Age‐ and Sex‐Related Differences in Efficacy With an Angiotensin II Receptor Blocker and a Calcium Channel Blocker in Asian Hypertensive Patients

Abstract

Overseas guidelines to manage hypertension recommend selecting different drugs depending on age, but no studies have investigated the relationship between drug selection and age‐ and sex‐related differences, although such information may help to reduce the risk of cardiovascular mortality. The Azilsartan Circadian and Sleep Pressure––the First Study (ACS1) trial was a multicentered, randomized, open‐label, two‐parallel group study comparing the effects of an angiotensin II receptor blocker (azilsartan) and a calcium channel blocker (amlodipine). The present study is a post hoc analysis of ACS1 to investigate age‐ and sex‐related differences in the antihypertensive effects between azilsartan and amlodipine. Azilsartan significantly reduced diastolic blood pressure in male patients younger than 60 years compared with amlodipine, but amlodipine significantly reduced systolic blood pressure in female patients 60 years and older compared with azilsartan. A randomized controlled trial to evaluate cardiovascular outcomes will demonstrate whether a diastolic blood pressure–lowering effect with azilsartan is significantly effective in male patients younger than 60 years.

For the treatment of hypertension to decrease the risk of cardiovascular events, the Eighth Joint National Committee (JNC 8) recommends target blood pressure (BP) goals of <150/90 mm Hg for persons 60 years and older and a BP goal of <140/90 mm Hg for those younger than 60 years.1 Although the American Society of Hypertension (ASH) and the International Society of Hypertension (ISH) guidelines recommend a target BP goal <140/90 mm Hg regardless of age, as for drug selection, an angiotensin II receptor blocker (ARB) or angiotensin‐converting enzyme inhibitor is recommended as the first‐line drug in patients younger than 60 years, while a calcium channel blocker (CCB) or thiazide diuretic is recommended in patients 60 years and older.2 The 2014 Japanese Society of Hypertension (JSH) guidelines, however, recommend a target BP goal of 140/90 mm Hg for all ages.3

It has recently been reported that regarding the relationship between cardiovascular events and diastolic BP (DBP) and systolic BP (SBP), one standard deviation (SD) increase (13.5 mm Hg) in SBP raises the risk of total mortality (hazard ratio [HR], 1.19; 95% confideince interval [CI], 1.08–1.30]) and cardiovascular mortality (HR, 1.51; 95% CI, 1.34–1.70) in patients of 50 years and older. In patients younger than 50 years, however, one SD increase (8.2 mm Hg) in DBP, not SBP, raises the risk of total mortality (HR, 2.05; 95% CI, 1.26–3.33) and cardiovascular mortality (HR, 4.07; 95% CI, 1.60–10.4).4 Another study on the relationship between DBP/SBP and cardiovascular events in patients younger than 50 years also reported that only SBP is associated with an increased risk of cardiovascular mortality in women, while both SBP and DBP are associated with a higher risk of cardiovascular mortality, independent of each other, in men. In men, the HR for the risk of cardiovascular mortality by isolated diastolic hypertension (IDH) (HR, 1.68; 95% CI, 1.29–2.17]) was similar to that of systolic diastolic hypertension (SDH) (HR, 1.77; 95% CI, 1.49–2.09), which showed a higher risk than isolated systolic hypertension (ISH) (HR, 1.23; 95% CI, 1.03–1.46).5 These recent reports indicate that proper management of DBP in younger male patients results in reduced risk of death caused by cardiovascular events and suggest that it is necessary to consider a differential approach to BP management based on age and sex to reduce the risk of death caused by cardiovascular events. However, there have been no reports at present that antihypertensive drug therapy is effective for younger male patients with ISH, and further investigation is warranted.6, 7 To the best of our knowledge, there are also no reports on the effectiveness of antihypertensive drug therapy for patients with IDH.

The results of the Azilsartan Circadian and Sleep Pressure––the First Study (ACS1), a comparative trial we conducted to investigate the effects of an ARB (20 mg azilsartan) and a CCB (5 mg amlodipine) by age of patients, showed that amlodipine was more effective than azilsartan in patients 60 years and older.8, 9 The present study was a post hoc analysis of the ACS1 study to compare and investigate the therapeutic effect of an ARB (azilsartan) and a CCB (amlodipine) by the age and sex of the patients. We also explored the determinants of the antihypertensive effects of azilsartan and amlodipine.

Methods

Study Design

This study was conducted in accordance with the principles of the Declaration of Helsinki and Title 45, U.S. Code of Federal Regulations, Part 46, Protection of Human Subjects. This study protocol was reviewed and approved by the institutional review boards of the participating study sites. All patients provided written informed consent.

The objective of the study was to compare the effects of 20 mg azilsartan and 5 mg amlodipine in Japanese patients with stage I or II primary hypertension. The study design was described in the previous ACS1 study report (ClinicalTrials.gov ID: NCT01762501).8 Briefly, after informed consent was obtained, participants underwent a 2‐week washout period. Ambulatory BP monitoring (ABPM) was then performed at the start of the run‐in period. The ABPM device was attached to patients at an outpatient visit to measure BP continuously, starting at 10 am (±2 hours) for at least 26 hours. BP was measured every 30 minutes. After the run‐in period (1 week), patients were randomized in a 1:1 ratio using a dynamic allocation algorithm to orally receive 20 mg of azilsartan (Takeda Pharmaceutical Company, Ltd, Osaka, Japan) or 5 mg of amlodipine (Pfizer Japan Inc, Tokyo, Japan) once daily before or after breakfast in the morning from week 0. Patients visited the study site every 2 weeks until the end of the treatment (week 8) and were measured by ABPM at the end of treatment.

Patients were screened for eligibility according to the inclusion and exclusion criteria, which are described in the previous ACS1 study report.8

Statistical Analysis

The differences between the azilsartan and amlodipine groups (each group included 359 cases) were determined using the full analysis set of the ACS1 study.9 For the comparison between the two groups, analysis of covariance was used with baseline as a covariate for change from baseline at week 8 in each subgroup, and chi‐square test was used for percentages of patients who achieved BP goals (control rate). For multivariate analysis, a stepwise method (both enter and stay, P=.15) was used for change in BP in each subgroup. The following values were used as covariates: baseline, sex (male, female), body mass index (BMI) (<25 or ≥25 kg/m²), smoking (yes/no), drinking (yes/no), complication of type 2 diabetes mellitus (yes/no), and duration of hypertension (<5 or ≥5 years). The tests were performed with a two‐sided significance level of 5%. Analysis was performed using SAS software version 9.4 (SAS Institute, Cary, NC).

Results

Patient Characteristics

Patient characteristics at baseline are shown in Table 1. Both the azilsartan and amlodipine groups consisted of 359 cases, and BP and other patient characteristics at baseline were similar in both groups (Table 1). When analyzed by age and sex, the baseline BP values of 24‐hour DBP (P=.0256) and awake DBP (P=.0409) in the amlodipine group were significantly higher than in the azilsartan group in male patients younger than 60 years. The average age of female patients was significantly higher in the azilsartan group (P=.0349) in patients younger than 60 years. In male patients aged 60 years and older, the number of smokers was significantly higher in the azilsartan group (P=.0440), and the values of awake SBP (P=.0139) and 2‐hour SBP after waking (P=.0287) were significantly higher in the amlodipine group.

Table 1.

Baseline Characteristics of Patients Overall

Variable	Azilsartan (n=359)	Amlodipine (n=359)	Total (N=718)
Age, mean (SD), y	61 (12)	61 (12)	61 (12)
Male, No. (%)	202 (56.3)	202 (56.3)	404 (56.3)
BMI, mean (SD), kg/m2	25 (4)	25 (4)	25 (4)
Smoker, No. (%)	73 (20.3)	63 (17.6)	136 (18.9)
Drinking, No. (%)	220 (61.3)	223 (62.1)	443 (61.7)
Duration of hypertension, mean (SD), d	1828 (2726)	1697 (2349)	1762 (2543)
Duration of hypertension <5 y, No. (%)	244 (68.0)	246 (68.5)	490 (68.3)
eGFR, mean (SD), mL/min/1.73 m2	75 (16)	73 (15)	74 (16)
Complication of type 2 diabetes mellitus, No. (%)	71 (19.8)	71 (19.8)	142 (19.8)
Previous hypertension drugs, No. (%)
ARB	85 (23.7)	77 (21.5)	162 (22.6)
CCB	66 (18.4)	68 (18.9)	134 (18.7)
Diuretics	3 (0.8)	2 (0.6)	5 (0.7)
β‐Blockers	3 (0.8)	2 (0.6)	5 (0.7)
Others	2 (0.6)	3 (0.8)	5 (0.7)
None	205 (57.1)	212 (59.1)	417 (58.1)
Baseline BP, mean (SD), mm Hg
Clinic SBP	149.6 (10.2)	150.5 (10.2)	150.1 (10.2)
Clinic DBP	90.3 (9.4)	89.8 (9.6)	90.1 (9.5)
24‐Hour SBP	150.6 (13.0)	152.4 (13.7)	151.5 (13.4)
24‐Hour DBP	89.3 (8.6)	90.4 (9.3)	89.8 (9.0)
Awake SBP	156.3 (13.3)	158.1 (14.0)	157.2 (13.7)
Awake DBP	92.8 (9.0)	93.8 (9.7)	93.3 (9.4)
Sleep SBP	138.8 (16.4)	140.1 (17.1)	139.5 (16.8)
Sleep DBP	81.8 (9.7)	82.9 (10.4)	82.3 (10.1)
2‐Hour SBP after waking	153.9 (16.5)	156.4 (18.9)	155.2 (17.8)
2‐Hour DBP after waking	92.7 (11.3)	94.3 (12.0)	93.5 (11.7)
Pulse rate, mean (SD), beats per min	73.4 (10.8)	72.7 (11.0)	73.1 (10.9)

Abbreviations: ARB, angiotensin II receptor blocker; BMI, body mass index; BP, blood pressure; CCB, calcium channel blocker; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; SBP, systolic blood pressure; SD, standard deviation.

Sex‐Related Changes in BP in Patients Younger Than 60 Years

Azilsartan reduced overall BP more than amlodipine in male patients younger than 60 years (Table 2). In particular, the changes in the azilsartan and amlodipine groups for 24‐hour DBP were −10.5 mm Hg and −8.5 mm Hg (P=.0407), respectively. In addition, the changes in the azilsartan and amlodipine groups for awake DBP were −11.3 mm Hg and −8.4 mm Hg (P=.0057), respectively. Therefore, there was a significant difference between the groups. The changes in the azilsartan and amlodipine groups for clinic DBP were −11.2 mm Hg and −8.5 mm Hg (P=.0550), respectively, showing a declining trend in the azilsartan group. In female patients, only 2‐hour SBP after waking was significantly reduced in the amlodipine group (P=.0031), and no other differences between the azilsartan and amlodipine groups were observed.

Table 2.

Antihypertensive Effects of Azilsartan (Az) and Amlodipine (Am), Stratified by Age (<60 or ≥60 Years) and Sex

Change in BP, mm Hg	Total			Male			Female
	Az	Am	P Value	Az	Am	P Value	Az	Am	P Value
Age <60 y	(n=152)	(n=148)		(n=94)	(n=86)		(n=58)	(n=62)
Clinic SBP	−17.9	−17.0	.5607	−17.1	−15.4	.3827	−19.2	−19.0	.9371
Clinic DBP	−11.6	−9.3	.0304	−11.2	−8.5	.0550	−12.2	−10.4	.2647
24‐Hour SBP	−15.4	−15.5	.9182	−14.8	−13.2	.3664	−16.2	−18.6	.2375
24‐Hour DBP	−10.2	−9.0	.1293	−10.5	−8.5	.0407	−9.8	−9.6	.8723
Awake SBP	−16.2	−15.6	.6939	−15.7	−13.3	.2013	−16.9	−18.8	.3883
Awake DBP	−11.0	−9.1	.0215	−11.3	−8.4	.0057	−10.7	−9.9	.5555
Sleep SBP	−14.2	−15.7	.3489	−13.4	−13.5	.9968	−15.4	−18.7	.1297
Sleep DBP	−8.8	−8.9	.9450	−9.3	−8.6	.5842	−8.1	−9.2	.4562
2‐Hour SBP after waking	−13.8	−16.5	.1850	−13.9	−12.3	.5576	−13.5	−22.0	.0031
2‐Hour DBP after waking	−9.5	−9.4	.9287	−10.5	−8.4	.1888	−8.1	−10.6	.1614
Age ≥60 y	(n=207)	(n=211)		(n=108)	(n=116)		(n=99)	(n=95)
Clinic SBP	−16.7	−21.2	.0009	−15.2	−18.5	.0490	−18.5	−24.3	.0041
Clinic DBP	−9.7	−10.6	.2916	−8.5	−9.3	.4579	−11.1	−12.1	.3359
24‐Hour SBP	−13.4	−18.4	<.0001	−14.4	−16.8	.1777	−12.4	−20.2	<.0001
24‐Hour DBP	−6.7	−8.4	.0070	−7.5	−7.8	.7475	−5.8	−9.1	.0003
Awake SBP	−14.4	−18.5	.0028	−15.1	−16.6	.4551	−13.5	−20.7	.0003
Awake DBP	−7.1	−8.4	.0581	−8.0	−7.8	.8027	−6.1	−9.2	.0023
Sleep SBP	−12.1	−18.2	<.0001	−13.7	−17.7	.0467	−10.2	−18.7	<.0001
Sleep DBP	−6.3	−8.3	.0036	−7.1	−8.2	.2656	−5.4	−8.5	.0015
2‐Hour SBP after waking	−12.5	−16.7	.0133	−13.8	−14.7	.6709	−11.2	−18.9	.0032
2‐Hour DBP after waking	−5.7	−8.0	.0212	−6.8	−7.1	.8368	−4.5	−9.2	.0020

Abbreviations: DBP, diastolic blood pressure; SBP, systolic blood pressure. Analysis of covariance (ANCOVA) with baseline blood pressure (BP) as a covariate.

Sex‐Related Changes in BP in Patients 60 Years and Older

In female patients 60 years and older, amlodipine significantly reduced the overall BP (Table 2). Particularly concerning SBP, amlodipine showed significantly greater reductions compared with azilsartan. Change in clinic SBP was −18.5 mm Hg on azilsartan compared with −24.3 mm Hg on amlodipine (P=.0041), change in 24‐hour SBP was −12.4 mm Hg on azilsartan compared with −20.2 mm Hg on amlodipine (P<.0001), change in awake SBP was −13.5 mm Hg on azilsartan compared with −20.7 mm Hg on amlodipine (P=.0003), change in sleep SBP was −10.2 mm Hg on azilsartan compared with −18.7 mm Hg on amlodipine (P<.0001), and change in 2‐hour SBP after waking was −11.2 mm Hg on azilsartan compared with −18.9 mm Hg on amlodipine (P=.0032). Although amlodipine reduced SBP compared with azilsartan in male patients, a significant difference was observed only in clinic SBP (P=.0490) and sleep SBP (P=.0467).

Control Rates

Based on the JSH 2014 guidelines,3 control rate, which is the percentage of patients who achieved target BP goals (clinic BP: SBP <140 mm Hg and DBP <90 mm Hg; 24‐hour BP: SBP <130 mm Hg and DBP <80 mm Hg; awake BP: SBP <135 mm Hg and DBP <85 mm Hg; sleep BP: SBP <120 mm Hg and DBP <70 mm Hg; and 2‐hour BP after waking: SBP <135 mm Hg and DBP <85 mm Hg), was analyzed in this study (Table 3). In male patients younger than 60 years, the control rates in the azilsartan group were significantly higher than those in the amlodipine group, except for clinic BP: 24‐hour BP (azilsartan vs amlodipine), 28.4% vs 11.4% (P=.0064); awake BP, 35.2% vs 12.7% (P=.0007); sleep BP, 29.5% vs 16.5% (P=.0459); and 2‐hour BP after waking, 39.1% vs 24.1% (P=.0380). In female patients younger than 60 years, there were no differences in control rates between the two groups. On the other hand, in female patients 60 years and older, control rates in the amlodipine group were significantly higher than those in the azilsartan group, except for 2‐hour BP after waking: clinic BP (azilsartan vs amlodipine), 69.1% vs 88.2% (P=.0015); 24‐hour BP, 31.4% and 53.9% (P=.0026); awake BP, 38.4% vs 53.9% (P=.0390); and sleep BP, 31.4% vs 48.3% (P=.0224). In male patients 60 years and older, there were no differences in control rates between the two groups.

Table 3.

Control Rates of Azilsartan (Az) and Amlodipine (Am), Stratified by Age (<60 or ≥60 Years) and Sex

Control Rate, %	Total			Male			Female
	Az	Am	P Value	Az	Am	P Value	Az	Am	P Value
Overall	(n=359)	(n=359)		(n=202)	(n=202)		(n=157)	(n=157)
Clinic BP	63.4	69.8	.0724	56.9	60.0	.5375	71.7	82.4	.0271
24‐Hour BP	32.0	29.0	.4096	31.7	18.3	.0028	32.4	42.6	.0748
Awake BP	35.4	30.8	.2149	34.4	19.4	.0011	36.7	45.3	.1399
Sleep BP	31.4	28.7	.4595	29.0	20.4	.0545	34.5	39.2	.4140
2‐Hour BP after waking	34.3	31.8	.5084	35.1	22.2	.0058	33.1	43.9	.0598
Age <60 y	(n=152)	(n=148)		(n=94)	(n=86)		(n=58)	(n=62)
Clinic BP	66.0	62.2	.5020	59.8	54.2	.4575	75.9	73.3	.7525
24‐Hour BP	30.5	17.4	.0104	28.4	11.4	.0064	34.0	25.4	.3223
Awake BP	34.8	21.0	.0106	35.2	12.7	.0007	34.0	32.2	.8434
Sleep BP	33.3	20.3	.0140	29.5	16.5	.0459	39.6	25.4	.1082
2‐Hour BP after waking	35.7	31.9	.4997	39.1	24.1	.0380	30.2	42.4	.1814
Age ≥60 y	(n=207)	(n=211)		(n=108)	(n=116)		(n=99)	(n=95)
Clinic BP	61.4	75.1	.0031	54.4	64.3	.1389	69.1	88.2	.0015
24‐Hour BP	33.2	37.2	.4040	34.7	23.4	.0735	31.4	53.9	.0026
Awake BP	35.9	37.8	.7034	33.7	24.3	.1386	38.4	53.9	.0390
Sleep BP	29.9	34.7	.3173	28.6	23.4	.3950	31.4	48.3	.0224
2‐Hour BP after waking	33.2	31.8	.7779	31.6	20.8	.0767	34.9	44.9	.1744

Control rate was clinic blood pressure (BP): systolic BP (SBP) <140 mm Hg and diastolic BP (DBP) <90 mm Hg; 24‐hour BP: SBP <130 mm Hg and DBP <80 mm Hg; awake BP: SBP <135 mm Hg and DBP <85 mm Hg; sleep BP: SBP <120 mm Hg and DBP <70 mm Hg; and 2‐hour BP after waking: SBP <135 mm Hg and DBP <85 mm Hg.

BP Determinants of SBP in Patients Younger Than 60 Years

Our results of multivariate analysis (Table 4) suggest that variables that affect 24‐hour SBP reduction by azilsartan include duration of hypertension, smoking status, and BMI. The estimated value (β) of the BP change was −4.86 mm Hg in patients with a duration of hypertension of less than 5 years (P=.0425), 4.53 mm Hg in smokers (P=.0451), and 4.45 mm Hg in patients with BMI ≥25 kg/m² (P=.0208). The change in morning SBP was −10.99 mm Hg in patients with a duration of hypertension of less than 5 years (P=.0029), 7.52 mm Hg in smokers (P=.0317), and 6.47 mm Hg in patients with BMI ≥25 kg/m² (P=.0281). The variable that affects BP reduction by amlodipine was shown to be sex. The β for BP change was 5.72 mm Hg in men (P=.0010). The change in morning SBP was 8.33 mm Hg (P=.0015).

Table 4.

Multivariate Analysis in Patients Younger Than 60 Years (SBP)^a

Variable	Clinic SBP		24‐Hour SBP		Daytime SBP		Nighttime SBP		Morning SBPb
	β	P Value	β	P Value	β	P Value	β	P Value	β	P Value
Azilsartan
Intercept	22.89	.1645	12.31	.2472	10.19	.3840	35.29	.0006	65.98	<.0001
Baseline SBP	−0.31	.0056	−0.18	.0103	−0.16	.0290	−0.35	<.0001	−.52	<.0001
BMI ≥25 kg/m2	5.96	.0123	4.45	.0208	4.20	.0469	4.87	.0367	6.47	.0281
Smoker	6.43	.0212	4.53	.0451	3.87	.1164	6.34	.0221	7.52	.0317
Duration of hypertension <5 y	ND	ND	−4.86	.0425	−4.87	.0628	−7.24	.0139	−10.99	.0029
Drinking	ND	ND	ND	ND	ND	ND	ND	ND	4.39	.1471
Amlodipine
Intercept	52.96	.0008	43.39	<.0001	45.88	<.0001	46.77	<.0001	40.58	.0002
Baseline SBP	−0.44	<.0001	−0.42	<.0001	−0.42	<.0001	−0.47	<.0001	−0.42	<.0001
Complication of type 2 diabetes mellitus	4.92	.0807	7.06	.0028	8.08	.0018	5.24	.0557	ND	ND
Male	3.44	.1020	5.72	.0010	6.25	.0011	4.47	.0277	8.33	.0015
Duration of hypertension <5 y	−8.46	.0018	ND	ND	ND	ND	ND	ND	ND	ND
BMI ≥25 kg/m2	ND	ND	ND	ND	ND	ND	ND	ND	4.08	.1133

Abbreviation: ND, not detectable.

^aStepwise method (enter: P=.15; stay: P=.15); Covariates: baseline, sex (male/female), body mass index (BMI) (<25/≥25 kg/m²), smoking (yes/no), drinking (yes/no), complication of type 2 diabetes mellitus (yes/no), and duration of hypertension (<5/≥5 years).

^bMorning systolic blood pressure (SBP): 2‐hour SBP after waking.

BP Determinants of DBP in Patients Younger Than 60 Years

Our results of multivariate analysis (Table 5) suggest that variables that affect 24‐hour DBP reduction by azilsartan include duration of hypertension and smoking status. The β for BP change was −3.69 mm Hg in patients with a duration of hypertension of less than 5 years (P=.0104) and 2.80 mm Hg in smokers (P=.0362). The change in morning DBP was −5.20 mm Hg in patients with a duration of hypertension of less than 5 years (P=.0177) and 5.07 mm Hg in smokers (P=.0147). The variable that affects the BP reduction by amlodipine was shown to be sex. The β for BP change was 3.05 mm Hg in men (P=.0030). The change in morning DBP was 4.74 mm Hg (P=.0036).

Table 5.

Multivariate Analysis in Patients Younger Than 60 Years (DBP)^a

Variable	Clinic DBP		24‐Hour DBP		Daytime DBP		Nighttime DBP		Morning DBPb
	β	P Value	β	P Value	β	P Value	β	P Value	β	P Value
Azilsartan
Intercept	17.85	.0541	12.11	.0653	11.95	.0908	25.11	.0001	49.34	<.0001
Baseline DBP	−0.32	.0007	−0.22	.0019	−0.21	.0048	−0.38	<.0001	−0.59	<.0001
Duration of hypertension <5 y	−3.43	.0789	−3.69	.0104	−4.50	.0035	−4.10	.0229	−5.20	.0177
Smoker	4.76	.0116	2.80	.0362	3.34	.0198	2.95	.0811	5.07	.0147
Complication of type 2 diabetes mellitus	ND	ND	2.07	.1418	ND	ND	ND	ND	ND	ND
BMI ≥25 kg/m2	3.54	.0270	ND	ND	ND	ND	2.07	.1447	2.55	.1452
Amlodipine
Intercept	26.58	.0009	35.12	<.0001	39.83	<.0001	30.89	<.0001	44.88	<.0001
Baseline DBP	−0.36	<.0001	−0.49	<.0001	−0.52	<.0001	−0.48	<.0001	−0.58	<.0001
Male	2.94	.0410	3.05	.0030	3.69	.0008	1.99	.1291	4.74	.0036
Duration of hypertension <5 y	−5.02	.0050	ND	ND	ND	ND	ND	ND	ND	ND
Smoker	ND	ND	ND	ND	ND	ND	ND	ND	−3.81	.0350

Abbreviation: ND, not detectable.

^aStepwise method (enter: P=.15; stay: P=.15); covariates: baseline, sex (male/female), body mass index (BMI) (<25/≥25 kg/m²), smoking (yes/no), drinking (yes/no), complication of type 2 diabetes mellitus (yes/no), and duration of hypertension (<5/≥5 years).

^bMorning diastolic blood pressure (DBP): 2‐hour DBP after waking.

BP Determinants in SBP of Patients 60 Years and Older

Our results of multivariate analysis (Table 6) suggest that variables that affect 24‐hour SBP reduction by azilsartan include duration of hypertension and smoking status. The β for BP change was −4.90 mm Hg in patients with duration of hypertension of less than 5 years (P=.0189) and 7.25 mm Hg in smokers (P=.0068). The change in morning SBP was −6.71 mm Hg in patients with a duration of hypertension of less than 5 years (P=.0089) and 9.62 mm Hg in smokers (P=.0033). Variables that affect BP reduction by amlodipine were sex and BMI. The β for BP change was 4.91 mm Hg in men (P=.0004) and 3.68 mm Hg in patients with BMI ≥25 kg/m² (P=.0076). The change in morning SBP was 5.20 mm Hg in men (P=.0145) and 5.72 mm Hg in patients with BMI ≥25 kg/m² (P=.0078).

Table 6.

Multivariate Analysis in Patients 60 Years and Older (SBP)^a

Variable	Clinic SBP		24‐Hour SBP		Daytime SBP		Nighttime SBP		Morning SBPb
	β	P Value	β	P Value	β	P Value	β	P Value	β	P Value
Azilsartan
Intercept	22.97	.1433	35.60	.0042	50.50	.0002	34.81	.0005	77.12	<.0001
Baseline SBP	−0.26	.0120	−0.31	.0002	−0.40	<.0001	−0.31	<.0001	−0.56	<.0001
Smoker	6.90	.0104	7.25	.0068	9.25	.0014	ND	ND	9.62	.0033
Duration of hypertension <5 y	ND	ND	−4.90	.0189	−5.22	.0197	−5.25	.0212	−6.71	.0089
BMI ≥25 kg/m2	−3.15	.1427	ND	ND	ND	ND	ND	ND	ND	ND
Amlodipine
Intercept	60.40	<.0001	48.31	<.0001	51.73	<.0001	53.58	<.0001	70.97	<.0001
Baseline SBP	−0.56	<.0001	−0.47	<.0001	−0.48	<.0001	−0.53	<.0001	−0.59	<.0001
Male	7.14	<.0001	4.91	.0004	5.65	.0003	2.95	.0516	5.20	.0145
BMI ≥25 kg/m2	ND	ND	3.68	.0076	3.63	.0203	3.59	.0191	5.72	.0078

Abbreviation: ND, not detectable.

^aStepwise method (enter: P=.15; stay: P=.15); covariates: baseline, sex (male/female), body mass index (BMI) (<25/≥25 kg/m²), smoking (yes/no), drinking (yes/no), complication of type 2 diabetes mellitus (yes/no), duration of hypertension (<5/≥5 years).

^bMorning systolic blood pressure (SBP): 2‐hour SBP after waking.

Discussion

In this post hoc analysis, azilsartan demonstrated significantly greater reduction of 24‐hour DBP and awake DBP than amlodipine in male patients younger than 60 years. In female patients 60 years and older, however, amlodipine demonstrated significantly greater reduction of 24‐hour SBP, awake and sleep SBP, and 2‐hour SBP after waking than azilsartan. Control rates in the azilsartan group were significantly higher than those in the amlodipine group in male patients younger than 60 years. In female patients 60 years and older, control rates in the amlodipine group were significantly higher than those in the azilsartan group. The results of multivariate analysis demonstrated that determinants of a BP‐lowering effect of azilsartan on 24‐hour BP were duration of hypertension less than 5 years and nonsmoking, regardless of age. The determinants of a BP‐lowering effect of amlodipine were female sex, regardless of age.

The JNC 8 guidelines for the management of high BP1 recommend different BP goals by age of patients, ie, younger than 60 years and 60 years and older. The ASH/ISH2 recommend ARBs as the first‐line drug for hypertensive patients younger than 60 years and CCBs for patients 60 years and older. In this report, we also followed the cutoff age of 60 years used by these guidelines.

According to the results of control rates in our study, azilsartan seems to be appropriate for male patients younger than 60 years and amlodipine seems to be appropriate for female patients 60 years and older. Therefore, it would be important to select ARBs or CCBs depending on age and sex. However, in the present study, 30% to 50% of patients with high BP were well‐controlled, except for patients with high clinic BP, suggesting that neither azilsartan nor amlodipine monotherapy provided sufficient control of 24‐hour, awake, sleep, and morning BP. It is therefore considered that combination therapy is required for treatment of some patients to achieve target BP goals.10

Li and colleagues reported that an increase in SBP in patients 50 years and older is a risk factor for increased mortality, and that an increase in DBP, not SBP, is a risk factor in patients younger than 50 years.4 According to a report by Yano and colleagues,5 cardiovascular mortality is the highest for IDH and SDH in male patients younger than 50 years, and the cardiovascular mortality risk is higher for IDH than ISH. These reports thus suggest that there is a need to emphasize management of DBP in younger male patients.

It has been reported that 2 years of treatment with an ARB (candesartan) in the prehypertension stage significantly reduced the incidence of hypertension for up to 2 years after the discontinuation of the active treatment compared with placebo according to the Trial of Preventing Hypertension (TROPHY) study.11 Therefore, ARBs are considered to be much more effective for patients with early‐stage hypertension. Our results of multivariate analysis support the notion that ARBs have a greater BP‐lowering effect in patients with early diagnosed stage 1 hypertension, indicating that ARBs should be administered at an earlier stage.

According to a report by the World Health Organization: Tobacco Atlas 2002,12 the smoking rate in adult males and females, respectively, is 25.7% and 21.5% in the United States, 27.0% and 26.0% in the United Kingdom, and 52.8% and 13.4% in Japan, indicating a higher smoking rate in Japanese men. Middlekauff and colleagues13 reported that tobacco smoke causes an increase in BP by activating the sympathetic nerves, and, because baroreflex sensitivity in long‐term smokers does not function properly, the activity of the sympathetic nerves is not suppressed during smoking. Therefore, renin‐angiotensin II increases in smokers due to activation of the sympathetic nerves and the effect of ARBs is considered to be poor in smokers.

According to a report by Schmieder and colleagues14 on the effects of CCB (amlodipine) monotherapy and CCB/ARB (olmesartan) combination therapy between the sexes, results demonstrated that a greater BP‐lowering effect on both SBP and DBP was observed in women compared with men. It has also been reported that this sex difference decreased as the dose of the ARB increased. Our results of multivariate analysis showed that CCBs had a greater BP‐lowering effect in women, but ARBs showed no sex differences, which is consistent with the results by Schmieder and colleagues.

Study Limitations

There are two limitations to this study. Firstly, the results were obtained by post hoc analysis of the ACS1 study, a randomized controlled trial. Secondly, the onset of cardiovascular events was not used as an endpoint.

Conclusions

The present post hoc analysis showed that ARBs are expected to be useful for the treatment of high DBP in male patients younger than 60 years, while CCBs are considered useful for the treatment of high SBP in female patients 60 years and older. Smoking and male sex appear to prevent the BP‐lowering effect of an ARB and a CCB, respectively. It has also been shown that early commencement of an ARB after the onset of hypertension may further enhance the antihypertensive effect. A randomized controlled trial with the onset of cardiovascular events as an endpoint will demonstrate whether an ARB significantly reduces the risk of cardiovascular events through a DBP‐lowering effect in male patients younger than 60 years.

Disclosures

This study was funded by Takeda Pharmaceutical Company, Ltd. A potential conflict of interest between the company and the Azilsartan Circadian and Sleep Pressure––the First Study (ACS1) Society, the study director, and other study‐related individuals, including the principal investigators, was disclosed at meetings of the Ethics and Conflict of Interest Committees. As a result, an agreement regarding the clinical research was signed by the study director and Takeda Pharmaceutical Company, Ltd, and it was decided that the company would fund ACS1.

J Clin Hypertens (Greenwich). 2016;18:672–678. DOI: 10.1111/jch.12733 © 2016 Wiley Periodicals, Inc.