National Cholesterol Education Program (NCEP). BACKGROUND: The ATP II has proposed guidelines for cholesterol reduction, but the long-term epidemiologic influence of its components has not been fully examined. METHODS: We used a calibrated, validated simulation of the U.S. population, aged 35 to 84 years to estimate the potential for the NCEP guidelines, under varying assumptions, to reduce coronary heart disease morbidity and mortality and overall mortality from the years 2000 to 2020. RESULTS: Primary prevention would yield only about half of the benefits of secondary prevention despite requiring nearly twice as many person-years of treatment. The projected increase in quality-adjusted years of life per year of treatment for secondary prevention was 3- to 12-fold higher than for primary prevention. To yield population-wide epidemiologic benefits equivalent to NCEP recommendations for secondary prevention, primary prevention would require a nearly sixfold increase in the number of persons treated compared with NCEP recommendations. All benefits of universal success of the NCEP primary prevention "screen and treat" guidelines could be achieved by a 11 mg/dl (8%) population-wide reduction in low-density lipoprotein cholesterol levels among persons without preexisting coronary heart disease. CONCLUSIONS: The NCEP guidelines for targeted primary prevention can be a useful component of a rational public health strategy, but only as a complement to the more appealing strategies of secondary prevention and "across-the-board" programs to lower all cholesterol levels.     

Statin therapy in heart failure: prognostic effects and potential mechanisms

The use of statins as therapy for heart failure remains controversial. Nevertheless, many of the pleiotropic effects of statins are potentially applicable in heart failure. Although early statin trials excluded patients with heart failure because of concerns that lowering serum cholesterol could worsen an already poor prognosis, statin treatment has not been shown to have adverse effects on either cardiovascular events or mortality, and recent experimental and clinical studies have shown promise of benefit. Two large, ongoing trials should provide definitive evidence of the value of statin therapy for patients with heart failure. Pending those results, it is reasonable to follow current National Cholesterol Education Program guidelines in this high-risk population.     

Evaluation and management of lipid disorders.

Plasma lipids play a key role in the development of atherosclerosis. Recent trial data support early identification of asymptomatic adults with high-risk lipid profiles for primary prevention of coronary heart disease. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors have been shown to reduce coronary events in both asymptomatic adults and those with known coronary heart disease. The optimal plasma low-density lipoprotein cholesterol for secondary coronary prevention remains controversial. The Second Report of the Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II), published in 1993 by the National Cholesterol Education Program, recommends guidelines for evaluation and diagnosis of lipids. Subsequently, several clinical trials have identified populations benefiting from pharmacologic intervention and new approaches to the management of lipid disorders. Consequently, these guidelines should be applied with the interval evidence in mind.     

Design and rationale of the ARBITER trial (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol)--a randomized trial comparing the effects of atorvastatin and pravastatin on carotid artery intima-media thickness

BACKGROUND: As a class, statins are remarkably effective in reducing low-density lipoprotein (LDL) cholesterol, and several of these drugs have now been shown to reduce coronary heart disease morbidity and mortality. However, several important controversies in the use of statins remain to be answered by clinical trials. For example, it is controversial whether marked cholesterol reduction to levels below 100 mg/dL would further reduce the incidence of coronary heart disease. Furthermore, concerns about differences among statins for nonlipid effects has raised the concern that the assumption of a class effect is premature until head-to-head clinical trials are completed. METHODS: Arterial Biology for the Investigation for the Treatment Effects of Reducing Cholesterol (ARBITER) is a single-center, randomized, active-controlled study comparing the efficacy of high-dose atorvastatin (80 mg/d) and pravastatin (40 mg/d) in patients being treated for either the primary or secondary prevention of coronary heart disease. This trial will enroll up to 200 patients for the primary end point of the mean change in intima-media thickness of the common carotid artery. This effect will be evaluated over a treatment duration of 12 months. Secondary end points include the effects of statin therapy on inflammatory and hemostatic markers (C-reactive protein and fibrinogen). CONCLUSION: ARBITER will provide important data on the role of marked LDL reduction and the "class effect" theory of statin therapy in cardiovascular medicine.     

Low-density lipoprotein reduction: Is the risk worth the benefit?

Outcomes from recent lipid-lowering trials have led to an update of the third Report of the National Cholesterol Education Program (NCEP) Adult Treatment Panel’s guidelines for treatment of hypercholesterolemia in adults. The updated NCEP guidelines now offer an optional goal of low-density lipoprotein (LDL) cholesterol of less than 70 mg/dL for high-risk individuals. Epidemiologic and clinical trial data suggest that for every 30-mg/dL change in LDL, the relative risk for coronary heart disease changes by about 30%. Statin therapy effectively lowers LDL and has an overall excellent safety profile in clinical trials. However, the use of high-dose statin therapy also entails greater risk of adverse events, such as myopathy and liver function test abnormalities, and this must be carefully weighed against the potential benefit for each patient. Alternative approaches targeting high-density lipoproteins and triglycerides may offer yet another option for coronary heart disease prevention in high-risk patients.     

The role of lipid-lowering therapy in preventing coronary heart disease in patients with type 2 diabetes

Coronary heart disease is the most common cause of death among diabetic patients. The increased risk of coronary heart disease in type 2 diabetes is due, in part, to lipid abnormalities often present in the diabetic patient. Diabetic dyslipidemia is characterized by elevated triglycerides, low high-density lipoprotein cholesterol (HDL-C) and an increased preponderance of small, dense low-density lipoprotein cholesterol (LDL-C) particles. Current guidelines for the prevention of coronary heart disease in diabetic patients identify elevated LDL-C as the primary target of lipid-lowering therapy, and recommend statins as the first-line treatment for diabetic dyslipidemia. This review evaluates the large statin trials that have included diabetic patients, and discusses the role of combination therapy in managing dyslipidemia in diabetic patients.