AASK

Published

Wright JT Jr., et al. "Intensive blood-pressure control in hypertensive chronic kidney disease". JAMA. 2002. 288(19):2421-2431.
PubMed • Full text • PDF

Clinical Question

Among African Americans with hypertensive kidney disease, does intensive blood pressure control slow progression of CKD more than usual BP control?

Bottom Line

Among African Americans with hypertensive kidney disease, intensive blood pressure control targeting MAP <92 mm Hg did not slow progression of kidney disease compared to conservative blood pressure control targeting MAP 102-107 mm Hg. Use of ACE-inhibitors slowed rate of GFR decline.

Major Points

African American adults experience a disproportionate burden of hypertension and hypertension-related chronic kidney disease when compared to white Americans. One small analysis from the MDRD trial suggested a potential benefit in prevention progression of kidney disease with intensive BP control. However, the appropriate management of these interrelated conditions was unknown in the 1990s.

Published in 2002, the African American Study of Kidney Disease and Hypertension (AASK) trial randomized 1,094 African American adults with hypertension and CKD (defined by a GFR 20-65 mL/min/1.73 m²) without a clear secondary cause of CKD to BP target (intensive BP with MAP ≤92 mm Hg or usual MAP 102-107 mm Hg) and BP agent (ramipril, amlodipine, or metoprolol) in a 2x3 factorial design. At 4 years, there was no difference in progression of CKD by BP target. Use of the ACE-inhibitor ramipril was associated with fewer CKD events or death. AASK in part solidified the use of ACE-inhibitors or ARBs among patients with CKD.

The AHA/ACC hypertension guidelines were updated in 2017 and reflected the findings from SPRINT, which demonstrated a mortality benefit among high-risk patients randomized to intensive BP control (systolic BP <120 mm Hg). These guidelines lowered the hypertension threshold to 130/80 mm Hg. Among low-risk adults, initiation of antihypertensive agents is recommended at 140/90 mm Hg. Those with high-risk BP-related conditions like prior ASCVD or HF are recommended to start antihypertensives at 130/80 mm Hg, mimicking intensive BP control in AASK and SPRINT. These guidelines recommend initiation of antihypertensives among adults with CKD at 130/80 mm Hg. Curiously, this strong recommendation (COR I, LOE SBP B-R; DBP C-EO) cites literature (including AASK) that did not identify benefit from intensive BP control in CKD.

Guidelines

2017 ACC AHA AAPA ABC ACPM AGS APhA ASH ASPC NMA PCNA Hypertension (2017, adapted)

• Target BP <130/80 if hypertension and CKD (COR I, SBP B-R, DBP C-EO)
• Use ACE-inhibitor if CKD stage III or worse or stage 1 or 2 with albuminuria (e.g., ≥300 mg/g albumin to creatinine ratio) (COR IIa, LOE B-R)
  • ARB as substitute if ACE intolerant (COR IIb, LOE C-EO)

Design

• Multicenter, randomized, 2x3 factorial, controlled trial
• N=1,094 African-American individuals
  • 2x3, BP (open-label):
    • Lower BP (n=540)
    • Usual BP (n=554)
  • 2x3, initial BP medication (blinded):
    • Beta blocker (n=441)
    • ACE-inhibitor (n=436)
    • CCB (n=217)
• Setting: 21 centers in the US
• Enrollment: 1995-1998
• Median follow-up: About 4 years
• Analysis: Not disclosed, likely intention-to-treat
• Primary outcomes:
  • Rate of change in eGFR
  • Progression of CKD or all-cause mortality

Population

Inclusion Criteria

• African-American
• Age 18-70
• Diastolic blood pressure ≥95 mm Hg
• Hypertensive renal disease
• eGFR 20-65 mL/min/1.73 m²

Exclusion Criteria

• Diabetes
• Urine protein:creatinine >2.5
• Malignant hypertension in prior 6 months
• Heart failure
• Serious comorbidities

Baseline Characteristics

From the lower BP arm.

• Demographics: Age 54 years, female sex 38%
• Physiological measurements: Weight 89 kg, BMI 20.5 kg/m², BP 152/96 mm Hg, MAP 115 mm Hg
• Renal data: eGFR 46 mL/min/1.73 m², U protein:creatinine ≥0.22 34%
  • Males: Creatinine 2.2 mg/dL, U protein:creatinine 0.33, U protein 0.61 g/24h
  • Females: Creatinine 1.7 mg/dL, U protein:creatinine 0.28, U protein 0.36 g/24h
• Antihypertensive use: 97%
  • Type: Diuretics 62%, ACE-inhibitors 38%, beta-blockers 28%, CCB 65%, dihydropyridine CCB 50%

Interventions

• Participants were randomized to a group:
  • Lower BP - Target MAP ≤92 (mean achieved: 128/78 mm Hg)
  • Usual BP - Target MAP 102-107 (mean achieved: 141/85 mm Hg)
• Participants were also randomized to an initial drug therapy:
  • ACE-inhibitor - Ramipril 2.5-10 mg/day
  • Beta-blocker - Metoprolol succinate 50-200 mg/day
  • CCB - Amlodipine 5-10 mg/day
• All participants were uptitrated to the highest tolerated dose of their initial drug therapy before starting additional therapies, which were furosemide, doxazosin, clonidine, and hydralazine or minoxidil
• As amlodipine is associated with an acute change in GFR at discontinuation, GFR comparisons were censored at the time of discontinuation of this medication. The median GFR follow-up was 3.8 years for CCB vs. 4.1 years for ACE-inhibitor and beta-blocker.

Outcomes

RR is risk reduction. The first presented group in the comparison is the reference. I.e., ACE-inhibitor associated with a +0.61 increase in GFR when compared to beta blocker.

Primary Outcomes

Rate of change in eGFR (total slope)

Lower BP vs. usual BP: -0.25 mL/min/1.73 m²/year (P=0.24)

ACE-inhibitor vs. beta-blocker: +0.61 mL/min/1.73 m²/year (P=0.007)

CCB vs. beta-blocker: +1.08 mL/min/1.73 m²/year (P=0.004)

ACE-inhibitor vs. CCB: -0.34 mL/min/1.73 m²/year (P=0.38)

Progression of CKD or all-cause mortality

Progression of CKD was defined as reduction in eGFR by ≥50% or drop by 25 mL/min/1.73 m², or ESRD.

Lower BP vs. usual BP: 2% RR (95% CI -22 to 21; P=0.85)

ACE-inhibitor vs. beta-blocker: 22% RR (95% CI 1 to 38; P=0.04)

CCB vs. beta-blocker: 20% RR (95% CI -10 to 41; P=0.17)

ACE-inhibitor vs. CCB: 38% RR (95% CI 14 to 56; P=0.004)

Secondary Outcomes

Progression of CKD

Lower BP vs. usual BP: -2% RR (95% CI -31 to 20; P=0.87)

ACE-inhibitor vs. beta-blocker: 22% RR (95% CI -2 to 41; P=0.07)

CCB vs. beta-blocker: 24% RR (95% CI -9 to 47; P=0.13)

ACE-inhibitor vs. CCB: 40% RR (95% CI 14 to 59; P=0.006

ESRD or all-cause mortality

Lower BP vs. usual BP: 12% RR (95% CI -13 to 32; P=0.31)

ACE-inhibitor vs. beta-blocker: 21% RR (95% CI -5 to 40; P=0.11)

CCB vs. beta-blocker: 42% RR (95% CI 17 to 60; P=0.003)

ACE-inhibitor vs. CCB: 49% RR (95% CI 26 to 65; P<0.001)

ESRD

Lower BP vs. usual BP: 6% RR (95% CI -29 to 31; P=0.72)

ACE-inhibitor vs. beta-blocker: 22% RR (95% CI -10 to 45; P=0.16)

CCB vs. beta-blocker: 59% RR (95% CI 36 to 74; P<0.001)

ACE-inhibitor vs. CCB: 59% RR (95% CI 36 to 74; P<0.001)

Additional Outcomes

BP achieved

Lower BP: 128/78 mm Hg

Usual BP: 141/85 mm Hg

ACE-inhibitor: 135/82 mm Hg

CCB: 133/81 mm Hg

Beta-blocker: 135/81 mm Hg

Subgroup Analysis

The investigators assessed by urinary protein:creatinine threshold of 0.22, details are on page 2427. Details of this subgroup analysis are incomplete in the report but there were "slight trends" for benefit of lower BP in those with a ratio >0.22 and benefit for higher BP in those with ratio ≤0.22.

Adverse Events

There were similar rates of adverse events except for more cough and angioedema in the ACE-inhibitor group.

Criticisms

• No ambulatory BP measurements.
• GFR is a surrogate endpoint for CKD.

Funding

• NIH
• King Pharmaceuticals, which provided monetary support and antihypertensive medications to each clinical center
• Pfizer, AstraZeneca, GlaxoSmithKline, Forest Laboratories, Pharmacia, and Upjohn, which donated antihypertensive medications