Methodological issues in the design of primary prevention trials.
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Anticarcinogenic Agents↗
Biomedical subjects
J E Buring
Publications and source records attributed to J E Buring.
Anti-platelet effects of 100 mg alternate day oral aspirin: a randomized, double-blind, placebo-controlled trial of regular and enteric coated formulations in men and women.
AIM: While regular use of low-dose aspirin has been recommended for several groups of patients at risk of vascular occlusion, the optimal dose of aspirin to produce a cardiovascular benefit whilst minimizing side effects is uncertain. Further, while enteric coated preparations may reduce gastrointestinal symptoms, the antiplatelet effects of these formulations have not been completely tested. In addition, exceptionally few data relating to these issues have been available in women. METHODS: To determine whether a 100 mg alternate day dose of aspirin given in regular and enteric coated formulations for a 2-week period is sufficient to inhibit platelet function in men and women, a randomized, double-blind, placebo-controlled trial was conducted among 22 healthy volunteers evaluating the effects of these preparations on platelet aggregation induced by arachidonic acid, adenosine diphosphate, and epinephrine, and on plasma concentrations of thromboxane and prostacyclin. RESULTS: During the active aspirin phase of the study, all subjects demonstrated a clinical anti-platelet effect as evidenced by failure of the platelets to aggregate in the presence of at least one platelet agonist, and mean thromboxane and prostacyclin levels decreased to 7.5 and 15.6% of baseline, respectively (both P < 0.001). After cessation of active aspirin, all subjects had fully recovery of platelet function as well as thromboxane and prostacyclin production. There were virtually no differences between regular and enteric coated formulations, or between men and women. CONCLUSION: These data indicate that an alternate day regimen of 100 mg aspirin given in either regular or enteric coated formulation is adequate to achieve functional platelet inhibition. The clinical efficacy of this dose and formulation of aspirin is being tested in the ongoing Women's Health Study, a randomized, double-blind, placebo-controlled trial of 40000 female health professionals designed in part to assess the benefits and risks of 100 mg alternate day aspirin in the primary prevention of cardiovascular disease.
Adenosine Diphosphate↗
Physical exercise and reduced risk of nonfatal myocardial infarction.
While the inverse association between physical activity and coronary heart disease risk is well documented, questions remain regarding the intensity of exercise, the potential for confounding by other risk factors for coronary heart disease, and the role of blood lipids and apolipoproteins. The authors examined these issues in the Boston Area Health Study, a case-control study of 340 patients (266 men, 74 women) who survived a first myocardial infarction between January 1, 1982, and December 31, 1983, and 340 controls matched on sex, age, and residence. The relative risk of myocardial infarction for those in the highest quartile of physical activity, compared with the lowest, was 0.50 (95 percent confidence interval (CI) 0.31-0.80) for men and 1.00 (95 percent CI 0.41-2.43) for women. When subjects were categorized by level of energy expenditure on moderate to vigorous sports alone, men in the most active category had 0.39 (95 percent CI 0.23-0.69) times the risk of those in the least active category, and women, 0.43 (95 percent CI 0.15-1.26) times the risk. Adjustment for body mass index, smoking, alcohol intake, diet, personal and family medical history, and personality type did not substantially change results nor did further adjustment for blood lipids. This was not surprising as total energy expenditure was uncorrelated with blood lipids or apolipoproteins. Moderate to vigorous sporting activity, however, appeared to be directly related to high density lipoprotein (HDL) cholesterol (p = 0.06), especially the HDL2 subfraction (p = 0.10). In these data, findings suggest that physical activity is inversely related to myocardial infarction risk, independently of other risk factors for coronary heart disease.
Adult↗
Psychosocial risk factors and nonfatal myocardial infarction.
BACKGROUND: Numerous psychosocial factors have been hypothesized to play a role in coronary heart disease. However, existing studies have yielded inconsistent results. METHODS AND RESULTS: The relations between type A personality as well as suppressed versus expressed anger and risk of nonfatal myocardial infarction (MI) were studied in 340 patients and 340 age-, sex-, and community-matched control subjects. Subjects were interviewed at home to assess behavioral and medical cardiovascular risk factors, and fasting blood samples were obtained. Type A personality was associated with nonfatal MI in crude matched-pair analysis (OR, 1.57; 95% CI, 1.12 to 2.20; P = .008). Adjusting for known cardiovascular risk factors (including treated hypertension, body mass index, treated diabetes, family history of premature MI, physical activity, smoking, alcohol, total calories per day, and saturated fat) did not substantially change the magnitude of the point estimate, although the finding was no longer statistically significant (OR, 1.43; 95% CI, 0.97 to 2.09; P = .069). Further adjustment for lipids, including total cholesterol, total HDL, its subfractions (HDL2, HDL3), LDL, VLDL, and triglycerides, markedly attenuated the association (OR, 1.12; 95% CI, 0.66 to 1.90; P = .687), an effect due almost entirely to HDL cholesterol. Suppressed anger was positively but not statistically significantly associated with increased risk of MI in crude matched-pair analysis (OR, 1.33; 95% CI, 0.98 to 1.81; P = .065), in analysis adjusted for behavioral and medical cardiovascular risk factors (OR, 1.26; 95% CI, 0.89 to 1.78; P = .193), or after adjustment for lipids (OR, 1.11; 95% CI, 0.67 to 1.82; P = .695). CONCLUSIONS: These findings suggest a possible association of type A but not suppressed anger with risk of nonfatal MI that may be mediated by alterations in HDL cholesterol level. If decreases in HDL are not in the same causal pathway, then the apparent association between type A personality and risk of MI is due to confounding, principally by HDL.
Anger↗
Fish consumption and cardiovascular disease in the physicians' health study: a prospective study.
The authors examined the association between dietary intake of fish and omega 3 fatty acids from seafood and the risk of cardiovascular disease in a prospective cohort study of 21,185 US male physicians who are participants in the Physicians' Health Study. In 4 years of follow-up, there were 281 incident cases of total (fatal and nonfatal) myocardial infarction, 173 cases of stroke, and 121 cardiovascular deaths. There was no evidence for association between dietary intake of fish and any cardiovascular endpoint, including myocardial infarction, stroke, and cardiovascular death. The relative risks of total myocardial infarction, adjusted for age and randomized treatment assignment, for categories of fish intake were: 1.0 for < 1 meal/week (referent), 1.6 (95% confidence interval (Cl) 1.1-2.3) for 1 fish meal/week; 1.4 (95% Cl 1.0-2.0) for 2-4 fish meals/week; and 1.2 (95% Cl 0.6-2.2) for > or = 5 fish meals/week; chi 2 for trend = 0.9, p = 0.34. The relative risks were similar for omega 3 fatty acid intake and for specific types of fish, and did not change after adjustment for history of hypertension, hypercholesterolemia, diabetes mellitus, or angina pectoris, parental history of myocardial infarction before age 60 years, obesity, exercise, smoking, alcohol use, saturated fat intake, and vitamin supplement use. These data do not support the hypothesis that moderate fish consumption lowers the risk of cardiovascular disease.
Aged↗
The primary prevention of coronary heart disease in women.
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Antioxidants↗
Migraine and subsequent risk of stroke in the Physicians' Health Study.
OBJECTIVE: To evaluate, in a prospective design, whether migraine is an independent risk factor for subsequent stroke. DESIGN: Evaluated as part of the Physicians' Health Study, a randomized, double-blind, placebo-controlled trial of aspirin and beta-carotene in the primary prevention of cardiovascular disease and cancer begun in 1982. The aspirin component of the study was terminated in 1988, with average follow-up of 60.2 months. SETTING: Conducted by mail among male physicians throughout the United States. PARTICIPANTS: A total of 22,071 US male physicians aged 40 to 84 years in 1982 with no prior history of cancer or cardiovascular diseases who were enrolled in the Physicians' Health Study. INTERVENTIONS: Participants were randomized to receive 325 mg of aspirin or aspirin placebo every other day and to receive 50 mg of beta-carotene or placebo on alternate days. MAIN OUTCOME MEASURES: The primary outcomes of the Physicians' Health Study were cardiovascular disease and cancer. Because stroke was a main outcome, this provided the opportunity to evaluate the association between migraine headaches and stroke. RESULTS: Physicians reporting migraine (n = 1479) had significantly increased risks of subsequent total stroke and ischemic stroke compared with those not reporting migraine. After adjustment for age, aspirin and beta-carotene treatment assignment, and a number of cardiovascular risk factors, the relative risks were 1.84 (95% confidence interval, 1.06 to 3.20) for total stroke and 2.00 (95% confidence interval, 1.10 to 3.64) for ischemic stroke. There were too few hemorrhagic strokes in the study to evaluate this end point. No associations were seen between ordinary nonmigraine headache and subsequent stroke or between migraine and subsequent myocardial infarction or cardiovascular death. CONCLUSION: These data raise the possibility that vascular events associated with migraine may also have causative importance in stroke but require confirmation in other studies specifically designed to evaluate this question.
Adult↗
beta-carotene and cancer chemoprevention.
Evidence supports the potential role of beta-carotene in cancer prevention. Basic research has demonstrated that beta-carotene can trap organic free radicals and/or deactivate excited oxygen molecules which may have an anticancer effect by preventing tissue damage. Although observational epidemiologic studies are not entirely consistent, many show an inverse association between dietary intake or blood levels of beta-carotene and subsequent cancer risk. Two large-scale randomized trials of beta-carotene have been completed. A Finnish trial demonstrated no benefit of beta-carotene among middle-aged male smokers, with those assigned to this supplement in fact experiencing an increased risk of lung cancer. However, because of the long latency period for cancer, which may be a decade or more, the six-year duration of treatment in this trial may have been inadequate to detect an anticancer effect. A Chinese trial demonstrated a modest reduction in cancer mortality from a combined regimen of beta-carotene, vitamin E, and selenium. The effect of the individual agents could not be assessed, and because the trial was carried out among a nutritionally deficient population, its results may not have direct relevance to well-nourished individuals. Several additional large-scale trials of beta-carotene are ongoing. The Physicians' Health Study, which is testing beta-carotene among 22,071 US male physicians, will have an average duration of treatment of 12.5 years at its scheduled termination in late 1995. Data in women will be available from the Women's Health Study, which began in 1992, and will randomize approximately 40,000 US female health professionals.(ABSTRACT TRUNCATED AT 250 WORDS)
Anticarcinogenic Agents↗
A prospective study of consumption of carotenoids in fruits and vegetables and decreased cardiovascular mortality in the elderly.
Recent evidence suggests that oxidative damage may be involved in atherogenesis, and thus dietary antioxidants, such as beta-carotene, may reduce the risks of cardiovascular disease (CVD). We examined the association between consumption of carotene-containing fruits and vegetables and CVD mortality among 1299 elderly Massachusetts residents who provided dietary information as a part of the Massachusetts Health Care Panel Study. During a mean follow-up of 4.75 years, there were 161 deaths attributable to CVD, 48 of which were due to myocardial infarction. For total CVD death and fatal myocardial infarction, risks were lower among those residents in the highest quartile for consumption of carotene-containing fruits and vegetables as compared with those in the lowest. For death due to CVD, the relative risk (RR) was 0.54 (95% confidence interval (CI), 0.34 to 0.86; P for trend across quartiles, 0.004). For myocardial infarction the RR was 0.25 (95% CI, 0.09 to 0.67; P for trend, 0.002). These observational data are compatible with the hypothesis that increased dietary intake of carotenoids decreases the risks of CVD mortality; however, confounding cannot be ruled out. This hypothesis requires rigorous evaluation in randomized trials of sufficient size to detect reliably whether carotenoids confer small-to-moderate but clinically important protection against CVD.
Aged↗
A secondary prevention trial of antioxidant vitamins and cardiovascular disease in women. Rationale, design, and methods. The WACS Research Group.
The evidence for a potential benefit of antioxidant vitamins in the prevention and therapy of atherosclerotic disease is derived from laboratory, clinical, and observational epidemiologic studies but remains inconclusive. Data from randomized clinical trials are sparse, particularly for women. Therefore, it is both timely and important to conduct large-scale primary and secondary prevention trials of antioxidants and cardiovascular disease (CVD). The Women's Antioxidant and Cardiovascular Study (WACS) is a randomized, double-blind, placebo-controlled secondary prevention trial of the balance of benefits and risks of antioxidant vitamins (vitamins E and C, and beta-carotene) among 8000 women with preexisting CVD. This secondary prevention trial will be conducted as a companion to the recently started Women's Health Study, a primary prevention trial of vitamin E and beta-carotene, as well as aspirin. In the WACS, US female health professionals aged 40 years and older with a history of myocardial infarction, angina pectoris, coronary revascularization, stroke, transient cerebral ischemia, carotid endarterectomy, or peripheral artery surgery will be randomly assigned, utilizing a 2 x 2 x 2 factorial design, to receive vitamin E, vitamin C, beta-carotene, and/or placebo. Cardiovascular end points include nonfatal myocardial infarction, nonfatal stroke, coronary revascularization procedures, and total CVD mortality. The present article describes the rationale, design, and methods of the trial.
Antioxidants↗
Antioxidant vitamin-cardiovascular disease hypothesis is still promising, but still unproven: the need for randomized trials.
The hypothesis that antioxidant vitamins might decrease the risk of cardiovascular disease (CVD) is a promising area of research. At present, however, it is far from certain whether antioxidant vitamins confer protection against CVD. Evidence for the antioxidant vitamin-cardiovascular disease hypothesis has accumulated from several lines of research. Laboratory research has identified biochemical properties of antioxidant vitamins that could explain their possible role in inhibiting and delaying coronary atherosclerosis. Epidemiologic studies have provided support for the hypothesis by showing that people who consume high amounts of antioxidant vitamins through diet or supplements, or those with high concentrations of these nutrients in their blood, tend to have lower risks of CVD. In the case of the former, however, laboratory findings may not have relevance to free-living humans. Observational epidemiologic studies cannot exclude the possibility that people who consume antioxidant-rich diets or who take vitamin supplements also share other lifestyle or dietary practices that actually account for their lower disease rates. Because of these uncertainties, the only way to determine reliably whether antioxidants play any role in reducing the risk of CVD is to conduct large-scale, randomized trials of these agents, in which adequate doses of antioxidant vitamins are tested for a sufficient duration to allow for any benefits to emerge. Several large-scale trials are now ongoing in both primary and secondary prevention. The results of these trials over the next several years should provide reliable evidence for this promising, but as yet unproven, hypothesis.
Antioxidants↗
Micronutrients and HIV-1 disease progression.
OBJECTIVE: To determine whether nutritional status affects immunological markers of HIV-1 disease progression. DESIGN: A longitudinal study, to evaluate the relationship between plasma levels of nutrients and CD4 cell counts, along and in combination with beta 2-microglobulin (beta 2M; AIDS index) over an 18-month follow-up. METHODS: Biochemical measurements of nutritional status including plasma proteins, zinc, iron and vitamins B1, B2, B6, B12 (cobalamin), A, E, C and folate and immunological markers [lymphocyte subpopulations (CD4) and beta 2M] were obtained in 108 HIV-1-seropositive homosexual men at baseline and over three 6-month time periods. Changes in nutrient status (e.g., normal to deficient, deficient to normal), were compared with immunological parameters in the same time periods using an autoregressive model. RESULTS: Development of deficiency of vitamin A or vitamin B12 was associated with a decline in CD4 cell count (P = 0.0255 and 0.0377, respectively), while normalization of vitamin A, vitamin B12 and zinc was associated with higher CD4 cell counts (P = 0.0492, 0.0061 and 0.0112, respectively). These findings were largely unaffected by zidovudine use. For vitamin B12, low baseline status significantly predicted accelerated HIV-1 disease progression determined by CD4 cell count (P = 0.041) and the AIDS index (P = 0.005). CONCLUSIONS: These data suggest that micronutrient deficiencies are associated with HIV-1 disease progression and raise the possibility that normalization might increase symptom-free survival.
Adult↗
Man-made vitreous fibers and risk of respiratory system cancer: a review of the epidemiologic evidence.
Because asbestos has been demonstrated to cause lung cancer, the issue regarding safety of other fibers, including man-made vitreous fibers (MMVF), has been raised. We reviewed the available evidence, in particular the epidemiologic data, on MMVF and the risk of respiratory system cancer. Glass fibers (especially glass wool) have been studied most extensively. Taken together, the data indicate that among those occupationally exposed, glass fibers do not appear to increase risk of respiratory system cancer. Of six studies that specifically examined rock and slag wool workers, three reported excesses in respiratory system cancer among such workers. Two of these three studies, however, did not control for cigarette smoking, a powerful predictor of such cancers. There are no published studies, in humans, of refractory ceramic fibers. Future studies evaluating the potential of MMVF to increase risk of respiratory system cancer will not add to existing knowledge if investigators do not address potential confounding by cigarette smoking and other workplace carcinogens.
Animals↗
Annotation: confounding in epidemiologic research.
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Confounding Factors, Epidemiologic↗
Contributions of observational evidence and clinical trials in cancer prevention.
Observational studies and randomized trials provide relevant and complementary information to a totality of evidence on which to base rational clinical decision making for patients and overall health policy for the general population. Observational studies are particularly useful for detecting moderate to large effects. The 15- to 20-fold greater risk of lung cancer among long term cigarette smokers was established by case-control and prospective cohort studies. The approximate 80% increased risk of coronary heart disease associated with current smoking also has been reliably demonstrated in observational studies. However, as the relative risk gets smaller, there is increasing concern that unmeasured or unknown confounding variables may account for all or part of any observed association. For these reasons, reliable inferences about interventions likely to confer small to moderate benefits will emerge only from randomized trials of sufficient sample size and duration of treatment and follow-up. Dietary variables have been postulated to account for as much as 35% of all human cancers. However, the hypothesized benefit of any specific dietary constituent, such as the antioxidant beta-carotene, is likely to be modest in size, on the order of a 20-30% reduction in risk. Therefore, although a large number of observational studies have demonstrated that individuals with higher dietary intakes or blood levels of beta-carotene have lower risks of cancer, only randomized trials can address this hypothesis definitively. Such trials, however, must be of sufficient duration to allow for the development of an anticancer effect. This may mean a decade or more based on the analogy with smoking cessation and decreased risks of lung cancer. Several ongoing large-scale trials are testing beta-carotene and other promising cancer chemoprevention agents, and their results will provide clear evidence on the balance of benefits and risks of these interventions.
Carotenoids↗
Nonsteroidal antiinflammatory drugs and colorectal cancer. A promising hypothesis but not yet proven.
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Anti-Inflammatory Agents, Non-Steroidal↗
Height, lung function, and mortality from cardiovascular disease among the elderly.
The relation between height and death from cardiovascular disease was studied in a cohort of 3,809 persons aged 65 years or older (85% of eligible individuals) enrolled in a population survey in 1982-1983 in East Boston, Massachusetts. Self-reported height and weight were obtained, and peak expiratory flow rate (PEFR) was measured using a mini-Wright peak flow meter (Armstrong Industries, North Brook, Illinois). Vital status and cause of death were obtained through 1988. The median height was 62 inches in women and 66 inches in men. After adjustment for age, body mass index, and cigarette smoking, the risk of cardiovascular death decreased with quintile of height in women, with relative risks of 1.65, 1.16, 1.15, 0.76, and 1.00 over successive quintiles, with the tallest as the referent (p trend = 0.015). The trend in men was not as strong, with relative risks of 1.22, 0.77, 0.90, 0.98, and 1.00 from the shortest to the tallest quintiles (not significant). In both men and women, the strongest association was found with height and height squared, indicating a curvilinear relation. Height remained a predictor in women after adjustment for PEFR and other risk factors. These data suggest that a relation between height and cardiovascular death that is not mediated by lung function exists in the elderly, at least among women.
Age Factors↗
Antioxidant vitamins--benefits not yet proved.
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Antioxidants↗