CSG Captopril Trial

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Lewis EJ, et al. "The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group.". The New England Journal of Medicine. 1993. 329(20):1456-1462.
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Contents

Clinical Question

Among patients with T1DM nephropathy, does addition of captopril reduce doubling time of creatinine when compared to placebo?

Bottom Line

Captopril reduces creatinine doubling time in patients with T1DM nephropathy when compared to placebo.

Major Points

Untreated diabetic nephropathy progresses to ESRD in most patients about 10 years after development of proteinuria. Furthermore, those with proteinuria have nine times the risk of all-cause mortality than the general population.[1] Early aggressive treatment of concurrent hypertension in this condition was shown to decrease rate of decline of kidney function by Parving et al. in 1983.[2] No large study had been performed with ACE-inhibitors in this disease.

The 1993 Collaborative Study Group (CSG) Captopril Trial randomized 409 type 1 diabetics with nephropathy characterized by proteinuria and varying degrees of renal dysfunction to the ACE-inhibitor captopril or placebo. With a median follow up of 3 years, captopril was associated with a lower rate of doubling of creatinine (12.1% vs. 21.3%; P=0.007; NNT 11), an effect likely independent of any change in blood pressure.[1] The renal protective effect was more pronounced in those with worse baseline kidney function.

The effect of ARBs in prevention of progression of diabetic nephropathy in type 2 diabetics was confirmed in the RENAAL study (2001). A similar study with ACE-inhibitors in type 2 diabetics has not been performed though the medications are typically used interchangeably.

Guidelines

ADA (2013):[3]

  • In the treatment of the nonpregnant patients with modestly elevated (30–299 mg/day) (level C) or higher levels (≥300 mg/day) of urinary albumin excretion (level A), either ACE inhibitors or ARBs are recommended

KDOQI Diabetes and CKD (2007):[4]

  • Recommend treatment of diabetics with hypertension and CKD stages 1-4 with an ACE-inhibitor or ARB, usually with a diuretic (Level A)
  • ACE-inhibitors and ARBs slow kidney disease with microalbuminuria in hypertensive patients with T1DM or T2DM (moderate)
  • ACE-inhibitors slow progression of kidney disease with macroalbuminuria more than other classes of blood pressure medications in patients with HTN and either T1DM (strong) or T2DM (weak; may slow progression)
  • ARBs slow progression of kidney disease with macroalbuminuria more than other antihypertensives in patients with HTN and either T1DM (weak; may slow progression) or T2DM (strong)

KDOQI Diabetes and CKD Update (2012):[5]

  • Recommend against using an ACE-inhibitor or ARB for the primary prevention of diabetic nephropathy in normotensive normoalbuminuric patients with diabetes (level 1A)
  • Suggest using an ACE-inhibitor or an ARB in normotensive diabetic patients with albuminuria levels >30 mg/g who are at high risk of diabetic nephropathy or its progression (level 2C)

Design

  • Multicenter randomized, double-blind, placebo-controlled trial
  • N=409
    • Captopril (n=207)
    • Placebo (n=202)
  • Setting: 30 US centers
  • Enrollment: 1987-1990
  • Median follow-up: 3 years
  • Analysis: Not explicitly stated
  • Primary outcome: Creatinine doubling

Population

Inclusion Criteria

  • Age 18-49 years
  • T1DM for ≥7 years with diagnosis before the age of 30
  • Diabetic retinopathy, protein excretion ≥500 mg/day, and creatinine ≤2.5 mg/dL
  • Patients on ACE-inhibitors or CCBs at baseline were eligible if their BP stayed within the study parameters upon cessation of these medications

Exclusion Criteria

  • ACE-inhibitors or CCBs at baseline and unable or unwilling to stop these medications
  • Pregnancy
  • Dietary patterns that "indicated marked departure from standard dietary recommendations"
  • WBC <2,500/mm3
  • HF with NYHA class III or IV symptoms
  • Potassium ≥6 mmol/L

Baseline Characteristics

From the captopril group. Comparisons are captopril vs. placebo.

  • Demographics: Age 35 years, male 52%, White race 91%, Black race 5%
  • Duration of DM: 22 years
  • PMH: HTN 75% (on antihypertensives 60%)
  • Baseline health data: BP 137/85 mmHg
  • Baseline laboratory values: Hemoglobin A1c 11.8%, creatinine 1.3 mg/dL (CrCl 84 mL/min), 24 hour urine protein 2,500 mg vs. 3,000 mg, 24 hour urine urea nitrogen 11 g

Interventions

  • Randomization to captopril 25 mg po TID or placebo
  • Goal BP <140/90 mmHg (if baseline SBP >150 mmHg, goal subsequent decrease was 10 mmHg with maximum SBP of 160 mmHg)
  • Dietary evaluation with recommended daily protein intake of 1g/kg of weight
  • Diabetes management by their previous treatment plans
  • Cessation of the intervention with creatinine doubling (primary endpoint), neutropenia, side effects (anticipated side effects from captopril, other side effects, or hyperkalemia), uncontrolled HTN, "intercurrent illness or condition," or pregnancy

Outcomes

Presented as captopril vs. placebo. RR is risk reduction. Statistics only given when presented. Percentages have been calculated by the WJC reviewers as they were not presented in the original publication.

Primary Outcome

Creatinine doubling
12.1% vs. 21.3% (RR 0.52; 95% CI 0.31-0.84; P=0.007; NNT 11)

Secondary Outcomes

Death
3.9% vs. 6.9%
Dialysis or transplant
9.7% vs. 15.3%
Death, dialysis, or transplant
11.1% vs. 20.8% (RR 0.50; 95% CI 0.30-0.82; P=0.006; NNT 10)
Neutropenia
1 vs. 1 patient (NS)
Anticipated side effect from captopril
<1% vs. <1%
Other side effects
1.4% vs. 1.5% (NS)
Hyperkalemia
1.4% vs. 0%
Uncontrolled HTN
<1% vs. 1.5%
"Intercurrent illness or condition"
5.3% vs. 3.5%
Pregnancy
1 vs. 1 patient (NS)
Other reason for discontinuation
9.1% vs. 5.4%
Proteinura
No data given, improved in the captopril group (P=0.001)

Subgroup Analysis

Creatinine doubling
Baseline creatinine ≥1.5 mg/dL: Percentages not given (RR 0.32; 95% CI 0.17-0.61; P<0.001)
Baseline creatinine <1.5 mg/dL: Percentages not given (RR 0.67; 95% CI 0.31-1.44; P=0.31)
Between-group interaction P=0.02

Criticisms

  • Relatively homogenous racial group[6]
  • Unclear method for measuring creatinine and rate of decline of creatinine clearance in normotensive patients[6]

Funding

  • Public health service
  • Bristol-Myers Squibb

Further Reading

  1. 1.0 1.1 Remuzzi G and Ruggenenti P. "Editorial: Slowing the progression of diabetic nephropathy." The New England Journal of Medicine. 1993;329:1496-1497.
  2. Parving HH, et al. "Early aggressive antihypertensive treatment reduces rate of decline in kidney function in diabetic nephropathy." The Lancet. 1983;321(8335):1175-1179.
  3. "Executive Summary: Standards of Medical Care in Diabetes—2013". Diabetes Care. 2013;36(s1):S4-S10.
  4. KDOQI. "KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney Disease." American Journal of Kidney Disease. 2007;49(supplement):S12-S154.
  5. Rocco MV et al. "KDOQI clinical practice guideline for diabetes and CKD: 2012 Update." American Journal of Kidney Diseases. 2012;60(5):850-886.
  6. 6.0 6.1 Multiple authors. "Correspondence: Effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy." The New England Journal of Medicine. 1994;330:937-938.