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Renoprotection by blocking the RAAS in diabetic nephropathy—fact or fiction? Author's reply
James McGill Professor of Epidemiology, Biostatistics and Medicine, McGill University, Division of Clinical Epidemiology, Royal Victoria Hospital 687 Pine Ave West, R4.29 Montreal, Quebec H3A 1A1 Canada
Correspondence and offprint requests to: S. Suissa. Email: samy.suissa{at}clinepi.mcgill.ca
Sir,
Dr Rossing and colleagues comment on several recent studies of the renal effect of ACE-inhibitors in diabetic patients, including our recently published observational cohort study [1]. This commentary raises several questions. One of the strong points of our observational study is the long-term follow-up that permits one to assess the risk as a function of the duration of ACE-inhibitor treatment. Our observational study suggested that the renal failure risk was in fact reduced during the first 3 years of ACE-inhibitor use and only starts to be elevated subsequently. Thus, statements in the Commentary such as ‘demonstrating that in type I diabetic patients, ACE-inhibitors was associated with a 50% reduced risk of dialysis, transplantation or death’ do not in any way contradict the observational study since they apply to short-term trials, in this case a 3-year study. The principal message of our observational study is that ACE-inhibitors can certainly be renoprotective early on, but that this effect can be reversed after a long period of use.
We were well aware that such an observational study could be subject to confounding by indication. This is precisely why we selected the time period prior to the knowledge about potential renoprotective effects for cohort entry. The fact that patients who started ACE-inhibitor use prior to such knowledge and continued to use them for >3 years will not lead to confounding by indication. Instead, confounding by indication only relates to the patients who had not started to use captopril before these renal benefits were known, but instead started only after that time.
The issue of dose is interesting. On the one hand, the authors criticize the insufficiently low doses of ACE-inhibitors in the ALLHAT study, while at the same time suggesting that the possibly elevated doses of captopril in the observational study may explain these findings. This is indeed possible and provides an interesting challenge for the optimal dosing of these drugs in balancing between effectiveness and safety. This dose issue would certainly deserve a careful assessment in all studies. In a related matter, the authors mention about the ALLHAT study that ‘the usual renoprotective treatment includes the combination of an agent blocking RAS and a diuretic’. This issue of combination treatment rather than an exclusive ACE-inhibitor renal effect should be also addressed across all studies.
The interpretation of the place of the ALLHAT study in the meta-analysis could just as well be interpreted differently. Indeed, reference 12 shows examples of situations where multiple small randomized trials were conducted and together provided a combined inference that was different from that of a large randomized controlled trial conducted subsequently [2]. Rossing and colleagues suggest that this discrepancy indicates that the ALLHAT study findings may be invalid. The reasoning of reference 12 proposes that we could equally conclude instead that the ALLHAT study may in fact provide more precise and accurate information than the cumulation of smaller trials.
In all, we agree with Rossing et al. that the data strongly suggest that these agents can certainly be renoprotective early on. However, there are no data suggesting that this benefit is sustained in the long term. Our observational study suggests that they may even be detrimental over the long run. A careful and critically balanced assessment of these points could lead to a better understanding of the renal effects of blockade of the renin–angiotensin system in diabetes.
Conflict of interest statement. None declared.
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- Suissa S, Hutchinson T, Brophy JM, Kezouh A. ACE-inhibitor use and the long-term risk of renal failure in diabetes. Kidney International 2006; 69: 913–919[CrossRef][Web of Science][Medline]
- LeLorier J, Gregoire G, Benhaddad A, Lapierre J, Derderian F. Discrepancies between meta-analyses and subsequent large randomized, controlled trials. New Engl J Med 2001; 337: 536–542
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