Current Strategies to Achieve Further Cardiac and ... - IngentaConnect

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Reviews on Recent Clinical Trials, 2011, 6, 134-146

Current Strategies to Achieve Further Cardiac and Renal Protection through Enhanced Renin-Angiotensin-Aldosterone System Inhibition Alfie J.*, Aparicio L.S. and Waisman G.D. Hospital Italiano de Buenos Aires, Hypertension Section, Internal Medicine Unit Abstract: An incomplete inhibition of the renin angiotensin aldosterone system (RAAS) may be responsible for the residual organ damage and event rate that still occur in spite of an apparent blood pressure control in patients with hypertension, diabetes, chronic kidney disease and heart failure treated with angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB). Additional antiproteinuric effect in diabetic and non diabetic chronic kidney disease, and reduction in hospitalizations in patients with heart failure already receiving a single RAAS antagonist, has been achieved by incremental inhibition of the RAAS with dual therapy or uptitration of an individual agent above conventional dosages. However, the synergistic increase in plasma renin activity (PRA) and the angiotensin II escape could reduce the expected benefit obtained with dual therapy. Results from ONTARGET showing a lack of additional outcome benefit over monotherapy, with a concomitant increase risk of hyperkalemia, renal impairment, and hypotension, discourage the use of the ACEI/ARB combination in patients at high risk of cardiovascular events. This occured despite a lower albumin excretion in dual versus single RAAS blockade, indicating that an incremental antiproteinuric effect is not automatically translated into clinical outcome benefit. The efficacy and safety of ACEI/ARB combination versus monotherapy in patients with overt proteinuria is currently evaluated by LIRICO and VA NEPHRON-D clinical trials. The long lasting direct renin inhibitor aliskiren, acting at the first and rate limiting step of the RAAS cascade, prevents the reactive increase in PRA when combined with ACEIs, ARBs or diuretics. The ASPIRE HIGHER programme, involving more than 35,000 patients with hypertension, heart failure, kidney disease and diabetes, is currently evaluating the efficacy and safety of aliskiren on top of standard therapy. The clinical benefit of adding mineralocorticoid receptor blockers (MRBs) in the control of resistant hypertension, proteinuric kidney diseases, and prevention of mortality in patients with heart failure on top of conventional treatment, evidences the pathogenic role of inadequately suppressed aldosterone as a cause of suboptimal response to conventional RAAS inhibition. The present review will focus on the pathophysiological ground, and the evidence provided by clinical trials assessing the efficacy and safety of recent strategies for the prevention of cardiovascular events and target organ damage progression via enhanced RAAS inhibition.

Key Words: RAS blockade, angiotensin converting enzyme inhibitor, angiotensin receptor blocker, combination therapy, direct renin inhibitor, aldosterone antagonists. INTRODUCTION Excessive production of angiotensin II (Ang II) relative to the existing plasma volume, promotes oxidative stress, endothelial dysfunction, cardiovascular remodeling, inflammation, fibrosis, and insulin resistance, via activation of AT1 receptors [1]. These effects are implicated in the etiology and pathogenesis of arterial hypertension, metabolic syndrome and atherosclerosis, and predispose patients to cardiovascular events and target organ damage. Today we can target AT1 receptor activation indirectly, by inhibiting the angiotensin generating enzymes renin and angiotensin-converting enzyme (ACE), or by directly blocking the receptor. Additionally we can antagonize aldosterone, a downstream mediator of Ang II, by blocking the mineralocorticoid receptor (see Fig. 1 and Table 1). The classical inhibitors of the renin angiotensin aldosterone system (RAAS), i.e. ACE-inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), exhibit equivalent blood pressure lowering efficacy, and prevent cardiovascular and

*Address correspondence to this author at the Unidad de Hipertension Arterial, Servicio de Clinica Medica, Hospital Italiano de Buenos Aires, Gascon 450 (1181), Buenos Aires-Argentina; Fax: 54-11-4958-2923; E-mail: [email protected] 1574-8871/11 $58.00+.00

renal events to a similar extent. ACEIs reduce bradykinin degradation, which in turn enhance vasodilatation but increase the rates of angioedema and cough. In contrast, ARBs are better tolerated than all other classes of antihypertensive agents and represent a good therapeutic alternative to ACEIinduced side effects [2-5]. While the main benefits of RAAS antagonists are largely dependent on blood pressure lowering per se [6], this type of drugs have an added value above other agents in patients with proteinuric kidney disease, chronic heart failure or heart failure after acute myocardial infarction, and in high cardiac risk profile patients, even without high blood pressure [613]. However, ACEIs and ARBs become less effective during long term treatment due to a compensatory response at other points of the hormonal cascade [14]. Landmark clinical trials demonstrating cardio or renoprotective effects of ACEIs and ARBs were performed using recommended doses extrapolated from treatment of essential hypertension [15]. Alternative pharmacological approaches, including combined therapy targeting more than one site of the RAAS and supramaximal dosages of a single agent, have been assessed to overcome resistance. This review will focus on the evidence provided by clinical trials assessing the efficacy and safety of recent strategies for the prevention of cardiovascular events and target organ damage progression via enhanced RAAS inhibition. © 2011 Bentham Science Publishers Ltd.

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ET-1

ACTH

Adipocite derived factors MRBs

Aldosterone Chymase

Ang 12

MR

Chymase

ARBs

Chymase and other non-ACE pathways

Angiotensinogen

Renin

DRIs

Ang I

Ang II

ACE

ACEIs (Pro)renin-R

ACE2 BK Ac-SDKP

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Inactive fragments Ang 1-7

AT1-R

Hypertension Organ damage

AT2-R MAS-R

Direct vasculotoxic effects?

Fig. (1). Main components of the RAAS and their respective pharmacological inhibitors. Alternative metabolic products of angiotensinogen, Ang I and Ang II are also shown. Dotted arrows indicate the physiological counter-regulatory pathways within the RAAS that are upregulated by ACEIs and ARBs, but downregulated by DRIs.

Rationale for Angiotensin II

a

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Intensive

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of

Beside factors such as non adherence [16], volume excess, or masked hypertension, a suboptimal inhibition of the RAAS could partially explain the residual organ damage and event rate that still occur in patients treated with conventional doses of RAAS inhibitors, in spite of an apparent blood pressure control. Ang II and aldosterone are not always completely suppressed during chronic ACEI treatment, and in patients with congestive heart failure a lack of a full hormonal suppression is associated with increased mortality [14]. These facts pinpoint the need for a more complete suppression of the RAAS to improve clinical outcome benefits. Dose-response studies in primary hypertension have demonstrated no further antihypertensive effect above 20 mg of enalapril or lisinopril, or above 50 mg of losartan [17-20]. Every additional step to block the RAAS by means of ACEIs or ARBs causes another rise in renin secretion, indirectly indicating that the previous blockade had not maximally inhibited the production or the action of Ang II [21]. Reactive hyperreninemia, with its subsequent rise in Ang I, is a major determinant of plasma Ang II during ACE inhibition [22]. About 16-22 hours after the administration of 20 mg of enalapril or benazepril, a 4-5 fold increase in Ang I availability restores Ang II and aldosterone levels, coinciding with a time when inhibition of the enzyme falls to suboptimal levels (below 90% of its baseline activity) [23]. Experimental data suggest that when given in combination RAAS inhibitors could exert unique therapeutic effects not reproduced by higher doses of individual agents. We must take into account that in order to suppress Ang II generation ACEIs need reductions greater than 90% of the enzymatic activity, and that tissue non-ACE enzymatic pathways could contribute to the Ang II escape. It has been estimated that about two thirds of Ang II formation in healthy human kidneys of subjects under a low salt diet occurs via the ACE pathway and about one third occurs via non-ACE-dependent pathways. Non-ACE enzymatic pathways may become more important under diseases such

as congestive heart failure, atherosclerosis and diabetic kidney, despite chronic treatment with ACEIs [24-26]. One of these non-ACE pathways, the serine protease chymase, generates tissue Ang II not only from Ang I but also from proAngiotensin-12, a novel angiotensinogen-derived dodecapeptide, bypassing both renin and ACE [27]. Beyond blocking Ang II binding of AT1 receptors, ARBs with distinct inverse agonistic activity like candesartan, valsartan and olmesartan, also inhibit the mechanical activation of AT1 receptor without the involvement of Ang II [28-30]. However, the compensatory increase in plasma Ang II levels evoked by the AT1 receptor blockade, not only stimulates unblocked AT2 receptors contributing to the therapeutic effects of ARBs, but also may displace the ARBs from AT1 receptors attenuating its therapeutic efficacy. Combined therapy provides an additive blockade of Ang II via blunting the rise in plasma Ang II evoked by ARB therapy and also by preventing binding to AT1 receptors of the Ang II that avoids ACE inhibition. In contrast to the rise in plasma Ang II, renal tissue Ang II decreases with ARB therapy, an effect that is likely due to a diminished internalization of the hormone mediated by AT1 receptors. A low dose ACEI/ARB combination provides a superior decrease in renal tissue Ang II than either drug alone at a high dose [31]. The combination of an ACE inhibitor with an ARB also upregulates ACE2, the enzyme that counteracts the vasoconstrictor and proliferative actions of Ang II by promoting its convertion to angiotensin 1-7, a potent vasodilatory, antifibrotic and natriuretic peptide [32]. Pharmacological studies indicate that the inhibition of the vascular effect of Ang II by ARBs is incomplete at trough, even with long lasting and insurmountable agents. Maximal recommended doses of losartan (100 mg) or telmisartan (80 mg) does not provide a complete 24-hour blockade of the Ang II effects when given once daily, as indicated by a 35% inhibition of the pressor response to exogenous Ang I given at trough. However, a long lasting blockade of the pressor response to Ang I at trough ( 77%) may be achieved with 100 mg of losartan BID or combined with lisinopril 20 mg, but not with 200 mg losartan OD. In contrast, the com-

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bination of telmisartan with lisinopril was more effective in extending the 24-h blockade than doubling to 160 mg of telmisartan as a single agent (79 versus 59% respectively) [33]. Lisinopril 20 mg or olmesartan 20 or 40 mg given as monotherapy produced a 60 % blockade of the blood pressure response to Ang I given 24 hours after the last dose of each treatment. Blockade increased to 80 % when olmesartan was given either in high doses (80 mg), or in standard doses (20 and 40 mg) in combination with lisinopril 20 mg [34]. In summary, an incomplete RAAS inhibition could underly the residual cardiovascular and renal morbidity and mortality despite ACEIs or ARBs monotherapy. Experimental studies provide the rationale for alternative strategies to achieve a more complete suppression of the RAAS showing that a high dose of a long lasting ARB is generally as effective as a standard dose of the drug combined with an ACEI in terms of blockading Ang II. In the following pages we will review the benefits and risks of different therapeutic modalities aimed to intensify the suppression of the RAAS. The Role of Aldosterone The pathogenic role of aldosterone in chronic heart failure, heart failure complicating an acute myocardial infarction, and in resistant hypertension, has recently become recognized [35-37]. In addition, recent evidence also supports the role of aldosterone in the progression of renal diseases [38]. These facts highlight the pathogenic role of inadequately suppressed aldosterone as a cause of suboptimal response to conventional RAAS inhibition. Aldosterone, the main salt retaining hormone, plays a major role in the development and maintenance of hypertension, heart failure and chronic renal disease. Beyond volume expansion and kaliuresis, the most significant contribution of aldosterone to both cardiovascular and renal disease results from nonepithelial, fibrotic and proinflammatory effects at a number of target organs, including heart and kidneys [39]. Aldosterone increases the expression of vascular Ang II receptors antagonizing the downregulatory action of Ang II associated with sodium depletion [40], upregulates tissue ACE and downregulates ACE2 levels [41]. Furthermore, aldosterone mediates the tissue remodelling effects of AngII, since aldosterone inhibition either by mineralocorticoid receptor antagonism or aldosterone synthase inhibition similarly decreases hypertrophy and interstitial fibrosis of the kidney and heart caused by AngII and a high salt intake [42]. AT1 and mineralocorticoid receptors are co-localized at the plasma membrane, where they maintain a cross-talk that stimulates cell growth, contraction, inflammation, collagen deposition, and migration [43], providing evidence for the potential therapeutic clinical benefits of combinating MRBs and ARBs, even in the absence of increased circulating aldosterone levels. The aldosterone "escape" or "breakthrough" is a determinant of clinical outcome in heart failure, as demonstrated by the consistent benefit obtained with the addition of a small dose MRB in patients with chronic heart failure and heart failure complicating myocardial infarction. Aldosterone reactivation also occurs despite persistent suppression of plasma AngII with captopril [44]. Potassium is as important

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as Ang II in stimulating aldosterone secretion [45]. Therefore, the small increase in serum potassium concentration secondary to angiotensin inhibition directly stimulates aldosterone secretion. Other mechanisms have been postulated to explain the stimulation of aldosterone secretion beyond AT1 receptors and potassium. Despite treatment with candesartan, aldosterone escaped and contributed to organ damage through activation of adrenal AT2 receptors in stroke-prone spontaneously hypertensive rats [46]. Endothelin-1, another hormone that increases in severe heart failure, has the potential to stimulate aldosterone secretion [47] despite treatment with ACE inhibitors or ARBs. Adipose tissue secretes factors that directly stimulate aldosterone secretion from adrenocortical cells and sensitize the cells to Ang II; this may shed light on the pathogenic link between obesity, metabolic syndrome and elevated plasma aldosterone levels [48]. Finally, evidence of a local renal aldosterone system is supported by the presence of renal cortical interstitial aldosterone of adrenalectomized rats. Renal aldosterone synthase mRNA is mainly expressed in the glomeruli, and increases in response to salt restriction and Ang II, mimicking the regulation in the adrenals. The renal transcript of the enzyme is also upregulated by hyperglycemia [49], providing a potential mechanism explaining the antiproteinuric effect of MRBs in diabetic nephropathy. Renin and Prorenin Given the recognized importance of circulating renin as first and rate limiting step in Ang II formation, and the role of the recently discovered renin receptors in tissue amplification of Ang II generation, the new generation of DRIs is expected to optimize the suppression of the RAAS and provide further organ protection [50]. Aliskiren provided comparable cardiac and renal protection to ARBs in double transgenic rats expressing human genes for renin and angiotensinogen. Interestingly, the inhibitory effect of aliskiren on markers of renal damage persisted after treatment withdrawal [51]. In healthy people on a low sodium diet, the renal vasodilator response with aliskiren was 40% larger than the response to ARBs and 2-fold the response to ACEIs, with persistence of the effect up to 48 hours after a single dose (when plasma aliskiren levels returned to baseline) [52] providing evidence of a more complete and long lasting inhibition of the RAAS at tissue level. Also, blood pressure reduction and plasma renin activity (PRA) suppression last for weeks after discontinuation of aliskiren. This persistent effect of aliskiren correlates with its ability to accumulate in renin secretory granules of yuxtaglomerular cells for weeks after drug discontinuation [53], with the potential of greater renoprotection than conventional RAAS blockade. While secretion of renin from yuxtaglomerular cells is highly regulated, secretion of its inactive precursor prorenin is constitutive. Prorenin circulates at a concentration 10-20 fold greater than renin and high plasma levels of prorenin precede the appearance of microvascular complications in diabetic patients. Some diabetic patients may even exhibit a combination of hyporeninemic hypoaldosteronism and high


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circulating prorenin [54]. In the vitreous fluid of patients with proliferative retinopathy, prorenin can reach levels 100 times greater than those found in plasma [55]. Contrasting with the normal negative feedback exerted by Ang II on yuxtaglomerular renin, in diabetes and in high renin models of hypertension, Ang II stimulates prorenin production by epithelial cells of the collecting duct [56]. This is important because binding to (pro)renin receptors (PRR) increases the catalytic activity of renin and also activates prorenin without the need of proteolytic cleavage. This occurs on the cell surface, in close proximity to ACE and AT1 receptors, amplifying the local generation and action of Ang II. Due to its much higher concentration in plasma and particularly in tissues, prorenin could contribute to microvascular complications. Aliskiren is able to block the enzymatic activity of receptor-bound renin and prorenin, therefore inhibiting not only circulating but also local generation of Ang II [57]. Apart from the enzymatic activation of renin and prorenin, binding to the PRR directly stimulates the production of fibrogenic cytokines, independently of Ang II generation. Aliskiren-bound renin and prorenin is still able to stimulate direct vasculotoxic effects through the activation of PRR. Since plasma renin concentration increases severalfold in response to diuretics, ACEIs and ARBs, negative

Table 1.

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consequences of stimulating the PRR could theoretically occur limiting their therapeutic efficacy, particularly when combined with aliskiren which exaggerates this reactive rise. The downregulation of PRR expression caused by aliskireninduced renin secretion, however, and the fact that in vivo prorenin circulates in picomolar concentrations rather than nanomolar concentrations used in experimental studies, make Ang II-independent effects of prorenin unlikely [57]. Renin and prorenin also bind the mannose-6-phosphate (M6P) receptor. This receptor binds M6P-containing renin and prorenin but it does not bind nonglycosylated prorenin. After binding, both renin and prorenin are rapidly internalized. Although internalized prorenin is proteolytically cleaved to renin, prorenin binding to M6P receptor does not result in extracellular or intracellular angiotensin generation. Thus, M6P receptors most likely serve as clearance receptors for both renin and prorenin, determining the extracellular levels of prorenin [58]. Role of Enhanced RAAS Suppression in Hypertension and Prevention of Cardiovascular Events Results from meta-analysis of randomized trials show that outcome benefits of antihypertensive drugs are proportional to their blood pressure lowering effect and that, at least in the case of hypertension, RAAS inhibitors are as effective

Potential therapeutic advantages and disadvantages of the four classes of RAAS inhibitors. PRA, plasma renin activity; Ang, angiotensin; ALDO, aldosterone; AT2R, angiotensin receptor type 2; Ac-SDKP, N-acetyl-seryl-aspartyl-lysyl-proline; PRR, (pro)renin receptor; NO, nitric oxide Distinct Disadvantages

Cough Angioedema

Class of Drug ACE Inhibitors (ACEIs)

Distinct Advantages Ang II Bradykinin

PRA and Ang I

Ang 1-7

Ang II escape

Ac-SDKP

ALDO escape PRA, Ang I and II

Angiotensin Receptor Blockers (ARBs)

ALDO escape

Tolerability similar to placebo Antagonize ligand dependent and ligand independent AT1R activation

Reduced blockade of Ang II effects at trough when given in standard doses

Neutralize Ang II escape Activate AT2 R (Bradykinin and NO) Ang 1-7

Renin secretion (direct effects through PRR?) Ang 1-7

Inhibit the 1rst limiting step of the RAAS activation (PRA, Ang I and II)

AT2R signalling

Tolerability similar to placebo (up to 600 mg)

Diarrhea over 600 mg

Long lasting effect

ALDO escape?

Inhibit non-proteolytic activation of receptor bound prorenin

Direct Renin Inhibitors (DRIs)

No increase the incidence of hyperkalemia when added to ACEIs or ARBs? PRA, Ang I and II Antiandrogenic (spironolactone) Hiperkalemia

Mineralocorticoid Receptor Blockers (MRBs)

Neutralize ALDO escape


as other main monotherapies [6]. The combination of an ARB with a calcium antagonist or a diuretic exerts a greater blood pressure lowering effect than the combination of an ARB with an ACEI [59]. Therefore, beyond patients with residual hypertension and high PRA [60], combined ACEIs and ARBs exert a small additive effect on blood pressure, and its routine use in uncomplicated hypertension is not recommended [61]. Addition of eplerenone to patients not controlled with ACEIs or ARBs alone provides a substantially greater blood pressure response [62], suggesting that a residual secretion of aldosterone contributes to reduce the antihypertensive response to RAAS inhibitors. Most patients with resistant hypertension have low PRA, and a substantial proportion have primary aldosteronism. Interestingly, the antihypertensive efficacy of spironolactone is not limited to patients with hyperaldosteronism, but also to essential low renin hypertensive patients who exhibit a comparable blood pressure response to the aldosterone blockade, consistent with the concept of aldosterone excess as a continuum from low-renin hypertension to primary hyperaldosteronism [63]. As expected from their lower plasma renin activity, the antihypertensive response to conventional doses of RAAS inhibitors is typically less in African-American patients. However, the ethnic difference in blood pressure response disappears when a high dose of ARB is used (valsartan 320640 mg), likely related to an insuppressible intrarenal RAAS at standard dosage [64]. This is in concordance with animal data demonstrating that a full inactivation of renal rather than systemic AT1 receptors is needed to prevent hypertension and left ventricular hypertrophy induced by Ang II [65]. Alternatively, a high dose of ARB would be needed to fully suppress aldosterone secretion in patients with low renin hypertension. Aliskiren is a low molecular weight nonpeptide renin inhibitor designed by molecular modeling. It is an extremely potent and selective competitive enzymatic inhibitor, with oral efficacy and long half life, overcoming the therapeutic limitations of early DRIs such as enalkiren, remikiren and zanikiren. Dose range of aliskiren is similar to that for irbesartan and valsartan. However, aliskiren looses its placebolevel tolerability because diarrhea becomes more frequent at 600 mg, without gaining further blood pressure lowering efficacy [21]. Aliskiren as a single agent is more effective in lowering blood pressure than hydrochlorothiazide at its standard dose of 25 mg [66]. As with ACE inhibitors and ARBs, the antihypertensive efficacy of aliskiren is directly related to PRA [67], and greater antihypertensive effects are easily achieved by adding a diuretic or a calcium channel blocker [68, 69]. Despite blocking the RAAS at its rate limiting step, aliskiren did not demonstrate superior antihypertensive efficacy than ARBs [21]. Compared with ACEIs, the antihypertensive efficacy of aliskiren is equivalent to lisinopril [70] but greater than ramipril [71]. Aliskiren also provided a more sustained action beyond the 24-h dosing interval compared to irbesartan or ramipril, with a significantly smaller loss in the BP-lowering effect 48-h after dose [72]. Unlike other RAAS blockers, aliskiren suppresses PRA, an effect that lasts for 4 weeks after stopping the drug,

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suggesting an inhibitory effect beyond the elimination halflife [71]. In combination with ACEIs or ARBs, aliskiren suppresses the reactive increase in PRA, providing a rationale for a new therapeutic strategy to achieve a more intensive inhibition of the RAAS [50]. However, even at maximal dosage, the combination of aliskiren with an ARB or an ACEI adds a small, albeit significant blood pressure reduction of 4-2 mmHg [21]. This is similar in magnitude to the marginal incremental drop in systolic blood pressure of 2-3 mmHg elicited by the combination of full dose ACEI and ARB [61]. Since combination of aliskiren with ACEIs, ARBs or diuretics results in a very large increase in plasma renin concentrations, it has been hypothesized that blockade of PRA with aliskiren could be overwhelmed leading to paradoxical increases in blood pressure [73]. However, stoichiometry analysis indicates that the number of molecules of aliskiren in plasma is more than sufficient to inhibit all the renin molecules [74]. Furthermore, a metaanalysis of data from eight clinical trials found no evidence of such a paradoxical rise in blood pressure [75]. The Combination aliskiren 300 mg/losartan 100 mg was no more effective in reducing left ventricular hypertrophy than either therapy alone in 465 overweight patients with essential hypertension in the ALLAY study [76]. This is consistent with the lack of an additive effect of combined treatment on left ventricular mass and volume over monotherapy in a subset of 297 patients from the ONTARGET study [77]. In contrast, eplerenone was as effective as enalapril in left ventricular hypertrophy regression and blood pressure control, and the combination of both agents was more effective in reducing left ventricular mass and systolic blood pressure than eplerenone alone [78]. The later finding is in line with experimental data describing a cross-talk between AT1 and mineralocorticoid receptors at the cardiac level [43]. The ONTARGET program evaluated whether the outcome benefits previously demonstrated for ramipril 10 mg in the HOPE study [9], were extensible to an ARB, and whether the combination of both drugs was more effective than ramipril alone. With this objective in mind this trial randomized 25620 well treated high risk patients with vascular diseases (history of coronary artery disease, stroke or transient ischemic attack, peripheral artery disease, or diabetes with evidence of end-organ damage) but without heart failure, to receive ramipril 10 mg, telmisartan 80 mg, or both agents in combination [5]. The results showed that telmisartan 80 mg was equivalent to ramipril 10 mg in preventing death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure, whereas the combination caused more adverse events (renal dysfunction, serum potassium > 5.5 meq/L, hypotensive symptoms and syncope) without offering advantages over ramipril alone [5]. The ONTARGET study also showed that despite reducing proteinuria to a greater extent than monotherapy, the combination worsened major renal outcomes [79]. However, only a small subset of the patients had advanced renal disease or overt proteinuria, and the renal outcomes were


secondary endpoints of the study. Whether the combination of an ACEI and an ARB halts the progression of renal disease in patients with chronic renal diseases with overt proteinuria resistant to monotherapy, remains to be proven. Post-hoc analysis of ONTARGET showed that all outcomes, with the exception of stroke, maintained a J-curve with in-treatment systolic blood pressure, with a nadir around 130 mmHg [80], questioning the value of further blood pressure lowering in high-risk patients without heart failure and systolic blood pressure in the high normal range. Besides the synergistic increase in PRA, the presence of a J-curve provides an alternative mechanism for the lack of additional outcome benefit associated with combined RAAS inhibition despite a small but significantly greater reduction of blood pressure (2.4/1.4 mm Hg) and improvement in albuminuria. In summary, combination of an ACEI with an ARB in full dose adds a smaller blood pressure reduction than the ussually achieved by adding a thiazide, a calcium channel blocker or a MRB. Furthermore, the lack of additional outcome benefit over monotherapy, and the risk of adverse events, does not justify the use of the ACEI/ARB combination in patients at high risk of cardiovascular events. Compared with ACEIs or ARBs, DRIs provides a more sustain blood pressure control. Aliskiren confers a greater blood pressure lowering efficacy and is better tolerated than ramipril. Aliskiren adds a small albeit significant reduction in blood pressure, and did not reduce left ventricular hypertrophy in hypertensive patients treated with an ARB. Completion of ALTITUDE, an ongoing randomized, doubleblind, placebo-controlled study, will help to define the future of dual therapy in type 2 diabetes at high risk for cardiovascular and renal events by evaluating cardiovascular and renal morbidity and mortality prevention with aliskiren in combination with an ACEI or an ARB [81]. Addition of a low-dose MRBs to an ACEI or an ARB improves hypertension control and reduces ventricular hypertrophy. However outcome clinical trials evaluating the addition of MRB to patients with essential hypertension, left ventricular hypertrophy or chronic kidney disease are lacking. Role of Enhanced RAAS Suppression in Heart Failure Heart failure is characterized by a vicious cycle in which the progression in myocardial dysfunction stimulates a compensatory neurohumoral activation that perpetuates left ventricular hypertrophy and dilation. Clinical trials have provided overwhelming evidence showing that ACEIs decrease cardiovascular mortality, myocardial infarction, and hospitalizations for heart failure in patients with left ventricular systolic dysfunction beyond the benefits gained with conventional treatment [7, 8]. However, upregulation of alternative non-ACE pathways under chronic treatment with ACEIs determines a gradual return of Ang II and aldosterone to baseline levels [14], with progression of the disease and persistence of symptoms. Despite the expected greater benefit of blocking AT1 receptors in the context of Ang II escape, ARBs administered in relatively high doses, reduced mortality and morbidity from heart failure to an extent equivalent to ACEIs, with the only advantage of a better tolerability [82-84].


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Two outcome clinical trials, the Val-HeFT [82] and the CHARM-added [83], demonstrated that the addition of maximal doses of the ARB valsartan 160 mg BID or candesartan 32 mg daily, respectively, offered additional clinical benefits (a significant 13-15 % reduction in CV deaths and hospital admissions for congestive heart failure) to patients with heart failure and a low ejection fraction that remain symptomatic despite treatment with an ACEI and a betablocker. The benefit of valsartan versus placebo was more pronounced in reducing the number of patients with recurrent heart failure hospitalization (-20.6%) than single hospitalizations (-8.7%) [85]. In both trials, the benefit of the addition of an ARB was counterbalanced by a higher rate of withdrawal because of increased creatinine and hyperkalemia. The VALIANT study [84], in the setting of heart failure after acute myocardial infarction, showed that valsartan 160 mg BID was as effective as captopril 50 mg three times daily in reducing the rates of death and other adverse cardiovascular outcomes. However, combination therapy (valsartan 80 mg BID with captopril 50 mg three times daily) did not improve overall survival. Val-HeFT and CHARM-added trials differed from the VALIANT study because patients were already receiving an ACEI, and no attempt was made to titrate it to the maximum dose before the addition of the ARB. In contrast, the simultaneous initiation of dual therapy targeted to full dosage in the setting of an acute coronary syndrome could contribute to the lack of additive benefit seen in VALIANT. As in Val-HeFT and the CHARM-added, dual therapy in VALIANT also resulted in an increase in the rate of adverse events. Outcome data from the ATLAS trial [86] in 3164 patients with class II-IV heart failure and left ventricular ejection fraction 30% showed fewer (-24%) heart failure hospitalizations with high-dose (32.5-35.0 mg/day) versus low-dose (2.5-5.0 mg/day) lisinopril. More recently, the HEAAL study [87] demonstrated the beneficial effect of high versus low dose losartan (50 vs 150 mg) on major clinical outcomes in 3846 patients with heart failure, left-ventricular ejection fraction 40%, and intolerance to ACEIs. Demonstrating that 50 mg is a low dose of losartan sheds light on the causes of why this ARB fails to show superiority over captopril 150 mg in previous heart failure trials [88]. The RALES study [35] showed that a low dose of spironolactone (25 mg OD) as an add-on therapy to ACEIs in patients with severe heart failure and a low left ventricular ejection fraction markedly reduces mortality and prevents worsening of heart failure. In addition, the EPHESUS trial [36] demonstrated that eplerenone (25-50 mg OD) reduces morbidity and mortality among patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure mostly treated with ACEIs. This is in variance with the lack of additive benefit of valsartan when combined to captopril in the VALIANT study [84]. Currently, there are no clinical studies demonstrating the benefit of adding MRBs on top of ARBs in heart failure. Data from Val-HeFT [89] showed that aldosterone levels remained suppressed over a period of 24 months with valsartan compared with placebo suggesting that there is no rationale for the use of aldosterone inhibitors in patients treated with ARBs. However, a continuous increase in aldosterone


throughout the 24 months of follow-up was observed in both groups, likely due to the progressive nature of the disease, suggesting that some degree of aldosterone escape still occurs despite treatment with an ARB. The existence of a crosstalk between AT1 and mineracolocticoid receptors at the cardiac level [43] provides an experimental support for this combination. The ALOFT study [90] showed further decrease in brain natriuretic peptide (BNP) and TN-proBNP by the addition of aliskiren 150 mg to existing treatment with ACEI or ARB plus a beta blocker in 302 patients with symptomatic heart failure. In contrast, in ASPIRE, addition of aliskiren to an ACEI or an ARB did not prevent left ventricular remodeling in high risk post-acute myocardial infarction patients, and was associated with hyperkalemia and hypotension [91]. In summary, addition of an ARB to patients with heart failure refractory to ACEI monotherapy, reduces heart failure hospitalizations but does not seem to improve survival. Similar benefit can be achieved by high-dose ACEI monotherapy, or high-dose ARB in patients who are ACEI intolerant. In contrast, addition of a low-dose MRBs to an ACEI or an ARB increases survival in chronic heart failure and in heart failure complicating a myocardial infarction. Addition of aliskiren to existing treatment with ACEI or ARB decreases BNP in patients with symptomatic heart failure but did not prevent ventricular remodeling in post-acute myocardial infarction patients. The benefit and safety of adding aliskiren to standard therapy in chronic and acute decompensated heart failure is being evaluated by two ongoing outcome trials, ATMOSPHERE (clinical trial NCT00853658) and ASTRONAUTE (clinical trial NCT00894387), respectively. Role of Enhanced RAAS Suppression in Chronic Kidney Disease Inhibition of the RAAS constitutes a central therapeutic strategy to protect the kidney from progression to renal insufficiency in diabetic nephropathy and in other renal diseases [10-13]. Ultrafiltered proteins are toxic to the kidney, and the rate of renal function loss depends on the level of proteinuria achieved, particularly in nephrotic patients [92]. A reduction in albuminuria was associated with a proportional effect on renal protection in patients with type 2 diabetic nephropathy in the RENAAL study, in which 50 to 100 mg of losartan reduced the number of patients whose creatinine doubled by 25%, and reduced the number of patients reaching a composite endpoint comprised of doubling of the creatinine, end stage renal disease (ESRD), or death by 16% [12]. In the LIFE study [93] a reduction in albuminuria was followed by a reduction in cardiovascular events. Specifically, it was estimated that about one-fifth of the superiority of losartan over atenolol in the subset of diabetic patients could be explained by the greater reduction of albuminuria associated with losartan. Furthermore, the IDNT study [11] demonstrated that 300 mg of irbesartan was more effective than 10 mg of amlodipine or placebo in slowing the progression of renal disease, even after correction for the difference in blood pressure. Despite the effectiveness of RAAS inhibitors in reducing proteinuria, progression of kidney disease still occurred in

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30% of treated patients. As shown in the RENAAL study, residual albuminuria despite 50-100 mg of losartan conferred the same adverse renal risk as the albuminuria level in the placebo arm [12]. In this regard, alternative options to achieve a more complete supression of the RAAS in renal patients with suboptimal response to monotherapy may be suitable [94]. However, evidence for clinical outcome benefits of dual RAAS inhibition in chronic kidney disease is still lacking. A metaanalysis that evaluated 16 studies comparing combination versus ARB therapy, and 23 comparing combination versus ACEI published up to 2006, found that ACEIs and ARBs were more effective in reducing proteinuria when given in combination ( 18-25%) than either drug alone [3]. The authors concluded that insufficient outcome and safety data limits the applicability of the combination in clinical practice. One study, the COOPERATE [95], which compared the antiproteinuric and renoprotective effects of 100 mg losartan, 3 mg trandolapril, or a combination of both at equivalent doses in 336 nondiabetic hypertensive patients with proteinuric kidney disease, was excluded from the metanalysis and was recently retracted from publication due to methodological flaws [96]. Recently, a series of open labeled and long follow-up trials showed that the progression of renal disease may be halted by targeting the RAAS with dual and even triple combination titrated to normalize proteinuria. One of them randomly assigned 90 nondiabetic hypertensive patients with proteinuric renal disease (protein excretion > 1.0 g/day) treated with an ACEI to additional treatment with 2 to 12 mg/d candesartan, or to continue with ACEI alone [97]. After 3 years, dual therapy resulted in greater reductions in proteinuria and a much lower rise in serum creatinine than patients maintained on ACEI alone, despite comparable blood pressure. Doubling of serum creatinine occurred in seven patients of the ACEI group and in none of the candesartan/ACEI group. Another long term multimodal intervention study [98] that included 5-20 mg/day ramipril and 50200 mg/day losartan titrated to normalize proteinuria in a cohort of 56 consecutive patients who had >3 g proteinuria/d despite ACEI therapy, achieved disease remission or regression in up to 50% of patients who otherwise would be expected to progress rapidly to ESRD on conventional therapy. Interestingly, no patient was withdrawn due to hyperkalemia during the median follow up of 4 years of treatment. A systematic review concluded that the addition of a MRB to an ACEI and/or ARB therapy was associated with an additional decrease in proteinuria ( 30-40 %), blood pressure, and in the rate of decline of glomerular filtration rate, with significant hyperkalemia in only 1 out of 8 randomized controlled trials. Again, the authors concluded that the routine use of MRBs as an additive therapy for this indication cannot be recommended yet [99]. In an open label study of 83 patients with chronic kidney disease already treated with an ACEI and/or an ARB, a reduction in proteinuria from 2.1 to 0.89 g/g creatinine was observed 1 year after adding 25 mg of spironolactone compared with the control group [100]. Despite an initial reduction in the glomerular filtration rate, spironolactone delayed the decline compared with control by the end of one year.


Furthermore, baseline aldosterone levels correlated with proteinuria and predicted the antiproteinuric effect of spironolactone. Interestingly, basal levels of aldosterone were lower in patients receiving ACEI/ARB combination than in those treated with only one of these agents. The greater degree of aldosterone suppression was concordant with the higher basal potassium concentration, the lower basal level of proteinuria, and the lesser antiproteinuric response to spironolactone observed in the group treated with ACEI/ARB combination. Whether a similar degree of aldosterone suppression would be achieved with a higher dose of a single agent is not known. Similar effects were observed in the first double blind trial that randomized 59 type 2 diabetic patients with macroalbuminuria despite long term use of ACEIs or ARBs to receive 25 to 50 mg spironolactone or placebo during one year [101]. Albuminuria decreased by 40 % and blood pressure by 7/3 mmHg with spironolactone, while they remained unchanged with placebo. Spironolactone was associated with a greater decline in glomerular filtration rate at the expense of a rapid initial fall which leveled-off over time. This is in contrast with the progressive, linear decrease in glomerular filtration rate in the placebo group. Spironolactone-induced decline in glomerular filtration rate correlated with the antialbuminuric effect and was reversible after treatment discontinuation. Dosage reduction from 50 to 25 mg was necessary in 35 % of patients, and 17% had to be excluded despite dose reduction due to hyperkalemia. We have described two different combinations: ACEI/ARB and ACEI/MRBs. The question remains to be which of these combinations is superior to the other one in patients with suboptimal response to ACEI. This issue was addressed in a study comparing the addition of ARB versus MRB to patients with diabetic nephropathy who were already receiving 80 mg lisinopril [102]. Interestingly, a significant reduction in albumin excretion was afforded by the addition of 25 mg of spironolactone, but not by 100 mg of losartan. The strong correlation between baseline aldosterone levels and the antiproteinuric effect of spironolactone shown in a previous study [100] suggests a possible role of the measurement of aldosterone levels to guide the addition of MRBs. More recently, a series of studies reporting promising results with the use of triple therapy (MRB plus ACEI plus ARB) in non-diabetic kidney disease have been published [103-105]. The most significant of them is an open label study that compared the rate of progression of idiopathic glomerulonephritis between an intensive regimen that included an ACEI, an ARB, spironolactone, and a high dose statin versus conventional therapy (ACEI plus low dose statin) [105]. After 3 years, the protein-creatinine ratio fell from a mean of 2.6 to 0.45 g/g and the glomerular filtration rate did not change with intensive treatment. In contrast, with conventional therapy the protein-creatinine ratio fell from a mean of 2.6 to 1.23 g/g whereas the glomerular filtration rate decreased. Mean systolic blood pressure was lower with intensive rather than conventional therapy (113 vs. 123 mmHg). Uptitration of one agent beyond the dosage recommended for blood pressure control represents another alter-


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native strategy for achieving a more complete inhibition of the RAAS in patients with residual proteinuria. In 590 hypertensive patients with type 2 diabetes and microalbuminuria randomized to either 150 or 300 mg irbesartan for 2 years, maximal blood pressure reduction was already obtained with 150 mg (143/83 mm Hg versus 141/83 mm Hg in the 300 mg group), whereas fewer patients in the 300 mg group progressed to diabetic nephropathy (5.2 versus 9.7 % respectively) [106]. The same group extended these findings further by a crossover study randomising 52 hypertensive type 2 diabetic patients with microalbuminuria to 300, 600, and 900 mg irbesartan OD, each dose for a 2 month period [107]. All doses significantly reduced albuminuria and glomerular filtration rate, but the patients who benefited the more with uptitration were those who presented greater proteinuria while on 300 mg. Uptitration of irbesartan also reduced systolic ambulatory blood pressure from baseline (4-13 mmHg) without difference among doses. The 3 groups experienced a 0.3-0.4 mEq/mL increase in serum potassium, but no patients developed severe hyperkalemia. It is important to emphazise that the initial fall in glomerular filtration rate seen with RAAS inhibition represents an attenuation of the hyperfiltration in remanent glomeruli, an event which otherwise would ultimately lead to their continuous loss. A dose response study of losartan indicated that the optimal antiproteinuric response in 10 nondiabetic patients with overt proteinuria was reached at 100 mg (-30 +/- 8%), whereas the 50 mg dose (-13 +/- 7%) was less effective, and the 150 mg dose (-28 +/- 8%) had no additional benefit [108]. Recently, the ROAD study [109] compared renoprotection between conventional dosage of 10 mg benazepril or 50 mg losartan versus their respective uptitrated dosage (1040 mg benazepril and 50-200 mg losartan) in 360 nondiabetic patients with persistent proteinuria (> 1 g/d) and a serum creatinine level of 1.5 to 5.0 mg/dl. Beyond decreasing proteinuria, individualized uptitration of benazepril and losartan reduced the primary end point (time to doubling serum creatinine, ESRD, or death) by 51% and 53% respectively. Uptitration was stopped in 5 patients before the optimal antiproteinuric dosage had been reached because of SBP 5.5 mEq/mL developed in 14 patients but only 1 required drug discontinuation. A further analysis of this study found a positive correlation between urinary albumin excretion rate and the change in systolic blood pressure. In the case of candesartan, 32 patients with persistent proteinuria (> 1 g/d) and mild renal impairment received a 4 week treatment with 16 mg before being randomized to either 32 or 64 mg for 12 weeks, after which patients were returned to 16 mg for another 4 weeks [112]. Proteinuria decreased significantly in the 64 mg group, and increased again when titrated back to 16 mg, whereas it remained unchanged in the 32 mg group. These data was recently extended by the SMART study [113], which randomized 269 patients mostly diabetics with persistent proteinuria (> 1 g/d) despite a course of 7 weeks receiving 16 mg/d candesartan, to 16, 64, or 128 mg for 30 weeks. Titration up to 128 mg was associated with an additional antiproteinuric effect compared with 64 mg, without any further influence on blood pressure. Serum potassium > 5.5 mEq/L led to early withdrawal of 11 patients. Promising results of the addition of aliskiren on surrogate renal end points was provided by the AVOID study [114] which showed that 150-300 mg aliskiren added to the maximal recommended dose of losartan (100 mg/day) produced a greater reduction of proteinuria than the ARB alone in 599 patients with type 2 diabetes and proteinuria without further decrease in blood pressure. In summary, additional reduction in proteinuria and delay in the progression of the renal disease can be achieved by individualized antiproteinuric dose of either ACEIs or ARBs [109], or by applying dual and even triple combination therapy including an aldosterone inhibitor in a low dose [97, 98, 100, 101, 103, 105]. In patients with type 2 diabetes, hypertension and nephropathy, aliskiren added to losartan improved the antiproteinuric effect of losartan and reduced the incidence of renal dysfunction. However, in light of the negative results from recent clinical trials, the value of proteinura reduction as surrogate of renoprotection is now questioned. The answer to this question awaits the completion of ongoing clinical outcome studies LIRICO [124], VA NEPHRON-D [125] and ALTITUDE [79]. Safety Issues Hypotension and volume depletion, either diureticinduced or secondary to episodes of diarrhea, dehydration, or fever, increase the risk of acute renal failure in vulnerable patients, particularly when treated with combined RAAS blockade. With the progression of heart failure or chronic kidney disease, the maintenance of blood pressure, glomerular filtration rate, and plasma potassium within normal levels becomes increasingly dependent on the compensatory increase of Ang II and aldosterone. As renal plasma blood flow and

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sodium delivery to the distal nephron necessary for potassium secretion decreases, the risk of hyperkalemia in response to RAAS suppression increases. At the same time, the increase activation of the RAAS accelerates the progression of the disease. Therefore, the more severe the heart or kidney failure, the greater the benefit of a more complete blockade of the RAAS, but concomitantly the greater the risk of renal impairment, hypotension and hyperkalemia. A meta-analysis of randomized controlled trials using the combination ACEI/ARB for symptomatic chronic heart failure or acute myocardial infarction complicated by left ventricular dysfunction found that, compared with control treatment, there is a higher discontinuation rate due to adverse events (RR, 1.38 [95% CI, 1.22-1.55] and RR, 1.17 [95% CI, 1.03-1.34]), worsening of renal function (RR, 2.17 [95% CI, 1.59-2.97] and RR, 1.61 [95% CI, 1.31-1.98]), hyperkalemia (RR, 4.87 [95% CI, 2.39-9.94] and RR, 1.33 [95% CI, 0.901.98]), and symptomatic hypotension (RR, 1.50 [95% CI, 1.09-2.07], and RR, 1.48 [95% CI, 1.33-3.18]), respectively [115]. In ATLAS, high-dose lisinopril given to patients with heart failure was associated with more dizziness (56%), hypotension (55%), worsening of renal function (35%), and hyperkalemia (86%) compared with low-dose, but side effects did not lead to stop the medication more frequently (17.0% versus 18.0%)[86]. Interestingly, compared with the low-dose group, fewer patients in the high-dose group experienced cough. Similarly, cough with benazepril was not dose related in the renal patients of the ROAD study [109]. In the HEAAL study [87], high-dose losartan was associated with 40-48% higher incidence of renal impairment, hypotension, and hyperkalemia compared with low-dose, but again, the excess of adverse events did not lead to significantly more treatment discontinuations. Conditions that predispose patients to hyperkalemia [116] during RAAS inhibition are those associated with hyporeninemic hypoaldosteronism, such as older age, diabetes mellitus, and chronic kidney disease. A more liberal use of dual RAAS inhibition, use of higher doses of spironolactone, consumption of NSAIDs and potassium-containing salt substitutes also contribute to increase the risk of hyperkalemia, limiting the routine prescription of dual inhibition. The 2009 ACCF/AHA [117] and the 2008 European Society of Cardiology [118] guidelines restrict the addition of MRBs or ARBs to patients with moderate to severe heart failure and reduced left ventricular ejection resistant to conventional therapy when creatinine is < 2.5 mg/dL and potasium is < 5.0 meq/L, and when close blood pressure and laboratory monitoring is feasible. The 2008 European Society of Cardiology [118] recommends a starting dose of 4-8 mg OD for candesartan and 40 mg BID for valsartan, which should be uptitrated to 32 mg OD and 160 mg BID respectively, if tolerated, with renal function and serum eletrolytes rechecked within 1-2 weeks after starting treatment and increasing dose. For example, in the Val-HeFT, the criteria for increasing the dose of valsartan from 40 mg BID to the target dose of 160 mg BID included an upright systolic blood pressure > 90 mm Hg, and a serum creatinine concentration < 2 mg/L or no more than 50 %


higher than baseline concentration. The guidelines also recommend serial monitoring of serum electrolytes and renal function (1-4 weeks after onset and after each dose uptitration, 2-3 months after achieving maintenance dose, and every 6 months thereafter) [118]. Doses should not exceed 25 mg OD when spironolactone is combined with another RAAS inhibitor, and combinations should be avoided when the glomerular filtration rate is < 30 ml/min (a threshold below which the risk of hyperkalemia is substantial). Jain et al. [38], provides suggestions for minimizing serious adverse events in chronic kidney disease patients treated with MRBs, including the addition of a thiazide or furosemide when serum K+ exceeds 4.5 mEq/L; decreasing the dose of MRBs, ACEIs or ARBs when serum K + exceeds 5 mEq/L, and stopping either of them when serum K + exceeds 5.5 mEq/L. The use of diuretics, by increasing the delivery of sodium to the collecting duct, attenuates the risk of hyperkalemia associated with RAAS inhibitors. However, inappropriately high-dose diuretics could also lead to hyponatremia and volume contraction, which can further increase the risk of hypotension and renal insufficiency. Hypotension and azotemia in the context of fluid retention may also occur as a result of worsening heart failure, which may be exacerbated by attempts to reduce the dose of diuretics. The safety of high-dose ARB treatment (1.5-5 fold greater than the maximum approved dose) was tested in chronic renal disease. During a mean follow-up of 40 +/- 24 months, a non significant trend to increases in serum K+ (0.2 ± 0.9 meq/L) and creatinine (0.3 ± 0.7 mg/dL), without a parallel change in blood pressure was observed [119]. Similarly, the addition of aliskiren did not increase the incidence of serum K+ above 5.5 mEq/L compared with an ACEI or an ARB alone in ALOFT (8.3% in both groups) [90], in ALLAY (2.7 versus 3.3%) [76] , and in AVOID (13.7 versus 10.8%) [114], suggesting a lower incidence of adverse events. Of note, in AVOID, renal dysfunction (defined as an elevation in serum creatinine >2 mg/dL) was significantly more frequent in the placebo group [120]. In contrast, in ASPIRE, the addition of aliskiren was associated with a higher rate of hyperkalemia (5.2% vs. 1.3%), hypotension (8.8% vs. 4.5%) and renal dysfunction (2.4% vs. 0.8%) compared with placebo. CONCLUSIONS Based on the lack of additional benefit and the increased incidence of adverse events, the use of ACEI/ARB combinations for primary or secondary cardiovascular prevention is discouraged. However, outcome data in patients with heart failure support the the use of high rather than low doses of ACEI (or ARB in patients intolerant to ACEI), and the addition of an ARB or an MRB to patients resistant to ACEI. A compensatory increase in plasma volume represents a source of resistance to the antihypertensive and antiproteinuric effects of Ang II inhibitors, which can be restored by a low salt diet and maximized dose of diuretics [121-123].


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Addition of a MRB on top of antihypertensive treatment now represents a valuable therapeutic resource for controlling refractory hypertension and organ damage. However, outcome data evaluating the benefit of adding a MRB in arterial hypertension or chronic kidney disease with proteinuria are lacking. Until the finalization of clinical outcome studies LIRICO [124] and VA NEPHRON-D [125], comparing ACEI/ARB combinations versus monotherapy in patients with proteinuria, and the completion of the ASPIRE HIGHER clinical trials programme evaluating the addition of aliskiren on top of conventional treatment in more than 35,000 patients with hypertension, heart failure, kidney disease and diabetes; combined RAAS therapy should be reserved to patients with resistant heart failure or proteinuria. Patients receiving combined or high dose RAAS therapy require close medical surveillance, and their susceptibility to hyperkalemia should be individualized. A role for enhanced inhibition of the RAAS in prevention and treatment of dementia has recently emerged from observational data. A prospective cohort of 819 491 participants aged 65 years or older, showed that treatment with ARBs was associated with reduced incidence and progression of dementia, with a dose response as well as an additive effect in combination with lisinopril [126], providing a rationale for future clinical trials. REFERENCES [1]

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Revised: August 24, 2010

Accepted: August 26, 2 010