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
The aim of this study was to compare the effects between calcium channel blockers and diuretics when used in combination with angiotensin II receptor blocker on aortic systolic blood pressure (BP) and brachial ambulatory systolic BP. We conducted a prospective, randomized, open-label, blinded end point study in 207 hypertensive patients (mean age: 68.4 years). Patients received olmesartan monotherapy for 12 weeks, followed by additional use of azelnidipine (n=103) or hydrochlorothiazide (n=104) for 24 weeks after randomization. The central BP by radial artery tonometry, aortic pulse wave velocity, and ambulatory BP were assessed at baseline and 24 weeks later. After adjustment for baseline covariates, the extent of the reduction in central systolic BP in the olmesartan/azelnidipine group was significantly greater than that in the olmesartan/hydrochlorothiazide group (the between-group difference was 5.2 mm Hg; 95% CI: 0.3 to 10.2 mm Hg; P=0.039), whereas the difference in the reduction in brachial systolic BP between the groups was not significant (2.6 mm Hg; 95% CI: −2.2 to 7.5 mm Hg; P=0.29). The aortic pulse wave velocity showed a significantly greater reduction for the olmesartan/azelnidipine combination than for the olmesartan/hydrochlorothiazide combination (0.8 m/s; 95% CI: 0.5 to 1.1 m/s; P<0.001) after adjustment for covariates. The extent of the reduction in brachial ambulatory systolic BP was similar between the groups. These data showed that the combination of olmesartan (20.0 mg) and azelnidipine (16.0 mg) had a more beneficial effect on central systolic BP and arterial stiffness than the combination of olmesartan (20.0 mg) and hydrochlorothiazide (12.5 mg), despite the lack of a significant difference in brachial systolic BP reduction between the 2 treatments.
- angiotensin II receptor blocker
- calcium channel blocker
- thiazide diuretic
- central blood pressure
- pulse wave velocity
- ambulatory blood pressure
Recent clinical trials have demonstrated that strict control of blood pressure (BP) is essential to prevent target organ damage and to reduce cardiovascular mortality in hypertensive patients.1–3⇓⇓ The angiotensin II receptor blocker (ARB) is one of the first-line antihypertensive drugs for most patients with hypertension, but monotherapy achieves the target BP recommended by the treatment guidelines4,5⇓ in only a limited number of patients, and, thus, combination therapy is required in a majority of patients.5 A thiazide diuretic is commonly used in combination with an ARB or angiotensin-converting enzyme inhibitor (ACE-I) because it has an additive effect on BP reduction because of the complementary mechanisms of action of the components,5 and the efficacy of these combinations has been demonstrated in clinical trials.1,2,6⇓⇓ On the other hand, the combination of a dihydropyridine calcium channel blocker (CCB) with an ARB or ACE-I has also become widely used because this regimen is effective in BP control and is well tolerated.7 Recently, the combination of an ACE-I and a CCB has been reported to be more effective than the combination of an ACE-I and a thiazide diuretic for decreasing cardiovascular events in high-risk hypertensive patients.8
In the Anglo-Scandinavian Cardiac Outcomes Trial,3 the CCB/ACE-I combination was more effective than a combination of β-blocker and thiazide diuretic for decreasing cardiovascular events in hypertensive patients. The Conduit Artery Function Evaluation Substudy of the Anglo-Scandinavian Cardiac Outcomes Trial9 demonstrated that such benefits may be attributable to the CCB/ACE-I, combination achieving a greater reduction of central than brachial systolic BP (SBP), because the central SBP is reported to be a better predictor of cardiovascular risk than brachial SBP.9,10⇓ In fact, renin-angiotensin system (RAS) inhibitors (ARB and ACE-I) and a CCB have been shown to effectively decrease central SBP by reducing arterial wave reflection,11 whereas a thiazide diuretic could not.12 These pieces of evidence have led to the hypothesis that, given a similar brachial SBP reduction, the RAS inhibitor/CCB combination may achieve a greater reduction in central SBP than the RAS inhibitor/thiazide diuretic combination.
The Japan-Combined Treatment With Olmesartan and a Calcium Channel Blocker Versus Olmesartan and Diuretics Randomized Efficacy (J-CORE) Study was designed to test the hypothesis that treatment with a CCB, azelnidipine, combined with an ARB, olmesartan, would reduce central SBP and ambulatory SBP more effectively than treatment with a thiazide diuretic, hydrochlorothiazide (HCTZ), combined with olmesartan. Azelnidipine, a dihydropyridine CCB, has been reported to have a BP-lowering effect over 24 hours equivalent to that of amlodipine.13
The study participants, aged 30 to 85 years, were recruited from the Outpatient Department of Internal Medicine, Mishima Clinic (Hagi, Japan). The entry period was from May 2006 to October 2007. We initially enrolled consecutive hypertensive patients who were or were not being treated and who agreed to participate in this study. Hypertension was defined as clinic SBP ≥140 mm Hg and/or diastolic BP (DBP) ≥90 mm Hg on ≥2 different occasions or by a previous diagnosis of hypertension with current antihypertensive medication use.4 During the 12-week run-in period, patients received a once-daily 20.0-mg dose of olmesartan monotherapy. The patients already being treated were instructed to change all of their current antihypertensive medications to olmesartan only. If clinic SBP and/or DBP exceeded the safety parameters of ≥200 mm Hg and/or 115 mm Hg, respectively, at any point during the run-in period, patients were withdrawn from the study. At the end of the run-in period, patients with a clinic BP ≥140 mm Hg and/or 90 mm Hg were eligible for the study. Patients were excluded if they had secondary hypertension, arrhythmias, current treatment for congestive heart failure, a history of stroke or coronary artery disease, clinically significant valvular heart disease, renal insufficiency (serum creatinine ≥2 mg/dL), mental disorders, severe noncardiovascular disease (eg, cancer or liver cirrhosis), or chronic inflammatory disease. Patients who were already being treated with olmesartan were also excluded. This study was approved by the institutional review board of Jichi Medical University, and written informed consent was obtained from all of the participants. Please see the online Data Supplement at http://hyper.ahajournals.org for the diagnostic criteria.
The J-CORE Study was a 24-week, prospective, randomized, open-label, blinded end point, parallel-group study with 2 treatment arms evaluating the effects of olmesartan/azelnidipine and olmesartan/HCTZ on central SBP and ambulatory SBP. Figure shows the study protocol. At the end of the 12-week period of olmesartan monotherapy, eligible patients were randomized to add either azelnidipine 16.0 mg or HCTZ 12.5 mg to the olmesartan 20.0 mg. The doses of azelnidipine and HCTZ were indirectly selected on the basis of previous reports that azelnidipine (16.0 mg) and amlodipine (5.0 mg) lowered the 24-hour SBP to a similar degree13 and that, in combination with ACE-I, HCTZ (12.5 mg) and amlodipine (5.0 mg) were the starting doses in a large clinical trial.8 For the randomization, the physician who enrolled the patients made a telephone call to an independent research center, and 1 of the 2 treatment arms was assigned in a blind manner. Both treatments were given as a fixed dose for 24 weeks, and dose titration was not permitted. Patients were instructed to take their medications after breakfast and were not permitted to receive any antihypertensive medication other than study medications. Other drugs that had the potential to interfere with the safety and efficacy of the study medications were also not allowed. At the baseline and the end of the study, central BP, aortic pulse wave velocity (PWV), and ambulatory BP were measured, and blood and urine tests were performed. Please see the online Data Supplement for further information.
Measurement of Central BP and Aortic PWV
Immediately before the pulse wave analysis, brachial BP at the clinic was recorded as the average of triplicate measurements taken at intervals of 1 minute using a validated oscillometric device (HEM-907, Omron Healthcare)14 after an initial 5 minutes of seated rest. Central BP and aortic PWV were measured using SphygmoCor software version 7.0 (AtCor Medical). Mean arterial pressure (MAP) was determined by mathematical integration of the radial pressure waveform and calibrated using the oscillometric value of brachial SBP and DBP. Pulse pressure (PP) amplification was calculated as the ratio of brachial PP:central PP. To assess the intraobserver reproducibility, a subset of 20 participants underwent repeated measurements of pulse wave analysis 2 weeks after their first assessment. The coefficient of variation was 6.2% for augmentation index (AIx) and 5.3% for PWV, respectively. Please see the online Data Supplement for the details of these measurements.
Ambulatory BP Monitoring
Noninvasive ambulatory BP monitoring was carried out twice on a weekday with an automatic device (TM-2431, A&D Co) that recorded BP every 30 minutes for 24 hours using the oscillometric method and pulse rate (PR). Please see the online Data Supplement for the details of ambulatory BP monitoring.
Sample size calculations were based on the results of the Conduit Artery Function Evaluation Study.9 The approximate variance of BP was also calculated from the 95% CI. We assumed a difference of 5 mm Hg in central SBP between the treatment groups, because this difference has been demonstrated to have prognostic significance.9 These assumptions required, assuming a 10% dropout rate, 110 patients per treatment arm with 80% power at the 5% significance level.
Statistical analysis was performed based on an intention-to-treat principal. Differences between the groups at baseline were analyzed with the unpaired t test for continuous variables or the χ2 test for categorical variables. ANCOVA was performed to compare the hemodynamic parameters between the 2 treatment groups, with age, sex, body mass index (BMI), previous antihypertensive medication, and each baseline value as covariates,6 because the mean of age stratified by sex (data not shown) and BMI were slightly different between the groups. For aortic PWV, adjustments for baseline MAP and its changes were also performed. The least-squares mean and 95% CI for between-treatment group differences were also calculated. Furthermore, multiple linear regression analysis was used to explore the determinants of the percentage reduction of central SBP. Stepwise variable selection was performed, including the percentage change of AIx, PWV, and left ventricular (LV) ejection duration as independent variables, with age, sex, BMI, and previous antihypertensive medication as covariates. Two-sided values of P<0.05 were considered to indicate statistical significance. All of the statistical analyses were performed with SAS version 8.2 (SAS Institute Inc).
Disposition of Patients
The flow of patients through each stage of the study is shown in Figure S1. Please see the online Data Supplement for details.
In the total intention-to-treat population, the mean age was 68.4±8.6 years (range: 42.0 to 82.0 years); there were 83 men and 124 women; 72% had been treated with antihypertensive medication. The baseline characteristics, including age, sex, height, BMI, and the type and number of previous antihypertensive medications, are shown in Table 1. The baseline BP and other hemodynamic parameters were similar between the 2 groups (Tables 2 through 4⇓⇓).
Changes in Brachial and Central BP
The brachial BP/PP and central BP/PP decreased significantly in the 2 treatment groups (all P<0.001). The extent of the reduction in central SBP in the olmesartan/azelnidipine group was significantly greater than that in the olmesartan/HCTZ group (the between-group difference was 5.2 mm Hg; 95% CI: 0.3 to 10.2 mm Hg; P=0.039), whereas the difference in the reduction in brachial SBP between the groups was not significant (P=0.29). The extents of the reductions in brachial DBP/MAP and central DBP in the olmesartan/azelnidipine group were significantly greater than those in the olmesartan/HCTZ group. Heart rate (HR) was significantly reduced only in the olmesartan/azelnidipine group (Table 2).
Changes in Aortic PWV and Aortic Functional Parameters
The aortic PWV decreased significantly in the 2 treatment groups (P<0.001). The extent of this reduction in the olmesartan/azelnidipine group was significantly greater than that in the olmesartan/HCTZ group (P<0.001). Even after adjustment for MAP, this greater reduction in the olmesartan/azelnidipine group did not change (0.5 m/s; 95% CI: 0.2 to 0.7 m/s; P<0.001). The reduction in AIx was similar between the groups, whereas the reduction of AIx adjusted for an HR of 75 bpm in the olmesartan/azelnidipine group was significantly greater than that in the olmesartan/HCTZ group. The increase in PP amplification in the olmesartan/azelnidipine group was significantly greater than that in the olmesartan/HCTZ group. The time to the foot of the reflected wave in the olmesartan/azelnidipine group was delayed more than that in the olmesartan/HCTZ group (Table 3).
Changes in Ambulatory BP
The reductions from baseline in 24-hour BP, awake BP, and sleep BP were significant in the 2 treatment groups (all P<0.001). The extents of the reductions in 24-hour BP, awake BP, and sleep BP were similar between the groups except that the reduction in awake DBP in the olmesartan/azelnidipine group was significantly greater than that in the olmesartan/HCTZ group. The 24-hour, awake, and sleep PRs in the olmesartan/azelnidipine group decreased more than those in the olmesartan/HCTZ group (Table 4).
Hemodynamic Factors Influencing the Reduction of Central SBP
For the percentage reduction of central SBP, aortic PWV and AIx were the determinants in the olmesartan/azelnidipine group, whereas aortic PWV and LV ejection duration were the determinants in the olmesartan/HCTZ group (Table 5).
Changes in Laboratory Data
Serum creatinine levels in the olmesartan/HCTZ group increased more than those in the olmesartan/azelnidipine group (from 0.72 to 0.80 mg/dL versus from 0.74 to 0.76 mg/dL; P<0.001). Fasting glucose, hemoglobin A1C, total cholesterol, low- and high-density lipoprotein cholesterol, and serum potassium before and after treatment were similar between the 2 groups.
The main finding of this study was that the central SBP in the olmesartan/azelnidipine group decreased more than that in the olmesartan/HCTZ group, despite the fact there was no significant difference in brachial SBP reduction between the 2 groups. In addition, the aortic PWV in the olmesartan/azelnidipine group decreased more than that in the olmesartan/HCTZ group even after adjustment for MAP. These differential effects on central aortic parameters between the 2 treatment groups deserve further discussion.
We showed that the reductions of AIx and aortic PWV played a significant role in the central SBP reduction in the olmesartan/azelnidipine group. Thus, 2 hemodynamic mechanisms may explain why the central SBP-lowering effect of olmesartan/azelnidipine was more potent than that of olmesartan/HCTZ: first, the intensity of wave reflection may have been reduced by a change in the reflection coefficient of the arterial system, and, second, the reflection wave arrival time may have been delayed because of changes in aortic PWV.
The first mechanism is supported by the finding that aortic AIx adjusted for HR decreased in the olmesartan/azelnidipine group more than in the olmesartan/HCTZ group. Unlike brachial SBP, central SBP is influenced by pressure waves that are reflected back toward the heart from branch points throughout the arterial tree.15 Several pharmacological trials have shown that various antihypertensive treatments have differential effects on central SBP, despite their similar effects on brachial SBP.6,9,11,12,16,17⇓⇓⇓⇓⇓ Vasodilating drugs, such as RAS inhibitors and CCBs, can markedly reduce the magnitude of the reflected wave by attenuating the vascular tone of peripheral muscular arteries, thereby leading to a decrease in central SBP.15,18⇓ Furthermore, although HR-lowering drugs are associated with higher AIx and central aortic pressure,9,16,17,19⇓⇓⇓ in the present study, AIx and central SBP in the olmesartan/azelnidipine group tended to be lower than those in the olmesartan/HCTZ group, suggesting that the former combination could strongly decrease the reflection coefficient at reflecting sites. On the other hand, it has been reported that diuretics are not as effective as vasodilating drugs in reducing central SBP,12,15,19⇓⇓ because diuretics poorly modify the microvascular structure.15,18⇓ Thus, the olmesartan/azelnidipine treatment may have achieved selective central SBP reduction by reducing the magnitude of peripheral wave reflection.
The second mechanism was confirmed by the fact that the aortic PWV in the olmesartan/azelnidipine group decreased more than that in the olmesartan/HCTZ group, even after adjustment for MAP. The reduction in PWV delays the return of the reflected wave from the periphery to the heart and, thus, decreases central SBP.15 Our result is consistent with a previous report20 that a CCB significantly decreased the aortic PWV but a diuretic did not. In both of these studies, however, brachial MAP was more significantly reduced in the group using CCBs than in the group using diuretics, which suggests that the reduction in aortic PWV may be potentially attributable to the reduction in MAP, a determinant of PWV. On the other hand, HR at pulse wave analysis and the 24-hour PR in the olmesartan/azelnidipine group decreased more than those in the olmesartan/HCTZ group. These results are consistent with previous reports in which azelnidipine decreased the HR at the clinic21 and the 24-hour PR,13 but amlodipine increased both of these parameters, despite achieving similar BP reductions.13,21⇓ This discrepancy can be explained by the finding that azelnidipine, compared with amlodipine, was a better inhibitor of sympathetic nervous activity via vasodilation-induced baroreceptor reflex.22 Furthermore, an experimental study has confirmed that azelnidipine has a dose-dependent effect on HR reduction.23 Other studies have reported that atenolol achieved a greater reduction in aortic PWV than RAS inhibitors, despite the similar reductions in MAP.16,24⇓ This phenomenon can be explained by the reduction in HR by atenolol,16,24⇓ because HR is an important factor in the intraindividual variation of PWV.25 The HR-lowering effect of azelnidipine through its sympathetic inhibition may be, in part, responsible for the greater effect of the olmesartan/azelnidipine combination on aortic PWV. However, this add-on effect of azelnidipine on arterial stiffness may not be applicable to other CCBs, because azelnidipine has the ability, in itself, to reduce HR.
PP amplification with the olmesartan/azelnidipine treatment significantly increased, and this increase was larger than that with the olmesartan/HCTZ treatment, although PP amplification decreased with HR slowing, because the arrival of the reflected wave at the central site occurred earlier in the prolonged systolic period.15 The regression of LV mass index, after 1 year of antihypertensive treatment, was independently associated with the increase of PP amplification.26 Our results suggested that the olmesartan/azelnidipine combination could act on central PP beyond brachial PP, and this may be associated with the reduction in LV load.
The J-CORE Study has some limitations that require consideration. First, this was not a double-blind study; however, the prospective, randomized, open-label, blinded, end point design is often used in large Japanese trials, and if prospective, randomized, open-label, blinded end point studies are designed and conducted properly, the results will not be biased.27 In the J-CORE Study, all of the critical observations (in particular, the pulse wave analysis and BP measurements) were performed by an investigator who was blinded regarding treatment allocation. Second, an experimental report that an ACE-I reduced central SBP and arterial stiffness more than a CCB28 might favor the role of an ACE-I on the magnitude of wave reflection but also favor the idea that pretreatment by a RAS inhibitor creates a bias of selection of patients. Third, HCTZ was used at a relatively low dose in the present study. When diuretics are used for combination therapy, low doses are generally used in consideration of both the antihypertensive effect and the metabolic effects.29 Therefore, our study was designed to obtain results comparable to those achieved in clinical practice. Fourth, a potential limitation of the method used herein is that the calibration of central aortic pressure depends on the variability and inaccuracy of the oscillometric brachial pressure measurements required for radial waveform calibration.30 In the J-CORE Study, however, multiple cuff measurements were averaged, and our oscillometric device has been fully validated against a mercury sphygmomanometer.14 Furthermore, the central aortic pressures derived from oscillometric BPs have been shown previously to be independent predictors of cardiovascular outcomes.9 Fifth, because the study period was relatively short, it will be important to evaluate longer-term treatment to clarify the effect of these combination therapies on the arterial structural change. Finally, this study was performed in a single institute, which limits its generalizability.
The J-CORE Study demonstrated that the olmesartan/azelnidipine combination resulted in greater reductions in central SBP and arterial stiffness compared with the olmesartan/HCTZ combination, although the 2 combinations achieved a similar reduction in 24-hour SBP. Because the central SBP9,10⇓ and aortic PWV31 are independent predictors of cardiovascular morbidity in hypertensive patients, the beneficial effect of the olmesartan/azelnidipine treatment on central hemodynamics may lead to a favorable effect on cardiovascular outcomes beyond that achieved by olmesartan/HCTZ treatment. Furthermore, future research is needed to confirm that the central SBP and aortic PWV are likely to be more useful targets for antihypertensive therapy than 24-hour brachial SBP.
We thank Takashi Sugioka (Kyoto University) for his statistical analysis and the research nurses for their assistance with the study.
Sources of Funding
The Japan-Combined Treatment With Olmesartan and a Calcium Channel Blocker Versus Olmesartan and Diuretics Randomized Efficacy Study was supported by Jichi Medical University School of Medicine.
M.F.O. is a founding director of AtCor Medical, manufacturer of the systems for analyzing the arterial pulse.
This trial has been registered at www.clinicaltrials.gov (identifier NCT00607035).
- Received February 25, 2009.
- Revision received March 17, 2009.
- Accepted July 6, 2009.
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