Effect of omega-3 fatty acids on cardiovascular events in high-risk patients with hypertriglyceridemia in Japan: a 3-year post-marketing surveillance study (OCEAN3 survey).

BACKGROUND: Studies on the efficacy of prescription omega-3 polyunsaturated fatty acids to reduce cardiovascular events have produced conflicting results. RESEARCH DESIGN AND METHODS: This 3-year prospective post-marketing surveillance study evaluated the effect of omega-3-acid ethyl esters (O3AEE; usual dosage 2 g/day) on cardiovascular events in high-risk statin-treated Japanese patients with hypertriglyceridemia. Statin-treated patients not receiving O3AEE were included as a reference cohort. The composite primary endpoint was cardiovascular death, myocardial infarction, stroke, angina requiring coronary revascularization, or peripheral arterial disease requiring surgery or peripheral arterial intervention. RESULTS: At 3 years, Kaplan-Meier estimated cumulative incidence of the primary endpoint was 2.5% (95% confidence interval, 2.1%-2.9%) in O3AEE-treated patients (N = 6,580) and 2.7% (2.4%-3.1%) in non-O3AEE-treated patients (N = 7,784; hazard ratio, 0.99; 95% confidence interval, 0.79-1.23). Incidence of heart failure requiring hospitalization was 0.4% with O3AEE versus 0.8% in non-O3AEE-treated patients (hazard ratio, 0.47; 95% confidence interval, 0.28-0.78; P < 0.05). CONCLUSIONS: Among patients receiving statins, cardiovascular event incidence did not differ significantly between O3AEE-treated patients and non-O3AEE-treated patients. Further studies are required before definitive conclusions can be drawn on the effect of O3AEE on cardiovascular event incidence in high-risk patients with hypertriglyceridemia. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02285166.

A Randomized, Single-Center, Double-Blind, Placebo-Controlled Multiple-Dose Phase 1 Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of Imarikiren in Healthy Adult Nonelderly and Elderly Male Subjects.

Imarikiren hydrochloride (TAK-272/ SCO-272) is a novel direct renin inhibitor. This randomized, double-blind, phase I study evaluated the safety and pharmacokinetics/pharmacodynamics of multiple oral administrations of imarikiren in healthy nonelderly (aged 20-45 years) and elderly (aged 65-85 years) Japanese male subjects. Subjects were randomized within 1 of 3 cohorts to receive imarikiren or placebo: Cohort 1 (imarikiren 80 mg; nonelderly), Cohort 2 (imarikiren 160 mg; nonelderly), or Cohort 3 (imarikiren 80 mg; elderly). Imarikiren or placebo was administered orally, once daily, for 7 days. Accumulation of imarikiren did not occur during the 7-day treatment period. Area under the plasma-concentration time curve and maximum plasma concentration of imarikiren were higher in elderly than in nonelderly subjects (52% and 39% higher, respectively). Inhibition of plasma renin activity was observed for 7 days and was maintained for at least 71 hours after the last imarikiren administration at the 80-mg (nonelderly and elderly) and 160-mg (nonelderly) doses. Plasma active renin concentration increased in nonelderly and elderly subjects; peak concentrations were higher on day 7 than on day 1. Increase from baseline in plasma active renin concentration was smaller in elderly than in nonelderly subjects during the 7-day treatment period and until 71 hours after last imarikiren administration. Treatment-emergent adverse events were reported in 33.3% (elderly) and 22.2% (nonelderly) of imarikiren subjects. Multiple oral administrations of imarikiren for 7 days were safe and well tolerated with no drug accumulation and strong and sustained suppression of plasma renin activity.

Efficacy and safety of ramelteon in Japanese adults with chronic insomnia: a randomized, double-blind, placebo-controlled study.

This randomized, double-blind, placebo-controlled study assessed the efficacy and safety of ramelteon 4 and 8 mg in Japanese adults with chronic insomnia. A secondary objective was to evaluate efficacy and safety when doses were uptitrated from placebo, ramelteon 4 and 8 mg to 4, 8 and 16 mg, respectively. Patient-reported sleep data were collected using sleep diaries. There was no statistically significant difference between ramelteon and placebo in the change in subjective sleep latency (sSL) in the full analysis set (n = 1130). Significant improvement was observed in the change in subjective total sleep time with ramelteon 8 mg at week 1. In post hoc analyses, ramelteon 8 mg reduced sSL in individuals with smaller fluctuations (within ±30 min) of sSL at baseline, in those with a shorter (<1 year) history of insomnia and in individuals who had not used benzodiazepines. Ramelteon up to 16 mg nightly was safe and well tolerated.

Long-term safety and efficacy of ramelteon in Japanese patients with chronic insomnia.

OBJECTIVE: To evaluate the safety of ramelteon, a highly selective MT1/MT2 melatonin receptor agonist, during 24 weeks' treatment of Japanese patients with chronic insomnia. METHODS: In a single-blind, flexible-titration, multicenter study incorporating placebo run-in and run-out periods, 190 adults with chronic insomnia received ramelteon 4 or 8 mg, titrated up to 16 mg if necessary, for 24 weeks. Primary endpoints included adverse events, residual effects, rebound insomnia, withdrawal symptoms, and dependence. Secondary endpoints included subjective sleep latency and total sleep time. RESULTS: Drug-related adverse events occurred in 11.6% of patients. No clinically important changes occurred in biochemical, hematological or endocrine parameters. There were no signs of next-day residual effect, rebound insomnia, withdrawal symptoms or dependence. Mean subjective sleep latency decreased significantly, and total sleep time increased significantly; both reached a plateau by week 20 and were sustained thereafter (P<0.0001). CONCLUSIONS: Ramelteon was well tolerated in adult Japanese patients with chronic insomnia and did not cause deterioration of efficacy, residual effects, rebound insomnia, withdrawal symptoms, or dependence after 24 weeks' treatment.