Clinical trial 359

Aliskiren in an alternate-day administration schedule in

hypertensive albuminuric patients
Georgios Spanos, Rigas G. Kalaitzidis, Despina P. Karasavvidou,
Xanthi Zikou and Kostas C. Siamopoulos

Objective It has been suggested that aliskiren has a long significant differences at any time during monitoring.
half-life and maintains a blood pressure (BP)-lowering Administration of aliskiren resulted in a median reduction
effect following a missed dose. We tested the hypothesis of urine albumin/creatinine ratio of 103 mg/g (od) and
that every other day (eod) administration of aliskiren has the 102 mg/g (eod). Differences in plasma renin activity, plasma
same effects as the once daily (od) dosing in albuminuric renin concentration, and aldosterone-level measurements
hypertensive patients. were not significant.
Methods Fifteen hypertensive patients, after a 4-week Conclusion The BP-lowering effect of eod aliskiren
wash-out period on clonidine, received 300 mg aliskiren od administration, although adequate, is less efficient
as the sole treatment. In patients who remained out of compared with od administration, despite the fact that
target, other nonrenin–angiotensin system blockers were in terms of reducing albuminuria, it appears to be
added. Patients who completed a 24-week (w24) treatment effective. Blood Press Monit 19:359–365 © 2014
period were switched to eod administration of aliskiren for Wolters Kluwer Health | Lippincott Williams & Wilkins.
an additional period of 24 weeks (w48). Blood Pressure Monitoring 2014, 19:359–365
Results Thirteen patients completed the full study protocol. Keywords: albuminuria, aliskiren, alternative-day administration,
The mean office BP was reduced at the end of w24 blood pressure, central hemodynamics
(− 9/3 mmHg), a reduction that continued to be observed Department of Nephrology, University Hospital of Ioannina, Ioannina, Greece
at w48 (− 11/1 mmHg). At the end of the study, the 48 h
Correspondence to Kostas C. Siamopoulos, MSc, MD, FRSH, FERA, School of
ambulatory BP monitoring was divided into two 24 h Health Sciences, Department of Internal Medicine, Division of Nephrology, Faculty
periods. The mean 24 h systolic BP, and the mean daytime of Medicine, University of Ioannina, GR 45110 Ioannina, Greece
Tel: + 30 265 10 07507; fax: + 30 265 10 07016; e-mail: [email protected]
systolic and diastolic BP were significantly lower (P < 0.05)
in the first 24 h (when aliskiren was taken) compared with Received 18 February 2014 Revised 19 June 2014 Accepted 9 July 2014
the second period. Central hemodynamics showed no

Introduction aliskiren has shown a renoprotective potential. However,

Hypertension is a major risk factor for cardiovascular and evidence showed that the agent should not be used in
renal disease. Its worldwide prevalence is more than 25% combination with other RAAS blockers and it should
[1]; however, it varies markedly in different regions [2]. preferably be used in nondiabetic patients. Adding alis-
Lifestyle and dietary adjustments are recommended to kiren to standard therapy in patients with type 2 diabetes
improve blood pressure (BP) control; however, drug and chronic kidney disease, with or without cardiovas-
treatment may often be necessary if these changes prove cular disease, did not improve outcomes and increased
ineffective or insufficient. Several classes of anti- adverse events [10].
hypertensive medications are available; among these,
drugs that blockade the renin–angiotensin aldosterone However, recent evidence showed that aliskiren use
system (RAAS) are preferable in proteinuric patients as among community-dwelling patients aged 66 years and
the first-line approach to the management of hyperten- older receiving therapy with an angiotensin-converting
sion [3]. enzyme inhibitor (ACEi) or an angiotensin-receptor
blocker (ARB) was not associated with hospitalization
Aliskiren is the first in a new class of orally effective, for hyperkalemia, acute kidney injury, or stroke [11].
nonpeptide, low-molecular-weight, and direct renin
inhibitor for the treatment of hypertension. It inhibits the It has been suggested that the drug has a long half-life,
enzyme renin by binding to its catalytic site, thus exceeding 40 h [12], provides smoothly sustained 24 h BP
blocking the RAAS at its point of activation [4]. control, and maintains a BP-lowering effect following a
missed dose [13]. This study tests the hypothesis that
In hypertensive patients, treatment with aliskiren once every other day (eod) administration of aliskiren as
daily (od) lowers BP effectively, with a safety and toler- monotherapy or in combination with other anti-
ability profile comparable to that of placebo [5]. In trials hypertensive agents in hypertensive patients with albu-
with patients with or without diabetes mellitus [6–9], minuria less than 500 mg/day is not inferior and has the
1359-5237 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI: 10.1097/MBP.0000000000000077

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
360 Blood Pressure Monitoring 2014, Vol 19 No 6

same antihypertensive and/or antiproteinuric effects as week 24, whereas 48 h ABPM was measured at week 48
the od dose, and the same central hemodynamic (the ABPM started the day that aliskiren was taken).
compliance.
Laboratory measurements
Methods All laboratory measurements were performed at the
Patients laboratory of biochemistry of our hospital by standardized
Patients were selected from the cohort that visited our methods using an Olympus AU 600 clinical chemistry
hypertension outpatient clinic. The inclusion criteria analyzer (Olympus Diagnostica, Hamburg, Germany).
were age 18 years or older, mild to moderate hyperten- Blood samples were obtained following a 12 h overnight
sion (grade 1 or 2), and a spot urine albumin to creatinine fast. Glomerular filtration rate was estimated using the
ratio higher than 17 mg/g in men, 25 mg/g in women, and Cockcroft–Gault formula. On the spot urine sample,
less than 500 mg/g. Key exclusion criteria were hyper- urine albumin and creatinine concentration were mea-
kalemia, suspected secondary hypertension on the basis sured within 8 h of specimen collection. Solid-phase
of clinical and laboratory findings, atrial fibrillation or fluorescence immunoassay was used to measure urinary
other cardiac rhythm disorders, and pregnancy. Informed albumin [14]. All assessments were performed according
consent was obtained from all patients. Our hospital to a standard protocol that conformed to the international
Ethics Committee approved this study protocol. standards for definitions and measurements.

Hemodynamic measurements
Study design
BP determinations were performed after a 5-min rest in a
This was a single-center, open-label, prospective, pilot
sitting position at each visit. Brachial BP was measured
study. In patients receiving antihypertensive treatment,
three times at 2-min intervals using an automated
BP medications were discontinued for a wash-out period
sphygmomanometer (Digital Blood Pressure Monitor
of 4 weeks, during which all patients received clonidine
705-IT; Οmron Health Care, Kyoto, Japan). The mean
300–600 mcg/day according to medical needs. At the end
value of the last two readings for both brachial SBP and
of the run-in period, patients received aliskiren 150 mg
DBP was used for calculation. Brachial pulse pressure
od and the administration of clonidine was interrupted. If
was calculated as SBP − DBP.
BP was not well controlled (sitting BP ≥ 140/90 mmHg)
after 2 weeks of treatment, aliskiren was titrated to Following the last measurement, three successive
300 mg. In patients who remained out of target after recordings, each over 10 s, of the radial artery pressure
4 weeks, diltiazem 300 mg or nebivolol 5 mg od was waveforms were sampled by applanation tonometry using
added according to medical indications. The third anti- the Sphygmocor system (Atcor, Sydney, New South
hypertensive agent that the patients received, if required Wales, Australia). Data that fulfilled the automatic quality
(BP ≥ 140/90 mmHg), was hydrochlorothiazide 12.5 mg controls specified by the Sphygmocor software were used
od. No other antihypertensive agent was permitted dur- to derive central aortic pressure waveforms by a pre-
ing the trial as it could interfere with the study evalua- viously validated generalized transfer function [15], from
tions and the interpretation of results. Those patients which central SBP, DBP, and pulse pressure values were
who completed the 24-week (w24) treatment period obtained. Brachial arterial BP was used to calibrate the
program were switched to eod administration of aliskiren radial pressure pulse. Central pressure waveforms were
300 mg for an additional period of 24 weeks (w48) with- subjected to further analysis by the Sphygmocor software
out changing the administration frequency of other to calculate the aortic augmentation index (AIx). AIx is
antihypertensive agents. The patients were instructed to defined as the increment in pressure from the first sys-
take the study medication once eod in the morning. tolic shoulder (inflection point) to the peak pressure of
the aortic pressure waveform expressed as a percentage
However, if, at any point during the study, sitting systolic
(of peak pressure) and provides a quantitative measure of
BP (SBP) and/or diastolic BP (DBP) exceeded the safety
augmentation of central BP [15]. AIx data were also
parameters of at least 160 mmHg and at least 100 mmHg,
corrected for a heart rate of 75 beats/min. Carotid-femoral
respectively, patients were withdrawn from the study and
pulse wave velocity (PWV) was determined from carotid
were treated accordingly. Similarly, if SBP was found to
and femoral pressure waveforms obtained noninvasively
be below 100 mmHg and DBP below 60 mmHg, patients
by applanation tonometry using the Sphygmocor system
were discontinued for safety reasons. Patients’ assess-
(Atcor).
ment with office BP measurements was performed at
screening and at the fourth week in the clonidine run-in Twenty-four hour and 48-h ABPM was performed non-
phase, as well as every 4 weeks thereafter, whereas invasively on the nondominant arm, using a SpaceLabs
indices of arterial stiffness (AS) and laboratory measure- device (model 90207; Spacelabs Healthcare, Snoqualmie,
ments were performed at baseline (run-in phase), week Washington, USA), spacing the readings at 15-min
24, and week 48. Twenty-four hour ambulatory BP intervals [3]. Patients were instructed to continue with
monitoring (ABPM) was measured at baseline and at their usual activities, return the following morning (for

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 Aliskiren in eod administration Spanos et al. 361

24 h ABPM) or after 48 h (for the 48 h ABPM) for device Table 1 Baseline characteristics
removal, and keep their arm extended and immobile at Patients 13
the time of the cuff’ s inflation. For this study, ABPM was Males 9 (69)
Smokers 3 (23)
considered valid only if at least 80% of BP measurements Age (years) 47 (42–65)
during the daytime and night-time periods (from patient Weight (kg) 83 (74.5–99)
diaries) were satisfactory. All of the valid recordings were Diabetes mellitus 2 (15)
BMI (kg/m2) 28.7 (26.7–33)
analyzed to determine a 24-h, 48-h, daytime, and night-
time mean SBP and DBP. The mean BP of the above
measurements was used for analyses in this study.
Albuminuria results
Administration of aliskiren in hypertensive patients with
Plasma renin activity-renin–aldosterone measurements albuminuria less than 500 mg/day resulted in a median
Plasma renin activity (PRA) was calculated by the reduction of urine albumin to creatinine ratio of 103 mg/
quantitative determination of angiotensin I in plasma g, P = 0.001 (reduction 80%). On the eod administration
samples. Angiotensin I was determined in two aliquots of of aliskiren, the agent appears to be equally effective.
the same sample: one incubated at 37°C for generation The reduction of albuminuria remained stable (80%)
of angiotensin I under conditions that prevent the compared with the baseline (102 mg/g, P = 0.003)
degradation of angiotensin I (presence of enzymatic (Table 2).
inhibitor phenylmethylsulfonyl fluoride) and are con-
sidered most suitable for renin activity and one non-
BP results
incubated that remained in an ice-bath (4°C).
Angiotensin I plasma levels were determined by radio- The mean office SBP was significantly reduced at the
immunoassay (DiaSorin, Stillwater, Minnesota, USA) and end of the w24 treatment period (134/79 vs. 143/82
PRA was calculated using the following formula: mmHg, P = 0.023), a reduction that continued to be
observed in the eod program at w48 (132/81, P = 0.025)
Angiotensin I in 371Cangiotensin I in 41C (Table 3). There was no significant difference in the
PRA ¼ 1:12 : mean office SBP and DBP between w24 and w48
Hours of incubation
(Table 3).
Aldosterone serum levels were determined by a compe-
titive radioimmunoassay (ZenTech, Liege, Belgium). Data analysis of the ABPM is shown in Tables 3 and 4.
Measurements of active renin were performed in plasma Both mean 24 h SBP and DBP were significantly reduced
samples using a two-site immunoradiometric assay at w24 compared with baseline (128/82 vs. 132/82 mmHg,
(Immunotech; Beckman Coulter, Prague, Czech P < 0.05) (Table 3). The decrease in mean 48 h ABPM at
Republic). w48, compared with baseline, was also evident (128/78
mmHg), but not statistically significant (P > 0.05)
(Table 4).
Statistical analysis
All data are expressed as median (first quartile, third When we divided the 48 h ABPM into two 24 h periods,
quartile). Treatment-related changes in parameters were the first when aliskiren was taken and the second when
analyzed using a nonparametric Wilcoxon signed-rank the patient did not receive the agent, our results showed
test. A P-value of less than 0.05 was considered statisti- that the mean 24 h SBP, mean daytime SBP, and DBP
cally significant. Statistical analysis was carried out using were lower in the first 24 h period (the day of aliskiren
SPSS version 20.0 (SPSS Inc., Chicago, Illinois, USA). administration) (P < 0.011, P < 0.016, and P < 0.009),
respectively (Table 4).

Results
Central hemodynamics and arterial stiffness
Fifteen patients entered the treatment period after the
measurements
4-week run-in phase. However, a total of 13 patients
Central BP wave reflections expressed with Alx and PWV
(nine men) completed the full study protocol and were
measurements are shown in Table 5. There were no
eligible for analysis. Two patients discontinued the study
significant differences in any of these measurements at
treatment because of uncontrolled hypertension during
any time during the monitoring.
the period of eod administration of aliskiren.
PRA, plasma renin concentration, and aldosterone levels
Additional antihypertensive agents were administered in
analysis are shown in Table 6. A noticeable increase in
seven patients to control BP. Diltiazem was administered
plasma renin concentration and a decrease in PRA were
in six patients, diuretic in two patients, and nebivolol in
observed, although these differences were not sig-
one patient.
nificant. Nine of the 13 patients also underwent aldos-
Table 1 shows the demographic characteristics of the terone measurements at baseline and at 24 and 48 weeks.
study patients. Of interest is that three of these patients (33.3%) showed

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362 Blood Pressure Monitoring 2014, Vol 19 No 6

Table 2 Biochemical characteristics

Baseline Week 24 Week 48
Serum creatinine (mg/dl) 1.1 (1.05–1.4) 1.05 (1–1.35) 1.125 (0.95–1.35)
eGFR (ml/min/1.73 m2) 91.9 (72.2–112.7) 87.5 (69.2–120.3) 85.2 (69.5–108.9)
K (mEq/l) 4.6 (4.3–4.75) 4.65 (4.0–4.895) 4.625 (4.225–4.8)
u-ACR (mg/g) 128 (53.5–326) 25 (4.5–40)* 26 (11–76)*

eGFR, estimated glomerular filtration rate (Cockcroft–Gault equation); K, potassium; u-ACR, urine albumin creatinine ratio.
*P < 0.05 compared with baseline.

Table 3 Brachial and ABPM measurements (mmHg)

mmHg Baseline Week 24 Week 48
Office mean SBP 143 (129–148) 134 (127.5–138)* 132 (125–140)*
Office mean DBP 82 (74–88.5) 79 (73.5–87.5) 81 (74–83.75)
Office mean PP 60 (49.5–72) 51 (49–58) 52.5 (44.25–59.5)
ABPM mean SBP 132 (125.5–138.5) 128 (120–130)* 128 (120–134.5)
ABPM mean DBP 82 (76–85.5) 82 (68.5–84.5)* 78 (71–82.5)*

ABPM, ambulatory blood pressure monitoring; DBP, diastolic blood pressure; PP, pulse pressure; SBP, systolic blood pressure.
*P < 0.05 compared with baseline.

Table 4 Analysis of the 48 h ABPM performed on week 48 (the first Discussion

24 h was the day that aliskiren was taken)
The most important finding of the present study is that
mmHg First 24 h ABPM Second 24 h ABPM P aliskiren in the eod administration program seems to lead
Mean 24 h SBP 127 (121.5–130) 128 (124–137.5) 0.011 to less adequate BP control. However, for reduction of
Mean 24 h DBP 78 (71–82.5) 78 (72–86.5) NS albuminuria, the agent was equally effective with the two
Mean daytime 129 (124.25–134.25) 133.25 (126.5–140.75) 0.016
SBP ways of treatment: od and eod administration.
Mean daytime 80 (75.5–84.75) 83.75 (77.5–92) 0.009
DBP The existing literature supports the notion that plasma
Mean night-time 120.25 (114.5–128.75) 121.5 (117.25–132.5) NS
SBP
half-life of aliskiren exceeds 24 h in healthy individuals
Mean night-time 73.5 (65.5–77.5) 70.5 (66.25–78.25) NS [16,17] and can be up to 40 h after multiple dosing [18].
DBP Data show that there is a notable reduction in BP, which
ABPM, ambulatory blood pressure monitoring; DBP, diastolic blood pressure; NS, is maintained for several days after the withdrawal of
nonsignificant; SBP, systolic blood pressure. aliskiren [13,19] and that the agent provides a sustained
BP-lowering effect beyond a 24-h dosing interval [20].
an increase in serum aldosterone levels from the indivi- However, our data differ from the existing literature as
dual baseline, a phenomenon called aldosterone break- we showed that in the common medical practice, aliski-
through (Table 7). In particular, patients K.G., S.X., and ren should not be used for BP reduction in eod admin-
A.S. showed an increase in their aldosterone levels by 30, istration, a fact that could potentially lead to a much lower
125, and 34%, respectively. cost of treatment. Even in our data, this is best exem-
plified by the two patients who discontinued the study
treatment because of uncontrolled hypertension during
the period of eod administration of aliskiren.
Adverse effects
The study found relatively few adverse effects. Patients’ This is the first study to investigate the administration of
kidney function and potassium levels were not sig- aliskiren on an eod program. To our knowledge, in
nificantly altered through the entire treatment period patients with hypertension, there are only a few studies
(Table 2). mainly, with the use of diuretics, in an eod administration

Table 5 Central hemodynamics measurements

Central hemodynamics Baseline Week 24 Week 48
Central SBP (mmHg) 133.5 (115.5–147) 127 (114–131.5) 129 (121–138.5)
Central DBP (mmHg) 83 (76–90) 80 (74–85) 84.25 (75.5–91.25)
Central PP (mmHg) 45 (34.5–64.5) 41 (35.5–47) 44.5 (37.25–54)
Alx 34.5 (18.5–37–5) 32 (15.5–38) 35.5 (25.5–41.75)
Alx 75% 28.7 (14.2–31.9) 27.3 (11.8–32.3) 30.9 (20.9–35.9)
PWV c-r (m/s) 8.5 (7.05–8.9) 8.15 (6.55–8.75) 8.075 (7.425–8.75)
PWV c-f (m/s) 9.1 (8–9.8) 9.1 (7.45–9.6) 9.53 (8.03–9.95)

Alx, augmentation index; c-f, carotid-femoral; c-r, carotid-radial; DBP, diastolic blood pressure; PP, pulse pressure; PWV, pulse wave velocity; SBP, systolic blood pressure.

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 Aliskiren in eod administration Spanos et al. 363

Table 6 PRA-renin-aldosterone measurements

PRA-renin and aldosterone measurements Baseline Week 24 Week 48
Upright PRA (pg/ml/h) 0.8 (0.23–1.66) 0.03 (0.01–0.19) 0.12 (0.05–0.21)
Supine PRA (pg/ml/h) 0.17 (0.09–0.41) 0.10 (0.01–2.48) 0.1 (0.03–0.19)
Upright PRC (pg/ml) 9.71 (5.04–12.89) 37.43 (12.44–45.10) 50.78 (41.72–95.31)
Supine PRC (pg/ml) 6.13 (4.33–9.47) 31.79 (10.89–58.33) 34.90 (28.35–58.37)
Upright aldosterone (pg/ml) 200.24 (118.73–279.24) 130.53 (102.48–238.98) 184.74 (90.24–416.41

PRA, plasma renin activity; PRC, plasma renin concentration.

Table 7 Aldosterone breakthrough Weir et al. [28] showed that the reduction in BP dominates
Baseline Baseline Week 24 Week 48 the antialbuminuric effect independent of the dose in both
office BP aldosterone aldosterone aldosterone valsartan prompt responders and delayed responders.
Patient Sex Age (mmHg) (pg/ml) (pg/ml) (pg/ml)
B.N. M 49 143/111 198.64 151.26 205.71
T.S. M 67 163/89 64.04 79.52 82.78
In our study, we found no significant differences in central
R.K. M 46 126/81 242.14 124.06 184.74 hemodynamics, which are more closely associated with
D.L. M 64 125/66 312.01 126.75 163.76 cardiovascular outcomes relative to brachial BP [29]. No
N.A. M 71 144/63 120.98 80.89 112.60
L.X. F 46 143/83 116.47 130.53 57.03 difference was observed in brachial BP, aortic SBP and
K.G. M 47 148/88 246.46 249.33 318.65 DBP, and PWV between the treatments periods at any
S.X. F 73 135/70 200.24 228.62 450.00
A.S. M 62 128/83 335.24 263.40 449.00
time during the monitoring. However, albuminuria was
reduced significantly in our patients and albuminuria
BP, blood pressure; F, female; M, male. was strongly related to AS, and this relationship was
enhanced in patients with hypertension and diabetes,
protocol [21–23]. These studies were designed to eval- among Chinese middle-aged adults [30]. A possible
uate the efficacy and the possible reduction of adverse explanation for our results is that the magnitude of AS in
effects, with various outcomes. To date, there are no data our cohort was far less than that of other studies because at
for aliskiren. On the basis of our results, the eod baseline, AS indices such as PWV were considerably lower
administration of aliskiren did not lead to a consistent than those observed in other trials. Hence, patients with
reduction in BP levels. lower PWV, as their collagen is better preserved, are not
that vulnerable to improvement by RAAS blockade.
However, contrary to the BP effect, in this 48-week protocol, Furthermore, the short follow-up time and the small
the antiproteinuric effect of aliskiren seems to be equally numbers of the patients studied are among the most rea-
effective in both eod and od administration. Our results sonable explanations for our results.
indicated that the agent might provide more complete and
thus more effective blockade of the RAAS, probably because
Changes in AS indices, with the use of aliskiren, have
renal vasodilation with aliskiren exceeded responses observed
been discussed in recently published studies [31–34].
previously with ACEis and ARBs [24]. Unambiguous evi-
However, our results are not in accordance with the study
dence of this blockade was identified 48 h after a single dose,
of Cherney et al. [31] who showed that aliskiren led to an
and the effect was dose related. The prolonged response was
improvement in the parameters of systemic vascular
consistent with tissue studies in animal models, which have
function, such as carotid Alx, and PWV in patients with
shown that in rats, aliskiren was accumulated in the glomeruli
uncomplicated type 1 diabetes. In another study, after
and the vasculature of the kidneys with a high affinity [25].
12 weeks of aliskiren-based therapy, clinic, ambulatory,
Recent evidence showed that the addition of aliskiren to the
and central BP values as well as brachial-ankle PWV were
maximal recommended dose of an ARB and a usual dose of
all significantly decreased compared with the baseline
amlodipine is more effective in reducing albuminuria and
levels [33]. Aliskiren, compared with the ACEi ramipril,
oxidant stress in hypertensive diabetic patients with chronic
similarly normalized brachial BP as well as central BP. Of
kidney disease [26].
note, PWV was significantly and similarly reduced by
Reduction of BP and albuminuria are independent both drugs; however, aliskiren induced a significantly
treatment targets for kidney protection, but whether this greater AIx reduction than ramipril [34]. In contrast, we
requires a different dose for titration is unknown. In recently showed that valsartan improves AS to a sig-
the study by Laverman et al. [27], it was found that the nificantly greater extent than aliskiren, despite a similar
absence of BP response to an ARB (losartan) does not antihypertensive and antiproteinuric effect [35]. Our
preclude a reduction in albuminuria, and optimal reduc- results in the present study should be considered as an
tion of albuminuria may require titration beyond the extension of the aforementioned study, albeit we showed
predefined BP target. Not all patients successfully that AS parameters such as Alx and PWV measurements
respond concordantly with BP and urinary albumin and central BP measurements in the 48-week follow-up
excretion rate reduction with a RAAS blockade. had not altered significantly.

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
364 Blood Pressure Monitoring 2014, Vol 19 No 6

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