'Trig-onometry': non-high-density lipoprotein cholesterol as a therapeutic target in dyslipidaemia.

Targeting elevations in low-density lipoprotein cholesterol (LDL-C) remains the cornerstone of cardiovascular prevention. However, this fraction does not adequately capture elevated triglyceride-rich lipoproteins (TRLs; e.g. intermediate-density lipoprotein, very low density lipoprotein) in certain patients with metabolic syndrome or diabetic dyslipidaemia. Many such individuals have residual cardiovascular risk that might be lipid/lipoprotein related despite therapy with first-line agents (statins). Epidemiological evidence encompassing > 100,000 persons supports the contention that non-high-density lipoprotein cholesterol (non-HDL-C) is a superior risk factor vs. LDL-C for incident coronary heart disease (CHD) in certain patient populations. In studies with clinical end-points evaluated in the current article, a 1:1 to 1:3 relationship was observed between reductions in non-HDL-C and in the relative risk of CHD after long-term treatment with statins, niacin (nicotinic acid) and fibric-acid derivatives (fibrates); this relationship increased to 1:5 to 1:10 in smaller subgroups of patients with elevated triglycerides and low HDL-C levels. Treatment with statin-, niacin-, fibrate-, ezetimibe-, and omega 3 fatty acid-containing regimens reduced non-HDL-C by approximately 9-65%. In a range of clinical trials, long-term treatment with these agents also significantly decreased the incidence of clinical/angiographic/imaging efficacy outcome variables. For patients with dyslipidaemia, consensus guidelines have established non-HDL-C treatment targets 30 mg/dl higher than LDL-C goals. Ongoing prospective randomised controlled trials should help to resolve controversies concerning (i) the clinical utility of targeting non-HDL-C in patients with dyslipidaemia; (ii) the most efficacious and well-tolerated therapies to reduce non-HDL-C (e.g. combination regimens); and (iii) associations between such reductions and clinical, angiographic, and/or imaging end-points.

Characteristics of US adults with the metabolic syndrome and therapeutic implications.

BACKGROUND: The third Adult Treatment Panel (ATP III) of the National Cholesterol Education Program defines clinical criteria for diagnosis of the metabolic syndrome, which increases cardiovascular risk and is a target for therapy. AIM: We analysed the third National Health and Nutrition Examination Survey (NHANES III; 1988-94) to determine how many US adults meet these criteria and are recommended for lipid-modifying drug therapy by ATP III. METHODS: NHANES III data were used to estimate the number of individuals with the metabolic syndrome and the number recommended for treatment by ATP III, based on 1990 census data. RESULTS: An estimated 36.3 million (23%) US adults have the metabolic syndrome. Of these, 84% met the criterion for obesity, 76% for blood pressure, 75% for HDL-C, 74% for triglycerides and 41% for glucose. Most (54%) are in the higher risk categories of ATP III, yet only 39% overall are recommended for drug therapy by ATP III cutpoints; of these, most will achieve LDL-C targets with reductions of 35-40%. Of the 15.3 million individuals with the metabolic syndrome and triglycerides > or = 2.26 mmol/l (200 mg/dl), non-HDL-C is above ATP III recommendations in 11.6 million. CONCLUSIONS: Of the large number of Americans with the metabolic syndrome, ATP III recommends drug therapy for only a minority, because LDL-C typically is not substantially elevated. Instead, high triglycerides and low HDL-C are more common; clinical trial data are needed to determine whether optimal therapy should focus on reductions in LDL-C or on comprehensive improvements to the lipid profile.

The fats of life: the role of omega-3 fatty acids in the prevention of coronary heart disease.

Epidemiological and clinical trial evidence suggests that omega-3 polyunsaturated fatty acids (PUFAs) might have a significant role in the prevention of coronary heart disease. Dietary sources of omega-3 PUFA include fish oils rich in eicosapentaenoic acid and docosahexaenoic acid along with plants rich in alpha-linolenic acid. Randomized clinical trials with fish oils (eicosapentaenoic acid and docosahexaenoic acid) and alpha-linolenic acid have demonstrated reductions in risk that compare favorably with those seen in landmark secondary prevention trials with lipid-lowering drugs. Several mechanisms explaining the cardioprotective effect of omega-3 PUFAs have been suggested, including antiarrhythmic, hypolipidemic, and antithrombotic roles. Although official US guidelines for the dietary intake of omega-3 PUFAs are not available, several international guidelines have been published. Fish is an important source of omega-3 PUFAs in the US diet; however, vegetable sources, including grains and oils, offer an alternative source for those who are unable to regularly consume fish.

Combination lipid-altering therapy: an emerging treatment paradigm for the 21st century.

For the care of an expanding segment of the US population with multiple coronary risk factors, combination lipid-altering therapy is emerging as a treatment imperative. The most recent National Cholesterol Education Program's consensus guidelines emphasize long-term global coronary heart disease (CHD) risk status, designate patients with CHD risk equivalents (eg, diabetes, peripheral arterial disease, 20% or more 10-year absolute CHD risk) for aggressive lipid-altering therapy, and deem the metabolic syndrome (eg, obesity, insulin resistance, hypertension, elevated triglycerides, low levels of high-density lipoprotein cholesterol, small dense low-density lipoprotein particles) as a secondary target for intervention. With the advancing age of the US population and the high prevalence of diabetes, the metabolic syndrome, and CHD, increasing numbers of patients will require a more balanced metabolic attack attainable only through combination lipid-altering regimens. Many of these patients, as well as persons at heightened risk for cardiovascular disease because of a range of heritable conditions (eg, familial hypercholesterolemia, familial combined hyperlipidemia), will undoubtedly require binary or ternary regimens involving statins in concert with niacin, fibric-acid derivatives, or bile acid resins. Such approaches enable the clinician to exploit the complementary effects of these agents, allowing them to be administered at low, optimally tolerable doses that are consistent with superior efficacy and a lower risk of adverse events as compared with escalating doses of monotherapy.

Clinical context: current concepts of coronary heart disease management.

Coronary heart disease (CHD) is the single greatest cause of death among adults in the United States. It is also a major cause of disability and is associated with direct and indirect costs that exceed $118 billion annually. Elevation of serum lipid levels, particularly low-density lipoprotein cholesterol (LDL-C) levels, is closely linked to the development of CHD. Lipid levels that increase the risk of CHD are present in nearly one third of the US population. Large-scale intervention studies have shown that decreasing LDL-C can significantly reduce the risk of cardiovascular mortality, adverse cardiovascular events, and the requirement for revascularization procedures. Statins are now thought the most effective agents for lowering LDL-C, and they also have positive effects on other components of the serum lipid profile. These drugs are also better tolerated than other lipid-lowering agents. Statin therapy significantly decreases the risk of cardiovascular disease and is a cost-effective cardiovascular treatment according to current standards. Because statins vary substantially in acquisition cost, using statins in the most cost-effective manner is important for controlling health-care costs. Optimizing the cost-effectiveness of statin therapy is a particular concern to managed care organizations in light of the large number of patients who are now considered candidates for this treatment.

"The lower the better" in hypercholesterolemia therapy: a reliable clinical guideline?.

Since the publication of the second set of guidelines by the National Cholesterol Education Program, a solid body of data from landmark clinical studies has demonstrated that reduction in low-density lipoprotein (LDL) cholesterol with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor ("statin") therapy sharply diminishes the risk for coronary artery disease. These trials include the Scandinavian Simvastatin Survival Study, the West of Scotland Coronary Prevention Study, the Air Force/Texas Coronary Atherosclerosis Prevention Study, the Cholesterol and Recurrent Events investigation, and the Long-Term Intervention with Pravastatin in Ischaemic Disease trial. Coronary event rates and, in some cases, all-cause mortality decreased significantly after about 5 years of statin therapy in patients at risk for and those who had coronary artery disease at baseline. In contrast, recent subgroup analyses of these pivotal studies have in the aggregate challenged the premise that lower LDL cholesterol levels necessarily lead to further declines in risk for coronary artery disease, particularly among the patients most likely to be seen by the clinician: those with moderately elevated or normal cholesterol profiles. Indeed, when LDL cholesterol levels are in this range, further lowering with statin therapy elicits diminishing returns in terms of coronary event rates. These findings are readily accommodated by the curvilinear, or log-linear, model between serum cholesterol level and risk for coronary artery disease, which is predicated on data from large epidemiologic studies. In light of the current climate involving competing health care costs, the pursuit of progressively diminishing returns in terms of reductions in coronary artery disease risk through more aggressive lowering of LDL cholesterol levels appears to be unwarranted. Until data are published from ongoing randomized, clinical trials that can more effectively resolve the clinical utility of aggressive lipid-lowering strategies to improve coronary event rates, a prudent, evidence-based strategy seems warranted.

Impact of evidence-based "clinical judgment" on the number of American adults requiring lipid-lowering therapy based on updated NHANES III data. National Health and Nutrition Examination Survey.

BACKGROUND: When the National Cholesterol Education Program Adult Treatment Panel II (ATP II) guidelines were published, National Health and Nutrition Examination Survey III data for 1988 to 1991 were used to estimate the number of Americans requiring lipid-lowering therapy based on ATP II cut points. However, the guidelines recommend using clinical judgment to determine whether to initiate drug therapy in individuals whose low-density lipoprotein cholesterol levels remain above treatment goals with diet therapy but below the initiation level for drug therapy. METHODS: We analyzed updated (1988-1994) National Health and Nutrition Examination Survey III data, based on a sample of 6796 adults aged 20 years and older, to estimate the numbers of American adults with an elevated low-density lipoprotein cholesterol level and requiring drug therapy using cut points vs clinical judgment as specified in ATP II guidelines. RESULTS: Assuming a 10% low-density lipoprotein cholesterol reduction with diet, an estimated 10.4 million American adults require drug therapy based on ATP II cut points. If we include individuals for whom the guidelines recommend clinical judgment, the estimate increases to 28.4 million. The largest increase occurs in individuals without known coronary heart disease but with 2 or more risk factors: from 5.5 to 17.5 million. These high-risk individuals have low-density lipoprotein cholesterol concentrations similar to those in patients with coronary heart disease. CONCLUSIONS: Since the ATP II guidelines were published, clinical judgment has been informed by abundant clinical trial evidence establishing the safety and benefit of lipid-lowering therapy. The large number of individuals at high risk for coronary heart disease emphasizes the need for cost-effective therapy to extend treatment to the greatest number of individuals who may benefit.

Use of a low-literacy patient education tool to enhance pneumococcal vaccination rates. A randomized controlled trial.

CONTEXT: Pneumococcal immunization rates for elderly and high-risk patients are only one third to one half the target rate of 60% established by the US Public Health Service. Limited or marginal literacy, which affects nearly 100 million Americans, especially the elderly, may contribute to these low rates of immunization. OBJECTIVE: To determine whether the use of a simple, low-literacy educational tool enhances patient-physician dialogue about pneumococcal vaccination and increases rates of immunization. DESIGN: A randomized controlled trial conducted between May and June of 1998. SETTING: Ambulatory care clinic of a 900-bed public teaching hospital serving a predominantly indigent, low-literate, African American, inner-city population. PARTICIPANTS: Of 433 patients who presented for routine primary care, had vaccine indications (age > or =65 years or chronic disease), and had not been previously vaccinated, 221 were randomly assigned to the intervention group and 212 to the control group. Of the total patient population (mean age, 63 years), 280 (64.7%) had less than a high school education, 401 (92.6%) were African American, and 300 (69.3%) were female. INTERVENTION: One-page, low-literacy (below fifth-grade level) educational handout encouraging patients to "ask your doctor about the pneumonia shot" vs a control group (1 -page, low-literacy educational handout conveying information about nutrition). MAIN OUTCOME MEASURES: Vaccination rates (documented by chart audit) of patients who received pneumococcal vaccination and rates of patients who self-reported having discussed vaccination with their physicians. RESULTS: Patients in the intervention group were 4 times more likely to have discussed the pneumococcal vaccine with their physicians than patients in the control group (87/221 [39.4%] vs 21/212 [9.9%]; relative risk [RR], 3.97 [95% confidence interval [CI], 2.71-5.83]), and were more than 5 times as likely to have received the pneumococcal vaccine than the control group (44/221 [19.9%] vs 8/212 [3.8%]; RR, 5.28 [95% CI, 2.80-9.93]). In a multivariate analysis controlling for race, sex, education, insurance status, age, level of physician training, health status, and vaccine indication, only assignment to the intervention group was statistically significantly related to the probability of being immunized or discussing the issue with their physicians (P<.001 for both trends). CONCLUSIONS: A simple, low-literacy educational tool increased pneumococcal vaccination rates and patient-physician discussions about the vaccine in an elderly, low-literate, indigent, minority population.

New perspectives on the management of low levels of high-density lipoprotein cholesterol.

A low serum high-density lipoprotein cholesterol (HDL-C) level is a potent predictor of coronary heart disease (CHD). It has been estimated that 11% of US men have isolated low HDL-C levels, and there is uncertainty regarding the management of these patients. A cause-and-effect relationship between low HDL-C levels and CHD is supported by epidemiological, animal, and human clinical studies. We reviewed the structure and function of HDL-C and its role in preventing atherosclerosis. We then suggested an approach to the patient with isolated low HDL-C that may be useful to the primary care physician. An algorithm was proposed for use in patients with existing CHD, while the decision to treat patients without CHD was based on their score on the Framingham Heart Study risk prediction chart.

Maximizing the cost-effectiveness of lipid-lowering therapy.

Cardiovascular disease, including coronary heart disease, is the leading cause of death both in men and in women in the United States. The purpose of this review is to describe the effectiveness of lipid-lowering therapy in reducing cardiovascular morbidity and mortality, which has recently been extended to patients with mild to moderate hypercholesterolemia, and the cost of providing therapy, which would be prohibitive if all persons with hypercholesterolemia received treatment. Cost-effectiveness analysis provides a rational means of allocating limited health care resources by allowing the comparison of the costs of lipid-lowering therapy, in particular, therapy with beta-hydroxy-beta-methylglutaryl-CoA (coenzyme A) reductase inhibitors (statins), with the costs of atherosclerosis that could be prevented by lowering cholesterol. To extend the benefits of treatment to the large number of persons not receiving therapy, we need to implement more cost-effective treatment by improving risk assessment, increasing treatment effectiveness, and reducing the cost of therapy.

Improving health outcomes without increasing costs: maximizing the full potential of lipid reduction therapy in the primary and secondary prevention of coronary heart disease.

To more efficiently reduce the risk of coronary heart disease with lipid lowering therapy, cost effectiveness analysis offers an important tool to best determine how to allocate inherently limited resources to improve the health of both individuals and society. Formal economic analysis of the most recent clinical trials with the 3-hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) suggest that secondary prevention of coronary heart disease is very cost effective compared to existing treatment and prevention strategies. Primary prevention is also cost effective but has a much wider range of cost effectiveness depending on an individual baseline risk. Cost effectiveness can be better maximized in primary prevention by treating patients at the highest absolute risk of coronary heart disease. The debate about lipid lowering therapy will now shift from that of efficacy and safety, to that of cost and cost effectiveness. Defining the optimal treatment thresholds for intervention in primary prevention will become a major focus of investigation.

Use of postmenopausal hormone replacement therapy by African American women. The importance of physician discussion.

BACKGROUND: Although nationally the use of hormone replacement therapy (HRT) has increased dramatically in the last decade, little is known about its use by disadvantaged, minority women or the role that physician discussion plays in determining its use. METHODS: In 1994, we surveyed a total of 328 predominantly indigent, African American women (refusals, 22) who attended public hospital medical continuity of care clinics staffed by internal medicine house officers. RESULTS: Of the 328 women who completed the survey, the mean age was 63 years, 302 women (92%) were African American, and 286 (87.3%) had yearly incomes of less than $10000. Of the 328 women, 52 (15.6%) were receiving HRT at the time of the survey, varying from 22 (28.2%) of 78 women aged 50 to 59 years to 1 (3%) of 33 women older than 80 years (P = .006). In a logistic regression model adjusting for age and ethnicity, women who had previously undergone a hysterectomy were significantly more likely to use HRT, with an odds ratio of 2.76 (95% confidence interval, 1.44-5.30; P = .002). The levels of education and income and the history of myocardial infarction were not significantly associated with the use of HRT (P > .20). Although all women who were currently receiving HRT recalled discussing HRT with their physicians, of the 276 women who were not receiving HRT, only 62 (22%) recalled any such discussion (P < .001). CONCLUSIONS: In poor, African American women who reside in the inner city, younger age, undergoing a hysterectomy, and physician discussion of HRT are significantly associated with current use of HRT. Physician discussion of HRT may need greater emphasis in internal medicine training programs.

Cost-effectiveness of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor therapy in the managed care era.

More than $100 billion is spent in the United States each year on cardiovascular disease, primarily for hospitalizations and revascularization procedures. This is more than for any other disease state. As the clinical practice of medicine shifts from the paradigm of private practice to the managed care environment, cost-effectiveness is becoming increasingly important. A primary measure in analyzing cost-effectiveness is the cost-effectiveness ratio, or the dollar cost per unit of improvement for a given expenditure. This measure allows healthcare planners to compare completely different interventions. With approximately 52 million adult U.S. citizens having elevated low-density lipoprotein (LDL) cholesterol levels, lipid-lowering therapy---with diet or 3-hydroxy-3methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors---is an important consideration for primary care physicians and managed care providers. The National Health and Nutrition Examination Survey (NHANES) III indicates that 75-88% of adults who have coronary artery disease (CAD) risk factors or CAD require only a moderate (20--30%) reduction in LDL cholesterol levels to reach National Cholesterol Education Program goals. The clinical literature shows that all 4 of the currently available HMG-CoA reductase inhibitors can provide appropriate, moderate LDL cholesterol reductions within their recommended dosage ranges. For the majority of patients who need a 20--30% reduction in LDL cholesterol, fluvastatin 20 or 40 mg once daily provides the most cost-effective HMG-CoA therapy, expressed as cost of therapy per 1% LDL cholesterol reduction. For patients who need a >30% LDL cholesterol reduction, a high-dose HMG-CoA reductase inhibitor (e.g., simvastatin 20 or 40 mg/day) or a combination of a lower-dose HMG-CoA reductase inhibitor and a bile acid resin is the preferred initial therapy. Although a true cost-effectiveness analysis would incorporate morbidity and mortality data from clinical trials, analysis using intermediate endpoints, such as LDL cholesterol reduction, suggests that fluvastatin is the preferred initial HMG-CoA reductase inhibitor for the treatment of moderate hyperlipidemia.

Breast and cervical cancer screening in an inner-city medical walk-in clinic: taking advantage of an often missed opportunity.

BACKGROUND: Despite established evidence that screening for breast and cervical cancer reduces mortality in women, screening is underutilized, especially in poor, minority women. We hypothesized that a high percentage of women presenting for care to an inner-city medical walk-in clinic would report inadequate screening for breast and cervical cancer by current standards, accept same-day screening, and comply with recommended follow-up. METHODS: To determine how many women presenting to our medical Walk-In Clinic were inadequately screened for breast and cervical cancer and how many were willing to undergo same-day screening, we surveyed all women at this site over a three month period. We then implemented a one-year, same-day screening program and contacted patients with abnormal screening results by letter or phone to encourage follow up. We tracked patients to assess compliance with follow-up. RESULTS: Of the 2,363 women in the initial survey, 1,230 (52%) reported inadequate screening, of whom 55% reported interest in same-day screening. Over the one year screening period, we screened 403 women for breast and/or cervical cancer. Of the 48 women with abnormal Pap tests, compliance with initial Gynecology Clinic follow-up was 56%. Compliance was 49% with mammography appointments, and 77% for follow-up to Breast Clinic for clinical and/or mammographic abnormalities. These compliance rates compare favorably to those for screening performed in more traditional settings. CONCLUSION: Our results support the establishment of cancer screening programs in nontraditional settings such as walk-in clinics and emergency departments to target patients who are at high risk for remaining unscreened.

Changes in plasma cholesterol levels after hospitalization for acute coronary events.

UNLABELLED: To retrospectively assess the changes in total cholesterol levels after a hospital admission for an acute coronary event, 287 patients were identified who had one isolated event: 130 patients with acute myocardial infarction, 122 patients after coronary artery bypass graft surgery, 35 patients after percutaneous transluminal coronary angioplasty. To be included, patients had to have a total cholesterol measurement within the 3 months prior to hospitalization and periodically after the acute coronary event. Total cholesterol measurements were recorded during four time periods: 0-3 months before hospital admission (baseline); and 0-3, 3-6, and 6-9 months after the hospitalization. Mean total cholesterol value was used if a patient had multiple measurements during a time period. RESULTS: There was no significant difference in the baseline total cholesterol levels among the three groups (acute myocardial infarction, coronary artery bypass graft surgery and percutaneous transluminal coronary angioplasty). In all three groups, there was a decrease in total cholesterol level after hospital admission compared to baseline (p < 0.0001). This decrease was significantly greater in coronary artery bypass graft surgery patients compared to the other two groups. Total cholesterol levels returned to baseline levels by 3 months after the hospitalization in all three groups. Total cholesterol decreased significantly from baseline in patients after an acute myocardial infarction; this decrease was significantly greater if they received thrombolytic therapy (p < 0.05). Total cholesterol returned to baseline 3 months after hospitalization in both groups. CONCLUSIONS: During the 3 months following hospital admission for an acute coronary event, total cholesterol levels are not representative of the patient's baseline values. Management of hypercholesterolemia in this setting requires the use of baseline (preadmission) total cholesterol values.

Efficacy and safety of pravastatin in African Americans with primary hypercholesterolemia.

BACKGROUND: Coronary artery disease strikes early and may prove particularly severe in persons of African-American descent. Therefore, we studied the lipid-lowering efficacy and safety of pravastatin sodium (20 mg/d), a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, in 245 African-American patients with primary hypercholesterolemia. METHODS: After 4 weeks on an American Heart Association phase I low-fat diet, patients were randomized in a double-blind manner to either pravastatin or placebo in a 3:1 ratio. RESULTS: After 12 weeks of pravastatin treatment, low-density lipoprotein cholesterol levels declined 25.8%, total cholesterol levels 20.3%, and triglyceride levels 6.2%, while high-density lipoprotein cholesterol levels remained essentially unchanged. Overall, 72% of pravastatin-treated patients achieved reductions in low-density lipoprotein cholesterol level in excess of 20%, and 44% attained declines in excess of 30% (both P < .01 vs placebo). Pravastatin was generally well tolerated in this population, with one patient (0.5%) exhibiting a reversible myopathy with creatine kinase elevations to 10 times the upper limit of normal. No substantial elevations of aminotransferase levels of two to three times the upper limit of normal occurred in either the pravastatin or the placebo group. Drug compliance was high, exceeding 90%. CONCLUSION: Pravastatin appears to be an effective and safe lipid-lowering agent and is the first 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor to be studied extensively in this underrepresented population.