Secondary analysis of the ACCOMPLISH trial suggests that in high-risk patients, combining a calcium-channel blocker (CCB) rather than a diuretic with an ACE-inhibitor reduces progression of nephropathy. An accompanying Comment, however, advises caution in interpreting the results, as they are unexpected and the outcome used is problematic.

ACCOMPLISH was a large (n=11,506) randomised controlled trial that compared benazepril (a standard ACE-inhibitor no longer marketed in the UK) plus amlodipine with benazepril plus hydrochlorothiazide in patients with hypertension who were at high risk for cardiovascular events. Primary outcome was cardiovascular mortality and morbidity; progression of chronic kidney disease was a pre-specified secondary outcome and was defined as doubling of serum creatinine concentration or end-stage renal disease (ESRD). The study was stopped early after less than three years mean follow-up due to apparent superiority of the benazepril plus CCB combination.

This paper reports the analysis of the secondary outcome. In the intention to treat analysis, there were 113 (2.0%) outcome events in the benazepril plus CCB group compared with 215 (3.7%) in the benazepril plus hydrochlorothiazide group (HR 0.52, 95% CI, 0.41 to 0.65, p<0.0001).

The difference was driven entirely by differences in patients reaching the doubling of serum creatinine outcome, with very few progressing to ESRD and no significant difference between the groups on this.

Patients on the CCB combination were more likely to report peripheral oedema (33.7% vs. 16.0%), and those with pre-existing chronic kidney disease had a greater incidence of angio-oedema (1.6% vs. 0.4%).

The authors conclude that adding a CCB to an ACE-inhibitor as initial antihypertensive treatment slows the progression of nephropathy to a greater extent than adding a diuretic.

An accompanying Comment, the authors express surprise at the outcome in view of the already-known benefits of treatment with the ACE-inhibitor plus diuretic combination.

They note that the early termination of the trial reduced its power, however they suggest that the major problem with the study was the composite outcome used. While doubling serum creatinine is generally assumed to reflect long-term structural decline in renal function, there are many factors that can affect this in different ways. In particular, they note that CCB can induce a short term rise in estimated glomerular filtration rate (eGFR), whereas diuretics cause a short term decline. Neither of these appears to relate to any underlying structural effects. Other data from this trial, published elsewhere, indicate that this did occur and that the subsequent changes were similar in both groups.

The authors conclude that the similar long-term effect of both treatments suggest no difference between them in renal protective properties. Overall, they warn that composite outcomes must be interpreted cautiously when results are driven by a single component of the composite, and that the design and interpretation of this trial should be considered before concluding that one combination is better than the other.