The results of ALLHAT challenged widely held beliefs about the renoprotective effect of renin-angiotensin-system (RAS) inhibition and so it is unsurprising that each of the correspondents raises this as an issue. However, it is the largest randomised double-blind trial with the longest follow-up of the effects of antihypertensive drugs on renal outcomes and it fulfilled our prespecified inclusion criteria. Exclusion of ALLHAT from our analysis would, quite rightly, have prompted great criticism since the trial provides around half the available evidence on renal outcomes.
Renal disease was a prespecified secondary outcome in the ALLHAT trial, not, as suggested by Hans-Henrik Parving and Peter Rossing, a post-hoc analysis.1
The incidence of competing cardiovascular endpoints was similar in all the ALLHAT treatment groups, so this is unlikely to introduce bias. The risk of developing end-stage renal disease varied substantially across all the studies, so it would be hard to justify excluding ALLHAT because of this. In any case one would generally expect the relative risk reduction to be independent of the absolute risk; indeed, treatment effects were similar in low-risk and high-risk patients in ALLHAT.2
If a weighted mean difference in systolic blood pressure of 2·5 mm Hg in the placebo-controlled trials referred to by Dick de Zeeuw and colleagues does not contribute to the benefits of RAS inhibition, then it is also unlikely to obscure the true effect of lisinopril in ALLHAT, as Amanda Adler and colleagues and de Zeeuw and colleagues suggest.
Parving and Rossing, as well as other correspondents, refer to “large trials” with renal outcomes that seem to support a beneficial effect of ACE inhibitors. However, to detect reliably an effect on end-stage renal disease by RAS inhibition of say a 10% relative risk reduction, a trial with an active comparator would need to recruit around 57 000 patients, and the only study that even approaches this size is ALLHAT.2
We addressed the discrepancy between large randomised trials and meta-analysis in our discussion.
We acknowledge that our definition of end-stage renal disease was reported incompletely; it did include peritoneal dialysis as an endpoint.
The treatment effect summary from a meta-analysis does not simply involve adding up all the events and individuals and treating them as a single large study, as Parving and Rossing suggest, without considering that they arise from different trials with different sample sizes. Trials without events in either group were excluded (as we stated in the supplementary information available online). However, the inclusion of the very small trials referred to by Parving and Rossing (three trials, 124 patients, and four renal events) yields a relative risk of 0·86 (95% CI 0·75—0·98), which is almost identical to the one we reported (0·87 [0·75—0.99]).
Johannes Mann and colleagues raise the issue of ecological fallacy in meta-regression analysis. If our meta-regression of blood pressure difference on renal outcomes is affected by this fallacy, then the conclusion must be that blood pressure is not itself a determinant of renal outcome. At least on this point the other correspondents seem to agree with us that it is.
We were aware of the possibility of selective reporting of outcomes and this was one reason for contacting study authors to obtain unpublished information. However, it is more likely that positive outcomes are selectively reported than negative ones, so if anything the effect sizes are likely to be even smaller than the ones we saw.
We disagree with Adler and colleagues about the mechanisms by which ACE inhibitors prevent cardiovascular events; this is achieved through blood-pressure reduction, as seems to be the case in renal disease. Thiazides4
or β blockers5
increase blood sugar by about 0·2 mmol/L, which is unlikely to destabilise diabetic control. Trials without blood pressure data represented only 9% of end-stage renal disease endpoints. The β coefficients for 1 mm Hg of systolic blood pressure difference were 0·03 (p=0·09) and 7·4 (p<0·001) for end-stage renal disease and albuminuria, respectively.
In response to de Zeeuw and colleagues and Mann and colleagues, good clinical practice involves appraising the totality of evidence relating to the effects of a treatment. Readers must decide whether misleading conclusions are more likely to arise from a systematic review of all relevant studies or a selective view of placebo-controlled data.
We do not say that renin-angiotensin inhibitors should not be used to lower blood pressure; indeed we expect that many patients will require treatment with more than one antihypertensive. Neither can we reliably exclude the possibility of a renoprotective effect over and above the effect of blood-pressure lowering. However, our study shows that there is an absence of evidence to support renoprotective effects of renin-angiotensin inhibitors independent of blood pressure lowering. The future challenge to trialists in nephrology is to design a randomised trial that compares RAS inhibitors with other antihypertensive drugs, and that has sufficient power to detect realistic reductions in clinically relevant endpoints.
ADH is a member of the Editorial Board of Drug and Therapeutics Bulletin. PV is a paid member of the Research Advisory Board for GlaxoSmithKline.