Effect of Diuretic or Calcium-Channel Blocker Plus Angiotensin-Receptor Blocker on Diastolic Function in Hypertensive Patients

Abstract

Background: Hypertension increases the risk of left ventricular (LV) diastolic dysfunction, and anti-hypertensive therapy may improve LV relaxation. The aim of this study was to investigate whether combining an angiotensin-receptor blocker (ARB) with either hydrochlorothiazide (HCTZ) or a calcium-channel blocker (CCB) improves LV relaxation in patients with hypertension and diastolic dysfunction.

Methods and Results: Hypertensive patients who had not achieved their target blood pressure with at least 4 weeks of ARB therapy were randomly assigned to receive either a fixed-dose combination of losartan and HCTZ (losartan/HCTZ; n=110) or a combination of amlodipine and a typical ARB dosage (CCB/ARB; n=121) and followed for 24 weeks. The primary endpoint was change in early diastolic mitral annular velocity (e’, cm/s). Systolic blood pressure decreased in both groups after switch to the combination therapies. E’ velocity increased both in the losartan/HCTZ (0.52 cm/s) and in the CCB/ARB (0.59 cm/s) groups. The mean (95% CI) treatment difference was −0.02 (−0.37 to 0.34) cm/s, indicating that improvement in LV relaxation was similar between the groups. The ratio of early mitral inflow velocity to e’ velocity and left atrial volume index were significantly decreased in the losartan/HCTZ group.

Conclusions: The combination of losartan and HCTZ is as effective as amlodipine plus ARB in improving LV relaxation in hypertensive patients. (Circ J 2016; 80: 426–434)

Hypertension increases the risk of developing left ventricular (LV) hypertrophy, myocardial fibrosis, and diastolic dysfunction.^1,2 LV diastolic dysfunction plays a pivotal role in the development of heart failure (HF), especially HF with preserved ejection fraction (HFpEF).² Although the number of patients with HFpEF has been dramatically increasing,³ conventional pharmacologic treatment for HF with reduced EF has failed to improve the prognosis of patients with HFpEF. Therefore, hypertension-related diastolic dysfunction is an appealing target for treatment and prevention of HF.

Previous studies have demonstrated that diastolic dysfunction is improved after anti-hypertensive therapy and that the degree of improvement is closely associated with the degree of reduction in blood pressure (BP) rather than with the type of anti-hypertensive agent used.^4,5 To obtain a sufficient reduction in BP, more than two-thirds of hypertensive patients require a combination of 2 or more drugs.⁶ Various therapeutic guidelines for hypertension recommend combination therapy with an angiotensin-receptor blocker (ARB) and hydrochlorothiazide (HCTZ) to treat uncontrolled hypertension.^7,8 We have previously published results from the Effect of ARB/Diuretics on Diastolic Function in Patients with Hypertension (EDEN) trial, which showed that the combination of losartan (an ARB) plus HCTZ improved LV relaxation.⁹

Reduction in BP with a calcium-channel blocker (CCB), however, was also reported to be associated with improved LV relaxation in our prior Clinical Impact of Azelnidipine on Left VentricuLar Diastolic Function and Outcomes in Patients with Hypertension (CALVLOC) trial,¹⁰ and the combination of ARB and CCB is another preferred combination therapy.^7,8 It remains unclear, however, which combination therapy is better for improving LV diastolic function. Hence, we conducted the EDEN2 trial to test the hypothesis that an ARB with HCTZ would be as effective at improving LV diastolic function in hypertensive patients with diastolic dysfunction as an ARB with a CCB.

Methods

Subjects

Men and women aged 20–85 years, with a history of stage 1 or 2 essential hypertension (mean systolic BP [SBP] >140 mmHg or diastolic BP [DBP] >90 mmHg), and who were or were not being treated, were initially enrolled in the study from 31 participating centers. Exclusion criteria were severe, uncontrolled hypertension (DBP ≥110 mmHg); secondary hypertension; atrial fibrillation at baseline; cardio- and cerebrovascular disease requiring inpatient treatment in the past 6 months; clinically significant valvular heart disease; insulin-treated diabetes mellitus, renal insufficiency (serum creatinine ≥2 mg/dl); history of gout or hyperuricemia (serum uric acid ≥8.0 mg/dl); and severe non-cardiovascular disease. Patients with measured DBP ≥110 mmHg at any time during the run-in period were removed from the study. BP was measured at the office and the average of 2 or more seated BPs was recorded by trained observers using standardized techniques.⁸ The definition of HFpEF was based on the current European Society of Cardiology statement.¹¹ All patients provided written informed consent. The study protocol was approved by the ethics committee of Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences and registered in the University Hospital Medical Information Network Clinical Trials Registry (identification number 000004080).

Study Protocol

The EDEN2 trial was a prospective, randomized, open-label, parallel-group, comparative multicenter study. The study protocol is given in Figure 1. During the run-in period of at least 4 weeks, patients received a typical dose of any ARB monotherapy approved by the Ministry of Health, Labour and Welfare in Japan (losartan, 50 mg/day; candesartan, 8 mg/day; olmesartan, 20 mg/day; telmisartan: 40 mg/day; valsartan: 80 mg/day). Patients already on anti-hypertensive drugs other than a renin-angiotensin-aldosterone system (RAAS) inhibitor, diuretic, or CCB who did not achieve the target BP received a typical dose of any ARB. All anti-hypertensive drugs prescribed before the run-in period were continued through the trial. At the end of the run-in period, all patients who did not reach the BP target defined by the Japanese Society of Hypertension (130/85 mmHg for patients aged <64 years, 140/90 mmHg for patients aged ≥65 years, and 130/80 mmHg for patients with diabetes mellitus and/or chronic kidney disease)⁸ underwent echocardiographic screening for systolic and diastolic function by a sonographer blinded to treatment allocation.

Figure 1.

Protocol of the Effect of ARB/Diuretics on Diastolic Function in Patients with Hypertension 2 (EDEN2) Trial. ^*1Patients already on anti-hypertensive drugs other than a renin-angiotensin-aldosterone system (RAAS) inhibitor, diuretic, or calcium-channel blocker (CCB) who did not achieve the target blood pressure (BP) received a typical dose of any angiotensin-receptor blocker (ARB). All anti-hypertensive drugs prescribed before the run-in period were continued through the trial. ^*2Japanese typical ARB dosages: losartan, 50 mg/day; candesartan, 8 mg/day; olmesartan, 20 mg/day; telmisartan, 40 mg/day; and valsartan, 80 mg/day. HCTZ, hydrochlorothiazide.

LV diastolic function was assessed via early diastolic mitral annular velocity (e’ velocity) from tissue Doppler imaging. LV diastolic dysfunction was defined as e’<10 cm/s for patients aged between 20 and 54 years, <9 cm/s for patients aged between 55 and 64 years, and <8 cm/s for patients ≥65 years of age; or an E/e’ ratio >15 for any age.¹²

Patients with preserved systolic function (LV ejection fraction [LVEF] >50%) and diastolic dysfunction were randomly assigned to receive either a fixed-dose combination of losartan (50 mg; changed from current ARB) and HCTZ (12.5 mg; losartan/HCTZ) or a combination of amlodipine (5 mg) and current ARB (CCB/ARB). If a patient did not reach the BP target by 8 weeks, an add-on treatment other than an RAAS inhibitor, diuretic, or CCB was initiated. BP measurement and medical interview were performed at baseline, 8 weeks after randomization, and at final follow-up. Echocardiography was reassessed at the end of the study, and blood and urine tests were also performed at baseline and at final follow-up. The primary efficacy endpoint was change in e’ velocity from baseline to 24 weeks after randomization. The secondary endpoints were changes in BP, heart rate, and New York Heart Association (NYHA) functional class; changes in other echocardiographic parameters, including E/e’; and laboratory test results.

Echocardiography

From the mitral flow velocity pattern, we measured the peak velocities of E and A waves on mitral flow velocity, the ratio of their peak velocities (E/A ratio), and the deceleration time of the E wave. Systolic mitral annular velocity (s’ velocity) and e’ velocity were measured at septal mitral annular sites on pulsed tissue Doppler imaging. Additional exploratory analyses included changes in chamber dimensions and LVEF. LV mass, and left atrial (LA) volume using an ellipsoid model, were measured¹³ and indexed to body surface area in m². Systolic pulmonary artery pressure was determined from peak tricuspid regurgitation jet velocity and inferior vena cava diameter and its change with respiration. All echocardiography was performed by experienced sonographers who underwent hands-on training in the technique of tissue Doppler imaging and were confirmed to be able to record images of sufficient quality for the trial.

Laboratory Tests

Blood samples were collected for measurement of B-type natriuretic peptide (BNP), high-sensitivity C-reactive protein, high-sensitivity troponin T (hsTnT), and adiponectin along with additional exploratory blood analyses, and urine was collected for measurement of albumin concentration.

Statistical Analysis

All data are expressed as mean±SD unless otherwise specified. Between-group comparisons of the primary efficacy variable were performed using analysis of covariance (ANCOVA), adjusting for baseline assessment of e’ velocity, SBP, and age. A similar ANCOVA model was used for between-group comparisons of secondary variables. Differences in continuous variables were assessed using unpaired t-test for normally distributed variables and Wilcoxon rank-sum test for non-normally distributed variables. Fisher’s exact test was used to evaluate categorical variables and the Cochran-Mantel-Haenszel test was used to evaluate the group difference in the change of categorical data. Correlations are expressed using Spearman’s correlation coefficient. The present study was designed to demonstrate the non-inferiority of losartan/HCTZ compared with CCB/ARB in terms of their effects on e’ velocity. A sample size of 194 patients in each group was required to achieve an 80% power to detect non-inferiority using a 1-sided, 2-sample t-test. The significance (α) of the test was 0.05. The non-inferiority margin of e’ velocity was ≤0.4 cm/s, and the true difference between the means was assumed to be zero (cm/s).⁵ An SD of ±1.4 was estimated. We estimated that there would be a 3% loss to follow-up. Thus, 400 participants were estimated to be required. P<0.05 was the threshold for statistical significance. All analyses were performed using SAS^® version 9.3 (SAS Institute, Cary, NC, USA).

Results

Patient Characteristics

A total of 297 hypertensive patients were considered eligible for the study. After the run-in period, 66 patients were excluded: 34 patients who met the exclusion criteria, 16 patients with insufficient data, 9 patients who violated the protocol, and 7 patients who did not fulfill the criteria for diastolic dysfunction. The remaining 231 patients were randomly allocated to 1 of the 2 combination therapies (110 to the losartan/HCTZ group and 121 to the CCB/ARB group). Of these patients, 16 in the losartan/HCTZ group (10 because of adverse events, 5 because of loss to follow-up, and 1 because of uncontrolled hypertension) and 16 in the CCB/ARB group (12 lost to follow-up and 4 because of adverse events) discontinued study treatment during the trial. No participant was excluded for poor compliance. Baseline characteristics of the 2 groups are listed in Table 1. There were no significant differences in baseline clinical characteristics, except for the prevalence of dyslipidemia, between the 2 randomized groups.

Table 1. Baseline Subject Demographic and Clinical Characteristics

Variable	Losartan/ARB (n=110)	CCB/ARB (n=121)	P-value
Mean age (years)	65.1±11.3	66.0±10.2	0.517
Women	41 (37.3)	55 (45.5)	0.230
Mean systolic BP (mmHg)	156.5±16.9	156.1±13.1	0.839
Mean diastolic BP (mmHg)	89.5±11.0	88.2±11.1	0.349
Mean pulse (beats/min)	72.8±11.5	74.0±12.5	0.421
Weight (kg)	62.8±12.6	62.5±12.4	0.843
Body mass index (kg/m2)	24.3±3.7	24.4±3.6	0.869
NYHA functional class			0.409
Class I	75 (68.2)	76 (62.8)
Class II	35 (31.8)	45 (37.2)
HFpEF	7 (9.9)	12 (6.4)	0.350
Diabetes mellitus	13 (11.9)	16 (13.2)	0.844
Dyslipidemia	29 (26.6)	53 (43.8)	0.009
Old myocardial infarction	3 (2.8)	5 (4.1)	0.725
Angina pectoris	11 (10.1)	10 (8.3)	0.654
Old cerebral infarction	2 (1.8)	3 (2.5)	1.000
Arteriosclerosis obliterans	1 (0.9)	2 (1.7)	1.000
Chronic kidney disease	2 (1.8)	4 (3.3)	0.686
Previous ARB			0.853
Losartan 50 mg	32 (29.1)	28 (23.1)
Candesartan 8 mg	22 (20.0)	29 (24.0)
Olmesartan 20 mg	20 (18.2)	21 (17.4)
Telmisartan 40 mg	16 (14.5)	19 (15.7)
Valsartan 80 mg	20 (18.2)	24 (19.8)

Data given as mean±SD or n (%). ARB, angiotensin-receptor blocker; BP, blood pressure; CCB, calcium-channel blocker; HCTZ, hydrochlorothiazide; HFpEF, heart failure with preserved ejection fraction; NYHA, New York Heart Association.

Changes in Hemodynamic Data and Clinical Status

After 24 weeks of treatment, SBP and DBP decreased significantly from baseline in both groups (Table 2). The reduction in SBP was small but significantly larger in the CCB/ARB group than in the losartan/HCTZ group (P=0.049), whereas the reduction in DBP did not differ significantly between groups (P=0.077; Figure 2A). Additional anti-hypertensive medications were given to 22 patients (13 in the losartan/HCTZ group and 9 in the CCB/ARB group). The medications used most commonly were β-blockers (to 6 patients in the losartan/HCTZ group and to 5 in the CCB/ARB group). Among patients without additional anti-hypertensives, the reductions in both SBP and DBP were similar between the 2 groups (change in SBP, −22±20 mmHg in the losartan/HCTZ group vs. −25±14 mmHg in the CCB/ARB group, P=0.167; change in DBP, −11±13 mmHg vs. −13±11 mmHg, P=0.293). Heart rate showed no significant changes in either group; NYHA functional class improved significantly, and to the same degree, in both groups (Table 2).

Table 2. Clinical and Echocardiographic Measures vs. Time and Treatment Group

Variables	Baseline			24 weeks			Change
	Losartan/ HCTZ (n=110)	CCB/ARB (n=121)	P-value	Losartan/ HCTZ (n=94)	CCB/ARB (n=105)	P-value	Losartan/ HCTZ (n=94)	CCB/ARB (n=105)	P-value
Systolic BP (mmHg)	157±17	156±13	0.839	134±16	130±13	0.055	−22±20*	−26±14*	0.049
Diastolic BP (mmHg)	90±11	88±11	0.349	78±12	75±11	0.036	−12±14*	−13±11*	0.077
Pulse (beats/min)	73±12	74±13	0.421	72±11	72±13	0.827	−0.6±11.3	−1.0±11.6	0.987
NYHA functional class	n=110	n=121		n=89	n=103
I	75 (68.2)	76 (62.8)	0.409	75 (84.3)*	76 (73.8)†	0.081	–	–	0.157
II	35 (31.8)	45 (37.2)		14 (15.7)*	27 (26.2)†		–	–
Echocardiographic parameters
e’ velocity (cm/s)	5.9±1.3	5.6±1.2	0.147	6.4±1.7	6.2±1.3	0.517	0.52±1.43*	0.59±1.18*	0.931
s’ velocity (cm/s)	7.2±1.2	6.9±1.4	0.067	7.9±1.6	7.2±1.4	0.003	0.65±1.36*	0.32±1.41†	0.013
E velocity (cm/s)	63.6±16.1	60.6±17.9	0.185	61.1±16.0	63.5±15.9	0.285	−2.5±14.2	3.1±13.1†	0.010
E/e’ ratio	11.4±3.8	11.0±3.2	0.410	10.2±3.4	10.6±2.8	0.443	−1.3±2.9*	−0.5±2.8	0.123
E/A ratio	0.82±0.20	0.81±0.26	0.758	0.85±0.25	0.87±0.28	0.664	0.03±0.20	0.04±0.24	0.512
DT (ms)	223.9±54.6	231.5±50.6	0.278	223.9±42.8	228.3±48.2	0.504	0.40±50.6	−3.0±56.2	0.911
LV end-diastolic diameter (mm)	45.4±3.8	46.0±4.8	0.253	44.4±0.4	45.7±0.5	0.035	−1.1±3.1†	−0.4±3.0	0.033
LV end-systolic diameter (mm)	28.2±3.9	29.3±4.7	0.067	27.6±3.8	28.5±4.3	0.123	−1.0±3.9†	−0.8±3.6†	0.214
LV ejection fraction (%)	67.1±6.9	65.2±7.0	0.047	67.7±6.2	66.1±6.7	0.099	0.8±7.1	0.8±5.6	0.463
LV mass index (g/m2)	103.6±29.3	99.8±27.7	0.341	94.8±31.3	93.1±19.4	0.680	−10.2±20.1*	−4.9±21.9†	0.286
LA volume index (mL/m2)	37.1±13.7	38.1±14.7	0.622	35.3±13.4	37.6±13.9	0.244	−2.3±7.6†	−0.3±8.3	0.103
Systolic PA pressure (mmHg)	26.5±7.4	27.3±6.7	0.587	25.9±6.4	26.9±7.2	0.526	−0.97±5.76	0.18±6.00	0.451

Data given as mean±SD or n (%). ^†P<0.05, *P<0.001 for within-group difference. DT, deceleration time; E/A ratio, ratio of early to late mitral inflow velocities; E/e’ ratio, ratio of early mitral inflow velocity to e’ velocity; LA, left atrial; LV, left ventricular; PA, pulmonary artery. Other abbreviations as in Table 1.

Figure 2.

Effects of 24 weeks of treatment on blood pressure (BP) and e’ velocity. (A) Systolic and diastolic BP decreased significantly from baseline in both groups. The reduction in systolic BP was greater in the calcium-channel blocker/angiotensin-receptor blocker (CCB/ARB) group than in the losartan/hydrochlorothiazide (losartan/HCTZ) group. (B) Early diastolic mitral annular velocity (e’ velocity) increased significantly and similarly in both groups. *P<0.001 compared with baseline.

Changes in Echocardiographic Parameters

Echocardiographic parameters at baseline and follow-up and their changes are shown in Table 2. e’ velocity significantly increased in both groups (P<0.001 for both intra-group comparisons; Figure 2B). The mean difference between the 2 treatment groups was −0.02 cm/s (95% CI: −0.37 to 0.34 cm/s), which was above the predefined non-inferiority limit of −0.4 cm/s, confirming non-inferiority between the 2 treatment groups. Comparison for superiority demonstrated no significant between-group difference (P=0.931). In both groups, e’ velocity significantly increased among patients who attained target BP after 24 weeks of treatment (losartan/HCTZ group, 5.8±1.3 to 6.2±1.7 cm/s, P=0.003; CCB/ARB group, 5.6±1.3 to 6.1±1.3 cm/s, P=0.002), and no significant between-group difference in the change in e’ velocity was observed (P=0.963).

LV mass index decreased significantly in both treatment groups. According to echocardiographic preload parameters, E/e’ and LA volume index showed a significant decrease in the losartan/HCTZ group (Figures 3A,B), suggesting that preload was effectively reduced by the losartan/HCTZ combination. Although there was no change in LVEF in either group, s’ velocity significantly increased in both groups, with a greater increase in the losartan/HCTZ group than in the CCB/ARB group (Figure 3C), suggesting that both ARB-based combination therapies improved LV long-axis contractile function but that adding HCTZ to losartan had a more powerful effect.

Figure 3.

Effects of 24 weeks of treatment on (A) ratio of early mitral inflow velocity to early diastolic mitral annular velocity (E/e’); (B) left atrial (LA) volume index; and (C) systolic mitral annular velocity (s’ velocity). (A,B) E/e’ and LA volume index decreased significantly in the losartan/hydrochlorothiazide (losartan/HCTZ). (C) s’ velocity significantly increased in both groups and its improvement was greater in the losartan/HCTZ group than that in the calcium-channel blocker/angiotensin-receptor blocker (CCB/ARB) group. ^†P<0.05, *P<0.001 vs. baseline.

Changes in Laboratory Parameters

Table 3 lists the changes in laboratory parameters at final follow-up. BNP significantly decreased in the losartan/HCTZ group, but the reduction did not differ significantly between groups. Although both treatments increased hsTnT in patients with low baseline hsTnT (<0.014 ng/ml) and the increase was significantly greater in the losartan/HCTZ group than in the CCB/ARB group, no patient exceeded a value of 0.030 ng/ml. Also, in the losartan/HCTZ group, hsTnT at 24 weeks showed a significant inverse correlation with estimated glomerular filtration rate (eGFR; r=−0.52, P<0.001). No significant increase in hsTnT was found in patients with high baseline hsTnT (≥0.014 ng/ml) in either group. Both blood urea nitrogen and creatinine significantly increased in the losartan/HCTZ group. eGFR decreased in both groups, and to a greater degree in the losartan/HCTZ group. Losartan/HCTZ increased uric acid in patients with low uric acid (<7.0 mg/dl) at baseline but not in those with high uric acid (≥7.0 mg/dl). Mean serum potassium decreased in the losartan/HCTZ group, but not in the CCB/ARB group. Despite the change in serum potassium, it remained in the normal range, and none of the participants discontinued the losartan/HCTZ treatment as a result of hypokalemia. No significant between-group differences were seen in hemoglobin A1c, and only high-density lipoprotein cholesterol decreased significantly in the CCB/ARB group, but the reduction did not differ significantly between groups (Table S1).

Table 3. Laboratory Measures vs. Time and Treatment Group

Variables	Baseline			24 weeks			Change
	Losartan/ HCTZ (n=110)	CCB/ARB (n=121)	P-value	Losartan/ HCTZ (n=94)	CCB/ARB (n=105)	P-value	Losartan/ HCTZ (n=94)	CCB/ARB (n=105)	P-value
BNP (pg/dl)	22.1 (10.5–48.2)	18.1 (10.1–37.3)	0.217	17.4 (8.3–46.7)	18.5 (10.3–35.5)	0.624	−3.8 (−13.9 to 3.3)†	−1.3 (−10.6 to 5.0)	0.265
HsTnT (ng/ml) (all)	0.003 (0.003–0.007)	0.003 (0.003–0.005)	0.175	0.006 (0.003–0.011)	0.005 (0.003–0.008)	0.019	0.002 (0.000–0.004)*	0.000 (0.000–0.003)*	0.016
HsTnT (<0.014) (ng/ml)	0.003 (0.003–0.006)	0.003 (0.003–0.005)	0.843	0.006 (0.003–0.009)	0.005 (0.003–0.008)	0.069	0.002 (0.000–0.004)*	0.000 (0.000–0.003)*	0.024
HsTnT (≥0.014) (ng/ml)	0.020 (0.016–0.036)	0.019 (0.016–0.029)	0.845	0.019 (0.011–0.030)	0.013 (0.003–0.016)	0.151	0.001 (−0.009 to 0.010)	−0.007 (−0.026 to −0.003)	0.118
BUN (mg/dl)	15.6±3.4	15.9±4.3	0.648	17.5±4.2	15.9±4.6	0.012	1.9±4.2*	0.2±3.9	0.002
Creatinine (mg/dl)	0.74±0.18	0.74±0.17	0.894	0.80±0.18	0.75±0.19	0.096	0.06±0.11*	0.02±0.09†	0.013
eGFR (ml/min/1.73 m2)	76.4±14.9	74.6±14.9	0.356	71.6±15.2	73.0±15.9	0.515	−5.3±11.1*	−1.5±8.3	0.011
Uric acid (mg/dl) (all)	5.4±1.3	5.2±1.2	0.430	5.7±1.4	5.4±1.4	0.057	0.3±1.0†	0.2±0.9†	0.300
Uric acid (<7.0) (mg/dl)	5.1±1.2	5.0±1.0	0.458	5.6±1.4	5.2±1.2	0.042	0.4±0.9*	0.2±0.9	0.063
Uric acid (≥7.0) (mg/dl)	7.4±0.3	7.5±0.4	0.465	7.1±1.0	7.8±1.3	0.236	−0.3±1.0	0.3±1.4	0.245
Na (mEq/dl)	141.8±1.7	141.6±1.9	0.522	141.2±2.0	141.3±2.0	0.578	−0.4±2.1	−0.3±1.9	0.859
K (mEq/dl)	4.33±0.50	4.26±0.32	0.244	4.13±0.36	4.25±0.31	0.015	−0.21±0.49*	−0.01±0.39	0.002
Cl (mEq/dl)	105.4±2.3	105.3±2.6	0.728	103.9±2.7	105.1±2.6	0.002	−1.4±2.6*	−0.2±2.0	<0.001

Data given as mean±SD or median (IQR). ^†P<0.05, *P<0.001 for within-group difference. BNP, B-type natriuretic peptide; BUN, blood urea nitrogen; eGFR, estimated glomerular filtration rate; hsTnT, high-sensitivity troponin T. Other abbreviations as in Table 1.

Adverse Events

No deaths or serious cardiovascular events occurred during the trial. There were 14 investigator-reported adverse events, which included hypotension and dizziness (5 in the losartan/HCTZ group and 2 in the CCB/ARB group), allergic reaction (2 in the losartan/HCTZ group and 1 in the CCB/ARB group), photosensitivity and photosensitivity eruption (2 in the losartan/HCTZ group), hyponatremia (1 in the losartan/HCTZ group), and general fatigue (1 in the CCB/ARB group).

Discussion

The present study has demonstrated that switching from ARB therapy to a combination of losartan and HCTZ was as effective as a combination of amlodipine and other ARB in improving LV relaxation in hypertensive patients with LV diastolic dysfunction.

Because LV diastolic function is a prognostic marker in hypertension,¹⁴ treatment of hypertensive patients should focus on improving LV diastolic dysfunction and lowering BP. In the current study, 3 types of anti-hypertensive drugs were mainly used. An ARB may have beneficial effect on myocardial relaxation and compliance by reducing BP and arterial stiffness and by reducing the deposition of interstitial collagen,¹⁵ but its superiority over non-RAAS inhibitors in improving diastolic function has not been demonstrated.⁴ Diuretics stabilize hemodynamics in patients with LV diastolic dysfunction by reducing preload. It is speculated that CCB improves diastolic function by enhancing collagen remodeling¹⁶ and reducing late systolic pressure by reducing aortic stiffness and delaying wave reflection.¹⁷ In the present study the increases in e’ velocity were equivalent between the losartan/HCTZ and CCB/ARB groups. Because SBP at the end of the study was slightly but significantly lower in the CCB/ARB group than in the losartan/HCTZ group and mean SBP did not reach the target level in either group, the same analysis was performed among patients who attained the target BP, and the increase in e’ velocity was observed to be similar between the 2 groups. We speculated from this result that, as has been demonstrated in prior reports, reduction in BP, rather than the type of drug taken in addition to an ARB, might have an important role in improving LV diastolic function.^4,5,9,10

Angiotensin II has been reported to induce LV hypertrophy either individually or in combination with the other signal pathways.¹⁸ Although blocking angiotensin II effectively reverses cardiac hypertrophy in experimental models,¹⁹ the time it takes to become effective in humans remains unknown. In a large trial, LV hypertrophy was improved after 1 year of losartan-based anti-hypertensive therapy.²⁰ In the other clinical trials, however, the regression of echocardiographic or electrocardiographic LV hypertrophy was demonstrated after 6 months of ARB-based combination therapy,^5,9,21 which is consistent with the present study. E/e’ and LA volume index, both of which are robust predictors of cardiovascular outcome in patients with preserved systolic function,^22,23 decreased significantly in the losartan/HCTZ group. Unlike E/e’, LA volume index reflects an average effect of LV filling pressures over time; therefore, adding HCTZ rather than a CCB to an ARB could have short- and long-term favorable effects on LV filling pressures, and this is supported by the decrease in BNP in the losartan/HCTZ group seen in the present study. Both combination therapies improved LV longitudinal contractile function (increase in s’ velocity), which is a potent prognostic indicator in patients with hypertension.¹⁴ Because elevated serum potassium was reported to be associated with the degree of LV systolic dyssynchrony, which attenuates subclinical systolic function evaluated by s’ velocity,²⁴ the mild decrease in serum potassium in the losartan/HCTZ group might improve LV longitudinal contractile function, as was observed in a previous trial.⁹ In contrast, long-acting CCB showed no significant increase in s’ velocity but improved longitudinal strain, which is more sensitive for myocardial function than pulsed tissue Doppler.²⁵ Thus, this could explain why the improvement of s’ velocity was more prominent in the losartan/HCTZ group than in the CCB/ARB group.

The previous large trial showed that the combination of angiotensin-converting enzyme inhibitor (ACEi) with a CCB was more beneficial with regard to morbidity and mortality reduction than the combination of the same ACEi with HCTZ in patients at high risk for cardiovascular events.²⁶ In contrast, another large multicenter study noted no differences in cardiovascular mortality and morbidity between the combination of ARB+CCB and ARB+diuretic in elderly hypertensive patients.²⁷ Given the conflicting results from these prior trials and the favorable effects of the losartan/HCTZ group on several prognosticators in the current study, further research is needed to determine the optimal drug combination that will improve cardiovascular outcomes, especially in hypertensive patients with relatively few risk factors. Both ARB and ACEi are listed as first-line drugs in anti-hypertensive treatment guidelines,^7,8 and have been shown to provide similar clinical benefits.^28,29 In the present trial, we selected anti-hypertensive treatment based on ARB, because they are more widely used in patients with other cardiovascular risk factors⁸ and fewer occurrences of angioedema³⁰ and subsequent discontinuation³¹ were expected as compared with ACEi-based treatment.

Anti-hypertensive treatment with diuretics is often associated with a negative effect on renal parameters because of reduced renal blood flow. In prior trials, the same fixed-dose combination of losartan with HCTZ used in the present study resulted in a small increase in serum creatinine and a decrease in eGFR.^9,32 Given that these results are consistent with the present results, the concomitant use of diuretics still requires careful attention to renal function. According to recent reports, however, neither a small increase in serum creatinine nor a decrease in eGFR after appropriate HF treatment is associated with outcome in patients with HF.^33,34 Therefore, the mild deterioration of renal parameters observed in the losartan/HCTZ group would not be associated with worse prognosis. The reason why improvement in LV relaxation in both groups and in LV longitudinal systolic function in the losartan/HCTZ group was observed despite hsTnT elevation, especially in the losartan/HCTZ group, remains unknown. The increase in hsTnT, however, was limited in patients with low baseline hsTnT, and no patient exceeded the cut-off of 0.03 ng/ml for predicting future cardiovascular events,³⁵ after 24 weeks of treatment. Moreover, hsTnT at 24 weeks was inversely correlated with eGFR in the losartan/HCTZ group, suggesting that the deterioration of renal parameters might result in an increase in hsTnT.³⁶

Thiazides can reduce the excretion of uric acid and thereby increase its concentration in plasma. The increase in uric acid in the losartan/HCTZ group, however, was limited in the subgroup of patients with relatively low uric acid (<7.0 mg/dl) at baseline, and this is consistent with prior studies.^9,32 Glucose metabolism can be impaired by a thiazide,³⁷ but we found no notable changes in serum hemoglobin A1c in either group. Thiazide-induced hypokalemia is clearly associated with the increased risk of cardiovascular events;³⁷ therefore, the present result of decreased potassium in the losartan/HCTZ group should be noted even though the magnitude of change was small, and final values were within the normal range.

Study Limitations

Some limitations should be noted. First, the number of study participants did not reach the sample size planned prior to the start of the trial. For 80% power to detect non-inferiority, we needed 194 patients in each arm, but only 231 patients were enrolled. We did not, however, extend the enrollment period; the results of the primary endpoint would likely not have been changed even if the subject group were increased, because the non-inferiority of the effect on e’ velocity had already been demonstrated in the sample size of 231 patients. Second, this was not a double-blind study. The prospective randomized open-label blinded end-point (PROBE) study design, however, is reported to be a feasible alternative to a double-blind study, and a properly designed and conducted PROBE trial provides a non-biased result.³⁸ Third, most of the study participants were mildly to moderately hypertensive and without clinical HF. Thus, the present findings may not be applicable to patients with severe HFpEF. Fourth, we used relatively low-dose ARB and further research is required to elucidate the effect of high-dose ARB-based combination therapy on LV relaxation. Fifth, we did not determine inter- and intra-observer variability for tissue Doppler measurements. As stated in the guidelines,³⁹ however, these measurements are highly reproducible with low variability when performed by experienced examiners. Sixth, although BP was measured at the office according to the current recommendation,⁸ we could not exclude the impact of white-coat hypertension.

Conclusions

The combination of losartan and HCTZ is as efficacious as the combination of amlodipine and an ARB in improving LV relaxation in hypertensive patients with LV diastolic dysfunction. The present results also suggest that the losartan/HCTZ combination may have additional benefits with regard to LV filling pressure. The combination of losartan and HCTZ was shown to be an effective therapeutic option for patients with hypertension and LV diastolic dysfunction.

Acknowledgments

This study was supported by the Osaka Foundation for the Prevention of Cancer and Cardiovascular Diseases. The authors thank the EDEN2 trial investigators: Shin Takiuchi, MD (Higashi Takarazuka Satoh Hospital); Naoto Tokunaga, MD (Kaneda Hospital); Masayasu Kusaka, MD (Kusaka Hospital); Fumiaki Nakamura, MD (Ibaraki Iseikai Hospital); Shota Fukuda, MD (Osaka Ekisaikai Hospital); Yukio Abe, MD (Osaka City General Hospital); Yoshinori Tani, MD (Okayama Rosai Hospital); Atsuko Furukawa, MD (Kansai Electric Power Hospital); Yasuki Hen, MD, Miho Kawaguchi, MD (Sakakibara Heart Institute Clinic); Shigeki Mori, MD (Mori Medical Clinic); Noriaki Kasayuki, MD, Hiroki Nishioka, MD (Ishikiriseiki Hospital); Yasuji Doi, MD (Osaka Saiseikai Senri Hospital); Masashi Ikushima, MD (Higashi Takarazuka Satoh Hospital); Kenichiro Suwa, MD, Kei Tawarahara, MD (Hamamatsu Red Cross Hospital); Ritsuko Terasaka, MD (Fukuyama City Hospital); Natsuki Takahashi, MD (Matsuyama Shimin Hospital); Yasuyo Takeuchi, MD (Seirei Mikatahara General Hospital); Taro Minagawa, MD (Minagawa Clinic); Hiroyuki Takase, MD (Enshu Hospital); Toshihiko Nagano, MD (Iwasa Hospital); Yoshimune Hiramoto, MD, Masahiro Izumi, MD (Kinki Central Hospital of Mutual Aid Association of Public School Teachers); Takahisa Yamada, MD (Osaka General Medical Center); Hideki Fujio, MD (Himeji Red Cross Hospital); Takeshi Takami, MD (Clinic Junguumae); Masahiro Yoshida, MD (Tsukushino Hospital); Hiroki Oe, MD (Ibara City Hospital Department of Cardiovascular Medicine); Yasuhiro Akazawa, MD (Osaka Police Hospital); and Takashi Murakami, MD (Okayama Heart Clinic).

Financial Support

This study was supported by the Osaka Foundation for the Prevention of Cancer and Cardiovascular Diseases (Osaka, Japan).

Disclosures

The authors declare no conflicts of interest.

Supplementary Files

Supplementary File 1

Table S1. Laboratory measures vs. time and treatment group

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-15-0815

References

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