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Prevalence and prognostic significance of hypercholesterolemia in men with hypertension: Prospective data on the primary screenees of the multiple risk factor intervention trial
Prevalence and Prognostic Significance of Hypercholesterolemia in Men with Hypertension Prospective Data on the Primary Screenees of the Multiple Risk Factor interventionTrial
JEREMIAH
STAMLER,
DEBORAH
WENT-WORTH,
JAMES
D. NEATON,
for the MRFIT Chicago,
Research
To assess the impact of serum cholesterol level on the risk of fatal coronary heart disease for men with high blood pressure, the sixyear follow& 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 liospltalizatlon for myocdrdial 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, ttie overalj 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 162 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 6.14. Thus, for men wlth.high blood pressure, serum cholesterol related to coronary heart disease risk in a strong, graded way, overthe 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 ihcrease 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.
M.D. M.P.H. Ph.D. Group
Illinois
From the Department of Community Health and Preventive Medicine, Northwestern Universitv Medical School, Chicago, Illinois and the Multiple Risk Factor Intervention Trial Coordinating Center, University of Minnssota, Minneapolis, Minnesota. These authors represent tha Multiple Risk Factor Intervention Trial Cooperative Research Group. Requests for reprints should be addressed to Dr. Jeremiah Stamler, Department of Community Health and Preventive ‘Medicine, Northwestern University Medical Schodl, 303 East Chicago Avenue, Chicago, Illinois 66611.
Population-based data on the prevalence and prognostic significance of hypercholesterolemia in people with high blood pressure have recently been published from several studies, e.g., the Chicago Heart Association Detection Project in Industry and the U.S. National Cooperative Pooling Project [1,2]. These data indicate that hypercholesterolemia is common in hypertensive persons and that it enhances the risk of coronary and cardiovascular death. The largest cohort in these published reports involved about 12,000 middle-aged men, of whom approximately 38 percent had high blood pressure at baseline. This article explores this problem with a much larger sample size, i.e., more than 100,000 men, aged 35 to 57 years, with high blood pressure
A complete list of participants in the Multiple Risk Factor Intervention Trial appears at the end of this article.
February
14, 1986
The American
Journal
of Medicine
Volume
60 (suppl
2A)
33
SYMPOSIUM
TABLE
ON INITIAL ANTIHYPERTENSIVE
I
Baseline Serum Cholesterol Hypertensive* Men without
Serum Cholesterol Pufntiles (mQ/dl)
‘Diastolic
THERAPY-STAMLEA
1 2 3 4 5
Cl62 162-202 203-220 221-244 2245
blood
pressure
Number of Deaths 67 111 160 221 406
ET AL
Levels and Six-Year Coronary Heart Disease Evidence of Myocardial Infarction at Baseline Number of Men 14,614 17,576 19,236 22,033 26,573
dial infarction at baseline. These men are primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT), surveyed in cities across the United States. AND METHODS
The data collection, screening, and follow-up methods used in this research have been published previously [3,4]. In brief, from November 1973 to November 1975,361,662 men, aged 35 to 57 years, were screened in 16 cities in the United States at 22 Multiple Risk Factor Intervention Trial clinical centers. Several methods of recruitment were used, including screening of employee, civic, and church groups, men identified by house-to-house canvassing, and respondents to mass media publicity. Blood pressure was measured according to a standardized protocol by certified technicians, with first and fifth Korotkoff phases recorded as systolic blood pressure and diastolic blood pressure, respectively. Three readings were taken with a standard stethoscope and mercury sphygmomanometer. The average of the second and third diastolic readings was used in this report. Serum cholesterol was determined at one of 14 local laboratories using an Auto Analyzer II, with standardization by the Lipid Standardization Program, Centers for Disease Control, United States Public Health Service, Atlanta, Georgia. The number of cigarettes smoked per day and demographic characteristics were ascertained by means of a short questionnaire. Replies were also obtained concerning two aspects of past medical history: (1) previous hospitalization of more than two weeks for “heart attack;” and (2) prescription of medication for diabetes. Vital status of this cohort is being ascertained on an ongoing basis from data provided by the Social Security System and the National Death Index. For decedents, death certifi-
TABLE
If
Baseflne Serum Cholesterol Hypertensive* Nonsmokers
Serum Cholesterol llulntlles (mQ/dl)
*Diastolic
34
1 2 3 4 5
~162 162-202 203-220 221-244 2245
blood
pressure
February
14,1986
95 Percent Confidence fntervaf
4.6 6.0 6.6 9.2 14.4
3.5-5.7 4.9-7.1 7.5-10.1 6.0-10.5 13.0-15.6
in 100,032 Relative Risk 1 .oo 1.30 1.91 2.00 3.13
2 90 mm Hg.
who did not have a history of hospitalization for myocar-
SUBJECTS
Age-Adjusted Rate/l ,000
Mortality
Number of Deaths 36 51 60 94 200
Levels wlthout
cates were obtained, abstracted, checked for correct match, and coded by one of two trained nosologists using the International Classification of Diseases (ICD), 9th revision, Clinical Modification, volume 1, Ann Arbor: Edwards Brothers Inc, 1961. For this report, coronary heat-f disease death is defined as ICD codes 410 through 414. The data are presented as six-year mortality rates. The direct method of standardization was used to adjust for differences in age distribution of subgroups, e.g., quintiles of serum cholesterol. Rates were standardized to the age distribution of the total group of 361,662 screenees. For men with elevated diastolic blood pressure who did not have a history of hospitalization for myocardial infarction, mortality rates are presented by quintile of serum cholesterol. Approximate quintiles of serum cholesterol were determined using the entire screened population; they are presented from the lowest (quintile 1) to highest (quintile 5). Elevated diastolic blood pressure was defined as a mean reading, as described earlier, equal to or greater than 90 mm Hg. RESULTS
Ranges of serum cholesterol for the five quintiles were: quintile quintile quintile
1, 60 to 182 mg/dl; quintile 2, 182 to 202 mg/dl; 3, 203 to 220 mg/dl; quintile 4, 221 to 244 mg/dl; 5, 245 to 998 mg/dl. Mean serum cholesterol lev-
els for these five quintiles were 163.7, 192.4, 211.5, 231.7, and 271.2 mg/dl, respectively. Of the total cohort (361,662 men), 356,222 did not have a history of hospitalization for myocardial infarction; 100,032 of these men had a mean diastolic blood pressure equal to or greater than 90 mm Hg at baseline (87,133, or 87.1 percent, had diastolic blood pressure in the range of 90 to 104 mm Hg, “mild” hypertension, with
and Six-Year Coronary Evidence of Yyocardlal
Number of Men 9,612 11,599 12,639 14,500 16,930
Heart Disease Mortality Infarction at Baseline
Age-Adjusted Reten ,000 3.7 4.0 5.6 5.6 10.7
2 90 mm Hg.
The American Journal of Medicine
Volume 80 (suppl 2A)
95 Percent Confidence interval 2.5-4.9 2.9-5.1 4.4-6.9 4.5-6.6 9.2-12.2
in 65,460 Male Relative Risk 1.00 1.06 1.51 1.51 2.69
SYMPOSIUM
TABLE III
Number of Deaths
(mfl/di)
&htih
1 2 3 4 5
1182 182-202 203-220 221-244 2245
blood
pressure
Ape-Adjutied
Number of Men
31 80 100 127 208
Rate/l ,000
5,002 5,977 6,397 7,533 9,643
95 Percent Confidence intetvai
6.3 10.0 15.5 16.8 21.4
1.00 1.59 2.46 2.63 3.40
4.1-8.5 7.5-12.5 12.5-18.5 13.8-l 9.5 18.5-24.3
COMMENTS The data from this study demonstrate clearly that in hypertensive middle-aged men, at generally increased risk of coronary death because of high blood pressure, the other two established major risk factors for coronary heart
Diastolic Blood Pressure and Six-Year Risk of Coronary Heart Disease Death by Serum Cholesterol Qulntlle In 356,222 Men without Evidence of Myocardlal Infarction at Baseline Risk Relative lo Men In Q&tile 1 with Diaslolic Blood Pressure 4B mm Ha’
Risk of Serum Cholestemi &htiies (mplldl) ~182 182-202 203-220 221-244 2245 All
*Compared 1 .OO.
Relative Risk
the lowest quintile of the sBrum cholesterol distribution (less than 182 mg/di). Table IV presents the data for the entire cohort of 358,222 men, stratified by blood pressure and serum cholesterol at baseline. For each of the quintiles of serum cholesterol, the six-year risk of fatal coronary heart disease was considerably greater for those with high blood pressure compared with those without; risk was 48 to 105 percent higher (79 percent on the average) for those with high blood pressure. For both those with normal diastolic blood pressure and those with high diastolic blood pressure, the higher the serum cholesterol level, the greater the risk. Compared with the men with diastolic blood pressure less than 90 mm Hg and serum cholesterol less than 182 mg/dl at baseline, those with high blood pressure had the following risk ratios, based on their serum cholesterol levels: for levels less than 182 mg/dl, risk was 1.84; for levels of 182 to 202 mg/dl, risk was 2.14; for levels of 203 to 220 mg/dl, risk was 3.14; for levels of 221 to 244 mg/dl, risk was 3.29; and for levels equal to or greater than 245 mg/dl, risk was 5.14; the overall risk was 3.32.
Age-Adjusted Ratetsn ,000
1 2 3 4 5
ET AL
z 90 mm Hg.
the remaining 12,899, or 12.9 percent, having diastolic blood pressure greater than 104 mm Hg). Of these 100,032 men, 987 died from coronary heart disease during the first six years of follow-up. The relationship between baseline serum cholesterol and the age-adjusted six-year coronary heart disease mortality rate is shown in Table I. Risk of coronary heart disease death rose progressively over the entire range of serum cholesterol levels from the second quintile through the fifth. For quintiies 2,3, 4, and 5, risk was increased by 30,91, 100, and 213 percent respectively, compared with quintiie 1. As is evident from Tables II and Ill, this relationship between serum cholesterol and risk of fatal coronary heart disease prevailed for hypertensive men who were nonsmokers and those who were smokers at baseline. For each of the quintiles of serum cholesterol, hypertensive smokers had six-year coronary heart disease mortality rates that were considerably higher than those of nonsmokers, i.e., both serum cholesterol level and smoking status were independently related to risk in hypertensive men. The range of risk for these men was from a low of 3.7 per 1,000 for nonsmokers in the lowest serum cholesterol quintile (Table II) to 21.4 per 1,000 for smokers in the highest serum cholesterol quintile-an almost sixfold increase in risk in six years. Of these 100,032 hypertensive men, only 9,812 (9.8 percent) were nonsmokers and in
TABLE IV
THERAPY-STAMLER
Basellne Serum Cholesterol Levels and Six-Year Coronary Heart Disease Mortality In 34,552 Male Hypertensive* Smokers without Evidence of Myocardlal Infarction at Baseline
SerumCholesterol
‘Diastolic
ON INITIAL ANTIHYPERTENSIVE
with stratum
DiastolicBloodPmssure
DiastolicBlood Pmssum
<90 mm H(I
Diastolic Blood Pressurn 290 mm tig
2.8 3.5 4.3 6.2 9.1 5.2
4.6 6.0 8.8 9.2 14.4 9.3
with diastolic
blood
pressure
1.84 2.14 3.14 3.29 5.14 3.32
1.64 1.71 2.05 1.48 1.58 1.79
< 90 mm Hg and serum
February 14,1986
z-90 mm Hff Relative to <90 mm Ha
cholesterol
c 182 mg/di (age-adjusted
The American Journal of Medlclne
rate 2.8/l ,000/6
years)
Volume 80 (auf@ 2A)
=
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SYMPOSIUM
ON INITIAL ANTIHYPERTENSIVE
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disease-serum cholesterol and cigarette use-strongly influenced prognosis. The ability of serum cholesterol to further increase coronary heart disease risk in hypertensive men was manifest across the whole range of this variable, from levels of approximately 180 mg/dl and higher. That is, risk is not limited to men with frank hypercholesterolemia as defined by current American standards (e.g., 220 mg/dl or more). Rather, the relationship was strong and graded. Thus, for hypertensive men with optimal serum cholesterol levels of less than 182 mg/dl, the risk of coronary heart disease death increased by 84 percent, compared with normotensive men with similar serum cholesterol levels. With high blood pressure plus serum cholesterol in the range 182 to 202 mg/dl, risk was more than doubled; with high blood pressure plus serum cholesterol of 203 to 220 mg/dl, there was a more than threefold greater risk; with high blood pressure plus serum cholesterol of 221 to 244 mg/dl, there was a 3.3-fold increase in risk; and with high blood pressure plus serum cholesterol equal to or greater than 245 mg/dl, there was more than a fivefold greater risk. This continuously greater risk of coronary heart disease death for hypertensive men in relation to the level of serum cholesterol was observed in both nonsmokers and smokers, with the latter generally having a risk at least double that of the former at any level of serum cholesterol. The analyses yielding the foregoing relationships were done by the classical method of multiple cross-classification, without use of multiple regression techniques to smooth the curves. These cross-classification analyses, involving subdivision of the cohort into 20 groups (men without and with high blood pressure, nonsmokers and smokers, five quintiles of serum cholesterol), were possible because of the extraordinary size of this cohort. With more than 358,000 men, over 100,000 of them with high blood pressure, this is undoubtedly the largest population with standardized baseline measurements of major coronary risk factors and long-term, prospective follow-up. The large sample size, with the consequent ample numbers of coronary heart disease deaths in each of the 20 groups, made it possible to use the method of multiple cross-
classification, thereby avoiding the statistical assumptions inherent when regression models are employed. It also made possible a high degree of precision, i.e., narrow confidence intervals, for each of the 20 estimates of ageadjusted six-year risk of coronary heart disease death. On the basis of these data, the conclusion is warranted that for the entire cohort, and for its large subgroups of hypertensive men and hypertensive nonsmokers and smokers, the relationship between serum cholesterol and coronary heart disease risk is a strong, graded one, and not a plateau relationship entailing a further increase in risk exclusively for those with severe hypercholesterolemia. Men with serum cholesterol levels associated with the lowest risk of coronary heart disease death (less than 182 mg/dl) made up only 15 percent of the 100,032 men with high blood pressure in this cohort; nonsmokers with serum cholesterol levels less than 182 made up only 10 percent. Thus, relatively low-risk hypertensive men were rare exceptions. The norm was high blood pressure combined with an elevated serum cholesterol level and, in a sizeable proportion of the cohort, cigarette use as well. The implications of these data in regard to the strategy for treatment of people with hypertension are virtually selfevident: treatment must be comprehensive and not limited to measures for controlling high blood pressure. In particular, careful and sustained nutritional and hygienic counseling is essential to convince hypertensive smokers to give up tobacco and to improve the dietary habits of all persons with high blood pressure. Long-term care must seek to achieve and maintain serum cholesterol concentrations at optimal levels, favorably influence other dietdependent risk factors, and favorably influence blood pressure itself, with the possibility of avoiding or at least minimizing the need for drugs [1,2,5]. The importance of these conclusions is underscored by recently published results from the two largest trials of antihypertensive drugs demonstrating that for people with excellent control of their high blood pressure, status with respect to the other major risk factors profoundly influences prognosis, especially the risk of that most frequent “complication” of hypertension, coronary heart disease [8,7].
REFERENCES
GiumettiD, Liu K, StamlerR, SchoenbergerJA, ShekelleRB, StamlerJ: Need to preventand controlhigh-normaland high blood pressure,particularly so-called“mild” hypertension:Epidemiologicand clinicaldata. Prev Med 1965; 14: 396-412. 2. StamlerJ, GiumettiD, Liu K, Stamler R, Dyer A: Risks with so-
blackand whitemalesfollowedfor fiveyears.Am HeartJ 1984;
1.
3.
1 OS: 759-769.
5. StamlerJ, StamlerR,Liu K: Highbloodpressure.In: ConnorWE, B&tow JD, eds. Coronaryheartdisease-prevention,complications,and treatment.Philadelphia:JB Lippincott,1965; S5-
called “mild” hypertension. In: Hofmann H, ed. Proceedings of the 1964 H(lhenreid Symposium (in press). Neaton JD, Broste S, Cohen L, Fishman EL, Kjelsberg MO, Bchoenberger J: The Multiple Risk Factor Intervention Trial
6.
(MRFIT).VII.A comparisonof riskfactorchangesbetweenthe 4.
36
two study groups. Prev Med 1961; 10: 519-543. Neaton JS, Kuller LH, Wentworth D, Borhani NO: Total and cardiovascular mortality in relation to cigarettesmoking, serum cholesterol concentration, and diastolic blood pressure among
February
14,1986
The American
Journal
of Medicine
7.
Volume
109. Hypertension Detection and Follow-up Program Cooperative Research Group: Mortality findings for stepped care and referred care participants in the Hypertension Detection and Follow-up Program, stratified by other risk factors. Prev Med 1965; 14: 312-335. Medical Research Council Working Party: MRC trial of treatment of mild hypertension: Principal results. Br Med J 1965; 291: 97-104.
80 (suppl
PA)
SYMPOSIUM
PARTICIPANTS INTERVENTION
IN THE MULTIPLE TRIAL
This research was carried out in the Multiple Risk Factor intervention Trial Centers as a collaborative research undertaking with contract support from the National Heart, Lung, and Blood Institute. The principal investigators and senior staff of the clinical, coordinating and support centers, the National Heart, Lung, and Blood Institute, and members of the Multiple Risk Factor Intervention Trial Policy Advisory Board and Mortality Review Committee are as follows: Steering Committee 0. Paul, M.D. (chairperson) American Health Foundation, Mahoney Institute for Health Maintenance, New York C. B. Arnold, M.D., M.P.H. (principal investigator) Ft. Mandriota, M.S., M.Ed. R. P. Ames, M.D. J. Ruff Eisenbach, R.N. E. Bohm Boston University, Boston H. E. Thomas, Jr., M.D. (principal investigator) W. 8. Kannel, M.D. (co-principal investigator) R. Rotondo, M.A. J. Connors, R.D. F. N. Brand, M.D. M. T. Prisco, R.N. P. Greene, M.A. Cox Heart Institute, Kettering, Ohio P. Kezdi, M.D. (principal investigator) E. L. Stanley, M.D. (co-principal investigator) W. L. Black, M.D. F. A. Ernst, Ph.D. E. J. Case, R.N., M.S. V. Bentley D. Covert, M.S. M. Lucius, R.D., M.M. F. Paris R. Semmett L. Skotko Dade County Department of Public Health, Miami G. Christakis, M.D., M.P.H. (principal investigator) J. M. Burr, M.D. (co-principal investigator) T. A. Gerace, Ph.D. (co-principal investigator) M. E. Wilcox, R.D., M.M. D. Bramson, R.D., MS. J. Benezra, M.M. J. Weddle J. Kaye, M.M. M. Padron Dalhousie University (Multiple Risk Factor Intervention Trial Electrocardiography Center), Halifax, Nova Scotia, Canada P. M. Rautaharju, M.D., Ph.D. (principal investigator) H. Wolf, Ph.D. 14, 1936
THERAPY-STAMLER
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Harvard University, Boston R. C. Benfari, Ph.D. (principal investigator) K. M. McIntyre, M.D., J.D. (co-principal investigator) 0. Paul, M.D. (co-principal investigator) E. Danielson, M.A. J. Ockene, Ph.D. D. Kousch-Howard, R.N. A. D. Baldwin, M.D. Kaiser Foundation Research Institute, Portland, Oregon J. B. Wild, M.D. (principal investigator) M. Greenlick, Ph.D. (co-principal investigator) J. Grover, M.D. (co-principal investigator) S. Lamb J. Bailey J. Dyer, M.P.H. B. Brokop, R.N. V. Stevens, Ph.D. G. Bailey, R.N. Lankenau Hospital, Philadelphia W. Holmes, Ph.D. (principal investigator) J. E. Pickering, M.D. (co-principal investigator) J. Allaire, M.Ed. E. L. Duffy, R.D. D. Fellon, R.N. B. Feinstein, M.S.A. D. Hutchins, M.D. G. Rubel, R.D. National Centers for Disease Control, Atlanta G. R. Cooper, Ph.D., M.D. (principal investigator) D. D. Bayse, Ph.D. D. T. Miller, Ph.D. A. Hainline, Jr., Ph.D. M. Kuchmak, Ph.D. D. A. Wiebe, Ph.D. C. L. Winn L. Taylor B. L. Botero J. B. Gill, Jr. New Jersey Medical School, Newark N. L. Lasser, M.D., Ph.D. (principal investigator) N. Hymowitz, Ph.D. (co-principal investigator) K. C. Mezey, M.D. B. Munves, Ph.D. E. Parell, R.D. S. Burgio, M.S., R.D. V. Lasser, M.A., R.D. 8. Johnson S. Jeffrey E. Rice Northwestern University, Chicago J. Stamler, M.D. (principal investigator) D. Moss, M.S. V. Persky, M.D. E. Robinson, M.S. L. Van Horn, Ph.D., R.D. K. Shannon, M.A.
RISK FACTOR
February
ON INITIAL ANTIHYPERTENSIVE
The
American
Journal
of Medicine
Volume
30
(suppl2A)
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SYMPOSIUM
ON INITIAL ANTIHYPERTENSIVE
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D. Meyers, M.D. University of Chicago L. Cohen, M.D. (principal investigator) J. Morgan, Ph.D. (co-principal investigator) G. Grundmann, M.S., RD. T. D. Vestal, P.A. B. Huang St. Joseph’s Hospital, Chicago D. M. Berkson, M.D. (principal investigator) G. Lauger, M.S. S. Grujic, M.D. D. Obradovic, M.D. E. Pardo S. Dua, M.S. S. McGowan Institutes of Medical Sciences-University of California, San Francisco and Berkeley J. Billings, Ph.D., M.P.H. (principal investigator) S. B. Hulley, M.D., M.P.H. (co-principal investigator) W. M. Smith, M.D., M.P.H. (co-principal investigator) S. L. Syme, Ph.D. (co-principal investigator) R. Cohen, M.S. L. Dzvonik, MA., RD. L. Roos M. Kahn, R.N. Institutes of Medical Sciences, San Francisco Central Laboratory, San Francisco G. M. Widdowson, Ph.D. (co-principal investigator) G. 2. Williams, M.D. (co-principal investigator) S. 8. Hulley, M.D., M.P.H. (co-principal investigator) M. L. Kuehneman (laboratory manager) Rush-Presbyterian-St. Luke’s Medical Center, Chicago J. A. Schoenberger, M.D. (principal investigator) J. C. Schoenenberger, Ph.D. R. B. Shekelle, Ph.D. G. S. Net-i, M.D. T. Dolecek, M.S., R.D. E. Betz, R.D. L. Skweres, R.D. F. Oppenheimer, R.D. N. Gernhofer, M.S., R.D. G. G. Hardy E. McGill, R.N. Y. Hall, M.S. Rutgers Medical School, Piscataway, New Jersey N. H. Wright, M.D., M.P.H. (principal investigator) S. A. Kopel, Ph.D. (co-principal investigator) K. R. Suckerman, Ph.D. M. Schorin, M.P.H., R.D. St. Louis Heart Association N. Simon, M.D. (principal investigator) J. D. Cohen, M.D. (co-principal investigator) E. Bunkers, R.D. B. Ronchetto, R.N. E. Grodsky
2s
February
14,1986
The American
Journal
oi Modklne
‘A. Fressola J. Daniel-Gentry, M.S., R.N. R. Treiman, M.D. W. Sullivan, M.D. University of Alabama in Birmingham H. W. Schnaper, M.D. (principal investigator) G. H. Hughes, Ph.D. (co-principal investigator) A. Oberman, M.D. C. C. Hill, Ph.D. R. Allen, P.A. C. Bragg, R.D. S. Stokes, R.D. P. Johnson University of California, Davis N. 0. Borhani, M.D. (principal investigator) C. Sugars, R.D. K. Kirkpatrick M. Lee, M.D. S. DeBourelando, M.P.H., R.D. F. LaBaw, R.N. J. Turner-Tucker University of Maryland, Baltimore R. W. Sherwin, M.B., B.Chir. (principal investigator) M. S. Sexton, Ph.D., M.P.H. (co-principal investigator) N. E. Cusack, R.D. Q. T. F. de Barros, M.S. P. C. Dischinger, Ph.D. J. Fox Spizler, M.S. J. D. Heiner, M.D. M. B. Pilkington, R.N., M.S.N. B. L. Scanlon, M.A. University of Minnesota, Minneapolis R. H. Grimm, Jr., M.D., M.P.H. (principal investigator) M. Mittelmark, Ph.D. (co-principal investigator) R. S. Crow, M.D. (co-principal investigator) H. Blackburn, M.D. (co-principal investigator) D. Jacobs, Ph.D. (co-investigator) D. Rains, M.S. M. McDonald, R.N., M.S. K. Lenz University of Minnesota Electrocardiography Coding Center, Minneapolis R. J. Prineas, M.B., Ph.D. (director) R. C. Crow, M.D. (associate director) University of Minnesota, Nutrition Coding Center, Minneapolis I. M. Buzzard, Ph.D. (director) P. V. Grambsch (former director) J. Wenz, MS. (associate director) University of Minnesota Coordinating Center, Minneapolis M. 0. Kjelsberg, Ph.D. (principal investigator) G. E. Bartsch, Sc.D. (co-principal investigator) J. D. Neaton, Ph.D. (co-principal investigator) B. M. Aus J. Bendickaon
Volume
80 (suppl2A)
SYMPOSIUM
S. K. Broste, MS. J. E. Connett, Ph.D. A. G. DuChene D. A. Durkin D. L. Gorder, M.S. P. V. Grambsch G. A. Grandits, M.S. A. Knickerbocker W. L. Rasmussen K. H. Svendsen, M.S. D. Wentworth, M.P.H. University of Pittsburgh L. H. Kuller, M.D., D.P.H. (principal investigator) 13. McDonald, M.D. (co-principal investigator) A. Caggiula, Ph.D. (co-principal investigator) L. Falvo-Gerard, M.N., M.P.H. (co-principal investigator) E. Meilahn, M.P.H. N. C. Milas, R.D., M.S. R. Russell, R.D., D.P.H. J. Horbiak, R.D., M.P.H. M. Alman, R.N. K. Southwick, A.S.C.P. R. Moyer E. Gahagan University of South Carolina, Columbia W. K. Giese, Ph.D. (principal investigator) J. F. Martin, M.D. (co-principal investigator) J. A. Keith, Ph.D. (co-principal investigator) H. H. Harrison, R.N. D. E. Mathis, M.A.T. C. K. Brown University of Southern California, Los Angeles E. Fishman, M.D. (principal investigator) L. Wampler, Ph.D. G. Newmark, M.A., R.D. F. Rosenfield, M.P.H. S. Siddiqui, M.D. W. Savage, MS., R.D.
February
14,1999
ON INITIAL ANTIHYPERTENSIVE
THERAPY-STAMLER
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A. Bradford, M.S., R.D. Policy Advisory Board W. Insull, Jr., M.D. (chairperson) J. W. Farquhar, M.D. C. D. Jenkins, Ph.D. E. Rapaport, M.D. D. J. Thompson, Ph.D. H. A. Tyroler, M.D. P. W. Willis III, M.D. W. T. Friedewald, M.D. W. Zukel, M.D. Mortality Review Committee J. T. Doyle, M.D. (chairman) H. B. Burchell, M.D. P. N. Yu, M.D. P. W. Willis III, M.D. (former member) National Heart, Lung, and Blood Institute Staff, Bethesda, Maryland W. T. Friedewald, M.D. (program director) C. D. Furberg, M.D. (project office director) J. A. Cutler, M.D. (scientific project officer) W. J. Zukel, M.D. (former program director) E. R. Passamani, M.D. (former scientific project officer) C. T. Kaelber, M.D. (former scientific project officer) M. E. Farrand, R.D., MS. J. L. Tillotson, R.D., M.A. J. I. Verter, Ph.D. M. C. Wu, Ph.D. T. Gordon M. Halperin, Ph.D. D. L. McGee, Ph.D. T. P. Blaszkowski, Ph.D. K. A. Eberlein, M.P.H. C. E. Harris P. L. Dern, M.D. L. M. Friedman, M.D. G. S. May, M.B., B.Chir. A. J. Vargosko, Ph.D.
The
American
Journal
of Medicine
Volume
90 (suppl
2A)
39
JEREMIAH
STAMLER,
DEBORAH
WENT-WORTH,
JAMES
D. NEATON,
for the MRFIT Chicago,
Research
To assess the impact of serum cholesterol level on the risk of fatal coronary heart disease for men with high blood pressure, the sixyear follow& 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 liospltalizatlon for myocdrdial 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, ttie overalj 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 162 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 6.14. Thus, for men wlth.high blood pressure, serum cholesterol related to coronary heart disease risk in a strong, graded way, overthe 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 ihcrease 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.
M.D. M.P.H. Ph.D. Group
Illinois
From the Department of Community Health and Preventive Medicine, Northwestern Universitv Medical School, Chicago, Illinois and the Multiple Risk Factor Intervention Trial Coordinating Center, University of Minnssota, Minneapolis, Minnesota. These authors represent tha Multiple Risk Factor Intervention Trial Cooperative Research Group. Requests for reprints should be addressed to Dr. Jeremiah Stamler, Department of Community Health and Preventive ‘Medicine, Northwestern University Medical Schodl, 303 East Chicago Avenue, Chicago, Illinois 66611.
Population-based data on the prevalence and prognostic significance of hypercholesterolemia in people with high blood pressure have recently been published from several studies, e.g., the Chicago Heart Association Detection Project in Industry and the U.S. National Cooperative Pooling Project [1,2]. These data indicate that hypercholesterolemia is common in hypertensive persons and that it enhances the risk of coronary and cardiovascular death. The largest cohort in these published reports involved about 12,000 middle-aged men, of whom approximately 38 percent had high blood pressure at baseline. This article explores this problem with a much larger sample size, i.e., more than 100,000 men, aged 35 to 57 years, with high blood pressure
A complete list of participants in the Multiple Risk Factor Intervention Trial appears at the end of this article.
February
14, 1986
The American
Journal
of Medicine
Volume
60 (suppl
2A)
33
SYMPOSIUM
TABLE
ON INITIAL ANTIHYPERTENSIVE
I
Baseline Serum Cholesterol Hypertensive* Men without
Serum Cholesterol Pufntiles (mQ/dl)
‘Diastolic
THERAPY-STAMLEA
1 2 3 4 5
Cl62 162-202 203-220 221-244 2245
blood
pressure
Number of Deaths 67 111 160 221 406
ET AL
Levels and Six-Year Coronary Heart Disease Evidence of Myocardial Infarction at Baseline Number of Men 14,614 17,576 19,236 22,033 26,573
dial infarction at baseline. These men are primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT), surveyed in cities across the United States. AND METHODS
The data collection, screening, and follow-up methods used in this research have been published previously [3,4]. In brief, from November 1973 to November 1975,361,662 men, aged 35 to 57 years, were screened in 16 cities in the United States at 22 Multiple Risk Factor Intervention Trial clinical centers. Several methods of recruitment were used, including screening of employee, civic, and church groups, men identified by house-to-house canvassing, and respondents to mass media publicity. Blood pressure was measured according to a standardized protocol by certified technicians, with first and fifth Korotkoff phases recorded as systolic blood pressure and diastolic blood pressure, respectively. Three readings were taken with a standard stethoscope and mercury sphygmomanometer. The average of the second and third diastolic readings was used in this report. Serum cholesterol was determined at one of 14 local laboratories using an Auto Analyzer II, with standardization by the Lipid Standardization Program, Centers for Disease Control, United States Public Health Service, Atlanta, Georgia. The number of cigarettes smoked per day and demographic characteristics were ascertained by means of a short questionnaire. Replies were also obtained concerning two aspects of past medical history: (1) previous hospitalization of more than two weeks for “heart attack;” and (2) prescription of medication for diabetes. Vital status of this cohort is being ascertained on an ongoing basis from data provided by the Social Security System and the National Death Index. For decedents, death certifi-
TABLE
If
Baseflne Serum Cholesterol Hypertensive* Nonsmokers
Serum Cholesterol llulntlles (mQ/dl)
*Diastolic
34
1 2 3 4 5
~162 162-202 203-220 221-244 2245
blood
pressure
February
14,1986
95 Percent Confidence fntervaf
4.6 6.0 6.6 9.2 14.4
3.5-5.7 4.9-7.1 7.5-10.1 6.0-10.5 13.0-15.6
in 100,032 Relative Risk 1 .oo 1.30 1.91 2.00 3.13
2 90 mm Hg.
who did not have a history of hospitalization for myocar-
SUBJECTS
Age-Adjusted Rate/l ,000
Mortality
Number of Deaths 36 51 60 94 200
Levels wlthout
cates were obtained, abstracted, checked for correct match, and coded by one of two trained nosologists using the International Classification of Diseases (ICD), 9th revision, Clinical Modification, volume 1, Ann Arbor: Edwards Brothers Inc, 1961. For this report, coronary heat-f disease death is defined as ICD codes 410 through 414. The data are presented as six-year mortality rates. The direct method of standardization was used to adjust for differences in age distribution of subgroups, e.g., quintiles of serum cholesterol. Rates were standardized to the age distribution of the total group of 361,662 screenees. For men with elevated diastolic blood pressure who did not have a history of hospitalization for myocardial infarction, mortality rates are presented by quintile of serum cholesterol. Approximate quintiles of serum cholesterol were determined using the entire screened population; they are presented from the lowest (quintile 1) to highest (quintile 5). Elevated diastolic blood pressure was defined as a mean reading, as described earlier, equal to or greater than 90 mm Hg. RESULTS
Ranges of serum cholesterol for the five quintiles were: quintile quintile quintile
1, 60 to 182 mg/dl; quintile 2, 182 to 202 mg/dl; 3, 203 to 220 mg/dl; quintile 4, 221 to 244 mg/dl; 5, 245 to 998 mg/dl. Mean serum cholesterol lev-
els for these five quintiles were 163.7, 192.4, 211.5, 231.7, and 271.2 mg/dl, respectively. Of the total cohort (361,662 men), 356,222 did not have a history of hospitalization for myocardial infarction; 100,032 of these men had a mean diastolic blood pressure equal to or greater than 90 mm Hg at baseline (87,133, or 87.1 percent, had diastolic blood pressure in the range of 90 to 104 mm Hg, “mild” hypertension, with
and Six-Year Coronary Evidence of Yyocardlal
Number of Men 9,612 11,599 12,639 14,500 16,930
Heart Disease Mortality Infarction at Baseline
Age-Adjusted Reten ,000 3.7 4.0 5.6 5.6 10.7
2 90 mm Hg.
The American Journal of Medicine
Volume 80 (suppl 2A)
95 Percent Confidence interval 2.5-4.9 2.9-5.1 4.4-6.9 4.5-6.6 9.2-12.2
in 65,460 Male Relative Risk 1.00 1.06 1.51 1.51 2.69
SYMPOSIUM
TABLE III
Number of Deaths
(mfl/di)
&htih
1 2 3 4 5
1182 182-202 203-220 221-244 2245
blood
pressure
Ape-Adjutied
Number of Men
31 80 100 127 208
Rate/l ,000
5,002 5,977 6,397 7,533 9,643
95 Percent Confidence intetvai
6.3 10.0 15.5 16.8 21.4
1.00 1.59 2.46 2.63 3.40
4.1-8.5 7.5-12.5 12.5-18.5 13.8-l 9.5 18.5-24.3
COMMENTS The data from this study demonstrate clearly that in hypertensive middle-aged men, at generally increased risk of coronary death because of high blood pressure, the other two established major risk factors for coronary heart
Diastolic Blood Pressure and Six-Year Risk of Coronary Heart Disease Death by Serum Cholesterol Qulntlle In 356,222 Men without Evidence of Myocardlal Infarction at Baseline Risk Relative lo Men In Q&tile 1 with Diaslolic Blood Pressure 4B mm Ha’
Risk of Serum Cholestemi &htiies (mplldl) ~182 182-202 203-220 221-244 2245 All
*Compared 1 .OO.
Relative Risk
the lowest quintile of the sBrum cholesterol distribution (less than 182 mg/di). Table IV presents the data for the entire cohort of 358,222 men, stratified by blood pressure and serum cholesterol at baseline. For each of the quintiles of serum cholesterol, the six-year risk of fatal coronary heart disease was considerably greater for those with high blood pressure compared with those without; risk was 48 to 105 percent higher (79 percent on the average) for those with high blood pressure. For both those with normal diastolic blood pressure and those with high diastolic blood pressure, the higher the serum cholesterol level, the greater the risk. Compared with the men with diastolic blood pressure less than 90 mm Hg and serum cholesterol less than 182 mg/dl at baseline, those with high blood pressure had the following risk ratios, based on their serum cholesterol levels: for levels less than 182 mg/dl, risk was 1.84; for levels of 182 to 202 mg/dl, risk was 2.14; for levels of 203 to 220 mg/dl, risk was 3.14; for levels of 221 to 244 mg/dl, risk was 3.29; and for levels equal to or greater than 245 mg/dl, risk was 5.14; the overall risk was 3.32.
Age-Adjusted Ratetsn ,000
1 2 3 4 5
ET AL
z 90 mm Hg.
the remaining 12,899, or 12.9 percent, having diastolic blood pressure greater than 104 mm Hg). Of these 100,032 men, 987 died from coronary heart disease during the first six years of follow-up. The relationship between baseline serum cholesterol and the age-adjusted six-year coronary heart disease mortality rate is shown in Table I. Risk of coronary heart disease death rose progressively over the entire range of serum cholesterol levels from the second quintile through the fifth. For quintiies 2,3, 4, and 5, risk was increased by 30,91, 100, and 213 percent respectively, compared with quintiie 1. As is evident from Tables II and Ill, this relationship between serum cholesterol and risk of fatal coronary heart disease prevailed for hypertensive men who were nonsmokers and those who were smokers at baseline. For each of the quintiles of serum cholesterol, hypertensive smokers had six-year coronary heart disease mortality rates that were considerably higher than those of nonsmokers, i.e., both serum cholesterol level and smoking status were independently related to risk in hypertensive men. The range of risk for these men was from a low of 3.7 per 1,000 for nonsmokers in the lowest serum cholesterol quintile (Table II) to 21.4 per 1,000 for smokers in the highest serum cholesterol quintile-an almost sixfold increase in risk in six years. Of these 100,032 hypertensive men, only 9,812 (9.8 percent) were nonsmokers and in
TABLE IV
THERAPY-STAMLER
Basellne Serum Cholesterol Levels and Six-Year Coronary Heart Disease Mortality In 34,552 Male Hypertensive* Smokers without Evidence of Myocardlal Infarction at Baseline
SerumCholesterol
‘Diastolic
ON INITIAL ANTIHYPERTENSIVE
with stratum
DiastolicBloodPmssure
DiastolicBlood Pmssum
<90 mm H(I
Diastolic Blood Pressurn 290 mm tig
2.8 3.5 4.3 6.2 9.1 5.2
4.6 6.0 8.8 9.2 14.4 9.3
with diastolic
blood
pressure
1.84 2.14 3.14 3.29 5.14 3.32
1.64 1.71 2.05 1.48 1.58 1.79
< 90 mm Hg and serum
February 14,1986
z-90 mm Hff Relative to <90 mm Ha
cholesterol
c 182 mg/di (age-adjusted
The American Journal of Medlclne
rate 2.8/l ,000/6
years)
Volume 80 (auf@ 2A)
=
35
SYMPOSIUM
ON INITIAL ANTIHYPERTENSIVE
THERAPY-STAMLER
ET AL
disease-serum cholesterol and cigarette use-strongly influenced prognosis. The ability of serum cholesterol to further increase coronary heart disease risk in hypertensive men was manifest across the whole range of this variable, from levels of approximately 180 mg/dl and higher. That is, risk is not limited to men with frank hypercholesterolemia as defined by current American standards (e.g., 220 mg/dl or more). Rather, the relationship was strong and graded. Thus, for hypertensive men with optimal serum cholesterol levels of less than 182 mg/dl, the risk of coronary heart disease death increased by 84 percent, compared with normotensive men with similar serum cholesterol levels. With high blood pressure plus serum cholesterol in the range 182 to 202 mg/dl, risk was more than doubled; with high blood pressure plus serum cholesterol of 203 to 220 mg/dl, there was a more than threefold greater risk; with high blood pressure plus serum cholesterol of 221 to 244 mg/dl, there was a 3.3-fold increase in risk; and with high blood pressure plus serum cholesterol equal to or greater than 245 mg/dl, there was more than a fivefold greater risk. This continuously greater risk of coronary heart disease death for hypertensive men in relation to the level of serum cholesterol was observed in both nonsmokers and smokers, with the latter generally having a risk at least double that of the former at any level of serum cholesterol. The analyses yielding the foregoing relationships were done by the classical method of multiple cross-classification, without use of multiple regression techniques to smooth the curves. These cross-classification analyses, involving subdivision of the cohort into 20 groups (men without and with high blood pressure, nonsmokers and smokers, five quintiles of serum cholesterol), were possible because of the extraordinary size of this cohort. With more than 358,000 men, over 100,000 of them with high blood pressure, this is undoubtedly the largest population with standardized baseline measurements of major coronary risk factors and long-term, prospective follow-up. The large sample size, with the consequent ample numbers of coronary heart disease deaths in each of the 20 groups, made it possible to use the method of multiple cross-
classification, thereby avoiding the statistical assumptions inherent when regression models are employed. It also made possible a high degree of precision, i.e., narrow confidence intervals, for each of the 20 estimates of ageadjusted six-year risk of coronary heart disease death. On the basis of these data, the conclusion is warranted that for the entire cohort, and for its large subgroups of hypertensive men and hypertensive nonsmokers and smokers, the relationship between serum cholesterol and coronary heart disease risk is a strong, graded one, and not a plateau relationship entailing a further increase in risk exclusively for those with severe hypercholesterolemia. Men with serum cholesterol levels associated with the lowest risk of coronary heart disease death (less than 182 mg/dl) made up only 15 percent of the 100,032 men with high blood pressure in this cohort; nonsmokers with serum cholesterol levels less than 182 made up only 10 percent. Thus, relatively low-risk hypertensive men were rare exceptions. The norm was high blood pressure combined with an elevated serum cholesterol level and, in a sizeable proportion of the cohort, cigarette use as well. The implications of these data in regard to the strategy for treatment of people with hypertension are virtually selfevident: treatment must be comprehensive and not limited to measures for controlling high blood pressure. In particular, careful and sustained nutritional and hygienic counseling is essential to convince hypertensive smokers to give up tobacco and to improve the dietary habits of all persons with high blood pressure. Long-term care must seek to achieve and maintain serum cholesterol concentrations at optimal levels, favorably influence other dietdependent risk factors, and favorably influence blood pressure itself, with the possibility of avoiding or at least minimizing the need for drugs [1,2,5]. The importance of these conclusions is underscored by recently published results from the two largest trials of antihypertensive drugs demonstrating that for people with excellent control of their high blood pressure, status with respect to the other major risk factors profoundly influences prognosis, especially the risk of that most frequent “complication” of hypertension, coronary heart disease [8,7].
REFERENCES
GiumettiD, Liu K, StamlerR, SchoenbergerJA, ShekelleRB, StamlerJ: Need to preventand controlhigh-normaland high blood pressure,particularly so-called“mild” hypertension:Epidemiologicand clinicaldata. Prev Med 1965; 14: 396-412. 2. StamlerJ, GiumettiD, Liu K, Stamler R, Dyer A: Risks with so-
blackand whitemalesfollowedfor fiveyears.Am HeartJ 1984;
1.
3.
1 OS: 759-769.
5. StamlerJ, StamlerR,Liu K: Highbloodpressure.In: ConnorWE, B&tow JD, eds. Coronaryheartdisease-prevention,complications,and treatment.Philadelphia:JB Lippincott,1965; S5-
called “mild” hypertension. In: Hofmann H, ed. Proceedings of the 1964 H(lhenreid Symposium (in press). Neaton JD, Broste S, Cohen L, Fishman EL, Kjelsberg MO, Bchoenberger J: The Multiple Risk Factor Intervention Trial
6.
(MRFIT).VII.A comparisonof riskfactorchangesbetweenthe 4.
36
two study groups. Prev Med 1961; 10: 519-543. Neaton JS, Kuller LH, Wentworth D, Borhani NO: Total and cardiovascular mortality in relation to cigarettesmoking, serum cholesterol concentration, and diastolic blood pressure among
February
14,1986
The American
Journal
of Medicine
7.
Volume
109. Hypertension Detection and Follow-up Program Cooperative Research Group: Mortality findings for stepped care and referred care participants in the Hypertension Detection and Follow-up Program, stratified by other risk factors. Prev Med 1965; 14: 312-335. Medical Research Council Working Party: MRC trial of treatment of mild hypertension: Principal results. Br Med J 1965; 291: 97-104.
80 (suppl
PA)
SYMPOSIUM
PARTICIPANTS INTERVENTION
IN THE MULTIPLE TRIAL
This research was carried out in the Multiple Risk Factor intervention Trial Centers as a collaborative research undertaking with contract support from the National Heart, Lung, and Blood Institute. The principal investigators and senior staff of the clinical, coordinating and support centers, the National Heart, Lung, and Blood Institute, and members of the Multiple Risk Factor Intervention Trial Policy Advisory Board and Mortality Review Committee are as follows: Steering Committee 0. Paul, M.D. (chairperson) American Health Foundation, Mahoney Institute for Health Maintenance, New York C. B. Arnold, M.D., M.P.H. (principal investigator) Ft. Mandriota, M.S., M.Ed. R. P. Ames, M.D. J. Ruff Eisenbach, R.N. E. Bohm Boston University, Boston H. E. Thomas, Jr., M.D. (principal investigator) W. 8. Kannel, M.D. (co-principal investigator) R. Rotondo, M.A. J. Connors, R.D. F. N. Brand, M.D. M. T. Prisco, R.N. P. Greene, M.A. Cox Heart Institute, Kettering, Ohio P. Kezdi, M.D. (principal investigator) E. L. Stanley, M.D. (co-principal investigator) W. L. Black, M.D. F. A. Ernst, Ph.D. E. J. Case, R.N., M.S. V. Bentley D. Covert, M.S. M. Lucius, R.D., M.M. F. Paris R. Semmett L. Skotko Dade County Department of Public Health, Miami G. Christakis, M.D., M.P.H. (principal investigator) J. M. Burr, M.D. (co-principal investigator) T. A. Gerace, Ph.D. (co-principal investigator) M. E. Wilcox, R.D., M.M. D. Bramson, R.D., MS. J. Benezra, M.M. J. Weddle J. Kaye, M.M. M. Padron Dalhousie University (Multiple Risk Factor Intervention Trial Electrocardiography Center), Halifax, Nova Scotia, Canada P. M. Rautaharju, M.D., Ph.D. (principal investigator) H. Wolf, Ph.D. 14, 1936
THERAPY-STAMLER
ET AL
Harvard University, Boston R. C. Benfari, Ph.D. (principal investigator) K. M. McIntyre, M.D., J.D. (co-principal investigator) 0. Paul, M.D. (co-principal investigator) E. Danielson, M.A. J. Ockene, Ph.D. D. Kousch-Howard, R.N. A. D. Baldwin, M.D. Kaiser Foundation Research Institute, Portland, Oregon J. B. Wild, M.D. (principal investigator) M. Greenlick, Ph.D. (co-principal investigator) J. Grover, M.D. (co-principal investigator) S. Lamb J. Bailey J. Dyer, M.P.H. B. Brokop, R.N. V. Stevens, Ph.D. G. Bailey, R.N. Lankenau Hospital, Philadelphia W. Holmes, Ph.D. (principal investigator) J. E. Pickering, M.D. (co-principal investigator) J. Allaire, M.Ed. E. L. Duffy, R.D. D. Fellon, R.N. B. Feinstein, M.S.A. D. Hutchins, M.D. G. Rubel, R.D. National Centers for Disease Control, Atlanta G. R. Cooper, Ph.D., M.D. (principal investigator) D. D. Bayse, Ph.D. D. T. Miller, Ph.D. A. Hainline, Jr., Ph.D. M. Kuchmak, Ph.D. D. A. Wiebe, Ph.D. C. L. Winn L. Taylor B. L. Botero J. B. Gill, Jr. New Jersey Medical School, Newark N. L. Lasser, M.D., Ph.D. (principal investigator) N. Hymowitz, Ph.D. (co-principal investigator) K. C. Mezey, M.D. B. Munves, Ph.D. E. Parell, R.D. S. Burgio, M.S., R.D. V. Lasser, M.A., R.D. 8. Johnson S. Jeffrey E. Rice Northwestern University, Chicago J. Stamler, M.D. (principal investigator) D. Moss, M.S. V. Persky, M.D. E. Robinson, M.S. L. Van Horn, Ph.D., R.D. K. Shannon, M.A.
RISK FACTOR
February
ON INITIAL ANTIHYPERTENSIVE
The
American
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of Medicine
Volume
30
(suppl2A)
37
SYMPOSIUM
ON INITIAL ANTIHYPERTENSIVE
THERAPY-STAMLER
ET AL
D. Meyers, M.D. University of Chicago L. Cohen, M.D. (principal investigator) J. Morgan, Ph.D. (co-principal investigator) G. Grundmann, M.S., RD. T. D. Vestal, P.A. B. Huang St. Joseph’s Hospital, Chicago D. M. Berkson, M.D. (principal investigator) G. Lauger, M.S. S. Grujic, M.D. D. Obradovic, M.D. E. Pardo S. Dua, M.S. S. McGowan Institutes of Medical Sciences-University of California, San Francisco and Berkeley J. Billings, Ph.D., M.P.H. (principal investigator) S. B. Hulley, M.D., M.P.H. (co-principal investigator) W. M. Smith, M.D., M.P.H. (co-principal investigator) S. L. Syme, Ph.D. (co-principal investigator) R. Cohen, M.S. L. Dzvonik, MA., RD. L. Roos M. Kahn, R.N. Institutes of Medical Sciences, San Francisco Central Laboratory, San Francisco G. M. Widdowson, Ph.D. (co-principal investigator) G. 2. Williams, M.D. (co-principal investigator) S. 8. Hulley, M.D., M.P.H. (co-principal investigator) M. L. Kuehneman (laboratory manager) Rush-Presbyterian-St. Luke’s Medical Center, Chicago J. A. Schoenberger, M.D. (principal investigator) J. C. Schoenenberger, Ph.D. R. B. Shekelle, Ph.D. G. S. Net-i, M.D. T. Dolecek, M.S., R.D. E. Betz, R.D. L. Skweres, R.D. F. Oppenheimer, R.D. N. Gernhofer, M.S., R.D. G. G. Hardy E. McGill, R.N. Y. Hall, M.S. Rutgers Medical School, Piscataway, New Jersey N. H. Wright, M.D., M.P.H. (principal investigator) S. A. Kopel, Ph.D. (co-principal investigator) K. R. Suckerman, Ph.D. M. Schorin, M.P.H., R.D. St. Louis Heart Association N. Simon, M.D. (principal investigator) J. D. Cohen, M.D. (co-principal investigator) E. Bunkers, R.D. B. Ronchetto, R.N. E. Grodsky
2s
February
14,1986
The American
Journal
oi Modklne
‘A. Fressola J. Daniel-Gentry, M.S., R.N. R. Treiman, M.D. W. Sullivan, M.D. University of Alabama in Birmingham H. W. Schnaper, M.D. (principal investigator) G. H. Hughes, Ph.D. (co-principal investigator) A. Oberman, M.D. C. C. Hill, Ph.D. R. Allen, P.A. C. Bragg, R.D. S. Stokes, R.D. P. Johnson University of California, Davis N. 0. Borhani, M.D. (principal investigator) C. Sugars, R.D. K. Kirkpatrick M. Lee, M.D. S. DeBourelando, M.P.H., R.D. F. LaBaw, R.N. J. Turner-Tucker University of Maryland, Baltimore R. W. Sherwin, M.B., B.Chir. (principal investigator) M. S. Sexton, Ph.D., M.P.H. (co-principal investigator) N. E. Cusack, R.D. Q. T. F. de Barros, M.S. P. C. Dischinger, Ph.D. J. Fox Spizler, M.S. J. D. Heiner, M.D. M. B. Pilkington, R.N., M.S.N. B. L. Scanlon, M.A. University of Minnesota, Minneapolis R. H. Grimm, Jr., M.D., M.P.H. (principal investigator) M. Mittelmark, Ph.D. (co-principal investigator) R. S. Crow, M.D. (co-principal investigator) H. Blackburn, M.D. (co-principal investigator) D. Jacobs, Ph.D. (co-investigator) D. Rains, M.S. M. McDonald, R.N., M.S. K. Lenz University of Minnesota Electrocardiography Coding Center, Minneapolis R. J. Prineas, M.B., Ph.D. (director) R. C. Crow, M.D. (associate director) University of Minnesota, Nutrition Coding Center, Minneapolis I. M. Buzzard, Ph.D. (director) P. V. Grambsch (former director) J. Wenz, MS. (associate director) University of Minnesota Coordinating Center, Minneapolis M. 0. Kjelsberg, Ph.D. (principal investigator) G. E. Bartsch, Sc.D. (co-principal investigator) J. D. Neaton, Ph.D. (co-principal investigator) B. M. Aus J. Bendickaon
Volume
80 (suppl2A)
SYMPOSIUM
S. K. Broste, MS. J. E. Connett, Ph.D. A. G. DuChene D. A. Durkin D. L. Gorder, M.S. P. V. Grambsch G. A. Grandits, M.S. A. Knickerbocker W. L. Rasmussen K. H. Svendsen, M.S. D. Wentworth, M.P.H. University of Pittsburgh L. H. Kuller, M.D., D.P.H. (principal investigator) 13. McDonald, M.D. (co-principal investigator) A. Caggiula, Ph.D. (co-principal investigator) L. Falvo-Gerard, M.N., M.P.H. (co-principal investigator) E. Meilahn, M.P.H. N. C. Milas, R.D., M.S. R. Russell, R.D., D.P.H. J. Horbiak, R.D., M.P.H. M. Alman, R.N. K. Southwick, A.S.C.P. R. Moyer E. Gahagan University of South Carolina, Columbia W. K. Giese, Ph.D. (principal investigator) J. F. Martin, M.D. (co-principal investigator) J. A. Keith, Ph.D. (co-principal investigator) H. H. Harrison, R.N. D. E. Mathis, M.A.T. C. K. Brown University of Southern California, Los Angeles E. Fishman, M.D. (principal investigator) L. Wampler, Ph.D. G. Newmark, M.A., R.D. F. Rosenfield, M.P.H. S. Siddiqui, M.D. W. Savage, MS., R.D.
February
14,1999
ON INITIAL ANTIHYPERTENSIVE
THERAPY-STAMLER
ET AL
A. Bradford, M.S., R.D. Policy Advisory Board W. Insull, Jr., M.D. (chairperson) J. W. Farquhar, M.D. C. D. Jenkins, Ph.D. E. Rapaport, M.D. D. J. Thompson, Ph.D. H. A. Tyroler, M.D. P. W. Willis III, M.D. W. T. Friedewald, M.D. W. Zukel, M.D. Mortality Review Committee J. T. Doyle, M.D. (chairman) H. B. Burchell, M.D. P. N. Yu, M.D. P. W. Willis III, M.D. (former member) National Heart, Lung, and Blood Institute Staff, Bethesda, Maryland W. T. Friedewald, M.D. (program director) C. D. Furberg, M.D. (project office director) J. A. Cutler, M.D. (scientific project officer) W. J. Zukel, M.D. (former program director) E. R. Passamani, M.D. (former scientific project officer) C. T. Kaelber, M.D. (former scientific project officer) M. E. Farrand, R.D., MS. J. L. Tillotson, R.D., M.A. J. I. Verter, Ph.D. M. C. Wu, Ph.D. T. Gordon M. Halperin, Ph.D. D. L. McGee, Ph.D. T. P. Blaszkowski, Ph.D. K. A. Eberlein, M.P.H. C. E. Harris P. L. Dern, M.D. L. M. Friedman, M.D. G. S. May, M.B., B.Chir. A. J. Vargosko, Ph.D.
The
American
Journal
of Medicine
Volume
90 (suppl
2A)
39