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Analysis of renal outcomes from ACCOMPLISH trial seem to favor addition of CCB rather than diuretic to ACE inhibitor therapy, although some researchers question findings

Tuesday, April 13 2010 | Comments

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What's This? Among patients with hypertension and a high risk of cardiovascular events, the combination of a calcium-channel blocker (CCB) and an angiotensin-converting enzyme (ACE) inhibitor may be preferable to a diuretic-ACE inhibitor combination for slowing the progression of nephropathy, according to data from a prespecified secondary analysis of the ACCOMPLISH trial.

However, in an accompanying editorial, researchers cautioned that the trial design and the interpretation of the data "should be more closely examined to verify the validity of the conclusions."

During the double-blind trial, 11,506 patients aged 55 years or older with hypertension and an increased risk of cardiovascular events were randomized to receive benazepril plus amlodipine or benazepril plus hydrochlorothiazide.

A prespecified endpoint of the trial was progression of chronic kidney disease (CKD), defined as a doubling of serum creatinine levels or end-stage renal disease (ESRD), with the latter defined as an estimated glomerular filtration rate (eGFR) <15 mL/min/1.73 m^2 or the need for dialysis.

During a mean follow-up of 2.9 years, there were 113 cases of the composite renal endpoint in the benazepril-amlodipine group (2%) and 215 cases in the benazepril-hydrochlorothiazide group (3.7%), yielding a hazard ratio (HR) for the composite endpoint of 0.52 (95% CI, 0.41-0.65; P<.0001) with amlodipine as compared with hydrochlorothiazide.

A similarly significant reduction in risk was observed with amlodipine when the combined endpoint of CKD progression and all-cause mortality was analyzed (6% vs 8.1%; HR, 0.73 [95% CI, 0.64-0.84]; P<.0001).

"This trial shows that in patients with hypertension at high risk for cardiovascular events, combination treatment with benazepril plus amlodipine reduces progression of CKD more effectively than does benazepril plus hydrochlorothiazide," the study authors wrote, adding that these findings could not be explained by the differences in blood pressure (BP) control during the trial. (Bakris GL, et al. Lancet 2010;375:1173-1181.)

However, in an accompanying editorial, Hiddo Lambers Heerspink and Dr. Dick de Zeeuw with the University of Groningen in the Netherlands criticized certain aspects of the trial design as well as the ACCOMPLISH authors' interpretation of the data.

Primarily, the editorialists explained, the composite renal endpoint was driven completely by a doubling of serum creatinine levels, with no between-group difference in rates of ESRD, which occurred infrequently. This finding, they suggested, should have prompted an analysis exploring whether between-group differences in the doubling of serum creatinine levels were due to a reversible hemodynamic effect on GFR or to a true effect on structural loss of renal function.

Other weaknesses that might undermine the authors' conclusions, the editorialists added, include reduced statistical power resulting from premature trial termination, the use of serum creatinine rather than GFR to assess changes in renal function, and the potential for bias due to the difference in BP control between the 2 groups (with a small [0.9/1.1 mm Hg] but significant difference favoring amlodipine). (Lancet 2010;375:1140-1142.)

This study was funded by Novartis AG.

This information concerns a use that has not been approved by the Food and Drug Administration.

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