The prevalence and cost of chronic kidney disease (CKD) among adults in the United States has continued to increase, and black persons with hypertension have been disproportionately affected compared with whites. Because the relationship between blood pressure (BP) and the progression of CKD is linear, the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) and other guideline committees recommended a more aggressive target, <130/80 mm Hg, for BP control in patients with CKD. This recommendation, however, is based mostly on observational data, with little clinical trial evidence from prospective randomized, controlled studies to support it.
The African American Study of Kidney Disease and Hypertension (AASK) evaluated the effects of intensive vs traditional targets for BP on CKD progression among African Americans with nondiabetic CKD and hypertension. At baseline, all patients in AASK were self-described African Americans aged between 18 and 70 years with a diastolic BP >95 mm Hg and a glomerular filtration rate (GFR) of 20 to 65 mL/min. Major exclusion criteria included diabetes, a urinary protein to creatinine ratio (UP/Cr) >2.5, malignant hypertension during the previous 6 months, secondary hypertension, serious systemic disease, heart failure, or a specific indication for, or contraindication to, a study medication. The study was conducted in two phases. The initial trial phase, previously published (JAMA. 2002;288:2421–2431), consisted of a prospective, randomized clinical trial with a 3×2 factorial design, which was followed by a nonrandomized observational cohort phase (the subject of the present paper). In the initial trial phase, 1094 patients between February 1995 and September 1998 were randomized to receive either intensive BP control (mean arterial pressure [MAP] <92 mm Hg, roughly corresponding to BP <130/80 mm Hg) or standard BP control (MAP, 102–107 mm Hg, roughly corresponding to BP 140/90 mm Hg). Within both BP target groups, patients were randomly assigned to 1 of 3 initial drug therapies: ramipril, an angiotensin-converting enzyme (ACE) inhibitor; metoprolol succinate, a sustained-release β-blocker; or amlodipine, a dihydropyridine calcium channel blocker (CCB). If the BP target was not achieved with the initial medication, other antihypertensive medications, including furosemide, doxazosin, clonidine, hydralazine, and minoxidil, were sequentially added. At the end of the initial randomized trial phase, all patients who had not experienced the primary CKD end point were invited to enroll in an observational cohort phase. Initiated in April 2002, all patients in the cohort phase were switched from their original blinded randomized therapy to open-label ramipril. If ramipril was not tolerated, the patient was switched to an angiotensin receptor blocker (ARB) selected by the clinical site investigator. Once again, as in the trial phase, if the BP target was not achieved with the highest-tolerated dose of ramipril, other medications, including furosemide, β-blockers, CCBs, centrally acting α-adrenergic blockers, and direct-acting vasodilators were added as needed to the regimen. At the start of the cohort phase, the BP target for all patients was <140/90 mm Hg; however, the target was subsequently lowered to <130/80 mm Hg in 2004 after the publication of JNC 7.
Both the initial trial and follow-up cohort phase had the same primary end point, a composite of death, a doubling of the serum creatinine level, or a diagnosis of end-stage renal disease (ESRD), defined as initiation of dialysis or kidney transplant. Based on evidence from other studies showing a beneficial effect of ACE inhibitors on the level of protein excretion and renal disease progression and a deleterious effect of dihydropyridine CCBs on the same two aspects of renal disease, the steering committee (blinded to the AASK data) requested that the Data Safety Monitoring Board be provided with information on the levels of proteinuria in the ramipril and amlodipine-treated patients during the initial trial phase, as an extension of the original primary comparison. They found a significant relationship between baseline proteinuria and the short-term and total mean GFR slopes. Therefore, a subgroup analysis was performed in trial-phase patients with baseline UP/Cr >0.22 (one third of participants, accounting for two thirds of all events) and <0.22 (two thirds of participants, accounting for one third of the events). The UP/Cr cut point of 0.22, corresponding to 300 mg/d of urinary protein, was therefore selected post hoc, independent of the original AASK protocol. Accordingly, as in the trial phase, a post hoc prespecified stratified analysis was performed during the cohort phase of the trial based on the presence or absence of clinical proteinuria (above or below baseline protein to creatinine ratio >0.22).
At baseline, the mean BP in the 1094 trial-phase patients was 150/95 mm Hg. Throughout the 4.1 mean years of follow-up in the initial trial phase, the mean BP was significantly lower in the intensive control group (130/78 mm Hg) as compared with the standard control group (142/86 mm Hg). During the 8 mean years of follow-up in the cohort phase, since all patients had a common target BP of <130/80 mm Hg, the difference was smaller (131/78 mm Hg in the intensively treated group vs 134/78 mm Hg in the standard group). Throughout the entire study, ACE inhibitor and ARB use was similar in both BP target groups.
Among all patients across both phases of the study, there was no significant difference between the intensive and standard BP control groups in the incidence of the primary end point (hazard ratio [HR], 0.91; 95% confidence interval [CI], 0.77–1.08; P=.27) or any secondary end point. However, the effects of the randomized BP target significantly differed according to the baseline protein to creatinine ratio (P=.02 for interaction). Among patients with a baseline protein to creatinine ratio <0.22, there was no difference in the primary end point across the entire study (HR, 1.18; 95% CI, 0.93–1.50; P=.16) and an inconsistent pattern for the outcome of a doubling of the serum creatinine or ESRD (HR, 1.39; 95% CI, 1.04–1.87; P=.03) and the outcome of ESRD or death (HR, 1.12; 95% CI, 0.87–1.45; P=.39). However, among patients with a baseline protein to creatinine ratio >0.22, those in the intensive-control group had a significant reduction in the risk of the primary end point (HR, 0.73; 95% CI, 0.58–0.93; P=.001) as well as the two secondary outcomes: a doubling of the serum creatinine or ESRD (HR, 0.76; 95% CI, 0.58–0.99; P=.04) and ESRD or death (HR, 0.67; 95% CI, 0.52–0.87; P=.002). Furthermore, the beneficial effect in the clinical proteinuria subgroup only reached clinical significance during the cohort follow-up phase of the study. Finally, during the entire course of the trial, while the rate of the composite end point remained similar in the two BP groups (about 7 events per 100 person-years), the overall incidence of the primary end point was nearly 3 times higher in those with, as compared with those without, proteinuria.
Overall, the AASK data do not support the guideline recommendation that a target BP of <130/80 mm Hg prevents progression of nondiabetic hypertensive renal disease in all patients. However, there may be differential effects based on baseline level of proteinuria, whereby more intensive BP reduction is of greater benefit in patients with significant proteinuria. Since this finding was largely based on observational subgroup analysis, further research is needed to clarify this issue.—Appel LJ, Wright JT, Green T, et al; for the AASK Collaborative Research Group. Intensive blood-pressure control in hypertensive chronic kidney disease. N Engl J Med. 2010;363:918–929.