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ACCOMPLISH: Nephropathy progression slower with benazepril–amlodipine
18 February 2010
MedWire News: Initial antihypertensive therapy with the combination of benazepril and amlodipine slows progression of nephropathy to a greater extent than does the combination of benazepril and hydrochlorothiazide (HCTZ), conclude the ACCOMPLISH trial investigators.
However, this result was driven primarily by a reduction in doubling of serum creatinine concentration. The investigators suggest that early termination of the trial may have limited the ability to discern a difference in progression to end-stage renal disease.
The ACCOMPLISH (Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension) trial included 11,506 patients with hypertension who were at high risk for cardiovascular disease owing to a history of coronary events, myocardial infarction, revascularization, stroke, chronic kidney disease (CKD), peripheral arterial disease, left ventricular hypertrophy, or diabetes.
As reported by MedWire, the trial was stopped early at a mean follow-up of 2.9 years because of the superior efficacy of the benazepril plus amlodipine combination in reducing cardiovascular events compared with benazepril plus HCTZ.
The present renal analysis shows that the prespecified endpoint of CKD progression, defined as doubling of serum creatinine concentration or end-stage renal disease (estimated glomerular filtration rate [eGFR] <15 ml/min/1.73 m2 or need for dialysis) occurred in 113 (2.0%) of the benazapril plus amlodipine group versus 215 (3.7%) of the benazepril plus HCTZ group. This equated to a significant near-halving of the relative risk for CKD progression, at a hazard ratio of 0.52 (p<0.0001).
The investigators note that blood-pressure control differences did not explain the finding.
A breakdown of the endpoint components showed that there was a significant reduction in serum creatinine concentration doubling (HR=0.51, p<0.0001) but a nonsignificant reduction in dialysis (HR=0.53; 95% CI: 021–1.35) and no difference in eGFR <15 ml/min/1.73 m2 (HR=1.06).
Reporting the results in The Lancet, the team comments that although a substantial proportion of patients enrolled had eGFR less than 60 ml/min/1.73 m2, only a very small proportion had albuminuria above 33.9 mg/mmol and were therefore at high risk for progression of CKD.
“A prospective study in patients with more advanced proteinuric nephropathy is needed to establish the superiority between these two different antihypertensive combination treatments on progression of CKD,” conclude George Bakris (University of Chicago, Illinois, USA) and team.
In an accompanying Comment article, Hiddo Lambers Heerspink and Dick de Zeeuw (University Medical Center Groningen, The Netherlands) say the result is “surprising” in light of apparently more favorable surrogate effects of the diuretic combination.
Although such effects do not always translate into benefits on hard endpoints, they add, “we believe that the ACCOMPLISH trial design and its interpretation should be more closely examined.”
In particular, they take issue with the composite endpoint used in the trial, as they say doubling of serum creatinine could reflect a reversible hemodynamic GFR change rather than structural worsening of kidney function.
Thus, they write, “when testing for renal outcome in trials, one should be certain that the doubling component is not driven by a hemodynamic effect alone, and that the end-stage renal disease part of the endpoint supports the doubling data.”
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