The presence of cardiovascular disease risk factors, clinical

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1 The Impact of JNC-VI Guidelines on Treatment Recommendations in the US Population Paul Muntner, Jiang He, Edward J. Roccella, Paul K. Whelton Abstract Using epidemiological and clinical trial evidence, the sixth report of the Joint National Committee on Prevention, Detection, and Treatment of High Blood Pressure (JNC-VI) updated previous guidelines to suggest that in addition to blood pressure, decisions on initial treatment should emphasize absolute cardiovascular disease risk. We estimated the impact of using cardiovascular disease risk on treatment recommendations for the US population using data from participants in the Third National Health and Nutrition Examination Survey. In the US population 20 years of age, 36% (62 million) had high-normal blood pressure or greater (systolic/diastolic blood pressure 130 mm Hg/ 85 mm Hg) or were taking antihypertensive medication. Of this population, 5.1% (3.2 million) were stratified into risk group A (no cardiovascular disease risk factors or prevalent cardiovascular disease), 66.3% (41.4 million) into risk group B ( 1 major risk factor), and 28.6% (17.9 million) into risk group C (diabetes mellitus, clinical cardiovascular disease, target organ damage). Also, 26% of this group (16.2 million) had high-normal blood pressure and were in risk groups A or B, a context in which vigorous lifestyle modification is recommended in the JNC-VI guidelines. Additionally, 11% (7.0 million) had high-normal blood pressure (systolic/diastolic, 130 to 139 mm Hg/85 to 89 mm Hg, respectively) or stage-1 hypertension (140 to 159 mm Hg/90 to 99 mm Hg), and at least 1 factor, placing them in risk group C, but they were not currently on antihypertensive medication. JNC-VI, but not previous JNC guidelines, specifically recommends drug therapy as initial treatment for these patients. We conclude that JNC-VI refines cardiovascular risk and enfranchises more Americans to undertake more aggressive risk reduction maneuvers. (. 2002;39: ) Key Words: guidelines treatment drug therapy lifestyle The presence of cardiovascular disease risk factors, clinical cardiovascular disease, and target organ damage significantly increases the absolute risk of cardiovascular disease associated with blood pressure. 1,2 The sixth report of the Joint National Committee on Prevention Detection, Evaluation, and Treatment of High Blood Pressure (JNC-VI) places a strong emphasis on risk factors, clinical cardiovascular disease, and target organ damage in classifying patients and advising treatment decisions. Specifically, the JNC-VI guidelines stratify persons into risk groups based on the presence or absence of major cardiovascular disease risk factors, clinical cardiovascular disease, and target organ damage. These risk groupings are used along with blood pressure level in guiding treatment recommendations (Table 1). 3 Tailoring of treatment guidelines, including use of the risk groupings in JNC-VI, may have a substantial impact on public health programs and health care policy. Therefore, we estimated the distribution of the US population into JNC-VI cardiovascular disease risk groups using data from a nationally representative data set, the Third National Health and Nutrition Examination Survey (NHANES III). In addition, we calculated the number of persons and percentage of the US population that should receive lifestyle modification and/or drug therapy as initial treatment using JNC-VI treatment guidelines that apply risk grouping in guiding initial treatment recommendations. This number was compared with the corresponding estimates based on JNC-V guidelines that primarily relied on blood pressure levels for guiding initial therapy. Methods NHANES III Detailed descriptions of the NHANES III survey have been previously published. 4 In brief, NHANES III was conducted by the National Center for Health Statistics (NCHS) of the Centers for Disease Control and Prevention between 1988 and 1994, and provides cross-sectional, nationally representative data on the health and nutritional status of the civilian, noninstitutionalized population of the United States. The current analysis was limited to adult NHANES III participants, defined as those 20 years of age. Standardized questionnaires were administered in the participant s Received November 30, 2001; first decision February 14, 2002; accepted February 14, From the Department of Epidemiology (P.M., J.H., P.K.W.), Tulane University School of Public Health and Tropical Medicine, and Department of Medicine (J.H., P.K.W.) Tulane University School of Medicine, New Orleans, La; and National Heart, Lung and Blood Institute (E.J.R.), Bethesda, Md. Correspondence to Paul Muntner, Department of Epidemiology, Tulane University SPHTM, 1430 Tulane Ave, SL-18, New Orleans, LA pmuntner@tulane.edu 2002 American Heart Association, Inc. is available at DOI: /01.HYP D 897

2 898 April 2002 TABLE 1. JNC-VI Risk Stratification and Treatment Recommendations* Blood Pressure Stages (SBP/DBP in mm Hg) High-normal blood pressure (SBP 130 to 139/DBP 85 to 89) Stage 1 hypertension (SBP 140 to 159/DBP 90 to 99) Stages 2 and 3 hypertension (SBP 160/DBP 100) Risk Group A (No Risk Factors No TOD/CCD) Risk Group B ( 1 Risk Factor, Not Including Diabetes; No TOD/CCD) Risk Group C (TOD/CCD and/or Diabetes, With or Without Other Risk Factors) Lifestyle modification Lifestyle modification Drug therapy Lifestyle modification (up to 12 months) Lifestyle modification (up to 6 months) Drug therapy Drug therapy Drug therapy Drug therapy TOD indicates target organ damage; CCD, clinical cardiovascular disease (heart diseases are left ventricular hypertrophy, angina/prior myocardial infarction, prior coronary revascularization; heart failure is stroke or transient ischemic attack, nephropathy, peripheral arterial disease, retinopathy). Risk factors include smoking, dyslipidemia, diabetes mellitus, age 60 years, gender (men and postmenopausal women), family history of cardiovascular disease, women 65 years or men 55 years). *Lifestyle modification should be adjunctive therapy for all patients recommended for drug therapy. For those with heart failure, renal insufficiency, or diabetes. For patients with multiple risk factors, clinicians should consider drugs as initial therapy plus lifestyle modification. home, followed by a detailed physical examination and blood collection at a mobile examination center. Data Collection During the home interview, demographic information including age, race, and gender were collected using a standardized questionnaire. Additional data that are relevant to the current analysis were collected during the in-home interview, including a selfreported history of myocardial infarction, stroke, diabetes, antihypertensive and lipid-lowering medication usage, cigarette smoking, and Rose questionnaire information on angina, transient ischemic attack, and peripheral artery disease. Peripheral artery disease was defined by responding to the Rose questionnaire that pain in the leg occurs while walking that does not begin while standing still; the pain occurs in the calf; it occurs when walking uphill or in hurry but not at flat levels; and the pain does not disappear while walking, but if the respondent stops or slows down, the pain goes away. Additionally, women were asked questions about their reproductive (menopausal) status. During the visit to the mobile examination center, blood was drawn from the participant s antecubital vein by a trained phlebotomist according to a standardized protocol to measure serum glucose, creatinine, and total and HDL cholesterol. Fundus photography was performed on all NHANES III participants, and an ECG was performed on participants 40 years of age. Blood Pressure Measurement and Classification Up to 6 blood pressure measurements were taken on 2 occasions using a standard protocol. The first set of 3 blood pressures was measured in the home by a lay interviewer, and a physician obtained the second set during the medical examination. Blood pressures were measured with the participant in the sitting position after 5 minutes of rest. Based on the average of all available measurements, patients were classified into mutually exclusive blood pressure categories using JNC-VI guidelines: optimal (SBP 120 mm Hg/DBP 80 mm Hg), normal (120 to 129 mm Hg/80 to 84 mm Hg), high-normal (130 to 139 mm Hg/85 to 89 mm Hg), stage 1 (140 to 159 mm Hg/90 to 99 mm Hg), stage 2 (160 to 179 mm Hg/100 to 109 mm Hg), and stage 3 ( 180 mm Hg/ 110 mm Hg) hypertension. Consistent with the recommendations in the JNC-VI guidelines, when systolic and diastolic blood pressure fell into different blood pressure categories, participants were classified into the higher category. Major Cardiovascular Disease Risk Factors Major cardiovascular disease risk factors used in JNC-VI risk stratification were defined as follows: self-reported cigarette smoking, age 60 years, male gender or postmenopausal status (no menses or pregnancy within the previous 12 months), and dyslipidemia (total cholesterol 240 mg/dl, HDL cholesterol 35 mg/dl, or self-reported lipid lowering medication use); the presence of diabetes mellitus was based on a self-reported history, a fasting serum glucose 126 mg/dl, or a nonfasting serum glucose 200 mg/dl. Assessment of Clinical Cardiovascular Disease and Target Organ Damage Clinical cardiovascular disease and target organ damage were defined as the presence of left-ventricular hypertrophy (ECG), angina, peripheral arterial disease, or stroke (Rose questionnaire), transient ischemic attack (Rose questionnaire, self report of 5 minutes during which the ability to speak or understand someone was problematic and at least 1 other symptom of neurological deficiency was noted dizziness, paralysis, loss of sensation, or numbness), prior myocardial infarction (self-report or evidence from the ECG), congestive heart failure (self-report), nephropathy (serum creatinine 3.0 mg/dl), and retinopathy (fundus photography). Statistical Analysis The prevalence of JNC-VI blood pressure categories was determined for the US population. Because of the small number of persons with stage 3 hypertension in the NHANES III sample (n 293) and the identical treatment recommendations for stage 2 and stage 3 hypertension, these 2 groups were combined with persons currently taking antihypertensive medication for all analyses. Next, the prevalence of major cardiovascular disease risk factors, clinical cardiovascular disease, and target organ damage was determined for the overall population and by gender and JNC-VI blood pressure subgroupings. Using the JNC-VI guidelines, persons with high-normal blood pressure or hypertension were further stratified into one of 3 mutually exclusive risk groups (Table 1). Persons with no major cardiovascular disease risk factors, clinical cardiovascular disease, or target organ damage were stratified into risk group A. Those with 1 major cardiovascular disease risk factor (male gender, postmenopausal status for females, age 60 years, smoking, dyslipidemia) but without diabetes mellitus, clinical cardiovascular disease, or target organ damage were stratified into risk group B. Finally, persons with diabetes mellitus, clinical cardiovascular disease, or target organ damage, regardless of the presence of other major cardiovascular disease risk factors, were stratified into risk group C. The distribution of the population was further stratified by JNC-VI blood pressure category and race-gender grouping (non-hispanic white men and women, non-hispanic black men and women, and Mexican- American men and women). In the race-gender specific analyses, risk strata prevalence were determined after each race-gender grouping was age-standardized to the distribution for the overall US population using the direct method with the overall population as the standard. Finally, the number and percentage of persons with high-normal blood pressure or hypertension recommended by

3 Muntner et al Impact of JNC-VI Risk Stratification 899 TABLE 2. Prevalence of Major Cardiovascular Disease Risk Factors (Male Gender, Age >60, Current Cigarette Smoking, Dyslipidemia, and Diabetes) by Gender and JNC-VI Blood Pressure Categories Among Adult (Age >20 Years) Participants in NHANES III Systolic/Diastolic Population Blood Pressure Range, mm Hg Any* Age 60 Current Smoking Dyslipidemia Diabetes Postmenopausal Men Overall Optimal 120/ Normal / High-normal / Stage / Stage / Female Overall Optimal 120/ Normal / High-normal / Stage / Stage 2 160/ *Dyslipidemia was defined as a total cholesterol 240 mg/dl. In addition to male gender. Diabetes mellitus defined as a self-reported history, fasting plasma glucose 126 mg/dl, or nonfasting plasma glucose 200 mg/dl. JNC-VI guidelines to receive drug therapy as initial treatment was calculated and compared with the corresponding number based on use of the JNC-V guidelines. All calculations were weighted to the civilian noninstitutionalized adult population of the US and took into account the complex survey design of NHANES III and nonresponse using complex survey commands in STATA software. 5 The content and conduct of the NHANES III were subject to an institutional review board. All individuals participating in the MEC examination were required to sign an informed consent document. Results Valid blood pressure measurements were available for 88% of the NHANES III participants 20 years of age (n ). Overall, 36% of the US population 20 years of age had high-normal or greater blood pressure or was on antihypertensive medication. Of these, 32% had high-normal blood pressure, 25% had stage 1 hypertension, and 43% had either stage 2 or greater hypertension or was currently taking antihypertensive medication. The prevalence of major cardiovascular disease risk factors varied by gender (Table 2). In addition to male gender, in itself a major cardiovascular disease risk factor in JNC-VI, 67% of men had 1 major cardiovascular disease risk factor, the most common of which was cigarette smoking. Overall, 65% of the female participants had 1 major cardiovascular disease risk factor. The most common major risk factor among women was being postmenopausal. Among both men and women, the presence of 1 major cardiovascular disease risk factor increased at higher levels of blood pressure. Among men and women with major cardiovascular disease risk factors the mean (95% confidence interval) number of risk factors present was 2.46 (2.43 to 2.48) and 1.94 (1.90 to 1.98), respectively. The prevalence of factors placing patients into risk group C (diabetes mellitus, clinical cardiovascular disease, or target organ damage) was similar among men (16.5%) and women (18.5%). A trend for higher prevalence of diabetes mellitus or any clinical cardiovascular disease and target organ damage at higher JNC-VI blood pressure categories was noted in both men and women (Table 3). Also, the prevalence of clinical cardiovascular disease and target organ damage investigated tended to be greater at progressively higher levels of blood pressure. Among both men and women, the most common clinical cardiovascular condition was myocardial infarction/ angina, and the most common condition classified as target organ damage was congestive heart failure. On average, persons with diabetes mellitus, clinical cardiovascular disease, and target organ damage had 1.34 (95% CI, 1.31 to 1.37) such conditions. Only 5.1% of the US population with high-normal or greater blood pressure or on antihypertensive medication had no other major cardiovascular disease risk factors, clinical cardiovascular disease or target organ damage (risk group A). In contrast, 66.3% were in risk group B, and 28.6% were in risk group C. After age adjustment, the prevalence of risk group A indicating the absence of major risk factors, clinical cardiovascular disease, and target organ damage was lower at higher blood pressure levels among non- Hispanic white and black women (Table 4). Although the prevalence of risk group A was similar for Mexican- American women with high-normal blood pressure and stage

4 900 April 2002 TABLE 3. Prevalence of Components of Risk Group C (Clinical Cardiovascular Disease, Target Organ Damage, and Diabetes Mellitus) Among the US Population by JNC-VI Blood Pressure Category and Gender Among Adult (Age >20 years) Participants in NHANES III Clinical Cardiovascular Disease Target Organ Damage Diabetes Mellitus TOTAL TOTAL Angina/MI Stroke/TIA PAD TOTAL LVH* CHF Nephropathy Retinopathy TOTAL Men BP Level Overall Optimal Normal High-normal Stage Stage Females BP Level Overall Optimal Normal High-normal Stage Stage MI indicates myocardial infarction; TIA, transient ischemic attack; PAD, peripheral artery disease; LVH, left ventricular hypertrophy; and CHF, congestive heart failure. *LVH was measured by electrocardiogram (ECG). Nephropathy was defined by a serum creatinine 3.0 mg/dl. 1 hypertension, it was significantly lower for those with stage 2 or greater hypertension. In contrast, the prevalence of risk group C increased with higher blood pressure in both non- Hispanic white and black women; among Mexican-American women, the prevalence of risk group C was similar for those with high-normal blood pressure and stage 1 hypertension but substantially higher among persons with stage 2 or greater hypertension. Because male gender is considered a major cardiovascular disease risk factor, no men were stratified into risk group A. Among men, the prevalence of risk group C was higher at higher blood pressure levels for all race groups. Using the distribution of blood pressure categories in the NHANES III, 62.4 million persons in the United States had high-normal blood pressure or hypertension at the time the survey was conducted. Of these, 42.8% had stage 2 or greater hypertension or were currently taking antihypertensive medication. In both the JNC-V and JNC-VI, there was a recommendation that all such persons (26.8 million) (Table 5) should receive drug therapy as initial treatment. Additionally, for the 12.5 million persons with stage 1 hypertension in risk groups A or B, JNC-V and JNC-VI recommended a period of lifestyle modification before the initiation of drug therapy. For the 16.2 million patients with high-normal blood pressure in risk groups A or B, JNC-V recommended physicians to consider providing advice about lifestyle modification, whereas JNC-VI strongly recommends lifestyle modification to lower blood pressure. Finally, 11.3% of the population with high-normal blood pressure or stage 1 hypertension had 1 factor (ie, diabetes mellitus, clinical cardiovascular disease, or target organ damage) that placed them in risk group C. This corresponds to 7 million persons in the United States for whom initial antihypertensive drug therapy is recommended in the JNC-VI guidelines, whereas this was not such an overt initial recommendation in previous JNC guidelines. Discussion The results of the current analysis provide insight into the potential impact of the JNC-VI treatment guidelines. Evidence from epidemiologic studies and clinical trials has accumulated over the past several years, showing that the absolute risk of cardiovascular disease associated with blood pressure level is modified by the presence of risk factors for cardiovascular disease, clinical cardiovascular disease, or target organ damage. Recent guidelines, including those of the JNC-VI committee and the Guidelines Subcommittee of the World Health Organization International Society of Mild Liaison Committee, built on their predecessor s recommendations by incorporating this evidence and by basing their treatment recommendations on the presence of cardiovascular disease risk factors, clinical cardiovascular disease, and target organ damage. 3,6 NHANES III findings suggest that the prevalence of high-normal blood pressure and hypertension is disturbingly high in the general population of the United States (36% of the noninstitutionalized adult population). In the United States, 19.9 and 15.8 million people have high-normal blood pressure and stage-1 hypertension, respectively, and are not receiving drug therapy. Of these populations, 18.9% (3.7 million) and 18.3% (3.4 million), respectively, have diabetes

5 Muntner et al Impact of JNC-VI Risk Stratification 901 TABLE 4. Age-Standardized* Prevalence of JNC-VI Risk Groupings for the US Population Stratified by Gender, Race, and JNC-VI Blood Pressure Categories Among Adult (Age >20 Years) Participants in NHANES III Men Women A B C A B C Non-Hispanic whites Blood pressure level Overall High-normal Stage Stage Non-Hispanic blacks Blood pressure level Overall High-normal Stage Stage Mexican-Americans Blood pressure level Overall High-normal Stage Stage *Age standardized to the US population using 4 age groupings (standard population): 20 to 40 years of age (44%), 40 to 60 years (33%), 60 to 75 years (17%), and 75 years (6%). Includes high-normal blood pressure and stage 1 and stage 2 hypertension. mellitus, clinical cardiovascular disease, or target organ damage and are recommended to receive drug therapy as initial treatment. A previous study investigated the distribution of JNC-VI risk groupings using data from the Framingham study. 7 The current report complements and extends the findings of that investigation in 3 important ways. First, the prevalence of hypertension and age distribution in the Framingham study differs significantly from that of the US population. Compared with the US population, the Framingham study population is older and more likely to have hypertension. Second, the data used in the current study are representative of the general US population regarding race/ethnicity subpopulations. The current analysis included non-hispanic blacks, Mexican-Americans, and persons 40 years of age; these populations were unavailable in the analysis using Framingham data. Finally, the current study assessed the potential impact of the JNC-VI treatment guidelines in the US population by comparing them with recommendations in the JNC-V and previous guidelines. Additionally, a previous study compared the number needed to treat to prevent a cardiovascular disease event or death from all causes by risk strata using data from the National Health and Nutrition Examination Survey Epidemiological Follow-up Study. 8 In that study, the number of patients who needed to receive treatment to prevent an event was substantially smaller in risk groups B and C compared with risk group A. Specifically, in order to prevent 1 death from all-causes among patients with high-normal, stage 1 hypertension, or stage 2 or stage 3 hypertension, treatment is required for 81, 60, and 23 persons in risk group A; 19, 16, and 9 persons in risk group B; and 14, 12, and 9 persons in risk group C, respectively. These results highlight the usefulness of using risk groups in arriving at treatment decisions. Several caveats should be considered in the interpretation of our findings. First, the presence of clinical cardiovascular disease and target organ damage was not comprehensively assessed. For example, a history of stroke was assessed through self-report, transient ischemic attack through a composite interview response, and nephropathy was assessed through serum creatinine, an imperfect measure of renal function. 9 Additionally, ECG measurements for left ventricular hypertrophy were not available for NHANES participants 40 years of age; however, the prevalence of left ventricular hypertrophy is low in this population. 10,11 Family history of cardiovascular disease, a major risk factor for cardiovascular disease, was not available from NHANES III. The absence of data on family history of cardiovascular disease may have resulted in an underestimation of the prevalence of persons in risk group B; however, it would not have affected the prevalence of risk group C or the difference in the impact of pharmacologic treatment recommendations in JNC-VI compared with those in the JNC-V and previous guidelines. Finally, the data used in this analysis were TABLE 5. Distribution and Counts of the Population With High-Normal Blood Pressure or Based on the Prevalence of JNC-VI Cardiovascular Risk Grouping and Blood Pressure Levels Among Adult (Age >20 Years) Participants in NHANES III Risk Group, Counts in Thousands (% of total population) JNC-VI Blood Pressure Stage A B C Total High-normal (2.6) (23.3) (5.9) (31.8) Stage 1 hypertension 673 (1.1) (18.9) (5.4) (25.4) Stage 2 hypertension 859 (1.4) (24.1) (17.3) (42.8) Total (5.1) (66.3) (28.6) (100.0)

6 902 April 2002 collected 10 years ago. Secular trends in coronary heart disease risk factors, including blood pressure, have been noted in the US population. It is crucial to note that the analyses we performed were based on data collected in a large population survey with the application of a set of treatment guidelines. As stated in both the JNC-V and VI guidelines, pharmacologic treatment in individual patients requires the consideration of several factors. Although, our results suggest that a substantial number of persons for whom the JNC-VI guidelines recommend pharmacologic treatment were not receiving such therapy, a thorough understanding of each individual patient is necessary before determining the need for drug therapy for that individual. Therefore, data from the current analysis should not be used to make judgments concerning the appropriateness of a specific treatment regimen for an individual patient. The development and updating of blood pressure treatment guidelines is an evolutionary process that relies on new evidence becoming available from epidemiologic studies and clinical trials. As additional evidence unfolds, treatment recommendations for control of high blood pressure and prevention of its concomitant morbidity and mortality should be modified. For example, future evidence may show that application of the DASH (Dietary Approaches to Stop ) diet might be warranted for persons whose blood pressure is below high-normal but above the optimum level. Likewise, results from the PROGRESS (Perindopril protection against REcurrent Stroke) study suggest that pharmacological anti-hypertensive therapy may be warranted in individuals with a history of stroke or a transient ischemic attack but a normal blood pressure. 12 Important results from several other studies including the ABCD (Appropriate Blood Pressure Control in Diabetes) and HOPE (Heart Outcomes Prevention Evaluation Study) clinical trials have been recently published and provide important data for updating the current guidelines. 13,14 Continued tailoring of the treatment guidelines highlights the importance of evidence derived from epidemiologic studies and clinical trials. The JNC-VI guidelines recommend pharmacologic therapy with conjunctive lifestyle modification to lower blood pressure as initial treatment for a large number of individuals in the US with high-normal blood pressure and stage 1 hypertension that are not currently taking anti-hypertensive medication. Given the knowledge that there are 62 million adults in the United States with high-normal blood pressure or hypertension, increased awareness, treatment, and control of high blood pressure are critical to the reduction of cardiovascular disease risk and prevention of the associated burden of illness. 15,16 Favorable secular trends in these factors have been reported, but the prevalence of most cardiovascular disease risk factors remains far from ideal. More complete adoption of the JNC-VI guidelines is likely to have a tremendous positive impact on the burden of blood pressure related cardiovascular disease and should be an important goal for clinicians and public health professionals. References 1. Stamler J, Stamler R, Neaton J. Blood pressure, systolic and diastolic, and cardiovascular risks. Arch Intern Med. 1993;153: Fuster V, Gotto AM, Libby P, Loscalzo J, McGill HC. 27th Bethesda Conference: matching the intensity of risk factor management with the hazard for coronary disease events: task force 1: pathogenesis of coronary disease: the biologic role of risk factors. J Am Coll Cardiol. 1996;27: The sixth report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Arch Intern Med. 1997;157: National Center for Health Statistics. Plan and operation of the third National Health and Nutrition Examination survey, US Department of Health and Human Services. Publication No Stata Statistical Software, release 5.0. College Station, Tex: Stata Corporation; Guidelines subcommittee. World Health Organization-International Society of guidelines for the management of hypertension. J Hypertens. 1999;1999:17: Lloyd-Jones DM, Evans JC, Larson MG, O Donnell CJ, Levy D. Differential impact of systolic and diastolic blood pressure level on JNC-VI staging: Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure ;34: Ogden LG, He J, Lydick E, Whelton PK. Long-term absolute benefit of lowering blood pressure in hypertensive patients according to the JNC VI risk stratification ;35: Perrone R, Madias N, Levey A. Serum creatinine as an index of renal function: new insights into old concepts. Clinical Chemistry. 1992;38: Kuch B, Hense HW, Gneiting B, Doring A, Muscholl M, Brockel U, Schunkert H. Body composition and prevalence of left ventricular hypertrophy. Circulation. 2000;102: Levy D, Savage DD, Garrison RJ, Anderson KM, Kannel WB, Castelli WP. Echocardiographic criteria for left ventricular hypertrophy: the Framingham Heart Study. Am J Cardiol. 1987;59: PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischemic attack. Lancet. 2001; 358: Estacio RO, Schrier RW. Antihypertensive therapy in type 2 diabetes: implications of the appropriate blood pressure control in diabetes (ABCD) trial. Am J Cardiol. 1998;82:9R 14R. 14. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients: the Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342: Burt VL, Culter JA, Higgins M, Horan MJ, Labarthe D, Whelton P, Brown C, Roccella EJ. Trends in the prevalence, awareness, treatment, and control of hypertension in the adult US population: data from the health examination surveys, 1960 to ;26: Burt VL, Whelton P, Roccella EJ, Brown C, Cutler JA, Higgins M, Horan MJ, Labarthe D. Prevalence of hypertension in the US adult population: results from the Third National Health and Nutrition Examination Survey, ;25: