Control of Hypertension in Adults With Chronic Kidney Disease in the United States

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1 Control of Hypertension in Adults With Chronic Kidney Disease in the United States Carmen A. Peralta, Leroi S. Hicks, Glenn M. Chertow, John Z. Ayanian, Eric Vittinghoff, Feng Lin, Michael G. Shlipak Abstract Although improved control of hypertension is known to attenuate progression of chronic kidney disease (CKD), little is known about the adequacy of hypertension treatment in adults with CKD in the United States. Using data from the Fourth National Health and Nutrition Survey, we assessed adherence to national hypertension guideline targets for patients with CKD (blood pressure 130/80 mm Hg), we assessed control of systolic ( 130 mm Hg) and diastolic ( 80 mm Hg) blood pressure, and we evaluated determinants of adequate blood pressure control. Presence of CKD was defined as glomerular filtration rate 60 ml/min per 1.73 m 2 or presence of albuminuria (albumin:creatinine ratio 30 g/mg). Multivariable logistic regression with appropriate weights was used to determine predictors of inadequate hypertension control and related outcomes. Among 3213 participants with CKD, 37% had blood pressure 130/ 80 mm Hg (95% confidence interval [CI], 34.5% to 41.8%). Of those with inadequate blood pressure control, 59% (95% CI, 54% to 64%) had systolic 130 mm Hg, with diastolic 80 mm Hg, whereas only 7% (95% CI, 3.9 to 9.8%) had a diastolic pressure 80 mm Hg, with systolic blood pressure 130 mm Hg. Non-Hispanic black race (odds ratio [OR], 2.4; 95% CI, 1.5 to 3.9), age 75 years (OR, 4.7; 95% CI, 2.7 to 8.2), and albuminuria (OR, 2.4; 95% CI, 1.4 to 4.1) were independently associated with inadequate blood pressure control. We conclude that control of hypertension is poor in participants with CKD and that lack of control is primarily attributable to systolic hypertension. Future guidelines and antihypertensive therapies for patients with CKD should target isolated systolic hypertension. (Hypertension. 2005; 45: ) Key Words: kidney race Progression of chronic kidney disease (CKD) to end-stage renal disease (ESRD) is a major public health problem in the United States. Prevalence of CKD is high, 1 and rates of ESRD have nearly doubled in the last 2 decades. 2 This accelerated incidence of ESRD far exceeds the rate of increase in the prevalence of CKD. 3 CKD has also been associated with increased risk of cardiovascular outcomes and mortality. 4 Hypertension is associated with more rapid progression of CKD. 5,6 Several studies have shown that treating hypertension in patients with CKD and proteinuria may attenuate the decline in glomerular filtration rate (GFR). 7 9 The Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VII) and the National Kidney Foundation Kidney Disease Outcome and Quality Initiative (NKF/KDOQI) identify CKD as a high-risk group warranting intensive hypertension treatment. 10,11 National guidelines recommend pharmacological therapy and lifestyle modification to achieve a blood pressure goal of 130/80 mm Hg for patients with CKD. 10,11 The prevalence and predictors of inadequate blood pressure control have not been well elucidated in adults with CKD. Guidelines for hypertension treatment in patients with CKD have focused equally on the control of systolic and diastolic blood pressure. 10,11 However, recent data in the general population suggest that the prevalence of isolated systolic hypertension is high, especially among the elderly. 12,13 Wide pulse pressure (systolic minus diastolic blood pressure) is also prevalent and has been shown to be a marker of arterial stiffness 14,15 as well as an independent risk factor for cardiovascular disease. 16,17 Although advanced CKD (including ESRD) has been associated with arterial stiffness, the prevalence of isolated systolic hypertension and wide pulse pressure in the CKD population is unknown. Using the Fourth National Health and Nutrition Examination Survey (NHANES IV), we aimed to determine the prevalence of inadequate blood pressure control in adults Received February 16, 2005; first decision February 25, 2005; revision accepted March 16, From the General Internal Medicine Section (C.A.P., M.G.S.), San Francisco Veterans Affairs Medical Center, California; Division of Nephrology (C.A.P., G.M.C., M.G.S.), Department of Medicine, University of California San Francisco; Department of Epidemiology and Biostatistics (G.M.C., E.V., F.L., M.G.S.), University of California San Francisco; Division of General Internal Medicine (L.S.H., J.Z.A.), Brigham and Women s Hospital, Boston, Mass; and Department of Health Care Policy (L.S.H., J.Z.A.), Harvard Medical School, Boston, Mass. Correspondence to Carmen A. Peralta, MD, General Internal Medicine, Department of Veterans Affairs, Box 111A1, 4150 Clement St, San Francisco, CA Carmen.Peralta@med.va.gov 2005 American Heart Association, Inc. Hypertension is available at DOI: /01.HYP

2 1120 Hypertension June 2005 with CKD, the clinical and demographic predictors of inadequate control, and the relative adequacy of control of systolic and diastolic pressure. Methods Overview We evaluated prevalence and determinants of inadequate blood pressure control in persons with CKD using data from NHANES IV, a complex, stratified, multistage probability sample of noninstitutionalized US civilians between 1999 and Adults 60 years of age, low-income individuals, Mexican Americans, and non-hispanic blacks were oversampled in NHANES IV. Study Population We estimated GFR for all adult participants (age 20 years) in NHANES IV with the Modification of Diet in Renal Disease equation, using calibrated serum creatinine. 21,22 Adults with estimated GFRs 60 ml/min per 1.73 m 2 or proteinuria (urine albumin/creatinine ratio 30 g/mg) were included. 10,21 We excluded participants with missing values for serum creatinine (n 1076) or missing blood pressure readings (n 154). Covariate Definitions Based on self-report, race/ethnicity was coded in NHANES IV as non-hispanic white, non-hispanic black, Mexican American, other Hispanic, and other/multiracial. We grouped Mexican American and other Hispanic into 1 category. Poverty was defined as income less than $ per year. Low educational level was defined by noncompletion of 12th grade. Primary language was the language spoken in the home. Insurance status was defined as any coverage. Diabetes was defined as self-report of physician diagnosis or as current or past user of insulin or oral hypoglycemic agent. We excluded diabetes diagnoses made during pregnancy. Obesity was defined as body mass index 30 kg/m 2. Outcomes Blood pressure was measured by a trained technician using a mercury sphygmomanometer and calculated as the average of 3 or 4 measurements, excluding the first measurement. Adequate blood pressure control was defined as systolic blood pressure 130 and diastolic blood pressure 80 mm Hg per national guidelines. 10,11 Pulse pressure was calculated as the difference between systolic and diastolic blood pressure; wide pulse pressure was defined as 80 mm Hg. Statistical Analysis We compared the characteristics of participants who had adequate control (blood pressure 130/80 mm Hg) with those who were poorly controlled. Categorical variables were expressed as proportions with 95% confidence intervals (95% CIs), and continuous variables were expressed as mean SD and compared using recommended survey procedures for NHANES IV. We evaluated the association of demographic and clinical characteristics with hypertension control using multivariable logistic regression. Race, age, ethnicity, and insurance and poverty status were principal predictors of interest. Multivariable models also included predictors significantly associated with poor control in unadjusted analysis (P 0.05) or those believed to affect hypertension control in clinical practice (serum creatinine, obesity). 23,24 We report adjusted odds ratios (ORs) with 95% CIs using model parameter coefficients and SEs, respectively. Two-tailed P values 0.05 were considered significant. All analyses were completed using STATA 8.0 to incorporate adequate sample weights and adjust for clustering and stratification of the sample design. Figure 1. Distribution of systolic blood pressure (mm Hg) among adults with CKD in NHANES IV. Results Characteristics Among adult participants in NHANES IV (n ), 3213 participants had a GFR of 60 ml/min per 1.73 m 2 or albuminuria (weighted prevalence of 16%; 95% CI, 15% to 17%), representing 47.2 million Americans. Of participants with CKD, 27% had diabetes (95% CI, 22% to 31%). The average age for the CKD cohort was 56 years, and 60% were women and 72% were white. Blood Pressure Control Among participants with CKD, only 37% had blood pressure controlled to 130/80 mm Hg (95% CI, 35% to 42%). Of those with poor control ( 130/80 mm Hg), 48% (95% CI, 40% to 53%) had systolic pressure 150 mm Hg. Using a less stringent target of 140/90 mm Hg, 56% of participants with CKD (95% CI, 52% to 60%) had controlled blood pressure. Systolic hypertension accounted for most of the inadequate control. Among participants with CKD and suboptimal control ( 130/80 mm Hg), 59% (95% CI, 54% to 64%) had systolic 130 mm Hg, with diastolic 80 mm Hg, whereas only 7% (95% CI, 4% to 10%) had a diastolic pressure 80 mm Hg, with systolic pressure 130 mm Hg (Figures 1 and 2). Mean pulse pressure for the CKD cohort was 67 mm Hg (95% CI, 64 to 69). Of those not achieving target levels of 130/80 mm Hg, 44% (95% CI, 38% to 49%) had a pulse pressure 80 mm Hg. Predictors of Blood Pressure Control Adults with CKD who did not meet blood pressure targets ( 130/80 mm Hg) were older and twice as likely to be non-hispanic black (Table 1). Inadequate blood pressure control was also associated with the presence of albuminuria and diabetes. Serum creatinine, insurance status, primary language, poverty, and health care utilization patterns were not significantly associated with hypertension control in univariate analyses.

3 Peralta et al Treatment of Hypertension in Chronic Kidney Disease 1121 TABLE 2. Predictors of Inadequate Blood Pressure Control (>130/80 mm Hg) in US Adults With CKD Figure 2. Distribution of diastolic blood pressure (mm Hg) among adults with CKD in NHANES IV. In multivariable analyses, non-hispanic black race remained independently associated with inadequate blood pressure control (Table 2). Non-Hispanic blacks with CKD had 2-fold odds of inadequate blood pressure control (OR, 2.4; 95% CI, 1.5 to 3.9) than whites. Age 75 years was associated with 4-fold odds of poor blood pressure control in adjusted analyses, and albuminuria was associated with a 2-fold odds of poor control. A diagnosis of diabetes was not independently associated with inadequate control in adjusted analysis. TABLE 1. Clinical and Demographic Characteristics of Adults With CKD by Blood Pressure Control Characteristic Age, years Blood Pressure 130/80 Blood Pressure 130/80 % or Mean (SEM) P Value* years Race/Ethnicity White African American 8 14 Hispanic Other 2 4 Female Poverty Education 12th grade Uninsured No. of visits to physician per year 0 to to Primary language not English Serum creatinine 1.2 (0.13) 1.2 (0.09) 0.98 Albuminuria Diabetes *Design-based F test for categorical variables, survey mean estimation, and survey linear regression for continuous variables. Characteristic OR (95% CI) P Value Adjusted OR (95%CI)* P Value Age, years ( ) ( ) ( ) ( ) Race/Ethnicity White 1.0 African American 2.0 ( ) ( ) Hispanic 0.8 ( ) ( ) 0.22 Poverty 0.7 ( ) ( ) 0.3 Education 1.4 ( ) ( ) th grade Uninsured 0.9 ( ) ( ) 0.2 Obesity 0.98 ( ) ( ) 0.2 Serum creatinine ( ) ( ) ( ) ( ) 0.2 Albuminuria 2.0 ( ) ( ) Diabetes 1.7 ( ) ( ) 0.3 *Adjusted for age, race, poverty, education, insurance, albuminuria, diabetes, creatinine level, and obesity. Predictors of Wide Pulse Pressure Among all participants with CKD, age 60 to 75 years was associated with a 6-fold odds of wide pulse pressure ( 80 mm Hg), and age 75 years was associated with a 13-fold higher odds of wide pulse pressure in the univariate analyses (Table 3). Race and presence of albuminuria were not significantly associated with wide pulse pressures. In multivariable analyses, age remained strongly and independently associated with wide pulse pressure, despite adjustment for race and ethnicity, albuminuria, serum creatinine, diabetes, and obesity. Discussion Although CKD patients are at high risk for cardiovascular disease 4 and there is evidence that blood pressure control reduces the rate of cardiovascular complications and attenuates the rate of GFR decline in those with proteinuria, 5 8 adequate control remains suboptimal. In this sample of Americans with CKD, 37% achieved the blood pressure target advocated by national guidelines ( 130/ 80 mm Hg). 10,11 These results are consistent with previous studies that document adherence rates to hypertension control guidelines between 25% and 45% in nationally representative samples of non-ckd patients, in which targets are higher ( 140/90 mm Hg) Isolated systolic hypertension was the primary cause of inadequate control. Previous studies have documented a high prevalence of systolic hypertension (systolic pressure 140 mm Hg, with diastolic 90 mm Hg) in the general population, 12,13 and data from clinical trials have documented

4 1122 Hypertension June 2005 TABLE 3. Predictors of High Pulse Pressure (>80 mm Hg) in Adults With CKD Characteristic OR (95% CI) P value Adjusted OR (95% CI)* P Value Age, years ( ) ( ) ( ) ( ) Race/Ethnicity White African American 0.91 ( ) ( ) 0.8 Hispanic 0.64 ( ) ( ) 0.9 Obesity 0.6 ( ) ( ) 0.5 Serum creatinine ( ) ( ) ( ) ( ) 0.8 Albuminuria 1.3 ( ) ( ) 0.01 Diabetes 1.9 ( ) ( ) 0.2 *Adjusted for age, race, serum creatinine, albuminuria, diabetes, and obesity. beneficial effects from treating isolated systolic hypertension in the elderly Because high systolic pressure is so prevalent in CKD and is a determinant of CKD progression, 32 systolic blood pressure control should be the focus of antihypertensive therapy in CKD. The association of CKD with isolated systolic hypertension (and wide pulse pressure) may be explained by increased vascular stiffness. Wide pulse pressure appears to be a marker of vascular stiffness and cardiovascular calcification, a predictor of cardiovascular risk in the elderly, 14,15,33 and it is associated with increased mortality in patients with renal disease. 19,34 Given the observed high prevalence of wide pulse pressure in CKD, vascular stiffness should be considered a potential mediator for the high cardiovascular risk of patients with CKD. It is unknown whether attempts to narrow the pulse pressure in patients with CKD would be associated with favorable or adverse outcomes. Our findings suggest that non-hispanic black race is an important determinant of inadequate control among NHANES IV participants with CKD. Higher prevalence rates of hypertension for non-hispanic blacks when compared with whites have been reported in NHANES IV. 35 Data on adequate control are conflicting, with some studies reporting similar rates of control for non-hispanic blacks and whites, 25,27 whereas others show lower rates of control for non-hispanic blacks. 28,36 Our finding that non-hispanic black race is associated with lower rates of control in participants with CKD may reflect the fact that successful blood pressure control in this group may be more difficult and requires more antihypertensive medications when compared with whites. 37 Adequate blood pressure control in non-hispanic blacks is critical because they have a 5-fold risk of progression from CKD to ESRD when compared with whites. 38 The observed disparity in blood pressure control in this study may partially explain the higher rates of progression to ESRD in non- Hispanic blacks. Hispanics had similar blood pressure control to non-hispanic whites in this study. Despite some evidence that ESRD rates are rising faster in Hispanics that in non- Hispanic whites, 2 there are few published data on the burden of CKD in Hispanics. Although older age is associated with increased rates of complications from CKD, 39,40 age 60 years was an independent predictor of inadequate blood pressure control in CKD. The mechanism for this association may be increased arterial stiffness because older age was associated with wider pulse pressure. Alternatively, treatment thresholds may vary by age; physicians may be less likely to add an additional antihypertensive agent in the elderly because of fear of adverse effects or a belief that higher systolic pressure is a normal phenomenon associated with aging. Some studies have suggested that clinicians are more likely to treat high diastolic pressure than high systolic pressure, 12,41 and they may be reluctant to treat isolated systolic hypertension for fear of excessively lowering diastolic pressure. 12 Our study suggests that new guidelines should focus on reducing systolic blood pressure in adults with CKD. Low adherence may be attributable to lack of awareness of the presence of CKD, because only 10% of this cohort reported awareness of the diagnosis, 1 or to the challenge to the clinician of choosing an appropriate antihypertensive regimen, typically requiring multiple medications. Treating systolic hypertension is beneficial in the elderly, 12,29 31 and JNC VII recommends thiazide diuretics as the first choice for the treatment of systolic hypertension. 10 Randomized clinical trials of patients with CKD have shown that adequate control is possible, but it requires close follow-up, a multidisciplinary team, and, on average, 3 to 4 antihypertensive medications. 7,8,37 JNC VII suggests adding additional agents depending on the CKD diagnosis and other comorbidities (especially angiotensin-converting enzyme [ACE] inhibitors and angiotensin receptor blockers) to achieve targets, 10 but data for the preferred treatment of isolated systolic hypertension in CKD are scant, with a few studies showing beneficial effects of losartan and candesartan Despite evidence of the benefit

5 Peralta et al Treatment of Hypertension in Chronic Kidney Disease 1123 of ACE inhibitors and ARBs in patients with CKD, studies suggest their use remains relatively low in the United States. 45,46 This study has some limitations. NHANES has a crosssectional design, which prevents our drawing conclusions on the temporal relationships of these observations. In addition, NHANES does not include institutionalized adults, and therefore, some of the sickest members of the population are excluded from these analyses. Adequate information on prescription medication use for the whole time period is not available, limiting conclusions regarding drug use for hypertension treatment in adults with CKD. We defined CKD as GFR 60 ml/min per 1.73 m 2 or albuminuria per NKF and JNC VII definitions. 10,11 NHANES IV participants with mild decrease in GFR ( 60 ml/min per 1.73 m 2 ) but no albuminuria were not considered to have CKD in these analyses. Spot urine albumin and creatinine were generally not repeated, and we are unable to adequately account for variability in the excretion of albumin in this sample, which may bias the results to increased prevalence of CKD. Because albuminuria is a marker of severity of kidney disease and is strongly associated with inadequate blood pressure control, this inclusion criterion may have biased our study toward a lower adherence to blood pressure control guidelines in the GFR group 60 ml/min per 1.73 m 2. Perspectives Adherence to established blood pressure targets is low for participants with CKD, despite growing evidence that control of hypertension can slow the decline of GFR, reduce proteinuria, and reduce the incidence of cardiovascular complications in CKD. 5 9 Because the CKD population is characterized by wide pulse pressure and isolated systolic hypertension, more aggressive campaigns focusing on systolic hypertension in this population are needed, and the role of vascular stiffness in the treatment of hypertension in CKD should be explored. Because non-hispanic blacks and older Americans with CKD are at increased risk for complications and have particularly inadequate blood pressure control, public health efforts should be directed at identifying barriers to hypertension control in these populations. Efforts to treat hypertension in CKD should focus on lowering systolic blood pressure preferentially to bridge the gap between evidence and clinical practice. Acknowledgments C.A.P. was supported by the general medicine fellowship at University of California, San Francisco. L.S.H. was supported by the Robert Wood Johnson Foundation Harold Amos Medical Faculty Development Program. G.M.C. was supported by National Institutes of Health National Institutes of Diabetes and Digestive and Kidney Diseases RO1 DK58411 and RO1 DK J.Z.A. was supported by the primary care research fund of Brigham and Women s Hospital. M.G.S. was supported by the American Federation for Aging Research and National Institute on Aging (Paul Beeson Scholars Program) and the Robert Wood Johnson Foundation (Generalist Faculty Scholars Program). References 1. Coresh J, Byrd-Holt D, Astor BC, Briggs JP, Eggers PW, Lacher DA, Hostetter TH. Chronic kidney disease awareness, prevalence, and trends among U.S. adults, 1999 to J Am Soc Nephrol. 2005;16: USRDS 2004 Annual Data Report: Atlas of End-Stage Renal Disease in the United States National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Md, 2004; Hsu CY, Vittinghoff E, Lin F, Shlipak MG. The incidence of end-stage renal disease is increasing faster than the prevalence of chronic renal insufficiency. Ann Intern Med. 2004;141: Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351: Shulman NB, Ford CE, Hall WD, Blaufox MD, Simon D, Langford HG, Schneider KA. Prognostic value of serum creatinine and effect of treatment of hypertension on renal function. Results from the hypertension detection and follow-up program. The Hypertension Detection and Follow-Up Program Cooperative Group. Hypertension. 1989; 13(suppl 5):I80 I Walker WG, Neaton JD, Cutler JA, Neuwirth R, Cohen JD. Renal function change in hypertensive members of the Multiple Risk Factor Intervention Trial. Racial and treatment effects. The MRFIT Research Group. J Am Med Assoc. 1992;268: Peterson JC, Adler S, Burkart JM, Greene T, Hebert LA, Hunsicker LG, King AJ, Klahr S, Massry SG, Seifter JL. Blood pressure control, proteinuria, and the progression of renal disease. The Modification of Diet in Renal Disease Study. Ann Intern Med. 1995;123: Wright JT Jr, Bakris G, Greene T, Agodoa LY, Appel LJ, Charleston J, Cheek D, Douglas-Baltimore JG, Gassman J, Glassock R, Hebert L, Jamerson K, Lewis J, Phillips RA, Toto RD, Middleton JP, Rostand SG. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. J Am Med Assoc. 2002;288: Jafar TH, Stark PC, Schmid CH, Landa M, Maschio G, de Jong PE, de Zeeuw D, Shahinfar S, Toto R, Levey AS. Progression of chronic kidney disease: the role of blood pressure control, proteinuria, and angiotensinconverting enzyme inhibition: a patient-level meta-analysis. Ann Intern Med. 2003;139: Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42: Kidney Disease Outcomes Quality Initiative (K/DOQI). K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease. Am J Kidney Dis. 2004;43(5 suppl 1):S1 S Chaudhry SI, Krumholz HM, Foody JM. Systolic hypertension in older persons. J Am Med Assoc. 2004;292: Lloyd-Jones DM, Evans JC, Larson MG, O Donnell CJ, Roccella EJ, Levy D. Differential control of systolic and diastolic blood pressure: factors associated with lack of blood pressure control in the community. Hypertension. 2000;36: Bielak LF, Turner ST, Franklin SS, Sheedy PF II, Peyser PA. Agedependent associations between blood pressure and coronary artery calcification in asymptomatic adults. J Hypertens. 2004;22: Safar ME, Blacher J, Mourad JJ, London GM. Stiffness of carotid artery wall material and blood pressure in humans: application to antihypertensive therapy and stroke prevention. Stroke. 2000;31: Franklin SS, Wong ND, Larson MG, Kannel WB, Levy D. How important is pulse pressure as a predictor of cardiovascular risk? Hypertension. 2002;39:E12 E Haider AW, Larson MG, Franklin SS, Levy D. Systolic blood pressure, diastolic blood pressure, and pulse pressure as predictors of risk for congestive heart failure in the Framingham Heart Study. Ann Intern Med. 2003;138: Blacher J, Guerin AP, Pannier B, Marchais SJ, Safar ME, London GM. Impact of aortic stiffness on survival in end-stage renal disease. Circulation. 1999;99: Klassen PS, Lowrie EG, Reddan DN, DeLong ER, Coladonato JA, Szczech LA, Lazarus JM, Owen WF Jr. Association between pulse pressure and mortality in patients undergoing maintenance hemodialysis. J Am Med Assoc. 2002;287: Safar ME, London GM, Plante GE. Arterial stiffness and kidney function. Hypertension. 2004;43: Levey AS, Coresh J, Balk E, Kausz AT, Levin A, Steffes MW, Hogg RJ, Perrone RD, Lau J, Eknoyan G. National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Ann Intern Med. 2003;139:

6 1124 Hypertension June Coresh J, Astor BC, McQuillan G, Kusek J, Greene T, Van Lente F, Levey AS. Calibration and random variation of the serum creatinine assay as critical elements of using equations to estimate glomerular filtration rate. Am J Kidney Dis. 2002;39: Coresh J, Wei GL, McQuillan G, Brancati FL, Levey AS, Jones C, Klag MJ. Prevalence of high blood pressure and elevated serum creatinine level in the United States: findings from the third National Health and Nutrition Examination Survey ( ). Arch Intern Med. 2001;161: Must A, Spadano J, Coakley EH, Field AE, Colditz G, Dietz WH. The disease burden associated with overweight and obesity. J Am Med Assoc. 1999;282: Hyman DJ, Pavlik VN. Characteristics of patients with uncontrolled hypertension in the United States. N Engl J Med. 2001;345: Hicks LS, Fairchild DG, Horng MS, Orav EJ, Bates DW, Ayanian JZ. Determinants of JNC VI guideline adherence, intensity of drug therapy, and blood pressure control by race and ethnicity. Hypertension. 2004;44: Borzecki AM, Wong AT, Hickey EC, Ash AS, Berlowitz DR. Hypertension control: how well are we doing? Arch Intern Med. 2003;163: He J, Muntner P, Chen J, Roccella EJ, Streiffer RH, Whelton PK. Factors associated with hypertension control in the general population of the United States. Arch Intern Med. 2002;162: Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). SHEP Cooperative Research Group. J Am Med Assoc. 1991;265: Ekbom T, Linjer E, Hedner T, Lanke J, De Faire U, Wester PO, Dahlof B, Schersten B. Cardiovascular events in elderly patients with isolated systolic hypertension. A subgroup analysis of treatment strategies in STOP-Hypertension-2. Blood Press. 2004;13: Savage PJ, Pressel SL, Curb JD, Schron EB, Applegate WB, Black HR, Cohen J, Davis BR, Frost P, Smith W, Gonzalez N, Guthrie GP, Oberman A, Rutan G, Probstfield JL, Stamler J. Influence of long-term, low-dose, diuretic-based, antihypertensive therapy on glucose, lipid, uric acid, and potassium levels in older men and women with isolated systolic hypertension: the Systolic Hypertension in the Elderly Program. SHEP Cooperative Research Group. Arch Intern Med. 1998;158: Young JH, Klag MJ, Muntner P, Whyte JL, Pahor M, Coresh J. Blood pressure and decline in kidney function: findings from the Systolic Hypertension in the Elderly Program (SHEP). J Am Soc Nephrol. 2002; 13: Franklin SS, Khan SA, Wong ND, Larson MG, Levy D. Is pulse pressure useful in predicting risk for coronary heart Disease? The Framingham Heart Study. Circulation. 1999;100: Blacher J, Guerin AP, Pannier B, Marchais SJ, London GM. Arterial calcifications, arterial stiffness, and cardiovascular risk in end-stage renal disease. Hypertension. 2001;38: Fields LE, Burt VL, Cutler JA, Hughes J, Roccella EJ, Sorlie P. The burden of adult hypertension in the United States 1999 to 2000: a rising tide. Hypertension. 2004;44: Kramer H, Han C, Post W, Goff D, Diez-Roux A, Cooper R, Jinagouda S, Shea S. Racial/ethnic differences in hypertension and hypertension treatment and control in the multi-ethnic study of atherosclerosis (MESA). Am J Hypertens. 2004;17: Hebert LA, Kusek JW, Greene T, Agodoa LY, Jones CA, Levey AS, Breyer JA, Faubert P, Rolin HA, Wang SR. Effects of blood pressure control on progressive renal disease in blacks and whites. Modification of Diet in Renal Disease Study Group. Hypertension. 1997;30: Hsu CY, Lin F, Vittinghoff E, Shlipak MG. Racial differences in the progression from chronic renal insufficiency to end-stage renal disease in the United States. J Am Soc Nephrol. 2003;14: McClellan WM, Flanders WD. Risk factors for progressive chronic kidney disease. J Am Soc Nephrol. 2003;14:S Shlipak MG, Fried LF, Stehman-Breen C, Siscovick D, Newman AB. Chronic renal insufficiency and cardiovascular events in the elderly: findings from the Cardiovascular Health Study. Am J Geriatr Cardiol. 2004;13: Berlowitz DR, Ash AS, Hickey EC, Friedman RH, Glickman M, Kader B, Moskowitz MA. Inadequate management of blood pressure in a hypertensive population. N Engl J Med. 1998;339: Kjeldsen SE, Dahlof B, Devereux RB, Julius S, Aurup P, Edelman J, Beevers G, de Faire U, Fyhrquist F, Ibsen H, Kristianson K, Lederballe- Pedersen O, Lindholm LH, Nieminen MS, Omvik P, Oparil S, Snapinn S, Wedel H. Effects of losartan on cardiovascular morbidity and mortality in patients with isolated systolic hypertension and left ventricular hypertrophy: a Losartan Intervention for Endpoint Reduction (LIFE) substudy. J Am Med Assoc. 2002;288: Asmar R, Lacourciere Y. A new approach to assessing antihypertensive therapy: effect of treatment on pulse pressure. Candesartan cilexetil in Hypertension Ambulatory Measurement of Blood Pressure (CHAMP) Study Investigators. J Hypertens. 2000;18: Papademetriou V, Farsang C, Elmfeldt D, Hofman A, Lithell H, Olofsson B, Skoog I, Trenkwalder P, Zanchetti A. Stroke prevention with the angiotensin II type 1-receptor blocker candesartan in elderly patients with isolated systolic hypertension: the Study on Cognition and Prognosis in the Elderly (SCOPE). J Am Coll Cardiol. 2004;44: Timpe EM, Amarshi N, Reed PJ. Evaluation of angiotensin-converting enzyme inhibitor use in patients with type 2 diabetes in a state managed care plan. Am J Manag Care. 2004;10: Luzier AB, DiTusa L. Underutilization of ACE inhibitors in heart failure. Pharmacotherapy. 1999;19: