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J Neaton

Publications and source records attributed to J Neaton.

17 recordsLinked to original sources
PubMed2006

The feasibility of clinical endpoint trials in HIV infection in the highly active antiretroviral treatment (HAART) era.

BACKGROUND: Planning clinical-endpoint trials in patients with HIV remain difficult as long-term follow-up of many patients is required. Cohort studies of patients with HIV can provide key estimates of the likely disease progression, required sample size and follow-up. OBJECTIVES: To verify the assumptions used in designing ESPRIT, a large randomized clinical trial assessing the clinical benefit of interleukin-2 treatment in patients with HIV infection, to use EuroSIDA to mimic the inclusion criterion of ESPRIT in order to compare the observed event rate in ESPRIT with the projected rate in EuroSIDA, and to project the required length of ESPRIT. METHODS: Patients in EuroSIDA who satisfied the ESPRIT recruitment criteria were selected. Patients were followed from baseline to new AIDS or death. RESULTS: The incidence of clinical progression in the selected EuroSIDA patients (N = 4482) was 1.5 per 100 PYFU (95% CI 1.3-1.7), and did not increase with increasing time from baseline, contrary to what was assumed in the design of the ESPRIT trial. In ESPRIT (N = 4150), for which the comparative data remain blinded, the incidence was 1.1 per 100 PYFU (95% CI 0.9-1.3), with no increase over time. The average follow-up required to complete ESPRIT and accrue the 320 events required by protocol would be seven years, 10 months using the projected rates from the EuroSIDA study, and seven years, 11 months if the observed event rate in ESPRIT continued unchanged. LIMITATIONS: Differences between patients recruited to observational studies or clinical trials cannot always be adjusted for. CONCLUSIONS: Event rates in EuroSIDA were similar in the first two years to those used in the design of ESPRIT, but did not increase over time, leading to an increase in the expected duration of ESPRIT. Clinical endpoint trials in HIV infection remain feasible, and large cohort studies are critical to the planning and ongoing assessment of design assumptions in such trials. The underlying assumptions of the clinical trial should be re-examined to ensure the original trial assumptions remain valid.

Acquired Immunodeficiency Syndrome↗
PubMed2000

Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial--the Losartan Heart Failure Survival Study ELITE II.

BACKGROUND: The ELITE study showed an association between the angiotensin II antagonist losartan and an unexpected survival benefit in elderly heart-failure patients, compared with captopril, an angiotensin-converting-enzyme (ACE) inhibitor. We did the ELITE II Losartan Heart Failure Survival Study to confirm whether losartan is superior to captopril in improving survival and is better tolerated. METHODS: We undertook a double-blind, randomised, controlled trial of 3,152 patients aged 60 years or older with New York Heart Association class II-IV heart failure and ejection fraction of 40% or less. Patients, stratified for beta-blocker use, were randomly assigned losartan (n=1,578) titrated to 50 mg once daily or captopril (n=1,574) titrated to 50 mg three times daily. The primary and secondary endpoints were all-cause mortality, and sudden death or resuscitated arrest. We assessed safety and tolerability. Analysis was by intention to treat. FINDINGS: Median follow-up was 555 days. There were no significant differences in all-cause mortality (11.7 vs 10.4% average annual mortality rate) or sudden death or resuscitated arrests (9.0 vs 7.3%) between the two treatment groups (hazard ratios 1.13 [95.7% CI 0.95-1.35], p=0.16 and 1.25 [95% CI 0.98-1.60], p=0.08). Significantly fewer patients in the losartan group (excluding those who died) discontinued study treatment because of adverse effects (9.7 vs 14.7%, p<0.001), including cough (0.3 vs 2.7%).

Aged↗
PubMed1999

Effects of losartan versus captopril on mortality in patients with symptomatic heart failure: rationale, design, and baseline characteristics of patients in the Losartan Heart Failure Survival Study--ELITE II.

BACKGROUND: In the Evaluation of Losartan in the Elderly (ELITE) heart failure study, a survival benefit (primarily because of a reduction in sudden deaths) was observed in symptomatic patients treated with losartan compared with captopril. METHODS AND RESULTS: The Losartan Heart Failure Survival Study--ELITE II (currently ongoing) is a double-blind, randomized clinical trial being conducted in 45 countries at 288 sites. ELITE II formally tests the hypotheses that losartan, compared with captopril, will reduce all-cause mortality (primary end point) and sudden cardiac death and/or resuscitated cardiac arrest (secondary end point). In addition, all-cause mortality and/or hospitalizations and cardiovascular mortality and/or hospitalizations will be evaluated. The trial has 90% power to detect a 25% treatment difference in all-cause mortality (event driven, 510 deaths). Substudies are examining quality of life, health care resource utilization, and mechanisms related to the reduction in sudden death. During recruitment (June 1997 to May 1998), 3,152 patients aged 60 years or older (mean age, 71.6 years), with New York Heart Association classes II (51%), III (44%), and IV (5%), and left ventricular ejection fraction of 40% or less (mean, 31%) were randomized to receive either 12.5 mg of losartan, titrated as tolerated to 50 mg once daily, or 12.5 mg of captopril, titrated as tolerated to 50 mg thrice daily. Randomization was stratified by clinical site and for baseline beta-blocker use. CONCLUSION: The ELITE II study will further define the role of losartan in the treatment of patients with symptomatic heart failure relative to the angiotensin-converting enzyme inhibitor captopril, an agent from a class currently considered standard treatment for this disease.

Aged↗
PubMed1998

Statistical issues for HIV surrogate endpoints: point/counterpoint. An NIAID workshop.

This paper summarizes the proceedings of an NIAID-sponsored workshop on statistical issues for HIV surrogate endpoints. The workshop brought together statisticians and clinicians in an attempt to shed light on some unresolved issues in the use of HIV laboratory markers (such as HIV RNA and CD4+ cell counts) in the design and analysis of clinical studies and in patient management. Utilizing a debate format, the workshop explored a series of specific questions dealing with the relationship between markers and clinical endpoints, and the choice of endpoints and methods of analysis in clinical studies. This paper provides the position statements from the two debaters on each issue. Consensus conclusions, based on the presentations and discussion, are outlined. While not providing final answers, we hope that these discussions have helped clarify a number of issues, and will stimulate further consideration of some of the highlighted problems. These issues will be critical in the proper assessment and use of future therapies for HIV disease.

Biomarkers↗
PubMed1995

Blood pressure and mortality among men with prior myocardial infarction. Multiple Risk Factor Intervention Trial Research Group.

BACKGROUND: The purpose of the present study was to describe the relation between blood pressure (systolic [SBP] and diastolic [DBP]) and death from coronary heart disease (CHD) and all causes for men with a history of myocardial infarction (MI). METHODS AND RESULTS: The study cohort consisted of men aged 35 to 57 years screened for the Multiple Risk Factor Intervention Trial (MRFIT) in 1973 through 1975 and followed for survival for an average of 16 years through 1990. There were 5362 men who reported prior hospitalization for a heart attack of at least 2 weeks' duration at the initial screening of MRFIT. There was a J-shaped relation between SBP and DBP with both CHD and all-cause mortality during the first 2 years of follow-up in older (age, 45 to 57 years) men only. Risk nadirs for SBP were 152 and 145 mm Hg, respectively, for CHD death and all-cause mortality; corresponding DBP risk nadirs were 94 and 90 mm Hg. After the first 2 years, there was a positive association between SBP and death from CHD and all causes. By 15 years, cumulative CHD mortality percentages for men with screening SBP < 120, 120 to 139, 140 to 159, and > or = 160 mm Hg were 19.7%, 21.3%, 27.5%, and 32.0%, respectively. When deaths only after year 2 were considered, although the linear DBP coefficient was significant, the quadratic term for DBP was no longer significant (P > .05). However, the relation still appeared J-shaped as cumulative mortality for those with DBP < 70, 70 to 79, 80 to 89, 90 to 99, and > or = 100 mm Hg was 24.3%, 20.8%, 21.1%, 25.5%, and 29.7%, respectively. When the joint relation of SBP and DBP was considered, there were no survival differences among the four cohorts (SBP > or = 140 and DBP < 80, SBP > or = 140 and DBP > or = 80, SBP < or = 140 and DBP < 80, and SBP < or = 140 and DBP > or = 80) during the first 2 years. After 2 years, both CHD and all-cause mortality rates were approximately 40% higher for participants with SBP > or = 140 mm Hg versus < 140 mm Hg regardless of DBP level (< 80 or > or = 80 mm Hg). CONCLUSIONS: In this large cohort of men with prior MI, the association of SBP and DBP with CHD and all-cause mortality varied over the 16-year follow-up period. During early follow-up, in older men only, J- or U-shaped relations were evident. However, after 2 years, these same relations had become positive and graded. Given the substantial excess mortality risk in this cohort associated with high blood pressure, particularly SBP, efforts to gradually lower blood pressure should receive high priority among hypertensive men with prior MI.

Adult↗
PubMed1994

On being poor with HIV.

Explore the source record for details and available documents.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Relationship of baseline major risk factors to coronary and all-cause mortality, and to longevity: findings from long-term follow-up of Chicago cohorts.

The focus here is on relationships between major risk factors and long-term mortality from coronary heart disease (CHD) and all causes, and on longevity, in Chicago cohorts: 25-year follow-up for Peoples Gas (PG) men aged 25-39 (n = 1,119), 30-year follow-up for PG men aged 40-59 (n = 1,235), 24-year follow-up for Western Electric (WE) men aged 40-55 (n = 1,882); also 15-year follow-up for five cohorts of the Chicago Heart Association (CHA) Study: men aged 25-39 (n = 7,873), 40-59 (n = 8,515), 60-74 (n = 1,490), and women aged 40-59 (n = 7,082) and 60-74 (n = 1,243); also 12-year findings for very low risk men (n = 11,098) and other men (n = 350,564) screened for the Multiple Risk Factor Intervention Trial (MRFIT). With a high degree of consistency, multivariate analyses showed independent positive relationships of baseline serum cholesterol, blood pressure and cigarette use to risk of death from CHD and all causes. For the WE cohort, with baseline nutrient data, dietary cholesterol was also independently related to these mortality risks. Combined risk factor impact was strong for both men and women of all baseline ages. Thus, for WE men, favorable compared to observed levels of serum cholesterol, blood pressure, cigarette use and dietary cholesterol were estimated to result in 24-year risk of CHD death 69% lower, all-cause death 42% lower and longevity 9 years greater. For CHA middle-aged and older women, favorable baseline levels of serum cholesterol, blood pressure and cigarette use were estimated to yield 15-year-CHD risk lower by about 60% and longevity greater by about 5 years. For MRFIT, very low risk men (serum cholesterol < 182 mg/dl, systolic/diastolic blood pressure < 120/<80), nonsmokers, nondiabetic, no previous heart attack), compared to all others, observed 12-year death rates were lower by 89% for CHD, 79% for stroke, 86% for all cardiovascular diseases, 30% for cancers, 21% for other causes, 53% for all causes, and longevity was estimated to be more than 9 years longer. These findings indicate great potentials for prevention of the CHD epidemic and for increased longevity with health for men and women, through improved life-styles and consequent lower risk factor levels.

Adult↗
PubMed1993

Improved ECG models for estimation of left ventricular hypertrophy progression and regression incidence by redefinition of the criteria for a significant change in left ventricular hypertrophy status. The MRFIT Research Group. Multiple Risk Factor Intervention Trial.

Three sets of left ventricular hypertrophy (LVH) criteria were evaluated in terms of their utility for LVH progression and regression incidence estimation. Incidence comparisons were performed with and without taking short-term variability into consideration using electrocardiographic records taken at the baseline and the first annual follow-up examination of 11,969 men, aged 37 to 55 years, at the baseline of the Multiple Risk Factor Intervention Trial. Short-term total technical and biologic variability (95% range) was determined from the records of 104 men invited for a repeat electrocardiographic recording at 2-week or shorter intervals from the first recording. The results indicated that after elimination of the false fraction due to normal variability, the residual incidence estimates are so low that their utility and statistical power in monitoring changes in LVH status is very limited. It is concluded that a redefinition of LVH progression and regression criteria is needed to enhance their utility in clinical trials.

Adult↗
PubMed1992

Report of the Conference on Low Blood Cholesterol: Mortality Associations.

BACKGROUND: A National Heart, Lung, and Blood Institute (NHLBI) Conference was held October 9-10, 1990, to review and discuss existing data on U-shaped relations found between mortality rates and blood total cholesterol levels (TC) in some but not other studies. Presentations were given from 19 cohort studies from the United States, Europe, Israel, and Japan. A representative of each study presented its findings and also submitted tables of proportional hazards regression coefficients for entry TC levels in regard to death, and these were incorporated into a formal statistical overview adjusted for age, diastolic blood pressure, cigarette smoking, body mass index, and alcohol intake, as available. METHODS AND RESULTS: The U-shape for total mortality in men and the flat relation in women resulted largely from a positive relation of TC with coronary heart disease death and an inverse relation with deaths caused by some cancers (e.g., lung but not colon), respiratory disease, digestive disease, trauma, and residual deaths. Risk for combined noncardiovascular, noncancer causes of death decreased steadily across the range of TC. The conference considered possible explanations for the statistical associations found between low TC levels or active TC lowering and certain causes of death. One is that TC is lowered by some disease conditions themselves, such as wasting in chronic pulmonary disease or reduced production and secretion of cholesterol-bearing lipoproteins with liver disease. In this sort of situation, the TC:mortality association found in observational studies may be due to preexisting disease. This was addressed by excluding early deaths from the analysis, which did not change the results. The conference considered as well the biological function of cholesterol, which, if seriously deranged, might hypothetically cause a wide variety of diseases and dysfunction. The conference also considered the biological functions that might provide plausible mechanisms for the associations found. CONCLUSIONS: Definitive interpretation of the associations observed was not possible, although most participants considered it likely that many of the statistical associations of low or lowered TC level are explainable by confounding in one form or another. The conference focused on the apparent existence and nature of these associations and on the need to understand their source rather than on any pertinence of the findings for public health policy. Further research is recommended to explain the observed associations of low TC levels (and TC lowering) with certain noncardiovascular diseases. This includes studies of the time course of TC change in disease, the relation of TC to morbidity, further studies of possible epidemiological confounding, monitoring of population trends in TC and mortality, further studies of the relations in women, auditing of noncardiovascular events in trials, studies of cell membrane, genetic and molecular links to cholesterol metabolism, TC level and disease, studies of disease manifestations in specific lipid disorders, and further study of the proposed causal mechanisms linking low TC and hemorrhagic stroke.

Alcohol Drinking↗
PubMed1991

Sodium chloride raises blood pressure in normotensive subjects. The study of sodium and blood pressure.

The effects of dietary sodium on blood pressure in normotensive adults is not well characterized. The Study of Sodium and Blood Pressure (SNaP) is a randomized, double-blind crossover trial using a placebo or 96 meq sodium in 4-week treatment periods separated by a 2-week washout period. Before capsule treatment periods, participants were instructed in a low sodium diet for 10 weeks to reduce urinary sodium excretion to less than 35 meq/8 hr. The low sodium diet was continued throughout the capsule treatment periods. Participants (n = 48; 47 white, 1 black) were 79% male and had an average age of 52 years, a body mass index of 27.6, and a baseline blood pressure of 131/84 mm Hg. Baseline overnight urinary sodium excretion was 51 meq/8 hr and 19 meq/8 hr after the low sodium diet run-in period, before the capsule treatment periods began. Resting, seated blood pressure was measured twice at each visit in a standard fashion. Differences between sodium and placebo treatment periods were as follows: systolic blood pressure, 123.9 versus 120.3 mm Hg, respectively (p less than 0.001); diastolic blood pressure, 78.7 versus 76.4 mm Hg, respectively (p = 0.005); and sodium excretion, 51.3 versus 30.9 meq/8 hr, respectively (p less than 0.001). Both systolic and diastolic blood pressures increased significant amounts in normotensive adults on a low sodium diet supplemented with 96 meq/day sodium. Long-term effects and dose-response relations need further study.

Adult↗
PubMed1990

Blood pressure, stroke, and coronary heart disease. Part 1, Prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias.

The associations of diastolic blood pressure (DBP) with stroke and with coronary heart disease (CHD) were investigated in nine major prospective observational studies: total 420,000 individuals, 843 strokes, and 4856 CHD events, 6-25 (mean 10) years of follow-up. The combined results demonstrate positive, continuous, and apparently independent associations, with no significant heterogeneity of effect among different studies. Within the range of DBP studied (about 70-110 mm Hg), there was no evidence of any "threshold" below which lower levels of DBP were not associated with lower risks of stroke and of CHD. Previous analyses have described the uncorrected associations of DBP measured just at "baseline" with subsequent disease rates. But, because of the diluting effects of random fluctuations in DBP, these substantially underestimate the true associations of the usual DBP (ie, an individual's long-term average DBP) with disease. After correction for this "regression dilution" bias, prolonged differences in usual DBP of 5, 7.5, and 10 mm Hg were respectively associated with at least 34%, 46%, and 56% less stroke and at least 21%, 29%, and 37% less CHD. These associations are about 60% greater than in previous uncorrected analyses. (This regression dilution bias is quite general, so analogous corrections to the relations of cholesterol to CHD or of various other risk factors to CHD or to other diseases would likewise increase their estimated strengths.) The DBP results suggest that for the large majority of individuals, whether conventionally "hypertensive" or "normotensive", a lower blood pressure should eventually confer a lower risk of vascular disease.

Adult↗
PubMed1990

The impact of dietary sodium, potassium and calcium on blood pressure.

A blood pressure survey was conducted in 3,886 male Taiwanese workers of a single Fukien ethnic group. Their mean age was 34 years. Hypertension defined as a systolic blood pressure of greater than or equal to 140 and/or diastolic blood pressure of greater than or equal to 90 mmHg was present in 370 subjects (9.5%). The high ethnic homogeneity in the study population allowed for an examination on the relationship between diet and blood pressure. A case control study was conducted in 161 subjects with elevated blood pressure and 154 subjects with normal blood pressure, randomly selected in each group, to assess the effects of dietary sodium, potassium and calcium on blood pressure. A 24-hour dietary recall was collected independently by a nutritionist. Using regression analysis, a significant (p less than 0.01) positive association of sodium intake and blood pressure was noted independent of age, body mass index and alcohol intake. The risk of elevated blood pressure was 2.5 times greater in men with a daily sodium intake of greater than 15g compared with those whose daily sodium intake was less than 15g. A negative association of calcium and potassium with blood pressure was noted in a group who ingested potassium greater than 2g and calcium greater than 0.5g daily. However, a statistical significance was achieved for calcium (p less than 0.01) but not for potassium (p = 0.15). These results indicate that dietary sodium and calcium are related to blood pressure and hypertension status within a unique and culturally homogeneous male group of Fukien ethnicity.

Adult↗
PubMed1989

Electrocardiographic left ventricular hypertrophy and effects of antihypertensive drug therapy in hypertensive participants in the Multiple Risk Factor Intervention Trial.

Data are reported on electrocardiographic left ventricular hypertrophy (ECG LVH) among 8,012 men classified as hypertensive at baseline in the Multiple Risk Factor Intervention Trial. Compared with those allocated to the usual care (UC) control group, men allocated to the special intervention (SI) group experienced a mean reduction of 4 mm Hg in diastolic blood pressure and 7 mm Hg in systolic blood pressure, over 6 years of follow-up. There were 378 new cases of ECG LVH during follow-up; the incidence in the SI group was about 23% less than that in the UC group (4.2 vs 5.4% 2P less than 0.01). Among the 189 men with ECG LVH at baseline, those in the SI group experienced about 24% more annual follow-up visits at which they were free of ECG LVH (4.6 vs 3.7 visits; 2P less than 0.01). This reduced incidence and increased reversal of ECG LVH in the SI group compared with that in the UC group was consistent with significant overall reductions (2P less than 0.001) among SI men in mean wave amplitude in those leads in which voltage is correlated with left ventricular mass (T wave in V1, R wave in aVL and S wave in V3). In SI and UC groups combined, the presence of ECG LVH either at baseline or at follow-up was associated with several-fold increases in death from cardiovascular diseases in general, and death from coronary artery disease in particular.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1986

Unexpected effects of treating hypertension in men with electrocardiographic abnormalities: a critical analysis.

The relationship between diuretic therapy and possible increased risk of coronary heart disease (CHD), especially sudden death, is controversial. The initial report from the Multiple Risk Factor Intervention Trial (MRFIT) raised the possibility that the increased CHD mortality observed in a subset of special intervention men with hypertension and certain electrocardiographic abnormalities on their baseline examination might be an unexpected adverse effect of diuretic therapy. Subsequent reports from the MRFIT have revealed a stronger association of CHD mortality to hydrochlorothiazide than to chlorthalidone. There was no consistent relationship of CHD mortality to the dose of either drug, to the most recent serum potassium level, or to the presence of ventricular premature beats. Unfavorable trends of the same magnitude were also seen among similar white men in the Hypertension Detection and Follow-up Program and in the Oslo hypertension trial, although the sample sizes in these two studies were too small to yield clearcut conclusions. Clinical studies have shown an increased risk of CHD death among hypertensive men with left ventricular hypertrophy. Such men are also noted to have a higher frequency of ventricular premature beats, even in the absence of diuretic therapy. Other studies have shown that diuretic-induced hypokalemia is accentuated in the presence of epinephrine and that low potassium levels decrease the threshold for ventricular fibrillation. Thus, although the evidence is still incomplete, it is possible that the excess CHD mortality among MRFIT special intervention men with electrocardiographic abnormalities may have been caused by a combination of increased left ventricular mass in the presence of coronary atherosclerosis, and hypokalemia caused by good compliance with diuretic therapy and accentuated by stress-induced increases in circulating catecholamines. Given the very large population of patients receiving diuretic therapy, further evaluation of this possibility is important.

Adult↗
PubMed1983

Environmental determinants, liver function, and high density lipoprotein cholesterol levels.

High density lipoprotein cholesterol (HDL-chol) is negatively associated with coronary heart disease. Environmental heart disease risk factors may partially be related to coronary heart disease through alterations in HDL-chol concentrations. Little is known about the underlying mechanisms by which environmental factors are related to HDL-chol. The authors investigated a possible mechanism: changes in liver function as a mediating link between risk factors and HDL-chol concentrations in marathon runners, alcoholics, and participants in the Multiple Risk Factor Intervention Trial. Liver function, as measured by liver enzymes, was related to both coronary heart disease risk factors and alcohol consumption, suggesting that the increased levels of HDL-chol associated with alcohol were primarily the result of changes in liver function. The relationship of obesity to HDL-chol could not be explained by the alterations in liver function.

Adult↗