AASK

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

Clinical Question

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

Bottom Line

Intensive blood pressure control did not slow progression of kidney disease compared to conservative blood pressure control.

Major Points

While JNC 7 guidelines recommend conservative BP control (goal SBP<140 for most and <150 for elderly), the SPRINT trial demonstrated a mortality benefit from more intensive BP control driven primarily by reduction in CHF. Among patients with hypertensive nephropathy, it is not known whether intense BP control provides additional benefit beyond standard BP control. Few trials have examined this comparison, with short follow-up and inconsistent results. The AASK trial was a large trial examining this questions in African Americans, finding no significant differences in progression of CKD with intensive (average BP 128/78) vs. conservative BP control (average BP 141/85), suggesting that a BP goal of 140/80 is reasonable even for patients with CKD.

Guidelines

Design

  • Multicenter, randomized, 2x3 factorial, controlled trial
  • N=1,094
    • 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) -- This arm was closed about a year early
  • Setting: 21 centers in the US
  • Enrollment: 1995-1998
  • Mean follow-up: Not disclosed, up to 6 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.

  • Sociodemographics: 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 (ie, 130/80)
    • Usual BP - Target MAP 102-107 (ie, 140/90)
  • Participants were also randomzied 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

Outcomes

RR is risk reduction.

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% (95% CI -10 to 41; P=0.13)
ACE-inhibitor vs. CCB: 38% (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=0.0060
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

Patient with baseline urinary protein to creatinine ratio <=0.22 were analyzed in trial and cohort phase

Rate per 100 person-year for doubling of serum creatinine level, ESRD, or death in Trial phase
4% vs. 3.6% (HR 1.14; 95% CI 0.80–1.63; P=0.46)
Rate per 100 person-year for doubling of serum creatinine level, ESRD, or death in Cohort phase
6.5% vs. 5.6% (HR 1.21; 95% CI 0.88–1.66; P=0.24)

Patient with baseline urinary protein to creatinine ratio >0.22 were analyzed in trial and cohort phase

Rate per 100 person-year for doubling of serum creatinine level, ESRD, or death in Trial phase
13.9% vs. 18.3% (HR 0.74; 95% CI 0.56–0.99; P=0.04)
Rate per 100 person-year for doubling of serum creatinine level, ESRD, or death in Cohort phase
13.7% vs. 21.1% (HR 0.66; 95% CI 0.43–1.03; P=0.06)

This suggests that among patients with a protein-to-creatinine ratio of more than 0.22, those in the intensive- control group had a significant reduction in the risk of primary outcome.

Adverse Events

Criticisms

  • The cohort phase was not a randomized trial, since all the patients had the same blood pressure target.
  • Adjustment of therapy was based on blood pressure as assessed by standard office readings, not on ambulatory blood pressure.
  • Significant subgroup results should be interpreted cautiously, given the potential for chance findings even when the subgroup is pre- specified.

Funding

  • National Institute of Diabetes and Digestive and Kidney Diseases; by the Office of Research in Minority Health (now the National Center on Minority Health and Health Disparities)
  • National Institutes of Health (M01 RR-00080, M01 RR-00071, M0100032, P20-RR11145, M01 RR00827, M01 RR00052, 2P20 RR11104, RR029887, and DK 2818-02)
  • 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

Further Reading