24-Hour ambulatory blood pressure control with triple-therapy amlodipine, valsartan and hydrochlorothiazide in patients with moderate to severe hypertension.
ABSTRACT: 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.
Project description:A clinical trial showed comparable blood pressure (BP) lowering by valsartan/hydrochlorothiazide and amlodipine/hydrochlorothiazide in obese hypertensive patients. Relative to amlodipine/hydrochlorothiazide, valsartan/hydrochlorothiazide reduced the hyperglycemic response to glucose challenge. An objective of this post hoc analysis was to determine whether this benefit extended to African Americans and whites. Treatments (160/12.5 mg of valsartan/hydrochlorothiazide force titrated to 320/25 mg of valsartan/hydrochlorothiazide at week 4 or 12.5 mg of hydrochlorothiazide force titrated to 25 mg of hydrochlorothiazide at week 4 with 5 and 10 mg of amlodipine added at weeks 8 and 12, respectively) were administered once daily. Both treatments reduced clinic BP from baseline to all visits (P < 0.0001), regardless of race/ethnicity (126 African Americans, 212 whites). In African Americans, there were no significant between-treatment differences in clinic or ambulatory BP lowering at weeks 8 or 16. Whites responded better to valsartan/hydrochlorothiazide. In both racial/ethnic subgroups, the addition of valsartan but not amlodipine mitigated the hyperglycemic response to hydrochlorothiazide through enhanced insulin secretion. Valsartan/hydrochlorothiazide was as effective as amlodipine/hydrochlorothiazide was in reducing BP in obese, hypertensive African Americans and better than amlodipine/hydrochlorothiazide in whites. In both racial/ethnic subgroups, the addition of valsartan to hydrochlorothiazide reduced the negative metabolic effects associated with thiazide therapy.
Project description:BACKGROUND:To compare the fixed-dose combination (FDC) of amlodipine/valsartan 5/80?mg with valsartan 160?mg monotherapy for efficacy and safety in hypertensive patients. METHODS:We designed this double-blind, randomized, and noninferiority trial in which patients with elevated systolic blood pressure (SBP) and/or diastolic blood pressure (DBP) were randomly assigned to receive amlodipine/valsartan 5/80?mg FDC or valsartan 160?mg monotherapy for 8 weeks. The primary endpoint was changes in office SBP and DBP from baseline to 8 weeks. Twenty-four-hour blood pressure (BP) and the incidence of adverse events were recorded. RESULTS:A total of 42 patients underwent randomization. At 8 weeks, office SBP changes were -16.5 ± 15.5 mmHg (p < 0.001) with amlodipine/valsartan 5/80?mg FDC and -6.9 ± 11.4 mmHg (p = 0.012) with valsartan 160?mg monotherapy while corresponding changes in office DBP were -9.8 ± 7.7 mmHg (p < 0.001) and -2.5 ± 6.6 mmHg (p = 0.095), respectively. The between-group differences were -9.6 mmHg (95% CI, -18.1 to -1.1; p = 0.028) for SBP and -7.3 mmHg (95% CI, -11.8 to -2.8; p = 0.002) for DBP. Furthermore, reductions in both 24-hour SBP (-9.2 mmHg; 95% CI, -16.4 to -2.1; p = 0.013) and DBP (-4.6 mmHg; 95% CI, -9.2 to -0.1; p = 0.048) were consistently greater with amlodipine/valsartan 5/80?mg FDC than with valsartan 160?mg. Overall, 27 and 23 adverse events occurred in the amlodipine/valsartan 5/80?mg FDC group and in the valsartan 160?mg monotherapy group, respectively. The majority were mild and were not related to study medications. There were no significant differences in safety between two treatments. CONCLUSION:Efficacy of amlodipine/valsartan 5/80?mg FDC was superior to that of valsartan 160?mg monotherapy while both treatments were well-tolerated.
Project description:The objective of this study was to develop a population pharmacokinetic (PK) and pharmacodynamic (PD) model to quantitatively describe the antihypertensive effect of combined therapy with amlodipine and valsartan.PK modelling was used with data collected from 48 healthy volunteers receiving a single dose of combined formulation of 10 mg amlodipine and 160 mg valsartan. Systolic (SBP) and diastolic blood pressure (DBP) were recorded during combined administration. SBP and DBP data for each drug alone were gathered from the literature. PKPD models of each drug and for combined administration were built with NONMEM 7.3.A two-compartment model with zero order absorption best described the PK data of both drugs. Amlodipine and valsartan monotherapy effects on SBP and DBP were best described by an Imax model with an effect compartment delay. Combined therapy was described using a proportional interaction term as follows: (D1 + D2 ) +ALPHA×(D1 × D2 ). D1 and D2 are the predicted drug effects of amlodipine and valsartan monotherapy respectively. ALPHA is the interaction term for combined therapy. Quantitative estimates of ALPHA were -0.171 (95% CI: -0.218, -0.143) for SBP and -0.0312 (95% CI: -0.07739, -0.00283) for DBP. These infra-additive interaction terms for both SBP and DBP were consistent with literature results for combined administration of drugs in these classes.PKPD models for SBP and DBP successfully described the time course of the antihypertensive effects of amlodipine and valsartan. An infra-additive interaction between amlodipine and valsartan when used in combined administration was confirmed and quantified.
Project description:This randomized, parallel-group study in patients inadequately controlled on olmesartan medoxomil/amlodipine (OLM/AML) 40/10 mg assessed the effects of adding hydrochlorothiazide (HCTZ) 12.5 mg and 25 mg, using seated blood pressure (SeBP) measurements and ambulatory blood pressure (BP) monitoring. Enrolled patients were screened and tapered off of therapy if required. All patients received OLM/AML 40/10 mg and those with mean seated BP (SeBP) ?140/90 mm Hg after 8 weeks (n=808) were randomized (1:1:1) to continue with OLM/AML 40/10 mg or receive OLM/AML/HCTZ 40/10/12.5 or 40/10/25 mg for a further 8 weeks. The primary endpoint was the change in seated diastolic BP (SeDBP) from the start to the end of the randomized treatment period. The addition of HCTZ 25 mg significantly reduced SeDBP (-2.8 mm Hg; P<.0001), lowered seated systolic BP (SeSBP) and ambulatory DBP and SBP, and improved BP goal rates. In patients uncontrolled on OLM/AML 40/10 mg, adding HCTZ led to further BP reductions, particularly in ambulatory BP.
Project description:Thiazide diuretics can impair glucose metabolism and increase new-onset diabetes. Adding an angiotensin receptor blocker to diuretics may protect against these metabolic effects; however, the mechanism of this protection is unclear.To explore potential mechanisms, a 16-week multicenter trial was conducted to ascertain the relative glucose metabolism effects of combined hydrochlorothiazide and angiotensin receptor blocker (valsartan) therapy compared with hydrochlorothiazide and calcium channel blocker (amlodipine) treatment in 412 centrally obese hypertensive individuals (BMI = 35 +/- 7 kg/m, seated BP = 159 +/- 8/94 +/- 8 mmHg, and mean age 56 years). Individuals were randomized to valsartan/hydrochlorothiazide, with force-titration to 320/25 mg or hydrochlorothiazide, with titration to hydrochlorothiazide 25 mg and amlodipine 10 mg, respectively. Changes from baseline to week 16 in fasting and 2-h postprandial glucose and insulin levels after an oral glucose load were measured.At week 16, clinic blood pressure reductions were similar (P > 0.05) in both groups. Fasting and 2-h glucose levels increased (P < 0.05) with the amlodipine combination but not with the valsartan combination. In concert with these glucose responses, postprandial insulin increases from baseline were substantially greater with valsartan than with amlodipine plus hydrochlorothiazide group (P = 0.001). The glucose responses were inversely related to insulin responses at the study conclusion.The novel observation of this investigation was that the combination of valsartan and hydrochlorothiazide was associated with greater glucose-stimulated insulin secretory and lesser glycemic excursion responses than the amlodipine combination group. Thus, this data suggests that adding an angiotensin receptor blocker attenuates the negative effects of thiazides on pancreatic beta-cell glucose-induced insulin secretion.
Project description:Combination therapy may reduce racial/ethnic differences in response to antihypertensives. In this post-hoc analysis, we evaluated treatment response by race/ethnicity among hypertensive adults enrolled in a 12-week, double-blind study in which patients previously uncontrolled (mean sitting systolic blood pressure [MSSBP] ?150 and <200 mm Hg) on angiotensin receptor blocker (ARB) monotherapy (other than valsartan) for 28 days or more (n = 728) were randomized to amlodipine/valsartan 10/320 mg (intensive) or 5/160 mg (moderate). Treatment-naïve patients (in previous 28 days) or those who failed on a non-ARB first underwent a 28-day run-in period with olmesartan 20 mg or 40 mg, respectively. Hydrochlorothiazide (HCTZ) 12.5 mg was added to both arms at week 4; optional up-titration to 25 mg at week 8 (if MSSBP >140 mm Hg). Intensive treatment provided greater BP lowering versus moderate treatment throughout the study, regardless of race/ethnicity (474 white, 198 African American, 165 Hispanic individuals). Least-square mean reductions from baseline to week 4 in MSSBP (primary outcome) ranged from 20.4 to 23.5 mm Hg (intensive) versus 17.5 to 19.0 mm Hg (moderate), across racial/ethnic subgroups. Both regimens were well tolerated. Amlodipine/valsartan/HCTZ combination therapy was efficacious across racial/ethnic subgroups. Maximal efficacy was obtained with intensive treatment.
Project description:The aim of the present study was to evaluate the efficacy and safety of S-amlodipine 2.5 and 5 mg/d in patients with hypertension who were treatment-naive or previously received antihypertensive monotherapy. During the 8-week treatment period, all patients received S-amlodipine 2.5 mg/d for the first 4 weeks, followed by S-amlodipine 5 mg/d for the second 4 weeks. For efficacy assessments, ambulatory and office blood pressure (BP) measurements were performed during the baseline, fourth-week, and eighth-week visits. For safety assessments, all adverse events and abnormal laboratory findings were recorded. This study is registered with ClinicalTrials.gov (NCT03038451). Of 43 patients evaluated at the screening visit, 33 were enrolled. In the treatment-naive arm, significant reductions in both office and ambulatory systolic BP (SBP) and diastolic BP (DBP) were observed with S-amlodipine 2.5 mg/d and additional significant reductions were achieved with dose titration (S-amlodipine 5 mg/d). At the end of the study, the rate of the treatment-naive patients with BP under control (SBP/DBP <140/90 mm Hg) was 53% with S-amlodipine 2.5 mg and increased to 78% with S-amlodipine 5 mg. For the noninferiority evaluation, S-amlodipine 2.5 and 5 mg/d treatments were generally noninferior to both office and ambulatory BP levels achieved with the medications that the patients received before participating in the study. Five nonserious adverse events likely to be associated with the study drug were observed. No serious adverse event was encountered. Consequently, S-amlodipine can be suggested as an effective and safe treatment option for patients with hypertension.
Project description:The relative efficacy of antihypertensive drugs/combinations is not well known. Identifying the most effective ones and the patients' characteristics associated with best performance of the drugs will improve management of hypertensive patients.To assess the blood pressure (BP) reduction attributed to antihypertensive drugs and identify characteristics associated with BP decrease.MEDLINE, Cochrane Central Register of Controlled Trials from inception through July 2012 and selected papers.Double-blind, randomized clinical trials whose main result was the reduction in BP by antihypertensive treatment, with study population ?50 or ?25 if the study was a crossover, follow-up of at least 8 weeks, and available required data.Study data were independently extracted by multiple observers and introduced in an electronic database. Inconsistencies were resolved by discussion and referral back to the original articles. Meta-analysis was performed according to PRISMA statement and using a Bayesian framework.Mean decrease in systolic (SBP) and diastolic blood pressure (DBP) achieved by each drug or combination.Two hundred eight trials including 94,305 patients were identified. In monotherapy, most drugs achieved 10 to 15?mm Hg SBP and 8 to 10?mm Hg DBP decreases.Olmesartan/amlodipine, olmesartan/hydrochlorothiazide, felodipine/metoprolol, and valsartan/hydrochlorothiazide were the combinations leading to the greatest mean SBP reductions (>20?mm Hg). Female sex and body mass index >25?kg/m were associated with more pronounced SBP and DBP reductions, whereas Afro-American ethnicity was associated with BP reductions smaller than the median. Results were adjusted by study duration, cardiovascular disease, and diabetes mellitus. Still, the estimation was performed using the mean administered doses, which do not exactly match those of the available drug formats.Data corresponded to those obtained in each of the included trials; the analysis of the combinations was limited to the most recent ones; estimations were performed using the mean administered doses.Certain drug combinations achieve BP reductions ranging from 20 to 25/10 to 15?mm Hg. Sex, ethnicity, and obesity are associated with antihypertensive response. This information can contribute to better selection of the antihypertensive drug, depending on the magnitude of pretreatment BP elevation. Guidelines should be revised.
Project description:Many angiotensin receptor blocker (ARB) monotherapy patients need at least two agents to control blood pressure (BP). We investigated whether initiating intensive treatment with combination amlodipine/valsartan was superior to moderate treatment with amlodipine/valsartan in patients previously uncontrolled on ARB monotherapy.In this 12-week study, patients aged at least 18 years on ARB (other than valsartan) for at least 28 days (with treatment-naïve patients or those not controlled on agents other than an ARB treated with open-label olmesartan 20 or 40 mg, respectively, for 28 days) and with uncontrolled mean sitting systolic blood pressure (MSSBP; ? 150-<200 mmHg) were randomized to amlodipine/valsartan 5/320 mg (n = 369) or 5/160 mg (n = 359). At week 2, the dose was increased to 10/320 mg in the intensive arm. Hydrochlorothiazide 12.5 mg was added to both arms at week 4. Optional up-titration with hydrochlorothiazide 12.5 mg at week 8 was allowed if MSSBP was more than 140 mmHg.At baseline, mean office sitting BP was comparable in the intensive (163.9/95.5 mmHg) and moderate (163.3/95.0 mmHg) groups. Intensive treatment provided greater BP reductions versus moderate treatment (P < 0.05) from week 4 (-23.0/-10.4 versus -19.2/-8.7 mmHg; primary endpoint) to week 12 (-29.0/-14.8 versus -25.3/-12.3 mmHg). Adverse events were reported by a similar percentage of patients in both groups (36.3% intensive, 37.6% moderate); peripheral edema was more common with intensive versus moderate treatment (8.7 versus 4.5%; P = 0.025).Initiating treatment with an intensive dose of amlodipine/valsartan provides significantly greater BP lowering versus moderate treatment in hypertensive patients unresponsive to ARB monotherapy. Both treatment regimens were generally well tolerated based on adverse event reports, but the lack of routine laboratory testing after screening limits conclusions on tolerability.
Project description:To compare the efficacy of valsartan in systolic (SBP) and diastolic blood pressure (DBP) reduction with other angiotensin II receptor blockers (ARBs) in essential hypertension.Systematic literature search of databases between October 1997 and May 2008. Meta-analysis of short-term, double-blind, parallel group, randomised controlled trials (RCTs) for treatment of adult hypertension (DBP: 90-115 mmHg). Random-effects meta-regression adjusting for baseline blood pressure (BP) was used to analyse the data. Mean change in SBP and DBP was estimated for each individual drug and dose combination.In all, 31 RCTs (n = 13,110 patients) were included in the analysis. Six studies include trial arms with candesartan, six irbesartan, 13 losartan, two olmesartan, five telmisartan and 12 valsartan. The weighted average reduction in mean SBP and DBP for valsartan 160 mg was -15.32 mmHg (95% CI: -17.09, -13.63) and -11.3 mmHg (95% CI: -12.15, -10.52) and for 320 mg was -15.85 mmHg (95% CI: -17.60, -14.12) and -11.97 mmHg (95% CI: -12.81, -11.16); these are statistically significantly greater reductions compared with losartan 100 mg, which was -12.01 mmHg (95% CI: -13.78, -10.25) and -9.37 mmHg (95% CI: -10.18, -8.54) for SBP and DBP respectively. There is evidence that valsartan 160 mg reduces SBP and DBP more than irbesartan 150 mg and reduced DBP more than candesartan 16 mg. No other statistically significant difference in efficacy is demonstrated.Valsartan administered at 160 or 320 mg is more effective at lowering BP than losartan 100 mg and shows comparable efficacy to other ARBs in patients with essential hypertension.