Nondiabetic patients with advanced renal insufficiency showed evidence of renal protection from benazepril therapy, along with conventional antihypertensive treatment, reported Dr. Fan Fan Hou of the Nanfang Hospital of Southern Medical University in Guangzhou, China, and associates.
The investigators reported that they observed substantial renal benefits in patients with advanced (stage 4 chronic) renal insufficiency in a randomized, double-blind controlled trial of benazepril (N. Engl. J. Med. 2006;354:131–40).
Based on the findings of the study, Dr. Hou and co-investigators suggested that treatment with ACE inhibitors be initiated at earlier stages of chronic kidney disease. ACE inhibitors have been shown to slow the progression of chronic kidney disease, but until now they have been limited to patients with serum creatinine levels of 3.0 mg/dL or less.
The 3-year study was conducted at the Nanfang (China) Hospital renal division. Patients were aged 18–70 years and had not received ACE inhibitors or angiotensin II-receptor antagonists for at least 6 weeks before screening. They had persistent proteinuria with serum creatinine levels of 1.5–5.0 mg/dL and creatinine clearance of 20–70 mL/min per 1.73 m
The study excluded patients if they had conditions such as renovascular disease, connective tissue disease, or obstructive uropathy, as well as patients being treated with corticosteroids, nonsteroidal anti-inflammatory drugs, or immunosuppressive drugs in the year preceding the trial.
The patients were divided into two groups: group 1 included patients with serum creatinine levels of 1.5–3.0 mg/dL, and group 2 consisted of patients with levels of 3.1–5.0 mg/dL.
During an 8-week run-in phase, patients were given benazepril 10 mg/day for 4 weeks with close monitoring. Then the dosage of the medication was increased to 10 mg twice a day for 4 weeks, and open-label antihypertensive agents were added as necessary.
After the run-in phase, benazepril was discontinued for 3 weeks. Antihypertensive agents were continued to control blood pressure.
After the 3 weeks, all patients in group 1 were given 10 mg of benazepril twice a day. Group 2 patients received either 10 mg of benazepril twice daily or placebo and antihypertensive agents.
“[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,” they said.
Of the 422 patients who participated in the run-in phase, 104 in group 1 and 112 in group 2 were assigned to benazepril 20 mg/day; another 112 in group 2 were assigned to placebo.
After a mean follow-up of 3 years, 107 patients assigned to benazepril in group 2 and 108 assigned to placebo were included in the efficacy analysis.
A total of 44 patients in group 2 assigned to benazepril reached the primary end point, compared with 65 patients on placebo.
Although all patients who received benazepril took the same dose, renal outcome was worse in group 2 than in group 1.
Benazepril treatment of the participants in group 2 resulted in a 43% reduction in the risk of reaching the primary end point, compared with placebo, and reduced the risk of end-stage renal disease by 40%. Also in group 2, benazepril was associated with reduced severity of proteinuria, compared with placebo, and was associated with a 23% reduction in the rate of decline in renal function.
Dry cough and an acute increase in serum creatinine level were reported mainly in the first 2 months of benazepril therapy. The incidence of hyperkalemia in group 2 was similar for patients who received benazepril and those who received placebo.
In an editorial comment accompanying the report, Dr. Lee Hebert of Ohio State University, Columbus, wrote that “although their results indicate that it may be time to change our practice, a number of caveats should be considered before we do so” (N. Engl. J. Med. 2006;354:189–91).
He said that the researchers used only half the maximal recommended dose of benazepril for patients with chronic kidney disease, as well as a twice-daily regimen that provides little opportunity for nocturnal recovery from any hyperkalemia.
Dr. Hebert added that although the results of the study support the continuation of the ACE inhibitor benazepril for treatment of chronic kidney disease, whether other types of ACE inhibitors would achieve the same results is not clear.