NEW YORK (Reuters Health) – As initial treatment of hypertension, a combination of benazepril plus amlodipine is more effective at preserving renal function compared to benazepril plus hydrochlorothiazide, investigators report.
They point out that while U.S. guidelines recommend that initial therapy of hypertension include a thiazide diuretic, studies have suggested that combining a renin-angiotensin system blocker – such as the angiotensin-converting enzyme (ACE) inhibitor benazepril – with a calcium channel blocker, such as amlodipine, has protective effects in the vasculature.
In the February 17 Online First issue of The Lancet, lead author Dr. George Bakris, from the University of Chicago, and his colleagues report on a prespecified analysis of data from the ACCOMPLISH study, a randomized trial in the U.S. and Europe that was stopped early when amlodipine plus benazepril proved more effective in reducing cardiovascular risk.
The current analysis focuses on the effects of treatment on chronic kidney disease outcomes.
All 11,506 participants took benazepril, 20 mg/day; after randomization, 5744 also took 5 mg of amlodipine, and the other 5762 took 12.5 mg of hydrochlorothiazide per day.
Benazepril was increased to 40 mg at one month, and after two months investigators titrated doses to achieve target blood pressures. Other drug classes could be added as needed. The prespecified renal outcome was a composite of doubling of serum creatinine and end-stage renal disease.
During a mean follow-up of 2.9 years, 113 patients (2.0%) in the amlodipine/benazepril group reached the prespecified outcome, vs 215 (3.7%) in the hydrochlorothiazide/benazepril group (HR 0.52, p < 0.0001).
Similarly, the combined endpoint of chronic kidney disease progression and all-cause mortality was lower in the amlodipine/benazepril group (6.0% vs 8.1%, HR 0.73, p < 0.001), and the decline in estimated glomerular filtration rate was smaller (-0.88 vs -4.22 mL/min/1.73 m2; p = 0.01).
In patients with chronic kidney disease, peripheral edema and angioedema were more frequent in the amlodipine group than in the hydrochlorothiazide group.
Dr. Bakris and colleagues report that people over age 75 had better chronic kidney disease outcomes with amlodipine/benazepril, and less dizziness and hypotension.
The researchers note that the ACCOMPLISH study was underpowered as a chronic kidney disease study. A prospective study in patients with more advanced nephropathy will be required to confirm their findings.
According to Dr. Hiddo Lambers Heerspink and Dr. Dick de Zeeuw from the University of Groningen, the Netherlands, “This renal outcome of the ACCOMPLISH trial is surprising,” because diuretics “enhance the alleged surrogate organ-protective properties” of ACE inhibitors, further lowering blood pressure, albuminuria, and intraglomerular pressure.
Dr. Heerspink and Dr. de Zeeuw point out in an editorial that the endpoint was driven by the doubling of serum creatinine, with no difference in end-stage renal disease. Furthermore, they say, declines in glomerular filtration rate over time may be influenced by other interventions – diet or medications, for example – and thus reflect a reversible hemodynamic change rather than a structural worsening of kidney function.
“Design and interpretation of this trial remains crucial before concluding that one drug combination is better than the other,” they conclude.
The ACCOMPLISH trial was funded by Novartis, which markets a benazepril/amlodipine combination as Lotrel and a benazepril/hydrochlorothiazide combination as Lotensin HCT/Cibadrex.