Maschio G, Alberti D, Janin G, Locatelli F, et al.
Effect of ACE inhibitor benazepril on the progression of
chronic renal insufficiency
N Engl J Med
(Apr) 334:939-945 1996
It is now established practice to treat diabetic nephropathy with ACE
inhibitors to slow the progression of renal injury. Although several
small reports have suggested that these drugs may be of benefit in
nondiabetic renal diseases also, this hypothesis has not been
Maschio et al report on the effect of once a day benazepril, a
nonsulfhydryl ACE inhibitor, on the course of renal insufficiency in a
prospective, double blind and randomized study conducted in Europe.
583 patients, with a variety of glomerular and tubulo-interstitial
diseases, were randomized to receive benazepril (300 patients) or
placebo (283 patients) following an observational period for three
months to ensure stability of renal function and to adequately control
blood pressure. The patients were followed for three years and the
primary endpoint of the study was doubling of serum creatinine or need
for dialysis. Patients were excluded from the study based on such
criteria as insulin dependent diabetes.
The clinical profiles of the patients in the two groups were similar.
Of the 300 patients in the benazepril group, 31 patients reached the
primary endpoint in three years compared to 57 of the 283 patients
treated with placebo (p<0.001), the overall risk reduction being 53%
in the benazepril group. The protective effect was greater in
patients with mild renal insufficiency (creatinine clearance 46 to 60
ml/min) compared to those with moderate impairment (creatinine
clearance 30 to 45 ml/min): 71% vs. 46%. Patients with diabetic and
nondiabetic glomerular diseases had a favorable response to
benazepril; a significant benefit was not seen in those with
polycystic kidney disease or tubulo-interstitial diseases.
Comment: I wonder whether a longer follow-up may have led to a
different conclusion in patients with tubulo-interstitial diseases, as
in 3 years of follow-up only 7 of 105 patients reached the endpoint.
Proteinuria was reduced by nearly 30% in patients treated with
benazepril. Blood pressures were lower in the benazepril treated
patients who, therefore, received fewer additional anti-hypertensive
drugs. The beneficial effect of benazepril on the course of renal
disease was not entirely explained by its anti-hypertensive action.
Adverse events in the benazepril group included more deaths (8 vs. 1),
cough and higher average serum potassium levels.
The strengths of the study include its prospective randomized and
double blinded strategy and representation of a variety of renal
diseases in the patient groups. The increase in the number of deaths
in a relatively brief follow-up period in the benazepril group is of
serious concern. The authors do not propose a mechanism for increase
in mortality. One wonders whether a continuous, round the clock blood
pressure monitoring in patients treated with benazepril would reveal
episodes of hypotension that, in the appropriate setting, may result
in coronary hypoperfusion. The lack of beneficial effect of
benazepril in the nonglomerular causes of renal insufficiency is also
intriguing. This raises the issue of whether the pathogenesis of
progression in tubulo-interstitial diseases is different from that in
B.S. Kasinath, M.D., University of Texas at San Antonio
The abstract of this paper is available from the National Library of
Medicine's PubMed site:
click here .