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    ORIGINAL CONTRIBUTION

    Effect of Blood Pressure Loweringand Antihypertensive Drug Class onProgression of Hypertensive Kidney DiseaseResults From the AASK Trial

    Jackson T. Wright, Jr, MD, PhD

    George Bakris, MD

    Tom Greene, PhD

    Larry Y. Agodoa, MD

    Lawrence J. Appel, MD, MPH

    Jeanne Charleston, RN

    DeAnna Cheek, MD

    Janice G. Douglas-Baltimore, MD

    Jennifer Gassman, PhD

    Richard Glassock, MD

    Lee Hebert, MD

    Kenneth Jamerson, MD

    Julia Lewis, MD

    Robert A. Phillips, MD, PhD

    Robert D. Toto, MDJohn P. Middleton, MD

    Stephen G. Rostand, MD

    for the African American Study ofKidney Disease and HypertensionStudy Group

    HYPERTENSION IS REPORTED TO

    be the second leading causeof end-stage renal disease(ESRD).1 African Americans

    are6 times more likely to develop ESRDfrom hypertension than whites.2 Obser-vational studies show a direct relation-ship between the level of blood pres-sure(BP) andrenal disease progression.3,4

    Post hoc analyses of clinical trials alsosuggest that lowering BP mayretardpro- Author Affiliations, FinancialDisclosures, andMem-

    bers of the African American Study of Kidney Dis-ease and Hypertension Study Group are listed at theend of this article.Corresponding Author and Reprints: Jackson T.Wright, Jr, MD, PhD, Case Western Reserve

    University, Departments of Medicine, UniversityHospitals of Cleveland and the Louis Stokes Cleve-land Department of Veterans Affairs Medical Cen-ter, 11000 Euclid Ave, Horwitz Tower, Suite 7311,Cleveland, OH 44106-5014 (e-mail: jxw20@po.cwru.edu).

    Context Hypertensionis a leading cause of end-stage renal disease (ESRD) in theUnitedStates, with no known treatment to prevent progressive declines leading to ESRD.

    Objective To compare the effects of 2 levels of blood pressure (BP) control and 3 an-tihypertensive drug classes on glomerular filtration rate (GFR) decline in hypertension.

    Design Randomized 32 factorial trial with enrollment from February 1995 to Sep-tember 1998.

    Setting and Participants A total of 1094 African Americans aged 18 to 70 yearswith hypertensive renal disease (GFR, 20-65 mL/min per 1.73 m2) were recruited from21 clinical centers throughout the United States and followed up for 3 to 6.4 years.

    Interventions Participants were randomly assigned to 1 of 2 mean arterial pressuregoals, 102 to 107 mm Hg (usual; n=554) or 92 mm Hg or less (lower; n=540), and toinitial treatment with either a -blocker (metoprolol 50-200 mg/d; n=441), an an-giotensin-converting enzyme inhibitor (ramipril 2.5-10 mg/d; n= 436) or a dihydropyri-dine calcium channel blocker, (amlodipine 5-10 mg/d; n= 217). Open-label agents wereadded to achieve the assigned BP goals.

    Main Outcome Measures Rate of change in GFR (GFR slope); clinical compositeoutcome of reduction in GFR by 50% or more (or25 mL/min per 1.73 m2) frombaseline, ESRD, or death. Three primary treatment comparisons were specified: lower

    vs usual BP goal; ramipril vs metoprolol; and amlodipine vs metoprolol.Results Achieved BP averaged (SD) 128/78 (12/8) mm Hg in the lower BP groupand 141/85 (12/7) mm Hg in the usual BP group. The mean (SE) GFR slope from base-line through 4 years did not differ significantly between the lower BP group (2.21[0.17] mL/min per 1.73 m2 per year) and the usual BP group (1.95 [0.17] mL/minper 1.73 m2 per year; P=.24), and the lower BP goal did not significantly reduce therate of the clinical composite outcome (risk reduction for lower BP group=2%; 95%confidence interval [CI], 22% to 21%; P=.85). None of the drug group compari-sons showed consistent significant differences in the GFR slope. However, comparedwith the metoprolol and amlodipine groups, the ramipril group manifested risk reduc-tions in the clinical composite outcome of 22% (95% CI, 1%-38%; P=.04) and 38%(95% CI, 14%-56%; P=.004), respectively. There was no significant difference in theclinical composite outcome between the amlodipine and metoprolol groups.

    Conclusions No additional benefit of slowing progression of hypertensive nephro-

    sclerosis was observed with the lower BP goal. Angiotensin-converting enzyme in-hibitors appear to be more effective than -blockers or dihydropyridine calcium chan-nel blockers in slowing GFR decline.

    JAMA. 2002;288:2421-2431 www.jama.com

    See also p 2466 and Patient Page.

    2002 American Medical Association. All rights reserved. (Reprinted) JAMA, November 20, 2002Vol 288, No. 19 2421

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    gression of renal disease and reduce car-diovascular risk.5-10 African Americans,however, were not well represented inthe aforementioned studies.5-7,9,11

    Several studies document that Afri-can Americanswithchronic kidney dis-

    ease have faster declines in renal func-tion compared with whites with similarBPs.12-14 In the first trial to randomizepatients to differentBP levelsand exam-ine the outcome on kidney disease pro-gression,theModificationofDietinRenalDiseasetrial,abenefitofthelowerBPgoal(92mmHg)wassuggestedinthesmallsubgroup of 53 African Americans.15

    However,whether a lowerBP goal actu-ally retards progression of renal diseasein African Americans is uncertain.16-20

    In trials thatenrolled individuals withrenal disease from diabetes and other

    etiologies, angiotensin-converting en-zyme inhibitors significantly reduceprogression of kidney disease. How-ever, few African Americans were in-cluded in such trials.21-24

    Angiotensin-converting enzyme in-

    hibitor use is lower in African Ameri-cans with hypertension and chronickidney disease compared with whites.This is a consequence of many factorsincluding a lack of clinical end pointand safety data and lower antihyper-tensive potency when they are used asmonotherapy compared with otherclasses of antihypertensive agents.

    The African American Study of Kid-ney Disease and Hypertension (AASK)prospectively addressed 2 questions inpatients with hypertensive nephro-sclerosis.25 First, does very aggressive

    lowering of BP result in slower de-clines in kidney function?Second, doesthe type of antihypertensive agent usedto initiate BP lowering matter with re-gard to kidney disease outcomes?

    METHODS

    Participants

    Thestudydesign hasbeenpreviously de-scribed.25,26 Briefly, participantswereself-identified African Americans with hy-pertension (n= 1094) who were aged 18to 70 years with a glomerular filtrationrate (GFR) between 20 and 65 mL/minper 1.73 m2 and no other identifiedcauses of renal insufficiency. Exclu-sion criteriaincludeddiastolic BP of lessthan 95 mm Hg, known history of dia-betes mellitus (fasting glucose, 140mg/dL or random glucose, 200 mg/

    dL), urinary protein to creatinine ratioof more than 2.5, accelerated or malig-nant hypertension within6 months, sec-ondary hypertension, evidence of nonBP-related causes of chronic kidneydisease, serious systemic disease, clini-cal congestive heart failure, or specificindication for or contraindication to astudydrug or study procedure. Thepro-tocol and procedures were approved bythe institutional review board at eachcenter, and all participants gave writ-ten informed consent. An independent

    data and safety monitoring board wasalso established by the National Insti-tute of Diabetes and Digestive and Kid-ney Diseases.

    Participantenrollmentbeganin Feb-ruary 1995 and ended in September1998. FIGURE 1 summarizes the num-bers of participants recruited, random-ized, and followed up. Planned fol-low-up to the end of the study inSeptember 2001 was 3 to 6.4 years. Onthe recommendation of the data andsafety monitoring board, the amlo-

    dipine arm was halted in September2000,25 at which point patients ran-domized to amlodipine were switchedto open-label medication. The studysvisit schedule, including GFR measure-ments, was continued and patients inall 3 drug groupsremained on their ran-domly assigned BP goals through theend of the trial.

    Figure 1. Participant Recruitment and Follow-up Flow Diagram

    2802 Screened

    1708 Not Randomized

    1148 GFR Exclusion

    214 Patient Refusal

    113 Medical Exclusion

    97 Study Team Preference

    82 Blood Pressure Exclusion

    54 Other

    540 Assigned to LowerBlood Pressure Goal(MAP 92 mm Hg)

    554 Assigned to UsualBlood Pressure Goal(MAP 102-107 mm Hg)

    436 Assigned toReceiveRamipril

    217 Assigned toReceiveAmlodipine

    441 Assigned toReceiveMetoprolol

    0 Withdrew62 Dialysis29 Died36 Had No

    GFR in FinalYear of

    Follow-up

    0 Withdrew90 Dialysis43 Died47 Had No

    GFR in FinalYear of

    Follow-up

    0 Withdrew81 Dialysis37 Died42 Had No

    GFR in FinalYear of

    Follow-up

    0 Withdrew36 Dialysis13 Died23 Had No

    GFR in FinalYear of

    Follow-up

    0 Withdrew73 Dialysis38 Died30 Had No

    GFR in FinalYear of

    Follow-up

    380 ActiveParticipantsat Endof Study

    374 ActiveParticipantsat Endof Study

    309 ActiveParticipantsat Endof Study

    145 ActiveParticipantsat Endof Study

    300 ActiveParticipantsat Endof Study

    1094 Randomized toa Blood Pressure Goal

    and to a Drug Intervention

    BLOOD PRESSURE GOAL

    INTERVENTION

    DRUG

    INTERVENTION

    GFR indicates glomerular filtration rate; MAP, mean arterial pressure. All deaths were prior to dialysis and thenumber of participants who were alive and not receiving dialysis and who did not have a GFR were measured inthe final year of follow-up. In all treatment groups combined, 96.7% of patients had at least 1 follow-up GFR.

    PROGRESSION OF HYPERTENSIVE KIDNEY DISEASE

    2422 JAMA, November 20, 2002Vol 288, No. 19 (Reprinted) 2002 American Medical Association. All rights reserved.

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