Amlodipine/Benazepril Best for Slowing Progression of Chronic Kidney Disease

February 18, 2010

February 18, 2010 (Chicago, Illinois) — Antihypertensive combination therapy with the angiotensin-converting enzyme (ACE) inhibitor benazepril plus the calcium-channel blocker amlodipine (Lotrel, Novartis) is more effective than treatment with the ACE inhibitor and a diuretic for slowing progression to chronic kidney disease (CKD), a new analysis shows [1]. After a mean follow-up of three years, amlodipine and benazepril significantly reduced the progression to CKD 48%, an absolute reduction of 1.7%, when compared with benazepril and hydrochlorothiazide.

"We wanted to see whether there would be a difference in the progression of kidney disease defined by the traditional criteria of doubling creatinine or progression to dialysis in this high-risk cardiovascular group," lead investigator Dr George Bakris (University of Chicago, IL) told heartwire . "Since we prespecified the end point, we had very definite criteria, so while this wasn't a primary outcome trial, it's about as close as you can get to one."

Published online February 18, 2010, in The Lancet, the findings are a prespecified analysis of the Avoiding Cardiovascular Events in Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial, a large morbidity and mortality study that compared the effects of two forms of antihypertensive combination therapies on major fatal and nonfatal cardiovascular events. Previously reported by heartwire , ACCOMPLISH showed that the single-tablet benazepril/amlodipine combination in high-risk hypertensive patients reduced the risk of morbidity and mortality by 20% compared with conventional therapy.

Assessing Treatment Effects on the Kidney

In this latest analysis, Bakris and colleagues assessed the effects of the drug combinations on the progression to CKD in 11 506 men and women aged 55 years or older who had systolic blood pressure >160 mm Hg. All patients were currently on antihypertensive therapy and had evidence of cardiovascular or renal disease or target-organ damage. The prespecified CKD end point was time to first event of doubling of serum creatinine concentration or end-stage renal disease, defined as an estimated glomerular filtration rate (eGFR) less than 15 mL/min/1.73 m2 or need for chronic dialysis.

After a mean follow-up of 2.9 years, 113 patients in the benazepril/amlodipine arm progressed to CKD compared with 215 patients treated with the benazepril/hydrochlorothiazide combination. This translated into an absolute risk reduction of 1.7%, or a 48% relative reduction in risk. Similarly, there were significant reductions in the combined renal and cardiovascular death end point, as well as reductions in renal and all-cause mortality events. Among the 1093 patients with CKD, the progression of disease did not alter between the two treatment arms.

Outcomes in the Intention-to-Treat Population

End point Benazepril plus amlodipine (n=5744), % Benazepril plus hydrochlorothiazide (n=5762), % Hazard ratio (95% CI)
Progression to CKD (primary end point) 1.97 3.73 0.52 (0.41–0.65)
Doubling of serum creatinine 1.83 3.61 0.51 (0.39–0.63)
Dialysis 0.12 0.23 0.53 (0.21–1.35)
eGFR <15 mL/min/1.73 m2 0.31 0.30 1.06 (0.54–2.05)
Progression to CKD and cardiovascular death 3.83 5.99 0.63 (0.53–0.74)
Progression to CKD and all-cause mortality 6.02 8.07 0.73 (0.64–0.84)

"Basically the study supports the notion--[incorporated] in the European guidelines--that you can start with any combination as long as you get good blood-pressure control, but if you start with agents that improve endothelial function, you have a better shot of getting an overall reduction in cardiovascular and renal events," said Bakris. "This is not to say not to use diuretics or diuretics don't work, it's not to say anything negative against them at all. It's just saying that there is nothing magical about starting with them initially."

In addition to the overall findings, researchers also showed a significant benefit in older individuals. Among those 65 years of age and older, the benazepril/amlodipine combination reduced the progression of CKD 50%, with similar reductions in the doubling of serum creatinine concentrations and a strong trend toward reductions in the need for chronic dialysis.

"This is really the first study to focus on an older age group and show a benefit of non–diuretic-based therapy in advanced kidney disease," added Bakris.

Change in GFR: A Hemodynamic Effect?

In an editorial accompanying the published study [2], Drs Hiddo Lambers Heerspink and Dick de Zeeuw (University of Groningen, Netherlands) argue that while the renal analysis is necessary to help clinicians make appropriate drug choices in high-risk patients, the design and interpretation of ACCOMPLISH "remain crucial before concluding that one drug combination is better than the other."

They point out that the trial was stopped early and as a result may lack statistical power.  They also take issue with measurements of changes in renal function, pointing out that changes were assessed by serum creatinine rather than true measurements of GFR. Specifically, they write that while a doubling of serum creatinine is an accepted part of a renal composite end point, because long-term changes in GFR are assumed to be related to declines in kidney function, hemodynamic effects might cause the change in the GFR.

"This point complicates interpretations of an end point that includes doubling of serum creatinine--the doubling could reflect a reversible hemodynamic GFR change or a structural worsening of kidney function," write Heerspink and de Zeeuw.

To heartwire , Bakris disputed this interpretation, saying that if that were true, results from other major trials, including RENAAL and IDNT, would be incorrectly interpreted as well. "Also, how do explain the difference in the dialysis rates?" said Bakris. "The hemodynamic argument is reasonable for short-term studies, but it's not a valid argument for studies with clinical outcomes. No hemodynamic effect is going to give you a doubling of creatinine, nor is it going to preserve or fallaciously increase kidney function after three years."

Bakris added that further study is still needed in patients with advanced proteinuric nephropathy. In ACCOMPLISH, the number of patients with proteinuria was small, an important caveat, he said, given new data suggesting that the level of proteinuria is an even better predictor of renal outcomes than the baseline level of GFR.

ACCOMPLISH was funded by Novartis. Bakris reports grants, consulting, or lecture fees from Novartis, Daiichi Sankyo, Merck, and Boehringer Ingelheim. Heerspink reports being an investigator on an Abbott-sponsored vitamin-D study. de Zeeuw has been involved in trials with AstraZeneca, Abbott, Amgen, Merck Sharp & Dohme, Novartis, and Johnson & Johnson; he has served as a consultant for Bristol-Myers Squibb, Noxxon, and Hemocue.