Dose Of Valsartan Research Articles

Very high doses of valsartan provide renoprotection independently of blood pressure in a type 2 diabetic nephropathy rat model

Angiotensin II type 1 receptor blockers (ARB) retard the progression of hypertensive diabetic kidney disease. Clinical evidence suggests that the dose of ARB required to correct hypertension is suboptimal for renoprotection evaluated by proteinuria. No systematic, prospective study has yet evaluated separately the effect of increasing doses of ARB on blood pressure and proteinuria. Over a period of 8 weeks, the effect of seven constant doses of an ARB, valsartan (4-160 mg/kg per day), on blood pressure and proteinuria taken as a surrogate marker of nephropathy in a hypertensive, type 2 diabetic rat model, the spontaneously hypertensive/NIH-corpulent rat (SHR/NDmcr-cp), was assessed. In this spontaneously hypertensive rat strain, a genetic mutation in the leptin receptor gene is associated with hyperphagia leading to obesity with metabolic syndrome and eventually to nephropathy. No additional blood pressure lowering was observed above 120 mg/kg per day of valsartan, suggesting that a dose of 80-120 mg/kg per day had a maximal effect. Nevertheless, higher doses of valsartan further reduced proteinuria in a dose-dependent fashion suggesting the absence of a maximal dose. Obesity, hyperglycaemia and hypercholesterolaemia were unaffected but hypertriglyceridaemia was partially corrected at various ARB doses. ARB improve renoprotection at doses above those required for a maximal effect on blood pressure. The mechanism of the renoprotection obtained at high doses of ARB is yet to be elucidated.

Late lumen loss and follow-up percent diameter stenosis at different doses of oral valsartan six months after bare-metal stent implantation in type B2/C coronary lesions

Higher doses of oral valsartan (160–320 mg) seem to reduce in-stent restenosis rate after bare-metal stent implantation. The value of 80, 160 or 320 mg valsartan should be analyzed by late lumen loss and follow-up percent diameter stenosis as surrogate parameters in a total of 60 patients with matched demographic, clinical and angiographic findings and continuous doses of valsartan. In each group 20 patients (14 males, 6 females) with a mean age of 62.1 ± 9.1, 64.3 ± 8.1 and 62.9 ± 11.6 years after implantation of a total of 22, 33 and 27 stents in 21, 25 and 23 lesions were included. Quantitative coronary angiography was performed with an automated contour analysis system; reference diameter, minimum diameter, late lumen loss, follow-up percent diameter stenosis and restenosis rate were determined. Results In-stent restenosis rate including persistent area was n = 5/21 (24%), n = 4/25 (16%) and n = 2/23 (8.7%) under 80, 160 and 320 mg valsartan. Late lumen loss was 0.79 ± 0.49 mm, 0.60 ± 0.43 mm and 0.37 ± 0.25 mm, respectively, with significant differences between 80 and 320 mg ( p < 0.001) and 160 and 320 mg ( p < 0.05). Follow-up percent diameter stenosis was 31.8 ± 18.6% under 80 mg, 25.2 ± 17.5% under 160 mg and 13.8 ± 9.4% with significant differences between 80 mg and 320 mg ( p < 0.0005) and 160 and 320 mg ( p < 0.01). Conclusions Different doses of oral valsartan over six months after BMS implantation show a linear response with regard to late lumen loss and follow-up percent diameter stenosis.

Effects of Angiotensin-Converting Enzyme Inhibitor Versus Valsartan on Cellular Signaling Events in Heart Transplant

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) provide similar biologic effects in model systems and similar clinical impacts in humans. The changes in the cardiac angiotensin system signaling pathways in the human heart in response to ACE inhibitors versus ARBs have been incompletely studied. To investigate the effects of ACE inhibitors versus valsartan on the angiotensin II signal transduction pathways in the transplanted human heart. Twenty-seven stable cardiac transplant recipients were randomized to remain on ACE inhibitor therapy (n = 8) or to receive valsartan (n = 19). Two additional endomyocardial biopsy samples were obtained at baseline and after 9 months of therapy. The expression of cardiac angiotensin type I and II receptors and atrial natriuretic factor (ANF) was measured by quantitative polymerase chain reaction. The expression and phosphorylation levels of selected signal transduction pathways were analyzed by immunoblotting. The mean dose of valsartan was 114 +/- 41 mg/day. The use of valsartan resulted in a similar impact on blood pressure and biochemistry profile. There were no significant changes in the expression of angiotensin type I and II receptors and ANF with valsartan. Similarly, no significant changes in the expression and phosphorylation of Jun N-terminal kinase, extracellular signal-regulated kinase 1 and 2, and p38 mitogen-activated protein kinases or AKT, and mammalian target of rapamycin was observed in the valsartan-treated group. Valsartan use is associated with similar clinical and molecular cardiac effects as ACE inhibitor therapy in stable long-term cardiac transplant recipients.

Effect of nicorandil on proteinuria in well controlled hypertensive patients

Proteinuria is an important risk factor for cardiovascular and renal morbidity and mortality. The effect of nicorandil on proteinuria in hypertensive patients well controlled by antihypertensive agents containing a low dose of valsartan has not been studied. A total of 136 proteinuric (300-3000 mg/day), valsartan-treated hypertensive patients with blood pressure less than 140/90 mmHg were randomized into three groups to receive placebo, isosorbide dinitrate (30 mg/day), or nicorandil (15 mg/day) for 6 months. The average dose of valsartan given to the patients was similar in the three groups. Creatinine clearance remained stable throughout the study in the three groups. Nicorandil, but not isosorbide dinitrate, significantly reduced proteinuria by 44% after 6 months (P < 0.0001). Urinary endothelin-1 levels significantly decreased after administration of nicorandil (P = 0.002), whereas placebo and isosorbide dinitrate had no effect. Urinary excretion of endothelin-1 was significantly correlated with improvement in urinary protein excretion in nicorandil-treated patients (r = 0.69, P < 0.0001). The urinary excretion of retinol-binding protein decreased after nicorandil administration, probably reflecting an improvement in tubular function. In contrast, the urinary excretion of immunoglobulin G did not change significantly throughout the study in the three groups. Multivariate analysis revealed that proteinuria was only significantly correlated with the use of nicorandil (model adjusted r = 0.35, P < 0.0001). The addition of nicorandil to treatment for patients with well controlled hypertension may have an additive effect on reducing proteinuria independent of hemodynamics and nitric oxide effects, possibly through inhibiting renal endothelin-1 synthesis and improving tubular function.

Coadministration of valsartan 160 and 320 mg and simvastatin 20 and 40 mg in patients with hypertension and hypercholesterolemia: A multicenter, 12-week, double-blind, double-dummy, parallel-group superiority study

Background: Together, high blood pressure (BP) and high cholesterol levels constitute a cumulative risk for coronary heart disease (CHD). Elevations in cholesterol increase BP through upregulation of angiotensin type 1 receptors, with a corresponding increase in cholesterol oxidation due to elevations in BP. Hence, control of low-density lipoprotein cholesterol (LDL-C) and BP through coadministration of an antihypertensive and a statin have potential benefit in the management of CHD.Objectives: This study examined the dose response to simvastatin 20 and 40 mg in reducing LDL-C and the efficacy and tolerability of a high dose of valsartan (320 mg) when administered with simvastatin.Methods: In this multicenter, 12-week, double-blind, double-dummy, parallel-group superiority study, patients with hypertension and hypercholesterolemia were randomized to receive valsartan 160 mg along with simvastatin 20 or 40 mg. At week 6, valsartan was titrated upward to 320 mg in both groups. The primary efficacy variable was the change in LDL-C, calculated using the Friedewald formula or measured directly (depending on triglyceride levels) and analyzed for superiority. Secondary efficacy variables were the change in LDL-C and the proportion of patients achieving LDL-C and BP control. Safety assessments included the occurrence of adverse events (AEs) and serious AEs, and changes in hematology and biochemistry variables, vital signs, and findings on physical examinations.Results: Eight hundred seventy-two patients were randomized to receive double-blind treatment, and the intent-to-treat population included 838 patients. The combination of valsartan 160 mg + simvastatin 40 mg was statistically superior to that of valsartan 160 mg + simvastatin 20 mg in reducing LDL-C at week 6 (least squares mean percent change from baseline: -38.5% vs -33.6%, respectively; P < 0.001); at week 12, the corresponding values were -36.8% in the valsartan 320 mg + simvastatin 40 mg group and -32.7% in the valsartan 320 mg + simvastatin 20 mg group (P = 0.002). Rates of combined LDL-C and BP control at week 6 were 35.1% (146/416) in the valsartan 160 mg + simvastatin 20 mg group and 37.4% (154/412) in the valsartan 160 mg + simvastatin 40 mg group; at week 12, rates of combined control were 50.7% (212/418) in the valsartan 320 mg + simvastatin 20 mg group and 50.0% (206/412) in the valsartan 320 mg + simvastatin 40 mg group. AEs occurred in 24.3% (102/420) of the valsartan 160/320 mg + simvastatin 20 mg group and 22.2% (93/419) of the valsartan 160/320 mg + simvastatin 40 mg group.Conclusions: In these patients with hypertension and hypercholesterolemia, coadministration of valsartan and simvastatin was well tolerated and was associated with significant reductions from baseline in BP and LDL-C. Coadministered with valsartan 160/320 mg in the evening, simvastatin 40 mg had superior LDL-C–lowering efficacy to simvastatin 20 mg. Clinical Trials Identification Number: NCT00254475.

Efficacy and Safety of the Angiotensin Receptor Blocker Valsartan in Children With Hypertension Aged 1 to 5 Years

The efficacy and safety of valsartan were studied in 90 children (mean age: 3.2 years; 60% male; 30% black) with systolic blood pressure (SBP) > or =95th percentile. Nineteen percent received valsartan in addition to previous antihypertensive therapy. Subjects were randomly assigned to low-, medium-, or high-dose valsartan for 2 weeks (phase 1) and then reassigned randomly to placebo or to remain on the same valsartan dose for 2 additional weeks (phase 2). After this, subjects were enrolled into a 52-week, open-label phase during which valsartan was dosed to achieve SBP <95th percentile. Statistically significant reductions in SBP and diastolic blood pressure of approximately 8.5 mm Hg and 5.7 mm Hg, respectively, were observed at the end of phase 1 in all of the valsartan dose groups. SBP and diastolic blood pressure were also significantly lower during phase 2 in valsartan recipients compared with placebo recipients. SBP <95th percentile was achieved in 77.3% of subjects during the open-label phase. Adverse events were minor and occurred at similar frequencies in each of the 3 dose groups in phase 1 and at equal frequencies in the valsartan and placebo arms in phase 2. Serious adverse events and drug-related adverse events occurred infrequently during both the double-blind (2.2% and 5.6%, respectively) and open-label (14.8% and 6.8%, respectively) portions of the study. Valsartan treatment had no demonstrable negative effects on growth and development. In this study, the first trial of an antihypertensive agent conducted in children <6 years of age, valsartan effectively lowered SBP and diastolic blood pressure compared with placebo.

Temporary Pretreatment With the Angiotensin II Type 1 Receptor Blocker, Valsartan, Prevents Ischemic Brain Damage Through an Increase in Capillary Density

We investigated the effect of temporary treatment with a nonhypotensive dose of valsartan on ischemic brain damage in C57BL/6 mice. We separated the mice into 3 groups of valsartan treatment before middle cerebral artery (MCA) occlusion: (1) for 4 weeks: Val (2W, 2W); (2) for 2 weeks followed by its cessation for 2 weeks: Val (2W, -); and (3) no treatment for 4 weeks: Val (-, -). Ischemic volume, DNA damage, superoxide production, and mRNA levels of monocyte chemoattractant protein-1 and tumor necrosis factor-alpha on the ipsilateral side after 24 hours of MCA occlusion were significantly reduced in both Val (2W, 2W) and Val (2W, -) mice compared with those in Val (-, -) mice, whereas these parameters were larger in Val (2W, -) mice than in Val (2W, 2W) mice. Moreover, mice in both the Val (2W, 2W) and Val (2W, -) groups exhibited an increase in cerebral blood flow in the peripheral territory of the MCA 1 hour after MCA occlusion, with increases in endothelial nitric oxide synthase activation and nitric oxide production. Before MCA occlusion, treatment with valsartan did not influence superoxide production or mRNA levels of monocyte chemoattractant protein-1 and tumor necrosis factor-alpha in the brain. However, the capillary density in the brain in both Val (2W, 2W) and Val (2W, -) mice was increased before MCA occlusion. Our results suggest that temporary valsartan treatment could protect against ischemic brain damage even after its cessation, at least in part due to an increase in capillary density.

Neuroprotective role of angiotensin II type 2 receptor after transient focal ischemia in mice brain

This study assessed the time course of angiotensin (Ang) II type 1 and type 2 receptor expression after 60 min of ischemia/reperfusion in mice treated with a nonhypotensive dose of valsartan, an angiotensin II type 1 receptor antagonist. We also examined the potential neuroprotective mechanisms mediated by angiotensin II type 2 receptor. Mice were divided into two groups ( n = 64, each): valsartan-treated and control, vehicle groups. Infarct volume and neurological deficit scores were evaluated at several time points after ischemia, while immunohistochemical analyses were performed at serial time points after reperfusion. Valsartan significantly reduced the infarct volume and improved the neurological deficit scores ( P < 0.05). Both angiotensin II type 1 and type 2 receptors were upregulated at 24 h and peaked at 72 h with type I receptors dominating in the ischemic penumbra of the vehicle group. Interestingly, angiotensin II type 2 receptor expression levels were significantly higher in the valsartan group than vehicle controls ( P < 0.001). Moreover, angiotensin II type 2 receptor upregulated phosphosignal transducer and activator of transcription-3, and B-cell lymphoma protein-2 ( P < 0.05). Our results indicated that angiotensin II type 2 receptor has antiapoptotic activity by activating the B-cell lymphoma protein-2 via the janus kinase/signal transducer and activator of transcription signaling pathway.

Comparison of Efficacy of Low- (80 mg/day) and High- (160–320 mg/day) Dose Valsartan in the Prevention of In-Stent Restenosis after Implantation of Bare-Metal Stents in Type B2/C Coronary Artery Lesions

Results from the VALVACE (VALsartan Versus ACE inhibition after bare metal stent implantation) trial suggest that prevention of in-stent restenosis after implantation of bare-metal stents in type B2/C coronary artery lesions is possible after administration of valsartan 80 mg/day. However, the restenosis rate in patients with stable angina was relatively high (27%) with this dosage and no different from patients taking ACE inhibitors. Therefore, a 1 : 1 matched comparison on a case-control basis was initiated in a prospective controlled registry using a higher dose of valsartan, 160-320 mg/day. A total of 450 patients (241 men, mean age 62.7 +/- 9.1 years) with matched demographic and angiographic characteristics to patients in the VALVACE trial were treated with high-dose oral valsartan 160-320 mg/day over 6 months until control angiography. Angiographic restenosis rate, target lesion revascularization (TLR) and target vessel revascularization (TVR) rates, major adverse cardiac event (MACE) rate (death, myocardial infarction, and stent thrombosis) and mean late lumen loss were analysed after 6 months. Results were compared with the results of the VALVACE trial. Analysis of the combined results of the current study together with the VALVACE trial data enabled calculation of the gender- and dose-dependent effects of valsartan. In the high-dose valsartan group, the angiographic restenosis rate in 368 patients with control angiography was 7.3% compared with 19.5% in the low-dose group (VALVACE) [p < 0.0001]. Mean late lumen loss was 0.37 +/- 0.3 mm in the high-dose group compared with 0.53 +/- 0.31 mm in the VALVACE trial (p < 0.01). TLR and TVR rates were 4.3% in the high-dose group compared with 9% in the VALVACE trial (p < 0.01). The MACE rate was 0% in the high-dose group compared with 1.5% in the VALVACE trial (p < 0.01). Summarizing the data for valsartan, the in-stent restenosis rates in men were 22.7%, 13.3%, 6.7%, and 5.4% in patients receiving 80, 160, 240, and 320 mg/day, respectively. In women, the in-stent restenosis rates were 13.3% and 6.3% in patients receiving 80 and 160 mg/day, respectively; no restenosis occurred in patients receiving higher doses. Administration of high-dose oral valsartan 160-320 mg/day after implantation of bare-metal stent in type B2/C coronary artery lesions reduces angiographic in-stent restenosis, TLR, TVR, late lumen loss, and MACE rates more effectively than low-dose valsartan 80 mg/day.

Effects of 12-Month Valsartan Therapy on Glycation and Oxidative Stress Markers in Type 2 Diabetic Subjects With Hypertension

Although it has been reported that angiotensin II receptor blockers inhibited the formation and accumulation of advanced glycation endproducts (AGEs) in vitro and in vivo, whether they can do so clinically is not clear. We investigated the effects of 12-month valsartan therapy on various markers of inflammation, glycation, and oxidation in type 2 diabetic subjects with hypertension. We started 40 mg/day valsartan treatment in 15 type 2 diabetic patients with hypertension. In 6 patients, the dose of valsartan was increased to 80 mg/day after 6 months and maintained until 12 months. Metabolic parameters including BMI and serum high molecular weight (HMW)-adiponectin, high-sensitivity C-reactive protein (hs-CRP) as an inflammation marker, AGEs, paraoxonase activity, platelet-activating factor (PAF)- acetylhydrolase activity, and urine 8-isoprostane levels were measured at baseline and after 6 and 12 months of treatment. Urine microalbumin level and carotid artery intima-media thickness (IMT) were also measured. Even after valsartan therapy, the blood pressure levels of the patients were not decreased significantly. Serum AGEs and urine 8-isoprostane levels decreased at both 6 and 12 months (P < 0.05 for both), although other metabolic and oxidative markers were unchanged. Though urine microalbumin levels tended to be decreased after 6 and 12 months of valsartan treatment, the changes were not significant. Mean IMT at 12 months was not changed from the baseline value. In conclusion, the findings suggest that treatment with valsartan, even at a low dose, may ameliorate some glycation and oxidative stress markers independently of an effect on blood pressure in hypertensive type 2 diabetic subjects.

Abstract 3398: Comparison of Once Versus Twice a Day Valsartan Dosing in Heart Failure -Results of the DESTINY Trial

Background. Valsartan causes a sustained 24-hour reduction in blood pressure (BP) in hypertensive patients, when given once a day (q.d.). Because many CHF patients have low baseline BP and concomitant chronic kidney disease, valsartan was prescribed twice a day (b.i.d.) in Val-HeFT (Valsartan in Heart Failure Trial) to avoid any possible adverse effects like symptomatic hypotension and worsening renal dysfunction with the q.d. dosing. Methods and Results. DESTINY-HF ( D iovan E valuation of S afety T w I ce vs o N ce dail Y study in H eart F ailure) was a 10-week double blind randomized trial designed to test the safety of q.d. (n=55) vs b.i.d. (n=60) dosing of valsartan in patients with NYHA class II–III heart failure receiving diuretics (87%), ACE-I (98%), beta-blockers (92%), aldosterone antagonists (25%) and digoxin (32%) over a 12-week period. Valsartan was started in the dose of 40 mg b.i.d. vs 80 mg q.d. and titrated to a maximum of 320 mg per day by doubling the dose every 2 weeks. Clinical and biochemical measurements were made at 2, 4, 6, and 10 weeks. The baseline characteristics of the two groups were similar. The average dose of valsartan at the end of study was 245 mg vs 256 mg in the bid vs qd dose groups (p=NS). The % of patients who tolerated the up-titration regimen at week 2, 4 and 6 and at the end of study were not significantly different between the dose groups (b.i.d. vs q.d., 75 vs 75, 74 vs 85, 77 vs 78, and 67 vs 68; p=NS). There was no difference in the reduction of systolic or diastolic BP, or in the incidence of hypotension, renal impairment, orthostatic dizziness or syncope between the groups at any time point. Changes in serum K + , creatinine, cystatin-C, and estimated GFR were also not different between the groups at any time point. Brain natriuretic peptide decreased, and by the same amount in both groups at all time points. Conclusions. These data demonstrate that the use of valsartan in q.d. dosing has the same safety profile as b.i.d. dosing in patients with moderate to severe heart failure.

Albuminuria response to very high-dose valsartan in type 2 diabetes mellitus

Renin-angiotensin system blockade is now standard in the management of the patient with type 2 diabetes mellitus. We aimed to investigate whether high doses of valsartan, an angiotensin receptor blocker, are superior to conventional doses to reduce urinary albumin excretion rates (UAER) in such patients. Three hundred and ninety-one hypertensive patients with type 2 diabetes mellitus and UAER 20-700 microg/min were randomized to 160, 320 or 640 mg valsartan. All received valsartan 160 mg for the first 4 weeks. Valsartan dose was then increased in two of three groups for 30 weeks. Overnight urine collections at baseline, 4, 16, and 30 weeks in triplicate were used to assess proteinuria. Comparable albuminuria reductions occurred in all groups at week 4 (P<0.001). Subsequently, a highly significant albuminuria fall occurred with valsartan 320 and 640 mg (P<0.001) versus a modest additional change with 160 mg (P=0.03). At week 30, twice as many patients returned to normal albuminuria with valsartan 640 mg versus 160 mg (24 versus 12%; P<0.01). High doses were well tolerated, with no dose-related increases in adverse events, including hypotension and hyperkalemia. High doses of valsartan reduced albuminuria more than the more commonly used 160 mg dose, apparently independent of blood pressure. Thus, at least in type 2 diabetes mellitus, higher doses of valsartan are required to optimize tissue protection than for blood pressure control.

Research on the effect of valsartan on atherosclerosis in rabbits and pro-oncogenes

目的 探讨缬沙坦对兔动脉粥样硬化管壁及相关基因的研究.方法 将白兔随机分成对照组,胆固醇组和不同剂量缬沙坦加胆固醇组.建立家兔动脉粥样硬化模型,观察各组家兔c-myc、c-fos变化及大动脉管壁、管腔和粥样斑变化.结果 (1)病理学上,高剂量组的主动脉斑块面积比明显降低(P＜0.05),低剂量组与胆固醇组比较差异无统计学意义.(2)胆固醇组的动脉粥样硬化相关基因c-mys、c-fos mRNA表达的阳性率较对照组显著增高,而高剂量组的阳性率则显著低于胆固醇组(P＜0.05),中、低剂量组与胆固醇组比较差异无统计学意义.结论 大剂量的缬沙坦能有效防止兔动脉粥样硬化形成和发展。

Efficacy and safety of combined use of aliskiren and valsartan in patients with hypertension: a randomised, double-blind trial

The aim of this study was to assess dual renin system intervention with the maximum recommended doses of aliskiren and valsartan, compared with each drug alone in patients with hypertension. In this double-blind study, 1797 patients with hypertension (mean sitting diastolic blood pressure 95-109 mm Hg and 8-h daytime ambulatory diastolic blood pressure > or =90 mm Hg) were randomly assigned to receive once-daily aliskiren 150 mg (n=437), valsartan 160 mg (455), a combination of aliskiren 150 mg and valsartan 160 mg (446), or placebo (459) for 4 weeks, followed by forced titration to double the dose to the maximum recommended dose for another 4 weeks. The primary endpoint was change in mean sitting diastolic blood pressure from baseline to week 8 endpoint. Analyses were done by intention to treat. This trial is registered at ClinicalTrials.gov with the number NCT00219180. 196 (11%) patients discontinued study treatment before the end of the trial (63 in the placebo group, 53 in the aliskiren group, 43 in the valsartan group, and 37 in the aliskiren/valsartan group), mainly due to lack of therapeutic effect. At week 8 endpoint, the combination of aliskiren 300 mg and valsartan 320 mg lowered mean sitting diastolic blood pressure from baseline by 12.2 mm Hg, significantly more than either monotherapy (aliskiren 300 mg 9.0 mm Hg decrease, p<0.0001; valsartan 320 mg, 9.7 mm Hg decrease, p<0.0001), or with placebo (4.1 mm Hg decrease, p<0.0001). Rates of adverse events and laboratory abnormalities were similar in all groups. The combination of aliskiren and valsartan at maximum recommended doses provides significantly greater reductions in blood pressure than does monotherapy with either agent in patients with hypertension, with a tolerability profile similar to that with aliskiren and valsartan alone.

Time to Achieve Blood-Pressure Goal: Influence of Dose of Valsartan Monotherapy and Valsartan and Hydrochlorothiazide Combination Therapy

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. 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 mm 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. 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. 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.

Effect of AT1 Angiotensin II Receptor Antagonists on the Sympathetic Response to a Cold Pressor Test in Healthy Volunteers

The aim of this study was to evaluate the effect of short-term administration of AT(1) angiotensin II receptor antagonists on the sympathetic response to a cold pressor test (CPT) in normotensive healthy volunteers. Eighty-two healthy volunteers were included in this double-blind placebo-controlled study. Blood pressure and heart rate were determined before and 175 minutes after oral administration of placebo, losartan (50 mg), valsartan (80 mg), or eprosartan (600 mg). Immediately, the subjects underwent a CPT and then the same hemodynamic parameters were measured. CPT increased arterial blood pressure (systolic, diastolic, and mean) and heart rate in the placebo-treated group. Pretreatment with a single dose of losartan, valsartan, or eprosartan blunted CPT-induced pressor response but not heart rate increase. Our results demonstrate that endogenous angiotensin II, through stimulation of AT(1) receptor, supports sympathetic-mediated stress response in humans.

Effects of Valsartan or Amlodipine Alone or in Combination on Plasma Catecholamine Levels at Rest and During Standing in Hypertensive Patients

To compare the effects of valsartan and amlodipine alone or in combination on plasma norepinephrine (NE) at rest and standing for 10 minutes in patients with hypertension, 47 patients with a sitting diastolic blood pressure (BP) (DBP)>95 mm Hg and<110 mm Hg were randomized in a double-blind fashion to either valsartan or amlodipine. During the first 4 weeks of treatment, patients received a low dose of either valsartan (80 mg) or amlodipine (5 mg). The patients were force-titrated to the high dose of either drug (160 or 10 mg) for 4 weeks. After 8 weeks of therapy, those who still had a DBP>90 mm Hg (nonresponders) received combination therapy with the other drug, whereas patients with a DBP<90 mm Hg (responders) continued on monotherapy. Decreases in ambulatory BP and clinic systolic BP and DBP were significant (P<.05) after 8 weeks' therapy with no difference between the 2 groups. Amlodipine but not valsartan as monotherapy consistently increased NE levels at rest and enhanced NE levels during standing. Valsartan decreased basal NE in responders. Combination therapy with valsartan and amlodipine did not attenuate the rise in NE levels induced by amlodipine. This study indicates that therapy with amlodipine increases peripheral sympathetic basal tone and reactivity to standing in patients with hypertension, whereas valsartan does not. Combined therapy with amlodipine/valsartan did not attenuate the sympathetic activation induced by amlodipine. The hypotensive action of valsartan may be mediated in part by an inhibition of the sympathetic baroreflex in patients with hypertension.

Comparison of Increasing Doses of Olmesartan Medoxomil, Losartan Potassium, and Valsartan in Patients With Essential Hypertension

This 12-week, randomized, double-blind, forced-titration study compared the efficacy of 3 angiotensin receptor blockers. Patients received olmesartan medoxomil 20 mg, losartan potassium 50 mg, valsartan 80 mg, or placebo once daily. At week 4, doses were titrated to 40, 100, and 160 mg once daily for olmesartan, losartan, and valsartan, respectively. At week 8, losartan was increased to 50 mg twice daily and valsartan increased to 320 mg once daily (olmesartan remained at 40 mg once daily). The primary end point was mean change from baseline in seated diastolic blood pressure (SeDBP) at week 8. All 3 medications significantly reduced mean SeDBP from baseline compared with placebo at weeks 4, 8, and 12 (P<.001). At week 8, olmesartan reduced mean SeDBP more than losartan (P<.001); more patients in the olmesartan medoxomil group achieved a blood pressure goal of <140/90 mm Hg (P<.001). Olmesartan did not reduce mean SeDBP significantly compared with valsartan, although more patients attained blood pressure goal with olmesartan (P=.031). At week 12, all agents lowered blood pressure equivalently.

Evaluation of the Dose Response With Valsartan and Valsartan/Hydrochlorothiazide in Patients With Essential Hypertension

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.

Successful Treatment of Refractory Angina Pectoris due to Multivessel Coronary Spasm with Valsartan

This case report describes a 78-year-old man with recurrent angina attacks due to coronary spasm. He was treated with maximum daily doses of antianginal and antioxidative medications, including isosorbide mononitrate (40 mg), diltiazem (200 mg), and tocopherol nicotinate (300 mg). Despite the use of these medications, rest angina occurred 2 or 3 times during sleep. Although his symptoms disappeared promptly with the use of sublingual glycerine trinitrate (GTN), an angiotensin II receptor blocker, valsartan (80 mg), was added on a daily basis with the intent of improving endothelial function and controlling his angina. After beginning 80 mg/day of valsartan, the number of the anginal attacks decreased by about 66%. The anginal attacks totally disappeared after the dose of valsartan was increased to 160 mg/day. To confirm the effect of valsartan on his angina, valsartan was stopped temporarily with his consent. His anginal attacks increased to the same frequency that was observed before valsartan; therefore, valsartan therapy was resumed. The data indicate that the addition of valsartan to maximum antianginal medications may be effective in helping to control angina attacks at rest due to coronary spasm.