Efficacy and safety of amlodipine/valsartan/hydrochlorothiazide single pill combination in Egyptian patients with hypertension uncontrolled on any dual therapy: an observational study.

Objective: Hypertension is a serious health problem in Egypt, with prevalence rate of 17% as reported in 2015. Despite receiving treatment, many do not achieve blood pressure (BP) control. The current study aimed to evaluate the efficacy and tolerability of amlodipine/valsartan/hydrochlorothiazide (Aml/Val/HCTZ) single pill combination (SPC) in patients with hypertension from Egypt, who were uncontrolled on any dual therapy.Methods: In this prospective, open label, multicenter, 12-week observational, cohort study, two doses of Aml/Val/HCTZ (5/160/12.5 mg or 10/160/25 mg) SPC were used to evaluate mean change in BP after 12 weeks (primary endpoint). Safety assessments included presence and intensity of ankle edema and other adverse events (AEs).Results: Data were collected from 1080 patients who were treated according to the routine medical practice across 47 centers in Egypt. Significant reduction in systolic and diastolic BP (SBP/DBP) was observed from 165.5 ± 12.83/100.8 ± 7.03 mmHg at baseline to 129.7 ± 8.35/80.6 ± 5.25 mmHg after 12 weeks of treatment (p < .0001). Majority of patients (76.85%) reached the BP goal of <140/90 mmHg. The most commonly reported AE was ankle edema (10.92%).Conclusions: Aml/Val/HCT SPC significantly reduced BP and was well tolerated in Egyptian patients with hypertension not controlled on any previous dual therapy.

Pharmacokinetic and Safety Profiles of a Fixed-Dose Combination of Amlodipine, Valsartan, and Atorvastatin: A 3-Period Replicate Crossover Study.

The objective of study was to compare the pharmacokinetic and safety profiles of a fixed-dose combination (FDC) formulation of 5/160/20 mg amlodipine/valsartan/atorvastatin with those of separate formulations of a 5/160-mg amlodipine/valsartan tablet and a 20-mg atorvastatin tablet. This was a randomized, open-label, single-dose, 3-sequence, 3-period replicate crossover study with 42 subjects. Serial blood samples for pharmacokinetic assessment were collected up to 72 hours postdose. For establishing bioequivalence (BE) for amlodipine, valsartan, and atorvastatin, a reference-scaled average BE approach was used if applicable, as well as the conventional limit of 0.80-1.25. The 90% confidence intervals (CIs) for the geometric mean ratios (GMRs) for the maximum plasma concentration (Cmax ) and the area under the curve to the last measurable concentration (AUCt ) between the FDC and separate formulations were within the 0.80-1.25 limit for all analytes but atorvastatin. The estimated within-subject standard deviation of the log-transformed values of the separate formulations, the reference intervention, was 0.3804 for the Cmax of atorvastatin, being set at 0.7489-1.3352 for the BE acceptance limit. For both the Cmax and AUCt for atorvastatin, the GMRs lay within 0.80-1.25, and the 90%CIs for the GMRs were within the BE acceptance limit. This 3-period replicate crossover study demonstrated the BE of the FDC formulation of amlodipine, valsartan, and atorvastatin and the separate formulations of an amlodipine/valsartan tablet and an atorvastatin tablet. A similar incidence of treatment-emergent adverse events (TEAEs) was observed in both interventions, and headache was the most common TEAE.

A randomized multicenter study on ambulatory blood pressure and arterial stiffness in patients treated with valsartan/amlodipine or nifedipine GITS.

In a pre-specified subgroup analysis of a 12-week randomized multicenter study, we investigated effects of valsartan/amlodipine 80/5 mg single-pill combination (n = 75) and nifedipine GITS 30 mg (n = 75) on ambulatory blood pressure (BP) and arterial stiffness assessed by brachial-ankle pulse wave velocity (PWV) in patients with uncontrolled hypertension. At week 12, the between-treatment mean differences in systolic/diastolic BP were smaller for 24-hour and daytime (-2.1/-1.7 and -2.0/-1.5 mm Hg, respectively, P ≥ 0.22) but greater (P < 0.01) for nighttime (-4.0/-2.8 mm Hg, P ≤ 0.09), especially in sustained uncontrolled hypertension (-5.0/-4.1 mm Hg, P ≤ 0.04) and non-dippers (-6.5/-3.7 mm Hg, P ≤ 0.07), in favor of valsartan/amlodipine. At week 12, PWV was significantly reduced from baseline by valsartan/amlodipine (n = 59, P < 0.0001) but not nifedipine (n = 59, P = 0.06). The changes in PWV were significantly associated with that in ambulatory systolic BP and pulse pressure in the nifedipine (P ≤ 0.0008) but not valsartan/amlodipine group (P ≥ 0.57), with a significant interaction (P ≤ 0.045). The valsartan/amlodipine combination was more efficacious than nifedipine GITS in lowering nighttime BP in sustained uncontrolled hypertension and non-dippers, and in lowering arterial stiffness independent of BP lowering.

A multicenter, randomized, and double-blind phase IV clinical trial to compare the efficacy and safety of fixed-dose combinations of amlodipine orotate/valsartan 5/160 mg versus valsartan/hydrochlorothiazide 160/12.5 mg in patients with essential hypertension uncontrolled by valsartan 160 mg monotherapy.

BACKGROUND: To determine whether the effectiveness and safety of fixed-dose combinations (FDCs) of amlodipine orotate/valsartan (AML/VAL) 5/160 mg are noninferior to those of valsartan/hydrochlorothiazide (VAL/HCTZ) 160/12.5 mg in hypertensive patients with inadequate response to valsartan 160 mg monotherapy. METHODS: This 8-week, active-controlled, parallel-group, fixed-dose, multicenter, double-blind randomized controlled, and noninferiority trial was conducted at 17 cardiovascular centers in the Republic of Korea. Eligible patients had mean sitting diastolic blood pressure (msDBP) ≥90 mm Hg despite monotherapy with valsartan 160 mg for 4 weeks. Patients were randomly assigned to treatment with AML/VAL 5/160 mg FDC (AML/VAL) group or VAL/HCTZ 160/12.5 mg FDC (VAL/HCTZ) group once daily for 8 weeks. A total of 238 patients were enrolled (AML/VAL group, n = 121; VAL/HCTZ group, n = 117), of whom 228 completed the study. RESULTS: At 8 weeks after randomization, msDBP was significantly decreased in both groups (-9.44 ±â€Š0.69 mm Hg in the AML/VAL group and -7.47 ±â€Š0.71 mm Hg in the VAL/HCTZ group, both P < .001 vs baseline). Between group difference was -1.96 ±â€Š1.00 mm Hg, indicating that AML/VAL 5/160 mg FDC was not inferior to VAL/HCTZ 160/12.5 mg FDC at primary efficacy endpoint. Control rate of BP defined as the percentage of patients achieving mean sitting SBP (msSBP) <140 mm Hg or msDBP <90 mm Hg (target BP) from baseline to week 8 was significantly higher in the AML/VAL group than that in the VAL/HCTZ group (84.3% [n = 102] in the AML/VAL group vs 71.3% [n = 82] in the VAL/HCTZ group, P = .016). At 8 weeks after randomization, mean uric acid level was significantly increased in the VAL/HCTZ group compared to that at baseline (0.64 ±â€Š0.08 mg/dL; P < .001). However, it was slightly decreased from baseline in the AML/VAL group (-0.12 ±â€Š0.08 mg/dL; P = .085). The intergroup difference was significant (P < .001). CONCLUSION: The effectiveness and safety AML/VAL 5/160 mg FDC are noninferior to those of VAL/HCTZ 160/12.5 mg FDC in patients with hypertension inadequately controlled by valsartan 160 mg monotherapy.

Electrospun fixed dose formulations of amlodipine besylate and valsartan.

Increasing numbers of elderly people require multi-drug therapies. One route to improve adherence rates is to prepare fixed dose combinations (FDCs), in which multiple active ingredients are loaded into a single formulation. Here, we report the use of electrospinning to prepare fast-dissolving oral FDCs containing amlodipine besylate and valsartan, two drugs prescribed as FDCs for the treatment of hypertension. Electrospun fibers were prepared loaded with one or both drugs, using polyvinylpyrrolidone as the polymer matrix. The fibers were largely cylindrical in morphology and comprise amorphous solid dispersions except with the highest loadings of amlodipine besylate. HPLC demonstrated drug entrapment efficiencies of >85% of the theoretical dose. The mats have folding endurances and thicknesses suitable for use as oral films. The amlodipine besylate-loaded systems are fast-dissolving, with >90% release obtained within 120 s. In contrast, valsartan release from its single-drug formulations took longer, ranging from 360 s to 24 min. With the FDC formulations, rapid release within 360 s was achieved when the loading was 5% w/w of each drug, but again the release time increased with drug loading. Electrospun fibers therefore have significant promise as FDCs, but the target drug and its loading need to be carefully considered.

Association Between Change in Central Nocturnal Blood Pressure and Urine Albumin-Creatinine Ratio by a Valsartan/Amlodipine Combination: A CPET Study.

BACKGROUND: We aimed to assess the association of changes in brachial or central nocturnal systolic blood pressure (SBP) with change in urine albumin-creatinine ratio (UACR) by a valsartan/amlodipine combination (80/5 mg) therapy in hypertensive patients. METHODS: Twenty-three patients (age range, 47-78 years; mean, 68.0 years; 35% men, 65% with chronic kidney disease) with clinic brachial BP ≥140/90 mm Hg were treated with valsartan/amlodipine combination therapy for 16 weeks. At baseline and 16 weeks later, we measured brachial and central nocturnal SBP using an oscillometric Mobil-O-Graph device and UACR by spot urine in 23 patients. RESULTS: The changes in brachial nocturnal SBP (r = 0.445, P = 0.033) and those in central nocturnal SBP (r = 0.616, P = 0.002) were significantly associated with change in UACR by intervention. In multivariable-adjusted multiple regression analyses including changes in both brachial and central nocturnal SBP jointly, only central nocturnal SBP change retained a statistically significant association with change in UACR (ß = 0.919, P = 0.020). CONCLUSIONS: Lowering central nocturnal SBP by a valsartan/amlodipine combination therapy was associated with reduction of UACR, independently of brachial nocturnal SBP reduction. Central nocturnal SBP may be a therapeutic target to protect the kidney. A larger scale interventional study will be needed to confirm the kidney protection conferred by lowering central nocturnal SBP. CLINICAL TRIALS REGISTRATION: Trial Number UMIN000013519.

Efficacy and effectiveness of valsartan/amlodipine and valsartan/amlodipine/hydrochlorothiazide in hypertension: randomized controlled versus observational studies.

OBJECTIVE: The aim of this post-hoc analysis was to compare the results from randomized controlled trials (RCTs) and real-world evidence (RWE) studies of valsartan/amlodipine (Val/Aml) and valsartan/amlodipine/hydrochlorothiazide (Val/Aml/HCTZ) in patients with uncontrolled hypertension (>140/90 mmHg). METHODS: Data was pooled from 15 RCTs (N = 5542) and 8 RWE studies (N = 1397) for Val/Aml; and 2 RCTs (N = 804) and 5 RWE studies (N = 9380) for Val/Aml/HCTZ. Patients who received Val/Aml (80/5, 160/5, 160/10, 320/5, or 320/10 mg), Val/Aml/HCTZ (160/5/12.5, 160/5/25, 160/10/12.5, 160/10/25, or 320/10/25 mg) or placebo were considered for this analysis. Only patients with both baseline and follow-up assessment within 60-90 days after baseline had been included in the analysis. Patients with missing values were excluded from the analysis. Using fitted linear mixed-effects model and random factors, treatment interactions and study design with mean sitting systolic blood pressure (msSBP), diastolic BP (msDBP) and pulse pressure (msPP) reductions from baseline to Week 8-12 of treatment were compared. RESULTS: Baseline demographics and patient characteristics were comparable between RCT and RWE datasets and within Val/Aml and Val/Aml/HCTZ treatment groups. In both RCT and RWE studies, least-squares mean (LSM) reduction in msSBP/msDBP and msPP from baseline were significant (p < .05) across all dosages. The efficacy of Val/Aml in RCTs was statistically significantly greater than in RWE studies for msSBP/msDBP (-23.1/-13.8 vs. -17.9/-9.1 mmHg) but the difference was non-significant for msPP (-8.6 vs. -9.3 mmHg; p = .77). For Val/Aml/HCTZ, no direct comparison was available but a similar trend was observed. The difference observed for msSBP and msDBP may be due to routine practice setting, larger populations may have more confounders and different behaviors towards treatment adherence. CONCLUSION: These findings demonstrate that the efficacy of Val/Aml and Val/Aml/HCTZ in RCTs was more pronounced compared with their effectiveness in RWE studies in different ethnic populations although the overall benefit was not different.

Comparison of morning vs bedtime administration of the combination of valsartan/amlodipine on nocturnal brachial and central blood pressure in patients with hypertension.

The aim of this study was to compare the effect of morning and bedtime administration of valsartan/amlodipine combination therapy (80/5 mg) on nocturnal brachial and central blood pressure (BP) measured by ambulatory BP monitoring in patients with hypertension. This was a 16-week prospective, multicenter, randomized, open-label, crossover, noninferiority clinical trial. Patients underwent 24-hour ambulatory BP monitoring at randomization, at switching, and at the end of the study. Twenty-three patients (mean age, 68.0 years) were studied. The difference in nocturnal brachial systolic BP between the morning and bedtime administrations of combination valsartan/amlodipine was -3.2 mm Hg, and the two-sided 95% confidence interval ranged from -6.8 to 0.4 mm Hg. The difference in nocturnal central systolic BP was -4.0 mm Hg (95% confidence interval, -7.6 to -0.4 mm Hg). The upper limit of the 95% confidence interval was below the margin of 3.0 mm Hg in both nocturnal brachial and central systolic BP, confirming the noninferiority of morning administration to the bedtime administration of valsartan/amlodipine combination therapy.

Efficacy and safety of valsartan/amlodipine single-pill combination in 11,422 Chinese patients with hypertension: an observational study.

INTRODUCTION: Single-pill combination (SPC) therapy of two drugs is recommended by international guidelines, including the Chinese guidelines (2010), for the treatment of hypertension in high-risk patients who require marked blood pressure (BP) reductions. Real-world data on the efficacy and safety of valsartan/amlodipine (Val/Aml) SPC are scarce. The present study is the first observational study in China to evaluate the efficacy (primary endpoint) and safety of Val/Aml (80/5 mg) SPC in Chinese patients with hypertension whose BP was not adequately controlled by monotherapy in a real-world setting. METHODS: This prospective, multicenter, open-label, post-marketing observational study included 11,422 Chinese adults (≥18 years) with essential hypertension from 238 sites of 29 provinces who were prescribed once-daily Val/Aml (80/5 mg) SPC. Patients were treated for 8 weeks. The primary efficacy variable of the study included changes in mean sitting systolic BP (MSSBP) and mean diastolic BP (MSDBP) from baseline to week 8 (end point). The secondary efficacy variable of the study included BP control rate and response rate at week 4 and 8. Safety assessments included recording and measurement of all adverse events (AEs) and vital signs in the safety population. RESULTS: A significant reduction of 27.1 mmHg in MSSBP (159.6 vs. 132.5 mmHg; P < 0.0001) and 15.2 mmHg in MSDBP (95.6 vs. 80.4 mmHg; P < 0.0001) from baseline was observed at week 8. The BP-lowering efficacy of Val/Aml SPC was independent of age and comorbidities. BP control of <140/90 mmHg was achieved in 76.8% (n = 8,692) of the patients. The most frequently reported AEs were dizziness (0.2%), headache (0.2%), upper respiratory tract infection (0.2%), and edema (0.2%). Only three serious AEs were reported and they were not drug-related. CONCLUSION: This is the first evidence-based real-world data in Chinese hypertensive patients which demonstrate the efficacy and safety of Val/Aml (80/5 mg) SPC.

Effect of food on the oral bioavailability of amlodipine/valsartan and amlodipine/valsartan/hydrochlorothiazide fixed dose combination tablets in healthy subjects.

A double fixed dose combination of amlodipine/valsartan and triple fixed dose combination of amlodipine/valsartan/HCTZ tablets have been developed to treat patients with moderate-to-severe hypertension. Here, we present the effect of food on the oral bioavailability of these two fixed dose combination tablets from two separate clinical studies in healthy subjects. Single oral doses of amlodipine/valsartan (10/160 mg) and amlodipine/valsartan/HCTZ (10/320/25 mg were administered under fasted or fed conditions. Blood samples were collected in both studies to determine the pharmacokinetic parameters of amlodipine, valsartan, and/or HCTZ using non-compartmental analysis. Following amlodipine/valsartan administration, the geometric mean ratios (GMRs, 90% CI) of AUC0-∞ and Cmax were 1.09 (1.05-1.13) and 1.03 (0.97-1.09) for amlodipine, and 0.94 (0.81-1.10) and 0.86 (0.73-1.02) for valsartan, respectively. Following amlodipine/valsartan/HCTZ administration, the GMRs (90%CI) of AUC0-∞ and Cmax were 1.09 (1.04-1.15) and 1.11 (1.05-1.08) for amlodipine, 1.14 (0.99-1.31) and 1.12 (0.98-1.29) for valsartan, and 1.09 (1.02-1.16) and 0.86 (0.79-0.93) for HCTZ, respectively. Considering the sample size and pharmacokinetic variability associated with analytes, these study results indicate that food effect is minimal or none when fixed dose combination tablets are administered with food. In conclusion, both fixed dose combination tablets can be administered without regards to meals.