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.     

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.     

Efficacy and safety profiles of a new S(-)-amlodipine nicotinate formulation versus racemic amlodipine besylate in adult Korean patients with mild to moderate hypertension: an 8-week, multicenter, randomized, double-blind, double-dummy, parallel-group, phase III, noninferiority clinical trial

BACKGROUND: "Chiral switching" from an existing racemate to a pure enantiomeric compound is a popular theme in drug development, especially when the enantiomer is found to have better efficacy and safety profiles. Amlodipine is a racemic mixture, composed of the S(-)-enantiomer, which is the pharmacologically active isomer, and the R(+)-enantiomer, which is 1000-fold less active. S(-)-amlodipine nicotinate, a chirally switched form of amlodipine nicotinate, has been developed and found to be bioequivalent to amlodipine besylate in Phase I clinical trials in Korea. OBJECTIVE: The aim of this study was to compare the efficacy and safety profiles of S(-)-amlodipine nicotinate with those of amlodipine besylate in adult Korean patients with mild to moderate hypertension (diastolic blood pressure [DBP] >or=90 mm Hg and or=90 and or=90 mm Hg). The primary end point was noninferiority of the difference in mean SiDBP from baseline to week 8 for S(-)-amlodipine nicotinate compared with amlodipine besylate. Secondary end points were as follows: (1) noninferiority of the difference in mean sitting systolic blood pressure (SiSBP) from baseline to week 8 between the study groups; and (2) SiDBP response rate (defined as the proportion of patients whose SiDBP was <90 mm Hg or whose SiDBP reduction was >or=10 mm Hg from baseline) after the 8-week treatment. Also, the incidence and severity of adverse events (AEs) and adverse drug reactions (ADRs) were reported. Severe AEs/ADRs were defined as those associated with any of the following: death; an event associated with a high risk of mortality; an event requiring hospitalization; or development of a permanent disability or congenital malformation. RESULTS: One hundred fifty-seven patients were assessed for inclusion in the study. Of these, 124 patients were randomly allocated to receive S(-)-amlodipine nicotinate (42 men, 21 women; mean [SD] age, 52.4 [10.3] years [range, 23-70 years]; weight, 67.7 [10.8] kg [range, 44-92 kg]) or amlodipine besylate (45 men, 16 women; mean [SD] age, 54.5 [10.0] years [range, 30-73]; weight, 68.9 [9.8] kg [range, 49-95 kg]). One hundred sixteen patients completed the study, but 11 patients (8.9%) were dropped from the per-protocol analysis due to violations; therefore, 105 patients were included in the modified intent-to-treat population analysis (S[-]-amlodipine nicotinate, 55 patients; amlodipine besylate, 50 patients). There were no significant between-group differences in the baseline characteristics. Baseline mean (SD) SiSBP and SiDBP were 142.6 (11.3) and 94.9 (4.8) mm Hg in the S(-)-amlodipine nicotinate group, and 141.8 (8.3) and 96.1 (4.9) mm Hg in the amlodipine besylate group. Mean (SD) changes in SiSBP were 17.6 (11.2) mm Hg in the S(-)-amlodipine nicotinate group and 18.6 (12.3) mm Hg in the amlodipine besylate group. The SiDBP response rates were 92.7% in the S(-)-amlodipine nicotinate group and 88.0% in the amlodipine besylate group. There were no significant between-group differences in the prevalence of AEs and ADRs. In the S(-)-amlodipine nicotinate group, 15 patients (23.8%) reported a total of 28 AEs, and 19 patients (31.1%) reported a total of 27 AEs in the amlodipine besylate group. Six patients (9.5%) in the S(-)-amlodipine nicotinate group and 7 patients (11.4%) in the amlodipine besylate group experienced a total of 19 ADRs (11 and 8, respectively). The most common ADRs were liver enzyme elevation (3/63 [4.8%]) in the S(-)-amlodipine nicotinate group and facial flushing (3/61 [4.9%]) in the amlodipine besylate group. No cases of severe AEs or ADRs were reported in either group. CONCLUSIONS: The reduction of SiDBP after 8 weeks of treatment with S(-)-amlodipine nicotinate was noninferior compared with that of racemic amlodipine besylate in these adult Korean patients with mild to moderate hypertension. The SiDBP response rate and the reduction of SiSBP after 8 weeks of treatment with S(-)-amlodipine nicotinate were not significantly different from those with racemic amlodipine besylate. Both treatments were generally well tolerated.     

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 efficacy and tolerability of amlodipine orotate versus amlodipine besylate in adult patients with mild to moderate hypertension: a multicenter, randomized, double-blind, placebo-controlled, parallel-group, 8-week follow-up, noninferiority trial

OBJECTIVE: The purpose of this study was to compare the efficacy and tolerability of amlodipine orotate with those of amlodipine besylate in Korean patients with mild to moderate hypertension. METHODS: This multicenter, randomized, double-blind, placebo-controlled, parallel-group study was designed as a noninferiority study. To be included in the study, previously untreated patients had to have a sitting diastolic blood pressure (SiDBP) of 90 to 109 mm Hg. Previously treated patients had to discontinue their current annhypertensive medications and have a baseline SiDBP between 90 and 109 mm Hg after a 2-week washout period. Patients who met the inclusion criteria were randomly assigned to receive 5 mg amlodipine orotate or 5 mg amlodipine besylate for 8 weeks. The medication dose was doubled (10 mg QD for either amlodipine orotate or amlodipine besylate) 4 weeks after enrollment if SiDBP was >or=90 mm Hg. The primary efficacy analysis was noninferiority of the difference in mean trough SiDBP changes from baseline for amlodipin eorotate as compared with amlodipine besylate after 8 weeks of treatment. For the secondary efficacy analysis, 2 other measures were analyzed after 8 weeks of treatment. The SiDBP response rate was defined as an SiDBP measurement<90 mm Hg at the last clinical follow-up visit or an absolute reduction of >or=10 mm Hg in SiDBP from baseline until the last clinical follow-up visit. In addition, noninferiority of the difference in mean trough sitting systolic blood pressure (SiSBP) changes from baseline was analyzed for amlodipine orotate as compared with amlodipine besylate. The drug compliance rate was estimated by pillcount. RESULTS: Eligible patients (n=109; 43 women and 66 men) were randomly assigned to receive amlodipine orotate (n=53) or amlodipine besylate (n=56). No significant differences were found in sex, age, weight, or current smoking between the groups (all, P=NS). The proportion of patients with previous antihypertensive medications was not different between the groups (47.2% [25/53] in the amlodipine orotate group and 50.0% [28/56] in the amlodipine besylate group; P=NS). No significant differences were found in baseline SiDBP (mean [SD], 100 [6] mm Hg [range, 90-109 mm Hg] in the amlodipine orotate group and 100 [6] mm Hg [range, 90-108 mm Hg] in the amlodipine besylate group; P=NS) or in baseline SiSBP (mean [SD], 149 [14] mm Hg [range, 125-179 mm Hg] in the amlodipine orotate group and 146 [10] mm Hg [range, 123-167 mm Hg] in the amlodipine besylate group; p=NS). The mean (SD) changes in SiDBP were -15.6 (6.3) mm Hg for the amlodipine orotate group and -14.5 (5.5) mm Hg for the amlodipine besylate groups was 1.1 (5.9) mm Hg (95% CI, -0.87 to infinity), and because the lower boundary of the 95% CI was greater than -5 mm Hg, amlodipine orotate was considered noninferior to amlodipine besylate. The response rate was 48 of 51 (94.1%) in the amlodipine orotate group compared with 50 (92.6%) of 54 in the amlodipine besylate group after 8 weeks of treatment (P=NS). The mean (SD) compliance rates were 97.6% (3.6%) in the amlodipine orotate group and 96.5% (4.3%) in the amlodipine besylate group (P=NS). The incidence of drug-related adverse events (AEs) was similar between the groups (1/53 [1.9%]) in the amlodipine orotate group vs 4/55 [7.3%] in the amlodipine besylate group; P=NS). The most common drug-related AE overall was peripheral edema (2/55 [3.6%]), and the most common of all the AEs was upper respiratory tract infection (4/55 [7.3%]) in the amlodipine besylate group. The most common drug-related AE was headache (1/53 [1.9%]) in the amlodipine orotate group and peripheral edema (2/55 [3.6%]) in the amlodipine besylate group. No severe AEs were found in either group. CONCLUSION: The reduction in SiDBP after 8 weeks of amlodipine orotate treatment was noninferior to that of amlodipine besylate in these Korean patients with mild to moderate hypertension. The SiDBP response rate and the reduction in SISBP after 8 weeks of amlodipine orotate treatment were not significantly different from those of amlodipine besylate treatment. Both agents were wel tolerated.     

Results of a phase III, 8-week, multicenter, prospective, randomized, double-blind, parallel-group clinical trial to assess the effects of amlodipine camsylate versus amlodipine besylate in Korean adults with mild to moderate hypertension

BACKGROUND: Amlodipine besylate has been used in Korea for the treatment of hypertension for >17 years, with well-established efficacy and tolerability. Amlodipine camsylate is a newer formulation developed for generic use. It has been assessed in terms of physical stability and pharmacokinetic and pharmacodynamic properties and been found to be effective in lowering blood pressure in preclinical and Phase I and II trials. However, to date, no studies have compared the clinical effectiveness of amlodipine camsylate and amlodipine besylate in treating hypertension. OBJECTIVE: This study was designed to determine the effectiveness and tolerability of amlodipine camsylate compared with amlodipine besylate in Korean patients with mild to moderate hypertension. METHODS: This Phase III, 8-week, prospective, randomized, double-blind, parallel-group study was conducted in 13 cardiology centers across the Republic of Korea. Male and female Korean patients aged 18 to 75 years having uncomplicated, mild to moderate, essential hypertension (sitting diastolic blood pressure [SiDBP] 90-<110 mm Hg) and receiving no antihypertensives in the 2 weeks before randomization were eligible. Patients were randomly assigned to receive oral treatment with amlodipine camsylate or amlodipine besylate. For the first 4 weeks, patients received amlodipine 5 mg QD (morning). After 4 weeks, if either blood pressure was > or =140/ > or =90 mm Hg or SiDBP had not decreased by > or =10 mm Hg from baseline, the dose of amlodipine was increased to 10 mg QD for 4 weeks. Trough blood pressure and heart rate were measured in duplicate with the patient in the sitting position at each clinic visit (baseline [week 0] and weeks 4 and 8 of treatment); mean values were calculated and recorded. At weeks 4 and 8, tolerability was assessed using history taking and laboratory analysis, and compliance was assessed using pill counts. The primary end point was change from baseline in SiDBP at week 8. Secondary end points were change from baseline in sitting systolic blood pressure (SiSBP) at week 8 in the total population and in the subgroup of patients who had previously received antihypertensive treatment versus those who had not. RESULTS: A total of 189 patients were enrolled (mean age, 53 years; 105 women, 84 men; mean body weight, 65.8 kg). One patient in the amlodipine camsylate group dropped out of the study at week 0 of treatment (this patient did not use any study medication) and was excluded from the modified intent-to-treat (ITT) analysis. Thus, 188 patients were treated and included in the ITT analysis (94 patients per treatment group; ITT analysis); 161 patients were included in the perprotocol (PP) analysis (n = 80 for amlodipine camsylate, n = 81 for amlodipine besylate) (14 patients in the amlodipine camsylate group and 13 patients in the amlodipine besylate group were excluded from the PP analysis due to consistent withdrawal or protocol violation). Mean (SD) SiSBP and SiDBP were significantly decreased from baseline in both groups (amlodipine camsylate, from 146.7 [12.3]/96.6 [5.4] to 127.9 [14.8]/83.4 [7.7] mm Hg [both, P < 0.001]; amlodipine besylate, from 146.8 [12.8]/96.7 [5.1] to 128.0 [10.1]/83.8 [7.5] mm Hg [both, P < 0.001]). The differences in SiSBP/SiDBP between the 2 groups at week 8 were not significant. The SiDBP response rates in the subgroups that had and had not been previously treated with antihypertensives were statistically similar (56/69 [81.2%] and 83/92 [90.2%], respectively). The prevalences of clinical adverse events (AEs) were not significantly different between the 2 treatment groups (amlodipine camsylate, 27.3 %; amlodipine besylate, 28.7%). The most common AEs were dizziness and dyspnea (both in 3/94 [3.2%] and 1/94 [1.1%] patients who received amlodipine camsylate and amlodipine besylate, respectively). CONCLUSION: The effectiveness and tolerability of amlodipine camsylate were not significantly different from those of amlodipine besylate in these Korean adults with mild to moderate hypertension.     

Influence of alcohol on the hemodynamic effects and pharmacokinetic properties of mirodenafil: A single-dose,randomized-sequence,open-label,crossover study in healthy male volunteers in Korea

Background: Mirodenafil is a phosphodiesterase type 5 (PDE-5) inhibitor developed for the treatment of erectile dysfunction. Mirodenafil has the possibility of being administered with alcohol.Objective: This study assessed the hemodynamic effects and pharmacokinetic properties of mirodenafil administered with alcohol.Methods: This single-dose, randomized-sequence, open-label, crossover study was conducted in healthy male volunteers at the Clinical Trials Center, Seoul National University Hospital, Seoul, Korea. Volunteers were randomly allocated to 1 of 3 randomized-sequence groups, each of which consisted of 3 administration phases, each separated by a 1-week washout period: oral mirodenafil 100 mg, alcohol 0.5 g/kg, and both. Vital signs (systolic blood pressure [SBP], dia-stolic BP [DBP], and pulse rate) were measured before (baseline) and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, and 24 hours after administration. Because volunteers were given a standardized meal at 4 hours after mirodenafil and/or alcohol administration, hemody-namic results were assessed using the maximum decrease from baseline during a period of up to 4 hours after administration. For pharmacokinetic assessment, serial blood samples were collected before (baseline) and at 0.5, 1, 1.25, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours after administration. Tolerability was assessed using monitoring of adverse events (AEs), clinical laboratory parameters, and results of 12-lead electrocardiography.Results: A total of 20 subjects participated in the study (mean [range] age, 25.5 years [20–41 years]; weight, 69.8 kg [57.4–87.2 kg]; and height, 174.7 cm [168–186 cm]). Up to 4 hours after the administration of mirodenafil, alcohol, and mirodenafil + alcohol, the mean (SD) maximum decreases in SBP were 8.5 (3.5), 13.5 (7.8), and 15.1 (6.7) mm Hg, respectively, and the maximum decreases in DBP were 6.4 (4.8), 13.3 (7.4), and 13.8 (5.2) mm Hg. Simultaneous administration of mirodenafil + alcohol was associated with additional mean (95% CI) decreases in SBP and DBP of 1.7 mm Hg (?6.0 to 2.6 mm Hg) and 0.6 mm Hg (?4.7 to 3.6 mm Hg) compared with alcohol alone. Pharmacokinetic parameters of mirodenafil were not significantly different when the drug was administered with or without alcohol. The mean (SD) AUC_0?t values were 842.0 (434.7) ng/mL/h with mirodenafil and 833.4 (398.2) ng/mL/h with mirodenafil + alcohol. The most common AEs considered at least possibly related to study drug were nasal congestion (7 subjects [35%]), headache (3 [15%]), nausea (1 [5%]), and hiccups (1 [5%]).Conclusions: The concurrent administration of mirodenafil with alcohol was not associated with clinically significant hemodynamic changes in these healthy male volunteers in Korea. The pharmacoki-netics of mirodenafil were not significantly altered by this concurrent administration. Mirodenafil administered with alcohol had a tolerability profile comparable to that of mirodenafil alone.     

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.     

A twelve-week, multicenter, randomized, double-blind, parallel-group, noninferiority trial of the antihypertensive efficacy and tolerability of imidapril and candesartan in adult patients with mild to moderate essential hypertension: the Iberian Multicenter Imidapril Study on Hypertension (IMISH)

OBJECTIVE: The aim of this study was to evaluate the annhypertensive efficacy and tolerability of the angiotensin-converting enzyme inhibitor imidapril and the angiotensin II type 1 receptor antagonist candesartan in mild to moderate essential hypertension. METHODS: The trial was conducted at 8 centers across Portugal and Spain (the Iberian Multicenter Imidapril Study on Hypertension [IMISH] Study Group). Patients aged between 30 and 70 years with essential hypertension were eligible. Following a 2- to 4-week, single-blind, placebo run-in period, patients were randomly assigned to receive imidapril at doses of up to 20 mg/d, or candesartan at doses up to 16 mg/d, once daily in a double-blind, parallel-group design with a 12-week active-treatment period. To achieve the target systolic/diastolic blood pressure (SBP/DBP) of <140/<90 mm Hg, imidapril was titrated from 5 to 20 mg/d and candesartan was titrated from 4 to 16 mg/d. The main end point was the change from baseline in sitting blood pressure (BP) at trough. Secondary end points were response rate, evaluation of SBP and DBP throughout the study, and change of SBP and DBP in subgroup of patients with moderate hypertension, as well as incidence and severity of adverse events related to treatment reported throughout the study. RESULTS: The intent-to-treat analysis consisted of 122 patients (imidapril group, 60 patients; 32 men, 28 women; mean [SD] age, 54.7 [9.2] years; white race, 59 [99.2%], Hispanic race, 1 [0.8%]; mean [SD] weight, 80.1 [12.8] kg; candesartan group, 62 patients; 36 men, 26 women; mean [SD] age, 53.9 [9.9] years; white race, 62 [100%]; mean [SD] weight, 77.6 [14.1] kg). In the imidapril group, the mean (SD) SBP and DBP were, respectively, 155.7 (10.2) and 96.7 (4.7) mm Hg at baseline and 139.4 (11.9) and 86.9 (7.6) mm Hg at the end of the 12-week treatment period (visit 5); SBP had decreased significantly from baseline, by 10.5% (mean [SD] Delta, -16.3 [12.3] mm Hg [95% CI, -19.5 to -13.1; P < 0.001]) and DBP had decreased significantly, by 10.1% (mean [SD] A, -9.8 [7.8] mm Hg [95% CI, -11.8 to -7.8; P < 0.001]). In the candesartan group, the mean (SD) SBP and DBP values were, respectively, 158.4 [11.2] and 98.3 [4.1] mm Hg at baseline and 139.8 [12.5] and 87.6 7.5] mm Hg at 12 weeks, corresponding to decreases of 11.7% in SBP (mean [SD] A, -18.6 [12.8] mm Hg [95% CI, -21.9 to -15.4; P < 0.001]) and 10.9% in DBP (mean [SD] A, -10.7 [7.3] mm Hg [95% CI, -12.5 to -8.8; P < 0.001]). Response rates were 78.3% (47/60) with imidapril and 69.4% (43/62) with candesartan, and BP normalization (<140/<90 mm Hg) was achieved in 55.0% (33/60) of patients with imidapril and 45.2% (28/62) of patients with candesartan. The incidences of adverse events were similar between groups. Most (73.9%) adverse events were mild in intensity. A serious adverse event (severe anxiety) was reported in the candesartan group and led to study discontinuation. No cases of dry cough or hypotension were reported. CONCLUSIONS: The results of this study suggest that imidapril once daily at doses up to 20 mg and candesartan once daily at doses up to 16 mg were effective in this population of mildly to moderately hypertensive patients. Both treatments were well tolerated.     

A systematic review and meta-analysis of the efficacy and safety of a fixed, low-dose perindopril-indapamide combination as first-line treatment of hypertension

BACKGROUND: A low-dose combination of perindopril and indapamide may effectively reduce blood pressure (BP) in hypertensive patients, but some factors related to study design might have contributed to the between-group differences in the rate of reduction of BP observed in some trials. OBJECTIVE: The aim of this study was to systematically assess the efficacy and safety profiles (through review of randomized, controlled trials) of the fixed, low-dose combination perindopril 2 mg and indapamide 0.625 mg given as 1 tablet daily as first-line antihypertensive therapy in patients with mild to moderate hypertension. METHODS: We searched MEDLINE (1966-April 2003), EMBASE (1980-March 2003), BIOSIS (1999-December 2002), and the Cochrane Library, using the medical subject headings with the search terms perindopril, indapamide, hypertension, randomized controlled trials, randomly, random, randomization, perindopril-indapamide, essential hypertension, and primary hypertension. Additional articles were obtained from the reference lists of relevant reviews and papers. RESULTS: We reviewed 11 trials (5936 individuals). In 5 studies of perindopril-indapamide versus placebo, the between-group weighted mean differences (WMDs) for both systolic and diastolic BP (SBP and DBP, respectively) favored perindopril-indapamide (SBP, -9.03 mm Hg [95% CI, -9.54 to -8.52]; DBP, -5.09 mm Hg [95% Cl, -5.42 to -4.77]; both P < 0.01 for z score for overall effect). In 6 studies of perindopril-indapamide versus routine antihypertensives, the between-group WMDs for SBP and DBP favored perindopril-indapamide (SBP, -3.72 mm Hg [95% CI, -7.11 to 0.33], P = 0.03 for z score for overall effect; DBP, -1.71 mm Hg [95% CI, -2.27 to -1.16], P < 0.01 for z score for overall effect). Five studies compared perindopril-indapamide and placebo; in the remaining 3 studies, which assessed perindopril-indapamide versus routine antihypertensives, the between-group WMDs for SBP and DBP favored perindopril-indapamide (SBP, -4.00 mm Hg [95% CI, -6.54 to -1.47], P < 0.01; DBP, -1.02 mm Hg [95% CI, -1.73 to -0.31], P < 0.01). Adverse events and withdrawals were not significantly different between perindopril-indapamide, placebo, or routine antihypertensive drugs. CONCLUSION: The studies in our analysis consistently demonstrated that a fixed, low-dose perindopril-indapamide combination has a favorable safety profile and may be efficacious as first-line treatment for patients with mild to moderate essential hypertension.     

Effects of fosinopril on blood pressure, lipid profile, and lipoprotein(a) levels in normotensive patients with type 2 diabetes and microalbuminuria: An open-label, uncontrolled study

Background: Patients with type 2 diabetes mellitus often have other cardiovascular risk factors, and alterations in lipid profile play an important role. The angiotensin-converting enzyme inhibitors are often used in these patients, particularly those with type 2 diabetes and proteinuria.Objective: This study evaluated the effects of fosinopril therapy on fasting plasma glucose (FPG), lipid profile, and lipoprotein(a), or Lp(a), levels in normotensive patients with type 2 diabetes mellitus and microalbuminuria.Methods: Normotensive (systolic blood pressure [SBP] <130 mm Hg and diastolic blood pressure [DBP] <85 mm Hg) patients with type 2 diabetes and microalbuminuria and a normal lipid profile were enrolled. Patients had their diabetes controlled by diet alone or diet plus oral hypoglycemic agents. Fosinopril 10 mg/d was administered for 6 months and then interrupted for 1 month. FPG, glycosylated hemoglobin, SBP, DBP, lipid profile (total cholesterol [TC], low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], and triglycerides), Lp(a), albumin excretion rate (AER), and creatinine levels were evaluated at baseline; 1, 3, and 6 months after initiation of treatment; and 1 month after interruption of treatment.Results: A total of 120 patients were enrolled (63 men, 57 women; mean age ± SD, 54 ± 10 years; duration of diabetes, 7 ± 2 years). Significant decreases versus baseline were observed in the following parameters at month 6: SBP (122 ± 7 vs 117 ± 9.1 mm Hg, P < 0.01), DBP (80 ± 4.8 vs 74 ± 4.5 mm Hg, P < 0.05), TC (186 ± 11 vs 176 ± 10 mg/dL, P < 0.05), LDL-C (124 ± 10 vs 114 ± 11 mg/dL, P < 0.05), Lp(a) (24 ± 10 vs 19 ± 7.5 mg/dL, P < 0.05), and AER (103 ± 45 vs 48 ± 21 mg/24 hours, P < 0.01). When fosinopril therapy was interrupted for 1 month, the values for all these parameters tended to return to baseline values; SBP, TC, and Lp(a) values were significantly different from month 6 values, whereas DBP, LDL-C, and AER did not change significantly during the washout period.Conclusions: Fosinopril therapy for 6 months resulted in a reduction of microalbuminuria and an improvement in lipid profile and Lp(a) levels in patients with type 2 diabetes. This suggests that fosinopril may improve lipid profile and reduce Lp(a) levels by lowering proteinuria or by other more direct actions on lipid and Lp(a) metabolism. Additional controlled studies are needed to confirm these results.     

Comparison of fixed-dose combinations of telmisartan/hydrochlorothiazide 40/12.5 mg and 80/12.5 mg and a fixed-dose combination of losartan/hydrochlorothiazide 50/12.5 mg in mild to moderate essential hypertension: pooled analysis of two multicenter, prospective, randomized, open-label, blinded-end point (PROBE) trials

BACKGROUND: High incidences of cardiovascular events coincide with a surge in blood pressure (BP) that occurs in the early morning hours at the time of arousal. Thus, control of BP at this time of day, using oral fixed-dose combinations (FDCs) as required, is important in reducing cardiovascular risk in hypertensive patients. OBJECTIVE: The aim of this analysis was to compare the antihypertensive efficacy in the early morning hours and tolerability of oral FDCs of telmisartan/hydrochlorothiazide (HCTZ) (40/12.5 mg [T40/H12.5] and 80/12.5 mg [T80/H12.5]) versus a low-dose FDC of losartan 50 mg/HCTZ 12.5 mg (L50/H12.5). METHODS: Data from 2 similarly designed prospective, randomized, open-label, blinded-end point (PROBE) studies were pooled and analyzed. The studies were conducted at 72 centers across the United States, and 70 centers in Canada, Europe (9 countries), and the Philippines. Adult male and female patients with mild to moderate essential hypertension (24-hour mean ambulatory diastolic BP [DBP], > or =85 mm Hg; seated cuff DBP, 90-109 mm Hg) were enrolled. Patients were randomly assigned to receive T40/H12.5, L50/H12.5, or T80/H12.5, QD (morning) for 6 weeks. Antihypertensive efficacy was assessed using 24-hour ambulatory BP monitoring (ABPM) and cuff sphygmomanometry at trough, performed at baseline and on completion of active treatment. The primary end point was the reduction from baseline in mean ambulatory DBP over the last 6 hours of the dosing interval. Secondary end points included other ABPM- and clinic-derived changes in DBP and systolic BP (SBP), and control and response rates (SBP response defined as 24-hour mean SBP <130 mm Hg and/or reduction from baseline > or =10 mm Hg; DBP response defined as 24-hour mean DBP <85 mm Hg or reduction from baseline > or =10 mm Hg; DBP control defined as 24-hour mean DBP <85 mm Hg). Tolerability was assessed using patient interview, spontaneous reporting, and clinical evaluation. RESULTS: A total of 1402 patients were enrolled(876 men, 525 women; mean [SD] age, 53.1 [9.9] years) (T40/H12.5, n = 517; L50/H12.5, n = 518; and T80/H12.5, n = 367). With T40/H12.5, the mean reduction in last-6-hour mean ambulatory DBP was 1.8 mm Hg greater compared with that achieved with L50/H12.5 (-11.3 [0.4] vs -9.4 [0.4] mm Hg; P < 0.001), and with T80/H12.5, the mean reduction was 2.6 mm Hg greater compared with that achieved with L50/H12.5 (-12.0 [0.4] vs -9.4 [0.4] mm Hg; P < 0.001). Analysis of secondary end points found that greater BP reduction occurred with T40/H12.5 and T80/H12.5 compared with L50/H12.5. ABPM SBP control and response rates were similar between the 3 groups, but the ABPM DBP control and response rates were significantly higher with T80/H12.5 compared with L50/H12.5 (46.6% vs 34.0% [P < 0.002] and 69.4% vs 55.0% [P < 0.001], respectively). Clinic SBP and DBP control and response rates were higher with T40/H12.5 and T80/H12.5 compared with L50/H12.5 (SBP response, 80.4% and 80.8% vs 68.5% [both, P < 0.001]; DBP response, 66.1% and 67.4% vs 54.4% [both, P < 0.001]; DBP control, 56.5% and 56.4% vs 44.1% [both, P < 0.001] ). The 2 most commonly recorded adverse events (AEs) were headache (T40/H12.5, 2.9%; L50/H12.5, 3.3%; and T80/H12.5, 3.0%) and dizziness (1.2%, 2.1%, and 3.0%, respectively). Most AEs were mild to moderate. CONCLUSIONS: The results of this pooled analysis of2 PROBE studies in adult patients with mild to moderate essential hypertension suggest that T40/H12.5 and T80/H12.5 conferred greater DBP and SBP control compared with low-dose L50/H12.5, including during the last 6 hours of the dosing interval. All 3 treatments were well tolerated.     

Blood pressure-lowering effects of extended-release niacin alone and extended-release niacin/laropiprant combination: A post hoc analysis of a 24-week,placebo-controlled trial in dyslipidemic patients

Background: Dyslipidemia and high blood pressure are both major cardiovascular disease risk factors. Niacin is an effective lipid-altering agent that has been reported to reduce the risk of cardiovascular disease. However, the more widespread use of niacin is limited, mainly due to the occurrence of flushing. Laropiprant (LRPT) is a selective antagonist of prostaglandin D₂ receptor subtype 1 that reduces extended-release niacin (ERN)-induced flushing without affecting its beneficial lipid effects. While the lipid effects of ERN are well known, the blood pressure effects are unclear.Objective: The aim of this analysis was to examine the blood pressure effects of ERN and ERN/LRPT.Methods: This was a post hoc analysis of a 24-week, worldwide, multicenter, double-blind, randomized, placebo-controlled, parallel, Phase III, previously published study of dyslipidemic patients, which examined the effect of ERN and ERN/LRPT on systolic blood pressure (SBP) and diastolic blood pressure (DBP).Results: A total of 1613 men and women, aged 21 to 85 years, with primary hypercholesterolemia or mixed dyslipidemia (66% on statins), were included in the original analysis. ERN alone, or in combination with LRPT, was associated with significant reductions in SBP and DBP at 24 weeks from baseline. The placebo-adjusted mean changes from baseline at week 24 in SBP were ?2.2 and ?3.1 mm Hg for the ERN and ERN/LRPT groups, respectively (P < 0.05 and P < 0.001). Similar changes in DBP were observed; ?2.7 and ?2.5 mm Hg in the ERN and ERN/ LRPT groups, respectively (both, P < 0.001).Conclusion: This post hoc analysis of a 24-week trial found that ERN alone, or in combination with LRPT, was associated with significant placebo-adjusted reductions from baseline in blood pressure in these hyperlipidemic hypertensive or normotensive subjects.     

Blood Pressure–lowering Effect of Fimasartan Versus Comparators: A Cross-inference With a Systematic Review and Meta-analysis Through a Quality-management System

PurposeFimasartan, one of the newest angiotensin receptor blockers (ARBs) available worldwide, has been investigated extensively since its initial development. Our study group conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) evaluating fimasartan and comparators for their blood pressure (BP)-lowering effect. Moreover, we employed a cross-inference (frequentist and Bayesian inference) system, which has never been used in the medical field, to confirm the results of our study. In addition, a quality management system was integrated throughout the study for data quality.MethodsPubMed, EMBASE, the Cochrane Central Register of Controlled Trials, ClinicalKey, and ClinicalTrial.gov were searched for RCT studies from March 1998 to March 2022. In each study, the mean differences (MD^s) and 95% CIs were identified for reductions in clinic sitting systolic and diastolic BP (SiSBP/SiDBP) or 24-hour mean systolic BP and diastolic BP by ambulatory BP monitoring (ASBP/ADBP) from baseline between the fimasartan and comparator groups, followed by meta-analysis. A subsequent meta-analysis was performed with frequentist and Bayesian inference as a tool in the cross-checking system.FindingsEleven RCTs with a total of 2459 subjects were included in the study. The clinic SiSBP/SiDBP–lowering effect of fimasartan was significantly greater relative to those of comparators (MD for clinic SiSBP, −2.58 mm Hg [95% CI, −4.35 to −0.81; P = 0.004]; MD for clinic SiDBP, −2.13 mm Hg [95% CI, −2.96 to −1.30; P = 0.00001]). The ASBP/ADBP–lowering effect of fimasartan was also significantly greater relative to those of comparators (MD for ASBP, −3.58 mm Hg [95% CI, −5.74 to −1.43; P = 0.001]; MD for ADBP, −1.99 mm Hg [95% CI, −3.34 to −0.63; P = 0.004]).ImplicationsFimasartan seems to be more effective in lowering BP than its comparators, including other ARBs. Although there is a limited amount of data and a minuscule number of study subjects available, the results of cross-inference (frequentist + Bayesian) were fairly consistent with the meta-analysis results through our quality management system.     

Effects of the fixed combination of manidipine plus delapril in the treatment of hypertension inadequately controlled by monotherapy with either component: a phase III, multicenter, open-label, clinical trial

Background: Failure to achieve good blood pressure (BP) control is probably the most important reason for high rates of morbidity and mortality in patients with hypertension. Combination therapy has been shown to increase the percentage of patients in whom BP control is achieved. One combination is a calcium channel blocker (CCB) and an angiotensin-converting enzyme inhibitor (ACE-I).Objective: The aim of this study was to assess the effects of the fixed combination of the CCB manidipine and the ACE-I delapril in the treatment of hypertensive patients already given monotherapy with either component but with poor results (ie, insufficient BP control or adverse events [AEs]).Methods: In this Phase III, multicenter, open-label, clinical trial, patients with mild to moderate hypertension were assigned to 1 of 2 groups. Group 1 comprised patients whose diastolic BP (DBP) was >90 mm Hg or who experienced AEs with manidipine 20 mg once daily. Group 2 comprised patients who had a DBP >90 mm Hg or who experienced AEs with delapril 30 mg BID. In both groups, patients aged <65 years were to be treated with a fixed combination of manidipine 10 mg plus delapril 30 mg once daily for 12 weeks, whereas patients aged ≥65 years were to be treated with manidipine 5 mg plus delapril 15 mg once daily for 2 weeks and then manidipine 10 mg plus delapril 30 mg once daily for 10 weeks. Patients were assessed at baseline and at 2, 4, 8, and 12 weeks of treatment. At each visit, systolic blood pressure (SBP), DBP, and heart rate were measured 24 hours after dosing, and AEs were recorded.Results: Group 1 included 154 patients (80 men, 74 women; mean [SD] age, 55 [6] years); group 2 included 158 patients (79 men, 79 women; mean [SD] age, 56 [5] years). Mean BP decreased significantly in both groups (P<0.01). Compared with baseline values, mean SBP/DBP decreased 16.2 (3.8)/10.1 (1.9) mm Hg in group 1 and 15.8 (3.1)/11.0 (1.5) mm Hg in group 2 at the last visit. The success rate—rate of normalized DBP (≤90 mm Hg) and responder rate (DBP reduction ≥10 mm Hg)—was 79% in group 1 and 82% in group 2. The rates of treatment-related AEs were 11% in group 1 and 8% in group 2. In group 1, heart rate significantly increased from baseline only at 2 weeks (P<0.05); in group 2, at each visit (P<0.05) except at week 12. However, none of these differences were clinically significant.Conclusion: In this study population of patients whose BP was not adequately controlled by monotherapy, the fixed combination of manidipine 10 mg plus delapril 30 mg, once daily, was effective and well tolerated.     

Comparison of 26-week efficacy and tolerability of telmisartan and atenolol, in combination with hydrochlorothiazide as required, in the treatment of mild to moderate hypertension: a randomized, multicenter study

OBJECTIVE: This study was undertaken to compare the efficacy and tolerability of telmisartan, a novel antihypertensive agent, and atenolol, a well-established beta-blocker, in the treatment of mild to moderate hypertension. METHODS: This 26-week, multicenter, randomized, double-blind, double-dummy, parallel-group, titration-to-response study compared doses of telmisartan (40 mg titrated to 80 mg titrated to 120 mg) with atenolol (50 mg titrated to 100 mg) required to achieve diastolic blood pressure (DBP) control (< or = 90 mm Hg or a decrease from baseline of > or = 10 mm Hg). Open-label hydrochlorothiazide (HCTZ) 12.5 or 25 mg was added if needed according to a prespecified titration rule. Men and women aged > 18 years with mild to moderate hypertension (morning mean supine DBP [SDBP] > or = 95 mm Hg and < or = 114 mm Hg) were eligible to participate. Patients with significant cardiovascular, metabolic, hepatic, or renal dysfunction or chronic obstructive pulmonary disease were excluded. The primary efficacy end point was trough SDBP response at 26 weeks; secondary efficacy end points included changes from baseline at trough in both standing and supine DBP and systolic blood pressure (SBP), and heart rate after 4, 8, 16, and 26 weeks; SBP control (reduction from baseline of > or = 10 mm Hg); normalization of supine SDBP to < or = 90 mm Hg; and the need for add-on HCTZ. Changes in quality of life were also examined. Adverse events were obtained from spontaneous reporting and recorded. Serious adverse events were reported to the sponsor according to predefined timelines. RESULTS: A total of 533 patients from 49 centers participated. Patients' mean age was 57.9 years (range, 22-79 years); 55.9% (298/533) of the population was male and 98.1% (523/533) was white. Of the 533 patients randomly assigned to treatment and included in the safety analysis, 520 (97.6%) were included in the efficacy analysis; 346 received telmisartan and 174 received atenolol. A total of 489 patients (91.7%) completed the study (325 [93.9%], telmisartan; 164 [94.2%], atenolol). Full SDBP response (trough SDBP < or = 90 mm Hg and/or a reduction from baseline of > or = 10 mm Hg) was observed in 84% and 78% of telmisartan- and atenolol-treated patients, respectively; this difference was not statistically significant. Final SBP/DBP reductions of 20.9/14.4 mm Hg were observed for the telmisartan regimen versus 16.7/13.3 mm Hg for the atenolol regimen; only the difference in SBP was significant (P = 0.005). Reduction from baseline in SBP of > or = 10 mm Hg was achieved by 80% of telmisartan-treated and 68% of atenolol-treated patients (P = 0.003). Adverse events were reported by 52.7% of patients given telmisartan and 61.2% of patients given atenolol; this difference was not statistically significant. Most events were mild or moderate. Although fatigue and male impotence were more common in atenolol-treated patients (3.4% and 4.0%, respectively), the incidence of these adverse events was too low to differentiate statistically. CONCLUSIONS: Telmisartan appears to be at least as effective as atenolol in the treatment of mild to moderate hypertension and may be better tolerated.     

Comparison of amlodipine and enalapril in the treatment of isolated systolic hypertension in the elderly: an open-label, randomized, parallel-group study

Background: The benefits of treating isolated systolic hypertension (ISH) are well established, but the most appropriate drug choice is still uncertain.Objective: The purpose of this study was to compare amlodipine, a calcium channel blocker, with enalapril, an angiotensin-converting enzyme inhibitor, in the treatment of ISH in a cohort of elderly patients (≥60 years of age).Methods: Ambulatory patients with ISH (seated systolic blood pressure [SBP] >160 mm Hg and <220 mm Hg; diastolic blood pressure [DBP] <95 mm Hg) who had not been treated previously or who had stopped their medication at least 4 weeks before the study were enrolled. Patients were randomized to receive amlodipine 5 mg/d or enalapril 10 mg/d. After 4 weeks of treatment, the dose was doubled for those patients whose sitting SBP had not decreased to <150 mm Hg or by >20 mm Hg, and treatment was continued for an additional 4 weeks.Results: A total of 89 patients were randomized to treatment, 46 to amlodipine and 43 to enalapril; 1 patient in the enalapril group died due to ischemic stroke despite adequate blood pressure control. The absolute reductions in seated and standing SBP/DBP were similar with both drugs after 8 weeks: 27 mm Hg/4.6 mm Hg with amlodipine and 23.9 mm Hg/3.9 mm Hg with enalapril (sitting) and 25.1 mm Hg/4.1 mm Hg and 21.3 mm Hg/4.2 mm Hg (standing) with amlodipine and enalapril, respectively (P = NS). At 4 weeks, 24 patients (52.2%) in the amlodipine group and 33 patients (76.7%) in the enalapril group had their medication dose doubled because their SBP was not adequately controlled with the initial dose (P < 0.01). At the end of the study, 24 patients were taking 10 mg amlodipine and 22 patients were taking 5 mg (mean dose 7.6 ± 2.5 mg); 33 patients were taking 20 mg enalapril and 10 patients were taking 10 mg (mean dose 17.8 ± 4.1 mg). Side effects occurred significantly more frequently in the amlodipine group (P = 0.01).Conclusion: The results of this study suggest that amlodipine and enalapril are similarly effective in treating ISH in elderly patients, with few side effects.     

Assessment of the antihypertensive efficacy of various doses of delapril by office and ambulatory blood pressure measurement: The DEFIND study

This study was undertaken to compare and verify the antihypertensive effects of various delapril doses versus placebo on office and ambulatory blood pressure (BP). After a 2-wk placebo period, 303 patients with mild to moderate essential hypertension were randomized in a double-blind study to 8 wk of treatment with placebo, or delapril 7.5 mg twice daily, delapril 15 mg twice daily, delapril 30 mg twice daily, or delapril 30 mg once daily. BP changes versus baseline and rates of normalized office systolic blood pressure (SBP) > 140 mm Hg and diastolic blood pressure (DBP) > 90 mm Hg, as well as responder office SBP > 140 mm Hg or reduction ≥20 mm Hg and office DBP > 90 mm Hg or reduction ≥10 mm Hg, were calculated. In the intention-to-treat population (n=296), office SBP and DBP reductions were more notable with 30 mg twice daily (15.6/11.5 mm Hg) and 15 mg twice daily (14.8/12.5 mm Hg) than with other delapril regimens (30 mg once daily: 11.8/10.5 mm Hg; 7.5 mg twice daily: 12.9/10.1 mm Hg) and placebo (P< .05 for DBP;P< .01 for SBP). The same was true for frequency of responders (63.8% and 60.3%; P≤.05 vs placebo) and normalized patients (58.6% and 53.4%;P< .05 vs placebo). Analysis of ambulatory BPs confirmed the accuracy of office BPs. Drug-related adverse events occurred in 3.4% to 6.7% of patients given delapril and in 6.5% of those given placebo. The lowest effective dose of delapril, 15 mg twice daily, may be recommended as the initial dose for patients who begin treatment with this agent.     

Evaluation of long-term efficacy and tolerability of irbesartan in elderly hypertensive patients with renal impairment in an open-label study

Background: Hypertension, left untreated, can lead to serious complications, including stroke myocardial infarction, and renal failure. Because lowering blood pressure correlates with slowing of renal disease progression, the control of hypertension in the presence of renal disease is essential.Objective: We evaluated the efficacy, tolerability, and safety of irbesartan alone or in combination with other antihypertensive agents in elderly patients with hypertension and chronic renal insufficiency.Methods: Patients > 65 years of age with hypertension (sitting diastolic blood pressure [SiDBP] 90-115 mm Hg) and chronic renal sufficiency that was mild (creatinine clearance [CrCL] 30-60 mL/min per 1.73 m²) or moderate to severe CrCL 10-29 mL/min per 1.73 m²) were enrolled. After a 3-week placebo run-in period, irbesartan was administered for 12 months at 150 mg/d. After 4 weeks of therapy, patients whose blood pressure was not adequately controlled (ie, SiDBP ≥90 mm Hg or <5 mm Hg decrease from baseline) had an additional antihypertensive agent added to their daily irbesartan regimen; dosage adjustment of the second drug was permitted after 2 weeks to optimize blood pressure control. Twenty-four-hour CrCL was determined, and renal clearance studies of inulin and p-aminohippurate were performed in a subset of patients.Results: A total of 32 patients (21 men, 11 women; mean age, 70.4 years) were enrolled. Thirty patients had mild renal insufficiency (mean CrCL, 44.45 mL/min per 1.73 m²) and 2 patients had moderate to severe renal insufficiency (mean CrCL 21.32 mL/min per 1.73 m²). Trough sitting blood pressures were reduced at the end of the first week of treatment in all groups. After 8 weeks, 12 weeks, and 1 year of treatment, the mean reductions in systolic blood pressure (SBP)/DBP were −11.9/−8.7 mm Hg, −10.8/−9.4 mm Hg, and −14.7/−12.1 mm Hg, respectively, in patients with mild renal insufficiency and −7.7/−6.3 mm Hg, −13.1/−11.8 mm Hg, and −14.1/−10.6 mm Hg in patients with moderate to severe renal insufficiency. CrCL, glomerular filtration rate, and effective renal plasma flow, as measured in a subset of 11 patients, were stable. Treatment was discontinued for 3 patients because of a clinical adverse event or laboratory parameter abnormality. Hyperkalemia (>6 mEq/L) requiring discontinuation of irbesartan occurred in 1 patient with moderate to severe renal insufficiency.Conclusion: The results of this study suggest that irbesartan, as monotherapy (150 mg once daily) or in combination with other antihypertensive drugs, is effective in reducing blood pressure in elderly hypertensive patients with chronic renal impairment and that irbesartan regimens are well tolerated in this population.     

Association between human atrial natriuretic peptide Val7Met polymorphism and baseline blood pressure, plasma trough irbesartan concentrations, and the antihypertensive efficacy of irbesartan in rural Chinese patients with essential hypertension

BACKGROUND: Individual variations in the pharmacokinetics and pharmacodynamics of antihypertensive drugs are influenced by genetic and environmental factors. The ANP gene, which encodes the precursor of atrial natriuretic peptide (ANP), is among the candidate genes for genetic susceptibility to hypertension. OBJECTIVE: This study examined the relationship between ANP Val7Met polymorphism (Single Nucleotide Polymorphism database ID: rs5063) and baseline blood pressure (BP), plasma trough irbesartan concentrations, and the antihypertensive efficacy of irbesartan in rural Chinese patients with essential hypertension. METHODS: Patients with essential hypertension who had taken no antihypertensive medications within 4 weeks of study initiation received oral irbesartan 150 mg/d for 4 weeks. Genotyping was performed for all patients. BP was measured before dosing on the 1st and 28th days of treatment. Plasma irbesartan concentrations were measured using high-performance liquid chromatography with fluorescent detection. Antihypertensive efficacy was defined as attainment of a diastolic BP (DBP) <90 mm Hg (DBP analysis), a systolic BP (SBP) <140 mm Hg (SBP analysis), and a DBP <90 mm Hg and SBP <140 mm Hg (DBP and SBP analysis). RESULTS: The study included 756 patients, 621 with the Val/Val genotype and 135 with the Val/Met+Met/Met genotypes. There were no significant differences in age, body mass index, sex, education level, occupation, alcohol consumption, or smoking status between the 2 groups. Patients with the Val/Met+Met/Met genotypes had a significantly lower mean baseline DBP compared with those with the Val/Val genotype (adjusted regression coefficient [SE]: -2.5 [1.0] mm Hg; P = 0.012) and significantly lower mean steady-state plasma trough irbesartan concentrations (adjusted regression coefficient: -12.6 [4.1]; P = 0.002). No significant association was found between antihypertensive efficacy and Val7Met polymorphism in the overall population, but in an analysis by baseline DBP status, patients with the Val/Met+Met/Met genotype a baseline DBP > or =100 mm Hg had significantly smaller reductions in DBP (adjusted regression coefficient: -5.7 [1.4] mm Hg; P < 0.001) and SBP compared with those with the Val/Val genotype and a baseline DBP > or =100 mm Hg (adjusted regression coefficient: -9.8 [2.9] mm Hg; P < 0.001). CONCLUSION: The findings of this study suggest that in these rural Chinese patients with essential hypertension, ANP Val7Met polymorphism may be a genetic marker for baseline DBP, plasma irbesartan concentrations, and the antihypertensive efficacy of short-term irbesartan therapy.