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(Accessed July 28, 2010, at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071612.pdf.)

European Medicines Agency recommends suspension of7.marketing authorization for sibutramine. Press release of the

European Medicines Agency, January 22, 2010. (Accessed July28, 2010, at http://www.ema.europa.eu/pdfs/human/referral/sibutramine/3940810en.pdf.)Copyright 2010 Massachusetts Medical Society.

Hypertension Control in African-American Patients

with Chronic Kidney DiseaseJulie R. Ingelfinger, M.D.

The risks of renal and cardiovascular disease conditions that are often associated with long-standing hypertension are far higher amongpeople of African-American heritage than amongthose in other racial or ethnic groups. The African-American Study of Kidney Disease and Hyperten-sion (AASK)1 is an important long-term study thatcompared standard with intensive therapy for hy-pertension among 1094 black patients with chron-

ic kidney disease, defined as a glomerular f iltra-tion rate (GFR) of 20 to 65 ml per minute per1.73 m2 of body-surface area. The study was con-ducted in a trial phase, followed by an observa-tional cohort phase. The primary clinical outcomewas the progression of chronic kidney disease.

The trial phase had a three-by-two factorialdesign in which intensive blood-pressure control(target mean arterial pressure, 92 mm Hg) wascompared with standard control (target meanarterial pressure, 102 to 107 mm Hg) and threemedications were compared: an angiotensin-convertingenzyme (ACE) inhibitor (ramipril), acalcium-channel blocker (amlodipine), and a long-acting beta-blocker (metoprolol). In this phase,intensive blood-pressure control did not slowthe progression of chronic kidney disease, as de-fined by a clinical composite outcome of a reduc-tion in the GFR of 50% or more (or 25 ml perminute per 1.73 m2) from baseline, end-stagerenal disease (ESRD), or death.1 However, patientsin the intensive-control group who received ini-tial therapy with an ACE inhibitor (as compared

with the two other medications) had a slowerdecline in the GFR. At the end of the trial(mean, 4.1 years), all patients who had not reachedESRD, regardless of their original study-groupassignment, were invited to enroll in the cohortphase of the study, during which the blood pres-sure target was less than 130/80 mm Hg, reflect-ing current recommendations2; 87% of eligiblepatients enrolled in the cohort phase.

In this issue of the Journal, Appel et al.3 re-port the results of the cohort phase. At a mean

of 12.2 years of follow-up, there was no signifi-cant difference in the progression of chronickidney disease between patients who had beenassigned to the intensive-control group duringthe trial phase and those who had been assignedto the standard-control group.

To understand the implications of the AASKresults, we need to consider the characteristicsof the patients who were enrolled in the two

phases. To enter the trial, patients needed tohave mild-to-moderate chronic kidney diseasewithout marked proteinuria; a renal biopsy wasnot required, although almost all of a subgroupof patients who underwent biopsy in the trialphase had renal vascular lesions, a finding thatsupports a diagnosis of hypertensive nephro-sclerosis.4 The age range at trial entry was broad(18 to 70 years), and African-American heritagewas self-reported. Thus, the patient group washeterogeneous. Patients who continued in thecohort phase tended to have less proteinuria atbaseline than those who did not continue (meanurinary protein-to-creatinine ratio at trial entry,0.19 and 0.55, respectively). At the time thecohort study began, the mean urinary protein-to-creatinine ratio was 0.38, indicating pro-gression in proteinuria, even among those con-tinuing in the cohort phase. Similarly, the GFRhad decreased in many patients. These changesover time are consistent with the increasing ageof the patients and the development of other con-ditions, such as diabetes and atherosclerosis.

At the end of the trial phase, the mean bloodpressure was 130/78 mm Hg in patients in theintensive-control group and 142/86 mm Hg inthe standard-control group. At the end of thecohort phase, the mean blood pressure levelswere 131/78 mm Hg and 134/78 mm Hg, respec-tively. Few patients in either study group hadpoorly controlled blood pressure. Whereas therewas no overall between-group difference in therate of disease progression, secondary analysesthat were stratif ied on the basis of clinically im-

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portant proteinuria showed different effectsaccording to the level of baseline proteinuria(P = 0.02 for interaction). Patients who had aninitial urinary protein-to-creatinine ratio above0.22 benefited from initial intensive therapy bythe end of the cohort phase (hazard ratio, 0.73;P = 0.01). In contrast, patients with a lower ini-

tial urinary protein-to-creatinine ratio appearednot to benefit (hazard ratio associated with in-tensive control, 1.18; P = 0.16).

What might explain these findings? The pa-tients with a higher protein-to-creatinine ratiowere somewhat younger, and one might specu-late that they had less vascular disease and lessinflammation and thus could benefit from blood-pressure control. The stratification of patientsaccording to the presence or absence of baselineproteinuria occurred shortly after the trial phasebegan, although before any data were available.

On the basis of study findings that were pub-lished during the early phases of AASK indicat-ing that baseline proteinuria had predictive val-ue,5 the investigators asked the data and safetymonitoring board to look at the presence or ab-sence of baseline proteinuria on 24-hour urinesamples among patients enrolled in AASK. Asthe authors state, in post hoc analyses, the in-vestigators, in concert with the data and safetymonitoring board, chose a cutoff protein-to-cre-atinine ratio of 0.22, a value that is compatiblewith a widely accepted threshold for proteinuriaof 300 mg per day.

Other studies support the concept that base-line proteinuria predicts progression of chronickidney disease and may predict benefit fromtreatment. In the Modification of Diet in RenalDisease (MDRD) trial,5 an intensive blood-pres-sure target, as compared with a standard target,did not affect the progression of kidney diseaseduring a 3-year period, as measured by the esti-mated GFR. Furthermore, a lower blood-pres-sure goal appeared to benefit patients with more

than 1 g of baseline proteinuria. However, in theMDRD trial, more patients in the intensive-con-trol group than in the standard-control groupwere taking ACE inhibitors, which could haveexplained the apparent benefit.5 In the recentEffect of Strict Blood Pressure Control and ACEInhibition on the Progression of CRF (ChronicRenal Failure) in Pediatric Patients (ESCAPE) trial(ClinicalTrials.gov number, NCT00221845), inten-sive blood-pressure control with a fixed dose ofan ACE inhibitor significantly slowed the pro-

gression of renal disease, and effects were larg-est among patients with substantial baseline pro-teinuria and hypertension and a reduced GFR.6In addition, a recent study involving Italianadults with idiopathic glomerular diseases asso-ciated with hypertension and proteinuria showeda benefit from intensive control.7 In the ACE In-

hibition in Progressive Renal Disease (AIPRD)study, which examined data on patients withoutdiabetes from 11 randomized trials of ACE in-hibitors, patients receiving ACE inhibitors hadbetter blood-pressure control, less proteinuria,and a significantly lower risk of kidney failurethan those who were not receiving ACE inhibi-tors.8 Thus, the concept of intensive control hassome data to support it and has been the basisof current guidelines of the National KidneyFoundations Kidney Disease Outcomes QualityInitiative for a blood-pressure target of under

130/80 mm Hg in patients who have chronickidney disease without diabetes.9

What about people at risk in the community?In an analysis of results of the Kidney EarlyEvaluation Program (KEEP), which screens adultsin the community who may be at risk for chronickidney disease, more black persons and those inother minority groups had prevalent albuminu-ria than did non-Hispanic whites.10 Furthermore,blood pressure was poorly controlled amongKEEP subjects, particularly among black men.The AASK cohort study clearly shows that targetblood-pressure levels are achievable in this pop-ulation, even though the primary outcome ofthe study was negative. However, given the im-portance of proteinuria as a predictor of pro-gression, this study lends hope to the conceptthat intensive treatment will improve renal out-comes in black patients with hypertension,chronic kidney disease, and microalbuminuria.

Disclosure forms provided by the author are available with thefull text of this article at NEJM.org.

Wright JT Jr, Bakris G, Greene T, et al. Effect of blood pres-1.

sure lowering and antihyper tensive drug class on progression ofhypertensive kidney disease: results from the AASK trial. JAMA2002;288:2421-31. [Erratum, JAMA 2006;295:2726.]

Chobanian AV, Bakris GL, Black HR, et al. Seventh report of2.the Joint National Committee on Prevention, Detection, Evalua-tion, and Treatment of High Blood Pressure. Hypertension2003;42:1206-52.

Appel LJ, Wright JT Jr, Greene T, et al. Intensive blood-3.pressure control in hypertensive chronic kidney disease. N EnglJ Med 2010;363:918-29.

Fogo A, Breyer JA, Smith MC, et al. Accuracy of the diagnosis4.of hypertensive nephrosclerosis in African Americans: a reportfrom the African American Study of Kidney Disease (AASK).Kidney Int 1997;51:244-52.




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Peterson JC, Adler S, Burkart JM, et a l. Blood pressure con-5.trol, proteinuria, and the progression of renal disease: the Mod-ification of Diet in Renal Disease Study. Ann Intern Med 1995;123:754-62.

The ESCAPE Trial Group. Strict blood-pressure control and6.progression of renal fai lure in children. N Engl J Med 2009;361:1639-50.

Bianchi S, Bigazzi R, Campese VM. Intensive versus conven-7.tional therapy to slow the progression of idiopathic glomerular

diseases. Am J Kidney Dis 2010;55:671-81.Jafar TH, Stark PC, Schmid CH, et al. Progression of chronic8.kidney disease: the role of blood pressure control, proteinuria,

and angiotensin-converting enzyme inhibition: a patient-levelmeta-analysis. Ann Intern Med 2003;139:244-52.

National Kidney Foundation. K/DOQI clinical practice9.guidelines on hypertension and antihypertensive agents inchronic kidney disease. (Accessed July 27, 2010, at http://www.kidney.org/professionals/kdoqi/guidelines_bp/guide_9.htm.)

Jolly SE, Burrows NR, Chen SC, et al. Racial and ethnic dif-10.ferences in albuminuria in individuals with estimated GFRgreater than 60 mL/min/1.73 m(2): results from the Kidney Early

Evaluation Program (KEEP). Am J Kidney Dis 2010;55:Suppl 2:S15-S22.Copyright 2010 Massachusetts Medical Society.

Fine-Tuning Therapy for Acute Coronary SyndromesValentin Fuster, M.D., Ph.D.

Aspirin and clopidogrel are mainstays of therapyfor patients presenting with an acute coronarysyndrome. National guidelines dictate that at thetime of the patients presentation to an emergency

department, these therapies should be given expe-ditiously, whether or not percutaneous coronaryintervention is planned. In this issue of theJournal,Mehta et al. report on the results of the Clopido-grel and Aspirin Optimal Dose Usage to ReduceRecurrent EventsSeventh Organization to AssessStrategies in Ischemic Syndromes (CURRENTOASIS 7) trial, which evaluated alternative dos-ing regimens for both of these agents.1

In this trial, in contrast to other recent acutecoronary syndrome trials,2,3 patients with anacute coronary syndrome were randomly assignedbefore their planned coronary angiographic as-sessment rather than after it. The trial had a2-by-2 randomized design with comparisons ofdouble-dose clopidogrel (a 600-mg loading doseon day 1 and 150 mg daily for 6 days, followedby 75 mg daily) with standard-dose clopidogrel (a300-mg loading dose, followed by 75 mg daily)and of higher-dose aspirin (300 to 325 mg daily)with lower-dose aspirin (75 to 100 mg daily). At30 days, there were no significant differences inthe primary outcome measure of cardiovascular

death, nonfatal myocardial infarction, or non-fatal stroke in either of the comparisons. Therates of major bleeding were higher in the double-dose clopidogrel group than in the single-doseclopidogrel group. In contrast, only the rates ofminor bleeding were increased in the higher-dose aspirin group as compared with the lower-dose aspirin group. Complete follow-up of pa-tients was outstanding at 99.9%.

On the basis of this robust trial, one couldreadily conclude that no change in practice is

warranted and close the books. However, thereare at least three important insights arisingfrom these data that I believe should guide clin-ical practice in the years to come.

First, when the dosing regimens of aspirinwere evaluated on a riskbenefit basis, the lower-dose regimen emerged the winner, with equiva-lent efficacy but lower rates of minor bleedingthan the higher-dose regimen. The lower rate ofminor bleeding may not impress clinical trial-ists, but it certainly has relevance for our pa-tients and their clinicians. It is time for theproponents of higher-dose aspirin to concededefeat and modify clinical practice.

Second, there were two components of thedouble-dose clopidogrel group: a 600-mg loadingdose (as compared with the standard 300-mgdose) and an additional 6 days of the double doseat 150 mg (as compared with 75 mg) per day. Awell-conducted meta-analysis has demonstratedthat the 600-mg loading dose is effective andsafe, and I concur with many of my colleagueswho have adopted this dosing in clinical prac-tice.4 However, there appears to be no role forthe routine double dosing of clopidogrel in thesubsequent 6 days, particularly in light of thehigher rates of major bleeding. The question of

whether a longer duration of double-dose clo-pidogrel might have proved to be effective wasbeyond the scope of the CURRENTOASIS 7trial, but it is compelling and deserves furtherconsideration. Although promising reductionsin the rate of stent thrombosis were noted, dou-ble-dose clopidogrel did not meet prespecifiedcriteria for superiority in the subgroup of pa-tients who underwent percutaneous coronaryintervention. Clinically significant stent-throm-bosis events leading to cardiovascular death or




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