Direct renin inhibitors: ONTARGET for success? - Springer Link

Int Urol Nephrol (2009) 41:341–355 DOI 10.1007/s11255-009-9556-7

NEPHROLOGY - REVIEW

Direct renin inhibitors: ONTARGET for success? Yasmin Pasha Æ Paul Gusbeth-Tatomir Æ Adrian Covic Æ David Goldsmith

Received: 23 February 2009 / Accepted: 27 February 2009 / Published online: 19 March 2009 Ó Springer Science+Business Media, B.V. 2009

Abstract Direct renin inhibitors are the first new class of antihypertensive to emerge since angiotensin II receptor blockers. We discuss their reno- and cardioprotective potential, based on extrapolation from animal models and phase three trials that are currently ongoing. This paper reviews the potential benefits of direct renin inhibitors (DRIs), the only new anti-hypertensive class developed in the last decade, as compared to pre-existing classes of drug inhibiting more downstream, such as Angiotensin Converting Enzyme inhibitors (ACEI), Angiotensin 2 Receptor Blockers (ARBS). Keywords ACE-inhibitor Angiotensin II receptor blocker Aliskiren Chronic kidney disease Direct renin inhibitors Renin angiotensin system Renin inhibitors

Y. Pasha Chelsea and Westminster Hospital, Fulham Road, London, UK P. Gusbeth-Tatomir (&) A. Covic Nephrology Clinic, Parhon University Hospital, ‘‘Gr.T. Popa’’ University of Medicine and Pharmacy, Iasi, Romania e-mail: [email protected] D. Goldsmith Renal Unit, Guy’s Hospital, London, UK

Introduction The recently reported ONTARGET trial [1, 2] now conclusively show that for all practical purposes the two classes of agents (ACE inhibitors—ACEI and Angiotensin Receptor Blockers—ARB) are effectively clinically equivalent in terms of cardiovascular risk reduction. Surprisingly, there were significant side-effects for both classes of drugs, and the combination of telmisartan and ramipril, though lowering BP further, was not accompanied by any additional clinical benefit (and was accompanied by more renal impairment and other side-effects). This, although answering some important questions, now raises a further series of clinical questions, chief amongst which is whether an ACEI, or an ARB, could summate the more effectively with an orallyactive direct inhibitor of renin synthesis. Kidneys synthesize renin, which acts on a plasma substrate to produce Angiotensin 1 (AT1). AT1 is converted enzymatically to Angiotensin 2 (AT2). AT2 is a powerful vasoconstrictor. Drugs exploiting this pathway have traditionally either interfered with the utilisation or formation of AT2 (see Fig. 1). The renin-angiotensin-aldosterone system (RAAS) is one of the most powerful regulators of arterial blood pressure and sodium balance. Hypovolemia, hypotension, stress and injury stimulate the macula densa, the baroreceptor reflex and the sympathetic nervous system. Each of these independently triggers renin release from the juxtaglomerular apparatus.

123

342 Fig. 1 The Renin Angiotensin Aldosterone System (RAAS) and site of actions of antihypertensive drugs

Int Urol Nephrol (2009) 41:341–355 Indicates points of blockade A. Site of action of a Direct renin inhibitor (e.g. Aliskiren) B. Site of action of an ACE inhibitor C. Site of action of an Angiotensin Receptor Blocker

↓ NaCI intake

↓ Arterial pressure

↓ ECF volume

Angiotensinogen

Stress traum a

Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Val-Tyr-Ser-R

Angiotensinogen I Asp-Arg-Val-Tyr-Lle-His-Pro-Phe-His-Leu

Angiotensin Converting Enzyme Chymase (heart)

Macula densa mechanism Baroreceptor mechanism Sympathetic nervous system

B

Angiotensinogen II

A Juxtaglomerular apparatus Cytosolic Ca cAMP

Asp-Arg-Val-Tyr-Ile-His-Pro-Phe

Renin Release

Angiotensinases

C

AT1 AT2 AT?

Metabolites Angiotensinogen (1-7) Angiotensinogen (2-8) Angiotensinogen (3-8) Inactive fragments

Angiotensinogen, produced in the liver is hydrolysed by renin into AT1. AT1 is converted to AT2, by the angiotensin-converting-enzyme (ACE). AT2 acts on the adrenal glands (zona glomerulosa) to stimulate aldosterone release. The kidneys increase Na? resorption, vasoconstriction and water retention, resulting in increased blood pressure. It is also key player in development of renal injury capable of causing systemic and glomerular hypertension. It reduces renal perfusion by intrarenal vasoconstriction causing ischemic damage. It can also directly and indirectly induce mesangial and tubular cell proliferation. This may lead to tubulointerstitial fibrosis [3].

Why RAAS worth inhibiting? Renal and cardiovascular benefits Beneficial effects of ACEI and ARBs are well documented in terms of improving cardiovascular mortality post-myocardial infarction and in patients with heart failure. Studies on diabetic and non diabetic populations have shown evidence of retardation of progression of renal failure and regression of proteinuria.

123

Receptor binding and biological actions

Do ACEI/ARBs have any benefit over antihypertensive action? A large meta-analysis conducted by Casas et al. [4] suggested that these benefits could be explained in terms of blood pressure rather than specific benefits of interrupting the RAAS. ACEI’s and ARB’s appear to have benefits at least partially independent of their antihypertensive action. These include reduction of albuminuria and improvement in histological appearance of glomeruli. However, the degree of improvement varies between patients and many trials comparing the efficacy of various antihypertensives have failed to show consistent results. Sarafidis et al. [5] suggest that ACEI do exert BPindependent reno-protective effects but only in the presence of advanced chronic kidney disease (CKD) stage III–IV and proteinuria. A prominent criticism of the Casas meta-study was that a third of the renal outcomes came from the ALLHAT trial, which did not study a representative sample, i.e. one that could be extrapolated to the European CKD population. The study excluded most high-renal risk patients, including all with a serum creatinine [177 mmol/l, concurrent heart failure, those already on ACEI/ARB, and all those on concurrent diuretics. Additionally, data on base-line

Int Urol Nephrol (2009) 41:341–355

microalbuminuria and proteinuria was not always provided. Indeed, when ALLHAT data was excluded form the meta-analysis then a clear benefit for RAAS inhibition, over and above BP control has been demonstrated [6].

Renoprotection: how is it measured? Microalbuminuria in hypertensive, diabetic or non diabetic is a recognised predictor of end-stage renal disease (ESRD), and early mortality as well as CV events [7]. Other markers used include doubling or trebling time of serum creatinine, years to dialysis or rate of decline of the glomerular filtration rate (GFR), time to transplantation or death. There is evidence to support the renoprotective benefits of RAAS inhibition in both diabetic and non diabetic disease. Two large meta-analyses consider the evidence. Cardiovascular (CV) benefits were demonstrated by the HOPE [8] trial, which showed reduced risk of cardiovascular events in diabetic patients with microalbuminuria, after treatment with ACE inhibitor. There was a significant reduction in the primary end point (MI/stroke/death) from 17.7% in placebo to 14.1% in the ramipril group, with a relative risk reduction of 22%. There was also a significant reduction in all-cause mortality (16% in the ramipril group). Similarly, the effects of the ARB losartan on CV mortality, studied in the LIFE trial [9] and extrapolation from the IDNT study [10] suggest that reduction of albuminuria during BP reduction reduces risk of CV events as well as development or progression of renal disease.

Trial data of RAAS inhibition in diabetics A meta-analysis of 12 placebo-controlled trials of ACE inhibition in type 1 diabetic patients, with normal BP and microalbuminuria demonstrated that ACEI were associated with a 62% reduction in risk of progression from micro to macroalbuminuria. There was a 300% increase in the probability of return to normo-albuminuria [11]. In Type I diabetics with overt proteinuria, captopril reduced the risk of progression of diabetic nephropathy by 48% compared to placebo, with a greater risk reduction at

343

higher baseline creatinine levels. ACEI also reduced combined end-point of dialysis, transplantation or death by 50%. The IDNT study [9] high-lighted the relationship between reducing proteinuria in type II diabetics and risk of renal failure. Patients were randomised to placebo, irbesartan or amlodipine. Halving the proteinuria reduced risk of ESRD by 50%. The reduction of albuminuria was also associated with a reduction in risk of CV events. Comparative studies of ACEI and ARBs are rare; one such study [12] observed the effects of telmisartan and enalapril on microalbuminuria of Type 2 diabetics and concluded that ramipril was not inferior to telmisartan. The ABCD trial [13] was a study with a 5.3 follow-up of intensive vs. moderate BP control on diabetic complications. Patients were randomised to enalapril, nisoldipine or placebo. No differences were found between intensive and moderate arms, or between ACEI and calcium-channel blockers (CCB). In hypertensive patients there was no difference in the secondary endpoint of urinary albumin excretion between intensive and moderate groups. But enalapril significantly reduced urinary albumin excretion. In normotensives, intensive BP control reduced progression to microalbuminuria. A synthesis of the main studies on nephroprotection in diabetic nepropathy is presented in Table 1 [14].

Trial data of RAAS inhibition in non-diabetics A meta-analysis of 11 randomised ACEI trials in subjects with non-diabetic renal disease demonstrated a 30% reduction of risk of ESRD or combined endpoint ESRD or doubling of creatinine, in ACEI arms. Greater benefits were consistently found in patients with greater proteinuria [15]. The GISEN group [16] examined the effect of ramipril on normal to hypertensive patients with proteinuria unrelated to diabetes. This placebo controlled double-blind study showed equal incidence of CV events in both arms; BP was comparable in both as conventional antihypertensives were given in the non-ACEI arm. Ramipril significantly slowed the decline in GFR in patients with proteinuria over 3 g/24 h. Ramipril also halved combined endpoint of doubling creatinine or ESRD. There was also significant lowering of urinary protein excretion by 55% at

123

Population

Study

123

ABCD

IRMA-2

MARVAL

IDNT

EUCLID

BENEDICT

n = 470

Type 2 DM and HTN

n = 590

Type 2 DM, HTN, microalbuminuria

n = 332

Type 2 DM and microalbuminuria ±HTN

n = 1,647

Type 2 DM, HTN, proteinuria, raised creatinine

n = 530

Type 1 DM, normomicroalbuminuria

n = 1,204

Type 2 diabetics with normoalbuminuria & HTN

n = 25,620

Persistent microalbuminuria

Composite; Death from cardiovascular causes, MI, CVA or admission for heart failure

Non inferior BP control

Primary endpoint

Randomised, blinded, 5.3 year mean follow up

Randomised, placebo, controlled, 2 year period

Randomised, double blind, 24 week trial

Change in 24 h creatinine clearance

Time to overt nephropathy

%change in UAER

The combination was associated with more adverse events without increase in benefit

Mean BP was lower in both the Telmisartan alone and combination groups than ramipril alone. Telmisartan alone was associated with less cough (1.1 vs. 4.2% P \ 0.001), less angioedema (0.1 vs. 0.3% P = 0.01), but more hypotensive symptoms (2.6 vs. 1.7%) than ramipril

Results

ACEI Lisinopril vs. Placebo

ARB reduced relative risk of diabetic nephropathy by 44% at low dose (150 mg/24 h) and by 68% at high dose (300 mg/24 h)

ARB reduced UAER by 44% compared to 8% with CCB, with similar BP in both groups

Enalapril vs. nisoldipine Intensive No difference in primary end-point BP control DBP aim 70 mmHg between ACEI and CCB. But fewer pts vs. mod 80–89 mmHg in the intensive BP group progressed from NA-MA (P = 0.012) and from MA to albuminuria (P = 0.028)

Irbesartan vs. placebo

Valsartan vs. amlodipine

ARB reduced relative risk of doubling creatinine by 33% compared to placebo and 37% vs. amlodipine

ACEI reduced UAER by 18.8% vs. placebo, treatment effect was far greater in microalbuminuric patients than normoalbuminuric patient

ACEI trandolapril vs. ACEI plus Both arms prevented microalbuminuria CCB (verapamil) vs. CCB alone 5.7% of MA prevented in combination arm vs. 6% in ACEI only arm, 11.9% in CCB only arm compared with 10% in placebo

Ramipril 10 mg vs. Telmisartan 80 mg vs. the combination

Intervention

Randomised, double blind Doubling time of creatinine, ARB Irbesartan vs. CCB ESFR, all cause mortality amlodipine or placebo

Randomised, doubleRate of change in urine blind, 2 year follow up albumin excretion rate

Randomised, double blind, placebo control 3.6 year follow up

ONTARGET Patients with high risk Randomised, double diabetes/vascular blind, non-inferiority disease without heart study, median follow failure up 56 months

Trial/Study

Table 1 Data on RAAS inhibition in Diabetic Renal Disease

344 Int Urol Nephrol (2009) 41:341–355

Time to 1st event of Losartan vs. placebo (both added composite doubling of on to conventional BP creatinine, ERSF or death treatment)

ARB reduced relative risk of doubling of creatinine by 25% and risk of ESRD by 28%. No effect on all cause mortality

345

n = 1,513

Type 2 DM, nephropathy RENAAL

Randomised, double blind, placebo controlled, 3.4 year follow up

Enalapril vs. nisoldipine Intensive No difference in primary end-point BP control 10 mmHg below between ACEI and CCB. No difference baseline vs. mod control 80– in progression from NA-MA or MA89 mmHg albuminuria. Subjects with albuminuria at base-line continued to show a decline in renal functions at both levels of BP control Change in 24 h creatinine clearance Type 2 DM and normotension n = 470 ABCD

Randomised, blinded, 5.3 year, mean follow up

Population Trial/Study

Table 1 continued

Study

Primary endpoint

Intervention

Results


36 months. This effect was greater than would be expected by BP control alone. The AASK study [17] compared effects of an ACEI, a beta-blocker (BB) and a CCB on African-American patients with hypertension-related decline in GFR. There was no association between the BP level and the endpoints reached. However, ramipril was significantly found to reduce risk of ESRD by 22% compared to metoprolol and by 38% compared to amlodipine. Both ramipril and metoprolol reduced the risk of ESRD alone and risk of ESRD or death, compared to amlodipine. At 3 years, the mean decline in GFR was 36% slower in patients on ramipril compared to amlodipine. A synthesis of the main studies on nephroprotection in non-diabetic CKD is presented in Table 2 [14].

Antiproteinuric activity of non-RAAS drugs Calcium channel blockers (CCB) cause dilatation of the afferent arterioles (in contrast to ACEI/ARB’s). In the presence of systemic hypertension, this may cause intraglomerular hypertension. The PREVEND study [18] looked at the incidence of microalbuminuria in non-diabetic renal patients on various antihypertensive agents, elevated urinary albumin was found in patients on dihydropyridine CCBs, but not in non-dihydropyridine CCBs. Of note, the same study showed that ACEI were only superior in protecting against microalbuminuria, when combined with a diuretic. Other classes such as diuretics, beta-blockers, and hydralazine do not induce efferent dilatation and are theoretically less likely to reduce intraglomerular hypertension. Non-selective beta-blockers—BB (e.g. propranolol) reduce GFR and renal perfusion by reducing cardiac output. A reflex rise in sympathetic activity results in raised systemic and renovascular resistance, via alpha-receptors. A few studies [19] have shown that selective BBs (e.g. metoprolol and atenolol), while reducing hypertension, do not reduce GFR or renal blood flow (RBF), although renovascular resistance increases. In patients with renovascular hypertension, treating with metoprolol has been shown to reduce plasma renin activity (PRA). A study using atenolol in diabetics with microalbuminuria showed also that BB may retard usual progression to renal failure [20]. However, all BBs cause sympathetic nervous system (SNS) and RAAS stimulation, resulting in increased levels of renin and noradrenaline.

123

346


Table 2 Data on RAAS inhibition in non diabetic renal disease Trial/Study

Population

GISEN group Normohypertensive pt with proteinuria

Study

Primary endpoint Intervention

Double blind, Rate of decline of ACE-I vs. placebo ie placebo GFR standard BP control controlled (non ACE/ARB agents used)

n = 117

AASK

African American 18–70 year with hypertensive renal disease

Results Ramipril significantly reduced decline in GFR in pts with[3 g/ 24 h of proteinuria. Ramipril also halved combined endpoint of doubling creatinine or death. Significant lowering of urinary protein excretion by 55% at 36 months

Randomised, double blind, placebo control

Rate of change in Amlodipine vs. ramipril No difference in MAP goal and GFR vs. metoprolol ±other usual goal in terms of decline in (secondary agents to reach MAP of GFR. Ramipril reduced relative composite) \92 or 102–107 mmHg risk of composite clinical endpoint by 22% metoprolol and by 38% vs. amlodipine

Randomised, controlled, 36 month follow up

Time to ESRD

Randomised, double blind 2.9 year follow up

Combined time to ARB losartan or ACEI doubling or trandolapril or creatinine or combination ESRD

Randomised, doubleblind, 24 weeks

Microalbuminuria Eplerenone vs. amlodipine Eplerenone significantly reduced urine albumin: creatinine ratio vs. amlodipine

Randomised, double blind, 8 months

Change in proteinuria

n = 1094 REIN-2

Non diabetic proteinurics n = 338

COOPERATE Non diabetic renal disease Cr133-398, GFR2070 ml/min

Ramipril (moderate BP control) or Ramipril ? felodipine (intensive BP control)

Despite better BP reduction in intensive group, cumulative incidence of ESRD, GFR decline and residual proteinuria was similar in both arms Combination treatment reduced relative risk of creatinine doubling/ESRD by 62% vs. trandolapril alone and by 60% vs. losartan alone

n = 263 White et al.

Systolic HTN n = 269

VVANNTT

Non diabetic nephropathy n = 69

Why inhibit renin? What can it achieve that other classes cannot? Neither ACEIs nor ARBs alone can inhibit the RAAS completely. Renin catalyses the rate-limiting step of RAAS. Renin is unique in specificity and only appears to recognise one known substrate, angiotensinogen. ACE, by comparison, recognises other peptides in addition to angiotensin, such as bradykinins. However, renin receptor occupancy with renin/prorenin also stimulates specific protein kinases ERK1 and ERK-2, which are mitogen-activated, without affecting AT generation [21]. This supports a pro-fibrotic role for renin, independent of its angiotensin

123

Trandolapril ? verapamil or amlodipine

Trandolapril alone significantly reduced proteinuria from baseline. Addition of CCB did not make any difference to proteinuria

generating effect. Recently, renin receptors have been identified in the glomerular mesangium and arterial sub-endothelium; this suggests potential additional advantages of renin inhibition, over and above ACE and angiotensin receptor blockade. Unlike ACEI and ARBs, renin inhibitors induce a marked and sustained reduction in PRA and consequently prevents the formation of both angiotensin 1 (AT1) and angiotensin 2 (AT2), consecutively reducing the levels of aldosterone—see Table 3 for a detailed comparison of ACEIs, ARBs and Direct Renin Inhibitors. ARBs usage leads to increased concentration of AT2. The therapeutic response achieved by both ACE and ARB may be attenuated by the reactive rise


347

Table 3 Comparison between different classes of antihypertensives involved in RAAS inhibition Drug class

ACE inhibitor

Angiotensin 1 receptor blocker Direct renin inhibitors

Aldosterone antagonist

Mechanism

Retard conversion AT1–AT2

Inhibit AT2 at receptor level

Aldosterone antagonist

Direct renin inhibition

ACEI ? ARBs

Bradykinin levels Up

Up (but less than ace)

No change

Increased

Angiotensinogen levels

Decreased

Decreased

No change

Additive effect

Plasma ACE

Inhibited

Not inhibited

Not inhibited

Inhibited

AT1 levels

Up

Up

Down

Additive effect

AT2 levels

Down(but long term increase)A2 escape

Up

Down

Down/normal

AT1 receptor

Not stimulated

Blocked

Not stimulated

Not stimulated and blocked

AT2 receptor

Not stimulated

Stimulated

Not stimulated

Minor stimulation

Renin concentrations

Up

Up

Down

Plasma renin activity

Increases

Increases

Inhibited

Serum aldosterone

Lower initially (then aldosterone escape, normal to high levels)

Lower initially (then aldosterone escape, normal to high levels)

Lower

Lower

Lower

MAP

Lower

Lower

Lower

Lower

Lower

Renovascular response

Yes

Yes. Greater than ACEI

Yes. Greater than ARB and ACEI

Effect on GFR

Increase

Increase

Greater increase

Intra-glomerular Lower (dilates efferent blood pressure arteriole)

Lower (dilates efferent arteriole)

Lower (dilates efferent arteriole)

Effect on proteinuria

Reduces

Reduces

Reduces

Tissue RAAS

Inhibited

Blocked

Inhibited

of renin [22] and therefore of angiotensin peptides, which does not occur with direct renin inhibition. Inhibition of ACE leads to accumulation of AT1. This AT1 can then potentially be converted to AT2 by alternative pathways not blocked by ACE inhibition. There is data to suggest that up to 30–40% of AT2 formation in the healthy human, during RAAS activation, occurs through renin dependent, but ACEindependent pathways [23, 24]. Angiotensin break-through or escape is the name given to the tendency of AT2 to rise toward pretreatment levels [25]. Additionally, polymorphism within the ACE gene means up to 45% of congestive heart failure (CHF) patients on long-term ACEinhibition continue to have elevated AT2 levels [26].

Up

Additive Additive

Lower

Reduces

Reduces Additive effect

It is worth noting that aldosterone independently contributes to renal injury as well. Pathways shown to promote this include inflammatory cytokines, generation of oxygen free radicals and up-regulation angiotensin II (type 1) receptors, which potentiate the damaging effects of ATII [27, 28].

Aldosterone escape ACE and ARBs initially reduced aldosterone levels, but in the longer term they lead to incomplete aldosterone suppression or aldosterone escape [29]. There is evidence to suggest that direct renin inhibitors (DRIs) such as aliskiren can reduce AT2

123

348

reactivation in ACE inhibition and aldosterone escape by ACEI or ARB, at least in RAAS-dependent aldosterone production. For RAAS-independent aldosterone production, DRIs and drugs such as eplerenone may be beneficial [29].

Plasma renin level and plasma renin activity (PRA) To measure the effect of various agents on renin concentration either the plasma renin activity or the plasma renin concentration can be used. Plasma renin activity (PRA) measures the enzymatic activity of renin and quantifies the amount of angiotensin I generated from renin activity. Hypertensive patients demonstrate a wide spectrum of plasma renin activity (PRA). Studies have shown the association between occurrence medium to high PRA in hypertensive and future cardiovascular events [30]. PRA is also a predictor of response to various antihypertensives. Lowering PRA is believed to be important in endorgan protection. PRA is an independent risk factor and direct surrogate marker for several cardio-renal diseases, such as myocardial infarction (MI) and chronic kidney disease (CKD). Direct renin inhibitors lower PRA, whereas most current anti-hypertensive drug classes such as ACE-Is and ARBs increase PRA levels (See Table 3 for a comparison of the actions ACEI, ARBs and DRIs). Currently aliskiren is the only orally-active DRI that has passed Phase III trials, despite drug development commencing some thirty years ago. This highly lipophilic formulation, aliskiren, has a half life of 24 h, improved bioavailability and undergoes under 1% metabolism by the liver negating the need for renal dosing in renal impairment and is unaffected by the p450 enzyme system. Aliskiren is able to inhibit PRA by up to 65% from baseline [31]. This is in contrast to ACE inhibitors and ARBs that interrupt feedback regulation by AT2, causing increased renin levels and increased PRA. When aliskiren is added to an ARB or ACE inhibitor, PRA is lower than with the ARB or ACE inhibitor alone and higher than with aliskiren monotherapy [32, 33]. Additionally, it can counteract the hydrochlothiazide (HCZ)-induced rise in PRA if used in combination [31, 34]. Aliskiren-induced inhibition of PRA persists for 3–6 h with lower doses (40–80 mg/day)

123


and 10–48 h with higher doses (160–640 mg/day). PRA is reduced in a dose-relatedly manner, with the greatest reductions occurring at the highest doses. On cessation of aliskiren, PRA does not return to pretreatment levels for up to 2 weeks. In contrast, both ACE inhibitors and ARBs have been observed to increase PRA to a greater extent than placebo. This occurs within a few hours of ACE inhibitor or ARB being administered. PRA remains elevated throughout therapy. The other method of quantifying renin is the measurement of plasma active renin, also known as active renin concentration (ARC). Measurement of ARC allows quantification of the amount of renin present, regardless of its activity. ARC is elevated early after treatment with aliskiren and remains elevated with repeated dosing. ARC does not return to pre-treatment levels until 2 weeks after withdrawal, suggesting that long-term protective effects could be derived at tissue level. Aliskiren causes a greater elevation in ARC than with valsartan [32]. ARC is likely to be increased because the amounts of both angiotensin I and angiotensin II are reduced by aliskiren for at least 24 h after treatment administration. A feedback loop signalling the kidneys to release more renin is triggered by low levels of angiotensin II; therefore, an increase in ARC is a marker of RAAS suppression. The higher ARC observed with aliskiren compared with that of ACE inhibitors or ARBs suggests that aliskiren provides more complete suppression of the RAAS. Although ARBs inhibit the action of angiotensin II at the level of the AT1 receptor and ACE inhibitors prevent the generation of angiotensin II, ARBs also increase both AT I and II, whereas ACE inhibitors increase AT I. Increased angiotensin I could lead to increased generation of angiotensin II by alternative pathways, and more angiotensin II could lead to increased stimulation of AT2 receptors, which are not blocked by ARBs. There are data [23] to suggest that up to 30–40% of AT2 formation in the healthy human, during RAAS activation, occurs through rennin-dependent but ACE-independent pathways. ARC may be higher with DRIs, because these inhibit the RAAS before these alternative pathways and targets the only known pathway for conversion of angiotensinogen to angiotensin I.


Direct renin inhibitors currently available As the initial and rate limiting step of the RAAS cascade, direct renin inhibition was expected to be the most effective means of inhibiting the RAAS. Earlier technical problems for drug development included low potency, poor bioavailability related to minimal gastro-intestinal absorption, substantial first-pass metabolism, weak antihypertensive ability and limited duration of action. Aliskiren is currently the only orally active DRI that has passed phase III clinical trials. However, others such as enalkiren and remikiren are under study. In healthy adults, with oral administration of aliskiren in doses of 40–640 mg/24 h, plasma concentration increased in a dose-dependant fashion. Peak concentrations were achieved within 3–6 h. Aliskiren plasma steady state concentrations were achieved in 5–8 days of treatment. Mean plasma half life was 23.7 h [35], allowing once daily dosing regimens. Pharmacokinetics deviate from dose linearity [36]. Oral bioavailability is 2.6% and food intake reduces the maximum concentration cmax by 19% and the area under the curve by 38% [37]. Elimination is primarily via the biliary route; the drug is excreted in unmetabolised form. Under 1% undergoes urinary excretion, this means there is no need for adjustment of the starting dose in patients with renal impairment [36, 38]. It is also not affected by cytochrome P450 system [39, 40].

What do we expect DRIs to do? Extrapolation from animal models The main biochemical difference between direct renin inhibitors and ACEIs or ARBs is that DRIs dramatically inhibit renin activity without altering angiotensinogen expression, indicated by decreases in both AT1 and AT2. In animal studies specifically, in the double-renin transgenic rat (developed to overexpress renin and angiotensin genes), aliskiren has demonstrated attenuation of cardiac and renal end organ damage in a similar fashion to valsartan. In addition to BP and microalbuminuria reduction, normalisation of the serum creatinine, and regression of LVH, aliskiren treated rats also showed improved overall survival [41]. ACE-inhibitors also block the proteolytic inactivation of bradykinin and substance P, leading to two

349

side-effects: dry cough (common) and angioedema (occasionally). While AII-antagonists show limited receptor subtype activity, several cases of angioedema have been reported; the mechanism remains unclear but may be due to the observation that ARBs can induce tissue, but not serum increase in bradykinin levels [42]. Because renin is upstream from these events, a therapeutic approach which targets this enzyme should be free from these side-effects and limitations; indeed, no cases of angioedema with aliskiren treatment have been reported so far. Increased levels of bradykinin, a vasodilatory peptide, after ACE inhibition are likely to be at least in part responsible for its superior antihypertensive properties of ACEI over both ARBS and potentially DRIs. But in addition to the irritating cough, it is possible that accumulating bradykinin (during ACE inhibition) may counteract the beneficial effects on end-organs of reducing AT2. The accumulating AT1 may be susceptible to conversion to AT2 by ACE-independent processes. This would not occur with direct DRIs. Therefore, it is possible that DRIs may offer better cardio- and renoprotection. This also suggests that DRIs maybe usefully in combination with ACEIs. Given the action of ACEIs, it was expected that ACEI should produce a more profound renovascular responses than DRI, as ACE leads to kinin degradation and induces vasodilator prostaglandin formation or activation of NO release. However, vasodilatation with enalkiren was superior to captopril [43]. In a follow up study, enalkiren and captopril were compared in a placebo-controlled randomised doubleblind trial. Captopril and enalkiren both led to striking renal vasodilatation, whereas placebo had no effect. The response to enalkiren was significantly larger than the response to captopril [44]. In fact, a meta-analysis suggested that the renal vasodilator response to DRI exceeds that of ACEI by up to 50% in healthy adults [24]. The magnitude of the responses confirmed a more recent study by the same authors (Fisher and Hollenberg) [45], with another direct renin inhibitor, zankiren, that induced a larger renal vasodilator response than could have been anticipated from the ACE inhibitor experience. These data suggest that a renin-dependant, ACE-independent pathway for AT2 generation maybe implicated. Similar results were obtained in the guinea-pig study by El-Amrani et al. [46], which examined the renovascular responses to

123

350

ACE lisinopril, ARB losartan and the DRI RO425892 in guinea pigs. Despite similar BP reduction, the increase in renal plasma flow, GFR, diuresis and natriuresis were significantly greater with DRIs. One explanation offered for the superiority of the DRI-induced vasodilatation over ACEI is ACE independent AT2 formation, another is better tissue penetration of the DRI. The new agents are highly lipophilic, which means they may have enhanced renal tissue penetration, perhaps allowing more effective local (renal) AT2 formation blockage.

Intrarenal AT2 formation in humans Sustained vascular activity of the DRI enalkiren in humans was noted to continue despite discontinuation of the drug. As expected, plasma concentrations fell sharply after end of the infusion, approximating a half-life of 90 min, but renal plasma flow continued to rise. This suggests that enalkiren exerts its main influence outside of the plasma compartment [47]. It is possible that enalkiren is interrupting local intrarenal AT2 formation and this accounts for both the sustained vasodilator response but also for the observation that it exceeds the response of ACE inhibition. In support of DRIs long-term effects being at tissue level, it is noted aliskiren concentrations in the kidneys are particularly high and persist for up to 3 weeks after discontinuation of the drug [48]. A recent study [34] looked at effects of aliskiren versus aliskiren ? hydrochlorothiazide on renin concentration and PRA specifically at the effects of drug withdrawal. After six months, on-treatment renin concentration rose in the aliskiren arm, but was even higher in the combination group. During withdrawal, some patients switched to placebo and the remainder continued on aliskiren. PRA remained suppressed in those who continued, but in the group switched to placebo, PRA remained over 50% below baseline at 4 weeks after withdrawal, although renin concentration had reduced to baseline by then. This again suggests continued renin inhibition beyond the drug’s half life.

What are the expected cardiac effects of DRIs? In rats, dogs and sheep with left ventricular failure, DRI treatment is associated with reduced left

123


ventricular end-diastolic pressure. Regression of LVH comparable to that achieved with by ACEI and ARBs has also been demonstrated [41]. Like ACEIs, DRIs induce vasodilatation, offering potential to improve arterial wall elasticity. Currently, there is not much (human) data for cardiovascular effects. Novartis is now recruiting for Phase III trials looking at aliskiren in hypertensive patients with LVH (the ALLAY trial). This trial will be comparing effects of aliskiren with losartan and combination of both over 9 months in LVH patients, the end-point being MRI assessment of LVH mass [49, 50]. In the ALOFT study by Recio-Mayoral et al. [51], aliskiren was added to optimum standard therapy in NYHA class II–IV heart failure. One hundred and fifty-six patients had aliskiren 150 mg or placebo added to an ACEI or ARB. Interim results of surrogate markers are positive; in the aliskiren arm, serum BNP was five times more reduced compared to standard therapy, where BNP levels are a surrogate measure of heart failure severity. In addition, tolerability of aliskiren was similar to placebo and there were no cases of worsening of heart failure on treatment, in contrast to recognised worsening of failure with some BB and CCB therapies.

What are the expected side effects of DRIs? Cough, one of the major side effects of ACE inhibition, was predicted to be unlikely, as renin inhibition does not affect bradykinin formation. The incidence of cough with aliskiren is slightly increased when compared with placebo, but still much lower than with ACEI. Angio-oedema occurs less often than with placebo. When hyperkalaemia [5.5 was reported this was usually in diabetics on concurrent ACE inhibition. Published safety data include Oh et al.’s [52] randomised double-blind multicenter placebo-controlled study, analysing the dose dependent efficacy and tolerability of aliskiren in patients with mild-tomoderate hypertension. Aliskiren was well tolerated with an adverse event profile similar to placebo at up to 300 mg. There was a higher rate of diarrhoea at 600 mg (11.4 vs. 1.2%, 1.8 and 1.2% for aliskiren 150, 300 and placebo respectively). There were four severe adverse events and no deaths. BP was lowered


in a dose-dependant manner. These were sustained over the 24 h dosing interval [52]. Weir et al.’s pooled analysis [53] examined the adverse event profile of DRI from seven randomised control trials, five of which were placebo-controlled. A total of 7,060 patients (50.2–72.5% male, 77.4% white, age range 50.2–59.8 year) with mild-to-moderate hypertension. DRIs showed similar tolerability to placebo. With doses of 75–600 mg of aliskiren, 39.8% complained of any side-effects, compared with 40.2% of placebo. The most common adverse events reported by over 2% of patients on aliskiren were headache, nasopharyngitis and diarrhoea. Headache was shown to reduce at higher doses. Diarrhoea was more frequent in all groups of aliskiren overall— 2.6% compared with placebo (1.2%). This was due mainly to higher frequency of diarrhoea—9.5% at higher (600 mg) dose. Overall, over 95% of adverse events with study drug were mild-moderate severity. However, there are limitations with estimating side effects of DRI therapy with the available data. Subjects are usually healthy volunteers or patients with mild disease. Higher-risk patients that are older, have renal failure etc are unlikely to be included. Study groups are also under more rigorous follow up. In addition, the numbers under study are too small to identify all side-effects that can occur with wider usage of the drug. As a class, DRIs are likely to have similar effects and contraindications to ACEI and ARBs. No lifethreatening complications of therapy have been reported thus far, but the possibility of hyperkalaemia and deterioration of already impaired renal function remain. DRIs should be avoided in renal artery stenosis and pregnancy. No information about teratogenicity is currently available. Total RAAS inhibition is another area where safety studies are needed; this may be achievable if aliskiren is used with another RAAS inhibitor. Special circumstances include elderly or salt deplete patients and patients with renal artery stenosis.

351

nephroprotection [54]. Synergistic antihypertensive effects with ACEI and ARBs have been demonstrated in both animal and human models. Combination of ACEI and ARB therapy has also been shown to have an increased anti-proteinuric effect and have been demonstrated to slow kidney disease progression more than either agent alone. The COOPERATE study [55] looked at the use of maximum doses of ACE1 and ARB used alone or in combination (still at maximal dose) in non-diabetic patients. Of those on combination treatments, 11% reached the endpoints of creatinine doubling or ESRD, compared with 23% of the patients on the trandolapril-only arm and 23% on the losartanonly arm. A further prospective randomised crossover study by Campbell et al. [56] examined a combination of sub-maximal doses of benazepril and valsartan, in one arm, compared with maximal doses of each agent alone, in the other two. The population treated were non-diabetic CKD patients. After 8 weeks of therapy, superior reduction in proteinuria was achieved by the half-dose combination, compared to both full dose agents alone, for equivalent changes in BP and GFR. ONTARGET has now shown us that we can achieve maximal blockade of the RAAS using an ACE inhibitor or an ARB, but that both is not necessarily better [1]. In practice, we now need to know which combination of an ACEI, or an ARB, with a drug such as aliskiren could bring additional cardioprotective benefit. Antihypertensive actions of diuretics are potentiated by targeting the compensatory increase in AT2 and aldosterone by coadministration of an ACE inhibitor [22]. This also allows greater tolerance and reduced side effects. Additional antihypertensive value of ACEI and ARBs, over and above single agent use, can also be achieved by adding in eplerenone, a selective aldosterone inhibitor, in patients resistant to monotherapy [57].

DRIs as synergistic agents In addition to a thiazide or versus thiazides

Synergy? Does more inhibition of the RAAS mean more renoprotection? Neither ACEI nor ARBs alone can completely suppress RAAS activity, this supports the possibility that DRIs are likely to provide more complete

Aliskiren (75 mg, 150 mg or 300 mg/day) has been evaluated both individually and in combination with hydrochlorothiazide (6.25 mg, 12. 5 mg or 25 mg/day) in a single-blind Phase II trial. Aliskiren was superior to placebo and combination treatment was superior to each monotherapy, alone. Renin inhibition also

123

352

managed to neutralise the compensatory increase in PRA induced by HCZ. This study also suggested there is a less risk of patients developing hypokalaemia as a result of diuretic treatment in this combination [31]. In addition to a calcium channel blockers In a Phase III trial, patients with a mean BP over 90 mmHg after 4 weeks of amlodipine 5 mg/day, entered a 6-week double-blind trial and were randomised to amlodipine 10 mg, amlodipine 5 mg with aliskiren 150 mg or to continue with amlodipine 5 mg/day. Mean systolic and diastolic BP reductions after 6 weeks were significantly greater than with 5 mg of amlodipine alone, for both the amlodipine 10 mg and CCB/DRI combination. Incidence of oedema in the combination group was also much less than high-dose CCB [58].


37.5 mg, 75 mg, 150 mg or 300 mg of aliskiren or 100 mg of losartan. After 1 month of therapy, ambulatory BP readings were performed. Mean reductions in systolic pressure were not significantly different between losartan 100 mg and aliskiren 150 mg and 300 mg [59]. Another double-blind phase 2 study compared irbesartan 150 mg with placebo and aliskiren 150 mg, 300 mg or 600 mg, once daily for 8 weeks. The endpoint was sitting-office BP. Aliskiren 150 mg was comparable to irbesartan 150 mg. Higher dose aliskiren had a significantly greater effect on DBP than 150 mg irbesartan [60]. A placebo controlled study (n = 1,123) of aliskiren 75–300 mg vs. valsartan 80–320 mg concluded that aliskiren and valsartan alone and in combination showed doserelated reduction in DBP and SBP. The combination had greater antihypertensive effect and was welltolerated [61].

In addition to an ACEI and versus ACEI therapy

What are DRIs intrarenal effects?

In a phase III double-blind study of hypertensive (both type 1 and 2) diabetics, patients were randomised (double-blinded) to either ramipril 5 mg, aliskiren 150 mg or the combination 150/5 mg/day. After 4 weeks, doses of each were increased to either ramipril 10 mg, aliskiren 300 mg or 300/10 mg for the combination. Aliskiren monotherapy was noninferior to ramipril monotherapy for diastolic BP reduction. Aliskiren was statistically superior to ramipril for systolic BP control. Combination therapy was superior to ramipril monotherapy. Renin concentration increased in all groups: aliskiren (115%), ramipril (68%), but greatest in combination (315%). PRA increased by 111% in ramipril arm, reduced to 68% in aliskiren group; the greatest overall reduction was with combination to 44% [33]. Nussberger et al. [36], in a well-done trial in healthy normotensive males, concluded 160 mg of aliskiren had an equivalent hormonal effect to enalapril 20 mg in terms of PRA inhibition—which was dose-dependant. There was no significant difference in BP or HR and aliskiren was well tolerated.

Animal studies using the DRI ciprokiren in the canine kidney demonstrated both prevention of the reduction of RBF and prevention of the increase of renal arterial resistance in response to decreased perfusion pressure [62]. Correspondingly, in sodium-depleted monkeys and normotensive guinea pigs, enalapril and the DRIs enalkiren and remikiren reduced renovascular resistance and increased renal perfusion with or without a rise in GFR [62]. In healthy hypertensive, sodium-depleted men, the renal circulation was studied in response to AT2 challenge, in the presence of placebo, enalkiren or captopril. Both agents significantly increased renal blood flow during AT2 infusion, compared with placebo [47]. A trial of once-daily remikiren 600 mg given to 14 hypertensive subjects with normal to impaired renal function, reduced mean BP from baseline by 11.2% at peak plasma concentration and 6.0% at trough. Renal vascular resistance and filtration fraction was reduced by 15 and 10%, without change in GFR. Proteinuria in six patients with abnormal renal function was reduced by 27% from a baseline of 5.8 g/day [63]. Two new trials report positive results of the antiproteinuric effect of aliskiren in diabetics. The first (open-label study) looked at type 2 diabetics with urine albumin/creatinine ratio (UACR) [30 mg/g,

Versus ARBs treatment Hypertensive patients were randomised (in a phase II trial) to the following double-blind treatment groups,

123


before and after aliskiren therapy with 300 mg/day. Outcome measures included BP and morning UACR. Systolic BP was significantly lower at 7 days with no further reduction after 28 days, returning to baseline within 7 days after cessation of treatment. Significant reductions in UACR were found at after 2–4 and 7 days, by 17%. There was further reduction in UACR after 28 days to 44% which continued for a week after withdrawal, without significant change in eGFR [64]. The AVOID [65] double blind randomised trial evaluated the benefit of combining aliskiren 150 mg or placebo with losartan 100 mg in 599 hypertensive type 2 diabetics. After 3 months, the aliskiren arm was up-titrated to 300 mg/day. Primary outcome measure was decline in early morning UACR. Aliskiren reduced UACR by 20% and UAER by 18% compared to placebo. 24.7% of aliskiren patients (compared with 12.5% of placebo) underwent a C50% reduction of UACR. GFR remained unchanged and as in the previous study changes in BP did not correlate well with reduction in albuminuria. These data suggest that aliskiren-induced renoprotection is independent of its antihypertensive effects in type 2 diabetics already on recommended ARB losartan, with acceptable BP control. ALTITUDE [49] is a much larger scale prospective study of type 2 diabetics that aims to determine whether aliskiren therapy can delay diabetic complications in diabetic nephropathics.

Conclusions. At what level and what combination and what criteria should we be judging it by? Current data suggest that DRIs are at least as effective as ARBs and ACEIs for short-term BP reduction. They also have fewer side effects. Obviously, these drugs are much more expensive than the alternatives, most of which are generically available. Long-term data is needed with regard to renal and cardiovascular protection. Until this is available, DRIs are likely to be used as add-on therapy in hypertensive patients who are failing on existing combinations. They might be particularly useful in combination with agents that cause a reactive increase in plasma renin activity such as diuretics, ARBs and ACEIs. DRIs may prove more useful in high-renin hypertensives such as young and Caucasian patients who have more active renin system

353

than blacks and older populations. However, pooled analysis of monotherapy efficacy studies demonstrates antihypertensive benefit of aliskiren 150 mg or 300 mg regardless of age, gender or race [53]. DRIs maybe useful in patients unable to tolerate ACE-inhibition. They may become important in diseases where AT2 activity is pathological. DRIs maybe indicated for patients requiring dual blockade of RAAS eg diabetics with albuminuria or in fibrotic renal diseases. The ONTARGET trial has now shown us that to all intents and purposes we can achieve maximal blockade of the RAAS using an ACE inhibitor or an ARB, but that both is not necessarily better. In practice, we now need urgently to know whether the combination of an ACEI, or an ARB, with a drug such as aliskiren could bring additional cardioprotective benefit. Conflict of interest statement Dres. Goldsmith and Covic received honoraria and speaker fees from Novartis.

References 1. Yusuf S, Teo K, Porge J et al (2008) Telmisartan, ramipril or both in patients at high risk for vascular events (ONTARGET Trial) NEJM 358:1547–1159 2. Mann JF, Schmieder RE, McQueen M et al (2008) Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet 372: 547–553 3. Dalla Vestra M, Simioni N, Masiero A (2009) Renal effects of dual renin-angiotensin-aldosterone system blockade in patients with diabetic nephropathy. Int Urol Nephrol 41:119–126 4. Casas JP, Chua W, Loukogeorgakis S et al (2005) Effect of inhibitors of the renin angiotensin system and other antihypertensive drugs on renal outcomes; systematic review and meta-analysis. Lancet 366:2026–2033 5. Sarafidis P, Khosla N, Bakri GL (2007) Antihypertensive therapy in the presence of proteinuria. Am J Kidney Dis 49:12–26 6. Covic A, Gusbeth-Tatomir P, Goldsmith DJA (2007) Current dilemmas in inhibiting the renin-angiotensin system: do not forget real life. Int Urol Nephrol 39:571–576 7. Bakris GL (2004) Clinical Importance of microalbuminuria in diabetes and hypertension. Curr Hypertens Rep 6:352–356 8. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G (2000) Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study

123

354

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

Int Urol Nephrol (2009) 41:341–355 Investigators. Study Investigators. N Engl J Med 342:145– 153 Ibsen H, Olsen MH, Wachtell K et al (2005) Reduction in albuminuria translates to reduction in cardiovascular events in hypertensive patients losartan intervention for endpoint reduction in hypertension study. Hypertension 45:198–202 Lewis EJ, Hunsicker LG, Clarke WR et al (2001) Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 345:851–860 Kasiske BL, Kalil RSN, Ma JZ, Liao M, Keane WF (1993) Effect of antihypertensive therapy on the kidney in patients with diabetes: a metaregression analysis. Ann Intern Med 118:129–138 Barnett AH (2005) Preventing renal complications in diabetic patients: the Diabetics Exposed to Telmisartan And enalaprIL (DETAIL) study. Acta Diabetol 42(Suppl 1):S42–S49 Estacio RO, Jeffers BW, Gifford N, Schrier RW (2000) Effect of blood pressure control on diabetic microvascular complications in patients with hypertension and type 2 diabetes. Diabetes Care 23(Suppl 2):B54–B64 Karalliedde J, Viberti G (2006) Evidence for renoprotection by blockade of the renin-angiotensin-aldosterone system in hypertension and diabetes. J Hum Hypertens 20:239–253 Jafar TH, Schmid CH, Landa M et al for the ACE inhibition in progressive renal disease study group (2001) Angiotensin converting enzyme inhibitors and progression of non diabetic renal disease: a meta-analysis of patient level data. Ann Intern Med 135:73–87 The GISEN Group (1997) Randomised placebo-controlled trial of the effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuria, non diabetic nephropathy. Lancet 349:1857–1863 Wright JT Jr, Bakris G, Green T et al for the American study of Kidney disease, Hypertension Study Group (2002) Effect of Blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease; results from the AASK trial. JAMA 228:2421–2431 Monster TBM, Janssen WMT, de Jong PE, den Berg LTG, for the PREVEND Study Group (2002) The impact of antihypertensive drug groups on urinary albumin excretion in a non-diabetic population. Br J Clin Pharmacol 53:31–36 Sugino G, Barg AP, O’Connor ST (1984) Renal perfusion is preserved during cardioselective beta blockade with metoprolol in hypertension. Am J Kidney Dis 3:357–361 Tindall H, Urquhart S, Stickland M et al (1991) Treatment with atenolol prevents progression of microalbuminuria in type 1 diabetic patients. Curr Med Res Opin 12:516–520 Nyugen G, Delarue F, Burckle C et al (2002) Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J Clin Invest 10:1417–1427 Brunner HR, Nussberger J, Weber B (1990) Various approaches to blockade of renin-angiotensin system: persistent renin response. J Hypertens 8(7):S149–S153 Hollenberg NK, Fisher ND, Price DA (1998) Pathways for angiotensin II generation in intact human tissue; evidence from comparative pharmacological interruption of the renin system. Hypertension 32:387–392

123

24. Hollenberg NK, Fisher NDL (1995) Renal circulation and blockade of the renin-angiotensin system. Hypertension 26:602–609 25. Wolf G, Ritz E (2005) Combination therapy with ACE inhibitors and angiotensin II receptor blockers to halt progression of chronic renal disease: pathophysiology and indications. Kidney Int 67:799–812 26. Van der Wal RM, Plokker HW, Lok DJ et al (2006) Determinants of increased angiotensin II levels in severe chronic heart failure patients despite ACE inhibition. Int J Cardiol 106:367–372 27. Blasi ER, Rocha R, Rudolph AE et al (2003) Aldosterone/ salt induces renal inflammation and fibrosis in hypertensive rats. Kidney Int 63:1791–1800 28. Iglarz M, Touyz RM, Viel EC, Amiri F, Schiffrin EL (2004) Involvement of oxidative stress in the profibrotic action of aldosterone; interaction with the renin angiotensin system. Am J Hypertens 17:597–603 29. Athyros VG, Mikhailides DP, Kakafika AI, Tziomalos K, Karagiannis A (2007) Angiotensin II reactivation and aldosterone escape phenomena in renin-angiotensin-aldosterone system blockade: is oral renin inhibition the solution? Expert Opin Pharmacother 8:529–535 30. Brunner HR, Laragh JH, Baer L et al (1972) Essential hypertension, renin, aldosterone, heart attacks, strokes. N Engl J Med 286:441–449 31. Villamil A, Chrysant SG, Calhoun D et al (2007) Renin inhibition with aliskiren provides additive antihypertensive efficacy when used in combination with hydrochlorothiazide. J Hypertens 25:217–225 32. Azizi M, Menard J, Bissery A, Bura-Riviere A, Vaidyanathan S, Camisasca RP (2004) Pharmacologic demonstration of the synergistic effects of a combination of the renin inhibitor aliskiren and the AT1 receptor antagonist valsartan on the angiotensin II-renin feedback interruption. J Am Soc Nephrol 15:3126–3133 33. Kilo C, Taylor A, Tschoepe D (2006) Aliskiren, a novel renin inhibitor for treatment of hypertension, enhances renin system suppression by reducing plasma renin activity alone or in combination with ramipril in patients with diabetes. Eur Heart J 25(Suppl):118 [Abstract P789] 34. Pool J, Gradman A, Kolloch R (2006) Aliskiren, a novel renin inhibitor, provides long term suppression of the renin system, when used alone or in combination with hydrochlorothiazide in the treatment of hypertension. Eur Heart J 25(Suppl):119 [Abstract P790] 35. Mitchell J, Oh B, Herron J et al (2006) Once daily aliskiren provides effective smooth 24 hour blood pressure control in patients with hypertension. J Clin Hypertens 8 (Suppl A):A93(P-209) 36. Nussberger J, Wuerzner G, Jensen C, Brunner HR (2002) Angiotensin II suppression in humans by orally active renin inhibitor aliskiren (SP100): comparison with enalapril. Hypertension 39:E1–E8 37. Azizi M, Webb R, Nussberger J, Hollenberg NK (2006) Renin inhibition with aliskiren: where are we now, and where are we going? J Hypertens 24:243–256 38. Tekturna (aliskiren) prescribing information. Available at http://www.fda.gov 39. Dieterle W, Corynen S, Vaidyanathan S et al (2005) Pharmacokinetic interactions of oral renin inhibitor


40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

aliskiren with lovastatin, atenolol, celecoxib and cimetidine. Int J Clin Pharmacol Ther 43:527–535 Dieterle W, Corynen S, Mann J (2004) Effect of oral renin inhibitor aliskiren, on pharmacokinetics and pharmacodynamics of a single dose of warfarin in healthy subjects. Br J Pharmacol 58:433–436 Pilz B, Shagdarsuren E, Wellner M et al (2005) Aliskiren, a human renin inhibitor, ameliorates cardiac and renal damage in double-transgenic rats. Hypertension 46:569–576 Cheng H, Harris RC (2006) Potential side effects of renin inhibitors-mechanisms based on comparison with other renin-angiotensin blockers. Expert Opin Drug Saf 5:631– 641 Cordero P, Fisher ND, Moore TJ et al (1991) Renal and endocrine responses to a renin inhibitor enalkiren, in normal humans. Hypertension 17:510–516 Fisher NDL, Allan D, Kifor I et al (1994) Responses to converting enzyme and renin inhibition: role of angiotensin II in humans. Hypertension 23:44–51 Fisher NDL, Hollenberg NK (1995) Renal vascular responses to renin inhibition with zankiren in men. Clin Pharmacol Ther 57:342–348 El-Amrani A-IK, Menard J, Gonzales MF, Michel JB (1993) Effects of blocking the angiotensin II receptor, converting enzyme and renin activity on the renal hemodynamics of normotensive guinea pigs. J Cardiovasc Pharmacol 22:231–239 Fisher NDL, Allan DR, Gaboury CL, Hollenberg NK (1995) Intrarenal angiotensin II formation in humans. Evidence from renin inhibition. Hypertension 25:935–939 Feldman DL, Persohn E, Schutz H et al (2006) Renal localisation of the renin inhibitor aliskiren. J Clin Hypertens 8(Suppl A):A80 Kapoor S (2008) Aliskiren: a rapidly, expanding role in the management of recalcitrant hypertension and renal disease. Int Urol Nephrol 40(4):1115–1116 Siamopoulos KC, Kalaitzidis RG (2008) Inhibition of the renin-angiotensin system and chronic kidney disease. Int Urol Nephrol 40:1015–1025 Recio-Mayoral A, Kaski JC, McMurray JJ et al (2007) Clinical trials update from the European Society of Cardiology Congress in Vienna, 2007: PROSPECT, EVEREST, ARISE, ALOFT, FINESSE, Prague-8, CARESS in MI and ACUITY. Cardiovasc Drugs Ther 21(6):459–465 Oh BH, Mitchell J, Herron JR et al (2007) Aliskiren, an oral renin inhibitor, provides dose-dependent efficacy and sustained 24-hour blood pressure control in patients with hypertension. J Am Coll Cardiol 49:1157–1163 Weir M, Bush C, Zhang J, Keefe D, Satlin A (2006) Antihypertensive efficacy and benefits of oral renin

355

54.

55.

56.

57.

58.

59.

60.

61.

62.

63.

64.

65.

inhibitor aliskiren in patients with hypertension. A pooled analysis. Eur Heart J 27(Suppl):299 [Abstract 1796] Segall L, Covic A, Goldsmith DJA (2007) Direct renin inhibitors: the dawn of a new era, or just a variation on a theme? Nephrol Dial Transplant 22:2435–2439 Nakao N, Yoshimura A, Morita H et al (2003) Combination treatment of angiotensin II receptor blocker and angiotensin converting enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomised control trial. Lancet 361:117–124 Campbell R, Sangalli F, Pertucci E et al (2003) Effects of combined ACE inhibitor and angiotensin II antagonist treatment in human chorionic nephropathies. Kidney Int 63:1094–1103 Krum H, Gilbert E (2007) Novel therapies blocking the renin-angiotensin-aldosterone system in the management of hypertension and related disorders. J Hypertens 25:25– 35 Munger MA, Drummond W, Essop MR (2006) Aliskiren as add-on to amlodipine provides significant additional blood pressure lowering without increased oedema associated with doubling the amlodipine dose. Eur Heart J 25(Suppl):117 [Abstract: P784] Stanton A, Jensen C, Nussberger J, O’Brien E (2003) Blood pressure lowering in essential hypertension with an oral renin inhibitor, aliskiren. Hypertension 42:1137–1143 Gradman A, Schmieder RE, Lins RL et al (2005) Aliskiren, a novel orally effective renin inhibitor, provides dose dependent antihypertensive efficacy and placebo like tolerability in hypertensive patients. Circulation 111:1012– 1018 Pool JL, Schmeider RE, Azizi M et al (2007) Aliskiren an orally effective renin inhibitor, provides antihypertensive efficacy alone and in combination with valsartan. Am J Hypertens 20:11–20 Clozel JP, Ve´niant MM, Qiu C, Sprecher U, Wolfgang R, Fischli W (1999) Renal vascular and biochemical responses to systemic renin inhibition in dogs at low renal perfusion pressure. J Cardiovasc Pharmacol 34:674–682 Van Paasen P, de Zeeuw D, Navis G, de Jong PE (2000) Renal and systemic effects of continued treatment with renin inhibitor remikiren in hypertensive patients with normal and impaired renal function. Nephrol Dial Transplant 15:637–643 Parving HH, Persson F, Lewis JB et al (2008) Aliskiren combined with losartan in type 2 diabetes and nephropathy. N Engl J Med 358:2433–2446 Persson F, Rossing P, Schjoedt KJ et al (2008) Time course of the antiproteinuric and antihypertensive effects of direct renin inhibition in type 2 diabetes. Kidney Int 73:1419– 1425

123