Efficacy and Safety of Benazepril for Advanced Chronic Renal Insufficiency
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《新英格兰医药杂志》
ABSTRACT
Background Angiotensin-converting–enzyme inhibitors provide renal protection in patients with mild-to-moderate renal insufficiency (serum creatinine level, 3.0 mg per deciliter or less). We assessed the efficacy and safety of benazepril in patients without diabetes who had advanced renal insufficiency.
Methods We enrolled 422 patients in a randomized, double-blind study. After an eight-week run-in period, 104 patients with serum creatinine levels of 1.5 to 3.0 mg per deciliter (group 1) received 20 mg of benazepril per day, whereas 224 patients with serum creatinine levels of 3.1 to 5.0 mg per deciliter (group 2) were randomly assigned to receive 20 mg of benazepril per day (112 patients) or placebo (112 patients) and then followed for a mean of 3.4 years. All patients received conventional antihypertensive therapy. The primary outcome was the composite of a doubling of the serum creatinine level, end-stage renal disease, or death. Secondary end points included changes in the level of proteinuria and the rate of progression of renal disease.
Results Of 102 patients in group 1, 22 (22 percent) reached the primary end point, as compared with 44 of 108 patients given benazepril in group 2 (41 percent) and 65 of 107 patients given placebo in group 2 (60 percent). As compared with placebo, benazepril was associated with a 43 percent reduction in the risk of the primary end point in group 2 (P=0.005). This benefit did not appear to be attributable to blood-pressure control. Benazepril therapy was associated with a 52 percent reduction in the level of proteinuria and a reduction of 23 percent in the rate of decline in renal function. The overall incidence of major adverse events in the benazepril and placebo subgroups of group 2 was similar.
Conclusions Benazepril conferred substantial renal benefits in patients without diabetes who had advanced renal insufficiency. (ClinicalTrials.gov number, NCT00270426 .)
Angiotensin-converting–enzyme (ACE) inhibitors slow the progression of chronic kidney disease in the presence or absence of diabetes, particularly in patients with mild-to-moderate renal insufficiency, as reflected by a serum creatinine level of 1.5 to 3.0 mg per deciliter (133 to 265 μmol per liter).1,2,3 Data, however, have been limited to patients with serum creatinine levels of 3.0 mg per deciliter or less. Many physicians are reluctant to use ACE inhibitors in patients with advanced renal insufficiency because of concern that serum creatinine or potassium levels will rise.4,5 Many infer that the unique benefits of these drugs in patients with advanced renal failure might not be superior to those afforded by blood-pressure control alone.4 As a result, patients with advanced chronic kidney disease have not been included in prospective, large-scale clinical trials of ACE inhibitors.1,6 Consequently, the renal outcome and the risk–benefit profile of ACE inhibitors in this population remain poorly defined.
In China, the primary cause of end-stage renal disease is nondiabetic chronic kidney disease.7,8 In 1999, 41,000 registered patients were receiving dialysis, accounting for 5 percent of the total population requiring renal-replacement therapy.7 Thus, therapy that could delay the progression of chronic kidney disease to end-stage renal disease is an essential management goal. Our previous open-label study involving a small number of patients with advanced chronic renal disease, some with and some without diabetes, suggested that benazepril, a nonsulfhydryl-containing ACE inhibitor, may confer renal benefits.9 The present randomized, double-blind study was designed to determine whether benazepril could slow the progression of renal dysfunction in patients without diabetes who had advanced renal insufficiency.
Methods
Study Design
The study was conducted at the Nanfang Hospital Renal Division, a center of kidney disease care in southern China. The catchment area of the center includes eight cities near Guangzhou with a total population of 29.8 million as of 2000. The principal investigator and the steering committee designed the study and wrote the article. An adjudicating committee, whose members were unaware of patients' treatment assignments, reviewed the data to determine which patients had reached study end points; this committee also evaluated safety. The study protocol was approved by the Nanfang Ethics Committee, and all subjects provided written informed consent. A study period of three years was chosen on the basis of the results of previous trials involving patients with nondiabetic chronic kidney disease, which suggested that a three-year follow-up is adequate to assess efficacy.1,2
Patients
Between May 1999 and May 2001, we screened consecutive patients with chronic kidney disease who were 18 to 70 years of age. All the patients were Chinese. Eligible patients had not received ACE inhibitors or angiotensin II–receptor antagonists for at least six weeks before screening and met the following inclusion criteria: a serum creatinine level of 1.5 to 5.0 mg per deciliter (133 to 442 μmol per liter) and a creatinine clearance10 of 20 to 70 ml per minute per 1.73 m2, with variations of less than 30 percent in the three months before screening; nondiabetic renal disease (as established on the basis of their history and the results of serum biochemical tests and renal biopsy); and persistent proteinuria (defined by urinary protein excretion of more than 0.3 g per day for three or more months without evidence of urinary tract infection or overt heart failure ). Exclusion criteria included an immediate need for dialysis; current treatment with corticosteroids, nonsteroidal antiinflammatory drugs, or immunosuppressive drugs; renovascular disease; myocardial infarction or cerebrovascular accident in the year preceding the trial; connective-tissue disease; and obstructive uropathy.
Treatment
Eligible patients were divided into two groups according to their serum creatinine levels: group 1 consisted of patients with serum creatinine levels of 1.5 to 3.0 mg per deciliter, and group 2 consisted of patients with serum creatinine levels of 3.1 to 5.0 mg per deciliter (274 to 442 μmol per liter). All patients entered an eight-week run-in phase during which they received 10 mg of benazepril per day for four weeks under close observation, including weekly measurements of blood pressure, serum creatinine, and serum potassium. The dose of benazepril was increased to 10 mg twice daily for an additional four weeks if serum creatinine levels remained unchanged or increased less than 30 percent, serum potassium levels remained below 5.6 mmol per liter, and no adverse events were reported. Open-label antihypertensive agents (diuretics, calcium-channel antagonists, alpha- or beta-blockers, or some combination of these medications, excluding ACE inhibitors and angiotensin II–receptor antagonists) were added as necessary to achieve a systolic blood pressure of less than 130 mm Hg and a diastolic blood pressure of less than 80 mm Hg.
After the run-in phase, benazepril was discontinued for three weeks and alternative antihypertensive agents (as described above) were administered as necessary to maintain blood-pressure control. After three weeks, all patients in group 1 received 10 mg of benazepril twice daily. Because of the known renal protective effects of ACE inhibitors in patients with this stage of chronic kidney disease, the ethics committee decided that these patients should not receive placebo. Patients in group 2 were randomly assigned to receive either 10 mg of benazepril twice daily or placebo, along with conventional antihypertensive therapy as required. A computer-generated list, maintained by a party not involved in the conduct of the study, was used for randomization.
A physician who was unaware of the patients' treatment assignments examined each patient every two weeks during the first month and every three months thereafter. At each examination, blood pressure was measured while the patient was seated three to four hours after the administration of the study drug and laboratory measurements were performed to assess whether adverse events had occurred or end points had been reached.
All patients were advised to reduce their salt intake to approximately 5 to 7 g of sodium chloride per day, to eat 0.5 to 0.7 g of protein per kilogram of body weight per day, and to restrict their intake of foods rich in potassium. Dietary compliance was assessed by evaluating daily urinary urea and chloride excretion.
Outcome Measures
The primary efficacy measure was the time to the first event in the composite end point of a doubling of the serum creatinine level, end-stage renal disease, or death. A doubling of the serum creatinine level was defined as two serum creatinine values obtained at least four weeks apart that were twice the baseline value. End-stage renal disease was defined by the need for long-term dialysis or renal transplantation.
Secondary end points included changes in the rate of urinary protein excretion and the progression of renal disease, as assessed by the reciprocal of the serum creatinine level,11 creatinine clearance, and the glomerular filtration rate, as calculated with the use of the four-component Modification of Diet in Renal Disease equation incorporating age, race, sex, and serum creatinine level12,13,14,15: estimated glomerular filtration rate = 186 x (serum creatinine level )–1.154 x (age )–0.203. For women, the product of this equation was multiplied by a correction factor of 0.742.
Statistical Analysis
The sample size was estimated before the study with the use of nQuery Advisor software. Our preliminary study9 of the treatment of patients with advanced renal dysfunction showed that the two-year rate of the primary end point among patients who were not taking an ACE inhibitor was 60 percent. It was estimated that ACE-inhibitor treatment would reduce this rate to 40 percent. Thus, the enrollment of 100 patients per group would provide the study with a statistical power of 80 percent at a two-sided significance level of 0.05.
The primary and secondary end points were analyzed according to the intention-to-treat principle. A Cox regression model was used to determine the hazard ratio for the primary end point. The risk reduction was calculated as 100 percent x (1 – the hazard ratio). Event curves are based on Kaplan–Meier analysis, and significance was assessed by means of the log-rank test.
Changes in the level of urinary protein excretion, creatinine clearance, and blood pressure were analyzed by repeated-measures analysis of variance. To identify interactions between the treatment groups and blood pressure, we used proportional-hazards regression and the most recent measurement of mean arterial pressure as a time-varying covariate. The relationship between the reduction in proteinuria and the rate of the decline in renal function was analyzed by Pearson correlation. SPSS software for Windows (version 12.0) was used for analyses.
Results
We screened 468 patients, and 422 entered the run-in phase: 141 had a serum creatinine level of 1.5 to 3.0 mg per deciliter and were therefore in group 1, and 281 had a serum creatinine level of 3.1 to 5.0 mg per deciliter and were thus in group 2 (Figure 1). Before randomization, 94 patients were excluded: 72 patients had a dry cough (17 percent, 30 in group 1 and 42 in group 2), 9 had an acute increase in the serum creatinine level of more than 30 percent (2 percent, 3 in group 1 and 6 in group 2), 5 had an increase in the serum potassium level to more than 5.6 mmol per liter (1 percent, 1 in group 1 and 4 in group 2), and 8 had a rate of adherence to medication of less than 80 percent (2 percent, 3 in group 1 and 5 in group 2). There were no significant differences in these events between the two groups.
Figure 1. Enrollment and Outcomes.
All 104 patients in group 1 received 20 mg of benazepril per day, whereas in group 2, 112 patients were randomly assigned to receive 20 mg of benazepril per day and 112 were assigned to receive placebo. The baseline characteristics of the patients were similar in the two subgroups of group 2 (Table 1). The average age and the distribution of the primary causes of renal dysfunction in the various groups were similar to those reported in the registry of the Chinese Society of Nephrology.7 The mean length of follow-up was 3.4 years (range, 2 to 5). Eleven patients were lost to follow-up (2 in group 1, 5 assigned to benazepril in group 2, and 4 assigned to placebo in group 2), leaving 102 patients in group 1 and 215 patients in group 2 (107 assigned to benazepril and 108 assigned to placebo) who could be included in the efficacy analysis.
Table 1. Baseline Characteristics of the Patients with Chronic Kidney Disease.
Primary Outcomes
In group 2, 44 patients assigned to benazepril reached the primary end point, as compared with 65 patients assigned to placebo (41 percent vs. 60 percent, P=0.004) (Figure 2). However, renal outcome, as measured by the number of patients who reached the primary end point, was worse among patients assigned to benazepril in group 2 than among patients in group 1, even though all patients received the same dose of benazepril (P=0.003) (Figure 2).
Figure 2. Kaplan–Meier Estimates of the Percentage of Patients Not Reaching the Primary Composite End Point of a Doubling of the Serum Creatinine Level, End-Stage Renal Disease, or Death.
Group 1 had a serum creatinine level of 1.5 to 3.0 mg per deciliter, and group 2 had a serum creatinine level of 3.1 to 5.0 mg per deciliter at baseline.
In group 2, treatment with benazepril, as compared with placebo, resulted in a 43 percent overall reduction in the risk of the primary end point (P=0.005). The decrease in the risk (hazard rate, 40 percent) remained significant after adjustment for differences in the mean arterial pressure (P=0.009). The intention-to-treat analyses of the individual components of the primary end point indicated that the risk of a doubling of the serum creatinine level was 51 percent lower among patients who received benazepril than among those given placebo (P=0.02). Benazepril also reduced the risk of end-stage renal disease by 40 percent (P=0.02).
Blood Pressure
Classes of conventional antihypertensive drugs used before and during the study are listed in Table 2. Blood pressure declined progressively during the study (Figure 3A). The decline in blood pressure was similar in the two groups (P=0.26) and in the two subgroups of group 2 (P=0.18).
Table 2. Use of Conventional Antihypertensive Medications at Baseline and during Study Treatment.
Figure 3. Changes in Blood Pressure (Panel A), the Level of Proteinuria (Panel B), and Creatinine Clearance (Panel C) during Follow-up.
Group 1 had a serum creatinine level of 1.5 to 3.0 mg per deciliter, and group 2 had a serum creatinine level of 3.1 to 5.0 mg per deciliter at baseline.
Secondary Outcomes
In group 2, there was a significantly greater reduction in the level of proteinuria among patients assigned to benazepril than among those assigned to placebo (52 percent vs. 20 percent, P<0.001) (Figure 3B). Urinary protein excretion was also decreased in group 1, with an average reduction of 49 percent (P=0.57 for the comparison with patients assigned to benazepril in group 2) (Figure 3B). Benazepril also reduced the rate of decline in renal function by 23 percent in group 2, as assessed by the reciprocal of the serum creatinine level (median slope, –0.09 dl per milligram per year among those assigned to benazepril, as compared with –0.11 dl per milligram per year among those assigned to placebo; P=0.02).
Likewise, benazepril was associated with a 24 percent reduction in the estimated decline in the glomerular filtration rate in group 2: the median rate of decline was 6.8 ml per minute per 1.73 m2 per year among the patients assigned to benazepril, as compared with 8.8 ml per minute per 1.73 m2 per year among the patients assigned to placebo (P=0.006). There was no significant difference between the two benazepril groups in the rate of decline in the estimated glomerular filtration rate (P=0.23) or creatinine clearance (P=0.19) (Figure 3C). However, there was a significant correlation between the extent of the reduction in proteinuria and the rate of decline in both the estimated glomerular filtration rate (P=0.03) and creatinine clearance (P=0.03) in patients with proteinuria of at least 1 g per day at baseline.
Safety
One patient assigned to benazepril in group 2 died of pneumonia. The last measurement obtained in this patient showed good blood-pressure control (120/80 mm Hg) and a normal serum potassium level. There were no significant differences in the number of nonfatal cardiovascular events between the two groups or between the two subgroups in group 2 (Table 3). The incidence of other adverse events was also similar in the two groups and in the two subgroups of group 2. Hyperkalemia (defined as a serum potassium level of at least 6.0 mmol per liter) occurred in 11 patients (5 percent) in group 2. Of these 11 patients, 8 were successfully treated with dietary modifications, concomitant diuretic therapy, and optimized acid–base balance. The remaining three patients withdrew from the study. Follow-up serum potassium levels in group 2 were higher among patients receiving benazepril than among those receiving placebo (P=0.001), but the differences never exceeded 0.5 mmol per liter. In group 2, the proportion of patients receiving recombinant human erythropoietin, the mean dose of recombinant human erythropoietin, and hemoglobin levels were similar in the two subgroups at baseline and during the study (data not shown).
Table 3. Adverse Events after Randomization.
Discussion
Our findings indicate that benazepril, along with conventional antihypertensive treatment, as needed, confers renal protection in patients without diabetes who have advanced renal insufficiency. Benazepril therapy reduced the risk of the primary end point by 43 percent among patients quite close to end-stage renal disease during an average follow-up of 3.4 years. The difference between the slopes of the reciprocal of the serum creatinine level and the slower decline in creatinine clearance and the glomerular filtration rate with benazepril therapy provide further evidence of the renal protection afforded by this ACE inhibitor. Thus, the primary analysis of this controlled trial provides evidence that treatment with the ACE inhibitor benazepril is beneficial in patients with stage 4 chronic kidney disease (defined by a glomerular filtration rate of 15 to 29 ml per minute per 1.73 m2). Although a previous secondary analysis suggested a benefit of ACE inhibitors among patients with severe renal dysfunction,16 evidence from a randomized, controlled trial is necessary to confirm the efficacy and tolerability of these agents in this patient population. Since current information indicates that 85 percent of patients with stage 4 chronic kidney disease are not offered such renal protective treatment,16 our results may have important implications for the development of new therapeutic guidelines.
Consistent with previous findings,16,17 our data suggest that the response to ACE inhibitors was independent of the baseline glomerular filtration rate. The rate of decrease in the glomerular filtration rate appeared to be higher among patients in group 2 than among those in group 1 and was moderately reduced by ACE inhibitors. This observation is consistent with the report that enalapril slowed the progression of advanced chronic kidney disease in patients without diabetes.18 The higher proportion of patients reaching the primary end point in group 2 might be explained by the fact that the ACE-inhibitor–associated reduction in risk is time-dependent18,19 and that patients with advanced chronic kidney disease had been treated for a shorter period than those with more preserved renal function. Thus, to achieve maximal renal protection, treatment with ACE inhibitors should arguably be initiated at earlier stages of chronic kidney disease.
Our study was also designed to determine whether the renal protective effect of benazepril in patients with advanced chronic kidney disease is dependent on its antihypertensive action. Blood pressure and the use of conventional antihypertensive drugs were similar at baseline and during treatment in both subgroups of group 2. Furthermore, the reduction in the risk of the primary end point changed little after correction for blood pressure, suggesting that the renal protection conferred by benazepril is not dependent on blood pressure when the drug is used as part of combination antihypertensive therapy.
The most striking difference between the patients who received benazepril and the patients who received placebo in group 2 was the change in urinary protein excretion. Benazepril greatly reduced urinary protein excretion in patients with advanced chronic kidney disease. This observation, as well as the close correlation between the extent of the reduction in proteinuria and the rate of decline in renal function, provides further support for, but does not prove, the hypothesis that proteinuria has a causal role in the progression of renal dysfunction.17,20
Patients with stage 4 chronic kidney disease are particularly vulnerable to the effects of ACE inhibitors on the glomerular filtration rate and potassium excretion.21,22 For safety's sake, as well as because of the higher incidence of dry cough among Chinese patients taking ACE inhibitors than among other ethnic groups receiving these drugs,23 we treated all eligible patients with benazepril and observed them closely during the run-in period. Dry cough and an acute increase in the serum creatinine level occurred mostly within the first two months after the initiation of benazepril therapy, but there were no significant differences in the incidence of these adverse events between patients in group 1 and those in group 2. Benazepril-associated cough was reported in 17 percent of patients during the run-in period, though as compared with patients in other studies, fewer of those with cough reported that this was an intolerable side effect.23 Nine patients had an increase in the serum creatinine level that exceeded 30 percent during the run-in phase, and five patients were evaluated for renal-artery stenosis (two in group 1 and three in group 2).
In the cohort with advanced renal dysfunction, the tolerability of benazepril and placebo was similar, as evidenced by the similar incidence of major adverse events in the two subgroups. As predicted, a nonsignificant trend toward a higher frequency of hyperkalemia was observed in group 2 as compared with group 1. However, the incidence of hyperkalemia was similar among patients who received benazepril and those who received placebo in group 2, and benazepril therapy resulted in an average increase in the serum potassium level that never exceeded 0.5 mmol per liter. Furthermore, benazepril had no significant effects on patients' hemoglobin levels or the dose of recombinant human erythropoietin. These data suggest that the addition of benazepril to a conventional regimen of antihypertensive therapy is acceptable, even in patients with serum creatinine levels exceeding 3.0 mg per deciliter. Nonetheless, blood pressure, renal function, and serum potassium levels should be monitored regularly in patients with advanced chronic kidney disease, especially during the first two months of ACE-inhibitor therapy and as renal function changes.
In summary, benazepril therapy was associated with a significant improvement in renal outcome and surpassed that attributable to blood-pressure control in patients without diabetes who had advanced renal dysfunction.
Supported by a National Nature and Sciences Grant for Major Projects (30330300) and a People's Liberation Army Grant for Major Clinical Research (to Dr. Hou) and in part by Novartis.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Renal Division, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Address reprint requests to Dr. Hou at the Renal Division, Nanfang Hospital, 1838 N. Guangzhou Ave., Guangzhou 510515, China, or at ffhou@public.guangzhou.gd.cn.
References
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.
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Ruggenenti P, Perna A, Benini R, Remuzzi G. Effects of dihydropyridine calcium channel blockers, angiotensin-converting enzyme inhibition, and blood pressure control on chronic, nondiabetic nephropathies. J Am Soc Nephrol 1998;9:2096-2101.
Bakris GL, Weir MR. Angiotensin-converting enzyme inhibitor-associated elevations in serum creatinine: is this a cause for concern? Arch Intern Med 2000;160:685-693.
Moser M. Angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists and calcium channel blocking agents: a review of potential benefits and possible adverse reactions. J Am Coll Cardiol 1997;29:1414-1421.
Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med 1993;329:1456-1462.
Dialysis and Transplantation Registration Group, Chinese Society of Nephrology. The report about the registration of dialysis and transplantation in China 1999. Chin J Nephrol 2001;17:77-8.
Hou FF, Ma ZG, Mei CL, et al. Cardiovascular disease in Chinese chronic renal insufficiency patients -- epidemiology survey. Zhonghua Yi Xue Za Zhi 2005;85:458-463.
Zhang GH, Hou FF, Zhang X, Liu QF. Can angiotensin-converting enzyme inhibitor be used in chronic kidney disease patients with serum creatinine level greater than 266 micromol/L? Zhonghua Nei Ke Za Zhi 2005;44:592-596.
Levey AS. Clinical evaluation of renal function. In: Greenberg A, ed. Primer on kidney diseases. 2nd ed. San Diego, Calif.: Academic Press, 1998:20-6.
Mitch WE, Walser M, Buffington GA, Lemann J Jr. A simple method of estimating progression of chronic renal failure. Lancet 1976;2:1326-1328.
Levey AS, Greene T, Kusek JW, Beck GJ. A simplified equation to predict glomerular filtration rate from serum creatinine. J Am Soc Nephrol 2000;11:155A-155A. abstract.
Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med 1999;130:461-470.
Coresh J, Astor BC, McQuillan G, et al. Calibration and random variation of the serum creatinine assay as critical elements of using equations to estimate glomerular filtration rate. Am J Kidney Dis 2002;39:920-929.
Zuo L, Ma YC, Zhou YH, Wang M, Xu GB, Wang HY. Application of GFR-estimating equations in Chinese patients with chronic kidney disease. Am J Kidney Dis 2005;45:463-472.
Ruggenenti P, Perna A, Remuzzi G, Gruppo Italiano di Studi Epidemiologici in Nefrologia. ACE inhibitors to prevent end-stage renal disease: when to start and why possibly never to stop: a post hoc analysis of the REIN trial results. J Am Soc Nephrol 2001;12:2832-2837.
Ruggenenti P, Perna A, Mosconi L, Pisoni R, Remuzzi G. Urinary protein excretion rate is the best independent predictor of ESRF in non-diabetic proteinuric chronic nephropathies. Kidney Int 1998;53:1209-1216.
Ihle BU, Whitworth JA, Shahinfar S, Cnaan A, Kincaid-Smith PS, Becker GJ. Angiotensin-converting enzyme inhibition in nondiabetic progressive renal insufficiency: a controlled double-blind trial. Am J Kidney Dis 1996;27:489-495.
Ruggenenti P, Perna A, Benini R, et al. In chronic nephropathies prolonged ACE inhibition can induce remission: dynamics of time-dependent changes in GFR. J Am Soc Nephrol 1999;10:997-1006.
Peterson JC, Adler S, Burkart JM, et al. Blood pressure control, proteinuria, and the progression of renal disease: the Modification of Diet in Renal Disease Study. Ann Intern Med 1995;123:754-762.
Reams GP, Bauer JH. Effect of lisinopril monotherapy on renal hemodynamics. Am J Kidney Dis 1988;11:499-507.
Reardon LC, Macpherson DS. Hyperkalemia in outpatients using angiotensin-converting enzyme inhibitors: how much should we worry? Arch Intern Med 1998;158:26-32.
Tomlinson B, Woo J, Thomas GN, Chau YM, Critchley JA. Randomized, controlled, parallel-group comparison of ambulatory and clinic blood pressure responses to amlodipine or enalapril during and after treatment in adult Chinese patients with hypertension. Clin Ther 2004;26:1292-1304.(Fan Fan Hou, M.D., Ph.D.,)
Background Angiotensin-converting–enzyme inhibitors provide renal protection in patients with mild-to-moderate renal insufficiency (serum creatinine level, 3.0 mg per deciliter or less). We assessed the efficacy and safety of benazepril in patients without diabetes who had advanced renal insufficiency.
Methods We enrolled 422 patients in a randomized, double-blind study. After an eight-week run-in period, 104 patients with serum creatinine levels of 1.5 to 3.0 mg per deciliter (group 1) received 20 mg of benazepril per day, whereas 224 patients with serum creatinine levels of 3.1 to 5.0 mg per deciliter (group 2) were randomly assigned to receive 20 mg of benazepril per day (112 patients) or placebo (112 patients) and then followed for a mean of 3.4 years. All patients received conventional antihypertensive therapy. The primary outcome was the composite of a doubling of the serum creatinine level, end-stage renal disease, or death. Secondary end points included changes in the level of proteinuria and the rate of progression of renal disease.
Results Of 102 patients in group 1, 22 (22 percent) reached the primary end point, as compared with 44 of 108 patients given benazepril in group 2 (41 percent) and 65 of 107 patients given placebo in group 2 (60 percent). As compared with placebo, benazepril was associated with a 43 percent reduction in the risk of the primary end point in group 2 (P=0.005). This benefit did not appear to be attributable to blood-pressure control. Benazepril therapy was associated with a 52 percent reduction in the level of proteinuria and a reduction of 23 percent in the rate of decline in renal function. The overall incidence of major adverse events in the benazepril and placebo subgroups of group 2 was similar.
Conclusions Benazepril conferred substantial renal benefits in patients without diabetes who had advanced renal insufficiency. (ClinicalTrials.gov number, NCT00270426 .)
Angiotensin-converting–enzyme (ACE) inhibitors slow the progression of chronic kidney disease in the presence or absence of diabetes, particularly in patients with mild-to-moderate renal insufficiency, as reflected by a serum creatinine level of 1.5 to 3.0 mg per deciliter (133 to 265 μmol per liter).1,2,3 Data, however, have been limited to patients with serum creatinine levels of 3.0 mg per deciliter or less. Many physicians are reluctant to use ACE inhibitors in patients with advanced renal insufficiency because of concern that serum creatinine or potassium levels will rise.4,5 Many infer that the unique benefits of these drugs in patients with advanced renal failure might not be superior to those afforded by blood-pressure control alone.4 As a result, patients with advanced chronic kidney disease have not been included in prospective, large-scale clinical trials of ACE inhibitors.1,6 Consequently, the renal outcome and the risk–benefit profile of ACE inhibitors in this population remain poorly defined.
In China, the primary cause of end-stage renal disease is nondiabetic chronic kidney disease.7,8 In 1999, 41,000 registered patients were receiving dialysis, accounting for 5 percent of the total population requiring renal-replacement therapy.7 Thus, therapy that could delay the progression of chronic kidney disease to end-stage renal disease is an essential management goal. Our previous open-label study involving a small number of patients with advanced chronic renal disease, some with and some without diabetes, suggested that benazepril, a nonsulfhydryl-containing ACE inhibitor, may confer renal benefits.9 The present randomized, double-blind study was designed to determine whether benazepril could slow the progression of renal dysfunction in patients without diabetes who had advanced renal insufficiency.
Methods
Study Design
The study was conducted at the Nanfang Hospital Renal Division, a center of kidney disease care in southern China. The catchment area of the center includes eight cities near Guangzhou with a total population of 29.8 million as of 2000. The principal investigator and the steering committee designed the study and wrote the article. An adjudicating committee, whose members were unaware of patients' treatment assignments, reviewed the data to determine which patients had reached study end points; this committee also evaluated safety. The study protocol was approved by the Nanfang Ethics Committee, and all subjects provided written informed consent. A study period of three years was chosen on the basis of the results of previous trials involving patients with nondiabetic chronic kidney disease, which suggested that a three-year follow-up is adequate to assess efficacy.1,2
Patients
Between May 1999 and May 2001, we screened consecutive patients with chronic kidney disease who were 18 to 70 years of age. All the patients were Chinese. Eligible patients had not received ACE inhibitors or angiotensin II–receptor antagonists for at least six weeks before screening and met the following inclusion criteria: a serum creatinine level of 1.5 to 5.0 mg per deciliter (133 to 442 μmol per liter) and a creatinine clearance10 of 20 to 70 ml per minute per 1.73 m2, with variations of less than 30 percent in the three months before screening; nondiabetic renal disease (as established on the basis of their history and the results of serum biochemical tests and renal biopsy); and persistent proteinuria (defined by urinary protein excretion of more than 0.3 g per day for three or more months without evidence of urinary tract infection or overt heart failure ). Exclusion criteria included an immediate need for dialysis; current treatment with corticosteroids, nonsteroidal antiinflammatory drugs, or immunosuppressive drugs; renovascular disease; myocardial infarction or cerebrovascular accident in the year preceding the trial; connective-tissue disease; and obstructive uropathy.
Treatment
Eligible patients were divided into two groups according to their serum creatinine levels: group 1 consisted of patients with serum creatinine levels of 1.5 to 3.0 mg per deciliter, and group 2 consisted of patients with serum creatinine levels of 3.1 to 5.0 mg per deciliter (274 to 442 μmol per liter). All patients entered an eight-week run-in phase during which they received 10 mg of benazepril per day for four weeks under close observation, including weekly measurements of blood pressure, serum creatinine, and serum potassium. The dose of benazepril was increased to 10 mg twice daily for an additional four weeks if serum creatinine levels remained unchanged or increased less than 30 percent, serum potassium levels remained below 5.6 mmol per liter, and no adverse events were reported. Open-label antihypertensive agents (diuretics, calcium-channel antagonists, alpha- or beta-blockers, or some combination of these medications, excluding ACE inhibitors and angiotensin II–receptor antagonists) were added as necessary to achieve a systolic blood pressure of less than 130 mm Hg and a diastolic blood pressure of less than 80 mm Hg.
After the run-in phase, benazepril was discontinued for three weeks and alternative antihypertensive agents (as described above) were administered as necessary to maintain blood-pressure control. After three weeks, all patients in group 1 received 10 mg of benazepril twice daily. Because of the known renal protective effects of ACE inhibitors in patients with this stage of chronic kidney disease, the ethics committee decided that these patients should not receive placebo. Patients in group 2 were randomly assigned to receive either 10 mg of benazepril twice daily or placebo, along with conventional antihypertensive therapy as required. A computer-generated list, maintained by a party not involved in the conduct of the study, was used for randomization.
A physician who was unaware of the patients' treatment assignments examined each patient every two weeks during the first month and every three months thereafter. At each examination, blood pressure was measured while the patient was seated three to four hours after the administration of the study drug and laboratory measurements were performed to assess whether adverse events had occurred or end points had been reached.
All patients were advised to reduce their salt intake to approximately 5 to 7 g of sodium chloride per day, to eat 0.5 to 0.7 g of protein per kilogram of body weight per day, and to restrict their intake of foods rich in potassium. Dietary compliance was assessed by evaluating daily urinary urea and chloride excretion.
Outcome Measures
The primary efficacy measure was the time to the first event in the composite end point of a doubling of the serum creatinine level, end-stage renal disease, or death. A doubling of the serum creatinine level was defined as two serum creatinine values obtained at least four weeks apart that were twice the baseline value. End-stage renal disease was defined by the need for long-term dialysis or renal transplantation.
Secondary end points included changes in the rate of urinary protein excretion and the progression of renal disease, as assessed by the reciprocal of the serum creatinine level,11 creatinine clearance, and the glomerular filtration rate, as calculated with the use of the four-component Modification of Diet in Renal Disease equation incorporating age, race, sex, and serum creatinine level12,13,14,15: estimated glomerular filtration rate = 186 x (serum creatinine level )–1.154 x (age )–0.203. For women, the product of this equation was multiplied by a correction factor of 0.742.
Statistical Analysis
The sample size was estimated before the study with the use of nQuery Advisor software. Our preliminary study9 of the treatment of patients with advanced renal dysfunction showed that the two-year rate of the primary end point among patients who were not taking an ACE inhibitor was 60 percent. It was estimated that ACE-inhibitor treatment would reduce this rate to 40 percent. Thus, the enrollment of 100 patients per group would provide the study with a statistical power of 80 percent at a two-sided significance level of 0.05.
The primary and secondary end points were analyzed according to the intention-to-treat principle. A Cox regression model was used to determine the hazard ratio for the primary end point. The risk reduction was calculated as 100 percent x (1 – the hazard ratio). Event curves are based on Kaplan–Meier analysis, and significance was assessed by means of the log-rank test.
Changes in the level of urinary protein excretion, creatinine clearance, and blood pressure were analyzed by repeated-measures analysis of variance. To identify interactions between the treatment groups and blood pressure, we used proportional-hazards regression and the most recent measurement of mean arterial pressure as a time-varying covariate. The relationship between the reduction in proteinuria and the rate of the decline in renal function was analyzed by Pearson correlation. SPSS software for Windows (version 12.0) was used for analyses.
Results
We screened 468 patients, and 422 entered the run-in phase: 141 had a serum creatinine level of 1.5 to 3.0 mg per deciliter and were therefore in group 1, and 281 had a serum creatinine level of 3.1 to 5.0 mg per deciliter and were thus in group 2 (Figure 1). Before randomization, 94 patients were excluded: 72 patients had a dry cough (17 percent, 30 in group 1 and 42 in group 2), 9 had an acute increase in the serum creatinine level of more than 30 percent (2 percent, 3 in group 1 and 6 in group 2), 5 had an increase in the serum potassium level to more than 5.6 mmol per liter (1 percent, 1 in group 1 and 4 in group 2), and 8 had a rate of adherence to medication of less than 80 percent (2 percent, 3 in group 1 and 5 in group 2). There were no significant differences in these events between the two groups.
Figure 1. Enrollment and Outcomes.
All 104 patients in group 1 received 20 mg of benazepril per day, whereas in group 2, 112 patients were randomly assigned to receive 20 mg of benazepril per day and 112 were assigned to receive placebo. The baseline characteristics of the patients were similar in the two subgroups of group 2 (Table 1). The average age and the distribution of the primary causes of renal dysfunction in the various groups were similar to those reported in the registry of the Chinese Society of Nephrology.7 The mean length of follow-up was 3.4 years (range, 2 to 5). Eleven patients were lost to follow-up (2 in group 1, 5 assigned to benazepril in group 2, and 4 assigned to placebo in group 2), leaving 102 patients in group 1 and 215 patients in group 2 (107 assigned to benazepril and 108 assigned to placebo) who could be included in the efficacy analysis.
Table 1. Baseline Characteristics of the Patients with Chronic Kidney Disease.
Primary Outcomes
In group 2, 44 patients assigned to benazepril reached the primary end point, as compared with 65 patients assigned to placebo (41 percent vs. 60 percent, P=0.004) (Figure 2). However, renal outcome, as measured by the number of patients who reached the primary end point, was worse among patients assigned to benazepril in group 2 than among patients in group 1, even though all patients received the same dose of benazepril (P=0.003) (Figure 2).
Figure 2. Kaplan–Meier Estimates of the Percentage of Patients Not Reaching the Primary Composite End Point of a Doubling of the Serum Creatinine Level, End-Stage Renal Disease, or Death.
Group 1 had a serum creatinine level of 1.5 to 3.0 mg per deciliter, and group 2 had a serum creatinine level of 3.1 to 5.0 mg per deciliter at baseline.
In group 2, treatment with benazepril, as compared with placebo, resulted in a 43 percent overall reduction in the risk of the primary end point (P=0.005). The decrease in the risk (hazard rate, 40 percent) remained significant after adjustment for differences in the mean arterial pressure (P=0.009). The intention-to-treat analyses of the individual components of the primary end point indicated that the risk of a doubling of the serum creatinine level was 51 percent lower among patients who received benazepril than among those given placebo (P=0.02). Benazepril also reduced the risk of end-stage renal disease by 40 percent (P=0.02).
Blood Pressure
Classes of conventional antihypertensive drugs used before and during the study are listed in Table 2. Blood pressure declined progressively during the study (Figure 3A). The decline in blood pressure was similar in the two groups (P=0.26) and in the two subgroups of group 2 (P=0.18).
Table 2. Use of Conventional Antihypertensive Medications at Baseline and during Study Treatment.
Figure 3. Changes in Blood Pressure (Panel A), the Level of Proteinuria (Panel B), and Creatinine Clearance (Panel C) during Follow-up.
Group 1 had a serum creatinine level of 1.5 to 3.0 mg per deciliter, and group 2 had a serum creatinine level of 3.1 to 5.0 mg per deciliter at baseline.
Secondary Outcomes
In group 2, there was a significantly greater reduction in the level of proteinuria among patients assigned to benazepril than among those assigned to placebo (52 percent vs. 20 percent, P<0.001) (Figure 3B). Urinary protein excretion was also decreased in group 1, with an average reduction of 49 percent (P=0.57 for the comparison with patients assigned to benazepril in group 2) (Figure 3B). Benazepril also reduced the rate of decline in renal function by 23 percent in group 2, as assessed by the reciprocal of the serum creatinine level (median slope, –0.09 dl per milligram per year among those assigned to benazepril, as compared with –0.11 dl per milligram per year among those assigned to placebo; P=0.02).
Likewise, benazepril was associated with a 24 percent reduction in the estimated decline in the glomerular filtration rate in group 2: the median rate of decline was 6.8 ml per minute per 1.73 m2 per year among the patients assigned to benazepril, as compared with 8.8 ml per minute per 1.73 m2 per year among the patients assigned to placebo (P=0.006). There was no significant difference between the two benazepril groups in the rate of decline in the estimated glomerular filtration rate (P=0.23) or creatinine clearance (P=0.19) (Figure 3C). However, there was a significant correlation between the extent of the reduction in proteinuria and the rate of decline in both the estimated glomerular filtration rate (P=0.03) and creatinine clearance (P=0.03) in patients with proteinuria of at least 1 g per day at baseline.
Safety
One patient assigned to benazepril in group 2 died of pneumonia. The last measurement obtained in this patient showed good blood-pressure control (120/80 mm Hg) and a normal serum potassium level. There were no significant differences in the number of nonfatal cardiovascular events between the two groups or between the two subgroups in group 2 (Table 3). The incidence of other adverse events was also similar in the two groups and in the two subgroups of group 2. Hyperkalemia (defined as a serum potassium level of at least 6.0 mmol per liter) occurred in 11 patients (5 percent) in group 2. Of these 11 patients, 8 were successfully treated with dietary modifications, concomitant diuretic therapy, and optimized acid–base balance. The remaining three patients withdrew from the study. Follow-up serum potassium levels in group 2 were higher among patients receiving benazepril than among those receiving placebo (P=0.001), but the differences never exceeded 0.5 mmol per liter. In group 2, the proportion of patients receiving recombinant human erythropoietin, the mean dose of recombinant human erythropoietin, and hemoglobin levels were similar in the two subgroups at baseline and during the study (data not shown).
Table 3. Adverse Events after Randomization.
Discussion
Our findings indicate that benazepril, along with conventional antihypertensive treatment, as needed, confers renal protection in patients without diabetes who have advanced renal insufficiency. Benazepril therapy reduced the risk of the primary end point by 43 percent among patients quite close to end-stage renal disease during an average follow-up of 3.4 years. The difference between the slopes of the reciprocal of the serum creatinine level and the slower decline in creatinine clearance and the glomerular filtration rate with benazepril therapy provide further evidence of the renal protection afforded by this ACE inhibitor. Thus, the primary analysis of this controlled trial provides evidence that treatment with the ACE inhibitor benazepril is beneficial in patients with stage 4 chronic kidney disease (defined by a glomerular filtration rate of 15 to 29 ml per minute per 1.73 m2). Although a previous secondary analysis suggested a benefit of ACE inhibitors among patients with severe renal dysfunction,16 evidence from a randomized, controlled trial is necessary to confirm the efficacy and tolerability of these agents in this patient population. Since current information indicates that 85 percent of patients with stage 4 chronic kidney disease are not offered such renal protective treatment,16 our results may have important implications for the development of new therapeutic guidelines.
Consistent with previous findings,16,17 our data suggest that the response to ACE inhibitors was independent of the baseline glomerular filtration rate. The rate of decrease in the glomerular filtration rate appeared to be higher among patients in group 2 than among those in group 1 and was moderately reduced by ACE inhibitors. This observation is consistent with the report that enalapril slowed the progression of advanced chronic kidney disease in patients without diabetes.18 The higher proportion of patients reaching the primary end point in group 2 might be explained by the fact that the ACE-inhibitor–associated reduction in risk is time-dependent18,19 and that patients with advanced chronic kidney disease had been treated for a shorter period than those with more preserved renal function. Thus, to achieve maximal renal protection, treatment with ACE inhibitors should arguably be initiated at earlier stages of chronic kidney disease.
Our study was also designed to determine whether the renal protective effect of benazepril in patients with advanced chronic kidney disease is dependent on its antihypertensive action. Blood pressure and the use of conventional antihypertensive drugs were similar at baseline and during treatment in both subgroups of group 2. Furthermore, the reduction in the risk of the primary end point changed little after correction for blood pressure, suggesting that the renal protection conferred by benazepril is not dependent on blood pressure when the drug is used as part of combination antihypertensive therapy.
The most striking difference between the patients who received benazepril and the patients who received placebo in group 2 was the change in urinary protein excretion. Benazepril greatly reduced urinary protein excretion in patients with advanced chronic kidney disease. This observation, as well as the close correlation between the extent of the reduction in proteinuria and the rate of decline in renal function, provides further support for, but does not prove, the hypothesis that proteinuria has a causal role in the progression of renal dysfunction.17,20
Patients with stage 4 chronic kidney disease are particularly vulnerable to the effects of ACE inhibitors on the glomerular filtration rate and potassium excretion.21,22 For safety's sake, as well as because of the higher incidence of dry cough among Chinese patients taking ACE inhibitors than among other ethnic groups receiving these drugs,23 we treated all eligible patients with benazepril and observed them closely during the run-in period. Dry cough and an acute increase in the serum creatinine level occurred mostly within the first two months after the initiation of benazepril therapy, but there were no significant differences in the incidence of these adverse events between patients in group 1 and those in group 2. Benazepril-associated cough was reported in 17 percent of patients during the run-in period, though as compared with patients in other studies, fewer of those with cough reported that this was an intolerable side effect.23 Nine patients had an increase in the serum creatinine level that exceeded 30 percent during the run-in phase, and five patients were evaluated for renal-artery stenosis (two in group 1 and three in group 2).
In the cohort with advanced renal dysfunction, the tolerability of benazepril and placebo was similar, as evidenced by the similar incidence of major adverse events in the two subgroups. As predicted, a nonsignificant trend toward a higher frequency of hyperkalemia was observed in group 2 as compared with group 1. However, the incidence of hyperkalemia was similar among patients who received benazepril and those who received placebo in group 2, and benazepril therapy resulted in an average increase in the serum potassium level that never exceeded 0.5 mmol per liter. Furthermore, benazepril had no significant effects on patients' hemoglobin levels or the dose of recombinant human erythropoietin. These data suggest that the addition of benazepril to a conventional regimen of antihypertensive therapy is acceptable, even in patients with serum creatinine levels exceeding 3.0 mg per deciliter. Nonetheless, blood pressure, renal function, and serum potassium levels should be monitored regularly in patients with advanced chronic kidney disease, especially during the first two months of ACE-inhibitor therapy and as renal function changes.
In summary, benazepril therapy was associated with a significant improvement in renal outcome and surpassed that attributable to blood-pressure control in patients without diabetes who had advanced renal dysfunction.
Supported by a National Nature and Sciences Grant for Major Projects (30330300) and a People's Liberation Army Grant for Major Clinical Research (to Dr. Hou) and in part by Novartis.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Renal Division, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Address reprint requests to Dr. Hou at the Renal Division, Nanfang Hospital, 1838 N. Guangzhou Ave., Guangzhou 510515, China, or at ffhou@public.guangzhou.gd.cn.
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