Once daily controlled-release pregabalin in the treatment of patients with fibromyalgia: a phase III, double-blind, randomized withdrawal, placebo-controlled study.

OBJECTIVE: Safety and efficacy of a once daily controlled-released (CR) formulation of pregabalin was evaluated in patients with fibromyalgia using a placebo-controlled, randomized withdrawal design. RESEARCH DESIGN AND METHODS: This multicenter study included 6 week single-blind pregabalin CR treatment followed by 13 week double-blind treatment with placebo or pregabalin CR. The starting dose of 165 mg/day was escalated during the first 3 weeks, up to 495 mg/day based on efficacy and tolerability. Patients with ≥50% reduction in average daily pain score at the end of the single-blind phase were randomized to continue pregabalin CR at the optimized dose (330-495 mg/day) or to placebo. The primary endpoint was time to loss of therapeutic response (LTR), defined as <30% pain reduction relative to single-blind baseline or discontinuation owing to lack of efficacy or adverse event (AE). Secondary endpoints included measures of pain severity, global assessment, functional status, tiredness/fatigue, and sleep. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01271933. RESULTS: A total of 441 patients entered the single-blind phase, and 63 were randomized to pregabalin CR and 58 to placebo. The median time to LTR (Kaplan-Meier analysis) was significantly longer in the pregabalin CR group than placebo (58 vs. 22 days, p = 0.02). By trial end, 34/63 (54.0%) pregabalin CR and 41/58 (70.7%) placebo patients experienced LTR. Significantly more patients reported 'benefit from treatment' (Benefit, Satisfaction, and Willingness to Continue Scale) in the pregabalin CR group; no other secondary endpoints were statistically significant. Most AEs were mild to moderate in severity (most frequent: dizziness, somnolence). The percentage of pregabalin CR patients discontinuing because of AEs was 12.2% and 4.8% in the single-blind and double-blind phases, respectively (placebo, 0%). CONCLUSIONS: Time to LTR was significantly longer with pregabalin CR versus placebo in fibromyalgia patients who initially showed improvement with pregabalin CR, indicating maintenance of response. Pregabalin CR was well tolerated in most patients. Generalizability may be limited by study duration and selective population.

Effects of eplerenone versus losartan in patients with low-renin hypertension.

BACKGROUND: Sodium retention and volume expansion, mediated in part by aldosterone, are prominent features in low-renin hypertension. Agents that block aldosterone at its receptor sites, therefore, should have significant clinical benefit in patients with low-renin hypertension. METHODS: This 16-week, multicenter, double-blind, active-controlled, parallel-group, titration-to-effect trial compared the blood pressure and neurohumoral responses of the selective aldosterone blocker eplerenone (100-200 mg/d; n = 86) with those of the angiotensin receptor blocker losartan (50-100 mg/d; n = 82) in patients with low-renin hypertension (active renin < or = 25 pg/mL [< or = 42.5 mU/L]). Patients with diastolic blood pressure > or = 90 mm Hg after 8 weeks of monotherapy received add-on therapy with hydrochlorothiazide 12.5 to 25 mg daily. RESULTS: After 8 weeks of therapy, eplerenone reduced blood pressure to a greater extent than losartan (systolic blood pressure -15.8 vs -10.1 mm Hg, P = .017; diastolic blood pressure -9.3 vs -6.7 mm Hg, P = .05). After 16 weeks of therapy, significantly fewer eplerenone-treated patients (32.5%) than losartan-treated patients (55.6%) required add-on hydrochlorothiazide as allowed per protocol for blood pressure control (P = .003). Eplerenone consistently reduced blood pressure regardless of baseline active plasma renin levels whereas losartan reduced blood pressure more effectively in patients with higher baseline active renin levels. There were no differences between treatments in adverse events (reported by 62.8% of eplerenone patients and by 72.0% of losartan patients). CONCLUSIONS: These data show that eplerenone was more effective than losartan in reducing blood pressure in patients with low-renin hypertension. Further studies evaluating the efficacy of eplerenone in difficult-to-treat or resistant hypertension are needed.

Efficacy of eplerenone versus enalapril as monotherapy in systemic hypertension.

This study compared the efficacy and tolerability of eplerenone and enalapril in 499 patients with stage 1 or 2 hypertension who were randomized to receive eplerenone or enalapril for 6 months in a 3-step titration-to-effect study. After 6 months, patients whose diastolic blood pressure (BP) was <90 mm Hg had their dosages down-titrated were followed for an additional 6 months. Diastolic BP was the primary end point. Eplerenone was as effective as enalapril in reducing both systolic BP (eplerenone, -14.5 mm Hg; enalapril, -12.7 mm Hg; p = 0.199) and diastolic BP (eplerenone, -11.2 mm Hg; enalapril, -11.3 mm Hg; p = 0.910) at 6 months. BP reductions at 12 months were also similar between groups (-16.5/-13.3 mm Hg for eplerenone, -14.8/-14.1 mm Hg for enalapril; p = 0.251 and 0.331, respectively). Withdrawal rates for adverse events (eplerenone 7.9%, enalapril 9.3% at 6 months) and treatment failures (eplerenone 23.3%, enalapril 22.8% at 6 months) were also equivalent. Approximately 2/3 of each group had normal BP with monotherapy treatment at 6 months. BP response was independent of renin levels in the eplerenone group, but not in the enalapril group. Both agents reduced albuminuria in patients who had an elevated value at baseline, with significantly greater improvement in patients treated with eplerenone versus enalapril (-61.5% vs -25.7%; p = 0.01). Both agents were similarly well tolerated, and there was no increased incidence of any sexual adverse events in the eplerenone group. Patients taking enalapril had a higher rate of cough. Both agents increased serum potassium levels, but <1% in each group reported adverse events from hyperkalemia. Eplerenone was as effective as enalapril as monotherapy in patients with stage 1 or 2 hypertension, was more effective in reducing albuminuria, and was well tolerated for 12 months.