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European Journal of Heart Failure 2007 9(11):1120-1127; doi:10.1016/j.ejheart.2007.09.002
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© 2007 European Society of Cardiology

Neurohumoral effects of the new orally active renin inhibitor, aliskiren, in chronic heart failure

Alison Seeda, Roy Gardnerb, John McMurraya,*, Chris Hillierc, David Murdochd, Robert MacFadyene, Alain Bobillierf, Jessica Mannf and Theresa McDonaghg

a Department of Cardiology, Western Infirmary Glasgow, United Kingdom
b Department of Cardiology, Royal Infirmary Glasgow, United Kingdom
c School of Biological and Biomedical Sciences, Caledonian University Glasgow, United Kingdom
d Department of Cardiology, Southern General Hospital Glasgow, United Kingdom
e University Department of Medicine, City Hospital Birmingham, United Kingdom
f Speedel Pharma AG Basel, Switzerland
g Department of Cardiology, Royal Brompton Hospital London, United Kingdom

* Corresponding author. Department of Cardiology, Western Infirmary, Glasgow, G12 8QQ, United Kingdom. Tel.: +44 141 330 3479; fax: +44 141 330 6955. E-mail address: j.mcmurray{at}bio.gla.ac.uk


   Abstract
Top
 Abstract
1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 References
 
Background: Suppression of the renin–angiotensin–aldosterone system (RAAS) is therapeutically valuable in chronic heart failure (CHF). RAAS inhibition can be achieved in a number of ways though an orally active renin inhibitor (RI) has never been studied before. We describe the neurohumoral effects of an RI.

Methods and results: 27 patients with NYHA class II or III CHF and an ejection fraction ≤0.35, were randomised to placebo, the ACE inhibitor ramipril or the RI aliskiren for 1week after a 5–7day washout period following ACE inhibitor withdrawal. Thereafter, patients were treated with either ramipril (target dose 10mg qd) or aliskiren (target dose 300mg qd) for a further 5weeks. Plasma renin activity (PRA), angiotensin II, aldosterone and B-type natriuretic peptide (BNP) were measured at baseline (pre-randomisation), after one week and at two week intervals thereafter. The mean changes (%) at the end of the study (6weeks), compared with baseline, were: PRA 164.9 (SD 149)% ramipril, –60.1 (24)% aliskiren (between groups p value<0.0001); angiotensin II 39.7 (138)% ramipril, –51.4 (40)% aliskiren (p<0.05); aldosterone –0.94 (67)% ramipril, 4.74 (60)% aliskiren (p=n.s.); BNP-7.51 (38)% ramipril, –1.79 (43)% aliskiren (p=n.s.).

Conclusions: Aliskiren appeared to suppress the RAAS as effectively as ramipril in the short term. RIs may offer an alternative therapeutic approach to the blockade of the RAAS.

Key Words: Heart failure • Renin • Angiotensin • Natriuretic peptides

Received May 22, 2007; Revised June 27, 2007; Accepted September 11, 2007


   1. Introduction
Top
 Abstract
 1. Introduction
2. Patients and methods
 3. Results
 4. Discussion
 References
 
The success of angiotensin converting enzyme (ACE) inhibitors as a treatment for chronic heart failure (CHF) [1,2] has encouraged the development of alternative approaches to the blockade of the renin-angiotensin-aldosterone system (RAAS) [3-5].

In part, this is because ACE inhibitors also block the breakdown of bradykinin. Accumulation of bradykinin appears to cause certain adverse effects (e.g. cough and angio-oedema) which lead to ACE inhibitor intolerance in a proportion of patients [3,6-9]. A more specific inhibitor of the RAAS should avoid these problems (although accumulation of bradykinin could also have benefits by promoting vasodilatation and fibrinolysis) [3-5].

ACE inhibition also results in accumulation of angiotensin I, which may competitively overcome enzyme inhibition and lead to "RAAS escape" [3]. Other enzymes, such as chymase, may also generate angiotensin II [10-12].

These and other considerations have led to the introduction of specific angiotensin II type 1 receptor blockers (ARBs) which have also been shown to be of benefit in CHF [3-5]. ARBs, however, lead to accumulation of angiotensin II and the consequences of this, through the actions of angiotensin II at other receptors, are unknown [13,14].

An alternative approach to the blockade of the RAAS is inhibition of renin, the rate limiting enzyme for the formation of angiotensin II [15,16]. Until recently, the introduction of renin inhibitors into clinical practice was limited by the low oral bio-availability, poor efficacy, short duration of action and high cost of chemical synthesis of previous compounds [15,16]. These problems have been overcome with the development of the new, orally active, non-peptide, specific renin inhibitor, aliskiren (SPP 100) [15]. This study describes the first administration of this agent to patients with CHF.


   2. Patients and methods
Top
 Abstract
 1. Introduction
 2. Patients and methods
3. Results
 4. Discussion
 References
 
2.1. Study aims and design
The primary scientific aims of this study were to compare the neuro-humoral actions of aliskiren with (i) placebo, because aliskiren has never been given to patients with CHF before and also (ii) to compare the actions of aliskiren with those of an effective dose of an ACE inhibitor, because comparable or greater effects than an ACE inhibitor are desirable. It is, however, practically and ethically difficult to design a comparison with placebo. This is because it is both hard to identify patients not started on treatment with an ACE inhibitor therapy, and undesirable to withdraw established ACE inhibitor treatment. Consequently, we adopted the study design in Fig. 1, involving only a short period (up to two weeks) of ACE inhibitor withdrawal. After a 5-7 day run-in period, patients were randomised to placebo (ACE inhibitor withdrawal), ramipril 5 mg once daily or aliskiren 75 mg once daily for one week. Thereafter, patients taking placebo switched to one or other of the active therapies for the remainder of the study (patients were treated with either ramipril (target dose 10 mg per day) or aliskiren (target dose 300 mg per day) for a further 5 weeks, Fig. 1).


Figure 01
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  		Fig. 1 Study design and assessments. BP = blood pressure, HR = heart rate, NH = neurohumoral. Study assessments were carried out at the appropriate visits as indicated (X).

 
This study was approved by the hospital Ethics Committee and all patients gave written informed consent.

2.2. Inclusion and exclusion criteria
All patients had symptomatically stable (for >1 month) NYHA classes II-IV CHF, were >50 years of age and had a left ventricular ejection fraction <0.35. Baseline treatment with ACE inhibitors and beta-blockers, had to have been given at a stable dosage for >1 month. There were few exclusion criteria, mainly related to recent clinical instability (e.g. myocardial infarction), disorders that might impair absorption of therapy (e.g. pancreatic disease) or a contra-indication to ramipril (including renal artery stenosis).

2.3. Study assessments
The primary assessments in this study were i) change in plasma renin activity and concentration of angiotensin II, aldosterone and B-type natriuretic peptide (BNP) from baseline to the end of one week of treatment (visit 3) [this involved a comparison of placebo, ramipril and aliskiren] and ii) change in these neurohumoral measures from baseline (visit 2) over visits 4-6 (i.e. during a further 5 weeks of therapy). Other assessments included clinical examination (body weight, heart rate and sitting and standing blood pressure) and routine biochemical and haematological measurements, made at baseline and varying intervals during the 6 weeks of randomised therapy, as indicated in Fig. 1.

2.4. Neurohumoral assays
Plasma BNP, angiotensin II and aldosterone concentrations were measured using established assays, as previously reported [17-19]. Plasma renin activity was also measured using a recognised assay [20].

2.5. Data analysis and presentation
Comparisons between the change in the neurohumoral measurements from the pre-treatment visit (visit 1) and those made after one week of therapy (placebo, ramipril or aliskiren, visit 2) were made using a Wilcoxon matched pairs test and the comparisons between visit 2 and visits 4-6 were made using one-way analysis of variance followed by Bonferroni's test for multiple comparisons.


   3. Results
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
4. Discussion
 References
 
3.1. Patient details
The details of the patients studied are given in Table 1. A total of 27 patients (3 female) were randomised. All had been taking an ACE inhibitor prior to randomisation. Two patients were withdrawn early from randomised therapy due to worsening heart failure, one after 15 days and the other after 35 days.


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  		Table 1 Patient characteristics

 
3.1.1. One week, three-way, treatment comparison (placebo vs. aliskiren vs. ramipril)
3.1.1.1. Plasma renin activity
Plasma renin activity (PRA) did not change with placebo. Even within one week of therapy, PRA was suppressed by aliskiren. As expected, PRA increased with ramipril (Table 2).


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  		Table 2 Three way comparison of the effect of one week's treatment with placebo, ramipril or aliskiren on plasma neurohumoral measures

 
3.1.1.2. Plasma angiotensin II concentration (Table 2)
The plasma concentrations of angiotensin II did not change with placebo or ramipril 5 mg. Angiotensin II, however, was clearly reduced by aliskiren 75 mg.

3.1.1.3. Plasma aldosterone concentration (Table 2)
Plasma aldosterone concentration did not change significantly with any of the three treatments.

3.1.1.4. Plasma BNP concentration (Table 2)
Plasma BNP concentration did not change substantially with any of the three treatments, although there was a nominally statistically significant decrease with ramipril.

3.1.1.5. Blood pressure
There were no significant changes in blood pressure in any of the three groups after one week of treatment (Table 3).


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  		Table 3 Systolic and diastolic blood pressure

 
3.1.2. Five week, two-way, treatment comparison (aliskiren vs. ramipril)
3.1.2.1. Plasma renin activity
As expected, aliskiren significantly reduced PRA, whereas PRA increased with ramipril (Fig. 2).


Figure 02
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  		Fig. 2 Effect of aliskiren and ramipril on plasma renin activity in patients with CHF. Ramipril n=14 Aliskiren n=13. Data are presented as the percentage change (mean±SD) from visit 2 (baseline). ***=p<0.0001.

 
3.1.2.2. Plasma angiotensin II concentration
Aliskiren also reduced plasma angiotensin II concentration whereas plasma concentrations of this peptide did not fall during ramipril treatment (Fig. 3).


Figure 03
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  		Fig. 3 Effect of aliskiren and ramipril on plasma concentrations of angiotensin II in patients with CHF. Ramipril n=14 Aliskiren n=13. Data are presented as the percentage change (mean±SD) from visit 2 (baseline). *=p<0.05.

 
3.1.2.3. Plasma aldosterone concentration
There was no clear change in plasma aldosterone concentration in response to either treatment (Fig. 4).


Figure 04
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  		Fig. 4 Effect of aliskiren and ramipril on plasma concentration of aldosterone in patients with CHF. Ramipril n=14 Aliskiren n=13. Data are presented as the percentage change (mean±SD) from visit 2 (baseline).

 
3.1.2.4. Plasma BNP concentration
There was no clear change in plasma BNP concentration in response to either treatment (Fig. 5).


Figure 05
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  		Fig. 5 Effect of aliskiren and ramipril on plasma concentration of B-type natriuretic peptide (BNP) in patients with CHF. Ramipril n=14 Aliskiren n=13. Data are presented as the percentage change (mean±SD) from visit 2 (baseline).

 
3.1.2.5. Blood pressure (Table 3)
There were comparable reductions from baseline in systolic and diastolic blood pressure with both treatments.

3.1.2.6. Safety and tolerability
Aliskiren and ramipril treatment were generally well-tolerated. A total of 24 adverse events (AEs) were reported in 9 patients during aliskiren treatment, and 15 AEs were reported in 9 patients during ramipril treatment. Dyspnoea (4 patients) and fatigue and dizziness (3 patients) were most frequently mentioned AEs. The frequency of AEs did not increase with the dose of aliskiren or ramipril.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
References
 
Though a number of renin inhibitors have been studied in healthy volunteers and in patients with hypertension, there is very little prior experience with these agents in CHF [16,20-24]. The short-term haemodynamic effects of the primate selective dipeptide inhibitor enalkiren (A-64662), administered intravenously, were reported over a decade ago [24]. In that uncontrolled study, enalkiren resulted in favourable changes in cardiac index, systemic and pulmonary vascular resistance, left ventricular filling pressure and other indices of cardiac function. We know of no other studies with renin inhibitors in CHF. In particular, we know of no chronic dosing studies with an orally active renin inhibitor. Aliskiren is such an agent, with a long duration of action. Aliskiren has been studied in healthy volunteers, where doses of 40 to 640 mg/d were compared with 20 mg enalapril/d or placebo, with each drug given for eight days [15]. In that study, aliskiren was well-tolerated and dose-dependently inhibited the RAAS to at least the same extent as enalapril [15]. Indeed, in healthy subjects, 160 mg aliskiren gave equivalent suppression of angiotensin II to 20 mg enalapril. More recently, the efficacy of aliskiren (37.5 mg, 75 mg, 150 mg and 300 mg once daily for 4 weeks) has also been compared with losartan (100 mg once daily) in patients with essential hypertension. In that study, 75 mg and 150 mg reduced blood pressure, and aliskiren 300 mg lowered blood pressure to the same extent as losartan 100 mg [25]. Subsequent studies have confirmed the effectiveness of aliskiren as an antihypertensive agent and compared it to other types of blood pressure lowering drugs [26-30]. We have now studied aliskiren in CHF.

At the doses used in this study, the orally active renin inhibitor aliskiren was at least as effective at suppressing the RAAS as the ACE inhibitor ramipril over a six-week period. This effect was apparent acutely, where one week of treatment with 75 mg of aliskiren reduced plasma angiotensin II concentrations, in contrast to 5 mg of ramipril. This effect was also apparent over the subsequent five weeks of treatment where 75-300 mg of aliskiren more clearly reduced angiotensin II than ramipril 5-10 mg.

In the first study in hypertension mentioned above, angiotensin II was not measured but PRA was reduced from baseline by 55% with 37.5 mg of aliskiren, by 60% with 75 mg, by 77% with 150 mg and by 83% with 300 mg (contrasting with a 110% rise in PRA with losartan) [25]. We found a comparable reduction (–60%) in PRA with aliskiren in patients with CHF (compared with a 165% increase with ramipril) in the present study.

Why might renin inhibitors be valuable in CHF? Renin is the rate limiting step in the RAAS cascade and has a very specific interaction with its substrate. Consequently, adverse effects should be uncommon with renin inhibitors. Secondly, renin inhibition is the only approach to RAAS suppression that reduces both angiotensins I and II. This has several potentially favourable consequences. The reflex increase in angiotensin I which occurs during treatment with ACE inhibitors and ARBs does not occur during renin inhibition. This increase may ultimately overcome ACE blockade and angiotensin I is also a substrate for other enzymes (e.g. chymase) capable of generating angiotensin II. Similarly, the excess angiotensin I produced during ACE inhibition (and the excess angiotensins I and II produced during treatment with an ARB) may be converted to other angiotensin peptides which may, directly and indirectly, produce both desirable and undesirable effects [31,32]. Similarly, the pros and cons of the bradykinin enhancing effects of ACE inhibitors (and the stimulating effect of angiotensin II on other AT receptors during treatment with an ARB) have already been alluded to. Overall, the pharmacological consequences of each separate approach to inhibit the RAAS are myriad and quite different. Whether the different net pharmacological effect of each approach results in a different therapeutic action is unknown and difficult to predict. However, given the clinical success of the established pharmacological approaches to RAAS inhibition in cardiovascular (and other) diseases, it must be of interest to examine the clinical effects of renin inhibition, especially in CHF.

As with any study of this type, there are limitations. A relatively small number of patients were randomised and treatment was administered for a comparatively short period. Necessarily, our patients were those tolerating chronic ACE inhibition and the study was really one of ACE inhibitor withdrawal (and placebo or aliskiren substitution). This may explain the somewhat curious observation that angiotensin II tended to increase over time in patients randomised to ramipril. The present study was not a dose response study, and investigated only one target dose of aliskiren. This was because 300 mg had already been identified as an effective and well-tolerated dose in the first hypertension study described above [25]. Though there were no safety concerns with aliskiren in the current study, the number of patients studied and duration of treatment were too limited to draw any firm conclusions.

In summary, this study shows that once daily dosing with aliskiren suppresses the RAAS as effectively as ramipril in the short term. This new approach to neurohumoral modulation is theoretically therapeutically attractive, especially in CHF, given the clinical success of the established pharmacological methods of suppressing the RAAS in this syndrome. Further studies of renin inhibition in CHF are justified.


   References
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 References
 

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Role of renin in heart failure and therapeutic potential of direct renin inhibition
Journal of Renin-Angiotensin-Aldosterone System, September 1, 2008; 9(3): 177 - 180.
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