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Identifying individuals with recent HIV infection is critical to research related to viral reservoirs, outbreak investigations and intervention applications. A multi-assay algorithm (MAA) for recency of infection was used in conjunction with self-reported date of infection and documented date of diagnosis to estimate the number of participants recently infected in the Strategic Timing of AntiRetroviral Treatment (START) trial. We tested samples for three groups of participants from START using a MAA: (1) 167 individuals who reported being infected ≤ 6 months before randomization; (2) 771 individuals who did not know their date of infection but were diagnosed within 6 months before randomization; and (3) as controls for the MAA, 199 individuals diagnosed with HIV ≥ 2 years before randomization. Participants with low titer and avidity and a baseline viral load > 400 copies/mL were classified as recently infected. A significantly higher percentage of participants who self-reported being infected ≤ 6 months were classified as recently infected compared to participants diagnosed ≥ 2 years (65% [109/167] vs. 2.5% [5/199], p < 0.001). Among the 771 individuals who did not know their duration of infection at randomization, 206 (26.7%) were classified as recently infected. Among those diagnosed with HIV in the 6 months prior to enrollment, the 373 participants who reported recent infection (n = 167) or who had confirmed recent infection by the MAA (n = 206) differed significantly on a number of baseline characteristics from those who had an unknown date of infection and were not confirmed by the MAA (n = 565). Participants recently infected by self-report and/or MAA were younger, more likely to be Asian, less likely to be black, less likely to be heterosexual, more likely to be enrolled at sites in the U.S., Europe or Australia, and have higher HIV RNA levels. There was good agreement between self-report of recency of infection and the MAA. We estimate that 373 participants enrolled in START were infected within 6 months of randomization. Compared to those not recently infected, these participants were younger, had higher HIV RNA levels and were more likely to come from high income countries and from populations such as MSM with more regular HIV testing.

Background: High-density lipoprotein (HDL) particles have properties beyond reverse cholesterol transport. We hypothesized that their protection extends to inflammation-related disease. The predictive value of HDL particle subclasses and inflammatory markers was studied for noncardiovascular, noncancer chronic inflammation-related death and hospitalization, and for incident cardiovascular disease (CVD)., Methods and Results: A multiethnic, multicenter, prospective observational study was conducted in 6475 men and women (aged 45 to 84 years) free of known CVD at baseline with median follow-up of 10.1 years. Fasting venous samples were analyzed for baseline lipid profile and lipoprotein particles. We focused on the HDL family of variables (small-, medium-, and large-diameter HDL particles and HDL cholesterol). Analyses identified the sum of small- plus medium-diameter HDL particles as important. Small- plus medium-diameter HDL particles were inversely associated with diagnostic code-based noncardiovascular, noncancer chronic inflammation-related death and hospitalization (n=1054) independent of covariates: relative risk per SD 0.85 (95% CI: 0.79 to 0.91, P<0.0001). Small- plus medium-diameter HDL particles were also associated with adjudicated fatal and nonfatal coronary heart disease events (n=423): relative risk per SD 0.88 (95% CI 0.77 to 0.98, P=0.02)., Conclusions: Small- plus medium-diameter HDL particles are an independent predictor for noncardiovascular, noncancer chronic inflammation-related death and hospitalization and for coronary heart disease events in subjects initially free of overt CVD. These findings support the hypothesis that smaller HDL particles of diameter <9.4 nm have anti-inflammatory properties in the general population., (© 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Kidney cancer incidence is increasing globally. Reasons for this rise are unclear but could relate to obesity and hypertension. We analyzed longitudinal relationships between hypertension and obesity and kidney cancer incidence in 156 774 participants of the Women's Health Initiative clinical trials and observational studies over 10.8 years. In addition, we examined the effect of blood pressure (BP) on kidney cancer deaths for over 25 years among the 353 340 men screened for the Multiple Risk Factor Intervention Trial (MRFIT). In the Women's Health Initiative, systolic BP (SBP) was categorized in 6 groups from <120 to >160 mm Hg, and body mass index was categorized using standard criteria. In age-adjusted analyses, kidney cancer risk increased across SBP categories (P value for trend <0.0001) and body mass index categories (P value for trend <0.0001). In adjusted Cox proportional hazards models, both SBP levels and body mass index were predictors of kidney cancer. In the MRFIT sample, there were 906 deaths after an average of 25 years of follow-up attributed to kidney cancer among the 353 340 participants aged 35 to 57 years at screening. The risk of death from kidney cancer increased in a dose-response fashion with increasing SBP (hazard ratio, 1.87 for SBP>160 versus <120 mm Hg; 95% confidence interval, 1.38-2.53). Risk was increased among cigarette smokers. Further research is needed to determine the pathophysiologic basis of relationships between both higher BP and the risk of kidney cancer, and whether specific drug therapies for hypertension can reduce kidney cancer risk.

Background: The results of cohort studies relating sodium (Na) intake to blood pressure-related cardiovascular disease (CVD) are inconsistent. To understand whether methodological issues account for the inconsistency, we reviewed the quality of these studies., Methods and Results: We reviewed cohort studies that examined the association between Na and CVD. We then identified methodological issues with greatest potential to alter the direction of association (reverse causality, systematic error in Na assessment), some potential to alter the direction of association (residual confounding, inadequate follow-up), and the potential to yield false null results (random error in Na assessment, insufficient power). We included 26 studies with 31 independent analyses. Of these, 13 found direct associations between Na and CVD, 8 found inverse associations, 2 found J-shaped associations, and 8 found null associations only. On average there were 3 to 4 methodological issues per study. Issues with greater potential to alter the direction of association were present in all but 1 of the 26 studies (systematic error, 22; reverse causality, 16). Issues with lesser potential to alter the direction of association were present in 18 studies, whereas those with potential to yield false null results were present in 23., Conclusions: Methodological issues may account for the inconsistent findings in currently available observational studies relating Na to CVD. Until well-designed cohort studies in the general population are available, it remains appropriate to base Na guidelines on the robust body of evidence linking Na with elevated blood pressure and the few existing general population trials of the effects of Na reduction on CVD.

We assessed the relation of inflammatory and coagulation biomarkers with electrocardiographic (ECG) evidence of myocardial ischemia. High-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), and D-dimer levels were measured at study entry for 3,085 human immunodeficiency virus-infected participants (mean age 44 years; 26.4% women; 24.6% black) in the Strategies for Management of Antiretroviral Therapy trial. Logistic regression models were used to examine the associations of these biomarkers with prevalent and incident myocardial ischemia. The latter analyses were performed for 1,411 participants who were randomly assigned to receive continuous antiretroviral therapy during follow-up to suppress the human immunodeficiency virus viral load and had ≥1 ECG reading during the follow-up period. The median hsCRP, IL-6, and D-dimer level was 1.65 μg/ml (interquartile range 0.69 to 4.11), 1.60 pg/ml (interquartile range 1.00 to 2.75), and 0.18 μg/ml (interquartile range 0.11 to 0.32), respectively. At baseline, the prevalence of major or minor Q-QS or ST-T ECG abnormalities was 18.6%. The biomarker levels were associated with prevalent major or minor ischemic abnormalities on the univariate analyses; however, adjustment for traditional risk factors attenuated these associations. The adjusted odds ratio for major or minor ischemic abnormalities and 95% confidence intervals for the greatest versus lowest quartiles was 1.3 (95% confidence interval 0.9 to 1.7) for hsCRP, 1.0 (95% confidence interval 0.7 to 1.3) for IL-6, and 1.1 (95% confidence interval 0.9 to 1.5) for D-dimer. During a median follow-up of 2.3 years, new definite or probable ischemic ECG abnormalities developed in 11.7% of participants receiving continuous antiretroviral therapy. Biomarker levels were not associated with incident abnormalities on unadjusted or adjusted analyses. In conclusion, higher levels of hsCRP, IL-6, and D-dimer were not associated with ischemic ECG abnormalities. Elevated biomarker levels and ECG abnormalities indicating myocardial ischemia might reflect different risk pathways for cardiovascular disease., (Copyright © 2013 Elsevier Inc. All rights reserved.)

On September 30, 2009, the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) conducted a workshop on strengthening biostatistics resources in sub-Saharan Africa (SSA). An increase in global spending on health research over the last decade has boosted funds available to conduct biomedical research in low- to mid-income countries. The HIV/AIDS pandemic, the re-emergence of malaria and tuberculosis, and other emerging infectious agents are major driving forces behind the increase in biomedical research and clinical care programs (clinical trials, observational studies and, other public health programs) in SSA (Exp. Biol. Med. 2008; 233:277-285). In addition, the increased engagement of the United States (U.S.) government through the Global Health Initiative, which expands the traditional focus beyond infectious diseases to other causes of poor health and to the recognition of need the to strengthen health systems for a sustainable response, only increases the need for in-depth in-country expertise in all aspects of biomedical research (White House Press Release, 2009). In this workshop, researchers both from the U.S. and SSA were invited to discuss their collaborative work, to discuss ways in which biostatistical activities are carried out within their research projects, and to identify both general and specific needs for capacity building in biostatistics. Capacity building discussions highlighted the critical need to increase the number of well-trained in-country biostatisticians, both to participate in ongoing studies and to contribute to an infrastructure that can produce the next generation of biostatistical researchers., (Copyright © 2011 John Wiley & Sons, Ltd.)

Background: A number of reports have highlighted problems of conducting publicly funded trials in Europe as a consequence of the European Union (EU) Clinical Trials Directive. The impact of the EU Directive on multi-national trials, which include sites in Europe that are funded by the US National Institutes of Health (NIH) have not been described., Methods: Four problems in the conduct of two international HIV treatment trials funded by NIH in the EU are described: (1) conflicting regulations on the continuing review of protocols by Institutional Review Boards/Research Ethics Committees; (2) US regulations requiring Federalwide Assurances for sites which are only partially funded by NIH; (3) EU guidance on the designation of studies as a trial of an investigational medicinal product; and (4) EU guidance on trial sponsorship and the requirements for insurance and indemnification. Following the description of the problems, recommendations for improving global collaborations are made to the US Office of Human Research Protections, to NIH, and to the EU and its Member States., Results: A lack of harmonization of regulations at multiple levels caused enrollment in one study to be interrupted for several months and delayed for one year the initiation of another study aimed at obtaining definitive evidence to guide the timing of the initiation of antiretroviral therapy for individuals infected with HIV. The delays and the purchase of insurance resulted in substantial increases in trial costs and caused substantial disruption at clinical sites among staff and study participants., Limitations: The problems cited and recommendations made pertain to trials funded by NIH and conducted by sites in the EU. There are many other challenges in the conduct of international research, public and private, that global harmonization would alleviate., Conclusions: Disharmony, at multiple levels, in international regulations and guidelines is stifling publicly funded global research. International scientific organizations and government groups should make the documentation and solution of these problems a priority.

Heart rate (HR) profile during exercise predicts all-cause mortality. However, less is known about its relation to sudden (vs nonsudden) death in asymptomatic people. The relation of exercise HR parameters (HR at rest, target HR achievement, HR increase, and HR recovery) with sudden death, coronary heart disease (CHD) death, myocardial infarction, and all-cause mortality was assessed in 12,555 men who participated in MRFIT. Subjects were 35 to 57 years old without clinical CHD, but with higher than average Framingham risk. Trial follow-up was 7 years, and extended follow-up after the trial for all-cause mortality was 25 years. After adjusting for cardiac risk factors, having to stop exercise before achieving 85% of age-specific maximal HR was associated with increased risk of sudden death (hazard ratio 1.8, 95% confidence interval [CI] 1.3 to 2.5, p = 0.001), CHD death (hazard ratio 1.4, 95% CI 1.2 to 1.5, p <0.001), and all-cause mortality (hazard ratio 1.3, 95% CI 1.2 to 1.4, p <0.001). Increased HR at rest (p = 0.001), attenuated HR increase (p = 0.02), delayed HR recovery (p = 0.04), and exercise duration (p <0.0001) were independent predictors of all-cause death in the overall study population and also in the subgroup that achieved target HR. In conclusion, middle-aged men without clinical CHD who stopped exercise before reaching 85% of maximal HR had a higher risk of sudden death. Other exercise HR parameters and exercise duration predicted all-cause mortality.

There is a well-established, strong association between socioeconomic position and mortality. Public health mortality analyses thus routinely consider the confounding effect of socioeconomic position when possible. Particularly in the absence of personally reported data, researchers often use area-based measures to estimate the effects of socioeconomic position. Data are limited regarding the relative merits of measures based on US Census tract versus ZIP code (postal code). ZIP-code measures have more within-unit variation but are also more easily obtained. The current study reports on 293,138 middle-aged men screened in 14 states in 1973-1975 for the Multiple Risk Factor Intervention Trial and having 25-year mortality follow-up. In risk-adjusted proportional hazards models containing either ZIP-code-based or tract-based median household income, all-cause mortality hazard ratios were 1.16 (95% confidence interval: 1.14, 1.17) per Dollars 10,000 less ZIP-code-based income and 1.15 (95% confidence interval: 1.13, 1.16) per Dollars 10,000 less tract-based income; adding either income variable to a risk-adjusted model improved model fit substantially. Both were significant independent predictors in a combined model; tract-based income was a slightly stronger mortality predictor (hazard ratios = 1.05 and 1.11 for ZIP-code-based and tract-based income, respectively). These patterns held across various causes of death, for both Blacks and non-Blacks, and with or without adjustment for ZIP-code-based income diversity or tract-based proportion below poverty.

Latinos are now the largest minority in the United States, but their distinctive health needs and mortality patterns remain poorly understood. Proportional hazards regressions were used to compare Latino versus White risk- and income-adjusted mortality over 25 years' follow-up from 5,846 Latino and 300,647 White men screened for the Multiple Risk Factor Intervention Trial. Men were aged 35-57 years and residing in 14 states when screened in 1973-1975. Data on coronary heart disease risk factors, self-reported race/ethnicity, and home addresses were obtained at baseline; income was estimated by linking addresses to census data. Mortality follow-up through 1999 was obtained using the National Death Index. The fully adjusted Latino/White hazard ratio for all-cause mortality was 0.82 (95% confidence interval (CI): 0.77, 0.87), based on 1,085 Latino and 73,807 White deaths; this pattern prevailed over time and across states (thus, likely across Latino subgroups). Hazard ratios were significantly greater than one for stroke (hazard ratio = 1.30, 95% CI: 1.01, 1.68), liver cancer (hazard ratio = 2.02, 95% CI: 1.21, 3.37), and infection (hazard ratio = 1.69, 95% CI: 1.24, 2.32). A substudy found only minor racial/ethnic differences in the quality of Social Security numbers, birth dates, soundex-adjusted names, and National Death Index searches. Results were not likely an artifact of return migration or incomplete mortality data.

Objectives: We explored differences between Black and White men for cardiovascular disease (CVD) mortality across major risk factor levels., Methods: Major CVD risk factors were measured among 300,647 White and 20,223 Black men aged 35 to 57 years who were screened for the Multiple Risk Factor Intervention Trial (MRFIT). Hazard ratios for CVD deaths for Black and White men over 25 years of follow-up were calculated for subgroups stratified according to risk factor levels., Results: CVD was responsible for 2518 deaths among Black men and 30,772 deaths among White men. The age-adjusted Black-to-White CVD hazard ratio was 1.35 (95% confidence interval [CI]=1.29, 1.40); the risk- and income-adjusted ratio was 1.05 (95% CI=1.01, 1.10). CVD mortality rates were dramatically lower in cases of favorable risk profiles. However, fully adjusted Black-to-White CVD hazard ratios within groups at low, intermediate, high, and very high levels of overall risk were 1.76, 1.20, 1.10, and 0.94, respectively. Similar gradients were evident for individual risk factors., Conclusions: Higher CVD mortality rates among Black men were largely mediated by risk factors and income. These data underscore the need for sustained primordial risk factor prevention among Black men.

Background: Measures of health status (including symptoms, functional status, or quality of life) assess patients' experiences of their disease, and may therefore be used to quantify the benefits and risks of treatment. The aim of this article is to provide recommendations to regulatory agencies and research sponsors regarding the use of health status measures in medical device trials., Methods and Results: A workshop jointly planned by the Heart Failure Society of America and the US Food and Drug Administration was convened in October 2003 in Washington, DC. A Working Group to address health status measures initiated its collaboration at the workshop and continued its efforts throughout the next year. The Working Group recommended assessment of health status in all studies of heart failure therapy. Standardized instruments known to be valid, reliable, responsive to changes, and available in the languages of target populations should be used. Minimizing bias may be accomplished by using blinded, independent evaluators; collecting multiple health status measures; using valid statistical methods; and creating a health status resource bank., Conclusion: Assessment of health status should be part of any device trial and should occur regardless of whether the device is intended as destination or bridging therapy. Health status endpoints should be chosen, collected, and analyzed with the same level of scientific rigor as traditional clinical endpoints. Regulatory agencies should require use of analytic methods that handle the complexity of health status data in addition to usual protocol protections.

Background: Weight loss and increased physical exercise reduce the risk for diabetes in people with impaired glucose tolerance. Randomized trial evidence on the effect of these interventions on people without impaired glucose tolerance is lacking., Objective: To examine the influence of a comprehensive intervention program on the risk for developing diabetes in men without impaired glucose tolerance and in a post hoc subgroup analysis by baseline cigarette smoking status., Design: Randomized, controlled trial., Setting: 22 clinical centers for the Multiple Risk Factor Intervention Trial (MRFIT)., Participants: 12,866 men age 35 to 57 years at risk for cardiovascular disease were randomly assigned to either a special intervention or usual care group and followed for 6 to 7 years; this report focuses on 11,827 men without diabetes or impaired glucose tolerance at entry for whom follow-up glucose measurements were available., Measurements: Cardiovascular disease risk factors, fasting blood glucose levels, and diabetes medication history were assessed before randomization and annually., Intervention: Men in the special intervention group were counseled to change diet (reduce saturated fat, cholesterol, and calorie intake), to stop smoking, and to increase physical activity. Blood pressure was treated more intensively in the special intervention group than in the usual care group., Results: 11.5% of the special intervention group and 10.8% of the usual care group developed diabetes over 6 years of follow-up (hazard ratio, 1.08 [95% CI, 0.96 to 1.20]). The special intervention-usual care hazard ratio for diabetes was 1.26 (CI, 1.10 to 1.45) among smokers (63%) and 0.82 (CI, 0.68 to 0.98) among nonsmokers (37%). These estimates differed significantly (P = 0.0003). Weight gain after smoking cessation and the use of antihypertensive drugs may have counterbalanced the beneficial effect of the lifestyle intervention for the special intervention group smokers, while the lifestyle intervention was beneficial among nonsmokers., Limitations: Principal findings are based on a post hoc subgroup analysis., Conclusions: In nonsmokers, an intervention program that included nutrition counseling to produce reductions in weight, serum cholesterol, and (along with antihypertensive medication) blood pressure reduced the risk for diabetes.

Background: The magnitude of coronary mortality risk associated with diabetes or prior myocardial infarction (MI) is debatable. Modulating effects of age, risk factors, and duration of follow-up may explain discrepancies in previous research. Associations with noncardiovascular mortality are little explored., Objectives: To compare mortality patterns in men with a history of diabetes or MI and to assess modulating effects on mortality of age, cardiovascular risk factors, and follow-up duration., Methods: We compared the 25-year mortality of 4809 men with diabetes only and 4625 men with MI only (all men aged 35-57 years)., Results: The adjusted hazard ratio (HR) for all-cause mortality for those with MI only vs those with diabetes only was 0.97 (95% confidence interval, 0.92-1.03; P =.32). The pattern of deaths was different: higher coronary mortality (HR = 1.37; P<.001) and lower mortality from noncardiovascular causes (HR = 0.66; P<.001) in those with MI only compared with those with diabetes only. This finding prevailed across all ages and levels of cardiovascular risk factors. Hazard ratios for coronary mortality significantly declined over follow-up (2.7, 1.7, 1.2, 1.1, and 1.0 for < or =5, 6-10, 11-15, 16-20, and >20 years of follow-up, respectively), whereas HRs for noncardiovascular mortality remained relatively constant., Conclusions: Overall, diabetes and MI were similarly strong predictors of total mortality. Higher mortality from noncardiovascular causes was observed in those with diabetes only, whereas prior MI was more strongly predictive of coronary mortality than diabetes at any age and level of cardiovascular risk factors. The difference in coronary mortality between the 2 groups was most evident in the first 10 years of follow-up.

Background: During the design phase of a clinical trial, sample size estimates should take into account medical screening criteria, the 'healthy volunteer' effect, consequences of run-in phases, and secular trends in the event rate of interest. All of these have been shown to relate to subsequent event rates, and hence trial power to detect intervention effects. The Multiple Risk Factor Intervention Trial (MRFIT) used three successive screenings of 361 662 men to enroll 12 866; observed coronary heart disease (CHD) mortality after a mean of 6.9 years was substantially lower than projected during design. We explore factors which may have contributed to these mortality differences and whether they persisted throughout follow-up., Methods: Proportional hazards models were used to compare 25-year mortality according to trial eligibility, self-exclusions, medical exclusions, and participation., Results: After adjustment for baseline risk factors and age, there was higher mortality among men excluded for presence of disease [hazard ratio (HR) 1.52, 95% confidence interval (CI) 1.43-1.61, for total; HR 1.92, CI 1.75-2.11, for CHD] compared to those not excluded which persisted throughout follow-up. Volunteers had lower total (HR 0.82, CI 0.76-0.87) and CHD (HR 0.79, CI 0.70-0.88) mortality than those discontinuing participation. Men excluded with characteristics deemed likely to interfere with adherence had higher total (HR 1.19, CI 1.07-1.33) and non-cardiovascular disease (CVD) (HR 1.32, CI 1.14-1.53) mortality but no higher CVD (HR 1.04, CI 0.88-1.23) or CHD (HR 0.98, CI 0.80-1.20) mortality compared to those not excluded. Differences in mortality were stronger during the first five years, but declined only slightly over 25 years., Conclusions: 25-year mortality was significantly higher for non-volunteers and exclusions. Differences between observed and predicted six-year total mortality for trial participants were largely attributable to volunteers and exclusions, but there were additional differences for CHD mortality, which were likely due to downward secular trends. These results emphasize the importance of anticipating these factors during clinical trial design, even for trials of short duration.

Objective: To estimate incidence and predictors of serious or life-threatening events that are not AIDS defining, AIDS events, and death among patients treated with highly active antiretroviral therapy (HAART) in the setting of 5 large multicenter randomized treatment trials conducted in the United States., Methods: Data were analyzed from 2,947 patients enrolled from December 1996 through December 2001. All patients were to receive antiretrovirals throughout follow-up. Data collection was uniform for all main outcome measures: serious or life-threatening (grade 4) events, AIDS, and death., Results: During follow-up, 675 patients experienced a grade 4 event (11.4 per 100 person-years); 332 developed an AIDS event (5.6 per 100 person-years); and 272 died (4.6 per 100 person-years). The most common grade 4 events were liver related (148 patients, 2.6 per 100 person-years). Cardiovascular events were associated with the greatest risk of death (hazard ratio = 8.64; 95% CI: 5.1 to 14.5). The first grade 4 event and the first AIDS event were associated with similar risks of death, 5.68 and 6.95, respectively., Conclusions: Grade 4 events are as important as AIDS events in the era of HAART. To adequately evaluate the impact of HAART on morbidity, comorbidities and other key factors must be carefully assessed.

The Evaluation of Subcutaneous Proleukin in a Randomized International Trial (ESPRIT) is a large ongoing randomized trial of subcutaneous interleukin-2 (IL-2) plus antiretroviral therapy versus antiretroviral therapy alone in patients with HIV (human immunodeficiency virus) disease and CD4 cell counts of at least 300 cells/mm(3). The primary objective is to determine whether the addition of IL-2 to combination antiretroviral therapy improves morbidity and mortality. The aim is to recruit 4000 participants and follow them for an average of 5 years. Eligible subjects will be recruited at 275 investigational sites in 23 countries around the world. Coupled with broad eligibility criteria this will ensure widely applicable results. A range of secondary objectives will also be addressed in this setting that will include the conduct of observational studies and nested substudies with a public health focus. This article describes the rationale supporting the trial in addition to reviewing the study design, coordination, and governance.

Context: 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., Objective: To measure long-term mortality rates for individuals with favorable levels for all 3 major risk factors, compared with others., Design: 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., Setting and Participants: 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)., Main Outcome Measures: 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., Results: 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., Conclusions: 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.

Background and Objectives: Limited prospective data are available on sexually transmitted infections (STIs) among HIV-infected patients. The incidence and predictors of STIs were assessed among HIV-infected women enrolled in a clinical trial., Study Design: Prospective cohort of 323 women., Results: Sixty-five percent had at least one STI based on history and/or examination at baseline. Most conditions identified at baseline were based on patient history; only 10 of 123 women with no history of an STI (8.1%) had one identified upon examination. During a median follow-up of 2.1 years, 25% developed a new/recurrent STI. Being African-American (odds ratio [OR] = 4.22, 95% confidence interval [CI]: 1.45-12.26), reporting sex with an intravenous drug user as an HIV risk behavior (OR = 2.29, 95% CI: 1.34-3.92), and a history/presence of STIs at baseline (OR = 1.79, 95% CI: 1.01-3.19) were factors associated with significantly increased risk of STI's., Conclusions: A substantial proportion of women developed new STIs during the course of the clinical trial. Prevention efforts should be emphasized among high risk HIV-infected patients.

Background: 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., Methods: 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., Results: 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., Conclusions: 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.

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 reflect 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.

Context: Diabetes is a frequent cause of end-stage renal disease (ESRD). However, the degree of risk is uncertain., Objective: To determine the relative risk (RR) of ESRD related to diabetes in the United States., Design: Nonconcurrent prospective cohort study., Participants: 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)., Main Exposure: Diabetes mellitus defined by self-reported use of medication for diabetes at baseline., Main Outcome: Incident ESRD through 1990 assessed from a national ESRD registry and by surveillance for death from renal disease., Results: 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)., Conclusions: 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.

Cigarette smoking has been associated with impaired immune defenses and an increased risk of certain infectious and neoplastic diseases in HIV-1 seronegative populations. We examined the relationship between cigarette smoking and clinical outcome in a prospective cohort of 3221 HIV-1-seropositive men and women enrolled in the Terry Beirn Community Programs for Clinical Research on AIDS. Differences in clinical outcomes between never, former, and current cigarette smokers were assessed using proportional hazards regression analysis. After adjustment for CD4+ cell count, prior disease progression, use of antiretroviral therapy, and other covariates, there was no difference between current smokers and never smokers in the overall risk of opportunistic diseases [relative hazard (RH) = 1.05; 95% confidence interval (CI) 0.90-1.23; p = 0.52] or death (RH = 1.00; 95% CI 0.86-1.18; p = 0.97). However, current smokers were more likely than never smokers to develop bacterial pneumonia (RH = 1.57; 95% CI 1.14-2.15; p = 0.006), oral candidiasis (RH = 1.37; 95% CI 1.16-1.62; p = 0.0002), and AIDS dementia complex (RH = 1.80; 95% CI 1.11-2.90; p = 0.02). In addition, current smokers were less likely to develop Kaposi's sarcoma (RH = 0.58; 95% CI 0.39-0.88; p = 0.01) and several other non-respiratory tract diseases. If confirmed by other studies, these findings have important clinical implications.

The association of cigarette smoking and mortality from prostate cancer was evaluated in 348,874 black and white men who were screened as part of the Multiple Risk Factor Intervention Trial (MRFIT). Current smoking status was assessed, serum cholesterol was measured, and demographics were recorded at screening; however, no information was collected on history of smoking, prostate screening, or diet. The vital status of each member of this cohort was ascertained through 1990. Death certificates were obtained from state health departments and coded by a trained nosologist. A total of 826 deaths due to prostate cancer occurred over an average of 16 years follow-up. The proportional hazards model was used to study the joint association of age, race, income, cigarette smoking, serum cholesterol level, and use of medication for diabetes mellitus on risk of death from prostate cancer. Statistically significant associations were observed with age (p < 0.01), cigarette smoking status (relative risk (RR) = 1.31, p < 0.01), black race (RR = 2.70, p < 0.01), and serum cholesterol (RR = 1.02 for 10 mg/dl higher cholesterol level, p < 0.05). Similar results were obtained when deaths that occurred during the first 5 years were excluded. Among cigarette smokers, there was some evidence of a dose-response relation (p = 0.20). The relative risk for those who reported that they smoked 1-25 cigarettes per day compared with nonsmokers was 1.21 (p = 0.04); the relative risk for those who reported smoking > or = 26 cigarettes per day compared with nonsmokers was 1.45 (p = 0.0003). These findings add to the limited evidence that cigarette smoking may be a risk factor for prostate cancer.

Objectives: This study examined socioeconomic differentials in risk of death from a number of causes in a large cohort of Black men in the United States., Methods: For 20 224 Black men screened for the Multiple Risk Factor Intervention Trial between 1973 and 1975, data were collected on median family income of Black households in zip code of residence, age, cigarette smoking, blood pressure, serum cholesterol, previous heart attack, and drug treatment for diabetes. The 2937 deaths that occurred over the 16-year follow-up period were grouped into specific causes and related to median Black family income., Results: There was an inverse association between age-adjusted all-cause mortality and median family income. There was no attenuation of this association over the follow-up period, and the association was similar for the 22 clinical centers carrying out the screening. The gradient was seen for most of the specific causes of death, although the strength of the association varied. Median income was markedly lower for the Black men screened than for the White men, but the relationship between income and all-cause mortality was similar., Conclusions: Socioeconomic position is an important determinant of mortality risk for Black men. Even though Blacks lived in areas with substantially lower median family income than Whites, the association of income with mortality was similar for Blacks and Whites.

Objectives: This study examined socioeconomic differentials in risk of death from a number of specific causes in a large cohort of White men in the United States., Methods: For 300 685 White men screened for the Multiple Risk Factor Intervention Trial between 1973 and 1975, data were collected on median income of White households in the zip code of residence, age, cigarette smoking, blood pressure, serum cholesterol, previous myocardial infarction, and drug treatment for diabetes. The 31 737 deaths that occurred over the 16-year follow-up period were grouped into specific causes and related to median White family income., Results: There was an inverse association between age- adjusted all-cause mortality and median family income. There was no attenuation of this association over the follow-up period, and the association was similar for the 22 clinical centers carrying out the screening. The gradient was seen for many-but not all-of the specific causes of death. Other risk factors accounted for some of the association between income and coronary heart disease and smoking-related cancers., Conclusions: Socioeconomic position, as measured by median family income of area of residence, is an important determinant of mortality risk in White men.

The design, conduct, and analysis of clinical trials that evaluate the safety and efficacy of treatment interventions in patients with HIV infection provide many scientific challenges. A recently completed randomized trial of didanosine (ddI) and zalcitabine (ddC), sponsored by the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA), is an especially valuable resource for illustrating these challenging issues and for providing insights into how they might be properly addressed. Establishing equivalence of treatment effects on clinical efficacy end points is illustrated through the use of the confidence interval approach. The striking changes in treatment efficacy results that occurred during the course of the CPCRA trial provide important insights into how a data and safety monitoring board can reduce the risk of inappropriate early study termination. The trial also provides valuable insights into how treatment effects should be assessed, revealing inconsistencies between effects on the CD4 surrogate end point and effects on primary clinical efficacy end points and showing the incompleteness of the standardly employed definition of AIDS progression. Finally, the results of this ddI/ddC trial are used to examine the role of covariate adjustment.

Unlabelled: The objective of this study was to investigate risk factors for death from different types of stroke among men screened for the Multiple Risk Factor Intervention Trial (MRFIT). A total of 353,340 men were screened by 20 centers for the MRFIT in 1973 to 1975; vital status has been ascertained over an average of 12 years of follow-up (range: 11 to 13 years). Death certificates were coded using the International Classification of Diseases (ICD), ninth revision. Deaths from stroke were classified as death from subarachnoid hemorrhage (ICD code 430), death from intracranial hemorrhage (ICD codes 431 and 432), death from nonhemorrhagic stroke (ICD codes 433 through 438), and death from any type of stroke (ICD codes 430 through 438)., Results: During an average of approximately 12 years of follow-up, 765 deaths from stroke were identified; 139 of these deaths were attributable to subarachnoid hemorrhage; 227, to intracranial hemorrhage; and 399 were classified as nonhemorrhagic stroke. Blood pressure and cigarette smoking were strongly related to each type of stroke. Systolic blood pressure was a stronger predictor than diastolic blood pressure. With the exception of subarachnoid hemorrhage, death rates from each type of stroke increased with age and were higher for black men. The positive association of age and race with subarachnoid hemorrhage was much weaker than for the other types of stroke and was not significant. Income was inversely associated with risk of death from nonhemorrhagic stroke and was not associated with either subarachnoid or intracranial hemorrhage.(ABSTRACT TRUNCATED AT 250 WORDS)

The National High Blood Pressure Education Program (NHBPEP) was launched 20 years ago based on data from population studies and clinical trials that showed high blood pressure (HBP) was a major unsolved--but soluble--mass public health problem. The present review summarizes recent data from US prospective population studies on blood pressure--systolic (SBP), diastolic (DBP)--and cardiovascular risk. The outcome variables include blood pressure-related risks, primarily incidence and mortality from coronary heart disease, stroke, other and all cardiovascular diseases (CVD); also cardiac abnormalities (roentgenographic, electrocardiographic, echocardiographic); also, all-cause mortality and life expectancy. Data accrued during the past 20 years confirm that SBP and DBP have continuous, graded, strong, independent, etiologically significant relationships to the outcome variables. These relationships are documented for young, middle-aged, and older men and for middle-aged and older women of varying socioeconomic backgrounds and ethnicity. Among persons aged 35 years or more, most have SBP/DBP above optimal (< 120/< 80 mm Hg); hence, they are at increased CVD risk, ie, the blood pressure problem involves most of the population, not only the substantial minority with clinical HBP. For middle-aged and older persons, SBP relates even more strongly to risk than DBP; at every DBP level, higher SBP results in greater CVD risk and curtailment of life expectancy. A great potential exists for improved health and increased longevity through control of the blood pressure problem. Its realization requires a strategy combining population wide and high-risk approaches, the former to prevent rise of blood pressure with age and to achieve primary prevention of HBP by nutritional-hygienic means; the latter to enhance detection, treatment, and control of HBP. The newly expanded goals of the NHBPEP, aimed at implementing this broader strategy for the solution of the blood pressure problem, merit active support from physicians and all health professionals.

Objective: To assess predictors of CVD mortality among men with and without diabetes and to assess the independent effect of diabetes on the risk of CVD death., Research Design and Methods: Participants in this cohort study were screened from 1973 to 1975; vital status has been ascertained over an average of 12 yr of follow-up (range 11-13 yr). Participants were 347,978 men aged 35-57 yr, screened in 20 centers for MRFIT. The outcome measure was CVD mortality., Results: Among 5163 men who reported taking medication for diabetes, 1092 deaths (603 CVD deaths) occurred in an average of 12 yr of follow-up. Among 342,815 men not taking medication for diabetes, 20,867 deaths were identified, 8965 ascribed to CVD. Absolute risk of CVD death was much higher for diabetic than nondiabetic men of every age stratum, ethnic background, and risk factor level--overall three times higher, with adjustment for age, race, income, serum cholesterol level, sBP, and reported number of cigarettes/day (P < 0.0001). For men both with and without diabetes, serum cholesterol level, sBP, and cigarette smoking were significant predictors of CVD mortality. For diabetic men with higher values for each risk factor and their combinations, absolute risk of CVD death increased more steeply than for nondiabetic men, so that absolute excess risk for diabetic men was progressively greater than for nondiabetic men with higher risk factor levels., Conclusions: These findings emphasize the importance of rigorous sustained intervention in people with diabetes to control blood pressure, lower serum cholesterol, and abolish cigarette smoking, and the importance of considering nutritional-hygienic approaches on a mass scale to prevent diabetes.

Two widely used criteria for determining whether an association between a risk factor and a disease is causal are dose response and independence from other factors. Data from a large US risk factor study (MRFIT) throw up a relation between cigarette smoking and suicide that meets these criteria, yet appears to be biologically implausible. It is likely that many more such associations, for other exposures and other diseases, are equally spurious, but are protected by their lack of obvious implausibility.

The association between leukocyte count and subsequent risk of major coronary heart disease events was examined using data from three prospective cohort studies--two from the United States and one from Great Britain. A total of 28,181 middle-aged men were followed for 6-12 years. A total of 1,768 men had a nonfatal myocardial infarction or died of coronary heart disease. In all three cohorts, there was a positive, statistically significant relation between baseline leukocyte count and risk of subsequent major coronary heart disease events after adjustment for age, serum total cholesterol, diastolic blood pressure, and number of cigarettes smoked per day (relative odds = 1.32 (p less than 0.0001), 1.15 (p = 0.0001), and 1.14 (p = 0.003), corresponding to a 2,000/mm3 difference in leukocyte count). The associations persisted when all nonsmokers (former smokers plus never smokers) and never smokers alone were considered and when those with evidence of preexisting coronary heart disease at baseline were excluded. Leukocyte count appears to be an indicator of a person's future risk of major coronary heart disease events.

We examined the relation between the serum total cholesterol level and the risk of death from stroke during six years of follow-up in 350,977 men, 35 to 57 years of age, who had no history of heart attack and were not currently being treated for diabetes mellitus. The diagnosis of stroke and the type of stroke were obtained from death certificates. Using proportional-hazards regression to control for age, cigarette smoking, diastolic blood pressure, and race or ethnic group, we found that the six-year risk of death from intracranial hemorrhage (International Classification of Diseases, ninth edition [ICD-9], categories 431 and 432) was three times higher in men with serum cholesterol levels under 4.14 mmol per liter (160 mg per deciliter) than in those with higher cholesterol levels (P = 0.05 by omnibus test across five cholesterol levels). On the other hand, a positive association was observed between the serum cholesterol level and death from nonhemorrhagic stroke (P = 0.007). The inverse association of the serum cholesterol level with the risk of death from intracranial hemorrhage was confined to men with diastolic blood pressure greater than or equal to 90 mm Hg, in whom death from intracranial hemorrhage is relatively common. We conclude that there is an inverse relation between the serum cholesterol level and the risk of death from hemorrhagic stroke in middle-aged American men, but that its public health impact is overwhelmed by the positive association of higher serum cholesterol levels with death from nonhemorrhagic stroke and total cardiovascular disease (ICD-9 categories 390 through 459).

The Multiple Risk Factor Intervention Trial (MRFIT) was a randomized primary prevention trial to test whether a special intervention (SI) program to reduce high blood pressure, elevated blood cholesterol, and/or cigarette smoking could lower coronary heart disease (CHD) mortality in middle-aged men at above average risk. After an average follow-up period of 7 years, risk factor levels were reduced substantially more in SI than in usual-care (UC) men; however, SI-UC differences in CHD mortality (7.1%) and total mortality (-2.1%) were not statistically significant. Subgroup analysis showed 35% fewer SI than UC CHD deaths (P = 0.14) but no all-causes mortality difference in men comparable to the cohort having dietary and smoking intervention in Oslo (the "Oslo-like" cohort). Among the subgroup hypertensive at entry, SI-UC differences in CHD and total mortality appeared to be heterogeneous: CHD mortality was 24% lower in SI than UC men with a normal resting ECG at baseline, but 67% higher if baseline ECG abnormalities were present (nominal P = 0.02, for difference in relative risk estimates). These findings were supported by within-group analyses and are generally consistent with results of other CHD/cardiovascular disease prevention trials. They pose a new hypothesis about possible adverse effects of diuretic therapy in a minority of the hypertensive population.

Among the 356,222 men screened for the Multiple Risk Factor Intervention Trial who had no history of hospitalization for heart attack at entry, more than 2,000 coronary deaths occurred during 6 years of follow-up. With this large data set, detailed cross-tabulations clearly and simply showed the strong graded relation between blood pressure and coronary heart disease death. This risk gradient was evident in each of five age groups ranging from 35 to 57 years and for levels of diastolic blood pressure ranging from less than 75 mm Hg to greater than 115 mm Hg. Systolic blood pressure was more strongly associated with coronary heart disease death than was diastolic blood pressure, and isolated systolic blood pressure elevation was found to be an important risk factor in these middle-aged men. The risk of coronary death was increased among hypertensive men who had elevated serum cholesterol levels or who smoked cigarettes. Because less than 10% of hypertensive men had cholesterol levels in the lowest quintile (below 182 mg/dl) and were nonsmokers, a multi-intervention approach for the large majority of hypertensive persons is clearly indicated. Risks of death were also substantially increased among those hypertensive men who already had end-organ damage, emphasizing the importance of early treatment to prevent such damage. These findings have implications for the design of prevention trials and clinical practice, as it is clear that systolic as well as diastolic blood pressure should be considered in treating hypertensive patients. Additionally, treatment goals should be directed at preventing not only death but many other morbid events, clinical and subclinical, that are associated with elevated blood pressure and that are preventable with appropriate treatment.

To examine the relation between diuretic use and ventricular premature complexes (VPCs) in the Multiple Risk Factor Intervention Trial, data derived from the baseline and annual rest electrocardiograms were analyzed for men in the special-intervention (SI) and usual-care (UC) groups. At baseline, age, diuretic use and presence of other rest electrocardiographic abnormalities were significantly associated with the prevalence of VPCs. Among diuretic users at baseline, those with lower serum potassium levels were most likely to have VPCs. Over the follow-up period among nonhypertensive persons the relative risk (SI/UC) for the occurrence of VPCs during follow-up was 0.83, and for hypertensives this relative risk increased linearly from 1.08 to 1.42, with higher levels of diastolic blood pressure at entry (p less than 0.01 for linear trend of relative risk estimates). This was due to an increasing risk among the SI group, and the risk was independent of the presence or absence of rest electrocardiographic abnormalities at baseline. The relative risk estimate, diuretic vs no diuretic, for development of VPCs was approximately 1.2 (p = 0.04) for SI men and 1.1 (p = 0.35) for UC men. The reduction in serum potassium level was greater for those with VPCs, and regression analysis showed that low serum potassium levels were significantly associated with the incidence of VPCs in both study groups. These data confirm and quantify the relation between diuretic drugs and VPCs and suggest that at least 1 mechanism of diuretic-induced VPCs is potassium depletion.

The 356,222 men aged 35 to 57 years, who were free of a history of hospitalization for myocardial infarction, screened by the Multiple Risk Factor Intervention Trial (MRFIT) in its recruitment effort, constitute the largest cohort with standardized serum cholesterol measurements and long-term mortality follow-up. For each five-year age group, the relationship between serum cholesterol and coronary heart disease (CHD) death rate was continuous, graded, and strong. For the entire group aged 35 to 57 years at entry, the age-adjusted risks of CHD death in cholesterol quintiles 2 through 5 (182 to 202, 203 to 220, 221 to 244, and greater than or equal to 245 mg/dL [4.71 to 5.22, 5.25 to 5.69, 5.72 to 6.31, and greater than or equal to 6.34 mmol/L]) relative to the lowest quintile were 1.29, 1.73, 2.21, and 3.42. Of all CHD deaths, 46% were estimated to be excess deaths attributable to serum cholesterol levels 180 mg/dL or greater (greater than or equal to 4.65 mmol/L), with almost half the excess deaths in serum cholesterol quintiles 2 through 4. The pattern of a continuous, graded, strong relationship between serum cholesterol and six-year age-adjusted CHD death rate prevailed for nonhypertensive nonsmokers, nonhypertensive smokers, hypertensive nonsmokers, and hypertensive smokers. These data of high precision show that the relationship between serum cholesterol and CHD is not a threshold one, with increased risk confined to the two highest quintiles, but rather is a continuously graded one that powerfully affects risk for the great majority of middle-aged American men.

The Multiple Risk Factor Intervention Trial screening program provided an opportunity (1) to study the association of diastolic blood pressure level, serum cholesterol concentration, and cigarettes per day with all-cause and cause-specific mortality after 5 years among 23,490 black males and (2) to compare these associations with those observed among 325,384 white males. The relationship of serum cholesterol concentration and reported cigarettes per day to all-cause, coronary heart disease (CHD), and cerebrovascular disease mortality was similar for black and white males. Diastolic blood pressure was more positively associated with cerebrovascular disease death among black males than white males (p = 0.047) according to logistic regression analysis. The lower CHD mortality among black males compared to white males was most apparent among hypertensive males (diastolic blood pressure greater than or equal to 90 mm Hg). The relative risk (black vs white) of CHD death adjusted for age, serum cholesterol concentration, and cigarettes per day was 0.69 for hypertensive males compared to 1.15 for nonhypertensive males (p = 0.012 for difference in relative risk estimates). These findings suggest that the causes of CHD and cerebrovascular disease may be different for black and white males, particularly in regard to how these disease processes relate to blood pressure.

To test the hypothesis that higher levels of high-density lipoprotein cholesterol (HDL-C) in black men than in white men may offer the former greater protection against coronary heart disease (CAD), the relation between HDL-C and 7-year incidence of CAD was examined in the 5,792 white men and in the 465 black men assigned to the usual-care group of the Multiple Risk Factor Intervention Trial. CAD events included nonfatal myocardial infarction diagnosed on the basis of serial electrocardiographic change or medical record review, and fatal CAD events including sudden CAD deaths, deaths attributed to myocardial infarction or congestive heart failure caused by CAD, and deaths associated with coronary artery bypass surgery. At baseline, mean diastolic blood pressure and prevalence of cigarette smoking were significantly higher in black men, but the reverse was true for serum cholesterol (246 vs 254 mg/dl, p less than 0.01). Mean HDL-C was higher in black men than in white men (49.3 vs 41.6 mg/dl, p less than 0.01), but low-density lipoprotein cholesterol (LDL-C) levels were similar (159 vs 160 mg/dl). An inverse association between HDL-C and socioeconomic status was observed in black men, whereas a direct association was observed in white men. During follow-up, small reductions occurred in HDL-C and LDL-C in both groups. No black men died of stroke; 16 black and 404 white men sustained CAD events (5.1 vs 10.4/1,000 person-years of risk). The black-white relative risk was 0.49 (p = 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

To assess the impact of serum cholesterol level on the risk of fatal coronary heart disease for men with high blood pressure, the six-year follow-up data from 361,662 men (aged 35 to 57 years) screened in 18 cities in the recruitment effort for the Multiple Risk Factor Intervention Trial were evaluated. Of these men, 356,222 reported no history of hospitalization for myocardial infarction; 100,032 of these 356,222 had a baseline mean diastolic blood pressure equal to or greater than 90 mm Hg. For those men with high blood pressure, the overall age-adjusted six-year rate of coronary heart disease death was 79 percent higher than for those with diastolic blood pressure less than 90 mm Hg. Compared with men with diastolic blood pressure less than 90 mm Hg and serum cholesterol below 182 mg/dl, men with diastolic blood pressure equal to or greater than 90 mm Hg had the following relative risks, based on the serum cholesterol level: for those with a serum cholesterol level less than 182 mg/dl, risk was 1.64; for those with a level of 182 to 202 mg/dl, risk was 2.14; for those with a level of 203 to 220 mg/dl, risk was 3.14; for those with a level of 221 to 244 mg/dl, risk was 3.29; and for those with a level equal to or greater than 245 mg/dl, risk was 5.14. Thus, for men with high blood pressure, serum cholesterol related to coronary heart disease risk in a strong, graded way, over the entire distribution of serum cholesterol, from levels of 182 mg/dl and higher. This was the case for hypertensive male smokers and nonsmokers, with cigarette use associated with a further marked increase in risk--at least a doubling of the mortality rate--at any level of serum cholesterol. These data underscore the necessity for a strategy of comprehensive care for persons with high blood pressure, including approaches to both nutritional and hygienic counseling and drug treatment, aimed at controlling all of the established major risk factors influencing prognosis.

The influence of risk factors on CHD and all-cause mortality rates in 35- to 57-year-old men is examined by means of data on 325,348 white men who were screened for the MRFIT. This large data set permits an unusually detailed analysis of factors associated with the 6968 deaths, including 2426 ascribed to CHD, that were detected in the Social Security Administration data set during 6 years of follow-up. Simple cross classification of the data confirms the independent effect of serum cholesterol concentration, diastolic blood pressure, and cigarette smoking as risk factors for CHD and all-cause mortality rates. A distinct escalation of risk is noted for combinations of these risk factors. The strength of the association of each of the risk factors with CHD and all-cause mortality rates diminished with increasing age, although the number of excess deaths attributable to the risk factors increased because of the higher death rates in older men. Comparison of these findings with those observed in the five populations studied in the Pooling Project revealed an overall similarity in the risk relationships. It is estimated that elimination of these risk factors has the potential for reducing the CHD mortality rate by two thirds in 35- to 45-year old men, and by one half in 46- to 57-year-old men.