Gastrointestinal side effects of etoricoxib in patients with osteoarthritis: results of the Etoricoxib versus Diclofenac Sodium Gastrointestinal Tolerability and Effectiveness (EDGE) trial.

OBJECTIVE: . To compare the gastrointestinal (GI) tolerability, safety, and efficacy of etoricoxib and diclofenac in patients with osteoarthritis (OA). METHODS: In total, 7111 patients (mean age 64 yrs) diagnosed with OA were enrolled in a randomized, double-blind trial. Patients received etoricoxib 90 mg qd (n = 3593) or diclofenac sodium 50 mg tid (n = 3518). Gastroprotective agents and low-dose aspirin were prescribed per treatment guidelines. The primary endpoint was the cumulative rate of discontinuations due to clinical and laboratory GI adverse experiences (AE). General safety was assessed, including adjudication of thrombotic cardiovascular (CV) safety data. Efficacy was evaluated using the least-square (LS) mean change from baseline patient global assessment of disease status (PGADS; 0-4 point scale). RESULTS: Mean (SD, maximum) duration of treatment was 9.3 (4.4, 16.5) and 8.9 (4.5, 16.6) months in the etoricoxib and diclofenac groups, respectively. The cumulative discontinuation rate due to GI AE was significantly lower with etoricoxib than diclofenac [9.4 vs 19.2 events per 100 patient-years (PY), respectively; hazard ratio (HR) 0.50 (95% CI 0.43, 0.58; p < 0.001). Rates of thrombotic CV events were similar with etoricoxib and diclofenac [1.25 vs 1.15 events per 100 PY, respectively; HR 1.07 (95% CI 0.65, 1.74)]. The incidence of patients who discontinued due to hypertension-related AE was significantly higher with etoricoxib compared to diclofenac (2.3% vs 0.7%; p < 0.001), although few AE were severe (3 etoricoxib, 1 diclofenac). Etoricoxib and diclofenac treatment resulted in similar improvements in PGADS from baseline of -0.78 (95% CI -0.80, -0.75) and -0.75 (95% CI -0.77, -0.72), respectively. CONCLUSION: Treatment with etoricoxib 90 mg was associated with significantly better GI tolerability compared to diclofenac in this population of patients with OA. Etoricoxib 90 mg, a dose 50% higher than indicated for OA, resulted in more discontinuations due to hypertension-related AE.

A multicenter, randomized, double-blind, parallel-group trial of the antihypertensive efficacy and tolerability of a combination of once-daily losartan 100 mg/hydrochlorothiazide 12.5 mg compared with losartan 100-mg monotherapy in the treatment of mild to severe essential hypertension.

BACKGROUND: Because patients with hypertension may require >1 antihypertensive agent to control blood pressure (BP), physicians often prescribe a fixed combination of antihypertensive medications. OBJECTIVE: This study evaluated the effect of adding low-dose hydrochlorothiazide 12.5 mg (HCTZ12.5) to high-dose losartan 100 mg (L100) in patients with hypertension whose BP was inadequately controlled with L100 monotherapy. METHODS: Enrolled in this multicenter, randomized, double-blind, parallel-group, filter study were patients aged > or =18 years with a mean trough sitting diastolic BP (SiDBP) of 95 to 120 mm Hg. Patients were treated with L100 QD for 4 weeks. Patients who did not achieve adequate BP control were randomly assigned to receive L100/HCTZ12.5 or L100 QD for 6 weeks. The primary efficacy measure was the mean change in trough SiDBP from baseline in the 2 groups. Responders were defined as patients with a mean trough SiDBP of <90 mm Hg or patients who had a > or =10-mm Hg decrease in mean trough SiDBP. RESULTS: Demographic characteristics were similar between treatment groups. The patients randomized to the double-blind treatment period were mostly white (65.1%) and male (57.5%), with a mean age of 53.8 years. The mean (SD) duration of hypertension at baseline was 9.7 (8.5) years. The proportion of patients previously treated with antihypertensive therapy was 76.7%. Of the 367 patients enrolled in the L100 filter period, 292 patients had BP inadequately controlled with L100 monotherapy and were randomized to receive L100 (n = 145) or L100/HCTZ12.5 (n = 147). At week 6 after randomization, mean trough SiDBP was significantly lower in the L100/HCTZ12.5 group than in the L100 group (-8.3 vs -5.2, respectively; P < 0.001). The between-group difference was -3.0 mm Hg (95 % CI, -4.6 to -1.40; P < 0.001), and the proportion of responders was significantly greater in the L100/HCTZ12.5 group than in the L100 group (63.0% vs 44.4%; P < 0.001). The incidence of adverse events (AEs) occurring in >2% of patients during the double-blind period was similar for both groups. AEs occurring in the L100 group and the L100/HCTZ12.5 group included respiratory tract infection (6.2% vs 3.4%, respectively), dizziness (2.1% vs 0.7%), and headache (0.7% vs 3.4%). CONCLUSIONS: After 6 weeks of therapy, L100/HCTZ12.5 was associated with greater antihypertensive efficacy than L100, as measured by the change in mean trough SiDBP The percentage of responders was significantly greater in the L100/HCTZ12.5 group than in the L100 group.

A double-blind, dose-response study of losartan in hypertensive children.

BACKGROUND: The aim of this study was to determine the dose-response relationship for losartan, 2.5 to 100 mg, and to assess the safety and tolerability of losartan in hypertensive children 6 to 16 years of age. METHODS: This was a multicenter, randomized, double-blind, dose-response study. In Period 1, a total of 175 patients were stratified by weight (<50 kg and >/=50 kg) and randomized to one of three dose groups by stratum (low, 2.5/5.0 mg; middle, 25/50 mg; or high, 50/100 mg) for 3 weeks. The ratio of the three dose levels for both weight strata was 1:10:20. In Period 2, patients in each dose group were randomized to continue the same treatment or placebo washout for 2 additional weeks. RESULTS: In Period 1, sitting trough diastolic blood pressure (DBP) decreased in a dose-dependent manner (P < .0001). At week 3, changes in DBP from baseline in the low-, middle-, and high-dose groups were -6.0 mm Hg, -11.7 mm Hg, and -12.2 mm Hg, respectively. In Period 2, DBP increased significantly in patients who switched from middle- and high-dose losartan to placebo (mean increase 6.0 mm Hg, P = .003) relative to DBP in patients who remained on active treatment; however, these levels remained stable in those patients who switched from low-dose losartan to placebo (mean increase 1.1 mm Hg, P = .628). CONCLUSIONS: In hypertensive children 6 to 16 years of age, losartan given once daily reduced blood pressure in a dose-dependent fashion. A once-daily starting dose of losartan, 0.75 mg/kg (maximum 50 mg) effectively lowered DBP within 3 weeks. Losartan up to a dosage of 1.44 mg/kg (maximum 100 mg) once daily is generally well tolerated.

A double-blind, placebo-controlled, dose-response study of the effectiveness and safety of lisinopril for children with hypertension.

BACKGROUND: Despite widespread use in hypertensive children, the safety and effectiveness of lisinopril had not been previously tested in a controlled study. METHODS: This study explored the dose-response relationship and safety of lisinopril in 115 hypertensive children, aged 6 to 16 years. Patients were randomized in a double-blind fashion for 2 weeks to one of three doses by body weight at baseline: <50 kg: low (0.625 mg), middle (2.5 mg), high (20 mg), and > or =50 kg: low (1.25 mg), middle (5 mg), high (40 mg). The dose-response for lisinopril was evaluated by analyzing the change in slope in sitting diastolic and systolic blood pressure (BP) by dose after 2 weeks of therapy compared to baseline. Patients then entered a double-blind withdrawal, where patients were either switched to placebo or continued their current lisinopril treatment for up to 2 weeks. Patients completed period II when their BP returned to baseline. Antihypertensive effectiveness, between placebo and lisinopril was determined for all doses. Adverse events were carefully monitored. RESULTS: There was a dose-response relationship between the lowest and each of the higher doses of lisinopril. Blood pressure in the placebo group increased after withdrawal of lisinopril. The dose-response relationship was consistent across all subgroups (ie, age, Tanner stage, ethnicity, gender). CONCLUSIONS: Lisinopril, once daily, is an effective and well-tolerated antihypertensive in children aged 6 to 16 years. An initial dose of 0.07 mg/kg, administered once daily, effectively lowered BP within 2 weeks. Blood pressure was reduced in a dose-dependent fashion.

A double-blind, placebo-controlled, dose-response study of the effectiveness and safety of enalapril for children with hypertension.

Despite widespread use to treat childhood hypertension, enalapril has never been studied systematically to determine effectiveness, dose response, and safety in a pediatric population. This study was conducted prospectively in 110 hypertensive children ages 6 to 16 years in two sequential phases. The primary outcome variable for both phases of the study was trough (24-h postdose) sitting diastolic blood pressure. The primary objective of the first phase of the study was to determine whether enalapril lowered blood pressure in children in a dose-dependent manner. During a 2-week, double-blind, randomized, dose-response period, patients were stratified by weight (< 50 kg or > or = 50 kg), then assigned to one of three dosing groups: low(0.625 or 1.25 mg), middle (2.5 or 5 mg), or high dose (20 or 40 mg). Reduction in blood pressure was examined as a function of dose ratio (1:4:32) and on a weight-adjusted basis. On completion of the dose-response phase of the study, patients entered a 2-week, double-blind, randomized withdrawal to either enalapril or placebo. Antihypertensive effectiveness, defined as the difference in sitting diastolic blood pressure between the placebo and enalapril groups, was determined. Adverse events were carefully recorded throughout the study. The dose-response relationship for enalapril had a negative slope and was linear over the chosen dosing range, suggesting that larger doses of enalapril were associated with a greater reduction in blood pressure. Randomized withdrawal to active drug orplacebo confirmed the antihypertensive effectiveness of enalapril in the middle- and high-dose groups. The antihypertensive effect of enalapril was maintained across age, gender, race, and Tanner stage. Enalapril appears to be an effective and generally well-tolerated antihypertensive agent in children ages 6 to 16 years. An initial dose of 2.5 mg in children weighing < 50 kg and 5 mg in children weighing > 50 kg (mean = 0.08 mg/kg) administered once daily effectively lowered blood pressure within 2 weeks in most patients. Blood pressure was reduced in a dose-dependent fashion, with larger doses resulting in a greater reduction.