Potential Benefits of Antihypertensive Drug Treatment Risks of Untreated Hypertension

- Potential Benefits of Antihypertensive Drug Treatment Risks of Untreated Hypertension Blood Pressure (Systolic and Diastolic) and Risk of Fatal Coronary Heart Disease Jeremiah Stamler, James D. Neaton, and Deborah N. Wentworth Downloaded from http://ahajournals.org by on November, 8 Among the 56, men screened for the Multiple Risk Factor Intervention Trial who had no history of hospitalization for heart attack at entry, more than, coronary deaths occurred during 6 years of follow-up. With this large data set, detailed cross-tabulations clearly and simply showed the strong graded relation between blood pressure and coronary heart disease death. This risk gradient was evident in each of five age groups ranging from 5 to 57 years and for levels of diastolic blood pressure ranging from less than 75 mm Hg to greater than 5 mm Hg. Systolic blood pressure was more strongly associated with coronary heart disease death than was diastolic blood pressure, and isolated systolic blood pressure elevation was found to be an important risk factor in these middle-aged men. The risk of coronary death was increased among hypertensive men who had elevated serum cholesterol levels or who smoked cigarettes. Because less than % of hypertensive men had cholesterol levels in the lowest quintile (below 8 mg/dl) and were nonsmokers, a multi-intervention approach for the large majority of hypertensive persons is clearly indicated. Risks of death were also substantially increased among those hypertensive men who already had end-organ damage, emphasizing the importance of early treatment to prevent such damage. These findings have implications for the design of prevention trials and clinical practice, as it is clear that systolic as well as diastolic blood pressure should be considered in treating hypertensive patients. Additionally, treatment goals should be directed at preventing not only death but many other morbid events, clinical and subclinical, that are associated with elevated blood pressure and that are preventable with appropriate treatment. {Hypertension 989;(suppl I):I- -) Many available data sets delineate the role of elevated blood pressure (BP) as a major, etiologically significant, established risk factor for coronary heart disease (CHD).'- 9 This report documents this relation further by drawing primarily on the findings that have recently become available for the 6,66 men screened in the recruitment effort of the Multiple Risk Factor Intervention Trial (MRFIT). i -'6 Advantage is taken of the large size of this sample and the standardized collection of BP data to explore in detail the relation of systolic BP (SBP) and diastolic BP (DBP) to the risk of CHD death. The influences of SBP and of DBP on age-specific CHD risk are described, considered separately, and then considered in combination. From the Department of Community Health and Preventive Medicine, Northwestern University Medical School, Chicago, Illinois (J.S.) and the Division of Biometry, University of Minnesota, Minneapolis, Minnesota (J.D.N. and D.N.W.). Address for correspondence: Jeremiah Stamler, MD, Department of Community Health and Preventive Medicine, Northwestern University Medical School, East Chicago Avenue, Chicago, IL 66. Participants and Methods Detailed reports have been published on the uniform methods used by the MRFIT clinical centers in the primary screening effort among men aged 5-57 years in 8 US cities during the period 97-975. -' 7 BP was measured by trained technicians according to a standardized protocol, with the first and fifth Korotkoff phases recorded as SBP and DBP, respectively. Three readings were taken with a standard mercury sphygmomanometer. Averages of the second and third readings are referred to as baseline BP. Of the 6,66 screenees (9.% white, 6.5% black), 5, gave a history of hospitalization for myocardial infarction; they were excluded from the data analyses presented here. Of the remaining 56, men, SBP data were available for 7,9. Death ascertainment was accomplished with data from the Social Security Administration. Death certificates were obtained from state health departments, and the cause of death was coded by a nosologist according to the 9th revision of the International Classification of Diseases (ICD 9). 8

Stamler et al Blood Pressure and Coronary Disease - TABLE. Baseline Diastolic Blood Pressure and 6-Year Coronary Heart Disease Mortality Rates in MRFIT Primary Screenees* Coronary heart disease mortality Diastolic blood pressure Age 5-9 Age - - Age 5-9 Age 5-5 Age 55-57 Age 5-57 <75 75-79 8-8 85-89 9-9 95-99 - 5-9 - >5 Relative risk >5/<75 7 7 5 7,8,698 7,5,6 8,66,9,6 86 9 9 7,77.6.9.6..6.9 (.) (5.8) (6.8) (.).5 (5.7) 9 5 8 8 6 6 8 95,69,5 7,85,7, 5,77,9,8 7 9 78,578...9.8.8 6. 7..5 (8.) (6.).8 (7.) ATt 56 56 9 88 57 6 7 6 5,98,6 8,695,97,55 6,65,86,7 99 7 8,9..6 6.5 7.7 8.6 6.8.5 7..5 6. ATf 85 85 9 7 9 6 6 8 5 798,69,688 7,89,959,865 6,8,,89,8 8 8,5 6.7 7. 7..5..5 5.5 9.5 6.7. 9.7.7 m 57 6 9 9 7 56 5 5 5 5,85 5,55 7,89 6,5 5,8,9,785 795 85 57 6,7 9.8.8.6.8. 8.5 5. 6..7... M 9 9 5 59 6 56 65,58 6,9 5, 79, 58, 6,6 5,88,69 6,9,78,69 56, Ageadjusted rate..7 5. 6.6. 7. 9.6..5.8. 6. MRFIT, Multiple Risk Factor Intervention Trial. *Coronary heart disease mortality is reported as age-specific rates (per, men) or as age-standardized rates for all 56, men aged 5-57 years with no history of hospitalization for myocardial infarction on entry into the MRFIT study. *Number of men. Death rate per, men. Rates in parentheses are based on < deaths for that stratum. Coronary heart disease is based on codes - of the International Classification ofdiseases." 5. Downloaded from http://ahajournals.org by on November, 8 Ascertainment is estimated to be 88% complete. 7 Six-year CHD mortality data (ICD 9 codes - ) are given in this report for men aged 5-9,-, 5-9, 5-5, and 55-57 years at screening, as well as age-standardized data for the entire cohort. Diastolic Blood Pressure, Systolic Blood Pressure, and Coronary Heart Disease Mortality in MRFIT Men Findings on the relation of BP to risk of CHD death were similar for white and black men in the MRFIT cohort," hence the data presented here are for the entire cohort. Tables and give detailed data on 6-year risk of CHD death by baseline DBP and baseline SBP, respectively, with BP grouped into 5 mm Hg intervals. For each 5-year age group, the CHD mortality rate increased progressively with higher DBP and SBP. Relative risks, that is, ratios of 6-year CHD mortality rates for men with the highest BP compared with men with the lowest BP, were all large, ranging from. to 7.6 (with exclusion of those values based on < CHD deaths). For men with DBP in the range 85-89 mm Hg, the age-specific risks relative to men with DBP less than 75 mm Hg ranged from.5 to.8; for men with SBP in the range - mm Hg compared with those with SBP less than 5 mm Hg, relative risks ranged from.8 to.75. Two thirds of these men had DBP levels greater than or equal to 8 mm Hg at baseline; %, with DBP greater than or equal to 85 mm Hg; 6%, with SBP levels greater than or equal to 5 mm Hg; and 6%, with SBP levels greater than or equal to mm Hg. Thus, in a majority of men aged 5-57 years, BP levels were found to be significantly above optimal. If the lowest levels of DBP and SBP, that is, DBP less than 75 mm Hg and SBP less than 5 mm Hg, are designated optimal, then based on DBP and SBP, 5% and 6%, respectively, of CHD deaths were excess deaths attributable to BP levels above optimal. These data give a precise estimate of the real scope of the BP problem among US adults. This problem is not limited to the substantial minority of people with BP levels in the hypertensive range, which is generally defined for clinical purposes as a mean DBP greater than or equal to 9 mm Hg or a mean SBP of greater than or equal to mm Hg. The data on relative risk in Tables and suggest that, at least at ages 5 years and above, there is a stronger association of SBP with CHD risk than there is with DBP and CHD risk. This matter is addressed further in the following section. Quintiles of Diastolic Blood Pressure, Systolic Blood Pressure, and Coronary Heart Disease Risk in MRFIT Men To facilitate comparisons of DBP and SBP distributions, quintile analyses were performed. Table presents data on quintiles of DBP and SBP and on age-specific and age-adjusted 6-year CHD death rates. The tabulation includes relative risks of 6- year CHD death for Quintile 5 compared with Quintile of DBP and SBP. With DBP and SBP,

- Supplement I Hypertension Vol, No 5, May 989 Downloaded from http://ahajournals.org by on November, 8 TABLE. Baseline Systolic Blood Pressure and 6-Year Coronary Heart Disease Mortality Rates in MRFIT Primary Screenees* Coronary heart disease mortality Systolic blood Age 5-9 Age - Age 5-9 Age 5-5 Age 55-57 Age 5-57 r\ T* A pi!!!!*a pressure <5 5-9 - 5-9 - 5-9 - 5-9 5-5 55-59 6-6 65-69 7-75 >75 Relative risk >75/<5 Aft 7 6 8 5 7,585 9,8,79,6 9,779 6,68,675,9,76 88 57 7 87 7 7,55.8. (.5) (.6). (.). (.6) (.) (.5) (.5) (.6) (5.) (.8). (8.5) 6 8 5 5 8 8, 9,67,6,75,8 7,5 5,,58,6,7 85 6 9 59 76,757.9.8.6.5..8.6 7.6 5.7.8.7 (7.) (9.) (.8).6 (7.8) 6 55 6 7 5 9 8 8 7 5 96,7 8,8,55,87,777 8,5 6,59,58,,95,6 8 56,7 8,65..8.. 5.6 8.7 7.6 9.6 7. 9...7 (.). 6. 7.6 6 9 56 7 86 75 9 57 6 7 8 5 759 9,9 7,8,6 9,9,6 8, 7,6,98,,5,959,6 9,75 8,5.8 5. 7. 8. 9..8. 5.9.7.9 8. 9.6 9.8 9. 6. 5 57 6 55 6 9 99,6,77,9,,87,77,,95,8,76,7 7 566,5 5,85 Rate! 8.6 8. 7.9.7.. 6.. 8.5 8..8 5. 6.6.9 7 7 9 66 8 65 6 6 9 5 9 8,6 9,86 7,6 5,6 6,95 5,79,5 7,5 7,, 8,67 5,95,5,58,675 7,9 Ageadjusted rate MRFIT, Multiple Risk Factor Intervention Trial. *Coronary heart disease mortality is reported as age-specific rates (per, men) or as age-standardized rates for all 7,9 men aged 5-57 years with no history of hospitalization for myocardial infarction on entry into the MRFIT study. *Number of men. Death rate per, men. Rates in parentheses are based on < deaths for that stratum. Coronary heart disease is based on codes - of the International Classification of Diseases.'* age-specific risk tended to rise progressively for men in Quintiles,,, and 5 when compared with men in Quintile, that is, 8% of the men were at increased risk. For the three older age groups, the relative risk, namely, the CHD death rate of the fifth quintile divided by the rate of the first quintile, was greater with SBP than with DBP. However, this was not the case for the two younger age groups. The relative risks based on age-adjusted rates for the entire cohort of men aged 5-57 years showed an overall greater impact of SBP than of DBP, risk ratios of. and., respectively. With this very large sample size, these estimates of relative risk are highly precise and have narrow confidence limits. Therefore, these estimates strongly support the conclusion that, at least for US men aged 5 years and older, SBP, considered separately, is a better indicator of CHD risk than is DBP. These data also underscore the soundness of the recommendation by the National High Blood Pressure Education Program and its Advisory Committee that a DBP of 85-89 mm Hg be designated as high-normal. Clearly, the same designation is appropriate for the -9 mm Hg SBP stratum. Further, these data support the judgment that the term "borderline" for the 9-9 mm Hg DBP stratum and the -59 mm Hg SBP stratum is archaic and...6. 5.9 6. 7.9 8.7.....5.7 6. should be abandoned. Adults aged years and older with such average blood pressure measurements from multiple readings are properly diagnosed as hypertensive, and, given their increased risks, the designation "mild" for the 9- mm Hg DBP stratum is also archaic. Diastolic Blood Pressure Greater Than or Equal to 85 mm Hg, Systolic Blood Pressure Greater Than or Equal to mm Hg, and Coronary Heart Disease Risk in MRFIT Men The cut points, SBP greater than or equal to mm Hg and DBP greater than or equal to 85 mm Hg, divide the MRFIT cohort approximately in half as noted above. Table summarizes the age-specific risks of 6-year CHD death for MRFIT men with DBP greater than or equal to 85 mm Hg and with SBP greater than or equal to mm Hg. Relative risks, that is, the ratios DBPs85/DBP<85 and SBP>/SBP< were higher in men with SBP greater than or equal to than in men with DBP greater than or equal to 85 from ages 5-9 years and older. Also, absolute excess risks, that is, the differences in 6-year CHD mortality rates between men with higher and lower BP, were from age 5-9 years and older greater in men with SBP greater 7.

Stamler et al Blood Pressure and Coronary Disease -5 TABLE. Six-Year Coronary Heart Disease Mortality Rates by Quintile of Blood Pressure in MRFIT Primary Screenees* Six-year coronary heart disease mortality Age j55-9 Age - Age 5-9 Age? >-5 Age! S5-57 Quintile ofbp 5 Q5/Q DBP <76 76-8 8-85 86-9 >9 All SBP <8 8-5- - > All DBP (mm.7...5... SBP Hg).7.9.9..5. 5. DBP SBP..6..9 6.7.6..... 8..6. DBP SBP. 5. 5.5 6. 9. 6....6. 7.. 6.. DBP SBP 6.5 7. 7... 9.. 5. 7.8 9. 6. 9.. DBP SBP..8.5...9. 6.7 8.5 9.5...9.5 Age 5-57t DBP SBP MRFIT, Multiple Risk Factor Intervention Trial; BP, blood pressure; DBP, diastolic blood pressure; and SBP, systolic blood pressure. *Coronary heart disease mortality is reported as age-specific rates (per, men) or as age-standardized rates for all 7,95 men aged 5-57 years with no history of hospitalization for myocardial infarction on entry into the MRFIT study, tage-adjusted rates...9 5. 6.8 9.5 6....9.9 6. III 6.. Downloaded from http://ahajournals.org by on November, 8 than or equal to mm Hg than in those with DBP greater than or equal to 85 mm Hg. Relative risks associated with elevated DBP tended to be lower in older men; absolute excess risks were progressively higher with increasing age based on either the SBP or the DBP cut point. Further, excess CHD deaths as a percentage of all CHD deaths for each age group were greater with SBP greater than or equal to mm Hg than with DBP greater than or equal to 85 mm Hg. The numbers of excess CHD deaths per, population in 6 years were substantial. As can readily be calculated from Tables and, most of these excess deaths came from the large strata with BP only "moderately" elevated (i.e., DBP in the range 85- mm Hg or SBP in the range -59 mm Hg). These are the strata where "the action is" regarding the reduction of the impact of the BP problem on CHD in the United States. Of course, severe elevations of DBP and SBP are a serious problem clinically, but their prevalence rates are relatively low nowadays, and hence, their control can make only a small contribution to further reducing the great toll of CHD attributable to above-optimal BP levels. Blood Pressure and Coronary Heart Disease Risk in Women The problem as summarized for men is similar for white and black women. No data set like MRFIT, with standardized BP measurements for a cohort of several hundred thousand persons, is available for women. Table 5 is representative of data extant for US women; these data include 9-year follow-up information for almost 9, white women in the Chicago Heart Association Detection Project in Industry study. 9 Risks of death from CHD, from all cardiovascular diseases, and from all causes were markedly increased for women with DBP in the range 9- mm Hg, and greater than or equal to 5 mm Hg. Again, most of the excess deaths attributable to elevated DBP were from the large 9- mm Hg stratum. Although the numbers of deaths were small, the data suggest that CHD risk was also increased among women with DBP in the range 8-89 mm Hg compared with those with DBP less than 8 mm Hg, as was clearly the case for the MRFIT men. More data for women are needed on this matter. TABLE. Age-Specific 6-Year Risk of Coronary Heart Disease Death by Level of Diastolic and Systolic Blood Pressure in MRFIT Primary Screenees Age (years) 5-9 - 5-9 5-5 55-57 Prevalence (%) DBP>85* 7 7 9 9 SBP==* 7 7 5 6 DBP&85*/ DBP<85*.8..7.77.58 Relative risk SBP>*/ SBP<*..97.8.9.5 Absolute excess risk per, DBP>85*- DBP<85* 87 5 67 SBP>*- SBP<* 75 5 68 Excess coronary heart disease deaths per, total population DBP&85* SBP>* 5 66 56 65 68 5 6 Excess coronary heart disease deaths as % of all CHD deaths DBP&85* 5 7 SBP>* 7 8 5 9 5 MRFIT, Multiple Risk Factor Intervention Trial; DBP, diastolic blood pressure; SBP, systolic blood pressure; and CHD, coronary heart disease. *AI blood pressure values are reported in mm Hg.

-6 Supplement I Hypertension Vol, No 5, May 989 TABLE 5. Baseline Diastolic Blood Pressure and Age-Adjusted 9-Year Risk of Death From Coronary Heart Disease, All Cardiovascular Diseases, and All Causes in the CHA* Nine-year mortality Baseline diastolic blood pressure <8 8-89 9-5 N,69,, 8,86 Coronary heart disease N Rate* 5 6.8 6. 9.. 6.9 8 5 7 Cardiovascular disease Rate* 7. 7.6 9.9.6. CHA, Chicago Heart Association Detection Project in Industry. Mortality is reported for white women aged 5-6 years free of myocardial infarction at entry. tage-adjusted death rate per, women; age adjustment by use of a linear regression model." Reprinted with permission from Preventive Medicine (985;:96-), Copyright 985, Academic Press. 8 8 7 9 All causes Rate* 9. 5. 7.8 7.6. Downloaded from http://ahajournals.org by on November, 8 Influence of Systolic Blood Pressure on Coronary Heart Disease Risk for Men With Elevated Diastolic Blood Pressure, MRFIT Men In the tabulations presented up to this point, DBP and SBP were considered separately. Based on the data for the large MRFIT primary screenee cohort, the conclusion is warranted that, for men aged 5-9 years and above but not for younger men, SBP is a better indicator of CHD risk than is DBP. Data from other prospective population studies lend support to this conclusion.5.-5 xhe large size of the MRFIT cohort made possible detailed direct exploration of a further important question: at any given level of elevated DBP (9-9, 95-99, -, 5-9, and - mm Hg), does the level of SBP contribute additional information about CHD risk? 6 Table 6 summarizes the key findings. At each level of DBP, the higher the SBP, the greater the agestandardized 6-year CHD death rate. Note also the unexpected finding: for men within each category of SBP above mm Hg, there does not seem to be a consistent graded relation between DBP and CHD risk. Differential treatment during follow-up may partly explain the similarity of the rates for these DBP groups; however, data on the use of antihypertensive treatment at baseline and during followup were not collected. Clearly, the massive MRFIT data show that SBP is important. It is a better discriminator of CHD risk than is DBP for men aged 5-9 years and older, and, for men in each 5 mm Hg category of elevated DBP, SBP gives additional information about CHD risk. For all those investigators who have been focusing almost exclusively on DBP, these data must be regarded as extremely revealing about the need for concern about SBP in epidemiological research, in the design of clinical trials, and in the practice of clinical medicine and public health. Isolated Systolic Blood Pressure Elevation in Middle-Aged MRFIT Men In recent years, much attention has been given to the impact of isolated systolic hypertension (ISH) TABLE 6. Age-Standardized 6-Year Mortality Rates From Coronary Heart Disease by Level of Systolic and Diastolic Blood Pressure in MRFIT Primary Screenees* Six-year adjusted coronary leart disease death rate Systolic blood pressure <IO -9-9 -9-9 5-59 a 6 Aft 5 5 9 58 DBP 9-9,6 9,8 6,9,6,79,5 5,77 (.) ().8 6. 7. 9.7 5.9 6.9 7 7 6 5 DBP 95-99 (mm Hg; ) 8 6,89 7,9 7,85,57,565,89 (.) (.) (.) 5.9 8.8. 6. 9. M 5 8 5 DBP -,97,66,6,67, (.) (.) (8.9) 7.6 6.5.. 9.7 M 7 8 DBP 5-9 6,,7, 5,78 MRFIT, Multiple Risk Factor Intervention Trial and DBP, diastolic blood pressure. *Mortality is reported per, men for men aged 5-57 years free of myocardial infarction at entry. tnumber of men. Age-adjusted rate per, men. Rates in parentheses are based on < deaths for that stratum. (.) (5.) (5.) (7.) 7.9.. Aft 7 DBP -. 96 9 88,9, Rate (.) (.) (.) (7.7)...8

Stamler et al Blood Pressure and Coronary Disease -7 TABLE 7. Systolic pressure <U -9-9 -9-9 5-59 a 6 Isolated Systolic Hypertension and 6-Year Mortality Rates From Coronary Heart Disease in MRFIT Primary Screenees* Six-year age-adjusted coronary mortality blood DBP 7-7 mm Hg DBP 75-79 mm Hg DBP 8-8 mm Hg Rate Aft 7 6 8 5 7, 6,,97,96,9 9.5..6 7. 9. (7.) (.) m 58 67 55 6,98 8,85 9,7 8,,76 585 8.6..7 6.7. (6.8) (.) MRFIT, Multiple Risk Factor Intervention Trial; DBP, diastolic blood pressure; and SBP, systolic blood pressure. *Mortality is reported per, men for men aged 5-57 years free of myocardial infarction at entry. tnumber of men. Age-adjusted rate per, men. Rates in parentheses are based on < deaths in that stratum. 8 6 7 7 57 7,59 6,,687 9, 6,6,779 659 (5.).. 8. 7..8 on risk in older persons. The Systolic Hypertension in the Elderly Program (SHEP), currently in progress, aims to determine whether drug treatment to reduce ISH is an effective long-term strategy to reduce the excess risk of cardiovascular events (especially strokes) in persons aged 6 years and older with ISH. 6 Until recently, 6 little attention has been paid to the matter of ISH in middle-aged persons. Again, the massive MRFIT data set gives a revealing insight (Table 7). For men with DBP in the ranges 7-7, 75-79, and 8-8 mm Hg at baseline, SBP in the range -9 and greater was Downloaded from http://ahajournals.org by on November, 8 TABLE 8. Diastolic Blood Pressure, Quintiles of Serum Cholesterol, Smoking Status, and 6-Year Age-Adjusted Coronary Heart Disease Mortality Rate in MRFIT Primary Screenees* Group serum cholesterol quintile (mg/dl) Nonsmokers (<8) (8-) (-) (-) 5 (a5) All Smokers (<8) (8-) (-) (-) 5 (>5) All All participants (<I8) (8-) (-) (-) 5 (>5) All Diastolic blood pressure <9 mm Hg 7 8 87 6 88 5 8 95 8 86 5 7 9 77 5 8,7 5,7,55,99, 6,996 59,66,7 9,675 8,8 9,9 8,97 96,5 55,758 5,8 5,75 9,55 5,9 56,9.6.5.7.8 6.. 5. 5.5 7... 8..8.5. 6. 9. 5. Diastolic blood pressure >9mm Hg 6 5 8 9 6 6 7 8 56 67 8 8 987 9,6,599,89,5 6,9 65,8 5, 5,977 6,97 7,5 9,6,55,6 7,576 9,6, 6,57,.7. 5.6 5.6.7 6. 6.. 5.5 6.6. 5..6 6. 8.8 9.. 9. 8 67 88 99 55 8 58,67 96 88 95 5 86,58 5,5 6,5,778,9,96 5, 5,9 5,65 5,9 6,65 8,55,8 7,7 7,8 69,987 7,58 7,76 56, MRFIT, Multiple Risk Factor Intervention Trial. *Mortality is reported per, men for men aged 5-57 years free of a history for hospitalization for myocardial infarction at entry. tnumber of men. Age-adjusted rate per, men. Reprinted with permission from The Journal of the American Medical Association (986;56:8-88), Copyright 986, American Medical Association...9.5. 8.. 6.7 9.5. 6.... 5.6 7.. 6.

-8 Supplement I Hypertension Vol, No 5, May 989 TABLE 9. Entry status Smoking status Nonsmoker Smoker Five-Year Mortality for Stepped Care and Referred Care Participants in the HDFP Major end-organ damaget Absent Present Treatment group* No. of people,69,,6,,668,66 87 79 No. of deaths All participants 7 8 8 5 7 5 8 Adjusted rate per, ±SEMt 8.7±.6 58.5±. 87.±6..±6.9 5.+. 6.5±.6.8±..8±. - 9.8 5.7.. xl(%) 6.8 5. 6.7 8. Downloaded from http://ahajournals.org by on November, 8 Smoking status Nonsmoker Smoker Major end-organ damaget Absent Present Participants with DBP 9- mm Hg and not on antihypertensive drugs at entry,77,795,,59,65,7 9 5 7 89 8 7 6 5 8 5.8+.8 5.±5.6 8.±8.5 95.8±9..±. 6. ±.9.8±8.8 5.6±. HDFP, Hypertension Detection and Follow-up Program. * is stepped care administered by the HDFP research centers; is referred care administered by participants' personal sources of medical care in the communities. trates were adjusted by the direct method for distributional differences in age, sex, and race; common standard population was all HDFP participants. tmajor end-organ damage at entry is defined as evidence of probable myocardial infarction, stroke, definite left ventricular hypertrophy on electrocardiogram, intermittent claudication, or serum creatininea.7 mg/dl. Reprinted with permission from Progress in Cardiovascular Diseases (l986;9(suppl):-), Copyright 986, Grune & Stratton, Incorporated. associated with higher CHD death rates than for men with SBP less than mm Hg. Once again, the data indicate the relevance of SBP. This particular problem, ISH in younger adults, needs to be given attention. Why are there increased risks, and what can be done safely about them?. 5.5 7.7.8. 6. 8.5 Impact of Other Risk Factors on Prognosis of People With High Blood Pressure To this point, this presentation has dealt only with BP and CHD risk. It is well established that the CHD epidemic has multiple causes. Other major risk factors like serum cholesterol levels and cigarette smoking markedly influence the CHD risk of people with high BP as well as those with normal BP. - 9 The massive data on the MRFT primary screenees add new documentation to these previously demonstrated phenomena. As Table 8 shows, for men with high DBP (>9 mm Hg), for nonsmokers and smokers alike, the higher the serum cholesterol level, the higher the risk of CHD death. 5 The additional increments in risk for hypertensive men with even "moderate" elevations of serum cholesterol were substantial, for example, a 6-year CHD death rate of 9./, for all hypertensive men with serum cholesterol in the range - mg/dl (Quintile ) versus.6/, for hypertensive men with serum cholesterol less than 8 mg/dl (Quintile ), that is, a further doubling of risk. Further, at any level of serum cholesterol, hypertensive men who were smokers were at much greater risk by. times overall than were hypertensive nonsmokers. These findings are concordant with those from many studies. - 88-7 The implications of these data for the management of people with high BP are clear: as much as can be done for them by controlling their blood pressure, if their smoking status and serum cholesterol levels are neglected, one is fighting the battle for improved prognosis with one arm tied behind the back. Note in Table 8 that less than % of the hypertensive men, 9,6 of,, were nonsmokers with optimal serum cholesterol levels of less than 8 mg/dl. Most hypertensive persons need counseling regarding the multiple aspects of lifestyle for control of the multiple risk factors influencing their prognosis. The data on the MRFIT 8.

Stamler et al Blood Pressure and Coronary Disease E v e n t AP or LVH Nonfatal Ml Nonfatal strokes e r Other deaths CVD deaths o «o o 5e Downloaded from http://ahajournals.org by on November, 8 FIGURE. Stacked bar graph of 5-year incidence per, (events per,) of mortality and morbidity for stepped-care () (n=,96) and referred-care () (n=,95) participants with mean diastolic blood pressure (BP) of 9- mm Hg who were not taking antihypertensive medication at entry to the study. Deaths attributed to cardiovascular diseases (CVD deaths) include International Classification of Diseases codes 9-58 and 76 (eighth revision). Only one event per person was counted. Thus, only nonfatal strokes among 5-year survivors were counted; nonfatal myocardial infarctions (MI) are exclusive of any Ml among decedents or persons with a nonfatal stroke; angina pectoris (AP) or left ventricular hypertrophy (LVH) include only events among persons not experiencing one of the other events. Reprinted with permission from Progress in Cardiovascular Diseases (986;9(suppl):-), Copyright 986, Grune & Stratton, Incorporated. men further show that, all else being equal, hypertensive men with a history of treatment for clinical diabetes have a 6-year risk of fatal CHD almost three times greater than nondiabetic hypertensive men. Most of these diabetic men almost certainly had non-insulin-dependent diabetes for which the key known risk factor is marked overweight. Overweight is also a key risk factor for high BP (along with high salt intake and excess alcohol consumption). Further, among the US and other populations habitually consuming a diet high in saturated fat and cholesterol, overweight adds significantly to the risk of hypercholesterolemia. With all these nutritional considerations and the direct independent effect of "rich" diet on CHD risk,9 the eating patterns of the tens of millions with hypertension must be of major concern, along with their smoking habits. -9 The situation is essentially the same for hypertensive women as it is for hypertensive men.8 Three quarters of the women in the Chicago Heart Association Detection Project in Industry cohort with DBP from 9 to mm Hg had one or more other risk factors; one quarter had an abnormal electrocardiogram. Risks of 9-year death from CHD, from all cardiovascular diseases, and from all causes were markedly increased for these women with DBP in the range 9- mm Hg who also had one or more of the other risk factors. Also, the prognosis for those with DBP in the range 9- mm Hg and an abnormal electrocardiogram compared with those with a normal electrocardiogram was much more unfavorable.8 This last finding (again, one which is representative of data from many population studies on men and women, whites and blacks) documents a further key strategic consideration, the importance of detecting and controlling high BP early before end-organ damage has occurred, to prevent that damage, and to prevent people from developing this higher plane of risk. Data from other trials further document the foregoing inferences as illustrated by the findings of the Hypertension Detection and Follow-up Program (HDFP) (Table 9).8 For all participants and for those with DBP 9- mm Hg not taking antihypertensive drugs at entry, the 5-year mortality for smokers in the stepped-care () and referred-care () groups was much higher than that for nonsmokers. (Neither nor treatment addressed the smoking problem.) The intensive drug treatment program for hypertension led to a lower mortality rate for nonsmokers and smokers compared with the corresponding subgroup, but the intensive could not overcome the added risk of cigarette use in the absence of a systematic effort to achieve smoking cessation. Similar results were recorded by the British Medical Research Council Trial.9 Regarding the impaired prognosis for persons with high BP who have end-organ damage, the HDFP data also demonstrate this forcefully. Even with highly effective drug treatment to achieve and maintain BP normalization, 5-year mortality was about three times greater for participants with major end-organ damage at entry than it was for those without such damage (Table 9).8 This finding for people with DBP 9- mm Hg and not on drug treatment at entry prevailed for the 9-9, 9599, and - mm Hg substrata. This finding underscores the soundness of the position adopted at the recent Kronberg Conference of the International Society of Hypertension and the World Health Organization; no one with end-organ damage, regardless of DBP, should be designated a "mild" hypertensive. If the word "mild" is to be used at all, it should be reserved only for people with DBP 9- mm Hg (or 9-99 mm Hg) not on drug treatment (so that the reading is a true one) and without signs of end-organ damage.

- Supplement I Hypertension Vol, No 5, May 989 Downloaded from http://ahajournals.org by on November, 8 TABLE. All Morbid Events for Participants in the USPHS Hospitals Cooperative Trial* Active drug treatment (/V=9) Morbid event n Rate* Death. Nonfatal cardiac event Myocardial infarction Other coronary heart disease Left ventricular hypertrophy LVS by electrocardiogram Cardiomegaly Congestive heart failure nonfatal cardiac events Other nonfatal events Stroke Renal insufficiency Arterial insufficiency Retinopathy fatal and nonfatal events Persons with Any of the above 6 6 8 89 59 5.7 None of the above 69. Incidence of diastolic blood pressure>! mm Hg. n 7 5 7 8 6 9 6 9 6 Placebot (N=96) USPHS, US Public Health Service. *Events are reported for persons aged -55 years at entry with "mild" hypertension, during 7- years of follow-up. tfor many participants originally randomized to placebo, active antihypertensive medication was prescribed during the course of the trial. tevent rate per, persons. Count of nonfatal events; because more than one event of each type could have occurred in any one person, no rate is given. Reprinted with permission from Circulation Research (977;(suppl I): -98-5), Copyright 977, American Heart Association. Blood Pressure and Nonfatal Plus Fatal Cardiac Events So far, this report has dealt only with BP and CHD mortality, and there are too many papers in the recent literature giving the false impression that mortality is the only consideration. Data from many research studies illustrate this vividly. The data in Table of the US Public Health Service (USPHS) Hospitals Trial and in Figure of the HDFP are representative. The USPHS Hospitals Trial involved younger people (average age of years compared with 5 years for the HDFP participants) without end-organ damage at baseline and with so-called mild hypertension. As Table shows, few deaths occurred during the 7- years of follow-up of the USPHS Hospital Trial participants. However, despite their age, their mild BP elevations, and their freedom from end-organ damage at baseline, morbid events were numerous: 6 in the placebo group in nearly one half the participants. Most of these were cardiac events, some clinical, some subclinical. All these events shifted these people to a new higher more-or-less irreversible plane of risk. Clearly, this is not a problem properly called mild. It is also obvious that any argument for deferring treatment based on the relatively low-order shortterm risk of death for such younger hypertensive individuals ignores the harsh reality of the greatly Rate!. 59. 5.8. increased long-term risk of death for such persons if left untreated (e.g., by age 65) and the toll exacted by nonfatal events. The 5-year follow-up data of the HDFP reinforce these conclusions. As shown in Figure, almost one quarter of participants with DBP in the range 9- mm Hg and not taking medication at entry experienced a major nonfatal or fatal event in 5 years. 8 There were nearly twice as many major nonfatal as fatal events, and these do not include such meaningful incidents as other electrocardiographic abnormalities, cardiomegaly on chest x-ray, congestive heart failure, renal insufficiency, arterial insufficiency, retinopathy, and severe hypertension. Note in Table and Figure the significant reduction in the incidence of combined nonfatal and fatal events with intensive sustained antihypertensive treatment, including the incidence of cardiac events. These combined end points are similar to the one used as the primary end point in the landmark Veterans Administration trial whose results ended the era of therapeutic nihilism and "judicious neglect" of high BP. For every trial reporting these data for such a combined end point, the outcome was favorable for the intensive-treatment group for this end point. This result also occurred for this end point in those trials with sample sizes too small to have had reasonable statistical power

Downloaded from http://ahajournals.org by on November, 8 to minimize the likelihood of a false-negative finding for such end points as all-cause death, coronary death, or nonfatal myocardial infarction plus coronary death. The consistent results from many trials on the efficacy of intensive treatment against cardiac and cardiovascular disease events further emphasizes the wisdom of early and comprehensive treatment of all hypertensive individuals. Summary The following points should be noted: ) Regarding the important role of BP as a major coronary risk factor, the BP problem is one involving the majority of adults aged 5 years and older in the US population. The BP problem encompasses but is not limited to those classed as hypertensive by the usual criteria (mean DBP > 9 mm Hg) and those currently called high-normal based on a DBP of 85-89 mm Hg. ) For men aged 5-9 years and older, SBP is more strongly associated with risk of CHD than is DBP. ) For persons with frankly elevated DBP (> 9 mm Hg) at any level of DBP, SBP gives additional information on risk. ) For persons with DBP less than 85 mm Hg, including middle-aged individuals (as well as the elderly), risk is a function of SBP. 5) For persons with elevated BP, risk is increased by the presence of other risk factors, for example, serum cholesterol levels above optimal (i.e., s 8 mg/dl), smoking, diabetes, and "rich" diet. 6) For persons with elevated BP, risk is also increased for those with end-organ damage. 7) For persons with elevated BP, risks include not only death but also many additional morbid events, clinical and subclinical, producing sickness, disability, or impairment of prognosis. 8) The extensive data base on the BP problem serves as the foundation for comprehensive treatment strategy, pharmacological and nonpharmacological, that is essential for prevention and control of elevated BP. - 7 Acknowledgments It is a pleasure to acknowledge the invaluable work of many colleagues in the two national cooperative studies and in the Chicago study whose data are cited here, the Multiple Risk Factor Intervention Trial (MRFIT), the Hypertension Detection and Follow-up Program (HDFP), and the Chicago Heart Association Detection Project in Industry. Extensive rosters of the responsible professional personnel in these investigations are given in the references to original reports and are cited in the "References" section to this article. These research endeavors were all supported by the National Heart, Lung, and Blood Institute. The Chicago Heart Association study was also supported by other grants as acknowledged in the cited article. l8 It is also a pleasure to thank W. McFate Smith and colleagues from the USPHS Hospitals Trial, whose data are also cited here, and to acknowledge the publishers of the journals in which the several data sets appeared, namely, Circulation Stamler et al Blood Pressure and Coronary Disease I- Research, Preventive Medicine, Progress in Cardiovascular Diseases, and the Journal of the American Medical Association. References. Stamler J: Lectures on Preventive Cardiology. Grune & Stratton, Inc, New York, 967, pp -. Inter-Society Commission for Heart Disease Resources. Atherosclerosis Study Group and Epidemiology Study Group: Primary prevention of the atherosclerotic diseases. Circulation I97O;:A55-A95. Stamler J: High blood pressure in the United States An overview of the problem and the challenge. National Conference on High Blood Pressure Education Report of Proceedings. US Dept of Health, Education, and Welfare, Public Health Service, National Institutes of Health, Dept of Health Education, and Welfare publication No. (NH) 7-86. Washington, DC, US Government Printing Office, 97, pp -66. Framingham Research Group and Pooling Project Research Group: The results of the Framingham Study applied to four other U.S.-based epidemiologic studies of cardiovascular disease, in Kannel WB, Gordon T (eds): The Framingham Study An Epidemiological Investigation of Cardiovascular Disease. Section, US Dept of Health, Education, and Welfare, Public Health Service, Dept of Health Education, and Welfare publication No. (NIH) 76-8. Washington, DC, US Government Printing Office, 976, pp -65 5. Pooling Project Research Group: Relationship of blood pressure, serum cholesterol, smoking habit, relative weight and ECG abnormalities to incidence of major coronary events: Final report of the Pooling Project. J Chronic Dis 978;:-6 6. American Heart Association Committee Report: Risk factors and coronary disease A statement for physicians. Circulation I98O;6:9A-55A 7. Working Group on Arteriosclerosis of the National Heart, Lung, and Blood Institute: Population-based research, in Report of the Working Group on Arteriosclerosis of the National Heart, Lung, and Blood Institute, vol. US Dept of Health and Human Services, Public Health Service, National Institutes of Health, publication No. (NIH) 8-5, Bethesda, MD, 98, pp 57-6 8. Inter-Society Commission for Heart Disease Resources. Atherosclerosis Study Group: Optimal resources for primary prevention of atherosclerotic diseases. Circulation 98; 7O:I5A-O5A 9. Stamler J: Epidemiology, established major risk factors, and the primary prevention of coronary heart disease, in Parmley WW, Chatterjee K (eds): Cardiology. Philadelphia, JB Lippincott, Co, 987, pp -. Sherwin R, Kaelber CT, Kezdi P, Kjelsberg MO, Thomas HE: The Multiple Risk Factor Intervention Trial (MRFIT). II. The development of the protocol. Prev Med 98; :-5. Neaton JD, Kuller LH, Wentworth D, Borhani NO: and cardiovascular mortality in relation to cigarette smoking, serum cholesterol concentration, and diastolic blood pressure among black and white males followed for five years. Am Heart J 98;8:759-769. Stamler J, Wentworth D, Neaton JD: Prevalence and prognostic significance of hypercholesterolemia in men with hypertension Prospective data on the primary screenees of the Multiple Risk Factor Intervention Trial. Am J Med 986; 8(suppl):-9. Kannel WB, Neaton JD, Wentworth D, Thomas HE, Stamler J, Hulley SB, Kjelsberg MO: Overall and coronary heart disease mortality rates in relation to major risk factors in 5,8 men screened for the MRFIT. Am Heart J 986; :85-86. Martin H, Hulley SB, Browner WS, Kuller LH, Wentworth D: Serum cholesterol, blood pressure, and mortality: Implications from a cohort of 6,66 men. Lancet 986,:9-96

- Supplement I Hypertension Vol, No 5, May 989 Downloaded from http://ahajournals.org by on November, 8 5. Stamler J, Wentworth D, Neaton JD: Is relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? Findings in 56, primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT). JAMA 986;56:8-88 6. Rutan GH, Kuller LH, Neaton JD, Wentworth DN, McDonald RH, Smith WM: Mortality associated with diastolic hypertension and isolated systolic hypertension among men screened for the Multiple Risk Factor Intervention Trial. Circulation 988;77:5-5 7. Wentworth D, Neaton JD, Rasmussen W: Evaluation of SSA master beneficiary files and the National Death Index in ascertainment of vital status. Am J Public Health 98; 7:7-7 8. International Classification of Diseases, 9th revision, vol.. Geneva, World Health Organization, 977, pp -77 9. Guimetti D, Liu K, Stamler R, Schoenberger JA, Shekelle RB, Stamler J: Need to prevent and control high-normal and high blood pressure, particularly so-called "mild" hypertension: Epidemiological and clinical trials. Prev Med 985; :96-. Kannel WB, Gordon T, Schwartz MJ: Systolic versus diastolic blood pressure and risk of coronary heart disease: The Framingham study. Am J Cardiol 97 ;7:5-6. Rosenman RH, Scholtz Rl, Brand RJ: A study of comparative blood pressure measures in predicting coronary heart disease. Circulation 976;5:5-58. Rabkin SW, Mathewson FAL, Tate RB: Predicting risk of ischemic heart disease and cerebrovascular disease from systolic and diastolic blood pressures. Ann Intern Med 978; 88:-5. Miall WE: Systolic or diastolic hypertension Which matters most? Clin Exp Hypertens 98;:-. Lichtenstein MJ, Shipley MJ, Rose G: Systolic and diastolic blood pressure as predictors of coronary heart disease mortality in the Whitehall study. BrMedJ 985;9:-5 5. Abernethy J, Borhani NO, Hawkins CM, Crow R, Entwisle G, Jones JW, Maxwell MH, Langford H, Pressel S: Systolic blood pressure as an independent predictor of mortality in the Hypertension Detection and Follow-up Program. Am J Prev Med 986;:- 6. Systolic Hypertension in the Elderly Program (SHEP) Cooperative Research Group: Rationale and design of a randomized clinical trial on prevention of stroke in isolated systolic hypertension. J Clin Epidemiol (in press) 7. Stamler J, Giumetti D, Liu K, Stamler R, Dyer A: Risks with so-called "mild" hypertension, in Hofmann H, Schrey A (eds): Control of Arterial Hypertension in the Prevention of Cardiovascular Disease. Stuttgart/New York, Schattauer, 986, pp - 8. Blaufox MD, Borhani NO, Curb JD, Daugherty SA, Hawkins CM, Langford HG, Payne GH, Stamler J, Editorial Board; Hypertension Detection and Follow-up Program Cooperative Group: Results and implications of the Hypertension Detection and Follow-up Program. Prog Cardiovasc Dis 986;9(suppl):- 9. Medical Research Council Working Party: M Trial of Treatment of Hypertension: Principal results. Br Med J 985;9:97-. Miall WE, Greenberg G, on behalf of the Medical Research Council's Working Party on Mild to Moderate Hypertension: Mild Hypertension: Is There Pressure to Treat? Cambridge/New York/Melbourne, Cambridge University Press, 987, pp -. Amery A, Anlauf M, Beilin LJ, Bock KD, Britov A, Buhler RF, Chalmers JP, Distler A, Doyle AE, Epstein FH, Faulhaber HD, Faulkner B, Fries ED, Fuller J, Furberg K, Ganter P, Gleichmann U, Hansson L, Holman A, Haydk K, Keil U, Langford H, Lasser N, Menard J, Miall WE, Oberman A, Peart S, Prineas RP, Skrabal F, Sleight P, Stamler J, Strasser T, Stumpe KO, Torok E, Tyroler A, Wilhelmsen L, Zanchetti A: 986 guidelines for the treatment of mild hypertension: Memorandum from a WHO/ISH meeting. Bull WHO 986;6:-5. International Classification of Diseases, 8th revision, vol. Geneva, World Health Organization, 967, pp -78. Smith WM: Treatment of mild hypertension Results of a ten year intervention trial. US Public Health Service Hospitals Cooperative Study Group. CircRes 977;(supplI):I-98-I-5. WHO Expert Committee on the Prevention of Coronary Heart Disease: Prevention of coronary heart disease, World Health Organization Technical Report Series No. 678, Geneva, World Health Organization, 98, pp -5 5. Stamler J, Stamler R, Liu K: High blood pressure, in Connor WE, Bristow JD (eds): Coronary Heart Disease Prevention, Complications, and Treatment. Philadelphia, JB Lippincott, Co, 985, pp 85-9 6. Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure: 98 Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 98; :5-57 7. Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure: Nonpharmacological approaches to the control of high blood pressure Final report of the subcommittee on nonpharmacological therapy of the 98 Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 986;8:-67 KEY WORDS epidemiology blood pressure cardiovascular risk factors coronary heart disease