24-Hour ambulatory blood pressure control with triple-therapy amlodipine, valsartan and hydrochlorothiazide in patients with moderate to severe hypertension.

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 (10/320/25 mg), valsartan/hydrochlorothiazide (320/25 mg), amlodipine/valsartan (10/320 mg) or amlodipine/hydrochlorothiazide (10/25 mg) 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 28.0/17.8 mm Hg, 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 18.3-22.6/11.1-14.3 mm Hg (P≤0.01, 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 ≤130/85 mm Hg at end point. Amlodipine/valsartan/hydrochlorothiazide combination therapy was well tolerated. Once-daily treatment with amlodipine/valsartan/hydrochlorothiazide (10/320/25 mg) reduces ABP to a significantly greater extent than component-based dual therapy and maintains its effectiveness over the entire 24-h dosing period.

Combination therapy with amlodipine/valsartan in essential hypertension: a 52-week, randomised, open-label, extension study.

BACKGROUND: A majority of hypertensive patients require > or = 2 agents to achieve target blood pressure (BP). METHODS: This 52-week, multicentre, open-label, randomised extension trial to a previously reported double-blind, placebo-controlled study evaluated the safety and efficacy of amlodipine/valsartan (Aml/Val) combination. Patients who successfully completed the core study without serious drug-related adverse events (AEs) and mean sitting systolic BP (MSSBP)/mean sitting diastolic BP (MSDBP) < or = 150/95 mmHg were eligible to enter the extension and be treated with Aml/Val 2.5/80 or 5/80 mg. After 4 weeks of treatment, patients underwent force-titration to receive 5/160 mg (low dose) or 10/160 mg (high dose) for 48 weeks. Addition of hydrochlorothiazide (HCTZ) 12.5 mg was permitted if BP was > or = 140/90 mmHg at Week 8 or later. Patients could be down-titrated to the prior lower combination dose with or without HCTZ if an intolerable AE occurred. Safety evaluations included monitoring of AEs. Efficacy variables were change from baseline in MSDBP (primary) and MSSBP (secondary). RESULTS: Of 1246 patients randomised, 1075 (86.3%) completed the extension study. At week 52 end-point, change in MSSBP/MSDBP from core study baseline was -22.1/-17.2 mmHg for low-dose regimen and -22.8/-18.1 mmHg for high-dose regimen. For both regimens, reductions in BP were sustained over 52 weeks and mean BP maintained below approximately 135/85 mmHg at all visits. Frequent AEs in the low- and high-dose regimens were peripheral oedema (9.7% and 17.1% respectively), nasopharyngitis (8.1% and 7.2%), and dizziness (5.2% and 7.0%). Incidence of serious AEs was 3.7% with low dose and 4.1% with high dose. CONCLUSION: The combination of Aml/Val with the optional addition of HCTZ produced clinically significant and persistent reductions in BP over 52 weeks with a favourable tolerability profile.

Achieving blood pressure goal: initial therapy with valsartan/hydrochlorothiazide combination compared with monotherapy.

The benefits of valsartan (Val)/hydrochlorothiazide (HCTZ) combination as initial treatment for hypertension were evaluated in a post hoc analysis of an 8-week, double-blind, placebo-controlled, parallel-group trial. The highest dose of Val/HCTZ combination (320/25 mg), component monotherapies (Val 320 mg, HCTZ 25 mg) and placebo were selected for this analysis (N=675, 52.1% men, 68.6% Caucasians, mean age 52.9 years, baseline blood pressure (BP) 150.6/99.1 mm Hg). As soon as 2 weeks after initiation of active therapy, greater BP control rates were observed with Val/HCTZ (320/25 mg) compared with Val (320 mg), HCTZ (25 mg) and placebo. Similar results were observed in subgroups of patients with stage 1 and stage 2 hypertension, as well as in diabetic patients. As baseline BP increased, the probability of achieving mean sitting systolic BP (<140 and <130 mm Hg) and mean sitting diastolic BP control (<90 and <80 mm Hg), determined using a logistic regression model, decreased with all treatments. However, at all levels of baseline BP, the probability of achieving BP control was greater with Val/HCTZ combination. The Val/HCTZ combination was well tolerated with overall incidence of adverse events similar to that observed with monotherapy and placebo. These results support the use of Val/HCTZ combination as initial therapy in hypertensive patients unlikely to achieve BP control with a single agent.

Efficacy and tolerability of amlodipine/valsartan combination therapy in hypertensive patients not adequately controlled on amlodipine monotherapy.

UNLABELLED: ABSTRACT (ARB), in essential hypertensive patients not adequately controlled by amlodipine monotherapy. METHODS: This was a multi-centre, randomised, double-blind, active-controlled study in patients with essential hypertension. After a washout period followed by a single-blind amlodipine 10 mg run-in period, patients with mean sitting diastolic blood pressure (msDBP) > or =90 mmHg and <110 mmHg were randomised to receive amlodipine/valsartan (10/160 mg o.d.) or amlodipine (10 mg o.d.) for 8 weeks. TRIAL REGISTRATION NUMBER: NCT00171002. MAIN OUTCOME MEASURES: The primary efficacy variable was change from baseline in msDBP at study endpoint. Secondary efficacy variables were change from baseline in mean sitting systolic blood pressure (msSBP), responder rate (msDBP <90 mmHg or > or =10 mmHg reduction from baseline) and DBP control rate (msDBP <90 mmHg). RESULTS: Of the 1283 patients enrolled in single-blind period, 944 were randomised to receive amlodipine/valsartan 10/160 mg (n = 473) and amlodipine 10 mg (n = 471). Statistically significant greater reductions (p < 0.0001) from baseline in msSBP/msDBP were observed with combination therapy (12.9/11.4 mmHg) compared to monotherapy (10.0/9.3 mmHg). Responder rate was significantly greater (p = 0.0011) with combination therapy (79.0%) compared to monotherapy (70.1%). The percentage of patients with controlled DBP was also significantly (p < 0.0001) higher with combination therapy (77.8%) compared to monotherapy (66.5%). Incidence of peripheral oedema was slightly higher with amlodipine monotherapy (9.4%) compared to combination therapy (7.6%). CONCLUSION: The combination of amlodipine/valsartan in this 8-week double-blind study provided additional BP control and was well tolerated in patients inadequately controlled with amlodipine monotherapy. Results should be interpreted with the knowledge that study entry criteria may limit application to a wider population.

Efficacy and tolerability of amlodipine/valsartan combination therapy in hypertensive patients not adequately controlled on valsartan monotherapy.

OBJECTIVE: To demonstrate additional BP-lowering effects of amlodipine/valsartan combination in patients whose BP was not adequately controlled on valsartan alone. METHODS: This was a multi-centre, randomised, double-blind, active-controlled study in patients with essential hypertension. After a washout period followed by a single-blind valsartan 160 mg run-in period, patients with mean sitting diastolic blood pressure (DBP) >or= 90 mmHg and < 110 mmHg were randomised to receive amlodipine/valsartan (10/160 mg or 5/160 mg o.d.) or valsartan (160 mg o.d.) for 8 weeks. TRIAL REGISTRATION: NCT00170963 MAIN OUTCOME MEASURES: Primary efficacy variable was change from baseline in mean DBP at study end. Secondary efficacy variables included change from baseline in mean sitting systolic blood pressure (SBP), responder rate (mean DBP < 90 mmHg or >or= 10 mmHg reduction from baseline), and DBP control rate (mean DBP < 90 mmHg). Safety was also assessed. RESULTS: Of 1136 patients enrolled in single-blind phase, 947 (mean age: 54.6 years) were randomised. Statistically significantly greater reductions in mean SBP/DBP were observed in both amlodipine/valsartan combinations (10/160 mg: 14.3/11.5 mmHg, 5/160 mg: 12.2/9.6 mmHg; both p < 0.0001) compared to valsartan 160 mg (8.3/6.7 mmHg). The 10/160 mg combination (p < 0.05) showed statistically significantly greater reductions in mean SBP/DBP compared to 5/160 mg (p < 0.001). Responder rates were higher in both combination therapy groups (10/160 mg: 81% [p < 0.0001]; 5/160 mg: 68% [p = 0.0018], respectively) compared to monotherapy (57%). Peripheral oedema was the most frequent adverse event, reported in amlodipine/valsartan 10/160 mg (9.1%), 5/160 mg (0.9%), and valsartan 160 mg (1.3%). CONCLUSIONS: The combination of amlodipine/valsartan in this 8-week double-blind study provided additional BP control and was well-tolerated in patients inadequately controlled with valsartan monotherapy.

Rationale and design of the Valsartan Heart Failure Trial: a large multinational trial to assess the effects of valsartan, an angiotensin-receptor blocker, on morbidity and mortality in chronic congestive heart failure.

BACKGROUND: To investigate the role of persistent angiotensin activity despite angiotensin-converting enzyme inhibitor therapy in the progression of heart failure, the Valsartan Heart Failure Trial has been designed to investigate the effect of the angiotensin-receptor blocker, valsartan, on morbidity and mortality. METHODS AND RESULTS: Nearly 5,000 patients with New York Heart Association classes II to IV heart failure, while receiving all standard therapy, are being randomized to treatment with valsartan, 160 mg twice daily, or placebo in a worldwide study. Follow-up will be continued until 906 deaths have been recorded. Additional end points will include the need for hospitalization, other major morbid events, quality--of life measurement, changes in neurohormone levels, and changes in left ventricular size and function. Substudies will explore exercise tolerance, arrhythmias, and magnetic resonance imaging. CONCLUSION: This study should help establish the role of angiotensin-receptor blockade in the treatment of heart failure.

Site-differential gastrointestinal absorption of benazepril hydrochloride in healthy volunteers.

The absorption of benazepril-HCl (BZPH), an orally active angiotensin-converting enzyme (ACE) inhibitor, in various regions of the gastrointestinal (GI) tract was investigated using an intestinal intubation technique. Thirteen subjects completed this single-dose, three-phase sequential crossover study. The drug (20 mg) was administered either as a 4-hr colonic infusion (COLON) or as a small intestinal infusion (SI) in the first two phases and as an oral bolus solution (ORAL) in the third phase, with a 2-week washout between each treatment. Serial plasma and urine samples were collected for up to 4 days after dosing. BZPH and its active metabolite benazeprilat (BZPL) were determined using a gas chromatography/mass spectrometry method. BZPH was absorbed rapidly into the bloodstream (Tmax = 0.5 hr after ORAL). Absorption was also rapid for SI, with a postinfusion half-life (0.57 hr) nearly identical to that for ORAL (0.59 hr). The absorption rate after COLON was much slower (lower Cmax and longer Tmax) compared to that after SI, and the apparent half-life (1.7 hr) was prolonged. SI delivered 90%, whereas COLON delivered 23%, of the drug into the systematic circulation as compared to ORAL. BZPL was rapidly formed upon drug absorption. The metabolite-to-drug AUC ratios were comparable for SI and ORAL (8.9 vs 9.7), indicating that first-pass metabolism of BZPH was neither saturable nor input rate dependent. The metabolite-to-drug AUC ratio was reduced for COLON (5.0), indicating that the mechanism of absorption of BZPH in the colon may be different than that after SI and ORAL. Urinary recovery data were consistent with plasma data.(ABSTRACT TRUNCATED AT 250 WORDS)