Is aliskiren superior to inhibitors of angiotensin-converting enzyme and angiotensin receptor blockers in renin-angiotensin system blockade?

Article (PDF Available)inMedical Archives 63(6):343-9 · January 2009with14 Reads
Source: PubMed
Abstract
The renin-angiotensin system (RAS) plays a crucial role in development of hypertension, heart failure, as well as in the whole process of nephropathy, particularly of diabetic nephropathy, with or without proteinuria. Blockade of RAS plays the key role in the management of hypertension and other cardiovascular diseases. Angiotensin-converting enzyme (ACE) inhibitors do not provide the full blockade of angiotensin II because it is produced through alternative pathways. Angiotensin receptor blockers (ARBs) also block the negative feedback of angiotensin II upon renin like ACE inhibitors, leading to a several fold increase in angiotensin II levels. Aliskiren is an orally-active, nonpeptidic, direct inhibitor of renin which simultaneously reduces angiotensin I, angiotensin II and plasma renin activity (PRA). This is the main point of action of aliskiren, making it completely different from ACE inhibitors and ARBs. Aliskiren introduces a new concept into the management of hypertension. However, the question concerning its real role in the management of heart failure and its place in the existing therapeutic schemes with ACE inhibitors, ARBs, beta blockers and antagonists of aldosterone receptor, will be answered by numerous ongoing studies and clinical trials. Aliskiren shows renoprotective and antiproteinuric effects similar to those of ACE inhibitors and ARBs. The available results demonstrate that aliskiren provides a new approach to the antagonism of the RAS, offering possibilities of a more efficacious and effective treatment of hypertension, heart failure and proteinuria in diabetic patient.
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Is Aliskiren Superior to Inhibitors of Angiotensin-Converting Enzyme and Angiotensin Receptor Blockers in Renin-Angiotensin System Blockade?
1. INTRODUCTION
Even now, at the beginning of the
new millennium and the new cen-
tury, hypertension is still the focus
of researchers and clinicians. In spite
of great number of antihypertensive
drugs, eective control of blood pres-
sure has not been achieved as expected.
Because of the availability of numerous
separate groups of antihypertensives
with dierent mechanisms of action,
there has been a small probability that
essential and fundamental progress in
the treatment of hypertension would
be made by arrival of a new antihyper-
tensive drug. However, it seems that
exactly something like this happened
when the direct renin inhibitor (DRI)
aliskiren was discovered. It diers from
the two most important groups of drugs
which block renin-angiotensin-system
(RAS), i.e. from angiotensin-convert-
ing enzyme inhibitors (ACE inhibitors)
and angiotensin II receptor blockers
(ARBs). DRI aliskiren blocks the RAS
at its point of origin, the renin–angio-
tensinogen reaction, and oers a novel
approach to the prevention or reversal
of target organ damage and cardiovas-
cular events (1). Undoubtedly, aliskiren
oers a new concept in the treatment
of hypertension, with new perspectives
and possibilities for the management of
the greatest non-infective epidemic in
the 21st century.
2. RENINANGIOTENSIN
SYSTEM, PRORENIN AND
RENIN
e hormone renin plays a central
role in the regulation of blood pressure
and in the regulation of extracellular
uid volume, sodium balance and car-
diovascular function (2). e most im-
portant tonic regulator of renin secre-
tion is the negative feedback of angio-
tensin on renin synthesis. Renin is an
aspartyl protease that is synthesized as
a preprohormone, cleaved and stored in
an inactive form (prorenin) in the jux-
taglomerular cells in the kidney. Pro-
renin is a precursor to renin which has
a 43 amino acid N-terminus overlying
the enzymatic cleft of the renin mol-
ecule, thus rendering it inactive. Pro-
renin is much more abundant than re-
nin in the circulation. Prorenin can be
activated both by proteolytic and non-
proteolytic pathways. e proteolytic
pathway takes place in the juxtaglomer-
ular apparatus in the kidney where the
43 amino acid N-terminus is removed
and leaves the active renin molecule.
Nonproteolytic activation of prorenin
takes place by binding to the (pro)re-
nin receptor. Prorenin thereby becomes
enzymatically active without losing its
N-terminus and this binding increases
its enzymatic activity 4- to 5-fold (3).
Both prorenin and active renin is
secreted from the juxtaglomerular
cells into the circulation as the answer
to reduction of the pressure in aer-
ent arterioles and to the stimulation of
the sympathetic nervous system. Pro-
renin and renin were originally thought
to exert their eects only through the
formation and binding of angioten-
sin II, but animal studies have demon-
strated that these substances can also
exert direct angiotensin-independent
eects through their receptors (4, 5).
(Pro)renin receptors are present in the
heart, liver, placenta, brain, and kidney
and can bind renin and prorenin with
high anity (6). Overexpression of the
(pro)renin receptor in rats has resulted
in elevated blood pressure, increased
plasma aldosterone, and increased cy-
clooxygenase-2 expression in the renal
cortex (7). e (pro)renin receptor ef-
fect may be clinically important in pa-
tients with diabetes and increased pro-
renin levels because this elevation has
been shown to be a powerful predictor
of microvascular complications. Clin-
ically, the incidence of microvascular
complications in diabetes is positively
associated with prorenin concentra-
tions (8, 9, 10, 11). When renin is bound
to the prorenin receptor, conversion of
angiotensinogen to angiotensin I is in-
creased vefold and there is activation
of mitogen stimulated protein kinase
which causes brosis.
Renin releases angiotensin from an-
other voluminous plasma alfa-2 glob-
ulin, called angiotensinogen, which is
produced by the liver. Renin converts
angiotensinogen to the inactive deca-
peptide angiotensin I. After cleaving
two amino acids, ACE converts angio-
tensin I to angiotensin II, octapeptide
with a powerful vasoconstrictive eect.
Angiotensin II causes a release of cate-
cholamine from the adrenal gland, ox-
idative stress, endothelial dysfunction,
Is Aliskiren Superior to Inhibitors
of Angiotensin-Converting
Enzyme and Angiotensin
Receptor Blockers in Renin-
Angiotensin System Blockade?
Vjekoslav Gerc
1
, Marko Buksa
1
, Vesna Loza
1
, Mehmed Kulic
2
Clinic for Heart Disease and Rheumatism, Clinical Centre University Sarajevo, Bosnia and
Herzegovina
1
Center for Heart, Clinical Centre University Sarajevo, Bosnia and Herzegovina
2
REVIEW
SUMMARY
e renin-angiotensin system (RAS) plays a crucial role in development of hypertension, heart failure, as well as
in the whole process of nephropathy, particularly of diabetic nephropathy, with or without proteinuria. Blockade
of RAS plays the key role in the management of hypertension and other cardiovascular diseases. Angiotensin-
converting enzyme (ACE) inhibitors do not provide the full blockade of angiotensin II because it is produced
through alternative pathways. Angiotensin receptor blockers (ARBs) also block the negative feedback of
angiotensin II upon renin like ACE inhibitors, leading to a several fold increase in angiotensin II levels. Aliskiren is
an orally-active, nonpeptidic, direct inhibitor of renin which simultaneously reduces angiotensin I, angiotensin II
and plasma renin activity (PRA). is is the main point of action of aliskiren, making it completely dierent from
ACE inhibitors and ARBs. Aliskiren introduces a new concept into the management of hypertension. However,
the question concerning its real role in the management of heart failure and its place in the existing therapeutic
schemes with ACE inhibitors, ARBs, beta blockers and antagonists of aldosterone receptor, will be answered by
numerous ongoing studies and clinical trials. Aliskiren shows renoprotective and antiproteinuric eects similar to
those of ACE inhibitors and ARBs. e available results demonstrate that aliskiren provides a new approach to
the antagonism of the RAS, oering possibilities of a more ecacious and eective treatment of hypertension,
heart failure and proteinuria in diabetic patient.
Keywords: renin angiotensin system, hypertension, aliskiren, organ protection
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Is Aliskiren Superior to Inhibitors of Angiotensin-Converting Enzyme and Angiotensin Receptor Blockers in Renin-Angiotensin System Blockade?
growth in vascular smooth muscles,
increase of broblasts, inammation,
vasoconstriction, thrombosis, vascu-
lar remodeling, and by means of me-
talloproteinase it can cause a rupture
of atherosclerotic plaque. Angiotensin
II inhibits renin release via a feedback
mechanism that tends to stabilize blood
pressure in the normal range in normo-
tensive individuals (12).
Renin was discovered by Tigersted
and Bergmann in 1898. From that time
on, including the fundamental works of
Braun-Menendeza, Goldblatta, Page,
Skeggs and other researchers on RAS,
the objective of how to block the sys-
tem has been consistently present (13).
e various approaches to renin inhibi-
tion included blockade at dierent lev-
els, starting with beta blockers, aldo-
sterone antagonists, and through ACE
inhibitors and ARBs a new group of
drugs DRI came on the scene. e rst
representative of this group was aliski-
ren, which inhibited RAS in a specic,
more sophisticated and dierent way
than the above mentioned medications.
3. DIRECT RENIN INHIBITORS
Early DRI were peptide analogues of
angiotensinogen. ey acted by com-
petitively displacing angiotensinogen
from the active side of renin. e rst
synthetic renin inhibitor was pepstatin,
peptide obtained from a microbial cul-
ture (14). e next drug was enalki-
ren (A-64662), which could be given
only intravenously (15, 16). Although
a number of DRIs, such as ditekiren,
enalkiren, zankiren and remikiren,
have been synthesized in the past, they
were not developed for clinical use due
to poor oral bioavailability, low ecacy,
short half-life and high cost of synthe-
sis. Structural modications have im-
proved bioavailability and ecacy have
been improved by making the inhibi-
tory process non-competitive (16).
4. MECHANISM OF ACTION
Aliskiren is an orally active, non-
peptidic inhibitor of renin, the enzyme
involved in the initial and rate-limit-
ing step of the RAS. Like ACE inhibi-
tors and ARBs, aliskiren causes a reac-
tive rise in plasma renin concentration
(PRC) due to interruption of the normal
feedback inhibition of renin release by
angiotensin II but, unlike these agents,
aliskiren inhibits plasma renin activity
(PRA) and therefore provides suppres-
sion of the entire renin system. us,
renin inhibitors may oer a therapeu-
tic prole distinct of that of ACE inhib-
itors and ARBs.
e renin system is regulated by a
negative feedback mechanism, in which
angiotensin II inhibits the release of re-
nin from the kidney, thereby reducing
PRC, PRA and the production of an-
giotensin I and angiotensin II. Both
ACE inhibitors and ARBs suppress this
negative-feedback loop: ACE inhibitors
lower II levels by blocking its enzymatic
generation from angiotensin I, whereas
ARBs block the activity of angiotensin
II at the angiotensin II type 1 receptor
(17). ACE inhibitors and ARBs there-
fore increase renin release from the kid-
ney, raising PRC and PRA. In the case
of ACE inhibitors, plasma levels of an-
giotensin I increase, and conversion to
angiotensin II can occur via ACE-inde-
pendent mechanisms such as the chy-
mases (18). e therapeutic potential
of these drug classes may therefore be
limited by increased levels of PRA and
incomplete suppression of angiotensin
II generation (19).
However, aliskiren causes a de-
crease in angiotensin I, angiotensin II
and PRA. is is a unique feature that
dierentiates aliskiren not only from
traditional antihypertensive drugs
which activate the renin angiotensin
system (such as diuretics and calcium
channel blockers), but also from ACE
inhibitors and ARBs (20). ere is evi-
dence that increased levels of PRA are
associated with a higher risk of cardio-
vascular complications. Aliskiren neu-
tralizes any compensatory increase in
PRA even during combined therapy
with a thiazide diuretic, an ACE inhibi-
tor, or an ARB (20, 21). However, aliski-
ren increases PRC like ACE inhibitors
and ARBs.
5. PHARMACOKINETICS
Aliskiren is one of the most potent
compounds yet identified with high
specicity for primate renin (22). e
concentration of aliskiren that pro-
duces 50% inhibition is 0,6 nmol/L (23).
In humans, plasma concentrations
of aliskiren increases depending on the
dosage after oral application of 40-640
mg daily. e maximal concentrations
are reached
3 to 6 hours after admin-
istration (24). Bioavailability of aliski-
ren in humans is 2.7%, and the plasma
half-life of 23.7 h with the range of 20-
45 h. Aliskiren binds to plasma proteins
from 47 to 51%. Peak plasma concen-
trations are reached 1 to 2 hours after
dosing, and steady state is reached af-
ter 5 to 8 days of once-daily adminis-
tration. Food intake reduces the max-
imum plasma concentration (C
max
) as
well as the exposition of the area under
curve (AUC), but with insignicant ef-
fect upon pharmacodynamics allow-
ing administration of the drug inde-
pendently of taking meals.
Approximately 1.4% out of the full
oral dosage is metabolized. e half-
life of elimination is about 40 hours,
or more precisely from 34 to 41 hours.
Volume of distribution is < 2 L/kg and
the drug is approximately 50% protein
bound (25). Aliskiren displays linear
pharmacokinetics across a dose range
of 75 to 600 mg (26).
In plasma, aliskiren circulates un-
changed and is excreted via the biliary
route with less than 1% being excreted
in the urine (24). Aliskiren has a long
half-life of 20 to 45 hours. e predicted
long duration of action has been con-
rmed in a number of studies using
ambulatory blood pressure monitoring.
Following oral administration, the
average plasma clearance is approxi-
mately 9 l/h. With doses from 75 to 600
mg, C
max
and AUC of aliskiren increase
linearly with the dosage. Pharmacoki-
netics of aliskiren is independent of age,
sex, liver and renal failures. If mild re-
nal failure is present, no adjustment of
the dose is needed. Although aliskiren
is eliminated via the biliary route, liver
disease did not aect the pharmaco-
kinetics after the single dose admin-
istration. It has been suggested that
dose reductions in patients with con-
comitant hepatic impairment will not
be needed (27).
6. INTERACTIONS
Aliskiren does not inhibit isoen-
zymes CYP450 (CYP1A2, 2C8, 2C9,
2C19, 2D6, 2E1, CYP3A) and does not
induce CYP3A4. Aliskiren is not me-
tabolized by cytochrome P450, and
thus has low potential for signicant in-
teractions with other drugs. ere has
no interaction recorded between aliski-
ren and the following drugs: acenocou-
marol, celecoxib, fenobrate, piogli-
tazone, allopurinol, isosorbid-5-mo-
nonitrat, irbesartan, ramipril and hy-
drochlorothiazide (HCTZ). In general,
it could be said that aliskiren has been
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Is Aliskiren Superior to Inhibitors of Angiotensin-Converting Enzyme and Angiotensin Receptor Blockers in Renin-Angiotensin System Blockade?
associated with few drug interactions.
Aliskiren does not signicantly inu-
ence on pharmacokinetics of atorvas-
tatin, valsartan, metformin or amlodip-
ine. is means that no modication of
doses is needed when aliskiren is ad-
ministered with these drugs.
No interaction of aliskiren was ob-
served with atenolol and digoxin. When
atorvastatin is administered in dose of
80 mg, the steady state AUC and C
max
of aliskiren (300 mg) is increased by
50%. Simultaneous administration of
ketoconazole (200 mg) and aliskiren
(300 mg) leads to an increase in plasma
concentration of aliskiren by 80% (AUC
and C
max
). Preclinical trials showed that
coadministration of aliskiren and ke-
toconazole intensies gastrointestinal
resorption of aliskiren and declines
its billiary excretion. The doubling
of aliskiren dose will not lead to any
change in the acquired plasma concen-
tration of the drug if atorvastatin and
ketoconazole are administered simul-
taneously (23).
A study which included healthy sub-
jects, demonstrated that cyclosporine A
(200-600 mg) increased C
max
of aliski-
ren (75 mg) 2.5-fold and AUC vefold.
is has been a reason why coadmin-
istration of aliskiren with cyclosporine
is not recommended.
Coadministration of aliskiren and
furosemide reduced AUC values for fu-
rosemide by 28% and C
max
by 49%. Be-
cause of that, modication of dose for
furosemide was needed to avoid possi-
ble inadequate dosage of furosemide in
volume overload.
Coadministration of aliskiren pro-
duced changes either of C
max
or AUC
with the following drugs: valsartan (de-
crease by 28%), metformin (decrease by
28%), amlodipine (increase by 29%), ci-
metidine (increase by 19%).
On the basis of experiences with
other drugs which aect RAS, it could
be concluded that coadministration
of aliskiren and potassium sparing di-
uretics could induce an increase in po-
tassium that requires precaution mea-
sures.
7. ADVERSE EFFECTS
OF ALISKIREN AND
TOLERABILITY
Safety of aliskiren was studied in
more than 8000 patients. More than
2300 patients were followed during six
months, and 1200 during one year. In-
cidence of adverse eects did not cor-
relate with sex, age, body mass index,
race. Aliskiren treatment was well tol-
erated . Short-term monotherapy with
aliskiren 150300 mg/day was gen-
erally well tolerated , with an adverse
event prole similar to that of placebo.
Adverse events commonly associ-
ated with aliskiren monotherapy in-
cluded headache, nasopharyngitis and
diarrhea. Although data indicate that
diarrhea may be more frequent with
aliskiren at dosages 300 mg/day than
with placebo, this and other gastroin-
testinal symptoms (which include ab-
dominal pain, dyspepsia and gastro-
intestinal reflux) are typically mild
and rarely result in discontinuation of
treatment. Long-term administration
of aliskiren-based therapy was well
tolerated for up to 1 year. Combining
aliskiren with HCTZ was as well toler-
ated as ramipril combined with HCTZ,
while aliskiren combined with amlo-
dipine was as well tolerated as HCTZ
combined with amlodipine, in terms
of the frequency of adverse events af-
ter six months. e most common ad-
verse event was diarrhea. Because renin
inhibitors do not aect substance P or
bradykinin concentrations, aliskiren is
not expected to cause the angioedema
and cough that is commonly associated
with ACE inhibitors therapy. e inci-
dence of cough after administration of
aliskiren (0.9%) was similar to that from
the placebo group (0.6%)(23).
8. CLINICAL TRIALS
WITH ALISKIREN IN
THE TREATMENT OF
HYPERTENSION
Numerous studies evaluated eects
of aliskiren, both as monotherapy and
in combination with other agents, in
mild to moderate hypertension. Clin-
ical trials in over 14,000 patients have
demonstrated that aliskiren, alone or in
combination with other antihyperten-
sive therapies, provides eective blood
pressure reduction with a good safety
and tolerability prole. Administration
of aliskiren to patients with hyperten-
sion leads to a long-term dose-depen-
dent decrease in both systolic and dia-
stolic pressure, depending on the dos-
age (28). Aliskiren was signicantly su-
perior to placebo in lowering mean sit-
ting diastolic blood pressure and sys-
tolic blood pressure (p<0.0001). e
maximum eect was seen after a few
weeks of treatment. Aliskiren 150–300
mg/day was eective in the treatment
of mild to moderate hypertension for
up to 1 year. ere was no evidence of
rebound hypertension following aliski-
ren withdrawal.
Some studies demonstrated that
aliskiren was comparably eective as
HCTZ, the ARBs irbesartan, losar-
tan, and valsartan, the calcium chan-
nel blocker amlodipine and the beta
blocker atenolol and may be slightly
more eective than ACE inhibitors in
lowering blood pressure (29, 30).
Aliskiren 150-300 mg/day lowered
mean diastolic blood pressure by 2.2-
12.3 mm Hg and mean systolic blood
pressure by 10-15.8 mm Hg in mono-
therapy trials (35). In comparator
groups, diastolic blood pressure was
reduced by 5.5-11.3 mm Hg and sys-
tolic blood pressure was reduced by 10-
16.5 mm Hg.
Aliskiren treatment in a study of
1124 patients, who were followed dur-
ing a year, showed signicantly greater
eect than HCTZ (31).
Trials of once-daily aliskiren have
shown it to be as eective as ARBs and
ACE inhibitors. If aliskiren is adminis-
tered in the dose of 150-300 mg, its an-
tihypertensive ecacy is present for 24
hours (32). Trough-to-peak-ratio of the
diastolic pressure is 98% for the dose
of 300 mg. After two weeks of aliski-
ren treatment, the maximum antihy-
pertensive eect was from 85 to 90%.
The antihypertensive effect was be-
ing maintained a year after the begin-
ning of the therapy. When the admin-
istration of aliskiren was discontinued,
blood pressure returned to the previous
values, without rebound phenomenon
concerning the pressure or PRA. Hy-
potension was uncommon when aliski-
ren was administered alone (0.1%), or
in combination with other antihyper-
tensive agents (<1%), in controlled clin-
ical trials.
9. ALISKIREN COMBINATION
THERAPY
Aliskiren demonstrated added
blood pressure control in combina-
tion with HCTZ, irbesartan, ramipril
or valsartan (33). Aliskiren combined
with either HCTZ or valsartan lowered
mean diastolic blood pressure by 10.4-
14.3 mm Hg and systolic blood pres-
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Is Aliskiren Superior to Inhibitors of Angiotensin-Converting Enzyme and Angiotensin Receptor Blockers in Renin-Angiotensin System Blockade?
sure by 15.3-21.2 mm Hg. e combi-
nation of aliskiren with either HCTZ
or ramipril demonstrated high toler-
ability. Combined administration of
aliskiren and ramipril was associated
with a decreased incidence of cough
(1.8% for aliskiren ramipril combina-
tion) then ramipril monotherapy (4.7%
ramipril alone).
e study in patients with hyper-
tension that was not adequately con-
trolled with amlodipine alone in the
dose of 5 mg showed that introduction
of 150 mg of aliskiren in the treatment
scheme synergistically reduced blood
pressure. e combined therapy was
safe and well tolerated (35). Edema oc-
curred more frequently with amlodip-
ine 10 mg (11.2%) than with combina-
tion therapy (2.1%) or amlodipine 5 mg
(3.4%). In conclusion, aliskiren 150 mg
plus amlodipine 5 mg shows similar
but not better blood pressure-lower-
ing ecacy when compared with am-
lodipine 10 mg in patients not com-
pletely responsive to amlodipine 5 mg.
Less edema was noted with combina-
tion therapy.
In a double-blind study in 1797 pa-
tients with hypertension, the patients
received aliskiren 150 mg, valsartan
160 mg, a combination of aliskiren 150
mg and valsartan 160 mg. e combina-
tion of aliskiren and valsartan achieved
signicantly greater reduction in blood
pressure than the applied monothera-
pies. e safety of the combination cor-
responded to that of the monotherapies,
with a tolerability prole similar to that
with aliskiren and valsartan alone (28).
Aliskiren was also eective and safe
in patients with diabetes and hyperten-
sion. In these patients, combination of
aliskiren and ramipril produced greater
reduction in arterial blood pressure
than monotherapy of either of these
drugs (36).
In obese patients
with hypertension
who failed to achieve blood pressure
control
with HCTZ, addition of aliski-
ren to the therapeutic scheme provided
an additive antihypertensive eect (37).
e achieved additive antihypertensive
eect was identical to that achieved by
introduction of irbesartan or amlodip-
ine into the therapeutic schemes.
10. PLACE OF ALISKIREN IN
THE MANAGEMENT OF
HYPERTENSION
On the basis of numerous clinical,
placebo controlled, randomized stud-
ies, it could be concluded that aliski-
ren is at least as eective as diuretics,
beta blockers, calcium channel block-
ers, ACE inhibitors and ARBs. Besides,
aliskiren has few adverse events, gener-
ally being mild and transient in nature.
Aliskiren is well tolerated. Because
of the long plasma half-life it is suit-
able for once-daily dosing, contribut-
ing to an adequate patient compliance.
It also has very good through-to-peak
ratio. e DRI can be combined with
other antihypertensive drugs produc-
ing synergistic antihypertensive eect.
Besides, aliskiren oers patients with
hypertension associated with cardio-
vascular disease and renal failure an
additional safety because it is predom-
inantly eliminated through the liver,
without the need for dose adjustment
for renal failure. Monotherapy with
aliskiren 150-300 mg once daily was
effective in lowering blood pressure
and providing 24-hour blood pressure
control. Blood pressure rises gradually
after aliskiren is withdrawn. It can be
expected that aliskiren, unlike to ACE
inhibitors and ARBs, owing to causing
sustained reduction in PRA may pro-
vide better end-organ protection. e
reduction in PRA amounts to 50-80%,
and is not dose-dependent. Just because
of that, aliskiren could be combined
with drugs causing signicant increase
in PRA, such as diuretics, ACE inhibi-
tors and ARBs. It must not be forgotten
that high PRA is associated with car-
diovascular events. Only beta-blockers
have been known to lower the secretion
rate of renin from the kidneys to reduce
its PRC, as well as PRA. However, there
is little evidence suggesting end-organ
protection eects by RAS blockade with
beta-blockers. Aliskiren does not in-
terfere with bradykinin or substance P
and because of that it should not cause
cough and angioneurotic edema, like
ACE inhibitors (24).Aliskiren’s side ef-
fect prole is rather comparable to that
of ARBs (ie, similar to that of a placebo).
Eventually, antihypertensive eect of
aliskiren is not dependent on age, sex,
body mass index or ethnicity. Contra-
indications for this drug are identical
as those for ACE inhibitors and ARBs,
such as pregnancy and bilateral renal
artery stenosis.
11. CARDIOPROTECTIVE
EFFECTS OF ALISKIREN
As far back as CONSENSUS study
demonstrated, for the rst time, that
introduction of ACE inhibitors into
the therapy already administered to
patients with heart failure NYHA III
and IV signicantly reduced mortal-
ity in these patients. As result of many
careful long and large trials, it is now
clear that ACE inhibitors give both pri-
mary and secondary protection from
cardiovascular disease, thereby inter-
rupting the vicious circle from risk fac-
tors to left ventricular failure at many
sites. e ARBs are very well tolerated,
and in several but not all outcome trials
give benets equal to the ACE inhibi-
tors. In view of that RAS blockade plays
the crucial role in the management of
heart failure it could be concluded that
the use of DRI may have a positive eect
upon complete course of heart failure.
Can aliskiren provide eects simi-
lar to that of ACE inhibitors and ARB
in patients with heart failure? A par-
tial answer to the question provided
Aliskiren Observation of Heart Fail-
ure Treatment (ALOFT) study (38).
In the Aliskiren Observation of Heart
Failure Treatment (ALOFT) study, in-
vestigators studied the eects of add-
ing aliskiren to an ACE inhibitor in
patients with heart failure. Patients (n
= 302) with New York Heart Associa-
tion II–IV heart failure and current or
past history of hypertension were in-
cluded in a randomized double blind
trial. ree months treatment of aliski-
ren 150 mg or placebo was added to a
previous regimen of ACE inhibitors or
ARBs and beta blocker. e mean N-
terminal pro-BNP level was approx-
imately 2100 pg/mL at baseline. e
plasma N-terminal pro-BNP rose by
762 (± 6123) pg/mL in the placebo group
and fell by 244 (±2015) pg/mL in the
aliskiren group after 12 weeks of treat-
ment. Total BNP and urinary aldoste-
rone were also reduced by aliskiren.
Aliskiren 150 mg added to standard
therapy provided reduction in markers
of heart failure progression compared
with placebo, independent of baseline
renal function and appeared to be well
tolerated. Aliskiren will without doubt
get and important place, together with
ACE inhibitors, ARBs, antagonists of
347
MED ARH 2009; 63(6) REVIEWS
Is Aliskiren Superior to Inhibitors of Angiotensin-Converting Enzyme and Angiotensin Receptor Blockers in Renin-Angiotensin System Blockade?
aldosterone receptors and beta block-
ers, in the management of heart failure.
However, the role of DRI in heart fail-
ure with preserved ejection fraction has
not yet been dened.
Eect of aliskiren on left ventricu-
lar hypertrophy was investigated in the
Aliskiren in Left Ventricular Hypertro-
phy (ALLAY) study (39). e study was
designed to assess primarily whether
the combination of aliskiren and losar-
tan was superior to losartan alone in
reducing left ventricular mass index.
Aliskiren was noninferior to losartan
in reducing left ventricular mass index,
but the combination was not superior
to losartan alone. e ndings suggest
that aliskiren could be successfully used
in patients with hypertension associ-
ated with left ventricular hypertrophy.
Renoprotective Eect of Aliskiren
The Aliskiren in the Evaluation
of Proteinuria in Diabetes (AVOID)
study evaluated renoprotective eects
of dual blockade RAS by adding treat-
ment with aliskiren to treatment with
the maximal dose of losartan and op-
timal antihypertensive therapy in pa-
tients who had hypertension and type
2 diabetes with nephropathy (40). e
study showed that overall aliskiren
(150 mg increasing to 300 mg daily)
reduced albuminuria by an additional
20% (p<0.001), when added to the max-
imum dose of losartan (100 mg), with
a reduction of 50% or more in 24.7% of
the patients who received aliskiren as
compared with 12.5% of those who re-
ceived placebo (P<0.001). A small dif-
ference in blood pressure was seen be-
tween the treatment groups by the end
of the study period. Data from AVOID
further showed that aliskiren added to
the maximum dose of losartan had sim-
ilar rates of adverse events as the pla-
cebo plus losartan group. Hyperkalie-
mia was reported as an adverse event
in 5.0% of patients taking aliskiren in
addition to losartan, compared to 5.7%
of those taking placebo plus losartan.
On the basis of the AVOID study,
one can conclude that aliskiren has
renoprotective, antiproteinuric, vascu-
loprotective eects comparable to ACE
inhibitors and ARBs, and that the ef-
fects are independent of its blood pres-
sure eects in patients with hyperten-
sion, type 2 diabetes, and nephropathy
who are receiving the recommended
renoprotective treatment.
12. ONGOING CLINICAL TRIALS
WITH ALISKIREN
Several clinical trials with aliskiren
are in progress (41, 42). Some of them
evaluate its antihypertensive eects, ac-
tivity, tolerability and safety in general.
However, many studies are focused on
application of the drug in highly vul-
nerable groups of patients with mul-
tiple risk factors, such as: in patients
with diabetes, with acute and chronic
congestive heart failure etc. e use of
aliskiren is investigated in elderly pa-
tients with or without high blood pres-
sure. e ecacy of this DRI alone or in
combination with other drugs is being
examined in numerous studies. One of
these is a study which evaluates the ef-
fects of aliskiren, alone or in combina-
tion, on ventricular remodelling after
acute coronary syndrome. Other trials
investigate whether blood-pressure re-
duction with amlodipine plus aliskiren
remains indenitely lower in the pa-
tients who start the two drugs simulta-
neously than in those treated sequen-
tially. Many other clinically relevant
issues, such as ecacy of aliskiren and
ramipril in elderly patients, have been
examined. Some of the ongoing studies
will be briey mentioned below:
e ALTITUDE study (Aliskiren
Trial in Type 2 Diabetes Using Car-
dio-Renal Endpoints) will determine
whether aliskiren, added to conven-
tional therapy, delays heart and kidney
complications in around 8,600 patients
with type 2 diabetes at high risk for car-
diovascular and renal events.
e ATMOSPHERE study (Aliski-
ren Trial to Mediate Outcome Preven-
tion in Heart FailuRE) will evaluate
the eects of aliskiren on cardiovascu-
lar morbidity and mortality in patients
with acute and chronic congestive heart
failure on top of standard therapy.
e APOLLO study (Aliskiren in
Prevention Of Later Life Outcomes),
the placebo-controlled trial, will be
conducted to evaluate aliskiren in pre-
venting cardiovascular morbidity and
mortality in elderly subjects with nor-
mal blood pressure, no overt cardiovas-
cular disease, and a high cardiovascu-
lar risk prole.
e AVANT-GARDE study (Aliski-
ren and Valsartan to Reduce NT-
proBNP via Renin-AnGiotensin-Aldo-
steRone System BlockaDE) (TIMI 43)
will evaluate whether aliskiren, valsar-
tan, or combination therapy will im-
prove ventricular remodeling in high-
risk patients who have been stabilized
following ACS.
e ACCELERATE study (Aliski-
ren and the Calcium ChannEL BlockER
Amlodipine Combination as Initial
TreatmEnt Strategy in Stage I and II
Hypertension) study will test the hy-
pothesis that blood pressure levels are
lower over 32 weeks of treatment in
patients receiving the combination of
aliskiren with amlodipine simultane-
ously from the beginning of the study
when compared with patients who re-
ceive this drugs sequentially.
e AGELESS study will assess and
compare the ecacy of aliskiren ver-
sus ramipril, alone or in combination
with HCTZ and amlodipine, in lower-
ing systolic blood pressure in patients
older than 65 years of age with systolic
hypertension.
The ASPIRE HIGHER program
which includes a comprehensive range
of short-to-medium term studies to as-
sess the potential organ protection ben-
ets of aliskiren across a broad range of
cardio-renal conditions including heart
failure, post-acute coronary syndromes,
post-myocardial infarction, left ventric-
ular hypertrophy, coronary artery dis-
ease and diabetic nephropathy (41, 42).
13. CONCLUSION
e RAS plays a crucial role in de-
velopment of hypertension, heart fail-
ure, as well as in the whole process of
nephropathy, particularly of diabetic
nephropathy, with or without protein-
uria. Inhibition of RAS is achieved us-
ing four big groups of drugs: ACE in-
hibitors, ARBs, beta blockers and aldo-
sterone antagonists. Unlike ACE inhibi-
tors and ARBs, renin inhibitors neutral-
ize any compensatory increase in PRA
and prevent the formation of both an-
giotensin I and angiotensin II.
is is the crucial moment of aliski-
ren’s effect that essentially distin-
guishes aliskiren from ACE inhibitors
and ARBs. ACE inhibitors block angio-
tensin II production, while ARBs block
AT
1
receptors and so disrupts the feed-
back loop by which angiotensin II nor-
mally inhibits renin release. Paradox-
ically, both ACE inhibitors and ARBs
activate RAS and stimulate renin re-
lease. ere were some attempts to re-
solve the paradox by combining ACE
inhibitors and ARBs. But these eorts
did not justify the expectations pre-
348
MED ARH 2009; 63(6) REVIEWS
Is Aliskiren Superior to Inhibitors of Angiotensin-Converting Enzyme and Angiotensin Receptor Blockers in Renin-Angiotensin System Blockade?
sented in ONTARGET study (ONgoing
Telmisartan Alone and in combination
with Ramipril Global Endpoint Trial).
At the present time, the only alternative
to drugs inhibiting RAS, which simul-
taneously stimulate renin and the in-
crease in PRA, is just aliskiren. Studies
in hypertensive patients, where aliski-
ren was administered alone or in com-
bination with other drugs, show aliski-
ren to have excellent antihypertensive
eect. Aliskiren can be combined with
ARBs producing excellent antihyper-
tensive eect. Unlike the combination
of ACE inhibitors and ARBs, which did
not provide signicant synergistic an-
tihypertensive eect but did report an
increasing number of serious adverse
events, described in the ONTARGET
study, the aliskiren combined with an
ARB shows much better eects. e
combination of aliskiren with ARBs
exerts synergistic antihypertensive ef-
fects. Besides, studies of aliskiren in
diabetic nephropathy patients showed
the antiproteinuric and renoprotective
eects identical with those of ACE in-
hibitors and ARBs. Also, the rst stud-
ies of aliskiren in heart failure patients,
when the drug was added to conven-
tional therapy, showed its cardiopro-
tective activity. However, the question
concerning its real role in the manage-
ment of heart failure and its place in
the existing therapeutic schemes with
ACE inhibitors, ARBs, beta blockers
and antagonists of aldosterone receptor,
will be answered by numerous ongo-
ing studies and clinical trials. It is pos-
sible that the arrival of renin inhibitor
has closed the circle of RAS blockade
at all levels. For the present, it is still
too early to have the answer relevant to
protection against end-organ damage.
It must be emphasized that aliskiren
blocks the RAS more completely than
do ACE inhibitors and ARBs. Renin in-
hibitors block the RAS at the highest
level, at its origin, and might thus oer
a new exciting approach for pharmaco-
therapy of arterial hypertension. How-
ever, the management of hypertension
still stays empirical, experimental and
palliative because its causes and cure
have not been known. rough arrival
of aliskiren, the DRI, new possibilities
and perspectives for the management of
hypertension and other cardiovascular
diseases have been opened. e possi-
bilities and perspectives may be greater
than those oered by ACE inhibitors,
ARBs, aldosterone antagonists and
beta blockers. For the time being, there
are no long-term studies with aliskiren
to reveal its inuence upon mortality.
Hopefully the ongoing studies and tri-
als, involving great number of patients
with dierent cardiovascular diseases,
may answer the questions concerning
the place of aliskiren in treatment of hy-
pertension, heart failure, nephropathy,
with or without proteinuria, as well as
concerning its coadministration with
other drugs.
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Corresponding author: Prof. Vjekoslav
Gerc, MD, PhD. Clinic for Heart Disease and
Rheumatism, Clinical Centre University Sarajevo,
71000 Sarajevo, Bolnička 25, e-mail: orinoko@bih.
net.ba
  • [Show abstract] [Hide abstract] ABSTRACT: High blood pressure is the leading risk factor for death and disability worldwide, and the prevalence is increasing. Effective treatment decreases the risk of adverse events in proportion to blood pressure reduction. Combination antihypertensive therapy reduces blood pressure promptly and effectively. Single-pill combinations reduce the pill burden and improve adherence, efficacy, and tolerability of treatment compared with single drug pills. A significant portion of the hypertensive population will require three drugs for adequate control. The single-pill combination of aliskiren, amlodipine, and hydrochlorothiazide is based on complementary mechanisms of action. Clinical trials have shown it to be a safe and effective treatment for hypertension. This combination is a reasonable choice in clinical practice for patients with hypertension that requires three drugs for effective treatment.
    Article · Jun 2013