Losartan versus valsartan in the treatment of patients with mild to moderate essential hypertension: data from a multicenter, randomized, double-blind, 12-week trial

BACKGROUND: Losartan, the first of the angiotensin II receptor blockers (ARBs) to be introduced, has been studied extensively in comparison with other classes of antihypertensive agents. Less research has been conducted on the efficacy and tolerability of losartan compared with that of other ARBs. OBJECTIVE: This randomized, multicenter, double-blind, parallel-group equivalence study was conducted to compare the antihypertensive efficacy and tolerability of a once-daily regimen of losartan with that of valsartan. METHODS: Patients > or = 21 years of age with mild to moderate hypertension, defined as a trough sitting diastolic blood pressure (SiDBP) between 95 and 115 mm Hg, were randomized to receive once-daily losartan (50 mg) or valsartan (80 mg) for 12 weeks. At the end of the sixth treatment week, patients in both groups with trough SiDBP > or = 90 mm Hg had their dose doubled for the remainder of the treatment period. Analysis of variance was used to compare treatment groups with respect to change in mean trough SiDBP from baseline to week 12. Within-treatment changes were analyzed using the paired t test. With at least 220 patients per treatment group, the study had 90% power to place a 90% CI on the difference between losartan and valsartan in SiDBP within the equivalence interval of +/- 2.5 mm Hg. RESULTS: A total of 495 patients were randomized, 247 to the losartan group and 248 to the valsartan group: 456 patients completed the study. Adjusted mean change from baseline values for trough SiDBP atthe end of 12 weeks of treatment were significantly different (P < 0.001) from zero in both the losartan group (-9.9 mm Hg) and the valsartan group (-10.1 mm Hg). At week 12, losartan was as effective as valsartan in lowering SiDBP, with a between-group difference of 0.2 mm Hg (90% CI, -1.3 to 1.7; P = 0.827). At week 6, the difference in SiDBP between groups was -1.3 mm Hg (90% CI, -2.7 to 0.0; P = 0.106). A similar pattern of results was obtained at weeks 6 and 12 for sitting systolic blood pressure. The percentage of patients reaching the SiDBP goal at week 6 (46% [112/2411 losartan; 42% [103/245] valsartan) and week 12 (57% [139/243] losartan; 59% [145/245] valsartan) was not significantly different between the treatment groups. Both losartan and valsartan were similarly well tolerated. Over the 12 weeks, the laboratory profiles of the 2 drugs were similar except for serum uric acid levels, which decreased from 6.0 to 5.7 mg/dL in the losartan group and increased from 5.9 to 6.0 mg/dL in the valsartan group (P = 0.001 for between-treatment difference). CONCLUSIONS: At starting and titrated doses, losartan and valsartan are similarly effective in reducing blood pressure in patients with mild to moderate hypertension. Losartan, but not valsartan, was associated with a decrease in serum uric acid levels.     

Effects of losartan and candesartan monotherapy and losartan/hydrochlorothiazide combination therapy in patients with mild to moderate hypertension. Losartan Trial Investigators

OBJECTIVE: The goal of this multicenter, double-blind, randomized, parallel-group study was to compare the effects of losartan potassium (hereafter referred to as losartan), candesartan cilexitil (hereafter referred to as candesartan), and losartan/hydrochlorothiazide (HCTZ) in patients with mild to moderate hypertension (sitting diastolic blood pressure [SiDBP] 95-115 mm Hg). METHODS: A total of 1161 patients were randomized in a 2:2:1 ratio to 12 weeks of treatment with losartan 50 mg QD, possibly titrated to 100 mg QD (n = 461); candesartan 8 mg QD, possibly titrated to 16 mg QD (n = 468); or losartan 50 mg QD, possibly titrated to losartan 50 mg plus HCTZ 12.5 mg QD (n = 232). At 6 weeks, the regimens of patients not reaching a goal SiDBP <90 mm Hg were titrated as described, whereas patients achieving this goal continued with low-dose monotherapy. The single primary end point at 12 weeks tested the equivalence of the 2 monotherapy regimens, predefined as a maximum between-treatment difference in the mean change from baseline trough SiDBP of 2.5 mm Hg. RESULTS: At 12 weeks, changes in SiDBP/sitting systolic blood pressure (SiSBP) of -12.4/-14.4 mm Hg with losartan 50 mg/100 mg and -13.1/-15.8 mm Hg with candesartan 8 mg/16 mg demonstrated equivalence between the 2 monotherapy regimens (95% CI for difference in SiDBP, -1.6 to 0.2). At 12 weeks, the losartan 50 mg/50 mg plus HCTZ 12.5 mg regimen had reduced SiDBP/SiSBP significantly more (-14.3/-18.0 mm Hg) than either the candesartan 8 mg/16 mg (SiDBP, P = 0.045; SiSBP, P = 0.017) or losartan 50 mg/100 mg regimen (SiDBP and SiSBP, P = 0.001). During the last 6 weeks, patients whose regimen had been titrated to losartan 50 mg plus HCTZ 12.5 mg (n = 114) showed a greater reduction in SiDBP/SiSBP (-14.5/ -18.7 mm Hg) than did those whose regimen had been titrated to either losartan 100 mg (-10.5/-12.3 mm Hg; n = 211) or candesartan 16 mg (-11.5/-13.2 mm Hg; n = 206), representing a clinically meaningful > or = 2.5-mm Hg) difference. All 3 treatments were well tolerated, with few patients experiencing drug-related adverse events (6.9% losartan 50 mg/100 mg, 7.5% candesartan 8 mg/16 mg, 3.0% losartan 50 mg/ 50 mg plus HCTZ 12.5 mg). Candesartan 8 mg/16 mg increased serum uric acid levels (0.13 mg/dL; 95% CI, 0.04 to 0.23), whereas losartan 50 mg/100 mg decreased them (-0.14 mg/dL; 95% CI, -0.24 to -0.04), and losartan 50 mg/50 mg plus HCTZ 12.5 mg left them unchanged (0.06 mg/dL; 95% CI, -0.07 to 0.20). CONCLUSIONS: Losartan 50 mg/100 mg and candesartan 8 mg/16 mg were comparable treatments in terms of blood pressure reduction. After titration, losartan 50 mg plus HCTZ 12.5 mg was superior to either candesartan 16 mg or losartan 100 mg in reducing hypertension. Losartan, but not candesartan, lowered serum uric acid levels and attenuated the expected increase in uric acid levels with HCTZ 12.5 mg.     

Antihypertensive efficacy and safety of losartan alone and in combination with hydrochlorothiazide in adult African Americans with mild to moderate hypertension

BACKGROUND: African Americans with hypertension, particularly those with more severe blood pressure elevations, are generally less responsive to monotherapy from any antihypertensive class. These patients usually require treatment with drugs from > or = 2 antihypertensive classes to achieve adequate blood pressure control. OBJECTIVE: The purpose of this study was to assess the antihypertensive efficacy and safety of losartan alone and in combination with hydrochlorothiazide (HCTZ) in African American adults with mild to moderate hypertension. METHODS: In this 12-week, multicenter, double-blind, randomized, parallel-group, placebo-controlled study, African American patients were randomized in a 3:3:1 ratio to I of 3 treatment groups: placebo, losartan monotherapy (50 to 150 mg), or losartan plus HCTZ (50/0 to 50/12.5 to 100/25 mg). Doses were titrated at weeks 4 and 8 if sitting diastolic blood pressure (SiDBP) was > or = 90 mm Hg. Safety was assessed by determining the incidence of clinical and laboratory Adverse events and evaluating mean changes in pulse, body weight, electrocardiographic parameters, and laboratory test results. RESULTS: A total of 440 patients were randomized-188 to placebo, 193 to losartan monotherapy, and 59 to losartan/HCTZ; 391 completed the study. At week 12, the response rate with losartan monotherapy was 45.8%, with a significant (P < or = 0.01) lowering in mean SiDBP by 6.6 mm Hg compared with placebo; the response rate with placebo was 27.2%, with a mean SiDBP reduction of 3.9 mm Hg. Sitting systolic blood pressure (SiSBP) was significantly lowered with losartan monotherapy, by 6.4 mm Hg, compared with placebo (reduction of 2.3 mm Hg). The response rate with losartan/ HCTZ was 62.7%, with reductions in SiSBP and SiDBP of 16.8 mm Hg and 10.8 mm Hg, respectively (P < or = 0.01 vs placebo and losartan monotherapy). The incidence of clinical adverse events was comparable in the 3 treatment groups. CONCLUSIONS: The results of this study suggest that in African American patients, losartan monotherapy was significantly more effective than placebo in lowering SiSBP and SiDBP. Moreover, the losartan/ HCTZ combination regimen resulted in significant and clinically meaningful additional reductions in SiSBP and SiDBP compared with losartan monotherapy or placebo. Losartan monotherapy and the losartan/HCTZ regimens were generally as well tolerated as placebo.     

Comparison of the effects of losartan and atenolol on common carotid artery intima-media thickness in patients with hypertension: results of a 2-year,double-blind,randomized, controlled study

BACKGROUND: Hypertension induces progressive pathologic changes in the arterial wall. Experimental findings suggest that these changes, which include intima-media thickening, may be mediated, at least in part, by angiotensin II (AII). OBJECTIVE: The Losartan Vascular Regression Study (LAARS) was a double-blind, parallel-group, randomized, controlled, multicenter study designed to compare the effects of the AII antagonist losartan and the beta-blocker atenolol on ultrasonographically determined intimamedia thickness (IMT) of the common carotid artery (CCA) in patients with mild to moderate essential hypertension. METHODS: The primary end point of the study was the yearly rate of change (YRC) from baseline of the mean IMT of the CCA (CCA-IMT(mean)) averaged over 2 years of treatment. Secondary end points included IMT of the common femoral artery and sitting systolic and diastolic blood pressures (SiSBP/SiDBP). Safety assessments of losartan and atenolol were made by statistical and clinical review of the incidence of adverse experiences as well as review of vital signs and laboratory values. A total of 414 patients with essential hypertension were screened for study inclusion at 36 study centers in Germany and Brazil. Patients received losartan (50 mg once daily) or atenolol (50 mg once daily) for 24 months. Target blood pressure (SiSBP/SiDBP <140/<90 mm Hg) was achieved by adding hydrochlorothiazide 12.5 mg once daily, doubling the dose of study drug, or adding an open-label calcium channel blocker sequentially, as needed. RESULTS: Of the original 414 patients screened, 280 hypertension patients (SiDBP 95-115 mm Hg), aged 35 to 65 years, with an IMT of 0.8 to 1.5 mm of the right or left CCA, were randomized to treatment with either losartan (n = 142) or atenolol (n = 138). Both losartan and atenolol therapy produced comparable reductions in CCA-IMTmean over 24 months compared with baseline; the average YRC was -0.038 +/- 0.004 mm/y (P < or = 0.001) for losartan and -0.037 +/- 0.004 mm/y (P < or = 0.001) for atenolol. There were no significant differences between groups. Losartan showed a greater reduction of femoral artery IMT than did atenolol; the average YRC was -0.024 mm/y (P < or = 0.05) for losartan and -0.017 mm/y for atenolol (P = NS), with no significant difference between groups. Both agents produced similar significant reductions in SiSBP and SiDBP and were generally well tolerated. Approximately 7% of losartan patients had drug-related clinical adverse events, compared with 12% of atenolol patients. Conclusions: The findings of LAARS, the first large study with an AII antagonist that examined IMT, suggest that AII antagonism reverses the early stages of vascular hypertrophy in patients with hypertension. Further studies are needed to delineate the relative importance of AII antagonism versus blood pressure reduction per se in mediating the beneficial vascular effects of losartan.     

Comparison of the blood pressure-lowering effects and tolerability of Losartan- and Amlodipine-based regimens in patients with isolated systolic hypertension

BACKGROUND: Elevated systolic blood pressure is a more important risk factor for cardiovascular and renal disease than elevated diastolic blood pressure. Isolated systolic hypertension (ISH) is the predominant form of hypertension in the elderly. Effects of angiotensin II on the vascular wall and endothelium may contribute to development of ISH. OBJECTIVE: The primary objective of this study was to compare the effects on trough sitting systolic blood pressure (SiSBP) of a regimen of losartan, a selective angiotensin II-receptor antagonist, and an amlodipine-based regimen in patients with ISH. METHODS: This multicenter, prospective, randomized, double-blind, parallel-group study consisted of a 4-week placebo phase and an 18-week active-treatment phase. The losartan-based regimen consisted of losartan 50 mg, increased as needed to losartan 50 mg/hydrochlorothiazide (HCTZ) 12.5 mg at week 6 and to losartan 100 mg/HCTZ 25 mg at week 12 to achieve a target SiSBP <140 mm Hg. the amlodipine-based regimen consisted of amlodipine 5 mg, increased as needed to amlodipine 10 mg at week 6 and to amlodipine 10 mg/HCTZ 25 mg at week 12. The primary efficacy measure was change in trough SiSBP from baseline to week 18. Information on the tolerability of study treatments was collected at each visit, including the investigator's and patient's observations of clinical adverse experiences (CAEs), laboratory adverse experiences, and responses to a symptom questionnaire. RESULTS: Eight hundred fifty-seven patients (65.6% female) were randomized to treatment, 432 in the losartan group and 425 in the amlodipine group. Their mean age was 67.6 years, and they had a mean duration of hypertension of 6.7 years at baseline. The losartan and amlodipine groups (intent-to-treat population) had baseline mean SiSBP values of 171.2 and 171.9 mm Hg, respectively. At week 18 (the primary end point), the mean change from baseline in SiSBP was -27.4 mm Hg for 426 patients who received losartan and -28.1 mm Hg for 419 patients who received amlodipine (estimated least-square mean difference, 0.3 mm Hg; 95% CI, -1.4 to 2.0), indicating that losartan's effect on systolic blood pressure was noninferior to that of amlodipine. The proportion of patients who responded (SiSBP <140 mm Hg or a > or =20-mm Hg decrease in SiSBP from baseline) was comparable between groups (73.9% losartan, 75.4% amlodipine). The incidence of CAEs and drug-related CAEs was significantly greater in the amlodipine group (amlodipine, 79.8% and 43.8%, respectively; losartan, 67.8% and 25.5%; P < or = 0.001). In addition, more patients in the amlodipine group discontinued therapy due to a drug-related CAE compared with patients in the losartan group (12.9% vs 4.4%, respectively; P < or = 0.001). Lower-extremity edema was the most common drug-related CAE in the amlodipine group (24.0% amlodipine, 2.5% losartan; P < or = 0.001); dizziness was the most common drug-related CAE in the losartan group (6.0% losartan, 4.0% amlodipine). CONCLUSIONS: In these patients with ISH, losartan and amlodipine produced comparable clinically relevant reductions in SiSBP; however, losartan was better tolerated, as evidenced by fewer CAEs and discontinuations compared with amlodipine. Losartan may be considered for the initial treatment of ISH.     

A double-blind ambulatory blood pressure monitoring study of the efficacy and tolerability of once-daily telmisartan 40 mg in comparison with losartan 50 mg in the treatment of mild-to-moderate hypertension in Taiwanese patients

Ambulatory blood pressure monitoring (ABPM) was used to compare the efficacy and tolerability of once-daily telmisartan 40 mg and once-daily losartan 50 mg in Taiwanese patients with mild-to-moderate essential hypertension in a randomised, double-blind, double-dummy, parallel-group study. The initial 2-week placebo run-in phase was followed by randomisation to treatment with telmisartan 40 mg (n = 31) or losartan 50 mg (n = 30) for 6 weeks. The reduction in 18- to 24-h mean (SE) ambulatory diastolic blood pressure (DBP) from baseline was significantly greater with telmisartan 40 mg (-12.1 +/- 1.6 mmHg, p = 0.036) than with losartan 50 mg (-7.0 +/- 1.8 mmHg). The reduction in 18- to 24-h mean (SE) ambulatory systolic blood pressure (SBP) from baseline was also greater with telmisartan 40 mg (-16.0 +/- 2.4 mmHg) than with losartan 50 mg (-11.8 +/- 2.7 mmHg), but did not achieve statistical significance. Telmisartan was well tolerated; no serious adverse events occurred.     

A comparison of initial treatment with losartan/HCTZ versus losartan monotherapy in chinese patients with mild to moderate essential hypertension

The antihypertensive efficacy and tolerability of losartan/hydrochlorothiazide (HCTZ) and losartan monotherapy as initial treatment were compared in a double-blind trial in Chinese patients with mild to moderate essential hypertension. Patients were randomised to initial treatment with either losartan/HCTZ (50 mg/12.5 mg) or losartan alone (50 mg). The doses were doubled after four weeks if diastolic blood pressure (SiDBP)was >90 mmHg. Both losartan/HCTZ and losartan alone significantly reduced SiDBP and SiSBP from baseline at the first measurement at 4 weeks (-10.1/-15.3 and -6.1/-6.9 mmHg, respectively; p<0.001) and at 8 weeks (-13.1/-18.5 and -8.7/-10.9 mmHg; p<0.001). The reductions with losartan/HCTZ were significantly greater than with losartan alone at weeks 4 and 8 (p<0.001). Both regimens were similarly well tolerated. In conclusion, initial therapy with losartan/HCTZ is effective and well tolerated in the treatment of Chinese patients with mild to moderate essential hypertension and produces a greater reduction in blood pressure than losartan alone.     

Increased efficacy and tolerability with losartan plus hydrochlorothiazide in patients with uncontrolled hypertension and therapy-related symptoms receiving two monotherapies

The efficacy and tolerability of losartan 100 mg/hydrochlorothiazide (HCTZ) 25 mg and enalapril 10 mg/HCTZ 25 mg were compared in a double-blind, randomized trial in hypertensive patients inadequately controlled and experiencing side effects on prior therapy. Patients with moderate or severe hypertension, currently treated with at least two single-agent drugs (excluding angiotensin-converting enzyme inhibitors), with a sitting diastolic blood pressure (DBP) above 90 mm Hg, and at least one undesirable drug-related symptom were randomized to once-daily treatment with one of the combinations for 12 weeks. Losartan/HCTZ lowered sitting DBP from the prior therapy baseline by 13.7 mm Hg and sitting systolic blood pressure 19.3 mm Hg; similar reductions occurred with enalapril/HCTZ. Trough sitting DBP was reduced to normal levels (< 90 mm Hg) in 63% of patients switched to the losartan combination and in 58% of those treated with the enalapril combination. Each combination was associated with improved tolerability compared with prior therapy, although fewer patients reported each of 24 undesirable symptoms after 12 weeks of losartan/HCTZ. The improvement from prior therapy in the occurrence of cough was significantly greater with losartan/HCTZ (P = .005). Enalapril/HCTZ, but not losartan/HCTZ, increased serum uric acid levels at week 12. In conclusion, the combination of losartan 100 mg/HCTZ 25 mg offers a beneficial therapeutic option for patients with a history of moderate to severe hypertension whose blood pressure is not adequately controlled or who exhibit side effects while on two or more single-agent antihypertensive drugs. In this population, the switch from prior antihypertensive therapies to once daily losartan 100 mg/HCTZ 25 mg improves blood pressure control and reduces side effects.     

Efficacy and Safety of 30-Mg Fimasartan for the Treatment of Patients With Mild to Moderate Hypertension: An 8-Week,Multicenter, Randomized,Double-Blind,Phase III Clinical Study

Purpose

The standard 60-mg dose of fimasartan, a newly developed selective angiotensin II receptor blocker, is effective and safe for use in patients with mild to moderate hypertension. This study aimed to compare the efficacy and safety of low-dose (30 mg) fimasartan and placebo or valsartan (80 mg) for 8 weeks in patients with mild to moderate hypertension.

Methods

In this randomized trial, 293 patients (219 men; mean age, 54.24 [9.77] years) with mild to moderate hypertension were enrolled. After randomization to receive 30-mg fimasartan (n = 115), placebo (n = 117), or 80-mg valsartan (n = 61), the treatment dose was kept constant without dose escalation for 8 weeks. The primary end point was improvement in sitting diastolic blood pressure (SiDBP) from baseline to 8 weeks that was compared between treatments with low-dose fimasartan and placebo. The secondary end point was the overall efficacy and safety of low-dose fimasartan compared with that of placebo or valsartan.

Findings

At week 8, SiDBP changed by –9.93 (8.86) mm Hg in the fimasartan group and by –2.08 (9.47) mm Hg in the placebo group, which indicated significant antihypertensive efficacy (P < 0.0001). Efficacy was shown at week 4 as measured by SiDBP (–9.96 [7.73] vs –2.27 [7.85] mm Hg; P < 0.0001) or sitting systolic blood pressure (SiSBP) (–16.18 [14.44] vs –1.95 [13.48] mmHg; P < 0.0001) and at week 8 as determined by SiSBP (–15.35 [16.63] vs –2.30 [14.91] mm Hg; P < 0.0001). The fimasartan group exhibited more potent antihypertensive efficacy than the valsartan group both at week 4 (SiDBP, –9.96 [7.73] vs –6.53 [9.58] mm Hg [P = 0.0123]; SiSBP, –16.18 [14.4] vs –7.65 [12.89] mm Hg [P = 0.0002]) and at week 8 (SiDBP, –9.93 [8.86] vs –5.47 [8.96] mm Hg [P = 0.0021]; SiSBP, –15.35 [16.63] vs –7.49 [13.68] mm Hg [P = 0.0021]). Most treatment-emergent adverse events (TEAEs) were mild (89 of 95), and there were no serious TEAEs. The incidence of TEAEs was 19.1% in the fimasartan group, 22.6% in the placebo group, and 13.6% in the valsartan group, with no significant differences.

Implications

Low-dose fimasartan (30 mg) was well tolerated during the study period with no significant TEAEs. Low-dose fimasartan had an effective blood pressure–lowering effect that was greater than that of 80-mg valsartan in patients with mild to moderate hypertension. ClinicalTrials.gov identifier: NCT01672476.     

Comparative efficacy of valsartan and olmesartan in mild-to-moderate hypertension: Results of 24-hour ambulatory blood pressure monitoring

The aim of this prospective, randomized, open-label, blinded endpoint (PROBE) study was to compare the antihypertensive efficacy of 2 angiotensin II (AII) receptor antagonists with different pharmacologic profiles, valsartan and olmesartan, in patients with mild-to-moderate essential hypertension. After an initial 2-week washout period, 114 patients (64 men, 50 women; aged 35–70 years) were randomly assigned to receive valsartan 160 mg or olmesartan 20 mg once daily for 8 weeks. After the washout period and after 2 and 8 weeks of treatment, 24-hour ambulatory blood pressure monitoring (ABPM) was performed using a noninvasive device, and casual blood pressure (BP) and heart rate were measured. Both olmesartan and valsartan had a clear-cut antihypertensive effect. However, significantly earlier and more pronounced antihypertensive activity was achieved with valsartan than with olmesartan, as demonstrated by (1) significantly lower 24-hour, daytime, and nighttime ABPM values after 2 weeks with valsartan (P < .01); (2) significantly lower percentage of abnormal BP readings with valsartan; (3) significantly higher trough-peak ratio and smoothness index with valsartan, suggesting a more prolonged and homogeneous antihypertensive effect; and (4) lower 24-hour postdose clinic systolic and diastolic BP values versus olmesartan. These findings show that pharmacodynamic and pharmacokinetic differences between All receptor antagonists, at clinically comparable dosages, may be associated with differences in anti hypertensive efficacy.     

Differential time effect profiles of amlodipine, as compared to valsartan, revealed by ambulatory blood pressure monitoring, self blood pressure measurements and dose omission protocol

Amlodipine and valsartan are once-daily antihypertensive agents. To date, no comparison between these agents given as monotherapies was reported. This study was aimed to evaluate the therapeutic coverage and safety of amlodipine and valsartan in mild-to-moderate hypertensive patients. Multicenter, double-blind, randomized, comparative study. After a 4-week placebo wash-out period, 246 outpatients with office diastolic blood pressure 95 < or = DBP < or =110 mmHg and systolic blood pressure (SBP) < 180 mmHg, in addition to a mean daytime SBP and/or DBP > 135/85 mmHg on 24-h ambulatory blood pressure monitoring (ABPM), were randomly allocated to once-daily amlodipine 5-10 mg or valsartan 40-80 mg, for 12 weeks. In a subgroup of patients, 48-h ABPM were performed at the end of the treatment period. Dose omission was simulated by a single-blind placebo dosing. The primary efficacy end-point was the 24-h trough office BP after 12 weeks of active therapy. The reductions in 24-h trough BP were more pronounced in amlodipine compared with valsartan group as well in office [SBP: -17.8 +/- 10.9 vs. -14.6 +/- 11.2, P = 0.025, DBP: -12.7 +/- 7.2 vs. -10.9 +/- 7.8 mmHg, P = 0.06) as in ambulatory BP (SBP/DBP: -13.0 +/- 13.7/-10.8 +/- 9.1 vs. -7.2 +/- 19.4/-4.9 +/- 13.4 mmHg, P < 0.05). Forty-eight hours after the last active dose, the slope of the morning BP surge (4-9 h) was less steep with amlodipine vs. valsartan [DBP (P < 0.04), SBP (n.s.)]. Ankle edema were more often reported in amlodipine group. These results suggest a superior BP lowering and a longer duration of action with amlodipine compared with valsartan.     

Effect of losartan therapy on endothelial function in hypertensive patients

The aim of the study was to evaluate the effect of losartan therapy on endothelial function by measuring serum nitric oxide (NO) levels and urinary excretion of NO in patients with essential hypertension. A group of 30 untreated stage 2 hypertensive patients (15 males and 15 females; age, 51.3 +/- 1.5 years) were included in the study. Office systolic and diastolic blood pressure (BP) was measured by using a mercury sphygmomanometer according to phase I and V of Korotkoff sounds. NO levels in serum and 24-hour urine were determined at baseline and after 6 weeks of daily dosing with losartan (50-100 mg). Losartan therapy resulted in a significant fall in systolic/diastolic BP (from 169.7 +/- 4.1/105 +/- 1.8 mm Hg at baseline to 146 +/- 2.7/91 +/- 1.9 mm Hg at the end of losartan treatment; P < 0.001). The therapy also caused significant increases in both serum NO level (32.74 +/- 3.01 microM/L at baseline versus 79.04 +/- 5.17 microM/L; P < 0.001 after therapy) and urinary NO excretion (58.21 +/- 3.72 microM/L at baseline versus 113.21 +/- 8.63 microM/L; P < 0.001 after therapy). Losartan therapy also reduced serum malondialdehyde (MDA), which is a measure of oxidative stress, by 0.201 nM (15.3%; P = 0.009). Losartan at a dose of 50 to 100 mg per day was effective in reducing elevated BP. The increase in serum NO levels and urinary NO excretion and a decrease in serum MDA levels by losartan treatment indicate a reduction in oxidative stress and enhances NO availability, both of which improve endothelial function. Thus, losartan therapy improves endothelial function in hypertensive patients with essential hypertension.     

Ambulatory monitoring of systolic hypertension in the elderly: Eprosartan/hydrochlorothiazide compared with losartan/hydrochlorothiazide (INSIST trial)

Introduction

Systolic hypertension is very common in the elderly and is strongly associated with the risk of cardiovascular and cerebrovascular events. The control of systolic hypertension is difficult and most patients require combination antihypertensive therapy. Few data are available regarding the efficacy of angiotensin II receptor antagonists on systolic hypertension of the elderly. The aim of this double-blind, double-dummy, randomized, parallel-group, multicenter study was to assess the efficacy of eprosartan 600 mg in combination with hydrochlorothiazide (HCTZ) 12.5 mg in comparison with losartan 50 mg in combination with HCTZ 12.5 mg, in reducing blood pressure in elderly patients with grade 2 systolic hypertension who did not optimally respond to eprosartan or losartan monotherapy.

Methods

After a 3-week placebo wash-out, 155 patients with an Office trough sitting systolic blood pressure (Office sitSBP) ≥160 mmHg and <180 mmHg were randomized to eprosartan 600 mg (n=78) or losartan 50 mg (n=77) once daily for 6 weeks. In patients not optimally responding to monotherapy (Office sitSBP≥130 mmHg) 12.5 mg HCTZ was added as fixed combination once daily for 6 weeks. A 24-hour ambulatory blood pressure monitoring (ABPM) was performed at the end of wash-out and at the end of the fixed-combination period.

Results

No statistically significant difference was found between eprosartan/HCTZ and losartan/HCTZ on the primary endpoint (24-hour ABPM SBP) with an adjusted mean difference between treatments of 3.1 mmHg (95% CI: ?0.32–6.59). However, the mean 24-hour ABPM SBP significantly decreased by 16.7 mmHg with eprosartan/HCTZ and 20.3 mmHg with losartan/HCTZ (P<0.001 vs. baseline). The mean Office sitSBP significantly decreased by 28.7 mmHg and 29.6 mmHg respectively, with eprosartan/HCTZ and losartan/HCTZ (P<0.001 vs.baseline and vs. monotherapy).

Conclusion

In this study, eprosartan/HCTZ did not demonstrate to be superior to losartan/HCTZ in reducing ABPM systolic hypertension in the elderly.     

Efficacy and tolerability of two formulations of ramipril in Korean adults with mild to moderate essential hypertension: An 8-week,multicenter, prospective,randomized, open-label,parallel-group noninferiority trial

Objective: This study was designed to compare the efficacy and tolerability of a new generic formulation of ramipril (test) and the branded formulation of ramipril (reference) to satisfy regulatory requirements for marketing of the generic product for use in Korean patients with mild to moderate hypertension.Methods: This was an 8-week, multicenter, prospective, randomized, open-label, parallel-group non-inferiority trial in adult patients (age > 18 years) with mild to moderate essential hypertension (sitting dia-stolic blood pressure [SiDBP] 90–109 mm Hg). After a 2-week washout of previous antihypertensive medications, eligible patients were randomized to receive either ramipril 5 mg/d in the morning (low-dose group: baseline SiDBP 90–99 mm Hg) or ramipril 10 mg/d (high-dose group: baseline SiDBP 100–109 mm Hg) for the first 4 weeks. If SiDBP was ≥ 90 mm Hg after 4 weeks of treatment, the dose was increased to 10 mg/d for the remaining 4 weeks in the low-dose group, and hydrochlorothiazide 12.5 mg was added to the regimen for the remaining 4 weeks in the high-dose group. The primary end point was the change in SiDBP from baseline to week 8. Secondary end points included a noninferiority analysis of the test and reference formulations with respect to the change in mean sitting systolic blood pressure (SiSBP) from baseline to week 8; SiDBP and SiSBP response rates (proportion of patients achieving an SiDBP < 90 mm Hg and SiSBP < 140 mm Hg, respectively) at 8 weeks; and changes from baseline in SiSBP, pulse wave velocity (PWV), exercise capacity, left-ventricular diastolic function (LVDF), and levels of brain natriuretic peptide (BNP) and high-sensitivity C-reactive protein (hs-CRP). Laboratory and clinical adverse events (AEs) were monitored at each study visit (4 and 8 weeks).Results: The modified intent-to-treat population consisted of 89 patients (45 test, 44 reference; 60 men, 29 women; mean age, 49.7 years; mean weight, 69.9 kg). At week 8, mean (SD) SiSBP and SiDBP were significantly decreased from baseline in both groups (test: from 145.0 [9.7]/98.1 [5.3] mm Hg to 132.2 [11.1]/ 91.8 [7.1] mm Hg [P < 0.001]; reference: from 145.1 [11.4]/98.0 [5.7] mm Hg to 134.0 [14.6]/92.5 [7.9] mm Hg [P < 0.001]). The changes in blood pressure at week 8 did not differ significantly between the test and reference groups or between the low- and highdose groups in a subgroup analysis. Blood pressure response rates at 8 weeks did not differ significantly between the groups receiving the test and reference formulations (SiDBP: 26.7% and 31.8%, respectively; SiSBP: 37.8% and 40.9%). In addition, there were no significant between-group differences in the change in PWV (?63.8 and ?38.7 cm/sec), LVDF at rest or after exercise, or levels of BNP or hs-CRP. The incidence of AEs was 64.4% in the test formulation group and 68.2% in the reference group formulation (P = NS). The most common AE in both groups was cough (10/45 [22.2%] and 10/44 [22.7%]).Conclusions: There were no significant differences in the efficacy and tolerability of the test and reference formulations of ramipril in these Korean adults with mild to moderate hypertension. The new generic formulation was noninferior to the reference formulation in terms of the change in SiDBP at week 8.     

Safe and effective management of hypertension with fixed-dose combination therapy: focus on losartan plus hydrochlorothiazide

Treatment of hypertensive patients with fixed-dose combination therapy consisting of losartan and hydrochlorothiazide (HCTZ) has several potential benefits over monotherapy with each of the individual components: more effective blood pressure control, a reduction in the likelihood of adverse effects, and facilitation of patients staying on therapy due to a simple once-daily regimen. Losartan plus HCTZ fixed-dose combination therapy lowers blood pressure in mild to moderate or severe hypertensive patients to a level comparable with other classes of antihypertensive drugs in combination with HCTZ. Fixed-dose combination therapy with losartan plus HCTZ is therefore an excellent choice for hypertensive patients in whom combination therapy is necessary to achieve additional blood pressure reductions.     

Ambulatory blood pressure-lowering effects of valsartan and enalapril after a missed dose in previously untreated patients with hypertension: a prospective, randomized, open-label, blinded end-point trial

Background: Approximately 3 days a month, some 15% to 20% of patients with hypertension do not recall having taken their antihypertensive medication. Individuals with this frequency of missed doses may be at increased risk for a cardiovascular event and may have a poorer long-term prognosis. Objective: This study used ambulatory blood pressure monitoring (ABPM) to compare the blood pressure (BP)-lowering effects of valsartan and enalapril over the 24 hours after missing 1 dose in previously untreated patients with mild to moderate essential hypertension. Methods: This was a prospective, randomized, open-label, parallel-group, blinded end-point trial in previously untreated patients (age >18 years) with mild to moderate essential hypertension (European Society of Hypertension-European Society of Cardiology guidelines: systolic BP 140-179 mm Hg or diastolic BP 90-109 mm Hg). Patients were randomly assigned to receive 16 weeks of treatment with valsartan 160 mg/d or enalapril 20 mg/d, taken on waking. ABPM was conducted for 48 consecutive hours at baseline and again after 16 weeks of therapy. Patients took a dose of their assigned treatment at the beginning of the final session of ABPM and were instructed to skip the next daily dose. Results: The study enrolled 148 Spanish patients (84 men, 64 women; mean [SD] age, 45.8 [10.7] years) with previously untreated hypertension. At the end of treatment, there were significant differences between groups during the first 24 hours of ABPM, starting in the final 6 hours of the dosing interval (P < 0.001). There was no significant change in BP reduction between the first and second 24-hour periods of ABPM with valsartan (-2.1/-1.4 mm Hg), whereas enalapril was associated with a significant increase in BP over this period (5.5/3.8 mm Hg; P < 0.001 vs first 24 hours; P = 0.032 vs valsartan). Conclusions: In this study in previously untreated patients with mild to moderate essential hypertension, valsartan was associated with a sustained BP-lowering effect beyond the initial 24 hours after dosing, whereas enalapril was not. There was no significant change in the efficacy of valsartan in the 24 hours after a missed dose. At the doses tested, valsartan was more effective than enalapril, both during active treatment and after a missed dose.     

氯沙坦和贝那普利的降压、降尿酸疗效比较

目的比较氯沙坦和贝那普利的降压疗效,及两者对高血压伴高尿酸血症的影响。方法60例原发性高血压伴高尿酸血症患者随机分为两组,分别给予氯沙坦50mg/d和贝那普利10mg/d治疗,疗程6周。观察两组的降压效果及对血尿酸水平的影响。结果氯沙坦组治疗后与治疗前比较血压、血尿酸均显著下降(P<0.05)。贝那普利组治疗后血压显著下降(P<0.05),血尿酸水平治疗前后无差异(P>0.05)。结论氯沙坦和贝那普利降压疗效相似;氯沙坦除有降压效应外,还可降低血尿酸水平,对高血压伴高尿酸血症的患者,以氯沙坦作为首选降压药无疑是治疗良策。     

氯沙坦与阿替洛尔对心脑血管事件影响的循证分析

目的为《中国基本药物目录》遴选血管紧张素Ⅱ受体阻断剂（ARB）类降压药物提供循证研究数据。方法以losartan、atenolol、clinicaltrial、氯沙坦、阿替洛尔、临床试验为检索词，计算机检索EMbase、PubMed、Cochrane图书馆、Clinicaltrials．gov、CNKI、VIP和CBM，纳入氯沙坦与阿替洛尔治疗高血压相关的临床试验，语种限中、英文。结果共纳入52篇义献，多数来源于氯沙坦减少高血压患者终点事件（LIFE）研究。其主要结果显示：①在降压效果相当的情况下，氯沙坦比阿替洛尔的耐受性更好、降低高血压患者的左室肥厚作用更好；②氯沙坦防治心脑血管事件的发生，特别是预防脑卒中首次发作的效果也更好；③氯沙坦对伴／不伴有糖尿病、伴／不伴有房颤、有低血红蛋白或高血尿酸，以及合用阿司匹林或氢氯噻嗪患者的治疗效果均优于阿替洛尔；④无论用氯沙坦还是阿替洛尔，强化降压治疗会增加有QRS间期延长的高血压患者发生心源性猝死的风险；⑤对吸烟、少量或大量饮酒的高血压患者，氯沙坦的作用均优于阿替洛尔；⑥氯沙坦和阿替洛尔在非洲裔、不同性别、血管紧张素转化酶基因突变的高血压患者中的作用无显著差别。结论氯沙坦与阿替洛尔的降压效果相当，但氯沙坦比阿替洛尔能更有效地降低高血压患者的左室肥厚，且氯沙坦带给高血压患者降压以外的益处远比阿替洛尔多，如降低尿蛋白和尿酸，不降低高密度脂蛋白等方面的作朋。     

Effects of valsartan/ hydrochlorothiazide and amlodipine on ambulatory blood pressure and plasma norepinephrine levels in high-risk hypertensive patients

The efficacy and tolerability of the combination of valsartan and hydrochlorothi-azide (HCTZ) were compared with that of amlodipine in reducing ambulatory blood pressure and plasma norepinephrine levels in patients with mild to moderate hypertension and at least 1 cardiovascular risk factor. At the end of a 2-week washout period, 92 outpatients with a sitting diastolic blood pressure ≥95 and <110 mm Hg, associated with at least 1 additional risk factor, were randomly assigned to receive either valsartan 160 mg and HCTZ 12.5 mg once daily (n=46) or amlodipine 10 mg alone once daily (n=46) for 12 weeks, according to a prospective, randomized, open-label, blinded end point, parallel-group design. At the end of the washout period and after 6 and 12 weeks of active treatment, 24-hour ambulatory blood pressure monitoring was performed, and clinical blood pressure and heart rate and plasma norepinephrine levels were assessed (by high-performance liquid chromatography). Both the valsartan/HCTZ combination and amlodipine had a demonstrable antihypertensive effect, but the combination showed an antihypertensive effect significantly greater than that of amlodipine, as demonstrated by the 24-hour (P < .001), daytime (P < .001), and nighttime ambulatory blood pressure values (P < .01) and by the clinical blood pressure values at trough, which were all significantly lower. Although the trough-to-peak ratios were similar in both groups, the smoothness indexes pertaining to both systolic and diastolic pressures were significantly higher (P < .05 andP < .001, respectively) in patients receiving valsartan/HCTZ, suggesting the combination produces a more homogeneous antihypertensive effect. A significant increase in plasma norepinephrine levels was associated with amlodipine (+9% at 6 weeks, +15% at 12 weeks) but not with the valsartan/HCTZ combination. The valsartan/HCTZ combination was better tolerated than amlodipine, which was associated with a higher frequency of ankle edema. These results indicate that the combination of valsartan 160 mg and HCTZ 12.5 mg provides more sustained and homogeneous control of blood pressure than does amlodipine 10 mg in high-risk hypertensive patients, without producing reflex sympathetic activation.     

血管紧张素Ⅱ受体拮抗剂对高血压病患者血尿酸影响的研究

目的　探讨血管紧张素Ⅱ受体拮抗剂氯沙坦 (Losartan)对高血压病患者血尿酸的影响。方法　采用前瞻性分析研究 ,将 6 0例高血压病患者随机分为两组 ,每组 30例。Losartan组 :给予Losartan 5 0mgqd ;西拉普利 (Cilazapril)组 ,给予Cilazapril2 5mgqd ;疗程 4周 ,观察治疗前后血尿酸的变化。结果　与基础值相比 ,Losartan组血尿酸明显降低 ,P <0 0 1,西拉普利组血尿酸轻度降低 ,但无统计学差异。结论　Losartan治疗高血压在降压同时具有降低血尿酸的作用。