Safety and Efficacy of Aliskiren/Amlodipine/Hydrochlorothiazide Triple Combination in Patients With Moderate to Severe Hypertension: A 54‐Week, Open‐Label Study

Abstract

J Clin Hypertens (Greenwich). 2012; 14:821–827. ©2012 Wiley Periodicals, Inc.

Combination antihypertensive therapies are recommended to attain blood pressure (BP) targets especially in high‐risk patients in whom rapid and pronounced BP control is essential. This 28‐ to 54‐week, open‐label, multicenter study evaluated the safety and efficacy of a triple combination, aliskiren with amlodipine and hydrochlorothiazide (HCTZ), in patients with moderate to severe hypertension. Following a washout period of up to 4 weeks, patients received aliskiren/HCTZ 300/12.5 mg for 1 week, followed by add‐on amlodipine 5 mg for 1 week. Thereafter, the doses of amlodipine and HCTZ were doubled. The first 206 of 564 patients who completed 28 weeks of study continued for an additional 26 weeks. Safety was assessed by recording all adverse events. Efficacy variables included changes in BP from baseline to endpoint and BP control rate. Of 564 patients, 493 completed the study. Peripheral edema (9.4%), headache (5.7%), nasopharyngitis (4.1%), and bronchitis (3.7%) were reported frequently. Clinically significant reductions in mean sitting systolic BP/mean sitting diastolic BP from baseline (−34.2/−20.3 mm Hg and −37.3/−21.8 mm Hg at weeks 28 and 54, respectively) were observed. Corresponding BP control rates were 69.1% and 77.1%. The aliskiren/amlodipine/HCTZ combination in patients with moderate to severe hypertension was well tolerated and provided clinically significant BP reductions and effective BP control.

The management of hypertension, a multifactorial disease, often requires multiple antihypertensive agents with complimentary modes of action to achieve better blood pressure (BP) control and to attenuate adverse events (AEs) of the constituent monotherapies. ¹ , ² However, despite the wide availability of antihypertensive agents, BP control remains unsatisfactory and most antihypertensive regimens fail to maintain efficacy during long‐term treatment. ³ As hypertension progresses, BP control becomes increasingly difficult to achieve. ⁴ Hence, patients with moderate to severe hypertension require prompt and intensive treatment, commonly with ≥2 antihypertensive agents, in order to achieve BP control and prevent life‐threatening hypertensive complications such as cardiovascular events.

The combination of an antihypertensive agent acting on the renin‐angiotensin‐aldosterone system (RAAS) such as angiotensin‐converting enzyme (ACE) inhibitors, angiotensin II type 1 receptor blockers (ARBs), or a direct renin inhibitor (DRI) with a calcium channel blocker (CCB) has been shown to be effective in lowering BP in patients with moderate to severe hypertension. ⁵ , ⁶ , ⁷ , ⁸ The direct relaxant effect of CCBs on vascular smooth muscle augments the BP‐lowering effects of RAAS agents.

Aliskiren is the first oral DRI approved for the treatment of hypertension at once‐daily doses of 150 mg and 300 mg. Long‐ and short‐term studies in patients with mild to moderate hypertension have shown that aliskiren provides clinically significant BP reductions with favorable tolerability when administered alone or in combination with a diuretic (hydrochlorothiazide [HCTZ]) or a CCB (amlodipine). ⁹ , ¹⁰ , ¹¹ The aim of the present study was to assess the tolerability and antihypertensive efficacy of aliskiren/amlodipine/HCTZ triple combination in patients with moderate to severe hypertension.

Methods

Patients

Male and female patients 18 years and older with essential hypertension (mean sitting SBP [msSBP] ≥160 mm Hg and <200 mm Hg, and/or mean sitting DBP [msDBP] ≥100 mm Hg and <120 mm Hg) were enrolled. Key exclusion criteria included history or evidence of secondary hypertension; severe cardiovascular or cerebrovascular disease; renal impairment (serum creatinine >1.5×upper limit of normal [ULN]), dialysis, or a nephrotic syndrome; serum potassium <3.5 and ≥5.5 mmol/L at screening; and use of any medication or any existing surgical or medical condition that might alter the absorption, distribution, metabolism, or excretion of the study medications. The study protocol was approved by the appropriate local ethical review boards and was conducted in accordance with the International Conference on Harmonization (ICH) guidelines and the Declaration of Helsinki. All patients gave written informed consent before undergoing any study procedure. The trial is registered with ClinicalTrials.gov (Identifier: NCT00667719).

Study Design

This 28‐ to 54‐week open‐label study conducted in 82 study centers in 8 countries (Belgium, Egypt, Germany, Poland, Slovakia, Spain, Turkey, and the United States) evaluated the safety and efficacy of aliskiren/amlodipine/HCTZ 300/10/25 mg combination therapy in patients with moderate to severe hypertension. Treatment‐naive hypertensive patients must meet the entry criteria for essential hypertension defined above at visits 1 and 2, and previously treated hypertensive patients must meet these entry criteria at visits 2, 3, or 4 (Figure 1). Antihypertensive treatment, if any, was withdrawn during the washout period, prior to entering the treatment phase of the study. Following a washout period (up to 4 weeks), patients who still met the study entry criteria at visit 4 (week 0) received treatment with aliskiren 300 mg and HCTZ 12.5 mg once daily for 1 week. At visit 5 (week 1), amlodipine 5 mg was added. At visit 6 (week 2), the dose of amlodipine was increased to 10 mg and HCTZ was increased to 25 mg, and all patients were treated with aliskiren/amlodipine/HCTZ 300/10/25 mg once daily for a further 28 weeks.

Figure 1.

 Study design. ALI indicates aliskiren; AML, amlodipine; HCTZ, hydrochlorothiazide. *One patient did not have any post‐baseline measurements during the second phase.

In order to further assess safety, the first 206 patients who successfully completed the 28 weeks of treatment were asked to continue treatment for a further 6 months (up to week 54). Other patients who completed 28 weeks of treatment but who did not enter the extended treatment period were considered to be study completers (Figure 1). Patients who had signs and symptoms of clinically significant hypotension (msSBP <100 mm Hg and/or msDBP <60 mm Hg) at any time during the study were permanently discontinued from the study. In addition, any patient who had an msSBP ≥180 mm Hg and/or an msDBP ≥110 mm Hg at any time after 4 weeks of therapy with aliskiren/amlodipine/HCTZ 300/10/25 mg were withdrawn from the study and appropriate therapy was instituted. The concomitant use of drugs approved for the treatment of hypertension was prohibited during the study, even if prescribed for another indication (with the exception of ophthalmic β‐blocker preparations).

Study Objectives

The primary objective of this study was to assess the safety and tolerability of aliskiren 300 mg in combination with amlodipine 10 mg and HCTZ 25 mg up to 54 weeks. The secondary objectives included assessment of the BP‐lowering efficacy (msSBP and msDBP) of the aliskiren/amlodipine/HCTZ 300/10/25 mg triple‐combination therapy from baseline to week 28 endpoint (last nonmissing post‐baseline value on or before week 28) and to week 54 endpoint (last nonmissing value after week 28), the proportion of patients achieving BP control (<140/90 mm Hg) at the end of the study, and the proportion of patients achieving a systolic BP (SBP) response (msSBP <140 mm Hg or a ≥20 mm Hg reduction from baseline) and a diastolic BP (DBP) response (msDBP <90 mm Hg or a ≥10 mm Hg reduction from baseline) at the end of the study. Exploratory objectives of this study in a subset of patients included the effect of aliskiren/amlodipine/HCTZ treatment on plasma renin concentration (PRC), plasma renin activity (PRA), and plasma aldosterone.

Safety Assessments

Safety assessments included monitoring and recording of all AEs and serious AEs (SAEs) and regular monitoring of hematology and blood chemistry values. All safety analyses were performed on the treated population, which was defined as all patients who received at least one dose of study medication.

Efficacy Assessments

Clinic BP was measured at every study visit using a standard mercury sphygmomanometer with appropriate cuff size in accordance with the 1988 American Heart Association Committee on Blood Pressure Determination. ¹² If a mercury sphygmomanometer was not available, an alternative calibrated method for the assessment of BP was consistently used throughout the study. Sitting BP was measured at trough (approximately 24±3 hours post‐dose) in the arm in which the higher DBP was found at the first study visit. Three sitting BP measurements were taken at 1‐ to 2‐minute intervals after the patient had been sitting for 5 minutes, and the average of these three sitting values was taken as the mean sitting BP for that visit. The treated population was used for all efficacy analyses. A subgroup analysis for efficacy was performed in patients with severe hypertension (msSBP ≥180 mm Hg and <200 mm Hg).

Exploratory Assessments

Blood samples were obtained for the measurement of PRC, PRA, and aldosterone concentration at baseline and at week 28 (or discontinuation) in a subset of patients who completed the study at 28 weeks. PRC was determined by a commercial radioimmunoassay (RIA) assay (CIS Bio International, Codolet, France); PRA by RIA (DiaSorin, Stillwater, MN); and aldosterone was measured by RIA using a commercial kit (Coat‐A‐Count Aldosterone, DPC, Los Angeles, CA).

Sample Size Determination

A sample size of approximately 500 patients was planned, which would provide safety data on the aliskiren/amlodipine/HCTZ combination in at least 300 patients for 6 months and 100 patients for 12 months, in accordance with guidelines from the ICH for long‐term safety data. ¹³

Statistical Analysis

Safety variables were summarized for the overall treated population. The primary assessment for safety was the reporting of any AEs and SAEs including death, discontinuations due to AEs, and abnormal laboratory data. Occurrence and frequency of AEs and SAEs were summarized by system organ class, preferred term, maximum severity, and relationship to study treatment. Summary statistics at baseline and at last visit were measured for laboratory values, and the occurrences of significant abnormal changes from baseline were summarized.

Summary statistics for the post‐baseline and the change‐from‐baseline measurements were presented by time point in msDBP and msSBP for the treated population. Summary statistics for the proportion of patients achieving BP control were presented by time point for the treated population. The frequency distributions of patients achieving a DBP response and SBP response were provided by time point for the treated population.

The biomarker assessments were conducted for a subset of patients. Summary statistics for the post‐baseline and change‐from‐baseline measurements were presented by visit for the following biomarkers: PRC, PRA, and plasma aldosterone for a subset of the treated population.

Results

Patient Demographics and Disposition

Of the 635 patients enrolled in the study, 564 entered the treatment phase (treated population) and 493 (87.4%) completed the study (either the first or second 6‐month treatment phase). Of 71 patients (12.6%) who discontinued, 60 patients discontinued during the first 6 months and 11 discontinued during the second 6‐month treatment period. The reasons for discontinuation were AEs (39 [6.9%]), withdrawal of patient consent (17 [3.0%]), loss to follow‐up (8 [1.4%]), protocol deviation (3 [0.5%]), unsatisfactory therapeutic effect (3 [0.5%]), and abnormal test procedure, which included meeting on‐study BP‐related discontinuation criterion (msSBP ≥180 mm Hg after at least 4 weeks of high‐dose triple therapy) (1 [0.2%]).

Of the 564 treated patients, the first 206 patients (only 205 had baseline and post–week 28 values) who completed the first 6‐month period entered the second 6‐month period as planned. Patient demographics and baseline characteristics are summarized in Table I. The mean age of patients was 55.9 years, 57.8% of patients were men, and the majority of the patients were either Caucasian (89.9%) or black (7.4%). Approximately half of the study population (51.8%) were obese (body mass index ≥30 kg/m²), 52.1% of the patients had metabolic syndrome, and 21.6% of patients had diabetes. The mean duration of hypertension was 8.9 years. The baseline BP was 166.1/101.8 mm Hg. Of the 564 patients, 70 patients had severe hypertension at baseline.

Table I.

 Patient Baseline and Demographic Characteristics (Treated Population)

Demographic Variables	N=564
Age, y	55.9±11.3
≥65 y, No. %	135 (23.9)
Sex, No. (%)
Male	326 (57.8)
Female	238 (42.2)
Race, No. (%)
Caucasian	507 (89.9)
Black	42 (7.4)
Other	15 (2.7)
Duration of hypertension, y	8.9±7.5
Patients with prior treatment, No. (%)	549 (97.3)
Diabetes, No. (%)	122 (21.6)
Metabolic syndrome, No. (%)a	294 (52.1)
BMI, kg/m2	31.2±6.1
BMI ≥30, kg/m2, No. (%)	292 (51.8)
msSBP, mm Hg	166.1±11.6
msDBP, mm Hg	101.8±7.7

Abbreviations: BMI, body mass index; msDBP, mean sitting diastolic blood pressure; msSBP, mean sitting systolic blood pressure. Values are expressed as mean±standard deviation unless otherwise stated. ^aMetabolic syndrome=Yes, if any three of the following are true: (1) waist circumference >102 cm (40 in) for men or 88 cm (35 in) for women; (2) triglycerides ≥150 mg/dL (1.69 mmol/L); (3) high‐density lipoprotein cholesterol <40 mg/dL (1.04 mmol/L) for men or <50 mg/dL (1.29 mmol/L) for women; (4) msSBP ≥130 mm Hg or msDBP ≥85 mm Hg; (5) fasting glucose ≥110 mg/dL (6.1 mmol/L).

Safety and Tolerability

Treatment with the aliskiren/amlodipine/HCTZ 300/10/25 mg combination for up to 54 weeks was generally well tolerated. In total, 291 patients (51.6%) reported at least one AE, but the majority of AEs were mild or moderate in intensity and transient in nature. The most frequently reported AEs were peripheral edema (a known effect of amlodipine), headache, nasopharyngitis, and bronchitis (Table II). Overall, peripheral edema was observed in 53 patients (9.4%) during the study period and it was the most common event leading to discontinuation (13 [2.3%]). There were no deaths during the study. Overall, 15 patients (2.7%) experienced SAEs; one patient reported 7 SAEs. Only one patient receiving initial low‐dose aliskiren/amlodipine/HCTZ 300/5/12.5 mg had an SAE, which was recorded as pain in the extremity. All other SAEs were recorded during treatment with the full dose of aliskiren/amlodipine/HCTZ 300/10/25 mg. One case each of cerebrovascular accident, palpitations, renal failure, and thrombocytopenia were suspected to be related to study drug. Six patients (1.1%) discontinued because of SAEs.

Table II.

 Tolerability of Study Treatments (Treated Population)

Adverse event, No. (%)	N=564
Any adverse event	291 (51.6)
Discontinuations due to adverse vents	39 (6.9)
Serious adverse event	15 (2.7)
AEs occurring in ≥2% of patients in any treatment group
Peripheral edema	53 (9.4)
Headache	32 (5.7)
Nasopharyngitis	23 (4.1)
Bronchitis	21 (3.7)
Diarrhea	16 (2.8)
Dizziness	15 (2.7)
Influenza	15 (2.7)
Back pain	13 (2.3)
Vertigo	13 (2.3)
Upper respiratory tract infection	12 (2.1)
Cough	11 (2.0)
Clinically notable changes in laboratory values
BUN >14.3 mmol/L	2 (0.4)
SCr >176.8 μmol/L	0 (0.0)
Potassium
<3.5 mmol/L	65 (11.7)
>5.5 mmol/L	15 (2.7)a
≥6.0 mmol/L	7 (1.3)a

Abbreviations: BUN, blood urea nitrogen; SCr, serum creatinine. ^aThree patients were recorded as having high potassium values (≥5.5 mmol/L) due to malfunction of a centrifuge; however, the potassium levels returned to normal in the subsequent visits.

In total, 15 patients (2.7%) exhibited serum potassium levels >5.5 mmol/L at any visit during the study (Table II) and 65 patients (11.7%) exhibited potassium levels <3.5 mmol/L (known effect of HCTZ). No patient discontinued due to abnormal laboratory findings. An AE of hypotension was reported in 6 patients (1.1%), of which 5 cases (0.9%) were suspected to be related to study drug and caused 4 patients to discontinue. An AE of orthostatic hypotension was reported in 3 patients (0.5%), and only 1 patient discontinued due to this event.

Efficacy

At week 4 (after 2 weeks of full‐dose aliskiren/amlodipine/HCTZ 300/10/25 mg), a clinically relevant reduction in mean BP (−32.2/−18.9 mm Hg) from baseline was observed. The BP reduction at week 28 endpoint was −34.2/−20.3 mm Hg and at week 54 endpoint was −37.3/−21.8 mm Hg. BP reductions were sustained from week 6 until both study endpoints (weeks 28 and 54; Figure 2). In the overall patient population, a BP control rate of 69.1% (390 patients) and 77.1% (158 patients) was observed at week 28 and week 54 endpoints, respectively (Figure 3). At week 4, the majority of patients (62.5%) achieved BP control (<140/90 mm Hg). The proportion of patients achieving systolic response (msSBP <140 mm Hg or a ≥20 mm Hg reduction from baseline) at week 28 was 90.2% (n=509) and at week 54 was 93.7% (n=192). The proportion of patients achieving diastolic response (msDBP <90 mm Hg or a ≥10 mm Hg reduction from baseline) at week 28 was 91.8% (n=518) and at week 54 was 96.6% (n=198).

Figure 2.

 (A) Change in mean sitting diastolic blood pressure (msDBP) from baseline by week. (B) Change from baseline to week 28 and week 54 endpoints. msBP indicates mean sitting blood pressure; msSBP, mean sitting systolic blood pressure. *One patient did not have any post‐baseline measurements during the second phase.

Figure 3.

 Proportion of patients achieving blood pressure (BP)control and BP response. BP control defined as <140/90 mm Hg; diastolic response defined as mean sitting diastolic blood pressure <90 mm Hg or a ≥10 mm Hg reduction from baseline; systolic response defined as mean sitting systolic blood pressure <140 mm Hg or a ≥20 mm Hg reduction from baseline. *One patient did not have any post‐baseline measurements during the second phase.

In patients with severe hypertension, aliskiren/amlodipine/HCTZ combination therapy showed mean reductions in msSBP/msDBP of −45.4/−20.2 mm Hg and −49.6/−22.6 mm Hg at week 28 and week 54 endpoints, respectively. The proportion of severe hypertensive patients achieving BP control with aliskiren/amlodipine/HCTZ combination therapy was 29/70 (41.4%) and 15/27 (55.6%) at week 28 and week 54 endpoints, respectively.

Biomarker Results

Summary statistics for biomarker levels at baseline and week 28 endpoint were carried out in a subset of patients for PRC, PRA, and plasma aldosterone. The geometric mean analysis showed an increase in PRC (1545.8%), a decrease in PRA (41.8%), and an increase in aldosterone (44.5%) from baseline to week 28 endpoint (Table III).

Table III.

 Biomarkers of RAAS Activity at Baseline and Week 28 Endpoint (Subset of Treated Population)

	No.	Baseline	Endpoint	Change from Baseline
PRA, ng/mL/hour	130	0.4	0.2	0.6
PRC, ng/L	129	6.0	98.9	16.5
Plasma aldosterone, pmol/L	130	172.3	249.0	1.5

Abbreviations: PRA, plasma renin activity; PRC, plasma renin concentration; RAAS, renin‐angiotensin‐aldosterone system. Data are expressed as geometric means.

Discussion

This study showed that aliskiren/amlodipine/HCTZ 300/10/25 mg triple combination therapy was well tolerated and efficacious as a treatment for up to 54 weeks in patients with moderate to severe hypertension. Clinical trial evidence shows that most patients with moderate to severe hypertension will require ≥2 antihypertensive agents to achieve their BP targets. ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ Hypertension treatment guidelines also recommend combination therapy as a possible initial treatment for patients with moderate to severe hypertension and for those at greater risk of cardiovascular events. ¹⁸ , ¹⁹ In this study, the most common AE was peripheral edema and it was the reason for most of the study discontinuations. It is well known that amlodipine is associated with peripheral edema; however, the incidence of peripheral edema with the aliskiren/amlodipine/HCTZ combination in this study was not higher than that observed in previous studies evaluating the combination of aliskiren with HCTZ or amlodipine. ¹⁰ , ¹¹ , ²⁰ , ²¹ Moreover, the combination of aliskiren and amlodipine has shown a relatively low risk of peripheral edema compared with amlodipine monotherapy. ¹⁰ , ¹¹ One potential safety concern of triple‐combination therapies is an excessive BP‐lowering effect that can eventually lead to hypotension. In this study, the number of patients experiencing hypotension or related AEs was very small and did not indicate any additional safety concerns. In general, minimal changes were observed in the laboratory parameters. However there was a notable proportion of patients who had serum potassium levels of <3.5 mmol/L at any visit post‐baseline, which is most likely to be driven by the HCTZ component of the triple combination as it is known to decrease potassium levels. The incidences are in line with a short‐term study (Data on File) that used the same triple combination, indicating that there is likely to be no increased risk of hypokalemia with 54 weeks of treatment. Overall, the AE and laboratory findings were consistent with the known safety profiles for the three component monotherapies when used alone or in combination.

The aliskiren/amlodipine/HCTZ combination provided marked reductions in mean BP of −34.2/−20.3 mm Hg at week 28 endpoint and −37.3/−21.8 mm Hg at week 54 endpoint, which were clinically significant. Patients with severe hypertension represent a difficult‐to‐treat group because they require extensive BP reductions to achieve BP control. In this study, the subgroup of patients with severe hypertension responded to aliskiren/amlodipine/HCTZ triple combination, achieving a pronounced reduction of −45.4/−20.2 mm Hg at week 28 and −49.6/−22.6 mm Hg at week 54 in mean BP, which clearly indicates the sustained efficacy over time. An earlier 56‐week study of a stepped‐care regimen using olmesartan medoxomil, amlodipine, and HCTZ (40/10/25 mg) in patients with moderate to severe hypertension demonstrated a reduction of −17.5/10.8 mm Hg in mean BP from baseline at randomization (after 8 weeks of initial amlodipine 5 mg treatment) to week 54. ⁸ The same triple combination in another long‐term study in patients with moderate to severe hypertension showed a reduction of −36.1/19.8 mm Hg in mean BP at week 52 from baseline. ²²

Aliskiren has been shown to suppress PRA when given as monotherapy, ²³ , ²⁴ while HCTZ reduces plasma volume, with consequent increases in PRA and aldosterone secretion, ²⁴ , ²⁵ aliskiren in combination therapy was shown to reduce elevations in PRA induced by HCTZ. ²⁶ A similar response is observed in this study with respect to PRA even when aliskiren is given in combination with HCTZ and amlodipine. Furthermore, aliskiren reduces the incidence of CCB‐related vasodilatory edema ⁹ , ²⁷ and diuretic‐related hypokalemia. ²¹ , ²⁸ , ²⁹ , ³⁰ One limitation of the current study is that no placebo or active comparator was included in the study design, but the study was designed to reflect common clinical practice. The results of this study are informative for using aliskiren/amlodipine/HCTZ in combination.

Conclusions

In this 28‐ to 54‐week open‐label study, the triple combination of aliskiren/amlodipine/HCTZ in patients with moderate to severe hypertension was well tolerated and resulted in clinically significant BP reductions and effective BP control. Aliskiren/amlodipine/HCTZ combination therapy continues to show promise in the treatment of patients with moderate to severe hypertension, rendering it a potential treatment option for this patient group.

Disclosures:  Alexander Murray: Compensated by Novartis and other pharmaceutical companies as a Principal Investigator for the conduct of clinical trials. Wolfgang Koenig: Honoraria for lectures from Novartis. Juan Garcia‐Puig: Received funding from the National Institutes of Health. Samir Patel, Alkaz Uddin, and Jack Zhang are employees of Novartis Pharmaceuticals Corporation, and are therefore eligible for Novartis stock and stock options.