A Noninferiority Comparison of Valsartan/Hydrochlorothiazide Combination Versus Amlodipine in Black Hypertensives
The objective of the study was to demonstrate that reduction in mean 24-hour diastolic blood pressure with 160 mg valsartan and 12.5 mg hydrochlorothiazide was not inferior to 10 mg amlodipine in hypertensive blacks. A total of 482 blacks with stage 1 and stage 2 hypertension (mean seated blood pressure 140 to 180/90 to 110 mm Hg) were enrolled in a double-blind, randomized, prospective study. After a placebo run-in period, patients were randomized to 160 mg valsartan or 5 mg amlodipine for 2 weeks, then force-titrated to 160 mg valsartan and 12.5 mg hydrochlorothiazide or 10 mg amlodipine for an additional 10 weeks. Blood pressure was assessed by 24-hour ambulatory blood pressure monitoring. Other assessments included quality of life, peripheral edema, and safety. Noninferiority of valsartan/hydrochlorothiazide to amlodipine was demonstrated by comparable reductions in mean 24-hour diastolic blood pressure with both treatments (−10.2±8.6 mm Hg versus −9.1±8.3 mm Hg, respectively; P<0.001 for noninferiority), as well as in mean 24-hour systolic blood pressure (−15.9±12.1 mm Hg versus −14.5±12.2 mm Hg; P<0.001 for noninferiority). The proportion of patients reporting adverse events and the incidence of most events were similar in both treatment groups, although more patients treated with amlodipine reported peripheral edema (5.8% versus 1.7%; P=0.03) and joint swelling (2.9% versus 0%; P=0.008) compared with valsartan/hydrochlorothiazide. We conclude that a starting dose of valsartan/hydrochlorothiazide (160/12.5 mg) is as effective as high-dose amlodipine (10 mg) in reducing blood pressure in blacks with stage 1 and stage 2 hypertension, and valsartan/hydrochlorothiazide is better tolerated.
Increasing levels of blood pressure (BP) are associated with increased risk of cardiovascular disease events, a relationship that is continuous and independent of other risk factors.1,2 Moreover, control of elevated BP has been shown conclusively to result in a significant reduction in cardiovascular events. Thus, the finding from the most recent analysis of the National Health and Nutrition Examination Survey (NHANES) of a reversal in the previously reported trend of an overall decline in hypertension prevalence is alarming: hypertension prevalence increased nearly 4% in 1999 to 2000 over 1988 to 1991 (28.7% versus 25.0%).3 It is also of concern that despite effective therapies and concerted efforts to control BP, only 31% of patients achieve adequate BP control (<140/90 mm Hg).3
These trends are even more alarming in blacks with hypertension. Not only is the prevalence of hypertension in this group among the highest in the world, but also, elevated BP levels occur earlier in life, average BPs are higher, the severity and impact of hypertension are increased, and cardiovascular and renal outcomes are poorer in black Americans compared with white Americans.1,2,4 In addition to the increased risk for and prevalence of hypertension, blacks have a high prevalence of type 2 diabetes mellitus, placing them at even higher risk for developing coronary heart disease, cardiovascular events, and end-stage renal disease. Yet, only 28% of non-Hispanic blacks achieve BP control,3 in part because of the unjustified misperceptions that it is medically more difficult to lower BP in blacks than in other groups of patients, and that some classes of antihypertensive agents are not effective in blacks.1,2
Antihypertensive agents that target the renin-angiotensin system (RAS) have generally been considered to be less effective in blacks. This supposed lack of effect has been attributed to the misperception that all of these patients have low-renin, salt-sensitive, volume-dependent hypertension.5,6 In fact, blacks represent a heterogeneous population with respect to renin levels,7 which may not accurately predict response to treatment.8,9 Any difference in effect from other classes of antihypertensive agents is eliminated when angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) are used in higher doses or in combination with a diuretic.1,2,6,9–12
The potent vasopressor properties of the principal effector of the RAS, angiotensin II, have long been recognized as contributing to elevations in BP. The more recent recognition of its nonhemodynamic actions (eg, ventricular hypertrophy, vascular remodeling, endothelial dysfunction, oxidative stress) that have established angiotensin II as an independent risk factor for the development and progression of cardiovascular disease is of prime importance in blacks.13–15 Independent of their BP-lowering effects, drugs that target the RAS ameliorate the development and progression of cardiovascular disease13,14,16 and slow the progression of renal disease in blacks with hypertensive nephrosclerosis.17 The multiplicity of beneficial effects as well as effective BP lowering that can be achieved from treatment with drugs that target the RAS suggest that they may be considered a therapy of first choice in high-risk blacks.2,13–15 However, they remain underused in this population.13,14,16
The African American Diovan (Valsartan) Amlodipine (Norvasc) Clinical Efficacy (AADVANCE) trial was undertaken to demonstrate that the addition of hydrochlorothiazide (HCTZ) in a low dose (12.5 mg) to a starting dose of valsartan (160 mg) would provide BP reduction that was not inferior to the most frequently prescribed dose of amlodipine (10 mg) in black patients with stage 1 and stage 2 hypertension. The efficacy of valsartan for BP lowering has been demonstrated in blacks with usual dietary salt intake and in combination with HCTZ.9 Valsartan is well tolerated and is not associated with the adverse effects that limit the use of ACE inhibitors.9,18,19 Amlodipine was selected as the comparator because it is a first-line antihypertensive agent in blacks, in part because of guideline recommendations suggesting that these patients respond better to calcium antagonists and diuretics than to other classes of antihypertensive agents.1 The maximum recommended dose of amlodipine, which is not uncommonly associated with pedal edema, often is required to control BP in black patients.20 Equivalent BP lowering and better tolerability with valsartan/HCTZ compared with amlodipine would support use of this combination as an alternate, first-line therapy in blacks with hypertension.
The multicenter, double-blind, randomized trial compared the efficacy of 160 mg valsartan combined with 12.5 mg HCTZ (VAL/HCTZ) with that of amlodipine for mean reduction in 24-hour diastolic BP (DBP) in black patients with mild to moderate hypertension. Black patients ≥18 years of age with a diagnosis of stable stage 1 and stage 2 hypertension, defined as an untreated mean seated systolic BP (SBP) of 140 to 180 mm Hg and a mean seated DBP of 90 to 110 mm Hg, were eligible for the study. Women had to have been postmenopausal for 1 year, surgically sterilized, or using a medically accepted method of contraception, and must have agreed to use an effective method of contraception throughout the study. Diabetics were excluded.
Screened patients entered a 2- to 3-week placebo run-in period, during which 24-hour ambulatory BP monitoring (ABPM) was performed, peripheral (ankle) edema was assessed, and a quality-of-life questionnaire was administered. Subjects meeting the diagnosis of mild to moderate hypertension and in whom the difference between the mean seated SBP and DBP measurements was ≤15 mm Hg and ≤10 mm Hg, respectively, at visits 7 days and 1 day before the randomization/dose-titration period were eligible for randomization to either the VAL/HCTZ or amlodipine treatment arm. During the titration period, the initial doses were 160 mg for valsartan alone and 5 mg for amlodipine. After 2 weeks, 12.5 mg HCTZ was added to 160 mg VAL, and the amlodipine dose was increased to 10 mg. Patients continued on these doses for the 10-week treatment period. During the titration and treatment periods, patients returned for assessments of vital signs and adverse events at 2-week intervals. At the end of treatment, 24-hour ABPM was repeated, as were assessments of edema and quality of life.
In addition to the primary objective of change from baseline to end of treatment in mean 24-hour DBP as measured by ABPM, secondary efficacy variables included change from baseline to end of treatment in mean 24-hour SBP as measured by ABPM. Other secondary efficacy variables were the change from baseline to end of treatment in the proportion of patients in each treatment group with peripheral edema and in the score for the physical and mental components of the Medical Outcomes Trust SF-12 Health Survey.
Routine clinical laboratory evaluations were performed at the beginning of the titration period and at the end of treatment. Urine sodium, protein, and creatinine were also measured, as well as serum levels of C-reactive protein, plasminogen activator inhibitor-1, and procollagen 1. (Results for inflammatory markers will be presented in a separate publication and are not discussed in this report.) Fasting plasma glucose and fasting serum insulin levels also were measured at the beginning and end of double-blind treatment.
Safety was assessed in all patients who received ≥1 dose of assigned study drug. The primary efficacy population, which was used for the primary and secondary ABPM efficacy analyses, was defined as all randomized patients who had valid baseline (end of placebo run-in period) and postbaseline BP values as measured by ABPM. The intent-to-treat population was defined as all randomized patients who had a baseline and ≥1 additional assessment for any secondary efficacy parameter.
The study was designed with 90% power to evaluate noninferiority of VAL/HCTZ to amlodipine with respect to change in mean 24-hour DBP assessed by ABPM in black patients with mild to moderate hypertension. All statistical analyses to test for noninferiority were conducted against a 1-sided alternative hypothesis at the 2.5% significance level. All other tests were conducted against a 2-sided alternative hypothesis using an overall α of 0.05.
To test the noninferiority of VAL/HCTZ to amlodipine, the null hypothesis that the reduction in mean 24-hour DBP from baseline to end of study with VAL/HCTZ was ≥3 mm Hg less than that with amlodipine was tested against the alternative hypothesis that the treatment effect of VAL/HCTZ was not less than that of the control by 3 mm Hg, as follows: Ho: μD ≤ μA −3 mm Hg versus Ha: μD > μA −3 mm Hg, where μD and μA were the change in mean 24-hour DBP from baseline to end of study for VAL/HCTZ and amlodipine, respectively. A similar analysis was performed for SBP, a secondary efficacy variable, except that the treatment effect of VAL/HCTZ was not less than that of the control by 4 mm Hg.
The quality-of-life secondary efficacy variables were analyzed using the same methods as for the primary efficacy variable but with 95% confidence intervals (CIs) between variables reported. The Cochran-Mantel–Haenszel procedure was used to compare the change in the proportions of patients with peripheral edema at baseline and at end of study stratified by treatment.
Of the 482 patients randomized to treatment, 417 completed the study, and 383 patients (195 VAL/HCTZ and 188 amlodipine) comprised the primary efficacy population (patients with valid baseline and postbaseline BP values measured by ABPM; Figure). The mean age of patients in the primary efficacy population was 50.7±10.4 years, with the majority of patients (91.4%) being <65 years of age; 48% were male (Table 1). The respective mean baseline seated SBP and DBP for the primary efficacy population were 152.6±10.3 mm Hg and 98.4±5.6 mm Hg, with no differences between treatment groups. The mean baseline 24-hour DBP as measured by ABPM was 93.4±9.2 mm Hg. Patients randomized to VAL/HCTZ had a longer duration of hypertension compared with those randomized to amlodipine (10.0±8.6 versus 8.5±7.5 years). Nearly twice as many patients treated with amlodipine discontinued treatment because of an adverse event compared with VAL/HCTZ (11 [4.6%] versus 6 [2.5%]).
Noninferiority of VAL/HCTZ to amlodipine was demonstrated by comparable reductions in mean 24-hour DBP measured by ABPM with both treatments: −10.2±8.6 versus −9.1±8.3 mm Hg, respectively (P<0.001 for noninferiority; 95% CI, −0.54, 2.86; Table 2). In addition, reductions in mean 24-hour SBP measured by ABPM were equivalent for both treatments (−15.9±12.0 mm Hg versus −14.5±12.2 mm Hg; P<0.001 for noninferiority; 95% CI, −1.05, 3.81).
Subgroup analyses by baseline mean 24-hour ABPM DBP and SBP levels, gender, and age were consistent with the overall findings of noninferiority of VAL/HCTZ to amlodipine. In the subgroup of patients with a baseline mean 24-hour ABPM DBP <100 mm Hg, the difference in the mean reduction in BP favored VAL/HCTZ (DBP Δ1.8 mm Hg, P=0.063; SBP Δ2.9 mm Hg, P=0.039). For subjects with a baseline mean 24-hour ABPM DBP ≥100 mm Hg, the difference between treatments was 0.8 mm Hg for the change in mean 24-hour DBP and 3.1 mm Hg for the change in mean 24-hour SBP. However, the sample size was too small for meaningful statistical analyses.
In the subgroup of patients with a baseline SBP <160 mm Hg, the magnitude of the mean 24-hour BP reduction with VAL/HCTZ also was greater than with amlodipine (DBP Δ1.4 mm Hg; SBP Δ2.0 mm Hg). For subjects with a baseline mean 24-hour ABPM SBP ≥160 mm Hg, the difference between treatments was 0.4 mm Hg for the change in mean 24-hour DBP and 2.6 mm Hg for the change in mean 24-hour SBP. Again, there were too few patients in this subgroup to make meaningful statistical comparisons.
The reductions from baseline in mean 24-hour DBP and SBP were numerically greater but not statistically significant with VAL/HCTZ than with amlodipine in the male and female subgroups as well as in the subgroup <65 years of age.
The reduction in mean ABPM nighttime (6 pm to 6 am) DBP was statistically greater with VAL/HCTZ compared with amlodipine (−10.5±9.9 mm Hg versus −8.5±9.8 mm Hg; P=0.046), and the reduction in nighttime SBP was numerically greater with VAL/HCTZ (−16.3±13.4 mm Hg versus −14.1±13.8 mm Hg). For both treatments, statistically significant reductions from baseline in mean 24-hour ABPM DBP, SBP, and pulse pressure were observed in the “dipper” and “nondipper” subgroups, with percent reductions in DBP and SBP being greater in the “nondipper” subgroup (Table 3). In “nondippers,” the difference in mean 24-hour ABPM DBP trended toward significance in favor of VAL/HCTZ (−12.7 mm Hg versus −10.3 mm Hg; P=0.067) and reached statistical significance (P=0.045) when adjusted for baseline 24-hour ABPM DBP level. Treatments were otherwise equivalent in “dippers” and “nondippers.”
The proportion of patients reporting adverse events was similar for both treatment groups, and most (93%) adverse events were of mild or moderate severity. The profile of adverse events for VAL/HCTZ reported in this study of blacks was similar to that observed in previous studies of the combination. The incidence of most adverse events was similar for both treatments (Table 4), although significantly more patients treated with amlodipine than with VAL/HCTZ reported joint swelling (2.9% versus 0%; P=0.008) and peripheral edema (5.8% versus 1.7%; P=0.031).
The incidence of peripheral edema at baseline was similar for the VAL/HCTZ and amlodipine treatment groups (9.8% versus 9.5%; Table 5). At the end of the 12-week treatment period, the incidence of peripheral edema decreased in the VAL/HCTZ group to 6.8%, whereas it increased to 10% in the amlodipine group. A greater proportion of patients treated with amlodipine than with VAL/HCTZ developed peripheral edema during the course of treatment (6.5% versus 2.9%). Most changes from baseline in clinical laboratory test results were not clinically significant.
There were no significant changes from baseline in either treatment group or between treatment groups for the physical and mental component scores of the quality-of-life questionnaire.
Improvement in poor rates of hypertension control has the potential to provide great benefit in blacks, in whom the prevalence of high BP is among the highest in the world, develops at an earlier age, and results in higher average BP levels. These differences are associated with higher mortality from cardiovascular and cerebrovascular disease and more hypertension-related end-stage renal disease than in the white American population.1,2
Calcium antagonists and diuretics are considered first-line therapy for hypertension in blacks because they generally are considered to have greater BP-lowering effects than agents that target the RAS (ie, ACE inhibitors, ARBs).1,2 However, blacks with hypertension do respond to appropriate (higher) doses of ACE inhibitors and ARBs.6 The augmented BP-lowering effect of drugs that target the RAS by the addition of a diuretic is accepted as another method to eliminate any race-specific difference in BP response.1,2,9,10,21 Lower-dose combination antihypertensive therapy avoids the metabolic and physiological adverse effects associated with higher doses of diuretics often required in blacks with hypertension.10
The use of RAS blockers is supported by evidence that ACE inhibitors help reduce progression of kidney disease,17 and ACE inhibitors and ARBs are associated with a diminished risk for new-onset diabetes16,22–24 and congestive heart failure.16,24,25 Although blacks have been traditionally underrepresented in many of the large-scale hypertension trials, a growing body of data confirms the efficacy of RAS blockade in these patients. For example, in the African American Study of Kidney Disease and Hypertension (AASK), ACE inhibitor treatment in combination with other agents delayed the progression of renal dysfunction in hypertensive patients with mild to moderate renal disease to a greater degree than treatment with a calcium channel blocker.17
The results of this trial demonstrate an equivalent BP-lowering effect with a dose of VAL/HCTZ (160 mg/12.5 mg) to that with maximum-dose amlodipine (10 mg), the standard calcium antagonist prescribed for blacks, and the VAL/HCTZ regimen was better tolerated. The mean 24-hour BP reduction from baseline to end of study measured by ABPM was highly significant for both treatment groups, although the magnitude of the reductions in DBP and SBP were numerically greater for the VAL/HCTZ subgroups of baseline mean 24-hour DBP <100 mm Hg and SBP <160 mm Hg as well as subgroups by gender and age. In addition to the BP-lowering effects, the incidence of peripheral edema decreased in patients treated with VAL/HCTZ but increased in those treated with amlodipine.
Overall 24-hour control of BP was comparable for both treatments. However, VAL/HCTZ produced greater reductions in nighttime (6 pm to 6 am) BP in the total population as well as in those patients more resistant to nighttime reductions in BP. In the entire population, the reduction in mean nighttime ABPM BP with VAL/HCTZ was −16.3/−10.5 mm Hg compared with −14.1/−8.5 mm Hg for amlodipine (significantly different for DBP). In the subgroup of patients considered “nondippers,” the reduction in mean 24-hour ABPM DBP was −12.7 mm Hg for VAL/HCTZ and −10.3 mm Hg for amlodipine, a difference that was significant when adjusted for baseline 24-hour ABPM DBP level.
Both treatments were well tolerated. Overall, a similar proportion of patients in each treatment group reported adverse events, with most being of mild or moderate severity. Significantly more patients treated with amlodipine reported peripheral edema and joint swelling as adverse events than did patients treated with VAL/HCTZ. Patients treated with VAL/HCTZ in this study reported neither cough nor angioedema, which are common adverse events with ACE inhibitors. In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, the occurrence of ACE inhibitor–induced angioedema was 2 to 4× greater in blacks with hypertension than in other patient groups.22
In blacks with stage 1 and stage 2 hypertension, VAL/HCTZ at a dose level of 160 mg/12.5 mg was as effective as the maximum recommended dose of amlodipine (10 mg) for reducing BP but with a better tolerability profile. The results of this study support the first-line use of VAL/HCTZ in blacks with hypertension as an alternate approach compared with a calcium antagonist.
- Received April 15, 2005.
- Revision received May 10, 2005.
- Accepted July 20, 2005.
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Agodoa LY, Appel L, Bakris GL, Beck G, Bourgoignie J, Briggs JP, Charleston J, Cheek D, Cleveland W, Douglas JG, Douglas M, Dowie D, Faulkner M, Gabriel A, Gassman J, Greene T, Hall Y, Hebert L, Hiremath L, Jamerson K, Johnson CJ, Kopple J, Kusek J, Lash J, Lea J, Lewis JB, Lipkowitz M, Massry S, Middleton J, Miller ER III, Norris K, O’Connor D, Ojo A, Phillips RA, Pogue V, Rahman M, Randall OS, Rostand S, Schulman G, Smith W, Thornley-Brown D, Tisher CC, Toto RD, Wright JT Jr, Xu S; African American Study of Kidney Disease and Hypertension (AASK) Study Group. Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: a randomized controlled trial. J Am Med Assoc. 2001; 285: 2719–2728.
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