- 1 Clinical Question
- 2 Bottom Line
- 3 Major Points
- 4 Guidelines
- 5 Design
- 6 Population
- 7 Interventions
- 8 Outcomes
- 9 Criticisms
- 10 Funding
- 11 Further Reading
In African Americans with hypertensive kidney disease, does intensive blood pressure control slow progression of CKD more than conservative BP control?
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.
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.
The hypertension guidelines were updated in 2017 and lowered the hypertension threshold to 130/80 mm Hg and initiation of antihypertensive agents universally at 140/90 mm Hg. Antihypertensive medications are recommended for higher risk groups at a threshold of 130/80 mm Hg, including adults with CKD. This strong recommendation (COR I, LOE SBP B-R; DBP C-EO) was largely based on the findings of AASK. Of note, the referenced manuscripts actually did not actually identify a clear benefit with lower BP goals.
2017 ACC AHA AAPA ABC ACPM AGS APhA ASH ASPC NMA PCNA Hypertension (2017, adapted)
- Target SBP <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)
- 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)
- 2x3, BP (open-label):
- 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
- Age 18-70
- Diastolic blood pressure ≥95 mm Hg
- Hypertensive renal disease
- eGFR 20-65 mL/min/1.73 m2
- Urine protein:creatinine >2.5
- Malignant hypertension in prior 6 months
- Heart failure
- Serious comorbidities
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%
- 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 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
- 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.
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.
- 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)
- 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)
- 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)
- 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
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.
There were similar rates of adverse events except for more cough and angioedema in the ACE-inhibitor group.
- 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.
- 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
- Klahr S et al. The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. Modification of Diet in Renal Disease Study Group. N. Engl. J. Med. 1994. 330:877-84.
- Ruggenenti P et al. Blood-pressure control for renoprotection in patients with non-diabetic chronic renal disease (REIN-2): multicentre, randomised controlled trial. Lancet 2005. 365:939-46.
- Upadhyay A et al. Systematic review: blood pressure target in chronic kidney disease and proteinuria as an effect modifier. Ann. Intern. Med. 2011. 154:541-8.
- Lv J et al. Effects of intensive blood pressure lowering on the progression of chronic kidney disease: a systematic review and meta-analysis. CMAJ 2013. 185:949-57.
- Jafar TH et al. Progression of chronic kidney disease: the role of blood pressure control, proteinuria, and angiotensin-converting enzyme inhibition: a patient-level meta-analysis. Ann. Intern. Med. 2003. 139:244-52.
- Whelton PK et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension 2017. :.