Aliskiren Alone or in Combination With Hydrochlorothiazide in Hispanic/Latino Patients With Systolic Blood Pressure 160 mm Hg to <180 mm Hg (Aliskiren Alone or in Combination With Hydrochlorothiazide in Patients With Stage 2 Hypertension to Provide Quick Intensive Control of Blood Pressure [ACQUIRE] Substudy)

Abstract

J Clin Hypertens (Greenwich). 2012;00:00–00. ©2012 Wiley Periodicals, Inc.

In a prespecified subgroup analysis of a 12‐week multinational, randomized, double‐blind, parallel‐group trial, self‐identified Hispanic/Latino adult men and women with systolic blood pressure 160 mm Hg to 179 mm Hg received combination aliskiren/hydrochlorothiazide (HCT) 150/12.5 mg or aliskiren 150 mg (force‐titrated to 300/25 mg and 300 mg, respectively, at week 1). At week 12, combination aliskiren/HCT provided greater reduction in mean sitting systolic blood pressure from baseline, the primary efficacy variable, compared with aliskiren monotherapy (−32.6 mm Hg vs −19.6 mm Hg; P<.0001). Differences in mean sitting diastolic blood pressure reductions followed a similar pattern (−13.5 mm Hg vs −7.1 mm Hg; P<.0001). Notable blood pressure reductions were evident at week 1 in both treatment groups, with near‐maximal effects reached by week 8. Results were consistent regardless of country of residence. Both treatments were well tolerated. Aliskiren alone or in combination with HCT is safe and effective in Hispanic/Latino patients with stage 2 hypertension. Combination aliskiren/HCT produced greater blood pressure reductions than aliskiren monotherapy.

More than half of the population growth in the United States during the past decade has been due to an increase in the Hispanic/Latino population. ¹ This ethnic group represents a unique and challenging cohort with respect to cardiovascular (CV) disease since Hispanics/Latinos are less likely to be aware of their high blood pressure (BP) or to have it adequately treated. ² , ³ , ⁴ , ⁵ , ⁶ , ⁷ Not surprisingly, hypertension‐related mortality has been increasing at a faster rate among Hispanic Americans than among non‐Hispanic white Americans.⁸ Historically, these ethnic differences have been attributed to sociodemographic factors, including (1) lower socioeconomic status, resulting in poor access to health care; (2) poor cultural competencies among non‐Hispanics treating Hispanics, and sometimes fatalistic attitudes towards disease; and (3) cultural factors such as lower linguistic skills and literacy, further limiting proper education and treatment regarding hypertension in this population, with this latter effect being magnified by a lack of Hispanic clinicians in the medical community. ⁹ , ¹⁰

A high prevalence of comorbidities such as obesity and metabolic syndrome may also account for the increasing rates of hypertension‐related mortality in the Hispanic population. ¹¹ , ¹³ Based on recent data from the National Health and Nutrition Examination Survey (NHANES), the age‐adjusted prevalence of obesity was 37.0% among Hispanic men and 41.4% among Hispanic women, rates that were higher than their non‐Hispanic white counterparts (36.2% and 32.2%, respectively). ¹¹ Age‐adjusted prevalence rates of metabolic syndrome were nearly identical and followed a similar pattern. ¹³ Levels of the adipocyte‐derived hormone leptin have been shown to be positively associated with hypertension, therefore constituting a putative association that accounts for an increased CV risk for the Hispanic/Latino population. ¹⁴ In addition, studies have shown a positive association between plasma leptin levels and plasma renin activity, both in lean and overweight or obese hypertensive patients, ¹⁵ and between plasma leptin levels and hypertension after adjusting for traditional factors such as age, sex, race/ethnicity, education, smoking, alcohol intake, body mass index, diabetes mellitus, and serum cholesterol. ¹⁴

More recent evidence suggests that the above ethnic differences may not be completely based on lifestyle or cultural grounds. In the New Jersey cohort of the Study of Women’s Health Across the Nation (SWAN), perimenopausal Hispanic women still had higher rates of CV risk factors relative to non‐Hispanic white women even though all participants were of the same relatively low socioeconomic status and 90% reported having their BP screened in the past 2 years, regardless of race/ethnicity. ¹⁶ Renin‐angiotensin‐aldosterone system (RAAS) gene polymorphisms may also play a role in the incidence of hypertension in Hispanics. Results of a case‐control study in this population found that Hispanic individuals with an angiotensin‐converting enzyme (ACE) DD genotype were 1.56 times more likely to be hypertensive than carriers of the ACE I allele. ¹⁷ More recently, in the Hispanic ethnic population, a genetic polymorphism of vascular endothelial growth factor was found to be associated with the development of hypertensive nephropathy, ¹⁸ as has a fetal variant in the GCM1 gene in pregnancy‐induced hypertension. ¹⁹ A pooled analysis from population‐based studies involving 10,550 adults showed that Andean Hispanics demonstrated augmentation indices (a measure of arterial wave reflection and, therefore, of stiffening arteries) similar to black Africans and higher than whites, which the authors postulated may account for differences in hypertension‐related target organ damage between ethnicities. ²⁰

Patients with stage 2 hypertension (systolic BP [SBP] ≥160 mm Hg and/or diastolic BP [DBP] ≥100 mm Hg) are at particularly high CV risk, and achieving BP goals is challenging because large absolute reductions in BP are required. Consequently, both US and European treatment guidelines recommend initiating antihypertensive therapy with ≥2 antihypertensive agents in these patients. ²¹ , ²² The Aliskiren Alone or in Combination With Hydrochlorothiazide in Patients With Stage 2 Hypertension to Provide Quick Intensive Control of Blood Pressure (ACQUIRE) study showed that the direct renin inhibitor (DRI) aliskiren alone or in combination with hydrochlorothiazide (HCT) produced substantial BP reductions from baseline to week 12 in patients whose BP was in the lower range of stage 2 hypertension, with significantly greater BP‐lowering efficacy for the combination. ²³ Here, we report the findings from a prespecified subgroup analysis of Hispanic/Latino participants in the ACQUIRE study.

Methods

The methods for the ACQUIRE study (ClinicalTrials.gov identifier: NCT00705575) have been published elsewhere. ²³ The conduct of the study was 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. The study protocol was approved by local and central ethical review boards, and all patients provided written informed consent prior to any study procedures.

Patients

Men and women 18 years and older with SBP ≥160 mm Hg and <180 mm Hg were enrolled. The exclusion criteria included DBP ≥110 mm Hg, receipt of combination regimens of >2 antihypertensive medications, history of severe CV disease, presence of Keith‐Wagener‐Barker grade III or IV hypertensive retinopathy, type 1 diabetes mellitus (DM), and poorly controlled (per investigator assessment) type 2 DM.

Study Design

This was a multinational (122 study centers across 7 countries [Ecuador, Germany, Guatemala, Italy, Switzerland, Turkey, and the United States]), randomized, double‐blind, parallel‐group study. After a screening visit, there was a 2‐ to 4‐week washout period (except for patients without antihypertensive use for at least 1 month before screening) during which current antihypertensive treatment was gradually discontinued and BP was telemonitored for safety. Eligible patients were subsequently randomized (1:1) to receive either combination therapy with aliskiren/HCT 150/12.5 mg or monotherapy with aliskiren 150 mg; at week 1, patients were force‐titrated to aliskiren/HCT 300/25 mg or aliskiren 300 mg, respectively, with treatment continued at these doses for 11 weeks. All study medication was to be administered once daily at approximately 8 am, except on the morning of clinic visits, when it was to be taken after completion of study procedures.

Study Assessments

Clinic BP measurements were made at 6 time points (screening, randomization [baseline], and weeks 1, 4, 8, and 12) using the supplied automated and validated BP‐measuring device, which was used to obtain 3 seated readings (at 1‐ to 2‐minute intervals) after the patient had been seated for 5 minutes. The mean of the 3 readings was calculated as the BP for that particular visit.

The primary efficacy variable was the change in mean sitting office SBP from baseline to week 12. Secondary efficacy variables included the change in mean sitting office DBP from baseline to week 12, as well as changes in SBP and DBP from baseline to week 8.

Regarding safety and tolerability assessments, adverse events (AEs), vital signs, and laboratory parameters were monitored throughout the study.

Statistical Methods

Details regarding sample size determination and primary statistical analyses for the main study have been published elsewhere. ²³ For the prespecified subgroup analysis of Hispanic/Latino patients reported here, patient demographic and baseline characteristics were summarized for the randomized population; ie, all patients who were randomized, regardless of whether they received study treatment. Least‐square mean (LSM) changes in BP from baseline were calculated post hoc for the full analysis population (all randomized patients who received study medication). For this full analysis set, between‐treatment differences in LSM BP reductions at the week 12 end point and at the week 8 end point (ie, the measurements at week 12 and week 8, respectively, or the last post‐baseline measurement carried forward [LOCF]) were assessed using a 2‐way analysis of covariance (ANCOVA) model with treatment and region as factors and baseline BP as a covariate. Additionally, a post hoc analysis of these same efficacy outcomes by country of residence (Ecuador, Guatemala, United States, and “other” [including Germany, Switzerland, and Italy]) was performed, with the addition of country as a factor and treatment by country interaction in the ANCOVA model. The proportion of patients achieving BP control (<140/90 mm Hg or <130/80 mm Hg for patients with DM) at the end of the 12 months was assessed with a logistic regression model with covariates. ²³ AE rates were calculated for the safety population, which included all randomized patients who received ≥1 dose of double‐blind study medication.

Results

Patients

Of the 688 ACQUIRE participants, ²³ 230 Hispanic/Latino patients were randomized to receive combination aliskiren/HCT (n=115) or aliskiren monotherapy (n=115). Patients in the 2 treatment groups were generally well matched for demographics and baseline characteristics (Table I). The aliskiren group, compared with the combination group, had slightly more women (67.0% vs 60.0%), was somewhat more obese (49.6% vs 44.3%), and had a longer mean duration of hypertension (7.8 vs 5.8 years). Overall, the Hispanic/Latino patients enrolled in the study were aged 56.6 years with a mean body mass index of 30 kg/m² and hypertension duration of 6.8 years, well matching average values of the main study population. Approximately 47% of the Hispanic/Latino participants were obese. Baseline BP was 167.1/94.1 mm Hg in the combination aliskiren/HCT group and 167.2/93.5 mm Hg in the aliskiren monotherapy group.

Table I.

 Demographic and Baseline Characteristics (Randomized Population of Hispanic/Latino Patients)

Characteristic	Aliskiren/HCT (n=115)	Aliskiren (n=115)
Age, y	56.5±11.5	56.6±12.1
≥65, No. (%)	24 (20.9)	32 (27.8)
Sex, No. (%)
Male	46 (40.0)	38 (33.0)
Female	69 (60.0)	77 (67.0)
Race, No. (%)
Caucasian	21 (18.3)	18 (15.7)
Black	2 (1.7)	2 (1.7)
Other	92 (80.0)	95 (82.6)
Diabetes mellitus, No. (%)	6 (5.2)	8 (7.0)
BMI, kg/m2	29.8±5.4	30.2±4.7
Obese, No. (%)a	51 (44.3)	57 (49.6)
Duration of hypertension, yb	5.8±6.3	7.8±7.0
SBP, mm Hg	167.1±5.4	167.2±5.2
DBP, mm Hg	94.1±10.1	93.5±9.5

Abbreviations: DBP, diastolic blood pressure; SBP, systolic blood pressure. Data are mean±standard deviation unless otherwise indicated. ^aBody mass index (BMI) ≥30 kg/m². ^bAliskiren/hydrochlorothiazide (HCT), n=103; aliskiren, n=105.

Enrollment of self‐identified Hispanic/Latino patients by country included 107, 81, 24, and 18 randomized patients for Ecuador, Guatemala, the United States, and other countries (including Germany, Switzerland, and Italy), respectively. Demographic and baseline characteristics for the Hispanic/Latino populations were generally similar across the various countries, although there were some differences including the distributions by sex and race and the proportion of patients with known DM (Table II).

Table II.

 Demographic and Baseline Characteristics by Country (Randomized Population of Hispanic/Latino Patients)

Characteristic	Ecuador (n=107)	Guatemala (n=81)	United States (n=24)	Other (n=18)
Age, y	57.6±12.2	54.8±11.1	54.5±8.5	61.4±14.2
≥65, No. (%)	33 (30.8)	14 (17.3)	3 (12.5)	6 (33.3)
Sex, No. (%)
Male	36 (33.6)	21 (25.9)	18 (75.0)	9 (50.0)
Female	71 (66.4)	60 (74.1)	6 (25.0)	9 (50.0)
Race, No. (%)
Caucasian	1 (0.9)	1 (1.2)	19 (79.2)	18 (100)
Black	3 (2.8)	0	1 (4.2)	0
Other	103 (96.3)	80 (98.8)	4 (16.7)	0
Diabetes mellitus, No. (%)	3 (2.8)	3 (3.7)	6 (25.0)	2 (11.1)
BMI, kg/m2	30.6±5.5	29.4±4.5	30.6±4.7	28.7±5.2
Obese, No. (%)b	56 (52.3)	34 (42.0)	12 (50.0)	6 (33.3)
Duration of hypertension, yb	7.5±6.9	6.7±7.1	7.3±5.7	2.5±2.7
SBP, mm Hg	167.0±4.8	167.8±5.7	165.5±4.6	166.9±6.5
DBP, mm Hg	92.7±9.2	93.4±10.5	98.6±8.6	95.1±10.4

Abbreviations: DBP, diastolic blood pressure; SBP, systolic blood pressure. Data are mean±standard deviation unless otherwise indicated. ^aBody mass index (BMI) ≥30 kg/m². ^bn=92, n=76, n=24, and n=16 for Ecuador, Guatemala, United States, and other countries, respectively.

Change From Baseline in Mean Sitting SBP and DBP

At week 12, combination aliskiren/HCT provided a significantly greater reduction in mean sitting SBP (MSSBP) from baseline compared with aliskiren monotherapy (LSM reductions, −32.6 vs −19.6 mm Hg; LSM difference, −12.9 mm Hg; 95% confidence interval [CI], −16.8 to −9.0; P<.0001). Likewise, the difference in mean sitting DBP (MSDBP) reductions was significant in favor of the combination (LSM reductions, −13.5 vs −7.1 mm Hg; LSM difference, −6.3 mm Hg; 95% CI, −8.5 to −4.2; P<.0001) (Figure 1a).

Figure 1.

 Least‐square mean (LSM) reductions in mean sitting systolic blood pressure (SBP) and diastolic blood pressure (DBP) from baseline to (a) week 12 end point and (b) week 8 end point (full analysis population of Hispanic/Latino patients). Error bars represent standard error. CI indicates confidence interval; HCT, hydrochlorothiazide. P values are based on an analysis of covariance model.

At week 8, combination aliskiren/HCT provided a significantly greater reduction in MSSBP from baseline compared with aliskiren monotherapy (LSM reductions, −28.7 vs −15.8 mm Hg; LSM difference, −13.0 mm Hg; 95% CI, −17.0 to −8.9; P<.0001). Likewise, the difference in MSDBP reductions was significant in favor of the combination (LSM reductions, −14.0 vs −6.4 mm Hg; LSM difference, −7.6 mm Hg; 95% CI, −9.9 to −5.4; P<.0001) (Figure 1b).

Both combination aliskiren/HCT and aliskiren monotherapy were effective in producing BP reductions as early as week 1 (Figure 2). MSSBP was reduced to <140 mm Hg at week 4 in the combination aliskiren/HCT group and remained below this threshold throughout the study, and MSDBP was reduced to <90 mm Hg as early as week 2 in both treatment groups.

Figure 2.

 Systolic blood pressure (SBP) and diastolic blood pressure (DBP) during the 12‐week double‐blind treatment (full analysis population of Hispanic/Latino patients). Data are presented as means. BP indicates blood pressure; HCT, hydrochlorothiazide.

Analysis of Efficacy by Country

Per‐country LSM reductions in SBP and DBP from baseline to weeks 8 and 12 were generally consistent with those for the entire Hispanic/Latino subgroup except for the “other” category, which included a small number of patients (Figure 3). At week 12, across the 3 major contributors (Ecuador, Guatemala and the United States), LSM reductions in SBP ranged from −29.5 to −41.0 mm Hg with combination aliskiren/HCT and from −15.1 to −28.3 mm Hg with aliskiren monotherapy. The corresponding LSM reductions in DBP ranged from −13.5 mm Hg to −18.5 mm Hg vs −5.6 mm Hg to −12.4 mm Hg. All between‐treatment group differences were statistically significant in favor of the combination (P<.05), except for MSDBP at week 12 in the United States (P=.14). Per‐country BP reductions at week 8 (Figure 3b) were generally similar to those observed at week 12 (Figure 3a).

Figure 3.

 By‐country least‐square mean (LSM) reductions in mean sitting systolic blood pressure (SBP) and diastolic blood pressure (DBP) from baseline to (a) week 12 end point and (b) week 8 end point (full analysis population of Hispanic/Latino patients). Error bars represent standard error. BP indicates blood pressure; CI, confidence interval; HCT, hydrochlorothiazide. P values are based on an analysis of covariance model. “Other” includes Germany, Switzerland, and Italy.

Adverse Events

In the overall ACQUIRE study population, the proportions of patients reporting any AE were 39.8% (139 of 349) in the combination aliskiren/HCT group and 37.8% (128 of 339) in the aliskiren monotherapy group, for which the most common AEs were dizziness (5.4% [19 of 349]) and headache (8.6% [29 of 339]), respectively. ²³ For the Hispanic/Latino participants, the corresponding AE incidences were 40.0% (46 of 115) and 44.3% (51 of 115), respectively, with the most frequent AEs found to be dizziness in aliskiren/HCT‐treated patients (10.4% [3.5% in the aliskiren group]) and headache in aliskiren‐treated patients (15.7% [7.0% in the aliskiren/HCT group]) (Table III). Of the Hispanic/Latino patients discontinuing treatment due to an AE, attributable AEs included hypotension in 4 of the 6 patients in the combination aliskiren/HCT group and hypertension in 1 of the 5 patients in the aliskiren monotherapy group. The most common laboratory abnormality was a serum potassium level <3.5 mmol/L, occurring in 2 of 114 evaluable patients (1.8%) in the combination aliskiren/HCT group and 3 of 110 evaluable patients (2.7%) in the aliskiren monotherapy group (Table III). There were patients with serum potassium elevations ≥6.0 mmol/L.

Table III.

 Safety and Tolerability (Safety Population of Hispanic/Latino Patients)

Safety/Tolerability Assessments	Aliskiren/HCT (n=115)	Aliskiren (n=115)
Any AE	46 (40.0)	51 (44.3)
Discontinuation due to an AE	6 (5.2)	5 (4.3)
Most frequent AEs (≥3% in either group)
Dizziness	12 (10.4)	4 (3.5)
Headache	8 (7.0)	18 (15.7)
Dyspepsia	4 (3.5)	3 (2.6)
Nausea	4 (3.5)	3 (2.6)
Diarrhea	3 (2.6)	4 (3.5)
Upper respiratory tract infection	1 (0.9)	6 (5.2)
Laboratory abnormalities
Serum potassiuma
<3.5 mmol/L	2 (1.8)	3 (2.7)
>5.5 mmol/L	0	1 (0.9)
≥6.0 mmol/L	0	0
Creatinine kinase >176.8 μmol/L	0	0
Serum urea nitrogen >14.28 mmol/L	0	0

Abbreviation: AE, adverse event. Data are expressed as number (percentage) of patients. ^aAliskiren/hydrochlorothiazide (HCT), n=114; aliskiren, n=110.

Discussion

This analysis focused on the Hispanic/Latino cohort of patients with lower ranges of stage 2 hypertension in the ACQUIRE study, with SBP as the primary end point. In general, this population has poor BP control rates and increased hypertension‐attributable mortality rates. Given this, and that the Hispanic/Latino population is increasing at a rapid rate in the United States, there is a need for better BP control in this patient group. After 12 weeks of treatment, aliskiren 300 mg reduced BP by approximately −20/−7 mm Hg in this population, and reductions with combination aliskiren/HCT 300/25 mg were even more pronounced (−33/−14 mm Hg; P<.0001 vs aliskiren monotherapy). Reductions in BP from baseline were rapid with both treatments, with notable BP lowering evident as early as week 1. By week 8, reductions appeared to be near maximal and mirrored those observed at week 12, showing maintenance of treatment effect. This mimics what has been observed in the general population. ²³

The 2 countries with the largest number of Hispanic/Latino participants were Ecuador (n=107) and Guatemala (n=81). In these countries, BP reductions were consistent with aliskiren and aliskiren/HCT. With combination aliskiren/HCT, BP reductions at week 12 were −41/−19 mm Hg for sites in Ecuador and −37/−15 mm Hg for sites in Guatemala. The corresponding results for aliskiren monotherapy were −28/−12 mm Hg and −20/−6 mm Hg.

When antihypertensive combination therapy is needed, an agent that blocks the RAAS plus HCT is considered one of the preferred options for quickly achieving meaningful BP reductions. Actually, HCT initially activates the RAAS, which may enhance the responsiveness to RAAS inhibitors. At the same time, RAAS inhibition with a DRI blocks the effects of the counter‐regulatory increase in renal release of renin that occurs in response to sodium depletion, thereby enhancing diuretic efficacy. ²⁴ , ²⁵ Additionally, considering the putative role of leptin in obese hypertensive patients, a thoughtful antihypertensive approach in Hispanics could comprise a RAAS inhibitor capable of lowering plasma renin activity as direct renin inhibitors. Previous studies have similarly demonstrated the antihypertensive efficacy of combination aliskiren/HCT in stage 2 hypertension, including in predominantly white obese patients, ²⁶ white older patients (older than 55 years), ²⁷ and African Americans. ²⁸ In a recent meta‐analysis, the weighted mean BP reduction after 8 weeks of treatment with combination aliskiren/HCT 300/25 mg in patients with stage 1 or 2 hypertension was −16.9/−11.6 mm Hg, less than that observed in our analysis, perhaps owing to the lower severity of baseline hypertension. ²⁹

Hispanic/Latino patients have not been systematically studied in randomized controlled trials of antihypertensive therapy and, as a result, guidelines do not specifically address the treatment of hypertension in this population. Indeed, only 2 large outcomes studies have reported results in subgroups of Hispanic/Latino patients. ²⁹ , ³⁰ , ³¹ In the Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), Hispanic patients were less likely than non‐Hispanics to have controlled BP (<140/90 mm Hg) at baseline, but after 6 to 12 months of treatment with ACE inhibitors, calcium channel blockers (CCBs), α₁‐blockers, or thiazide‐like diuretics (with step‐up combination treatment as needed), more Hispanic patients had their BP controlled than did non‐Hispanics. ² After 4 years of follow‐up, BP was controlled in 72% of Hispanic whites, 69% of Hispanic blacks, 67% of non‐Hispanic whites, and 59% of non‐Hispanic blacks. In the International Verapamil SR/Trandolapril Study (INVEST), hypertensive Hispanics with coronary artery disease treated with either CCB‐based therapy or β‐blocker–based therapy achieved better BP control than non‐Hispanic hypertensive patients. ³⁰ After 24 months, mean SBP was reduced by −21.3 mm Hg in Hispanics and by −17.4 mm Hg in non‐Hispanics (P<.001); DBP reductions were similar (−10.2 and −10.0 mm Hg; P=.36). Importantly, Hispanic patients also experienced significantly fewer CV outcomes, including nonfatal myocardial infarction, nonfatal stroke, or all‐cause death (6.9% vs 11.8%; hazard ratio, 0.87 [95% CI, 0.78–0.97]). A separate analysis of women participating in INVEST reported similar findings. ³¹

That BP reductions tend to be greater among Hispanics vs non‐Hispanics is a finding we also observed on a numeric basis (statistical comparisons between Hispanics and non‐Hispanics were not conducted as part of our preplanned analysis). Compared with BP reductions from the entire ACQUIRE population, ²³ BP was lowered in Hispanic/Latino patients by an additional −2.6/−0.9 mm Hg with combination aliskiren/HCT. This also appears to be the case for the antihypertensive agent nebivolol, for example. In a study of 277 self‐identified Hispanics, BP was lowered by a mean of −14.1/−11.1 mm Hg after 8 weeks of treatment with nebivolol (5 mg titrated up to 40 mg), ³² which was higher than that observed in a pooled analysis of three 12‐week studies of the same agent. ³³ Taken together with ALLHAT and INVEST, these results suggest that BP control is an achievable goal among Hispanics and Latinos, at least in the setting of a clinical trial where participants have equal access to health care and medications at no cost. ² Combination therapy is often necessary as it results in the most pronounced BP reductions, particularly in high‐risk patients.

The biological reasons for an ethnic difference in response to the DRI aliskiren, alone or in combination with HCT, are not certain but may relate to modulation of endothelial function of stiffening arterial walls, ³⁴ higher sensitivity to the decreased production of angiotensin II, ³⁵ or other mechanisms that remain to be established. The analysis of drug effects on select populations, in any event, can uncover ethnic differences in the response to drug treatment. This suggests a potential pharmacologic tool to further understand the influence of genetic determinants and fostering a population‐based approach to treat diseases with a high impact on public health.

Strengths and Limitations

The majority of studies that have examined the antihypertensive efficacy in subgroups of Hispanic/Latino patients have included RAAS inhibitors, namely, ACE inhibitors ² , ³⁰ , ³¹ , ³⁶ and angiotensin II receptor blockers. ³⁷ , ³⁸ , ³⁹ , ⁴⁰ , ⁴¹ , ⁴² However, they have not been adequately powered to allow comparisons between Hispanic and non‐Hispanic subgroups. In general, these studies have found that these agents produce significant and sustained reductions in BP among Hispanic cohorts, and that when RAAS inhibitors are included as part of the antihypertensive regimen, a large percentage of Hispanic patients achieve BP goals. Ours is the first study to present the full results evaluating the safety and efficacy of a DRI in a Hispanic/Latino population. Nevertheless, our study has some limitations in that the analysis, although prespecified, was conducted in a subset of patients enrolled in a large study. While our data suggest that antihypertensive efficacy can be achieved across all countries analyzed, the sample sizes in some of the countries (eg, United States) were too small to allow for meaningful conclusions. Further limiting interpretation of the results from the United States is that although this country contains a very diverse group of Hispanics/Latinos, we did not capture the country of origin of patients from the different ethnic subgroups—our study evaluated Hispanic/Latino patients in their country of residence, which may or may not have been their country of origin. Secondly, the patients studied in the trial were a low‐CV‐risk population, in that <10% had diabetes and patients with renal dysfunction or severe CV disease were excluded from the trial. Thus, the findings of this 12‐week study cannot be extrapolated to very high‐risk patients in the general population. Future studies might compare two homogeneous populations (eg, Mexican Americans vs Eurocentric) with more comorbidities to assess whether one population achieves more efficacy from antihypertensive medications than another.

Both treatments were well tolerated in our study. There were no unexpected AEs in this Hispanic/Latino population compared with those observed in the entire ACQUIRE population. ²³

Our safety findings were consistent with previous studies in other hypertensive populations. ²⁷ , ²⁸ , ⁴³ The overall AE rate in the combination aliskiren/HCT group (40.0%) was similar to that previously reported in 8‐week hypertension studies involving predominantly white patients (41.0%), ⁴³ older (mean age, 65 years) white patients (43.2%), ²⁷ and African American patients (44.6%). ²⁸ Likewise, the discontinuation rate due to AEs in our combination aliskiren/HCT arm (5.2%) was within the range previously reported (2.9%–7.2%). ²⁷ , ²⁸ , ⁴³

Conclusions

This prespecified analysis from this 12‐week study shows that aliskiren alone or in combination with HCT is safe and effective in Hispanic/Latino patients with stage 2 hypertension. The combination of aliskiren plus HCT produced greater BP reductions than aliskiren monotherapy.