Coronary heart disease prevention in women: focus on lipids.

Coronary heart disease (CHD) remains an urgent and leading threat to women's health and well-being. Clinical trials have demonstrated a clear cut benefit of low density lipoprotein cholesterol (LDL-C) lowering in both women as well as men with coronary disease. While the case for primary prevention of CHD with LDL-C lowering is less secure in both men and women, there is little doubt that patients at high risk of CHD, even without a prior history of vascular events, will in the long run benefit from LDL-C lowering. Thus, all available evidence indicates that lipid interventions should be pursued aggressively in both women and men at risk of CHD.

Prevention and treatment of coronary heart disease: who benefits?

Coronary heart disease (CHD) remains a leading cause of morbidity and mortality in the United States, despite our better understanding of the pathobiology of atherosclerosis, our knowledge of risk factors, the widespread availability of inexpensive cholesterol screening, and the availability of effective and well-tolerated cholesterol-lowering agents. Advances in these areas have created controversies regarding who should be screened and treated for primary or secondary prevention of coronary events. The advent of the statin class of lipid-lowering agents represented a major advance, because they are much more effective and better tolerated than previous agents. There is general agreement that patients with hypercholesterolemia and established CHD require treatment for secondary prevention of recurrent coronary events. Primary prevention is controversial in all patient groups except those with diabetes, because their risk of developing CHD is dramatically increased. Postmenopausal women and the elderly are undertreated, whereas young adults may be underdiagnosed and undertreated. Several ongoing trials may resolve the controversies about which patient groups will benefit from different prevention and treatment strategies.

Enhancing drug compliance in lipid-lowering treatment.

Hyperlipidemia and the atherosclerotic conditions that result from it are well recognized as major contributors to coronary heart disease (CHD). Fortunately, several large-scale clinical trials have shown that there are effective treatments that can substantially lower atherogenic lipid levels and thereby reduce the risk of CHD mortality and morbidity. However, duplication of these dramatic trial results can be negatively affected in "real life" clinical practice by an important issue: compliance. No medications will work if patients do not take them. Unfortunately, patients who need lipid-lowering therapy are likely to need it long-term, perhaps for a lifetime. Yet, many do not adhere to the prescribed medication regimen. This article reviews some major studies of compliance for lipid-lowering drugs. The reasons why patients do not take them as prescribed vary: poor education, lack of understanding, cost, provider indifference, and others. Achieving compliance requires a multifaceted approach. It can be enhanced by encouraging patients to talk openly about their medication habits and by convincing them of the long-term benefits of reaching and maintaining target low-density lipoprotein cholesterol levels. Although more studies focusing on compliance specifically regarding CHD are needed, the current literature does provide some guidance. Arch Fam Med. 2000;9:1169-1175

Effect of statins on risk of coronary disease: a meta-analysis of randomized controlled trials.

CONTEXT: Lowering low-density lipoprotein cholesterol (LDL-C) is known to reduce risk of recurrent coronary heart disease in middle-aged men. However, this effect has been uncertain in elderly people and women. OBJECTIVE: To estimate the risk reduction of coronary heart disease and total mortality associated with statin drug treatment, particularly in elderly individuals and women. DATA SOURCES: Trials published in English-language journals were retrieved by searching MEDLINE (1966-December 1998), bibliographies, and authors' reference files. STUDY SELECTION: Studies in which participants were randomized to statin or control treatment for at least 4 years and clinical disease or death was the primary outcome were included in the meta-analysis (5 of 182 initially identified). DATA EXTRACTION: Information on sample size, study drug duration, type and dosage of statin drug, participant characteristics at baseline, reduction in lipids during intervention, and outcomes was abstracted independently by 2 authors (J.H. and S.V.) using a standardized protocol. Disagreements were resolved by consensus. DATA SYNTHESIS: Data from the 5 trials, with 30 817 participants, were included in this meta-analysis. The mean duration of treatment was 5.4 years. Stati n drug treatment was associated with a20% reduction in total cholesterol, 28% reduction in LDL-C, 13% reduction in triglycerides, and 5% increase in high-density lipoprotein cholesterol. Overall, statin drug treatment reduced risk 31 % in major coronary events (95% confidence interval [CI], 26%-36%) and 21 % in all-cause mortality (95% CI, 14%-28%). The risk reduction in major coronary events was similar between women (29%; 95% Cl, 13 %-42 %) and men (31 %; 95% CI, 26%-35%), and between persons aged at least 65 years (32%; 95% CI, 23%-39%) and persons younger than 65 years (31 %; 95% CI, 24%-36%). CONCLUSIONS: Our meta-analysis indicates that reduction in LDL-C associated with statin drug treatment decreases the risk of coronary heart disease and all-cause mortality. The risk reduction was similar for men and women and for elderly and middle-aged persons.

Future cardiovascular end point studies: where will the research take us?

Coronary artery disease is the most common cause of death in the world. Emerging concepts of atherosclerosis imply that atherosclerosis is a diffuse disease, and cannot be definitively treated with local, anatomic interventions, such as coronary artery bypass graft surgery or angioplasty. Cholesterol lowering, on the other hand, has been shown to dramatically lower the rate of both morbid and mortal coronary events. In trials with new statin drugs, coronary risk has been lowered by approximately 30%. Additional risk reduction will require other approaches, including (1) intervention for other risk factors, (2) more aggressive cholesterol lowering, or (3) increased attention to primary prevention. The last requires a combination of public health measures to change harmful diet and life-style patterns as well as case findings to identify and treat at-risk subjects. For all these approaches, measures that will increase compliance by both physicians and patients to regimens with proven benefits are required.

Academic medicine and managed care: seeking common ground.

The authors report the highlights of a one-day symposium, "Academic Medicine and Managed Care: Seeking Common Ground," sponsored in early 1997 by Tulane University Medical Center. The meeting was held to foster better understanding of the gap between managed care organizations (MCOs) and academic health centers (AHCs) and to define their common ground. There were 62 participants, mainly executives froin AHCs and MCOs, plus government officials and policy researchers interested in the interface of academic medicine and managed care. The participants agreed that there are indeed some common areas in which the two types of organizations can develop programs and interests that serve the missions of both. These include (1) a commitment to high-quality health care, objectively measured by outcomes; (2) issues of "customer service"; (3) certain areas of research (e.g., examining outcomes of medical interventions; measuring cost and cost-effectiveness; measuring quality of care); and (4) preventive medicine, an area in which both AHCs and MCOs are still relatively weak. On the other hand, large elements of AHCs' basic missions of education and research are not seen by MCOs as areas for developing a common agenda. Participants agreed that AHCs must do their best to improve and demonstrate the quality of their care, address the challenges of the market (i.e., take "customer service" seriously), address the issue of how many specialists and how many generalists should be trained, and define the cost of each of their missions. On the other hand, managed care must acknowledge that the missions of AHCs greatly benefit patients and society. Participants agreed that all approaches to AHC-MCO interfaces must be flexible and local, that common ground does exist, and that understanding can grow between these two kinds of organizations if acrimonious exchanges are avoided and serious efforts are made to work together for solutions.

The role of diet and exercise in the statin era.

Coronary atherosclerosis begins to develop in late adolescence and early adulthood. If intervention in coronary risk factors is delayed until middle-age, it is likely that a considerable number of patients will be lost to irreversible disease. Even with the dramatic cholesterol lowering that can be induced by statin drugs, coronary events can be reduced by only 25% to 40%, leaving most at-risk patients unprotected. Diet, exercise, and other nonpharmacological interventions have a role in the age of statins, not only to augment the effects of these drugs in high-risk patients, but also, by preventing atherogenesis in the first place, to reduce the number of at-risk patients.

Women, dyslipoproteinemia, and estrogens.

The most common cause of death in both men and women is coronary atherosclerosis, although atherosclerotic death in women occurs 5 to 10 years later than it does in men. Major risk factors predict coronary risk in both. Available evidence suggests that women benefit from cholesterol lowering just as men do. The role of exogenous estrogenic compounds in favorably affecting lipoprotein levels and promoting antiatherogenesis in both men and women is a promising area for future research.

Cholesterol & atherosclerosis: a controversy resolved.

We should regard the so-called cholesterol "controversy" as resolved. Elevated cholesterol levels cause coronary disease and probably are an essential ingredient for the development of atherosclerosis. Elevated cholesterol levels should be a cause for concern. From a public health point of view, the ultimate treatment of atherosclerosis will depend on major changes in the lifestyles of populations in developed countries, including a shift to diets that are largely vegetarian, as well as the elimination of tobacco use, an increase in regular exercise, and a reduction in the propensity of to increase weight, particularly with age. For patients at high risk for coronary events, including those with other coronary risk factors and with clinically established coronary disease, cholesterol lowering is absolutely essential. In the majority of cases, it will require not only dietary change but also cholesterol-lowering medication. Taken together, these public health and medical measures can massively reduce, if not eliminate, the burden of atherosclerosis that currently plaques developed countries and now threatens the developing world.

Atherogenesis and its relationship to coronary risk factors.

A new model for the development of atherosclerosis is emerging (1,2). This development process, called atherogenesis, is now thought to begin with metabolic dysfunction of the endothelial cells that line the innermost portion of the arterial wall. Endothelial dysfunction precedes visible changes in endothelial structure. Dysfunctional endothelium loses its ability to maintain vascular smooth muscle relaxation and instead promotes vasospasm, chemotaxis and inflammation, platelet aggregation, and diminished clot lysis. Endothelial dysfunction appears to occur diffusely, rather than discretely, in affected vessels. Accordingly, local anatomical interventions, such as bypass surgery or angioplasty, can be expected to have only limited success in the treatment of patients with atherosclerotic disease. More definitive treatments must be directed at the risk factors initiating or enhancing atherogenesis. Such interventions are more likely to be medical than surgical or mechanical. With appropriate understanding of the underlying process of atherogenesis and its clinical manifestations, such medical interventions can be carried out within the boundaries of everyday practice.

Psyllium-enriched cereals lower blood total cholesterol and LDL cholesterol, but not HDL cholesterol, in hypercholesterolemic adults: results of a meta-analysis.

We conducted a meta-analysis to determine the effect of consumption of psyllium-enriched cereal products on blood total cholesterol (TC), LDL cholesterol (LDL-C) and HDL cholesterol (HDL-C) levels and to estimate the magnitude of the effect among 404 adults with mild to moderate hypercholesterolemia (TC of 5.17-7.8 mmol/L) who consumed a low fat diet. Studies of psyllium cereals were identified by a computerized search of MEDLINE and Current Contents and by contacting United States-based food companies involved in psyllium research. Published and unpublished studies were reviewed by one author and considered eligible for inclusion in the meta-analysis if they were conducted in humans, were randomized, controlled experiments, and included a control group that ate cereal providing /=50 y) on blood lipids. The meta-analysis showed that subjects who consumed a psyllium cereal had lower TC and LDL-C concentrations [differences of 0.31 mmol/L (5%) and 0.35 mmol/L (9%), respectively] than subjects who ate a control cereal; HDL-C concentrations were unaffected in subjects eating psyllium cereal. There was no effect of sex, age or menopausal status on blood lipids. Results indicate that consuming a psyllium-enriched cereal as part of a low fat diet improves the blood lipid profile of hypercholesterolemic adults over that which can be achieved with a low fat diet alone.

Triglycerides and coronary risk in women and the elderly.

There seems little doubt that triglycerides are causally related to the progress of atherogenesis. Mechanisms for this effect include adverse quantitative and qualitative changes in circulating lipoproteins. In particular, the effects of lower high-density lipoprotein levels and the production by hypertriglyceridemia of small, dense low-density lipoproteins are of great significance. The role of triglyceride-rich remnant particles in atherogenesis is likely important. These remnants, which are lipoproteins rich in both cholesterol and triglycerides, can be shown to produce cholesteryl ester-laden macrophages in vitro and are probably atherogenic in vivo. Triglyceride levels are a significant risk factor for coronary artery disease in women, more so than in men. Triglyceride levels also increase in older patients and continue to be predictors of coronary risk in both men and women older than 65 years. It is unclear whether triglyceride intervention efforts should be directed at lowering triglyceride levels (such as is accomplished with niacin or fibric acid derivatives) or lowering low-density lipoprotein levels in patients with high triglyceride levels, assuming triglyceride levels are only a passive marker of atherosclerotic risk. Until more is known about the precise role of hypertriglyceridemia in atherogenesis in women and older patients, use of triglyceride-lowering drugs should be conservative and limited to those individuals with high triglyceride levels (> 4.5 mmol/L [> 400 mg/dL]) who do not respond to diet modifications and who are at risk of coronary disease either because of a history of vascular disease or the presence of other risk factors.

Cholesterol management in women and the elderly.

Women, like men, die mostly of coronary atherosclerosis, although atherosclerotic death in women occurs 5-10 years later than in men. Major risk factors predict coronary risk in women and men. What evidence is available suggests that women, similar to men, benefit from cholesterol lowering. Older individuals with symptomatic coronary disease but a relatively good prognosis should be offered the same benefits from secondary prevention as younger individuals.

Estrogen replacement therapy and coagulation: relationship to lipid and lipoprotein changes.

OBJECTIVE: To examine the relationship of estrogen-induced changes in lipids and lipoproteins with alterations in the coagulation system. METHODS: Coagulation and lipid indices were measured in 31 postmenopausal women, ages 40-60 years, after a 3-month course of 0.625-mg conjugated equine estrogen. We analyzed changes in variables from baseline to 3 months using t tests for paired samples or the Wilcoxon matched-pairs signed-rank test. RESULTS: Unopposed estrogen replacement therapy produced statistically significant decreases in antithrombin-III antigen (P = .006) and activity (P = .001) and total protein S (P = .003) and a significant increase in protein C antigen (P = .017). C4b-binding protein also decreased significantly from baseline to 3 months (P < .001). Mean fibrinogen level decreased by 18.2 mg/dL, not a statistically significant change (P = .213). Estrogen produced the expected statistically significant changes in lipids and lipoproteins. Several correlations between changes in lipids and lipoproteins and coagulation indices were statistically significant. Protein C antigen and activity changes correlated directly with high-density lipoprotein cholesterol changes (r = .52, P < or = .005; r = .38, P < or = .05; respectively), and protein C antigen also correlated directly with increases in apoprotein A-I (r = .54, P < or = .005). Triglyceride changes correlated directly with changes in protein C antigen (r = .36, P < or = .05) and activity (r = .49, P < or = .005) and inversely with C4b-binding protein (r = -.58, P < or = .01). Apoprotein B was correlated with free protein S (r = .48, P < or = .01). CONCLUSIONS: Although several estrogen-induced changes may decrease atherosclerotic potential and hypercoagulability, others may promote coagulability. These divergent effects may be manipulated pharmacologically by other estrogen compounds or by the addition of various progestins.

The pharmacology and effectiveness of specific lipid-active drugs: estrogen/sex steroids.

Estrogen has favorable effects on lipid and lipoprotein coronary risk factors when given orally. These effects are less evident when estrogen is given in non-oral forms. The effects of progestins and androgens are generally opposed to those of estrogen, although their effects on lipoprotein (a) [Lp(a)] do not follow this general rule. Estrogen-progestin and androgens have been shown to reduce Lp(a), but Lp(a) reduction is less when conjugated estrogens and medroxyprogesterone are combined than when estrogen is used alone. Overall, the effects of estrogens (both alone and in combination with progestin) on lipid levels and other coronary risk factors, are beneficial. Whether these effects translate into beneficial effects on clinical coronary disease is a question that awaits the outcome of clinical trials in progress.