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Dual blockade of the renin-angiotensin system: are two better than one?

The beneficial effects of blood pressure-lowering treatments on the risks of major cardiovascular events are well established [1]. Interruption of the renin–angiotensin system (RAS) with angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) has been shown to be an effective strategy for lowering blood pressure. Randomized trials have shown that ACEi can lower blood pressure by an average of 5/2 mmHg and reduce the risks of cardiovascular events and cardiovascular mortality by ∼20% (and total mortality by 10%) [2–6]. ARBs produce similar reductions in blood pressure and vascular events (although fewer patients have received them in randomized trials) [7–9]. Further, RAS blockade has been reliably shown to reduce the risk of kidney disease progression [10–15]. A meta-analysis of ACEi and ARB monotherapy in diabetic nephropathy demonstrated reductions in end-stage renal disease (ESRD) of around one-quarter for both treatments [16]. Similarly, an individual patient data meta-analysis of ACEi in non-diabetic kidney disease showed a relative risk reduction of 31% (95% CI 5–49%). The major trials of ACEi or ARB monotherapy in various patient populations are summarized in Table 1. As shown in Table 1, among patients at a low risk of renal progression ESRD occurs rarely, and only after many years or even decades. This probably explains the lack of renal benefit reported in large general population trials and meta-analyses of such trials [17–19]. Furthermore, there is some evidence that even the relative benefit might depend on baseline risk, making it even less likely that any true benefit could be detected in existing trials [10]. Whether the observed benefits of RAS blockade are only mediatedbytheirbloodpressure-loweringeffectorwhether other effects also play a role remains controversial; there is some evidence that interruption of the RAS provides more benefit than would simply be expected by the degree of blood pressure reduction alone [5,7,20]. It has been suggested that incomplete blockade of the RAS with ACEi or ARB monotherapy can cause a phenomenon called ‘aldosterone escape’, in which the lack of negative feedback from end-products of the RAS causes a reactive increase in renin and consequent increases in angiotensin I and II concentrations which overwhelm the pharmacological blockade [21]. Dual blockade would therefore be attractive as ACEi and ARB inhibit the RAS at different steps. However, there is continuing uncertainty about the balance of benefits and harms of dual RAS blockade, both in terms of cardiovascular risk and progression of kidney disease. This question will be discussed here in the context of recent evidence from randomized controlled trials.