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NDT Advance Access published online on May 8, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn239
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© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Maximizing inhibition of the renin–angiotensin system with high doses of converting enzyme inhibitors or angiotensin receptor blockers

Tomas Berl

Division of Nephrology, University of Colorado Health Sciences, Denver, CO 80262, USA

Correspondence and offprint requests to: Tomas Berl, Division of Nephrology, University of Colorado Health Sciences, 4200 East Ninth Avenue, Box C281, Biomedical Research Building, Room 423, Denver, CO 80262, USA. Tel: +1-303-315-7204; Fax: +1- 303-315-0189; E-mail: Tomas.Berl{at}uchsc.edu

Over the last 20 years, inhibitors of the renin–angiotensin–aldosterone system (RAAS) have become the cornerstone in the treatment of hypertension. Likewise, these drugs have found an increasing use in patients with underlying renal disease, as numerous lines of evidence have pointed to their having a blood pressure lowering independent antiproteinuric effect [1]. This effect of renin–angiotensin system (RAS) inhibitors gains in significance as several large interventional studies have uniformly found that proteinuria is a major risk factor for progression of renal disease [2–5]. In fact, in some of these studies [3,4] the reduction of proteinuria in patients with diabetic nephropathy was associated with a decreased risk of reaching a renal endpoint which included doubling of serum creatinine and end-stage renal disease (ESRD). A similar observation has been made in non-diabetic kidney disease with lower levels of baseline proteinuria [5], demonstrating the importance of lowering protein excretion in a variety of renal disorders and across a broad spectrum of protein excretions.

In view of the above-described observations, it is not surprising that there have been attempts to determine whether inhibition of the renin–angiotensin system at various levels could produce additive renoprotective effects. With the advent of a direct renin inhibitor (DRI), in addition to converting enzyme inhibitors (ACEs) and angiotensin receptor blockers (ARBs), there are no less than four potential drug combinations. Furthermore, since antagonists of aldosterone have been shown to decrease protein excretion in patients with renal diseases [6,7], the option of also employing aldosterone inhibitors doubles the potential combination of drugs to eight (Table 1). As would be expected, the most frequently used combination is that of an ACE with an ARB. Many of the studies that have been undertaken with this approach suffer from the confounding effect of further blood pressure lowering with the dual treatment, particularly when the doses used in the combination were the same as those employed in the comparator monotherapies [8]. However, when taken together, in a thoroughly and carefully performed meta-analysis, the combination therapy does emerge as providing the more robust antiproteinuric effect when looked at both at early (1–4 months) and later (5–8 months) time points [9]. A similar result was also obtained in another meta-analysis [10]. Also, a preliminary study that combined an ARB with a DRI also showed a greater further antiproteinuric effect in the combination therapy group [11]. In addition, a study that did not rely on proteinuria as surrogate endpoint but used doubling of serum creatinine and ESRD as the primary endpoint, the combination treatment of angiotensin II receptor blocker and angiotensin converting enzyme inhibitor in non-diabetic renal disease (COOPERATE), the risk of meeting the primary endpoint was significantly lower in the combination therapy group [12]. Some controversy has surrounded this study as relates to the interpretation of ambulatory blood pressure [13]. Furthermore, one of the secondary endpoints of the recently reported Ongoing Telmisartan Alone and in Combination With Rimapril Global Endpoint Trial (ONTARGET), a study performed in patients at high risk for cardiovascular events, was nephropathy. In this study the number of patients that doubled their serum creatinine was not different in the ACE group (rimapril at 10 mg/day), ARB group (telmisartan at 80 mg/day) or the combination of the two agents [14]. It must be noted that this was not a study of patients with underlying nephropathy, although 13% of patients in each group had microalbuminuria. The outcome of this subgroup of patients will presumably be analyzed in a separate report. A VA cooperative study, to be initiated soon, will compare the combination of an ACE with an ARB to monotherapy in the treatment of diabetic nephropathy and should complement and perhaps validate the observations made in the COOPERATE trial.


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  		Table 1 Options for improving RAAS inhibition

 
An alternative to combining two drugs that inhibit the RAS involves the use of an ACE or an ARB at doses that exceed those that are FDA approved for blood pressure lowering, as this was the effect for which they obtained regulatory approvals. I will herein summarize the data that have been garnered by studies that have examined such an approach.



   Studies with high doses of ACE inhibitors (Table 2)
Top
 Studies with high doses...
Studies with high doses...
 Dosing and RAS blockade
 Safety considerations
 Summary and conclusions
 References
 
The data with increasing doses of ACE inhibitors are somewhat limited and not always consistent. Thus, two studies with a limited number of patients that uptitrated lisinopril from 10 to 40 mg/day in patients with non-diabetic nephropathies came to different conclusions, as in one the uptitration was associated with decreases in urinary albumin excretion [15] while no such effect was seen in the other [16]. More recently in a preliminary report, Schjoedt et al. [17] studied 56 patients with type 1 diabetes and nephropathy, who in a double masked crossover trial received 20, 40 or 60 mg/day of lisinopril. The 40 mg/day dose provided a greater antiproteinuric effect than 20 mg/day but 60 mg/day did not afford further renoprotection. However, the difference in protein excretion observed between the 20 and 40 mg/day dose was lost when adjustments were made to changes in 24-h ambulatory blood pressure. A recent randomized control study in patients with non-diabetic proteinuria, Renoprotection of Optimal Antiproteinuric Doses (ROAD), employed doubling of serum creatinine, ESRD and death as a primary endpoint [18]. Of the 83 patients who received what was designated as conventional dose of benazepril (10 mg/day), 26 reached a primary endpoint. In contrast, only 15 of 84 patients in whom the dose was uptitrated to 40 mg/day reached the endpoint, a 51% risk reduction, 95% CI (4.8–73.3), P = 0.028. This was unchanged when adjusted for systolic blood pressure or baseline protein excretion. It is of note that in terms of reduction in protein excretion, a secondary endpoint of the study, optimal efficacy was obtained in the majority (61%) of patients with 20 mg/day of benazepril, while 16% reached it at 30 mg/day and only 6% at doses of 40 mg/day or higher. The mean dose of benazepril at the end of the uptitration was 20.8 mg/day. Taken together, the available evidence does not support the notion that doses of ACE inhibitors that greatly exceed those recommended by the FDA provide significant additive nephroprotection.


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  		Table 2 Studies with increasing doses of ACE inhibitor

 


   Studies with high doses of ARBs (Table 3)
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 Studies with high doses...
 Studies with high doses...
Dosing and RAS blockade
 Safety considerations
 Summary and conclusions
 References
 
Several studies have been undertaken to examine the optimal renoprotective doses of ARBs (Table 3). Some of these studies found that such a dose is well within the FDA approved maximal doses. Thus, Andersen et al. [19] reported in a dose titration study of 50 patients with type 1 diabetic nephropathy that both blood pressure lowering and maximal antiproteinuric effects were achieved at 100 mg/day of losartan. Likewise, Rossing et al. studied 23 type 2 diabetic patients with hypertension and nephropathy [20]. They found, in a double-blind randomized crossover study employing 8, 16 or 32 mgs/day of candesartan, that optimal blood pressure as well as protein lowering effect was obtained with 16 mgs of candesartan. In contrast, a subsequent study employing the same ARB was undertaken by Schmieder et al. [21]. These authors studied 32 patients with >1 and <10 g of protein in a randomized prospective trial. On the background of pretreatment with 16 mgs of candesartan, the dose was increased to either 32 or 64 mgs/day. There was no significant further reduction in protein excretion when the dose was increased to 32 mgs, but there was a significant (P = 0.017) decrement at 64 mgs/day. This effect was not related to changes in blood pressure. It is of interest that in a recent preliminary report [22] of the large (n = 346) SMART trial (Supra Maximal Atacand Renal Trial) there was no significant change in protein excretion when the standard dose of 16 mgs/day was compared with 64 mgs/day, but the administration of 128 mgs/day brought about a 33% decrease in protein excretion, 95% CI (–45% to –17%), P < 0.001, in patients with >1 g of protein/day.


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  		Table 3 Studies with increasing doses of ARB

 
Other ARBs have also been studied at higher than conventional doses. Thus, Rossing et al. studied 52 patients with type 2 diabetes and microalbuminuria in a double-blind randomized crossover study, employing 300, 600 and 900 mgs of irbesartan [23]. The 900 mg/day dose provided an additional 15% reduction in protein excretion compared to the lower doses (P = 0.02), without additional blood pressure changes. The patients whose albumin excretion remained >300 mg/24 h on 300 mgs of irbesartan were the ones most likely to respond to the 900 mg/day dose.

Hollenberg et al. undertook a double-blind multicenter study of 391 patients with type 2 diabetes and hypertension who excreted between 20 and 700 µg of protein/min randomized to receiving 160, 320 or 640 mgs/day of valsartan [24]. The two higher doses of valsartan lowered albumin excretion more than the standard dose of 160 mgs/day but were not different from each other. However a somewhat higher percentage of patients on the 640 mgs/day dose became normoalbuminuric (24.3%) versus 19.2% on 320 mgs/day and only 12.4% on the 160 mgs/day dose. These effects were independent of changes in blood pressure.

Aranda et al. employed a different strategy to increase the delivered dose of ARB [25]. Instead of giving 80 mgs of telmisartan once a day, as commonly prescribed, the authors gave 80 mgs bid in a randomized open label study of 78 non-diabetic proteinuric patients. While the blood pressures in the two arms were identical, those receiving twice daily telmisartan had a greater decrement urinary protein and maintained their estimated GFR better than those on a single daily dose.

The aforementioned ROAD trial [18] also compared the effects of increasing doses of losartan up to 200 mg/day to a conventional but low dose of losartan 50 mg/day. The study employed ‘hard’ endpoints of doubling serum creatinine, ESRD and death. While 26 of the 88 patients on the conventional dose reached the primary endpoint, only 13 of 84 patients in the uptitration arm did so, P = 0.022. It is of note that in this arm, 57% of the patients achieved their maximal antiproteinuric effect at what would be considered the standard dose of 100 mgs/day. However, 14% did so at 150 mgs/day and another 11% reached this target at 200 mgs/day. This observation, along with some of the others described above, suggests that while most patients achieve their maximum benefit at conventional doses, there is a residual group of patients who may do so at higher doses of RAS inhibition.



   Dosing and RAS blockade
Top
 Studies with high doses...
 Studies with high doses...
 Dosing and RAS blockade
Safety considerations
 Summary and conclusions
 References
 
The rationale that underlies both the use of either combination therapy with an ACE and an ARB or the higher dosing of either alone is that such an approach will lead to a complete inhibition of the RAS. It is clinically difficult to establish the degree to which such blockade is or is not achieved with any employed regimen. In this regard, the study by Forclaz et al. is of interest [26]. These investigators examined the pressor response to angiotensin I as a ‘bioassay’ for the degree of achieved RAS inhibition in 20 healthy normotensive subjects. Standard doses of either losartan (100 mg/day) or telmisartan (80 mg/day) did not provide an adequate 24-h blockade. However, either the addition of an ACE to these regimens or the administration of losartan as 100 mg bid or the doubling of the dose of the longer acting telmisartan to 160 mg/day enhanced the RAS blockade. These observations suggest that the response to treatment may depend on the degree of RAS inhibition achieved over a 24-h period.



   Safety considerations
Top
 Studies with high doses...
 Studies with high doses...
 Dosing and RAS blockade
 Safety considerations
Summary and conclusions
 References
 
Few of the high-dose studies reported safety concerns as the dose of the agents was increased. Rossing et al. [23] noted that among the 52 patients who completed the high-dose irbesartan study, dizziness was reported in one at 300 mgs and three each at 600 and 900 mgs of the drug. All the three groups experienced a 0.3 to 0.4 mEq/L increase in serum potassium but no patient developed severe hyperkalaemia. The trial by Hollenberg et al. [24] reported a higher incidence of headaches and dizziness in the patients receiving 320 and 640 mgs/day of valsartan. There were 14 episodes of hyperkalaemia (>5.5 mEq/L), but they were not dose related and in 13 cases readily reversible. Only one patient in the 640 mg/day group required discontinuation of the drug. Finally the ROAD study did not identify any safety concerns either [18]. As expected there was a higher incidence of cough in patients receiving benazepril, but this was not dose related. Hyperkalaemia occurred in 10 patients in the uptitration arms and in 6 at the conventional dose arms of the study.



   Summary and conclusions
Top
 Studies with high doses...
 Studies with high doses...
 Dosing and RAS blockade
 Safety considerations
 Summary and conclusions
References
 
Most, but not all, studies performed with higher than recommended doses of either ACE inhibitors or particularly ARBs suggest that the approach is associated with a further decrement in protein excretion. The majority of patients probably attain their optimal therapeutic response at standard doses, but a smaller residual group has further therapeutic benefit. Since patients who would benefit from higher doses are not a prior identifiable, a temporary trial at higher doses of these drugs seems cogent in order to provide more robust antiproteinuric benefit to such patients. The cost of doing so in terms of side effects is low and warrants the approach. It must be noted that studies with hard endpoints are sorely lacking. Furthermore, there is a complete absence of trials that compare the administration of high doses of ACEs or ARBs to a combination of these two classes of agents given at conventional doses. It appears likely from the available experience that these two approaches would yield comparable results.

Conflict of interest statement. None declared.



   References
Top
 Studies with high doses...
 Studies with high doses...
 Dosing and RAS blockade
 Safety considerations
 Summary and conclusions
 References
 

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  21. Schmieder RE, Klingbeil AU, Fleischmann EH, et al. Additional antiproteinuric effect of ultrahigh dose candesartan: a double-blind, randomized, prospective study. J Am Soc Nephrol (2005) 16:3038–3045.[Abstract/Free Full Text]
  22. Burgess E, Muirhead N, Rene De Cotret P. A double-blind randomized controlled trial of high dose candesartan cilexetil in proteinuira renal disease—results from SMART (Supra Maximal Atacand Renal Trial). J Am Soc Nephrol (2007) 18:57A.
  23. Rossing K, Schjoedt KJ, Jensen BR, et al. Enhanced renoprotective effects of ultrahigh doses of irbesartan in patients with type 2 diabetes and microalbuminuria. Kidney Int (2005) 68:1190–1198.[CrossRef][ISI][Medline]
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Received for publication: 3. 4.08
Accepted in revised form: 7. 4.08


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