Effect of Ramipril vs Amlodipine on Renal Outcomes in Hypertensive ...
Effect of Ramipril vs Amlodipine on Renal Outcomes in Hypertensive ...
Effect of Ramipril vs Amlodipine on Renal Outcomes in Hypertensive ...
Create successful ePaper yourself
Turn your PDF publications into a flip-book with our unique Google optimized e-Paper software.
ORIGINAL CONTRIBUTIONJAMA-EXPRESS<str<strong>on</strong>g>Effect</str<strong>on</strong>g> <str<strong>on</strong>g>of</str<strong>on</strong>g> <str<strong>on</strong>g>Ramipril</str<strong>on</strong>g> <str<strong>on</strong>g>vs</str<strong>on</strong>g> <str<strong>on</strong>g>Amlodip<strong>in</strong>e</str<strong>on</strong>g> <strong>on</strong> <strong>Renal</strong><strong>Outcomes</strong> <strong>in</strong> <strong>Hypertensive</strong> NephrosclerosisA Randomized C<strong>on</strong>trolled TrialLawrence Y. Agodoa, MD; LawrenceAppel, MD, MPH; George L. Bakris, MD;Gerald Beck, PhD; Jacques Bourgoignie,MD; Joseph<strong>in</strong>e P. Briggs, MD; JeanneCharlest<strong>on</strong>, RN; DeAnna Cheek, MD;William Cleveland, MD; Janice G. Douglas,MD; Margaret Douglas, MPH; D<strong>on</strong>naDowie, MD; Marquetta Faulkner, MD;Avril Gabriel, RN; Jennifer Gassman, PhD;Tom Greene, PhD; Yvette Hall, RN;Lee Hebert, MD; Leena Hiremath, PhD;Kenneth Jamers<strong>on</strong>, MD; Carolyn J. Johns<strong>on</strong>,RN; Joel Kopple, MD; John Kusek, PhD;James Lash, MD; Janice Lea, MD; Julia B.Lewis, MD; Michael Lipkowitz, PhD; ShaulMassry, MD; John Middlet<strong>on</strong>, MD; Edgar R.Miller III, MD; Keith Norris, MD; DanielO’C<strong>on</strong>nor, MD; Ak<strong>in</strong>lou Ojo, MD; RobertA. Phillips, MD, PhD; Velvie Pogue, MD;Mahboob Rahman, MD, MS; Otelio S.Randall, MD; Stephen Rostand, MD;Gerald Schulman, MD; W<strong>in</strong>ifred Smith,MPH; Denyse Thornley-Brown, MD;C. Craig Tisher, MD; Robert D. Toto, MD;Jacks<strong>on</strong> T. Wright, Jr, MD, PhD; ShichenXu, MD; for the African American Study<str<strong>on</strong>g>of</str<strong>on</strong>g> Kidney Disease and Hypertensi<strong>on</strong>(AASK) Study GroupAuthor Affiliati<strong>on</strong>s and Study Group Members and F<strong>in</strong>ancialDisclosures are listed at the end <str<strong>on</strong>g>of</str<strong>on</strong>g> this article.Corresp<strong>on</strong>d<strong>in</strong>g Author and Repr<strong>in</strong>ts: Jacks<strong>on</strong> T.Wright, Jr, MD, PhD, Case Western Reserve University,Cl<strong>in</strong>ical Hypertensi<strong>on</strong> Program, University Hospitals<str<strong>on</strong>g>of</str<strong>on</strong>g> Cleveland and the Louis Stokes Cleveland VeteransAffairs Medical Center, 10900 Euclid Ave, WoodBldg Room W-165, Cleveland, OH 44106-4982(e-mail: jxw20@po.cwru.edu).For editorial comment see p 2774.C<strong>on</strong>text Incidence <str<strong>on</strong>g>of</str<strong>on</strong>g> end-stage renal disease due to hypertensi<strong>on</strong> has <strong>in</strong>creased <strong>in</strong>recent decades, but the optimal strategy for treatment <str<strong>on</strong>g>of</str<strong>on</strong>g> hypertensi<strong>on</strong> to prevent renalfailure is unknown, especially am<strong>on</strong>g African Americans.Objective To compare the effects <str<strong>on</strong>g>of</str<strong>on</strong>g> an angiotens<strong>in</strong>-c<strong>on</strong>vert<strong>in</strong>g enzyme (ACE) <strong>in</strong>hibitor(ramipril), a dihydropyrid<strong>in</strong>e calcium channel blocker (amlodip<strong>in</strong>e), and a -blocker(metoprolol) <strong>on</strong> hypertensive renal disease progressi<strong>on</strong>.Design, Sett<strong>in</strong>g, and Participants Interim analysis <str<strong>on</strong>g>of</str<strong>on</strong>g> a randomized, doublebl<strong>in</strong>d,32 factorial trial c<strong>on</strong>ducted <strong>in</strong> 1094 African Americans aged 18 to 70 yearswith hypertensive renal disease (glomerular filtrati<strong>on</strong> rate [GFR] <str<strong>on</strong>g>of</str<strong>on</strong>g> 20-65 mL/m<strong>in</strong> per1.73 m 2 ) enrolled between February 1995 and September 1998. This report comparesthe ramipril and amlodip<strong>in</strong>e groups follow<strong>in</strong>g disc<strong>on</strong>t<strong>in</strong>uati<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> the amlodip<strong>in</strong>e<strong>in</strong>terventi<strong>on</strong> <strong>in</strong> September 2000.Interventi<strong>on</strong>s Participants were randomly assigned to receive amlodip<strong>in</strong>e, 5 to 10mg/d (n=217), ramipril, 2.5 to 10 mg/d (n=436), or metoprolol, 50 to 200 mg/d(n=441), with other agents added to achieve 1 <str<strong>on</strong>g>of</str<strong>on</strong>g> 2 blood pressure goals.Ma<strong>in</strong> Outcome Measures The primary outcome measure was the rate <str<strong>on</strong>g>of</str<strong>on</strong>g> change<strong>in</strong> GFR; the ma<strong>in</strong> sec<strong>on</strong>dary outcome was a composite <strong>in</strong>dex <str<strong>on</strong>g>of</str<strong>on</strong>g> the cl<strong>in</strong>ical end po<strong>in</strong>ts<str<strong>on</strong>g>of</str<strong>on</strong>g> reducti<strong>on</strong> <strong>in</strong> GFR <str<strong>on</strong>g>of</str<strong>on</strong>g> more than 50% or 25 mL/m<strong>in</strong> per 1.73 m 2 , end-stage renaldisease, or death.Results Am<strong>on</strong>g participants with a ur<strong>in</strong>ary prote<strong>in</strong> to creat<strong>in</strong><strong>in</strong>e ratio <str<strong>on</strong>g>of</str<strong>on</strong>g> 0.22 (corresp<strong>on</strong>d<strong>in</strong>gapproximately to prote<strong>in</strong>uria <str<strong>on</strong>g>of</str<strong>on</strong>g> more than 300 mg/d), the ramipril grouphad a 36% (2.02 [SE, 0.74] mL/m<strong>in</strong> per 1.73 m 2 /y) slower mean decl<strong>in</strong>e <strong>in</strong> GFR over3 years (P=.006) and a 48% reduced risk <str<strong>on</strong>g>of</str<strong>on</strong>g> the cl<strong>in</strong>ical end po<strong>in</strong>ts <str<strong>on</strong>g>vs</str<strong>on</strong>g> the amlodip<strong>in</strong>egroup (95% c<strong>on</strong>fidence <strong>in</strong>terval [CI], 20%-66%). In the entire cohort, there was nosignificant difference <strong>in</strong> mean GFR decl<strong>in</strong>e from basel<strong>in</strong>e to 3 years between treatmentgroups (P=.38). However, compared with the amlodip<strong>in</strong>e group, after adjustmentfor basel<strong>in</strong>e covariates the ramipril group had a 38% reduced risk <str<strong>on</strong>g>of</str<strong>on</strong>g> cl<strong>in</strong>ical endpo<strong>in</strong>ts (95% CI, 13%-56%), a 36% slower mean decl<strong>in</strong>e <strong>in</strong> GFR after 3 m<strong>on</strong>ths (P=.002),and less prote<strong>in</strong>uria (P.001).C<strong>on</strong>clusi<strong>on</strong> <str<strong>on</strong>g>Ramipril</str<strong>on</strong>g>, compared with amlodip<strong>in</strong>e, retards renal disease progressi<strong>on</strong><strong>in</strong> patients with hypertensive renal disease and prote<strong>in</strong>uria and may <str<strong>on</strong>g>of</str<strong>on</strong>g>fer benefit topatients without prote<strong>in</strong>uria.JAMA. 2001;285:2719-2728www.jama.comTHE MORTALITY FROM HYPERTENsivevascular disease has decl<strong>in</strong>edprogressively over thepast 2 decades <strong>in</strong> the UnitedStates, a decl<strong>in</strong>e ascribed <strong>in</strong> part to improvedtreatment <str<strong>on</strong>g>of</str<strong>on</strong>g> high blood pressure(BP). Dur<strong>in</strong>g the same period, the<strong>in</strong>cidence <str<strong>on</strong>g>of</str<strong>on</strong>g> end-stage renal disease(ESRD) due to hypertensi<strong>on</strong> has <strong>in</strong>creasedsteadily, particularly am<strong>on</strong>g AfricanAmericans. 1 In certa<strong>in</strong> age groups,the risk <str<strong>on</strong>g>of</str<strong>on</strong>g> hypertensive ESRD for AfricanAmericans is 20-fold greater than<strong>in</strong> whites. 1,2 The optimal strategy fortreatment <str<strong>on</strong>g>of</str<strong>on</strong>g> hypertensi<strong>on</strong> to prevent renalfailure has rema<strong>in</strong>ed elusive. Recentdata <strong>in</strong> participants with diabeticand prote<strong>in</strong>uric n<strong>on</strong>diabetic kidney dis-©2001 American Medical Associati<strong>on</strong>. All rights reserved. (Repr<strong>in</strong>ted) JAMA, June 6, 2001—Vol 285, No. 21 2719Downloaded from www.jama.com at Medical Library <str<strong>on</strong>g>of</str<strong>on</strong>g> the PLA, <strong>on</strong> August 9, 2007
RAMIPRIL VS AMLODIPINE AND HYPERTENSIVE RENAL DISEASEease have suggested significant benefitswith angiotens<strong>in</strong>-c<strong>on</strong>vert<strong>in</strong>g enzyme<strong>in</strong>hibitors (ACEIs). 3-7 The impact<str<strong>on</strong>g>of</str<strong>on</strong>g> ACEIs <strong>on</strong> progressi<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> renal disease<strong>in</strong> African Americans is unknowns<strong>in</strong>ce all published trials had to<str<strong>on</strong>g>of</str<strong>on</strong>g>ew African Americans randomized tosuch agents. 8,9 Although animal studieshave dem<strong>on</strong>strated preventi<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g>glomerulosclerosis by calcium channelblockers (CCBs), 10-12 human studieshave not c<strong>on</strong>sistently c<strong>on</strong>firmedtheir renoprotective effects. 5,12-16The African American Study <str<strong>on</strong>g>of</str<strong>on</strong>g> KidneyDisease and Hypertensi<strong>on</strong> (AASK)was designed to evaluate the impact <strong>on</strong>progressi<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> hypertensive kidney disease<str<strong>on</strong>g>of</str<strong>on</strong>g> 2 different BP goals (low andusual), and treatment regimens <strong>in</strong>itiatedwith 1 <str<strong>on</strong>g>of</str<strong>on</strong>g> 3 antihypertensive drugclasses, a -blocker (BB, metoprolol),a dihydropyrid<strong>in</strong>e (DHP) CCB (amlodip<strong>in</strong>e),or an ACEI (ramipril). 17 Todate, AASK is the largest comparativedrug <strong>in</strong>terventi<strong>on</strong> trial that has focused<strong>on</strong> renal outcomes c<strong>on</strong>ducted <strong>in</strong>any populati<strong>on</strong> and the first cl<strong>in</strong>ical endpo<strong>in</strong>t trial with sufficient sample sizeto evaluate the effect <str<strong>on</strong>g>of</str<strong>on</strong>g> <strong>in</strong>hibiti<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> theren<strong>in</strong>-angiotens<strong>in</strong>-aldoster<strong>on</strong>e system<strong>in</strong> African Americans. Recruitment <strong>in</strong>tothe full-scale trial began <strong>in</strong> February1995, with planned follow-up throughSeptember 2001.The present report summarizes dataobta<strong>in</strong>ed through September 2000,when, at the recommendati<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> thedata and safety m<strong>on</strong>itor<strong>in</strong>g board(DSMB), the amlodip<strong>in</strong>e arm was term<strong>in</strong>ated.The DSMB recommendati<strong>on</strong>was based <strong>on</strong> safety c<strong>on</strong>cerns that arosebecause <strong>in</strong>terim analyses showed aslower decl<strong>in</strong>e <strong>in</strong> mean glomerular filtrati<strong>on</strong>rate (GFR) and a reduced rate<str<strong>on</strong>g>of</str<strong>on</strong>g> cl<strong>in</strong>ical end po<strong>in</strong>ts (rapid decl<strong>in</strong>e <strong>in</strong>renal functi<strong>on</strong>, ESRD, or death) <strong>in</strong> theramipril and metoprolol groups relativeto the amlodip<strong>in</strong>e group <strong>in</strong> participantswith prote<strong>in</strong>uric n<strong>on</strong>diabetic kidneydisease. Term<strong>in</strong>ati<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> the entireamlodip<strong>in</strong>e arm, not just <str<strong>on</strong>g>of</str<strong>on</strong>g> participantswith high levels <str<strong>on</strong>g>of</str<strong>on</strong>g> prote<strong>in</strong>uria,was recommended, partly because prote<strong>in</strong>excreti<strong>on</strong> <strong>in</strong>creased significantlyboth <strong>in</strong> participants with prote<strong>in</strong>uriaand without prote<strong>in</strong>uria and becausec<strong>on</strong>diti<strong>on</strong>al power calculati<strong>on</strong>s <strong>in</strong>dicatedkey c<strong>on</strong>clusi<strong>on</strong>s were unlikely tochange with c<strong>on</strong>t<strong>in</strong>uati<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> this arm.However, both the ramipril <str<strong>on</strong>g>vs</str<strong>on</strong>g> metoprololcomparis<strong>on</strong> and the comparis<strong>on</strong><str<strong>on</strong>g>of</str<strong>on</strong>g> the 2 BP groups will c<strong>on</strong>t<strong>in</strong>ue untilthe scheduled end <str<strong>on</strong>g>of</str<strong>on</strong>g> the study. S<strong>in</strong>cethe study <strong>in</strong>vestigators must rema<strong>in</strong>bl<strong>in</strong>ded to the ramipril <str<strong>on</strong>g>vs</str<strong>on</strong>g> metoprololand low <str<strong>on</strong>g>vs</str<strong>on</strong>g> usual BP comparis<strong>on</strong>s, thisreport compares <strong>on</strong>ly the amlodip<strong>in</strong>eand ramipril arms, with all results averagedbetween the 2 BP groups.METHODSParticipantsParticipants were self-identified AfricanAmericans with hypertensi<strong>on</strong>(n=1094), aged 18 to 70 years, with GFRbetween 20 to 65 mL/m<strong>in</strong> per 1.73 m 2and no other identified causes <str<strong>on</strong>g>of</str<strong>on</strong>g> renal<strong>in</strong>sufficiency. Exclusi<strong>on</strong> criteria were asfollows: (1) diastolic BP (DBP) less than95 mm Hg, (2) known history <str<strong>on</strong>g>of</str<strong>on</strong>g> diabetesmellitus (fast<strong>in</strong>g glucose 140 mg/dL[7.8 mmol/L] or random glucose200 mg/dL [11.1 mmol/L]), (3) ur<strong>in</strong>aryprote<strong>in</strong> to creat<strong>in</strong><strong>in</strong>e ratio (UP/Cr) greater than 2.5, (4) accelerated ormalignant hypertensi<strong>on</strong> with<strong>in</strong> 6m<strong>on</strong>ths, (5) sec<strong>on</strong>dary hypertensi<strong>on</strong>, (6)evidence <str<strong>on</strong>g>of</str<strong>on</strong>g> n<strong>on</strong>-BP–related causes <str<strong>on</strong>g>of</str<strong>on</strong>g> renaldisease, (7) serious systemic disease,(8) cl<strong>in</strong>ical c<strong>on</strong>gestive heart failure,or (9) specific <strong>in</strong>dicati<strong>on</strong> for orc<strong>on</strong>tra<strong>in</strong>dicati<strong>on</strong> to a study drug or studyprocedure. An antihypertensive washoutperiod was believed to be unethical.Thus, potential participants were<strong>on</strong>ly required to have at least 1 DBP read<strong>in</strong>ghigher than 95 mm Hg or their antihypertensivemedicati<strong>on</strong> dose tapereduntil they met the BP entry criteria.The protocol and procedures were approvedby the <strong>in</strong>stituti<strong>on</strong>al review boardat each center, and all participants gavewritten <strong>in</strong>formed c<strong>on</strong>sent. Participantenrollment began <strong>in</strong> February 1995 andended <strong>in</strong> September 1998.Study DesignAASK uses a 32 factorial design. 17 Participantswere randomized to a usualmean arterial pressure (MAP) goal <str<strong>on</strong>g>of</str<strong>on</strong>g> 102to 107 mm Hg or to a low MAP goal <str<strong>on</strong>g>of</str<strong>on</strong>g>92 mm Hg or lower and to treatmentwith 1 <str<strong>on</strong>g>of</str<strong>on</strong>g> 3 antihypertensive study drugs:a susta<strong>in</strong>ed-release BB, metoprolol; anACEI, ramipril; or a DHP-CCB, amlodip<strong>in</strong>e.Dosages were 50 to 200 mg/d, 2.5to 10 mg/d, and 5 to 10 mg/d, respectively.If the BP goal was not achievedwhile the participants were tak<strong>in</strong>g thestudy drug, additi<strong>on</strong>al unmasked drugswere added <strong>in</strong> the follow<strong>in</strong>g recommendedorder: furosemide, doxazos<strong>in</strong>mesylate, cl<strong>on</strong>id<strong>in</strong>e hydrochloride, hydralaz<strong>in</strong>ehydrochloride, and m<strong>in</strong>oxidil.The dosage <str<strong>on</strong>g>of</str<strong>on</strong>g> each drug was <strong>in</strong>creasedto the maximum tolerated dosebefore the additi<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> a subsequent agent.A randomizati<strong>on</strong> scheme that resulted<strong>in</strong> a 2:2:1 (metoprolol-ramiprilamlodip<strong>in</strong>e)ratio was used becauseAASK pilot data revealed an early <strong>in</strong>crease<strong>in</strong> GFR <strong>in</strong> the DHP-CCB groupcompared with the ACEI and BBgroups. 18 This <strong>in</strong>creased the projectedstatistical power for the DHP-CCB <str<strong>on</strong>g>vs</str<strong>on</strong>g>BB comparis<strong>on</strong>, allow<strong>in</strong>g a smallersample size for the amlodip<strong>in</strong>e group.Study drug assignment but not BP goalwas double masked.Measurement <str<strong>on</strong>g>of</str<strong>on</strong>g> BPand <strong>Renal</strong> Functi<strong>on</strong>Three c<strong>on</strong>secutive seated BPs were measuredus<strong>in</strong>g a Hawksley random zerosphygmomanometer after at least 5 m<strong>in</strong>utesrest, 17,19 with the mean <str<strong>on</strong>g>of</str<strong>on</strong>g> the last2 read<strong>in</strong>gs recorded. All pers<strong>on</strong>nel measur<strong>in</strong>gBPs were centrally tra<strong>in</strong>ed andcertified annually. Dur<strong>in</strong>g the 6 m<strong>on</strong>thsfollow<strong>in</strong>g randomizati<strong>on</strong>, antihypertensivedrugs were adjusted at m<strong>on</strong>thlyprotocol and <strong>in</strong>terim visits to achievethe BP goal. Subsequent protocolvisits occurred at 2-m<strong>on</strong>th <strong>in</strong>tervals.Glomerular filtrati<strong>on</strong> rate was assessedby 125 iothalamate clearance at basel<strong>in</strong>etwice, then at 3, 6, and every 6 m<strong>on</strong>thsthereafter. 20 Serum and ur<strong>in</strong>ary levels<str<strong>on</strong>g>of</str<strong>on</strong>g> creat<strong>in</strong><strong>in</strong>e and prote<strong>in</strong> were measuredby a central laboratory at 6-m<strong>on</strong>th<strong>in</strong>tervals.Trial <strong>Outcomes</strong>The primary analysis <str<strong>on</strong>g>of</str<strong>on</strong>g> renal functi<strong>on</strong>is based <strong>on</strong> the rate <str<strong>on</strong>g>of</str<strong>on</strong>g> change <strong>in</strong> GFR2720 JAMA, June 6, 2001—Vol 285, No. 21 (Repr<strong>in</strong>ted) ©2001 American Medical Associati<strong>on</strong>. All rights reserved.Downloaded from www.jama.com at Medical Library <str<strong>on</strong>g>of</str<strong>on</strong>g> the PLA, <strong>on</strong> August 9, 2007
RAMIPRIL VS AMLODIPINE AND HYPERTENSIVE RENAL DISEASE(GFR slope). The GFR slope was determ<strong>in</strong>edseparately dur<strong>in</strong>g the first 3m<strong>on</strong>ths after randomizati<strong>on</strong> (acutephase) and dur<strong>in</strong>g the rema<strong>in</strong>der <str<strong>on</strong>g>of</str<strong>on</strong>g> follow-up(chr<strong>on</strong>ic phase), because previousstudies <strong>in</strong>dicated that drug <strong>in</strong>terventi<strong>on</strong>scould result <strong>in</strong> acute changes<strong>in</strong> GFR that differ from l<strong>on</strong>g-termeffects <strong>on</strong> renal disease progressi<strong>on</strong>.5,21-25 The analytic plan called fordeterm<strong>in</strong><strong>in</strong>g both the mean chr<strong>on</strong>icslope and the mean total slope frombasel<strong>in</strong>e to end <str<strong>on</strong>g>of</str<strong>on</strong>g> follow-up, <strong>in</strong>clud<strong>in</strong>gboth phases, and for <strong>in</strong>ferr<strong>in</strong>g a def<strong>in</strong>itivebeneficial effect <strong>on</strong> renal functi<strong>on</strong><str<strong>on</strong>g>of</str<strong>on</strong>g> an <strong>in</strong>terventi<strong>on</strong> that significantlyreduced the magnitude <str<strong>on</strong>g>of</str<strong>on</strong>g> both thechr<strong>on</strong>ic and total mean slopes. Themean total slope assesses the effect <str<strong>on</strong>g>of</str<strong>on</strong>g><strong>in</strong>terventi<strong>on</strong>s <strong>on</strong> renal functi<strong>on</strong> dur<strong>in</strong>gthe study period, while the chr<strong>on</strong>icslope is <strong>in</strong>terpreted as the parametermore likely to reflect l<strong>on</strong>g-term diseaseprogressi<strong>on</strong>.The protocol also designated a sec<strong>on</strong>darycl<strong>in</strong>ical-outcome analysis, based<strong>on</strong> the time from randomizati<strong>on</strong> to any<str<strong>on</strong>g>of</str<strong>on</strong>g> the follow<strong>in</strong>g end po<strong>in</strong>ts: (1) a c<strong>on</strong>firmedreducti<strong>on</strong> <strong>in</strong> GFR by 50% or by25 mL/m<strong>in</strong> per 1.73 m 2 from the mean<str<strong>on</strong>g>of</str<strong>on</strong>g> the 2 basel<strong>in</strong>e GFRs; (2) ESRD, def<strong>in</strong>edas need for renal replacementtherapy; or (3) death. The cl<strong>in</strong>ical endpo<strong>in</strong>t analysis was identified as the pr<strong>in</strong>cipalassessment <str<strong>on</strong>g>of</str<strong>on</strong>g> patient benefit. Inc<strong>on</strong>trast to the analysis <str<strong>on</strong>g>of</str<strong>on</strong>g> GFR slope,which addresses the mean drug effect<strong>on</strong> renal functi<strong>on</strong> <strong>in</strong> all participants, <strong>in</strong>clud<strong>in</strong>gthose with little or no GFR decl<strong>in</strong>e,the cl<strong>in</strong>ical end po<strong>in</strong>t analysis isbased <strong>on</strong> events <str<strong>on</strong>g>of</str<strong>on</strong>g> clear cl<strong>in</strong>ical impact,either large decl<strong>in</strong>es <strong>in</strong> renal functi<strong>on</strong>or death.Ur<strong>in</strong>ary prote<strong>in</strong> excreti<strong>on</strong>, expressedas the ur<strong>in</strong>e prote<strong>in</strong>–creat<strong>in</strong><strong>in</strong>eratio (UP/Cr), was also specifiedas a sec<strong>on</strong>dary outcome variable.Statistical MethodsThe protocol specified 3 primary comparis<strong>on</strong>s(ramipril <str<strong>on</strong>g>vs</str<strong>on</strong>g> metoprolol, amlodip<strong>in</strong>e<str<strong>on</strong>g>vs</str<strong>on</strong>g> metoprolol, and low <str<strong>on</strong>g>vs</str<strong>on</strong>g> usualMAP goal). The ramipril <str<strong>on</strong>g>vs</str<strong>on</strong>g> amlodip<strong>in</strong>ecomparis<strong>on</strong> was designated asa sec<strong>on</strong>dary rather than a primary comparis<strong>on</strong>because the amlodip<strong>in</strong>e andramipril <strong>in</strong>terventi<strong>on</strong>s were expected toproduce acute changes <strong>in</strong> opposite directi<strong>on</strong>s,complicat<strong>in</strong>g the comparis<strong>on</strong><str<strong>on</strong>g>of</str<strong>on</strong>g> these 2 groups.The primary renal functi<strong>on</strong> analysiswas based <strong>on</strong> a mixed-effects model withrandom <strong>in</strong>tercepts and random acuteand chr<strong>on</strong>ic slopes. The mean acute,chr<strong>on</strong>ic, and total slopes were estimatedby restricted maximum likelihoodfor each treatment group. Totalmean slopes were estimated as timeweightedaverages <str<strong>on</strong>g>of</str<strong>on</strong>g> the acute andchr<strong>on</strong>ic slopes. The effects <str<strong>on</strong>g>of</str<strong>on</strong>g> the treatment<strong>in</strong>terventi<strong>on</strong>s were tested by compar<strong>in</strong>gthe mean slopes. The model <strong>in</strong>cludedcl<strong>in</strong>ical center and the follow<strong>in</strong>gprespecified basel<strong>in</strong>e factors as covariates:prote<strong>in</strong>uria (expressed as the logtransformed UP/Cr to account for positiveskewness), history <str<strong>on</strong>g>of</str<strong>on</strong>g> heart disease,mean arterial pressure, sex, and age.A formal stopp<strong>in</strong>g rule was c<strong>on</strong>structedbased <strong>on</strong> the primary renalfuncti<strong>on</strong> analysis with separate O’Brien-Flem<strong>in</strong>g 26 boundaries for the chr<strong>on</strong>icand total mean slopes for each <str<strong>on</strong>g>of</str<strong>on</strong>g> the 3primary treatment group comparis<strong>on</strong>s.The stopp<strong>in</strong>g rule stipulated thata treatment arm should be disc<strong>on</strong>t<strong>in</strong>uedat <strong>on</strong>e <str<strong>on</strong>g>of</str<strong>on</strong>g> the study’s annual <strong>in</strong>terimanalyses if the stopp<strong>in</strong>g boundaries<strong>in</strong>dicat<strong>in</strong>g faster progressi<strong>on</strong> werecrossed <strong>in</strong> the same directi<strong>on</strong> for boththe chr<strong>on</strong>ic and total mean slopes.Dur<strong>in</strong>g the trial, members <str<strong>on</strong>g>of</str<strong>on</strong>g> thesteer<strong>in</strong>g committee became aware <str<strong>on</strong>g>of</str<strong>on</strong>g> externalcl<strong>in</strong>ical studies, published afterthe <strong>in</strong>itiati<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> the AASK, that suggesteda slow<strong>in</strong>g <str<strong>on</strong>g>of</str<strong>on</strong>g> the progressi<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g>renal disease by ACEIs <strong>in</strong> participantswith elevated prote<strong>in</strong>uria, as well asstudies suggest<strong>in</strong>g DHP-CCBs may <strong>in</strong>creasethe level <str<strong>on</strong>g>of</str<strong>on</strong>g> prote<strong>in</strong>uria and notslow the progressi<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> renal disease.4,6,7,14,15,25 C<strong>on</strong>sequently, the steer<strong>in</strong>gcommittee (which was bl<strong>in</strong>ded tothe AASK data) requested that the coord<strong>in</strong>at<strong>in</strong>gcenter provide the DSMB withdata <strong>on</strong> the ramipril <str<strong>on</strong>g>vs</str<strong>on</strong>g> amlodip<strong>in</strong>e comparis<strong>on</strong><strong>in</strong> relati<strong>on</strong> to the level <str<strong>on</strong>g>of</str<strong>on</strong>g> prote<strong>in</strong>uria.Therefore, subsequent reportsto the DSMB <strong>in</strong>cluded an extensi<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g>the primary renal functi<strong>on</strong> model with<strong>in</strong>teracti<strong>on</strong> terms between log basel<strong>in</strong>eUP/Cr and the ramipril <str<strong>on</strong>g>vs</str<strong>on</strong>g> amlodip<strong>in</strong>ecomparis<strong>on</strong>. This analysis identifiedsignificant <strong>in</strong>teracti<strong>on</strong>s withbasel<strong>in</strong>e prote<strong>in</strong>uria for the acute andtotal mean GFR slopes. After <strong>in</strong>teracti<strong>on</strong>swere detected, subgroup analyseswere performed <strong>in</strong> participants withbasel<strong>in</strong>e UP/Cr 0.22 and 0.22 (avalue corresp<strong>on</strong>d<strong>in</strong>g approximately tothe threshold <str<strong>on</strong>g>of</str<strong>on</strong>g> 300 mg/d for cl<strong>in</strong>icallysignificant prote<strong>in</strong>uria). The subgroupwith basel<strong>in</strong>e UP/Cr 0.22<strong>in</strong>cludes <strong>on</strong>e third <str<strong>on</strong>g>of</str<strong>on</strong>g> the study participants,with the rema<strong>in</strong><strong>in</strong>g two thirdsbel<strong>on</strong>g<strong>in</strong>g to the subgroup with a basel<strong>in</strong>eUP/Cr 0.22. The UP/Cr cutpo<strong>in</strong>t<str<strong>on</strong>g>of</str<strong>on</strong>g> 0.22 was post hoc but wasselected because <str<strong>on</strong>g>of</str<strong>on</strong>g> cl<strong>in</strong>ical relevanceand was <strong>in</strong>dependent <str<strong>on</strong>g>of</str<strong>on</strong>g> the AASK data.S<strong>in</strong>ce UP/Cr was <strong>in</strong>versely associatedwith GFR at basel<strong>in</strong>e, the <strong>in</strong>teracti<strong>on</strong><str<strong>on</strong>g>of</str<strong>on</strong>g> the treatment groups with basel<strong>in</strong>eGFR was also c<strong>on</strong>sidered. Forsubgroup analyses, a cutpo<strong>in</strong>t <str<strong>on</strong>g>of</str<strong>on</strong>g> basel<strong>in</strong>eGFR <str<strong>on</strong>g>of</str<strong>on</strong>g> 40 mL/m<strong>in</strong> per 1.73 m 2 wasused. This cutpo<strong>in</strong>t matched the cutpo<strong>in</strong>t<str<strong>on</strong>g>of</str<strong>on</strong>g> 0.22 for basel<strong>in</strong>e UP/Cr by splitt<strong>in</strong>gthe <strong>on</strong>e third <str<strong>on</strong>g>of</str<strong>on</strong>g> participants withlowest basel<strong>in</strong>e GFR from the two thirdswith highest basel<strong>in</strong>e GFR.The DSMB’s recommendati<strong>on</strong> to term<strong>in</strong>atethe amlodip<strong>in</strong>e arm was basedprimarily <strong>on</strong> results related to the <strong>in</strong>teracti<strong>on</strong><str<strong>on</strong>g>of</str<strong>on</strong>g> the treatment <strong>in</strong>terventi<strong>on</strong>swith basel<strong>in</strong>e prote<strong>in</strong>uria and not<strong>on</strong> the orig<strong>in</strong>al stopp<strong>in</strong>g rule, which wasnot triggered for any <str<strong>on</strong>g>of</str<strong>on</strong>g> the 3 primarycomparis<strong>on</strong>s. Because the decisi<strong>on</strong> toexam<strong>in</strong>e the treatment <strong>in</strong>terventi<strong>on</strong>s <strong>in</strong>relati<strong>on</strong> to basel<strong>in</strong>e prote<strong>in</strong>uria wasprompted by other studies <str<strong>on</strong>g>of</str<strong>on</strong>g> ACEI regimens,3-6,10,14,22,25-29 the DSMB recommendedthat comparis<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> the ramipriland amlodip<strong>in</strong>e groups rather than theamlodip<strong>in</strong>e and metoprolol groups be<strong>in</strong>cluded <strong>in</strong> this report.Analyses <str<strong>on</strong>g>of</str<strong>on</strong>g> the cl<strong>in</strong>ical outcomeevents and new occurrences <str<strong>on</strong>g>of</str<strong>on</strong>g> cl<strong>in</strong>icallysignificant prote<strong>in</strong>uria (def<strong>in</strong>ed byUP/Cr 0.22) were performed by Coxregressi<strong>on</strong> with adjustment for the samecovariates as the analysis <str<strong>on</strong>g>of</str<strong>on</strong>g> GFR slope.All analyses are <strong>in</strong>tent-to-treat, with participantsanalyzed accord<strong>in</strong>g to their©2001 American Medical Associati<strong>on</strong>. All rights reserved. (Repr<strong>in</strong>ted) JAMA, June 6, 2001—Vol 285, No. 21 2721Downloaded from www.jama.com at Medical Library <str<strong>on</strong>g>of</str<strong>on</strong>g> the PLA, <strong>on</strong> August 9, 2007
RAMIPRIL VS AMLODIPINE AND HYPERTENSIVE RENAL DISEASErandomized treatment assigment regardless<str<strong>on</strong>g>of</str<strong>on</strong>g> medicati<strong>on</strong>s received or durati<strong>on</strong><str<strong>on</strong>g>of</str<strong>on</strong>g> follow-up. P values and 95%c<strong>on</strong>fidence <strong>in</strong>tervals (CIs) are reported<strong>on</strong> a comparis<strong>on</strong>-wise basis,without adjustment for multiple analyses.This strategy is c<strong>on</strong>servative for theprimary renal functi<strong>on</strong> analysis, s<strong>in</strong>ceboth the chr<strong>on</strong>ic and total slopes analysesneeded to reach significance for adef<strong>in</strong>itive c<strong>on</strong>clusi<strong>on</strong>. This report isbased <strong>on</strong> the trial database as <str<strong>on</strong>g>of</str<strong>on</strong>g> September22, 2000.RESULTSBasel<strong>in</strong>e CharacteristicsTABLE 1 displays selected basel<strong>in</strong>e cl<strong>in</strong>icaland demographic characteristics <str<strong>on</strong>g>of</str<strong>on</strong>g>all participants randomized to ramipriland amlodip<strong>in</strong>e and for the subgroupswith basel<strong>in</strong>e UP/Cr 0.22 (∼300mg/d). The mean basel<strong>in</strong>e BP wasTable 1. Basel<strong>in</strong>e Characteristics*<str<strong>on</strong>g>Ramipril</str<strong>on</strong>g>(n = 436)All151/96 mm Hg for the 2 groups, with46% <str<strong>on</strong>g>of</str<strong>on</strong>g> the participants receiv<strong>in</strong>g aDHP-CCB at entry. The ur<strong>in</strong>e prote<strong>in</strong>excreti<strong>on</strong> result was positively skewed,with a median <str<strong>on</strong>g>of</str<strong>on</strong>g> 112 mg/d. Prote<strong>in</strong>uriawas <strong>in</strong>versely associated with renalfuncti<strong>on</strong>, with median UP/Cr equalto 0.47, 0.07, and 0.04, respectively, forGFR less than 30, 30 to 60, and greaterthan 60 mL/m<strong>in</strong> per 1.73 m 2 .Treatment CharacteristicsThe median durati<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> GFR follow-upwas 36 m<strong>on</strong>ths <strong>in</strong> the amlodip<strong>in</strong>egroup and 37 m<strong>on</strong>ths <strong>in</strong> theramipril group. Additi<strong>on</strong>al details <strong>on</strong> recruitmentand retenti<strong>on</strong> are provided<strong>in</strong> FIGURE 1. Follow-up BP results weresubstantially lower than basel<strong>in</strong>e valuesbut did not differ significantly betweentreatment groups (P.10 formean follow-up values <str<strong>on</strong>g>of</str<strong>on</strong>g> systolic BP,<str<strong>on</strong>g>Amlodip<strong>in</strong>e</str<strong>on</strong>g>(n = 217)Basel<strong>in</strong>e UP/Cr 0.22†<str<strong>on</strong>g>Ramipril</str<strong>on</strong>g>(n = 144)<str<strong>on</strong>g>Amlodip<strong>in</strong>e</str<strong>on</strong>g>(n = 69)Age, y 54.2 (10.9) 54.4 (10.7) 49.8 (11.2) 50.9 (10.3)Women, % 38.8 40.1 34.7 34.8Blood pressure, mm HgSystolic 151.0 (23.3) 150.0 (25.3) 156.0 (21.8) 157.3 (26.0)Diastolic 96.0 (14.5) 95.7 (14.1) 99.8 (14.9) 100.3 (14.4)Mean arterial pressure, mm Hg 114.6 (15.9) 114.0 (16.7) 118.7 (15.6) 119.5 (17.2)Glomerular filtrati<strong>on</strong> rate,46.1 (13.6) 46.8 (13.2) 37.7 (12.2) 40.1 (13.3)mL/m<strong>in</strong> per 1.73 m 2Serum creat<strong>in</strong><strong>in</strong>e, mg/dL‡Men 2.18 (0.74) 2.27 (0.83) 2.62 (0.81) 2.76 (0.93)Women 1.76 (0.59) 1.75 (0.56) 2.13 (0.66) 1.98 (0.53)Ur<strong>in</strong>e prote<strong>in</strong>, g/d‡Men 0.61 (1.01) 0.57 (0.99) 1.55 (1.24) 1.50 (1.25)Women 0.40 (0.75) 0.38 (0.73) 1.18 (1.01) 1.17 (1.02)UP/Cr†Men 0.34 (0.51) 0.30 (0.48) 0.84 (0.58) 0.77 (0.56)Women 0.32 (0.52) 0.30 (0.55) 0.93 (0.63) 0.93 (0.74)History <str<strong>on</strong>g>of</str<strong>on</strong>g> heart disease, % 50.5 54.8 50.7 53.6Years <str<strong>on</strong>g>of</str<strong>on</strong>g> hypertensi<strong>on</strong> 13.3 (9.9) 14.6 (10.0) 12.6 (9.0) 11.7 (9.2)Antihypertensive use, %Angiotens<strong>in</strong>-c<strong>on</strong>vert<strong>in</strong>g39.9 41.5 36.8 40.6enzyme <strong>in</strong>hibitor-Blocker 25.9 28.1 25.7 23.2Calcium channel blocker 62.8 61.3 72.9 63.8Dihydropyrid<strong>in</strong>e calcium46.6 44.7 54.2 55.1channel blocker*Values are expressed as mean (SD) unless otherwise <strong>in</strong>dicated. N<strong>on</strong>e <str<strong>on</strong>g>of</str<strong>on</strong>g> the variables c<strong>on</strong>sidered differed significantlybetween the ramipril and amlodip<strong>in</strong>e groups, either <strong>in</strong> the full study or <strong>in</strong> the subgroup with ur<strong>in</strong>e prote<strong>in</strong>–creat<strong>in</strong><strong>in</strong>e(UP/Cr) levels 0.22.†Expressed as ur<strong>in</strong>e prote<strong>in</strong> (mg/d) to ur<strong>in</strong>e creat<strong>in</strong><strong>in</strong>e (mg/d) ratio. UP/Cr <str<strong>on</strong>g>of</str<strong>on</strong>g> 0.22 corresp<strong>on</strong>ds approximately to prote<strong>in</strong>uria<str<strong>on</strong>g>of</str<strong>on</strong>g> 300 mg/d.‡To c<strong>on</strong>vert creat<strong>in</strong><strong>in</strong>e mg/dL to µmol/L, multiply by 88.4. To c<strong>on</strong>vert ur<strong>in</strong>e prote<strong>in</strong> g/d to mg/d, multiply by 1000.diastolic BP, and MAP after the 3-m<strong>on</strong>thvisit) (TABLE 2). After the 3-m<strong>on</strong>th visit,there was no significant difference <strong>in</strong>the number <str<strong>on</strong>g>of</str<strong>on</strong>g> antihypertensive drugsprescribed or <strong>in</strong> the percentage <str<strong>on</strong>g>of</str<strong>on</strong>g> participantsreceiv<strong>in</strong>g the highest doses <str<strong>on</strong>g>of</str<strong>on</strong>g>ramipril or amlodip<strong>in</strong>e (57.4% and56.7%, respectively). There were als<strong>on</strong>o significant differences between theramipril and amlodip<strong>in</strong>e groups <strong>in</strong> thepercentage <str<strong>on</strong>g>of</str<strong>on</strong>g> visits for which each <str<strong>on</strong>g>of</str<strong>on</strong>g>the <strong>in</strong>dividual add-<strong>on</strong> antihypertensiveclasses were prescribed. At 32m<strong>on</strong>ths <str<strong>on</strong>g>of</str<strong>on</strong>g> follow-up, 80.1% <str<strong>on</strong>g>of</str<strong>on</strong>g> activeparticipants <strong>in</strong> the ramipril group and83.3% <strong>in</strong> the amlodip<strong>in</strong>e group werestill tak<strong>in</strong>g their study drug.<strong>Renal</strong> Functi<strong>on</strong> AnalysisOverall. Dur<strong>in</strong>g the chr<strong>on</strong>ic phase, themean (SE) decl<strong>in</strong>e <strong>in</strong> GFR was 2.07(0.21) and 3.22 (0.33) mL/m<strong>in</strong> per 1.73m 2 /y <strong>in</strong> the ramipril and amlodip<strong>in</strong>egroups, respectively. The mean decl<strong>in</strong>ewas 1.15 mL/m<strong>in</strong> per 1.73 m 2 /y(95% CI, 0.41-1.90) or 36% slower <strong>in</strong>the ramipril group (P=.002). However,dur<strong>in</strong>g the 3-m<strong>on</strong>th acute phase,GFR <strong>in</strong>creased 4.19 mL/m<strong>in</strong> per 1.73m 2 /y (95% CI, 2.64-5.73) more <strong>in</strong> theamlodip<strong>in</strong>e than ramipril group(P.001) (mean [SE] change <strong>in</strong> GFRwas−0.16 [0.46] and 4.03 [0.64] mL/m<strong>in</strong> per 1.73 m 2 <strong>in</strong> the ramipril and amlodip<strong>in</strong>egroups, respectively); c<strong>on</strong>sequently,the mean total slope (<strong>in</strong>clud<strong>in</strong>gacute and chr<strong>on</strong>ic phases) did not differsignificantly (P=.38) between thetreatment groups (difference <strong>in</strong> totalmean slopes=0.34 mL/m<strong>in</strong> per 1.73m 2 /y, 95% CI,−0.41 to 1.08). As describedbelow, the different results forchr<strong>on</strong>ic and total slopes are clarified bytak<strong>in</strong>g <strong>in</strong>to account the level <str<strong>on</strong>g>of</str<strong>on</strong>g> basel<strong>in</strong>eprote<strong>in</strong>uria.<str<strong>on</strong>g>Effect</str<strong>on</strong>g> <str<strong>on</strong>g>of</str<strong>on</strong>g> Basel<strong>in</strong>e Prote<strong>in</strong>uria. Theacute rise <strong>in</strong> GFR produced by amlodip<strong>in</strong>ewas c<strong>on</strong>f<strong>in</strong>ed to the participantswith basel<strong>in</strong>e UP/Cr 0.22 (approximateprote<strong>in</strong> excreti<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> 300mg/d or lower). As a c<strong>on</strong>sequence, therewere highly significant <strong>in</strong>teracti<strong>on</strong>s <str<strong>on</strong>g>of</str<strong>on</strong>g>the treatment regimen with basel<strong>in</strong>eprote<strong>in</strong>uria for both the acute GFRslope (P=.001) and the total mean slope2722 JAMA, June 6, 2001—Vol 285, No. 21 (Repr<strong>in</strong>ted) ©2001 American Medical Associati<strong>on</strong>. All rights reserved.Downloaded from www.jama.com at Medical Library <str<strong>on</strong>g>of</str<strong>on</strong>g> the PLA, <strong>on</strong> August 9, 2007
RAMIPRIL VS AMLODIPINE AND HYPERTENSIVE RENAL DISEASE(P.001). The mean (SE) total decl<strong>in</strong>e<strong>in</strong> GFR to 3 years (FIGURE 2A) was1.22 (0.44) mL/m<strong>in</strong> per 1.73 m 2 /y faster<strong>in</strong> the ramipril group than <strong>in</strong> the amlodip<strong>in</strong>egroup am<strong>on</strong>g participants withbasel<strong>in</strong>e UP/Cr 0.22 (∼300 mg/d)(P =.006) (mean [SE] total slopeswere−1.02 [0.25] and 0.20 [0.39] mL/m<strong>in</strong> per 1.73 m 2 /y <strong>in</strong> the ramipril andamlodip<strong>in</strong>e groups, respectively). However,am<strong>on</strong>g participants with basel<strong>in</strong>eUP/Cr 0.22, the total decl<strong>in</strong>e to3 years was 2.02 (0.74) mL/m<strong>in</strong> per1.73 m 2 /y, or 36%, slower <strong>in</strong> theramipril group (P=.006) (mean [SE]total slopes were−3.60 [0.34] and−5.62 [0.65] mL/m<strong>in</strong> per 1.73 m 2 /y <strong>in</strong>the ramipril and amlodip<strong>in</strong>e groups)(Figure 2B).Dur<strong>in</strong>g the chr<strong>on</strong>ic phase, mean GFRdecl<strong>in</strong>ed at a substantially faster rate <strong>in</strong>participants with higher basel<strong>in</strong>e prote<strong>in</strong>uria(UP/Cr 0.22) than <strong>in</strong> participantswithout prote<strong>in</strong>uria (UP/Cr0.22; P.001). The rate <str<strong>on</strong>g>of</str<strong>on</strong>g> GFR decl<strong>in</strong>edur<strong>in</strong>g the chr<strong>on</strong>ic phase was 2.37(0.80) mL/m<strong>in</strong> per 1.73 m 2 /y less <strong>in</strong> theramipril group than <strong>in</strong> the amlodip<strong>in</strong>egroup <strong>in</strong> participants with basel<strong>in</strong>eUP/Cr 0.22 (P=.003) (mean [SE] decl<strong>in</strong>es<str<strong>on</strong>g>of</str<strong>on</strong>g> 3.55 [0.41] and 5.92 [0.69]mL/m<strong>in</strong> per 1.73 m 2 /y <strong>in</strong> the ramipriland amlodip<strong>in</strong>e groups, respectively).Am<strong>on</strong>g participants with basel<strong>in</strong>eUP/Cr 0.22, the difference <strong>in</strong> meanchr<strong>on</strong>ic GFR slope between ramipriland amlodip<strong>in</strong>e groups was slightlysmaller (0.80 [0.43] mL/m<strong>in</strong> per 1.73m 2 /y; P=.07) (mean [SE] decl<strong>in</strong>es <str<strong>on</strong>g>of</str<strong>on</strong>g>1.22 [0.25] and 2.02 [0.38] <strong>in</strong> theramipril and amlodip<strong>in</strong>e groups,respectively). However, the <strong>in</strong>teracti<strong>on</strong><str<strong>on</strong>g>of</str<strong>on</strong>g> the drug regimens with basel<strong>in</strong>eprote<strong>in</strong>uria was not significant(P=.21).<str<strong>on</strong>g>Effect</str<strong>on</strong>g> <str<strong>on</strong>g>of</str<strong>on</strong>g> Basel<strong>in</strong>e GFR. C<strong>on</strong>sistentwith the <strong>in</strong>verse associati<strong>on</strong> betweenGFR and prote<strong>in</strong>uria at basel<strong>in</strong>e, significant<strong>in</strong>teracti<strong>on</strong>s were also observedbetween basel<strong>in</strong>e GFR and thetreatment <strong>in</strong>terventi<strong>on</strong>s <strong>on</strong> the acuteslopes (P=.006) and total mean slopes(P =.003). The total mean GFR decl<strong>in</strong>eto 3 years was 0.97 (0.47) mL/m<strong>in</strong> per 1.73 m 2 /y faster <strong>in</strong> the ramiprilgroup than the amlodip<strong>in</strong>e group forparticipants with basel<strong>in</strong>e GFR levels<str<strong>on</strong>g>of</str<strong>on</strong>g> at least 40 mL/m<strong>in</strong> per 1.73 m 2(mean [SE] decl<strong>in</strong>es <str<strong>on</strong>g>of</str<strong>on</strong>g> 1.53 [0.26]and 0.55 [0.42] mL/m<strong>in</strong> per 1.73 m 2 /y<strong>in</strong> the ramipril and amlodip<strong>in</strong>e groups)(Figure 2C). However, it was 1.61Figure 1. Trial Pr<str<strong>on</strong>g>of</str<strong>on</strong>g>ile436 Randomized to Receive <str<strong>on</strong>g>Ramipril</str<strong>on</strong>g>3 Did Not Receive <str<strong>on</strong>g>Ramipril</str<strong>on</strong>g>433 Received <str<strong>on</strong>g>Ramipril</str<strong>on</strong>g> as Assigned20 No Follow-up GFR50 No GFR <strong>in</strong> F<strong>in</strong>al Year <str<strong>on</strong>g>of</str<strong>on</strong>g> Follow-up †0 Withdrawn47 Dialysis18 Death321 Active Participants ‡ 1707 Not Randomized(0.62) mL/m<strong>in</strong> per 1.73 m 2 /y faster <strong>in</strong>the amlodip<strong>in</strong>e group for subjects withbasel<strong>in</strong>e GFR less than 40 mL/m<strong>in</strong> per1.73 m 2 (mean [SE] decl<strong>in</strong>es <str<strong>on</strong>g>of</str<strong>on</strong>g> 2.73[0.32] and 4.33 [0.54] mL/m<strong>in</strong> per 1.73m 2 /y <strong>in</strong> the ramipril and amlodip<strong>in</strong>egroups) (Figure 2D).2801 Screened ∗1147 Glomerular Filtrati<strong>on</strong> Rate (GFR) Exclusi<strong>on</strong>214 Patient Refusal113 Medical Exclusi<strong>on</strong>97 Study Team Preference82 Blood Pressure Exclusi<strong>on</strong>54 Other1094 Randomized441 Randomized toReceive Metoprolol217 Randomized to Receive <str<strong>on</strong>g>Amlodip<strong>in</strong>e</str<strong>on</strong>g>6 Did Not Receive <str<strong>on</strong>g>Amlodip<strong>in</strong>e</str<strong>on</strong>g>211 Received <str<strong>on</strong>g>Amlodip<strong>in</strong>e</str<strong>on</strong>g> as Assigned7 No Follow-up GFR23 No GFR <strong>in</strong> F<strong>in</strong>al Year <str<strong>on</strong>g>of</str<strong>on</strong>g> Follow-up †0 Withdrawn32 Dialysis13 Death149 Active Participants ‡Asterisk <strong>in</strong>dicates those seen at a screen<strong>in</strong>g visit but not the participants prescreened by chart review or teleph<strong>on</strong>escreen<strong>in</strong>g. Dagger <strong>in</strong>dicates the number <str<strong>on</strong>g>of</str<strong>on</strong>g> participants who were alive and not receiv<strong>in</strong>g dialysis andwho did not have a GFR measured <strong>in</strong> the f<strong>in</strong>al year. Double dagger <strong>in</strong>dicates the number <str<strong>on</strong>g>of</str<strong>on</strong>g> participants whowere alive, were not receiv<strong>in</strong>g dialysis, and who had at least 1 GFR <strong>in</strong> the f<strong>in</strong>al year <str<strong>on</strong>g>of</str<strong>on</strong>g> follow-up prior to September22, 2000.Table 2. Antihypertensive Therapy and Blood Pressure Dur<strong>in</strong>g Follow-up*<str<strong>on</strong>g>Ramipril</str<strong>on</strong>g><str<strong>on</strong>g>Amlodip<strong>in</strong>e</str<strong>on</strong>g>Basel<strong>in</strong>e M<strong>on</strong>th 3(n = 436) (n = 375)Follow-upAfter 3 M<strong>on</strong>ths(n = 418)Basel<strong>in</strong>e M<strong>on</strong>th 3(n = 217) (n = 189)Follow-upAfter 3 M<strong>on</strong>ths(n = 209)Blood pressure,mean, mm HgSystolic 151.0 134.4 134.5 150.0 134.0 132.9Diastolic 96.0 84.0 82.2 95.7 83.1 81.4Mean arterial pressure, 114.6 101.0 99.8 114.0 100.3 98.8mm HgTotal No. <str<strong>on</strong>g>of</str<strong>on</strong>g> drugs 2.40 2.80 2.75 2.48 2.64 2.75Assigned therapy, % NA 91.2 78.5 NA 91.7 83.5Crossover, % NA 5.77 11.6 NA 5.07 7.1*No. <str<strong>on</strong>g>of</str<strong>on</strong>g> patients with blood pressure measurements at <strong>in</strong>dicated times. NA <strong>in</strong>dicates not applicable.©2001 American Medical Associati<strong>on</strong>. All rights reserved. (Repr<strong>in</strong>ted) JAMA, June 6, 2001—Vol 285, No. 21 2723Downloaded from www.jama.com at Medical Library <str<strong>on</strong>g>of</str<strong>on</strong>g> the PLA, <strong>on</strong> August 9, 2007
RAMIPRIL VS AMLODIPINE AND HYPERTENSIVE RENAL DISEASECl<strong>in</strong>ical End Po<strong>in</strong>t AnalysisThe results <str<strong>on</strong>g>of</str<strong>on</strong>g> the analysis <str<strong>on</strong>g>of</str<strong>on</strong>g> cl<strong>in</strong>ical endpo<strong>in</strong>ts are presented <strong>in</strong> TABLE 3 andFIGURE 3. The top 2 rows <str<strong>on</strong>g>of</str<strong>on</strong>g> Table 3provides the frequencies <str<strong>on</strong>g>of</str<strong>on</strong>g> GFR eventsand ESRD, irrespective <str<strong>on</strong>g>of</str<strong>on</strong>g> the order <str<strong>on</strong>g>of</str<strong>on</strong>g>the events. The 143 composite events<strong>in</strong> the ramipril and amlodip<strong>in</strong>e groupsFigure 2. Mean Change <strong>in</strong> Glomerular Filtrati<strong>on</strong> Rate (GFR) Under 2-Slope ModelChange <strong>in</strong> GFR (SE), mL/m<strong>in</strong>per 1.73 m 2 /yChange <strong>in</strong> GFR (SE), mL/m<strong>in</strong>per 1.73 m 2 /y1050–5–101050–5–10ACBasel<strong>in</strong>e UP/Cr ≤0.22<str<strong>on</strong>g>Amlodip<strong>in</strong>e</str<strong>on</strong>g>Mean Basel<strong>in</strong>e GFR ≥40 mL/m<strong>in</strong> per 1.73 m 2<str<strong>on</strong>g>Amlodip<strong>in</strong>e</str<strong>on</strong>g><str<strong>on</strong>g>Ramipril</str<strong>on</strong>g><str<strong>on</strong>g>Ramipril</str<strong>on</strong>g>0 3 122436M<strong>on</strong>ths50–5–10–15–2050–5–10–15–20BDBasel<strong>in</strong>e UP/Cr >0.22<str<strong>on</strong>g>Amlodip<strong>in</strong>e</str<strong>on</strong>g>Mean Basel<strong>in</strong>e GFR
RAMIPRIL VS AMLODIPINE AND HYPERTENSIVE RENAL DISEASElower (95% CI, 37%-69%; P.001) forthe ramipril group than for the amlodip<strong>in</strong>egroup.Figure 3. Cumulative Incidence <str<strong>on</strong>g>of</str<strong>on</strong>g> <strong>Renal</strong> Events and DeathCumulative Incidence, %2520151050No. at RiskAGFR Event, ESRD, or Death<str<strong>on</strong>g>Amlodip<strong>in</strong>e</str<strong>on</strong>g><str<strong>on</strong>g>Ramipril</str<strong>on</strong>g>0 3 122436M<strong>on</strong>thsCOMMENTThis report suggests that <strong>in</strong>itial antihypertensivetherapy with ramipril, anACEI, <str<strong>on</strong>g>of</str<strong>on</strong>g>fers greater benefit <strong>in</strong> slow<strong>in</strong>gdeteriorati<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> renal functi<strong>on</strong> than amlodip<strong>in</strong>e,a DHP-CCB, <strong>in</strong> participantswith mild-to-moderate chr<strong>on</strong>ic renal <strong>in</strong>sufficiencyassociated with hypertensivenephrosclerosis. This c<strong>on</strong>clusi<strong>on</strong>is supported by 3 f<strong>in</strong>d<strong>in</strong>gs based <strong>on</strong>analyses <str<strong>on</strong>g>of</str<strong>on</strong>g> the entire cohort <strong>in</strong> this trial.Participants randomized to the ramiprilgroup experienced significant reducti<strong>on</strong>scompared with those <strong>in</strong> the amlodip<strong>in</strong>egroup <strong>in</strong> (1) risk <str<strong>on</strong>g>of</str<strong>on</strong>g> the importantcl<strong>in</strong>ical end po<strong>in</strong>ts, that is,marked decl<strong>in</strong>e <str<strong>on</strong>g>of</str<strong>on</strong>g> renal functi<strong>on</strong>, ESRD,or death; (2) mean chr<strong>on</strong>ic decl<strong>in</strong>e <strong>in</strong>GFR from 3 m<strong>on</strong>ths postrandomizati<strong>on</strong>;and (3) prote<strong>in</strong>uria.Because reports published dur<strong>in</strong>g thecourse <str<strong>on</strong>g>of</str<strong>on</strong>g> the trial suggested that ACEIshad a greater relative benefit <strong>in</strong> patientswith prote<strong>in</strong>uria, analyses were stratifiedby level <str<strong>on</strong>g>of</str<strong>on</strong>g> basel<strong>in</strong>e ur<strong>in</strong>e prote<strong>in</strong> excreti<strong>on</strong>.3-6,10,14,22,25-28 Participants with prote<strong>in</strong>excreti<strong>on</strong> greater than 2.5 g/d werenot <strong>in</strong>cluded <strong>in</strong> AASK, but <strong>on</strong>e third <str<strong>on</strong>g>of</str<strong>on</strong>g>participants had basel<strong>in</strong>e prote<strong>in</strong> excreti<strong>on</strong>with UP/Cr 0.22 or approximately300 mg/d, a value that def<strong>in</strong>escl<strong>in</strong>ically significant prote<strong>in</strong>uria. Participantswith prote<strong>in</strong> excreti<strong>on</strong> above thislevel showed the greatest benefit <str<strong>on</strong>g>of</str<strong>on</strong>g>ramipril compared with those receiv<strong>in</strong>gamlodip<strong>in</strong>e <strong>in</strong> all outcome parameters,<strong>in</strong>clud<strong>in</strong>g the comb<strong>in</strong>ed cl<strong>in</strong>ical endpo<strong>in</strong>t, the mean GFR slope from basel<strong>in</strong>eand from 3 m<strong>on</strong>ths, and ur<strong>in</strong>ary prote<strong>in</strong>excreti<strong>on</strong>. C<strong>on</strong>sistent with other reports,prote<strong>in</strong>uria was a str<strong>on</strong>g predictor<str<strong>on</strong>g>of</str<strong>on</strong>g> GFR decl<strong>in</strong>e, and the majority <str<strong>on</strong>g>of</str<strong>on</strong>g> participantswho experienced a cl<strong>in</strong>ical endpo<strong>in</strong>t had basel<strong>in</strong>e prote<strong>in</strong> excreti<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g>UP/Cr 0.22. 7,14The benefit <str<strong>on</strong>g>of</str<strong>on</strong>g> ramipril <strong>on</strong> the totalchange <strong>in</strong> GFR observed <strong>in</strong> participantswith higher basel<strong>in</strong>e ur<strong>in</strong>e prote<strong>in</strong> excreti<strong>on</strong>did not extend to those participantswithout prote<strong>in</strong>uria. Becausetreatment with a DHP-CCB–based antihypertensivedrug regimen produced anacute rise <strong>in</strong> GFR that was c<strong>on</strong>f<strong>in</strong>ed toparticipants without prote<strong>in</strong>uria, theramipril regimen did not significantlyslow the total mean GFR decl<strong>in</strong>e comparedwith the amlodip<strong>in</strong>e regimen foreither the subgroup without prote<strong>in</strong>uriaor the entire cohort. There is someevidence that <strong>in</strong>creases <strong>in</strong> GFR observedafter <strong>in</strong>itiati<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> a DHP-CCB maynot c<strong>on</strong>fer benefit <strong>on</strong> l<strong>on</strong>g-term renaloutcome. In animal studies, DHP-CCBs produce an acute rise <strong>in</strong> GFR bycaus<strong>in</strong>g afferent arteriolar vasodilati<strong>on</strong>and loss <str<strong>on</strong>g>of</str<strong>on</strong>g> renal autoregulati<strong>on</strong>. 30-32 Asa c<strong>on</strong>sequence, <strong>in</strong>traglomerular pressuretypically rises, even when systemicarterial pressure falls. 30,32 In c<strong>on</strong>trast,ACEIs generally reduce <strong>in</strong>traglomerularpressure and do not <strong>in</strong>terfere with autoregulati<strong>on</strong>.30,32 These observati<strong>on</strong>s,taken together with cl<strong>in</strong>ical studies show<strong>in</strong>g<strong>in</strong>creases <strong>in</strong> prote<strong>in</strong>uria with DHP-CCBs, raise the possibility that pressuremediatedglomerular <strong>in</strong>jury couldc<strong>on</strong>tribute to the greater <strong>in</strong>crease <strong>in</strong> prote<strong>in</strong>uriaand more rapid decl<strong>in</strong>e <strong>in</strong> GFRobserved <strong>in</strong> AASK participants receiv<strong>in</strong>gthese agents. 10,14,16,22,33,34While the total change <strong>in</strong> GFR dur<strong>in</strong>gthe study period did not differ significantlybetween treatment groups,ESRD or Death0 3 122436M<strong>on</strong>ths<str<strong>on</strong>g>Amlodip<strong>in</strong>e</str<strong>on</strong>g> 216 209191 131216 210193139<str<strong>on</strong>g>Ramipril</str<strong>on</strong>g> 432 422391 278432 428405290B<str<strong>on</strong>g>Amlodip<strong>in</strong>e</str<strong>on</strong>g><str<strong>on</strong>g>Ramipril</str<strong>on</strong>g>GFR <strong>in</strong>dicates glomerular filtrati<strong>on</strong> rate; ESRD, end-stage renal disease. The adjusted risk reducti<strong>on</strong> for ramipril<str<strong>on</strong>g>vs</str<strong>on</strong>g> amlodip<strong>in</strong>e for the GFR event, ESRD, or death composite outcome was 38% (95% c<strong>on</strong>fidence <strong>in</strong>terval [CI],13%-56%; P = .005) (A) and for ESRD or death was 41% (95% CI, 14%-60%; P = .007) (B). The risk reducti<strong>on</strong>sare adjusted for basel<strong>in</strong>e levels <str<strong>on</strong>g>of</str<strong>on</strong>g> log transformed ur<strong>in</strong>e prote<strong>in</strong>–creat<strong>in</strong><strong>in</strong>e ratio, history <str<strong>on</strong>g>of</str<strong>on</strong>g> heart disease,mean arterial pressure, sex, and age.Figure 4. Percent Changes <strong>in</strong> Prote<strong>in</strong>uria From Basel<strong>in</strong>e% Change <strong>in</strong> UP/Cr (SE)A230125500–35–55–70Basel<strong>in</strong>e UP/Cr ≤0.22<str<strong>on</strong>g>Amlodip<strong>in</strong>e</str<strong>on</strong>g><str<strong>on</strong>g>Ramipril</str<strong>on</strong>g>0 6 122436M<strong>on</strong>thsBBasel<strong>in</strong>e UP/Cr >0.22<str<strong>on</strong>g>Amlodip<strong>in</strong>e</str<strong>on</strong>g><str<strong>on</strong>g>Ramipril</str<strong>on</strong>g>0 6 122436M<strong>on</strong>thsUP/Cr <strong>in</strong>dicates ur<strong>in</strong>ary prote<strong>in</strong> to creat<strong>in</strong><strong>in</strong>e ratio. Shown are the estimated percentage changes from basel<strong>in</strong>e<strong>in</strong> the geometric mean UP/Cr. Basel<strong>in</strong>e UP/Cr <str<strong>on</strong>g>of</str<strong>on</strong>g> 0.22 corresp<strong>on</strong>ds approximately to prote<strong>in</strong>uria <str<strong>on</strong>g>of</str<strong>on</strong>g> 300mg/d. Error bars represent SE.©2001 American Medical Associati<strong>on</strong>. All rights reserved. (Repr<strong>in</strong>ted) JAMA, June 6, 2001—Vol 285, No. 21 2725Downloaded from www.jama.com at Medical Library <str<strong>on</strong>g>of</str<strong>on</strong>g> the PLA, <strong>on</strong> August 9, 2007
RAMIPRIL VS AMLODIPINE AND HYPERTENSIVE RENAL DISEASEother AASK results suggest the benefit<str<strong>on</strong>g>of</str<strong>on</strong>g> ramipril over amlodip<strong>in</strong>e may extendto <strong>in</strong>dividuals without prote<strong>in</strong>uria.The analysis <str<strong>on</strong>g>of</str<strong>on</strong>g> total GFR slope isstr<strong>on</strong>gly <strong>in</strong>fluenced by acute changes <strong>in</strong>participants with little overall diseaseprogressi<strong>on</strong>, while both the cl<strong>in</strong>ical endpo<strong>in</strong>ts and chr<strong>on</strong>ic slope outcomes betterreflect l<strong>on</strong>g-term disease progressi<strong>on</strong>.These outcomes dem<strong>on</strong>strate significantbenefits <str<strong>on</strong>g>of</str<strong>on</strong>g> ACEI for the entirecohort. The benefit <str<strong>on</strong>g>of</str<strong>on</strong>g> ACEI <strong>in</strong> the cl<strong>in</strong>icalend po<strong>in</strong>t analysis is particularlycompell<strong>in</strong>g s<strong>in</strong>ce it is based <strong>on</strong> eventswith direct patient impact.The <strong>in</strong>crease <strong>in</strong> prote<strong>in</strong>uria <strong>in</strong> the amlodip<strong>in</strong>egroup compared with theramipril group was significant for bothbasel<strong>in</strong>e prote<strong>in</strong>uria strata. Furthermore,<strong>in</strong> AASK participants with basel<strong>in</strong>eUP/Cr 0.22, the time until the rati<str<strong>on</strong>g>of</str<strong>on</strong>g>irst reached the 0.22 cutpo<strong>in</strong>t wassignificantly shorter for the amlodip<strong>in</strong>ethan for the ramipril group.Thus, treatment <str<strong>on</strong>g>of</str<strong>on</strong>g> a patient withoutprote<strong>in</strong>uria with a DHP-CCB may result<strong>in</strong> the development <str<strong>on</strong>g>of</str<strong>on</strong>g> prote<strong>in</strong>uriaand potentially a greater risk <str<strong>on</strong>g>of</str<strong>on</strong>g> l<strong>on</strong>gtermrenal disease. N<strong>on</strong>etheless, therelatively low rates <str<strong>on</strong>g>of</str<strong>on</strong>g> renal disease progressi<strong>on</strong><strong>in</strong> the participants without prote<strong>in</strong>uriaand data suggest<strong>in</strong>g that ACEIshave a larger benefit <strong>in</strong> participants withprote<strong>in</strong>uria than those without prote<strong>in</strong>uriamake the evidence for a renoprotectivebenefit <str<strong>on</strong>g>of</str<strong>on</strong>g> ACEIs <strong>in</strong> these participantswithout prote<strong>in</strong>uria lessdef<strong>in</strong>itive. 25A limitati<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> the analyses <str<strong>on</strong>g>of</str<strong>on</strong>g> GFRslope <strong>in</strong> this report is that the occurrence<str<strong>on</strong>g>of</str<strong>on</strong>g> ESRD, death, or patient dropoutprevented observati<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> GFRs overthe entire study period for a substantialfracti<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> participants (Figure 1).This could have biased our results depend<strong>in</strong>g<strong>on</strong> the relati<strong>on</strong>ship <str<strong>on</strong>g>of</str<strong>on</strong>g> the pattern<str<strong>on</strong>g>of</str<strong>on</strong>g> miss<strong>in</strong>g data with the GFRslopes. 35 However, the results <str<strong>on</strong>g>of</str<strong>on</strong>g> theGFR slope analyses changed little underalternative models for the miss<strong>in</strong>gGFRs 36 (data not shown), suggest<strong>in</strong>gthat the missed GFRs did not affect ourc<strong>on</strong>clusi<strong>on</strong>s. A sec<strong>on</strong>d limitati<strong>on</strong> is thatthe <strong>in</strong>vestigati<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> the ramipril <str<strong>on</strong>g>vs</str<strong>on</strong>g> amlodip<strong>in</strong>ecomparis<strong>on</strong> <strong>in</strong> relati<strong>on</strong> to basel<strong>in</strong>eprote<strong>in</strong>uria was not specified <strong>in</strong> theprotocol prior to the study. However,the decisi<strong>on</strong> to <strong>in</strong>vestigate the <strong>in</strong>fluence<str<strong>on</strong>g>of</str<strong>on</strong>g> prote<strong>in</strong>uria <strong>on</strong> the treatment effectswas made by study <strong>in</strong>vestigatorswho were bl<strong>in</strong>ded to AASK outcomedata, reduc<strong>in</strong>g the risk <str<strong>on</strong>g>of</str<strong>on</strong>g> a spuriouspost hoc f<strong>in</strong>d<strong>in</strong>g. The cutpo<strong>in</strong>t <str<strong>on</strong>g>of</str<strong>on</strong>g> 0.22used for stratificati<strong>on</strong> by basel<strong>in</strong>e UP/Cralso was selected <strong>in</strong>dependently <str<strong>on</strong>g>of</str<strong>on</strong>g> theAASK data based <strong>on</strong> cl<strong>in</strong>ical and statisticalc<strong>on</strong>siderati<strong>on</strong>s. However, thesample size <str<strong>on</strong>g>of</str<strong>on</strong>g> this study is not sufficientto determ<strong>in</strong>e a precise thresholdwhere the advantage <str<strong>on</strong>g>of</str<strong>on</strong>g> ACEIs becomesdef<strong>in</strong>itive. 7In aggregate, our results are c<strong>on</strong>sistentwith prior observati<strong>on</strong>s <strong>in</strong> participantswith both diabetic and n<strong>on</strong>diabeticrenal disease that ACEIs have arenoprotective effect 3,4,6,28 and that treatmentwith a DHP-CCB <strong>in</strong>creasesprote<strong>in</strong>uria and may not slow the progressi<strong>on</strong><str<strong>on</strong>g>of</str<strong>on</strong>g> established renal diseasedespite substantial reducti<strong>on</strong>s <strong>in</strong>BP. 10,14-16,22,25,28,33,34 Interim results <str<strong>on</strong>g>of</str<strong>on</strong>g> theAASK trial, taken together with previoustrials, support the use <str<strong>on</strong>g>of</str<strong>on</strong>g> an ACEI as<strong>in</strong>itial therapy <strong>in</strong> a multidrug regimenover a DHP-CCB–based regimen <strong>in</strong> AfricanAmerican and white participantswith mild-to-moderate chr<strong>on</strong>ic renal <strong>in</strong>sufficiencyand levels <str<strong>on</strong>g>of</str<strong>on</strong>g> prote<strong>in</strong>uria def<strong>in</strong>ed<strong>in</strong> this report. 3-6,14,27 These resultsfurther provide documentati<strong>on</strong> extend<strong>in</strong>gthe renoprotective acti<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> an ACEIbasedregimen to African Americans withthis disorder, a populati<strong>on</strong> previouslythought to be less resp<strong>on</strong>sive to theseagents. For participants with hypertensi<strong>on</strong>without prote<strong>in</strong>uria and those at lowrisk for progressive renal disease, the evidenceis less c<strong>on</strong>clusive. By design, <strong>on</strong>lypers<strong>on</strong>s with hypertensi<strong>on</strong> and mild-tomoderaterenal disease were studied <strong>in</strong>the AASK, and the effect <str<strong>on</strong>g>of</str<strong>on</strong>g> amlodip<strong>in</strong>eand ramipril <strong>on</strong> renal functi<strong>on</strong> was themajor focus <str<strong>on</strong>g>of</str<strong>on</strong>g> the study. The study wasnot designed to evaluate the effect <str<strong>on</strong>g>of</str<strong>on</strong>g>these agents <strong>on</strong> cardiovascular and cerebrovascularcomplicati<strong>on</strong>s, the mostfrequent complicati<strong>on</strong>s <str<strong>on</strong>g>of</str<strong>on</strong>g> hypertensi<strong>on</strong>.The risk <str<strong>on</strong>g>of</str<strong>on</strong>g> these complicati<strong>on</strong>s hasbeen shown to be lowered by DHP-CCBs <strong>in</strong> a number <str<strong>on</strong>g>of</str<strong>on</strong>g> cl<strong>in</strong>ical end po<strong>in</strong>ttrials. 37-40 However, cl<strong>in</strong>icians should beaware that use <str<strong>on</strong>g>of</str<strong>on</strong>g> DHP-CCBs both <strong>in</strong> thisand other trials not <strong>in</strong>volv<strong>in</strong>g AfricanAmericans are associated with the development<str<strong>on</strong>g>of</str<strong>on</strong>g> prote<strong>in</strong>uria. 7,10,14-16,22,28,33Thus, measurement <str<strong>on</strong>g>of</str<strong>on</strong>g> ur<strong>in</strong>ary prote<strong>in</strong>excreti<strong>on</strong> is recommended to guide <strong>in</strong>itialtherapy selecti<strong>on</strong>.Author Affiliati<strong>on</strong>s: Nati<strong>on</strong>al Institute <str<strong>on</strong>g>of</str<strong>on</strong>g> Diabetes andDigestive and Kidney Diseases, Bethesda, Md (Drs Agodoa,Briggs, and Kusek); Department <str<strong>on</strong>g>of</str<strong>on</strong>g> PreventiveMedic<strong>in</strong>e, Johns Hopk<strong>in</strong>s University, Baltimore, Md (DrsAppel and Miller and Ms Charlest<strong>on</strong>); Department <str<strong>on</strong>g>of</str<strong>on</strong>g>Preventive Medic<strong>in</strong>e, Rush-Presbyterian-St Luke’sMedical Center, Chicago, Ill (Dr Bakris); Department<str<strong>on</strong>g>of</str<strong>on</strong>g> Biostatistics, Cleveland Cl<strong>in</strong>ic Foundati<strong>on</strong>, Cleveland,Ohio (Drs Beck, Gassman, and Greene); Department<str<strong>on</strong>g>of</str<strong>on</strong>g> Medic<strong>in</strong>e, University <str<strong>on</strong>g>of</str<strong>on</strong>g> Miami, Coral Gables,Fla (Dr Bourgoignie); Department <str<strong>on</strong>g>of</str<strong>on</strong>g> Medic<strong>in</strong>e, MedicalUniversity <str<strong>on</strong>g>of</str<strong>on</strong>g> South Carol<strong>in</strong>a, Charlest<strong>on</strong> (Dr Cheek);Department <str<strong>on</strong>g>of</str<strong>on</strong>g> Medic<strong>in</strong>e, Morehouse School <str<strong>on</strong>g>of</str<strong>on</strong>g> Medic<strong>in</strong>e,Atlanta, Ga (Dr Cleveland and Mr Smith); Department<str<strong>on</strong>g>of</str<strong>on</strong>g> Medic<strong>in</strong>e, Case Western Reserve UniversityHospitals, Cleveland, Ohio (Drs Douglas, Rahman,and Wright, and Ms Hall); Department <str<strong>on</strong>g>of</str<strong>on</strong>g> Medic<strong>in</strong>e,Emory University Medical Center, Atlanta, Ga (MsDouglas and Dr Lea); Department <str<strong>on</strong>g>of</str<strong>on</strong>g> Medic<strong>in</strong>e, HarlemHospital Center, New York, NY (Drs Dowie and Pogue);Department <str<strong>on</strong>g>of</str<strong>on</strong>g> Medic<strong>in</strong>e, Meharry Medical College,Nashville, Tenn (Dr Faulkner); Department <str<strong>on</strong>g>of</str<strong>on</strong>g> Medic<strong>in</strong>e,Mount S<strong>in</strong>ai School <str<strong>on</strong>g>of</str<strong>on</strong>g> Medic<strong>in</strong>e, New York, NY(Ms Gabriel and Drs Lipkowitz and Phillips); Department<str<strong>on</strong>g>of</str<strong>on</strong>g> Medic<strong>in</strong>e, Ohio State University, Columbus(Drs Hebert and Hiremath); Department <str<strong>on</strong>g>of</str<strong>on</strong>g> Medic<strong>in</strong>e,University <str<strong>on</strong>g>of</str<strong>on</strong>g> Michigan, Ann Arbor (Drs Jamers<strong>on</strong>and Ojo); Department <str<strong>on</strong>g>of</str<strong>on</strong>g> Medic<strong>in</strong>e, Harbor MedicalCenter, University <str<strong>on</strong>g>of</str<strong>on</strong>g> California, Los Angeles (DrKopple); Department <str<strong>on</strong>g>of</str<strong>on</strong>g> Medic<strong>in</strong>e, University <str<strong>on</strong>g>of</str<strong>on</strong>g> Ill<strong>in</strong>ois,Chicago (Dr Lash); Department <str<strong>on</strong>g>of</str<strong>on</strong>g> Medic<strong>in</strong>e,Vanderbilt University, Nashville, Tenn (Drs Lewis andSchulman); Department <str<strong>on</strong>g>of</str<strong>on</strong>g> Medic<strong>in</strong>e, University <str<strong>on</strong>g>of</str<strong>on</strong>g>Southern California, Los Angeles (Dr Massry); Department<str<strong>on</strong>g>of</str<strong>on</strong>g> Medic<strong>in</strong>e, University <str<strong>on</strong>g>of</str<strong>on</strong>g> Texas SouthwesternMedical Center, Dallas (Drs Middlet<strong>on</strong> and Toto);Department <str<strong>on</strong>g>of</str<strong>on</strong>g> Medic<strong>in</strong>e, Mart<strong>in</strong> L. K<strong>in</strong>g–Charles R.Drew Medical Center, Los Angeles, Calif (Dr Norris);Department <str<strong>on</strong>g>of</str<strong>on</strong>g> Medic<strong>in</strong>e, University <str<strong>on</strong>g>of</str<strong>on</strong>g> California, SanDiego (Dr O’C<strong>on</strong>nor); Department <str<strong>on</strong>g>of</str<strong>on</strong>g> Medic<strong>in</strong>e,Howard University, Wash<strong>in</strong>gt<strong>on</strong>, DC (Drs Randall andXu); Department <str<strong>on</strong>g>of</str<strong>on</strong>g> Medic<strong>in</strong>e, University <str<strong>on</strong>g>of</str<strong>on</strong>g> Alabama,Birm<strong>in</strong>gham (Drs Rostand and Thornley-Brown and Ms Johns<strong>on</strong>); Department <str<strong>on</strong>g>of</str<strong>on</strong>g> Medic<strong>in</strong>e, University<str<strong>on</strong>g>of</str<strong>on</strong>g> Florida, Ga<strong>in</strong>esville (Dr Tisher); and LouisStokes Cleveland VA Medical Center, Cleveland, Ohio(Dr Wright).Author C<strong>on</strong>tributi<strong>on</strong>s: Study c<strong>on</strong>cept and design: Agodoa,Appel, Bakris, Beck, Cheek, M. Douglas, Dowie,Gabriel, Gassman, Greene, Hebert, Jamers<strong>on</strong>, Johns<strong>on</strong>,Kopple, Kusek, Lash, Lewis, Lipkowitz, Massry, Norris,O’C<strong>on</strong>nor, Ojo, Phillips, Pogue, Randall, Rostand,Schulman, Thornley-Brown, Toto, Wright.Acquisiti<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> data: Agodoa, Appel, Bakris, Bourgoignie,Charlest<strong>on</strong>, Cheek, Cleveland, J. G. Douglas, M.Douglas, Dowie, Faulkner, Gabriel, Gassman, Hall, Hebert,Hiremath, Jamers<strong>on</strong>, Johns<strong>on</strong>, Kopple, Lash, Lea,Lewis, Lipkowitz, Massry, Middlet<strong>on</strong>, Miller, Norris,O’C<strong>on</strong>nor, Ojo, Phillips, Pogue, Rahman, Randall, Rostand,Schulman, Smith, Thornley-Brown, Tisher, Toto,Wright, Xu.Analysis and <strong>in</strong>terpretati<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> data: Agodoa, Appel,Bakris, Briggs, J. G. Douglas, Gabriel, Gassman, Greene,Hebert, Jamers<strong>on</strong>, Kusek, Lash, Lewis, Lipkowitz,Massry, Middlet<strong>on</strong>, Miller, Norris, O’C<strong>on</strong>nor, Phillips,Pogue, Rahman, Toto, Wright.2726 JAMA, June 6, 2001—Vol 285, No. 21 (Repr<strong>in</strong>ted) ©2001 American Medical Associati<strong>on</strong>. All rights reserved.Downloaded from www.jama.com at Medical Library <str<strong>on</strong>g>of</str<strong>on</strong>g> the PLA, <strong>on</strong> August 9, 2007
RAMIPRIL VS AMLODIPINE AND HYPERTENSIVE RENAL DISEASEDraft<strong>in</strong>g <str<strong>on</strong>g>of</str<strong>on</strong>g> the manuscript: Agodoa, Appel, Bakris,Briggs, J. G. Douglas, Gassman, Greene, Hebert, Hiremath,Lewis, Norris, Toto, Wright.Critical revisi<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> the manuscript for important <strong>in</strong>tellectualc<strong>on</strong>tent: Agodoa, Appel, Bakris, Beck, Bourgoignie,Briggs, Charlest<strong>on</strong>, Cheek, Cleveland, J. G.Douglas, M. Douglas, Dowie, Faulkner, Gabriel, Gassman,Greene, Hall, Hebert, Jamers<strong>on</strong>, Johns<strong>on</strong>, Kopple,Kusek, Lash, Lea, Lewis, Lipkowitz, Massry, Middlet<strong>on</strong>,Miller, Norris, O’C<strong>on</strong>nor, Ojo, Phillips, Pogue, Rahman,Randall, Rostand, Schulman, Smith, Thornley-Brown, Tisher, Toto, Wright.Statistical expertise: Beck, Gassman, Greene.Obta<strong>in</strong>ed fund<strong>in</strong>g: Agodoa, Appel, Beck, Hebert,Johns<strong>on</strong>, Kusek, Lewis, Massry, Middlet<strong>on</strong>, Norris,O’C<strong>on</strong>nor, Ojo, Randall, Rostand, Thornley-Brown,Tisher, Toto, Wright, Xu.Adm<strong>in</strong>istrative, technical, or material support: Agodoa,Appel, Bakris, Beck, Briggs, J. G. Douglas, M.Douglas, Dowie, Faulkner, Gabriel, Gassman, Greene,Hall, Hiremath, Jamers<strong>on</strong>, Kopple, Kusek, Lewis, Lipkowitz,Massry, Middlet<strong>on</strong>, Miller, Norris, O’C<strong>on</strong>nor,Ojo, Phillips, Pogue, Rahman, Randall, Toto, Wright,Xu.Study supervisi<strong>on</strong>: Agodoa, Appel, Bakris, Briggs,Cleveland, J. G. Douglas, Dowie, Gabriel, Johns<strong>on</strong>,Kopple, Kusek, Lea, Lewis, Lipkowitz, Massry, Middlet<strong>on</strong>,Miller, Norris, O’C<strong>on</strong>nor, Ojo, Phillips, Pogue,Rostand, Thornley-Brown, Toto, Wright.African American Study <str<strong>on</strong>g>of</str<strong>on</strong>g> Kidney Disease and Hypertensi<strong>on</strong>(AASK) Study Group <strong>in</strong>cludes: Case WesternReserve University: Pr<strong>in</strong>cipal Investigator: J. Wright,Study Coord<strong>in</strong>ators: Y. Hall, R. Haynie, C. Mbanefo,M. Rahman, M. Smith, B. Crenshaw, R. Dancie, L. Jaen;Emory University: Pr<strong>in</strong>cipal Investigators: J. Lea, A.Chapman, L. Dean, Study Coord<strong>in</strong>ators: M. Douglas,D. Watk<strong>in</strong>s, B. Wilken<strong>in</strong>g, L. Williams, C. Ross; Harbor-UCLAMedical Center: Pr<strong>in</strong>cipal Investigator: J.Kopple, Study Coord<strong>in</strong>ators: L. Milad<strong>in</strong>ovich, P. Oleskie;Harlem Hospital Center: Pr<strong>in</strong>cipal Investigator: V.Pogue, Study Coord<strong>in</strong>ators: D. Dowie, H. Anders<strong>on</strong>,L. Herbert, R. Locko, H. Nurse, J. Cheng, G. Darkwa,V. Dowdy, B. Nicholas; Howard University: Pr<strong>in</strong>cipalInvestigators: O. S. Randall, G. Ali, T. Retta, Study Coord<strong>in</strong>ators:S. Xu, T. Alexander, M. Ketete, E. Mathew,D. Ordor, C. Tilghman; Johns Hopk<strong>in</strong>s University: Pr<strong>in</strong>cipalInvestigator: L. Appel, Study Coord<strong>in</strong>ators: J.Charlest<strong>on</strong>, C. Diggs, C. Harris, P. E. Miller, T. Shields,M. Sotomayer; Mart<strong>in</strong> Luther K<strong>in</strong>g, Jr/Charles R. DrewMedical Center: Pr<strong>in</strong>cipal Investigators: K. Norris, H.Ward, Study Coord<strong>in</strong>ators: M. Miller, H. Howell, D.Mart<strong>in</strong>s; Medical University <str<strong>on</strong>g>of</str<strong>on</strong>g> South Carol<strong>in</strong>a: Pr<strong>in</strong>cipalInvestigators: D. Cheek, C. Gadegbeku, D. Ploth,Study Coord<strong>in</strong>ators: D. Brooks, N. M<strong>on</strong>estime, S.Murner, S. Thomps<strong>on</strong>; Meharry Medical College: Pr<strong>in</strong>cipalInvestigators: M. Faulkner, O. Adeyele, Study Coord<strong>in</strong>ators:K. Phillips, G. Sanford, C. Weaver; MorehouseSchool <str<strong>on</strong>g>of</str<strong>on</strong>g> Medic<strong>in</strong>e: Pr<strong>in</strong>cipal Investigators: W.Cleveland, A. Howard, K. Chapman, S. Plater, StudyCoord<strong>in</strong>ators: W. Smith; Mount S<strong>in</strong>ai School <str<strong>on</strong>g>of</str<strong>on</strong>g> Medic<strong>in</strong>e:Pr<strong>in</strong>cipal Investigators: R. Phillips, M. Lipkowitz,Study Coord<strong>in</strong>ators: A. Gabriel, A. Travis, J. Williams;Ohio State University: Pr<strong>in</strong>cipal Investigators:L. Hebert, M. Falkenha<strong>in</strong>, S. Lads<strong>on</strong>-W<str<strong>on</strong>g>of</str<strong>on</strong>g>ford, N. Nahman,K. Osei, Study Coord<strong>in</strong>ators: L. Hiremath, A. Dodley,J. Parks, D. Veley; Rush-Presbyterian-St Luke’sMedical Center: Pr<strong>in</strong>cipal Investigators: G. Bakris, J.Lash, Study Coord<strong>in</strong>ators: L. F<strong>on</strong>dren, L. Bagnuolo,J. Cohen, M. Powell, A. Smith, D. White, G. Henry,A. Johns<strong>on</strong>, T. Coll<strong>in</strong>s, S. Koshy, E. Afante; University<str<strong>on</strong>g>of</str<strong>on</strong>g> Alabama, Birm<strong>in</strong>gham: Pr<strong>in</strong>cipal Investigators:S. Rostand, D. Thornley-Brown, R. Gay, StudyCoord<strong>in</strong>ators: C. Johns<strong>on</strong>, B. Key; University <str<strong>on</strong>g>of</str<strong>on</strong>g> California,San Diego: Pr<strong>in</strong>cipal Investigators: D. O’C<strong>on</strong>nor,F. Gabbai, R. Parmer, F. Rao, J. Little, T. Makrogiannis,Study Coord<strong>in</strong>ators: J. Mount, A. Ogundipe, A.Stephens<strong>on</strong>; University <str<strong>on</strong>g>of</str<strong>on</strong>g> Florida: Pr<strong>in</strong>cipal Investigators:C. Tisher, D. Allen, Study Coord<strong>in</strong>ators: L. Burg<strong>in</strong>,A. Diaz, C. Sarmiento; University <str<strong>on</strong>g>of</str<strong>on</strong>g> Miami: Pr<strong>in</strong>cipalInvestigators: J. Bourgoignie, G. C<strong>on</strong>treras, D.Florence-Green, Study Coord<strong>in</strong>ators: A. Doss, J. Junco,D. Merrill, J. Vassallo, A. de Velasco; University <str<strong>on</strong>g>of</str<strong>on</strong>g>Michigan: Pr<strong>in</strong>cipal Investigators: K. Jamers<strong>on</strong>, F. Port,M. Keshishian, A. Ojo, S. Steigerwalt, Study Coord<strong>in</strong>ators:D. Cornish-Zirker, T. Graham, A. Johns<strong>on</strong>, J.Layne, S. Nesbitt, K. Manchester, W. Bloembergen;University <str<strong>on</strong>g>of</str<strong>on</strong>g> Southern California: Pr<strong>in</strong>cipal Investigators:S. Massry, V. Campese, M. Smogorzewski,Study Coord<strong>in</strong>ator: A. Richards<strong>on</strong>; University <str<strong>on</strong>g>of</str<strong>on</strong>g> TexasSouthwestern Medical Center, Dallas: Pr<strong>in</strong>cipal Investigators:J. Middlet<strong>on</strong>, E. Kuo, S. Leach, R. D. Toto,K. J<strong>on</strong>es, K. Hart, Study Coord<strong>in</strong>ators: T. Lightfoot,L. Littm<strong>on</strong>, B. McNeill, C. Y<strong>in</strong>g; Vanderbilt University:Pr<strong>in</strong>cipal Investigators: J. Lewis, G. Schulman, S.McLeroy, Study Coord<strong>in</strong>ators: N. Rogers, M. Sika; andNati<strong>on</strong>al Institute <str<strong>on</strong>g>of</str<strong>on</strong>g> Diabetes and Digestive and KidneyDiseases: L. Y. Agodoa, J. P. Briggs, J. W. Kusek;Steer<strong>in</strong>g Committee Chair: J. Douglas; Cleveland Cl<strong>in</strong>icFoundati<strong>on</strong>: (Data Coord<strong>in</strong>at<strong>in</strong>g Center): J. Gassman,G. Beck, V. Dennis, T. Greene, M. Kutner, StudyCoord<strong>in</strong>ator: K. Britta<strong>in</strong>, S. Sherer, R. Stewart, L. Tuas<strong>on</strong>,S-R. Wang, W. Zhang; Central Biochemistry Laboratory:F. Van Lente, J. Waletzky, C. O’Laughl<strong>in</strong>, C.Peck; Central GFR Laboratory: P. Hall, D. Pexa, H. Rol<strong>in</strong>;Blood Pressure C<strong>on</strong>sultant: R. By<strong>in</strong>gt<strong>on</strong>; PsychologicalC<strong>on</strong>sultant: P. Greene; Data Safety and M<strong>on</strong>itor<strong>in</strong>gCommittee: R. Luke, V. Ch<strong>in</strong>chilli, C. Cook, B.Falkner, C. Ford, R. Glassock, T. Karris<strong>on</strong>, T. Kotchen,E. Saunders, M. Secundy, D. Wess<strong>on</strong>; and ManuscriptPreparati<strong>on</strong>: L. Agodoa, L. Appel, G. Bakris, J.Breyer-Lewis, J. G. Douglas, T. Greene, J. Gassman,L. Hebert, K. Norris, R. Toto, J. T. Wright, Jr.F<strong>in</strong>ancial Disclosures: The follow<strong>in</strong>g authors have receivedh<strong>on</strong>oraria from 1 or more pharmaceutical companiesthat manufacture antihypertensive medicati<strong>on</strong>s:Bakris, Cheek, Cleveland, J. G. Douglas, Hebert,Jamers<strong>on</strong>, Kopple, Lash, Lea, Lewis, Massry, Middlet<strong>on</strong>,Norris, O’C<strong>on</strong>nor, Ojo, Phillips, Pogue, Rahman,Randall, Rostand, Tischer, Toto, Wright. The follow<strong>in</strong>gauthors have received fund<strong>in</strong>g for research from1 or more pharmaceutical companies that manufactureantihypertensive medicati<strong>on</strong>s: Appel, Bakris, Bourgoignie,Briggs, Cheek, Cleveland, J. D. Douglas, M.Douglas, Gassman, Greene, Jamers<strong>on</strong>, Kopple, Lash,Lewis, Massry, Middlet<strong>on</strong>, Norris, O’C<strong>on</strong>nor, Phillips,Pogue, Rahman, Randall, Rostand, Schulman,Smith, Thornley-Brown, Toto, Wright. The follow<strong>in</strong>gauthors have served <strong>on</strong> the advisory panel for 1 ormore pharmaceutical companies that manufacture antihypertensivemedicati<strong>on</strong>s: J. G. Douglas, Hebert, Jamers<strong>on</strong>,Kopple, Lipkowitz, Massry, Norris, Ojo, Randall,Schulman, Toto, Wright. The follow<strong>in</strong>g authorshave stock <strong>in</strong> 1 or more pharmaceutical companiesthat manufacture antihypertensive medicati<strong>on</strong>s: Beck,Cleveland, Faulkner, Hebert, Jamers<strong>on</strong>, Key, Middlet<strong>on</strong>,Norris, Rostand, Schulman, Tischer, Toto. DrKopple has provided expert testim<strong>on</strong>y for 1 or morepharmaceutical companies that manufacture antihypertensivemedicati<strong>on</strong>s. The follow<strong>in</strong>g authors had nodisclosures: Agodoa, Charlest<strong>on</strong>, Dowie, Gabriel, Hall,Hiremath, Johns<strong>on</strong>, Kusek, Miller, Xu. Specific f<strong>in</strong>ancialdisclosures are available <strong>on</strong> the JAMA Web siteat http://jama.ama-assn.org/issues/v285n21/abs/joc10545.html.Fund<strong>in</strong>g/Support: Study drugs and some f<strong>in</strong>ancial supportwere provided by Pfizer Inc, Astra-Zeneca Pharmaceuticals,and K<strong>in</strong>g Pharmaceuticals Inc. In additi<strong>on</strong>to fund<strong>in</strong>g under a cooperative agreement fromNati<strong>on</strong>al Institute <str<strong>on</strong>g>of</str<strong>on</strong>g> Diabetes and Digestive and KidneyDiseases, this study was supported <strong>in</strong> part by thefollow<strong>in</strong>g general cl<strong>in</strong>ical research center grants fromthe Nati<strong>on</strong>al Institutes <str<strong>on</strong>g>of</str<strong>on</strong>g> Health: M01 RR-00080,5M01 RR-00071, M0100032, P20-RR11145, M01RR00827, and 2P20 RR11104.Acknowledgment: We gratefully acknowledge supportfrom the Office <str<strong>on</strong>g>of</str<strong>on</strong>g> Research <strong>in</strong> M<strong>in</strong>ority Health.A special acknowledgment is extended to the AASKparticipants for their time and commitment to thetrial.REFERENCES1. US <strong>Renal</strong> Data System. USRDS 1999 Annual DataReport. Bethesda, Md: Nati<strong>on</strong>al Institutes <str<strong>on</strong>g>of</str<strong>on</strong>g> Health,Nati<strong>on</strong>al Institute <str<strong>on</strong>g>of</str<strong>on</strong>g> Diabetes, Digestive, and KidneyDiseases; 1999.2. Klag MJ, Whelt<strong>on</strong> PK, Randall BL, et al. Blood pressureand end-stage renal disease <strong>in</strong> men. N Engl J Med.1996;334:13-18.3. Lewis EJ, Hunsicker LG, Ba<strong>in</strong> RP, Rohde RD, for theCollaborative Study Group. The effect <str<strong>on</strong>g>of</str<strong>on</strong>g> angiotens<strong>in</strong>c<strong>on</strong>vert<strong>in</strong>g-enzyme<strong>in</strong>hibiti<strong>on</strong> <strong>on</strong> diabetic nephropathy.N Engl J Med. 1993;329:1456-1462.4. Maschio G, Alberti D, Jan<strong>in</strong> G, et al. <str<strong>on</strong>g>Effect</str<strong>on</strong>g> <str<strong>on</strong>g>of</str<strong>on</strong>g> theangiotens<strong>in</strong>-c<strong>on</strong>vert<strong>in</strong>g-enzyme <strong>in</strong>hibitor benazepril <strong>on</strong>the progressi<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> chr<strong>on</strong>ic renal <strong>in</strong>sufficiency. N EnglJ Med. 1996;334:939-945.5. Bakris GL, Copley JB, Vicknair N, Sadler R, LeurgansS. Calcium channel blockers versus other antihypertensivetherapies <strong>on</strong> progressi<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> NIDDM associatednephropathy. Kidney Int. 1996;50:1641-1650.6. Randomised placebo-c<strong>on</strong>trolled trial <str<strong>on</strong>g>of</str<strong>on</strong>g> effect <str<strong>on</strong>g>of</str<strong>on</strong>g>ramipril <strong>on</strong> decl<strong>in</strong>e <strong>in</strong> glomerular filtrati<strong>on</strong> rate and risk<str<strong>on</strong>g>of</str<strong>on</strong>g> term<strong>in</strong>al renal failure <strong>in</strong> prote<strong>in</strong>uric, n<strong>on</strong>-diabeticnephropathy. The GISEN Group (Gruppo Italiano diStudi Epidemiologici <strong>in</strong> Nefrologia). Lancet. 1997;349:1857-1863.7. Perna A, Remuzzi G. Abnormal permeability to prote<strong>in</strong>sand glomerular lesi<strong>on</strong>s: a meta-analysis <str<strong>on</strong>g>of</str<strong>on</strong>g> experimentaland human studies. Am J Kidney Dis. 1996;27:34-41.8. Rahman M, Douglas JG, Wright JT. Pathophysiologyand treatment implicati<strong>on</strong>s <str<strong>on</strong>g>of</str<strong>on</strong>g> hypertensi<strong>on</strong> <strong>in</strong>the African-American populati<strong>on</strong>. Endocr<strong>in</strong>ol MetabCl<strong>in</strong> North Am. 1997;26:125-144.9. Weir MR, Dwork<strong>in</strong> LD. Antihypertensive drugs, dietarysalt, and renal protecti<strong>on</strong>: how low should yougo and with which therapy? Am J Kidney Dis. 1998;32:1-22.10. Koshy S, Bakris GL. Therapeutic approaches toachieve desired blood pressure goals: focus <strong>on</strong> calciumchannel blockers. Cardiovasc Drugs Ther. 2000;14:295-301.11. Dwork<strong>in</strong> LD, Fe<strong>in</strong>er HD, Parker M, Tolbert E. <str<strong>on</strong>g>Effect</str<strong>on</strong>g>s<str<strong>on</strong>g>of</str<strong>on</strong>g> nifedip<strong>in</strong>e and enalapril <strong>on</strong> glomerular structureand functi<strong>on</strong> <strong>in</strong> un<strong>in</strong>ephrectomized SHR. KidneyInt. 1991;39:1112-1117.12. Dwork<strong>in</strong> LD, Benste<strong>in</strong> JA, Parker M, Tolbert E,Fe<strong>in</strong>er HD. Calcium antag<strong>on</strong>ists and c<strong>on</strong>vert<strong>in</strong>g enzyme<strong>in</strong>hibitors reduce renal <strong>in</strong>jury by different mechanisms.Kidney Int. 1993;43:808-814.13. Bakris GL, Mangrum A, Copley JB, Vicknair N,Sadler R. <str<strong>on</strong>g>Effect</str<strong>on</strong>g> <str<strong>on</strong>g>of</str<strong>on</strong>g> calcium channel or beta-blockade<strong>on</strong> the progressi<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> diabetic nephropathy <strong>in</strong> AfricanAmericans. Hypertensi<strong>on</strong>. 1997;29:744-750.14. Ruggenenti P, Perna A, Ben<strong>in</strong>i R, Remuzzi G. <str<strong>on</strong>g>Effect</str<strong>on</strong>g>s<str<strong>on</strong>g>of</str<strong>on</strong>g> dihydropyrid<strong>in</strong>e calcium channel blockers, angiotens<strong>in</strong>-c<strong>on</strong>vert<strong>in</strong>genzyme <strong>in</strong>hibiti<strong>on</strong>, and bloodpressure c<strong>on</strong>trol <strong>on</strong> chr<strong>on</strong>ic, n<strong>on</strong>diabetic nephropathies.Gruppo Italiano di Studi Epidemiologici <strong>in</strong> Nefrologia(GISEN). J Am Soc Nephrol. 1998;9:2096-2101.15. Tarif N, Bakris GL. Preservati<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> renal functi<strong>on</strong>:the spectrum <str<strong>on</strong>g>of</str<strong>on</strong>g> effects by calcium-channelblockers. Nephrol Dial Transplant. 1997;12:2244-2250.16. Guasch A, Parham M, Zayas CF, Campbell O,Nzerue C, Mac<strong>on</strong> E. C<strong>on</strong>trast<strong>in</strong>g effects <str<strong>on</strong>g>of</str<strong>on</strong>g> calciumchannel blockade versus c<strong>on</strong>vert<strong>in</strong>g enzyme <strong>in</strong>hibiti<strong>on</strong><strong>on</strong> prote<strong>in</strong>uria <strong>in</strong> African Americans with n<strong>on</strong><strong>in</strong>sul<strong>in</strong>-dependentdiabetes mellitus and nephropathy.J Am Soc Nephrol. 1997;8:793-798.17. Wright JT Jr, Kusek JW, Toto RD, et al. Design©2001 American Medical Associati<strong>on</strong>. All rights reserved. (Repr<strong>in</strong>ted) JAMA, June 6, 2001—Vol 285, No. 21 2727Downloaded from www.jama.com at Medical Library <str<strong>on</strong>g>of</str<strong>on</strong>g> the PLA, <strong>on</strong> August 9, 2007
RAMIPRIL VS AMLODIPINE AND HYPERTENSIVE RENAL DISEASEand basel<strong>in</strong>e characteristics <str<strong>on</strong>g>of</str<strong>on</strong>g> participants <strong>in</strong> the AfricanAmerican Study <str<strong>on</strong>g>of</str<strong>on</strong>g> Kidney Disease and Hypertensi<strong>on</strong>(AASK) Pilot Study. C<strong>on</strong>trol Cl<strong>in</strong> Trials. 1996;17(4 suppl):3S-16S.18. Hall WD, Kusek JW, Kirk KA, et al. Short-term effects<str<strong>on</strong>g>of</str<strong>on</strong>g> blood pressure c<strong>on</strong>trol and antihypertensivedrug regimen <strong>on</strong> glomerular filtrati<strong>on</strong> rate: the African-American Study <str<strong>on</strong>g>of</str<strong>on</strong>g> Kidney Disease and Hypertensi<strong>on</strong>Pilot Study. Am J Kidney Dis. 1997;29:720-728.19. Perl<str<strong>on</strong>g>of</str<strong>on</strong>g>f D, Grim C, Flack J, et al. Human blood pressuredeterm<strong>in</strong>ati<strong>on</strong> by sphygmomanometry. Circulati<strong>on</strong>.1993;88(5 pt 1):2460-2470.20. Coresh J, Toto RD, Kirk KA, et al. Creat<strong>in</strong><strong>in</strong>e clearanceas a measure <str<strong>on</strong>g>of</str<strong>on</strong>g> GFR <strong>in</strong> screenees for the African-American Study <str<strong>on</strong>g>of</str<strong>on</strong>g> Kidney Disease and Hypertensi<strong>on</strong> pilotstudy. Am J Kidney Dis. 1998;32:32-42.21. De Cesaris R, Ranieri G, Filitti V, Andriani A, B<strong>on</strong>fant<strong>in</strong>oMV. <str<strong>on</strong>g>Effect</str<strong>on</strong>g>s <str<strong>on</strong>g>of</str<strong>on</strong>g> atenolol and enalapril <strong>on</strong> kidneyfuncti<strong>on</strong> <strong>in</strong> hypertensive diabetic patients. J CardiovascPharmacol. 1993;22:208-214.22. ter Wee PM, De Micheli AG, Epste<strong>in</strong> M. <str<strong>on</strong>g>Effect</str<strong>on</strong>g>s<str<strong>on</strong>g>of</str<strong>on</strong>g> calcium antag<strong>on</strong>ists <strong>on</strong> renal hemodynamics andprogressi<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> n<strong>on</strong>diabetic chr<strong>on</strong>ic renal disease. ArchIntern Med. 1994;154:1185-1202.23. Bakris GL, Weir MR. Angiotens<strong>in</strong>-c<strong>on</strong>vert<strong>in</strong>g enzyme<strong>in</strong>hibitor-associated elevati<strong>on</strong>s <strong>in</strong> serum creat<strong>in</strong><strong>in</strong>e:is this a cause for c<strong>on</strong>cern? Arch Intern Med.2000;160:685-693.24. Short-term effects <str<strong>on</strong>g>of</str<strong>on</strong>g> prote<strong>in</strong> <strong>in</strong>take, bloodpressure, and antihypertensive therapy <strong>on</strong> glomerularfiltrati<strong>on</strong> rate <strong>in</strong> the Modificati<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> Diet <strong>in</strong> <strong>Renal</strong>Disease Study. J Am Soc Nephrol. 1996;7:2097-2109.25. Ruggenenti P, Perna A, Gherardi G, et al. Renoprotectiveproperties <str<strong>on</strong>g>of</str<strong>on</strong>g> ACE-<strong>in</strong>hibiti<strong>on</strong> <strong>in</strong> n<strong>on</strong>diabeticnephropathies with n<strong>on</strong>-nephrotic prote<strong>in</strong>uria.Lancet. 1999;354:359-364.26. O’Brien PC, Flem<strong>in</strong>g TR. A multiple test<strong>in</strong>g procedurefor cl<strong>in</strong>ical trials. Biometrics. 1979;35:549-556.27. Keane WF, Eknoyan G. Prote<strong>in</strong>uria, album<strong>in</strong>uria,risk, assessment, detecti<strong>on</strong>, elim<strong>in</strong>ati<strong>on</strong> (PARADE):a positi<strong>on</strong> paper <str<strong>on</strong>g>of</str<strong>on</strong>g> the Nati<strong>on</strong>al Kidney Foundati<strong>on</strong>.Am J Kidney Dis. 1999;33:1004-1010.28. Kloke HJ, Branten AJ, Huysmans FT, Wetzels JF.Antihypertensive treatment <str<strong>on</strong>g>of</str<strong>on</strong>g> patients with prote<strong>in</strong>uricrenal diseases: risks or benefits <str<strong>on</strong>g>of</str<strong>on</strong>g> calcium channelblockers? Kidney Int. 1998;53:1559-1573.29. Jafar T, Schmid C, Landa M, et al. The effect <str<strong>on</strong>g>of</str<strong>on</strong>g>angiotens<strong>in</strong>-c<strong>on</strong>vert<strong>in</strong>g-enzyme <strong>in</strong>hibitors <strong>on</strong> the progressi<strong>on</strong><str<strong>on</strong>g>of</str<strong>on</strong>g> n<strong>on</strong>-diabetic renal disease: a pooled analysis<str<strong>on</strong>g>of</str<strong>on</strong>g> <strong>in</strong>dividual patient data from 11 randomized c<strong>on</strong>trolledtrials. Ann Intern Med. In press.30. Anders<strong>on</strong> S. <strong>Renal</strong> hemodynamic effects <str<strong>on</strong>g>of</str<strong>on</strong>g> calciumantag<strong>on</strong>ists <strong>in</strong> rats with reduced renal mass. Hypertensi<strong>on</strong>.1991;17:288-295.31. Griff<strong>in</strong> KA, Picken MM, Bakris GL, Bidani AK. Classdifferences <strong>in</strong> the effects <str<strong>on</strong>g>of</str<strong>on</strong>g> calcium channel blockers<strong>in</strong> the rat remnant kidney model. Kidney Int. 1999;55:1849-1860.32. Kvam FI, Ofstad J, Iversen BM. <str<strong>on</strong>g>Effect</str<strong>on</strong>g>s <str<strong>on</strong>g>of</str<strong>on</strong>g> antihypertensivedrugs <strong>on</strong> autoregulati<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> RBF and glomerularcapillary pressure <strong>in</strong> SHR. Am J Physiol. 1998;275(pt 2):F576-F584.33. Mimran A, Insua A, Ribste<strong>in</strong> J, Br<strong>in</strong>ger J, M<strong>on</strong>nierL. Comparative effect <str<strong>on</strong>g>of</str<strong>on</strong>g> captopril and nifedip<strong>in</strong>e<strong>in</strong> normotensive patients with <strong>in</strong>cipientdiabetic nephropathy. Diabetes Care. 1988;11:850-853.34. Demarie BK, Bakris GL. <str<strong>on</strong>g>Effect</str<strong>on</strong>g>s <str<strong>on</strong>g>of</str<strong>on</strong>g> different calciumantag<strong>on</strong>ists <strong>on</strong> prote<strong>in</strong>uria associated with diabetesmellitus. Ann Intern Med. 1990;113:987-988.35. Little RJA, Rub<strong>in</strong> DB. Statistical Analysis WithMiss<strong>in</strong>g Data. New York, NY: John Wiley & S<strong>on</strong>s Inc;1987.36. Schluchter M, Greene T, Beck G. Analysis <str<strong>on</strong>g>of</str<strong>on</strong>g>change <strong>in</strong> the presence <str<strong>on</strong>g>of</str<strong>on</strong>g> <strong>in</strong>formative censor<strong>in</strong>g: Applicati<strong>on</strong>to to l<strong>on</strong>gitud<strong>in</strong>al cl<strong>in</strong>ical trial <str<strong>on</strong>g>of</str<strong>on</strong>g> progressiverenal disease. Stat Med. 2001;20:989-1007.37. Staessen JA, Fagard R, Thijs L, et al. Randomiseddouble-bl<strong>in</strong>d comparis<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> placebo and active treatmentfor older patients with isolated systolic hypertensi<strong>on</strong>.Lancet. 1997;350:757-764.38. Wang JG, Liu G, Wang X, et al. L<strong>on</strong>g-term bloodpressure c<strong>on</strong>trol <strong>in</strong> older Ch<strong>in</strong>ese patients with isolatedsystolic hypertensi<strong>on</strong>: a progress report <strong>on</strong> theSyst-Ch<strong>in</strong>a trial. J Hum Hypertens. 1996;10:735-742.39. Hanss<strong>on</strong> L, L<strong>in</strong>holm LH, Niskanen L, et al. <str<strong>on</strong>g>Effect</str<strong>on</strong>g><str<strong>on</strong>g>of</str<strong>on</strong>g> angiotens<strong>in</strong>-c<strong>on</strong>vert<strong>in</strong>g-enzyme <strong>in</strong>hibiti<strong>on</strong> comparedwith c<strong>on</strong>venti<strong>on</strong>al therapy <strong>on</strong> cardiovascularmorbidity and mortality <strong>in</strong> hypertensi<strong>on</strong>: the CaptoprilPreventi<strong>on</strong> Project (CAPPP) randomized trial. Lancet.1999;353:611-616.40. Neal B, MacMah<strong>on</strong> S, Chapman N. <str<strong>on</strong>g>Effect</str<strong>on</strong>g>s <str<strong>on</strong>g>of</str<strong>on</strong>g> ACE<strong>in</strong>hibitors, calcium antag<strong>on</strong>ists, and other blood- pressure-lower<strong>in</strong>gdrugs: results <str<strong>on</strong>g>of</str<strong>on</strong>g> prospectively designedoverviews <str<strong>on</strong>g>of</str<strong>on</strong>g> randomised trials. Blood PressureLower<strong>in</strong>g Treatment Trialists’ Collaborati<strong>on</strong>.Lancet. 2000;356:1955-1964.F<strong>in</strong>ancial Disclosures: The follow<strong>in</strong>g authors have received h<strong>on</strong>oraria for serv<strong>in</strong>g as a speaker for pharmaceutical companies: DeAnna Cheek (Pfizer); William Cleveland(Pfizer); Janice G. Douglas (Solvay, Novartis, BMS, AstraZeneca, Pfizer, K<strong>in</strong>g/M<strong>on</strong>arch); Lee Hebert (BMS, AstraZeneca, Amgen, Abbott); Kenneth Jamers<strong>on</strong>(AstraZeneca, Pfizer, Merck, Solvay, Pharmacia, Novartis); Joel Kopple (Sigma-Tau, OrthoBiotech, Baxter); James Lash (Amgen); Janice Lea (Merck, M<strong>on</strong>arch, Pfizer,OrthoBiotech); Julia A. Lewis (Pfizer, AstraZeneca, Bristol-Meyers Squibb, Parke-Davis, Merck, Novartis, San<str<strong>on</strong>g>of</str<strong>on</strong>g>i W<strong>in</strong>throp); Shaul Massry (Solvay, Servier Amerique,H<str<strong>on</strong>g>of</str<strong>on</strong>g>fman LaRoche); John Middlet<strong>on</strong> (Merck, Pfizer); Keith Norris (B<strong>on</strong>e Care Internati<strong>on</strong>al, Abbott, Genzyme, Amgen); Daniel O’C<strong>on</strong>nor (Meri<strong>on</strong> Merrell Dow,AstraZeneca); Ak<strong>in</strong>lou Ojo(AstraZeneca, Merck, Pfizer, Pharmacia, Searle); Robert A. Phillips (Pfizer, Merck, AstraZeneca, BMS, Solvay); Velvie Pogue (Pfizer, Astra-Zeneca, Merck); Mahboob Rahman (Abbott, Solvay); Otelio Randall (Merck, Pfizer, Boehr<strong>in</strong>ger Ingelheim, Solvay); Stephen Rostand (Pfizer); C. Craig Tisher (Pfizer);Robert D. Toto (Merck, Pfizer, AstraZeneca, Solvay, Bristol-Myers Squibb, Amgen, Ortho Biotech, Boehr<strong>in</strong>ger Ingelheim, Searle, Novartis, Sandoz); Jacks<strong>on</strong> T. Wright(AstraZenca, Aventis, Bristol-Myers Squibb, K<strong>in</strong>g/M<strong>on</strong>arch, Merck, Novartis, Pfizer, Searle, Unimed, Forest Labs).The follow<strong>in</strong>g authors have received fund<strong>in</strong>g/grants for research projects from pharmaceutical companies: Lawrence Appel (Merck); George L. Bakris (Aventis, Alte<strong>on</strong>,AstraZeneca, Boehr<strong>in</strong>ger-Igelheim, Bristol-Myers Squibb, Forest Labs, Glaxo-Smith Kl<strong>in</strong>e, Merck, M<strong>on</strong>arch/K<strong>in</strong>g, Novartis, Pfizer, Sanyo); Jacques Bourgoignie (Pfizer);Joseph<strong>in</strong>e P. Briggs (Warner-Lambert); DeAnna Cheek (Pfizer, Solvay, Bayer); William Cleveland (Pfizer, Amgen); Janice G. Douglas (Merck, Glaxo-Smith Kl<strong>in</strong>e);Margaret Douglas (Novartis); Jennifer Gassman (Baxter Healthcare); Tom Greene (Baxter Healthcare); Kenneth Jamers<strong>on</strong> (AstraZeneca, Novartis); Joel Kopple (Sigma-Tau, Baxter Healthcare); James Lash (Merck); Shaul Massry (Pfizer, Servier Amerique, H<str<strong>on</strong>g>of</str<strong>on</strong>g>fman LaRoche, Abbott, Amgen); Julia A. Lewis (Bristol-Meyers Squibb, SciosNova); John Middlet<strong>on</strong> (Bristol-Myers Squibb, Amgen); Keith Norris (Bristol-Myers Squibb, Searle, Merck); Daniel O’C<strong>on</strong>nor (Serle/Pharmacia, Bristol-Myers Squibb);Robert A. Phillips (Pfizer, Merck, Solvay, AstraZeneca, BMS); Velvie Pogue (Amgen, Bayer, Parke-Davis); Mahboob Rahman (AstraZeneca, Eli Lilly); Otelio Randall(Merck); Stephen Rostand (Abbott, Pfizer); Gerald Shulman (Geltex, Genzyme, Bayer, Amgen, Ortho Pharmaceuticals, Bristol-Myers Squibb); W<strong>in</strong>ifred Smith (Amgen,Pfizer); Denyse Thornley-Brown (OrthoBiotech); Robert D. Toto (Merck, Searle, Amgen, Fujisawa, Luitpold, Bristol-Myers Squibb); Jacks<strong>on</strong> T. Wright (AstraZenca,Aventis, Bristol-Myers Squibb, Eli Lilly, Forest Labs, H<str<strong>on</strong>g>of</str<strong>on</strong>g>fman LaRoche, Merck, Novartis, Pfizer, Searle, Unimed). Michael Lipkowitz (K<strong>in</strong>g/M<strong>on</strong>arch);The follow<strong>in</strong>g authors have served as a c<strong>on</strong>sultant/advisory panel for pharmaceutical companies: George L. Bakris (Aventis, Alte<strong>on</strong>, AstraZeneca, Boehr<strong>in</strong>ger-Igelheim, Bristol-Myers Squibb, Forest Labs, Glaxo-Smith Kl<strong>in</strong>e, Merck, M<strong>on</strong>arch/K<strong>in</strong>g, Novartis, Pfizer, Sanyo); Janice G. Douglas (Merck, Aventis, Novartis); LeeHebert (Abbott); Kenneth Jamers<strong>on</strong> (Solvay, Pfizer); Joel Kopple (Sigma-Tau, Baxter); Shaul Massry (Pfizer, Abbott, Genzyme, Servier Amerique); Keith Norris (B<strong>on</strong>eCare Internati<strong>on</strong>al, Amgen); Ak<strong>in</strong>lou Ojo (Novartis); Otelio Randall (Merck, Pfizer, Novartis, Solvay); Gerald Shulman (Kureha, Sanyo); Robert D. Toto (Amgen); Jacks<strong>on</strong>T. Wright (Aventis, Bristol-Myers Squibb, Boehr<strong>in</strong>ger Ingelheim).The follow<strong>in</strong>g authors own stock or have stock opti<strong>on</strong>s <strong>in</strong> pharmaceutical companies: Gerald Beck (Eli Lilly, Pfizer, Amgen); William Cleveland (Pfizer, Merck); MarquettaFaulkner (Amgen); Lee Hebert (Baxter, Bristol-Myers Squibb); Kenneth Jamers<strong>on</strong> (Bristol-Myers Squibb); John Middlet<strong>on</strong> (Amgen); Keith Norris (Medimmune);Stephen Rostand (Pfizer, Merck); Gerald Shulman (Bristol-Myers, Squibb); C.Craig Tisher (Merck, Pharmacia); Robert D. Toto (Amgen).The follow<strong>in</strong>g author has provided expert testim<strong>on</strong>y for pharmaceutical companies: Joel Kopple (Baxter Healthcare, Sigma-Tau).N<strong>on</strong>e <str<strong>on</strong>g>of</str<strong>on</strong>g> the authors owns a patent related to any <str<strong>on</strong>g>of</str<strong>on</strong>g> the antihypertensives <strong>in</strong> the study or has received royalties from any company.2728 JAMA, June 6, 2001—Vol 285, No. 21 (Repr<strong>in</strong>ted) ©2001 American Medical Associati<strong>on</strong>. All rights reserved.Downloaded from www.jama.com at Medical Library <str<strong>on</strong>g>of</str<strong>on</strong>g> the PLA, <strong>on</strong> August 9, 2007