Olmesartan compared with other angiotensin II receptor antagonists: Head-to-head trials

Background: Drugs that block the renin-angiotensin system represent one of the most significant therapeutic interventions available for the treatment of hypertension. The angiotensin II receptor antagonists (AIIRAs), also known as sartans, are one such class of drugs that block the effects of angiotensin II by antagonizing the angiotensin II type 1 receptor. Olmesartan is the newest member of this class.Objective: The present article reviews 3 head-to-head trials directly comparing the antihypertensive efficacy of olmesartan with that of 4 other AURAS, at recommended maintenance doses, already in clinical use for the treatment of hypertension.Results: In the first study, olmesartan 10 mg/d was compared with losartan 50 mg/d in 316 patients with mild to moderate hypertension (mean baseline diastolic blood pressure [DBP], 95–114 mm Hg). Dosage was doubled at week 4 and hydrochlorothiazide was added at week 12 if blood pressure response was inadequate. Olmesartan was significantly more effective than losartan with respect to the reduction in blood pressure at weeks 2, 4, and 12, and to the responder rate at weeks 2 and 4 (with the starting dose of the respective drug). In a second study, olmesartan 20 mg/d was shown to be significantly more effective than losartan 50 mg/d, valsartan 80 mg/d, and irbesartan 150 mg/d in 588 patients with mild to moderate hypertension (mean sitting baseline DBP, 100–115 mm Hg) (P ⩽ 0.05). At week 2, the reduction in blood pressure observed with olmesartan was significantly greater than that of the comparator treatments (P ⩽ 0.05). The superiority of olmesartan was maintained at week 8. The third study involved 643 evaluable patients with moderate to severe hypertension (mean DBP, 100–120 mm Hg; mean systolic blood pressure, >150 mm Hg). Olmesartan 20 mg/d was more effective than candesartan 8 mg/d in lowering 24-hour blood pressure at week 8 (P ⩽ 0.05). Most of this treatment effect was evident after only 1 or 2 weeks, with greater reductions in blood pressure compared with candesartan.Conclusions: These data indicate that, at the doses studied, olmesartan is more effective than other AIIRAs tested at their recommended doses, in terms of reduction of cuff or 24-hour ambulatory blood pressure, in patients with essential hypertension. These differences in blood pressure reduction between these agents may be clinically relevant and have important long-term implications. Additional studies will further define the role of olmesartan in the management of cardiovascular diseases, such as atherosclerosis.     

Clinical Efficacy and Safety of Lower-Dose Indapamide Therapy in the Treatment of Patients with Mild to Moderate Hypertension

Previous clinical studies with indapamide, an indoline antihypertensive drug with diuretic and vasodilating activities, have shown a dose relationship associated with potassium loss. Two placebo-controlled, randomized, double-blind, parallel clinical studies were, therefore, done to evaluate the safety and efficacy of a low dose (1.25 mg) of indapamide and to determine if an improved safety profile could be produced while maintaining efficacy with a 1.25-mg dose in patients with mild to moderate essential hypertension. Four hundred seventeen (417) adult patients with mild to moderate essential hypertension (sitting diastolic blood pressure greater-than-or-equal 95 mmHg and less-than-or-equal 110 mmHg) were enrolled in two clinical studies; 209 patients were randomized to indapamide 1.25 mg and 208 patients to placebo. Patients received single-blind placebo for a 4-week washout period followed by an 8-week double-blind treatment period during which patients received either indapamide 1.25 mg or placebo. The primary efficacy endpoint was the mean change from baseline to week 8 in sitting diastolic blood pressure. Secondary efficacy variables were the proportion of patients whose sitting diastolic blood pressure had decreased greater-than-or-equal 10 mmHg and/or had a sitting diastolic blood pressure of less-than-or-equal 90 mmHg (treatment success) at all visits and at endpoint, mean changes from baseline in sitting diastolic blood pressure at designated timepoints and at endpoint, and mean changes from baseline in standing diastolic blood pressure and in sitting and standing systolic blood pressure at all visits and at endpoint. Results of these trials were pooled in order to have a larger patient population in an attempt to detect trends not readily apparent with a smaller sample size. In the primary analysis, indapamide produced statistically significantly (p = 0.0001) greater reductions in sitting diastolic blood pressure than placebo after 8 weeks of therapy. In the secondary analysis, the percentage of indapamide-treated patients who achieved treatment success after 8 weeks of therapy was statistically significantly (p < 0.0001) higher compared to placebo-treated patients. In addition, indapamide produced a statistically significantly (p = 0.0001) superior reduction compared to placebo in sitting systolic and standing systolic and diastolic blood pressure after 8 weeks of therapy. The incidence of drug-related adverse events between patients in the indapamide and placebo groups was similar. There were no clinically meaningful differences in laboratory values, including serum potassium, between the patients in the indapamide and placebo groups. Low-dose (1.25 mg) indapamide proved to be safe and effective in the treatment of mild to moderate hypertension.     

Amlodipine besylate/olmesartan medoximil fixed combination for the treatment of hypertension

National and international guidelines recommend the use of combination drugs as a first-line therapy for persons with stage 2 hypertension (blood pressure >160/100 mmHg). Although hypertension is common (30% of adults in the USA), its control to recommended blood pressure levels of under 140/90 mmHg remains low, at 36.8%. In the past, fixed-drug combinations included a diuretic with another antihypertensive drug. Recently, combinations of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers mostly with dihydropyridine calcium channel blockers have been developed and approved for the treatment of hypertension. One of these, olmesartan medoxomil in combination with amlodipine besylate has been shown to be effective and safe for the treatment of hypertension. In a large, randomized, placebo-controlled study (Combination of Olmesartan medoxomil and Amlodipine besylate in Controlling High blood pressure [COACH]) of 1940 patients, the high-dose combinations of olmesartan medoxomil and amlodipine besylate 40/10 mg/day reduced the sitting systolic and diastolic blood pressure by 29/19 mmHg from baseline (p < 0.001) and resulted in 54% of patients achieving blood pressure goals. It also decreased the pedal edema induced by amlodipine monotherapy 10 mg/day by 36.1%. This drug combination, besides being effective, is also safe and well tolerated.     

Evaluation of the dose—response relationship of aliskiren,a direct renin inhibitor,in an 8-week,multicenter, randomized,double-blind,parallel-group,placebo-controlled study in adult patients with stage 1 or 2 essential hypertension

Background: Aliskiren is approved for the treatment of hypertension at once-daily doses of 150 or 300 mg by the US Food and Drug Administration and the European Commission. It is generally well tolerated and provides 24-hour, dose-dependent blood pressure (BP) reduction; however, the effect of the 75-mg dose has been inconsistent in previous trials.Objectives: This study was designed to assess the efficacy and tolerability of once-daily administration of aliskiren 75 mg and to evaluate the dose-response relationship across all 3 doses of aliskiren (75, 150, and 300 mg).Methods: In this 8-week, multicenter, randomized, double-blind, parallel-group, placebo-controlled study, patients aged ≥18 years with stage 1 or 2 essential hypertension entered a 3- to 4-week, single-blind, placebo run-in period. Eligible patients were randomized (1:1:1:1) to receive oral, once-daily doses of aliskiren 75, 150, or 300 mg or placebo. The primary efficacy variable was the change from baseline in mean sitting diastolic BP (msDBP) at the week-8 end point. Tolerability was assessed by monitoring and recording all adverse events (AEs).Results: A total of 642 patients (mean [SD] age, 52.0 [10.73] years; 60.0% male; 80.8% white; mean body weight, 89.2 [18.4] kg [range, 50–160 kg]) were included in the study. Overall, 576 patients (89.7%) completed the double-blind treatment period. The most frequent reasons for discontinuation were unsatisfactory therapeutic effect (27/642 randomized patients [4.2%]) and AEs (17/642 [2.6%]). At end point, aliskiren 150 and 300 mg significantly reduced msDBP (both, P < 0.001) and mean sitting systolicConclusions: This study found a positive linear dose-response relationship in BP reduction with aliskiren 75, 150, and 300 mg dosed once daily, but only aliskiren 150 and 300 mg provided statistically significant reductions from baseline compared with placebo. All 3 doses of aliskiren were generally well tolerated.     

Retracted: Effects of an olmesartan/amlodipine fixed dose on blood pressure control,some adipocytokines and interleukins levels compared with olmesartan or amlodipine monotherapies

What is known and Objective: To evaluate the effects of an olmesartan/amlodipine single pill combination compared with olmesartan or amlodipine monotherapies on blood pressure control, lipid profile, insulin sensitivity and some adipocytokines levels. Methods: Two hundred and seventy‐six patients were enroled in the study and were randomly assigned to take olmesartan 20 mg, amlodipine 10 mg, or a single pill containing an olmesartan/amlodipine combination 20 mg/5 mg for 12 months. We evaluated at the baseline, and after 6 and 12 months: body weight, body mass index, systolic and diastolic blood pressure (SBP and DBP), fasting plasma glucose (FPG), fasting plasma insulin (FPI), lipid profile, adiponectin (ADN), resistin (r), interleukin‐1β (IL‐1β) and interleukin‐5 (IL‐5). At the baseline, and after 6 and 12 months, patients underwent an euglycemic, hyperinsulinemic clamp to assess insulin sensitivity (M value). Results and Discussion: There was a similar decrease in SBP and DBP after 6 and 12 months in all groups, even if olmesartan/amlodipine combination gave a major decrease in SBP and DPB compared with amlodipine and olmesartan monotherapies. Olmesartan/amlodipine combination decreased FPG after 12 months compared with amlodipine monotherapy. Olmesartan/amlodipine combination decreased FPI and HOMA index and increased M value both compared with baseline and compared with olmesartan and amlodipine monotherapies. Both olmesartan and olmesartan/amlodipine increased ADN and reduced r, without significant differences between the two groups. Regarding interleukins, no differences emerged in group to group comparison. What is new and Conclusion: Olmesartan/amlodipine combination resulted more effective than olmesartan and amlodipine monotherapies in reducing blood pressure, and in increasing insulin sensitivity parameters, but not resulted more effective in improving adipocytokines and interleukins levels analysed, compared with amlodipine or olmesartan monotherapy in hypertensive patients in this double‐blind, randomized clinical trial.     

Blood pressure-lowering efficacy of olmesartan relative to other angiotensin II receptor antagonists: an overview of randomized controlled studies

The aim of the present work was to review published studies investigating the dose-related efficacy on blood pressure (BP) of olmesartan and of other commercially available angiotensin II type I receptor blockers (ARBs). Patient population comprises mild to moderate hypertensive adult patients. We selected studies with comparable design and dose ranges. Dose-effect relationship plots were fitted for diastolic (DBP) and systolic (SBP) BP to the simplified E(max) model. We also examined controlled studies of olmesartan vs. other individual ARBs. Our overview was based on 7280 patients, of which 5769 received an ARB and 1511 received placebo. Except for losartan, the data fitted correctly to the E(max) model, with correlation coefficients ranging from 0.77 to 0.99. BP-lowering efficacy defined as E(max) was superior with olmesartan, (DBP/SBP mmHg: -9.0/-12.4) when compared with candesartan (-6.7/-11.3), irbesartan (-6.5/-11.2) and valsartan (-6.3/-8.9). Head-to-head comparisons of olmesartan to each of the other ARBs used at per-label 'recommended doses', support the finding of a greater BP-lowering effect of olmesartan. This overview suggests that clinically relevant differences in maximal efficacy, as well as in efficacy of per-label recommended doses can be evidenced among individual ARBs. Olmesartan efficacy was consistently at the highest end of the range of efficacy of ARBs studied.     

A Study of the Efficacy and Safety of Moexipril in Mild to Moderate Hypertension

This placebo-controlled, double-blind, multicenter study examined the efficacy, safety, and tolerability of the angiotensin-converting enzyme inhibitor, moexipril, in lowering blood pressure in mildly to moderately hypertensive patients. Patients were initially randomized into four groups, two of which received moexipril 7.5 mg per day and two received moexipril 15 mg per day, for first 12 weeks of treatment. Patients then entered a withdrawal phase with one of the groups in each dose category continuing that dose of moexipril and one receiving placebo for 12 more weeks. From 223 patients randomized initially, 190 completed the 12-week withdrawal phase. In the two dosage groups from baseline to 12 weeks, sitting diastolic blood pressure decreased from 101.1 to 92.8 mm Hg for the 7.5-mg group and from 100.7 to 91.3 mm Hg for the 15-mg group (p < 0.05 baseline to week 12 in both groups) with a significant difference between those groups attained at week 12 only (p = 0.03). By the end of the withdrawal phase (24-week evaluation), the group that continued to receive 7.5 mg moexipril decreased diastolic blood pressure by 8.2 mm Hg, whereas the corresponding placebo group decreased diastolic blood pressure by 3.7 mm Hg. Although the difference between these two groups was not significant at the 24-week end point, all other time points differed significantly between groups at p less-than-or-equal 0.017. Similarly, whereas the corresponding placebo group had a mean reduction in diastolic blood pressure of 4.6 mm Hg, the group that continued 15 mg of moexipril showed a mean diastolic blood pressure reduction of 10.6 mm Hg (p < 0.001 between groups). No comparison between the two moexipril dosage groups was significant, however, during the withdrawal phase. These results during medication withdrawal indicate that moexipril is effective in significantly lowering diastolic blood pressure.     

Olmesartan medoxomil: the seventh angiotensin receptor antagonist

OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and adverse effects of olmesartan medoxomil, an angiotensin II receptor antagonist for the treatment of hypertension. DATA SOURCES: Information was obtained from MEDLINE searches (1996-April 2002) of English-language medical literature. Search terms included CS-866, olmesartan, olmesartan medoxomil, RNH-6270 (active metabolite of olmesartan), Benicar, angiotensin receptors, and antihypertensive agents. In addition, references from relevant articles were reviewed for additional citations. The authors independently reviewed literature identified in the searches. Studies evaluating olmesartan (i.e., abstracts, clinical trials, data on file with manufacturer) were considered for inclusion. STUDY SELECTION: All articles identified from data sources with pertinent information regarding olmesartan medoxomil were evaluated, and all information deemed relevant was included in this review. DATA SYNTHESIS: Olmesartan medoxomil is a competitively priced addition to the class of angiotensin II receptor antagonists. Monotherapy with olmesartan medoxomil in once-daily doses of 20-40 mg has produced significant reductions in systolic and diastolic blood pressure in hypertensive patients. Adverse effects have been minimal with olmesartan medoxomil, with dizziness being the only adverse effect occurring more often than with placebo in clinical trials. Additionally, animal studies indicate that olmesartan medoxomil may prove to be useful treatment for diabetic nephropathy, as well as atherosclerosis. CONCLUSIONS: Olmesartan medoxomil has a favorable safety and efficacy profile, with blood pressure-lowering effects comparable to those of other angiotensin receptor blockers (i.e., losartan, valsartan, irbesartan). At this time, formulary decisions will be driven primarily by economic issues. Theoretical benefits of olmesartan medoxomil in reducing atherogenesis and lowering angiotensin II concentrations better than the alternative agents will be determined only with more extensive research.     

Nighttime administration of high-dose,sustained-release melatonin does not decrease nocturnal blood pressure in African-American patients: Results from a preliminary randomized,crossover trial

ObjectivesThis preliminary study tested whether a high-dose, sustained-release form of melatonin reduced 24-hour blood pressure in African-Americans.DesignRandomized, placebo-controlled, crossover pilot study of 40 self-defined African-American patients with essential hypertension.Settings/locationUrban, academic medical center and associated outpatient clinics.InterventionsPatients ingested either melatonin (high dose [24 mg], sustained-release formulation] or placebo in randomized order over a 4-week period.Outcome measuresMean nighttime and daytime systolic and diastolic blood pressures, as measured with 24-hour ambulatory blood pressure monitors. The primary outcome was mean nighttime systolic blood pressure.ResultsThere were no statistically differences between melatonin and placebo conditions in mean nighttime or daytime systolic or diastolic blood pressures.ConclusionsIn contrast with studies in other populations, this preliminary study showed that nighttime dosing of continuous-release melatonin had no significant effect on nocturnal blood pressure in African Americans with essential hypertension when compared to placebo.     

Effectiveness of hydrochlorothiazide in combination with telmisartan and olmesartan in adults with moderate hypertension not controlled with monotherapy: a prospective, randomized, open-label, blinded end point (PROBE), parallel-arm study

Background:The potential combinations of antihypertensive agents are many, and making rational choices depends on the characteristics of each drug and on their complementary mechanisms of action.Objective: The aim of this study was to evaluate the effectiveness of adding hydrochlorothiazide (HCTZ) 12.5 mg to olmesartan 20 mg or telmisartan 80 mg on blood pressure (BP) in patients with moderate hypertension.Methods: Consecutive outpatients at the Centro per l'Ipertensione e la Fisiopatologia Cardiovascolare, University of Pavia, Pavia, Italy, of both sexes aged 39 to 75 years were considered eligible for enrollment if they had a sitting diastolic BP (DBP) ->99 mm Hg and <110 mm Hg at the end of an initial 2-week washout period. Patients were random- ized to olmesartan 20 mg QD or telmisartan 80 mg QD according to a prospective, open-label, blinded end point, parallel-arm design. After 8 weeks of monotherapy, patients whose BP was not controlled (DBP ->90 mm Hg) received HCTZ 12.5 mg QD for 8 additional weeks. Clinical and ambulatory BPs were measured at the end of the washout period and at the end of both treatment periods. Adverse events (AEs) were recorded from spontaneous reports and direct inquiry from investigators.Results: One hundred forty-five patients, all of whom were white, were recruited for the study. After the initial washout period, 13 patients did not meet the inclusion criteria and 6 refused to continue. A total of 126 white patients (69 men, 57 women; mean [SD] age, 60.2 [11.6] years) were randomized to receive monotherapy. Of these, 35 patients (56%) in the olmesartan group and 33 (52%) in the telmisartan group had previously received antihypertensive therapy. At the end of monotherapy, the 52 patients in the olmesartan group and the 49 patients in the telmisartan treatment group who were still in the study and had their BP inadequately controlled by treatment had HCTZ 12.5 mg QD added to their treatment regimen. Both combinations induced a greater ambulatory mean (SD) systolic BP (SBP) and DBP reduction than monothera- py (SBP: 145.3 [6.1] in the olmesartan group and 140.1 [6.4] in the telmisartan group, P < 0.05; DBP: 88.1 [5.1] in the olmesartan group and 84.9 [4.9] in the telmisartan group, P < 0.05). The mean (SD) reduction from baseline in the telmisartan/HCTZ-treated patients (21.5 [10.1]/14.6 [5.2] mm Hg for 24 hours, 21.8 [10.2]/14.9 [5.2] mm Hg for daytime, and 20.4 [10.3]/13.7 [5.9] mm Hg for nighttime; all, P < 0.001 vs baseline) was significantly greater than that observed in the olmesartan/HCTZ-treated patients (18.8 [9.8]/12.3 [4.9] mm Hg for 24 hours, 19.3 [9.8]/12.8 [4.9] mm Hg for daytime, and 17.4 [10.2]/10.6 [5.5] mm Hg for nighttime; all, P < 0.001 vs baseline), with a significant difference between the 2 treatment groups (P < 0.01). Compared with mono- therapy, the add-on effect of HCTZ 12.5 mg QD administration was significantly greater in the telmisartan group than in the olmesartan group (P < 0.05); the differ- ence being more evident for nighttime BP values (SBP, P 0.031; DBP, P 0.025). Reported AEs were similar in the olmesartan/HCTZ and the telmisartan/HCTZ groups (4 patients [7%] vs 3 patients [6%]).Conclusion: The addition of HCTZ 12.5 mg to telmisartan 80 mg monothera- py was associated with greater BP reduction than the addition of the same dose of HCTZ to olmesartan 20 nag monotherapy in these patients previously uncontrolled on monotherapy.     

Olmesartan medoxomil: an angiotensin II-receptor blocker

BACKGROUND: Regulation of the activity of the renin-angiotensin-aldosterone system has become important in the management of cardiovascular disease. Olmesartan medoxomil (CS-866) is the newest selective angiotensin II-receptor blocker (ARB) to be approved for the treatment of hypertension. OBJECTIVE: This review describes the mechanism of action, pharmacokinetics, adverse-effect profile, drug-interaction potential, and dosing of olmesartan medoxomil. The results of relevant clinical efficacy and safety trials are also discussed. METHODS: This review is based on data from published clinical efficacy and safety trials and abstracts of conference presentations. To identify appropriate English-language publications for review, MEDLINE (1966-October 2002) and EMBASE (1990-2002) were searched using the terms olmesartan medoxomil, CS-866, angiotensin II-receptor blocker, and hypertension. RESULTS: Olmesartan medoxomil has been reported to be an effective agent for the treatment of hypertension. Its blood pressure-lowering effects were comparable to those of other antihypertensive agents and other ARBs. Effects were seen as early as 2 weeks and persisted when olmesartan medoxomil was administered long term (for 1 year). The maximum recommended daily dose is 40 mg, except in the presence of severe renal insufficiency (creatinine clearance <20 mL/min) or moderate hepatic insufficiency (Child-Pugh score 7-9), when the daily dose should not exceed 20 mg. Olmesartan medoxomil was well tolerated. The most commonly reported adverse effect occurring significantly more often with olmesartan medoxomil than with placebo was dizziness (seen in approximately 3% of patients). The occurrence of clinically significant drug interactions was minimal. CONCLUSIONS: Based on the available literature, olmesartan medoxomil is an effective ARB for the treatment of hypertension, with a favorable adverse-effect and drug-interaction profile.     

The effect of pramipexole on mood and motivational symptoms in parkinson's disease: A meta-analysis of placebo-controlled studies

Background: Mood and motivational symptoms have been reported in up to 35% and 51%, respectively, of patients with Parkinson's disease (PD). Preliminary evidence indicates that pramipexole may have a positive effect on these symptoms.Objective: This analysis was conducted to evaluate the effects of pramipexole on mood and motivational symptoms in patients with PD.Methods: Data for the meta-analysis were extracted from all randomized, double-blind, placebo-controlled trials of pramipexole in the manufacturer's database that included part I of the Unified Parkinson's Disease Rating Scale (UPDRS) as an outcome measure. Only patients with baseline scores >0 (range, 0–4) on item 3 (mood) and item 4 (motivation) were included. Separate analyses were performed for mood and motivational symptoms. The outcome of interest was improvement in scores, with no improvement including both unchanged and increased scores. Odds ratios (ORs), 95% CIs, and Cochran-Mantel-Haenszel tests were calculated to compare rates of improvement and no improvement, stratified by trial.Results: Fourteen randomized, double-blind, placebo-controlled trials of pramipexole were identified, all employing the severity of motor symptoms of PD as a primary outcome. Seven of these trials (N = 1296) employed part I of the UPDRS as a secondary outcome measure and were included in the meta-analysis; no other measure of mood or motivational symptoms was used in any of the 14 studies. Six of the 7 studies included patients with motor fluctuations due to levodo-pa treatment, and the remaining study included patients who did not yet require levodopa. Six studies were published in peer-reviewed journals, and all 7 were included in the New Drug Application for pramipexole. The published study reports were usually limited to motor symptoms; only 1 reported on mood and motivation. However, for the purpose of this meta-analysis, the authors had access to data that were not reported in the original publications. In the pooled data set, 480 patients (59.8% male; mean age, 63.3 years) had a baseline score >0 on item 3 (mood). These mood symptoms improved in 64.7% of patients treated with pramipexole and 43.4% of those receiving placebo (OR weighted by trial = 2.41; P < 0.001). Five hundred seventy patients (64.9% male; mean age, 64.1 years) had a baseline score >0 on item 4 (motivation). These motivational symptoms improved in 63.2% of patients treated with pramipexole and 45.0% of those receiving placebo (OR weighted by trial = 2.06; P < 0.001).Conclusions: This meta-analysis of 7 randomized controlled trials suggests that pramipexole had a beneficial effect on mood and motivational symptoms in PD patients who did not have major depressive disorder. The clinical value of pramipexole in the treatment of depressive and apathetic syndromes requires further investigation.     

Low-dose combination treatment for hypertension versus single-drug treatment-bisoprolol/hydrochlorothiazide versus amlodipine, enalapril, and placebo: combined analysis of comparative studies

To assess the efficacy and safety of 2.5, 5, and 10 mg bisoprolol/6. 25 mg hydrochlorothiazide (HCTZ), 2.5, 5, and 10 mg amlodipine; and 5, 10, 20, and 40 mg enalapril in subjects (n = 541) with a sitting diastolic blood pressure of 95 to 114 mm Hg, data from two comparative studies were pooled. All drugs were titrated to a diastolic blood pressure 90 mm Hg or less. Both studies were double-blind, randomized, parallel dose escalation trials with similar designs and included three active treatments. The second study also had a placebo group. The mean change from baseline of systolic and diastolic blood pressure for placebo (n = 79) was -0. 1/-2.2 mm Hg; amlodipine (n = 154), -12.4/-10.3 mm Hg; enalapril (n = 155), -9.4/-8.2 mm Hg; and bisoprolol/HCTZ (n = 155), -14.0/-12.0. Overall efficacy analyses documented a statistically significant decrease in sitting diastolic blood pressure for bisoprolol/6.25 mg HCTZ compared with placebo, amlodipine, and enalapril. There was a significant reduction in sitting systolic blood pressure for bisoprolol/6.25 mg HCTZ compared with placebo and enalapril but not amlodipine. Also, there was a significant decrease in sitting heart rate for bisoprolol/6.25 mg HCTZ (-6.2 beats/min) compared with placebo (+0.1 beats/min), amlodipine (+1.2 beats/min), and enalapril (+0.5 beats/min). The control rate (diastolic blood pressure < or = 90 mm Hg) for bisoprolol/6.25 mg HCTZ (66.5%) was significantly better than for placebo (21.8%) and enalapril (47.1%) but not amlodipine (58.4%). Of those patients achieving and maintaining control, 49% of the bisoprolol/6.25 mg HCTZ subjects were on the lowest two doses compared with 30% of the amlodipine and 26% of the enalapril subjects. Percentages of patients reporting at least one drug-related adverse event through week 12 were 27%, 24%, 28%, and 25% for placebo, bisoprolol/6.25 mg HCTZ, amlodipine, and enalapril (not significant). Lower doses of two drugs in fixed combination can provide as good or better blood pressure control compared with higher doses of a single drug with similar tolerability and safety.     

Candesartan cilexetil: comparison of once-daily versus twice-daily administration for systemic hypertension. Candesartan Cilexetil Study Investigators.

This randomized, double-masked, placebo-controlled, forced-titration, parallel-arm study was designed to compare the blood pressure (BP)-lowering effect of candesartan cilexetil, a potent antagonist of the angiotensin II receptor subtype AT1, administered once daily with that of the same agent administered twice daily at the same total daily dose of 16 mg. After a 4- to 5-week placebo run-in period, 277 patients with a sitting diastolic BP of 95 to 109 mm Hg were randomly allocated to receive placebo (n = 92) or candesartan cilexetil 8 mg once daily for 4 weeks, followed by forced titration to either 16 mg once daily (n = 91) or 8 mg twice daily (n = 94) for 4 weeks. At 8 weeks, mean reductions in trough sitting diastolic BP were similar for the once- and twice-daily treatment groups (9.4 and 10.3 mm Hg, respectively). After 8 weeks of treatment, no statistically significant differences were observed in diastolic or systolic BP, peak or trough BP, or sitting or standing BP between the 2 active-treatment groups. The rates of positive responses (defined as a trough sitting diastolic BP of <90 mm Hg or a decrease in BP of > or =10 mm Hg) were also similar (approximately 60%) in the once- and twice-daily candesartan cilexetil groups. Furthermore, placebo-corrected trough-to-peak ratios for sitting diastolic BP exceeded 75% for both candesartan cilexetil regimens, indicating a persistent 24-hour duration of drug effect. Ambulatory BP monitoring performed in a subset of patients (n = 44) confirmed the consistent 24-hour BP-lowering effect and preservation of diurnal variation with once-daily dosing. No significant between-group differences were observed in the incidence or severity of clinical or laboratory adverse events. The results of this study suggest that identical daily doses of candesartan cilexetil administered once or twice daily have comparable efficacy and tolerability and that no additional clinical benefit is derived from twice-daily administration.     

Efficacy of valsartan in patients aged > or =65 years with systolic hypertension

OBJECTIVE: This randomized, double-blind, placebo-controlled, parallel-group, multicenter trial investigated the effects of valsartan, an angiotensin II receptor blocker, on systolic blood pressure (SBP) in patients aged > or =65 years with systolic hypertension, with or without diastolic hypertension. BACKGROUND: Hypertension in older persons is a public health problem of epidemic proportions. SBP, which increases with age, is a better predictor of cardiovascular morbidity and all-cause mortality than is diastolic blood pressure (DBP). SBP is now thought to be a major modifiable risk factor for cardiovascular disease. METHODS: The study population consisted of 146 outpatients (74 female and 72 male) with a mean (+/- SD) age of 73.0+/-6.7 years and a trough mean sitting SBP > or =160 mm Hg; 88.4% were white. Patients with clinically relevant cardiac valvular disease, documented or suspected renal artery stenosis, and a serum creatinine level >2.5 mg/dL were excluded from the study. After a 2- to 4-week, single-blind, placebo run-in period, patients were randomly assigned to receive valsartan 80 mg or placebo once daily for 4 weeks and were then force-titrated to valsartan 160 mg or matching placebo once daily for an additional 4 weeks. Median DBP was 90 mm Hg, and >50% of the patients had isolated systolic hypertension. RESULTS: For the primary efficacy variable, the change from baseline to end point in trough mean sitting SBP, treatment with valsartan was superior to placebo, with reductions of 19.2 mm Hg compared with 8.8 mm Hg, respectively (P < 0.001, 95% CI -15.7, -5.5). Valsartan also produced superior reductions in trough mean sitting DBP (5.2 mm Hg and 1.2 mm Hg for valsartan and placebo, respectively; P < 0.001, 95% CI -6.4, -2.3). The tolerability of valsartan was comparable to that of placebo, with adverse events occurring in 31 (42.5%) valsartan-treated patients compared with 28 (38.4%) patients who received placebo. CONCLUSIONS: In this patient population of hypertensive patients aged > or =65 years, valsartan was effective and well tolerated and offers a promising new approach to the treatment of systolic hypertension.     

Two multicenter, 8-week, randomized, double-blind, placebo-controlled, parallel-group studies evaluating the efficacy and tolerability of amlodipine and valsartan in combination and as monotherapy in adult patients with mild to moderate essential hypertension

BACKGROUND: Patients with hypertension may require combination therapy to attain the blood pressure targets recommended by US and European treatment guidelines. Combination therapy with a calcium channel blocker and an angiotensin II-receptor blocker would be expected to provide enhanced efficacy. OBJECTIVES: Two studies were conducted to compare the efficacy of various combinations of amlodipine and valsartan administered once daily with their individual components and placebo in patients with mild to moderate essential hypertension (mean sitting diastolic blood pressure [MSDBP] >/=95 and < 110 mm Hg). A secondary objective was to evaluate safety and tolerability. METHODS: The 2 studies were multinational, multicenter, 8-week, randomized, double-blind, placebo-controlled, parallel-group trials. In study 1, patients were randomized to receive amlodipine 2.5 or 5 mg once daily, valsartan 40 to 320 mg once daily, the combination of amlodipine 2.5 or 5 mg with valsartan 40 to 320 mg once daily, or placebo. In study 2, patients were randomized to receive amlodipine 10 mg once daily, valsartan 160 or 320 mg once daily, the combination of amlodipine 10 mg with valsartan 160 or 320 mg once daily, or placebo. The primary efficacy variable in both studies was change from baseline in MSDBP at the end of the study. Secondary variables included the change in mean sitting systolic blood pressure (MSSBP), response rate (the proportion of patients achieving an MSDBP <90 mm Hg or a >/= 10-mm Hg decrease from baseline), and control rate (the proportion of patients achieving an MSDBP <90 mm Hg). Safety was assessed in terms of adverse events (spontaneously reported or elicited by questioning), vital signs, and laboratory values. RESULTS: A total of 1911 patients were randomized to treatment in study 1 (1022 amlodipine + valsartan; 507 valsartan; 254 amlodipine; 128 placebo); 1250 were randomized to treatment in study 2 (419, 415, 207, and 209, respectively). In all treatment groups in both studies, the majority of patients were white (79.5% study 1, 79.4% study 2) and male (53.5% and 50.3%, respectively). The overall mean age was 54.4 years in study 1 and 56.9 years in study 2. The mean weight of patients in study 1 was higher than that in study 2 (88.8 vs 79.7 kg). The overall baseline mean sitting BP was 152.8/99.3 mm Hg in study 1 and 156.7/99.1 mm Hg in study 2. With the exception of a few combinations that included amlodipine 2.5 mg, the combination regimens in both studies were associated with significantly greater reductions in MSDBP and MSSBP compared with their individual components and placebo (P < 0.05). A positive dose response was observed for all combinations. The highest response rate in study 1 was associated with the highest dose of combination therapy (amlodipine 5 mg + valsartan 320 mg: 91.3%). Amlodipine 5 mg, valsartan 320 mg, and placebo were associated with response rates of 71.9%, 73.4%, and 40.9%, respectively. In study 2, the 2 doses of combination therapy were associated with similar response rates (amlodipine 10 mg + valsartan 160 mg: 88.5%; amlodipine 10 mg + valsartan 320 mg: 87.5%). Amlodipine 10 mg was associated with a response rate of 86.9%; valsartan 160 and 20 mg were associated with response rates of 74.9% and 72.0%, respectively; and placebo was associated with a response rate of 49.3%. Control rates followed a similar pattern. The incidence of peripheral edema with combination therapy was significantly lower compared with amlodipine monotherapy (5.4% vs 8.7%, respectively; P = 0.014), was significantly higher compared with valsartan monotherapy (2.1%; P < 0.001), and did not differ significantly from placebo (3.0%). CONCLUSIONS: In these adult patients with mild to moderate hypertension, the combination of amlodipine + valsartan was associated with significantly greater blood pressure reductions from baseline compared with amlodipine or valsartan monotherapy or placebo. The incidence of peripheral edema was significantly lower with combination therapy than with amlodipine monotherapy.     

Prevention of migraine with olmesartan in patients with hypertension/prehypertension

OBJECTIVE: To explore the effects of olmesartan on frequency and severity of migraine attacks in patients with comorbid hypertension and prehypertension. BACKGROUND: A randomized, double-blind, placebo-controlled, crossover study with a total of 60 patients has demonstrated the efficacy and safety of the angiotensin II receptor blocker candesartan in migraine prophylaxis. We study the potential efficacy and tolerability of olmesartan in preventing migraine in patients with hypertension and prehypertension. DESIGN/METHODS: Twenty-four adults, aged 27 through 76, with either hypertension or prehypertension, were included in this open-label study. Participants suffered from migraines (diagnosed according to International Headache Society classifications) for at least 3 months. Patients were treated with 10 to 40 mg of olmesartan per various observational periods of at least 3 months. Frequency and severity were recorded by office visits or by telephonic interview. RESULTS: Patients reported an 82.5% average reduction in the frequency of migraine attacks. Patients also experienced a 45% average reduction in the severity of migraine attacks measured on a numeric pain scale of 1 to 10. The only undesired effect was dizziness or presyncope. No serious adverse events occurred and no adverse event caused a premature termination. Two patients had no reduction in headache frequency, intensity, and blood pressure. CONCLUSIONS: The favorable results and low rate of adverse effects, in this open migraine prevention study in patients with hypertension or prehypertension, are similar to results of the randomized, double-blind, placebo-controlled, crossover study in patients taking candesartan. Olmesartan shows a potential as an effective and well-tolerated migraine prophylactic agent for patients with comorbid hypertension and prehypertension.     

Role of selective cyclooxygenase-2 inhibitors in exacerbation of inflammatory bowel disease: A systematic review and meta-analysis

Background: In the general population, selective cyclooxygenase (COX)-2 inhibitors have been associated with fewer gastrointestinal adverse effects (AEs) than NSAIDs, but whether they are associated with exacerbations in patients with inflammatory bowel disease (IBD) remains controversial.Objective: The aim of this study was to review published and unpublished findings to determine whether the use of COX-2 inhibitors increased the risk for IBD exacerbations relative to placebo in the treatment of IBD.Methods: A systematic search of MEDLINE (1966-July 2007), EMBASE (1980-July 2007), the Cochrane Library (2007 Issue 4), US Food and Drug Administration records, and data on file at Novartis Pharmaceuticals Corporation, Pfizer US Pharmaceutical Group, and Merck & Co., Inc., using the search terms celecoxib, rofecoxib, valdecoxib, etoricoxib, lumiracoxib, cyclooxygenase 2 inhibitor, Crohn's disease, ulcerative colitis, and inflammatory bowel disease, was performed to identify randomized, placebo-controlled clinical trials of 5 COX-2 inhibitors in patients with IBD. The publications were fully reviewed for quality. Data on trial design, patient characteristics, intervention drugs, dosages, and outcomes were collected using a predetermined data-extraction form. A meta-analysis was performed based on the publications that met the inclusion/exclusion criteria.Results: Of 588 studies identified in the electronic search, 574 were excluded after screening the titles and abstracts. Fourteen related to the use of COX-2 inhibitors in patients with IBD were reviewed. Two randomized, controlled trials comparing COX-2 inhibitors with placebo were identified. In the first trial, 82 patients were randomized to receive etoricoxib (60-120 mg/d) and 77 to receive placebo. The exacerbation rates were 10.5% (8/76) in the active-treatment group and 11.4% (8/70) in the placebo group (relative risk [RR], 0.92; 95% CI, 0.37-2.32). In the second trial, 112 patients were treated with celecoxib (200 mg BID) and 110 received placebo. The exacerbation rates were 3.7% (4/107) in the celecoxib group and 2.7% (3/110) in the placebo group (RR, 0.73; 95% CI, 0.17-3.18). Of these patients, 5 were lost to follow-up because of AEs. In the meta-analysis comparing COX-2 inhibitors and placebo, the RR was 0.86 (95% CI, 0.39-1.88). No statistically significant differences in IBD relapse rates were found between COX-2 inhibitors and placebo.Conclusions: The results from this meta-analysis suggest that insufficient data were available to determine the impact of COX-2 inhibitors on IBD exacerbations. The relatively smaller risk for AEs makes the short-term use of COX-2 inhibitors potentially attractive, but the long-term benefits remain unclear. Further studies with sound methodology and large sample sizes are needed to evaluate the tolerability of COX-2 inhibitors in the treatment of IBD.     

Assessment of once-daily eprosartan, an angiotensin II antagonist, in patients with systemic hypertension. Eprosartan Study Group.

A multicenter, randomized, double-masked, placebo-controlled trial was conducted to assess the efficacy of once-daily eprosartan, a nonbiphenyl, nontetrazole angiotensin II-receptor antagonist, in 243 patients with mild-to-moderate systemic hypertension (sitting diastolic blood pressure [SitDBP], 95-114 mm Hg). After a 3-to 5-week single-masked placebo run-in period to obtain baseline values, patients were randomly allocated to receive 600 mg eprosartan once daily or placebo for 8 weeks. All clinic blood pressure measurements were made 24 hours +/-90 minutes after dosing. Eprosartan produced statistically and clinically significant reductions in SitDBP(-7.5+/-0.8 mm Hg) and sitting systolic blood pressure (SitSBP) (-6.0+/-1.3 mm Hg) compared with placebo (SitDBP -1.9+/-0.7 mm Hg; SitSBP 0.8+/-1.2 mm Hg). The 95% confidence intervals for the difference from placebo were -8.1 to 4.1 for SitDBP and -11.0 to -4.0 for SitSBP (both, P<0.0001). The proportion of patients responding (SitDBP was <90 mm Hg or had decreased by > or =10 mm Hg from baseline at study end point) to eprosartan was significantly higher than the proportion of those responding to placebo (42% vs. 21%, respectively; P = 0.0003). Similar results were obtained in a subgroup analysis comparing patients aged <65 years with those aged > or =65 years. The total number of adverse events was similar in the eprosartan and placebo groups. Eprosartan 600 mg once daily was both well tolerated and effective, providing significant blood pressure reduction 24 hours after dosing in patients with mild-to-moderate systemic hypertension, regardless of age.     

Effects of hydroalcoholic extract of Berberis Integerrima on the anthropometric indices and metabolic profile in active rheumatoid arthritis patients

ObjectivesSince, the main cause of death in Rheumatoid arthritis (RA) patients is the presence of type 2 diabetes, abnormal increase in blood lipids, blood pressure and obesity, the aim of this study was to assess the effects of Barberry on the anthropometric indices and metabolic profile in patients with RA.Designpresent study was a double-blinded, placebo-controlled randomized clinical trial.Setting70 active RA patients were randomly allocated into intervention or placebo groupInterventionParticipants received 6 capsules of 500 mg barberry extract or placebo for 3 months.Main outcome measuresSerum levels of fasting blood sugar (FBS), triglyceride (TG), LDL cholesterol (LDL-C) and HDL cholesterol (HDL-C), systolic and diastolic blood pressure and anthropometric factors were assessed at baseline and at the end of the trial.ResultsThe results of intervention on 62 patients showed that weight, BMI, and conicity index increased in both groups, but this was significant only in the placebo group (p < 0.001). Waist and hip circumference were decreased in the intervention group and increased significantly in the placebo group (p < 0.001). Body fat percent (p = 0.04), LDL-C (p = 0.05) and SBP (p = 0.02) significantly were decreased in the intervention group. The results showed a significant decrease in body fat percent (p = 0.05), hip circumference (p < 0.001), FBS (p = 0.03) and HDL-C (p = 0.03) in the intervention group compared to the placebo. Conclusions: Overall, the results of this study demonstrated that the extract of Berberis Integerrima had beneficial effects on metabolic profile and anthropometric indices in RA patients.