Efficacy and duration of action of the four selective angiotensin II subtype 1 receptor blockers, losartan, candesartan, valsartan and telmisartan, in patients with essential hypertension determined by home blood pressure measurements

Our objective was to compare the efficacy and duration of action of 4 angiotensin II receptor blockers (ARBs)--losartan (25-100 mg), candesartan (2-12 mg), valsartan (40-80 mg), and telmisartan (10-40 mg)-in patients with essential hypertension using self-measurement of blood pressure at home (home BP) and to examine the differential effect of the four ARBs on home pulse pressure (home PP). After a 2-week run-in period, each of the 4 ARBs was assigned to subjects who were diagnosed as having hypertension on the basis of home BP and who were over 30 years old. The subjects were asked to take the ARB once daily in the morning and to measure home BP once in the evening and in the morning. We compared the efficacy of each ARB on home BP and home PP and assessed the duration of the BP-lowering effect using the morning effect versus evening effect ratio (M/E ratio). The antihypertensive effects of telmisartan on home systolic BP (SBP) both in the evening and in the morning and on home diastolic BP (DBP) in the morning were significantly greater than those of losartan. The effect of each ARB on home BP in the morning and in the evening was expressed as a ratio (M/E ratio). The M/E ratios of SBP/DBP in patients treated with losartan, candesartan, valsartan, and telmisartan were 0.49/0.16, 0.69/1.01, 0.82/0.88, and 0.88/0.88, respectively. The home PP-lowering effect was greater for valsartan and telmisartan than for losartan and candesartan in the morning. Among the 4 ARBs, the duration of the BP-lowering effect of losartan did not persist throughout 24 hr. The effects of the other 3 ARBs, in particular telmisartan, persisted over 24 hr when they were administered once daily in the morning. In addition, the duration of the PP-lowering effect was similar to that of the BP-lowering effect. Such long-acting property of several ARBs is essential for the modern antihypertensive treatment, and home BP measurements are useful for determining the duration of action of antihypertensive drugs. Losartan, 25 mg a day, which is usually used as an initial dose in Japan, is apparently insufficient to obtain adequate antihypertensive effect and sufficient duration of action.     

Efficacy and Duration of Action of the Four Selective Angiotensin II Subtype 1 Receptor Blockers,Losartan, Candesartan,Valsartan and Telmisartan,in Patients with Essential Hypertension Determined by Home Blood Pressure Measurements

Our objective was to compare the efficacy and duration of action of 4 angiotensin II receptor blockers (ARBs)—losartan (25–100 mg), candesartan (2–12 mg), valsartan (40–80 mg), and telmisartan (10–40 mg)—in patients with essential hypertension using self-measurement of blood pressure at home (home BP) and to examine the differential effect of the four ARBs on home pulse pressure (home PP). After a 2-week run-in period, each of the 4 ARBs was assigned to subjects who were diagnosed as having hypertension on the basis of home BP and who were over 30 years old. The subjects were asked to take the ARB once daily in the morning and to measure home BP once in the evening and in the morning. We compared the efficacy of each ARB on home BP and home PP and assessed the duration of the BP-lowering effect using the morning effect versus evening effect ratio (M/E ratio). The antihypertensive effects of telmisartan on home systolic BP (SBP) both in the evening and in the morning and on home diastolic BP (DBP) in the morning were significantly greater than those of losartan. The effect of each ARB on home BP in the morning and in the evening was expressed as a ratio (M/E ratio). The M/E ratios of SBP/DBP in patients treated with losartan, candesartan, valsartan, and telmisartan were 0.49/0.16, 0.69/1.01, 0.82/0.88, and 0.88/0.88, respectively. The home PP-lowering effect was greater for valsartan and telmisartan than for losartan and candesartan in the morning. Among the 4 ARBs, the duration of the BP-lowering effect of losartan did not persist throughout 24 hr. The effects of the other 3 ARBs, in particular telmisartan, persisted over 24 hr when they were administered once daily in the morning. In addition, the duration of the PP-lowering effect was similar to that of the BP-lowering effect. Such long-acting property of several ARBs is essential for the modern antihypertensive treatment, and home BP measurements are useful for determining the duration of action of antihypertensive drugs. Losartan, 25 mg a day, which is usually used as an initial dose in Japan, is apparently insufficient to obtain adequate antihypertensive effect and sufficient duration of action.     

Combination angiotensin-receptor blocker (ARB)/calcium channel blocker with HCTZ vs the maximal recommended dose of an ARB with HCTZ in patients with stage 2 hypertension: the exforge as compared to losartan treatment in stage 2 systolic hypertension (EXALT) study

This study compared the efficacy and safety of combination angiotensin-receptor blocker (ARB)/calcium-channel blocker (CCB) with hydrochlorothiazide (valsartan/amlodipine/HCTZ 160/5/2mg) vs maximal available combination doses of an ARB with HCTZ (losartan/HCTZ 100/25 mg) in the management of stage 2 hypertension. After 1 to 2 weeks of antihypertensive drug washout, patients with a mean sitting systolic blood pressure (MSSBP) of ≥ 160 mm Hg and <200 mm Hg were randomized to valsartan/amlodipine 160/5 mg (n = 241) or losartan 100 mg (n = 247). At week 3, HCTZ 25 mg was added to both treatments. The primary end point, reduction in MSSBP from baseline to week 6, was significantly greater in the valsartan/amlodipine group than in the losartan group (least-squares [LS] mean change, -31.8 mm Hg vs -26.4 mm Hg; P<.001). Additional reductions occurred after titrating to 320/10/25 mg at week 6 in the valsartan/amlodipine group and switching from losartan/HCTZ to valsartan/amlodipine/HCTZ (week 6, 160/5/25 mg; week 9, 320/10/25 mg) in the losartan group. Achievement of blood pressure <140/90 mm Hg also favored the valsartan/amlodipine group. Dizziness was the only adverse event reported in >5% of patients (5.4% valsartan/amlodipine group, 3.6% losartan group). Moderate doses of an ARB/CCB combination with HCTZ reduced blood pressure more effectively than the maximal dose of an ARB with HCTZ.     

A prospective, randomized, open-label trial comparing telmisartan 80 mg with valsartan 80 mg in patients with mild to moderate hypertension using ambulatory blood pressure monitoring

OBJECTIVE: To compare the antihypertensive efficacy and tolerability of telmisartan 80 mg with valsartan 80 mg throughout a 24 h dosing interval. DESIGN: A prospective, randomized, open-label, blinded end point, parallel group study. Treatment efficacy was compared using ambulatory blood pressure monitoring (ABPM), cuff sphygmomanometry and calculated responder rates. Tolerability was assessed by physical examination, laboratory parameters, 12-lead electrocardiogram, blood pressure and heart rate monitoring, and evaluation of adverse events. SETTING: Thirty-five centres in the United States. PATIENTS: Four hundred and twenty-six patients with mild to moderate essential hypertension entered the study. Ninety-two per cent (n=393) completed the study. INTERVENTIONS: Patients underwent a four-week, single-blind, placebo run-in period before being randomly assigned to once-daily oral telmisartan 80 mg (n=214) or valsartan 80 mg (n=212) for an eight-week, open-label treatment period. RESULTS: Treatment with telmisartan was associated with a significantly greater mean reduction from baseline in the last 6 h ABPM mean for diastolic blood pressure compared with the valsartan-treated group (-7.5+/-0.6 mmHg versus -5.2+/-0.6 mmHg, respectively, P<0.01). Secondary analyses showed significantly greater efficacy with telmisartan 80 mg than with valsartan 80 mg, including greater mean reductions from baseline of ABPM (systolic blood pressure and diastolic blood pressure) during the daytime (06:00 to 21:59) and morning (06:00 to11:59) hours, and larger decreases in trough cuff blood pressure (P<0.01). Both treatments showed placebo-like tolerability profiles. CONCLUSIONS: Telmisartan 80 mg once daily was superior to valsartan 80 mg once daily in reducing diastolic blood pressure during the last 6 h of the 24 h dosing interval. These results may be due to telmisartan's longer plasma half-life or to a higher potency compared with valsartan, such that a higher dose of valsartan may produce effects similar to those of 80 mg telmisartan. These data confirm the long duration of action of telmisartan with consistent and sustained control of blood pressure over 24 h and during the last 6 h of the dosing interval. Both treatments were well tolerated; the adverse event data confirmed the excellent tolerability profiles of telmisartan and valsartan that have been reported previously.     

Additivity of nebivolol/valsartan single‐pill combinations versus other single‐pill combinations for hypertension

The single‐pill combination (SPC) comprising nebivolol (5 mg), a vasodilatory β₁‐selective antagonist/β₃‐agonist, and valsartan (80 mg), a renin‐angiotensin‐aldosterone system inhibitor, is the only Food and Drug Administration–approved β‐blocker/renin‐angiotensin‐aldosterone system inhibitor SPC for hypertension. Additive effects of four nebivolol/valsartan SPC doses (5 mg/80 mg, 5/160 mg, 10/160 mg, 10/320 mg nebivolol/valsartan) were compared with five Food and Drug Administration–approved non–β‐blocker/renin‐angiotensin‐aldosterone system inhibitor SPCs (aliskiren/hydrochlorothiazide, aliskiren/amlodipine, valsartan/amlodipine, aliskiren/valsartan, and telmisartan/amlodipine). Additivity is the ratio of placebo‐adjusted SPC blood pressure (BP) reduction to the placebo‐adjusted monotherapy component BP reduction sums. A weighted average of comparator scores was calculated and compared vs nebivolol/valsartan. Additivity ratio scores for nebivolol/valsartan SPCs (diastolic BP range: 0.735–0.866; systolic BP range: 0.717–0.822) were similar to the comparator weighted average (diastolic BP: 0.837; systolic BP: 0.825). Among the nebivolol/valsartan SPCs, 5/80 mg had the greatest additivity (diastolic BP: 0.866; systolic BP: 0.822). BP reduction contributions with monotherapy were similar for nebivolol/valsartan 5/80 mg SPC. Additivity scores for nebivolol/valsartan and select non–β‐blocker/renin‐angiotensin‐aldosterone system inhibitor SPCs were comparable.     

The differential effects of angiotensin II type 1 receptor blockers on microalbuminuria in relation to low-grade inflammation in metabolic hypertensive patients

BACKGROUND: A dual angiotensin type 1 receptor blocker (ARB)/peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist telmisartan may be more useful for microalbuminuria reduction than ARBs with no PPARgamma agonistic action. We investigated whether there is a difference between the effects of telmisartan and valsartan with respect to microalbuminuria reduction, and the association with improvement of metabolic features or suppression of the inflammatory state. METHODS: Fifty-three patients who had metabolic syndrome and had been taking valsartan were recruited. All of these patients were randomly assigned to replace valsartan by telmisartan (telmisartan group; n = 30) or to keep taking valsartan (control group; n = 21). Various parameters were measured at baseline and 12 weeks after randomization. RESULTS: There were no significant changes in blood pressure (BP), glucose, and lipid parameters between baseline and 12 weeks after randomization in either group. There was a significant increase in high molecular weight adiponectin in the telmisartan group (4.6 v 5.0 microg/mL, P = .024), whereas there was no significant change in the control group. The reductions of microalbuminuria and high-sensitivity C-reactive protein (hs-CRP) were significant in the telmisartan group (28.1 v 18.9 mg/g.Cr and 0.77 v 0.60 mg/L, respectively, P = .001 and P = .022), whereas there was no significant change in the control group. The reductions of microalbuminuria and hs-CRP were significantly correlated with each other (gamma = 0.413, P = .003). CONCLUSIONS: The dual ARB/PPARgamma agonist telmisartan achieved more microalbuminuria reduction than an ARB with no PPARgamma agonistic action, possibly through suppression of the inflammatory state in metabolic hypertensive patients.     

Evaluation of angiotensin II receptor blockers for 24-hour blood pressure control: meta-analysis of a clinical database

Angiotensin II receptor blockers are well tolerated and improve compliance in hypertensive patients. The need for 24-hour blood pressure control has focused attention on whether all agents in this class maintain smooth antihypertensive effects over a 24-hour period. Insight into this issue emerged from a meta-analysis of five large, multicenter trials in which ambulatory blood pressure monitoring was used to compare the antihypertensive effects of three angiotensin II receptor blockers: telmisartan, losartan, and valsartan. These trials used either a double-blind, placebo-controlled or a prospective, randomized, open-label, blinded-end point design. Initial analysis established the validity of combining ambulatory blood pressure monitoring data from the double-blind, placebo-controlled and prospective, randomized, open-label, blinded-end point designs. Subsequent analyses revealed that telmisartan 80 mg was significantly more effective than losartan 50 mg and valsartan 80 mg for reducing 24-hour mean blood pressure. Furthermore, telmisartan 80 mg was comparable to amlodipine 5 mg for controlling the early morning surge in blood pressure.     

Effects of telmisartan 80 mg and valsartan 160 mg on ambulatory blood pressure in patients with essential hypertension

OBJECTIVES: This trial investigated and compared the antihypertensive efficacy of telmisartan and valsartan, two angiotensin II receptor blockers, used in monotherapy at their maximum recommended dose in hypertensive patients. METHODS: We studied 70 subjects (32 men and 38 women) aged 47.6 +/- 12.2 (mean +/- SD) years, with mild to moderate essential hypertension; they were randomly assigned to receive monotherapy with either telmisartan (80 mg) or valsartan (160 mg), in the form of a single daily tablet upon awakening. Blood pressure was measured by ambulatory monitoring every 20 min during the day and every 30 min at night for 48 consecutive hours before and after 3 months of treatment. Physical activity was simultaneously monitored every minute by wrist actigraphy to calculate accurately the diurnal and nocturnal means of blood pressure on a per subject basis. RESULTS: There was a highly significant blood pressure reduction during the 24 h with both drugs. The blood pressure reduction in the 24-h mean was significantly larger for valsartan 160 mg (18.6 and 12.1 mmHg for systolic and diastolic blood pressure, respectively) than for telmisartan 80 mg (10.8 and 8.4 mmHg; P < 0.001 between treatment-groups). There was also a highly significant reduction (P < 0.001) of 6.5 mmHg in the 24-h mean of pulse pressure after valsartan administration only. The trough : peak ratio and the smoothness index were slightly higher in systolic, but similar in diastolic blood pressure, for telmisartan as compared to valsartan. CONCLUSIONS: Despite a shorter half-life, 160 mg/day valsartan was more effective in lowering blood pressure over 24 h than 80 mg/day telmisartan. Furthermore, valsartan was also more effective in lowering arterial pulse pressure, an observation that may have important therapeutic implications, given the mounting evidence that pulse pressure may be a risk factor for future cardiovascular events.     

Efficacy of Low-Dose Hydrochlorothiazide in Combination with Telmisartan on Early Morning Blood Pressure in Uncontrolled Hypertensive Patients

Hypertensive patients whose BP was uncontrolled despite the use of antihypertensive agents, including an ARB (candesartan 8 mg/day or valsartan 80 mg/day), were enrolled. The patients were randomly assigned to combination therapy with telmisartan 40 mg/day (changed from current ARB) and hydrochlorothiazide (HCTZ) 12.5 mg/day (T?+?H, n?=?32) or to no change in their current drug regimen (CTL, n?=?32). The observation period was 12 weeks. The office and home BPs were significantly reduced in the T?+?H compared to those in the CTL. A sufficient and long-acting BP lowering effect, as reflected in decreased early morning BP, was obtained with the combination of low-dose HCTZ and telmisartan without apparent metabolic deterioration.     

Efficacy and safety of two single-pill fixed-dose combinations of angiotensin II receptor blockers/calcium channel blockers in hypertensive patients (EXAMINER study)

Background: There is some controversy regarding which single-pill fixed-dose combinations of angiotensin II type 1 receptor blockers (ARBs) and calcium channel blockers (CCBs) are effective at reducing blood pressure (BP). Methods: Sixty hypertensive patients who received a single-pill fixed-dose combination of valsartan 80?mg/day and amlodipine 5?mg/day were enrolled (UMIN Registration 000013460). They were randomly divided into two treatment groups [single-pill fixed-dose combination therapy with valsartan 80?mg/day and amlodipine 5?mg/day (Val/Am group), or irbesartan 100?mg/day and amlodipine 5?mg/day (Irb/Am group)] and treated for 16 weeks. If the patient did not reach the target office BP at 8 weeks, they received double doses of amlodipine (10?mg/day). Results: In the Irb/Am group, systolic BP (SBP) and diastolic BP (DBP) were significantly decreased at 16 weeks. There were no significant changes in SBP or DBP in the Val/Am group. In the Irb/Am group, serum uric acid (UA) was significantly decreased at 8 weeks and patients who had hyperuricemia showed significantly decreased serum UA at 16 weeks. In addition, the levels of triglycerides (TG) were significantly decreased at 16 weeks in the Irb/Am group. Conclusion: A single-pill fixed-dose combination therapy with irbesartan 100?mg/day and amlodipine 5?mg/day was superior to the combination of valsartan 80?mg/day and amlodipine 5?mg/day with respect to significant decreases in BP, serum UA and TG in patients with hypertension.     

Effects of the angiotensin II receptor blockers telmisartan versus valsartan on the circadian variation of blood pressure: impact on the early morning period

BACKGROUND: Ambulatory blood pressure (BP) monitoring has shown that BP typically declines by 10% to 20% during sleep and increases fairly rapidly in the early morning period. Because the early morning period has been associated with both loss of hypertension control and increased rates of myocardial infarction and stroke, there has been interest in evaluating the effects of antihypertensive therapy at this particular time of the day. The purpose of this study was to assess the effects of a long half-life (telmisartan, 24 h) versus intermediate half-life (valsartan, 6 to 9 h) on early morning BP in two scenarios: after an active dose and after a missed dose of each agent. METHODS: The study was a double-blind, randomized trial that compared telmisartan (40 to 80 mg once daily) versus valsartan (80 to 160 mg once daily) on early morning BP in 490 patients with hypertension. Ambulatory BP recordings were performed at baseline after a placebo period and again after 6 and 8 weeks of double-blind therapy in a randomized cross-over design. The monitoring patients received either an active dose or a placebo dose (to mimic a "missed" dose). The primary study end point was reduction in the BP in the early morning period (last 6 h of the dosing period). RESULTS: After the active dose, telmisartan reduced the BP during the last 6 h of the dosing period by -11/-7.6 +/- 0.8/0.6 mm Hg compared to -8.7/-5.8 +/- 0.8/0.6 mm Hg on valsartan (P = .02 for systolic BP and.01 for diastolic BP). On the day of the missed dose, telmisartan reduced the early morning BP by -9.0/-6.3 +/- 0.7/0.6 mm Hg versus -7.4/-5.1 +/- 0.7/0.4 mm Hg on valsartan (P = .09 for systolic BP and.06 for diastolic BP). On the day of the missed dose, reductions in 24-h average BP for the two antihypertensive agents were -10.3/-6.9 mm Hg for telmisartan versus -8.7/-5.9 mm Hg for valsartan (P = .06 for systolic BP and.056 for diastolic BP). CONCLUSIONS: On a day of active therapy, telmisartan lowered both systolic and diastolic BP to a greater extent than valsartan for the last 6 h of the dosing interval. On a day in which a dose was missed, there was a notable trend for greater BP reduction during the latter part of the dosing interval on telmisartan versus valsartan. These results demonstrate that telmisartan achieved a greater effect than valsartan on BP during the early morning period in patients with hypertension.     

Comparison of the effects of three angiotensin II receptor type 1 blockers on metabolic parameters in hypertensive patients with type 2 diabetes mellitus

ObjectiveIn a previous study involving 18 hypertensive patients with type 2 diabetes mellitus, we found that replacement of valsartan and candesartan by telmisartan significantly improved insulin sensitivity and significantly increased serum adiponectin levels in the patients. We investigated the effects of 3 angiotensin II type 1 receptor blockers (ARBs)—telmisartan, candesartan, and valsartan—on metabolic parameters in hypertensive patients with type 2 diabetes.MethodsA total of 308 hypertensive patients with diabetes were enrolled in our multicentre, randomized, open-label study. The patients received 40 mg telmisartan, 8 mg candesartan, or 80 mg valsartan for 3 months, and the data of 227 patients (telmisartan: n = 74, candesartan: n = 79, and valsartan: n = 74) were analysed.ResultsThe systolic and diastolic blood pressures significantly decreased in all the groups at the end of the study; the decrease was comparable among the 3 groups. The changes in fasting plasma glucose, fasting insulin, glycated haemoglobin (HbA1c), total cholesterol, triglyceride, high-density lipoprotein (HDL) cholesterol, adiponectin, free fatty acids, high-sensitivity C-reactive protein (hs-CRP), and plasminogen activator inhibitor-1 (PAI-1) were comparable between the 3 groups. Telmisartan and candesartan administration tended to lower urinary albumin excretion.ConclusionsLow dose telmisartan had a neutral effect on metabolic dysfunction in hypertensive patients with type 2 diabetes; the effect produced by 40 mg telmisartan was comparable with that of 8 mg candesartan and 80 mg valsartan. Failure to detect metabolic differences among the various ARB treatments could have been due to the low statistical power of the study design.     

Effectiveness of using long-acting angiotensin II type 1 receptor blocker in Japanese obese patients with metabolic syndrome on morning hypertension monitoring by using telemedicine system (FUJIYAMA Study)

Aim: Recently, obesity patients have been diagnosed as metabolic syndrome. The aim of this study was to evaluate which angiotensin type 1 receptor blockers (ARBs), telmisartan or candesartan, is superior for the control of home blood pressure (BP) in the morning when the outpatient clinic BP was well controlled in the patients with metabolic syndrome.

Methods: The patients with metabolic syndrome were enrolled. Home BP was monitored by using a telemedicine system. After a 2- to 4-week control period to establish baseline home BP values, these patients were randomly divided into telmisartan (20–80?mg) and candesartan (4–12?mg) groups. These end points were evaluated by using the telemedicine system during steady-state active therapy. A total of 356 patients attending 60 outpatient Japanese centers were recruited.

Results: On a day of active therapy, telmisartan significantly lowered both systolic and diastolic home BP in the morning to a greater extent compared to candesartan. At the end of the study, reductions in systolic and diastolic home BP in the morning, in telmisartan group were significantly larger compared to the changes in the candesartan group (systolic; Tel: 12.0?±?8.9 versus Can: 8.1?±?17.1?mmHg, p?=?0.0292, diastolic; Tel: 7.4?±?6.1 versus Can: 3.7?±?6.8?mmHg, p?=?0.0053). Additionally in the telmisartan treated group, LDL-cholesterol showed significant reduction (p?=?0.037), but candesartan did not.

Conclusion: The present study by using the telemedicine system clearly demonstrated that telmisartan has a strong effect on reducing morning home BP, and a good effect on lipid metabolism in patients with metabolic syndrome.     

Results of increasing doses of hydrochlorothiazide in combination with an angiotensin receptor blocker in patients with uncontrolled hypertension

This study examined the effects of increasing the thiazide diuretic dose in a fixed-dose ARB/diuretic combination in patients with uncontrolled hypertension despite 6 weeks' open-label treatment with the ARB/diuretic combination, telmisartan 80 mg/hydrochlorothiazide 12.5 mg (T80/H12.5). 713 patients with trough seated DBP =90 mmHg were then randomized to 8 weeks' double-blind treatment with telmisartan 80 mg and an increased dose of 25 mg of hydrochlorothiazide (T80/H25) or T80/H12.5. Adjusted mean seated DBP changes from baselines of 95.3 (T80/H25) and 95.0 mmHg (T80/H12.5) were -7.1 and --5.5 mmHg (difference: 1.6 mm Hg), respectively (P=.0012). Changes in systolic blood pressure from 147.9 mmHg (T80/H25) and 147.4 mmHg (T80/H12.5) were -9.8 and -7.1 mmHg (difference: 2.7 mm Hg) (P=.0003). Adverse events occurred in 31.5% (T80/H25) and 29.6% (T80/H12.5), with serious events in 1.4% and 0.8%, respectively. Hypokalemia was rare. These results show that higher-dose thiazide diuretic in combination with T80 in patients with hypertension uncontrolled by T80/H12.5 provides additional blood pressure reductions and is well tolerated.     

Combined treatment with an AT1 receptor blocker and angiotensin converting enzyme inhibitor has an additive effect on inhibiting neointima formation via improvement of nitric oxide production and suppression of oxidative stress.

Accumulating evidence shows that inhibition of the vascular renin-angiotensin system results in suppression of injury-elicited neointima formation. We attempted to determine whether or not combined treatment with an angiotensin II type 1 receptor blocker (ARB) and angiotensin converting enzyme inhibitor (ACEI) has an additive inhibitory effect on balloon-injury-elicited neointima formation in the carotid artery. Male Sprague-Dawley rats were treated with an ARB (valsartan: 3 mg/kg/day) and/or an ACEI (benazepril: 0.3 mg/kg/day) from 1 week before until 2 weeks after balloon injury. Experiments were also conducted with one-third of the dose combination used in the original experiments. Both ARB and ACEI inhibited neointima formation without any blood pressure changes. The full-dose combination lowered blood pressure and suppressed neointima formation significantly compared with the levels in the groups treated with either ACEI or ARB alone. The low-dose combination without blood pressure reduction also inhibited neointima formation to a similar extent as the full-dose combination. We measured 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha), a marker of oxidative stress, and nitrite and nitrate (NOx), an index of nitric monoxide production, in media conditioned by the injured artery. NOx production was lower and 8-iso-PGF2alpha was higher in the media of the injured artery, compared with those in the normal artery. ACEI restored NOx production more dramatically than ARB, and ARB suppressed 8-iso-PGF2alpha markedly compared with ACEI. These results suggest that the combination of an ARB and an ACEI exerts an additive inhibitory effect, presumably through an increase in production and bioavailability of NO from the endothelium.     

Comparison of the efficacy of morning versus evening administration of telmisartan in essential hypertension

Valsartan administration at bedtime as opposed to on wakening improves the sleep time-relative blood pressure decline toward a more dipper pattern without loss in 24-hour efficacy. Yet to be determined is whether this administration time-dependent efficacy is a class-related feature, characteristic of all angiotensin receptor blockers or specific only to valsartan. Terminal half-life is a major difference between angiotensin receptor blockers, being largest ( approximately 24 hours) for telmisartan. This trial investigated the administration time-dependent antihypertensive efficacy of telmisartan. We studied 215 patients with hypertension (114 men and 101 women), 46.4+/-12.0 years of age, randomly assigned to receive telmisartan (80 mg/d) as a monotherapy either on awakening or at bedtime. Blood pressure was measured for 48 hours before and after 12 weeks of treatment. The significant blood pressure reduction after treatment was similar for both groups. Bedtime administration of telmisartan, however, was more efficient than morning dosing in reducing the nocturnal blood pressure mean. The sleep time-relative blood pressure decline was slightly reduced after telmisartan on awakening but significantly increased with bedtime dosing, thus reducing the prevalence of nondipping from baseline by 76%. Telmisartan administered at bedtime, as opposed to morning dosing, improved the sleep time-relative blood pressure decline toward a more dipper pattern without loss in 24-hour efficacy. Nocturnal BP regulation is significantly better achieved with bedtime dosing of telmisartan. Results from this prospective trial suggest that these beneficial features of bedtime dosing may be class related for angiotensin receptor blockers. These results should be taken into account when prescribing this class of antihypertensive medication for treatment of essential hypertension.     

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

OBJECTIVE: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.     

Beneficial effect of lisinopril plus telmisartan in patients with type 2 diabetes, microalbuminuria and hypertension

Angiotensin-converting enzyme (ACE) inhibitors have favourable effects on hypertension and diabetic nephropathy, but persistent use may result in incomplete blockade of the renin-angiotensin system. Long-term effects of dual blockade using the ACE inhibitor lisinopril and the long-acting angiotensin II receptor blocker (ARB) telmisartan on blood pressure and albumin excretion rate (AER) were evaluated. Patients with type 2 diabetes mellitus, hypertension (systolic blood pressure [SBP] >or=140 mmHg or diastolic blood pressure [DBP] >or=90 mmHg) and microalbuminuria (AER 30-300 mg/24h) received 20mg of lisinopril or 80 mg of telmisartan once a day for 24 weeks. Patients were then randomised to continuing treatment with the respective monotherapy or with lisinopril plus telmisartan for a further 28 weeks. Significant (P<0.001) declines in SBP (11.1 mmHg versus 10.0 mmHg), DBP (5.6 mmHg versus 5.3 mmHg) and AER (98 mg/24 h versus 80 mg/24 h) were achieved with lisinopril (n=95) or telmisartan (n=97), respectively, after 24 weeks. Subsequent treatment with lisinopril plus telmisartan for 28 weeks resulted in further significant reductions (P<0.001) in SBP, DBP and AER compared with either monotherapy. All treatments were well tolerated. Lisinopril plus telmisartan thus provides superior blood pressure and AER control than either monotherapy. We conclude that use of dual blockade may provide a new approach to prevention of diabetic nephropathy in patients with type 2 diabetes, hypertension and microalbuminuria.     

Efficacy and tolerability of a single-pill combination of amlodipine/valsartan in Asian hypertensive patients not adequately controlled with valsartan monotherapy

This randomized, double-blind study evaluated efficacy of a single-pill combination of amlodipine/valsartan (Aml/Val) in Asian patients with hypertension not responding to Val 80 mg. Patients with mean sitting diastolic blood pressure (DBP) ≥90-≤110 mmHg were randomized to Aml/Val 5/80, Val 80, or Val 160 mg for 8 weeks. At week-8 endpoint, significantly greater reductions in BP were seen with Aml/Val 5/80 mg than valsartan monotherapies (p < 0.0001). The BP control was greater with Aml/Val 5/80 (70.5%) than Val (44.1-58.6%) monotherapies. The combination was well tolerated. In conclusion, single-pill combination with Aml/Val provided significant additional BP reduction and control in hypertensive patients not responding to Val 80 mg.     

Reduction of proteinuria with angiotensin receptor blockers

Renal pathophysiology is elicited by activation of angiotensin II type 1 (AT(1)) receptors at all stages of renovascular disease. Angiotensin receptor blockers (ARBs) that specifically block the AT(1) receptor offer the potential to prevent or delay progression to end-stage renal disease independently of reductions in blood pressure. Proteinuria--an early and sensitive marker for progressive renal dysfunction--is reduced by ARB use in patients with type 2 diabetic nephropathy and microalbuminuria or macroalbuminuria. Retrospective analysis of data available from early trials has confirmed this finding and has shown that albuminuria reduction is associated with lessening of cardiovascular risk. The ARB telmisartan is equivalent to enalapril in preventing glomerular filtration rate decline, and equivalent to valsartan in reducing proteinuria. Telmisartan is more effective than conventional therapy in lowering the risk of transition to overt nephropathy in hypertensive and normotensive patients. An additive effect has been seen in smaller studies when telmisartan has been added to lisinopril therapy, and high-dose telmisartan reduces albuminuria better than low-dose telmisartan. Similar data were obtained with other ARBs such as candesartan, losartan, valsartan, or irbesartan. These data support the proposition that blockade of the renin-angiotensin system beyond that required for maximum blood pressure reduction provides optimum renal protection.