The multiple risk factor intervention trial (MRFIT). VII. A comparison of risk factor changes between the two study groups

Risk factor changes over 4 years for MRFIT Special Intervention (SI) participants are compared with risk factor changes made by Usual Care (UC) participants. Differences between the two study groups are compared with original design assumptions. After 4 years of follow-up, serum cholesterol differences averaged 50% of what was predicted; diastolic blood pressure differences between the two study groups averaged 67% of that predicted; cigarette smoking reductions in the Special Intervention group relative to the Usual Care group have exceeded what was predicted each year based on reported histories. When serum thiocyanate is used to verify reported cessation the SI-UC difference is reduced but still averages greater than the reductions predicted in the third and fourth years of follow-up.     

The multiple risk factor intervention trial (MRFIT): I. Historical perspectives

The beginnings of the Multiple Risk Factor Intervention Trial (MRFIT) for the primary prevention of coronary heart disease (CHD) are chronicled. Over the period 1960–1970, various scientific panels had urged the undertaking of primary CHD prevention trials but with limited consensus on the specific type of study needed. The Task Force on Arteriosclerosis convened by the National Heart and Lung Institute (NHLI) in 1971 recommended that a national diet-heart trial not be supported but, instead, that the NHLI undertake multiple risk factor intervention trials in individuals at high risk of CHD due to combinations of elevated serum lipids, hypertension, and cigarette smoking. Late in 1971, the NHLI invited proposals for MRFIT. Its primary purpose was to determine whether a special risk factor intervention program directed at the reduction of elevated serum cholesterol, elevated diastolic blood pressure, and cigarette smoking in men at high risk of death from CHD (but still free of clinical evidence of CHD) would result in a significant reduction in CHD mortality; nonfatal myocardial infarction or CHD mortality; cardiovascular mortality; and mortality from all causes—over a 6-year period. In 1972–1973, funds to conduct such a study among 12,000 randomized men were awarded to 22 clinical centers, a coordinating center, central laboratory, standardization laboratory, ECG centers, and a drug distribution center. The evolution of the organization of this research undertaking is described.     

The multiple risk factor intervention trial (MRFIT).: II. The development of the protocol

The detailed development of the MRFIT protocol is discussed, beginning with the general plan outlined by the National Heart and Lung Institute in the initial solicitation of contract proposals. The protocol is designed to test the hypothesis that lowering serum cholesterol by diet, reducing high blood pressure by diet and drugs, and cessation of cigarette smoking will result in a reduced risk of (a) death from coronary heart disease (CHD), (b) combined fatal CHD and nonfatal myocardial infarction, (c) deaths from all cardiovascular disease, and (d) death from all causes, over a period of 6 years among men aged 35–57 without initial evidence of CHD. After screening 361,662 men, from 1974 to early 1976, 12,866 from the upper end of the risk spectrum of CHD on the basis of serum cholesterol, blood pressure, and smoking habits, were randomly assigned either to a program of Special Intervention (SI) directed toward altering these risk factors or to their usual source of medical care (UC). Men in the UC group have been evaluated once each year in the clinic without direct intervention on the risk factors. Men in the SI group participated in an initial intensive series of group sessions designed to assist in modification of behavior relating to the three risk factors. The SI men have since been invited to the clinic at least three times each year to maintain and increase risk factor change. Changes in the intervention protocol have resulted mainly from difficulty in achieving the expected response in serum cholesterol. These changes have included greater emphasis on control of body weight, the recommendation of more rigorous dietary specifications for those with persistently elevated levels of serum cholesterol, and advice to increase physical activity.     

The multiple risk factor intervention trial (MRFIT): V. Intervention on smoking

The development, implementation, and results of the smoking cessation program of the Multiple Risk Factor Intervention Trial (MRFIT) are presented. The MRFIT is a 6-year clinical trial designed to investigate the effects of reducing cardiovascular risk factors—elevated cholesterol, hypertension, and cigarette smoking—in a group of asymptomatic men at high risk of cardiovascular disease. The men participated in an integrated intervention program that offered both group and individual formats, a structured maintenance program for those who stopped smoking, and an extended intervention program for those unable to quit initially. Results among the original 4,103 smokers included a 47.3% quit rate 4 months after program initiation and a 45.9% quit rate after 4 years. Of those reporting no smoking at 4 months, 56% were abstinent at all visits through 48 months. Most recidivism occurred soon after initial cessation, with 17% of the men who reported quitting at 4 months reporting smoking 4 months later. The quit rates were strongly associated with the initial level of smoking, with light smokers reporting higher quit rates and lower recidivism rates at all visits through 4 years. Results exceed trial goals whether measured by self-reports or by thiocyanate levels, an objective assessment of smoking behavior. Discussion focuses on understanding the variables contributing to smoking cessation and to achieving the goals of reduction of risk of cardiovascular disease.     

The multiple risk factor intervention trial (MRFIT): IV. Intervention on blood lipids

The results are presented for the first 4 years of the Multiple Risk Factor Intervention Trial (MRFIT) nutrition intervention program. Study participants were at high risk (upper 10–15%) for Coronary Heart Disease (CHD). The Special Intervention (SI) group reached and sustained the goals of an eating pattern originally designed to limit cholesterol intake to less than 300 mg/day, with less than 10% of calories as saturated fat and not more than 10% as polyunsaturated fat. By the end of the first year, mean serum total cholesterol had fallen by 6.3% from the mean initial value of 254 mg/dl. The magnitude of the decrease became slightly greater in the ensuing years, reaching 7.4% by the fourth annual visit. Substantially larger decreases in mean serum cholesterol level were observed in the subgroups with the highest baseline level, greatest weight loss, in those who did not smoke, and in those who had normal blood pressure on entry. The changes in cholesterol level were accompanied by parallel changes in mean plasma LDL cholesterol, which also fell by 6.6% over the 4 years, but mean HDL cholesterol was not substantially altered. Comparison with earlier population data suggests that the overall responses to the MRFIT eating pattern were limited by the apparent fact that participants had already made self-initiated changes toward the fatcontrolled dietary pattern before they entered the study.     

Multiple risk factor intervention trial (MRFIT).: VI. Intervention on blood pressure

The MRFIT blood pressure data derived from the Special Intervention (SI) group of men over the first 4 years are presented, and the results of the hypertension treatment program are reviewed. A therapeutic goal diastolic blood pressure (DBP) was established for each man determined to be hypertensive which included men with DBP ?90 mm Hg and men who were already taking antihypertensive drugs. A stepped care protocol was used to guide the drug treatment. At the fourth annual examination, 63.8% of the 5,790 SI men seen had been previously declared hypertensive. The mean baseline blood pressure (BP) for the hypertensive group was 140.3 mm Hg, systolic, and 94.5 mm Hg, diastolic, and at the 48-month visit, the mean BP was 120.7 mm Hg, systolic, and 82.5 mm Hg, diastolic. Of the hypertensive men seen at 48 months, 87.3% were taking antihypertensive drugs, 65.4% were at or below their goal pressure, and 83.5% had a DBP <90 mm Hg. Most men on antihypertensive drug therapy were at protocol Step 1 or Step 2, receiving a diuretic agent alone (32.9%), or in combination with an antiadrenergic drug (40.4%). Data for specific drug regimens are presented. Older men and men with higher BP levels at entry had a better response. The MRFIT BP results, achieved within a context of a multiple-risk-factor intervention program, compare favorably with the results from recently reported trials that focused solely on the treatment of mild hypertension.     

A randomized trial of aspirin and beta-carotene among U.S. physicians

The Physicians' Health Study is a randomized, placebo-controlled, double-blind clinical trial underway in the United States to assess the effects of aspirin (325 mg q.o.d.) on total cardiovascular mortality, and of beta-carotene (50 mg q.o.d.) on cancer incidence. The participants are 22,071 U.S. male physicians between the ages of 40-84 years. The design of the study is 2 x 2 factorial, which enables us to address two important research questions simultaneously. The trial is conducted entirely by mail, which involves sending calendar packs of drugs and questionnaires on health status and compliance, initially at six-month then at annual intervals. Compliance and follow-up rates to date are excellent. The large size of the trial, its simple design, and the use of highly motivated, dedicated, and health-conscious physicians should allow us to perform definitive tests of whether low-dose aspirin consumption reduces total cardiovascular mortality and beta-carotene decreases cancer incidence in a healthy population.     

Estrogen use and myocardial infarction risk: a case-control study

A case-control study was conducted to examine the relationship of estrogen use to myocardial infarction in postmenopausal white women. After exclusion of proxy responses and of controls with discharge diagnoses of gynecologic or gallbladder diseases, there remained 39 matched sets (33 pairs and 6 triplets). The unadjusted relative odds ratio (RO) for past estrogen use was found to be 0.83. However, after simultaneous adjustment for cardiovascular diseases, smoking, education, and type of menopause, the net RO was 0.61. Type of menopause was found to interact with estrogen use, in that the protective effect was seen mainly in surgical menopause women, in whom the net RO for estrogen use was 0.37. Although none of the results reached statistical significance, they are consistent with recent results indicating a protective effect for estrogen therapy in regard to coronary heart disease, mainly among women undergoing surgical menopause.     

Preventing and treating periodontal disease with the keyes technique: A preliminary assessment

This article uses data from 190 patient records in 18 dental practices to conduct a shortterm assessment of the effectiveness and costs of the Keyes technique, a nonsurgical method for treating and preventing periodontal disease. The results of this study, based on nonexperimental data, suggest that controlled clinical trials are called for in assessing the long-term effectiveness of the Keyes technique. If clinical trials support the study's short-term results, then the Keyes technique would provide a cost-effective alternative to surgery for the prevention and treatment of periodontal disease.     

Synergism between radiation and other risk factors for breast cancer

The question of whether the risk of radiation-induced breast cancer is additive or multiplicative (synergistic) with other risk factors for breast cancer has important implications for determining optimal guidelines for mammographic screening. Data from a follow-up study of 571 women given X-ray therapy for acute postpartum mastitis in Rochester, New York, and 993 control women were analyzed to examine this question. No synergism was found between breast irradiation and family history of breast cancer, late parity, oral contraceptive use, menopausal hormone use, or a composite of ovarian-related factors. Results indicated that women with a history of breast irradiation who develop benign breast disease, particularly cystic disease, are at high risk for breast cancer and should be carefully monitored. Women who were irradiated at the time of their first childbirth are also at especially high risk for breast cancer.     

Baseline chronic disease risk factors in a racially heterogeneous elementary school population: The "Know Your Body" program, Los Angeles

The Los Angeles "Know Your Body" (KYB) program is an organized health education activity for children designed to encourage positive health behavior and discourage or interrupt behavioral patterns that are linked to illness, injury, disability, or death. Components of KYB include a 20-week curriculum; a survey of health knowledge, attitudes, and behaviors; in-service training for elementary school teachers; and a clinical screening that provides feedback to students on selected indices. As part of a KYB field demonstration in Los Angeles conducted by the UCLA Division of Cancer Control, Jonsson Comprehensive Cancer Center, 1,503 Los Angeles and Santa Monica-Malibu children ages 9-11 in grades 4 and 5 underwent baseline health screening evaluations in March 1981, measuring height, weight, triceps skinfold thickness, serum cholesterol, pulse rate recovery following exercise, and blood pressure. The population mean for serum cholesterol was 182.6 mg/dl, with no significant racial/ethnic, sex, or age differences. Significant racial/ethnic differences were found in obesity, with Hispanics having the highest prevalence, Asians the lowest. Black students scored significantly higher in pulse rate recovery following exercise, suggesting better relative cardiovascular fitness, and Asians scored lowest. Blacks were more likely to exceed the 95th percentile in diastolic and systolic blood pressure. Overall, 48% of the children had one or more chronic disease risk factors.     

Analysis of a study of menses induction using a vaginal suppository containing 3.0 mg 15(S)-15-methyl-PGF2α methyl ester

Peripheral blood levels of 15-methyl-PGF2α, human chorionic gonadotropin (hCG) and progesterone were determined in patients treated for the induction of menses with a single vaginal suppository containing 3.0 mg 15(S)-15-methyl-PGF2α methyl ester. The mean blood levels of 15-methyl-PGF2α were higher in the successful cases than in the failures or in cases that were defined as partial successes. The plasma level of 15-methyl-PGF2α increased faster in the successful cases than in the failure cases, and was maintained at elevated levels longer in the successful cases than in the partially successful cases. Serum concentrations of hCG declined following treatment in both the successful and unsuccessful cases. At the follow-up visit (approximately 2 weeks after treatment), the level of hCG was significantly lower in the successful cases than in the unsuccessful cases. Serum concentrations of progesterone did not change significantly in any of the groups during the first 10 hr after treatment. However, at the follow-up visit the concentration of progesterone in the successful cases was significantly lower than in the failure cases. A larger percentage of the patients in whom menses was successfully induced had gastrointestinal side effects than patients who were considered treatment failures. This analysis has demonstrated a distinct relationship between blood levels of 15-methyl-PGF2α and the efficacy of these vaginal suppositories for menses induction. The successful induction of menses was associated with a more rapid increase in the plasma concentration of 15-methyl-PGF2α and with mean concentrations of drug that were significantly higher than in the cases that were considered failures. The higher blood levels of drug were also associated with a higher incidence of gastrointestinal side effects. The experience accumulated to date indicates that a vaginal delivery system for 15(S)-15-methyl-PGF2α methyl ester that releases the drug faster and in a more predictable fashion than the vaginal suppository is required for the successful induction of menses.     

Multivariate prediction of smoking cessation following physician advice to quit smoking: A validation study

A multivariate predictive model was developed to classify patients with respiratory disease as to their smoking status following physician advice to quit (L. L. Pederson, J. C. Baskerville, and J. M. Wanklin, Prev. Med.11, 536–549 (1982)). The purpose of this study was to validate this model on a new group of patients by comparing their predicted smoking behavior with their actual behavior. Using a probability of 0.50 as the cutoff for prediction, overall accuracy was 89.6%. However, the sensitivity for detecting those who would actually quit was low. By reducing the cutoff probability to 0.20, overall accuracy remained high and sensitivity was increased. A discussion of the implications of different types of classification errors is presented based on cost-effectiveness considerations. The clinical usefulness of prediction models is discussed.     

Attitudes and practices of physicians regarding hypertension and smoking: The Stanford Five City Project

A survey was sent to 318 physicians in Monterey County, California, to assess their attitudes and practices regarding hypertension and cigarette smoking. After three mailings, 62% returned completed questionnaires. Eight percent of the respondents were smokers, 5% were women, and 34% were in primary care specialties. Older physicians and primary care specialists were less aggressive in their treatment of high blood pressure, but none of the assessed attitudes was significantly associated with treatment practice. Only half of the sample advised all patients to quit smoking. Physicians who doubted the effectiveness of their anti-smoking advice or who did not know what to say to smoking patients were less likely to provide advice. Most physicians felt that their smoking patients lacked sufficient motivation to quit. Programs to encourage physicians to increase smoking cessation activities should address these attitudes.     

Seasonal patterns of asthma: A clue to etiology

An extensive data set of daily hospital emergency room visits for asthma for two geographic areas (1953–1977 in New Orleans and 1969–1977 in New York City) was examined for seasonality. Previous studies using smaller data bases have reported an autumn increase (principally during October and November) in the number of emergency room visits for asthma in many locations in this country (including New Orleans and New York City). The results of this study indicated that for every hospital and every year of observation in New York City the number of asthma emergency room visits increased in September, reached a peak in October and November and declined in December. In contrast, in New Orleans an autumn increase in the number of asthma emergency room visits was not consistently observed, being absent or reduced during many years. The distribution of asthma epidemic days (days on which the number of asthma emergency room visits was greatly elevated) by month was also examined. In New York City, there was a tendency for these days to occur during September, October, and November while in New Orleans there was an equal likelihood of epidemic days occurring in April, May, and June as well as during September, October, and November. The observations tend to suggest different etiologies for asthma attacks in the two geographic areas.     

Evaluating an early secondary smoking prevention intervention

Given the documented link between smoking and later debilitating health conditions, a need exists to investigate educational programs aimed at reducing rates of smoking among school-age children. The present study involved an entire class of ninth graders in a treatment condition featuring either role-playing and discussion, or only discussion. While both treatments effectively reduced levels of smoking among early smokers, few changes were noted for youngsters manifesting long-term, more entrenched habits. Levels of smoking for children monitored in a control school remained about the same. These data suggest that early preventive programs might be most efficacious in curtailing smoking among school-age children.     

The influence of passive smoking on pulmonary function—A study of 1,351 office workers

Until now it has been difficult to ascertain how much passive inhalation of tobacco smoke affects bronchopulmonary function. To answer this question, an investigation involving 1,351 white collar workers was carried out. Information about active and passive tobacco smoke exposure was obtained by a standardized questionnaire. This made it possible to subdivide the overall group into five subgroups: Never smokers, passive smokers, ex-smokers, current smokers, and other smokers. Forced expiratory vital capacity (FVC) and maximal expiratory flow-volume (MEFV) curves were used for lung function analysis. From these curves FVC, forced mid-expiratory flow (FEF 25/75), forced end-expiratory flow (FEF 75/85), and maximal mid-expiratory flow (MEF 25/75) were determined and standardized for sex, age, height, and body weight. Passive smokers evaluated by this method showed essentially no decrease in parameters describing ventilatory function. It is concluded from the dose-and time-effect relationships obtained in active smokers between the lung function parameters and the duration of tobacco smoke exposure on the one hand and the daily consumption of cigarettes on the other that passive smoking in small doses may have no essential effect on pulmonary function.     

The Oslo Study: diet and antismoking advice. Additional results from a 5-year primary preventive trial in middle-aged men

In this randomized, primary prevention trial of 1,232 high-risk, middle-aged Oslo men, advice during 5 years about diet and smoking brought about a significant reduction (47%) in incidence of first major coronary heart disease (CHD) events in the intervention group compared with controls. Data are presented indicating that the net difference of 10% in serum cholesterol between groups was the main cause for this achievement and that the antismoking factor, due to a rather small net difference in quit rates (17 and 24% in control and intervention groups, respectively), contributed to a lesser degree. Analysis of social class reveals that the favorable results in the intervention group were present in all social strata, despite the unexpected finding that lower class men experienced a lower CHD incidence than men of higher socioeconomic status. Antismoking advice was especially effective in lower class intervention group men. Among cigarette quitters, lower social class men reduced their serum cholesterol more than higher social class men. However, for the total intervention group, higher status men had at least as great a reduction in serum cholesterol as did lower status men. With endpoint follow-up extended to 8.5-10 years, additional cases of CHD (nonfatal and fatal myocardial infarction and sudden death) numbered 7 and 10 in the intervention and control groups, respectively; CHD cases throughout the trial totaled 25 and 45 (P approximately equal to 0.02). Total deaths numbered 19 and 31, respectively (P approximately equal to 0.05).     

Intrauterine devices and menstrual blood loss. A comparative study of eight devices during the first six months of use

An experiment was conducted to determine changes in menstrual blood loss caused by IUDs. 78 volunteer women of similar age and parity were randomly selected from among those requesting IUDs from the outpatient department of the National Medical Center of the Mexican Institute of Social Security. Menstrual blood loss and hemoglobin were measured for 1-2 control cycles and for 6 postinsertion cycles. Of the 8 different types of IUDs used, the Lippes Loop and the copper-releasing devices caused a statistically significant increase in blood loss and a related decrease in hemoglobin. The steroid-releasing devices caused no significant increase in blood loss and no significant changes in hemoglobin concentration. The rigid copper devices caused the greatest increase in blood loss. The noted changes were clearly established by the 3rd postinsertion cycle.