Value through Innovation28 July 2015

Scientific Publications

Boehringer Ingelheim offers an overview of scientific publications on the following pages. This overview represents all publications of the last three years (YTD) where employees of Boehringer Ingelheim worldwide were involved.

20 publications regarding Clinical Studies
  • Author:
    Hohlfeld JM; Furtwaengler A; Könen-Bergmann M; Wallenstein G; Walter B; Bateman ED
    Title:
    Cardiac safety of tiotropium in patients with COPD: A combined analysis of Holter-ECG data from four randomised clinical trials
    Source:
    Int J Clin Pract 69 (1), 72-80 (2015)
    Abstract:
    Background Tiotropium is generally well tolerated; however, there has been debate whether antimuscarinicsarticularly tiotropium administered via Respimat® Soft Mist. Inhaler, may induce cardiac arrhythmias in a vulnerable subpopulation with cardiovascular comorbidity. The aim of this study was to provide evidence of the cardiac safety of tiotropium maintenance therapy. Methods Combined analysis of Holter electrocardiogram (ECG) data from clinical trials of tiotropium in chronic obstructive pulmonary disease (COPD). Trials in the Boehringer Ingelheim clinical trials database conducted between 2003 and 2012, involving tiotropium HandiHaler® 18 .g and/or tiotropium Respimat® (1.25-, 2.5-, 5.0- and 10-.g doses) were reviewed. All trials involving Holter-ECG monitoring during this period were included in the analysis. Men and women aged . 40 years with a smoking history of . 10 pack-years, and a clinical diagnosis of COPD were included. Holter ECGs were evaluated for heart rate (HR), supraventricular premature beats (SVPBs), ventricular premature beats (VPBs) and pauses. Quantitative and categorical end-points were derived for each of the Holter monitoring days. Results Four trials (n = 727) were included in the analysis. Respimat® (1.25-10 .g) or HandiHaler® (18 .g) was not associated with changes in HR, SVPBs, VPBs and pauses compared with placebo or the pretreatment baseline period. In terms of cardiac arrhythmia end-points, there was no evidence for an exposure-effect relationship. Conclusions In this analysis, tiotropium maintenance therapy administered using Respimat® (1.25-10 .g) or HandiHaler® (18 .g) once daily for periods of up to 48 weeks was well tolerated with no increased risk of cardiac arrhythmia in patients with COPD.
  • Author:
    Knudsen S; Jensen T; Hansen A; Mazin W; Lindemann J; Kuter I; Laing N; Anderson E
    Title:
    Development and validation of a gene expression score that predicts response to fulvestrant in breast cancer patients
    Source:
    PLoS ONE 9 (2) atr.no. e87415 (2014)
    Abstract:
    Fulvestrant is a selective estrogen receptor antagonist. Based on the measured growth inhibition of 60 human cancer cell lines (NCI60) in the presence of fulvestrant, as well as the baseline gene expression of the 60 cell lines, a gene expression score that predicts response to fulvestrant was developed. The score is based on 414 genes, 103 of which show increased expression in sensitive cell lines, while 311 show increased expression in the non-responding cell lines. The sensitivity genes primarily sense signaling through estrogen receptor alpha, whereas the resistance genes modulate the PI3K signaling pathway. The latter genes suggest that resistance to fulvestrant can be overcome by drugs targeting the PI3K pathway. The level of this gene expression score and its correlation with fulvestrant response was measured in a panel of 20 breast cancer cell lines. The predicted sensitivity matched the measured sensitivity well (CC = -0.63, P = 0.003). The predictor was applied to tumor biopies obtained from a Phase II clinical trial. The sensitivity of each patient to treatment with fulvestrant was predicted based on the RNA profile of the biopsy taken before neoadjuvant treatment and without knowledge of the subsequent response. The prediction was then compared to clinical response to show that the responders had a significantly higher sensitivity prediction than the non-responders (P = 0.01). When clinical covariates, tumor grade and estrogen receptor H-score, were included in the prediction, the difference in predicted senstivity between responders and non-responders improved (P = 0.003). Using a pre-defined cutoff to separate patients into predicted sensitive and predicted resistant yielded a positive predictive value of 88% and a negative predictive value of 100% when compared to clinical data. We conclude that pre-screening patients with the new gene expression predictor has the potential to identify those postmenopausal women with locally advanced, estrogen-receptor-positive breast cancer most likely to respond to fulvestrant. © 2014 Knudsen et al.
  • Author:
    Gallagher AM; Van Staa TP; Murray-Thomas T; Schoof N; Clemens A; Ackermann D; Bartels DB
    Title:
    Population-based cohort study of warfarin-treated patients with atrial fibrillation: Incidence of cardiovascular and bleeding outcomes
    Source:
    BMJ Open art.no.e003839 (2014)
    Abstract:
    Objectives: Atrial fibrillation (AF) is the most common cardiac rhythm disorder with a significant health burden. The aim of this study was to characterise patients with recently diagnosed AF and to estimate the rates of comorbidities and outcome events requiring hospitalisation in routine clinical practice. Design: Pharmacoepidemiological cohort study using observational data. Methods/setting: This study included 16 513 patients with a first diagnosis of AF between 1 January 2005 and 28 February 2010 (newly diagnosed patients) using data from the UK Clinical Practice Research Datalink (CPRD) linked to Hospital Episode Statistics (HES) and the Office for National Statistics mortality data. Exposure was stratified by vitamin K antagonist (VKA) exposure (non-use, current, recent and past exposure) based on prescriptions and/or international normalised ratio measurements, and followed for outcome events of interest based on diagnosis codes in the databases, that is, vascular outcomes, bleeding events and oters. The main focus of the study was on outcome events requiring hospitalisation using the HES data. Results: The incidence of vascular outcome hospitalisations (myocardial infarction (MI), stroke or systemic arterial peripheral embolism) was 3.8 (95% CI 3.5 to 4.0)/100 patient-years. The incidence of stroke was 0.9 (0.8 to 1.1) during current VKA exposure, 2.2 (1.6 to 2.9) for recent, 2.4 (1.9 to 2.9) for past and 3.4 (3.1 to 3.7) during non-use. MI incidence was 0.7 (0.6 to 0.9) for current VKA exposure, 0.7 (0.4 to 1.2) for recent, 1.1 (0.8 to 1.5) for past and 1.9 (1.7 to 2.1) during non-use. The incidence of bleeding event hospitalisations was 3.8 (3.4 to 4.2) for current VKA exposure, 4.5 (3.7 to 5.5) for recent, 2.7 (2.2 to 3.3) for past and 2.9 (2.6 to 3.2) during non-use; 38% of intracranial bleeds and 6% of gastrointestinal bleeds were fatal. Conclusions: This population-based study from recent years provides a comprehensive characterisation of newly diagnosed patients with AF and incidence estimates of common outcomes with a focus on hospitalised events stratified by VKA exposure. This study will help to place future data on new oral anticoagulants into perspective.
  • Author:
    Mück T
    Title:
    Useful combination in cold symptoms? Study on acetylsalicylic acid plus pseudoephedrine [Sinnvolle kombination bei erkältungssymptomen? Studie zu acetylsalicylsäure plus pseudoephedrin]
    Source:
    Dtsch Apoth Ztg 153 (38), 44-45 (2013)
    Abstract:
    no abstract available
  • Author:
    Roden M; Weng J; Eilbracht J; Delafont B; Kim G; Woerle HJ; Broedl UC
    Title:
    Empagliflozin monotherapy with sitagliptin as an active comparator in patients with type 2 diabetes: a randomised, double-blind, placebo-controlled, phase 3 trial
    Source:
    Lancet Diabetes Endocrinol Article in press (2013)
    Abstract:
    Background: We aimed to investigate the efficacy and tolerability of empagliflozin, an oral, potent, and selective inhibitor of sodium-glucose co-transporter 2, in patients with type 2 diabetes who had not received drug treatment in the preceding 12 weeks. Methods: In our multicentre, randomised, placebo-controlled, phase 3 trial, we enrolled adults (aged .18 years) who had not received oral or injected anti-diabetes treatment in the previous 12 weeks. Eligible patients had HbA1c concentrations of 7-10%. We randomly allocated patients (1:1:1:1) with a computer-generated random sequence, stratified by region, HbA1c, and estimated glomerular filtration rate at screening, to placebo, empagliflozin 10 mg, empagliflozin 25 mg, or sitagliptin 100 mg once daily for 24 weeks. Patients and investigators were masked to treatment assignment. The primary endpoint was change from baseline in HbA1c at week 24 by ANCOVA in all randomly allocated patients who were treated with at least one dose of study drug and had a baseline HbA1c value. This study is completed and registered with ClinicalTrials.gov, number NCT01177813. Findings: Between Aug 12, 2010, and March 19, 2012, we randomly allocated 228 patients to receive placebo, 224 to receive empagliflozin 10 mg, 224 to receive empagliflozin 25 mg, and 223 to receive sitagliptin. Compared with placebo, adjusted mean differences in change from baseline HbA1c at week 24 were -0.74% (95% CI -0.88 to -0.59; p<0.0001) for empagliflozin 10 mg, -0.85% (-0.99 to -0.71; p<0.0001) for empagliflozin 25 mg, and -0.73% (-0.88 to -0.59; p<0.0001) for sitagliptin. 140 (61%) patients in the placebo group reported adverse events (four [2%] severe and six [3%] serious), as did 123 (55%) patients in the empagliflozin 10 mg group (eight [4%] severe and eight [4%] serious), 135 (60%) patients in the empagliflozin 25 mg group (seven [3%] severe and five [2%] serious), and 119 (53%) patients in the sitagliptin group (five [2%] severe and six [3%] serious). Interpretation: Empagliflozin provides a tolerable and efficacious strategy to reduce HbA1c in patients with type 2 diabetes who had not previously received drug treatment. Funding: Boehringer Ingelheim and Eli Lilly. © 2013 Elsevier Ltd. All rights reserved.
  • Author:
    Hijazi Z; Oldgren J; Wallentin L; Andersson U; Connolly SJ; Yusuf S; Ezekowitz MD; Hohnloser SH; Reilly PA; Vinereanu D; Siegbahn A
    Title:
    Response to Ietter regarding article, "cardiac biomarkers are associated with an increased risk of stroke and death in patients with atrial fibrillation: A randomized evaluation of long-term anticoagulation therapy (RE-LY) substudy"
  • Author:
    Lang I; Köhne C-H; Folprecht G; Rougier P; Curran D; Hitre E; Sartorius U; Griebsch 1; Van Cutsem E
    Title:
    Quality of life analysis in patients with KRAS wild-type metastatic colorectal cancer treated first-line with cetuximab plus irinotecan, fluorauraeil and leucovorin
    Source:
    Eur J Cancer 49 (2), 439-448 (2013)
    Abstract:
    Background: ln the CRYSTAL study adding cetuximab to first-line FOLFIRI significantly improved outcome in patients with KRAS wild-type metastatic colorectal cancer. Quality of life (Qol)was assessed, and associations with tumour response and survival were investigated. Patients and methods: The European Organization for Research and Treatment of Cancer Qoql uestionnaire­ core 30 was used, focusing on global health status (GHS)/Qoal nd social functioning scales. Radiological responsewas assessed by an independent review committee. Results: Qowl as evaluable in 627/666 patients (94%) with KRAS wild-type tumours; of these 52% received FOLFIRI, and 48% FOLFIRI plus cetuximab. Pattern mixture analysis revealed no significant differences for GHS/Qo(lP = 0.12) and social functioning scores (P = 0.43) between the treatment arms. ln additional analyses: early skin reactions in patients receiving cetuximab Background: ln the CRYSTAL study adding cetuximab to first-line FOLFIRI significantly improved outcome in patients with KRAS wild-type metastatic colorectal cancer. Quality of life (Qol)was assessed, and associations with tumour response and survival were investigated. Patients and methods: The European Organization for Research and Treatment of Cancer Qoql uestionnaire­ core 30 was used, focusing on global health status (GHS)/Qoal nd social functioning scales. Radiological responsewas assessed by an independent review committee. Results: Qowl as evaluable in 627/666 patients (94%) with KRAS wild-type tumours; of these 52% received FOLFIRI, and 48% FOLFIRI plus cetuximab. Pattern mixture analysis revealed no significant differences for GHS/Qo(lP = 0.12) and social functioning scores (P = 0.43) between the treatment arms. ln additional analyses: early skin reactions in patients receiving cetuximab did not significantly affect these Qosl cales, and tumour response was more common (58% versus 40%, P = 0.0002) and survivallonger (Hazard ratio 1.68, P < 0.0001) in asymptomatic compared with symptomatic patients at baseline. Adding cetuximab to FOLFIRI was associated with significantly higher tumour response irrespective of patient baseline symptomatic status, and enhanced symptom relieffrom baseline in those whose tumours had responded. Conclusion: Adding cetuximab to FOLFIRI improved response rate and survival without either improving or negatively impacting on GHS/QoL and social functioning. © 2012 Elsevier Ud. All rights reserved.
  • Author:
    Lacy BE; Wang F; Bhowal S; Schaefer E
    Title:
    On-demand hyoscine butylbromide for the treatment of self-reported functional cramping abdominal pain
    Source:
    Scand J Gastroenterol 48 (8), 926-935 (2013)
    Abstract:
    Objective. Hyoscine butylbromide (HBB) has been used for 60 years to treat cramping abdominal pain, but scientific evidence to support on-demand use is limited. The aim of this study was to identify a meaningful efficacy end point that differentiates between the effects of HBB (20-100 mg/day) and placebo when used on demand. Materials & methods. 175 patients were treated in a randomized, double-blind, placebo-controlled, two-arm parallel group study. After a 4-week run-in period, patients used HBB to treat 2 distinct episodes of abdominal pain associated with cramping (APC). Patients entered data into an electronic diary for up to 4 h/episode. Pain intensity was assessed using an 11-point numerical pain rating scale (NPRS). Patients were allowed to self-medicate with up to 4 additional doses of HBB every 30 min. Results. The adjusted mean difference for the change from baseline during the 4-h observation period for a reduction in abdominal pain was -0.7 (95% confidence interval (CI) -1.3, -0.1, p = 0.016) for episode 1 and -0.6 (95% CI -1.2, 0.0, p = 0.051) for episode 2. Patients in the HBB group recorded a clinically relevant reduction of at least 2 points on the NPRS (approximately 30% pain relief) earlier than patients in the placebo group (HBB: 45 min, placebo: 60 min). Reported adverse events were infrequent in both groups (10.2% and 10.3%). Conclusions. HBB is effective in the treatment of recurrent APC and is safe and well tolerated when used on demand. The change from baseline in the intensity of APC using the 11-point NPRS distinguished HBB from placebo. © 2013 Informa Healthcare.
  • Author:
    Sulkowski MS; Bourlière M; Bronowicki J-P; Asselah T; Pawlotsky J-M; Shafran SD; Pol S; Mauss S; Larrey D; Datsenko Y; Stern JO; Kukolj G; Scherer J; Nehmiz G; Steinmann GG; Böcher WO
    Title:
    Faldaprevir combined with peginterferon alfa-2a and ribavirin in chronic hepatitis C virus genotype-1 patients with prior nonresponse: SILEN-C2 trial
    Source:
    Hepatology 57 (6), 2155-2163 (2013)
    Abstract:
    Faldaprevir (BI 201335) is a potent, hepatitis C virus (HCV) NS3/4A protease inhibitor. In all, 290 noncirrhotic HCV genotype (GT)-1 patients with prior null (&lt;1 log10 viral load [VL] drop at any time on treatment) or partial response (?1 log10 VL drop but never undetectable on treatment) were randomized 2:1:1 to receive 48 weeks of peginterferon alfa-2a and ribavirin (PegIFN/RBV) in combination with faldaprevir 240 mg once daily (QD) with 3 days PegIFN/RBV lead-in (LI), 240 mg QD without LI, or 240 mg twice daily (BID) with LI. Patients in the 240 mg QD/LI group achieving maintained rapid virologic response (mRVR; VL &lt;25 IU/mL [Roche TaqMan] at week 4 and undetectable at weeks 8 to 20) were rerandomized to cease all treatment at week 24 or continue PegIFN/RBV up to week 48. Sustained virologic response (SVR) rates were 32%, 50%, and 42% in prior partial responders, and 21%, 35%, and 29% in prior null responders in the faldaprevir 240 mg QD/LI, 240 mg QD, and 240 mg BID/LI groups, respectively. In the 240 mg QD/LI group, a significantly higher proportion of mRVR patients rerandomized to 48 weeks' treatment achieved SVR compared with those assigned to 24 weeks treatment (72% versus 43%; P = 0.035). Rates of gastrointestinal disorders, jaundice, dry skin, and photosensitivity were increased at 240 mg BID compared with the 240 mg QD dose. Faldaprevir discontinuations owing to adverse events occurred in 6%, 4%, and 23% of patients in the 240 mg QD/LI, 240 mg QD, and 240 mg BID/LI groups, respectively. Conclusion: Faldaprevir 240 mg QD with PegIFN/RBV was safe and tolerable and produced substantial SVR rates in prior null and partial responders. The 240 mg QD dose is currently undergoing phase 3 evaluation. © 2013 American Association for the Study of Liver Diseases.
  • Author:
    Sulkowski MS; Asselah T; Lalezari J; Ferenci P; Fainboim H; Leggett B; Bessone F; Mauss S; Heo J; Datsenko Y; Stern JO; Kukolj G; Scherer J; Nehmiz G; Steinmann GG; Böcher WO
    Title:
    Faldaprevir combined with pegylated interferon alfa-2a and ribavirin in treatment-naïve patients with chronic genotype1 HCV: SILEN-C1 trial
    Source:
    Hepatology 57 (6), 2143-2154 (2013)
    Abstract:
    Faldaprevir (BI 201335) is a potent, hepatitis C virus (HCV) NS3/4A protease inhibitor with pharmacokinetic properties supportive of once-daily (QD) dosing. Four hundred and twenty-nine HCV genotype (GT)-1 treatment-naïve patients without cirrhosis were randomized 1:1:2:2 to receive 24 weeks of pegylated interferon alfa-2a and ribavirin (PegIFN/RBV) in combination with placebo, faldaprevir 120 mg QD with 3 days of PegIFN/RBV lead-in (LI), 240 mg QD with LI, or 240 mg QD without LI, followed by an additional 24 weeks of PegIFN/RBV. Patients in the 240 mg QD groups achieving maintained rapid virologic response (mRVR; viral load [VL] <25 IU/mL at week 4 and undetectable at weeks 8-20) were rerandomized to cease all treatment at week 24 or continue receiving PegIFN/RBV up to week 48. VL was measured by Roche TaqMan. Sustained virologic response (SVR) rates were 56%, 72%, 72%, and 84% in the placebo, faldaprevir 120 mg QD/LI, 240 mg QD/LI, and 240 mg QD groups. Ninety-two percent of mRVR patients treated with faldaprevir 240 mg QD achieved SVR, irrespective of PegIFN/RBV treatment duration. Eighty-two percent of GT-1a patients who received faldaprevir 240 mg QD achieved SVR versus 47% with placebo. Mild gastrointestinal disorders, jaundice resulting from isolated unconjugated hyperbilirubinemia, and rash or photosensitivity were more common in the active groups than with placebo. Discontinuations resulting from adverse events occurred in 4%, 11%, and 5% of patients treated with 120 mg QD/LI, 240 mg QD/LI, and 240 mg QD of faldaprevir versus 1% with placebo. Conclusion: Faldaprevir QD with PegIFN/RBV achieved consistently high SVR rates with acceptable tolerability and safety at all dose levels. The 120 and 240 mg QD doses are currently undergoing phase 3 evaluation. © 2013 American Association for the Study of Liver Diseases.
  • Author:
    Kjeldsen SE; Schumacher H; Neldam S; Guthrie RM
    Title:
    Telmisartan/Hydrochlorothiazide Combination Therapy for the Treatment of Hypertension: A Pooled Analysis in Older and Younger Patients
    Source:
    J Clin Hypertens 15 (6), 380-388 (2013)
    Abstract:
    Older patients frequently receive angiotensin II receptor blocker/diuretic combinations to control blood pressure (BP), although there have been relatively few trials specifically examining this patient population. A pooled analysis was performed of data from 7 randomized trials of telmisartan/hydrochlorothiazide combinations or telmisartan monotherapy in older (65 years and older) and younger (younger than 65 years) patients to better understand the response of older patients to a telmisartan/hydrochlorothiazide combination. Telmisartan doses were 40 mg and 80 mg (T40 and T80). Hydrochlorothiazide doses were 12.5 mg and 25 mg (H12.5 and H25). A total of 3654 patients were included and the mean treatment duration was approximately 8 weeks. BP reductions with telmisartan/hydrochlorothiazide combinations were broadly similar in older and younger patients. In older patients, mean BP reductions from baseline were -30.1/-19.0 mm Hg with the T80/H25 combination and -21.7/-13.0 mm Hg with T80 monotherapy. Tolerability was similar regardless of age, and the incidence of adverse events in both older and younger patients was similar to placebo. The telmisartan/hydrochlorothiazide combination, particularly high-dose T80/H25, is effective and well tolerated in patients 65 years and older as well as in younger patients. © 2013 Wiley Periodicals, Inc.
  • Author:
    Bezemer I D; Roemer W H; Penning-van Beest F J A; van Eekelen E; Kramer M H H
    Title:
    INR control calculation: Comparison of Dutch and international methods
    Source:
    Neth J Med 71 (4), 194-198 (2013)
    Abstract:
    Results of trials with new oral anticoagulant drugs and vitamin K antagonists (VKA) might not be directly applicable to Dutch clinical practice due to the high level of control of anticoagulation in the Netherlands. In addition, the Dutch method for assessing anticoagulation control uses cross-sectional international normalised ratio (INR) test results while the method used in the trials is based on person-time. To enable comparisons, the two calculation methods were applied to INR data of a cohort of 5422 atrial fibrillation patients treated with VKA. Overall, 74% of test results and 77% of person-time were in the therapeutic range [2.0-3.5]. For the narrower target INR interval [2.5-3.5], 59% of test results and 61% of person-time were in range. It was only between two and six months after the start of treatment that the percentage of person-time in range was lower than the percentage of test results in range. Control of anticoagulation, expressed as a percentage of person-time spent in range, in this Dutch dataset was similar to recent trials with new oral anticoagulants, although it should be noted that the Dutch INR target is higher than the target in these trials. INR control as estimated by the two calculation methods (cross-sectional and longitudinal) was similar. © Van Zuiden Communications B.V. All rights reserved.
  • Author:
    Roskell NS; Samuel M; Noack H; Monz BU
    Title:
    Major bleeding in patients with atrial fibrillation receiving vitamin K antagonists: A systematic review of randomized and observational studies
    Source:
    Europace 15 (6), 787-797 Cited 1 time (2013)
    Abstract:
    Aims Clinical trials have shown that anticoagulation with vitamin K antagonists (VKAs), e.g. warfarin, decreases the risk of stroke in patients with atrial fibrillation (AF); however, increased bleeding risk is one of the safety concerns. The primary objective was to conduct a systematic review of the published literature, assessing the risk of major bleeding and mortality in patients with AF treated with VKAs. Methods and resultsOnline searches of MEDLINE, EMBASE, BIOSIS, and the Cochrane Library were performed to a pre-specified protocol from 1960 to March 2012 for randomized controlled trials (RCTs) and from January 1990 to March 2012 for observational studies. A total of 47 studies (16 RCTs and 31 observational studies) were included. Cumulative follow-up was 61 563 patient-years for RCTs and 484 241 patient-years for observational studies. The overall median incidence of major bleeding was 2.1 per 100 patient-years (range, 0.9-3.4 per 100 patient-years) for RCTs and 2.0 per 100 patient-years (range, 0.2-7.6 per 100 patient-years) for observational studies. With study year as a proxy for changing management patterns, some evidence of bleeding rates and/or their reporting increasing over time was noted. Mortality rates from observational studies were inadequately reported to allow comparison with those from RCT data. Conclusion The median rate of major bleeding in observational studies and RCTs is similar. The larger heterogeneity in bleeding rates observed in a real-life setting could reflect a high variability in standard of care of patients on VKAs and/or methodological differences between observational studies and/or variability in data sources. © 2012 The Author.
  • Author:
    Hu S; Zhan L; Liu B; Gao Y; Li Y; Tong R; Wu L; Yu B; Gao S
    Title:
    Economic burden of individual suffering from atrial fibrillation-related stroke in China
    Source:
    Value Health Reg Issues 2 (1), 135-140 (2013)
    Abstract:
    Objective: Atrial fibrillation (AF) is an important risk factor for stroke. The primary purpose of this study was to estimate the 1-year direct and indirect costs of ischemic stroke in Chinese patients with AF. Method: A total of 300 charts were selected and reviewed in 18 hospitals from neurology departments in six major cities of China nationwide. Patients with primary diagnosis of ischemic stroke and secondary diagnosis of AF were selected for review. A total of 63 patients were selected from the chart review pool and followed up for 1 year to record their resource utilization and absenteeism from work following discharge. Results: The mean±SD age of the cohort was 70.2±11.8 years, with an average hospitalization duration of stay of 17.9 days. The mean total direct cost for AF-related stroke was estimated at 30,438.3 China Yuan (CNY) per patient-year. The major cost driver for direct cost was stroke's acute hospitalization expense, which accounted for 61.5% (CNY 18,706.1). Among the seven patients not reaching the legal retirement age, the indirect cost per person-year totaled 16,838.9 CNY, most of which (63.0%) was a result of early retirement. The analysis also suggested that higher hospital ranking (based on the tier system), longer hospital stay, higher modified Rankin Scale score, taking surgery during hospitalization, receiving thrombolysis therapy, and incidence of complications such as pneumonia or cerebral edema predicted higher inpatient costs. Conclusions: Hospital costs due to strokes among patients with AF are the predominant contributor to the total direct cost, which is consistent with current hospital-centered treatment pattern in China. However, literature suggested that AF-induced strokes are highly preventable with drugs and clinical procedures, which highlights the importance of optimal clinical management of stroke prevention in patients with AF. © 2013 International Society for Pharmacoeconomics and Outcomes Research (ISPOR).
  • Author:
    Gelez H; Greggain-Mohr J; Pfaus J G; Allers K A; Giuliano F
    Title:
    Flibanserin treatment increases appetitive sexual motivation in the female rat
    Source:
    J Sex Med 10 (5), 1231-1239 (2013)
    Abstract:
    Introduction.: Flibanserin is a mixed 5-HT1A agonist/5-HT2A antagonist that has been developed for the treatment of hypoactive sexual desire disorder in women. Aim.: To assess the acute and chronic dose-response effects of flibanserin on measures of sexual desire and copulation in ovariectomized rats primed with estradiol benzoate (EB) alone or in combination with progesterone (P). Methods.: In Experiment 1, sexually experienced ovariectomized (OVX) rats at one testing site were rendered fully sexually receptive with EB+P priming and tested weekly with a sexually active male in bi-level pacing chambers following daily flibanserin treatment for 28 days. In Experiment 2, sexually experienced OVX rats at a different testing site received EB alone and were tested weekly with sexually active males following daily flibanserin treatment. Main Outcome Measures.: Female appetitive behaviors (solicitations, hops and darts, anogenital investigations), defensive behaviors, pacing, lordosis, and male copulatory responses (intromissions and ejaculations) were measured during each 30-minute copulation test. Results.: Acute flibanserin or 1 week of chronic flibanserin treatment did not modify sexual responses in fully (EB+P) or partially (EB-alone) primed females. After 2 weeks of chronic treatment, fully primed females displayed significantly more solicitations than the three other groups. After 3 weeks of chronic treatment, a significant increase in female solicitations was observed in both hormone-treatment groups. Conclusion.: This study shows the first evidence that chronic, but not acute, flibanserin treatment augments appetitive sexual behaviors in OVX female rats primed with EB+P or EB alone. Given the positive effect of flibanserin in clinical trials, these results confirm previous reports that solicitations in the female rat are a predictive animal model of human female sexual desire. © 2013 International Society for Sexual Medicine.
  • Author:
    Ring A; Rathgen K; Stangier J; Reilly P; Clemens A; Friedman J
    Title:
    Dabigatran does not prolong the QT interval with supratherapeutic exposure: A thorough qt study in healthy subjects
    Source:
    Clin Drug Invest 33 (5), 333-342 (2013)
    Abstract:
    Background: Dabigatran etexilate is a pro-drug of the oral reversible direct thrombin inhibitor dabigatran that interacts with the active site in the catalytic domain of the thrombin molecule. Objective: To assess the electrophysiological effects of therapeutic and supratherapeutic doses of dabigatran etexilate in healthy subjects, a thorough QT study was performed. Methods: In this single-centre, blinded, placebo- and active-controlled, four-period, crossover study, 40 healthy Caucasian subjects (20 women and 20 men) received single oral doses of dabigatran etexilate (150 mg and 600 mg), moxifloxacin 400 mg (positive control) or placebo, in a randomized order. Electrocardiogram (ECG) profiles were recorded at baseline and during the randomized study treatment in each period. The individually heart-rate-corrected QT interval (QTcI) was the primary parameter. The primary endpoint was the mean of these QTcI values obtained at 1.5, 2 and 3 h following study drug administration minus the mean of the time-matched QTcI values obtained at baseline day -1. The hypothesis tested was that the difference between each of the two doses of dabigatran etexilate (150 mg and 600 mg) and placebo, for the mean time-matched change from baseline (CfB) of QTcI between 1.5 and 3 h (the primary endpoint), was greater than or equal to 10 ms. Secondary endpoints were the time-matched CfB of QTcI between 0.5 and 24 h post-dose. Results: All subjects completed the study without premature discontinuation and all treatments were well tolerated. Following dabigatran etexilate administration, the mean values of the placebo-adjusted time-matched CfB of QTcI between 1.5 and 3 h post-dose were close to 0; the upper bound of the two-sided 90 % confidence interval (CI) was 1.4 ms for dabigatran etexilate 150 mg and 1.3 ms for dabigatran etexilate 600 mg. The placebo-adjusted time-matched CfB of QTcI remained close to 0 at all time points, and all 90 % CIs were between -5 ms and 5 ms, well below the pre-defined non-inferiority margin of 10 ms. Conclusion: This thorough QT study demonstrated that therapeutic and fourfold supratherapeutic doses of dabigatran etexilate do not prolong QT intervals. © 2013 The Author(s).
  • Author:
    Esperester A; Schütt T; Ottilinger B
    Title:
    The evidence of the clinical effectiveness of edema-protective agents and their pitfalls [Der Nachweis der klinischen Wirksamkeit von Ödemprotektiva und seine Tücken]
    Source:
    Med Monatsschr Pharm 36 (2) (2013)
    Abstract:
    no Abstract available
  • Author:
    Johnson B H; Smoyer-Tomic K E; Siu K; Walker D R; Sander S; Huse D; Smith D M; Song X; Amin A
    Title:
    Readmission among hospitalized patients with nonvalvular atrial fibrillation
    Source:
    Am J Health-Syst Pharm 70 (5), 414-422 (2013)
    Abstract:
    Purpose: Hospital readmission rates for patients with nonvalvular atrial fibrillation (NVAF), as well as reasons and risk factors for rehospitalization, were investigated. Methods: Demographic, clinical, and prescription claims data on patients hospitalized for atrial fibrillation (AF) over a five-year period were extracted from insurance claims databases; from that data set, a subset of adults with NVAF on whom continuous data were available before and after the index admission (n = 6439) was identified, and their 30-day readmission rate was examined. Results: The overall 30-day readmission rate was 18.0%. The five most common readmission diagnoses (grouped per International Classification of Diseases codes) were general and other nonspecific symptoms (12.8% of readmitted patients), AF (10.2%), ischemic heart disease (7.2%), heart failure (7.1%) and cerebrovascular disease (6.0%). Controlling for demographic and clinical variables, index admission factors associated with an increased risk of readmission included a longer hospital length of stay, higher Charlson Comorbidity Index scores, and admission through the emergency room (p ? 0.01 for all). For the subset of patients discharged from the index admission to home self-care (n = 1161), no individual follow-up care measure evaluated (a physician or other medical office visit, International Normalized Ratio testing, filling an anticoagulant prescription) taken within 7 days of discharge correlated with reduced readmission risk during postdischarge days 8-30. Conclusion: The 30-day readmission rate for patients hospitalized with NVAF was comparable to rates previously documented among patients with other cardiac conditions. Symptoms, AF, ischemic heart disease, heart failure, and cerebrovascular disease were the most common reasons for readmission. Copyright © 2013, American Society of Health-System Pharmacists, Inc. All rights reserved.
  • Author:
    Araki E; Kawamori R; Inagaki N; Watada H; Hayashi N; Horie Y; Sarashina A; Thiemann S; von Eynatten M; Dugi K; Woerle H-J
    Title:
    Long-term safety of linagliptin monotherapy in Japanese patients with type 2 diabetes
    Source:
    Diabetes Obes Metab 15 (4), 364-371 (2013)
    Abstract:
    Aims: In a phase III study conducted among Japanese patients with type 2 diabetes mellitus (T2DM), linagliptin 5 and 10mg showed clinically meaningful improvements in glycaemic parameters after 12 and 26weeks compared with placebo and voglibose, respectively. This extension study assessed long-term tolerability of linagliptin over 52weeks. Methods: Japanese patients with T2DM who completed either phase of a 12-week/26-week study comparing linagliptin monotherapy with placebo or voglibose were eligible to enrol. In the extension study, the comparator groups switched to linagliptin 5 or 10mg, while the linagliptin groups maintained dosage. Results: In all, 540 patients received at least one dose of linagliptin 5 or 10mg and 494 completed the extension. Long-term treatment with linagliptin was well tolerated; adverse events (AEs) of special interest and serious AEs occurred in small percentages of patients. Drug-related AEs occurred in 10.2 and 10.6% of patients in the linagliptin 5- and 10-mg groups, respectively, and discontinuations due to drug-related AEs occurred in 1.1 and 0.7%, respectively. Only one (0.4%) patient in each dose group experienced investigator-defined hypoglycaemia during the treatment period (both events were non-severe). Body weight was not clinically altered in either group. The glycated haemoglobin A1c profiles over time were similar with linagliptin 5 and 10mg. Conclusions: These findings provide evidence for the safety and tolerability of oral linagliptin at either 5 or 10mg for up to 52weeks for the treatment of Japanese patients with T2DM, without clinically relevant increase in the risk of hypoglycaemia or weight gain. © 2012 Blackwell Publishing Ltd.
  • Author:
    Wagner C L; Visvanathan S; Elashoff M; Mcinnes I B; Mease P J; Krueger G G; Murphy F T; Papp K; Gomez-Reino JJ; Mack M; Beutler A; Gladman D; Kavanaugh A
    Title:
    Markers of inflammation and bone remodelling associated with improvement in clinical response measures in psoriatic arthritis patients treated with golimumab
    Source:
    Ann Rheum Dis 72 (1), 83-88 (2013)
    Abstract:
    Objective: To determine serum biomarker associations with clinical response to golimumab treatment in patients with psoriatic arthritis (PsA). Methods: GO-REVEAL was a randomised, placebo-controlled study of golimumab in patients with active PsA. Samples were collected from 100 patients at baseline, week 4 and week 14, and analysed for serum-based biomarkers and protein profiling (total 92 markers); data were correlated with clinical measures at week 14. Results: Serum levels of a subset of proteins (apolipoprotein C III, ENRAGE, IL-16, myeloperoxidase, vascular endothelial growth factor, pyridinoline, matrix metalloproteinase 3, C-reactive protein (CRP), carcinoembryonic antigen, intercellular adhesion molecule 1 and macrophage inflammatory protein 1?) at baseline or week 4 were strongly associated with American College of Rheumatology 20% improvement (ACR20) response and/or disease activity score in 28 joints (DAS28) at week 14. A smaller subset of proteins was significantly associated with a 75% improvement in the psoriasis area and severity index score (PASI75) at week 14, (adiponectin, apolipoprotein CIII, serum glutamic oxaloacetic transaminase, and tumour necrosis factor ?). Subsets of proteins were identified as potentially predictive of clinical response for each of the clinical measures, and the power of these biomarker panels to predict clinical response to golimumab treatment was stronger than for CRP alone. Conclusions: This analysis provides insight into several panels of markers that may have utility in identifying PsA patients likely to have ACR20, DAS28, or PASI75 responses following golimumab treatment. Copyright Article author (or their employer) 2012.