Multiple Risk Factor Intervention Trial Research Articles

On the Effect of Treatment among Would-Be Treatment Compliers: An Analysis of the Multiple Risk Factor Intervention Trial

The Multiple Risk Factor Intervention Trial (MRFIT) was a major trial that examined the efficacy of a multifactor intervention on reducing coronary heart disease mortality. After a mean follow-up of 7 years, treatment was not significantly different from control, and extensive investigation was undertaken to explain the result. This article examines how the effect of treatment varies with compliance with treatment. The basic idea is that the binary characteristic “would comply with treatment” is balanced between groups by randomization, even though it is unobservable before randomization and only observed after randomization in the treatment group. Using baseline covariates, a prediction model for this observed characteristic is developed in the treatment group, and estimated probabilities of treatment compliance are calculated for all patients in both groups. The assumption that patients who would not comply with treatment must have the same mean response in both groups is avoided. Two methods for examining how the effect of treatment depends on treatment compliance are described. Under the first approach, the predicted probabilities of treatment compliance are used to specify a treatment by covariate interaction. Under the second approach, a regression model is specified where the covariate “would comply with treatment” has an interaction with treatment. This produces a standard regression model in the treatment group and a mixture model with mixing over the unobserved binary covariate in the control group. The two methods are applied to MRFIT and the results compared.

Are vacations good for your health? The 9-year mortality experience after the multiple risk factor intervention trial.

The objective of this study was to determine the risk for various causes of posttrial death associated with vacation frequency during the Multiple Risk Factor Intervention Trial (MRFIT). Middle-aged men at high risk for coronary heart disease (CHD) were recruited for the MRFIT. As part of the questionnaires administered during the first five annual visits, men were asked whether they had had a vacation during the past year. For trial survivors (N = 12,338), the frequency of these annual vacations during the trial were used in a prospective analysis of posttrial all-cause and cause-specific mortality during the 9-year follow-up period. The relative risk (RR) associated with more annual vacations during the trial was 0.83 (95% confidence interval [CI], 0.71-0.97) for all-cause mortality during the 9-year follow-up period. For cause of death, the RRs were 0.71 (95% CI, 0.58-0.89) and 0.98 (95% CI, 0.78-1.23) for cardiovascular and noncardiovascular causes, respectively. The RR was 0.68 (95% CI, 0.53-0.88) for CHD (including acute myocardial infarction). These associations remained when statistical adjustments were made for possible confounding variables, including baseline characteristics (eg, income), MRFIT group assignment, and occurrence of a nonfatal cardiovascular event during the trial. The frequency of annual vacations by middle-aged men at high risk for CHD is associated with a reduced risk of all-cause mortality and, more specifically, mortality attributed to CHD. Vacationing may be good for your health.

Relationship of baseline serum cholesterol levels in 3 large cohorts of younger men to long-term coronary, cardiovascular, and all-cause mortality and to longevity.

Based on observational and interventional data for middle-aged cohorts (aged 40-64 years), serum cholesterol level is known to be an established major risk factor for coronary heart disease (CHD). However, findings for younger people are limited, and the value of detecting and treating hypercholesterolemia in younger adults is debated. To evaluate the long-term impact of unfavorable serum cholesterol levels on risk of death from CHD, cardiovascular disease (CVD), and all causes. Three prospective studies, from which were selected 3 cohorts of younger men with baseline serum cholesterol level measurements and no history of diabetes mellitus or myocardial infarction. A total of 11,017 men aged 18 through 39 years screened in 1967-1973 for the Chicago Heart Association Detection Project in Industry (CHA); 1266 men aged 25 through 39 years examined in 1959-1963 in the Peoples Gas Company Study (PG); and 69,205 men aged 35 through 39 years screened in 1973-1975 for the Multiple Risk Factor Intervention Trial (MRFIT). Cause-specific mortality during 25 (CHA), 34 (PG), and 16 (MRFIT) years of follow-up; mortality risks; and estimated life expectancy in relation to baseline serum cholesterol levels. Death due to CHD accounted for 26%, 34%, and 28% of all deaths in the CHA, PG, and MRFIT cohorts, respectively; and CVD death for 34%, 42%, and 39% of deaths in the same cohorts, respectively. Men in all 3 cohorts with unfavorable serum cholesterol levels (200-239 mg/dL [5.17-6.18 mmol/L] and >/=240 mg/dL [>/=6.21 mmol/L]) had strong gradients of relative mortality risk. For men with serum cholesterol levels of 240 mg/dL or greater (>/=6.21 mmol/L) vs favorable levels (<200 mg/dL [<5.17 mmol/L]), CHD mortality risk was 2.15 to 3.63 times greater; CVD disease mortality risk was 2.10 to 2.87 times greater; and all-cause mortality was 1.31 to 1.49 times greater. Hypercholesterolemic men had age-adjusted absolute risk of CHD death of 59 per 1000 men in 25 years (CHA cohort), 90 per 1000 men in 34 years (PG cohort), and 15 per 1000 men in 16 years (MRFIT cohort). Absolute excess risk was 43.6 per 1000 men (CHA), 81.4 per 1000 men (PG), and 12.1 per 1000 men (MRFIT). Men with favorable baseline serum cholesterol levels had an estimated greater life expectancy of 3.8 to 8.7 years. These results demonstrate a continuous, graded relationship of serum cholesterol level to long-term risk of CHD, CVD, and all-cause mortality, substantial absolute risk and absolute excess risk of CHD and CVD death for younger men with elevated serum cholesterol levels, and longer estimated life expectancy for younger men with favorable serum cholesterol levels. JAMA. 2000;284:311-318

Do triglycerides provide meaningful information about heart disease risk?

Prior research suggests that adding triglyceride determinations to measurements of total cholesterol and cholesterol subfractions may improve the prediction of coronary heart disease (CHD). To determine the additional value of measuring triglyceride levels, in addition to cholesterol levels and subfractions, for predicting CHD. A set of secondary analyses of previously reported studies. We performed secondary analyses of data from the Multiple Risk Factor Intervention Trial, the Lipid Research Clinics Coronary Primary Prevention Trial, and the Lipid Research Clinics Prevalence and Mortality Follow-Up Study. Predictor variables included the levels of fasting triglycerides, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and fasting blood glucose; age; blood pressure; cigarette smoking; body mass index; and postmenopausal estrogen use. Analytic methods included Cox proportional hazards models, calculation of stratified crude incidence rates, and measurement of the area under the receiver operating characteristic curve. Outcome variables were fatal and nonfatal myocardial infarctions. With few exceptions, no significant interactions between cholesterol subfractions and triglyceride levels were found and receiver operating characteristic curve analyses revealed that triglyceride measurements did not improve discrimination between those subjects who did and did not suffer CHD events. In men, categorical analyses employing both triglyceride and cholesterol levels were similar to those using cholesterol categories alone. In the one study of women, those subjects with both a high-risk cholesterol profile and high triglyceride levels were more likely to have a CHD event, though this finding was based on fewer subjects and CHD events. These data suggest that, in men, measurement of serum triglyceride levels does not provide clinically meaningful information about CHD risk beyond that obtainable by measurement of serum cholesterol subfractions alone.

Dietary folate and the risk of cardiovascular disease mortality: Results from the multiple risk factor intervention trial (MRFIT)

Dietary folate and the risk of cardiovascular disease mortality: Results from the multiple risk factor intervention trial (MRFIT)

Clinical Advisory Statement. Importance of systolic blood pressure in older Americans.

This clinical advisory statement from the Coordinating Committee of the National High Blood Pressure Education Program is intended to advance and clarify the recommendations of the Sixth Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI, 1997).1 The advisory addresses several interrelated issues about blood pressure (BP) that affect people approaching the later decades of life. On the basis of the wealth of currently available evidence, the committee now recommends a major paradigm shift in urging that systolic BP become the major criterion for diagnosis, staging, and therapeutic management of hypertension, particularly in middle-aged and older Americans. Several lines of strong evidence support the initiative to emphasize systolic BP. Pathophysiologically, there are strong associations among aging, increased stiffness of large arteries, increased systolic BP, increased pulse pressure, and the prevalence of cardiac and vascular disease. Epidemiologically, isolated systolic hypertension is the most common form of hypertension and is present in approximately two thirds of hypertensive individuals >60 years of age. Diagnostically, classification and staging of hypertension are more precise when systolic rather than diastolic BP is used as the principal criterion. Risk stratification for major complications of hypertension (stroke, myocardial infarction, heart failure, and kidney failure) is actually confounded by the use of diastolic BP; in older people with systolic hypertension, diastolic BP is inversely related to cardiovascular risk. Clinical benefits of treatment of isolated systolic hypertension include reductions in stroke, myocardial infarction, heart failure, kidney failure, and overall cardiovascular disease morbidity and mortality. Currently, only 1 in 4 Americans with hypertension falls below JNC VI–recommended values of 140/90 mm Hg in uncomplicated hypertension or 130/85 mm Hg in individuals with kidney disease or diabetes. Hypertension control rates are poorest in older people, primarily as a result of inadequate …

Vitality index in survival modeling: how physiological aging influences mortality.

We investigated the relation of the age trajectory of physiological indicators of the average metabolic activity of organisms in a population to the age-specific population mortality rate. We show that a metabolic rate indicator (MRI) can be estimated using traditional physiological measures, such as homeostatic serum glucose concentration, vital capacity, and such. Estimates of the MRI were made from data collected in the Multiple Risk Factor Intervention Trial (MRFIT) study. The relation of the empirical mortality rate and MRI was also tested using MRFIT data. The age trajectory of MRI was evaluated using Swedish mortality data. The mortality results reproduce the "Strehler and Mildvan effect." The average rate of decline of MRI with age coincides with estimates predicted by Strehler using other methods. Possible extensions of the method are discussed.

The effect of weight cycling on blood lipids and blood pressure in the Multiple Risk Factor Intervention Trial Special Intervention Group.

To assess whether weight cycling has adverse effects on blood lipids or blood pressure. Cohort study, six years of follow-up, comparing net change in blood lipids and blood pressure among weight cyclers and non-cyclers. Men (n = 4353), age 35-57 y, at high risk for heart disease because of smoking, high blood pressure, and elevated cholesterol concentration in the Multiple Risk Factor Intervention Trial (MRFIT)--a 22-site, multi-center collaborative primary prevention trial conducted in the US, 1973-1983. A weight cycle was defined as loss and regain of at least 5% of mean weight. Outcome measures were changes from baseline to year six in total serum cholesterol, high density lipoprotein cholesterol (HDL), the ratio of total cholesterol to HDL, and diastolic blood pressure. Analysis of covariance models were developed, with number of weight cycles as the predictor variable. The hypothesis was that men who weight cycled would experience less improvement in blood lipids and blood pressure than those who did not cycle. Adjustments were made for net weight change and other factors affecting each outcome. Men who weight cycled did not have the predicted smaller improvements in total cholesterol, HDL, the ratio of total cholesterol to HDL, or diastolic blood pressure, compared with noncyclers. An adverse effect of weight cycling on blood pressure or blood lipids was not found. The excess mortality previously reported among weight cyclers in this population can probably not be attributed to effects on these CVD risk factors.

Low risk-factor profile and long-term cardiovascular and noncardiovascular mortality and life expectancy: findings for 5 large cohorts of young adult and middle-aged men and women.

Three major coronary risk factors-serum cholesterol level, blood pressure, and smoking-increase incidence of coronary heart disease (CHD) and related end points. In previous investigations, risks for low-risk reference groups were estimated statistically because samples contained too few such people to measure risk. To measure long-term mortality rates for individuals with favorable levels for all 3 major risk factors, compared with others. Two prospective studies, involving 5 cohorts based on age and sex, that enrolled persons with a range of risk factors. Low risk was defined as serum cholesterol level less than 5.17 mmol/L (<200 mg/dL), blood pressure less than orequal to 120/80 mm Hg, and no current cigarette smoking. All persons with a history of diabetes, myocardial infarction (MI), or, in 3 of 5 cohorts, electrocardiogram (ECG) abnormalities, were excluded. In 18 US cities, a total of 72144 men aged 35 through 39 years and 270671 men aged 40 through 57 years screened (1973-1975) for the Multiple Risk Factor Intervention Trial (MRFIT); in Chicago, a total of 10025 men aged 18 through 39 years, 7490 men aged 40 through 59 years, and 6229 women aged 40 through 59 years screened (1967-1973) for the Chicago Heart Association Detection Project in Industry (CHA) (N = 366559). Cause-specific mortality during 16 (MRFIT) and 22 (CHA) years, relative risks (RRs) of death, and estimated greater life expectancy, comparing low-risk subcohorts vs others by age strata. Low-risk persons comprised only 4.8% to 9.9% of the cohorts. All 5 low-risk groups experienced significantly and markedly lower CHD and cardiovascular disease death rates than those who had elevated cholesterol level, or blood pressure, or smoked. For example, age-adjusted RRs of CHD mortality ranged from 0.08 for CHA men aged 18 to 39 years to 0.23 for CHA men aged 40 through 59 years. The age-adjusted relative risks (RRs) for all cardiovascular disease mortality ranged from 0.15 for MRFIT men aged 35 through 39 years to 0.28 for CHA men aged 40 through 59 years. The age-adjusted RR for all-cause mortality rate ranged from 0.42 for CHA men aged 40 through 59 years to 0.60 for CHA women aged 40 through 59 years. Estimated greater life expectancy for low-risk groups ranged from 5.8 years for CHA women aged 40 through 59 years to 9.5 years for CHA men aged 18 through 39 years. Based on these very large cohort studies, for individuals with favorable levels of cholesterol and blood pressure who do not smoke and do not have diabetes, MI, or ECG abnormalities, long-term mortality is much lower and longevity is much greater. A substantial increase in the proportion of the population at lifetime low risk could contribute decisively to ending the CHD epidemic.

Is cholesterol a risk factor for stroke?: Yes.

A THEROSCLEROSIS is the most common cause of coronary artery disease (CAD), peripheral vascular disease, and stroke worldwide. Atherogenesis is a multifactorial process involving cholesterol internalization, vascular smooth muscle cell proliferation, inflammation, “foam cell” formation, and connective tissue production. Experimental and epidemiological studies of CAD, peripheral vascular disease, and stroke have identified powerful risk factors that directly affect these multifactorial processes and include hypertension, diabetes, smoking, and aging. The relevance of cholesterol, however, has only been definitively associated with CAD and peripheral vascular disease, and has a seemingly tentative and controversial role with strokes. For example, in the Framingham Study no correlation was found between cholesterol and vascular disease of the brain. The Honolulu Heart Study of Japanese American men showed no significant association with cerebral infarction but an inverse relationship with intracerebral hemorrhage. However, in the large Multiple Risk Factor Intervention Trial of more than 350 000 men, death from nonhemorrhagic strokes correlated with elevated cholesterol, suggesting but not proving an association with atherothrombotic brain infarction (ABI). The Eastern Stroke and Coronary Heart Disease Collaborative Research Group study of 69 767 participants revealed a trend toward a reduction in the risk of nonhemorrhagic stroke with decreasing cholesterol concentrations. How can this apparent paradox be explained and resolved when it is recognized that the arterial tree throughout the body is continuous, and the expectation is that risk factors for atherosclerosis for one area, such as the coronary circulation, might be the same as another, such as the cerebral circulation? A possible explanation may be that the cerebral vasculature has inherent biological processes that differ from other vascular beds with respect to endothelial cell function and does not experience the same degree of mechanical trauma exerted on the heart or other peripheral vessels that augment shear and stress forces that provoke and aggravate atherogenesis. In addition, previous studies have technical limitations in their analyses of cholesterol fractionation and of stroke subtypes, particularly distinguishing strokes due to atherosclerosis from other causes. However, while these inaccuracies may help to clarify the presumed paradox, the multifactorial process of atherogenesis cannot be reduced to these factors alone. For example, genetic, racial, environmental, and other as yet to be proven factors, such as hyperhomocysteinemia, are recognized to play a role. Nonetheless, laboratory evidence supports the major role of cholesterol trafficking in the molecular biology of atherothrombotic brain infarction (ABI). For example, patients with ABI have demonstrated abnormal dynamic synthesis and turnover for highdensity lipoprotein cholesterol and low-density lipoprotein cholesterol (LDL-C) compared with healthy individuals and longitudinal follow-up results of subjects with carotid stenoses show plasma LDL-C levels to strongly predict stenosis progression. Despite these mounting evidences implicating an association of cholesterol in ABIs, they have eluded appreciation. A methodological problem with stroke diagnosis is the fact that “stroke” is not a diagnosis of a single pathological entity but rather a generic term for a variety of cerebrovascular disorders. These include subarachnoid hemorrhage, intracerebral hemorrhage, and cerebral infarction. And the last may be due to ABI, or a variety of other arterial diseases, emboli from heart or aorta, and prothrombotic states. Only definitive cases of ABI should be correlated with cholesterol levels, but, unfortunately, other stroke subtypes have often been included in analyses of cholesterol in “strokes.” Thus, the inclusion of patients with cardioembolic stroke due to atrial fibrillation or lacunar stroke due to hypertension or diabetes dilutes the stroke group with stroke due to atherosclerosis. Of course, the only reliable way to differentiate these stroke subtypes is by precise neuroimaging and/or autopsy information, which were less commonly performed or available when most studies had been done during the 1960s and 1970s. Unfortunately, death certificate information, without autopsy study, is often used, yet both are particularly unreliable, especially between counFrom the Departments of Neurology, University of Texas–Houston Medical School, Houston (Drs Demchuk and Yatsu), Medical College of Georgia and Veterans Affairs Medical Center, Augusta, Ga (Dr Hess), and Yale University School of Medicine, and Veterans Affairs Medical Center, New Haven, Conn (Dr Brass). CONTROVERSIES IN NEUROLOGY

Does social integration confound the relation between alcohol consumption and mortality in the Multiple Risk Factor Intervention Trial (MRFIT)?

It has been proposed that social integration would act as a confounder in the relationship between alcohol consumption and all-cause mortality. This study tested the assumption that the J-shaped relationship between drinking and all-cause mortality may partly reflect a protective effect of social integration, to the extent that moderate drinkers are more socially integrated than either abstainers or heavy drinkers, and to the extent that social integration offers direct protection from mortality. This hypothesis was tested using data from 10,832 of the 12,866 men in the Multiple Risk Factor Intervention Trial (MRFIT). Indicators of social integration were derived from an exploratory factor analysis of 25 relevant items in the MRFIT data and from a scale of six items selected by the investigators. We failed to confirm a direct protective effect of social integration. Nondrinkers had the highest rates of all-cause mortality. Compared with heavy drinking, relative risks of all-cause mortality for abstinence, light and moderate drinking were unaffected by inclusion of social integration variables in the proportional hazards models. The MRFIT data fail to confirm a confounding effect of social integration.

The progression of chronic renal failure: a harmful quartet

The progression of chronic renal failure (CRF) remains one of the main challenges in clinical nephrology. Over the last quarter of a century, animal experimentation has identified many of the pathophysiological mechanisms underlying the associated renal scarring process. Consequently, research has implicated a wide range of mediators, including prominent roles for cytokines, chemokines and growth factors.1 This has suggested therapies based on the manipulation of these mediators and aimed at the prevention of progressive renal fibrosis and functional decline.1 Unfortunately, the relevance of these interventions and their applicability to patients with progressive renal insufficiency remain uncertain. Meanwhile, nephrologists continue to be faced with an increasing number of patients with progressive CRF. It is therefore imperative to review available clinical interventions based on the manipulation of known clinical risk factors for the progression of CRF. Hypertension has been linked to the progression of chronic renal failure (CRF) since the pioneering days of Richard Bright in the 19th century and Volhard and Farr early this century. More recently, a large body of evidence has suggested that the progression of CRF is accelerated by raised systemic blood pressure.2,,3 The Multiple Risk Factor Intervention Trial (MRFIT) identified systemic hypertension as a significant risk factor for the development of endstage renal disease (ESRD).4 This study also confirmed the increased susceptibility of hypertensive Black patients to progressive renal failure.4 The Modification of Diet in Renal Disease (MDRD) study showed that the progression of CRF was linked to the level of systemic blood pressure with Black as well as proteinuric patients both at increased risk.5 More recently, the North Italian Cooperative Study Group identified a mean arterial blood pressure (MAP) value of 107 mmHg (around 140/90 mmHg) as discriminatory, with patients with higher values having an accelerated loss of …

Primary prevention of cardiovascular disease in high-risk patients: physiologic and demographic risk factor differences between african american and white american populations

Ischemic heart disease is the leading cause of death in the United States among Americans of African as well as of European ancestry. African Americans have the highest overall coronary heart disease (CHD) mortality rate and the highest out-of-hospital coronary death rates of any ethnic group in the United States, particularly at younger ages. The reasons for this excess CHD mortality among African Americans have not been fully elucidated but may be attributed to a high prevalence of coronary risk factors, patient delays in seeking medical care, limited access to and utilization of cardiac services, and undertreatment of high-risk individuals. The high prevalence of modifiable risk factors in African Americans provides a major opportunity for CHD prevention and risk reduction in this high-risk population. Hypertension, left ventricular hypertrophy (LVH), diabetes mellitus, cigarette smoking, obesity, physical inactivity, and multiple CHD risk factors all occur more frequently in African Americans than in whites. –7 The predictive value of most conventional risk factors for CHD appears to be similar for African Americans and whites. However, the risk of death and other sequelae attributable to some risk factors, such as hypertension and diabetes, is disproportionately greater for African Americans, –11 and current risk assessment algorithms may not have the same predictive value in African Americans as in whites. Hypertension and LVH are more prevalent, develop at younger ages, and are associated with three to five times higher mortality rates in African Americans than in whites. Moreover, African Americans experience greater cardiovascular and renal damage at any level of hypertension than do whites. Elevations in both diastolic and systolic blood pressures increase cardiovascular risk. However, elevated systolic blood pressure is a more powerful predictor of CHD, heart failure, stroke, end-stage renal disease, and overall mortality than is elevated diastolic blood pressure. LVH, when present, is more predictive of CHD morbidity and mortality than is hypertension, cigarette smoking, or hypercholesterolemia. Hypertension and LVH increase the predisposition to arrhythmia and potentially lethal silent ischemic events. –10,12 Both hypertension and LVH impart a particular risk for a poor outcome in African Americans. In a study of African Americans with LVH and coronary disease, LVH accounted for 40% of the attributable risk of death. In the Meharry–Hopkins physician cohort study, hypertension was the best predictor of cardiac events in African American physicians, whereas smoking, cholesterol, and a family history of CHD were better predictors of cardiac events in white physicians. Thus, both hypertension and LVH are common and important risk factors for CHD events in African Americans. Risk prediction algorithms that do not include hypertension and LVH may have less predictive value in African Americans than in other populations. The prevalence of diabetes in African Americans has tripled during the past 30 years, is two to three times greater than in whites, and is associated with a greater burden of macrovascular and microvascular disease complications. Individuals with diabetes are two to three times more likely to experience a CHD event than are nondiabetics, with approximately 60% of deaths in diabetics due to CHD. It is not known why diabetes is substantially more prevalent in African Americans and other high-risk minorities than in whites or why the disease appears to run a more aggressive clinical course in these populations. The cornerstones of effective cardiovascular disease prevention and risk reduction in patients with diabetes are glycemic control, vigorous modification of other CHD risk factors, and ongoing patient monitoring to facilitate early disease detection and prompt intervention. Most population-based surveys indicate that African Americans have lower total serum cholesterol levels and a similar or lower prevalence of hypercholesterolemia compared with whites. – 6,18 The relation between total cholesterol levels and CHD mortality was the same among 23,490 black men screened for the Multiple Risk Factor Intervention Trial (MRFIT) as among 325,384 white men during an average follow-up period of approximately 12 years. However, the first National Health and Nutrition Examination Survey epidemiologic folFrom the Division of Cardiovascular Medicine, State University of New York Health Science Center at Brooklyn, Brooklyn, New York. Requests for reprints should be addressed to Luther T. Clark, MD, Division of Cardiovascular Medicine, State University of New York Health Science Center at Brooklyn, 450 Clarkson Avenue, Brooklyn, New York 11203.

Preventive medicine in a diabetes clinic: an opportunity to make a difference

Preventive medicine in a diabetes clinic: an opportunity to make a difference

Sixteen-year coronary mortality in black and white men with diabetes screened for the Multiple Risk Factor Intervention Trial (MRFIT).

Risk of coronary heart disease (CHD) mortality associated with diabetes is high and it is unclear to what extent the high mortality is due to modifiable risk factors. To explore this, mortality and predictors of CHD death are compared in a large cohort of black and white men with diabetes. In all, 610 black and 3997 white men who reported taking medication for diabetes and had no history of hospitalization for heart attack were screened by 22 centres for the Multiple Risk Factor Intervention Trial (MRFIT). At screening major risk factors for CHD were determined. Participants have been followed for an average of 16 years for vital status. Cause-specific mortality and predictors of CHD are compared for blacks and whites using proportional hazards regression. Serum cholesterol and systolic blood pressure levels were similar in blacks and whites with diabetes, while diastolic blood pressure and percentage of smokers were higher in blacks (89 versus 86 mmHg and 47% versus 34%) and median income was lower. Coronary heart disease was the leading cause of death, accounting for 31% (68/221) and 44% (564/1293) of deaths among blacks and whites, respectively. Adjusted relative risks of CHD death and all cause mortality for blacks compared to whites were 0.71 (95% CI: 0.53-0.95) and 0.94 (95% CI: 0.75-1.11). Differences in reporting cause of death probably account for some of the black/white difference in CHD. High serum cholesterol, high blood pressure, and smoking increased risk of CHD death similarly in blacks and whites. Serum cholesterol, blood pressure, and smoking are major influences on CHD mortality risk in both white and black men with diabetes. High prevalence of these factors indicates substantial potential for CHD prevention in both ethnic groups.

Mortality differences between black and white men in the USA: contribution of income and other risk factors among men screened for the MRFIT

Summary Background Studies of underlying differences in adult mortality between black and white individuals in the USA have been constrained by limitations of data or small study size. We investigated the extent to which differences in socioeconomic position between black and white men contribute to differences in all-cause and cause-specific mortality. Methods 361 662 men were screened for the Multiple Risk Factor Intervention Trial between 1973 and 1975, in 22 sites. Median family income of households by zipcode (postal) area of residence was available for 20 224 black and 300 685 white men as well as data on age, cigarette smoking, blood pressure, serum cholesterol, previous heart attack, and treatment for diabetes. We classified deaths during 16 years of follow-up into specific causes and compared differences in death rates between black men and white men, before and after adjustment for differences in income and other risk factors. Findings Age-adjusted relative risk of death (black vs white) was 1·47 (95% CI 1·42–1·53). Adjustment for diastolic blood pressure, serum cholesterol, cigarette smoking, medication for diabetes, and previous admission to hospital for heart attack decreased the relative risk to 1·40 (1·35–1·46). Adjustment for income but not the other risk factors decreased the risk to 1·19 (1·14–1·24) and adjustment for other risk factors did not alter this estimate. For cardiovascular death, relative risk on adjustment for income was decreased from 1·36 to 1·09; for cancer from 1·47 to 1·25; and for non-cardiovascular and non-cancer deaths from 1·71 to 1·26. For some specific causes of death, including prostate cancer, myeloma, and hypertensive heart disease, the higher death rates among black men did not seem to reflect differences in income. Rates of death for suicide and melanoma were lower among black than white men, as were those for coronary heart disease after adjustment for income. Interpretation Socioeconomic position is the major contributor to differences in death rates between black and white men. Differentials in mortality from some specific causes do not simply relect differences in income, however, and more detailed investigations are needed of how differences are influenced by environmental exposures, lifetime socioeconomic conditions, lifestyle, racism, and other sociocultural and biological factors.

Prospective association between lipid soluble antioxidants and coronary heart disease in men. The Multiple Risk Factor Intervention Trial.

A nested case-control study was performed using participants enrolled in the Multiple Risk Factor Intervention Trial (MRFIT). The cases involved nonfatal myocardial infarction or death from coronary heart disease. Serum samples (n = 734) obtained at baseline and frozen for approximately 20 years were analyzed for the antioxidants, carotenoids, retinol, and alpha-, gamma-, and total tocopherol. The concentrations of antioxidants were in the expected range and their association with low density lipoprotein (LDL) cholesterol reflected their absorption and transport mechanisms. Among nonsmokers, the odds ratios (95% confidence intervals (CI)) for quartile IV versus quartile I were 1.40 (0.40-4.89), 0.77 (0.20-2.96), 1.45 (0.38-5.56), 2.34 (0.56-9.81), and 2.40 (0.52-11.07) for retinol, total carotenoids, and alpha-, gamma-, and total tocopherol, respectively. The equivalent odds ratios (95% CI) for smokers were 0.90 (0.34-2.41), 0.66 (0.23-1.84), 0.67 (0.21-2.13), 2.04 (0.88-4.73), and 0.52 (0.16-1.67), respectively. This analysis of antioxidant concentrations by quartiles indicated no significant association of antioxidant levels with the risk of coronary disease death or nonfatal myocardial infarction.

Risk of end-stage renal disease in diabetes mellitus: a prospective cohort study of men screened for MRFIT. Multiple Risk Factor Intervention Trial

Diabetes is a frequent cause of end-stage renal disease (ESRD). However, the degree of risk is uncertain. To determine the relative risk (RR) of ESRD related to diabetes in the United States. Nonconcurrent prospective cohort study. A total of 332544 men aged 35 to 57 years from 18 US cities screened in 1973 to 1975 for participation in the Multiple Risk Factor Intervention Trial (MRFIT). Diabetes mellitus defined by self-reported use of medication for diabetes at baseline. Incident ESRD through 1990 assessed from a national ESRD registry and by surveillance for death from renal disease. Over an average follow-up of 16 years, there were 136 cases of ESRD in 5147 diabetic men and 678 cases in 327397 nondiabetic men. Age-adjusted incidence of all-cause ESRD in the diabetic men was 199.8 per 100000 person-years compared with 13.7 per 100000 person years in their nondiabetic counterparts (RR, 12.7; 95% confidence interval [CI], 10.5-15.4). Diabetic men were also at higher risk for ESRD ascribed to causes other than diabetes (RR=4.3; 95% CI, 3.2-5.9). With simultaneous adjustment for age, ethnicity, income, blood pressure, serum cholesterol level, and history of myocardial infarction, diabetic men remained at higher risk for all-cause ESRD (RR, 9.0; 95% CI, 7.4-11.0), ESRD ascribed to diabetes (RR, 92.3; 95% CI, 64.6-131.9), and ESRD ascribed to nondiabetic causes (RR, 3.0; 95% CI, 2.2-4.1). Diabetes mellitus is a strong independent risk factor for ESRD, even for ESRD ascribed to causes other than diabetes. Improvements in the prevention and control of diabetes should produce substantial reductions in ESRD incidence.

Risk of End-stage Renal Disease in Diabetes Mellitus

<h3>Context.</h3> —Diabetes is a frequent cause of end-stage renal disease (ESRD). However, the degree of risk is uncertain. <h3>Objective.</h3> —To determine the relative risk (RR) of ESRD related to diabetes in the United States. <h3>Design.</h3> —Nonconcurrent prospective cohort study. <h3>Participants.</h3> —A total of 332 544 men aged 35 to 57 years from 18 US cities screened in 1973 to 1975 for participation in the Multiple Risk Factor Intervention Trial (MRFIT). <h3>Main Exposure.</h3> —Diabetes mellitus defined by self-reported use of medication for diabetes at baseline. <h3>Main Outcome.</h3> —Incident ESRD through 1990 assessed from a national ESRD registry and by surveillance for death from renal disease. <h3>Results.</h3> —Over an average follow-up of 16 years, there were 136 cases of ESRD in 5147 diabetic men and 678 cases in 327 397 nondiabetic men. Age-adjusted incidence of all-cause ESRD in the diabetic men was 199.8 per 100 000 person-years compared with 13.7 per 100 000 person years in their nondiabetic counterparts (RR, 12.7; 95% confidence interval [Cl], 10.5-15.4). Diabetic men were also at higher risk for ESRD ascribed to causes other than diabetes (RR=4.3; 95% Cl, 3.2-5.9). With simultaneous adjustment for age, ethnicity, income, blood pressure, serum cholesterol level, and history of myocardial infarction, diabetic men remained at higher risk for all-cause ESRD (RR, 9.0; 95% Cl, 7.4-11.0), ESRD ascribed to diabetes (RR, 92.3; 95% Cl, 64.6-131.9), and ESRD ascribed to nondiabetic causes (RR, 3.0; 95% Cl, 2.2-4.1). <h3>Conclusions.</h3> —Diabetes mellitus is a strong independent risk factor for ESRD, even for ESRD ascribed to causes other than diabetes. Improvements in the prevention and control of diabetes should produce substantial reductions in ESRD incidence.

Heart rate adjustment of exercise-induced ST-segment depression identifies men who benefit from a risk factor reduction program.

Whether subjects identified as being at increased risk of coronary heart disease (CHD) death by heart rate adjustment of exercise-induced ST-segment depression will benefit from therapy aimed at reducing risk factors has not been examined. Exercise ECGs were performed in 11,880 men from the Usual Care (UC) and Special Intervention (SI) groups of the Multiple Risk Factor Intervention Trial. UC men were referred to customary sources of care in the community; SI men received counseling on smoking cessation and dietary reduction of cholesterol, and stepped-care therapy for hypertension. An abnormal ST-segment response to exercise was defined according to standard criteria as > or = 100 microV of additional horizontal or downsloping ST-segment depression and by an ST-segment/heart rate (ST/HR) index >1.60 microV/bpm. After 7 years of follow-up, CHD mortality was significantly lower in SI than UC men with an abnormal ST/HR index (2.4%, 19/786 versus 5.3%, 39/729, P=.005) but was comparable in SI and UC men with a normal ST/HR index (1.6%, 84/5154 versus 1.3%, 70/5211, P=NS). Risk reduction in SI men with an abnormal ST/HR index was independent of age and other cardiac risk factors. In contrast, there was no significant difference in CHD death rate between the smaller groups of SI and UC men with an abnormal test by standard criteria (3.6%, 7/192 versus 2.7%, 5/186, P=NS). An abnormal ST/HR index identifies men in whom therapy aimed at reducing CHD risk factors reduces the risk of CHD death by 61%. These findings support the application of heart rate adjustment of ST depression for screening of asymptomatic subjects at increased risk of CHD to identify those who will benefit most from risk factor-reduction programs.