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To determine the effectiveness and safety of once-daily combination therapy with amlodipine, valsartan and hydrochlorothiazide for reducing ambulatory blood pressure (ABP) in patients with moderate to severe hypertension, a multicenter, double-blind study was performed (N=2271) that included ABP monitoring in a 283-patient subset. After a single-blind, placebo run-in period, patients were randomized to receive amlodipine/valsartan/hydrochlorothiazide (10/320/25mg), valsartan/hydrochlorothiazide (320/25mg), amlodipine/valsartan (10/320mg) or amlodipine/hydrochlorothiazide (10/25mg) each morning for 8 weeks. Efficacy assessments included change from baseline in 24-h, daytime and night time mean ambulatory systolic BP (SBP) and diastolic BP (DBP). Statistically significant and clinically relevant reductions from baseline in all these parameters occurred in all treatment groups (P<0.0001, all comparisons versus baseline). At week 8, least squares mean reductions from baseline in 24-h, daytime and night time mean ambulatory SBP/DBP were 30.3/19.7, 31.2/20.5 and 28.0/17.8mmHg, respectively, with amlodipine/valsartan/hydrochlorothiazide; corresponding reductions with dual therapies ranged from 18.8–24.1/11.7–15.5, 19.0–25.1/12.0–16.0 and 18.3–22.6/11.1–14.3mmHg (P0.01, all comparisons of triple versus dual therapy). Treatment with amlodipine/valsartan/hydrochlorothiazide maintained full 24-h effectiveness, including during the morning hours; all hourly mean ambulatory SBP and mean ambulatory DBP measurements were 130/85mmHg at end point. Amlodipine/valsartan/hydrochlorothiazide combination therapy was well tolerated. Once-daily treatment with amlodipine/valsartan/hydrochlorothiazide (10/320/25mg) reduces ABP to a significantly greater extent than component-based dual therapy and maintains its effectiveness over the entire 24-h dosing period.
The blood pressure (BP) surge that occurs between 6 and noon1 has been associated with a peak in the incidence of cardiovascular events and sudden death.2 This surge in BP (~10–30mmHg in systolic BP (SBP) and 7–23mmHg in diastolic BP (DBP))2 coincides with an increase in pulse rate and sympathetic tone and activation of the renin-angiotensin-aldosterone system.3, 4, 5, 6 In turn, activation of the renin-angiotensin-aldosterone system results in increased levels of aldosterone and angiotensin II, a potent vasoconstrictor that modulates vasomotor tone, cell growth and extracellular matrix deposition.7 Several studies have shown that among patients who appear to have well-controlled morning BP, as assessed by office measurements, ~60% have poorly controlled morning BP when assessed by ambulatory BP monitoring (ABPM).8, 9
It is well established that the majority of patients with hypertension require two or more antihypertensive agents from complementary classes to achieve BP control,10, 11, 12, 13 and the results from several recent studies indicate that ~23–54% of patients with hypertension require three or more agents.10, 14, 15, 16, 17 Results were recently reported for the first large-scale, randomized, double-blind clinical trial designed to compare the effectiveness and safety of once-daily triple therapy with the calcium channel blocker amlodipine (Aml), the angiotensin receptor antagonist valsartan (Val) and the thiazide diuretic hydrochlorothiazide (HCTZ) (10/320/25mg) versus component-based dual therapy with Val/HCTZ, Aml/Val or Aml/HCTZ for the treatment of moderate to severe hypertension.18 The results of this study showed that triple therapy with Aml/Val/HCTZ was well tolerated and was significantly more effective in reducing mean sitting SBP (MSSBP) and mean sitting DBP (MSDBP) and in providing BP control than component-based dual therapy. The current article reports the results of ABPM in a subgroup of patients who participated in this triple-therapy study. The objective was to determine the effectiveness of triple therapy for controlling BP throughout the 24-h interval.
This study was a randomized, double-blind, parallel-group, active-control trial conducted in 15 countries. The study design, patient selection criteria and disposition of all patients enrolled were reported in detail by Calhoun et al.18
The study included an antihypertensive washout period and single-blind, placebo run-in period of up to 4 weeks, followed by an 8-week, double-blind treatment period (Figure 1). At the end of the placebo run-in period, patients were randomly assigned (1:1:1:1) to receive triple therapy with Aml/Val/HCTZ (10/320/25mg) or dual therapy with Val/HCTZ (320/25mg), Aml/Val (10/320mg) or Aml/HCTZ (10/25mg). Randomization was achieved using a validated, interactive, voice-response system. As shown in Figure 1, the study design included a two-step dose-escalation period in the triple-therapy arm and a single-step dose-escalation period in each of the dual-therapy arms over the first 2 weeks, followed by 6 weeks of treatment at full dosage administered once-daily at 8 . On study visit days, patients were instructed not to take their study medication until assessments were completed.
Patients 18–85 years of age with moderate or severe hypertension (grade 2 or 3 or stage 2;19, 20 MSSBP 145 and <200mmHg and MSDBP 100 and <120mmHg) were eligible to participate. Patients were excluded if, at screening, they were receiving four or more antihypertensive agents; three antihypertensive agents and had an MSSBP/MSDBP 140/90mmHg; two antihypertensive agents and had an MSSBP/MSDBP 180/110mmHg; or no antihypertensive agents and had an MSSBP/MSDBP <140/90mmHg. Other key exclusion criteria included significant cardiovascular, hepatic, and renal disease and concomitant type 1 diabetes or uncontrolled type 2 diabetes, as previously described.18
Patients meeting the screening criteria were immediately randomly assigned to receive treatment if MSSBP was 180mmHg or MSDBP was 110mmHg. The remaining patients were randomly assigned to receive treatment after a placebo run-in period of up to 4 weeks if MSSBP was 145mmHg and MSDBP was 100mmHg. Patients were removed from the study if they experienced MSSBP 200mmHg or MSDBP 120mmHg at any time during the study.
The MSSBP and MSDBP measurements were obtained at each study visit, as reported by Calhoun et al.18 Per protocol, 24-h ABPM was conducted at baseline before randomization (week 1) and after 8 weeks of double-blind treatment (week 9) in a subset of patients enrolled in the study. Patients were fitted on the non-dominant arm with a Spacelabs 90207 ABPM device (Spacelabs Healthcare Supplies, Issaquah, WA, USA) between 0700 hours and 1000 hours on the first day of each monitoring period, and the device was calibrated to within ±7mmHg against the mean of three DBP readings.21 Pressure cuffs were set to inflate every 20min over a 24-h time period and to deflate at a rate of 8mmHg per 2 heartbeats. The ABPM device was removed on the second or third day of each period after a minimum of 24h, and the ABPM data were downloaded and evaluated on site using study-specific ABPM software (Medifacts International, Rockville, MD, USA). If the ABPM data did not meet pre-specified quality control criteria, the entire ABPM procedure could be repeated at the discretion of the study investigator.
The primary efficacy variables were change from baseline in MSSBP and MSDBP at week 9, as described by Calhoun et al.18 Secondary end points reported herein included the change from baseline in 24-h, daytime (0600 hours to 2200 hours) and night time (2200 hours to 0600 hours) mean ambulatory SBP (MASBP) and mean ambulatory DBP (MADBP). Mean 24-h ABPM data from the intent-to-treat population were analyzed using an analysis of covariance model for repeated measures with treatment, region and postdosing hour as factors, baseline 24-h mean ABPM results as a covariate, and treatment by postdosing-hour interactions. Daytime and night time ABPM data from the intent-to-treat population were analyzed using an analysis of covariance model for repeated measures with treatment, region and time (daytime, night time) as factors, baseline 24-h mean ABPM results as a covariate, and treatment-by-time interactions. The mean changes from baseline in MASBP and MADBP (with 95% confidence intervals) were assessed at week 9. The differences in the mean changes from baseline in MASBP and MADBP between the triple-therapy arm and the dual-therapy arms were estimated using least squares mean data. MASBP and MADBP at each hour were summarized at baseline and end point for each treatment group.
Further, post hoc analyses of morning (0600 hours to 2400 hours) MASBP and MADBP were individually performed using an analysis of covariance model with treatment and region as factors and baseline 24-h mean ABPM results as a covariate.
Multiplicity adjustment for P-values from the analyses of primary efficacy variables was described by Calhoun et al.18 No multiplicity adjustment was made for P-values from the analyses of ABPM data.
Additionally, post hoc summary statistics were performed to assess the mean reductions in 24-h ambulatory BP (ABP) in patients grouped according to the severity of hypertension at baseline as assessed by clinic SBP (140 and <160mmHg; 160 and <200mmHg; 180 and <200mmHg).
Of the 4285 patients enrolled, 2271 were assigned to double-blind treatment and 2060 (90.7%) completed treatment,18 including all 283 patients who underwent 24-h ABPM. The demographic and baseline characteristics of the subgroup of patients undergoing ABPM were similar between treatment arms (Table 1), and similar to those of the study population as a whole.18 Of the patients undergoing ABPM, baseline MSSBP/MSDBP was 165.2/105.2mmHg and MASBP/MADBP was 148.2/93.4mmHg.
All four treatments resulted in clinically relevant and statistically significant reductions from baseline in least squares MASBP and MADBP over the 24-h dosing period and during the daytime and night time hours (Figure 2; P<0.0001 versus baseline for all comparisons). However, the improvements in 24-h, daytime and night time ABP were greatest in patients receiving Aml/Val/HCTZ (P0.01 for all comparisons). Among the patients receiving triple therapy, the 24-h MASBP decreased by 30.3mmHg (95% confidence interval: −31.7, −28.8) and the 24-h MADBP decreased by 19.7mmHg (95% confidence interval: −20.7, −18.7). Consistent results were observed for the daytime and night time hours.
The absolute 24-h, daytime and night time MASBP/MADBP levels at study end point were lowest in the triple-therapy group (119/75, 123/78 and 111/68mmHg, respectively).
Mean hourly ABPM data obtained at baseline and at week 9 are presented in Figure 3. At baseline, MASBP levels were >130mmHg and MADBP levels were >80mmHg at all time points throughout the 24-h dosing period in all treatment groups. At the end of the study (week 9), all (100%) of the hourly MASBP levels were 130mmHg in the Aml/Val/HCTZ group. In comparison, 91.7, 83.3 and 41.7% of the hourly MASBP levels were <130mmHg in the Val/HCTZ, Aml/Val and Aml/HCTZ groups, respectively. All hourly end point MADBP levels were <85mmHg in the triple-therapy group and 87.5% (21 of 24) of the hourly levels were <80mmHg.
Statistically significant greater reductions from baseline in morning MASBP and MADBP were observed in patients receiving triple therapy (30.2/20.6mmHg) compared with Val/HCTZ (24.5/15.7mmHg; P<0.01), Val/Aml (24.6/15.4mmHg; P<0.01) and HCTZ/Aml (19.7/12.4mmHg; P<0.0001). MASBP/MADBP between 0600 hours and 1200 hours was 124/80mmHg in the triple-therapy group.
Reductions in 24-h MASBP were greater across all treatment groups in the subgroups of patients with baseline MSSBP 160 and <200mmHg or baseline MSSBP 180 and <200mmHg, compared with the reductions in patients with baseline MSSBP 140 and <160mmHg (Figure 4). In patients with baseline MSSBP 160 and <200mmHg or and patients with baseline MSSBP 180 and <200mmHg, decreases in MASBP were greater with Aml/Val/HCTZ (34.2 and 37.0mmHg, respectively) than with dual therapy (range: 21.0–26.4 and 22.5–31.2mmHg, respectively). Similarly, decreases in MASBP in patients with baseline MSSBP 140 and <160mmHg were also greater with triple therapy than with dual therapy.
This is the first large-scale, controlled trial to prospectively study the effects of once-daily triple therapy with Aml/Val/HCTZ versus component-based dual therapy for controlling ABP throughout the 24-h interval. The ABPM data from this subgroup of patients corroborate the clinic BP findings from the entire study population.18 Overall, the ABPM data show that treatment with Aml/Val/HCTZ lowered MASBP/MADBP by ~30/20mmHg throughout the 24-h period, which was significantly better than the reductions achieved in patients receiving dual therapy. An even greater improvement in MASBP (reductions of 37mmHg) was observed among triple-therapy patients with severe systolic hypertension at baseline (MSSBP 180 and <200mmHg).
The results from the current study further show that the reductions in ABP are relatively uniform throughout the 24-h dosing period. Notably, at end point, hourly MASBP/MADBP levels among patients receiving Aml/Val/HCTZ remained 130/85mmHg for every hour of the 24-h dosing period, including the early morning hours. MASBP/MADBP between 0600 hours and 1200 hours, the hours coinciding with the morning surge in BP, was 124/80mmHg in the triple-therapy group. The ABP levels achieved with triple therapy are clinically relevant considering the 24-h, daytime and night time means were lower than the lower end of the European Society of Hypertension/European Society of Cardiology SBP/DBP target goal ranges for ABP (125–130/80, 130–135/85 and 120/70mmHg, respectively).20
The results from this ABPM subgroup analysis, in conjunction with the results from the primary efficacy analysis,18 have important implications for the management of patients with moderate to severe hypertension. The consistent reductions in ABP observed in this study throughout the 24-h dosing interval are important, because ABP has been shown to be a strong predictor of cardiovascular morbidity and mortality.22, 23 Moreover, ABPM over 24h is the most accurate method of assessing the effectiveness of antihypertensive therapy24 and can characterize BP during the early morning hours, when cardiovascular and cerebrovascular events are most likely to occur.2 At the same time, however, there is a lack of evidence that controlling the morning BP surge translates into a reduction in cardiovascular events.25 Nonetheless, attaining 24-h BP control is a goal of antihypertensive therapy. In this regard, several studies (including the recently completed effects of force-titrated valsartan/hydrochlorothiazide versus amlodipine/hydrochlorothiazide on ambulatory blood pressure in patients with stage 2 hypertension (EVALUATE) study26) have shown that dual therapy with angiotensin receptor blockers in combination with a non-renin-angiotensin-aldosterone system antihypertensive agent is effective for controlling ABP throughout the day, including the high-risk hours coinciding with the morning surge in BP.27, 28, 29, 30, 31, 32 The results from this study show that additional improvements in ABP can be achieved throughout the day, including the morning hours, with angiotensin receptor blocker-based triple therapy that incorporates agents with complementary mechanisms of action.
Our study excluded individuals who were on four or more antihypertensive agents. This exclusion may have led to a greater percentage of patients responding to triple therapy as well as dual therapy in our study. However, for ethical reasons, it was not considered appropriate to enroll patients who were in need of four or more antihypertensive agents because the trial only allowed for a maximum of three drugs per patient. As with all clinical trials, study entry criteria can limit extrapolation of results to a broader patient population.
In patients with moderate to severe hypertension, once-daily therapy with Aml/Val/HCTZ (10/320/25mg) reduces ABP throughout the 24-h dosing interval, including the overall 24-h, daytime and night time periods, to a significantly greater extent than component-based dual therapy. Aml/Val/HCTZ lowers MASBP/MADBP by ~30/20mmHg throughout the day in these patients with even greater reduction observed in those patients with more severe systolic hypertension. Notably, triple therapy with Aml/Val/HCTZ effectively controls MASBP to 130mmHg for every hour throughout the day, including early morning hours.
We acknowledge Fran Karo, PhD and Michael S McNamara, MS, of Oxford PharmaGenesis, Inc., for their editorial support in the development of this manuscript. This study was funded by Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
Yves Lacourcière and David Calhoun received research funding from Novartis Pharmaceuticals Corporation for the current study. Robert Glazer, Joseph Yen and Nora Crikelair are employees of Novartis Pharmaceuticals Corporation.
The principal investigator and the co-authors made the decision to submit the manuscript for publication and take responsibility for the content.
This study is registered as clinical trial number NCT00327587.