Correction for biases in a population-based study of family history and coronary heart disease. The Newcastle Family History Study I.

In this paper, the authors report on the design of a population-based case-control study of family history as a risk factor for coronary heart disease (CHD). They studied the characteristics of subjects who completed a detailed family history questionnaire in 1992-1994 as well as the accuracy of recall of family history in order to quantify both selection and recall biases. Coronary disease cases were enrolled through the Newcastle MONICA Project (Monitoring Trends and Determinants in Cardiovascular Disease), which registered all suspected heart attacks and sudden cardiac deaths in the Lower Hunter region of New South Wales, Australia, between August 1984 and March 1994. Controls were selected at random from the New South Wales electoral roll. The response rate was 76% in cases and 62% in controls; the major factor associated with participation in the study was perceived family history of CHD, more so in the control series than in the case series. Accuracy was determined by comparing information obtained from the proband with that recorded on death certificates. In first-degree relatives, sensitivity of CHD recall was 85% (95% confidence interval (CI) 74-92%) in cases and 95% (95% CI 84-99%) in controls, while specificity was 59% (95% CI 49-69%) and 74% (95% CI 65-82%), respectively. The net bias in both selection and recall is toward the null and hence the comparisons provide a conservative estimate of risk of CHD associated with a positive family history.

Risk associated with various definitions of family history of coronary heart disease. The Newcastle Family History Study II.

The authors carried out a population-based case-control study to estimate the risk of an acute coronary disease event associated with various definitions of a family history of coronary heart disease (CHD). A detailed family history questionnaire was completed by 403 cases and 236 controls in Newcastle, New South Wales, Australia from 1992 to 1994. Odds ratios of an acute coronary disease event adjusted for proband age and sex ranged from 2.7 (95% confidence interval (CI) 1.8-4.1) for the simplest definition (one or more first-degree relatives with CHD at any age) to 5.4 (95% CI 1.7-16.8) for the most stringent definition (two or more first-degree relatives with CHD before age 55 years). In a series of nested models, the authors examined the improvement in model fit as each component of the detailed family history was added. Additional information was provided by accounting for "don't know" responses, the number of affected relatives, the age of the affected relative, and whether the first-degree relative was a sibling rather than a parent. The results were similar when the data were analyzed as a cohort design with proband disease status as the exposure variable. The authors suggest that, to facilitate preventive efforts in a population, more detailed family history definitions should be used to better target high risk subjects.

Reproducibility of brachial ultrasonography and flow-mediated dilatation (FMD) for assessing endothelial function.

BACKGROUND: High-resolution brachial artery ultrasonography is used to study vasodilator response induced by physiologic reactive hyperaemia. We examined the reproducibility of measuring flow-mediated dilatation (FMD) on two occasions. AIMS: To determine the degree of variability of this technique in our vascular laboratory for the design of clinical research studies. METHODS: Nineteen subjects were studied on two separate occasions using an Acuson 128 ultrasound device and a 7.0 MHz linear array transducer. Reactive hyperaemia was induced in the brachial artery by inflation and release of a blood pressure cuff. Nitrate-induced dilatation was assessed in 11 of the 19 subjects. Measurements were made by two observers blinded to subject details. RESULTS: The 11 subjects given sublingual GTN during the first ultrasound study had a mean nitrate-induced dilatation of 20.7% (sd 9.6). The mean vessel diameter of 3.78 mm (sd 0.7) at rest and 3.89 mm (sd 0.7) during reactive hyperaemia yielded a mean FMD of only 3.0% (sd 2.7). The mean difference in FMD within-observers was 0.13% (sd 2.07), between-observers 0.06% (sd 2.17) and between-studies was 0.57% (sd 6.83). CONCLUSIONS: The reproducibility of FMD measured by brachial artery ultrasound was poor and likely to render the measurements inaccurate for clinical research in our hands. Between-study variation contributed the largest proportion of total study variability. We suggest that investigators using this technique conduct their own careful reproducibility studies in order to avoid the misinterpretation of 'negative' studies.

Assay of plasma homocysteine: light sensitivity of the fluorescent 7-benzo-2-oxa-1, 3-diazole-4-sulfonic acid derivative, and use of appropriate calibrators.

The recognition of homocysteine as a vascular risk factor has led to increased clinical interest in assaying plasma homocysteine concentrations. Our aim was to improve the reliability of a widely used assay based on HPLC of the fluorescent 7-benzo-2-oxa-1, 3-diazole-4-sulfonic acid (SBD) derivative. We found that SBD derivatives of homocysteine, cysteine, and N-acetylhomocysteine were highly unstable in light but essentially stable in the dark for several hours at either 0 degree C or 25 degrees C. As our primary calibrator, we chose homocystine added to human serum for more consistent results than homocysteine or homocystine in an aqueous buffer. N-acetylcysteine was effective as an internal recovery standard. We observed a previously unreported peak with a prolonged elution time in some plasma samples from subjects who had ingested methionine. Our findings suggest improvements in this and other assay procedures for plasma homocysteine.

The benefits of reducing cholesterol levels: the need to distinguish primary from secondary prevention. 2. Implications for heart disease prevention in Australia.

OBJECTIVE: To estimate the number of coronary heart disease (CHD) events arising from the primary and secondary prevention populations of middle-aged Australian men, and the potential impact in each setting of lipid-lowering therapy on death from CHD. DESIGN: Analysis based on results of a meta-analysis of drug trials to lower cholesterol levels and data from the Hunter Region Heart Disease Prevention Programme. MAIN OUTCOME MEASURE: Death from CHD. RESULTS: Over a five-year period, 1520 fatal CHD events would be expected in a population of 100,000 men aged 35 to 69 years. Approximately 52% would arise from subjects already known to suffer from CHD. We predict that treating everyone in the secondary prevention group who has a blood cholesterol level of greater than 5.2 mmol/L (approximately 5000 subjects) would prevent 118 deaths, compared with 51 deaths prevented by treating those in the primary prevention group who have cholesterol levels of greater than 6.2 mmol/L (approximately 30,000 subjects). The outcome is maintained in several sensitivity analyses. CONCLUSIONS: The majority of persons in whom death from CHD might be prevented by treatment to lower cholesterol levels can be identified by targeting subjects for secondary prevention. Therapy in the secondary prevention setting is much more efficient than in primary prevention.

The benefits of reducing cholesterol levels: the need to distinguish primary from secondary prevention. 1. A meta-analysis of cholesterol-lowering trials.

OBJECTIVE: To use meta-analysis to estimate the benefits of drug treatment to lower cholesterol levels in the primary and secondary prevention of coronary heart disease (CHD) events. DATA SOURCES: MEDLINE search from 1967 to 1990; bibliographies of review articles. STUDY SELECTION: Nine trials met the entry criteria: they were monofactorial, randomised and controlled. DATA EXTRACTION: Two independent, unblinded observers. DATA SYNTHESIS: The odds ratio (and 95% Cl) for death from CHD was 0.85 (0.64, 1.14) in primary prevention and 0.84 (0.75, 0.95) in secondary prevention studies when calculated by the method of Peto. The event rate in the secondary prevention studies was higher than that in the primary prevention studies, and the absolute risk reduction achieved by therapy in the former (3.2%) was much higher than that in the latter (0.1%). The number of subjects needing to be treated to prevent one death from CHD was 38 in secondary prevention and 675 in primary prevention. Results with the method of DerSimonian and Laird were similar. CONCLUSIONS: The benefits of cholesterol lowering to prevent death from CHD are substantially greater in the secondary prevention setting than in primary prevention.

Estimating the benefits of cholesterol lowering: are risk factors for coronary heart disease multiplicative?

It is often stated that the major risk factors for coronary heart disease (CHD)--smoking, high blood pressure and high serum cholesterol--are not merely additive but act together such that each multiplies the effects of the others. Economic analyses in which the benefits of risk factor modification are estimated often reflect this. This paper explains how predictive models based on the simplest form of the multiple logistic function inevitably predict greater benefit from cholesterol lowering in those in whom other risk factors are adverse; this results from the model itself, rather than the data. CHD death rates from the screenee population of the Multiple Risk Factor Intervention Trial are examined: these suggest that the relationship between cholesterol and both other major risk factors is closer to additive than to multiplicative. When the benefits of cholesterol lowering are estimated, a model based on additive risk, specifying product ("interaction") terms, is to be preferred.

Left ventricular volumes in moderate alcohol users: a study from the workplace.

We measured resting and exercise left ventricular volumes by a count-based, nongeometric radionuclide method in 23 healthy volunteers grouped according to reported average daily alcohol consumption: 0-20 g (Gp A), 21-50 g (Gp B) and greater than 50 g (Gp C). No patient had measurable alcohol in his blood at the time of study. Mean resting LV Ejection Fraction (EF) was 65 +/- 2% in Group A, 64 +/- 2% in Group B, and 65 +/- 3% in Group C. Exercise EF was 76 +/- 1,75 +/- 3 and 74 +/- 4%, respectively. Resting Endsystolic Volume Indices in the three groups were 19.2 +/- 3, 18.9 +/- 2 and 21.8 +/- 3 ml/m2; exercise values were 15.9 +/- 2, 12.8 +/- 2 and 13.3 +/- 2 ml/m2, respectively. This cohort was selected for absence of markers of alcohol-related illness, and all subjects were employed. We found no evidence for impaired left ventricular systolic function with moderate alcohol usage using a sensitive radionuclide technique.

Impact of left ventricular hypertrophy on survival in end-stage renal disease.

We examined the prognostic significance of left ventricular hypertrophy determined by echocardiography in a cohort beginning renal replacement therapy. No patient had hemodynamically significant valvular disease or echocardiographic signs of obstructive cardiomyopathy. Using the Cox proportional hazards model, left ventricular hypertrophy was significantly associated with survival. The relative risk, based on comparison of upper and lower quintiles of left ventricular mass index, was 3.7 (95% confidence intervals, 1.6 to 8.3) for all-cause mortality and 3.7 (95% confidence intervals, 1.2 to 11.1) for cardiac mortality. The independent risk, adjusted for age, known coronary artery disease, diabetes, level of systolic blood pressure, and treatment (dialysis or transplantation), was 2.9 (95% confidence intervals, 1.3 to 6.9) for all-cause mortality and 2.7 (95% confidence intervals, 0.9 to 8.2) for cardiac mortality. Therefore, left ventricular hypertrophy appears to be an important, independent, determinant of survival in patients receiving therapy for end-stage renal failure.

Role of anemia in the pathogenesis of left ventricular hypertrophy in end-stage renal disease.

Left ventricular (LV) hypertrophy is common in end-stage renal disease, yet the factors associated with its development are poorly understood. LV mass index was determined by echocardiography in 78 patients who had been treated by dialysis for at least 3 months. A significant relation was evident between anemia and LV hypertrophy. The mean LV mass index was 158 +/- 6 g/m2 (mean +/- standard error) in patients in the lowest quartile of serum hemoglobin and 140 +/- 10, 132 +/- 7 and 120 +/- 8 g/m2 in the second, third and uppermost quartiles, respectively (p = 0.005). This relation persisted after adjusting for systolic blood pressure, treatment mode and suspected coronary artery disease. Forty-eight patients had paired studies. In these, LV mass index increased as hemoglobin decreased (coefficient = -0.81 g/m2/g/liter, p less than 0.025). These data indicate that anemia contributes to the development of LV hypertrophy in patients with end-stage renal disease.

Restoration of flow in acute coronary obstructive syndromes: consequences of different management strategies.

Although much necessary evidence is not yet available, there is sufficient information from recent therapeutic trials to necessitate a nationwide review of the management of acute coronary obstructive syndromes. On the basis of present information it is evident that, in addition to heparin, all patients suffering from suspected acute myocardial infarction should receive immediate low dose aspirin which should be continued for one to six months. This treatment, if generally applied, can be expected to save 1200 lives per year in Canada at negligible cost. Addition of intravenous streptokinase infusion to all patients (in whom there are no contraindications) available for treatment from 0 to 24 h from the onset, can be expected to save an additional 1088 lives at an additional cost of approximately $11,000 per life. Other thrombolytic agents involve additional cost and the gains in terms of mortality are not yet demonstrated. The evidence for thrombolytic treatment in acute unstable angina is still uncertain but the treatment of all cases with aspirin from the earliest possible moment is clearly indicated.