Objective To assess the dose-response relationship for reduction in mean systolic blood pressure (MSBP) with valsartan solution, in young children with hypertension with or without chronic kidney disease (CKD). Methods In this multicenter, randomized, double-blind, double-dummy study, 127 young children aged 1-5 years with hypertension (MSBP >= 95th percentile) were randomized (1:1) to receive valsartan 0.25 or 4 mg/kg/day for 6 weeks, followed by a 20 week open-label phase, where patients received valsartan 1 mg/kg/day for 4 weeks, and then optionally titrated to 2 mg/kg/day or up to 4 mg/kg/day. The primary endpoint was the change in MSBP from baseline at Week 6 during the double-blind phase. Results Overall, 120 patients (94.5%) completed the study; 63 had CKD. A clinically and statistically significant reduction in MSBP from baseline to Week 6 was observed with the valsartan 4 mg/kg group compared with the valsartan 0.25 mg/kg group (8.5 vs 4.1 mmHg; p = .0157). A positive dose-response relationship for MSBP reduction was observed between the 0.25 mg/kg and 4 mg/kg groups (p = .0012). In the CKD subgroup, a significant reduction in MSBP was observed with 4 mg/kg (9.2 mmHg) versus 0.25 mg/kg (1.2 mmHg; p = .0096). In the non-CKD subgroup, a numerically greater decrease in MSBP was observed with 4 mg/kg (7.8 mmHg) versus 0.25 mg/kg (6.9 mmHg; p = .6531). Incidence of adverse events was lower with valsartan 4 mg/kg than 0.25 mg/kg (41.9% vs 51.6%) and similar between CKD and non-CKD subgroups (48.4% vs 45.3%) irrespective of dose. Increase in serum potassium (>20% compared to baseline) was observed more frequently in patients with CKD compared to non-CKD patients. Conclusion Valsartan was efficacious and well tolerated in children 1 to 5 years of age with hypertension, with or without CKD.

The present study aimed to assess the long-term safety and tolerability of valsartan in hypertensive children aged 6–17 years, with or without chronic kidney disease (CKD).

Abstract Objective: To compare the antihypertensive efficacy and safety of once-daily triple therapy with amlodipine (Aml) 10 mg, valsartan (Val) 320 mg, and hydrochlorothiazide (HCTZ) 25 mg versus dual-therapy combinations of these components in patients with moderate to severe hypertension. Research design: Subgroup analysis of a multinational, randomized, double-blind, parallel-group, active-controlled trial. Methods: After antihypertensive washout and a placebo run-in of up to 4 weeks, 2271 patients were randomly allocated in a 1:1:1:1 ratio to receive Aml/Val/HCTZ triple therapy or dual therapy with Val/HCTZ, Aml/Val, or Aml/HCTZ for 8 weeks. Forced titration to the full dose was done over the first 2 weeks of treatment. Efficacy and safety parameters were determined by age group (<65 vs. ≥65 years), gender, race (White vs. Black), ethnicity (Hispanic/Latino vs. non-Hispanic/Latino), and body mass index (BMI, <30 vs. ≥30 kg/m2). Main outcome measures: Change from baseline to endpoint in mean sitting systolic blood pressure (MSSBP) and mean sitting diastolic blood pressure (MSDBP); blood pressure (BP) control rate <140/90 mmHg. Results: Triple therapy was numerically superior and, for the majority of comparisons, statistically superior to each dual therapy in reducing MSSBP and MSDBP and in improving BP control rates in all subgroups. Across subgroups, triple therapy reduced MSSBP by 5.7–10.7 mmHg more than Val/HCTZ, 3.4–8.3 mmHg more than Aml/Val, and 4.4–9.4 mmHg more than Aml/HCTZ. Triple therapy was well tolerated across all subgroups. Limitations of our analysis included the lack of stratification of patients by subgroup at randomization and the small sample size of some subgroups (e.g., Blacks, elderly). Conclusions: Triple therapy with Aml/Val/HCTZ is effective and well tolerated in patients with moderate to severe hypertension regardless of age, gender, race, ethnicity, or BMI. Trial registration number: NCT00327587.

Achieving target blood pressure (BP) is influenced by baseline BP. Post hoc analyses of a placebo-controlled trial of amlodipine/valsartan versus monotherapies were conducted to characterize BP control by baseline BP. Hypertensive patients were randomized to amlodipine 10 mg, valsartan 160 or 320 mg, amlodipine/valsartan 10/160 or 10/320 mg, or placebo. Analysis of BP control rates focused on patients receiving the highest combination and monotherapy doses, with adverse events assessed for all doses. Analyses included 834 patients (mean age: 57 years; male: 51.3%; white: 79.4%; stage 2 hypertension: 61%; mean BP: 157/99 mm Hg). Two weeks after starting therapy, BP control (<140/90 mm Hg) rates were greater with amlodipine/valsartan 10/320 mg (49%) versus monotherapies (32%-38%) and placebo (16%). Consistent results were observed in stage 1 and 2 patients. Among patients receiving combination therapy, statistically significant differences were observed at endpoint versus comparators. At all baseline BP levels, the probability of achieving BP lower than 140/90 or lower than 130/80 mm Hg was greater with amlodipine/valsartan than monotherapies and placebo. Overall adverse events incidence was similar with combination versus monotherapies and placebo. Initial therapy with amlodipine/valsartan results in early, more effective BP control compared with monotherapy, irrespective of baseline BP.

Objective: This post hoc analysis evaluated the efficacy and safety of triple therapy with amlodipine/valsartan+hydrochlorothiazide (Aml/Val+HCTZ) vs dual therapy with Aml+HCTZ in stage 2 hypertensive patients. Methods: The analysis included patients from an eight-week, multicenter, double-blind study, randomized to Aml/Val 10/160 mg or Aml 10 mg groups, who received add-on HCTZ 12.5 mg at week 4 if mean sitting systolic blood pressure (msSBP) was >130 mmHg. Results: Of the patients receiving Aml/Val+HCTZ and Aml+HCTZ, 98% (N = 133/136) and 96% (N = 200/208) completed the study, respectively. Baseline characteristics were similar across groups (Caucasians, 80.2%; diabetics, 14.8%; age, 58.6 years [28.2% ≥ 65 years]; body mass index, 31 kg/m2; mean sitting blood pressure (msBP), 171.5/95.5 mmHg [18% msSBP ≥ 180 mmHg]). Aml/Val+HCTZ provided significantly greater msBP reductions from baseline to week 8 than Aml+HCTZ (30.5/13.8 vs 24.3/8.3 mmHg, P < 0.0001). The incremental msBP reduction (week 4 to 8) with HCTZ added to Aml/Val was greater than when added to Aml (6.9/3.5 vs 3.1/1.0 mmHg, P < 0.01). Treatments were well tolerated with similar overall incidence of adverse events (Aml/Val+HCTZ: 33.8%, Aml+HCTZ: 33.2%). Conclusion: Aml/Val+HCTZ provided significantly greater BP reductions than Aml+HCTZ in patients with stage 2 hypertension. Aml/Val+HCTZ triple therapy may be a suitable option for patients requiring more than two agents to reach target BP.

An 8-week trial of amlodipine/valsartan/hydrochlorothiazide (Aml/Val/HCTZ) for moderate or severe hypertension demonstrated more-pronounced blood pressure (BP)-lowering effects compared with dual-component therapies. To elucidate the effects of time and baseline BP on the observed responses, exploratory analyses were performed.

Background and objective Baseline blood pressure (BP) is a strong predictor of response to antihypertensive therapy and the patient's ability to reach BP goals. The objective of this study was to evaluate the role of baseline BP as a determinant of systolic BP (SBP) and treatment outcome to assist in the choice of initial therapy. Methods This was a double-blind, placebo-controlled clinical trial (n = 1329) in patients with essential hypertension (mean sitting diastolic BP [DBP] > or = 95 mmHg and Results The final SBP and DBP were lowest in the combination therapy groups across all baseline BPs and in subgroups of patients categorized by age (> or = 65 years, Conclusion These secondary analyses suggest that characterizing the relationship between baseline SBP and achieved SBP can assist in the choice of initial therapy in a broad hypertensive population. Initial therapy with the combination of valsartan/HCTZ is more effective than monotherapy in lowering BP at all baseline BP levels, is consistent in this respect among all subgroups, and is well tolerated.

OBJECTIVE:To evaluate the long-term tolerability and efficacy of the amlodipine/valsartan 5/320 mg once daily (o.d.) combination in hypertensive patients.METHODS:This was a 54-week, multicenter, open-label extension study in patients with mild-to-moderate essential hypertension selected after successfully completing a core study during which they received either placebo, amlodipine, valsartan or combination therapy. Eligible patients (mean sitting diastolic blood pressure [MSDBP] < or = 95 mmHg and mean sitting systolic blood pressure [MSSBP] < or = 150 mmHg; n = 403) were started with amlodipine/valsartan 2.5/160 mg o.d. Following the initial 2-week treatment period, patients were force titrated to amlodipine/valsartan 5/320 mg o.d. for the remainder of the trial. Only the first 150 patients who successfully completed 28 weeks of the extension study were eligible to continue further treatment for 12 months. Efficacy variables were change from core study baseline in MSDBP and MSSBP at study (extension) endpoint. Safety assessments consisted of monitoring and recording all adverse events and serious adverse events.RESULTS:Reductions in MSDBP and MSSBP were achieved at each extension visit. At endpoint, the reductions in MSDBP and MSSBP were 17.0 and 24.2 mmHg. Summary statistics by subgroup indicate that the combination of amlodipine/valsartan 5/320 mg was effective regardless of age, gender, or stage of hypertension. Peripheral edema occurred in 1.2% of the patients. No case of edema was classified as serious or severe, and no patient was discontinued due to edema. No deaths or clinically significant laboratory findings were observed during this extension study.CONCLUSIONS:Long-term treatment with the amlodipine/valsartan 5/320 mg combination was well-tolerated. Clinically significant and persistent reductions in blood pressure were achieved. Limitations included an open-label design and inclusion of only those patients at or near goal blood pressure after the preceding core trial.

Background and Objective: Baseline blood pressure (BP) is a strong predictor of response to antihypertensive therapy and the patient’s ability to reach BP goals. The objective of this study was to evaluate the role of baseline BP as a determinant of systolic BP (SBP) and treatment outcome to assist in the choice of initial therapy.

Many patients with hypertension require ≥3 agents to achieve target blood pressure (BP). The efficacy/safety of the dual combinations of valsartan (Val)/hydrochlorothiazide (HCTZ) and amlodipine (Aml)/Val in hypertension are well established. This randomized, double-blind study evaluated the efficacy/safety of triple therapy with Aml/Val/HCTZ for moderate or severe hypertension (mean sitting systolic BP: ≥145 mm Hg; mean sitting diastolic BP: ≥100 mm Hg). The study included a single-blind, placebo run-in period, followed by double-blind treatment for 8 weeks; patients were randomly assigned to 1 of 4 groups titrated to Aml/Val/HCTZ 10/320/25 mg, Val/HCTZ 320/25 mg, Aml/Val 10/320 mg, or Aml/HCTZ 10/25 mg once daily. Dual-therapy recipients received half of the target doses of both agents for the first 2 weeks, titrating to target doses during week 3. Those on triple therapy received Val/HCTZ 160.0/12.5 mg during week 1, Aml/Val/HCTZ 5.0/160.0/12.5 mg during week 2, and target doses of all 3 of the agents during week 3. Of the 4285 patients enrolled, 2271 were randomly assigned to treatment, and 2060 completed the study. Triple therapy was significantly superior to all of the dual therapies in reducing mean sitting systolic BP and mean sitting diastolic BP from baseline to end point (all P <0.0001). Significantly more patients on triple therapy achieved overall BP control (<140/90 mm Hg; P <0.0001) and systolic and diastolic control ( P ≤0.0002) compared with each dual therapy. Aml/Val/HCTZ was well tolerated. The benefits of triple therapy over dual therapy were observed regardless of age, sex, race, ethnicity, or baseline mean sitting systolic BP. In conclusion, this study demonstrates the efficacy/safety of treating moderate and severe hypertension with Aml/Val/HCTZ 10/320/25 mg.

ABSTRACT Objective: Most patients with severe hypertension are at high risk for cardiovascular events and require prompt blood pressure (BP)-lowering and combination therapy to achieve BP goals. This study evaluated the therapeutic efficacy and tolerability of initial treatment with the combination of valsartan and hydrochlorothiazide (HCTZ) compared with valsartan monotherapy in patients with severe hypertension. Research design and methods: This was a 6-week, randomized, double-blind, multicenter, forced titration study that compared initial therapy with the combination of valsartan/HCTZ 160/12.5 mg (force titrated to 160/25 mg after 2 weeks and to 320/25 mg after 4 weeks) to monotherapy with valsartan 160 mg (force titrated to 320 mg after 2 weeks and sham-titrated to 320 mg after 4 weeks). Eligible patients were 18–80 years old with severe essential hypertension (mean sitting diastolic BP ≥ 110 mmHg and <120 mmHg and mean sitting systolic BP ≥ 140 mmHg and <200 mmHg). The Clinical Trial Registry number was NCT00273299. Main outcome measures: The primary efficacy variable was the rate of BP control (mean sitting BP < 140/90 mmHg) at Week 4. Tolerability was evaluated by monitoring all adverse events, vital signs, and laboratory tests including hematology and biochemistry. Results: A total of 608 patients were randomized to either valsartan/HCTZ (n = 307) or valsartan monotherapy (n = 301). Significantly more patients achieved overall BP control (<140/90 mmHg) with valsartan/HCTZ compared to monotherapy at Week 4 (primary efficacy variable and timepoint) (39.6% vs. 21.8%; p < 0.0001) and Week 6 (48.2% vs. 27.2%; p < 0.0001). Mean reductions in BP at Week 4 were significantly greater for valsartan/HCTZ (30.8/22.7 mmHg vs. 21.7/17.5 mmHg; p < 0.0001), with further reductions at Week 6. BP control rates were greater with combination therapy as early as Week 2. The overall incidence of adverse events was comparable between the combination therapy (34.9%) and monotherapy (36.7%) treatment groups. A potential limitation of the forced-titration design is that some patients were titrated to higher doses despite having achieved goal BP. This may impact the interpretation of the incidence of dose-dependent adverse events. Conclusions: Initial therapy with valsartan/HCTZ is effective and well tolerated in patients with severe hypertension.

Patients with difficult to control hypertension typically require 2 or more agents to achieve goal blood pressure (BP) levels. Fixed‐dose combination therapies with lower doses generally are well tolerated and more effective than higher‐dose monotherapy. The authors performed prespecified and post hoc subgroup analyses of 2 double‐blind, randomized, placebo‐controlled trials that assessed the efficacy and safety of amlodipine and valsartan, alone and in combination, in patients with mild to moderate hypertension. Patients were randomized to amlodipine (study 1: 2.5 or 5 mg/d; study 2: 10 mg/d), valsartan (study 1: 40, 80, 160, or 320 mg/d; study 2: 160 or 320 mg/d), combination therapy across the same dose ranges, or placebo. Analyses were performed on changes from baseline in mean sitting systolic and diastolic BP and the occurrence of adverse events in specific subgroups of patients (ie, those with stage 2 hypertension [post hoc], the elderly [65 years or older], and blacks [both prespecified]). Amlodipine + valsartan combination therapy was associated with greater BP‐lowering effects in the subgroups compared with each respective monotherapy and placebo. These findings were consistent with the primary efficacy analysis results from the overall study populations. Combination regimens were generally well tolerated by all patient subgroups.

Background: One third of patients treated for hypertension attain adequate blood pressure (BP) control, and multidrug regimens are often required. Given the lifelong nature of hypertension, there is a need to evaluate the long-term efficacy and tolerability of higher doses of combination antihypertensive therapies. Objective: This study investigated the efficacy and tolerability of valsartan (VAL) or hydrochlorothiazide (HCTZ) monotherapy and higher-dose combinations in patients with essential hypertension.Methods: The first part of this study was an 8-week, multicenter, randomized, double-blind, placebocontrolled, parallel-group trial. Patients with essential hypertension (mean sitting diastolic BP [MSDBP], >= 95 mm Hg and < 110 mm Hg) were randomized to 1 of 8 treatment groups: VAL 160 or 320 mg; HCTZ 12.5 or 25 mg; VAL/HCTZ 160112.5, 320/12.5, or 320/25 mg; or placebo. Mean changes in MSDBP and mean sitting systolic BP (MSSBP) were analyzed at the 8-week core study end point. VAL/HCTZ 320/12.5 and 320/25 mg were further investigated in a 54-week, open-label extension. Response was defined as MSDBP < 90 mm Hg or a >= 10 mm Hg decrease compared to baseline. Control was defined as MSDBP < 90 mm Hg compared with baseline. Tolerability was assessed by monitoring adverse events at randomization and all subsequent study visits and regular evaluation of hematology and blood chemistry.Results: A total of 1346 patients were randomized into the 8-week core study (734 men, 612 women; 924 white, 291 black, 23 Asian, 108 other; mean age, 52.7 years; mean weight, 92.6 kg). All active treatments were associated with significantly reduced MSSBP and MSDBP during the core 8-week study, with each monotherapy significantly contributing to the overall effect of combination therapy (VAL and HCTZ, P < 0.001). Each combination was associated with significantly greater reductions in MSSBP and MSDBP compared with the monotherapies and placebo (all, P < 0.001). The mean reduction in MSSBP/MSDBP with VALJHCTZ 320/25 ing was 24.7/ 16.6 mm Hg, compared with 5.9/7.0 mm Hg with placebo. The reduction in MSSBP was significantly greater with VAL/HCTZ 320/25 mg compared with VAL/HCTZ 160112.5 mg (P < 0.002). Rates of response and BP control were significantly higher in the groups that received combination treatment compared with those that received monotherapy. The incidence of hypokalemia was lower with VAL/HCTZ combinations (1.8%-6.1%) than with HCTZ monotherapies (7.1%-13.3%). The majority of adverse events in the core study were of mild to moderate severity. The efficacy and tolerability of VAL/HCTZ combinations were maintained during the extension (797 patients).Conclusions: In this study population, combination therapies with VAL/HCTZ were associated with significantly greater BP reductions compared with either monotherapy, were well tolerated, and were associated with less hypokalemia than HCTZ alone.

This patient data meta‐analysis included 9 randomized, double‐blind, placebo‐controlled trials (N=4278) of once‐daily valsartan 80, 160, or 320 mg or valsartan/hydrochlorothiazide 80/12.5, 160/12.5, 160/25, 320/12.5, or 320/25 mg given for 4 to 8 weeks. Efficacy variables included: (1) mean change in systolic blood pressure (BP) and diastolic BP; and (2) proportion of patients reaching BP goal (<140/90 mm Hg) at the end of the study. Results showed that incremental systolic and diastolic BP reductions were achieved with increasing doses. Starting doses of valsartan 160 mg provided greater BP reductions and a higher proportion of patients reaching goal than 80 mg; combination therapy was more effective than monotherapy. BP goal rates increased incrementally with higher doses. With valsartan/hydrochlorothiazide 320/25 mg, 74.9% overall, 88.8% of stage 1, and 62.1% of stage 2 patients reached BP goal. The rate of discontinuation due to adverse events was low with both monotherapy and combination treatment. Higher starting doses may enable patients to achieve greater initial BP reductions and reach BP goal more rapidly.

Background: our objective was to assess time to achieve blood-pressure (BP) goal with incremental doses of valsartan alone, and together with hydrochlorothiazide (HCTZ), in patients with uncomplicated hypertension.Methods: This analysis pooled patient-level data from nine randomized, double-blind, fixed-dose, placebo-controlled trials (N = 4278) of once-daily valsartan 80 mg, 160 mg, and 320 mg, and valsartan/hydrochlorothiazide (HCTZ) 80/12.5 mg, 160/12.5 mg, 160/25 mg, 320/12.5 mg, and 320/25 mg. Kaplan-Meier methods estimated the cumulative proportion of patients achieving BP < 140/90 rum Hg over 8 weeks and the median time to BP goal. The HCTZ 12.5-mg and 25-mg doses were pooled for the time-to-goal analysis in patients receiving combinations with valsartan 160 mg or 320 mg.Results: Overall, the median time-to-goal was 8.1 weeks with valsartan 160 mg, 6.1 weeks with valsartan 320 mg, 2.6 weeks with valsartan 160 mg/HCTZ, and 2.1 weeks with valsartan 320 mg/HCTZ. In patients with stage 2 hypertension, the median time-to-goal was 4.3 weeks with valsartan 160 mg/HCTZ and 2.4 weeks with valsartan 320 mg/HCTZ. Goal rates by Week 4 for valsartan[HCTZ exceeded rates by Week 8 with the same doses of valsartan alone. Overall, the proportion that achieved BP goal by Week 8 was 32.6% with valsartan 80 mg, 48.4% with valsartan 160 mg, 54.2% with valsartan 320 mg, 74.6% with valsartan 160 mg[HCTZ, and 84.8% with valsartan 320 mg/HCTZ, versus 24.2% with placebo. With valsartan 320 mg/HCTZ, 75.8% of stage 2 patients and 94% of stage 1 patients reached BP goal by Week 8. Discontinuation rates due to adverse events were generally low across doses.Conclusions: In both stage 1 and stage 2 hypertension, BP control is achieved more frequently and promptly when patients receive higher doses of valsartan monotherapy or valsartan combination therapy, with a favorable benefit-risk profile. Am J Hypertens 2007;20:807-815 (c) 2007 American Journal of Hypertension, Ltd.

Angiotensin receptor blockers have been hypothesized to have synergistic effects with statins. We evaluated the effects of valsartan alone or combined with simvastatin on blood pressure (BP) and indexes of inflammation and oxidant stress in hypertensive patients with hyperlipidemia. In this double-blind trial, 404 patients were randomized to 12 weeks valsartan 160 mg (V) or valsartan 160 mg plus simvastatin 20 mg (V/S20) or 80 mg (V/S80). Twenty-four-hour mean ambulatory BP and biochemical marker measurements were recorded at baseline and study end. There were no statistically significant between-treatment differences for least-square mean reductions from baseline in systolic BP (V, -9.22; V/S20, -9.25; V/S80, -9.58 mm Hg; p < 0.0001 for all within-treatment changes vs baseline). Plasma high-sensitivity C-reactive protein decreased with the combinations but not with V alone (least-square mean median change from baseline, -0.16, -0.20, -0.70 mg/L; p = 0.0001 for V/S80 vs baseline; p = 0.045 for V/S20 vs baseline; p = 0.0023 for V/S80 vs V/S20; p = 0.0045 for V/S80 vs V). Monocyte chemoattractant protein-1 was reduced by V, with no evidence for additional lowering with V/S combinations. In conclusion, addition of simvastatin to valsartan did not incrementally lower BP. However, V/S80 was superior to V and V/S20 in reducing high-sensitivity C-reactive protein. (C) 2007 Elsevier Inc. All rights reserved.

Background: Patients with hypertension may require combination therapy to attain the blood pressure targets recommended by US and European treatment guidelines. Combination therapy with a calcium channel blocker and an angiotensin II-receptor blocker would be expected to provide enhanced efficacy.Objectives: Two studies were conducted to compare the efficacy of various combinations of amlodipine and valsartan administered once daily with their individual components and placebo in patients with mild to moderate essential hypertension (mean sitting diastolic blood pressure [MSDBP] >= 95 and < 110 mm Hg). A secondary objective was to evaluate safety and tolerability.Methods: The 2 studies were multinational, multicenter, 8-week, randomized, double-blind, placebo-controlled, parallel-group trials. In study 1, patients were randomized to receive amlodipine 2.5 or 5 mg once daily, valsartan 40 to 320 mg once daily, the combination of amlodipine 2.5 or 5 mg with valsartan 40 to 320 mg once daily, or placebo. In study 2, patients were randomized to receive amlodipine 10 mg once daily, valsartan 160 or 320 mg once daily, the combination of amlodipine 10 mg with valsartan 160 or 320 mg once daily, or placebo. The primary efficacy variable in both studies was change from baseline in MSDBP at the end of the study. Secondary variables included the change in mean sitting systolic blood pressure (MSSBP), response rate (the proportion of patients achieving an MSDBP < 90 mm Hg or a >= 10-rmn Hg decrease from baseline), and control rate (the proportion of patients achieving an MSDBP < 90 mm Hg). Safety was assessed in terms of adverse events (spontaneously reported or elicited by questioning), vital signs, and laboratory values.Results: A total of 1911 patients were randomized to treatment in study 1 (1022 amlodipine + valsartan; 507 valsartan; 254 amlodipine; 128 placebo); 1250 were randomized to treatment in study 2 (419, 415, 207, and 209, respectively). In all treatment groups in both studies, the majority of patients were white (79.5% study 1, 79.4% study 2) and male (53.5% and 50.3%, respectively). The overall mean age was 54.4 years in study 1 and 56.9 years in study 2. The mean weight of patients in study 1 was higher than that in study 2 (88.8 vs 79.7 kg). The overall baseline mean sitting BP was 152.8/99.3 mm Hg in study 1 and 156.7/99.1 mm Hg in study 2. With the exception of a few combinations that included amlodipine 2.5 mg, the combination regimens in both studies were associated with significantly greater reductions in MSDBP and MSSBP compared with their individual components and placebo (P < 0.05). A positive dose response was observed for all combinations. The highest response rate in study I was associated with the highest dose of combination therapy (amlodipine 5 mg + valsartan 320 mg: 91.3%). Amlodipine 5 mg, valsartan 320 mg, and placebo were associated with response rates of 71.9%, 73.4%, and 40.9%, respectively. In study 2, the 2 doses of combination therapy were associated with similar response rates (amlodipine 10 mg + valsartan 160 mg: 88.5%; amlodipine 10 mg + valsartan 320 mg: 87.5%). Amlodipine 10 mg was associated with a response rate of 86.9%; valsartan 160 and 320 mg were associated with response rates of 74.9% and 72.0%, respectively; and placebo was associated with a response rate of 49.3%. Control rates followed a similar pattern. The incidence of peripheral edema with combination therapy was significantly lower compared with amlodipine monotherapy (5.4% vs 8.7%, respectively; P = 0.014), was significantly higher compared with valsartan monotherapy (2.1%; P < 0.001), and did not differ significantly from placebo (3.0%).Conclusions: In these adult patients with mild to moderate hypertension, the combination of amlodipine + valsartan was associated with significantly greater blood pressure reductions from baseline compared with amlodipine or valsartan monotherapy or placebo. The incidence of peripheral edema was significantly lower with combination therapy than with amlodipine monotherapy.

BACKGROUND:Most patients with hypertension in the United States and Europe fail to achieve the recommended target blood pressure (BP) of <140/90 mm Hg. Combination therapy is required in approximately two thirds of all patients whose BP is >20/10 mm Hg above the goal. Combination therapy with agents having complementary mechanisms of action, such as a calcium channel blocker and an angiotensin II-receptor blacker, would be a potentially useful therapeutic option. OBJECTIVES:This study evaluated the overall safety profile of combination therapy with amlodipine plus valsartan compared with a combination of lisinopril plus hydrochlorothiazide (HCTZ) in patients with stage 2 hypertension (mean sitting diastolic BP [MSDBP] >or=110 and <120 mm Hg) over the short term (6 weeks). A secondary objective was to evaluate the efficacy of the 2 regimens in achieving BP reduction. METHODS:This was an international, multicenter, randomized, double-blind, active-controlled, parallel-group study. Patients were randomized to receive once-daily treatment with amlodipine 5 to 10 mg + valsartan 160 mg or lisinopril 10 to 20 mg + HCTZ 12.5 rig for 6 weeks. Safety assessments included monitoring of all adverse events, vital signs, and hematology and biochemistry variables. Efficacy variables included the changes from baseline in MSDBP and mean sitting systolic BP (MSSBP), the response rate (MSDBP <90 mm Hg, or a >or= 10-mm Hg reduction from baseline), and the rate of DBP control (<90 mm Hg). The overall rate of BP control (proportion of patients with MSSBP/MSDBP <140/90 mm Hg) was evaluated in a post hoc analysis. Efficacy variables were summarized at each visit and at the end of the study (week 6, applying last-observation-carried-forward methodology) using descriptive statistics for the intent-to-treat population (all randomized patients with a baseline BP measurement and at least 1 post baseline BP measurement). Subgroup analyses of BP changes were performed in prespecified age groups (<65 and >or=65 years) and post hoc in patients with a baseline systolic BP <180 and >or=180 mm Hg. RESULTS:: Of 130 patients who were randomized to treatment, 128 completed the study: 63 in the amlodipine + valsartan group and 65 in the lisinopril + HCTZ group. The majority of patients in both groups were white (amlodipine + valsartan: 59.4% lisinopril + HCTZ: 60.6%) and female (57.8% and 54.5%, respectively). The mean age was similar in the 2 groups (56.5 and 57.6 years), as was the mean weight (85.1 and 82.0 kg). Both regimens were generally well tolerated. Adverse events were mild to moderate in severity, and most were not considered related to study drug. At the 6-week end point, both the amlodipine + valsartan and lisinopril + HCTZ groups had achieved significant reductions from baseline in MSSBP (-35.8 [11.8] and -31.8 [14.7] mm Hg, respectively; both, P < 0.001) and MSDBP (-28.6 [7.7] and -27.6 [8.6] mm Hg; both, P < 0.001). Response rates were similar for the 2 treatment groups (100% and 95.5%), as were rates of DBP control (79.7% and 77.3%). CONCLUSIONS:: The combinations of amlodipine 5 to 10 rug + valsartan 160 mg and lisinopril 10 to 20 mg + HCTZ 12.5 mg were well tolerated and efficacious, and both treatments were associated with achievement of BP goals in the majority of these adult patients with stage 2 hypertension.

BACKGROUND:Clinical trials emphasize mortality and morbidity endpoints.AIMS:To bring relevance of trial results to point of care by examining the prognostic and therapeutic value of individual signs and symptoms (S&S).METHODS:We analysed data from 5010 patients with stable chronic heart failure and left ventricular dysfunction who were participants in the Val-HeFT study. Individual S&S were stratified by severity. Treatment differences between valsartan and placebo were analysed by S&S strata at baseline and endpoint by logistical regression, and an overall S&S score by ANCOVA. Hazard ratios of S&S strata were calculated for mortality and heart failure hospitalisation. Prognostic contributions of S&S to other variables were determined by multivariate analysis.RESULTS:At endpoint, there were significantly fewer valsartan and more placebo patients with severe symptoms. Over time, improvement in the S&S overall score was significantly more favourable for valsartan than placebo. S&S strata were significantly predictive of risk for hospitalisation and death. S&S were each independent and incremental predictors of mortality compared to other variables. Symptom strata separated out moderately symptomatic patients with a mortality rate which was intermediate between that for NYHA Class II and III.CONCLUSION:Risk stratification of individual S&S defined prognosis, identified patients with an intermediate mortality between Class II and III, and treatment benefits of valsartan over placebo.