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PubMed2006

Valsartan inhibits platelet activity at different doses in mild to moderate hypertensives: Valsartan Inhibits Platelets (VIP) trial.

BACKGROUND: Previous in vitro studies have suggested that valsartan produces significant inhibition of human platelets, probably targeting angiotensin I platelet receptors. To test whether valsartan inhibits platelet activity in mild to moderate hypertensives we conducted the randomized Valsartan Inhibits Platelets (VIP) trial. METHODS AND RESULTS: Seventy-five patients with mild to moderate hypertension were randomized to valsartan 80 (n = 25), valsartan 160 (n = 29), or valsartan 320 mg/d (n = 21) for 9 weeks. Platelet function was assessed at baseline, week 5, and week 9 by aggregometry, flow cytometry, and cartridge-based analyzer. Independently of dose and duration, valsartan provided early sustained significant inhibition of adenosine diphosphate-induced platelet aggregation, decreased shear-induced activation measured with PFA-100 analyzer, and diminished expression of GP IIb/IIIa activity measured by PAC-1 antibody, GPIb (CD42b), vitronectin receptor (CD51/61), P-selectin (CD62p), lysosome-associated membrane protein (CD107a), and CD40-ligand (CD154). The antiplatelet properties of valsartan were more profound in patients with diabetes (n = 28) when compared with the nondiabetic group (n = 47). In subgroup analyses of patients with diabetes there appeared to be stronger inhibition of the platelet receptors, a significant decrease of adenosine diphosphate- and collagen-induced platelet aggregation, and more profound inhibition of GP IIb/IIIa activity. CONCLUSIONS: In the randomized VIP trial, valsartan produced sustained inhibition of platelet aggregation and major platelet receptors. The antiplatelet properties of valsartan were not dose or time dependent. In subgroup analyses patients with diabetes with mild to moderate hypertension tended to have greater platelet inhibition, a finding which, if confirmed in future studies suggests possible additional advantages for using valsartan in this high-risk population.

Aged↗

PubMed2004

Comparison of valsartan 160 mg with lisinopril 20 mg, given as monotherapy or in combination with a diuretic, for the treatment of hypertension: the Blood Pressure Reduction and Tolerability of Valsartan in Comparison with Lisinopril (PREVAIL) study.

BACKGROUND: The goal of antihypertensive therapy is to provide good blood pressure (BP) control without eliciting adverse effects. OBJECTIVE: This study compared the risk-benefit profile of the angiotensin II receptor blocker valsartan with that of the angiotensin-converting enzyme inhibitor lisinopril in patients with mild to severe hypertension. The primary objective was to show that the equipotent BP-lowering effect of the valsartan-based treatment is accompanied by a better tolerability profile. METHODS: This 16-week, randomized, double-blind, parallel-group study was conducted at 88 outpatient centers across Italy. After a 2-week placebo run-in period, patients aged > or = 18 years with mild to severe hypertension (systolic BP [SBP], 160-220 mm Hg; diastolic BP [DBP], 95-110 mm Hg) were eligible. Patients were randomized to receive once-daily, oral, self-administered treatment with valsartan 160-mg capsules or lisinopril 20-mg capsules under double-blind conditions for 4 weeks. Responders continued monotherapy, whereas nonresponders had hydrochlorothiazide 12.5 mg added for the final 12 weeks of the study. The 2 primary variables used to assess the equivalence of therapeutic efficacy of the 2 regimens were sitting SBP and sitting DBP, which were measured at weeks 0 (baseline), 4, 8, and 16. The rate of drug-related adverse events (AEs) was used to assess whether 1 treatment had a better tolerability profile than the other. Tolerability was assessed by collecting information about AEs by means of questioning the patient or physical examination at each visit. RESULTS: A total of 1213 patients were enrolled (635 men, 578 women; mean [SD] age, 54.5 [10.1] years [range, 28-78 years]). The study was completed by 1100 patients (553 receiving valsartan and 547 receiving lisinopril). Fifty-one patients (8.4%) treated with valsartan and 62 (10.2%) [corrected] treated with lisinopril withdrew, mainly because of AEs (9 [1.5%] and 23 patients [3.8%], respectively). The valsartan- and lisinopril-based treatments were similarly effective in reducing sitting BP, with mean SBP/DBP reductions of 31.2/15.9 mm Hg and 31.4/15.9 mm Hg, respectively. At the end of the study, BP was controlled in 82.6% [corrected] of the patients receiving valsartan and 81.6% of those receiving lisinopril. AEs were experienced by 5.1% of the patients treated with valsartan and 10.7% of those treated with lisinopril (P=.0001), with dry cough observed in 1.0% and 7.2% of patients, respectively (P<0.001). CONCLUSIONS: Valsartan and lisinopril were both highly effective in controlling BP in these patients with mild to severe hypertension, but valsartan was associated with a significantly reduced risk for AEs, especially cough.

Adult↗

PubMed2001

Combination of hydrochlorothiazide or benazepril with valsartan in hypertensive patients unresponsive to valsartan alone.

OBJECTIVE: The aim of this open multicentric study was to investigate the efficacy and safety of the addition of an angiotensin converting enzyme (ACE) inhibitor (benazepril, 10 mg/day) or a diuretic (hydrochlorothiazide, 12.5 mg/day) for 4 weeks in patients with mild to moderate essential hypertension having been treated for 4 weeks by an angiotensin II antagonist (valsartan, 80 mg/day) but still having a diastolic blood pressure (BP) > 90 mmHg on this medication given alone. METHODS: A total of 327 patients were included in the trial and 153 patients (46%) had their diastolic BP </= 90 mmHg after 4 weeks of valsartan monotherapy. These patients continued the same treatment regimen for the next 4 weeks, but no further blood pressure reduction was observed. The remaining patients were randomized to either the valsartan-hydrochlorothiazide or the valsartan-benazepril combination. RESULTS: The two combinations induced an additional significant BP reduction, which was of similar magnitude for diastolic BP (-4.5 during valsartan-hydrochlorothiazide treatment and -3.3 mmHg during valsartan-benazepril treatment), but of greater magnitude for systolic BP during valsartan-hydrochlorothiazide (-6.77 mmHg) than during valsartan-benazepril co-administration (-3.2 mmHg). At the end of the trial, the BP of the responders to the valsartan monotherapy was lower than that of patients having required a combination therapy. Valsartan given alone or in association with hydrochlorothiazide or benazepril was well tolerated. CONCLUSION: These data therefore show that in patients not responding sufficiently to angiotensin II receptor blockade BP can be further and safely lowered by adding a small dose of a diuretic or an ACE inhibitor, with the diuretic-containing combination tending to being more effective in controlling systolic BP.

Aged↗

PubMed2004

Effects of valsartan and valeryl 4-hydroxy valsartan on human platelets: a possible additional mechanism for clinical benefits.

Valsartan selectively blocks angiotensin II binding to the AT1 receptor. ince platelet activation plays a key role in the pathogenesis of vascular disease, and because AT1 receptors are present on the platelet surface, we assessed the in vitro effects of valsartan and its metabolite, valeryl 4-hydroxy valsartan (V4HV), on platelets in 30 subjects with multiple risk factors for cardiovascular disease. Platelet characteristics in blood samples pretreated and incubated with 10 nmol to 100 micromol concentrations of valsartan and V4HV were assessed by aggregometry, rapid platelet analyzers, and by flow cytometry. Pretreatment of blood with valsartan and V4HV resulted in inhibition of conventional plasma (ADP, P = 0.0001, valsartan; epinephrine, P = 0.0001, V4HV) and whole blood collagen-induced (P = 0.01, valsartan; P =.0001, V4HV) platelet aggregation. Closure time was delayed (P = 0.02, valsartan; P = 0.03, 4VHV), indicating platelet inhibition in whole blood under high shear conditions. Expression of many surface platelet receptors, namely GP IIb/IIIa antigen, and activity, vitronectin, p-selectin, and LAMP-1 was significantly reduced compared with autologous baseline activity. Intensity of platelet-leukocyte formation and other platelet activation markers remained unchanged. Platelet inhibition was not dose dependent and was more potent for 4VHV than valsartan in the therapeutic range.Valsartan and 4VHV exhibited significant in vitro inhibition of human platelets. Their antiplatelet properties, especially more potent activity of the metabolite appear to be independent of those of other antiplatelet agents. Whether valsartan reduces vascular ischemic events via additional pathways of platelet inhibition in patients with myocardial infarction and ischemic stroke requires further clinical research.

Adult↗

PubMed2002

Effects of valsartan on circulating brain natriuretic peptide and norepinephrine in symptomatic chronic heart failure: the Valsartan Heart Failure Trial (Val-HeFT).

BACKGROUND: Brain natriuretic peptide (BNP) and norepinephrine (NE) are strongly related to severity of and are independent predictors of outcome in heart failure. The long-term effects of angiotensin receptor blockers on BNP and NE in heart failure patients are not known. METHODS AND RESULTS: Both BNP and NE were measured in 4284 patients randomized to valsartan or placebo in the Valsartan Heart Failure Trial (Val-HeFT) at baseline and 4, 12, and 24 months after randomization. The effects of valsartan were tested by ANCOVA, controlling for baseline values and concomitant ACE inhibitors and/or beta-blockers. BNP and NE concentrations were similar at baseline in the 2 groups and were decreased by valsartan starting at 4 months and up to 24 months. BNP increased over time in the placebo group. At the end point, least-squares mean (+/-SEM) BNP increased from baseline by 23+/-5 pg/mL in the placebo group (n=1979) but decreased by 21+/-5 pg/mL (n=1940) in the valsartan group (P<0.0001). NE increased by 41+/-6 pg/mL (n=1979) and 12+/-6 pg/mL (n=1941) for placebo and valsartan, respectively (P=0.0003). Concomitant therapy with both ACE inhibitors and beta-blockers significantly reduced the effect of valsartan on BNP but not on NE (P for interaction=0.0223 and 0.2289, respectively). CONCLUSIONS: In Val-HeFT, the largest neurohormone study in patients with symptomatic chronic heart failure, BNP and NE rose over time in the placebo group. Valsartan caused sustained reduction in BNP and attenuated the increase in NE over the course of the study. These neurohormone effects of valsartan are consistent with the clinical benefits reported in Val-HeFT.

Adrenergic beta-Antagonists↗

PubMed2004

Multinational economic evaluation of valsartan in patients with chronic heart failure: results from the Valsartan Heart Failure Trial (Val-HeFT).

BACKGROUND: The Valsartan Heart Failure Trial (Val-HeFT) compared valsartan versus placebo in 5010 patients taking prescribed background therapy for New York Heart Association class II to IV heart failure. Valsartan reduced the risk of heart failure hospitalization and improved clinical signs and symptoms of heart failure. We sought to compare resource use, costs, and health outcomes among patients taking prescribed therapy for heart failure and randomly assigned to receive valsartan or placebo. METHODS: Measures of resource use were based on data collected during the trial. Unit cost estimates were collected from individual countries and converted to 1999 US dollars. Total costs were estimated for hospitalizations, inpatient and outpatient physician services, ambulance transportation, deaths outside the hospital, and outpatient cardiovascular medications. RESULTS: Mean follow-up was 23 months. Mean costs for heart failure hospitalizations were 423 dollars lower among patients receiving valsartan (95% CI, -706 to -146). Mean total costs were 9008 dollars for patients receiving valsartan and 8464 dollars for patients receiving placebo, a net incremental cost of 545 dollars (95% CI, -149 to 1148), including the cost of valsartan. There was an overall reduction in total costs of 929 dollars (95% CI, -3243 to 1533) among patients not receiving an ACE inhibitor at baseline but a slight increase in costs of 334 dollars (95% CI, -497 to 1199) among those receiving an ACE inhibitor without a beta-blocker and a 1246 dollars increase (95% CI, 54 to 2230) in patients receiving both an ACE inhibitor and a beta-blocker at baseline. CONCLUSIONS: Valsartan provided clinical benefits at a mean incremental cost of 285 dollars per year during the trial. In patients not taking ACE inhibitors, valsartan was economically attractive, increasing survival while reducing or marginally increasing overall costs.

Adrenergic beta-Antagonists↗

PubMed2005

Antihypertensive efficacy and tolerability of two fixed-dose combinations of valsartan and hydrochlorothiazide compared with valsartan monotherapy in patients with stage 2 or 3 systolic hypertension: an 8-week, randomized, double-blind, parallel-group trial.

BACKGROUND: Combination therapy with at least 2 antihypertensive agents is usually needed to achieve appropriate blood pressure (BP) control in patients with isolated or predominant systolic hypertension. A currently recommended combination is a diuretic added to an angiotensin-receptor blocker. OBJECTIVE: This was a study of the effects on sitting systolic BP (SBP)of 2 combinations of valsartan and hydrochlorothiazide (HCTZ) compared with valsartan monotherapy in patients with stage 2 or 3 systolic hypertension (SBP > or =160 mm Hg and < or =200 mm Hg) with or without other cardiovascular risk factors. METHODS: After a placebo run-in period, patients were randomized to receive double-blind treatment with either valsartan 80 mg OD(monotherapy group) or valsartan 160 mg OD (combination-therapy groups) for 4 weeks, followed by forced titration to valsartan 160 mg OD (V160), valsartan 160 mg plus HCTZ 12.5 mg OD (V160 +HCTZ12.5), or valsartan 160 mg plus HCTZ 25 mg OD (V160 +HCTZ25) for an additional 4 weeks. End points were the change in SBP between the groups receiving combination therapy and the monotherapy group, between-group changes in diastolic BP (DBP), responder rates (SBP <140 mm Hg or a reduction in SBP of > or =20 mm Hg), and tolerability. RESULTS: A total of 774 patients were randomized to treatment: 261 to V160, 258 to V160+HCTZ12.5, and 255 to V160 +HCTZ25. The intent-to-treat population consisted of 767 patients (411 men, 356 women; mean age, 60 years; mean weight, 84 kg; clinic mean [SD] baseline BP, 167.5 [8.1]/93.4 [9.1] mm Hg). All treatments produced significant reductions in SBP from baseline (mean [SD] reduction, 20.7 [15.7] mm Hg with V160, 27.9 [13.8] mm Hg with V160 +HCTZ12.5, and 28.3 [13.1] mm Hg with V160+HCTZ25; all, P < 0.05). DBP was reduced by 6.6 (8.9) mm Hg in the V160 group and by 10.2 (7.7) and 10.1 (7.8) mm Hg in the V160+HCTZ12.5 and V160 +HCTZ25 groups, respectively (all, P < 0.05). The additional reductions in BP with V160+HCTZ25 did not reach statistical significance compared with V160+HCTZ12.5. Responder rates were 56.9% in the V160 group, 74.4% in the V160+HCTZ12.5 group, and 75.0% in the V160 +HCTZ25 group P < 0.05, combination therapy vs monotherapy). Adverse events were reported by 27.5% of patients in the monotherapy group, compared with 28.6% and 34.0% in the groups that received V160+HCTZ12.5 and V160+HCTZ25, respectively; the differences were not significant between treatment groups. CONCLUSIONS: Monotherapy with V160 was effective in these patients with stage 2 or 3 systolic hypertension. Significant additional reductions in SBP and DBP and an increase in responder rates were achieved with the addition to V160 of HCTZ12.5 and HCTZ25, with no significant effect on tolerability.

Antihypertensive Agents↗

PubMed2006

Comparison between valsartan and valsartan plus cilnidipine in type II diabetics with normo- and microalbuminuria.

Cilnidipine, an L-/N-type calcium channel blocker, dilates the efferent glomerular arterioles in an experimental model and shows a renoprotective effect, but its clinical benefits and safety have not yet been assessed in type II diabetics with albuminuria. The objective of this trial was to evaluate the effect of reducing albuminuria in type II diabetic patients with a combination therapy consisting of valsartan plus cilnidipine versus monotherapy with valsartan. An open-label, randomized controlled trial was conducted from April 2002 to October 2003 in 87 Japanese patients aged 31-90 years with type II diabetes showing albuminuria (urinary albumin/creatinine ratio: 10-300 mg/g). The patients were randomized to receive either valsartan (n=41) or valsartan plus cilnidipine (n=46) once daily for 1 year. The primary end point was the percent change in the albumin/creatinine ratio. The secondary end points were the progression/regression of albuminuria, blood pressure (BP), renal function, and safety. After 1 year, the albumin/creatinine ratio was found to have decreased more markedly in the valsartan plus cilnidipine group than in the valsartan group (reduction rate -44+/-11% (s.e.) versus -9+/-7% (s.e.); P=0.014 by analysis of covariance). Although a significant reduction was observed in the systolic and diastolic BP of both groups from baseline to 1 year (P<0.0001, respectively), there was no significant difference in the change in the BP between the two groups (systolic BP, P=0.066; diastolic BP, P=0.391). There were also no significant differences in the side effects between the two groups. Cilnidipine was thus found to show an additive effect with valsartan and thereby caused a reduction in albuminuria in type II diabetics.

Aged↗

PubMed2003

Sustained reduction of aldosterone in response to the angiotensin receptor blocker valsartan in patients with chronic heart failure: results from the Valsartan Heart Failure Trial.

BACKGROUND: Aldosterone has been implicated in the progression of heart failure. The Valsartan Heart Failure Trial (Val-HeFT) provided the first opportunity to examine the long-term effects of an angiotensin receptor blocker on plasma aldosterone levels in patients with NYHA class II through IV heart failure. METHODS AND RESULTS: Plasma aldosterone was measured by radioimmunoassay in core laboratories at baseline and during follow-up in patients assigned to valsartan at a target dose of 160 mg twice daily or placebo. In the placebo group, aldosterone (baseline, 150+/-160 pg/mL, mean+/-SD; n=2025) increased at 4, 12, and 24 months. In the valsartan group, aldosterone (baseline, 137+/-124 pg/mL, mean+/-SD; n=2023) decreased at 4 months and remained suppressed for up to 2 years. At end point (last measurement in each patient), mean aldosterone increased by 17.8+/-3.0 pg/mL (SEM) (11.9%) in the placebo group and decreased by 23.8+/-3.0 pg/mL (SEM) (-17.4%) in the valsartan group (P<0.00001). The effect of valsartan was similar in all subgroups, including those receiving neither ACE inhibitors (ACE-I) nor beta-blockers (BB) at baseline and those receiving concomitant ACE-I or BB. In contrast, outcome effects varied in the 4 subgroups, with a statistically significant reduction in the combined mortality/morbidity end point in those receiving neither neurohormonal inhibitor and an adverse trend in those treated with both drugs. CONCLUSIONS: Valsartan added to background therapy for heart failure produces sustained reduction in plasma aldosterone, consistent with the observed significant reduction in the combined mortality/morbidity end point. A similar reduction in all subgroups based on ACE-I or BB therapy, despite differing clinical outcomes in these subgroups, suggests that aldosterone plasma levels may not be a critical marker of the progression of heart failure.

Aldosterone↗

PubMed2005

Effect of valsartan on quality of life when added to usual therapy for heart failure: results from the Valsartan Heart Failure Trial.

BACKGROUND: The effect on quality of life (QOL) of valsartan administered in addition to prescribed background heart failure therapy was assessed as a secondary endpoint in the Valsartan Heart Failure Trial (Val-HeFT). METHODS AND RESULTS: QOL was assessed in 3010 patients receiving either valsartan (160 mg twice daily) or placebo in addition to prescribed background therapy (beta-blockers or angiotensin-converting enzyme inhibitors), using the Minnesota Living with Heart Failure (MLWHF) questionnaire. Treatment differences were compared at intervals to 36 months after randomization and at endpoint (last observation) using analysis of covariance and repeated measures mixed-effects, and at endpoint using a Mantel-Haenszel chi-squared test. Scores lower than baseline were indicative of improved QOL. Valsartan had a significant beneficial effect on the least-square mean change in overall MLWHF score from baseline to study endpoint (+/- standard error) (average followup 23.0 months) compared with placebo (0.19 +/- 0.47 versus 1.94 +/- 0.48; P = .005 respectively). The placebo group was characterized by a deterioration in QOL as the trial progressed. More patients on valsartan reported a clinically meaningful improvement in MLWHF score (a decrease of > or =5 points) than on placebo (34.0% versus 30.2%). CONCLUSION: Valsartan compared to placebo added to prescribed therapy slows progressive worsening of QOL in patients with heart failure.

Adrenergic beta-Antagonists↗

PubMed1997

Pharmacological profile of valsartan, a non-peptide angiotensin II type 1 receptor antagonist. 1st communication: antihypertensive effects of valsartan in hypertensive models.

The antihypertensive effects of valsartan ((S)-N-valeryl-N-¿[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl¿ valine, CAS 137862-53-4, CGP 48933), an angiotensin II type 1 receptor antagonist, were examined in hypertensive rats and dogs. In normotensive rats and deoxycorticosterone acetate (DOCA)/salt hypertensive rats, valsartan had no effect on blood pressure. Single oral administrations of valsartan at doses of 3-30 mg/kg reduced blood pressure dose-dependently in renal (2 kidney 1 clip, 2K1C) hypertensive and spontaneously hypertensive rats (SHR). Repeated oral administrations of valsartan to these hypertensive rats controlled blood pressure throughout a treatment period of 4 weeks, and showed no rebound phenomenon following drug withdrawal. This drug at 30 mg/kg p.o. decreased blood pressure in renal (2K1C) hypertensive dogs by single and repeated administrations. The extent and duration of the hypotensive action of valsartan were similar to those of enalapril. Valsartan would thus appear as useful as enalapril.

Aldosterone↗

PubMed2005

Valsartan reduces the incidence of atrial fibrillation in patients with heart failure: results from the Valsartan Heart Failure Trial (Val-HeFT).

BACKGROUND: Atrial fibrillation (AF) in heart failure (HF) is generally considered a negative prognostic factor. Recent studies indicate that the incidence of AF might be decreased by renin angiotensin aldosterone system inhibitors. The identification of a treatment to prevent its occurrence is likely to improve patients outcome. The aims of these subanalyses of Val-HeFT were to assess (a) the effects of valsartan in the prevention of AF, (b) the independent predictors of this event, and (c) the prognostic role of AF occurrence. METHODS AND RESULTS: The occurrence of AF was evaluated based on adverse event reports in the patients with HF enrolled in Val-HeFT. Patients were randomized to valsartan or placebo on top of their prescribed treatments for HF. During the mean 23 months of follow-up, AF was reported in 287/4395 patients (6.53%) in sinus rhythm at baseline, of whom 113/2205 (5.12%) were allocated to valsartan and 174/2190 (7.95%) to placebo (P = .0002). Multivariable analysis showed that brain natriuretic peptide (BNP) levels at baseline above the median value (HR 2.28, 95% CI 1.75-2.98), age over 70 years (HR 1.51, 95% CI 1.17-1.95), male sex (HR 1.53, 95% CI 1.07-2.18), and the valsartan treatment (HR 0.63, 95% CI 0.49-0.81) were independently associated with AF occurrence. Cox multivariable regression analysis showed that occurrence of AF was independently associated with a worse prognosis, with the adjusted hazard risks for all-cause mortality and combined mortality/morbidity of 1.40 (95% CI 1.16-1.58) and 1.38 (95% CI 1.12-1.70), respectively. CONCLUSIONS: The results of the present study demonstrate that (a) adding valsartan to prescribed therapy for HF significantly reduces the incidence of AF by 37%; (b) BNP level and advanced age were the strongest independent predictors for AF occurrence; and (c) AF occurrence further worsens the outcome in patients with HF.

Aged↗

PubMed2006

Effect of valsartan, an angiotensin II receptor blocker, on markers of oxidation and glycation in Japanese type 2 diabetic subjects: blood pressure-independent effect of valsartan.

AIMS: Although it has been reported that angiotensin II receptor blocker inhibited the formation and accumulation of advanced glycation endproducts (AGEs) in vitro and in vivo, whether it can do so clinically is unknown. We therefore examined the effect of valsartan on markers of oxidation and glycation. METHODS: We started 40mg/day valsartan treatment in 15 type 2 diabetic subjects with hypertension, and metabolic parameters, lipid peroxide, paraoxonase activity, platelet-activating factor acethylhydrolase activity, AGEs and urine 8-isoprostane were measured at baseline and after 3 and 6 months of treatment. RESULTS: Even after valsartan treatment, the blood pressure level of the patients did not change during the study. However, AGEs and urine 8-isoprastane levels had decreased at 6 months (p<0.05 and <0.01) as well as urine microalbumin level (p<0.01), although other oxidative stress markers were unchanged. CONCLUSION: In this study, low-dose valsartan treatment decreased serum AGEs level, whereas blood pressure level was unchanged. The effect of valsartan on AGEs might be a blood pressure-independent effect in type 2 diabetic subjects.

Angiotensin Receptor Antagonists↗

PubMed2006

The effect of valsartan, captopril, or both on atherosclerotic events after acute myocardial infarction: an analysis of the Valsartan in Acute Myocardial Infarction Trial (VALIANT).

OBJECTIVES: We attempted to compare the effect of an angiotensin-converting enzyme (ACE) inhibitor and angiotensin receptor blocker (ARB) on atherosclerotic events. BACKGROUND: Angiotensin-converting enzyme inhibitors and ARBs interrupt the renin-angiotensin system by distinct mechanisms. It is not clear whether ARBs reduce atherosclerotic events such as myocardial infarction (MI) like ACE inhibitors. This evidence gap may reflect the nature of the studies conducted, to date. Placebo-controlled studies enrolled cohorts at low risk of atherosclerotic events (e.g., patients with chronic heart failure, most treated with an ACE inhibitor). One of the main active controlled trials was confounded by a blood pressure difference between treatments. METHODS: We compared the effects of captopril, valsartan, and their combination on atherosclerotic events in 14,703 patients randomized in the Valsartan in Acute Myocardial Infarction Trial (VALIANT). RESULTS: The number of individuals adjudicated as having a fatal or non-fatal MI in the captopril group was 559 (total investigator reported events 798), 587 (796) in the valsartan group, and 554 (756) in the combination group; valsartan versus captopril, p = 0.651 (0.965); combination versus captopril, p = 0.187 (0.350). Overall, all atherosclerotic events examined occurred at a similar frequency in the captopril and valsartan groups. CONCLUSIONS: Angiotensin receptor blockers appear to be as effective as ACE inhibitors in reducing atherosclerotic events, even when used in addition to other secondary preventive treatments. These data, although not conclusive, also support the hypothesis that adding an ARB to an ACE inhibitor may have a small additional anti-infarction effect, a possibility that needs to be prospectively tested.

Aged↗

PubMed2000

Safety of the combination of valsartan and benazepril in patients with chronic renal disease. European Group for the Investigation of Valsartan in Chronic Renal Disease.

OBJECTIVE: Several experimental and clinical studies indicate that the renin system may play a pivotal role in progressing renal disease. The combination of an angiotensin-converting enzyme inhibitor and an angiotensin receptor blocker could provide a higher degree of blockade of the renin-angiotensin system than either agent alone. Such enhanced suppression might be of benefit for patients exhibiting a progressive decline in renal function because of chronic renal disease. METHODS: A pilot multinational, multicentre, randomized, active-controlled, parallel group open-label study has been conducted in a group of patients with progressive chronic renal failure (creatinine clearance 20-45 ml/min) either with or without proteinuria and hypertension. The primary aim of the study was to investigate the safety and tolerability of the combination of valsartan and benazepril. Patients were randomly assigned to one of three groups: group 1 received valsartan 160 mg once daily (n = 22); group 2 received valsartan 80 mg once daily plus benazepril 5 or 10 mg once daily (n = 42); group 3 received valsartan 160 mg once daily plus benazepril 5 or 10 mg once daily (n = 44). The study lasted for 5 weeks, and in groups 2 and 3 benazepril was added on top of valsartan after the first week of therapy with the angiotensin receptor blocker. RESULTS: Serum creatinine increased in all three groups (mean change within a group: 11 micromol/l in group 1, P= 0.045; 9 micromol/l in group 2, P= 0.030; 15 micromol/l in group 3, P= 0.0006). Serum potassium also increased in all three groups of patients (mean change within a group: 0.28 mmol/l in group 1, P= 0.28; 0.48 mmol/l in group 2, P= 0.0008; 0.36 mmol/l in group 3, P= 0.02). After 5 weeks of treatment, the largest decrease in blood pressure was observed in group 3 (the mean change from baseline in seated diastolic blood pressure (SDBP) and seated systolic blood pressure (SSBP), respectively, were: -2.0 and -11.5 mmHg in group 1; -7.6 and -15.4 mmHg in group 2; -12.6 and -21.6 mmHg in group 3). In addition, both combination treatments resulted in the reduction of proteinuria. The total number of patients with adverse experiences were 10 (45.5%), 14 (33.3%) and 11 (25%) in groups 1,2 and 3, respectively. In six patients (5.6%) therapy was discontinued as a result of adverse experiences. Only one patient in each of the combined therapy groups withdrew from the study because of hyperkalaemia and no patients were forced to withdraw because of an increase in serum creatinine, acute renal failure or hospitalization. CONCLUSIONS: These results indicate that short-term combination of an angiotensin-converting enzyme inhibitor and an angiotensin receptor blocker is safe and well tolerated in patients with moderate chronic renal failure.

Aged↗

PubMed2006

Acute administration of a single dose of valsartan improves left ventricular functions: a pilot study to assess the role of tissue velocity echocardiography in patients with systemic arterial hypertension in the TVE-valsartan study I.

BACKGROUND: The advent of colour-coded tissue velocity echocardiography (TVE) has now made it possible to quantify left ventricular (LV) functions in patients with systemic arterial hypertension (HTN). Hypothesis In this project, we have studied the cardiac effects of a single dose of orally administered valsartan in patients with known HTN. METHODS: Fifty-five patients with HTN with a mean age of 56 +/- 10 years were given an early morning dose of 80 mg valsartan withholding regular antihypertensive medications on the day of investigation. TVE images, acquired on VIVID systems were digitized for postprocessing of longitudinal and radial peak systolic velocities, strain rate, and systolic and diastolic time intervals before (pre) and 5 h after (post) administration of the drug. RESULTS: Blood pressure (mmHg) pre and post, respectively, were 147 +/- 15 versus 137 +/- 14 systolic and 90 +/- 7 versus 86 +/- 7 diastolic (all P<0.01). LV longitudinal systolic velocities (cm s(-1)) were significantly higher post in LV septum (5.7 +/- 1.1 versus 6.4 +/- 1.6; P<0.001) with similar results obtained in other LV walls. Radial strain rate (1 s(-1)) was significantly higher post compared with pre valsartan (2.1 +/- 0.6 versus 2.3 +/- 0.9; P<0.01). Regional diastolic filling and ejection times (ms) were significantly shorter post (390 +/- 122 versus 370 +/- 120 and 275 +/- 32 versus 163 +/- 36 respectively; all P<0.05). CONCLUSIONS: Within 5 h after oral administration of valsartan, improvement in regional myocardial systolic functions could be registered. Although the changes could well be secondary to afterload reduction, additional effects of the drug, evidenced by improved strain rate that is relatively load-independent, may have contributed in this improvement.

Adult↗

PubMed1997

Pharmacological profile of valsartan, a non-peptide angiotensin II type 1 receptor antagonist. 2nd communication: valsartan prevents end-organ damage in spontaneously hypertensive stroke-prone rats during 1-year treatment.

Valsartan ((S)-N-valeryl-N-¿[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl¿ valine, CAS 137862-53-4, CGP 48933), a non-peptide angiotensin II type 1 receptor antagonist, or enalapril was administered to spontaneously hypertensive rats stroke-prone (SHR-SP) for 1 year from 8 weeks to 56 weeks of age under a normal diet without saline load. During 48 weeks, control rats showed increase in systolic blood pressure from 180 to 250 mmHg accompanying stroke-related behaviour, cardiac and aortic hypertrophy, hyperreactive contractility of mesenteric vascular beds, proteinuria, high water turnover and death. Valsartan at 3, 10 and 30 mg/kg/d p.o. and enalapril at 1 and 10 mg/kg/d p.o suppressed the increase in blood pressure dose-dependently. Systolic blood pressure was steadily controlled to around 180 mmHg at the highest dose of either drug throughout the study. In proportion to the antihypertensive action of the drugs, end-organ damage was prevented. During 1-year administration, effects of enalapril and valsartan were much the same, indicating the clinical usefulness of valsartan being comparable to enalapril.

Angiotensin Receptor Antagonists↗

PubMed1997

Pharmacological profile of valsartan, a non-peptide angiotensin II type 1 receptor antagonist. 5th communication: hemodynamic effects of valsartan in dog heart failure models.

Hemodynamic effects of valsartan ((S)-N-valeryl-N-¿[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]meth yl¿valine, CAS 137862-53-4, CGP 48933), a non-peptide angiotensin II type 1 receptor antagonist were examined in dogs with heart failure induced acutely by coronary artery ligation and chronically by rapid-ventricular pacing. Coronary artery ligation induced decrease in cardiac output and increase in left ventricular end-diastolic pressure. Valsartan at 10 mg/kg i.v. reduced blood pressure, heart rate, left ventricular pressure, left ventricular end-diastolic pressure and total systemic resistance. Similar changes were observed with enalaprilat at 0.1 mg/kg i.v. Rapid left ventricular pacing for 2 weeks reduced cardiac contractility. Valsartan, administered at a dose of 100 mg/kg/d p.o. for 2 weeks, lowered left ventricular end-diastolic pressure. Valsartan reduced preload and afterload in these two dog heart failure models.

Angiotensin Receptor Antagonists↗