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Abstract

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

J Clin Hypertens (Greenwich). © 2010 Wiley Periodicals, Inc.

Patients with stage 2 hypertension (systolic blood pressure [SBP] ≥160 mm Hg and/or diastolic blood pressure [DBP] ≥100 mm Hg) are at high cardiovascular risk and require intensive blood pressure (BP)–lowering therapy. This randomized double-blind study is the first prospective trial specifically designed to evaluate the direct renin inhibitor aliskiren in patients with a mean sitting SBP ≥160 mm Hg and <180 mm Hg (the lower ranges of stage 2 systolic hypertension). After a 2- to 4-week washout period, 688 patients were randomized to once-daily aliskiren/hydrochlorothiazide (HCT) 150/12.5 mg or aliskiren 150 mg for 1 week and then double the doses for 11 weeks. Baseline BP was 167.1/95.0 mm Hg. At week 12, both aliskiren/HCT and aliskiren provided substantial BP reductions from baseline (30.0/12.6 mm Hg and 20.3/8.2 mm Hg, respectively). Aliskiren/HCT lowered BP significantly more than aliskiren (least-squares mean between-treatment differences [95% confidence interval] were –9.7 [−12.0 to −7.4] for SBP and −4.5 [−5.8 to −3.2] for DBP; both P<.0001). Similar BP reductions were seen in the subgroups of patients with isolated systolic hypertension and obesity. Aliskiren, with or without HCT, provides clinically significant BP reductions and may therefore be an effective treatment option in patients with stage 2 hypertension. J Clin Hypertens (Greenwich). 2010;12:917–926. © 2010 Wiley Periodicals, Inc.

In the United States, an estimated 73.6 million adults have high blood pressure (BP)1 and approximately 25% have stage 2 hypertension2 (systolic BP [SBP] ≥160 mm Hg and/or diastolic BP [DBP] ≥100 mm Hg).3 The INTERHEART study reported that the risk of myocardial infarction is almost twice as high in patients with hypertension than in those without high BP.4 Moreover, patients with stage 2 hypertension are at especially high risk for cardiovascular (CV) events because there is a continuous relationship between elevated BP and CV morbidity and mortality.5

In patients with stage 2 hypertension, effective treatment is a challenge because large and clinically relevant BP reductions are required to reach BP goals (<140/90 mm Hg or <130/80 mm Hg for patients with diabetes mellitus [DM] or at high CV risk).3,6 Current US and European hypertension guidelines therefore recommend initiating therapy with a combination of antihypertensive agents in patients whose BP is >20/10 mm Hg above goal.3,6 A widely used approach is to combine the complementary BP-lowering actions of a thiazide diuretic and an agent that targets the renin-angiotensin-aldosterone system (RAAS).3,6

Aliskiren, a direct renin inhibitor (DRI), targets the rate-limiting step of the RAAS and thereby reduces all components of the system (angiotensin I and II, aldosterone, and plasma renin activity [PRA]). Thus, aliskiren may provide greater inhibition of the RAAS than angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), as these agents increase PRA.7 Increased baseline PRA has been associated with a greater risk of mortality in the Valsartan Heart Failure Trial (Val-HeFT)8 and the Heart Outcomes Prevention Evaluation (HOPE) study.9 Elevated baseline PRA has also been associated with increased risk of cardiac events and mortality in patients with coronary artery disease.10–13

Aliskiren produces highly effective BP lowering as monotherapy,14 and the combination of aliskiren with the diuretic hydrochlorothiazide (HCT) provides up to 50% greater BP reduction than HCT alone.15 Single-pill combinations of aliskiren and HCT (aliskiren/HCT 150/12.5 mg, 150/25 mg, 300/12.5 mg, and 300/25 mg) are approved in the European Union for treating hypertension in patients whose BP is not at goal with either agent alone and in the United States for the initial treatment of hypertension in patients likely to need multiple drugs to achieve their BP goals.

The Aliskiren Alone or in Combination With Hydrochlorothiazide in Patients With Stage 2 Hypertension to Provide Quick Intensive Control of Blood Pressure (ACQUIRE) study is the first prospective, randomized, double-blind clinical trial specifically designed to evaluate aliskiren therapy in patients with the lower ranges of stage 2 hypertension. ACQUIRE compared the efficacy, safety, and tolerability of once-daily aliskiren/HCT 300/25 mg combination treatment with aliskiren 300 mg monotherapy for 12 weeks in patients with baseline SBP ≥160 mm Hg and <180 mm Hg (the lower ranges of stage 2 systolic hypertension).

Patients and Methods

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

Patients

Men and women aged 18 years and older with SBP ≥160 mm Hg and <180 mm Hg were eligible for inclusion in the study. The main exclusion criteria included DBP ≥110 mm Hg, combination therapy with >2 classes of antihypertensive agent, a history of severe CV disease, known Keith–Wagener–Barker grade III or IV hypertensive retinopathy, type 1 DM, and type 2 DM that in the investigator’s opinion was not well controlled. Women of child-bearing potential were required to use effective contraceptive methods for inclusion in the study; pregnant or nursing women were excluded.

All patients provided written informed consent before participating in any study procedures. The study was conducted in accordance with the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Guidelines for Good Clinical Practice and the Declaration of Helsinki, and received approval from the relevant local and central ethical review boards. The trial is registered with ClinicalTrials.gov (identifier: NCT00705575).

Study Design

This randomized, double-blind, parallel-group study was conducted at 122 study centers in 7 countries (Ecuador, Germany, Guatemala, Italy, Switzerland, Turkey, and the United States). After the initial screening visit, eligible patients entered a 2- to 4-week washout period during which their existing antihypertensive medication was gradually withdrawn. Patients who had not received any antihypertensive medications for at least 1 month before screening did not undergo washout.

During the washout period, all patients were instructed to measure their BP twice daily (before dosing and approximately 12 hours after dosing) with an automated telemedicine self-measured BP device. BP data were automatically uploaded to a database viewable to study centers. If BP exceeded predefined levels (SBP ≥200 mm Hg and/or DBP ≥120 mm Hg), patients were instructed to immediately contact the study center physician to schedule a visit. If SBP was ≥180 mm Hg and/or DBP ≥110 mm Hg at the subsequent clinic visit, the patient was excluded from the study.

After the washout period, eligible patients were randomized (1:1 ratio) to once-daily aliskiren/HCT 150/12.5 mg or aliskiren 150 mg alone. Patients were instructed to take study medication at approximately 8 am every day, except on the day of a study visit, when it was to be taken at the end of the visit. This study included an innovative early forced-titration step: after 1 week, the initial doses were doubled and treatment continued for a further 11 weeks. Patients were discontinued from the study for clinically significant hypotension (DBP <60 mm Hg, SBP <100 mm Hg, and/or a difference of ≥20 mm Hg between sitting and standing BP measurements) or if SBP was ≥180 mm Hg and/or DBP ≥110 mm Hg. Patients were randomized to study treatment using a validated system, which automates the random assignment of treatment arms to randomization numbers. The randomization scheme was reviewed by a biostatistics quality assurance group at Novartis and locked by them after approval. A double-dummy design was used to ensure study blinding.

Study Assessments

The primary objective was to compare the efficacy of aliskiren/HCT 300/25 mg combination therapy with aliskiren 300 mg monotherapy, as evaluated by the mean reduction in SBP from baseline to week 12. Secondary efficacy measures included the mean changes in SBP from baseline at week 8 and DBP at weeks 8 and 12. The proportions of patients achieving BP goal (BP <140/90 mm Hg [<130/80 mm Hg for patients with DM]) and those considered “responders” (SBP <140 mm Hg [<130 mm Hg for patients with DM] or ≥20 mm Hg decrease) were assessed at weeks 8 and 12.

Analyses of BP changes from baseline were performed for prespecified subgroups of patients according to age (younger than 55 and 55 years and older; younger than 65 and 65 years and older); those with a body mass index (BMI) <30 kg/m2 or ≥30 kg/m2; baseline SBP (160 mm Hg to <170 mm Hg and 170 mm Hg to <180 mm Hg); baseline estimated glomerular filtration rate (<60 mL/min/1.73 m2 and ≥60 mL/min/1.73 m2); and diabetic status. The subgroup of patients with isolated systolic hypertension (ISH [SBP ≥160 mm Hg and <180 mm Hg and DBP ≤90 mm Hg at baseline]) was also assessed.

Clinic BP was measured at screening, randomization (baseline), and weeks 1, 4, 8, and 12 using an automated and validated BP measuring device with the appropriate cuff size. BP was measured in the nondominant arm or from the arm with the higher reading if there was a clinically relevant difference (SBP ≥10 mm Hg and/or DBP ≥5 mm Hg) between arms 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 mean of these readings was calculated.

Plasma renin activity was measured in all patients from study centers in Germany and the United States by radioimmunoassay. Blood samples were collected after a fast of at least 8 hours at randomization (between 7 am and 10 am) and at week 12 (±1 hour of first collection time). Samples were centrifuged within 5 minutes of collection and plasma was immediately frozen at −70°C or −20°C before analysis.

All adverse events (AEs) and serious AEs were recorded throughout the study and assessed for their relationship to study medication by the investigator. Other safety assessments, including vital signs, physical examination, 12-lead electrocardiography, and the monitoring of hematology and blood chemistry occurred at regular intervals during the study.

Statistical Analyses

The primary efficacy endpoint (mean change in SBP from baseline at week 12) was assessed using a 2-way analysis of covariance (ANCOVA) model with treatment and region as factors and baseline as a covariate. The analysis assessed the superiority of the aliskiren/HCT combination over aliskiren monotherapy. A sample size of 594 patients completing the study (297 patients per arm) was targeted to provide 90% power for the superiority test at a 2-sided significance level of .05, assuming a clinically relevant treatment difference in SBP of 4 mm Hg and a standard deviation of 15 mm Hg. The study aimed to randomize a total of 660 patients (330 patients per arm) to provide at least 594 patients who completed the study. Other BP changes from baseline were also analyzed by ANCOVA.

The proportion of patients who achieved BP goal and the proportion of responders were assessed using a logistic regression model with treatment and region as factors and baseline SBP as a covariate. Randomized patients who had a baseline and at least one post-baseline efficacy measurement were included in the efficacy analyses. A last-observation-carried-forward approach was used for the week 8 and week 12 analyses. The safety population consisted of all randomized patients who received at least one dose of study medication.

Plasma renin activity data are presented as geometric means and corresponding 95% confidence intervals (CIs). Between-treatment differences in the log-transformed ratio of PRA at week 12 to baseline were analyzed by ANCOVA, with treatment as a factor and log-transformed baseline PRA as a covariate. Least-squares means and 95% CIs from the ANCOVA model were back-transformed to give the ratio of the geometric mean at week 12 to that at baseline. The P value for the between-treatment comparison was presented at a 2-sided significance level of .05. Within-treatment statistical differences from baseline at the 5% level were determined as 95% CIs that did not span unity. All statistical analyses were performed using SAS software version 8.2 (SAS Institute, Inc, Cary, NC).

Results

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

Patient Disposition and Baseline Characteristics

A total of 962 patients were enrolled in the ACQUIRE study and of those, 688 patients met the inclusion criteria and were randomized to study treatment (aliskiren/HCT, n=349; aliskiren monotherapy, n=339). Overall, 619 patients (90.0%) completed the study, with a higher proportion of completers in the aliskiren/HCT group (93.4%) than in the aliskiren monotherapy group (86.4%). The most common reason for study discontinuation was AEs (n=26 [3.8%]), with a similar number of patients discontinuing for this reason in each treatment group (Figure 1). Of the 962 patients enrolled in the washout period, a total of 870 provided telemedicine self-measured BP monitoring data. The majority of patients had between 1 and 12 alerts. The proportion of patients with alerts for very high BP (SBP ≥200 mm Hg and/or DBP >120 mm Hg) was low and greater for patients monitored during the washout period for 2 weeks (16.1%) than for those monitored for 3 weeks (4.5%) or 4 weeks (2.6%).

image

Figure 1.  Patient flow diagram for the Aliskiren Alone or in Combination With Hydrochlorothiazide in Patients With Stage 2 Hypertension to Provide Quick Intensive Control of Blood Pressure (ACQUIRE) study. *All randomized patients were included in the full analysis set. aIncluded all patients who were randomized to study treatment and completed the double-blind treatment period. bIncluded all patients who were randomized to study treatment and completed the double-blind treatment period without any major protocol deviations. HCT indicates hydrochlorothiazide.

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Patients in the two treatment groups were well matched for demographic and baseline characteristics (Table I). The mean age of the study population was 56.9 years, with 23.8% of patients 65 years or older. Almost half of the patients (45.5%) were obese (BMI ≥30 kg/m2). Mean duration of hypertension was 6.8 years, and overall SBP/DBP at baseline was 167.1/95.0 mm Hg. Baseline BP was similar between the two treatment groups (Table I).

Table I.   Patient Demographics and Baseline Characteristics (Randomized Population)
 Aliskiren/HCT 300/25 mg (n=349)Aliskiren 300 mg (n=339)
  1. Abbreviations: BMI, body mass index; DBP, diastolic blood pressure; SBP, systolic blood pressure. an=348. bAliskiren/hydrochlorothiazide (HCT), n=323; aliskiren, n=319. The remaining patients were newly diagnosed with hypertension (aliskiren/HCT, n=26; aliskiren, n=20). Data are shown as mean ± standard deviation unless otherwise indicated.

Age, y57.4±10.356.4±10.7
 ≥65, No. (%)84 (24.1)80 (23.6)
Sex, No. (%)
 Male180 (51.6)167 (49.3)
 Female169 (48.4)172 (50.7)
Race, No. (%)
 Caucasian234 (67.0)223 (65.8)
 Black23 (6.6)20 (5.9)
 Other92 (26.4)96 (28.3)
BMI, kg/m229.7±5.5a30.3±5.6
 Obesity (BMI ≥30 kg/m2), No. (%)148 (42.4)a165 (48.7)
History of diabetes mellitus, No. (%)22 (6.3)31 (9.1)
Duration of hypertension, y6.5±6.8b7.1±7.2b
SBP, mm Hg167.1±5.4167.0±5.2
DBP, mm Hg94.9±9.195.1±9.1

Efficacy

Aliskiren/HCT provided significantly greater mean reductions from baseline in SBP than aliskiren monotherapy at week 12 (30.0 mm Hg vs 20.3 mm Hg; P<.0001) (Figure 2a), corresponding to an additional mean reduction in SBP of 9.7 mm Hg for patients receiving aliskiren/HCT compared with those on aliskiren monotherapy (Table II). Mean reductions in DBP were also significantly greater with aliskiren/HCT compared with aliskiren alone (P<.0001) (Figure 2a and Table II). Similar reductions in SBP and DBP were obtained at week 8 (Table II).

image

Figure 2.  Mean blood pressure (BP) following treatment with aliskiren/hydrochlorothiazide (HCT) combination therapy and aliskiren monotherapy. (a) Change in systolic BP (SBP) and diastolic BP (DBP) from baseline to week 12 end point and (b) SBP and DBP during the 12-week study period (full-analysis set). (a) Data are least-squares mean ± standard error of the mean. Values within bars indicate the number of patients. (b) Data are means. At each time point, only patients with available data at both baseline and that time point are included. Data presented below the graph show mean change in BP from baseline for the time point indicated. On-treatment standard deviations were in the ranges 13.7 mm Hg to 15.7 mm Hg for SBP and 9.6 mm Hg to 10.1 mm Hg for DBP. *P<.0001 vs aliskiren 300 mg.

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Table II.   Antihypertensive Efficacy of Aliskiren/HCT and Aliskiren Monotherapy at Week 12 and Week 8 (Full-Analysis Set)
 LSM Change From Baseline ± SEM, mm HgLSM Difference,a mm Hg95% CIP Value
Aliskiren/HCT 300/25 mg (n=346)Aliskiren 300 mg (n=335)
Week 12b
 SBP−30.0±1.1−20.3±1.1−9.7−12.0 to −7.4<.0001
 DBP−12.6±0.6−8.2±0.6−4.5−5.8 to −3.2<.0001
Week 8b
 SBP−30.1±1.1−20.8±1.1−9.3−11.7 to −7.0<.0001
 DBP−13.7±0.6−8.0±0.6−5.7−7.0 to −4.4<.0001
 Patients Achieving BP Goal, No. (%)Estimated Odds Ratioc95% CIP Value
Aliskiren/HCT 300/25 mg (n=346)Aliskiren 300 mg (n=335)
  1. Abbreviations: BP, blood pressure; SEM, standard error of the mean. aLeast-squares mean (LSM) change for aliskiren/hydrochlorothiazide (HCT) 300/25 mg minus LSM change for aliskiren 300 mg. bLSM, 95% confidence interval (CI), and P value were from an analysis of covariance model with treatment and region as factors and the baseline systolic BP (SBP) or diastolic BP (DBP) as a covariate. cEstimated odds ratio, 95% CI, and P value were from a logistic regression model with treatment and region as factors and baseline SBP as a covariate. Odds ratio >1 favors aliskiren/HCT 300/25 mg over aliskiren 300 mg alone. dBP goal defined as SBP <140 mm Hg and DBP <90 mm Hg (SBP <130 mm Hg and DBP <80 mm Hg for patients with diabetes mellitus).

Week 12
 BP goald189 (54.6)108 (32.2)2.92.0–4.0<.0001
Week 8
 BP goald185 (53.5)102 (30.4)2.92.1–4.1<.0001

Both treatment regimens produced clinically significant reductions in BP as early as 1 week after starting treatment (Figure 2b). In patients receiving aliskiren/HCT, mean BP was reduced to <140/90 mm Hg within 4 weeks of starting treatment, and these reductions were maintained throughout the study.

The number of patients with ISH was similar in each treatment group (aliskiren/HCT, n=98; aliskiren, n=92). Patients with ISH who received aliskiren/HCT achieved a significant 10.6 mm Hg additional reduction from baseline in SBP compared with those on aliskiren monotherapy at week 12 (Figure 3a). Similar reductions in SBP were observed at week 8.

image

Figure 3.  Change from baseline in systolic blood pressure (SBP) following treatment with aliskiren/hydrochlorothiazide (HCT) combination therapy and aliskiren monotherapy for (a) patients with isolated systolic hypertension at week 12 and week 8 endpoints and (b) for the subgroups of patients by age, obesity, baseline SBP, baseline renal function, and diabetic status at week 12 endpoint (full-analysis set). (a) Data are least-squares mean ± standard error of the mean. (b) Data are means. Standard deviations were in the range 15.2 mm Hg to 19.2 mm Hg. Values within bars indicate the number of patients. *P<.0001 vs aliskiren 300 mg; **P=.0010 vs aliskiren 300 mg. BMI indicates body mass index; eGFR, estimated glomerular filtration rate.

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Prespecified descriptive analyses of the subgroups of patients by age, baseline SBP, BMI, baseline renal function, and diabetic status showed reductions in SBP with aliskiren/HCT and aliskiren monotherapy that were consistent with the overall patient population (Figure 3b). Aliskiren/HCT combination therapy produced SBP reductions of 28.0 mm Hg to 32.0 mm Hg and aliskiren monotherapy lowered SBP by 18.8 mm Hg to 23.3 mm Hg from baseline across the subgroups of patients by age and BMI. Aliskiren/HCT provided SBP reductions of 33.6 mm Hg in the subgroup of patients with baseline SBP 170 mm Hg to <180 mm Hg and 29.5 mm Hg in those with SBP 160 mm Hg to <170 mm Hg. A similar trend was observed for aliskiren monotherapy (Figure 3b). A post hoc ANCOVA was performed to compare treatments and confirmed that between-treatment differences (aliskiren/HCT vs aliskiren) were statistically significant for each of these subgroups (data not shown). BP reductions were slightly smaller in patients with impaired renal function or DM than in those without these conditions, although the small number of patients in these subgroups makes it difficult to draw any firm conclusions.

Based on a noncumulative analysis, the proportion of patients achieving their BP goal with aliskiren/HCT combination therapy (54.6%) at week 12 was significantly higher than the proportion reaching goal with aliskiren monotherapy (32.2%; P<.0001) (Table II). Similar findings were observed at week 8. Noncumulative responder rates were also significantly higher with aliskiren/HCT combination therapy than with aliskiren monotherapy at week 12 (75.4% vs 56.7%; P<.0001) and week 8 (75.4% vs 52.5%; P<.0001). As the BP goal and responder rates were analyzed on an individual rather than cumulative basis, these data may represent a conservative estimate of the rates achieved.

Aliskiren alone and in combination with HCT provided significant reductions in PRA at week 12 (P<.05 based on nonoverlapping 95% CIs). The reductions in PRA with aliskiren monotherapy (−73% [baseline 0.51 ng/mL/hour]; n=138) were significantly greater (P<.0001) than those with aliskiren/HCT (–45% [baseline 0.42 ng/mL/hour]; n=151).

Safety and Tolerability

Aliskiren was generally well tolerated as monotherapy or in combination with HCT during the study, with a similar incidence of AEs observed in the 2 groups (Table III). Few patients (n=6 [0.9%]) reported serious AEs, and there were no deaths or discontinuations due to serious AEs during the study. The number of discontinuations due to AEs was similar with aliskiren/HCT and aliskiren alone. The most common AEs leading to discontinuation were hypertension (5 patients in the aliskiren monotherapy group) and hypotension (4 patients in the aliskiren/HCT group). All 4 patients who were discontinued due to hypotension exhibited DBP <60 mm Hg, one of the predefined discontinuation criteria. Three patients also discontinued due to dizziness, 1 in the aliskiren/HCT group and 2 in the aliskiren group. However, none of the discontinuations due to hypotension or dizziness was associated with the forced dose-titration step after 1 week of treatment. The most common AEs overall were headache, dizziness, and nasopharyngitis (Table III), and the majority of AEs were judged to be mild or moderate in severity. The incidence of individual AEs was generally similar in the 2 groups, although more patients reported headache with aliskiren monotherapy and more patients reported dizziness with aliskiren/HCT treatment. Syncope occurred in only 2 patients (0.3%) during the study (1 in each treatment group) and was not associated with dose titration at week 1.

Table III.   Safety and Tolerability of Aliskiren/HCT Combination Therapy and Aliskiren Monotherapy (Safety Population)
 Aliskiren/HCT 300/25 mg (n=349)Aliskiren 300 mg (n=339)
  1. Abbreviations: AE, adverse event; HCT, hydrochlorothiazide. Data are shown as number (%) of patients.

Any AE139 (39.8)128 (37.8)
Serious AE2 (0.6)4 (1.2)
Discontinuation due to AE11 (3.2)15 (4.4)
Most frequent AEs (≥3% in either group)
 Dizziness19 (5.4)10 (2.9)
 Headache14 (4.0)29 (8.6)
 Nasopharyngitis14 (4.0)9 (2.7)
Laboratory abnormalities
 Serum potassiumn=338n=319
  <3.5 mmol/L4 (1.2)5 (1.6)
  >5.5 mmol/L03 (0.9)
  ≥6.0 mmol/L01 (0.3)
 Creatinine kinasen=340n=322
  >176.8 μmol/L01 (0.3)
 Blood urea nitrogenn=340n=322
  >14.28 mmol/L00

Very few patients had elevated serum potassium levels during the study (Table III). Three patients, all in the aliskiren monotherapy group, exhibited serum potassium >5.5 mmol/L and 1 patient had a level ≥6.0 mmol/L. Overall, 9 patients (1.4%) had serum potassium levels <3.5 mmol/L (aliskiren/HCT, n=4; aliskiren monotherapy, n=5). There were 3 discontinuations due to abnormal laboratory values, all from the aliskiren monotherapy group. Two patients discontinued treatment owing to elevated serum amylase levels and 1 patient because of elevated serum glucose levels. In all 3 patients, these abnormalities were present at baseline and were not affected by study treatments.

Discussion

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

The ACQUIRE study is the first prospective trial specifically designed to evaluate the BP-lowering effects of aliskiren in patients with the lower ranges of stage 2 systolic hypertension (SBP ≥160 mm Hg and <180 mm Hg). We demonstrated substantial reductions in both SBP and DBP with aliskiren/HCT 300/25 mg (30/13 mm Hg) and aliskiren 300 mg monotherapy (20/8 mm Hg). In addition, the majority of patients (55%) in the aliskiren/HCT group achieved their BP goal. The reductions in BP with aliskiren, both alone and in combination with HCT, were consistent across subgroups of age, baseline SBP, obesity, and diabetic status; SBP reductions in patients with ISH were also similar to those in the overall study population. Aliskiren/HCT combination therapy and aliskiren monotherapy were both well tolerated. Thus, aliskiren, alone or in combination with HCT, may be an effective potential initial therapy for patients with stage 2 hypertension with or without additional CV risk factors.

Patients with stage 2 hypertension, especially those with ISH or predominantly systolic hypertension, are notoriously difficult to treat because reductions in SBP of ≥20 mm Hg and/or in DBP of ≥10 mm Hg are necessary if BP goals are to be achieved. Indeed, an analysis of data from the General Medical Systems Electronic Medical Records database found that only half of the 4665 patients with all levels of stage 2 hypertension had their BP at goal after 1 year of antihypertensive therapy.16

In light of this clear unmet need, the present study shows that an important additional treatment option is available for lowering BP in patients with stage 2 hypertension: namely, the DRI aliskiren, either alone or in combination with HCT. Our study demonstrates prompt and robust BP reductions after 12 weeks’ treatment with aliskiren/HCT 300/25 mg combination therapy as well as with aliskiren 300 mg alone, which were maintained at weeks 8 and 12. Importantly, clinically relevant BP reductions in both treatment groups were observed within 4 weeks of initiating therapy (SBP reductions of 28 mm Hg with aliskiren/HCT and 19 mm Hg with aliskiren alone). The findings of this study are consistent with subsequent studies of aliskiren/HCT combination therapy in patients with stage 2 hypertension (Table IV).17–19 Hence, the data from the ACQUIRE study are part of a growing body of evidence that aliskiren, alone or in combination with HCT, provides both sustained and clinically meaningful BP reductions in patients with stage 2 hypertension. The BP reductions observed with aliskiren/HCT combination therapy in patients with stage 2 hypertension are similar and comparable with those seen with ACE inhibitors or ARBs in combination with HCT.20–25

Table IV.   BP-Lowering Efficacy of Aliskiren/HCT 300/25 mg Combination Therapy in Patients With the Lower Ranges of Stage 2 Hypertension From Aliskiren Clinical Trials
 ASTRIDE Study17ATTAIN Study18ACTION Study19
  1. Abbreviations: ACTION, Aliskiren Hydrochlorothiazide in Older Patients With Stage 2 Hypertension; ATTAIN, Aliskiren Hydrochlorothiazide vs Ramipril in Obese Patients (Body Mass Index ≥30 kg/m2) With Stage 2 Hypertension; ASTRIDE, Aliskiren Hydrochlorothiazide Compared to Amlodipine in Patients With Stage 2 Systolic Hypertension and Diabetes Mellitus; BP, blood pressure; DBP, diastolic blood pressure; HCT, hydrochlorothiazide; SBP, systolic blood pressure. aChanges are shown as least-squares mean. bChanges are shown as mean.

Patient populationPatients with SBP 160 mm Hg to <200 mm Hg and type 2 diabetes mellitusObese patients with SBP 160 mm Hg to <200 mm HgPatients 55 years and older with SBP 160 mm Hg to <200 mm Hg
Total number of patients860386451
Mean change from baseline with aliskiren/HCT 300/25 mg, mm Hg
 Week 8 end pointWeek 8 end pointWeek 4 end point
SBP−28.8a−28.1b−29.6a
DBP−9.9a−10.1b−9.3a

The past decade has seen greater focus on the importance of achieving prompt reductions in BP, especially for SBP—the more accurate predictor of CV disease than DBP.5,26 However, SBP is generally more difficult to control than DBP, therefore more intensive therapy is typically required.27,28 This is particularly the case in stage 2 hypertension, where large reductions from baseline are required. Treatment guidelines reflect these considerations, recommending more aggressive therapy for these patients.3,6

Long-term outcome studies, such as the Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) study,29,30 the Antihypertensive and Lipid-Lowering Trial to Prevent Heart Attack Trial (ALLHAT),31 and the Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial,32,33 suggested that reducing BP within the timeframe seen in the ACQUIRE trial is important for the prevention of strokes and other CV events. Indeed, in the VALUE study, patients who showed a BP response after 1 month of therapy had a significantly lower risk of cardiac events (12%; P<.01), stroke (17%; P<.05), or death (10%; P<.05) compared with those who did not show a prompt response.30 Similarly, in the Systolic Hypertension in Europe (SYST-Eur) study, early antihypertensive therapy with nitrendipine was associated with a consistent reduction in stroke, cardiovascular complications, and mortality compared with delayed treatment.34

The present study also confirmed that aliskiren significantly reduced PRA in combination with HCT (−45%) and as monotherapy (−73%). This is also consistent with previous studies of aliskiren monotherapy and aliskiren/HCT combination therapy.15,35

Conclusions

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

ACQUIRE is the first prospective study of aliskiren, with or without HCT, specifically in patients with the lower ranges of stage 2 hypertension, with or without additional CV risk factors. Aliskiren provided clinically significant reductions in both SBP and DBP (as much as a 30-mm Hg reduction in SBP with the combination). Aliskiren was well tolerated both as monotherapy and in combination with HCT and thus provides us with an additional therapeutic option for effective antihypertensive therapy where we need it most.

Acknowledgments

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

Acknowledgements and disclosures: The authors would like to thankEdna Cahill(Novartis Pharmaceuticals Corporation) for providing project management support. All authors participated in the development and writing of the paper and approved the final manuscript for publication. The authors take full responsibility for the content of the paper and thankDr Mark Rolfe(Oxford PharmaGenesis Ltd) for medical writing support, editorial assistance and collation, and incorporation of comments from all authors. This work was funded by Novartis Pharmaceuticals Corporation, East Hanover, NJ. HRB has received research support from Novartis and has acted as a consultant for Novartis, Gilead, Daiichi-Sankyo, NiCox, Boehringer-Ingelheim, Servier, and BioSante. AK has received research support from Novartis. FAP has no conflicts of interest to report. MB (Novartis Healthcare Pvt Ltd, Madhapur/Hyderabad, India), AKL, and FB (both Novartis Pharma AG, Basel, Switzerland) are employees of Novartis and are therefore eligible for Novartis stock and stock options.

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  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgments
  8. References
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