High-dose Valsartan Research Articles

Efficacy, Safety and Tolerability of High dose Valsartan Hydrochloride in Essential Hypertension

Background: Studies across the world have demonstrated the efficacy of valsartan in lowering blood pressure in a variety of patient populations, several of them investigated higher doses of the drug. This study focuses on revealing safety and efficacy of valsartan at higher doses in Bangladeshi population. Current study is planned to evaluate the efficacy, safety and tolerability of daily dose of Valsartan 160 or 320 mg in the treatment of essential hypertension. Method: This is a multi-center, open-label, observational, non-comparative, clinical decision based titration, involving about 31 centers in Bangladesh. A total of 334 newly diagnosed adult patients with essential hypertension received valsartan at a dose of 160 mg or 320 mg as deemed necessary by physician were included to allow for an assessment of efficacy, safety and tolerability. The total duration of treatment with valsartan was 16 weeks. Primary parameter for efficacy was percentage responders to valsartan at 16 weeks, reduction in Mean sitting systolic blood pressure (MSSBP) and Mean sitting Diastolic blood pressure MSDBP, control rate (% patients) achieving SBP <140 mmHg and DBP <90 mmHg at end point and Global assessment of efficacy and tolerability to valsartan treatment by the physician and patient. Result: Mean age of the patient was 53.31±8.8 years and 56.5% were male. A clearly evident decline is evident in mean Systolic BP and diastolic BP over the study duration. Average reduction of 30.4 ± 17.4 mmHg was seen in systolic BP, 18.4 ± 11.2 mmHg in diastolic BP and 3.5 ± 3.1/ minute in heart rate. The reduction was highly significant in both systolic BP and diastolic BP and heart rate as well (P<.001). At 16 weeks only 3.4% were found to be refractory to the treatment. Global assessment of safety and efficacy was assessed on four point scale, around 30.2% of the physician rated the efficacy as excellent, around 56% rated as very good and 13.8% rated as good. Tolerability of the treatment was also assessed based on the opinion of the patient and physician concerned on four point scale. Around 34.1% of the physician rated the tolerability as excellent, around 49.7% rated as very good and 16.2% rated as good. Conclusion: Sixteen week treatment with valsartan at 160mg daily or 320 mg daily is an effective treatment for patients with essential hypertension. The drug is found to be well tolerated with minimal adverse event during the course of treatment. DOI: http://dx.doi.org/10.3329/cardio.v5i2.14323 Cardiovasc. j. 2013; 5(2): 182-189

Improved Blood Pressure Control with Nifedipine GITS/Valsartan Combination Versus High‐Dose Valsartan Monotherapy in Mild‐to‐Moderate Hypertensive Patients from Asia: Results from the ADVISE Study, a Randomized Trial

ADVISE was a 12-week, multicenter, randomized, prospective, open-label, parallel-group study comparing combination therapy of nifedipine GITS 30 mg plus valsartan 80 mg (N + V) with high-dose valsartan (160 mg) monotherapy (V160) in Asian patients with hypertension. Patients with hypertension inadequately controlled with valsartan 80 mg for at least 4 weeks were randomized. The coprimary endpoints were the mean changes in clinic systolic and diastolic blood pressures (SBP and DBP, respectively) at Week 12. Other endpoints included blood pressure (BP) control rate, response rate, and adverse events. The full analysis set (FAS) comprised 359 patients. Least squares (LS) mean changes in SBP were -18.3 mmHg (N + V; n = 177) and -16.5 mmHg (V160; n = 182) (difference: -1.9 mmHg; P = 0.0998). DBP LS mean changes were -9.8 mmHg (N + V) and -7.4 mmHg (V160) (difference: -2.4 mmHg; P = 0.0011). BP control rates were significantly higher in the N + V group (Week 4: 51.2% vs. 38.4%, P = 0.0138; Week 8: 68.3% vs. 50.3%, P = 0.0004; and Week 12: 71.2% vs. 55.5%, P = 0.0024). Similar findings were observed when patients were stratified according to smoking status, SBP baseline quartiles, and ESC/ESH guideline-defined added-risk category. The BP response rate was also higher in the N + V group compared with the V160 group. Rates of adverse drug reactions (all mild-to-moderate) were similar: 4.5% (N + V) and 4.4% (V160). Although one of the coprimary endpoints did not reach statistical significance, combination treatment with N + V provided a greater early and more consistent BP-lowering effect than monotherapy with V160, including superior reduction in DBP and BP control rates.

Improved blood pressure control with nifedipine GITS/valsartan combination versus high-dose valsartan monotherapy in mild-moderate hypertensive patients from Asia: results from the ADVISE study, a randomized trial

Improved blood pressure control with nifedipine GITS/valsartan combination versus high-dose valsartan monotherapy in mild-moderate hypertensive patients from Asia: results from the ADVISE study, a randomized trial

Effectiveness and Safety of Valsartan in Children Aged 6 to 16 Years With Hypertension

The effectiveness and safety of valsartan have not been assessed in hypertensive children. Therefore, hypertensive patients aged 6 to 16 years (n=261) were randomized to receive weight-stratified low- (10/20 mg), medium- (40/80 mg), or high-dose (80/160 mg) valsartan for 2 weeks. After 2 weeks, patients were randomized to a 2-week placebo-controlled withdrawal phase. Dose-dependent reductions in sitting systolic blood pressure (SSBP) and sitting diastolic blood pressure (SDBP) were observed after 2 weeks (low dose, -7.9/-4.6 mm Hg; medium dose, -9.6/-5.8 mm Hg; high dose, -11.5/-7.4 mm Hg [P<.0001 for all groups]). During the withdrawal phase, SSBP and SDBP were both lower in the pooled valsartan group than in the pooled placebo group (SSBP, -2.7 mm Hg [P=.0368]; SDBP, -3.0 mm Hg [P=.0047]). Similar efficacy was observed in all subgroups. Valsartan was well tolerated and headache was the most commonly observed adverse event during both the double-blind and 52-week open-label phases.

Valsartan decreases TGF-β1 production and protects against chlorhexidine digluconate-induced liver peritoneal fibrosis in rats

Peritoneal fibrosis (PF) is a recognized complication of long-term peritoneal dialysis (PD) and can lead to ultrafiltration failure. The present study was designed to investigate the protective effects of valsartan on chlorhexidine digluconate-induced PF by decreasing TGF-β1 production in rats. PF was induced in Sprague–Dawley rats by daily administration of 0.5 ml 0.1% chlorhexidine digluconate in normal saline via peritoneal dialysis (PD) tube for 1 week. Rats received daily intravenous injections of low dose valsartan (1 mg/kg) or high dose valsartan (3 mg/kg) for 1 week. After 7 days, conventional 4.25% Dianeal (30 ml) was administered via a PD catheter with a dwell time of 4 h and assessed of peritoneal function. At the end of dialysis, rats were sacrificed and the liver peritoneum was harvested for microscopically and immunohistochemistry. There was no significant difference in mean arterial pressure and heart rate between groups. After 4 h of PD, the D 4/P 4Urea level was reduced, the D 4/D 0 glucose level, serum and dialysate transforming growth factor-β1 (TGF-β1) level was increased, the liver peritoneum was markedly thicker, and the expression of TGF-β1, alpha-smooth muscle actin (α-SMA), fibronectin, collagen, and vascular endothelial growth factor (VEGF) were elevated in the PF group compared with the vehicle group. High dose of valsartan decreased the serum and dialysate TGF-β1 level, decreased the thickness of the liver peritoneum, and decreased the expression of TGF-β1, α-SMA, fibronectin, collagen, and VEGF-positive cells in liver peritoneum. The low dose of valsartan did not protect against chlorhexidine digluconate-induced PF in rat. Valsartan protected against chlorhexidine digluconate-induced PF in rats by decreasing TGF-β1 production.

E0349 Clinical observation on different dosage of valsartan in treatment of heart failure

ObjectiveTo explore the clinical value of different dosage of valsartan in treatment of chronic heartfailure (CHF).Methods99 patient s with CHF were randomly divided into three groups: benazepril group (group A,...

Effectiveness and safety of high-dose valsartan monotherapy in hypertension treatment: the ValTop study

Early combination therapy is increasingly recommended in hypertension management because of increased risk of adverse effects with high-dose monotherapy. However, this risk is not necessarily increased for high doses of angiotensin receptor blockers (ARB). ValTop study compared efficacy and safety of high vs. conventional dose of valsartan in hypertensive patients. ValTop was a controlled, randomized, double-blind trial. Of 6035 screened subjects, 4004 mild-to-moderate hypertensive patients (mean seated diastolic blood pressure (MSDBP) 90-109 mm Hg) started 4-week open-label treatment with valsartan 160 mg. Of them, 3776 were randomized to receive valsartan 160 mg (N=1900) or 320 mg (N=1876) o.d. for 4 weeks. In 28-week open-label extension study, all participating patients (N=642) received valsartan 320 mg. Valsartan 160 mg reduced MSDBP by 10.0 mm Hg in the initial open-label phase. Further BP reductions in the double-blind phase were significantly (P<0.0001) greater in the 320 mg group than in the 160 mg group for MSDBP (1.6 ± 0.18 mm Hg vs. 0.5 ± 0.18 mm Hg) and mean seated systolic BP (3.3 ± 0.31 mm Hg vs. 0.7 ± 0.31 mm Hg). The size of the additional effect of the 320 mg dose on BP was similar in subjects controlled or not by the initial 160 mg dose. Adverse event (AE) rates were similar in both treatment groups, drug-related AEs occurring in <5% of subjects in each phase. High-dose valsartan is safe and effective in uncomplicated mild-to-moderate hypertension independently of the initial response to a moderate dose. High-dose ARB monotherapy may thus be a viable option in hypertension management.

Effect of high-dose valsartan on inflammatory and lipid parameters in patients with Type 2 diabetes and hypertension

Aims The present study aimed to explore the impact of the angiotensin type 1 receptor blocker valsartan (VAL) on inflammatory-/lipid-/glucose parameters in hypertensive diabetic patients with and without coronary artery disease (CAD). Methods This was a 16-week, randomized, double-blind, placebo-controlled two-center study with VAL 320 mg/d in 109 hypertensive diabetic patients ( n = 56 non-CAD; n = 53 CAD). Results VAL treatment did not significantly affect serum interleukin-6 (IL-6) or tumor necrosis factor α (TNFα) levels in the overall study population but significantly reduced serum IL-6 in the subgroup with high inflammatory load at baseline (IL-6 > median (2.0 ng/L), n = 54: [median, ng/L]): VAL: from 3.5 to 2.4; placebo: from 3.2 to 3.5; p = 0.035). VAL significantly lowered total- and LDL-cholesterol in the whole study population: [median, mg/dL]: total cholesterol: VAL: from 178 to 168; placebo: from 174 to 173, p = 0.039; LDL-cholesterol: VAL: from 96 to 90, placebo: from 102 to 103, p = 0.006, whereas glycemic parameters were not affected. Conclusions The present study demonstrates significant anti-inflammatory efficacy of VAL in hypertensive diabetic patients with enhanced inflammatory burden. High-dose VAL therapy significantly lowered total- and LDL-cholesterol levels. The combined actions of cholesterol and blood pressure lowering by VAL may provide additional clinical benefits for these high-risk patients.

ADMINISTRATION TIME OF HIGH-DOSE VALSARTAN IN NON DIPPER HYPERTENSIVE PATIENTS: PP.33.306

Previous results with angiotensin II receptor blockers have shown their efficacy in reducing blood pressure (BP) throughout the 24 hours, independently of the administration time. However, the intake of these ARBs at night increased the diurnal/nocturnal ratio of BP. That is the reason why in this study we have analysed the chronotherapeutic efficacy of high-dose Valsartan in non dipper hypertensive patients. 45 patients (24 women) aged 62.3 ± 11.4 years-old with non-treated essential hypertension confirmed by ambulatory BP monitoring (ABPM) and with a non dipper circadian pattern were studied. After clinical and biological assessment, patients were assigned to two treatment groups according to the administration time of Valsartan 320 mg/day: on awakening (AWA) or at bedtime (BED). ABPM was performed (Spacelabs 90207 device), before and after 3 months of treatment and both the antihypertensive efficacy and the changes in the circadian pattern of BP were compared. After 3 months of treatment, there was a significant decrease in 24h-BP and diurnal BP (p < 0,001), similar in both groups, with proved antihypertensive efficacy throughout the 24 hours (decrease in 24h-SBP/DBP: 16.6/10 mmHg on AWA, 18.8/11.6 mmHg at BED; decrease diurnal SBP/DBP: 16.6/10.2 mmHg on AWA, 17.1/10.4 mmHg at BED). However, there were a higher nocturnal BP decrease in patients taking Valsartan 320 mg at bedtime (decrease in nocturnal SBP/DBP: 15.5/9,7 mmHg on AWA; 24.3/15.5 mmHg at BED; p < 0.001). Diurnal/nocturnal ratio of BP showed no change with Valsartan AWA (−0.4/+0.1%) but it increased in a significant way with Valsartan BED (+6.3/+7.4; p < 0.001) so 69.9% of the patients changed to a dipper circadian pattern. Administration of Valsartan 320 mg/day in non dipper hypertensive patients shows an excellent antihypertensive efficacy independently of the administration time. Nevertheless, when the medication is taken at bedtime, there is a higher decrease of nocturnal BP together with an increase in the diurnal/nocturnal ratio of BP which, in many cases, restores to normal the altered circadian pattern of these patients.

The Effect of High-Dose Valsartan on Left Ventricular Function Following Primary Percutaneous Coronary Intervention

REFER TO THE PAGE 77-83 The study by Kim et al.1) revealed that while improvement of regional function by valsartan was more effective in the high-dose (160 or 320 mg) valsartan group, compared with the low-dose group, high-dose valsartan did not have effects on left ventricular ejection fraction (LVEF) and lift ventriculal (LV) size. Angiotensin-receptor blockers (ARBs) should be used in post-ST-segment elevation myocardial infarction (STEMI) patients with evidence of LV dysfunction who are intolerant to angiotensin-converting enzyme (ACE) inhibitors.2) ARBs reduce mortality and morbidity rates in patients with heart failure (HF) and reduced LVEF. Investigators of the Val-HeFT3) and CHARM4) trials reported that high doses of ARBs improved clinical outcomes. Recently, the HEAAL study5) demonstrated that high-dose (losartan 150 mg) is superior to low-dose ARB (losartan 50 mg) in patients with HF and reduced LVEF. In contrast to the latter ARB trials, the VALIANT study6) focused on patients with HF after acute myocardial infarction (MI) and demonstrated that a high-dose ARB (valsartan 320 mg) was not inferior to an ACE inhibitor (captopril 150 mg). However, the VALIANT study did not evaluate dose-dependent clinical outcomes. The study by Kim et al.1) is helpful to understand changes in dose-dependent LV remodeling. However, this study has several limitations in terms of dose-dependent echocardiographic changes. First, the study population size was too small to compare LVEF and LV size between two groups. In the VALIANT Echo study, the small improvement in LVEF was observed in 610 patients. Second, baseline LVEF was too high (mean EF 52.7 ± 8.1%) to evaluate LV remodeling, compared to other remodeling studies such as the VALIANT (EF ≤ 35%) and HEAAL (EF ≤ 40%) studies. Third, the results do not definitively answer the question of why improvement of segmental wall motion was better in the high-dose than in the low-dose group. If additional information, such as myocardial microcirculation by myocardial contrast echocardiography and drugs affecting LV function were provided, the results would be more convincing. Valsartan (Diovan) is an oral angiotensin II-receptor antagonist with specificity for the angiotensin II type 1 receptor subtype. It has been shown to attenuate the progression of chronic HF and to reduce mortality in patients with myocardial infarction. Although based on clinical trials high-dose ARB (Valsartan 160 mg BID) is recommended for the improvement of LV function in heart failure, low-dose ARB is preferred in clinical practice in patients with HF. The ARB dose may vary according to race and personal preferences. In the VALIANT study, discontinuation of valsartan (160 mg BID) was observed in 1,675 (34%) patients. However, in the study by Kim et al.1), discontinuation of high-dose valsartan was seen in 43 (68%) patients. By comparing two groups prospectively after randomization, the present study concludes that high-dose valsartan is more effective than low-dose valsartan in improving segmental wall motion. Even though this is a small study to compare dose-dependent echocardiographic LV remodeling, it reveals the benefit of high-dose treatment, which may allow recommendation of high-dose valsartan even in post-STEMI cases.

Evaluation of Cardiac Function by Transthoracic Echocardiography in Subjects with ST-Segment Elevation Myocardial Infarction Following Primary Percutaneous Coronary Intervention according to Valsartan Dose: The Valsartan One Center Trial

The aim of this study was to evaluate the mid-term changes in cardiac function by transthoracic echocardiogram (TTE) in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI) according to valsartan dose. Between April 2006 and February 2009, 78 subjects (mean age: 57 ± 12 years, M : F = 74 : 4) with STEMI who underwent primary PCI were enrolled. Fifty three patients received low dose valsartan (40 or 80 mg) and 25 patients received high dose valsartan (160 or 320 mg). Follow-up TTE was done approximately 2 years later. We evaluated the changes in left ventricular (LV) function between initial and final TTE after primary PCI and compared the changes between low and high dose valsartan group. The mean follow-up TTE duration was 24 ± 8 months. Deceleration time (188.6 ± 56.3 msec vs. 221.5 ± 71.3 msec, p = 0.01), E/e' (12.24 ± 5.2 vs. 10.1 ± 4.9, p = 0.002), ejection fraction (52.7 ± 8% vs. 55.2 ± 8.4%, p < 0.01), and wall motion score index (1.45 ± 0.30 vs. 1.33 ± 0.32, p < 0.01) showed significant changes during the follow-up period. Wall motion improvement in injured myocardial segments was more frequently observed in the high-dose valsartan group compared to the low-dose group [18/25 (72%) vs. 24/53 (43.7%), p = 0.03]. There was no significant difference in the changes in cardiac dimensions and function between the low and high dose valsartan group. In patients with STEMI who undergoing primary PCI, high-dose valsartan treatment may be more helpful than low-dose in improving wall motion in the injured myocardium.

Evaluation of arterial stiffness in morning hypertension under high-dose valsartan compared to valsartan plus low-dose diuretic

Morning hypertension has been reported to be an important risk factor for cardiovascular events, and arterial stiffness bears a relationship with cardiovascular risk. The aim of this study was to evaluate whether high-dose angiotensin II receptor blocker (ARB) treatment has a more beneficial effect on arterial stiffness than regular-dose ARB plus low-dose diuretic treatment in patients with morning hypertension. Forty-three patients, in whom the home systolic blood pressure (BP) in the morning was higher than 140 mm Hg and in the evening was lower than 135 mm Hg, despite treatment with 80 mg valsartan, were randomly assigned to receive 160 mg valsartan (V group, n=22) or 80 mg valsartan plus low-dose trichlormethiazide (1 mg) (V+D group, n=21) for 6 months. There were no differences in the patient background characteristics between the two groups. There were no significant differences in BP measured at home between the two groups. The brachial-ankle pulse wave velocity (baPWV) at the time of diagnosis of morning hypertension was similar in the two groups; however, after 6 months of treatment, a greater degree of reduction of the baPWV and a greater degree of reduction of BP in the supine position were observed in the V group compared with the V+D group. Thus, though both high-dose valsartan and valsartan plus diuretic reduced the BP to a similar degree in patients with morning hypertension, high-dose valsartan exerted a greater beneficial effect on arterial stiffness than did valsartan plus diuretic.

Valsartan improves l-NAME-exacerbated cardiac fibrosis with TGF-β inhibition and apoptosis induction in spontaneously hypertensive rats

This study was designed to investigate whether chronic angiotensin II type 1 receptor blockade inhibits ventricular interstitial fibrosis with the induction of programmed cell death (apoptosis) in prolonged nitric oxide synthase (NOS) inhibition using N(G)-nitro-l-arginine methyl ester (L-NAME) in spontaneously hypertensive rats (SHR). Four groups of 20-week-old male SHR were studied for 3 weeks: the control group; the L-NAME group given 80 mg/L L-NAME in drinking water; and the groups given 1 or 30 mg/(kg day) of valsartan, respectively, with L-NAME. The L-NAME group showed marked cardiac tissue injuries with elevated blood pressure such as interstitial fibrosis, intimal thickening of small arteries, and myocardial necrosis. Caspase-3, an apoptosis inducer, immunoreactivity was increased in interstitial cells, and the tissue RNA expression of transforming growth factor-ß(1) (TGF-ß(1)) was also increased in the L-NAME group. Low-dose valsartan treatment did not affect blood pressure or cardiac weight but alleviated the L-NAME-induced interstitial fibrosis with increased mRNA level of caspase-3 in interstitial fibroblasts. High-dose valsartan significantly lowered blood pressure and decreased the mRNA levels of caspase-3 and TGF-ß(1). These data suggest that low-dose valsartan inhibits interstitial fibrosis by promoting apoptosis of the fibroblasts without blood pressure changes, which may provide the TGF-ß(1) inhibition in the development of interstitial fibrosis in severe hypertension rat model.

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.

High-dose valsartan for prevention of in-stent restenosis

High-dose valsartan for prevention of in-stent restenosis

Which Strategy Is More Effective for the Treatment of Cardiovascular Disease

Angiotensin II type 1 (AT(1)) receptor antagonists (blockers) [ARBs] are highly selective for the AT(1) receptor and block the diverse effects of angiotensin II. When high BP is not controlled by low-dose ARB monotherapy, physicians need to employ another strategy, either high-dose ARB monotherapy or combination therapy with calcium channel antagonists (blockers) [CCBs], diuretics, or other agents. High-dose ARB monotherapy is more effective for decreasing proteinuria than low-dose ARB monotherapy or CCBs. Although the ARB valsartan has been shown to prevent coronary restenosis in a clinical study (Val-PREST [Valsartan for prevention of restenosis after stenting of type B2/C lesions]), it is still unclear whether ARBs help to prevent restenosis. The results reported by Peters in this issue highlight the relative efficacies of low- (80 mg/day) and high-dose valsartan (160-320 mg/day) for the prevention of in-stent restenosis after the implantation of bare-metal stents, and suggest that high-dose valsartan can reduce the in-stent restenosis rate, target lesion revascularization and target vessel revascularization rates, late lumen loss, and major adverse cardiac events rate more effectively than low-dose valsartan. A better understanding of the differences in the efficacies of high- and low-dose ARBs could be useful in the treatment of patients with cardiovascular disease and may resolve the issue of whether ARBs prevent coronary restenosis. Clinical benefits may be induced by complete blockade of the renin-angiotensin system using high-dose ARB monotherapy. Therefore, physicians need to select a strategy carefully; i.e. either high-dose ARB monotherapy or combination therapy.

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.

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.

Cardioprotective effect of angiotensin II type 1 receptor antagonist associated with bradykinin-endothelial nitric oxide synthase and oxidative stress in Dahl salt-sensitive hypertensive rats

The interactions between eNOS or oxidative stress and bradykinin under long-term treatment of angiotensin II type 1 receptor antagonists (ATRA) remain unknown. To elucidate the molecular mechanisms of the cardioprotective effect of ATRA, we evaluated whether valsartan affects the bradykinin-eNOS and nicotinamide adenine dinucleotide (NAD(P)H) oxidase pathway. After 5 weeks of feeding an 8% NaCl diet to 6-week-old Dahl salt-sensitive hypertensive (DS) rats, a distinct stage of concentric left ventricular hypertrophy (LVH) was noted. Six-week-old DS rats were treated with one of the following drug combinations for 5 weeks until the onset of LVH: vehicle; bradykinin B2 receptor antagonist FR172,357 alone; high-dose hydralazine; low-dose hydralazine; high-dose valsartan; low-dose valsartan; high and low-dose valsartan plus FR172,357. Age-matched Dahl salt-resistant rats fed the same diet served as controls. eNOS expression and activity, which was decreased in hypertrophy, was increased by high or low-dose valsartan, but not by high and low-dose valsartan plus FR172,357 or FR172,357 alone or high and low-dose hydralazine. The increased expression of NAD(P)H oxidase p22phox, p47phox, p67phox, and gp91phox in DS rats was suppressed by high or low-dose valsartan, but not by high or low-dose valsartan plus FR172,357 or FR172,357 alone or high and low-dose hydralazine. Valsartan effectively inhibited vascular lesion formation and suppressed the expression of transforming growth factor-beta1, connective tissue growth factor, and type I collagen, but not valsartan plus FR172,357 or FR172,357 alone or high and low-dose hydralazine. These findings suggest that valsartan may have cardioprotective effects in this model, partly associated with the bradykinin-eNOS and oxidative stress pathway.

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。