Hyperlipidemia in coronary heart disease. I. Lipid levels in 500 survivors of myocardial infarction.

Plasma cholesterol and triglyceride levels were measured after an overnight fast in 500 consecutively studied 3-mo survivors of myocardial infarction. Virtually all patients under 60 yr of age (95% ascertainment) and a randomly chosen group of older survivors admitted to 13 Seattle hospitals during an 11 mo period were included. A comparison of their lipid values with those of 950 controls demonstrated that 31% had hyperlipidemia. These lipid abnormalities were most commonly found in males under 40 yr of age (60% frequency) and in females under 50 yr of age (60% frequency). Elevation in triglyceride levels with (7.8%) or without (15.6%) an associated elevation in cholesterol levels was three times more common in survivors than a high cholesterol level alone (7.6%). These results raise the possibility that hypertriglyceridemia may be as an important a risk factor for coronary atherosclerosis as hypercholesterolemia. The identification of hyperlipidemic survivors of myocardial infarction provided a unique source of probands for family studies designed to disclose the genetic origin of hyperlipidemia in coronary heart disease.

Hyperlipidemia in coronary heart disease. II. Genetic analysis of lipid levels in 176 families and delineation of a new inherited disorder, combined hyperlipidemia.

To assess the genetics of hyperlipidemia in coronary heart disease, family studies were carried out in 2520 relatives and spouses of 176 survivors of myocardial infarction, including 149 hyperlipidemic and 27 normolipidemic individuals. The distribution of fasting plasma cholesterol and triglyceride values in relatives, together with segregation analyses, suggested the presence of five distinct lipid disorders. Three of these-familial hypercholesterolemia, familial hypertriglyceridemia, and familial combined hyperlipidemia-appeared to represent dominant expression of three different autosomal genes, occurring in about 20% of survivors below 60 yr of age and 7% of all older survivors. Two other disorders-polygenic hypercholesterolemia and sporadic hypertriglyceridemia-each affected about 6% of survivors in both age groups. The most common genetic form of hyperlipidemia identified in this study has hitherto been poorly defined and has been designated as familial combined hyperlipidemia. Affected family members characteristically had elevated levels of both cholesterol and triglyceride. However, increased cholesterol or increased triglyceride levels alone were also frequently observed. The combined disorder was shown to be genetically distinct from familial hypercholesterolemia and familial hypertriglyceridemia for the following reasons: (a) the distribution pattern of cholesterol and triglyceride levels in relatives of probands was unique; (b) children of individuals with combined hyperlipidemia did not express hypercholesterolemia in contrast to the finding of hypercholesterolemic children from families with familial hypercholesterolemia; and (c) analysis of informative matings suggested that the different lipid phenotypes owed their origin to variable expression of a single autosomal dominant gene and not to segregation of two separate genes, such as one elevating the level of cholesterol and the other elevating the level of triglyceride. Heterozygosity for one of the three lipid-elevating genes identified in this study may have a frequency in the general population of about 1%, constituting a major problem in early diagnosis and preventive therapy.

Primary care practice adherence to National Cholesterol Education Program guidelines for patients with coronary heart disease.

BACKGROUND: Clinical trials demonstrate significant benefit from cholesterol management for patients with cardiovascular disease (CVD). National guidelines recommending goals for screening and treatment were published in 1993 and widely disseminated. This study examines cholesterol screening and management by primary care physicians after the guidelines were released. METHODS: Medical records and patient surveys provided data for 603 patients with CVD, aged 27 to 70 years, from 45 practices in 4 states during 1993 to 1995. Physician surveys measured estimated performance and other variables. Physician and patient factors associated with adherence, or lack of adherence, to national guidelines were examined using univariate and multivariate analyses. RESULTS: A total of 199 patients (33%) with CVD were not screened with lipid panels, 271 patients (45%) were not receiving dietary counseling, and 404 (67%) were not receiving cholesterol medication. Only 84 patients (14%) with CVD had achieved the recommended low-density lipoprotein level of less than 2.58 mmol/L (100 mg/dL) and 302 (50%) had triglyceride levels lower than 2.26 mmol/L (200 mg/dL). Patients with a revascularization history and higher low-density lipoprotein and/or triglyceride levels were more likely to receive treatment, but other patient factors, including CVD risk factors, did not predict treatment. Physician specialty was not associated with differences in treatment, but physicians in practice for fewer years ordered more lipid panels. CONCLUSIONS: Most patients with CVD in primary care were not receiving cholesterol screening and management as recommended by the National Cholesterol Education Program guidelines in the 2 years after their release. Increasing cholesterol screening and treatment should be a priority for practice quality improvement and could result in significant reductions in CVD events for high-risk patients.

Factors associated with glucose and insulin levels in healthy postmenopausal women.

OBJECTIVE: Little is known about the covariates of hyperglycemia and hyperinsulinemia. We examined candidate factors in postmenopausal women. RESEARCH DESIGN AND METHODS: We determined the cross-sectional associations of sociodemographic, body-size, lifestyle, reproductive, and menopausal factors with pretrial fasting and postchallenge glucose and insulin levels in 869 postmenopausal women aged 45-65 years. Women were participants in the Postmenopausal Estrogen/Progestin Interventions study who were not taking estrogen or insulin. RESULTS: Plasma glucose levels increased significantly with age; serum insulin levels did not. BMI and waist-to-hip ratio (WHR) each showed graded positive and independent associations with glucose and insulin levels. Alcohol intake, cigarette smoking, physical activity, parity, education, and income were also associated with insulin or glucose in age-adjusted models. In multivariable models, BMI and WHR explained 18% of the variability in fasting glucose, 16% in postchallenge glucose, 28% in fasting insulin, and 17% in postchallenge insulin. Age and all other factors combined accounted for < 6% of the variance in glucose or insulin. In multiply adjusted models, African-American and Hispanic women had higher fasting and 2-h insulin levels than non-Hispanic white women. CONCLUSIONS: Most of the variance in glycemia and insulin is unexplained. Measures of obesity and fat distribution account for nearly all the explained variance.

Myotonic dystrophy: opportunities for prenatal prediction.

Prenatal prediction of the inheritance of myotonic dystrophy in a family with affected individuals feasible in special cases when analysis of linkage to the secretor gene (determing ABH substances) can be carried out. We report a large kindred having multiple members affected with variable degrees of severity of myotonic dystrophy and having several matings for which linkage analysis is feasible. Even though this approach is not applicable for most families and although the process of genetic recombination complicates the analysis, in individual cases the use of linkage in prenatal or postnatal prediction of myotonic dystrophy may be very helpful for early diagnosis, more precise genetic counseling, and family planning.

Efficacy and safety of pravastatin in patients with primary hypercholesterolemia. II. Once-daily versus twice-daily dosing.

This 8-week multicenter, placebo-controlled trial compared the efficacy and safety of the HMG-CoA reductase inhibitor, pravastatin, when administered either as single doses of 40 mg in the morning (AM) or evening (PM) or 20 mg twice daily (bid) in 196 diet-stabilized outpatients with primary type II hypercholesterolemia. Mean reductions in total and low-density lipoprotein (LDL) cholesterol concentrations were observed in all pravastatin groups after 1 week and were sustained throughout the study (P less than or equal to 0.001 versus baseline and placebo). At week 8, mean reductions from baseline in the pravastatin treatment groups were 23-27% for total cholesterol and 30-34% for LDL cholesterol. LDL cholesterol was reduced greater than or equal to 15% by pravastatin in all patients in the group treated with 40 mg PM and in 88 and 96% in those receiving 20 mg bid and 40 mg AM, respectively. High density lipoprotein cholesterol was elevated (up to 8%) and triglycerides were reduced (up to 25%) by all pravastatin regimens (P less than or equal to 0.05). Pravastatin was well tolerated and was associated with a low incidence of adverse events. No patient withdrew from the study due to a pravastatin-related adverse event. Once-daily pravastatin is a safe and effective treatment for patients with primary hypercholesterolemia and has a favorable safety profile.

Enhanced low-density lipoprotein cholesterol reduction and cost-effectiveness by low-dose colestipol plus lovastatin combination therapy.

A total of 96 patients with moderate elevations of low-density lipoprotein (LDL) cholesterol were randomly assigned to 4 different double-blind treatment regimens: placebo; colestipol 5 g and lovastatin 20 mg/day (C5 + L20); colestipol 10 g and lovastatin 20 mg/day (C10 + L20); and lovastatin 40 mg/day (L40). During 12 weeks of therapy, C10 + L20 achieved the greatest reduction in total cholesterol (-32%) and LDL cholesterol (-48%) levels from baseline. This combination also exhibited significantly greater reductions in LDL cholesterol levels than the C5 + L20 and L40 groups (p < 0.01). The differences in total and LDL cholesterol reduction between the C5 + L20 and L40 groups were not significant. Similar changes and differences between treatments were seen in apolipoprotein B levels. Whereas mean total apolipoprotein A-I levels increased with all treatments (p < 0.05), lipoprotein particles A-I were significantly increased in the C10 + L20 group (p < 0.01) only. Results demonstrate that the combination of low-dose lovastatin (20 mg/day) with low-dose colestipol (5 or 10 g/day) produces LDL cholesterol reductions equal to or greater than higher doses of lovastatin (40 mg/day). In addition, low-dose combinations are > 25% more cost-effective than high-dose monotherapy.

Study of the incidence of hypospadias in Rochester, Minnesota, 1940-1970, and a case-control comparison of possible etiologic factors.

PIP: A community-wide (Rochester, Minnesota), case-control study of the incidence severity, trends, and possible etiologic factors, both environmental and genetic, of hypospadias, between 1940-1970, is presented. Of 13,776 live male births, 113 cases 8.2/1000) of hypospadias were found. There was no significant variation in the rates by 5-year periods and no cyclic pattern noted. In 7 instances, 2 brothers were affected, and in 4 families, the father was also affected. There was no difference between index and control mothers with respect to drug usage. Hydroxyprogesterone caproate, i.m., had been given to 4 index mothers and 1 control mother, 3 index mothers had received thyroid therapy during the first trimester, 1 index mother and 4 control mothers had received meclizine, 4 control mothers had received estrogen, and 9 index mothers and 5 control mothers had taken oral contraceptives (combination) within 9 months of their last menstrual period. There was a larger proportion of testicular anomalies which might have adversely affected spermatogenesis and semen quality among index fathers than among control fathers. These data suggest a multifactorial etiology of hypospadias fitting a polygenic model.^ieng

Effect of hormone replacement therapy on the validity of the Friedewald equation in postmenopausal women: the postmenopausal estrogen/progestins interventions (PEPI) trial.

The Friedewald equation is often used to estimate low-density lipoprotein cholesterol (LDL-C). Hormone therapy is known to raise triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C) and alter lipid contents of lipoproteins. We compared Friedewald estimated LDL-C to measured LDL-C in PEPI participants on placebo or four different hormone treatment groups. At baseline, the 0.2 coefficient for triglyceride (TG) was accurate for all five treatment groups. Among women who took >80% of their pills and whose TG was <4.5 mmol/l (400 mg/dl), LDL-C was underestimated for 69-82% of the participants in the active treatment groups, compared to 50% in the placebo group. After 3 years of therapy, the TG coefficient that offered a better fit of the Friedewald equation in the active treatment groups was 0.39 for the equation in mmol/l (0.17 for the equation in mg/dl). Using this coefficient is clearly warranted for greater accuracy in research studies.

Myocardial infarction in the familial forms of hypertriglyceridemia.

Among 74 hypertriglyceridemic patients who were referred for study because of hypertriglyceridemia, family investigations detected 19 with familial hypertriglyceridemia and 24 with familial combined hyperlipidemia. The frequency of myocardial infarction among adult living hyperlipidemic relatives of patients with familial combined hyperlipidemia was 17.5% (10/57). Five of these relatives had their infarct between the ages of 40 and 50 yr of age, and five before the age of 40 yr. The frequency of myocardial infarction in living hyperlipedemic relatives with familial hypertriglyceridemia was 4.7% (2/43) and was similar to the frequency of myocardial infarction among normolipidemic relatives (4.5%) or among spouse controls (5.2%). Mortality data due to myocardial infarction among relatives of index patients failed to contribute meaningful information.

Model workshop on nutrition counseling for dietitians.

The purpose of the workshop on nutrition counseling was twofold: (a) to enhance nutritionists' and dietitians' knowledge of counseling and basic interviewing skills, behavioral weight control counseling skills, and adherence counseling skills and (b) to quantitatively evaluate improvement and maintenance of the newly acquired skills. Changes in these areas indicated that it is possible to improve certain skills and to maintain those improvements over time.

The cost of reaching National Cholesterol Education Program (NCEP) goals in hypercholesterolaemic patients. A comparison of atorvastatin, simvastatin, lovastatin and fluvastatin.

OBJECTIVE: Recognising the importance of treating hyperlipidaemia, the National Cholesterol Education Program (NCEP) has established widely accepted treatment goals for low density lipoprotein cholesterol (LDL-C). Medications used most commonly to achieve these LDL-C goals are HMG-CoA reductase inhibitors. The relative resource utilisation and cost associated with the use of reductase inhibitors of different LDL-C lowering efficacy are unknown, but are major health and economic concerns. The objective of this study was to determine the mean total cost of care to reach NCEP goals with various reductase inhibitors. DESIGN: In a randomised, 54-week, 30-centre controlled trial we compared resources used and costs associated with treating patients to achieve NCEP goals using 4 reductase inhibitors: atorvastatin, simvastatin, lovastatin and fluvastatin. PATIENTS AND PARTICIPANTS: The trial studied 662 patients; 318 had known atherosclerotic disease. INTERVENTIONS: Reductase inhibitor therapy was initiated at recommended starting doses and increased according to NCEP guidelines and package insert information. For patients who did not reach the goal at the highest recommended dose of each reductase inhibitor, the resin colestipol was added. MAIN OUTCOME MEASURES AND RESULTS: Patients treated with atorvastatin, compared-with other reductase inhibitors, were more likely to reach NCEP goals during treatment (p < 0.05), required fewer office visits (p < 0.001) and less adjuvant colestipol therapy (p = 0.001). Consequently, the mean total cost of care (1996 values) to reach NCEP goals was lower with atorvastatin [$US1064; 95% confidence interval (CI): $US953 to $US1176] compared with simvastatin ($US1471, 95% CI: $US1304 to $US1648), lovastatin ($US1972; 95% CI: $US1758 to $US2186) and fluvastatin ($US1542; 95% CI: $US1384 to $US1710). Results were similar for patients with or without known atherosclerotic disease. CONCLUSIONS: In patients requiring drug therapy for hypercholesterolaemia, NCEP LDL-C goals are achieved significantly more often using fewer resources with atorvastatin compared with simvastatin, lovastatin or fluvastatin.

Lipid-altering efficacy and safety of simvastatin 80 mg/day: long-term experience in a large group of patients with hypercholesterolemia. World Wide Expanded Dose Simvastatin Study Group.

BACKGROUND: Elevated levels of low-density lipoprotein (LDL) cholesterol promote the development of atherosclerosis and coronary heart disease. HYPOTHESIS: Simvastatin 80 mg/day will be more effective than simvastatin 40 mg/day at reducing LDL cholesterol and will be well tolerated. METHODS: Two similar, randomized, multicenter, controlled, double-blind, parallel-group, 48-week studies were performed to evaluate the long-term lipid-altering efficacy and safety of simvastatin 80 mg/day in patients with hypercholesterolemia. One study conducted in the US enrolled patients meeting the National Cholesterol Education Program (NCEP) LDL cholesterol criteria for pharmacologic treatment. In the other multinational study, patients with LDL cholesterol levels > or = 4.2 mmol/l were enrolled. At 20 centers in the US and 19 countries world-wide, 1,105 hypercholesterolemic patients, while on a lipid-lowering diet, were randomly assigned at a ratio of 2:3 to receive simvastatin 40 mg (n = 436) or 80 mg (n = 669) once daily for 24 weeks. Those patients completing an initial 24-week base study were enrolled in a 24-week blinded extension. Patients who had started on the 80 mg dose in the base study continued on the same dose in the extension, while those who had started on the 40 mg dose were rerandomized at a 1:1 ratio to simvastatin 40 or 80 mg in the extension. RESULTS: There was a significant advantage in the LDL cholesterol-lowering effect of the 80 mg dose compared with that of the 40 mg dose, which was maintained over the 48 weeks of treatment. The mean percentage reductions (95% confidence intervals) from baseline in LDL cholesterol for the 40 and 80 mg groups were 41% (42, 39) and 47% (48, 46), respectively, for the 24-week base study, and 41% (43, 39) and 46% (47, 45), respectively, after 48 weeks of treatment (p < 0.001 between groups). Larger reductions in total cholesterol and triglycerides were also observed with the 80 mg dose compared with the 40 mg dose at Weeks 24 and 48. Both doses were well tolerated, with close to 95% of patients enrolled completing the entire 48 weeks of treatment. Myopathy (muscle symptoms plus creatine kinase increase > 10 fold upper limit of normal) and clinically significant hepatic transaminase increases (> 3 times the upper limit of normal) occurred infrequently with both doses. There was no significant difference between the groups in the number of patients with such increases, although there were more cases for both with the 80 mg dose. CONCLUSIONS: Compared with the 40 mg dose, simvastatin 80 mg produced greater reductions in LDL cholesterol, total cholesterol, and triglycerides. Both doses were well tolerated.

Effect of spouse support and health beliefs on medication adherence.

This study addressed the issue of social support for patients' adherence to medical regimens. Social support of wives was assessed by structured interview of 150 male participants in the Coronary Primary Prevention Trial, their wives, and medical staff. In addition, wives were interviewed about their beliefs related to their husbands' health and participation in the trial. Unobtrusive packet counts were used as the measure of adherence. The participants were classified as having high spouse support if wife support scores were in the top one third of the distribution and as having low spouse support if scores were in the bottom one third as measured from inquiry of the participant, the spouse, and the staff. The adherence of men having low support averaged 70 percent, significantly lower than the high-support group, which averaged 96 percent. The correlations between spouses' health beliefs and their level of support were significant for three of four health belief variables. In particular, highly adhering men had wives who believed more strongly in the benefits of the Coronary Primary Prevention Trial.

Improving prevention systems in primary care practices: the Health Education and Research Trial (HEART)

BACKGROUND: The Health Education and Research Trial (HEART) was a multicenter clinical trial designed to test methods to improve primary care practice systems for heart disease prevention services. We present the trial methodology, the practices' use of medical record tools, and changes in documentation of cardiovascular risk factor screening and management. METHODS: Primary care practices were recruited from 4 Midwestern states. The factorial design resulted in 4 study groups: conference only, conference and quality improvement consultations, conference and prevention coordinator, and all interventions combined. Medical record audits and physician, staff, and patient surveys assessed practice change in cardiovascular disease risk factor documentation. RESULTS: Practices participated fully in this project, set goals to improve preventive services, and implemented recommended medical record tools. The number of goals set and the increase in the use of medical record tools were greatest in the combined intervention group, with improvements noted in all groups. The use of patient history questionnaires, problem lists, and flow sheets was significantly higher in the combined intervention group when compared with the conference-only group. Documentation of risk factor screening in a recommended-medical record location improved in all intervention groups, with significant sustained improvements in the practices that received the combined intervention. Documented risk factor management significantly improved in all intervention groups compared with the conference-only control. CONCLUSION: Primary care practices are interested in improving prevention systems and can change these systems in response to supportive external interventions. Promoting organizational change to produce sustained improvement in preventive service clinical outcomes is a complex process that requires further research.

Managing lipid disorders.

We have reviewed the importance of treating hypercholesterolemia and hypertriglyceridemia. Unfortunately, most physicians are not experienced in prescribing diets to lower blood cholesterol; the use of cholesterol lowering drugs, especially resins and niacin, is not within the experience of most doctors. Although promising medications are on the horizon, the long-term safety of these drugs is not determined.

Recruitment by screening entire communities. The Iowa Lipid Research Clinic Experience.

Screening of entire communities arose out of the demographic characteristics of the area served by the Iowa LRC. The process included three components: access to names and addresses of age-eligible persons who could be contacted through a direct-mail announcement of the screening program; support of local media and community leaders; and effective on-site screening teams. Responses to direct mailings were enhanced by a coordinated mass media campaign, in which print media was more effective than radio or television. The likelihood of an age-eligible man participating in the initial contact screening for the CPPT was greater for residents of smaller than larger communities.

Effect of atorvastatin on blood lipid levels in the first 2 weeks of treatment: a randomized, placebo-controlled study.

BACKGROUND: The rate and degree of LDL cholesterol reduction, in the first 2 weeks of therapy, may relate to the early benefit of hydroxymethyl glutaryl coenzyme A reductase inhibitor therapy. In patients with similar baseline LDL cholesterol levels as in the Cholesterol and Recurrent Events (CARE) trial, we report the results of a 2-week placebo-controlled, double-blind investigation of 10 mg/day atorvastatin. METHODS AND RESULTS: The 22 participants were non-Hispanic whites younger than age 72 (average age 47 years) who were modestly overweight and had normal blood pressure. There were no significant baseline lipid and lipoprotein differences. By day 5, there were significant (P <.01) reductions in total cholesterol and LDL levels. The total cholesterol level fell by 25% (226 mg/dL to 169 mg/dL) and LDL cholesterol fell 35% by day 14 (P <.001). Triglyceride levels declined by 24% (from 137 mg/dL to 104 mg/dL) by day 14, but this was not statistically significant. There was no significant difference in HDL cholesterol. The total/HDL level dropped from 4.54 (day 0) to 3.32 (day 14), and the LDL/HDL level dropped from 2.92 to 1.88; both results were highly significant (P <. 001). CONCLUSION: The rapid lipid reduction observed with atorvastatin may benefit the vascular endothelium.