- Email: [email protected]
Choice of Antihypertensive Combination Therapy Based on Daily Salt Intake
CLINICAL INVESTIGATION
Choice of Antihypertensive Combination Therapy Based on Daily Salt Intake Shigeru Toyoda, MD, PhD, Shu Inami, MD, PhD, Toru Kato, MD, PhD, Kinji Tsukada, MD, PhD, Akiya Nakamoto, MD, PhD, Yoshinobu Kikegawa, MD, PhD, Akihiro Suzuki, MD, PhD, Yukitaka Anraku, MD, PhD, Koichi Node, MD, PhD and Teruo Inoue, MD, PhD
Abstract: Background: It is unclear whether thiazide diuretics (TZs) or calcium channel blockers (CCBs) are more effective as add-on therapy to angiotensin receptor blockers (ARBs) in controlling hypertension. Because TZs are a rational choice in salt-sensitive hypertension, patients with high salt intake might preferentially benefit from ARB/TZ over ARB/CCB combination therapy. Methods: Hypertensive patients who failed to reach blood pressure goals despite treatment with ARBs alone were randomly assigned to receive either ARB/TZ or ARB/CCB combination therapy. Estimated daily sodium intake was calculated from spot urine values of sodium and creatinine. Results: Blood pressure was measured at baseline, and at 4, 8 and 12 weeks after starting combination therapy. For all study patients (n 5 87), diastolic blood pressure reduction was greater in patients receiving ARB/CCB treatment. However, in the 37 patients with a baseline estimated daily salt intake greater than 10 g and baseline systolic blood pressure (SBP) ranging from 150 to 200 mm Hg, SBP was lower (P , 0.05) and SBP reduction was greater (P , 0.05) 4 weeks after starting combination therapy in those receiving ARB/TZ treatment. In the 31 patients whose estimated daily salt intake increased at 12 weeks compared with baseline, SBP at 12 weeks was lower in those receiving ARB/TZ treatment (P , 0.05). Conclusions: Estimated daily salt intake is a useful tool for guiding antihypertensive therapy and should be measured repeatedly during the therapeutic course.
compliance. However, it has yet to be determined which drug class, the TZs or the CCBs, is more efficacious as add-on therapy to ARBs in controlling hypertension. The Avoiding Cardiovascular Events Through COMbination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial found that cumulative 5-year composite cardiovascular events were 20% lower in high-risk hypertensive patients treated with an ACEI/CCB combination, compared with those treated with an ACEI/TZ combination. This finding may have been due to the greater antihypertensive effect of the ACEI/CCB combination relative to the ACEI/TZ combination.5 However, it has been suggested that TZs should be more effective in salt-sensitive hypertension.6 Because RAA system activity is accelerated in patients with the metabolic syndrome,7 the RAS inhibitors, ARB and ACEI, are considered the agent of choice in these patients. However, the metabolic syndrome is often complicated by salt-sensitive hypertension.8,9 Therefore, the ARB/TZ combination might be a rational therapeutic choice in patients with the metabolic syndrome and salt-sensitive hypertension. This study was designed to test which of the combination treatment is better on a high salt diet intake to lower blood pressure, ARB/TZ or ARB/CCB.
Key Indexing Terms: Angiotensin receptor blockers; Thiazide diuretics; Calcium channel blockers; Combination pills; Daily salt intake. [Am J Med Sci 2015;350(3):160–166.]
METHODS
R
ecent evidence suggests that strict blood pressure control can improve cardiovascular morbidity and mortality in patients with hypertension. Angiotensin II type 1 (AT1) receptor blockers (ARBs), which act by selectively blocking the binding of angiotensin II to the AT1 receptor, are widely used in the treatment of hypertension.1–3 To achieve strict blood pressure control, the Japanese Society of Hypertension (JSH) guidelines4 recommend combination therapy with multiple antihypertensive agents, including rennin-angiotensin-aldosterone (RAA) system inhibitors such as angiotensin converting enzyme inhibitors (ACEIs) and ARBs. Recently, various ARB combination pills have been developed, including ARBs combined with thiazide diuretics (TZs) and calcium channel blockers (CCBs). One benefit of combination medications is increased patient From the Department of Cardiovascular Medicine (ST, SI, TI), Dokkyo Medical University, Mibu, Japan; Department of Clinical Research (TK), National Hospital Organization, Tochigi Medical Center, Utsunomiya, Japan; Tochigi Medical Association (ST, KT, AN, YK, AS, YA, TI), Utsunomiya, Japan; and Department of Cardiovascular Medicine (KN), Saga University, Saga, Japan. Submitted January 8, 2015; accepted in revised form June 2, 2015. The authors have no financial or other conflicts of interest to disclose. Correspondence: Shigeru Toyoda, MD, PhD, Department of Cardiovascular Medicine, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Tochigi 321-0293, Japan (E-mail: [email protected]).
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Study Design This study was designed as a prospective randomized trial. Recruited were 107 hypertensive patients who did not achieve blood pressure goals, defined as systolic blood pressure (SBP) ,140 mm Hg or diastolic blood pressure (DBP) ,90 mm Hg, despite treatment with ARBs alone for over 4 weeks. Patients were recruited in 8 clinics belonging to the Tochigi Medical Association and in 5 hospitals in Tochigi prefecture and its surrounding areas. Patients with cardiovascular diseases, such as coronary artery disease, heart failure or cerebrovascular disease, were excluded. All patients were randomly assigned to switch from ARBs into either an ARB/TZ (80 mg valsartan/12.5 mg hydrochlorothiazide) combination pill or an ARB/CCB (80 mg valsartan/5 mg amlodipine) combination pill. Study end point was the changes in blood pressure from the baseline values to the values after switching into each combination pills during the 12 weeks’ observation period. After primary analysis in overall patients, subgroup analysis based on estimated daily salt intake was proposed before the data correction (a priori analysis). The study protocol was approved by the local medical ethics committees and informed consent was obtained from all patients. Measurements Blood pressure and heart rate were measured at baseline and at 4, 8 and 12 weeks after starting combination therapy. After the patient rested in the seated position for 5 minutes,
The American Journal of the Medical Sciences
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TABLE 1. Baseline characteristics Age (yr) Male gender, n (%) Heart rate/min Body mass index (kg/m2) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Medications Statins Antidiabetic agents Hemoglobin A1c (%) Total cholesterol (mg/dL) LDL cholesterol (mg/dL) Triglyceride (mg/dL) Na (mEq/L) K (mEq/L) Creatinine (mg/dL) eGFR (mL$min21$1.73 m22) Urinary albumin (mg/g$Cr) Uric acid (mg/dL) Estimated daily salt intake (g)
ARB/TZ group (n 5 38)
ARB/CCB group (n 5 49)
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67 6 13 22 (58) 73 6 11 24 6 3 156 6 17 86 6 12
62 6 13 26 (53) 75 6 11 26 6 7 162 6 19 95 6 13
0.09 0.48 0.66 0.91 0.13 0.0005
10 (26) 7 (18) 5.6 6 1.2 206 6 44 132 6 34 142 6 72 142 6 3 4.3 6 0.4 0.78 6 0.24 76 6 18 28 6 32 6.0 6 1.7 10.6 6 3.7
14 (29) 10 (20) 5.4 6 0.5 196 6 35 118 6 33 143 6 79 141 6 6 4.4 6 0.5 0.76 6 0.17 76 6 17 28 6 40 5.5 6 1.5 9.8 6 3.1
0.63 0.72 0.14 0.22 0.06 0.95 0.34 0.28 0.65 0.96 0.99 0.17 0.30
ARB, angiotensin receptor blocker; CCB, calcium channel blocker; eGFR, estimated glomerular filtration rate; LDL, low-density lipoprotein; TZ, thiazide diuretics.
blood pressure was measured twice, with an interval of at least 5 minutes between each measurement. Blood pressure was measured in the same arm at each visit using a mercury sphygmomanometer with an appropriately sized cuff and recorded to the nearest 2 mm Hg. Height, weight, waist circumference and body mass index (BMI) were measured at baseline. The authors defined visceral fat-type obesity as a waist circumference greater than 85 cm for men and greater than 90 cm for women. Blood and urine testing was performed at baseline and at 12 weeks. Serum creatinine levels were measured using an enzymatic method, and the estimated glomerular filtration rate (eGFR) was calculated by a formula provided by the Japanese Society of Nephrology Chronic Kidney Disease (CKD) Practice Guide: eGFR (mL$min21$1.73 m22) 5 194 3 (serum creatinine level [mg/dL])21.094 3 (age [y])20.287. The product of this equation was multiplied by a correction factor of 0.739 for women.10 Spot urinary albumin levels were determined using a turbidimetric immunoassay and were multiplied by the urine creatinine level (enzymatic method). The authors defined CKD as eGFR less than 60 mL$min21$1.73 m22 and/or urinary albumin level greater than 30 mg/g$Cr.11 Serum uric acid levels were determined by the uricase peroxidase method, and serum levels of sodium and potassium were measured by the electrode method. Total cholesterol and triglyceride levels were determined using enzymatic methods, HDL cholesterol was measured using the precipitation method and low-density lipoprotein (LDL) cholesterol was calculated using the Friedewald formula: LDL cholesterol 5 total cholesterol 2 HDL cholesterol 2 (triglyceride/5). LDL-cholesterol could not be calculated for those patients with a triglyceride level over 400 mg/dL. Hemoglobin (Hb) A1c was measured by high-performance liquid chromatography and values were expressed according to the National Glycohemoglobin Standardization Program. Copyright © 2015 by the Southern Society for Clinical Investigation.
Serum and urinary levels of sodium and potassium were measured by the electrode method. The estimated 24-hour sodium excretion was calculated from spot urine levels of sodium (mEq/L) and creatinine (mg/L) according to the following formula: estimated 24-hour sodium excretion (mEq/d) 5 21.98 3 ([sodium/creatinine]/10 3 estimated 24-hour urinary creatinine excretion)0.392, where the estimated 24-hour urinary creatinine excretion 5 22.04 3 age (y) + 14.89 3 body weight (kg) + 16.14 3 height (cm) 2 2,244.45. The estimated 24-hour sodium excretion was converted into the estimated daily sodium intake according to the following formula: estimated daily sodium intake (g/d) 5 estimated 24-hour sodium excretion (mEq/d) 3 0.0585.12 Data Analysis Data are expressed as mean 6 SD. The authors 1st assessed the normal distribution of each variable using the Kolmogorov-Smirnov test with Lilliefor’s correlation. The distribution of all values was parametric; hence, changes between baseline values and values 12 weeks after treatment initiation were assessed by the paired t test. Serial changes in blood pressure were assessed by repeated measures analysis of variance (ANOVA). Comparisons between 2 groups were assessed by the unpaired t test. In subgroup analysis, a test of interaction for assessing subgroup treatment effects was performed. A P value ,0.05 was considered statistically significant.
RESULTS Of all patients recruited for the study, 87 had complete data sets and were thus included in the study (57 men and 30 women, aged 64 6 13 years). Study patients were randomly assigned to receive either the ARB/TZ combination pill (38 patients including 27 men and 11 women, aged 67 6 13 years) or the ARB/CCB combination pill (49 patients including
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30 men and 19 women, aged 62 6 13 years). Baseline characteristics of both groups are shown in Table 1. Baseline DBP was significantly higher in patients receiving ARB/CCB treatment compared with those receiving ARB/TZ treatment (P 5 0.0005). Although SBP tended to be lower and LDL cholesterol level tended to be higher in the ARB/TZ group compared with the ARB/CCB group, differences between the 2 groups were not statistically significant. Age, gender, heart rate, BMI, renal function, serum levels of sodium, potassium and uric acid, HbA1c and lipid profile (excluding LDL cholesterol level) were comparable between the 2 groups. The baseline estimated daily sodium intake was also similar between the 2 groups.
cholesterol; 132 6 34 mg/dL–124 6 32 mg/dL) or the ARB/ CCB group (HbA1c; 5.4% 6 0.5%–5.4% 6 0.5%, LDL cholesterol; 118 6 33 mg/dL–111 6 27 mg/dL). The serum levels of sodium and potassium did not also change significantly at 12 weeks compared with baseline in either the ARB/TZ group (sodium; 142 6 3 mEq/L–140 6 3 mEq/L, potassium; 4.3 6 0.4 mEq/L–4.3 6 0.5 mEq/L) or the ARB/CCB group (sodium; 141 6 6 mEq/L–142 6 2 mEq/L, potassium; 4.4 6 0.5 mg/dL– 4.3 6 0.5 mg/dL). Similarly, uric acid levels did not change significantly at 12 weeks compared with baseline in either the ARB/TZ group (6.0 6 1.7 mg/dL–6.4 6 1.9 mg/dL) or the ARB/CCB group (5.5 6 1.5 mg/dL–5.6 6 1.5 mg/dL).
Primary Analysis In all 87 patients, SBP and DBP decreased after switching to combination pills, regardless of treatment group (Figure 1A). Although the magnitude of the SBP reduction was similar in each group, the magnitude of DBP reduction was greater in patients receiving ARB/CCB treatment, compared with patients receiving ARB/TZ treatment (11 6 10 mm Hg versus 6 6 12 mm Hg, P 5 0.027 at 4 weeks; 12 6 11 mm Hg versus 5 6 11 mm Hg, P 5 0.011 at 8 weeks; 13 6 11 mm Hg versus 7 6 9 mm Hg, P 5 0.015 at 12 weeks, respectively) (Figure 1B). The values of HbA1c and LDL cholesterol did not change significantly at 12 weeks compared with baseline in either the ARB/TZ group (HbA1c; 5.6% 6 1.2%–5.7% 6 1.2%, LDL
Subgroup Analysis Based on Estimated Daily Salt Intake Among the 87 patients enrolled in the study, 47 were found to have a baseline estimated daily salt intake greater than 10 g (29 men and 18 women, aged 64 6 10 years) (Figures 1C and 1D). In this subgroup of patients, the magnitude of DBP reduction was greater in patients receiving ARB/ CCB treatment (n 5 21) than in those receiving ARB/TZ treatment (n 5 26) (14 6 12 mm Hg versus 5 6 13 mm Hg, respectively, P 5 0.019 at 4 weeks; 16 6 12 mm Hg versus 5 6 13 mm Hg, respectively, P 5 0.010 at 8 weeks; 16 6 12 mm Hg versus 8 6 10 mm Hg, respectively, P 5 0.021 at 12 weeks, P for interaction 5 0.843). The magnitude
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FIGURE 1. A, Serial change in blood pressure in all study participants (n 5 87). Baseline diastolic blood pressure (DBP) was significantly higher in the angiotensin receptor blocker (ARB)/calcium channel blocker (CCB) treatment group (n 5 49), compared with the ARB/thiazide diuretic (TZ) treatment group (n 5 38). Although baseline systolic blood pressure (SBP) tended to be lower in the ARB/ TZ group, this difference was not statistically significant. After the introduction of combination therapy, both groups demonstrated a time-dependent decrease in SBP and DBP (black and white circles indicate ARB/TZ and ARB/CCB treatment groups, respectively). B, Blood pressure reduction in all study participants. Although SBP reduction was similar in both groups, DBP reduction was greater in the ARB/CCB group than in the ARB/TZ group (black and white arrows indicate ARB/TZ and ARB/CCB treatment groups, respectively). C, Serial changes in blood pressure in patients with baseline estimated daily salt intake greater than 10 g (n 5 47). Baseline blood pressure was higher in the ARB/CCB group compared with the ARB/TZ group. D, Blood pressure reduction in patients with baseline estimated daily salt intake greater than 10 g. DBP reduction was greater in the ARB/CCB treatment group than in the ARB/TZ treatment group, whereas SBP reduction was similar in both groups.
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of SBP reduction was similar in both groups (Figure 1D). It was noted, however, that among patients in this subgroup, baseline blood pressure was higher in the ARB/CCB group compared with the ARB/TZ group (SBP: 166 6 17 mm Hg versus 157 6 19 mm Hg, respectively, P 5 0.050, P for interaction 5 0.652; DBP: 96 6 12 mm Hg versus 85 6 12 mm Hg, respectively, P 5 0.0031, P for interaction 5 0.437) (Figure 1C). The authors therefore further analyzed data from the 37 patients (21 men and 16 women, aged 64 6 10 years) with baseline estimated daily salt intake over 10 g and baseline SBP ranging from 150 to 200 mm Hg. In this subgroup analysis, baseline blood pressure was similar among patients who received either combination therapy (Figure 2). In this limited patient set, SBP at 4 weeks was lower in the ARB/TZ group (n 5 15) compared with the ARB/CCB group (n 5 22) (130 6 12 mm Hg versus 141 6 17 mm Hg, respectively, P 5 0.025, P for interaction 5 0.261) (Figure 2A). Consequently, the magnitude of SBP reduction at 4 weeks was greater in the ARB/TZ group compared with the ARB/CCB group (35 6 17 mm Hg versus 24 6 17 mm Hg, respectively, P 5 0.048, P for interaction 5 0.236). At 8 and 12 weeks, however, the reduction in SBP was comparable in both groups (Figure 2B). Notably, the estimated daily salt intake in this subgroup decreased at 12 weeks compared with baseline (ARB/TZ group: 12.0 6 1.4 g/d–9.4 6 2.7 g/d, P 5 0.0039; ARB/CCB group: 12.0 6 1.6 g/d–10.3 6 2.2 g/d, P 5 0.0062) (Figure 2C). The authors next analyzed data from 31 patients (21 men and 10 women, aged 62 6 15 years) whose estimated daily salt intake increased at 12 weeks compared with baseline (Figure 3). In this subgroup of patients, the estimated daily salt intake increased from 9.1 6 2.6 g/d to 12.0 6 3.2 g/d (P , 0.0001) in the ARB/TZ group (n 5 10) and from 9.1 6 2.0 g/d to 11.0 6 2.2 g/d (P 5 0.0015) in the ARB/CCB group (n 5 21) (Figure 3C). Although baseline SBP was similar in both groups, the SBP 12 weeks after starting combination therapy was lower in the ARB/TZ group compared with the ARB/CCB group (131 6 8 mm Hg versus 139 6 10 mm Hg, respectively, P 5 0.022, P for interaction 5 0.302) (Figure 3A). Although SBP reduction seemed to be greater at 8 and 12 weeks in the ARB/TZ group compared with the ARB/CCB group, the differences did not reach statistical significance (Figure 3B).
In the subgroup of 47 patients with the baseline estimated daily salt intake greater than 10 g, the serum levels of sodium and potassium did not also change significantly at 12 weeks compared with baseline in either the ARB/TZ group (sodium: 142 6 3 mEq/L–140 6 4 mEq/L; potassium: 4.4 6 0.3 mEq/L–4.2 6 0.5 mEq/L) or the ARB/CCB group (sodium: 141 6 2 mEq/L– 142 6 2 mEq/L; potassium: 4.4 6 0.4 mg/dL–4.2 6 0.5 mg/dL). Further Subgroup Analysis Next, the authors performed further subgroup analyses as an exploratory manner (post hoc). Of the 87 patients enrolled in the study, 44 were observed to have visceral fat-type obesity (34 men and 10 women, aged 62 6 13 years). Serial blood pressure measurements in this subgroup revealed that baseline blood pressure was similar in patients receiving ARB/TZ (n 5 18) versus ARB/CCB treatment (n 5 26), but SBP at 4 weeks was lower in the ARB/TZ group than in the ARB/CCB group (130 6 12 mm Hg versus 144 6 17 mm Hg, respectively, P 5 0.0079, P for interaction 5 0.506). Consequently, the magnitude of SBP reduction at 4 weeks was greater in the ARB/TZ group than in the ARB/CCB group (28 6 19 mm Hg versus 18 6 15 mm Hg, respectively, P 5 0.049, P for interaction 5 0.427) (Figures 4A and 4B). Finally, the authors analyzed changes in blood pressure in 35 patients (21 men and 14 women, aged 65 6 13 years) with CKD. Although blood pressure reduction seemed to be greater in the ARB/CCB group compared with the ARB/TZ group, the difference did not reach statistical significance (Figures 4C and 4D).
DISCUSSION In this study, the authors compared the add-on blood pressure lowering effects of TZ and CCB medications in patients who did not reach blood pressure goals with ARB treatment alone. The blood pressure was found to be significantly decreased in patients receiving either ARB/TZ or ARB/ CCB combination therapy. Among all 87 patients enrolled in the study, DBP reduction was stronger in patients receiving ARB/CCB treatment compared with those receiving ARB/TZ treatment. SBP reduction was comparable in both groups.
FIGURE 2. A, Serial blood A B C pressure measurements in pag/day SBP mmHg 200 0 15 tients with baseline estimated daily salt intake greater than 10 g 10 and baseline systolic blood SBP 164 ** 20 pressure (SBP) between 150 and 12.0 164 200 mm Hg (n 5 37). Baseline 150 24 30 141 12.0 133 blood pressure was similar in 136 31 29 32 33 35 40 patients receiving either angio10.3 130 134 132 10 tensin receptor blocker/thiazide 50 P=0.048 diuretic (ARB/TZ) or ARB/cal9.4 DBP P=0.025 0 cium channel blocker (CCB) 100 91 P=0.0062 vs baseline * 83 combination therapy, but SBP at 81 86 78 5 ** P=0.0039 vs baseline 4 weeks was lower in the ARB/ 77 78 78 TZ group. B, Blood pressure * 10 9 9 8 12 8 7 DBP reduction in patients with base50 5 line estimated daily salt intake mmHg 8W 4W baseline 4W 8W 12W 12W baseline 12W greater than 10 g and baseline SBP between 150 and 200 mm Hg. SBP reduction at 4 weeks was greater in the ARB/TZ group compared with the ARB/CCB group. At 8 and 12 weeks, SBP and diastolic blood pressure (DBP) reduction was similar in both groups. C, Change in estimated daily salt intake between baseline and 12 weeks in patients with baseline estimated daily salt intake greater than 10 g and baseline SBP between 150 and 200 mm Hg. In both the ARB/TZ and the ARB/CCB groups, the estimated daily salt intake decreased at 12 weeks compared with baseline (black circles and arrows indicate ARB/TZ group, and white circles and arrows indicate ARB/CCB groups). Copyright © 2015 by the Southern Society for Clinical Investigation.
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FIGURE 3. A, Serial blood pressure measurements in pa200 tients with an increased estimated daily salt intake at 12 ** 15 10 weeks compared with baseline SBP (n 5 31). Although baseline 158 20 17 16 12.0 systolic blood pressure (SBP) 159 18 150 18 140 was similar in both groups, SBP 136 139 30 at 12 weeks was lower in the 28 28 142 134 angiotensin receptor blocker/ 131 40 10 thiazide diuretic (ARB/TZ) group 11.0 DBP 9.1 P=0.022 compared with the ARB/calcium 0 100 94 9.1 * channel blocker (CCB) group. B, 87 85 88 88 5 Blood pressure reduction in pa3 4 83 84 tients with an increased esti86 * P=0.0015 vs baseline 10 8 8 mated daily salt intake at 12 P<0.0001 vs baseline DBP 10 ** 10 50 5 weeks compared with baseline. mmHg 4W 8W 12W baseline 4W 8W 12W Although SBP reduction seemed baseline 12W to be greater in the ARB/TZ group at 8 and 12 weeks relative to the ARB/CCB group, the difference did not reach statistical significance. C, Changes in estimated daily salt intake in patients with an increased estimated daily salt intake at 12 weeks compared with baseline. The estimated daily salt intake increased in both the ARB/TZ and ARB/CCB groups (black circles and arrows indicate ARB/TZ group, and white circles and arrows indicate ARB/CCB groups).
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FIGURE 4. A, Serial blood pressure measurements in patients with visceral fat-type obesity (n 5 44) treated with either angiotensin receptor blocker/calcium channel blocker (ARB/CCB) or ARB/thiazide diuretic (TZ) combination therapy. Baseline blood pressure was equivalent in both groups, but at 4 weeks, systolic blood pressure (SBP) was lower in the ARB/TZ group compared with the ARB/CCB group. B, Blood pressure reduction in patients with visceral fat-type obesity. SBP reduction at 4 weeks was greater in the ARB/TZ group compared with the ARB/CCB group. C, Serial blood pressure changes in patients with chronic kidney disease (CKD) (n 5 35) treated with either ARB/CCB or ARB/TZ combination therapy. Although baseline blood pressure seemed to be higher in the ARB/CCB group compared with the ARB/TZ group, this difference did not reach statistical significance. D, Blood pressure reduction in patients with CKD. Although blood pressure reduction seemed to be greater in the ARB/CCB group compared with the ARB/TZ group, this difference did not reach statistical significance (black circles and arrows indicate ARB/TZ group, and white circles and arrows indicate ARB/CCB groups).
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receiving ARB/TZ treatment compared with those receiving ARB/CCB treatment. Furthermore, patients with visceral fattype obesity who were treated with ARB/TZ were found to have a greater reduction in SBP at 4 weeks than those who were treated with ARB/CCB. Finally, ARB/CCB and ARB/ TZ combination therapy produced comparable blood pressure reduction in patients with CKD, although the reduction tended to be greater in patients receiving ARB/CCB treatment. The ACCOMPLISH trial demonstrated a stronger cardiovascular risk reduction in patients who received ACEI/CCB compared with those who received ACEI/TZ combination therapy. This result is thought to be due to the enhanced blood pressure–lowering effects of ACEI/CCB treatment. It has remained unclear whether similar blood pressure and cardiovascular risk reduction would be observed if CCBs and TZs were combined with other RAS inhibitors. Several studies have found that ARB/CCB and ARB/TZ combinations have similar blood pressure–lowering effects.13,14 It has been suggested that the ARB/ CCB combination is a more effective antihypertensive therapy in elderly patients.15,16 In contrast, Nishiwaki et al17 demonstrated that the ARB/TZ combination is more effective at reducing SBP. Patients in the study by Nishiwaki et al were found to have a lower cardiovascular risk compared with patients in the ACCOMPLISH trial. In elderly patients and in patients at high risk for atherosclerotic cardiovascular diseases, CCBs might be more effective antihypertensive agents given their ability to cause vasodilation and decreased arterial stiffness. In this study, patients who had cardiovascular complications, such as coronary artery disease, heart failure and/or cerebrovascular disease, were excluded, and the authors were unable to test this hypothesis. Nevertheless, when data from all 87 of the study participants were analyzed, the authors found that the ARB/CCB combination produced a greater reduction in DBP than did the ARB/TZ combination. It is possible that the mixed findings of the previous studies are due to the synergistic effect of ARB/TZ combination therapy in patients with high salt intake.18 Recently, Hasegawa et al19 demonstrated that estimated salt excretion predicts the efficacy of ARB/TZ treatment in patients with ARB resistance, suggesting that the ARB/TZ combination might be preferable in patients with high salt intake. This study was the 1st to compare the antihypertensive effects of ARB/TZ and ARB/CCB combination therapy on the basis of patients’ salt intake. In patients with SBP between 150 and 200 mm Hg and a baseline salt intake greater than 10 g/d, short-term blood pressure reduction was found to be greater in those receiving ARB/TZ combination therapy compared with those receiving ARB/CCB combination therapy. In addition, in patients who demonstrated an increased salt intake over the course of the study, the antihypertensive effect of the ARB/TZ combination was stronger than that of the ARB/CCB combination. These results suggest that estimated daily salt intake may help to determine which medication will be more efficacious as add-on therapy to ARB treatment alone. Furthermore, estimated daily salt intake should be measured repeatedly during the therapeutic course. It has been suggested that the ARB/TZ combination is a rational therapeutic choice in patients with the metabolic syndrome, as these patients are salt sensitive and demonstrate accelerated RAA system activity. Ibuki et al20 recently used an ambulatory blood pressure monitoring system to demonstrate that the ARB/TZ combination leads to a greater reduction in nocturnal blood pressure in obese hypertensive patients than in nonobese patients. Similarly, in patients with visceral fat-type obesity, which can be considered a surrogate for the metabolic syndrome or premetabolic syndrome, ARB/TZ combination therapy was found to lead to greater short-term reduction in blood pressure than did ARB/CCB combination therapy. Copyright © 2015 by the Southern Society for Clinical Investigation.
It has been widely established that inhibition of the RAA system by ARBs or ACEIs confers cardiovascular protection in hypertensive patients with CKD21,22 and is the 1st-line therapeutic strategy in Western countries23,24 and in Japan.4 However, in those patients with CKD in whom RAA system inhibition alone does not provide sufficient antihypertensive effects, it has been unclear whether TZs or CCBs should be selected as add-on therapy. Subgroup analysis of hypertensive patients with CKD in the ACCOMPLISH trial revealed that treatment with the ACEI/CCB combination was associated with a decreased incidence of renal events compared with treatment with the ACEI/TZ combination.25 In elderly hypertensive patients with CKD, the ARB/CCB combination provided more effective blood pressure reduction and was associated with fewer cardiovascular events, compared with an increased dose of ARBs.26 Furthermore, the ARB/CCB combination has been reported to be more effective than the ARB/TZ combination in decreasing blood pressure in hypertensive patients with CKD.27 Similarly, the authors observed more robust antihypertensive effects with ARB/CCB treatment than with ARB/TZ treatment in patients with hypertension and CKD. Study Limitations There are several potential limitations in this study. First, the study included a small sample size, so this trial was not adequately powered, especially with subgroup analyses. In the subgroup analysis, different patients’ number and baseline SBP between 2 groups of each combination pill may have biased the findings of this study regarding the magnitude of blood pressure reduction. In fact, this study has inherent limitations of subgroup analyses in randomized controlled trials, such as reduced statistical power, failure to specify the subgroup of interest a priori, failure to account for examining large numbers of subgroups, lack of strong rationale for biological response modification and performing analyses based on variables measured postrandomization or in trials showing no overall difference between treatments. Next, the end point of this study was blood pressure reduction, but not onset of cardiovascular events. In more recent subgroup analysis of the ACCOMPLISH trial, a higher event rate was shown in the ACEI/TZ treatment group, compared with the ARB/CCB treatment group, although there was a trend on ambulant blood pressure monitoring to have a lower BP in the ACEI/TZ treatment group.28 So future studies should additionally assess cardiovascular morbidity and mortality in high salt diet patients as therapeutic targets. Finally, the subjects of this study were Japanese population, many of whom are considered to be salt sensitive, similarly to African. Furthermore, Japanese diet is known to be one of the highest in the world for sodium intake, so the results of this study can not necessarily be generalized to the United States or Europe. Pathogenesis of salt-sensitive hypertension is heterogeneous and the effect of dietary salt intake on blood pressure may be related to several genetic polymorphisms, such as genes of RAA system, aldosterone synthase and cytochrome p450. The direction of BP lowering in high salt intake participants as a group may not be extrapolated to care of individual patients. High salt intake individuals with TZs-sensitive Na+-Cl-cotransporter (NCC)-mediated salt-sensitive hypertension may respond to TZs better than other high salt-intake individuals.29
CONCLUSIONS In patients with moderate hypertension and high salt intake, ARB/TZ combination therapy produces greater shortterm blood pressure reduction than does ARB/CCB combination therapy. Estimated daily salt intake can help guide the
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choice of add-on therapy to ARB treatment alone and should be measured repeatedly during the therapeutic course. ACKNOWLEDGMENTS The authors acknowledge those additional physicians who participated in patient enrollment and follow-up: Naoyuki Otani, Takahisa Nasuno, Isao Taguchi (Dokkyo Medical University), Koetsu Anraku (Utsunomiya Higashi Hospital), Yoshihisa Takada (Takada Clinic), Nobuhiko Nakayama (Nakayama Medical and Cardiovascular Clinic), Akira Fujinuma (Fujinuma Clinic) and Hirotada Maezawa (Maezawa Medical Clinic). They also thank Mikie Ogawa, Research Associate in the Department of Cardiovascular Medicine, Dokkyo Medical University, for her efforts in data acquisition and technical support and Kiyoso Yamagata, Statistical Analysis Section, Kureha Special Laboratory Co, Ltd, for his assistance with statistical analysis. REFERENCES 1. Siragy HM, Bedigian M. Mechanism of action of angiotensin-receptor blocking agent. Curr Hypertens Rep 1999;1:289–95. 2. Siragy HM. AT(1) and AT(2) receptors in the kidney: role in disease and treatment. Am J Kidney Dis 2000;36(suppl 1):S4–9. 3. Weir MR, Dzau VJ. The rennin-angiotensin-aldosterone system: a specific target for hypertension management. Am J Hypertens 1999;12:205S–13S. 4. Ogihara T, Kikuchi K, Matsuoka H, et al. The Japanese Society of Hypertension guidelines for the management of hypertension (JSH 2009). Hypertens Res 2009;32:3–107. 5. Jamerson K, Weber MA, Bakins GL, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertention in high risk patients. N Engl J Med 2008;359:2417–28. 6. Zhou MS, Jaimes EA, Raij L. Benazepril combined with either amlodipine or hydrochlorothiazide is more effective than monotherapy for blood pressure control and prevention of end-organ injury in hypertensive Dahl rats. J Cardiovasc Pharmacol 2006;48:857–61. 7. Engeli S, Böhnke J, Gorzelniak K, et al. Weight loss and the renninangiotensin-aldosteron system. Hypertension 2005;45:356–62. 8. Uzu T, Kimura G, Yamaguchi A, et al. Enhanced sodium sensitivity and disturbed circadian rhythm of blood pressure in essential hypertension. J Hypertens 2006;24:1627–32. 9. Hoffmann IS, Cubeddu LX. Increased blood pressure reactivity to dietary salt in patients with metabolic syndrome. J Hum Hypertens 2007;21:438–44.
losartan/hydrochlorothiazide vs. candesartan/amlodipine. Hypertens Res 2007;30:831–7. 15. Kato J, Yokota N, Tamaki N, et al. Comparison of combination therapies, including the angiotensin receptor blocker olmesartan and either a calcium channel blocker or a thiazide diuretics, in elderly patients with hypertension. Hypertens Res 2011;34:331–5. 16. Matsui Y, Eguchi K, O’Rourke MF, et al. Differential effects between a calcium channel blocker and a diuretic when used in combination with angiotensin II receptor blocker on central aortic pressure in hypertensive patients. Hypertension 2009;54:716–23. 17. Nishiwaki M, Hosoai H, Ikewaki K, et al. Efficacy and effects on lipid metabolism of combination treatment with losartan + hydrochlorothiazide versus losartan + amlodipine: a 48-week prospective, multicenter, randomized, open-label trial. Clin Ther 2013;35:461–73. 18. Zhou BF, Stamler J, Dennis B, et al. Nutrient intakes of middleaged men and women in China, Japan, United Kingdom, and United States in the late 1990s: the INTERMAP study. J Hum Hypertens 2003;17:623–30. 19. Hasegawa H, Kanozawa K, Asakura J, et al. Significance of estimated salt excretion as a possible predictor of the efficacy of concomitant angiotensin receptor blocker (ARB) and low-dose thiazyde in patients with ARB resistance. Hypertens Res 2013;36:776–82. 20. Ibuki C, Seino Y, Otsuka T, et al. The fixed-dose combination of losartan/hydrochlorothiazide elicits potent blood pressure lowering during nighttime in obese hypertensive patients. J Clin Med Res 2014;6:8–16. 21. Ruilope LM, Salvetti A, Jamerson K, et al. Renal function and intensive lowering of blood pressure in hypertensive participants of the hypertension optimal treatment (HOT) study. J Am Soc Nephrol 2001;12:218–25. 22. Solomon SD, Rice MM, A Jablonski K, et al. Prevention of events with ACE inhibition (PEACE) Investigators. Renal function and effectiveness of angiotensin-converting enzyme inhibitor therapy in patients with chronic stable coronary disease in the prevention of events with ACE inhibition (PEACE) trial. Circulation 2006;114:26–31. 23. Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Hypertension 2003;42:1206–52. 24. Mancia G, De Backer G, Dominiczak A, et al. 2007 Guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J 2007;28: 1462–536.
10. Matsuo S, Imai E, Horio M, et al. Revised equation for estimating glomerular filtration rate (GFR) from serum creatinin in Japan. Am J Kidney Dis 2009;53:982–92.
25. Bakris GI, Sarafidis PA, Weir MR, et al. Renal outcomes with different fixed-dose combination therapies in patients with hypertension at high risk for cardiovascular events (ACCOMPLISH): a predispecified secondary analysis of a randomized controlled trial. Lancet 2010;375:1173–81.
11. Sarnak MJ, Levey AS, Schoolwerth AC, et al. Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Circulation 2003;108:2154–69.
26. Kim-Mitsuyama S, Ogawa H, Matsui K, et al. An angiotensin II receptor blocker-calcium channel blocker combination prevents cardiovascular events in elderly high-risk hypertensive patients with chronic kidney disease better than high-dose angiotensin II receptor blockade alone. Kidney Int 2012;83:167–76.
12. Kawano Y, Tsuchihashi T, Matsuura H, et al. Report of the working group for dietary salt reduction of the Japanese Society of Hypertension: (2) assessment of salt intake in the management of hypertension. Hypertens Res 2007;30:887–93.
27. Ishimitsu T, Ohno E, Nakano N, et al. Combination of angiotensin II receptor antagonist with calcium channel blocker or diuretic as antihypertensive therapy for patients with chronic kidney disease. Clin Exp Hypertens 2011;33:366–72.
13. Ishimitsu T, Numabe A, Masuda T, et al. Angiotensin-II receptor antagonist combined with calcium channel blocker or diuretic for essential hypertension. Hypertens Res 2009;32:962–8.
28. Jamerson KA, Devereux R, Bakris GL, et al. Efficacy and duration of benazepril plus amlodipine or hydrochlorothiazide on 24-hr ambulatory systolic blood pressure control. Hypertension 2011;57:174–9.
14. Shimosawa T, Gohchi K, Yatomi Y, et al. Effectiveness of add-on low-dose diuretics in combination therapy for hypertension:
29. Sanada H, Jones JE, Jose PA. Genetics of salt-sensitive hypertension. Curr Hypertens Rep 2011;13:55–66.
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Choice of Antihypertensive Combination Therapy Based on Daily Salt Intake Shigeru Toyoda, MD, PhD, Shu Inami, MD, PhD, Toru Kato, MD, PhD, Kinji Tsukada, MD, PhD, Akiya Nakamoto, MD, PhD, Yoshinobu Kikegawa, MD, PhD, Akihiro Suzuki, MD, PhD, Yukitaka Anraku, MD, PhD, Koichi Node, MD, PhD and Teruo Inoue, MD, PhD
Abstract: Background: It is unclear whether thiazide diuretics (TZs) or calcium channel blockers (CCBs) are more effective as add-on therapy to angiotensin receptor blockers (ARBs) in controlling hypertension. Because TZs are a rational choice in salt-sensitive hypertension, patients with high salt intake might preferentially benefit from ARB/TZ over ARB/CCB combination therapy. Methods: Hypertensive patients who failed to reach blood pressure goals despite treatment with ARBs alone were randomly assigned to receive either ARB/TZ or ARB/CCB combination therapy. Estimated daily sodium intake was calculated from spot urine values of sodium and creatinine. Results: Blood pressure was measured at baseline, and at 4, 8 and 12 weeks after starting combination therapy. For all study patients (n 5 87), diastolic blood pressure reduction was greater in patients receiving ARB/CCB treatment. However, in the 37 patients with a baseline estimated daily salt intake greater than 10 g and baseline systolic blood pressure (SBP) ranging from 150 to 200 mm Hg, SBP was lower (P , 0.05) and SBP reduction was greater (P , 0.05) 4 weeks after starting combination therapy in those receiving ARB/TZ treatment. In the 31 patients whose estimated daily salt intake increased at 12 weeks compared with baseline, SBP at 12 weeks was lower in those receiving ARB/TZ treatment (P , 0.05). Conclusions: Estimated daily salt intake is a useful tool for guiding antihypertensive therapy and should be measured repeatedly during the therapeutic course.
compliance. However, it has yet to be determined which drug class, the TZs or the CCBs, is more efficacious as add-on therapy to ARBs in controlling hypertension. The Avoiding Cardiovascular Events Through COMbination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial found that cumulative 5-year composite cardiovascular events were 20% lower in high-risk hypertensive patients treated with an ACEI/CCB combination, compared with those treated with an ACEI/TZ combination. This finding may have been due to the greater antihypertensive effect of the ACEI/CCB combination relative to the ACEI/TZ combination.5 However, it has been suggested that TZs should be more effective in salt-sensitive hypertension.6 Because RAA system activity is accelerated in patients with the metabolic syndrome,7 the RAS inhibitors, ARB and ACEI, are considered the agent of choice in these patients. However, the metabolic syndrome is often complicated by salt-sensitive hypertension.8,9 Therefore, the ARB/TZ combination might be a rational therapeutic choice in patients with the metabolic syndrome and salt-sensitive hypertension. This study was designed to test which of the combination treatment is better on a high salt diet intake to lower blood pressure, ARB/TZ or ARB/CCB.
Key Indexing Terms: Angiotensin receptor blockers; Thiazide diuretics; Calcium channel blockers; Combination pills; Daily salt intake. [Am J Med Sci 2015;350(3):160–166.]
METHODS
R
ecent evidence suggests that strict blood pressure control can improve cardiovascular morbidity and mortality in patients with hypertension. Angiotensin II type 1 (AT1) receptor blockers (ARBs), which act by selectively blocking the binding of angiotensin II to the AT1 receptor, are widely used in the treatment of hypertension.1–3 To achieve strict blood pressure control, the Japanese Society of Hypertension (JSH) guidelines4 recommend combination therapy with multiple antihypertensive agents, including rennin-angiotensin-aldosterone (RAA) system inhibitors such as angiotensin converting enzyme inhibitors (ACEIs) and ARBs. Recently, various ARB combination pills have been developed, including ARBs combined with thiazide diuretics (TZs) and calcium channel blockers (CCBs). One benefit of combination medications is increased patient From the Department of Cardiovascular Medicine (ST, SI, TI), Dokkyo Medical University, Mibu, Japan; Department of Clinical Research (TK), National Hospital Organization, Tochigi Medical Center, Utsunomiya, Japan; Tochigi Medical Association (ST, KT, AN, YK, AS, YA, TI), Utsunomiya, Japan; and Department of Cardiovascular Medicine (KN), Saga University, Saga, Japan. Submitted January 8, 2015; accepted in revised form June 2, 2015. The authors have no financial or other conflicts of interest to disclose. Correspondence: Shigeru Toyoda, MD, PhD, Department of Cardiovascular Medicine, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Tochigi 321-0293, Japan (E-mail: [email protected]).
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Study Design This study was designed as a prospective randomized trial. Recruited were 107 hypertensive patients who did not achieve blood pressure goals, defined as systolic blood pressure (SBP) ,140 mm Hg or diastolic blood pressure (DBP) ,90 mm Hg, despite treatment with ARBs alone for over 4 weeks. Patients were recruited in 8 clinics belonging to the Tochigi Medical Association and in 5 hospitals in Tochigi prefecture and its surrounding areas. Patients with cardiovascular diseases, such as coronary artery disease, heart failure or cerebrovascular disease, were excluded. All patients were randomly assigned to switch from ARBs into either an ARB/TZ (80 mg valsartan/12.5 mg hydrochlorothiazide) combination pill or an ARB/CCB (80 mg valsartan/5 mg amlodipine) combination pill. Study end point was the changes in blood pressure from the baseline values to the values after switching into each combination pills during the 12 weeks’ observation period. After primary analysis in overall patients, subgroup analysis based on estimated daily salt intake was proposed before the data correction (a priori analysis). The study protocol was approved by the local medical ethics committees and informed consent was obtained from all patients. Measurements Blood pressure and heart rate were measured at baseline and at 4, 8 and 12 weeks after starting combination therapy. After the patient rested in the seated position for 5 minutes,
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TABLE 1. Baseline characteristics Age (yr) Male gender, n (%) Heart rate/min Body mass index (kg/m2) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Medications Statins Antidiabetic agents Hemoglobin A1c (%) Total cholesterol (mg/dL) LDL cholesterol (mg/dL) Triglyceride (mg/dL) Na (mEq/L) K (mEq/L) Creatinine (mg/dL) eGFR (mL$min21$1.73 m22) Urinary albumin (mg/g$Cr) Uric acid (mg/dL) Estimated daily salt intake (g)
ARB/TZ group (n 5 38)
ARB/CCB group (n 5 49)
P
67 6 13 22 (58) 73 6 11 24 6 3 156 6 17 86 6 12
62 6 13 26 (53) 75 6 11 26 6 7 162 6 19 95 6 13
0.09 0.48 0.66 0.91 0.13 0.0005
10 (26) 7 (18) 5.6 6 1.2 206 6 44 132 6 34 142 6 72 142 6 3 4.3 6 0.4 0.78 6 0.24 76 6 18 28 6 32 6.0 6 1.7 10.6 6 3.7
14 (29) 10 (20) 5.4 6 0.5 196 6 35 118 6 33 143 6 79 141 6 6 4.4 6 0.5 0.76 6 0.17 76 6 17 28 6 40 5.5 6 1.5 9.8 6 3.1
0.63 0.72 0.14 0.22 0.06 0.95 0.34 0.28 0.65 0.96 0.99 0.17 0.30
ARB, angiotensin receptor blocker; CCB, calcium channel blocker; eGFR, estimated glomerular filtration rate; LDL, low-density lipoprotein; TZ, thiazide diuretics.
blood pressure was measured twice, with an interval of at least 5 minutes between each measurement. Blood pressure was measured in the same arm at each visit using a mercury sphygmomanometer with an appropriately sized cuff and recorded to the nearest 2 mm Hg. Height, weight, waist circumference and body mass index (BMI) were measured at baseline. The authors defined visceral fat-type obesity as a waist circumference greater than 85 cm for men and greater than 90 cm for women. Blood and urine testing was performed at baseline and at 12 weeks. Serum creatinine levels were measured using an enzymatic method, and the estimated glomerular filtration rate (eGFR) was calculated by a formula provided by the Japanese Society of Nephrology Chronic Kidney Disease (CKD) Practice Guide: eGFR (mL$min21$1.73 m22) 5 194 3 (serum creatinine level [mg/dL])21.094 3 (age [y])20.287. The product of this equation was multiplied by a correction factor of 0.739 for women.10 Spot urinary albumin levels were determined using a turbidimetric immunoassay and were multiplied by the urine creatinine level (enzymatic method). The authors defined CKD as eGFR less than 60 mL$min21$1.73 m22 and/or urinary albumin level greater than 30 mg/g$Cr.11 Serum uric acid levels were determined by the uricase peroxidase method, and serum levels of sodium and potassium were measured by the electrode method. Total cholesterol and triglyceride levels were determined using enzymatic methods, HDL cholesterol was measured using the precipitation method and low-density lipoprotein (LDL) cholesterol was calculated using the Friedewald formula: LDL cholesterol 5 total cholesterol 2 HDL cholesterol 2 (triglyceride/5). LDL-cholesterol could not be calculated for those patients with a triglyceride level over 400 mg/dL. Hemoglobin (Hb) A1c was measured by high-performance liquid chromatography and values were expressed according to the National Glycohemoglobin Standardization Program. Copyright © 2015 by the Southern Society for Clinical Investigation.
Serum and urinary levels of sodium and potassium were measured by the electrode method. The estimated 24-hour sodium excretion was calculated from spot urine levels of sodium (mEq/L) and creatinine (mg/L) according to the following formula: estimated 24-hour sodium excretion (mEq/d) 5 21.98 3 ([sodium/creatinine]/10 3 estimated 24-hour urinary creatinine excretion)0.392, where the estimated 24-hour urinary creatinine excretion 5 22.04 3 age (y) + 14.89 3 body weight (kg) + 16.14 3 height (cm) 2 2,244.45. The estimated 24-hour sodium excretion was converted into the estimated daily sodium intake according to the following formula: estimated daily sodium intake (g/d) 5 estimated 24-hour sodium excretion (mEq/d) 3 0.0585.12 Data Analysis Data are expressed as mean 6 SD. The authors 1st assessed the normal distribution of each variable using the Kolmogorov-Smirnov test with Lilliefor’s correlation. The distribution of all values was parametric; hence, changes between baseline values and values 12 weeks after treatment initiation were assessed by the paired t test. Serial changes in blood pressure were assessed by repeated measures analysis of variance (ANOVA). Comparisons between 2 groups were assessed by the unpaired t test. In subgroup analysis, a test of interaction for assessing subgroup treatment effects was performed. A P value ,0.05 was considered statistically significant.
RESULTS Of all patients recruited for the study, 87 had complete data sets and were thus included in the study (57 men and 30 women, aged 64 6 13 years). Study patients were randomly assigned to receive either the ARB/TZ combination pill (38 patients including 27 men and 11 women, aged 67 6 13 years) or the ARB/CCB combination pill (49 patients including
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30 men and 19 women, aged 62 6 13 years). Baseline characteristics of both groups are shown in Table 1. Baseline DBP was significantly higher in patients receiving ARB/CCB treatment compared with those receiving ARB/TZ treatment (P 5 0.0005). Although SBP tended to be lower and LDL cholesterol level tended to be higher in the ARB/TZ group compared with the ARB/CCB group, differences between the 2 groups were not statistically significant. Age, gender, heart rate, BMI, renal function, serum levels of sodium, potassium and uric acid, HbA1c and lipid profile (excluding LDL cholesterol level) were comparable between the 2 groups. The baseline estimated daily sodium intake was also similar between the 2 groups.
cholesterol; 132 6 34 mg/dL–124 6 32 mg/dL) or the ARB/ CCB group (HbA1c; 5.4% 6 0.5%–5.4% 6 0.5%, LDL cholesterol; 118 6 33 mg/dL–111 6 27 mg/dL). The serum levels of sodium and potassium did not also change significantly at 12 weeks compared with baseline in either the ARB/TZ group (sodium; 142 6 3 mEq/L–140 6 3 mEq/L, potassium; 4.3 6 0.4 mEq/L–4.3 6 0.5 mEq/L) or the ARB/CCB group (sodium; 141 6 6 mEq/L–142 6 2 mEq/L, potassium; 4.4 6 0.5 mg/dL– 4.3 6 0.5 mg/dL). Similarly, uric acid levels did not change significantly at 12 weeks compared with baseline in either the ARB/TZ group (6.0 6 1.7 mg/dL–6.4 6 1.9 mg/dL) or the ARB/CCB group (5.5 6 1.5 mg/dL–5.6 6 1.5 mg/dL).
Primary Analysis In all 87 patients, SBP and DBP decreased after switching to combination pills, regardless of treatment group (Figure 1A). Although the magnitude of the SBP reduction was similar in each group, the magnitude of DBP reduction was greater in patients receiving ARB/CCB treatment, compared with patients receiving ARB/TZ treatment (11 6 10 mm Hg versus 6 6 12 mm Hg, P 5 0.027 at 4 weeks; 12 6 11 mm Hg versus 5 6 11 mm Hg, P 5 0.011 at 8 weeks; 13 6 11 mm Hg versus 7 6 9 mm Hg, P 5 0.015 at 12 weeks, respectively) (Figure 1B). The values of HbA1c and LDL cholesterol did not change significantly at 12 weeks compared with baseline in either the ARB/TZ group (HbA1c; 5.6% 6 1.2%–5.7% 6 1.2%, LDL
Subgroup Analysis Based on Estimated Daily Salt Intake Among the 87 patients enrolled in the study, 47 were found to have a baseline estimated daily salt intake greater than 10 g (29 men and 18 women, aged 64 6 10 years) (Figures 1C and 1D). In this subgroup of patients, the magnitude of DBP reduction was greater in patients receiving ARB/ CCB treatment (n 5 21) than in those receiving ARB/TZ treatment (n 5 26) (14 6 12 mm Hg versus 5 6 13 mm Hg, respectively, P 5 0.019 at 4 weeks; 16 6 12 mm Hg versus 5 6 13 mm Hg, respectively, P 5 0.010 at 8 weeks; 16 6 12 mm Hg versus 8 6 10 mm Hg, respectively, P 5 0.021 at 12 weeks, P for interaction 5 0.843). The magnitude
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FIGURE 1. A, Serial change in blood pressure in all study participants (n 5 87). Baseline diastolic blood pressure (DBP) was significantly higher in the angiotensin receptor blocker (ARB)/calcium channel blocker (CCB) treatment group (n 5 49), compared with the ARB/thiazide diuretic (TZ) treatment group (n 5 38). Although baseline systolic blood pressure (SBP) tended to be lower in the ARB/ TZ group, this difference was not statistically significant. After the introduction of combination therapy, both groups demonstrated a time-dependent decrease in SBP and DBP (black and white circles indicate ARB/TZ and ARB/CCB treatment groups, respectively). B, Blood pressure reduction in all study participants. Although SBP reduction was similar in both groups, DBP reduction was greater in the ARB/CCB group than in the ARB/TZ group (black and white arrows indicate ARB/TZ and ARB/CCB treatment groups, respectively). C, Serial changes in blood pressure in patients with baseline estimated daily salt intake greater than 10 g (n 5 47). Baseline blood pressure was higher in the ARB/CCB group compared with the ARB/TZ group. D, Blood pressure reduction in patients with baseline estimated daily salt intake greater than 10 g. DBP reduction was greater in the ARB/CCB treatment group than in the ARB/TZ treatment group, whereas SBP reduction was similar in both groups.
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of SBP reduction was similar in both groups (Figure 1D). It was noted, however, that among patients in this subgroup, baseline blood pressure was higher in the ARB/CCB group compared with the ARB/TZ group (SBP: 166 6 17 mm Hg versus 157 6 19 mm Hg, respectively, P 5 0.050, P for interaction 5 0.652; DBP: 96 6 12 mm Hg versus 85 6 12 mm Hg, respectively, P 5 0.0031, P for interaction 5 0.437) (Figure 1C). The authors therefore further analyzed data from the 37 patients (21 men and 16 women, aged 64 6 10 years) with baseline estimated daily salt intake over 10 g and baseline SBP ranging from 150 to 200 mm Hg. In this subgroup analysis, baseline blood pressure was similar among patients who received either combination therapy (Figure 2). In this limited patient set, SBP at 4 weeks was lower in the ARB/TZ group (n 5 15) compared with the ARB/CCB group (n 5 22) (130 6 12 mm Hg versus 141 6 17 mm Hg, respectively, P 5 0.025, P for interaction 5 0.261) (Figure 2A). Consequently, the magnitude of SBP reduction at 4 weeks was greater in the ARB/TZ group compared with the ARB/CCB group (35 6 17 mm Hg versus 24 6 17 mm Hg, respectively, P 5 0.048, P for interaction 5 0.236). At 8 and 12 weeks, however, the reduction in SBP was comparable in both groups (Figure 2B). Notably, the estimated daily salt intake in this subgroup decreased at 12 weeks compared with baseline (ARB/TZ group: 12.0 6 1.4 g/d–9.4 6 2.7 g/d, P 5 0.0039; ARB/CCB group: 12.0 6 1.6 g/d–10.3 6 2.2 g/d, P 5 0.0062) (Figure 2C). The authors next analyzed data from 31 patients (21 men and 10 women, aged 62 6 15 years) whose estimated daily salt intake increased at 12 weeks compared with baseline (Figure 3). In this subgroup of patients, the estimated daily salt intake increased from 9.1 6 2.6 g/d to 12.0 6 3.2 g/d (P , 0.0001) in the ARB/TZ group (n 5 10) and from 9.1 6 2.0 g/d to 11.0 6 2.2 g/d (P 5 0.0015) in the ARB/CCB group (n 5 21) (Figure 3C). Although baseline SBP was similar in both groups, the SBP 12 weeks after starting combination therapy was lower in the ARB/TZ group compared with the ARB/CCB group (131 6 8 mm Hg versus 139 6 10 mm Hg, respectively, P 5 0.022, P for interaction 5 0.302) (Figure 3A). Although SBP reduction seemed to be greater at 8 and 12 weeks in the ARB/TZ group compared with the ARB/CCB group, the differences did not reach statistical significance (Figure 3B).
In the subgroup of 47 patients with the baseline estimated daily salt intake greater than 10 g, the serum levels of sodium and potassium did not also change significantly at 12 weeks compared with baseline in either the ARB/TZ group (sodium: 142 6 3 mEq/L–140 6 4 mEq/L; potassium: 4.4 6 0.3 mEq/L–4.2 6 0.5 mEq/L) or the ARB/CCB group (sodium: 141 6 2 mEq/L– 142 6 2 mEq/L; potassium: 4.4 6 0.4 mg/dL–4.2 6 0.5 mg/dL). Further Subgroup Analysis Next, the authors performed further subgroup analyses as an exploratory manner (post hoc). Of the 87 patients enrolled in the study, 44 were observed to have visceral fat-type obesity (34 men and 10 women, aged 62 6 13 years). Serial blood pressure measurements in this subgroup revealed that baseline blood pressure was similar in patients receiving ARB/TZ (n 5 18) versus ARB/CCB treatment (n 5 26), but SBP at 4 weeks was lower in the ARB/TZ group than in the ARB/CCB group (130 6 12 mm Hg versus 144 6 17 mm Hg, respectively, P 5 0.0079, P for interaction 5 0.506). Consequently, the magnitude of SBP reduction at 4 weeks was greater in the ARB/TZ group than in the ARB/CCB group (28 6 19 mm Hg versus 18 6 15 mm Hg, respectively, P 5 0.049, P for interaction 5 0.427) (Figures 4A and 4B). Finally, the authors analyzed changes in blood pressure in 35 patients (21 men and 14 women, aged 65 6 13 years) with CKD. Although blood pressure reduction seemed to be greater in the ARB/CCB group compared with the ARB/TZ group, the difference did not reach statistical significance (Figures 4C and 4D).
DISCUSSION In this study, the authors compared the add-on blood pressure lowering effects of TZ and CCB medications in patients who did not reach blood pressure goals with ARB treatment alone. The blood pressure was found to be significantly decreased in patients receiving either ARB/TZ or ARB/ CCB combination therapy. Among all 87 patients enrolled in the study, DBP reduction was stronger in patients receiving ARB/CCB treatment compared with those receiving ARB/TZ treatment. SBP reduction was comparable in both groups.
FIGURE 2. A, Serial blood A B C pressure measurements in pag/day SBP mmHg 200 0 15 tients with baseline estimated daily salt intake greater than 10 g 10 and baseline systolic blood SBP 164 ** 20 pressure (SBP) between 150 and 12.0 164 200 mm Hg (n 5 37). Baseline 150 24 30 141 12.0 133 blood pressure was similar in 136 31 29 32 33 35 40 patients receiving either angio10.3 130 134 132 10 tensin receptor blocker/thiazide 50 P=0.048 diuretic (ARB/TZ) or ARB/cal9.4 DBP P=0.025 0 cium channel blocker (CCB) 100 91 P=0.0062 vs baseline * 83 combination therapy, but SBP at 81 86 78 5 ** P=0.0039 vs baseline 4 weeks was lower in the ARB/ 77 78 78 TZ group. B, Blood pressure * 10 9 9 8 12 8 7 DBP reduction in patients with base50 5 line estimated daily salt intake mmHg 8W 4W baseline 4W 8W 12W 12W baseline 12W greater than 10 g and baseline SBP between 150 and 200 mm Hg. SBP reduction at 4 weeks was greater in the ARB/TZ group compared with the ARB/CCB group. At 8 and 12 weeks, SBP and diastolic blood pressure (DBP) reduction was similar in both groups. C, Change in estimated daily salt intake between baseline and 12 weeks in patients with baseline estimated daily salt intake greater than 10 g and baseline SBP between 150 and 200 mm Hg. In both the ARB/TZ and the ARB/CCB groups, the estimated daily salt intake decreased at 12 weeks compared with baseline (black circles and arrows indicate ARB/TZ group, and white circles and arrows indicate ARB/CCB groups). Copyright © 2015 by the Southern Society for Clinical Investigation.
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FIGURE 3. A, Serial blood pressure measurements in pa200 tients with an increased estimated daily salt intake at 12 ** 15 10 weeks compared with baseline SBP (n 5 31). Although baseline 158 20 17 16 12.0 systolic blood pressure (SBP) 159 18 150 18 140 was similar in both groups, SBP 136 139 30 at 12 weeks was lower in the 28 28 142 134 angiotensin receptor blocker/ 131 40 10 thiazide diuretic (ARB/TZ) group 11.0 DBP 9.1 P=0.022 compared with the ARB/calcium 0 100 94 9.1 * channel blocker (CCB) group. B, 87 85 88 88 5 Blood pressure reduction in pa3 4 83 84 tients with an increased esti86 * P=0.0015 vs baseline 10 8 8 mated daily salt intake at 12 P<0.0001 vs baseline DBP 10 ** 10 50 5 weeks compared with baseline. mmHg 4W 8W 12W baseline 4W 8W 12W Although SBP reduction seemed baseline 12W to be greater in the ARB/TZ group at 8 and 12 weeks relative to the ARB/CCB group, the difference did not reach statistical significance. C, Changes in estimated daily salt intake in patients with an increased estimated daily salt intake at 12 weeks compared with baseline. The estimated daily salt intake increased in both the ARB/TZ and ARB/CCB groups (black circles and arrows indicate ARB/TZ group, and white circles and arrows indicate ARB/CCB groups).
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FIGURE 4. A, Serial blood pressure measurements in patients with visceral fat-type obesity (n 5 44) treated with either angiotensin receptor blocker/calcium channel blocker (ARB/CCB) or ARB/thiazide diuretic (TZ) combination therapy. Baseline blood pressure was equivalent in both groups, but at 4 weeks, systolic blood pressure (SBP) was lower in the ARB/TZ group compared with the ARB/CCB group. B, Blood pressure reduction in patients with visceral fat-type obesity. SBP reduction at 4 weeks was greater in the ARB/TZ group compared with the ARB/CCB group. C, Serial blood pressure changes in patients with chronic kidney disease (CKD) (n 5 35) treated with either ARB/CCB or ARB/TZ combination therapy. Although baseline blood pressure seemed to be higher in the ARB/CCB group compared with the ARB/TZ group, this difference did not reach statistical significance. D, Blood pressure reduction in patients with CKD. Although blood pressure reduction seemed to be greater in the ARB/CCB group compared with the ARB/TZ group, this difference did not reach statistical significance (black circles and arrows indicate ARB/TZ group, and white circles and arrows indicate ARB/CCB groups).
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receiving ARB/TZ treatment compared with those receiving ARB/CCB treatment. Furthermore, patients with visceral fattype obesity who were treated with ARB/TZ were found to have a greater reduction in SBP at 4 weeks than those who were treated with ARB/CCB. Finally, ARB/CCB and ARB/ TZ combination therapy produced comparable blood pressure reduction in patients with CKD, although the reduction tended to be greater in patients receiving ARB/CCB treatment. The ACCOMPLISH trial demonstrated a stronger cardiovascular risk reduction in patients who received ACEI/CCB compared with those who received ACEI/TZ combination therapy. This result is thought to be due to the enhanced blood pressure–lowering effects of ACEI/CCB treatment. It has remained unclear whether similar blood pressure and cardiovascular risk reduction would be observed if CCBs and TZs were combined with other RAS inhibitors. Several studies have found that ARB/CCB and ARB/TZ combinations have similar blood pressure–lowering effects.13,14 It has been suggested that the ARB/ CCB combination is a more effective antihypertensive therapy in elderly patients.15,16 In contrast, Nishiwaki et al17 demonstrated that the ARB/TZ combination is more effective at reducing SBP. Patients in the study by Nishiwaki et al were found to have a lower cardiovascular risk compared with patients in the ACCOMPLISH trial. In elderly patients and in patients at high risk for atherosclerotic cardiovascular diseases, CCBs might be more effective antihypertensive agents given their ability to cause vasodilation and decreased arterial stiffness. In this study, patients who had cardiovascular complications, such as coronary artery disease, heart failure and/or cerebrovascular disease, were excluded, and the authors were unable to test this hypothesis. Nevertheless, when data from all 87 of the study participants were analyzed, the authors found that the ARB/CCB combination produced a greater reduction in DBP than did the ARB/TZ combination. It is possible that the mixed findings of the previous studies are due to the synergistic effect of ARB/TZ combination therapy in patients with high salt intake.18 Recently, Hasegawa et al19 demonstrated that estimated salt excretion predicts the efficacy of ARB/TZ treatment in patients with ARB resistance, suggesting that the ARB/TZ combination might be preferable in patients with high salt intake. This study was the 1st to compare the antihypertensive effects of ARB/TZ and ARB/CCB combination therapy on the basis of patients’ salt intake. In patients with SBP between 150 and 200 mm Hg and a baseline salt intake greater than 10 g/d, short-term blood pressure reduction was found to be greater in those receiving ARB/TZ combination therapy compared with those receiving ARB/CCB combination therapy. In addition, in patients who demonstrated an increased salt intake over the course of the study, the antihypertensive effect of the ARB/TZ combination was stronger than that of the ARB/CCB combination. These results suggest that estimated daily salt intake may help to determine which medication will be more efficacious as add-on therapy to ARB treatment alone. Furthermore, estimated daily salt intake should be measured repeatedly during the therapeutic course. It has been suggested that the ARB/TZ combination is a rational therapeutic choice in patients with the metabolic syndrome, as these patients are salt sensitive and demonstrate accelerated RAA system activity. Ibuki et al20 recently used an ambulatory blood pressure monitoring system to demonstrate that the ARB/TZ combination leads to a greater reduction in nocturnal blood pressure in obese hypertensive patients than in nonobese patients. Similarly, in patients with visceral fat-type obesity, which can be considered a surrogate for the metabolic syndrome or premetabolic syndrome, ARB/TZ combination therapy was found to lead to greater short-term reduction in blood pressure than did ARB/CCB combination therapy. Copyright © 2015 by the Southern Society for Clinical Investigation.
It has been widely established that inhibition of the RAA system by ARBs or ACEIs confers cardiovascular protection in hypertensive patients with CKD21,22 and is the 1st-line therapeutic strategy in Western countries23,24 and in Japan.4 However, in those patients with CKD in whom RAA system inhibition alone does not provide sufficient antihypertensive effects, it has been unclear whether TZs or CCBs should be selected as add-on therapy. Subgroup analysis of hypertensive patients with CKD in the ACCOMPLISH trial revealed that treatment with the ACEI/CCB combination was associated with a decreased incidence of renal events compared with treatment with the ACEI/TZ combination.25 In elderly hypertensive patients with CKD, the ARB/CCB combination provided more effective blood pressure reduction and was associated with fewer cardiovascular events, compared with an increased dose of ARBs.26 Furthermore, the ARB/CCB combination has been reported to be more effective than the ARB/TZ combination in decreasing blood pressure in hypertensive patients with CKD.27 Similarly, the authors observed more robust antihypertensive effects with ARB/CCB treatment than with ARB/TZ treatment in patients with hypertension and CKD. Study Limitations There are several potential limitations in this study. First, the study included a small sample size, so this trial was not adequately powered, especially with subgroup analyses. In the subgroup analysis, different patients’ number and baseline SBP between 2 groups of each combination pill may have biased the findings of this study regarding the magnitude of blood pressure reduction. In fact, this study has inherent limitations of subgroup analyses in randomized controlled trials, such as reduced statistical power, failure to specify the subgroup of interest a priori, failure to account for examining large numbers of subgroups, lack of strong rationale for biological response modification and performing analyses based on variables measured postrandomization or in trials showing no overall difference between treatments. Next, the end point of this study was blood pressure reduction, but not onset of cardiovascular events. In more recent subgroup analysis of the ACCOMPLISH trial, a higher event rate was shown in the ACEI/TZ treatment group, compared with the ARB/CCB treatment group, although there was a trend on ambulant blood pressure monitoring to have a lower BP in the ACEI/TZ treatment group.28 So future studies should additionally assess cardiovascular morbidity and mortality in high salt diet patients as therapeutic targets. Finally, the subjects of this study were Japanese population, many of whom are considered to be salt sensitive, similarly to African. Furthermore, Japanese diet is known to be one of the highest in the world for sodium intake, so the results of this study can not necessarily be generalized to the United States or Europe. Pathogenesis of salt-sensitive hypertension is heterogeneous and the effect of dietary salt intake on blood pressure may be related to several genetic polymorphisms, such as genes of RAA system, aldosterone synthase and cytochrome p450. The direction of BP lowering in high salt intake participants as a group may not be extrapolated to care of individual patients. High salt intake individuals with TZs-sensitive Na+-Cl-cotransporter (NCC)-mediated salt-sensitive hypertension may respond to TZs better than other high salt-intake individuals.29
CONCLUSIONS In patients with moderate hypertension and high salt intake, ARB/TZ combination therapy produces greater shortterm blood pressure reduction than does ARB/CCB combination therapy. Estimated daily salt intake can help guide the
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choice of add-on therapy to ARB treatment alone and should be measured repeatedly during the therapeutic course. ACKNOWLEDGMENTS The authors acknowledge those additional physicians who participated in patient enrollment and follow-up: Naoyuki Otani, Takahisa Nasuno, Isao Taguchi (Dokkyo Medical University), Koetsu Anraku (Utsunomiya Higashi Hospital), Yoshihisa Takada (Takada Clinic), Nobuhiko Nakayama (Nakayama Medical and Cardiovascular Clinic), Akira Fujinuma (Fujinuma Clinic) and Hirotada Maezawa (Maezawa Medical Clinic). They also thank Mikie Ogawa, Research Associate in the Department of Cardiovascular Medicine, Dokkyo Medical University, for her efforts in data acquisition and technical support and Kiyoso Yamagata, Statistical Analysis Section, Kureha Special Laboratory Co, Ltd, for his assistance with statistical analysis. REFERENCES 1. Siragy HM, Bedigian M. Mechanism of action of angiotensin-receptor blocking agent. Curr Hypertens Rep 1999;1:289–95. 2. Siragy HM. AT(1) and AT(2) receptors in the kidney: role in disease and treatment. Am J Kidney Dis 2000;36(suppl 1):S4–9. 3. Weir MR, Dzau VJ. The rennin-angiotensin-aldosterone system: a specific target for hypertension management. Am J Hypertens 1999;12:205S–13S. 4. Ogihara T, Kikuchi K, Matsuoka H, et al. The Japanese Society of Hypertension guidelines for the management of hypertension (JSH 2009). Hypertens Res 2009;32:3–107. 5. Jamerson K, Weber MA, Bakins GL, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertention in high risk patients. N Engl J Med 2008;359:2417–28. 6. Zhou MS, Jaimes EA, Raij L. Benazepril combined with either amlodipine or hydrochlorothiazide is more effective than monotherapy for blood pressure control and prevention of end-organ injury in hypertensive Dahl rats. J Cardiovasc Pharmacol 2006;48:857–61. 7. Engeli S, Böhnke J, Gorzelniak K, et al. Weight loss and the renninangiotensin-aldosteron system. Hypertension 2005;45:356–62. 8. Uzu T, Kimura G, Yamaguchi A, et al. Enhanced sodium sensitivity and disturbed circadian rhythm of blood pressure in essential hypertension. J Hypertens 2006;24:1627–32. 9. Hoffmann IS, Cubeddu LX. Increased blood pressure reactivity to dietary salt in patients with metabolic syndrome. J Hum Hypertens 2007;21:438–44.
losartan/hydrochlorothiazide vs. candesartan/amlodipine. Hypertens Res 2007;30:831–7. 15. Kato J, Yokota N, Tamaki N, et al. Comparison of combination therapies, including the angiotensin receptor blocker olmesartan and either a calcium channel blocker or a thiazide diuretics, in elderly patients with hypertension. Hypertens Res 2011;34:331–5. 16. Matsui Y, Eguchi K, O’Rourke MF, et al. Differential effects between a calcium channel blocker and a diuretic when used in combination with angiotensin II receptor blocker on central aortic pressure in hypertensive patients. Hypertension 2009;54:716–23. 17. Nishiwaki M, Hosoai H, Ikewaki K, et al. Efficacy and effects on lipid metabolism of combination treatment with losartan + hydrochlorothiazide versus losartan + amlodipine: a 48-week prospective, multicenter, randomized, open-label trial. Clin Ther 2013;35:461–73. 18. Zhou BF, Stamler J, Dennis B, et al. Nutrient intakes of middleaged men and women in China, Japan, United Kingdom, and United States in the late 1990s: the INTERMAP study. J Hum Hypertens 2003;17:623–30. 19. Hasegawa H, Kanozawa K, Asakura J, et al. Significance of estimated salt excretion as a possible predictor of the efficacy of concomitant angiotensin receptor blocker (ARB) and low-dose thiazyde in patients with ARB resistance. Hypertens Res 2013;36:776–82. 20. Ibuki C, Seino Y, Otsuka T, et al. The fixed-dose combination of losartan/hydrochlorothiazide elicits potent blood pressure lowering during nighttime in obese hypertensive patients. J Clin Med Res 2014;6:8–16. 21. Ruilope LM, Salvetti A, Jamerson K, et al. Renal function and intensive lowering of blood pressure in hypertensive participants of the hypertension optimal treatment (HOT) study. J Am Soc Nephrol 2001;12:218–25. 22. Solomon SD, Rice MM, A Jablonski K, et al. Prevention of events with ACE inhibition (PEACE) Investigators. Renal function and effectiveness of angiotensin-converting enzyme inhibitor therapy in patients with chronic stable coronary disease in the prevention of events with ACE inhibition (PEACE) trial. Circulation 2006;114:26–31. 23. Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Hypertension 2003;42:1206–52. 24. Mancia G, De Backer G, Dominiczak A, et al. 2007 Guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J 2007;28: 1462–536.
10. Matsuo S, Imai E, Horio M, et al. Revised equation for estimating glomerular filtration rate (GFR) from serum creatinin in Japan. Am J Kidney Dis 2009;53:982–92.
25. Bakris GI, Sarafidis PA, Weir MR, et al. Renal outcomes with different fixed-dose combination therapies in patients with hypertension at high risk for cardiovascular events (ACCOMPLISH): a predispecified secondary analysis of a randomized controlled trial. Lancet 2010;375:1173–81.
11. Sarnak MJ, Levey AS, Schoolwerth AC, et al. Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Circulation 2003;108:2154–69.
26. Kim-Mitsuyama S, Ogawa H, Matsui K, et al. An angiotensin II receptor blocker-calcium channel blocker combination prevents cardiovascular events in elderly high-risk hypertensive patients with chronic kidney disease better than high-dose angiotensin II receptor blockade alone. Kidney Int 2012;83:167–76.
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27. Ishimitsu T, Ohno E, Nakano N, et al. Combination of angiotensin II receptor antagonist with calcium channel blocker or diuretic as antihypertensive therapy for patients with chronic kidney disease. Clin Exp Hypertens 2011;33:366–72.
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