Vol.29 (2006) No.12
Aliskiren, a Novel Oral Renin Inhibitor, Provides
Dose-Dependent Efficacy and Placebo-Like
Tolerability in Japanese Patients with Hypertension
Toshio KUSHIRO1), Hiroshige ITAKURA2), Yoshihisa ABO3), Hiromi GOTOU4),
Shinji TERAO5), and Deborah L. KEEFE6)
Aliskiren is a novel orally active renin inhibitor for the treatment of hypertension. This study evaluated the
antihypertensive efficacy, safety and tolerability of aliskiren in Japanese patients with hypertension. Forty
hundred and fifty-five Japanese men and women with a mean sitting diastolic blood pressure of 95–110
mmHg were randomized to receive once-daily double-blind treatment for 8 weeks with aliskiren 75, 150 or
300 mg or placebo. Aliskiren produced significant, dose-dependent reductions in mean sitting diastolic
blood pressure (p<0.0005 vs. placebo for each dose) and mean sitting systolic blood pressure (p<0.001 vs.
placebo for each dose). The placebo-corrected reductions in mean sitting systolic/diastolic blood pressure
were 5.7/4.0, 5.9/4.5 and 11.2/7.5 mmHg in the aliskiren 75, 150 and 300 mg groups, respectively. After 8
weeks’ treatment, 27.8%, 47.8%, 48.2% and 63.7% of patients in the placebo and aliskiren 75, 150 and 300
mg groups, respectively, achieved a successful treatment response (diastolic blood pressure <90 mmHg
and/or reduced by ≥10 mmHg from baseline; p<0.005 vs. placebo for each dose). Aliskiren treatment was
well tolerated, with the incidence of adverse events reported in the active treatment groups (53–55%) being
similar to that in the placebo group (50%). This study, which is the first to assess the antihypertensive effi-
cacy and safety of aliskiren in Japanese patients with hypertension, demonstrates that the once-daily oral
renin inhibitor aliskiren provides significant, dose-dependent reductions in blood pressure with placebo-like
tolerability. (Hypertens Res 2006; 29: 997–1005)
Key Words: hypertension, aliskiren, renin inhibitor, Japanese, renin-angiotensin system
Hypertension affects 15–37% of the global adult population
(1), accounts for 13% of global mortality and is predicted to
substantially increase over the next 20 years (2). Although
this highly prevalent condition is treatable, in the US approx-
imately 30% of adults with hypertension are unaware that
they have a problem, more than 40% are not on treatment and
only about one-third of treated patients have their high blood
pressure (BP) controlled (3). Similarly in Japan, approxi-
mately 30% of hypertensive adults over the age of 40 years
are not receiving treatment, and in about half of treated
patients, BP is not controlled to the target level (4).
The most recent advances in antihypertensive therapies
include drugs targeting the renin-angiotensin-aldosterone
system (RAAS) (5), and antihypertensive agents that suppress
RAAS have been increasingly utilized in Japan (6). The
From the 1)Department of Cardiology, Nihon University Surugadai Hospital, Tokyo, Japan; 2)Department of Internal Medicine, Shinagawa East One
Medical Clinic, Tokyo, Japan; 3)Department of Internal Medicine, Kita Aoyama D Clinic, Tokyo, Japan; 4)Clinical Research Department and 5)Medical
Information Processing and Statistics Department, Novartis Pharma K.K., Tokyo, Japan; and 6)Novartis Pharmaceuticals Corp., Clinical Research and
Development, East Hanover, USA.
Address for Reprints: Toshio Kushiro, M.D., Department of Cardiology, Nihon University Surugadai Hospital, 1–8–13 Kandasurugadai, Chiyoda-ku,
Tokyo 101–8309, Japan. E-mail: firstname.lastname@example.org
Received May 12, 2006; Accepted in revised form August 16, 2006.
Hypertens Res Vol. 29, No. 12 (2006)
RAAS, via angiotensin II and aldosterone, is a key regulator
of BP and body fluid volume. In the RAAS, renin converts
angiotensinogen to angiotensin I, which is then converted to
the potent vasoconstrictor angiotensin II, primarily by angio-
tensin converting enzyme (ACE). The binding of angiotensin
II to the angiotensin II type 1 (AT1) receptor on target cells
results in increased peripheral vascular resistance and ele-
vated BP. Increased and continued activation of the RAAS
leads to chronic hypertension and is a major underlying cause
of end-organ damage and cardiovascular events—which are
both long term consequences of hypertension (7, 8).
Suppression of RAAS with ACE inhibitors or angiotensin
receptor blockers (ARBs) has proven to be clinically effec-
tive, producing a reduction in BP and evidence of end organ
protection. ACE inhibitors reduce production of angiotensin
II by inhibiting its conversion from angiotensin I by ACE,
while ARBs suppress the action of angiotensin II by blocking
binding to AT1 receptors (9–11). In addition to their antihy-
pertensive efficacy, ACE inhibitors produce further benefi-
cial effects, such as improved insulin sensitivity via the
inhibition of kininase II and subsequent increase in bradyki-
nin levels (12). However, elevated bradykinin levels are
thought to be responsible for the dry cough that is reported by
up to 20% of patients receiving treatment with this drug class
(10, 13). ACE inhibitors also fail to block angiotensin II pro-
duction via ACE independent mechanisms (14, 15). Mean-
while, ARBs have been shown to suppress cardiovascular
remodelling via inhibition of AT1 receptor function (16, 17).
However, increased circulating levels of angiotensin II may
lead to the stimulation of the angiotensin II type 2 (AT2)
receptor population. The precise physiological role of AT2
receptors has yet to be determined, but they have been
reported to be involved in the development of left ventricular
hypertrophy (16, 18). In addition to these effects, both ACE
inhibitors and ARBs cause an increase in plasma renin activ-
ity (PRA) (19, 20). Therefore, the optimal means of suppress-
ing the RAAS may be to directly inhibit renin and thereby
target the system at its point of activation. This would 1)
reduce angiotensin II production; and 2) prevent a rise in PRA
by inactivating the renin released as a result of compensatory
feedback mechanisms (21, 22). Through this strategy, it is
unlikely that renin inhibitors would produce detrimental
Fig. 1. Patient flow diagram.
Kushiro et al: BP Lowering by Aliskiren in Japanese Patients
vascular events with an antihypertensive regimen of amlo-
dipine adding perindopril as required versus atenolol adding
bendroflumethiazide as required, in the Anglo-Scandina-
vian Cardiac Outcomes Trial−Blood Pressure Lowering
Arm (ASCOT-BPLA): a multicentre randomised controlled
trial. Lancet 2005; 366: 895–906.
11. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais
G, The Heart Outcomes Prevention Evaluation Study Inves-
tigators: Effects of an angiotensin-converting−enzyme
inhibitor, ramipril, on cardiovascular events in high-risk
patients. N Engl J Med 2000; 342: 145–153.
12. Tomiyama H, Kushiro T, Abeta H, et al: Kinins contribute
to the improvement of insulin sensitivity during treatment
with angiotensin converting enzyme inhibitor. Hyperten-
sion 1994; 23: 450–455.
13. Israili ZH, Hall WD: Cough and angioneurotic edema asso-
ciated with angiotensin-converting enzyme inhibitor ther-
apy. A review of the literature and pathophysiology. Ann
Intern Med 1992; 117: 234–242.
14. Hollenberg NK, Fisher ND, Price DA: Pathways for angio-
tensin II generation in intact human tissue: evidence from
comparative pharmacological interruption of the renin sys-
tem. Hypertension 1998; 32: 387–392.
15. Wolny A, Clozel JP, Rein J, et al: Functional and biochemi-
cal analysis of angiotensin II−forming pathways in the
human heart. Circ Res 1997; 80: 219–227.
16. Okazaki H, Minamino T, Tsukamoto O, et al: Angiotensin
II type 1 receptor blocker prevents atrial structural remodel-
ing in rats with hypertension induced by chronic nitric oxide
inhibition. Hypertens Res 2006; 29: 277–284.
17. Williams B: Angiotensin II and the pathophysiology of car-
diovascular remodeling. Am J Cardiol 2001; 87: 10C–17C.
18. Senbonmatsu T, Ichihara S, Price E Jr, Gaffney FA,
Inagami T: Evidence for angiotensin II type 2 receptor−
mediated cardiac myocyte enlargement during in vivo pres-
sure overload. J Clin Invest 2000; 106: R25–R29.
19. Azizi M, Menard J, Bissery A, et al: Pharmacologic demon-
stration 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 2004; 15: 3126–3133.
20. Nussberger J, Wuerzner G, Jensen C, Brunner HR: Angio-
tensin II suppression in humans by the orally active renin
inhibitor Aliskiren (SPP100): comparison with enalapril.
Hypertension 2002; 39: E1–E8.
21. Skeggs LT Jr, Kahn JR, Lentz K, Shumway NP: The prepa-
ration, purification, and amino acid sequence of a polypep-
tide renin substrate. J Exp Med 1957; 106: 439–453.
22. Fisher ND, Hollenberg NK: Renin inhibition: what are the
therapeutic opportunities? J Am Soc Nephrol 2005; 16:
23. Kokubu T, Hiwada K, Murakami E, Muneta S, Kitami Y,
Salmon PF: ES-8891, an orally active inhibitor of human
renin. Hypertension 1990; 15: 909–913.
24. Weber MA, Neutel JM, Essinger I, Glassman HN, Boger
RS, Luther R: Assessment of renin dependency of hyperten-
sion with a dipeptide renin inhibitor. Circulation 1990; 81:
25. Neutel JM, Luther RR, Boger RS, Weber MA: Immediate
blood pressure effects of the renin inhibitor enalkiren and
the angiotensin-converting enzyme inhibitor enalaprilat. Am
Heart J 1991; 122: 1094–1100.
26. van den Meiracker AH, Admiraal PJ, Derkx FH, et al:
Comparison of blood pressure and angiotensin responses to
the renin inhibitor Ro 42-5892 and the angiotensin convert-
ing enzyme inhibitor enalapril in essential hypertension. J
Hypertens 1993; 11: 831–838.
27. Kobrin I, Viskoper RJ, Laszt A, Bock J, Weber C, Charlon
V: Effects of an orally active renin inhibitor, Ro 42-5892, in
patients with essential hypertension. Am J Hypertens 1993;
28. Fisher ND, Hollenberg NK: Is there a future for renin inhib-
itors? Expert Opin Investig Drugs 2001; 10: 417–426.
29. Wood JM, Maibaum J, Rahuel J: Structure-based design of
aliskiren, a novel orally effective renin inhibitor. Biochem
Biophys Res Commun 2003; 308: 698–705.
30. Rahuel J, Rasetti V, Maibaum J, et al: Structure-based drug
design: the discovery of novel nonpeptide orally active
inhibitors of human renin. Chem Biol 2000; 7: 493–504.
31. Vaidyanathan S, Limoges D, Yeh C-M, Dieterich H-A:
Aliskiren, an orally effective renin inhibitor, shows dose
linear pharmacokinetics in healthy volunteers. Clin Phar-
macol Ther 2006; 79: P64.
32. Gradman AH, Schmieder RE, Lins RL, et al: Aliskiren, a
novel orally effective renin inhibitor, provides dose-depen-
dent antihypertensive efficacy and placebo-like tolerability
in hypertensive patients. Circulation 2005; 111: 1012–
33. Stanton A, Jensen C, Nussberger J, O’Brien E: Blood pres-
sure lowering in essential hypertension with an oral renin
inhibitor, aliskiren. Hypertension 2003; 42: 1137–1143.
34. Williams B, Poulter NR, Brown MJ, et al: Guidelines for
management of hypertension: report of the fourth working
party of the British Hypertension Society, 2004-BHS IV. J
Hum Hypertens 2004; 18: 139–185.
35. Frattola A, Parati G, Cuspidi C, Albini F, Mancia G: Prog-
nostic value of 24-hour blood pressure variability. J Hyper-
tens 1993; 11: 1133–1137.
36. Neutel JM, Smith DH, Weber MA: Low-dose combination
therapy: an important first-line treatment in the manage-
ment of hypertension. Am J Hypertens 2001; 14: 286–292.