Marc Israel was an employee of Novartis Pharmaceuticals Corporation at the time of study completion and analysis review; he is currently employed by Regeneron Pharmaceuticals Ltd.
Comparative Efficacy and Safety of Combination Aliskiren/Amlodipine and Amlodipine Monotherapy in African Americans With Stage 2 Hypertension
Version of Record online: 20 JUN 2011
© 2011 Wiley Periodicals, Inc.
The Journal of Clinical Hypertension
Volume 13, Issue 8, pages 571–581, August 2011
How to Cite
Black, H. R., Weinberger, M. H., Purkayastha, D., Lee, J., Sridharan, K., Israel, M., Hilkert, R. and Izzo, J. (2011), Comparative Efficacy and Safety of Combination Aliskiren/Amlodipine and Amlodipine Monotherapy in African Americans With Stage 2 Hypertension. The Journal of Clinical Hypertension, 13: 571–581. doi: 10.1111/j.1751-7176.2011.00483.x
- Issue online: 1 AUG 2011
- Version of Record online: 20 JUN 2011
- Manuscript received November 29, 2010; Revised: February 28, 2011; Accepted: March 4, 2011
J Clin Hypertens (Greenwich). 2011;13:571–581. ©2011 Wiley Periodicals, Inc.
Initial multiple drug therapy for hypertension achieves greater and quicker reductions and higher blood pressure (BP) control rates than monotherapy. This 8-week, prospective, multicenter, randomized, double-blind study compared the efficacy and safety of the initial combination of aliskiren/amlodipine with amlodipine monotherapy in African Americans with stage 2 hypertension. After a 1- to 4-week washout, patients received aliskiren/amlodipine 150/5 mg or amlodipine 5 mg for 1 week and then were force-titrated to aliskiren/amlodipine 300/10 mg or amlodipine 10 mg for 7 weeks. At week 8, greater reductions in mean sitting systolic BP were obtained with aliskiren/amlodipine (n=220) than with amlodipine (n=223) (least squares mean change [standard error of the mean], −34.1 [1.14] mm Hg vs −28.9 [1.12] mm Hg; P<.001). Ambulatory and central BP measures were consistent with clinic BP findings, although these were conducted in a small subset of patients (n=94 in ambulatory BP monitoring substudy and n=136 for central BP). More patients achieved goal BP (<140/90 mm Hg) with aliskiren/amlodipine than with amlodipine at week 8 (57.3% vs 48.0%; P = .051). Both treatment groups had similar adverse event rates (35.0% and 32.7%, respectively). The most common adverse events were peripheral edema (7.7% with aliskiren/amlodipine and 9.0% with amlodipine), headache, fatigue, and nausea. The combination of aliskiren/amlodipine reduced peripheral, ambulatory, and central BP more than amlodipine alone with similar tolerability in African Americans with stage 2 hypertension.
The disease burden of hypertension, as measured by prevalence, age of onset, measured blood pressure (BP) range, degree of target organ damage (TOD), is higher in African Americans than non-Hispanic whites, and the pattern of response to many types of antihypertensive drugs is different.1 The factors responsible for the disproportionately high rates of hypertension-related morbidity and mortality remain to be fully defined, but this population also has a higher prevalence of obesity, inactivity, diabetes, salt sensitivity,2,3 and a different pattern of activity of the renin-angiotensin system (RAS),4,5 all of which may contribute to the observed differences.
In African Americans with hypertension, monotherapy with thiazide diuretics and calcium channel blockers (CCBs) has been reported to provide greater BP-lowering than with RAS blockers.2 However, when a RAS blocker is combined with a diuretic, BP efficacy is similar in African American and white populations.6,7 Similar to most patients with hypertension,8 African Americans usually require ≥2 antihypertensive agents to achieve BP goal. β-Blocker/diuretic, RAS blocker/diuretic, RAS blocker/CCB, diuretic/CCB, and diuretic/aldosterone antagonist are all considered effective2; however, the combination of a RAS blocker with a CCB or, alternatively, in edematous or volume-overload states, a RAS blocker with a diuretic, is recommended.9 Combination antihypertensive drug therapy with an angiotensin receptor blocker (ARB) and the CCB amlodipine also achieves prompt, effective reductions in BP and higher BP control rates than amlodipine monotherapy in this patient population.10,11
Aliskiren is a direct renin inhibitor that acts at the rate-limiting step of the RAS cascade, inhibiting the formation of angiotensin I from angiotensinogen.12 Unlike angiotensin-converting enzyme (ACE) inhibitors or ARBs, aliskiren does not cause a compensatory increase in plasma renin activity (PRA).13 Furthermore, aliskiren attenuates the increase in PRA caused by diuretics and many other antihypertensives.14–16 However, the antihypertensive efficacy of aliskiren in African Americans, like that of ACE inhibitors and ARBs,2 appears to be lower than that observed in white or Asian patients.17 In persons with stage 1 hypertension (systolic BP [SBP] 140–159 mm Hg and/or diastolic BP [DBP] 90–99 mm Hg) who do not respond vigorously to amlodipine 5 mg daily, the addition of aliskiren 150 mg daily provides similar BP reductions to titrating amlodipine to 10 mg but with improved tolerability.18 However, data on aliskiren at a dose of 300 mg combined with amlodipine 10 mg in patients with stage 2 hypertension (SBP ≥160 mm Hg and/or DBP 100 mm Hg) are lacking. Accordingly, in this study, we compared the effects on clinic BP of aliskiren/amlodipine 300/10 mg combination therapy with amlodipine 10 mg monotherapy in African American patients with stage 2 hypertension.
Since ambulatory BP monitoring (ABPM) appears to be more reliable than clinic BP measurements in predicting TOD and morbidity,19,20 and elevated central SBP is another validated risk factor for cardiovascular (CV) outcomes that may be more closely related to CV disease risk than brachial SBP in African American men,21–23 we also studied 24-hour ambulatory BP measures and central BP values from pulse-wave analysis in a subset of individuals.
The Aliskiren Amlodipine Combination in African AmEricans With Stage 2 HypertenSion (AACESS) study was conducted in self-identified African American men and women 18 years and older. An institutional review board, independent ethics committee, or research ethics board approved this study at each center, and all patients provided written informed consent before inclusion in the study in accordance with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice with applicable local regulations and the ethical principles of the current Declaration of Helsinki (NCT00853957).
Patients who were newly diagnosed and treatment-naïve or those taking ≤3 antihypertensive drugs were eligible for participation if they had mean sitting SBP (msSBP) ≥160 mm Hg and <200 mm Hg. Other exclusion criteria are listed in Table I. In addition, exclusion criteria specific to ABPM substudy were patients with an arm circumference >42 cm, night shift workers, or those with sleep apnea.
|Mean sitting systolic blood pressure (msSBP) ≥200 mm Hg or mean sitting diastolic BP (msDBP) ≥110 mm Hg|
|Patients treated with ≥4 antihypertensive agents|
|Patients with refractory hypertension (blood pressure [BP] >140/90 mm Hg despite optimal-dose triple-drug therapy including a diuretic)|
|Patients with severe uncontrolled hypertension (msSBP >180 mm Hg) while taking ≥1 antihypertensive agent at screening|
|Type 1 diabetes or poorly controlled type 2 diabetes|
|History of hypertensive encephalopathy, cerebrovascular accident, transient ischemic attack, heart failure (New York Heart Association class II-IV), coronary bypass graft surgery, percutaneous coronary intervention (PCI), unstable angina pectoris, or myocardial infarction in the past 12 months|
|Serum sodium level below the lower limit of normal (<130 mEq/L)|
|Serum potassium level <3.5 mEq/L or ≥5.5 mEq/L|
|Premenopausal women who were pregnant, nursing, or not using an effective form of contraception were also excluded|
This was an 8-week, prospective, multicenter, randomized, double blind, active-controlled, parallel-group study conducted at 67 centers in the United States between February and August 2009 (Figure 1). Following screening and a 1- to 4-week washout period, eligible patients were randomized to treatment with a combination of aliskiren/amlodipine 150/5 mg or amlodipine monotherapy 5 mg. After the first week, doses were force-titrated to aliskiren/amlodipine 300/10 mg or amlodipine 10 mg for an additional 7 weeks.
Study drugs were supplied as 150 mg tablets (aliskiren) and 5 mg capsules (amlodipine) and matching placebo tablets and capsules to be taken once daily with water between 7 am and 10 am, except on the morning of clinic visits when they were taken after clinic procedures were completed. To ensure study blinding, all patients took 2 tablets and 2 capsules each day throughout the 8-week treatment period. During the study, patients were not permitted to take any nonstudy antihypertensive drugs or potassium supplements. Antidepressants, antipsychotic agents, oral corticosteroids, diuretics, antiarrhythmics, chronic sympathomimetic drugs (nasal decongestants, bronchodilators), and nonsteroidal anti-inflammatory drugs were also prohibited during the study period. Phosphodiesterase type 5 inhibitors (sildenafil, vardenafil, and tadalafil) were allowed if they were taken >48 hours before any scheduled visit.
A total of 29 sites participated in the ABPM substudy. At screening, a patient’s willingness to participate in the ABPM study was identified and was enrolled in the substudy. The same patients were also enrolled for central BP measurements. Following the 1- to 4-week washout, patients who met eligibility criteria and were willing to participate in the ABPM study returned to the clinic the day before randomization and had the ABPM device (SpaceLabs 90207, Redmond, WA) placed on their arm. On the day of randomization, if ABPM was successful, they were randomized into the ABPM substudy. If ABPM was unsuccessful, their randomization was postponed and the ABPM device was re-applied within 48 hours. After the completion of the second ABPM measurement, if successful, the patient was randomized into the study. However, after two unsuccessful attempts to measure mean 24-hour ABPM, patients were discontinued from the ABPM substudy but were allowed to continue in the main study.
The primary objective of this study was to evaluate the superiority of aliskiren/amlodipine combination vs amlodipine monotherapy for change from baseline in msSBP at week 8. Secondary objectives were comparisons between treatment groups for change from baseline at week 8 in mean seating DBP (msDBP), percentage of patients achieving BP goal (msSBP/msDBP <140/90 mm Hg), safety, tolerability, and incidence of peripheral edema. When the updated International Society on Hypertension in Blacks (ISHIB) Consensus Statement was issued,9 we also performed a retrospective analysis to determine the number of patients in each group whose msSBP/msDBP was <135/85 mm Hg at week 8. Additional objectives included evaluation at baseline and at week 8 of PRA, plasma renin concentration (PRC), urinary albumin:creatinine ratio (UACR), and, in a prespecified subgroup of randomized patients, central aortic pressures, 24-hour mean ambulatory SBP (maSBP) and DBP (maDBP), and urinary aldosterone and urinary albumin excretion rate (UAER).
Clinic Sitting BP Sitting BP was measured at trough (24±3-hours postdose) using a calibrated standard mercury sphygmomanometer and the recommended cuff sizes.24 Three measurements were made at 1- to 2-minute intervals in the sitting position with the mean recorded as the BP for that visit.
Ambulatory BP A 24-hour ABPM study was performed in a subset of patients at baseline and at week 8. Following clinic BP measurement, the ABPM device was placed on the patient’s nondominant arm. Readings were correlated with measurements taken with an office mercury sphygmomanometer at the time of device placement. Following the correlation procedure, BP and heart rate were recorded every 15 minutes during the 24-hour monitoring period. Ambulatory BP readings that met satisfactory quality-control criteria were defined as a monitoring period of at least 23 hours with at least 80% of valid readings and one valid reading per hour. Data were processed by a central laboratory (Medifacts International, Rockville, MD).
Central BP In the ABPM subgroup, central arterial pressure was also measured at baseline and at week 8 by radial artery applanation tonometry (SphygmoCor, AtCor Medical, Sydney, Australia) on the dominant arm immediately following measurement of BP by standard sphygmomanometry. At each time point, the patient’s mean trough sitting BP 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 were processed through a central laboratory (AtCor Medical, Itasca, IL).25
Safety was assessed by the investigator in all randomized patients who received ≥1 dose of study medication. Safety assessments included monitoring for and recording of all adverse events (AEs), serious AEs, and patient discontinuations as well as the regular monitoring of hematology, blood chemistry, urinalysis, and vital signs and the performance of physical examinations.
A sample size of 442 patients (221 per treatment group) was required to establish superiority between the two treatments for change in msSBP from baseline at week 8 with 85% power to detect a treatment difference of 4 mm Hg in msSBP at a two-sided significance level of 0.05, assuming a standard deviation (SD) of 14 mm Hg.
A subset of approximately 140 randomized patients (70 per arm) was included for evaluation of the 24-hour ABPM and specific biomarker profiles. Although the analysis was prespecified, the sample size for the exploratory analysis of the ABPM and selected biomarkers was not determined based on statistical considerations.
Baseline and safety data are presented for the entire randomized population who received at least one dose of study medication. All efficacy analyses, including tests for the superiority of the aliskiren/amlodipine combination regimen vs the amlodipine monotherapy regimen, were carried out for the full analysis set, consisting of patients to whom study medications had been assigned, using the last-observation-carried-forward (LOCF) method to replace missing postbaseline values.
Changes in msSBP and msDBP from baseline at week 8 were evaluated using an analysis of covariance (ANCOVA) model with baseline assessment as a covariate and treatment and pooled center as factors in the model. Means, mean differences, least square (LS) means, LS mean differences, 95% confidence intervals (CIs), and treatment P values for the comparisons of the aliskiren/amlodipine treatment regimen to the amlodipine treatment regimen were recorded. The percentage of patients whose BPs were lowered to <140/90 mm Hg at the specified time point was analyzed using a Cochran–Mantel–Haenszel (CMH) chi-square test stratifying for pooled center and using only the observed cases.
For 24-hour ambulatory measures of BP and arterial compliance (central BP), analyses were based on the patients who met the study criteria for randomization and had a measurement at baseline. For all exploratory efficacy measures, the primary analysis time point was week 8 and the analyses were performed using only those on treatment, with the same methods employed to analyze the primary efficacy variable.
Changes in plasma and urinary biomarkers were analyzed using log-transformed data and nonparametric tests. LS means and standard errors, LS mean difference, 95% CI on the LS mean difference, and treatment P value for the comparison of aliskiren/amlodipine treatment regimen against amlodipine treatment regimen were reported.
All statistical analyses were performed using SAS®-version 9.1.3 (SAS Institute Inc, Cary, NC) under the responsibility of the Novartis trial statistician (DP).
Patient Disposition and Baseline Characteristics
Of the 729 African American patients who were screened, 443 met the eligibility criteria and were randomized to either aliskiren/amlodipine (n=220) or amlodipine alone (n=223; Figure 2). Two hundred and eighty-six patients were not eligible for randomization to a treatment regimen. The most common reason(s) for patient ineligibility for enrollment were unacceptable laboratory values or test procedure results and consent withdrawal. Of the randomized patients, 410 (aliskiren/amlodipine, n=206; amlodipine, n=204) completed the study. A total of 33 patients (aliskiren/amlodipine, n=14; amlodipine, n=19) were discontinued from the study. The most common reasons for patient withdrawal were AEs (9 patients in the aliskiren/amlodipine group and 3 patients in the amlodipine group), withdrawal of consent (4 in the aliskiren/amlodipine group and 5 in the amlodipine group), lost to follow-up (1 in the aliskiren/amlodipine group and 6 in the amlodipine group), lack of therapeutic efficacy (2 in the amlodipine group), and protocol deviations (3 in the amlodipine group).
Demographic and baseline characteristics were similar between the two treatment groups (Table II). The average age in the overall study cohort was 52.8±10.0 years and more than half (53.7%) were women. Most patients were younger than 65 and the mean body mass index was 33.8±7.9 kg/m2. Nearly half (44.5%) of the patients had metabolic syndrome according to National Cholesterol Education Program Adult Treatment Panel III diagnostic criteria.26 About 18% of the study population had diabetes mellitus. In addition, at least 60% of the patients (265 overall; 139 [63%] patients in the aliskiren/amlodipine group and 126 [57%] in the amlodipine group) had at least one secondary prevention risk including diabetes, metabolic syndrome, urinary albumin:creatinine ratio of >200 mg/g; eGFR <60 mL/min per 1.73 m2, prediabetes based on impaired fasting glucose levels of 100 to <126 mg/d, or presence of CV disease based on medical history. More than 80% of the patients were taking antihypertensive agents within the last 30 days prior to screening. The most common prior antihypertensive medications (≥10% of the patients in either treatment group) were lisinopril, amlodipine, and hydrochlorothiazide. The mean baseline sitting BP was similar between the two groups: 167.4/96.2 mm Hg for the aliskiren/amlodipine group vs 167.4/97.2 mm Hg for the amlodipine group.
|Aliskiren/Amlodipine (n=220)||Amlodipine (n=223)||Between-Treatment P Value|
|Age group, No. (%)|
|<65 y||198 (90.0)||199 (89.2)||.877|
|≥65 y||22 (10.0)||24 (10.8)|
|Sex, No. (%)|
|Male||97 (44.1)||108 (48.4)||.391|
|Female||123 (55.9)||115 (51.6)|
|BMI, kg/m2||33.8±8.1 (n=218)||33.9±7.8||.836|
|Waist circumference, cm||103.6±15.7 (n=216)||103.7±16.9 (n=220)||.943|
|Metabolic syndrome, No. (%)b||96 (43.6)||101 (45.3)||.847|
|Diabetes, No. (%)c||41 (18.6)||38 (17.0)||.710|
|Prior antihypertensive medication, No. (%)d||182 (82.7)||187 (83.9)|
|msSBP, mm Hg||167.4±8.2||167.4±8.1||.943|
|msDBP, mm Hg||96.2±9.5||97.2±8.2||.236|
|maSBP, mm Hg||152.8±14.7 (n=50)||147.5±12.9 (n=44)||.071|
|maDBP, mm Hg||94.1±12.5 (n=50)||92.3±9.9 (n=44)||.446|
|Central SBP, mm Hg||154.9±12.5 (n=72)||153.8±9.5 (n=64)||.588|
|Central DBP, mm Hg||97.3±11.2 (n=72)||100.4±8.3 (n=64)||.075|
|PRA, ng/mL/h||.978±2.178 (n=198)||.976±3.405 (n=188)||.994|
A total of 147 patients, 76 in the aliskiren/amlodipine group and 71 in the amlodipine group, were initially enrolled in the central BP-ABPM substudy. At baseline, adequate radial tonometry studies were available for 72 patients in the aliskiren/amlodipine group and 64 patients in the amlodipine group, and adequate ABPM measurements were available for 50 patients in the aliskiren/amlodipine group and 44 patients receiving amlodipine monotherapy. Baseline characteristics among individuals participating in the ABPM substudy were similar to the overall population and did not differ between the two treatment groups. Mean baseline sitting BP was 168.4/96.6 mm Hg for the aliskiren/amlodipine group vs 167.2/97.9 mm Hg for the amlodipine group. Mean 24-hour ABPM measures were 152.8/94.1 mm Hg for the aliskiren/amlodipine group vs 147.5/92.3 mm Hg for the amlodipine group. Central BP values at baseline were 154.9/97.3 mm Hg for the aliskiren/amlodipine group vs 153.8/100.4 mm Hg for the amlodipine group.
Clinic Sitting BP Patients who received the aliskiren/amlodipine combination treatment had significantly greater reductions from baseline in msSBP at week 8 (LOCF, the primary efficacy variable) than those who received amlodipine monotherapy (LS mean change [standard error of the mean, SEM], −34.1 [1.1] mm Hg vs −28.9 [1.1] mm Hg; LS mean difference, −5.2; 95% CI, −7.7 to −2.7; P<.001) (Figure 3A). The change in msDBP from baseline to week 8 was also significantly greater with aliskiren/amlodipine than with amlodipine monotherapy (LS mean change [SEM], −14.3 [0.68] mm Hg vs −10.5 [0.67] mm Hg; LS mean difference, −3.8; 95% CI, −5.3 to −2.3; P<.001) (Figure 3B). Significantly greater reduction from baseline in msSBP and msDBP with aliskiren/amlodipine than with amlodipine monotherapy was also observed at week 4 (msSBP LS mean change [SEM], −31.2 [1.1] mm Hg vs −27.7 [1.1] mm Hg; LS mean difference, −3.5; 95% CI, −5.9 to −1.1; P=.005; and msDBP LS mean change [SEM], −13.4 [0.7] mm Hg vs −10.9 [0.7] mm Hg; LS mean difference, −2.4; 95% CI, −4.0 to −0.9; P=.002) (Figure 3C).
Goal BP Rates At week 4, more patients in the aliskiren/amlodipine treatment group had achieved BP of <140/90 mm Hg compared with the amlodipine group (54.5% vs 43.5%; between-treatment difference, 11.0% [95% CI, 1.5–20.5; P=.022]). At week 8, the rate of patients achieving BP <140/90 mm Hg trended higher with aliskiren/amlodipine than amlodipine (57.3% vs 48.0%; between-treatment difference, 9.2%; P=.051) (Figure 4). At the same time point, using the ISHIB criteria of BP goal (<135/85 mm Hg) for African Americans with elevated BP without TOD, preclinical CV disease, or overt CV disease,9 a significantly higher goal rate was achieved with aliskiren/amlodipine compared with amlodipine monotherapy (37.9% vs 28.4%; P=.036) (Figure 4).
Ambulatory BP Among the patients who participated in the ABPM substudy, maSBP at baseline was approximately 15 mm Hg to 20 mm Hg lower in both treatment arms than were seen in clinic msSBP values (Table II), and the combination aliskiren/amlodipine caused greater reductions in maSBP from baseline than amlodipine (LS mean change from baseline in maSBP at week 8, −19.0 mm Hg with aliskiren/amlodipine and −15.2 mm Hg with amlodipine monotherapy; LS mean difference between groups, −3.7 mm Hg; 95% CI, −8.0 to 0.5; P=.086) (Figure 5).
Significantly greater reductions from baseline in 24-hour maDBP were observed with combination aliskiren/amlodipine compared with amlodipine monotherapy (LS mean, −11.9 mm Hg vs −9.0 mm Hg; LS mean difference, −2.9 mmHg; 95% CI, −5.5 to −0.3; P=.032). Similar findings were also observed by repeated measure analysis (LS mean, −12.0 mm Hg vs −8.5 mm Hg; LS mean difference, −3.6 mm Hg; 95% CI, −6.9 to −0.3; P=.035; for fixed-effects dose-hour factor, P<.001) (Figure 5).
More than half of the patients participating in the ABPM substudy were nondippers (37 in the combination aliskiren/amlodipine arm and 27 in the amlodipine arm). A total of 39 patients (18 in the combination aliskiren/amlodipine arm and 21 in the amlodipine arm) were dippers. In nondippers, change from baseline in maSBP was similar between the combination therapy and monotherapy groups: −17.9 mm Hg with aliskiren/amlodipine vs −16.3 mm Hg with amlodipine (P=.6). In dippers, however, combination aliskiren/amlodipine caused significantly greater maSBP reductions from baseline vs amlodipine (−20.7 mm Hg vs −13.2 mm Hg; P=.03). In nondippers, as observed for maSBP, change from baseline in maDBP was similar between combination therapy and monotherapy groups: LS mean, −11.9 mm Hg with aliskiren/amlodipine vs −9.6 mm Hg for amlodipine (P=.2). In dippers, reductions from baseline in maDBP were numerically higher with combination aliskiren/amlodipine than with amlodipine (LS mean, −11.8 mm Hg with aliskiren/amlodipine vs −8.1 mm Hg for amlodipine, P=.08); although significance between combination therapy and amlodipine was not reached. Of note, similar magnitude of reduction from baseline in maDBP was observed with combination aliskiren/amlodipine in both dippers and nondippers.
Central BP As with the clinic BP and ambulatory BP findings, LS mean reductions of central SBP from baseline at week 8 were significantly greater with aliskiren/amlodipine (−29.8 mm Hg) than with amlodipine monotherapy (−24.2 mm Hg) (LS mean difference between groups, −5.6 mm Hg; 95% CI, −10.5 to −0.7; P=.026) (Figure 5). Likewise, LS mean reductions from baseline at week 8 in central DBP were −16.0 mm Hg and −9.9 mm Hg with aliskiren/amlodipine and amlodipine, respectively (LS mean difference between groups −6.0 mm Hg; 95% CI, −9.1 to −2.9; P<.001) (Figure 5).
Biomarkers Pretreatment geometric mean PRA at baseline was 0.37 (SD 1.3) ng/mL/h in the aliskiren/amlodipine group and 0.39 (SD 1.2) ng/mL/h in the amlodipine group. At week 8, the geometric mean of PRA was 0.14 (SD 0.8) ng/mL/h for aliskiren/amlodipine (representing a 61.7% reduction from baseline; P<.001) and 0.57 (SD 1.3) ng/mL/h for amlodipine (representing an increase from baseline by 50%; P<.001). The difference between the treatment groups at week 8 was statistically significant (P<.001). Pretreatment geometric mean PRC at baseline was 4.38 (SD 1.2) ng/L and 4.11 (SD 1.0) ng/L in the aliskiren/amlodipine and amlodipine groups, respectively. At week 8, the geometric mean of PRC was 26 (SD 1.3) ng/L for aliskiren/amlodipine, representing a 495.4% increase from baseline (P<.001) and 5.7 (SD 1.1) ng/L for amlodipine, representing an increase from baseline by 34.8% (P<.001). The difference between the treatment groups at week 8 was statistically significant (P<.001).
For the other biomarkers of UAER, UACR, and urinary aldosterone, there were no significant changes from baseline with either treatment at week 8.
Safety and Tolerability
Overall, 35.0% (77 of 220) of patients in the aliskiren/amlodipine treatment group and 32.7% (73 of 223) in the amlodipine monotherapy group experienced at least one treatment-emergent AE (Table III). The most common AEs experienced in the aliskiren/amlodipine and amlodipine groups, respectively, were peripheral edema (7.7% and 9.0%; spontaneously reported by the patient or discovered by the investigator), headache (3.6% and 5.4%), fatigue (2.3% and 2.7%), and nausea (3.2% and 1.8%). Most AEs were considered by the investigator to be of mild or moderate severity (21.4% mild, 11.7% moderate, and 0.7% severe AEs) and were not suspected to be treatment-related. Among all 443 patients, 62 patients (14.0%) had AEs suspected of being related to treatment (12.7% in the aliskiren/amlodipine group and 15.2% in the amlodipine group). Most of the AEs that were suspected of being treatment-related occurred in <2% of patients in either treatment group, except for peripheral edema, which occurred in 10 patients (4.5%) in the aliskiren/amlodipine group and 12 patients (5.4%) in the amlodipine group.
|Any AE||77 (35.0)||73 (32.7)|
|AEs leading to discontinuation||9 (4.0)||3 (1.3)|
|Serious AEs||1 (0.5)a||1 (0.4)b|
|Suspected treatment-related AEs||28 (12.7)||34 (15.2)|
|AEs occurring in ≥2% of patients in any treatment group|
|Peripheral edema||17 (7.7)||20 (9.0)|
|Headache||8 (3.6)||12 (5.4)|
|Fatigue||5 (2.3)||6 (2.7)|
|Nausea||7 (3.2)||4 (1.8)|
The incidence of serious AEs was low with only one patient in each treatment group experiencing a serious AE, neither of which was suspected of being related to study treatment. In the aliskiren/amlodipine group, one patient developed unstable angina, underwent coronary artery stent placement, and was discontinued from the study. In the amlodipine monotherapy group, one patient developed pneumonia and back pain that subsequently resolved and the patient completed the study. Overall, 9 patients in the aliskiren/amlodipine arm and 3 in the amlodipine arm were discontinued from the study due to AEs. The AEs leading to discontinuation in the combination group included unstable angina, vertigo, peripheral edema, chest pain, rash, and hypotension. The AEs resulting in discontinuation of amlodipine included peripheral edema, pruritus, and increased BP. No patient deaths occurred during the study period.
The present study reports the efficacy and safety of combination aliskiren/amlodipine compared with amlodipine monotherapy in an African American population with stage 2 hypertension. A prior open-label study of the combination of aliskiren/amlodipine, with or without a diuretic, reported effective reduction of BP in patients with stage 2 hypertension.27 A randomized trial that compared combination aliskiren/amlodipine at a low-dose of 150/5 mg with amlodipine 10 mg monotherapy in patients with stage 1 hypertension showed similar efficacy between the two treatments, with a lower incidence of peripheral edema reported for the aliskiren/amlodipine combination.18 The present results are similar to those from the EX-STAND study. The reduction in msSBP with aliskiren/amlodipine reported in this study (34.1 mm Hg) are almost identical to the valsartan/amlodipine arm in EX-STAND (33.3-mm Hg reduction). Similarly, the reduction in msSBP with amlodipine monotherapy here (28.9 mm Hg) was similar (26.6 mm Hg) to prior data in African American patients with stage 2 hypertension.10 In our study, the safety of aliskiren/amlodipine was comparable to amlodipine monotherapy, with most AEs considered by the investigators to be of mild to moderate severity (most commonly peripheral edema, headache, fatigue, and nausea). The incidence of peripheral edema was similar between the two treatment groups, possibly attributed to the lack of routine assessment at each visit and method of reporting edema, in that peripheral edema was not quantified directly.
Suppression of the RAS by aliskiren would be expected to have a complementary and additive effect with amlodipine that would reduce BP in a similar fashion to other combinations of amlodipine with a RAS blocker.28 Present findings indicate that the combination of aliskiren/amlodipine provides greater reductions in BP and higher BP control rates than amlodipine monotherapy over an 8-week period in African American patients with stage 2 hypertension and has a similar tolerability profile. Indeed, using the BP goal <135/85 mm Hg, as recommended by the updated ISHIB guidelines for African Americans with elevated BP without TOD, preclinical CV disease, or overt CV disease,9 significantly greater BP control rate was achieved with combination of aliskiren/amlodipine than with amlodipine monotherapy. Overall, 23.8% of patients in the aliskiren/amlodipine group vs 10.3% patients in the amlodipine group achieved BP <130/80 mm Hg (P<.001), the goal recommended for high-risk African American patients, but this demonstrates that many such patients will need ≥3 antihypertensive agents to get to goal.
There is considerable debate as to whether any class of antihypertensive drugs has CV benefits beyond BP reduction.29,30 It is possible that central hemodynamics may provide a more sensitive analysis of the risk of CV events than brachial BP measurements, particularly in African American patients.25,31,32 In outwardly healthy, young normotensive African American men, brachial SBP is often similar to that of an analogous cohort of white men, but aortic and carotid SBP can be significantly higher in the African Americans.32 The higher central BP among African American men is associated with more microvascular and macrovascular dysfunction (carotid hypertrophy, central artery stiffness, endothelial dysfunction) than in white men despite normal and nearly identical brachial BPs in both groups.32 It is also known that different classes of antihypertensive agents have differential effects on brachial and central pressures. For example, the Conduit Artery Function Evaluation (CAFE) study found that amlodipine-based therapy and atenolol-based therapy had similar effects on peripheral BP but the amlodipine-based treatment had greater effects on central BP.25 This difference could potentially explain the more favorable effect of amlodipine-based therapy on the composite CV disease outcome (total CV events/procedures and the development of renal impairment).25
Combination of aliskiren with hydrochlorothiazide has been compared with amlodipine in African American patients with stage 2 hypertension; with greater central SBP reductions obtained with the combination therapy compared with amlodipine monotherapy (despite similar peripheral BP reductions with either treatment).33 In our study, combination aliskiren/amlodipine provided similar reductions using both peripheral and central measures, with a treatment-difference of approximately 5.2 mm Hg between combination and amlodipine monotherapy maintained in both measures of SBP. Physiologically, the data suggest a greater reduction of cardiac load with combination aliskiren/amlodipine compared with amlodipine. However, whether these differences will translate into better clinical outcomes needs to be tested.
Our results of reduction in PRA and increase in PRC with combination aliskiren/amlodipine are consistent with findings from previous studies.18,34 Previously, Drummond and colleagues18 reported that the addition of aliskiren to amlodipine avoids the increase in PRA level observed with amlodipine 10 mg. In that study, combination therapy with aliskiren/amlodipine produced a 74.4% reduction in PRA at study end (6 weeks) compared with baseline, and amlodipine 10 mg increased PRA level by 58.0%. Findings from our study are similar to that reported by Drummond and colleagues, with a 61.7% reduction from baseline with combination therapy and a 50% increase in PRA level with amlodipine 10 mg. Moreover, the increase in PRC observed with combination aliskiren/amlodipine in our study is similar to that reported by Brown and colleagues34 after treatment with the maximal doses of aliskiren 300 mg in combination with amlodipine 10 mg. As with previous findings, amlodipine 10 mg caused a slight increase in both PRA and PRC in our study.
Study Limitations There are several limitations to our study. The number of patients who enrolled in the ABPM and arterial compliance (central pressure) substudies, and for whom baseline BP measures were available, was very small. At least 20 patients in each treatment arm who agreed to enroll in the ABPM study did not have a valid baseline measure and were discontinued from the ABPM substudy. The failure to enroll enough potential patients limits the value of the substudy. Another potential limitation of the substudies was having only one postbaseline measure (at week 8 only), thus limiting our analysis to observed cases and use of on-treatment analysis. Although exploratory analysis may provide clinically relevant information, the use of on-treatment analysis limits generalization as the results are provided only for a specific subgroup of patients.
Overall, the results of this study indicate that the aliskiren/amlodipine combination produces greater reductions in BP with similar tolerability compared with amlodipine monotherapy regardless of the BP measure used (clinic, ambulatory, or central) and that the combination of aliskiren and amlodipine provides an effective treatment option in the African American population.
Acknowledgments and Conflicts of interest: This study was supported by Novartis Pharmaceuticals Corporation. Dr Black, Dr Weinberger, and Dr Izzo provided detailed verbal discussion of the manuscript during the Publication Steering Committee meeting held in November 2009. All authors edited the manuscript for scientific content and approved the final version of the manuscript submitted for publication. The authors wish to thank Richard Edwards, PhD, of Complete Healthcare Communications for technical assistance in preparing this manuscript. The authors also thank the participating investigators for their contributions to the conduct of the study, the patients who volunteered to participate, and study coordinators at the investigative sites for their diligent efforts. Dr Black has served as a consultant for Gilead, Novartis Pharmaceuticals Corporation, Daiichi-Sankyo, Xoma, Boehringer-Ingelheim, Biosante, Servier, Nicox, CVRx, Valeant, Aren, and Orexigen; and has received a research grant from Novartis and AHRQ. Dr Weinberger has served on advisory boards and/or speakers bureaus for Daiichi-Sankyo, Forest, Merck, and Novartis pharmaceutical firms. Dr Izzo has served as a consultant at Boehringer-Ingelheim, NicOx, Novartis Pharmaceuticals Corporation, Daiichi-Sankyo, Takeda. Grant support: GlaxoSmithKline, Novartis Pharmaceuticals Corporation. Stock ownership/financial interests: none. Das Purkayastha, Joleen Lee, Kanaka Sridharan, and Robert Hilkert are employees of Novartis Pharmaceuticals Corporation, East Hanover, NJ.
Funding: This study was funded by Novartis Pharmaceuticals Corporation, East Hanover, NJ.
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- 202007 Guidelines for the Management of Arterial Hypertension: the task force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2007;25:1105–1187., , , et al.
- 24Recommendations for blood pressure measurement in humans and experimental animals: part 1: blood pressure measurement in humans: a statement for professionals from the Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure Research. Hypertension. 2005;45:142–161., , , et al.
- 26Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285:2486–2497.
- 28Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet. 2005;366:895–906., , , et al.
- 33Responses to aliskiren/HCTZ versus amlodipine on peripheral and central blood pressure in African American patients with stage 2 hypertension. J Am Coll Cardiol. 2010;55:A61., , , et al.