Correspondence
Effect of Benazepril in Chronic Renal Insufficiency
N Engl J Med 1996; 335:596-598August 22, 1996
- Article
To the Editor:
Maschio et al. (April 11 issue)1 focus their conclusions on a specific renoprotective effect of benazepril in patients with chronic renal insufficiency. However, we question whether the drug has a specific renoprotective effect, because control of both diastolic and systolic blood pressure was better in the benazepril-treated patients. In their analysis, the authors adjusted only for the difference in control of diastolic blood pressure between the benazepril and placebo groups, but Figure 3 shows that the difference in systolic blood pressure between the two groups was even greater. Several investigators have stressed the importance of aggressive control of blood pressure in preventing the deterioration of renal function in patients with renal disease. In the Modification of Diet in Renal Disease Study, there was a strong correlation between lack of control of blood pressure and decline in renal function.2 In the Northern Italian Cooperative Study of hypertension and chronic renal insufficiency, a difference of only 4 mm Hg in mean arterial pressure was associated with either slow or fast progression of renal failure.3 We wonder whether the beneficial effect of benazepril in the study by Maschio et al. would still have been present if adjustments had been made for the differences in both systolic and diastolic blood pressure over time.
Even if the beneficial effect of benazepril persists after adjustment for systolic blood pressure, to prove that benazepril or angiotensin-converting–enzyme inhibitors as a group have a specific renoprotective effect will require a study in which blood pressure in the treatment and control groups is titrated to the same level.
3 ReferencesAlfred J. Apperloo, M.D., Ph.D.
Pieter L. Rensma, M.D., Ph.D.
St. Elisabeth Hospital, 5022 GC Tilburg, the Netherlands1
Maschio G ,Alberti D ,Janin G , et al. Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency. N Engl J Med 1996;334:939-945
Full Text | Web of Science | Medline2
Peterson JC ,Adler S ,Burkart JM , et al. Blood pressure control, proteinuria, and the progression of renal disease. Ann Intern Med 1995;123:754-762
Web of Science | Medline3
Alberti D ,Locatelli F ,Graziani G , et al. Hypertension and chronic renal insufficiency: the experience of the Northern Italian Cooperative Study Group. Am J Kidney Dis 1993;21:Suppl 2:124-130
Web of Science | Medline
To the Editor:
Maschio et al. conclude that “benazepril provides protection against the progression of renal insufficiency in patients with various renal diseases.” Although benazepril had beneficial effects on renal survival, blood pressure, serum creatinine concentrations, and urinary protein excretion, the overall mortality rate was significantly higher in the benazepril group (1 death per 93 patient-years, as compared with 1 death per 656 patient-years in the placebo group). The authors contend that the overall number of deaths from cardiovascular causes in their study was low as compared with that in other studies of similar patients. However, they do not discuss the significantly higher death rate in the benazepril group, except to state that the drug was not responsible for the deaths. Were there differences between the groups with respect to a history of or risk factors for cardiovascular disease? Were the excess deaths in the benazepril group associated with particular renal diseases?
Catherine G. Curren, Pharm.D.
North Carolina Baptist Hospital, Winston-Salem, NC 27157Author/Editor Response
The authors reply:
To the Editor: Control of blood pressure is important in protecting against deterioration in renal function. As we concluded in our article, the protective effect of benazepril was “associated with a substantial decrease in blood pressure.” We considered patients to have hypertension if they had a diastolic blood pressure over 90 mm Hg or used antihypertensive drugs; blood pressure was considered controlled if the diastolic pressure was 90 mm Hg or less. During the trial, we adjusted antihypertensive therapy in both groups as needed to control blood pressure. Nonetheless, systolic and diastolic pressures were lower in the benazepril group. We made a statistical adjustment only for diastolic pressure (to be consistent with the protocol definitions), in order to distinguish the protective contribution of benazepril's renal effects from its systemic pharmacodynamic effects. We found that the beneficial effect of benazepril was not due exclusively to its systemic antihypertensive action.
Blood-pressure control is a major factor in renal preservation,1,2 but not the only one. The conditions in which benazepril had the greatest benefit (glomerulopathies, including diabetic nephropathy and overt proteinuria) were those in which experimental studies have indicated pathologic involvement of the renin–angiotensin system.3
Mortality was not a primary study end point. We would expect an angiotensin-converting–enzyme inhibitor to reduce mortality from vascular disease, and mortality was slightly lower during benazepril treatment than during the screening period (1 death per 93 patient-years vs. 1 death per 59 patient-years). The anomaly in our study was the unexpectedly low mortality in the placebo group. The number of nonfatal cardiovascular events leading to the discontinuation of treatment was similar in the two groups. All deaths during the treatment period were due to vascular causes and were considered to be consistent with the patients' known clinical problems; no death was thought to be related to the study drug. The treatment groups were slightly unbalanced at entry with respect to conditions that might predispose the patients to death from cardiac causes (15 patients in the benazepril group and 12 in the placebo group had coronary artery disease). We do not believe that the imbalance in mortality is of clinical importance.
3 ReferencesGiuseppe Maschio, M.D.
Ospedale Civile, I-37126 Verona, ItalyDaniele Alberti, M.D.
Ciba–Geigy, I-21040 Origgio, ItalyFrancesco Locatelli, M.D.
Ospedale di Lecco, I-22053 Lecco, Italy1
Klahr S ,Levey AS ,Beck GJ , et al. The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. N Engl J Med 1994;330:877-884
Full Text | Web of Science | Medline2
Locatelli F ,Marcelli D ,Comelli M , et al. Proteinuria and blood pressure as causal components of progression to end-stage renal failure. Nephrol Dial Transplant 1996;11:461-467
Web of Science | Medline3
Maki DD ,Ma JZ ,Louis TA ,Kasiske BL . Long-term effects of antihypertensive agents on proteinuria and renal function. Arch Intern Med 1995;155:1073-1080
CrossRef | Web of Science | Medline
