Our objective was to investigate the efficacy and safety of alvimopan, a peripherally acting mu-opioid receptor (PAM-OR) antagonist, in subjects with non-cancer pain and opioid-induced bowel dysfunction (OBD), and to identify at least one treatment regimen that improves OBD. Following a 2-week baseline period, 522 subjects reporting <3 spontaneous bowel movements (SBMs)/week (with >or=25% accompanied by a sensation of incomplete evacuation, straining, or lumpy hard stools), requiring analgesia equivalent to >or=30 mg oral morphine/day were randomized to alvimopan 0.5mg twice daily (BID), 1mg once daily (QD), 1mg BID, or placebo for 6 weeks. Compared with placebo, there was a statistically and clinically significant increase in mean weekly SBM frequency over the initial 3 weeks of treatment (primary endpoint) with alvimopan 0.5mg BID (+1.71 mean SBMs/week), alvimopan 1mg QD (+1.64) and alvimopan 1mg BID (+2.52); P<0.001 for all comparisons. Increased SBM frequency and additional treatment effects, including improvements in symptoms such as straining, stool consistency, incomplete evacuation, abdominal bloating/discomfort, and decreased appetite, were sustained over 6 weeks. The most frequently reported adverse events were abdominal pain, nausea, and diarrhea, occurring more frequently in the higher dosage groups. The alvimopan 0.5mg BID regimen demonstrated the best benefit-to-risk profile for managing OBD with alvimopan in this study population, with a side effect profile similar to that of placebo. There was no evidence of opioid analgesia antagonism. Competitive peripheral antagonism of opioids with alvimopan can restore GI function and relieve OBD without compromising analgesia.

BackgroundAtrial fibrillation is associated with higher mortality. Identification of causes of death and contemporary risk factors for all‐cause mortality may guide interventions.Methods and ResultsIn the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study, patients with nonvalvular atrial fibrillation were randomized to rivaroxaban or dose‐adjusted warfarin. Cox proportional hazards regression with backward elimination identified factors at randomization that were independently associated with all‐cause mortality in the 14 171 participants in the intention‐to‐treat population. The median age was 73 years, and the mean CHADS 2 score was 3.5. Over 1.9 years of median follow‐up, 1214 (8.6%) patients died. Kaplan–Meier mortality rates were 4.2% at 1 year and 8.9% at 2 years. The majority of classified deaths (1081) were cardiovascular (72%), whereas only 6% were nonhemorrhagic stroke or systemic embolism. No significant difference in all‐cause mortality was observed between the rivaroxaban and warfarin arms (P=0.15). Heart failure (hazard ratio 1.51, 95% CI 1.33–1.70, P<0.0001) and age ≥75 years (hazard ratio 1.69, 95% CI 1.51–1.90, P<0.0001) were associated with higher all‐cause mortality. Multiple additional characteristics were independently associated with higher mortality, with decreasing creatinine clearance, chronic obstructive pulmonary disease, male sex, peripheral vascular disease, and diabetes being among the most strongly associated (model C‐index 0.677).ConclusionsIn a large population of patients anticoagulated for nonvalvular atrial fibrillation, ≈7 in 10 deaths were cardiovascular, whereas <1 in 10 deaths were caused by nonhemorrhagic stroke or systemic embolism. Optimal prevention and treatment of heart failure, renal impairment, chronic obstructive pulmonary disease, and diabetes may improve survival.Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT00403767.

No abstract

Objective: Therapies that lower blood glucose and provide weight loss may provide meaningful benefits for obese patients with type 2 diabetes mellitus (T2DM). This study assessed the efficacy of taspoglutide compared with placebo on glycemic control and weight in obese patients with T2DM inadequately controlled with metformin monotherapy. Design and Methods: In a 24-week, randomized, double-blind, placebo-controlled, multicenter trial, obese adults with T2DM were randomized (1:1) to weekly subcutaneous taspoglutide 20 mg (10 mg for first 4 weeks) (n ¼ 154) or placebo (n ¼ 151) for 24 weeks. Efficacy measures included hemoglobin A1c (HbA1c) levels, body weight, percentage of patients achieving HbA1c 6.5 and 7.0%, and fasting plasma glucose (FPG). Adverse events (AEs) were assessed. Results: Mean baseline HbA1c was 7.55% and mean baseline BMI was 36.7 kg/m 2 . HbA1c reductions from baseline were significantly greater with taspoglutide than placebo (least square mean [LSMean], À0.81% vs. À0.09%; P < 0.0001). Weight loss at week 24 was significantly greater with taspoglutide than placebo (LSMean, À3.16 vs. À1.85 kg; P < 0.01). In the taspoglutide and placebo groups, target HbA1c levels ( 6.5%) were achieved by 49 and 16% of patients, respectively, while 72 and 36% achieved HbA1c levels 7%. Decreases in FPG were significantly greater with taspoglutide than placebo (À23.59 vs. 0.09 mg/dl; P < 0.0001). Nausea and vomiting were the most common AEs associated with taspoglutide, but tended to be transient and generally mild or moderate. Conclusions: In obese patients with T2DM, once-weekly taspoglutide provided the combined benefits of glycemic control and weight loss.

Using acute low back pain, a model with a high degree of heterogeneity and intrinsic variability, DDS-06C was superior to placebo on measures of pain intensity and relief, and was well-tolerated.