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Abstract

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Conclusions
  8. Acknowledgments
  9. References

Efficacy of antihypertensive agents on central blood pressure (BP) in African Americans is not well studied. The authors report on an 8-week double-blind, randomized study of African American patients with stage 2 hypertension that compared brachial and central BP responses (substudy of 53 patients) to combination aliskiren/hydrochlorthiazide (HCTZ) and amlodipine monotherapy. Following a 1- to 4-week washout, initial therapy was aliskiren/HCTZ 150/12.5 mg (n=166) or amlodipine 5 mg (n=166) for 1 week, forced-titrated to aliskiren/HCTZ 300/25 mg or amlodipine 10 mg for 7 weeks. Mean seated systolic BP reductions from baseline was similar with both treatments (−28.6 mm Hg with aliskiren/HCTZ vs −28.2 mm Hg with amlodipine). In the substudy, significantly greater reductions in central systolic BP was observed with aliskiren/HCTZ vs amlodipine (−30.1 mm Hg vs −21.2; P=.031), although 24-hour mean ambulatory BP reductions between the two groups were similar. Central pressure is considered an important risk factor in African Americans, and these findings may suggest a new treatment option for these patients. J Clin Hypertens (Greenwich). 2011;13:366–375. ©2011 Wiley Periodicals, Inc.

African American adults have a greater prevalence of hypertension, an earlier onset, greater pressure–related end organ damage, and low blood pressure (BP) control rates compared with their white American counterparts (32% vs 23%).1,2 In addition, African Americans have diffuse macrovascular and microvascular dysfunction manifesting as increased stiffness of the carotid artery and aorta,3,4 heightened-resistance artery constriction, and blunted-resistance artery dilation,5 all of which correlate directly with end organ damage.6,7 Although the prognostic value of brachial BP for future cardiovascular events has been well established, arterial stiffness and microvascular dysfunction significantly influence central BP, while brachial pressure is less influenced by these changes.8

The findings from the Strong Heart Study, which noninvasively determined central pulse pressure is more strongly related to vascular hypertrophy, extent of atherosclerosis, and cardiovascular events than is brachial BP, support the use of central pressure as a treatment target in clinical trials.9 To date, findings from at least 7 longitudinal studies show that central BP is a stronger predictor of cardiovascular outcomes than brachial pulse pressure.8,10 Although prospective data are needed, central BP may be pathophysiologically more relevant than peripheral (brachial) BP in the pathogenesis of cardiovascular disease.8 A recent study conducted in young (mean age, 21.7 years) and healthy (normotensive) African American and white men (mean age, 23.6 years) reported higher central BP and stiffer blood vessels in African American men compared with their white counterparts, signs that African American men are developing hypertension early and with few symptoms.11

Calcium channel antagonists and diuretics have long been preferred as an antihypertensive therapy in blacks as monotherapy, especially compared with agents that act on the renin-angiotensin-aldosterone system (RAAS) and β-blockers, because of their greater average reductions in BP.2 In African Americans, clinical evidence suggests a decreased response to monotherapy with agents that act on the RAAS and this is speculated to be related to increased sodium intake, volume expansion, and low plasma renin activity in this population compared with whites.2,12–15 Addition of a thiazide diuretic or calcium channel blocker (CCB), however, ameliorates or removes any racial differences in BP response with angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and β-blockers.16,17

Aliskiren is the first-available direct renin inhibitor18–20 that acts at the rate-limiting step of angiotensin (Ang) II synthesis, inhibiting the conversion of angiotensinogen to Ang I and, unlike ACE inhibitors or ARBs, does not cause a compensatory increase in plasma renin activity (PRA).21 Moreover, aliskiren attenuates the increase in PRA caused by hydrochlorothiazide (HCTZ) and other antihypertensives.22–25 Thus, aliskiren may provide comprehensive RAAS suppression compared with ACE inhibitor or ARB therapy.26 Aliskiren has demonstrated antihypertensive efficacy in black patients, although a pooled analysis of 7 randomized trials found that the effect was lower than that observed in Asian or white patients.27 This finding is similar to those observed with ACE inhibitor or ARB monotherapy. The combined use of aliskiren and HCTZ has been previously shown to provide additional BP reductions and improved BP control in patients with hypertension who were nonresponsive to HCTZ 25 mg28 or aliskiren.23 We undertook the Blood Pressure Lowering of Aliskiren HCTZ vs Amlodipine in African Americans With Stage 2 Hypertension (ATLAAST) study to compare the BP-lowering efficacy and tolerability of combination aliskiren/HCTZ with the calcium channel antagonist amlodipine, the class of antihypertensives frequently used in African Americans with stage 2 hypertension. Very few studies have reported a differential effect of antihypertensive agents on central and peripheral BP measurements.29 We compared the brachial BP-lowering efficacy of combination aliskiren/HCTZ with amlodipine monotherapy with central BP measures in a subset of patients, predefined to enroll in an ambulatory BP measurement (ABPM) substudy.

Methods

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Conclusions
  8. Acknowledgments
  9. References

Patients

This study was conducted in self-identified African American men and women, 18 years or older, with stage 2 hypertension (defined as mean sitting systolic BP [MSSBP] ≥160 mm Hg and <200 mm Hg. Ethics committee and/or institutional review board approval was granted at all participating centers, and participating patients gave written informed consent prior to enrollment. The study was conducted in accordance with the ethical principles of the current Declaration of Helsinki.

Excluded from the study were patients with MSSBP ≥200 mm Hg and/or a mean sitting diastolic BP (MSDBP) ≥110 mm Hg at any visit, patients with secondary hypertension or resistant hypertension unresponsive to triple therapy (including a diuretic) at the optimal dose of each component, and patients taking ≥4 antihypertensive agents. In addition, patients with a history of cerebrovascular accident, transient ischemic cerebral attack, heart failure, myocardial infarction, coronary bypass surgery, or any percutaneous coronary intervention within the past 12 months of randomization; patients with type 1 diabetes; and patients with type 2 diabetes requiring insulin, with glycosylated hemoglobin >10% or who were not taking a stable dose of antihyperglycemic medication were excluded. Patients with serum sodium levels less than the lower limit of normal (<130 mEq/L) and serum potassium levels <3.5 or ≥5.5 mEq/L were also excluded. Also excluded were women who were pregnant, nursing, or of child-bearing potential and not using an acceptable method of contraception.

Study Design

This was an 8-week prospective, multicenter, randomized, double-blind, double-dummy, active-control, parallel group study conducted in 53 centers in the United States. After screening and a 1- to 4-week washout period of prior antihypertensive medications, eligible patients (office MSSBP ≥160 mm Hg and <200 mm Hg) were randomized in a 1:1 ratio to either a fixed-dose combination of aliskiren/HCTZ 150/12.5 mg or amlodipine 5 mg monotherapy for 1 week. Patients were then forced-titrated to aliskiren/HCTZ 300/25 mg or amlodipine 10 mg for the remaining 7 weeks (Figure 1).

image

Figure 1.  Study design. Ambulatory blood pressure measurements (ABPMs) were made at randomization and at the end of the study. HCTZ indicates hydrochlorothiazide.

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Study drugs were supplied as aliskiren/HCTZ tablets (or matching placebo tablets) and amlodipine capsules (or matching placebo capsules). To maintain double-blinding of the study, each patient was administered a total of 3 (2 tablets and 1 capsule) identically appearing tablets/capsules per day. All of the study medications were taken with water between 7 am and 10 am, except on the morning of clinic visits when medications were taken after visit procedures. Patients were not permitted to take additional drugs indicated for the treatment of hypertension during the study. Medications known to affect BP, such as diuretics of any kind, certain classes of antidepressants, chronic sympathomimetic agents (nasal decongestants), oral corticosteroids, or antiarrhythmic drugs were prohibited throughout the study period. Sildenafil, vardenafil, and tadalafil were allowed if administered 48 hours after a scheduled visit. Potassium supplements and salt substitutes containing potassium were also avoided throughout the study. Following the principles of Good Clinical Practices, patients were monitored at every visit regarding intake of concomitant medication, including nondrug therapy, by verbal inquiry.

Study Objectives

The primary objective of this study was to evaluate the superiority in the change in MSSBP from baseline after 8 weeks of treatment with combination aliskiren/HCTZ with that of amlodipine. Secondary objectives included evaluation of the superiority of aliskiren/HCTZ vs amlodipine in the change from baseline in MSDBP at week 8, the change in mean sitting pulse pressure (MSPP), the percentage of patients achieving BP control (defined as MSSBP <140 mm Hg and MSDBP <90 mm Hg), and safety and tolerability.

In a prespecified subgroup of randomized patients (aliskiren/HCTZ, n=29; amlodipine, n= 29), 24-hour mean ambulatory systolic (MASBP) and diastolic BPs (MADBP) were performed at baseline and week 8. Prespecification of ABPM was based on selection of prespecified centers (25 centers) and enrolled patients’ willingness to participate in the study. Central arterial pressures were also assessed at baseline and at week 8 in this subgroup of patients.

The impact of treatments on selected biomarkers, including the change from baseline in PRA, plasma renin concentration (PRC), and cystatin C in patients after 8 weeks of treatment with aliskiren/HCTZ or amlodipine was also assessed. Urinary aldosterone was assessed in the same subset of patients enrolled for the ABPM study.

BP Measurements

Clinic sitting BP was measured at trough (24±3 hours post-dose) using a calibrated standard mercury sphygmomanometer and the recommended cuff sizes in accordance with the 2005 American Heart Association Committee Report on Recommendations for Blood Pressure Measurements in Humans.30After sitting for 5 minutes, 3 sitting BP measurements were made at 1- to 2-minute intervals, and the mean value was taken as the average BP for that visit. In the event that mercury sphygmomanometers were not available, an alternative calibrated method for the assessment of BP was used.

ABP measurements were performed by attaching the ABPM device to the nondominant arm of the patient. A correlation was made between the ABPM device readings and measurements taken with an office mercury sphygmomanometer. Following the correlation procedure, BP and heart rate were measured using the ABPM device every 15 minutes during the 24-hour monitoring period. The ambulatory BP readings had to meet satisfactory quality control criteria, which were defined as a monitoring period of at least 24 hours with at least one valid reading per hour and at least 75% of valid readings. The ABPM device was worn for at least 24 hours before removal at the clinic. Data were processed by a central laboratory (Medifacts International, Rockville, MD).

Radial artery applanation tonometry8,31 was used to measure central aortic pressure in the ABPM subgroup of patients using a SphygmoCor (AtCor Medical, Itasca, IL) apparatus and associated software. Radial artery tonometry was performed on the dominant arm, as with the standard sphygmomanometric measurements. The patient was asked to sit quietly for 5 minutes, and radial artery applanation tonometry measurements were obtained immediately following measurement of BP by standard sphygmomanometry. These measurements were taken right after the office BPs were obtained and just prior to the placement of ambulatory BP monitor on the patient. At each time point, the patient’s mean trough sitting BP by sphygmomanometry was entered into the SphygmoCor system as the calibrating BP prior to the first tonometric measurement. Three radial artery tonometry measurements were required at each visit and data was processed through a central laboratory (AtCor Medical). The BP values taken at the time of tonometry were entered into the SphygmoCor software for calibration purposes.

Biomarker Assessments

Biomarker measurements including PRA, PRC, cystatin C, and high-sensitivity C-reactive protein (hs-CRP) obtained at baseline and week 8 in all patients. Urinary aldosterone measurements were collected and evaluated only in patients participating in the ABPM substudy. Urinary albumin creatinine ratio (UACR) was measured in patients excluding those enrolled in the ABPM study. Biomarker samples were processed by a central laboratory (CRL Medinet, Lenexa, KS).

Safety

Safety assessments consisted of monitoring and recording all adverse events (AEs) and serious AEs, regardless of suspected relation to study medication, and monitoring patient discontinuations, hematology, blood and urine chemistry, vital signs, and the performance of physical examinations including electrocardiography at baseline. The incidence of treatment-emergent AEs and serious AEs was summarized.

Statistical Analysis

A sample size of 330 patients (165 per treatment regimen) was required to ensure that the study had approximate 85% power to test for superiority of combination aliskiren/HCTZ vs amlodipine for change from baseline in MSSBP at week 8, assuming a treatment difference of 4 mm Hg in MSSBP between the two treatment arms, and a standard deviation (SD) of 12 mm Hg with a 2-sided significance level of 0.05. Efficacy data are presented for the intent-to-treat (ITT) population, which consisted of all randomized patients who received at least one dose of study medication and had at least one valid post-baseline assessment of the primary efficacy variable, and was analyzed using both last-observation-carried-forward (LOCF) and observed cases (OC) methods.

The primary efficacy variable, change in MSSBP from baseline at week 8, was assessed with an analysis of covariance (ANCOVA) model with baseline assessment as a covariate and with treatment and ABPM participation status at baseline as factors in the model. Mean differences, least squares (LS) mean differences, 95% confidence intervals (CIs), and treatment P values for the comparisons of the aliskiren/HCTZ treatment regimen with the amlodipine treatment regimen were reported. Tests for the superiority of aliskiren/HCTZ vs amlodipine were based on the null hypothesis of equal mean change in MSSBP at week 8 for the aliskiren/HCTZ and amlodipine groups with a 2-sided test at 5% level of significance. An ANCOVA model similar to that used for analyses of the primary efficacy variable was used for analyses of two of the secondary efficacy variables, change from baseline in MSDBP, and change from baseline in MSPP. The secondary efficacy variable of patients achieving BP control (MSSBP/MSDBP <140/90 mm Hg) was analyzed using the Cochran-Mantel-Haenszel test.

For the 24-hour ABPM and central BP measures, the primary analysis time point was week 8, and analyses were performed using the same methods used to analyze the primary efficacy variable. Biomarkers were analyzed using nonparametric tests and log-transformed data. Baseline and safety data are presented for the entire randomized population. All statistical analyses were performed using SAS version 8.2. (SAS Institute Inc, Cary, NC).

Results

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Conclusions
  8. Acknowledgments
  9. References

Patient Demographics and Disposition

The disposition of patients throughout the trial and reasons for discontinuations in each group are shown in Figure 2. A total of 607 patients were screened, of whom 275 were not eligible for randomization. A total of 332 patients were randomly assigned to either aliskiren/HCTZ (n=166) or amlo-dipine monotherapy (n=166). Forty-two patients (25 in the aliskiren/HCTZ group and 17 in the amlodipine group) withdrew prior to completion of the study. The most common reasons for patient discontinuation from the study were AEs and withdrawal of consent. Twice as many patients in the aliskiren/HCTZ treatment group than in the amlodipine group (7.2% vs 3.6%) were discontinued due to an AE. Four patients in the aliskiren/HCTZ group experienced >1 AE that resulted in discontinuation. A total of 8 patients (4 in each arm) were excluded from the ITT population because they had no post-baseline MSSBP assessments. A total of 58 randomized patients participated in the ABPM substudy (29 in each treatment arm).

image

Figure 2.  Patient disposition. AEs indicate adverse events; HCTZ, hydrochlorothiazide.

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Demographic and baseline characteristics were comparable between the two treatment groups (Table I). Patients enrolled were an average of 52.5 years of age, with >15% older than 65 years, and had an average body mass index of 34.1 kg/m2. Only 20% of all patients enrolled were diabetic and 82% of patients were taking antihypertensive agents prior to enrollment. Mean plasma renin activity was similar between the two treatment groups, with a mean of 1.04 ng/mL/h. As with the overall population, patients enrolled in the ABPM substudy had similar baseline characteristics with no difference between the two treatment groups: average age, 55 years; 48% men (n=28); 20% patients older than 65 years; average body mass index, 32.3 kg/m2; and 12% diabetic (n=7). The mean office BP of patients in the overall study was 168.2/95.4 mm Hg and that for patients enrolled in the ABPM study was 167.8/96.2 mm Hg.

Table I.   Demographic and Baseline Characteristics of Randomized Study Participants
 Aliskiren/HCTZ (n=166)Amlodipine (n=166)
  1. Abbreviations: BMI, body mass index; eGFR, estimated glomerular filtration rate; HCTZ, hydrochlorothiazide; MSDBP, mean sitting diastolic blood pressure; MSSBP, mean sitting systolic blood pressure; PRA, plasma renin activity; PRC, plasma renin concentration; SD, standard deviation; UAER, urinary albumin excretion rate. aNumbers based on intent-to-treat (ITT) population. bValues expressed as geometric mean after logarithmic transformation.

Age, mean±SD, y52.0 (11.3)53.1 (11.6)
 <65 y, No. (%)141 (84.9)143 (86.1)
 ≥65 y, No. (%)25 (15.1)23 (13.9)
Sex
 Male, No. (%)81 (48.8)75 (45.2)
 Female, No. (%)85 (51.2)91 (54.8)
Antihypertensive use in the past 30 days, No. (%)133 (80.1)140 (84.3)
Diabetes, No. (%)30 (18.1)39 (23.5)
BMI, mean ±SD, kg/m234.7 (8.5)33.5 (7.9)
MSSBP, mean±SD, mm Hga168.2 (8.5)168.1 (8.0)
MSDBP, mean±SD, mm Hga96.0 (9.8)95.0 (8.9)
PRA, mean±SD, ng/mL/hb0.35 (1.3)0.40 (1.3)
PRC, mean±SD, ng/Lb4.19 (1.1)4.52 (1.1)
eGFR, mean±SD, mL/min;91.7 (23.9)93.0 (22.0)
UAER, mean±SD, mg/24-hour11.7 (13.4)38.8 (82.5)
Populations
 ITT, No. (%)a162 (97.6)162 (97.6)
 Safety population, No. (%)166 (100)166 (100)

BP Reduction

Clinic BP (Brachial BP).  The primary efficacy parameter was change in MSSBP from baseline to week 8 (LOCF). Patients in both treatment groups had a significantly greater reduction in MSSBP from baseline at week 8 (LOCF) with similar reduction observed between treatments (LS mean: 28.6 vs 28.1 mm Hg for aliskiren/HCTZ and amlodipine, respectively; P=.8). (Figure 3A andTable II). As with MSSBP findings, significant reductions from baseline in MSDBP at week 8 (LOCF) was observed in both treatment groups, with no difference between treatments (LS mean: 9.4 vs 10.9 mm Hg for aliskiren/HCTZ and amlodipine, respectively; P=.2) (Figure 3A andTable II).

image

Figure 3.  Least squares mean (LSM) changes from baseline to week 8 in (A) office mean sitting systolic blood pressure (MSSBP) and mean sitting diastolic blood pressure MSDBP and (B) central systolic blood pressure (SBP) and diastolic blood pressure (DBP) in the intent-to-treat (ITT) population. N is the number of ITT patients with both baseline and end point nonmissing values. Last-observation-carried-forward (LOCF) approach is used. CI indicates confidence interval; HCTZ, hydrochlorothiazide.

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Table II.   BP Indices and Pulse Pressure Amplification Ratio at Baseline and Week 8
BP IndicesAliskiren/HCTZAmlodipineAliskiren/HCTZ vs Amlodipine; LS Mean Difference (95% CI)
BaselineWeek 8Change from Baseline, LS MeanBaselineWeek 8Change from Baseline, LS Mean
  1. Abbreviations: BP, blood pressure; CI, confidence interval; DBP, diastolic blood pressure; HCTZ, hydrochlorothiazide; LS, least squares; MADBP, mean ambulatory diastolic blood pressure; MAPP, mean ambulatory pulse pressure; MASBP, mean ambulatory systolic blood pressure; MSDBP, mean sitting diastolic blood pressure; MSPP, mean systolic pulse pressure; MSSBP, mean sitting systolic blood pressure; PP, pulse pressure; SBP, systolic blood pressure. aN is an intent-to-treat population (162 in each group); bn=29 in each group; cn=27 in aliskiren/HCTZ and n=25 in amlodipine group; PP amplification ratio calculated as ratio of brachial PP/central PP. Data are mean±SD. dP<.05. echange from baseline, actual mean.

Peripheral BPa
 MSSBP, mm Hg168.2±8.5138.8±18.2−28.61168.1±8.0139.1±14.5−28.18−0.42 [−3.8, 2.9]
 MSDBP, mm Hg96.0±9.886.0±12.0−9.4195.0±8.984.0±9.7−10.891.48 (−0.63 to 3.59)
 MSPP, mm Hg72.2±12.152.7±14.9−19.1673.1±11.655.1±12.1−17.31−1.85 (−4.39 to 0.69)
24-H Ambulatory BPb
 MASBP, mm Hg148.0±13.0134.4±16.6−12.54148.0±8.5135.4±5.9−12.12−0.42 (−7.4 to 6.6)
 MADBP, mm Hg90.4±10.083.4±9.0−6.4290.9±8.483.6±5.0−6.870.46 (−3.6 to 4.5)
 MAPP, mm Hg57.6±10.951.0±11.8−6.3157.1±7.851.8±4.7−5.06−1.24 (−4.9 to −2.4)
Central BPc
 SBP, mm Hg153.9±10.8123.0±12.1−30.13153.2±10.5132.3±11.6−21.22−8.91d (−16.9 to −0.87)
 DBP, mm Hg96.8±10.584.9±11.7−11.0395.2±8.987.8±7.7−7.03−4.0 (−9.42 to −1.41)
 PP, mm Hg57.3±15.938.2±13.6−19.0658.0±12.544.5±12.0−14.20−4.86 (−11.2 to −1.49)
 PP amplification ratio1.28±0.191.35±0.17[UPWARDS ARROW]0.13e1.28±0.21.25±0.17[DOWNWARDS ARROW]0.02e0.11d (0.01–0.2)

24-Hour ABPM.  In the subset of patients included for ABPM substudy, at week 8, both treatments significantly reduced mean ambulatory systolic BP and diastolic BP from baseline. However, there was no difference between treatments (Table II).

Central BP.  The same subset of patients included for ABPM were also included for central BP measures. At week 8, both treatments significantly decreased central systolic BP from baseline. Aliskiren/HCTZ decreased mean central systolic BP from a baseline of 153.9±10.8 mm Hg (mean±SD) to 123.0±12.1 mm Hg (P<.0001), and amlodipine decreased mean central systolic BP from 153.2±10.5 mm Hg at baseline to 132.3±11.6 mm Hg (P<.0001). However, in contrast to clinic measures of MSSBP, the reductions in central systolic BP from baseline to week 8, observed with aliskiren/HCTZ was significantly greater compared with those observed with amlodipine (LS mean: −30.1 mm Hg vs −21.2 mm Hg; LS mean difference between treatments −8.9; 95% CIs [−16.9 to −0.87]; P=.03) (Figure 3B andTable II).

As observed for central systolic BP, both treatments significantly decreased central diastolic BP from baseline. Aliskiren/HCTZ reduced central diastolic BP from 96.8±10.5 mm Hg at baseline to 84.9±11.7 mm Hg (P<.0001), and amlodipine from 95.2±8.9 mm Hg at baseline to 87.8±7.7 mm Hg (P=.006). The difference between the two treatment groups, however, was not statistically significant (Figure 3B andTable II).

Pulse Pressure Amplification Ratio

In the subset study of 58 patients included for central pressure measures, at baseline, the pulse pressure amplification ratio (calculated as a ratio of brachial pulse pressure over central pulse pressure) was 1.28±0.2 in both the aliskiren/HCTZ group and amlodipine group. At week 8, this ratio significantly increased to 1.35±0.2 in the aliskiren/HCTZ group (P=.0002 from baseline), whereas there was no change in the amlodipine group (P=.64 from baseline). The LS mean difference between the two treatment groups was significant in favor of aliskiren/HCTZ (P=.03) (Figure 4 andTable II).

image

Figure 4.  Pulse pressure (PP) amplification ratio at baseline and week 8. HCTZ indicates hydrochlorothiazide; LSM, least squares mean.

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BP Control

The percentage of patients achieving BP control (<140/90 mm Hg) by the end of the study was similar between the two treatment groups: 53.8% in the aliskiren/HCTZ arm and 48.7% in the amlodipine arm.

Biomarkers

Pretreatment geometric mean PRA in randomly assigned patients was 0.35 ng/mL/h in the aliskiren/HCTZ group and 0.40 ng/mL/h in the amlodipine group. At end of study, combination aliskiren/HCTZ significantly reduced PRA by 40%. In contrast, amlodipine led to a 101% increase in PRA. Combination aliskiren/HCTZ raised plasma renin concentrations from baseline (geometric mean increase, 943%), as did amlodipine (geometric mean increase, 60%); however, the increase with aliskiren/HCTZ was significantly greater than with amlodipine (P<.0001).

There were no differences from baseline in both treatment groups in any of the other biomarker assays including hs-CRP, urinary F2 isoprostanes, or urinary aldosterone and UACR.

Safety

Of the 332 patients in the safety population, overall, 131 (39.5%) reported at least one AE, with 74 (44.6%) in the aliskiren/HCTZ treatment group and 57 (34.3%) in the amlodipine treatment group. The AEs experienced by at least 2% of patients in either treatment regimen were headache, diarrhea, nausea, hypokalemia, nasopharyngitis, upper respiratory tract infection, peripheral edema, and pain in an extremity. The incidence of these AEs was similar between treatment groups (Table III). Most AEs were considered by the investigator to be of mild or moderate severity and most were, in the investigator’s opinion, not suspected to be treatment-related. Only 8.4% (10.8% aliskiren/HCTZ and 6% amlodipine) of the overall AEs were suspected by the investigator as study-related. Overall, 23.2% of patients experienced mild AEs (27.7% aliskiren/HCTZ and 18.7% amlodipine), 12.7% of patients experienced moderate AEs (12.7% in each treatment group), and 3.6% of patients experienced severe AEs (4.2% aliskiren/HCTZ and 3.0% amlo-dipine). The severe AEs experienced by patients in the aliskiren/HCTZ group were acute myocardial infarction, congestive cardiac failure, chronic renal failure, hypertension, encephalitis herpes, cerebral hemorrhage, appendicitis, cellulitis, gastric ulcer hemorrhage, muscle spasms, disturbance in attention, and headache. The severe AEs experienced by patients with amlodipine were back pain, musculoskeletal chest pain, myocardial infarction, coronary artery disease, and peripheral edema.

Table III.   Summary of Adverse Events (AEs)
 Aliskiren/Hydrochlorothiazide (n=166)Amlodipine (n=166)
Any AE, No. (%)74 (44.6)57 (34.3)
Serious AE, No. (%)5 (3.0)3 (1.8)
Discontinuation due to an AE, No. (%)12 (7.2)6 (3.6)
Suspected due to treatment, No. (%)18 (10.8)10 (6.0)
AEs occurring in at least ≥2% of patients in any treatment group, No. (%)
 Headache6 (3.6)7 (4.2)
 Diarrhea6 (3.6)4 (2.4)
 Nausea6 (3.6)4 (2.4)
 Hypokalemia6 (3.6)3 (1.8)
 Nasopharyngitis2 (1.2)5 (3.0)
 Upper respiratory  tract infection5 (3.0)2 (1.2)
 Peripheral edema2 (1.2)4 (2.4)
 Pain in extremity1 (0.6)5 (3.0)

Serious AEs were reported in 8 patients: 5 in the aliskiren/HCTZ group and 3 in the amlodipine group. The 5 patients in the aliskiren/HCTZ group experienced acute myocardial infarction, appendicitis, encephalitis herpes, cellulitis, rhabdomyolysis, hypokalemia, and cerebral hemorrhage. The 3 patients in the amlodipine group experienced musculoskeletal chest pain, myocardial infarction, and acute myocardial infarction. All 8 patients discontinued from the study. Other AEs leading to discontinuation in the aliskiren/HCTZ group included congestive cardiac failure, chronic renal failure, hypertension, cerebral hemorrhage, gastric ulcer hemorrhage, nausea, muscle spasms, disturbance in attention, and headache. In the amlodipine group, AEs leading to discontinuation included hypokalemia, exertional dyspnea, and peripheral edema. There were no deaths in the study.

Discussion

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Conclusions
  8. Acknowledgments
  9. References

We observed significant and similar reductions in MSSBP from baseline (approximately 28.0 mm Hg) at week 8 in African American patients with stage 2 hypertension treated with either combination aliskiren/HCTZ or amlodipine. The primary end point of superiority with aliskiren/HCTZ in reducing MSSBP from baseline at week 8 compared with amlodipine monotherapy was not met. At the end of the study, combination aliskiren/HCTZ significantly reduced PRA by 40%. In contrast, amlodipine led to a 101% increase in PRA, consistent with previously reported findings.22–25 The ABPM reductions observed in a subset of patients mirrored the overall findings. In this subset of patients, the central systolic BP in the aliskiren/HCTZ group decreased more than that in the amlodipine group in contrast to similar brachial systolic BP changes. As a result, the pulse pressure amplification ratio (defined as ratio of brachial pulse pressure/central pulse pressure) increased more with aliskiren/HCTZ compared with amlodipine.

Few studies in the literature have compared the peripheral and central BP effects of antihypertensive agents. Previously, Mackenzie and colleagues,29 in a 10-week study in patients with isolated systolic hypertension, compared the effects of 4 major classes of antihypertensive agents: ACE inhibitor (perindopril), dihydropyridine CCB (lercanidipine), diuretic (bendrofluazide), and β-blocker (atenolol), on peripheral vs central pressure and reported that although peripheral systolic BP and peripheral pulse pressure were reduced similarly after treatment with all 4 classes of drugs, central pulse pressure was only reduced significantly by perindopril, lercanidipine, and bendrofluazide, whereas atenolol had no effect.29

The effects of aliskiren monotherapy on central BP have not been previously reported. However, diuretic monotherapy has been reported to lower brachial and central BP to a similar extent.32 In a small randomized clinical study of untreated patients with essential hypertension (systolic BP >150 mm Hg), HCTZ32 at 2 doses (25/50 mg) and analyzed together, showed a similar reduction on both peripheral and central systolic BP (−15.2 mm Hg and −15.0 mm Hg, respectively) as well as pulse pressure (−10.7 mm Hg and −10.0 mm Hg, respectively), compared with placebo.32 Dihydropyridine CCBs either as monotherapy or when used in combination with RAAS blockers have been reported to effectively reduce central BP to a greater extent than peripheral BP.32,33 The findings from the Conduit Artery Function Evaluation (CAFÉ) study provide the most important data regarding the effect of dihydropyridine CCBs on central BP.31 The CAFÉ study is the vascular substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) that compared in a randomized controlled manner the effect of atenolol±thiazide vs amlodipine±perindopril on central BP. In a select subgroup of 2199 patients, it was shown that although peripheral systolic BP was similar, the patients randomized to an amlodipine-based regimen had a significantly lower level of central systolic BP (4.3 mm Hg lower) and central aortic pulse pressure (3.0 mm Hg lower) during the study than patients taking the atenolol-based regimen. These differences could not be detected at the level of the brachial artery. Although lack of availability of baseline data on central hemodynamics was a major limitation of this study, the CAFÉ study provided evidence regarding differential effect of antihypertensive agents on central and peripheral BP. Secondly, it also showed that a CCB/ACE inhibitor regimen is better than a β-blocker/diuretic regimen. Among the agents acting on the RAAS, there is convincing evidence for the presence of additional central BP-lowering capacity beyond peripheral BP reduction for the ACE inhibitors; however, more data are needed for ARBs.32 Our study is the first trial describing the efficacy of treatment with the direct renin inhibitor, aliskiren, in combination with a diuretic on central BP-lowering compared with amlodipine monotherapy. Although limited by sample size, of interest was that amlodipine monotherapy reduced peripheral systolic BP more effectively than central systolic BP, while the magnitude of reductions observed with combination aliskiren+HCTZ was similar for peripheral and central BP measures.

Most patients with stage 2 hypertension require combination therapy with ≥2 agents. This is particularly true for African Americans.2 The findings from the CAFÉ study did suggest a beneficial effect for combination ACE inhibitor/CCB on central BP. The only other study that evaluated the efficacy of combination therapy on central BP was the REASON study, where combination ACE inhibitor/diuretic was compared with atenolol.34 Findings from this trial showed that the combination of an ACE inhibitor (perindopril) with a diuretic (indapamide) decreased central systolic BP significantly more than an atenolol-based regimen despite similar brachial diastolic BP reductions.34 Our study showed similar findings in that central systolic BP reductions were significantly greater with combination aliskiren/HCTZ compared with amlodipine monotherapy despite similar office BP reductions.

Most AEs were considered by the investigators to be mild to moderate in severity. The most common AE in both treatment groups were headache, diarrhea, and nausea. Hypokalemia was commonly reported with aliskiren/HCTZ. There were no drug-related incidences of hyperkalemia reported in our study.

Limitations

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Conclusions
  8. Acknowledgments
  9. References

The ABPM and central BP measures were conducted in a small subgroup of patients randomized to the trial. The overall study was not specifically designed to evaluate the effects of combination aliskiren/HCTZ and amlodipine on central BP measures. The findings reported in favor of combination aliskiren/HCTZ on the central BP measurements were from a small subset of patients. Thus, we lack the ability to draw any firm conclusions based solely on the central BP data.

Conclusions

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Conclusions
  8. Acknowledgments
  9. References

In our study, combination of aliskiren/HCTZ was as effective as amlodipine in reducing office BP. While the effects of combination aliskiren/HCTZ therapy on central hemodynamics needs to be confirmed in larger studies, our measurements in a small subset of African American patients suggests that for similar reductions in brachial BP, combination aliskiren/HCTZ is more effective than amlodipine monotherapy in reducing central BP. Central BP is considered an independent cardiovascular risk factor and our findings suggest that the use of combination aliskiren/HCTZ therapy is a beneficial treatment option from a peripheral as well as a central pressure standpoint in African Americans with stage 2 hypertension.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Conclusions
  8. Acknowledgments
  9. References

Acknowledgements and disclosures:  The authors express their appreciation to Edite O’Hern of Novartis Pharmaceuticals Corporation for expert assistance in project management. ClinicalTrials.gov identifier: NCT00739596. The authors wish to thank Kanaka Sridharan of Novartis Pharmaceuticals Corporation and Richard Edwards, PhD, of Complete Heath Care Communications for technical assistance and styling the manuscript to the journal requirements. All authors approved the final version of the manuscript submitted for publication. This study was funded by Novartis Pharmaceuticals Corporation, East Hanover, NJ. Dr Ferdinand has received research support and honoraria from AstraZeneca Pharma-ceuticals LP; Merck & Co. Inc; Novartis Pharmaceuticals Corporation; Pfizer Inc; Forest Labs; and Daiichi Sankyo. Dr Pool is engaged in research and/or serves as a consultant for the Agency for Healthcare and Research Quality (AHRQ), Boehringer Ingelheim, Bristol-Myers Squibb, Forest Research Institute, Merck & Co., Novartis Pharmaceuticals Corpora-tion, National Institutes of Health (NIH) and Sanofi Aventis. Dr Weitzman and Dr Purkayastha are employees of Novartis Pharmaceuticals Corporation. Dr Townsend receives research support from the National Institutes of Health and Novartis Pharmaceuticals Corporation. Dr Townsend has received honoraria from the American Society of Nephrology and the American Society of Hypertension and has a consultant/advisory board relationship with GlaxoSmithKline and Roche Pharmaceuticals. The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official views of NIH.

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  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Conclusions
  8. Acknowledgments
  9. References
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