John Adler

Ximelagatran versus warfarin forstroke prevention in patientswith nonvalvular atrial fibrillation: SPORTIF ii: a dose-guiding, tolerability, and safety study

OBJECTIVES We sought to compare the tolerability and safety of three fixed doses of ximelagatran versus warfarin in patients with nonvalvular atrial fibrillation (NVAF). BACKGROUND Anticoagulants such as warfarin lower the risk of stroke in patients with NVAF. Ximelagatran is a novel, oral direct thrombin inhibitor with predictable pharmacokinetics and no known food or pharmacokinetic drug interactions. METHODS This was a 12-week, randomized, parallel-group, dose-guiding study of NVAF patients with at least one additional risk factor for stroke. The primary end point was the number of thromboembolic events and bleedings. Three groups received ximelagatran (n = 187) at 20, 40, or 60 mg twice daily, given in a double-blind fashion, without routine coagulation monitoring. In a fourth group, warfarin (n = 67) was managed and monitored according to normal routines, aiming for an International Normalized Ratio of 2.0 to 3.0. RESULTS A total of 254 patients received study drug. One ischemic stroke (nonfatal) and one transient ischemic attack (TIA) occurred in the ximelagatran group. Two TIAs occurred in the warfarin group. No major bleeds were observed in the ximelagatran group. One major bleed occurred in a warfarin-treated patient. The number of minor and multiple minor bleeds was low, but there was a slight increase by ximelagatran dose. The 60-mg dose resulted in the same number of bleeding events as that with warfarin. S-alanine aminotransferase was increased in eight patients (4.3%) taking ximelagatran, but normalized with continuous treatment or cessation of the drug. CONCLUSIONS Fixed oral doses of ximelagatran up to 60 mg twice daily were well tolerated, without the need for dose adjustment or coagulation monitoring.OBJECTIVES We sought to compare the tolerability and safety of three fixed doses of ximelagatran versus warfarin in patients with nonvalvular atrial fibrillation (NVAF). BACKGROUND Anticoagulants such as warfarin lower the risk of stroke in patients with NVAF. Ximelagatran is a novel, oral direct thrombin inhibitor with predictable pharmacokinetics and no known food or pharmacokinetic drug interactions. METHODS This was a 12-week, randomized, parallel-group, dose-guiding study of NVAF patients with at least one additional risk factor for stroke. The primary end point was the number of thromboembolic events and bleedings. Three groups received ximelagatran (n = 187) at 20, 40, or 60 mg twice daily, given in a double-blind fashion, without routine coagulation monitoring. In a fourth group, warfarin (n = 67) was managed and monitored according to normal routines, aiming for an International Normalized Ratio of 2.0 to 3.0. RESULTS A total of 254 patients received study drug. One ischemic stroke (nonfatal) and one transient ischemic attack (TIA) occurred in the ximelagatran group. Two TIAs occurred in the warfarin group. No major bleeds were observed in the ximelagatran group. One major bleed occurred in a warfarin-treated patient. The number of minor and multiple minor bleeds was low, but there was a slight increase by ximelagatran dose. The 60-mg dose resulted in the same number of bleeding events as that with warfarin. S-alanine aminotransferase was increased in eight patients (4.3%) taking ximelagatran, but normalized with continuous treatment or cessation of the drug. CONCLUSIONS Fixed oral doses of ximelagatran up to 60 mg twice daily were well tolerated, without the need for dose adjustment or coagulation monitoring.

Response burden and questionnaire length: is shorter better? A review and meta-analysis.

BACKGROUND Response burden is often defined as the effort required by the patient to answer a questionnaire. A factor that has been proposed to affect the response burden is questionnaire length, and this burden is manifested in, for example, response rate. Even though response burden is frequently mentioned as a reason for abridging questionnaires, evidence to support the notion that shorter instruments are preferable is limited. OBJECTIVES This study aimed to accumulate, analyze, and discuss evidence regarding the association between response burden, as measured by response rate, and questionnaire length. METHODS A systematic literature review and meta-analysis of studies reporting response rates in relation to questionnaire length was performed. A Cochran-Mantel-Haenszel test stratified by study using the Breslow-Day test was undertaken to investigate homogeneity of the odds ratios. RESULTS Thirty-two reports were identified, of which 20 were eligible for inclusion in the meta-analysis. Three studies used patient input as main outcome when evaluating response burden. In the meta-analysis, a general association between response rate and questionnaire length was found (P ≤ 0.0001). Response rates were lower for longer questionnaires, but because the P value for test of homogeneity was P = 0.03, this association should be interpreted with caution because it is impossible to separate the impact of content from length of the questionnaires. CONCLUSION Given the inherently problematic nature of comparing questionnaires of various lengths, it is preferable to base decisions on use of instruments on the content rather than the length per se.

Effects of Lesogaberan on Reflux and Lower Esophageal Sphincter Function in Patients With Gastroesophageal Reflux Disease

BACKGROUND & AIMS Transient lower esophageal sphincter relaxations (TLESRs) are a major mechanism behind reflux. This study assessed the effects of lesogaberan (AZD3355), a novel gamma-aminobutyric acid type B receptor agonist, on reflux and lower esophageal sphincter (LES) function when used as add-on treatment in patients with reflux symptoms despite proton pump inhibitor (PPI) treatment. METHODS In this randomized, double-blind, placebo-controlled, crossover study, patients received lesogaberan (65 mg) or placebo twice on day 1 (morning/evening) and once on day 2 (morning), in addition to existing PPI treatment. Patients consumed a standardized meal 45-60 minutes after morning doses. Ambulatory impedance-pH monitoring was conducted for 24 hours after the first dose on day 1. Stationary manometry and impedance-pH monitoring was conducted for 4 hours after the third dose on day 2. RESULTS Of 27 randomized patients, 21 were included in the per-protocol efficacy analysis. During the 24 hours after treatment start, lesogaberan reduced the mean number of reflux events by approximately 35% compared with placebo. During the 3 postprandial hours on day 2, lesogaberan reduced the geometric mean number of TLESRs by 25% and increased geometric mean LES pressure by 28% compared with placebo. The most common adverse events were headache (placebo: 11/27 patients; lesogaberan: 8/25 patients) and paresthesia (transient; placebo: 3/27 patients; lesogaberan: 5/25 patients). CONCLUSIONS In patients with reflux symptoms despite PPI treatment, lesogaberan decreased the number of TLESRs and reflux episodes, and increased LES pressure compared with placebo. These findings support further evaluation of lesogaberan as an add-on treatment in patients partially responding to PPIs.

Esomeprazole 20 mg vs. pantoprazole 20 mg for maintenance therapy of healed erosive oesophagitis: results from the EXPO study

Background : Following initial healing of erosive oesophagitis, most patients require maintenance therapy to prevent relapse.

Effect of lesogaberan, a novel GABA(B)-receptor agonist, on transient lower oesophageal sphincter relaxations in male subjects.

Aliment Pharmacol Ther 31, 1208–1217

Randomized, Double-Blind, Placebo-Controlled Trial of the 5-HT 1A Receptor Antagonist AZD7371 Tartrate Monohydrate (Robalzotan Tartrate Monohydrate) in Patients With Irritable Bowel Syndrome

OBJECTIVES:To investigate the efficacy and safety of the 5-hydroxytrypamine 1A (5-HT1A) receptor antagonist AZD7371 tartrate monohydrate (robalzotan tartrate monohydrate), termed AZD7371 here, in patients with irritable bowel syndrome (IBS).METHODS:Patients meeting the Rome II criteria for IBS (N = 402) were randomized to treatment with AZD7371 20 mg or 5 mg or matching placebo tablets twice daily for 12 wk. The patients completed daily and weekly diary assessments, reporting abdominal discomfort or pain and description of bowel movements. They also completed validated symptom and quality-of-life questionnaires.RESULTS:Neither AZD7371 regimen was significantly more effective than placebo in providing adequate relief from IBS symptoms in at least 2 out of 4 wk per month over the 12 wk of treatment. There was also no significant difference between the treatment groups and placebo in the change in score in the validated symptom and quality-of-life questionnaires. Overall, 22.1% of patients experienced adverse events (AEs) attributed to the study medication: 44 of 133 (33.1%) in the 20 mg AZD7371 group, 27 of 131 (20.6%) in the 5 mg AZD7371 group, and 17 of 134 (12.7%) in the placebo group. Also, 31 of 57 (54%) of AEs leading to discontinuation were central nervous system-related. Hallucinations or hallucination-like AEs were reported by eight patients taking AZD7371, and by none of the patients in the placebo group. After these events led to discontinuation in six patients, the study was prematurely terminated.CONCLUSIONS:In view of the AE profile and lack of efficacy in IBS, the clinical development of AZD7371 has been stopped.

M1911 Effect of Food On the Bioavailability of AZD3355, a Novel Reflux Inhibitor, in Healthy Subjects

G A A b st ra ct s (vomiting, dehydration, apnea, and stridor). Conclusions: In infants aged 1 through 11 mo with a clinical diagnosis of GERD, the 1.2-mg/kg equivalent dose provided statistically significant increases in mean gastric pH and percentage of time with gastric pH >4, and decreases in normalized AUC of esophageal H+ activity compared to baseline. For both doses, esophageal reflux area and normalized AUC of esophageal H+ activity decreased, indicating that the increase in the gastric pH did, in fact, result in a reduction of the pH of the refluxate. Both doses were well tolerated. The results support the choice of the 1.2mg/kg dose for infants 1 through 11 months when short-term treatment with pantoprazole is being considered.