Dual RAS Therapy Not on Target, but Fully Alive

Inhibitors of the renin-angiotensin system (RAS) form a cornerstone in the treatment of kidney disease. These drugs lower blood pressure and albuminuria, and afford renal protection. Dual therapy with an angiotensin-converting enzyme inhibitor and angiotensin receptor blocker have been shown to be more effective in reducing blood pressure and albuminuria than the single use of these agents. It was therefore expected that the combination of these drugs could delay the progression of renal disease. However, the ONTARGET renal analysis suggests that the use dual-agent RAS leads to increased renal risk. This led to vivacious discussions about the benefits and risks of dual-agent RAS in patients with nephropathy. We will review the ONTARGET trial design and interpretation, and offer implications for novel trials. Copyright © 2010 S. Karger AG, Basel Published online: June 1, 2010 H.J. Lambers Heerspink, Department of Clinical Pharmacology University Medical Centre Groningen, University of Groningen Ant Deusing laan 1, NL–9713 AV Groningen (The Netherlands) Tel. +31 50 363 2810, Fax +31 50 363 2812 E-Mail h.j.lambers.heerspink @ med.umcg.nl © 2010 S. Karger AG, Basel 1660–2110/10/1162–0137$26.00/0 Accessible online at: www.karger.com/nec D ow nl oa de d by : 54 .1 91 .4 0. 80 9 /1 6/ 20 17 8 :1 8: 15 P M Lambers Heerspink/de Zeeuw Nephron Clin Pract 2010;116:c137–c142 c138 RAS. The blood pressure-lowering effects of angiotensinconverting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARBs) are well documented and they have been demonstrated to improve clinical outcomes in both diabetic and non-diabetic renal disease [11–14] . Elevated levels of albuminuria can be detected in early stages of kidney disease and its presence is associated with progressive renal function loss. Besides the blood pressure-lowering effects of agents intervening in the RAS, they also appear to lower albuminuria. A systematic review of clinical trials with ACEIs and ARBs has shown that either agent reduces albuminuria by approximately 35% [15] . The reduction in albuminuria achieved with RAS blockade may be a critical step towards achieving renoprotection. In the early work of Rossing et al. [16] and Apperloo et al. [17] it was shown that the magnitude of albuminuria reduction during the first months of therapy with an ACEI in patients with diabetic and non-diabetic disease was linearly associated with the degree of estimated glomerular filtration rate loss decline during long-term follow-up. This observation was later on confirmed in individuals with diabetic nephropathy. Posthoc analysis of the IDNT and RENAAL trial showed that the degree of the initial albuminuria reduction by irbesartan or losartan, respectively, was the most important predictor for long-term renal protection and turned out to be independent of changes in blood pressure [18–20] . Similar observations were made in the IRMA-2 trial, evaluating the effect of the angiotensin-II antagonist irbesartan [21] . This trial in hypertensive type 2 diabetic individuals at early stages of kidney disease showed that albuminuria can be substantially lowered and that this is associated with a lower rate of progression of kidney disease. The renoprotective effects of irbesartan observed in this trial appeared to be independent of blood pressure, as assessed by 24-hour ambulatory blood pressure measurement [22] . Interestingly, the relation between initial albuminuria reduction and long-term renoprotection is not only observed in individuals participating in a trial but also on a meta-trial level. A joint analysis of multiple randomized clinical trials investigating the effects of RAS inhibitors on renal disease progression illustrates that the larger the albuminuria reduction achieved during the first months of treatment within a trial, the higher the relative risk reduction for renal events in that trial during long-term follow-up ( fig. 1 ). The aforementioned studies indicate that lowering albuminuria with ACEI or ARB therapy is associated with renoprotection independent of blood pressure changes. However, although of interest, these studies are post-hoc analyses of clinical trials which were not specifically designed to demonstrate that targeting albuminuria result in long-term renoprotection. More direct evidence that treatment regimens pursuing maximal reduction of albuminuria afford renoprotection comes from a study in subjects with non-diabetic kidney disease. Hou et al. [12] demonstrated that titrating the dose of an ACEI or ARB to maximal albuminuria lowering did not further lower blood pressure but delayed the rate of progressive renal function decline. These data thus support treatment strategies focusing on lowering albuminuria to levels as low as possible to achieve maximal renoprotection. Dual therapy with both an ACEI and an ARB has been shown to be more effective in reducing albuminuria and blood pressure than single therapy with either an ACEI or ARB. One of the earliest studies in which the albuminuria response to a combination of an ACEI and ARB (candesartan 16 mg + lisinopril 20 mg) was compared versus single-agent therapy reported an additional 34% (95% CI: 3–55) reduction in albuminuria versus ARB therapy and an additional 18% (95% CI: –20 to 44) reduction versus ACEI therapy [23] . Since then, numerous studies have confirmed that combination therapy is more beneficial in terms of blood pressure and albuminuria reduction than single-agent RAS therapy. These studies have been systematically reviewed by Kunz et al. [15] . This systematic review illustrated an overall additional 25% reduction in albuminuria with combined ACEI and ARB therapy versus single-agent therapy. These data have led to an expectation that, when compared to singleagent RAS blockade, dual therapy will provide greater protection against major adverse renal outcomes. However, the results of studies on hard outcomes are scarce and those conducted to date are invalid or show unanticipated results. The COOPERATE trial in patients with CKD and high levels of albuminuria reported that the combination of an ACEI and ARBs confers renal protection in terms of fewer patients reaching dialysis [24] . However, serious concerns about the validity of the COOPERATE trial have been raised which resulted in an institutional investigation into the COOPERATE trial [25, 26] . The investigational committee reviewed all medical records of the patients participating in the COOPERATE trial and concluded that ‘it was unable to prove the authenticity of the data’ [27] . The conclusions of this investigation mean that the COOPERATE trial cannot be used anymore for clinical decision-making. D ow nl oa de d by : 54 .1 91 .4 0. 80 9 /1 6/ 20 17 8 :1 8: 15 P M Dual-Agent RAS Blockade Nephron Clin Pract 2010;116:c137–c142 c139 Recently, the ONTARGET trial was published [28] . The ONTARGET trial included patients at risk for cardiovascular disease rather than kidney disease and randomly assigned these individuals to treatment with ramipril 10 mg/day, telmisartan 80 mg/day or the combination of both. As expected, systolic and diastolic blood pressure levels were 2.4 and 1.4 mm Hg lower in the combination therapy group compared to ramipril 10 mg/day. Likewise, the increase in albuminuria level was also lower in the individuals assigned to combination therapy. However, despite the lower blood pressure and smaller increase in albuminuria, the combination of an ACEI and ARB did not afford cardiovascular protection in this population. Furthermore, a post-hoc analysis of this trial suggested that combination therapy increased the risk for renal disease [29] . After 56 months of followup the primary renal outcome had occurred in 1,233 (14.5%), 1,147 (13.4%) and 1,150 (13.5%) individuals assigned to combination therapy, telmisartan 80 mg/day, or ramipril 10 mg/day, respectively. The results of the ONTARGET trial have led several authors to state that ‘dual RAS therapy is dead’ and that albuminuria is not a valid surrogate for renal protection [5] . However, such general and firm conclusions, based on a specific trial including a specific population, negate the value of all the single RAS inhibition therapy trials where the relation between the initial fall of albuminuria and long-term outcome has been demonstrated in different patient populations. A thorough review of the ONTARGET trial is therefore warranted to put the results and subsequent communications into perspective. Furthermore, the renal outcome data of the ONTARGET trial have to be interpreted with some care, since the trial was clearly not set up a 10 20 30 40 50 1.5