J Clin Med Res

Journal of Clinical Medicine Research, ISSN 1918-3003 print, 1918-3011 online, Open Access

Article copyright, the authors; Journal compilation copyright, J Clin Med Res and Elmer Press Inc

Journal website http://www.jocmr.org

Original Article

Volume 10, Number 1, January 2018, pages 41-49

Improvement of Diurnal Blood Pressure Variation by Azilsartan

Figure 1. Changes of office BP and PR. At the Final, the last values are shown including patients who experienced deviation. Office BP and PR were compared between before switching and each time point after switching by the t-test. Office SBP and DBP decreased significantly from 1 month after switching, while office PR increased significantly from 3 months. BP: blood pressure; PR: pulse rate; SBP: systolic BP; DBP: diastolic BP; mo: month(s).

Figure 2. Changes of home morning BP and PR. Home morning BP and PR were compared between before switching and each time point after switching by the t-test. Home morning SBP was significantly decreased from 1 month after switching and home morning DBP was significantly decreased from 3 months. Home morning PR only showed a significant decrease at 1 month. BP: blood pressure; PR: pulse rate; SBP: systolic BP; DBP: diastolic BP; mo: month(s).

Figure 3. Changes of home evening BP and PR. Home evening BP and PR were compared between before switching and each time point after switching by the t-test. Home evening SBP showed a significant decrease at 3 and 6 months after switching, while home evening DBP and home evening PR did not change significantly. BP: blood pressure; PR: pulse rate; SBP: systolic BP; DBP: diastolic BP; mo: month(s).

**Table 1.** Characteristics of the Patients (n = 265)
IQR: interquartile range; BMI: body mass index; DM: diabetes mellitus; DL: dyslipidemia; CKD: chronic kidney disease; CVD: cardiovascular disease.
Age, median (IQR), years	72 (62 - 81)
Male gender, n (%)	142 (54)
Current smoking, n (%)	52 (20)
Drinking alcohol, n (%)	128 (48)
BMI, median (IQR), years	24.1 (21.6 - 26.5)
DM, n (%)	66 (25)
DL, n (%)	130 (49)
CKD, n (%)	1 (0.4)
Stroke, n (%)	26 (10)
CVD, n (%)	38 (14)

Table 1. Characteristics of the Patients (n = 265)

IQR: interquartile range; BMI: body mass index; DM: diabetes mellitus; DL: dyslipidemia; CKD: chronic kidney disease; CVD: cardiovascular disease.

Age, median (IQR), years

72 (62 - 81)

Male gender, n (%)

142 (54)

Current smoking, n (%)

52 (20)

Drinking alcohol, n (%)

128 (48)

BMI, median (IQR), years

24.1 (21.6 - 26.5)

DM, n (%)

66 (25)

DL, n (%)

130 (49)

CKD, n (%)

1 (0.4)

Stroke, n (%)

26 (10)

CVD, n (%)

38 (14)

**Table 2.** ARB Therapy Before Switching to Azilsartan
ARB	n	Dose (mg)	n
The number of patients using each ARB before switching is shown with the dosages. ARB: angiotensin II receptor blocker.
Losartan	35	25	1
		50	32
		100	2
Candesartan	87	4	3
		8	77
		6	1
		12	6
Valsartan	58	20	2
		40	3
		80	45
		160	7
		Unknown	1
Olmesartan	42	10	3
		20	27
		30	2
		40	10
Telmisartan	23	40	22
		80	1
Irbesartan	18	50	1
		100	15
		200	2
Unknown	2		2
Total	265		265

Table 2. ARB Therapy Before Switching to Azilsartan

ARB

Dose (mg)

The number of patients using each ARB before switching is shown with the dosages. ARB: angiotensin II receptor blocker.

Losartan

100

Candesartan

Valsartan

160

Unknown

Olmesartan

Telmisartan

Irbesartan

100

200

Unknown

Total

265

**Table 3.** Changes of the Dose of Azilsartan
Azilsartan dose (mg)	Dose just after switching (n)	Final dose (n)	Dose reduction (n)	Dose escalation (n)
The number of patients receiving each dose at initiation of azilsartan, the number of patients receiving each dose at final assessment (including drop-outs), and the number of patients with dose escalation or reduction are shown. A total of 214 patients were switched to 20 mg of azilsartan, followed by switching to 40 mg in 48 patients. At final assessment, 191 patients were receiving 20 mg and 67 patients were receiving 40 mg (including 21 patients with dose escalation from 20 mg).
5	0	1	1 (from 20 mg)	0
10	2	5	4 (from 20 mg)	0
20	214	191	2 (from 40 mg)	1 (from 10 mg)
40	48	67	0	21 (from 20 mg)
Unknown	1	1	0	0
Total	265	265	7	22

Table 3. Changes of the Dose of Azilsartan

Azilsartan dose (mg)

Dose just after switching (n)

Final dose (n)

Dose reduction (n)

Dose escalation (n)

The number of patients receiving each dose at initiation of azilsartan, the number of patients receiving each dose at final assessment (including drop-outs), and the number of patients with dose escalation or reduction are shown. A total of 214 patients were switched to 20 mg of azilsartan, followed by switching to 40 mg in 48 patients. At final assessment, 191 patients were receiving 20 mg and 67 patients were receiving 40 mg (including 21 patients with dose escalation from 20 mg).

1 (from 20 mg)

4 (from 20 mg)

214

191

2 (from 40 mg)

1 (from 10 mg)

21 (from 20 mg)

Unknown

Total

265

**Table 4.** Changes of Office BP and PR After Switching From the Standard Dose or Higher Dose of Other ARBs
	Before switch (mm Hg) (SD)	Final (mm Hg) (SD)	P value
After switching from the standard dose of other ARBs to azilsartan (20 mg), a significant decrease of office SBP was always observed. Except with irbesartan, there was also a significant decrease of office DBP after switching from the standard dose of other ARBs to azilsartan (20 mg). Office PR increased significantly after switching from valsartan (80 mg) to azilsartan (20 mg). Comparison of office SBP between before switching and final assessment was performed by using the t-test. AZ: azilsartan; SD: standard deviation; CA: candesartan; IR: irbesartan; LO: losartan; OL: olmesartan; TE: telmisartan; VA: valsartan; NS: not significant; SBP: systolic blood pressure; DBP: diastolic blood pressure; PR: pulse rate.
All patients (258)	149 (10)	83 (11)	72 (11)	132 (16)	76 (12)	74 (11)	< 0.001	< 0.001	< 0.005
CA 8 mg → AZ 20 mg (62)	148 (11)	85 (9)	71 (11)	129 (14)	78 (11)	73 (12)	< 0.001	< 0.001	0.071
CA 12 mg → AZ 40 mg (5)	150 (11)	75 (11)	73 (7)	150 (16)	77 (4)	78 (6)	NS	NS	NS
IR 100 mg → AZ 20 mg (10)	147 (8)	83 (14)	65 (11)	131 (10)	77 (10)	70 (16)	< 0.005	NS	NS
IR 200 mg → AZ 40 mg (2)	130 (28)	85 (7)	66 (8)	122 (3)	70 (3)	61 (16)	NS	NS	NS
LO 50 mg → AZ 20 mg (29)	150 (9)	84 (9)	73 (11)	132 (16)	74 (13)	73 (9)	< 0.001	< 0.001	NS
LO 100 mg → AZ 40 mg (2)	154 (6)	93 (14)	73 (8)	146 (5)	85 (10)	68 (1)	NS	NS	NS
OL 20 mg → AZ 20 mg (20)	155 (12)	81 (11)	73 (12)	140 (18)	77 (12)	75 (12)	< 0.001	<0.05	NS
OL 40 mg → AZ 40 mg (7)	149 (14)	84 (15)	71 (15)	131 (15)	76 (8)	77 (18)	0.052	NS	NS
TE 40 mg → AZ 20 mg (14)	149 (8)	85 (14)	74 (11)	138 (14)	73 (17)	78 (12)	< 0.01	< 0.005	NS
TE 80 mg → AZ 40 mg (1)	159 (-)	81 (-)	(-)	135 (-)	70 (-)	(-)
VA 80 mg → AZ 20 mg (36)	148 (9)	81 (9)	71 (10)	130 (18)	73 (13)	74 (11)	< 0.001	< 0.005	< 0.05
VA 160 mg → AZ 40 mg (5)	152 (17)	83 (17)	67 (19)	128 (15)	72 (11)	69 (13)	< 0.05	< 0.05	NS

Table 4. Changes of Office BP and PR After Switching From the Standard Dose or Higher Dose of Other ARBs

Before switch (mm Hg) (SD)

Final (mm Hg) (SD)

P value

SBP

DBP

SBP

DBP

SBP

DBP

After switching from the standard dose of other ARBs to azilsartan (20 mg), a significant decrease of office SBP was always observed. Except with irbesartan, there was also a significant decrease of office DBP after switching from the standard dose of other ARBs to azilsartan (20 mg). Office PR increased significantly after switching from valsartan (80 mg) to azilsartan (20 mg). Comparison of office SBP between before switching and final assessment was performed by using the t-test. AZ: azilsartan; SD: standard deviation; CA: candesartan; IR: irbesartan; LO: losartan; OL: olmesartan; TE: telmisartan; VA: valsartan; NS: not significant; SBP: systolic blood pressure; DBP: diastolic blood pressure; PR: pulse rate.

All patients (258)

149 (10)

83 (11)

72 (11)

132 (16)

76 (12)

74 (11)

< 0.001

< 0.005

CA 8 mg → AZ 20 mg (62)

148 (11)

85 (9)

71 (11)

129 (14)

78 (11)

73 (12)

< 0.001

0.071

CA 12 mg → AZ 40 mg (5)

150 (11)

75 (11)

73 (7)

150 (16)

77 (4)

78 (6)

IR 100 mg → AZ 20 mg (10)

147 (8)

83 (14)

65 (11)

131 (10)

77 (10)

70 (16)

< 0.005

IR 200 mg → AZ 40 mg (2)

130 (28)

85 (7)

66 (8)

122 (3)

70 (3)

61 (16)

LO 50 mg → AZ 20 mg (29)

150 (9)

84 (9)

73 (11)

132 (16)

74 (13)

73 (9)

< 0.001

LO 100 mg → AZ 40 mg (2)

154 (6)

93 (14)

73 (8)

146 (5)

85 (10)

68 (1)

OL 20 mg → AZ 20 mg (20)

155 (12)

81 (11)

73 (12)

140 (18)

77 (12)

75 (12)

< 0.001

<0.05

OL 40 mg → AZ 40 mg (7)

149 (14)

84 (15)

71 (15)

131 (15)

76 (8)

77 (18)

0.052

TE 40 mg → AZ 20 mg (14)

149 (8)

85 (14)

74 (11)

138 (14)

73 (17)

78 (12)

< 0.01

< 0.005

TE 80 mg → AZ 40 mg (1)

159 (-)

81 (-)

(-)

135 (-)

70 (-)

(-)

VA 80 mg → AZ 20 mg (36)

148 (9)

81 (9)

71 (10)

130 (18)

73 (13)

74 (11)

< 0.001

< 0.005

< 0.05

VA 160 mg → AZ 40 mg (5)

152 (17)

83 (17)

67 (19)

128 (15)

72 (11)

69 (13)

< 0.05

**Table 5.** Morning-Evening Difference of Home SBP, DBP, and PR
	Before change	Final	P value
Comparison between before switching and final assessment was performed by using the t-test. SD: standard deviation; SBP: systolic blood pressure; DBP: diastolic blood pressure; PR: pulse rate; NS: not significant.
Morning-evening SBP difference, mean (SD), n = 20	14.6 (16.2)	6.6 (14.6)	0.09
Morning-evening DBP difference, mean (SD), n = 20	7.5 (9.2)	4.4 (10.5)	NS
Morning-evening PR difference, mean (SD), n = 17	1.7 (5.1)	4.5 (6.1)	< 0.05

Table 5. Morning-Evening Difference of Home SBP, DBP, and PR

Before change

Final

P value

Comparison between before switching and final assessment was performed by using the t-test. SD: standard deviation; SBP: systolic blood pressure; DBP: diastolic blood pressure; PR: pulse rate; NS: not significant.

Morning-evening SBP difference, mean (SD), n = 20

14.6 (16.2)

6.6 (14.6)

0.09

Morning-evening DBP difference, mean (SD), n = 20

7.5 (9.2)

4.4 (10.5)

Morning-evening PR difference, mean (SD), n = 17

1.7 (5.1)

4.5 (6.1)

< 0.05

**Table 6.** Changes of Various Parameters After Switching to Azilsartan
	Before switching	3 months after	P value	6 months after	P value	12 months after	P value
After switching to azilsartan, eGFR decreased significantly (3, 6, and 12 months) and uric acid increased significantly (12 months). On the ECG, SV1 + RV5 was significantly reduced at 12 months. The t-test was used to assess significance if the distribution was normal, while Wilcoxon’s signed rank test was used if the distribution was not normal. Hb: hemoglobin; γ-GTP: γ-glutamyl transferase; eGFR: estimated glomerular filtration rate; UA: uric acid; Na: sodium; K: potassium; HbA1c: hemoglobin A1c; UP: urine protein; SD: standard deviation; IQR: interquartile range; NS: not significant.
Hb, g/dL, mean (SD)	13.4 (1.5)	13.3 (1.6)	0.07	13.3 (1.5)	NS	13.4 (1.6)	NS
γGTP, U/L, median (IQR)	27 (19 - 48)	29.5 (20 - 50)	NS	28 (19 - 47)	NS	26.5 (18 - 46)	NS
eGFR, mL/min/1.73 m², mean (SD)	64.2 (16.5)	62.8 (16.5)	< 0.05	59.8 (16.2)	< 0.001	60.4 (17.4)	< 0.001
UA, mg/dL, mean (SD)	5.5 (1.4)	5.6 (1.3)	NS	5.7 (1.2)	NS	5.8 (1.5)	< 0.05
Na, mmol/L, mean (SD)	141 (2)	141 (2)	NS	141 (3)	NS	141 (2)	NS
K, mmol/L, mean (SD)	4.3 (0.4)	4.3 (0.5)	NS	4.4 (0.4)	NS	4.4 (0.5)	NS
HbA1c, %, mean (SD)	6.1 (1.0)	6.2 (1.0)	NS	6.3 (1.0)	NS	6.1 (0.9)	NS
UP qualitative, median (IQR)	0 (0 - 0)	0 (0 - 0)	NS	0 (0 - 0)	NS	0 (0 - 0)	NS
SV1 + RV5 (cm), mean (SD)	2.6 (0.8)	2.4 (0.8)	NS	2.5 (0.8)	0.09	2.5 (0.6)	< 0.05

Table 6. Changes of Various Parameters After Switching to Azilsartan

Before switching

3 months after

P value

6 months after

P value

12 months after

P value

After switching to azilsartan, eGFR decreased significantly (3, 6, and 12 months) and uric acid increased significantly (12 months). On the ECG, SV1 + RV5 was significantly reduced at 12 months. The t-test was used to assess significance if the distribution was normal, while Wilcoxon’s signed rank test was used if the distribution was not normal. Hb: hemoglobin; γ-GTP: γ-glutamyl transferase; eGFR: estimated glomerular filtration rate; UA: uric acid; Na: sodium; K: potassium; HbA1c: hemoglobin A1c; UP: urine protein; SD: standard deviation; IQR: interquartile range; NS: not significant.

Hb, g/dL, mean (SD)

13.4 (1.5)

13.3 (1.6)

0.07

13.3 (1.5)

13.4 (1.6)

γGTP, U/L, median (IQR)

27 (19 - 48)

29.5 (20 - 50)

28 (19 - 47)

26.5 (18 - 46)

eGFR, mL/min/1.73 m², mean (SD)

64.2 (16.5)

62.8 (16.5)

< 0.05

59.8 (16.2)

< 0.001

60.4 (17.4)

< 0.001

UA, mg/dL, mean (SD)

5.5 (1.4)

5.6 (1.3)

5.7 (1.2)

5.8 (1.5)

< 0.05

Na, mmol/L, mean (SD)

141 (2)

141 (3)

141 (2)

K, mmol/L, mean (SD)

4.3 (0.4)

4.3 (0.5)

4.4 (0.4)

4.4 (0.5)

HbA1c, %, mean (SD)

6.1 (1.0)

6.2 (1.0)

6.3 (1.0)

6.1 (0.9)

UP qualitative, median (IQR)

0 (0 - 0)

SV1 + RV5 (cm), mean (SD)

2.6 (0.8)

2.4 (0.8)

2.5 (0.8)

0.09

2.5 (0.6)

< 0.05

**Table 7.** Correlations Between the Final Change of Blood Pressure and Various Parameters Before Switching to Azilsartan
Parameter	Spearman’s rank correlation coefficient	P value
Correlations were tested by Spearman’s rank correlation coefficient analysis. The antihypertensive effect of azilsartan was stronger in patients with a lower BMI, higher SBP, higher Hb, lower HbA1c, and lower SV1 + RV5 at initiation of treatment. BMI: body mass index; SBP: systolic blood pressure; DBP: diastolic blood pressure; PR: pulse rate; Hb: hemoglobin; γ-GTP: γ-glutamyl transferase; eGFR: estimated glomerular filtration rate; TG: triglycerides; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; UA: uric acid; Na: sodium; K: potassium; HbA1c: hemoglobin A1c; UP: urine protein; NS: not significant.
Age	0.29	NS
BMI	0.14	< 0.05
SBP	0.38	< 0.001
DBP	0.09	NS
PR	0.008	NS
Hb	0.149	< 0.05
γ-GTP	0.007	NS
eGFR	0.025	NS
TG	0.073	NS
HDL-C	0.055	NS
LDL-C	0.12	NS
UA	0.7	NS
HbA1c	0.21	< 0.05
Na	0.08	NS
K	0.072	NS
UP	0.15	0.06
SV1 + RV5	0.401	< 0.005

Table 7. Correlations Between the Final Change of Blood Pressure and Various Parameters Before Switching to Azilsartan

Parameter

Spearman’s rank correlation coefficient

P value

Correlations were tested by Spearman’s rank correlation coefficient analysis. The antihypertensive effect of azilsartan was stronger in patients with a lower BMI, higher SBP, higher Hb, lower HbA1c, and lower SV1 + RV5 at initiation of treatment. BMI: body mass index; SBP: systolic blood pressure; DBP: diastolic blood pressure; PR: pulse rate; Hb: hemoglobin; γ-GTP: γ-glutamyl transferase; eGFR: estimated glomerular filtration rate; TG: triglycerides; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; UA: uric acid; Na: sodium; K: potassium; HbA1c: hemoglobin A1c; UP: urine protein; NS: not significant.

Age

0.29

BMI

0.14

< 0.05

SBP

0.38

< 0.001

DBP

0.09

0.008

0.149

< 0.05

γ-GTP

0.007

eGFR

0.025

0.073

HDL-C

0.055

LDL-C

0.12

0.7

HbA1c

0.21

< 0.05

0.08

0.072

0.15

0.06

SV1 + RV5

0.401

< 0.005

**Table 8.** Changes of SBP in Patients With or Without Other Concomitant Antihypertensive Agents at Switching From Candesartan (8 mg) to Azilsartan (20 mg)
Antihypertensive agent (n)	Change of SBP (mm Hg) (SD)	P value
Comparisons were performed by the two-sample t-test or Welch’s test. There were no significant differences of the antihypertensive effect of azilsartan between patients with or without concomitant diuretics, calcium antagonists, or β-blockers. SBP: systolic blood pressure; SD: standard deviation.
Diuretic (-) (49)	-17.7 (14.4)	NS
Diuretic (+) (13)	-20.2 (9.7)
Calcium antagonist (-) (29)	-16.2 (13.6)	NS
Calcium antagonist (+) (33)	-20 (13.4)
β-blocker (-) (53)	-18 (12.8)	NS
β-blocker (+) (9)	-19.6 (18.3)

Table 8. Changes of SBP in Patients With or Without Other Concomitant Antihypertensive Agents at Switching From Candesartan (8 mg) to Azilsartan (20 mg)

Antihypertensive agent (n)

Change of SBP (mm Hg) (SD)

P value

Comparisons were performed by the two-sample t-test or Welch’s test. There were no significant differences of the antihypertensive effect of azilsartan between patients with or without concomitant diuretics, calcium antagonists, or β-blockers. SBP: systolic blood pressure; SD: standard deviation.

Diuretic (-) (49)

-17.7 (14.4)

Diuretic (+) (13)

-20.2 (9.7)

Calcium antagonist (-) (29)

-16.2 (13.6)

Calcium antagonist (+) (33)

-20 (13.4)

β-blocker (-) (53)

-18 (12.8)

β-blocker (+) (9)

-19.6 (18.3)