Nephrol Dial Transplant (1999) 14: 2855-2856
© 1999 European Renal Association-European Dialysis and Transplant Association
Personal Opinion
Is it wise to combine an ACE inhibitor and an angiotensin receptor antagonist?
Hypertension Unit, Hospital 12 de Octubre, Madrid, Spain
Correspondence and offprint requests to: Dr Luis M. Ruilope, Unidad de Hipertension, Hospital 12 de Octubre, 28041 Madrid, Spain.
Blockade of the effects of angiotensin II through the administration of angiotensin converting enzyme inhibitors (ACEi) has proven to be an effective therapy for the treatment of different forms of cardiovascular (CV) disease [1], and to reduce the velocity of progression of chronic renal failure [2,3]. A series of questions related to blockade of the renin–angiotensin system and the renal outcome remain to be answered however.
Is the nephroprotection of ACE inhibition an artifact due to blood pressure control?
The first question is whether part, if not all, of the benefit of ACEi simply depends on the attainment of adequate blood pressure (BP) control in patients treated with ACEi in the different studies. It is well known that strict BP control is needed to ensure renal protection [4]. A small but significant difference in BP was observed in patients treated with an ACEi when compared to those receiving placebo in the initial studies in diabetic [5] and non-diabetic renal diseases [6]. In principle this confounding factor could explain the difference in the outcome favouring the use of ACEi. Recent data have shown, however, that at equal levels of BP control ACE inhibition confers better renal protection when compared to other therapies [3]. Recently published guidelines [7,8] indicate that in patients with renal disease pharmacologic therapy has to be started at lower threshold BP values (BP>130/85 mmHg). The decrease in BP needed to attain the expected goal BP is then going to be lower as compared to that described in previous studies of patients with higher baseline BP levels. In this case, the selection of the class of antihypertensive agents may matter even more in particular when proteinuria or microalbuminuria is present. With a relatively small fall in mean blood pressure it is difficult to achieve a decrease in protein excretion unless angiotensin II effects are blocked [9].
Is it natural to titrate the dose of ACE inhibitors according to proteinuria?
The second question deals with the possibility that progressive titration of ACEi or angiotensin receptor antagonists (ARA) could permit to obtain more effective blockade of the effects of angiotensin II and therefore a better renal outcome. There are two arguments against this possibility. First, the great majority of ACEi accumulate at their normal high doses when renal function is decreased and their positive pharmacologic effects would not necessarily increase with further titration [10]; and second, some evidence seems to indicate that the antiproteinuric capacity of ACEi which constitutes the best armamentarium of this drug to predict a good renal outcome, could be dose independent [11].
Is it rational to combine ACE inhibitors and angiotensin receptor antagonists?
The third question refers to the possibility that the association of an ACEi and an ARA could be of greater benefit for the kidney than each drug given alone. This possibility is based on the concept that these are different classes of agents, acting through different mechanisms and that their combination could implement the degree of blockade of angiotensin II. In fact, data obtained in animal models [12] have shown a synergistic effect with the combined administration of an ACEi and an ARA. In humans the combined administration of the two classes of drugs has been shown to be safe for renal function and unwanted side-effects, in particular hyperkalaemia [13]. Some preliminary data indicate that the association could be of benefit to further decrease proteinuria [14] and to improve the clinical status of patients with heart failure [15].
Ongoing studies will be required to increase our knowledge in this field. In the meantime the combination of these two classes of drugs may be considered in any patient with proteinuria which exceeds the desirable goal of 1 g/day.
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