Clin Exp Nephrol DOI 10.1007/s10157-013-0914-5
ORIGINAL ARTICLE
Effect of aliskiren in chronic kidney disease patients with refractory hypertension undergoing hemodialysis: a randomized controlled multicenter study Satoru Kuriyama • Keitaro Yokoyama • Yoichiro Hara • Naoki Sugano • Takashi Yokoo Tatsuo Hosoya
•
Received: 18 August 2013 / Accepted: 8 November 2013 Ó Japanese Society of Nephrology 2013
Abstract Background Applying a direct renin inhibitor (DRI) to advanced stage chronic kidney disease (CKD) patients is a matter of controversy. The purpose of this study was to evaluate the effect of the DRI, aliskiren, in patients with therapy-resistant hypertension undergoing hemodialysis (HD). Methods The study was a prospective, randomized multicenter trial exploring the antihypertensive effect of aliskiren in comparison with amlodipine, a calcium channel blocker, in patients undergoing HD. A total of 83 participants whose blood pressure (BP) had previously been treated with more than one antihypertensive agent and not having achieved the BP goal of \140/90 mmHg were randomly assigned to either aliskiren 150 mg or amlodipine 5 mg as an add-on therapy. Results A significant decrease in pre-dialysis clinic BP and home BP was found only in the amlodipine group and not in the aliskiren group. In contrast, there was a significant decrease in atrial natriuretic peptide (ANP) in the aliskiren group but not in the amlodipine group. N-terminal pro-B-type natriuretic hormone remained unchanged in both groups. Aliskiren significantly reduced angiotensin I and II, plasma renin activity, and increased plasma renin
S. Kuriyama (&) K. Yokoyama Y. Hara N. Sugano T. Yokoo Division of Kidney and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan e-mail: [email protected] T. Hosoya Department of Pathophysiology and Therapy in Chronic Kidney Disease, Jikei University School of Medicine, Tokyo, Japan
content. However, such changes were not observed in the amlodipine group. Conclusion Amlodipine, not aliskiren, effectively reduces BP in CKD patients with refractory hypertension undergoing HD. Aliskiren suppresses the renin-angiotensin system and reduces ANP. Whether the DRI is beneficial in improving cardiovascular events in patients undergoing HD remains to be elucidated in future studies. Keywords Aliskiren Hemodialysis Hypertension Renin-angiotensin-aldosterone ANP
Introduction Strict blood pressure (BP) reduction is indispensable for improving patient prognosis, since inadequate control of BP leaves patients at a high risk of cardiovascular disease. Of note is that despite the increasing awareness of antihypertensive treatment, only a small proportion of patients achieve the recommended target goals [1]. For instance, the BP goals set by hypertension management guidelines of the Japanese Society of Hypertension are currently being achieved in only about 40 % of treated patients [2, 3]. Similar low achievement rates of hypertension control have been reported worldwide [4, 5]. The necessity of lowering BP has been highlighted in patients with chronic kidney disease (CKD). Even in dialyzed patients who are at high cardiovascular risk if BP is extremely hypotensive, lowering BP to the region of 140/90 mmHg is recommended [6]. In general, hypertension in dialysis patients is therapy-resistant. Accordingly, efficacious BP reductions for such patients often need multiple antihypertensive medications. Aliskiren, the first direct renin inhibitor (DRI) recently launched in clinical practice is unique in that it acts directly
123
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on renin that leads to the suppression of the renin-angiotensin system (RAS) at the most upstream point [7]. The clinical usefulness of aliskiren has been evaluated in patients with mild to moderate hypertension in several studies [8–12]. However, the effect of aliskiren has not been fully investigated in advanced CKD patients, especially in those undergoing hemodialysis (HD). The scant information about aliskiren in dialysis patients leads to the absence of guideline recommendations on this drug. Thus, it appeared crucial to test the antihypertensive effectiveness and safety of the DRI in patients undergoing dialysis. To address this clinical concern, we conducted a prospective randomized multicenter trial in which aliskiren was compared with the most commonly used antihypertensive agent, amlodipine, a calcium (Ca) channel blocker (CCB) in terms of antihypertensive potency and the effects on various clinical parameters in patients undergoing HD.
Materials and methods Study subjects Eligible patients were hypertensive men and women aged between 20 and 75 years undergoing maintenance HD (average age 60.7 ± 11.6 years, average HD vintage 113 ± 76 months). The inclusion criteria were outpatients whose pre-dialysis clinic BP was [140/90 mmHg despite the preceding antihypertensive treatment prescribed for [3 months prior to study entry. The patients were also required to measure home BP in the morning. Exclusion criteria were patients who had previously been given either aliskiren or amlodipine prior to entry to the study. Patients who had a ‘within 24 weeks’ past history of myocardial infarction, cerebral apoplexy, dissection of aorta, amputation of peripheral arterial diseases, coronary arterial bypass graft or angioplasty were also excluded from the trial. The baseline medications were dual therapy in 60 % and therapy with C3 drugs in 40 % of patients. The majority of patients were taking angiotensin receptor blockers (ARBs) (72 %) or CCBs (54 %), with only low numbers taking beta-blockers (6 %), alpha-blockers (6 %), or angiotensinconverting enzyme inhibitors (ACE-Is) (5 %). Study protocol All institutions received prior ethics committee and/or institutional review board (IRB) approval, and the trial was conducted in accordance with the principles of Good Clinical Practice and the ethical principles of the concurrent Declaration of Helsinki which also protected the privacy of the patients. All patients gave written informed consent. The study protocol design was a multicenter,
123
prospective, randomized, open-label, blinded-endpoint to evaluate the antihypertensive effect of a DRI, aliskiren (IRB approval by ethical committee of Jikei University School Medicine, clinical trial number 21-224 6102). The study was conducted at the participating clinics or institutions—Jikei University, Shinagawa Jin Clinic, Aoto Jin Clinic, and Iidabashi-Murai Clinic. After obtaining written informed consent, the patients were then allocated to either one of the agents on a randomized basis (aliskiren 150 mg or amlodipine 5 mg) without changing the preceding antihypertensive treatment, and were then followed for 24 weeks. Advice on life-style modification such as a daily salt intake of B6 g was carried out throughout the study. A daily potassium intake to \1.5 g/day was also advised. Endpoints The primary endpoint was a change in clinic and home systolic and diastolic BP after 24 weeks of treatment. Secondary endpoints included changes in atrial natriuretic peptide (ANP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), components of the RAS including angiotensin I (AI), angiotensin II (AII), plasma renin activity (PRA), plasma renin content (PRC), prorenin, aldosterone and other blood chemical parameters. BP measurements and laboratory tests The clinic BP was measured just before starting the HD session on the first day of the week in a sitting position during a morning visit (9–11 am) every 4 weeks. At the end of the HD session of the same day, BP was also measured in a sitting position. We followed all American Heart Association Recommendations published in 1988, including using a 47 9 13 cm cuff and 24 9 13 cm bladder to avoid cuff hypertension [13]. Patients were required to measure home BP in the morning in a sitting position within 30 min after awakening before taking medications in a fasting state. Commercially available BP measuring devices equipped with an upper arm cuff were encouraged to be used for home BP. The averages of several measured values were used for analysis. Laboratory tests were carried out at the beginning of the first visit of the week and after 24 weeks of treatment. After drawing blood from the HD circuit, measurements were made on ANP, NT-proBNP, serum creatinine (Cr) concentration and electrolytes, estimated glomerular filtration rate (eGFR), serum uric acid (UA), and lipid profiles. Plasma NT-proBNP was measured using highsensitivity, noncompetitive radioimmunoassay (ShionoRIA NT-proBNP; Shionogi Inc., Osaka, Japan). ANP, AI,
Clin Exp Nephrol
AII, PRA, PRC, prorenin and aldosterone were also measured by commercially available methods provided by SRL (Tokyo, Japan).
Table 1 Basal characteristics of patients
N
Amlodipine
Aliskiren
34
40
P
Causative diseases (%)
Statistical analyses The paired and unpaired student’s t test, Wilcoxon’s signed rank test, and chi-squared test were carried out as deemed necessary with JMP 9.0 software. The computer used for analysis was a Dynabook Satellite 2590X (Toshiba, Tokyo, Japan). Data are presented as the mean ± standard deviation, unless otherwise indicated, for continuous variables with normal distribution. Continuous variables without normal distribution are presented as median and interquartile range (IQR) with 25 and 75 percentiles. Because of the skewed distribution, logarithmic transformation of NT-proBNP, ANP, and PRA values was performed as the geometric means with 95 % confidence intervals as deemed necessary. A P value of \0.05 was considered statistically significant.
DM
11 (32)
11 (30)
0.9901
CGN
15 (44)
15 (43)
0.8882
31 (91)
34 (85)
0.4179
Gender (%) Male HD (%) 4 h/3 times/week
31 (91)
32 (80)
0.1917
Other regime
3 (9)
8 (20)
0.2112
MI
3 (9)
1 (3)
0.2306
AP
1 (3)
3 (8)
0.3874
Stroke
1 (3)
5 (13)
0.1333
Malignancy
3 (9)
2 (5)
0.5137
Infection
1 (3)
4 (10)
0.2280
60.5 ± 11.3
60.9 ± 11.9
0.8964
Height (cm)
164.1 ± 8.5
165.7 ± 7.4
0.5022
DW (kg)
59.1 ± 9.7
61.3 ± 13.4
0.4806
HD vintage (months)
111 ± 69
114 ± 83
0.9784
SBP
166 ± 16
167 ± 19
0.8555
DBP
88 ± 15
88 ± 14
0.9200
Past history (%)
Complications (%)
Age (years)
Morning BP (mmHg)
Results Backgrounds of enrolled patients
BP before HD (mmHg)
A total of 83 patients were registered in the study, of whom 9 were excluded (6 had protocol violations, and 3 had inadequate data for analyses). Consequently a total of 74 patients with clinical index data were assessable in the analysis (Fig. 1). The patients’ characteristics are shown in Table 1. There was no difference in systolic and diastolic BP between the aliskiren group and the amlodipine group. Other parameters were also comparable between the two groups.
Aliskiren 42
Drop-out
Drop-out
7
2
Assessable
Assessable
34
40
Fig. 1 Flow chart of study patients
164 ± 17
0.6564
83 ± 10
82 ± 11
0.5608
SBP
147 ± 21
148 ± 18
0.9610
DBP
77 ± 8
80 ± 11
0.3028
Lipids (mg/dl) LDL
88 ± 27
78 ± 27
0.0580
HDL
48 ± 14
48 ± 16
0.8784
TG
94 ± 39
111 ± 75
0.4752
SRLa
83 cases
41
165 ± 19
DBP BP after HD (mmHg)
Admitted & randomized
Amlodipine
SBP
HS-CRP (ng/ml)
789 (181–46,400)
527 (87–21,400)
0.3263
ANP (pg/ml)
158 (24–337)
164 (36–551)
0.3826
NT-proBNP (pg/ml)
5,599 (424–32,700)
10,103 (446–35,000)
0.3224
PRA (ng/ml)
2.6 (0.1–18)
1.7 (0.1–20)
0.4839
PRC (pg/ml)
19 (2–200)
13 (2–400)
0.4803
Prorenin (ng/ml)
1.3 (0.4–10)
0.9 (0.4–10)
0.3398
DM diabetes mellitus, CGN chronic glomerulonephritis, MI myocardial infarction, AP angina pectoris, DW dry weight, SBP systolic blood pressure, DBP diastolic blood pressure, LDL low-density lipoprotein cholesterol, HDL high-density lipoprotein cholesterol, TG triglyceride, HS-CRP high-sensitivity CRP, ANP atrial natriuretic peptide, NT-proBNP N-terminal pro-B-type natriuretic peptide, PRA plasma renin activity, PRC plasma renin content, SRL special reference laboratory tests a
Median (min–max)
123
Clin Exp Nephrol Fig. 2 Effect of aliskiren on morning BP and HR. SBP systolic blood pressure, DBP diastolic blood pressure, HR heart rate
(mmHg) 95.0
(mmHg)
175.0
P=0.269
P=0. 819
P=0.209
170.0
80.0 90.0
167
165.0
Amlodipine Aliskiren
(beats/min) 85.0
166
88
88
77
77
75.0
163 86
P=0.179
85.0
160.0
P=0.069
P=0.166
70.0
71 69
155.0
81
155
80.0 65.0 150.0
P
ORIGINAL ARTICLE
Effect of aliskiren in chronic kidney disease patients with refractory hypertension undergoing hemodialysis: a randomized controlled multicenter study Satoru Kuriyama • Keitaro Yokoyama • Yoichiro Hara • Naoki Sugano • Takashi Yokoo Tatsuo Hosoya
•
Received: 18 August 2013 / Accepted: 8 November 2013 Ó Japanese Society of Nephrology 2013
Abstract Background Applying a direct renin inhibitor (DRI) to advanced stage chronic kidney disease (CKD) patients is a matter of controversy. The purpose of this study was to evaluate the effect of the DRI, aliskiren, in patients with therapy-resistant hypertension undergoing hemodialysis (HD). Methods The study was a prospective, randomized multicenter trial exploring the antihypertensive effect of aliskiren in comparison with amlodipine, a calcium channel blocker, in patients undergoing HD. A total of 83 participants whose blood pressure (BP) had previously been treated with more than one antihypertensive agent and not having achieved the BP goal of \140/90 mmHg were randomly assigned to either aliskiren 150 mg or amlodipine 5 mg as an add-on therapy. Results A significant decrease in pre-dialysis clinic BP and home BP was found only in the amlodipine group and not in the aliskiren group. In contrast, there was a significant decrease in atrial natriuretic peptide (ANP) in the aliskiren group but not in the amlodipine group. N-terminal pro-B-type natriuretic hormone remained unchanged in both groups. Aliskiren significantly reduced angiotensin I and II, plasma renin activity, and increased plasma renin
S. Kuriyama (&) K. Yokoyama Y. Hara N. Sugano T. Yokoo Division of Kidney and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan e-mail: [email protected] T. Hosoya Department of Pathophysiology and Therapy in Chronic Kidney Disease, Jikei University School of Medicine, Tokyo, Japan
content. However, such changes were not observed in the amlodipine group. Conclusion Amlodipine, not aliskiren, effectively reduces BP in CKD patients with refractory hypertension undergoing HD. Aliskiren suppresses the renin-angiotensin system and reduces ANP. Whether the DRI is beneficial in improving cardiovascular events in patients undergoing HD remains to be elucidated in future studies. Keywords Aliskiren Hemodialysis Hypertension Renin-angiotensin-aldosterone ANP
Introduction Strict blood pressure (BP) reduction is indispensable for improving patient prognosis, since inadequate control of BP leaves patients at a high risk of cardiovascular disease. Of note is that despite the increasing awareness of antihypertensive treatment, only a small proportion of patients achieve the recommended target goals [1]. For instance, the BP goals set by hypertension management guidelines of the Japanese Society of Hypertension are currently being achieved in only about 40 % of treated patients [2, 3]. Similar low achievement rates of hypertension control have been reported worldwide [4, 5]. The necessity of lowering BP has been highlighted in patients with chronic kidney disease (CKD). Even in dialyzed patients who are at high cardiovascular risk if BP is extremely hypotensive, lowering BP to the region of 140/90 mmHg is recommended [6]. In general, hypertension in dialysis patients is therapy-resistant. Accordingly, efficacious BP reductions for such patients often need multiple antihypertensive medications. Aliskiren, the first direct renin inhibitor (DRI) recently launched in clinical practice is unique in that it acts directly
123
Clin Exp Nephrol
on renin that leads to the suppression of the renin-angiotensin system (RAS) at the most upstream point [7]. The clinical usefulness of aliskiren has been evaluated in patients with mild to moderate hypertension in several studies [8–12]. However, the effect of aliskiren has not been fully investigated in advanced CKD patients, especially in those undergoing hemodialysis (HD). The scant information about aliskiren in dialysis patients leads to the absence of guideline recommendations on this drug. Thus, it appeared crucial to test the antihypertensive effectiveness and safety of the DRI in patients undergoing dialysis. To address this clinical concern, we conducted a prospective randomized multicenter trial in which aliskiren was compared with the most commonly used antihypertensive agent, amlodipine, a calcium (Ca) channel blocker (CCB) in terms of antihypertensive potency and the effects on various clinical parameters in patients undergoing HD.
Materials and methods Study subjects Eligible patients were hypertensive men and women aged between 20 and 75 years undergoing maintenance HD (average age 60.7 ± 11.6 years, average HD vintage 113 ± 76 months). The inclusion criteria were outpatients whose pre-dialysis clinic BP was [140/90 mmHg despite the preceding antihypertensive treatment prescribed for [3 months prior to study entry. The patients were also required to measure home BP in the morning. Exclusion criteria were patients who had previously been given either aliskiren or amlodipine prior to entry to the study. Patients who had a ‘within 24 weeks’ past history of myocardial infarction, cerebral apoplexy, dissection of aorta, amputation of peripheral arterial diseases, coronary arterial bypass graft or angioplasty were also excluded from the trial. The baseline medications were dual therapy in 60 % and therapy with C3 drugs in 40 % of patients. The majority of patients were taking angiotensin receptor blockers (ARBs) (72 %) or CCBs (54 %), with only low numbers taking beta-blockers (6 %), alpha-blockers (6 %), or angiotensinconverting enzyme inhibitors (ACE-Is) (5 %). Study protocol All institutions received prior ethics committee and/or institutional review board (IRB) approval, and the trial was conducted in accordance with the principles of Good Clinical Practice and the ethical principles of the concurrent Declaration of Helsinki which also protected the privacy of the patients. All patients gave written informed consent. The study protocol design was a multicenter,
123
prospective, randomized, open-label, blinded-endpoint to evaluate the antihypertensive effect of a DRI, aliskiren (IRB approval by ethical committee of Jikei University School Medicine, clinical trial number 21-224 6102). The study was conducted at the participating clinics or institutions—Jikei University, Shinagawa Jin Clinic, Aoto Jin Clinic, and Iidabashi-Murai Clinic. After obtaining written informed consent, the patients were then allocated to either one of the agents on a randomized basis (aliskiren 150 mg or amlodipine 5 mg) without changing the preceding antihypertensive treatment, and were then followed for 24 weeks. Advice on life-style modification such as a daily salt intake of B6 g was carried out throughout the study. A daily potassium intake to \1.5 g/day was also advised. Endpoints The primary endpoint was a change in clinic and home systolic and diastolic BP after 24 weeks of treatment. Secondary endpoints included changes in atrial natriuretic peptide (ANP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), components of the RAS including angiotensin I (AI), angiotensin II (AII), plasma renin activity (PRA), plasma renin content (PRC), prorenin, aldosterone and other blood chemical parameters. BP measurements and laboratory tests The clinic BP was measured just before starting the HD session on the first day of the week in a sitting position during a morning visit (9–11 am) every 4 weeks. At the end of the HD session of the same day, BP was also measured in a sitting position. We followed all American Heart Association Recommendations published in 1988, including using a 47 9 13 cm cuff and 24 9 13 cm bladder to avoid cuff hypertension [13]. Patients were required to measure home BP in the morning in a sitting position within 30 min after awakening before taking medications in a fasting state. Commercially available BP measuring devices equipped with an upper arm cuff were encouraged to be used for home BP. The averages of several measured values were used for analysis. Laboratory tests were carried out at the beginning of the first visit of the week and after 24 weeks of treatment. After drawing blood from the HD circuit, measurements were made on ANP, NT-proBNP, serum creatinine (Cr) concentration and electrolytes, estimated glomerular filtration rate (eGFR), serum uric acid (UA), and lipid profiles. Plasma NT-proBNP was measured using highsensitivity, noncompetitive radioimmunoassay (ShionoRIA NT-proBNP; Shionogi Inc., Osaka, Japan). ANP, AI,
Clin Exp Nephrol
AII, PRA, PRC, prorenin and aldosterone were also measured by commercially available methods provided by SRL (Tokyo, Japan).
Table 1 Basal characteristics of patients
N
Amlodipine
Aliskiren
34
40
P
Causative diseases (%)
Statistical analyses The paired and unpaired student’s t test, Wilcoxon’s signed rank test, and chi-squared test were carried out as deemed necessary with JMP 9.0 software. The computer used for analysis was a Dynabook Satellite 2590X (Toshiba, Tokyo, Japan). Data are presented as the mean ± standard deviation, unless otherwise indicated, for continuous variables with normal distribution. Continuous variables without normal distribution are presented as median and interquartile range (IQR) with 25 and 75 percentiles. Because of the skewed distribution, logarithmic transformation of NT-proBNP, ANP, and PRA values was performed as the geometric means with 95 % confidence intervals as deemed necessary. A P value of \0.05 was considered statistically significant.
DM
11 (32)
11 (30)
0.9901
CGN
15 (44)
15 (43)
0.8882
31 (91)
34 (85)
0.4179
Gender (%) Male HD (%) 4 h/3 times/week
31 (91)
32 (80)
0.1917
Other regime
3 (9)
8 (20)
0.2112
MI
3 (9)
1 (3)
0.2306
AP
1 (3)
3 (8)
0.3874
Stroke
1 (3)
5 (13)
0.1333
Malignancy
3 (9)
2 (5)
0.5137
Infection
1 (3)
4 (10)
0.2280
60.5 ± 11.3
60.9 ± 11.9
0.8964
Height (cm)
164.1 ± 8.5
165.7 ± 7.4
0.5022
DW (kg)
59.1 ± 9.7
61.3 ± 13.4
0.4806
HD vintage (months)
111 ± 69
114 ± 83
0.9784
SBP
166 ± 16
167 ± 19
0.8555
DBP
88 ± 15
88 ± 14
0.9200
Past history (%)
Complications (%)
Age (years)
Morning BP (mmHg)
Results Backgrounds of enrolled patients
BP before HD (mmHg)
A total of 83 patients were registered in the study, of whom 9 were excluded (6 had protocol violations, and 3 had inadequate data for analyses). Consequently a total of 74 patients with clinical index data were assessable in the analysis (Fig. 1). The patients’ characteristics are shown in Table 1. There was no difference in systolic and diastolic BP between the aliskiren group and the amlodipine group. Other parameters were also comparable between the two groups.
Aliskiren 42
Drop-out
Drop-out
7
2
Assessable
Assessable
34
40
Fig. 1 Flow chart of study patients
164 ± 17
0.6564
83 ± 10
82 ± 11
0.5608
SBP
147 ± 21
148 ± 18
0.9610
DBP
77 ± 8
80 ± 11
0.3028
Lipids (mg/dl) LDL
88 ± 27
78 ± 27
0.0580
HDL
48 ± 14
48 ± 16
0.8784
TG
94 ± 39
111 ± 75
0.4752
SRLa
83 cases
41
165 ± 19
DBP BP after HD (mmHg)
Admitted & randomized
Amlodipine
SBP
HS-CRP (ng/ml)
789 (181–46,400)
527 (87–21,400)
0.3263
ANP (pg/ml)
158 (24–337)
164 (36–551)
0.3826
NT-proBNP (pg/ml)
5,599 (424–32,700)
10,103 (446–35,000)
0.3224
PRA (ng/ml)
2.6 (0.1–18)
1.7 (0.1–20)
0.4839
PRC (pg/ml)
19 (2–200)
13 (2–400)
0.4803
Prorenin (ng/ml)
1.3 (0.4–10)
0.9 (0.4–10)
0.3398
DM diabetes mellitus, CGN chronic glomerulonephritis, MI myocardial infarction, AP angina pectoris, DW dry weight, SBP systolic blood pressure, DBP diastolic blood pressure, LDL low-density lipoprotein cholesterol, HDL high-density lipoprotein cholesterol, TG triglyceride, HS-CRP high-sensitivity CRP, ANP atrial natriuretic peptide, NT-proBNP N-terminal pro-B-type natriuretic peptide, PRA plasma renin activity, PRC plasma renin content, SRL special reference laboratory tests a
Median (min–max)
123
Clin Exp Nephrol Fig. 2 Effect of aliskiren on morning BP and HR. SBP systolic blood pressure, DBP diastolic blood pressure, HR heart rate
(mmHg) 95.0
(mmHg)
175.0
P=0.269
P=0. 819
P=0.209
170.0
80.0 90.0
167
165.0
Amlodipine Aliskiren
(beats/min) 85.0
166
88
88
77
77
75.0
163 86
P=0.179
85.0
160.0
P=0.069
P=0.166
70.0
71 69
155.0
81
155
80.0 65.0 150.0
P
