Benazepril in Severe CKD

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Hou FF, et al. "Effect and Safety of Benazepril for Advanced Chronic Renal Insufficiency". The New England Journal of Medicine. 2006. 354(2):131-140.
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Clinical Question

Among non-diabetic patients with advanced (stage 4) CKD, does benazepril slow renal disease progression?

Bottom Line

Benazepril slows renal disease progression in patients with stage 4 non-diabetic CKD when compared to placebo.

Major Points

Blood pressure reduction improves cardiovascular outcomes and may reduce progression of kidney disease in patients with CKD, especially those with albuminuria. Furthermore, several subgroup and post-hoc analyses suggest that treatment with either an ACE inhibitor or an ARB compared to other BP-lowering agents may further reduce kidney disease progression when albuminuria is present (AASK, HOPE, CASE J, TRANSCEND). Most of these studies did not include patients with advanced CKD, leading to uncertainty in whether the same treatment guidelines should be applied to these patients. Some practitioners also feared that further GFR reduction from RAAS blockade would reduce residual renal function and possibly accelerate renal deterioration[1]. While evidence from other trials (RENAAL, REIN) suggested evidence to the contrary, a trial investigating the role of ACE inhibitors and/or ARBs in patients with advanced CKD for prevention of renal function deterioration was needed.

Published in 2006, the double-blinded, double-dummy randomized control trial "Effect and Safety of Benazepril for Advanced Chronic Renal Insufficiency" conducted in China randomized 224 patients (Group 2) with severe CKD (mean eGFR: 26, SD 5) to either benazepril or placebo. The primary composite outcome (creatinine doubling, ESRD, or death) was significantly reduced in patients treated with benazepril in their blood pressure lowering regimen (41% vs. 60%; HR 0.57; NNT = 5). A separate, non-placebo controlled group of patients (Group 1; n=141) with less severe CKD (mean eGFR: 37, SD 6) treated with benazepril demonstrated less overall renal decline compared to patients with more severe CKD. Side effects were not significantly greater in the treatment group compared to placebo. BP was similar between groups. There was no difference in the rate in decline of renal function when comparing those group 1 with those in the group 2 benazepril arm.

This study provides high quality evidence demonstrating both the safety and efficacy of the use of ACE inhibitors in severe CKD for preventing renal progression, beyond its effects in controlling BP. Patients in group 2 predominantly have stage 4 CKD, and therefore it is unclear if the results of this trial can be applied to patients with stage 5 CKD. Based on the results of this trial and other available data, the 2012 KDIGO BP guidelines do not suggest discontinuing ACE inihibitors or ARBs in patients with advanced CKD in order to preserve residual renal function, although this remains an area of controversy.

Guidelines

KDIGO CKD-BP Guidelines (2012, adapted)[1]

CKD-ND: Non-diabetic chronic kidney disease

  • CKD-ND patients with urine albumin excretion <30 mg/24h should be treated with BP-lowering drugs to a target of <140/90 (1B)
  • CKD-ND patients with urine-albumin excretion of 30-300mg/24h (2D) and >300 mg/24h (2C) should be treated with BP-lowering agents to a target of <130/80
  • CKD-ND patients with urine albumin excretion of 30-300 mg/24h (2D) or >300mg/24h (1B) should be treated with ACE-I/ARB when BP-lowering drugs are indicated
  • The current evidence does not support discontinuing ACE-Is or ARBs in patients with advanced CKD in an effort to preserve residual kidney function (no grade)

Design

  • Single center, double-blinded, randomized control trial
  • N=422 patients with advanced non-diabetic CKD (Cr 1.5-5mg/dL)
    • Group 1: serum creatinine 1.5-3.0 mg/dL
      • Benazepril (n=104)
      • No placebo arm
    • Group 2: serum creatinine 3.1-5.0 mg/dL
      • Benazepril (n=112)
      • Placebo (n=112)
    • Mean follow-up: 3.4 years
  • Enrollment 1999-2001
  • Analysis: Intention-to-treat
  • Primary outcome: Creatinine doubling, ESRD, or death

Population

Inclusion Criteria

  • 18-70 years old non-diabetic patients
  • Serum creatinine of 1.5-5.0 mg/dL
  • CrCl 20-70 mL/min/1.73m2 (by MDRD)
  • CrCl variations of <30% in 3 months before screening
  • Nondiabetic renal disease (determined by history, biochemical testing, and renal biopsy information)
  • Persistent proteinuria (>0.3g/d without heart failure or UTI)
  • ACE inhibitor or ARB use in prior 6 weeks

Exclusion Criteria

  • Immediate need for dialysis
  • Corticosteroid treatment
  • NSAID use
  • Immunosupressive medications
  • Renovascular disease
  • MI or CVA in prior year
  • Connective tissue disease
  • Obstructive uropathy

Baseline Characteristics

Group 1

  • Demographics: Age 45 years, female 51%
    • Ethnicity: 100% Chinese
  • Health data: BMI 23 kg/m2, BSA 1.7 m2, BP 151/86 mm Hg
  • Renal data: Creatinine 2.3 mg/dL, eGFR 37 mL/min/1.73 m2, CrCl 38 mL/min/1.73 m2, urinary protein excretion 1.6 g/day
  • PMH: Hypertension: 88%
    • CKD etiology: Glomerular 60%, hypertension 18%, PCKD 12%, intertitial disease 2%, unknown 8%
  • Antihypertensives: 2
  • Other labs: Tchol 4.6 mmol/L (178 mg/dL), TG 1.9 mmol/L (168 mg/dL), K 4.4 mmol/L, hgb 11.3 g/dL, urinary urea 5 g/day, urinary chloride 107 mmol/day

Group 2, benazepril arm.

  • Demographics: Age 44 years, female 50%
    • Ethnicity: 100% Chinese
  • Health data: BMI 23 kg/m2, BSA 1.8 m2, BP 153/87
  • Renal data: Creatinine 4.0 mg/dL, eGFR 26 mL/min/1.73 m2, CrCl 27 mL/min/1.73 m2, urinary protein excretion 1.6 g/day
  • PMH: Hypertension 91%
    • CKD etiology: Glomerular disease 61%, hypertension 17%, PCKD 12%, interstitial disease 3%, unknown 7%
  • Antihypertensives: 2
  • Other labs: Tchol 4.7 mmol/L (182 mg/dL), TG 2.0 mmol/L (177 mg/dL), K 4.5 mmol/L, hgb 10.1 g/dL, urinary urea 5 g/day, urinary chloride 104 mmol/day

Interventions

  • Patients were enrolled to a group, those in group 2 were randomized to the subgroup:
  • Group 1 - Creatinine 1.5 to 3.0 mg/dL
    • All patients received benazepril 10mg po BID
      • There was no placebo arm as it was deemed unethical as ACE inhibitors have well-documented in this stage of CKD
  • Group 2 - Creatinine 3.1 to 5.0 mg/dL
      • Benazepril - Benazepril 10mg po BID
      • Placebo arm
  • All participants underwent an 8 week run-in: 4 weeks of benazepril 10mg po daily then 4 weeks of benazepril 10mg po BID
    • Patients were excluded for dry cough, creatinine increase of >30%, hyperkalemia, or poor adherence
  • All groups received:
    • Conventional antihypertensive therapy were added in addition to assigned treatment, including open-label diuretics, CCBs, alpha or beta blockers, or combinations of these medications
    • Dietary advice: salt intake of 5-7g NaCl/day, 0.5-0.7g protein/kg/day, restriction of potassium-rich foods

Outcomes

Comparisons are group 1 vs. group 2 benazepril vs. group 2 placebo except where specified.

Primary Outcome

Creatinine doubling, ESRD, or death
ESRD defined by dialysis or renal transplantation.
22% vs. 41% vs. 60%
Group 2 only: 41% vs. 60% (HR 0.57; P=0.004; NNT=5)
Adjusted for BP: Lower in benazepril subgroup (HR 0.40; P=0.009)

Secondary Outcomes

Doubling of serum creatinine level
Group 2 only: Lower in benazepril subgroup (HR 0.49; P=0.02)
ESRD
Group 2 only: Lower in benazepril subgroup (HR 0.60; P=0.02)
Reduction in proteinuria
Group 2 only: 52% vs. 20% (P<0.001)
Rate of GFR decline (mL/min/1.73m2/year)
Group 2 only: 6.8 vs. 8.8 (HR 0.76; P=0.006)
There was no difference in the rate of decline between group 1 and group 2 benazepril (P=0.23).
Rate of renal function decline (slope of the reciprocal of serum creatinine level)
Group 2 only: -0.09 dL/mg/year vs. -0.11 dL/mg/year (P=0.02)

Additional Outcomes

Relationship of eGFR and proteinuria
More significant proteinuria associated with faster eGFR and CrCl decline when proteinuria >1g/d (P=0.03)
Blood pressure
Achieved BP was similar between groups

Adverse Events

Any
9 vs. 19 vs. 22
Death
0 vs. 1 vs. 0 (Pneumonia)
Myocardial infarction
3 vs. 5 vs. 8
Heart failure
1 vs. 3 vs. 5
Stroke
1 vs. 2 vs. 3
Hyperkalemia
2 vs. 6 vs. 5
Acute renal function decline
1 vs. 1 vs. 1
Dry cough
0 vs. 1 vs. 0
Hypotension
1 vs. 0 vs. 0

Criticisms

  • Higher ACE activity due to genetic differences may enhance the efficacy of ACE inhibitors in Asians compared to Caucasians[2]
  • No data on medication and diet compliance
  • Major etiologies of CKD studied significantly different from Western populations (diabetes, hypertension)
  • Does not apply to patients with stage 5 CKD

Funding

  • Novartis (manufacturer of benazepril, brand name Lotensin)
  • National Nature and Sciences Grant for Major Projects
  • People's Liberation Army Grant for Major Clinical Research

Further Reading