African American Study of Kidney Disease and Hypertension - AASK

Sep 01, 2010
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
National Institute of Diabetes and Digestive and Kidney Diseases, the National Center on Minority Health and Health Disparities; King Pharmaceuticals provided financial support and donated antihypertensive medications to each clinical center. Pfizer, AstraZeneca, GlaxoSmithKline, Forest Laboratories, Pharmacia, and Upjohn also donated antihypertensive medications
Date Presented:
01/01/2001
Date Published:
01/01/2010
Date Updated:
09/01/2010
Original Posted Date:
09/01/2010
References

Description:

Although the relationship between elevated blood pressure and progression to renal disease is considered causal, very few randomized data have tested the effects of intensive blood pressure control on the progression of renal impairment. The current trial sought to study the effects of an intensive blood pressure target, as compared with a traditional blood-pressure target, on the progression of chronic kidney disease among black patients with hypertensive chronic kidney disease.

Hypothesis:

Intensive blood pressure control would be superior to standard blood pressure control for hypertensive renal disease progression in African Americans.

Study Design

  • Blinded
  • Factorial
  • Parallel
  • Randomized

Patients Screened: 2,802
Patients Enrolled: 1,094
Mean Follow Up: 8.8-12.2 years (amlodipine stopped early)
Mean Patient Age: 54.6 years
Female: 39%

Patient Populations:

  • Self-identified African Americans
  • Ages 18-70 hypertensive
  • Free from diabetes or other major health problems
  • Have hypertensive-related kidney disease (diastolic blood pressure >95 mm Hg) with GFR between 20-65 ml/min per 1.73 m2 and no other identified causes of renal insufficiency

Exclusions:

  • Diastolic blood pressure <95 mm Hg
  • Known history of diabetes mellitus (fasting glucose ≥140 mg/dl [≥7.8 mmol/L] or random glucose >200 mg/dl [>11.1 mmol/L])
  • Urinary protein-to-creatinine ratio >2.5
  • Accelerated or malignant hypertension within 6 months
  • Secondary hypertension
  • Evidence of nonblood pressure-related causes of renal disease
  • Serious systemic disease
  • Clinical congestive heart failure
  • Specific indication for or contraindication to a study drug or study procedure

Primary Endpoints:

  • Progression of chronic kidney diseaseD, defined as a doubling of creatinine, a diagnosis of ESRD, or death

Secondary Endpoints:

  • Doubling of creatinine (reduction in GFR of more than 50%)
  • ESRD
  • Death

Drug/Procedures Used:

The AASK study had two phases: an initial randomized trial phase, followed by a cohort phase. The trial phase of AASK had a 3 x 2 factorial design. The blood pressure target was a mean arterial pressure of 92 mm Hg or less in the intensive-control group and 102-107 mm Hg in the standard-control group. Participants were also randomly assigned to receive amlodipine, 5-10 mg/day; ramipril, 2.5-10 mg/day; or metoprolol, 50-200 mg/day, with other agents added to achieve blood pressure goals as needed.

Principal Findings:

A total of 1,094 patients were enrolled, 540 to intensive blood pressure control, and 554 to standard blood pressure control. Baseline characteristics were fairly similar between the two arms, except for current smoking, which was higher in the intensive control arm (33.7% vs. 25.1%). Baseline estimated glomerular filtration rate (GFR) was about 47 ml/min/1.73 m2, which corresponded to a mean baseline creatinine of about 2.0 mg/dl. The median urinary protein excretion was 0.12 g/day, with a median urinary protein-to-creatinine ratio of 0.08.

Patients had at least 3 years of follow-up in the trial phase. The period between 3 and 6.5 years was a mixed period that encompassed the trial phase for some enrollees and the cohort phase for others. After 6.5 years, all data were for the cohort patients. The maximum duration of follow-up was 12.2 years. At baseline, the mean blood pressure was 152/96 mm Hg in the intensive-control group and 149/95 mm Hg in the standard-control group. Throughout the trial phase, the mean blood pressure was significantly lower in the intensive control arm than in the standard-control arm (130/78 mm Hg vs. 141/86 mm Hg). During the cohort phase, differences in blood pressure were smaller in magnitude, because all patients had a common blood pressure target; the mean blood pressure was 131/78 mm Hg in the intensive-control arm and 134/78 mm Hg in the standard-control arm. Throughout the study, use of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin-receptor blockers (ARB) was similar in the two arms.

Through both phases of the study, there was no difference in the primary endpoint (doubling of serum creatinine, end-stage renal disease [ESRD], or death) between the intensive and standard blood pressure control arms (7.3% vs. 7.5% per 100 patient-years [PY], hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.77-1.08, p = 0.27). This was true of the trial portion of the study as well (7.0% vs. 7.3% per 100 PY, p = 0.24). Similarly, there was no difference in any of the secondary endpoints, including doubling of serum creatinine or ESRD (5.5% vs. 5.5% per 100 PY, p = 0.59) and ESRD or death (5.8% vs. 6.3% per 100 PY,  p = 0.08).

There was evidence of significant effect modification based on baseline urinary protein-to-creatinine ratio of ≤0.22 vs. >0.22. In patients with a protein-to-creatinine ratio of >0.22, the primary outcome was significantly lower in the intensive control arm compared with the standard control arm (13.8% vs. 19.0% per 100 PY, HR 0.73, 95% CI 0.58-0.93, p = 0.01). This was true of both phases of the study. Similarly, the secondary outcomes of doubling of serum creatinine or ESRD (11.6% vs. 16.1% per 100 PY, p = 0.04) and ESRD or death (10.8% vs. 16.1% per 100 PY, p = 0.002) were lower in the intensive control arm. In patients with protein-to-creatinine ratio of ≤0.22, there was no difference in the primary endpoint between the two arms (5.1% vs. 4.5% per 100 PY, p = 0.16). In fact, there was a 39% higher incidence of the secondary outcome of doubling of serum creatinine or ESRD in the intensive control arm (3.4% vs. 2.7% per 100 PY, p = 0.03), but not ESRD or death (3.9% vs. 3.6% per 100 PY,  p = 0.39).  

On the factorial analysis, among participants with a urinary protein-to-creatinine ratio of >0.22 (corresponding approximately to proteinuria of more than 300 mg/day), the ramipril group had a 36% (2.02 [SE, 0.74] ml/min per 1.73 m2/y) slower mean decline in GFR over 3 years (p = 0.006) and a 48% reduced risk of the clinical endpoints versus the amlodipine group (95% CI 20-66%). In the entire cohort, there was no significant difference in mean GFR decline from baseline to 3 years between treatment groups (p = 0.38). However, compared with the amlodipine group, after adjustment for baseline covariates, the ramipril group had a 38% reduced risk of clinical endpoints (95% CI 13-56%), a 36% slower mean decline in GFR after 3 months (p = 0.002), and less proteinuria (p < 0.001).

Interpretation:

African American patients with hypertensive renal disease have a high rate of progression to worsening renal function, ESRD, or death (approximately 7.4% per 100 PY). The results of the AASK study, encompassing both its randomized trial and cohort phases, suggest that there is no difference in chronic kidney disease progression with intensive blood pressure control compared with standard blood pressure control in African American patients with impaired renal function at baseline, over a follow-up period of about 10 years. There is, however, significant effect modification based on baseline urinary protein-to-creatinine ratio, such that patients with a value >0.22 seem to have a significant reduction in the incidence of doubling of serum creatinine, ESRD, or death with intensive control compared with standard control, whereas those with a value ≤0.22 seem to derive no benefit, and may paradoxically have a higher incidence of doubling of serum creatinine or ESRD with intensive blood pressure control. These effects were independent of ACEI or ARB use, since their use was similar between the two arms over the duration of follow-up. These results are very important, since renal failure is associated with a high incidence of morbidity and mortality.

In the factorial analysis, ramipril, compared with amlodipine, retards renal disease progression in patients with hypertensive renal disease and proteinuria, and may be associated with benefit in patients without proteinuria. On the basis of this interim analysis, the amlodipine arm was terminated early.

References:

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

JAMA 2001;285:2719-28.

Keywords: Angiotensin Receptor Antagonists, Hypertension, Renal, Kidney Failure, Chronic, Nephritis, Blood Pressure, Proteinuria, Creatinine, Ramipril, Calcium Channel Blockers, Smoking, Glomerular Filtration Rate, Amlodipine, Metoprolol, Renal Insufficiency, Chronic, Diabetes Mellitus, Disease Progression


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