Value through Innovation18 April 2014

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.

197 publications regarding Cardiovascular
  • Author:
    Eikelboom JW; Brueckmann M; Van de Werf F
    Title:
    Dabigatran versus warfarin in patients with mechanical heart valves: Reply
    Source:
    J Thromb Haemost 12 (3), 426-426 (2014)
    Abstract:
    no abstract available
  • Author:
    Kratz MT; Schumacher H; Sliwa K; Schmieder R; Pöss J; Mahfoud F; Unger T; Lonn E; Koon T; Mancia G; Sleight P; Yusuf S; Böhm M
    Title:
    Heart rate and blood pressure interactions in the development of erectile dysfunction in high-risk cardiovascular patients
    Source:
    Eur J Prev Cardiol 21 (3), 272-280 (2014)
    Abstract:
    Aims: Erectile dysfunction (ED) is associated with cardiovascular risk factors as elevated systolic blood pressure (SBP), resting high heart rate (HR), and endothelial dysfunction and predicts cardiovascular events. However, the interaction between high HR and SBP and the development of ED remains unclear. Methods and Results: We evaluated 1015 male patients enrolled in the ED substudy of ONTARGET and TRANSCEND, examining the influence of mean HR and mean SBP obtained over all study visits (mean 10.9-1.4 study visits) and their interaction with ED. In patients without pre-existing ED, new onset ED was detected in 29% of patients below, and 41% of patients above, the median of mean HR (OR 1.72, 95% CI 1.8-2.5, p=0.0047). In patients with pre-existing ED, high HR had no add-on effect. With or without pre-existing ED, high SBP had no influence after adjustment for covariates (OR 1.03, 95% CI 0.66-1.59, p=0.91). In a continuous model, it was shown that effects of high HR were prominent at low Koiner (Cologne) Evaluation of Erectile Function (KEED) score baseline values and in the presence of SBP above the median. Conclusions: In patients at risk for cardiovascular events, high HR is associated with ED, whereas the effect of high SBP was not significant. High resting HR might represent a cardiovascular risk indicator. Whether HR represents a potential treatment target to improve ED in high-risk individuals must be scrutinized in prospective trials. © 2013 The European Society of Cardiology.
  • Author:
    Huisman MV; Lip GYH; Diener HC; Dubner SJ; Halperin JL; Ma CS; Rothman KJ; Teutsch C; Zint K; Ackermann D; Clemens A; Bartels DB
    Title:
    Design and rationale of Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation: A global registry program on long-term oral antithrombotic treatment in patients with atrial fibrillation
    Source:
    Am Heart J 167 (3), 329-334 (2014)
    Abstract:
    Background Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting 1% to 2% of the population and raising the risk of stroke 5-fold. Until recently, the only treatment choices for stroke prevention in patients with AF have been vitamin K antagonists (VKA) or antiplatelet drugs. With approval of novel oral anticoagulants (NOACs) antithrombotic treatment, patterns are changing. The Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation is designed to investigate patient characteristics influencing choice of antithrombotic treatment of stroke prevention in patients with nonvalvular AF and to collect data on outcomes of antithrombotic therapy in clinical practice. Methods The GLORIA-AF is a large, international, observational registry involving patients with newly diagnosed nonvalvular AF at risk for stroke, enrolling up to 56,000 patients in nearly 50 countries. We will collect and analyze data from routine care using an inception cohort design. Phase I includes patients before approval of NOACs. Phase II, beginning early after approval of dabigatran, monitors dabigatran safety and addresses potential channeling across treatment options based on propensity scoring to assess comparability of baseline characteristics of patients treated with dabigatran or VKA. Phase III entails analysis of large treatment groups, adjusting for differences in propensity score, to provide information about the relative effectiveness and safety of NOACs and VKA in routine clinical care. Conclusions Novel features of this registry program will add data from clinical practice to those from randomized trials to expand knowledge of antithrombotic treatment in patients with AF. © 2014 Mosby, Inc.
  • Author:
    van Ryn J; Schurer J; Goss A; Clemens A
    Title:
    Assessment Of Ex Vivo and In Vivo Dabigatran Interactions With Concomitant Heparin Administration Using the Activated Clotting Time (ACT) Assay
    Source:
    American College of Cardiology, Washington D.C.,USA, March 29-31, 2014
  • Author:
    Grottke O; Honickel M; van Ryn J; Rossaint R; ten Cate H; Spronk H
    Title:
    A Specific Antidote (aDabi-Fab) to Dabigatran reduces Blood Loss in Dabigatran- and Trauma-induced Bleeding in Pigs
    Source:
    American College Cardiology, Washington D.C.,USA, March 29-31,2014
  • Author:
    Grottke O; Honickel M; van Ryn J; ten Cate H; Rossaint R; Spronk H
    Title:
    The use of a specific antidote to dabigatran (idarucizumab) reduces blood loss and mortality in dabigatran- and traumainduced bleeding
  • Author:
    Mueller S; Pfannkuche M; Breithardt G; Bauersachs R; Maywald U; Kohlmann T; Wilke T
    Title:
    The quality of oral anticoagulation in general practice in patients with atrial fibrillation
    Source:
    Eur J Intern Med 25 (3), 247-254 (2014)
    Abstract:
    Background The aims of this study were to evaluate the quality of oral anticoagulation (OAC) in AF patients in the practices of general practitioners (GPs) in Germany and to investigate possible causal factors which influence OAC quality. Methods We conducted a multi-center, non-interventional, prospective observational cohort study among general practitioners (GPs) in Germany. To assess the quality of OAC on the basis of the prospectively documented international normalized ratio (INR) values, the time in therapeutic range (TTR) was calculated using the Rosendaal linear trend method. The causes of poor OAC quality were identified by a multivariate analysis model (logistical regression; poor OAC quality: TTR < 60%). Results and conclusions For 525 OAC patients (66.8%; patients with at least 2 prospectively documented INR values) the average TTR (target range of 2.0-3.0) was 67.6%. About 34.7% of the patients had a TTR < 60%. None of the variables representing characteristics of the medical practices were capable of explaining the occurrence of poor OAC quality. However, with regard to care provision-based variables, the existence of a brief discontinuation of medication was important. As the existence of adherence barriers increased, the probability of poor anticoagulation quality increased. In conclusion, the provision of OAC in the German health care system is to be regarded as good, but far from ideal. Our causal analysis shows that patient-based factors should be addressed through the provision of improved training and that the rationale behind the interruption of OAC treatment should be critically examined. © 2014 European Federation of Internal Medicine.
  • Author:
    Grottke O; van Ryn J; Rossaint R
    Title:
    In a trauma experimental pig model prothrombin complex concentrates and a specific antidote (idarucizumab) are effective to reverse the anticoagulant effects of dabigatran
    Source:
    Internation Symposium on Intensive Care and Emergency Medicine (ISICEM), Brussels, Belgium, March 18-21, 2014
  • Author:
    Grottke O; van Ryn J; Zentai C; ten Cate H; Rossaint R; Spronk H
    Title:
    Resuscitation with Different Infusion Solutions does not Influence Binding of Dabigatran to its Specific Antidote in a Pig Model of Hemorrhagic Shock
    Source:
    2013 Scientific Sessions of the American Heart Association, Dallas, USA, Nov 16-20, 2013
  • Author:
    Schulman S; Kakkar AK; Goldhaber SZ; Schellong S; Eriksson H; Mismetti P; Christiansen AV; Friedman J; Maulf FL; Peter N; Kearon C
    Title:
    Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis
    Source:
    Circulation 129 (7), 764-772 (2014)
    Abstract:
    no Abstract available
  • Author:
    Kratz MT; Schumacher H; Sliwa K; Schmieder R; Pöss J; Mahfoud F; Unger T; Lonn E; Koon T; Mancia G; Sleight P; Yusuf S; Böhm M
    Title:
    Heart rate and blood pressure interactions in the development of erectile dysfunction in high-risk cardiovascular patients
    Source:
    Eur J Prev Cardiol 21 (3), 272-280 (2014)
    Abstract:
    no Abstract available
  • Author:
    Huisman MV; Lip GYH; Diener HC; Dubner SJ; Halperin JL; Ma CS; Rothman KJ; Teutsch C; Zint K; Ackermann D; Clemens A; Bartels DB
    Title:
    Design and rationale of Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation: A global registry program on long-term oral antithrombotic treatment in patients with atrial fibrillation
    Source:
    Am Heart J 167 (3), 329-334 (2014)
    Abstract:
    no Abstract available
  • 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:
    Behnes M; Brueckmann M; Lang S; Weiß C; Ahmad-Nejad P; Neumaier M; Borggrefe M; Hoffmann U
    Title:
    Connective tissue growth factor (CTGF/CCN2): Diagnostic and prognostic value in acute heart failure
    Source:
    Clin Res Cardiol 103 (2), 107-116 (2014)
    Abstract:
    Background: As a mediator of ECM homeostasis, connective tissue growth factor (CTGF) appears to be involved in adverse structural remodeling processes in the heart. However, the diagnostic and prognostic value of CTGF levels in acute heart failure (AHF) in addition to natriuretic peptide testing has not yet been evaluated. Methods and results: A total of 212 patients presenting with acute dyspnea and/or peripheral edema to the Emergency Department were evaluated. CTGF and NT-proBNP plasma levels were measured at the initial presentation. All patients were followed up to 1 and 5 years. The first endpoint tested was the diagnostic non-inferiority of combined CTGF plus NT-proBNP compared to NT-proBNP alone for AHF diagnosis. Afterwards, the additional diagnostic value of CTGF plus NT-proBNP was tested. CTGF levels were higher in NYHA class III/IV and AHA/ACC class C/D patients compared to lower class patients (p = 0.04). Patients with HFREF revealed highest CTGF levels (median 93.3 pg/ml, IQR 18.2-972 pg/ml, n = 48) compared to patients with a normal heart function (i.e., without HFREF and HFPEF) (median 25.9, IQR <1-82.2 pg/ml, n = 37) (p < 0.05), followed by patients with HFPEF (median 82.2 pg/ml, IQR 11.5-447 pg/ml, n = 32) as assessed by echocardiography. Finally, CTGF levels were higher in patients with AHF (median 77.3 pg/ml, IQR 22.5-1012 pg/ml, n = 66) compared to those without (p = 0.002). CTGF plus NT-proBNP was non-inferior to NT-proBNP testing alone for AHF diagnosis (AUC difference 0.01, p > 0.05). CTGF plus NT-proBNP improved the diagnostic capacity for AHF (accuracy 82 %, specificity 83 %, positive predictive value 66 %, net reclassification improvement +0.11) compared to NT-proBNP alone (p = 0.0001). CTGF levels were not able to differentiate prognostic outcomes after 1 and 5 years. Conclusions: Additional CTGF measurements might lead to a better discrimination of higher functional and structural heart failure stages and might identify patients of an increased risk for an acute cardiac decompensation. © 2013 Springer-Verlag Berlin Heidelberg.
  • Author:
    Gosse P; Schumacher H
    Title:
    Effect of telmisartan vs. ramipril on 'dipping' status and blood pressure variability: Pooled analysis of the PRISMA studies
    Source:
    Hypertens Res 37 (2), 151-157 (2014)
    Abstract:
    A retrospective pooled analysis of the 'Prospective, Randomized Investigation of the Safety and Efficacy of MICARDIS vs. Ramipril Using ABPM' studies conducted in Europe and South Africa (PRISMA I) and in the United States of America and Canada (PRISMA II) was carried out to investigate the effects of telmisartan and ramipril on dipper status (extreme dippers, dippers, non-dippers, risers/reverse dippers), and blood pressure (BP) variability in 1279 patients (with normal sleeping patterns and valid 24-h ambulatory BP monitoring recordings at baseline and end point). After 14 weeks' treatment, telmisartan had a greater systolic BP (SBP) reduction and higher smoothness index in all four dipper groups compared with ramipril. In addition, the tendency toward dipping was significantly higher in patients treated with) telmisartan than ramipril (P=0.032; odds ratio for telmisartan vs. ramipril: 1.27 (95% confidence interval: 1.102-1.58)). In patients with an early morning SBP surge .35 mm Hg, telmisartan treatment was associated with significantly greater reductions from baseline in the night-time low mean, early morning mean and early morning SBP surge compared with ramipril (P=0.026, P<0.0001 and P=0.0006, respectively). In this retrospective analysis, telmisartan was shown to normalize the circadian BP pattern to a dipper profile in a larger proportion of patients than ramipril, and reduce early-morning SBP surge in high-risk patients, indicative of a cardioprotective effect. These findings need to be confirmed in long-term prospective trials and observational studies. © 2014 The Japanese Society of Hypertension All rights reserved.
  • Author:
    Reilly PA; Lehr T; Haertter S; Connolly SJ; Yusuf S; Eikelboom JW; Ezekowitz MD; Nehmiz G; Wang S; Wallentin L
    Title:
    The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: The RE-LY trial (Randomized Evaluation of Long-Term Anticoagulation Therapy)
    Source:
    J Am Coll Cardiol 63 (4), 321-328 (2014)
    Abstract:
    Objectives The goal of this study was to analyze the impact of dabigatran plasma concentrations, patient demographics, and aspirin (ASA) use on frequencies of ischemic strokes/systemic emboli and major bleeds in atrial fibrillation patients. Background The efficacy and safety of dabigatran etexilate were demonstrated in the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial, but a therapeutic concentration range has not been defined. Methods In a pre-specified analysis of RE-LY, plasma concentrations of dabigatran were determined in patients treated with dabigatran etexilate 110 mg twice daily (bid) or 150 mg bid and correlated with the clinical outcomes of ischemic stroke/systemic embolism and major bleeding using univariate and multivariate logistic regression and Cox regression models. Patient demographics and ASA use were assessed descriptively and as covariates. Results Plasma concentrations were obtained from 9,183 patients, with 112 ischemic strokes/systemic emboli (1.3%) and 323 major bleeds (3.8%) recorded. Dabigatran levels were dependent on renal function, age, weight, and female sex, but not ethnicity, geographic region, ASA use, or clopidogrel use. A multiple logistic regression model (c-statistic 0.657, 95% confidence interval [CI]: 0.61 to 0.71) showed that the risk of ischemic events was inversely related to trough dabigatran concentrations (p = 0.045), with age and previous stroke (both p < 0.0001) as significant covariates. Multiple logistic regression (c-statistic 0.715, 95% CI: 0.69 to 0.74) showed major bleeding risk increased with dabigatran exposure (p < 0.0001), age (p < 0.0001), ASA use (p < 0.0003), and diabetes (p = 0.018) as significant covariates. Conclusions Ischemic stroke and bleeding outcomes were correlated with dabigatran plasma concentrations. Age was the most important covariate. Individual benefit-risk might be improved by tailoring dabigatran dose after considering selected patient characteristics. (Randomized Evaluation of Long Term Anticoagulant Therapy [RE-LY] With Dabigatran Etexilate; NCT00262600) © 2014 by the American College of Cardiology Foundation.
  • Author:
    Scowcroft ACE; Cowie MR
    Title:
    Atrial fibrillation: Improvement in identification and stroke preventive therapy - Data from the UK Clinical Practice Research Datalink, 2000-2012
    Source:
    Int J Cardiol 171 (2), 169-173 (2014)
    Abstract:
    Objective To investigate recent trends in the diagnosis and treatment of atrial fibrillation. Methods Time trend analysis in the UK Clinical Practice Research Datalink (CPRD - previously the GPRD), 2000-2012. Results The incidence of AF in men rose from 1.274 (1.271, 1.276) per 1 000 patient years in 2000 to 1.972 (1.969, 1.975) in 2012. In women, it rose from 1.209 (1.207, 1.211) to 1.609 (1.606, 1.611). 55 847 patients with AF first diagnosed between 2000 and 2012 were included in the study. 54% of men were initiated on anticoagulation therapy in the first year following diagnosis of atrial fibrillation, compared to 45% of women (P < 0.0001). This increased from 48% in men and 40% in women in 2000 to 58% in men and 52% in women in 2012. Conclusions Identification of atrial fibrillation has improved in recent years, as has treatment for stroke prevention. Although there has historically been a bias towards men in the treatment of stroke prevention in atrial fibrillation, this study shows that the gap has been closing in recent years. Despite this improvement, this study shows that there are still many patients with atrial fibrillation who are not treated optimally to prevent stroke. © 2013 Published by Elsevier Ireland Ltd.
  • Author:
    Lund SS; Gong Y
    Title:
    Effects of metformin versus glipizide on cardiovascular outcomes in patients with type 2 diabetes and coronary artery disease.
    Source:
    Diabetes Care 37 (1), e19-20e (2013)
    Abstract:
    no abstract available
  • Author:
    Huisman MV; Lip GYH; Diener HC; Dubner SJ; Halperin JL; Ma CS; Rothman KJ; Teutsch C; Zint K; Ackermann D; Clemens A; Bartels DB
    Title:
    Design and rationale of Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation: A global registry program on long-term oral antithrombotic treatment in patients with atrial fibrillation
    Source:
    Am Heart J Article in press (2014)
    Abstract:
    Background: Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting 1% to 2% of the population and raising the risk of stroke 5-fold. Until recently, the only treatment choices for stroke prevention in patients with AF have been vitamin K antagonists (VKA) or antiplatelet drugs. With approval of novel oral anticoagulants (NOACs) antithrombotic treatment, patterns are changing. The Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation is designed to investigate patient characteristics influencing choice of antithrombotic treatment of stroke prevention in patients with nonvalvular AF and to collect data on outcomes of antithrombotic therapy in clinical practice. Methods: The GLORIA-AF is a large, international, observational registry involving patients with newly diagnosed nonvalvular AF at risk for stroke, enrolling up to 56,000 patients in nearly 50 countries. We will collect and analyze data from routine care using an inception cohort design. Phase I includes patients before approval of NOACs. Phase II, beginning early after approval of dabigatran, monitors dabigatran safety and addresses potential channeling across treatment options based on propensity scoring to assess comparability of baseline characteristics of patients treated with dabigatran or VKA. Phase III entails analysis of large treatment groups, adjusting for differences in propensity score, to provide information about the relative effectiveness and safety of NOACs and VKA in routine clinical care. Conclusions: Novel features of this registry program will add data from clinical practice to those from randomized trials to expand knowledge of antithrombotic treatment in patients with AF. © 2013 Mosby, Inc. All rights reserved.
  • Author:
    Zhu D; Gao P; Holtbruegge W; Huang C
    Title:
    A randomized, double-blind study to evaluate the efficacy and safety of a single-pill combination of telmisartan 80 mg/amlodipine 5 mg versus amlodipine 5 mg in hypertensive Asian patients
    Source:
    J Int Med Res 42 (1), 52-66 (2014)
    Abstract:
    Objective: To investigate the efficacy and safety of telmisartan 80 mg/amlodipine 5 mg (T80/A5) single-pill combination versus A5 in patients with essential hypertension not adequately controlled on A5 monotherapy. Methods: Asian patients .18 years old, with inadequately controlled blood pressure (BP) at enrolment, who failed to achieve a seated diastolic BP (DBP) goal (.90 mmHg) following 6-weeks' open-label A5 treatment, were randomly allocated 1: 1 to 8 weeks' double-blind treatment with T80/A5 single-pill combination or A5. Results: A total of 324 patients entered the double-blind treatment phase. The adjusted mean ± SE reduction in seated trough DBP from baseline to week 8 was significantly greater with T80/A5 (12.4 ± 1.0 mmHg) than A5 (10.2 ± 0.9 mmHg [primary endpoint, n = 314]). Results were similar in the subset of 262 Chinese patients. Treatment-related adverse events were 1.9% with T80/A5 and 2.4% with A5. Conclusion: sIn Asian patients with hypertednsion, T80/A5 single-pill combination provided improved BP reduction after 8 weeks' treatment compared with A5 monotherapy. Both treatments were well tolerated. © The Author(s) 2014.
  • Author:
    Kishimoto W; Ishiguro N; Ludwig-Schwellinger E; Ebner T; Schaefer O
    Title:
    In vitro predictability of drug-drug interaction likelihood of P-glycoprotein-mediated efflux of dabigatran etexilate based on [I] 2/IC50 threshold
    Source:
    Drug Metab Dispos 42 (2), 257-263 (2014)
    Abstract:
    Dabigatran etexilate, an oral, reversible, competitive, and direct thrombin inhibitor, is an in vitro and in vivo substrate of Pglycoprotein (P-gp). Dabigatran etexilate was proposed as an in vivo probe substrate for intestinal P-gp inhibition in a recent guidance on drug-drug interactions (DDI) from the European Medicines Agency (EMA) and the Food and Drug Administration (FDA). We conducted transcellular transport studies across Caco-2 cell monolayers with dabigatran etexilate in the presence of various P-gp inhibitors to examine how well in vitro IC50 data, in combination with mathematical equations provided by regulatory guidances, predict DDI likelihood. From a set of potential P-gp inhibitors, clarithromycin, cyclosporin A, itraconazole, ketoconazole, quinidine, and ritonavir inhibited P-gp-mediated transport of dabigatran etexilate over a concentration range that may hypothetically occur in the intestine. IC50 values of P-gp inhibitors for dabigatran etexilate transport were comparable to those of digoxin, a well established in vitro and in vivo P-gp substrate. However, IC50 values varied depending whether they were calculated from efflux ratios or permeability coefficients. Prediction of DDI likelihood of P-gp inhibitors using IC 50 values, the hypothetical concentration of P-gp inhibitors, and the cut-off value recommended by both the FDA and EMA were in line with the DDI occurrence in clinical studies with dabigatran etexilate. However, it has to be kept in mind that validity of the cut-off criteria proposed by the FDA and EMA depends on in vitro experimental systems and the IC50-calculation methods that are employed, as IC50 values are substantially influenced by these factors. Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics.
  • Author:
    Ishiguro N; Kishimoto W; Volz A; Ludwig-Schwellinger E; Ebner T; Schaefer O
    Title:
    Impact of endogenous esterase activity on in vitro P-glycoprotein profiling of dabigatran etexilate in Caco-2 monolayers
    Source:
    Drug Metab Dispos 42 (2), 250-256 (2014)
    Abstract:
    Dabigatran etexilate, a double prodrug of dabigatran, is a reversible, competitive, direct thrombin inhibitor that has been approved for use in many countries. A recent guideline from the European Medicines Agency on drug-drug interactions proposed dabigatran etexilate as a sensitive in vivo and in vitro probe substrate for intestinal P-glycoprotein (P-gp) inhibition. We therefore performed a series of in vitro studies to determine the best experimental conditions for evaluation of P-gp involvement on the transport process of dabigatran etexilate across colorectal adenocarcinoma Caco-2 cell monolayers. Experiments using expressed carboxylesterase 1 (CES1) and CES2 bactosomes revealed that dabigatran etexilate was hydrolyzed into BIBR 1087 by CES1 expressed in our Caco-2 cells. The impact of CES1-mediated BIBR 1087 formation during transcellular transport experiments was assessed by comparing several combinations of three experimental approaches: radioactivity detection using [14C]dabigatran etexilate as substrate, liquid chromatographytandem mass spectrometry (LC-MS/MS) quantification of dabigatran etexilate, and in the presence and absence of a CES inhibitor bis(p-nitrophenyl) phosphate (BNPP). The experimental approach that was based on the use of nonlabeled dabigatran etexilate together with LC-MS/MS quantification and the addition of BNPP was selected as the most favorable condition in which to correctly evaluate the permeability coefficient (Papp) of dabigatran etexilate and its transcellular transport by P-gp. The in vitro Caco-2 study at the selected condition revealed that dabigatran etexilate is a P-gp substrate with an efflux ratio of 13.8 and an intrinsic Papp, which is the Papp under the condition of complete blockage of P-gp by P-gp inhibitor, of 29 × 10-6 cm/s. Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics.
  • Author:
    Glund S; Stangier J; Schmohl M; De Smet M; Gansser D; Lang B; Moschetti V; Ramael S; Reilly P
    Title:
    A specific antidote for Dabigatran: Immediate, complete and sustained reversal of Dabigatran induced anticoagulation in healthy male volunteers
    Source:
    Am Heart Assoc - Annual Meeting, 2013
  • Author:
    Scowcroft ACE; Cowie MR
    Title:
    Atrial fibrillation: Improvement in identification and stroke preventive therapy -Data from the UK Clinical Practice Research Datalink, 2000-2012
    Source:
    Int J Cardiol Article in press (2014)
    Abstract:
    Objective: To investigate recent trends in the diagnosis and treatment of atrial fibrillation. Methods: Time trend analysis in the UK Clinical Practice Research Datalink (CPRD -previously the GPRD), 2000-2012. Results: The incidence of AF in men rose from 1.274 (1.271, 1.276) per 1 000 patient years in 2000 to 1.972 (1.969, 1.975) in 2012. In women, it rose from 1.209 (1.207, 1.211) to 1.609 (1.606, 1.611). 55 847 patients with AF first diagnosed between 2000 and 2012 were included in the study. 54% of men were initiated on anticoagulation therapy in the first year following diagnosis of atrial fibrillation, compared to 45% of women (P < 0.0001). This increased from 48% in men and 40% in women in 2000 to 58% in men and 52% in women in 2012. Conclusions: Identification of atrial fibrillation has improved in recent years, as has treatment for stroke prevention. Although there has historically been a bias towards men in the treatment of stroke prevention in atrial fibrillation, this study shows that the gap has been closing in recent years. Despite this improvement, this study shows that there are still many patients with atrial fibrillation who are not treated optimally to prevent stroke. © 2013 The Authors.
  • Author:
    Clemens A; Fraessdorf M; Friedman J
    Title:
    Cardiovascular outcomes during treatment with dabigatran: Comprehensive analysis of individual subject data by treatment
    Source:
    Vasc Health Risk Manage 9 (1), 599-615 (2013)
    Abstract:
    Background: Dabigatran 150 mg twice daily was shown to be superior to warfarin in preventing stroke in subjects with nonvalvular atrial fibrillation (SPAF) in the RE-LY (Randomized Evaluation of Long-term anticoagulation therapY) trial. Numerically, more myocardial infarctions occurred in patients receiving dabigatran compared with well-controlled warfarin. This observation prompted a comprehensive analysis of cardiovascular outcomes, including myocardial infarction, in all completed Phase II and III trials of dabigatran etexilate. Methods: The analysis included comparisons of dabigatran with warfarin, enoxaparin, and placebo. Data were analyzed for the occurrence of cardiovascular events from 14 comparative trials (n = 42, 484) in five different indications. Individual study data were evaluated, as well as pooled subject-level data grouped by comparator. Results: In the pooled analysis of individual patient data comparing dabigatran with warfarin (SPAF and venous thromboembolism treatment indications), myocardial infarction occurrence favored warfarin (odds ratio [OR] 1.30, 95% confidence interval [CI] 0.96-1.76 for dabigatran 110 mg twice daily and OR 1.42, 95% CI 1.07-1.88 for dabigatran 150 mg twice daily). The clinically relevant composite endpoint of myocardial infarction, total stroke, and vascular death demonstrated numerically fewer events in dabigatran 150 mg patients (OR 0.87, 95% CI 0.77-1.00), but was similar for dabigatran 110 mg (OR 0.99, 95% CI 0.87-1.13). Dabigatran had similar myocardial infarction rates when compared with enoxaparin or placebo. Conclusion: These analyses suggest a more protective effect of well-controlled warfarin, but not enoxaparin, compared with dabigatran in preventing myocardial infarction in multiple clinical settings. Dabigatran showed an overall positive benefit-risk ratio for multiple clinically important cardiovascular composite endpoints in all evaluated clinical indications. In conclusion, these data suggest that myocardial infarction is not an adverse drug reaction associated with use of dabigatran. © 2013 Clemens et al.
  • Author:
    Behnes M; Brueckmann M; Lang S; Espeter F; Weiss C; Neumaier M; Ahmad-Nejad P; Borggrefe M; Hoffmann U
    Title:
    Diagnostic and prognostic value of osteopontin in patients with acute congestive heart failure
    Source:
    Eur J Heart Fail 15 (12), 1390-1400 (2013)
    Abstract:
    Aims Toevaluate the diagnostic and prognostic value of osteopontin in patients with acute dyspnoea and/or peripheral oedema suspected of having acute congestive heart failure (aCHF). Methods and results A total of 401 patients presenting with acute dyspnoea and/or peripheral oedema to the emergency department were prospectively enrolled and followed up for up to 5 years. Blood samples for biomarker measurements were collected on admission to the emergency department. Osteopontin combined with NT-proBNP vs. NT-proBNP alone for diagnosis of aCHF was tested. Additionally, osteopontin vs. NT-proBNP for prognostic outcomes (i.e. all-cause mortality, aCHF-related rehospitalization, and both in combination) was tested. The diagnostic and prognostic capacity of osteopontin was tested by C-statistics, reclassification indices, and multivariable Cox prediction models. Osteopontin plus NT-proBNP improved the diagnostic capacity for aCHF diagnosis [accuracy 76%, 95% confidence interval (CI) 72-80%; specificity 74%, 95% CI 69-79%, net reclassification improvement (NRI) +0.10] compared with NT-proBNP alone in the emergency department (P = 0.0001). Osteopontin independently predicted all-cause mortality and aCHFrelated rehospitalization after 1 and 5 years. Compared with NT-proBNP, osteopontin was of superior prognostic value, specifically in aCHF patients and for the prognostic outcome of aCHF-related rehospitalization. Conclusion Osteopontin improves aCHF diagnosis when combined with NT-proBNP. Osteopontin identifies aCHF patients with high 1- and 5-year mortality and rehospitalization risk, and adds prognostic value to NT-proBNP. Trial registration NCT00143793. © The Author 2013.
  • Author:
    Majeed A; Hwang H-G; Connolly SJ; Eikelboom JW; Ezekowitz MD; Wallentin L; Brueckmann M; Fraessdorf M; Yusuf S; Schulman S
    Title:
    Management and outcomes of major bleeding during treatment with dabigatran or warfarin
    Source:
    Circulation 128 (21), 2325-2332 (2013)
    Abstract:
    BACKGROUND - : The aim of this study was to compare the management and prognosis of major bleeding in patients treated with dabigatran or warfarin. METHODS AND RESULTS - : Two independent investigators reviewed bleeding reports from 1034 individuals with 1121 major bleeds enrolled in 5 phase III trials comparing dabigatran with warfarin in 27 419 patients treated for 6 to 36 months. Patients with major bleeds on dabigatran (n=627 of 16 755) were older, had lower creatinine clearance, and more frequently used aspirin or non-steroid anti-inflammatory agents than those on warfarin (n=407 of 10 002). The 30-day mortality after the first major bleed tended to be lower in the dabigatran group (9.1%) than in the warfarin group (13.0%; pooled odds ratio, 0.68; 95% confidence interval, 0.46-1.01; P=0.057). After adjustment for sex, age, weight, renal function, and concomitant antithrombotic therapy, the pooled odds ratio for 30-day mortality with dabigatran versus warfarin was 0.66 (95% confidence interval, 0.44-1.00; P=0.051). Major bleeds in dabigatran patients were more frequently treated with blood transfusions (423/696, 61%) than bleeds in warfarin patients (175/425, 42%; P<0.001) but less frequently with plasma (dabigatran, 19.8%; warfarin, 30.2%; P<0.001). Patients who experienced a bleed had shorter stays in the intensive care unit if they had previously received dabigatran (mean 1.6 nights) compared with those who had received warfarin (mean 2.7 nights; P=0.01). CONCLUSIONS - : Patients who experienced major bleeding on dabigatran required more red cell transfusions but received less plasma, required a shorter stay in intensive care, and had a trend to lower mortality compared with those who had major bleeding on warfarin. CLINICAL TRIAL REGISTRATION - : URL: http://www.ClinicalTrials.gov. Unique identifiers: NCT00262600, NCT00291330, NCT00680186, NCT00329238 and NCT00558259. © 2013 American Heart Association, Inc.
  • Author:
    Hamdam J; Sethu S; Smith T; Alfirevic A; Alhaidari M; Atkinson J; Ayala M; Box H; Cross M; Delaunois A; Dermody A; Govindappa K; Guillon J-M; Jenkins R; Kenna G; Lemmer B; Meecham K; Olayanju A; Pestel S; Rothfuss A; Sidaway J; Sison-Young R; Smith E; Stebbings R; Tingle Y; Valentin J-P; Williams A; Williams D; Park K; Goldring C
    Title:
    Safety pharmacology - Current and emerging concepts
    Source:
    Toxicol Appl Pharmacol 273 (2), 229-241 (2013)
    Abstract:
    Safety pharmacology (SP) is an essential part of the drug development process that aims to identify and predict adverse effects prior to clinical trials. SP studies are described in the International Conference on Harmonisation (ICH) S7A and S7B guidelines. The core battery and supplemental SP studies evaluate effects of a new chemical entity (NCE) at both anticipated therapeutic and supra-therapeutic exposures on major organ systems, including cardiovascular, central nervous, respiratory, renal and gastrointestinal. This review outlines the current practices and emerging concepts in SP studies including frontloading, parallel assessment of core battery studies, use of non-standard species, biomarkers, and combining toxicology and SP assessments. Integration of the newer approaches to routine SP studies may significantly enhance the scope of SP by refining and providing mechanistic insight to potential adverse effects associated with test compounds. © 2013 Elsevier Inc.
  • Author:
    Nishimura S; Kusakawa K; Okumura H; Nakamura I; Yagi N; Akimoto T
    Title:
    Distinct blood pressure lowering effect of telmisartan in naïve patients with hypertension: Sub-analysis of prospective, practice-based use surveillance of telmisartan
    Source:
    Ther Res 34 (10), 1317-1327 (2013)
    Abstract:
    Distinct blood pressure (BP) lowering effect is thought to be important for the prevention of cardiovascular events in hypertensive patients. Therefore we examined the BP lowering effect of telmisartan during 12 months for the treatment in naïve hypertensive patients (n = 2361) who were extracted from prospective practice-based post-marketing surveillance of telmisartan. Additionally, the augmentation of BP lowering effect by raising the telmisartan dose from 20 mg/day to 40 mg/day and the add-on effect of CCB were examined. Telmisartan produced a distinct reduction of BP from baseline (168.3/95.6 mmHg) after 1 month (23.3/11.0 mmHg, p < 0.0001), after 6 month (30.3/15.2 mmHg, p < 0.0001) and after 12 month (31.7/15.7 mmHg, p < 0.0001), respectively. Additionally, in 1872 hypertensive patients who received telmisartan monotherapy throughout the study (monotherapy subgroup), BP decreased by 23.6/11.1 mmHg(p < 0.0001) after 1 month from baseline (166.3/94.4 mmHg), by 29.1/14.7 mmHg(p < 0.0001) after 6 month and 30.2/14.9 mmHg (p < 0.0001) after 12 month. The effect by raising the telmisartan dose from 20 mg/day to 40 mg/day produced significant BP reduction by 13.4/6.5 mmHg in all naïve hypertensive patients and by 12.9/7.1 mmHg in monotherapy subgroup. The effect adding on CCB to telmisartan monotherapy gave BP reduction by 14.8/7.9 mmHg, suggesting that the combination therapy is effective. Incidence of the adverse drug reactions was 5.25% in all naïve patients and 5.13% in the monotherapy subgroup patients (n = 1872). These results indicate that telmisartan based therapy is appropriate for the treatment of naïve hypertensive patients.
  • Author:
    Zhu D-L; Gao P-J; Liu S-W; Jeong MH; Mattheus M; Voelker B
    Title:
    Efficacy and tolerability of a single-pill combination of telmisartan/ hydrochlorothiazide 80/25 mg in Chinese and Korean patients with moderate to severe hypertension: A subgroup analysis of a randomized, double-blind, active-controlled trial
    Source:
    Chin Med J 126 (21), 4072-4077 (2013)
    Abstract:
    Background Hypertension is an important issue in Asia, responsible for up to 66% of cardiovascular disease cases. This randomized controlled trial subgroup analysis compared telmisartan 80 mg (T80)/hydrochlorothiazide 25 mg (H25) singlepill combination with T80 monotherapy, specifically in Chinese and Korean patients. Methods Patients with grade 2/3 hypertension were randomized to receive telmisartan 40 mg (T40)/hydrochlorothiazide 12.5 mg (H12.5) combination or T40 monotherapy for one week, before uptitrating the dose to T80/H25 or T80, respectively, for the remaining 6 weeks. The primary endpoint was systolic blood pressure (SBP) mean change from baseline. Secondary endpoints included mean diastolic blood pressure (DBP) change from baseline, and blood pressure (BP) goal achievement. Adverse events were recorded. Results Of a total 888 patients who were treated, efficacy analyses for Chinese and Korean patients included 127 patients treated with T80/H25 and 54 patients treated with T80. At week 7, mean SBP reductions from baseline were -37.5 mmHg (1 mmHg=0.133 kPa) and -26.9 mmHg in the T80/H25 and T80 groups (adjusted mean difference, -10.6 mmHg; 95% confidence interval (CI), -15.6 to -5.7). Mean DBP reductions were -19.0 and -14.1 mmHg in the T80/H25 and T80 groups (adjusted mean difference, -4.9 mmHg; 95% CI, -8.0 to -1.8). In total, 56.7% of patients receiving T80/ H25 achieved BP goal (<140/90 mmHg) compared with 35.2% receiving T80. SBP goal attainment (<140 mmHg) and DBP goal attainment (<90 mmHg) were also higher in the T80/H25 group compared with the T80 group (SBP: 69.3% vs. 48.1%; DBP: 62.2% vs. 46.3%). A small number of treatment-related adverse events were observed in both T80/H25 (nine patients, 6.9%) and T80 monotherapy (two patients, 3.6%) groups. Conclusions In Chinese and Korean patients with moderate-to-severe hypertension, treatment with T80/H25 provided large reductions in mean SBP and DBP, and high BP goal attainment rates. This once-daily combination is effective and well tolerated in this patient group. (ClinicalTrials.gov identifier NCT00926289).
  • Author:
    Goldie FC; Fulton RL; Dawson J; Bluhmki E; Lees KR
    Title:
    Exploration of time-course combinations of outcome scales for use in a global test of stroke recovery
    Source:
    Int J Stroke Article in press (2013)
    Abstract:
    Background: Clinical trials for acute ischemic stroke treatment require large numbers of participants and are expensive to conduct. Methods that enhance statistical power are therefore desirable. Aims: We explored whether this can be achieved by a measure incorporating both early and late measures of outcome (e.g. seven-day NIH Stroke Scale combined with 90-day modified Rankin scale). Methods: We analyzed sensitivity to treatment effect, using proportional odds logistic regression for ordinal scales and generalized estimating equation method for global outcomes, with all analyses adjusted for baseline severity and age. We ran simulations to assess relations between sample size and power for ordinal scales and corresponding global outcomes. We used R version 2.12.1 (R Development Core Team. R Foundation for Statistical Computing, Vienna, Austria) for simulations and SAS 9.2 (SAS Institute Inc., Cary, NC, USA) for all other analyses. Results: Each scale considered for combination was sensitive to treatment effect in isolation. The mRS90 and NIHSS90 had adjusted odds ratio of 1.56 and 1.62, respectively. Adjusted odds ratio for global outcomes of the combination of mRS90 with NIHSS7 and NIHSS90 with NIHSS7 were 1.69 and 1.73, respectively. The smallest sample sizes required to generate statistical power .80% for mRS90, NIHSS7, and global outcomes of mRS90 and NIHSS7 combined and NIHSS90 and NIHSS7 combined were 500, 490, 400, and 380, respectively. Discussion: When data concerning both early and late outcomes are combined into a global measure, there is increased sensitivity to treatment effect compared with solitary ordinal scales. This delivers a 20% reduction in required sample size at 80% power. Combining early with late outcomes merits further consideration. © 2013 World Stroke Organization.
  • Author:
    Toni D; Di Angelantonio E; Di Mascio MT; Vinisko R; Bath PM
    Title:
    Types of stroke recurrence in patients with ischemic stroke: A substudy from the PRoFESS trial
    Source:
    Int J Stroke Article in press (2013)
    Abstract:
    Background: Risk profiles for stroke recurrence are poorly characterized. Aims: We determined the variation in the risk and type of recurrent stroke among index ischemic stroke subtypes, and whether index stroke subtype and conventional stroke risk factors were predictors of stroke recurrence. Methods: Patients enrolled in the Prevention Regimen for Effectively Avoiding Second Strokes trial were included in this study. Results: In 1794 patients' recurrent stroke subtypes were the same as the index stroke in: 48.3% of patients with large artery atherothrombosis stroke; 50% of patients with cardioembolic stroke; 48.7% of patients with small artery occlusion stroke; 8.1% of patients with stroke of other etiology, and 45.3% of patients with undetermined etiology stroke. Patients with cardioembolic stroke, who were unwilling or unable to take oral anticoagulants, had the greatest risk of stroke recurrence. Predictors of stroke recurrence in multivariable analysis were: older age and previous stroke among large artery atherothrombosis strokes; older age, male sex, previous stroke, previous transient ischemic attack, hypertension, diabetes, and tobacco use among small artery occlusion strokes; older age among cardioembolic strokes; atrial fibrillation and anti-diabetic medications among other etiology strokes; older age, previous stroke and atrial fibrillation among undetermined etiology strokes. Predictors of brain hemorrhage as recurrent stroke were index small artery occlusion stroke, older age, previous stroke, and antiplatelet treatment with aspirin plus extended-release dipyridamole. Conclusions: Risk predictors for stroke recurrence and for brain hemorrhage differ by index ischemic stroke subtype, information that is important when initiating secondary prevention therapy. © 2013 World Stroke Organization.
  • Author:
    Hauel N; Clemens A; Nar H; Priepke H; van Ryn J; Wienen W
    Title:
    The Discovery of Dabigatran Etexilate
    Source:
    Analogue-Based Drug Discov. III, 241-267 (2012)
    Abstract:
    no abstract available
  • Author:
    Monz BU; Connolly SJ; Korhonen M; Noack H; Pooley J
    Title:
    Assessing the impact of dabigatran and warfarin on health-related quality of life: Results from an RE-LY sub-study
    Source:
    Int J Cardiol 168 (3), 2540-2547 (2013)
    Abstract:
    Background Anticoagulation is recommended in patients with atrial fibrillation (AF) to prevent strokes. Vitamin K antagonists, such as warfarin, are associated with numerous practical limitations - frequent anticoagulation monitoring, lifestyle and dietary restrictions - that complicate patient management and may impact health-related quality of life (HRQoL). This study derived HRQoL estimates for AF patients receiving warfarin or dabigatran etexilate (dabigatran), a new oral anticoagulant not requiring anticoagulation monitoring, during one year of stable treatment, i.e. in the absence of outcome events, such as strokes or major bleedings. Methods Changes in HRQoL over time and between treatments were assessed using the EQ-5D (utility and Visual Analogue Scale (VAS) scores) at baseline, 3 and 12 months in a sub-group of 1435 patients participating in the RE-LY trial. RE-LY was a phase III study that compared the safety and efficacy of warfarin, dabigatran 150 mg bid and dabigatran 110 mg bid for stroke prevention in patients with AF. Results Utilities ranged from 0.805 (dabigatran 150 mg bid) to 0.811 (dabigatran 110 mg bid) at baseline, and did not change over the one year observation period. No differences between the dabigatran groups and warfarin were statistically significant except for the dabigatran 150 mg bid group at 3 months. Similarly, none of the within-group or between-group differences in VAS scores were statistically significant. Conclusions Over the course of one year, all anticoagulated patients without outcome events (e.g. strokes or major bleedings) had stable HRQoL. Scores between dabigatran and warfarin were comparable, which was unexpected given the known complexities of warfarin treatment. © 2013 Elsevier Ireland Ltd. All rights reserved. © 2013 Elsevier Ireland Ltd. All rights reserved.
  • Author:
    Behnes M; Brueckmann M; Lang S; Weiß C; Ahmad-Nejad P; Neumaier M; Borggrefe M; Hoffmann U
    Title:
    Connective tissue growth factor (CTGF/CCN2): diagnostic and prognostic value in acute heart failure
    Source:
    Clin Res Cardiol, 1-10 Article in Press (2013)
    Abstract:
    Background: As a mediator of ECM homeostasis, connective tissue growth factor (CTGF) appears to be involved in adverse structural remodeling processes in the heart. However, the diagnostic and prognostic value of CTGF levels in acute heart failure (AHF) in addition to natriuretic peptide testing has not yet been evaluated. Methods and results: A total of 212 patients presenting with acute dyspnea and/or peripheral edema to the Emergency Department were evaluated. CTGF and NT-proBNP plasma levels were measured at the initial presentation. All patients were followed up to 1 and 5 years. The first endpoint tested was the diagnostic non-inferiority of combined CTGF plus NT-proBNP compared to NT-proBNP alone for AHF diagnosis. Afterwards, the additional diagnostic value of CTGF plus NT-proBNP was tested. CTGF levels were higher in NYHA class III/IV and AHA/ACC class C/D patients compared to lower class patients (p = 0.04). Patients with HFREF revealed highest CTGF levels (median 93.3 pg/ml, IQR 18.2-972 pg/ml, n = 48) compared to patients with a normal heart function (i.e., without HFREF and HFPEF) (median 25.9, IQR <1-82.2 pg/ml, n = 37) (p < 0.05), followed by patients with HFPEF (median 82.2 pg/ml, IQR 11.5-447 pg/ml, n = 32) as assessed by echocardiography. Finally, CTGF levels were higher in patients with AHF (median 77.3 pg/ml, IQR 22.5-1012 pg/ml, n = 66) compared to those without (p = 0.002). CTGF plus NT-proBNP was non-inferior to NT-proBNP testing alone for AHF diagnosis (AUC difference 0.01, p > 0.05). CTGF plus NT-proBNP improved the diagnostic capacity for AHF (accuracy 82 %, specificity 83 %, positive predictive value 66 %, net reclassification improvement +0.11) compared to NT-proBNP alone (p = 0.0001). CTGF levels were not able to differentiate prognostic outcomes after 1 and 5 years. Conclusions: Additional CTGF measurements might lead to a better discrimination of higher functional and structural heart failure stages and might identify patients of an increased risk for an acute cardiac decompensation. © 2013 Springer-Verlag Berlin Heidelberg.
  • Author:
    Chaykovska L; Alter ML; Von Websky K; Hohmann M; Tsuprykov O; Reichetzeder C; Kutil B; Kraft R; Klein T; Hocher B
    Title:
    Effects of telmisartan and linagliptin when used in combination on blood pressure and oxidative stress in rats with 2-kidney-1-clip hypertension
    Source:
    J Hypertens 31 (11), 2290-2299 (2013)
    Abstract:
    OBJECTIVE:: To investigate the effects of linagliptin alone and in combination with the angiotensin II receptor blocker (ARB), telmisartan on blood pressure (BP), kidney function, heart morphology and oxidative stress in rats with renovascular hypertension. METHODS:: Fifty-seven male Wistar rats underwent unilateral surgical stenosis of the renal artery [2-kidney-1-clip (2k1c) method]. Animals were randomly divided into four treatment groups (nâ..=â..14-18 per group) receiving: telmisartan (10â..mg/kg per day in drinking water), linagliptin (89â..ppm in chow), combination (linagliptin 89â..ppmâ..+â.. telmisartan 10â..mg/kg per day) or placebo. An additional group of 12 rats underwent sham surgery. BP was measured one week after surgery. Hypertensive animals entered a 16-week dosing period. BP was measured 2, 4, 8, 12 and 16 weeks after the initiation of treatment. Blood and urine were tested for assessment of kidney function and oxidative stress 6, 10, 14 and 18 weeks after surgery. Blood and urine sampling and organ harvesting were finally performed. RESULTS:: Renal stenosis caused an increase in meanâ. .±â..SD systolic BP as compared with the sham group (157.7â..±â..29.3 vs. 106.2â..±â..20.5â.. mmHg, respectively; Pâ..<â..0.001). Telmisartan alone and in combination with linagliptin, normalized SBP (111.1â..±â..24.3â. .mmHg and 100.4â..±â..13. 9â..mmHg, respectively; Pâ..<â ..0.001 vs. placebo). Telmisartan alone and in combination with linagliptin significantly prevented cardiac hypertrophy, measured by heart weight and myocyte diameter. Renal function measured by cystatin C was not affected by 2k1c surgery. Telmisartan significantly increased plasma concentration of cystatin C. 2k1c surgery initiated fibrosis in both kidneys. Telmisartan promoted further fibrotic changes in the clipped kidney, as measured by protein expression of Col1a1 and histology for interstitial fibrosis and glomerulosclerosis. In non-clipped kidneys, telmisartan demonstrated antifibrotic properties, reducing Col1a1 protein expression. Plasma levels of oxidized low-density lipoprotein were higher in the placebo-treated 2k1c rats as compared to sham-operated animals. The increase was abolished by linagliptin alone (Pâ..=â..0.03 vs. placebo) and in combination with telmisartan (Pâ..=â..0.02 vs. placebo). Combination therapy also significantly reduced plasma concentration of carbonyl proteins (Pâ..= â..0.04 vs. placebo). CONCLUSION:: Inhibition of type 4 dipeptidyl peptidase with linagliptin did not counter BP-lowering effects of ARB in 2k1c rats. Linagliptin reduced lipid and protein oxidation in 2k1c rats, and this effect was BP-independent. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.
  • Author:
    Punzi HA; Dahlöf B; Webster D; Majul CR; Oigman W; Olvera R; Seeber M; Kobe M; Schumacher H
    Title:
    The effects of telmisartan and amlodipine in treatment-naïve and previously treated hypertensive patients: A subanalysis from a 4 × 4 factorial design study
    Source:
    Clin Exp Hypertens 35 (5), 330-340 (2013)
    Abstract:
    The subanalysis of a 4 × 4 factorial, 8-week study to evaluate the efficacy and tolerability of telmisartan (T) 40-80 mg/amlodipine (A) 5-10 mg used in treatment-naïve patients (n = 231) and patients previously treated with antihypertensive agents (n = 880). Similar blood pressure (BP) reductions were achieved with T + A, regardless of their pretreatment status. Highest reductions were achieved with T80 + A10 (treatment-naïve -26.5/-18.2 mm Hg and previously treated -25.6/-19.9 mm Hg). Most patients (treatment-naïve 72.4% and previously treated 77.6%), including those with added risk, achieved BP goal (<140/90 mm Hg) with T80 + A10. Tolerability was comparable in both groups. Copyright © Informa Healthcare USA, Inc.
  • Author:
    Zalesak M; Siu K; Francis K; Yu C; Alvrtsyan H; Rao Y; Walker D; Sander S; Miyasato G; Matchar D; Sanchez H
    Title:
    Higher persistence in newly diagnosed nonvalvular atrial fibrillation patients treated with dabigatran versus warfarin
    Source:
    Circ Cardiovasc Qual Outcomes 6 (5), 567-574 (2013)
    Abstract:
    Background-Oral anticoagulation therapy is the primary tool in reducing stroke risk in patients with nonvalvular atrial fibrillation but is underused. Patients nonpersistent with therapy contribute to this underuse. The objective of this study was to compare persistence rates in newly diagnosed nonvalvular atrial fibrillation patients treated with warfarin versus dabigatran as their oral anticoagulation. Methods and Results-US Department of Defense administrative claims were used to identify patients receiving warfarin or dabigatran between October 28, 2010, and June 30, 2012. Patient records were examined for a minimum of 12 months before index date to restrict the analyses to those newly diagnosed with nonvalvular atrial fibrillation and naive-to-treatment, identifying 1775 on warfarin and 3370 on dabigatran. Propensity score matching was used to identify 1745 matched pairs. Persistence was defined as time on therapy to discontinuation. Kaplan-Meier curves were used to depict persistence over time. Cox proportional hazards model was used to determine the factors significantly associated with persistence. Using a 60-day permissible medication gap, the persistence rates were higher for dabigatran than for warfarin at both 6 months (72% versus 53%) and 1 year (63% versus 39%). Patients on dabigatran with a low-to-moderate risk of stroke (CHADS 2&lt;2) or with a higher bleed risk (HEMORR2HAGES&gt;3) had a higher likelihood of nonpersistence (hazard ratios, 1.37; 95% confidence interval, 1.17-1.60; P&lt;0.001; and hazard ratios, 1.24; 95% confidence interval, 1.04-1.47; P=0.016). Conclusions-Patients who initiated dabigatran treatment were more persistent than patients who began warfarin treatment. Within each cohort, patients with lower stroke risk were more likely to discontinue therapy. © 2013 American Heart Association, Inc.
  • Author:
    Eikelboom JW; Connolly SJ; Brueckmann M; Granger CB; Kappetein AP; Mack MJ; Blatchford J; Devenny K; Friedman J; Guiver K; Harper R; Khder Y; Lobmeyer MT; Maas H; Voigt J-U; Simoons ML; Van De Werf F
    Title:
    Dabigatran versus warfarin in patients with mechanical heart valves
    Source:
    N Engl J Med 369 (13), 1206-1214 (2013)
    Abstract:
    BACKGROUND: Dabigatran is an oral direct thrombin inhibitor that has been shown to be an effective alternative to warfarin in patients with atrial fibrillation. We evaluated the use of dabigatran in patients with mechanical heart valves. METHODS: In this phase 2 dose-validation study, we studied two populations of patients: those who had undergone aortic- or mitral-valve replacement within the past 7 days and those who had undergone such replacement at least 3 months earlier. Patients were randomly assigned in a 2:1 ratio to receive either dabigatran or warfarin. The selection of the initial dabigatran dose (150, 220, or 300 mg twice daily) was based on kidney function. Doses were adjusted to obtain a trough plasma level of at least 50 ng per milliliter. The warfarin dose was adjusted to obtain an international normalized ratio of 2 to 3 or 2.5 to 3.5 on the basis of thromboembolic risk. The primary end point was the trough plasma level of dabigatran. RESULTS: The trial was terminated prematurely after the enrollment of 252 patients because of an excess of thromboembolic and bleeding events among patients in the dabigatran group. In the as-treated analysis, dose adjustment or discontinuation of dabigatran was required in 52 of 162 patients (32%). Ischemic or unspecified stroke occurred in 9 patients (5%) in the dabigatran group and in no patients in the warfarin group; major bleeding occurred in 7 patients (4%) and 2 patients (2%), respectively. All patients with major bleeding had pericardial bleeding. CONCLUSIONS: The use of dabigatran in patients with mechanical heart valves was associated with increased rates of thromboembolic and bleeding complications, as compared with warfarin, thus showing no benefit and an excess risk. Copyright © 2013 Massachusetts Medical Society.
  • Author:
    Segura J; De La Sierra A; Fernández S; Ruilope LM
    Title:
    Relevance of diabetes in high cardiovascular risk hypertensive patients [Influencia de la diabetes sobre la prevalencia de lesión de órganos diana y enfermedad cardiovascular en los pacientes hipertensos de alto riesgo]
    Source:
    Med Clin (Barc) 141 (7), 287-291 (2013)
    Abstract:
    Background and objective: The aim of this cross-sectional study was to compare the prevalence of target organ damage (TOD) and established cardiovascular disease (CVD) in a cohort of nondiabetic hypertensive patients with 3 or more cardiovascular risk factors (CVRF) against a group of hypertensives with type 2 diabetes. Patients and method: We included 4,725 hypertensive patients, 62% male, mean age 64 (SD 12) years, with type 2 diabetes mellitus, independently of the number of associated CVRF (N = 2,608), or non-diabetics, in which case we required the presence of 3 CVRF (N = 2,117). The prevalence of established CVD (clinical interview) and TOD (left ventricular hypertrophy by electrocardiogram, microalbuminuria and estimated glomerular filtration rate) were estimated. Results: Hypertensive patients with type 2 diabetes had an older age and more marked obesity. Furthermore, these patients showed a higher prevalence of micro- and macroalbuminuria, renal failure, left ventricular hypertrophy, atherosclerotic plaques in carotid arteries and CVD compared with nondiabetic hypertensive patients with 3 or more CVRF. Multivariate analysis showed that the risk of TOD or established CVD were associated independently with the presence of diabetes. Conclusion: Hypertensive patients with type 2 diabetes have a higher prevalence of LOD and CVD compared to nondiabetic hypertensive patients with 3 or more CVRF. Although both situations are included in the high cardiovascular risk stratum, it would be expected an increased incidence of cardiovascular complications in hypertensive diabetic patients. © 2013 Elsevier España, S.L. Todos los derechos reservados.
  • Author:
    Hall TS; Herrscher T; Jarolim P; Fagerland MW; Jensen T; Hallén J; Agewall S; Atar D
    Title:
    Obstructive sleep apnea: no independent associationto troponins
    Source:
    Sleep Breath, 1-8 Article in press (2013)
    Abstract:
    Background: Cardiac troponins (cTn) are to date the most sensitive and specific biochemical markers of myocardial injury. Abnormal breathing patterns in patients with obstructive sleep apnea (OSA) may cause myocardial cell stress detectable by novel cTn assays. The objectives of this study were to investigate whether a new single-molecule cTnI (S-cTnI) assay and a commercially available high-sensitivity cTnT (hs-cTnT) assay would detect myocyte injury in individuals evaluated for possible OSA, and to explore their relation to variables of disordered breathing during sleep. Methods: Consecutive individuals referred to Lovisenberg Diakonale Hospital's sleep laboratory between 1 October 2009 and 1 March 2010 were included. We measured cTn in specimens collected the morning after sleep and studied these in relation to variables recorded during polygraphy or polysomnography. Results: All 222 (100 %) individuals had measurable cTn levels using either assay. Stratified into categories according to the apnea-hypopnea index (AHI), patients with OSA (AHI .5) had a different distribution of S-cTnI (P = 0.036) and hs-cTnT (P = 0.002) compared to those without (AHI <5). The median (quartiles 1-3) were 3.0 (1.9-6.0) versus 2.3 (1.6-3.8) ng/l for S-cTnI, and 7.0 (5.5-8.7) versus 6.2 (4.9-7.2) ng/l for hs-cTnT. However, in multiple median regression analyses adjusted for conventional predictors, neither S-cTnI (P = 0.57) nor hs-cTnT (P = 0.80) were significantly associated with AHI. Conclusions: This study reveals no association independent of conventional predictors between OSA and myocardial cell injury measured by S-cTnI and hs-cTnT assays. Our findings support a search for novel biomarkers for prognostication of OSA. © 2013 Springer-Verlag Berlin Heidelberg.
  • Author:
    Ferreira J; Ezekowitz MD; Connolly SJ; Brueckmann M; Fraessdorf M; Reilly PA; Yusuf S; Wallentin L
    Title:
    Dabigatran compared with warfarin in patients with atrial fibrillation and symptomatic heart failure: A subgroup analysis of the RE-LY trial
    Source:
    Eur J Heart Fail 15 (9), 1053-1061 (2013)
    Abstract:
    AimsWe evaluated the effects of dabigatran compared with warfarin in the subgroup of patients with previous symptomatic heart failure (HF) in the RE-LY trial.Methods and resultsRE-LY compared two fixed and blinded doses of dabigatran (110 and 150 mg twice daily) with open-label warfarin in 18 113 patients with AF at increased risk for stroke. Among 4904 patients with HF, annual rates of stroke or systemic embolism (SE) were 1.92% for patients on warfarin compared with 1.90% for dabigatran 110 mg [hazard ratio (HR) 0.99, 95% confidence interval (CI) 0.69-1.42] and 1.44% for dabigatran 150 mg (HR 0.75, 95% CI 0.51-1.10). Annual rates of major bleeding were 3.90% for the group on warfarin, compared with 3.26% for dabigatran 110 mg (HR 0.83, 95% CI 0.64-1.09) and 3.10% for dabigatran 150 mg (HR 0.79, 95% CI 0.60-1.03). Rates of intracranial bleeding were significantly lower for both dabigatran dosages compared with warfarin in patients with HF (dabigatran 110 mg vs. warfarin, HR 0.34, 95% CI 0.14-0.80; dabigatran 150 mg vs. warfarin, HR 0.39, 95% CI 0.17-0.89). The relative effects of dabigatran vs. warfarin on the occurrence of stroke or SE and major bleeding were consistent among those with and without HF and those with low (.40%) or preserved (>40%) LVEF (P interaction not significant).ConclusionsThe overall benefits of dabigatran for stroke/SE prevention, and major and intracranial bleeding, relative to warfarin in the RE-LY trial were consistent in patients with and without HF. © The Author 2012. Published by Oxford University Press on behalf of the European Society of Cardiology
  • Author:
    Eikelboom JW; Connolly SJ; Hart RG; Wallentin L; Reilly P; Oldgren J; Yang S; Yusuf S
    Title:
    Balancing the benefits and risks of 2 doses of dabigatran compared with warfarin in atrial fibrillation
    Source:
    J Am coll Cardiol 62 (10), 900-908 (2013)
    Abstract:
    Objectives This study sought to compare the net clinical benefit of dabigatran 110 mg bid and 150 mg bid with that of warfarin in patients with atrial fibrillation (AF). Background In patients with AF, dabigatran 110 mg bid and 150 mg bid are associated with similar rates of death. However, the higher dose reduces ischemic stroke and increases bleeding compared with the lower dose. Therefore, there is uncertainty about how to evaluate the overall benefit of the 2 doses. Methods In 18,113 AF patients in the RE-LY (Randomized Evaluation of Long Term Anticoagulant Therapy) trial, we used a previously developed method for integrating ischemic and bleeding events as "ischemic stroke equivalents" in order to compare a weighted benefit of 2 doses of dabigatran with each other, and with that of warfarin. Results Compared with warfarin, there was a significant decrease in ischemic stroke equivalents with both dabigatran doses: -0.92 per 100 patient years (95% confidence interval [CI]: -1.74 to -0.21, p = 0.02) with dabigatran 110 mg bid and -1.08 (95% CI: -1.86 to -0.34, p = 0.01) with dabigatran 150 mg bid. There was no significant difference in ischemic stroke equivalents between the 2 doses: -0.16 (95% CI: -0.80 to 0.43) comparing dabigatran 150 mg bid with 110 bid. When including death in the weighted benefit calculations, the results were similar. Conclusions On a group level both doses of dabigatran as compared with warfarin have similar benefits when considering a weighted estimate including both efficacy and safety. The similar overall benefits of the 2 doses of dabigatran versus warfarin support individualizing the dose based on patient characteristics and physician and patient preferences. (Randomized Evaluation of Long Term Anticoagulant Therapy [RE-LY] With Dabigatran Etexilate; NCT00262600) © 2013 by the American College of Cardiology Foundation.
  • Author:
    van Ryn J; Goss A; Hauel N; Wienen W; Priepke H; Nar H; Clemens A
    Title:
    The discovery of dabigatran etexilate
    Source:
    Front Pharmacol 4 Art No 12 (2013)
    Abstract:
    Thromboembolic disease is a major cause of mortality and morbidity in the developed world and is caused by an excessive stimulation of coagulation. Thrombin is a key serine protease in the coagulation cascade and numerous efforts have been made to develop safe and effective orally active direct thrombin inhibitors (DTIs). Current anticoagulant therapy includes the use of indirect thrombin inhibitors (e.g., heparins, low-molecular-weight-heparins) and vitamin K antagonists such as warfarin. However there are several caveats in the clinical use of these agents including narrow therapeutic window, parenteral delivery, and food- and drug-drug interactions. Dabigatran is a synthetic, reversible DTI with high affinity and specificity for its target binding both free and clot-bound thrombin, and offers a favorable pharmacokinetic profile. Large randomized clinical trials have demonstrated that dabigatran provides comparable or superior thromboprophylaxis in multiple thromboembolic disease indications compared to standard of care. This minireview will highlight the discovery and development of dabigatran, the first in a class of new oral anticoagulant agents to be licensed worldwide for the prevention of thromboembolism in the setting of orthopedic surgery and stroke prevent in atrial fibrillation. © 2013 van Ryn, Goss, Hauel, Wienen, Priepke, Nar and Clemens.
  • Author:
    Hamdam J; Sethu S; Smith T; Alfirevic A; Alhaidari M; Atkinson J; Ayala M; Box H; Cross M; Delaunois A; Dermody A; Govindappa K; Guillon J-M; Jenkins R; Kenna G; Lemmer B; Meecham K; Olayanju A; Pestel S; Rothfuss A; Sidaway J; Sison-Young R; Smith E; Stebbings R; Tingle Y; Valentin J-P; Williams A; Williams D; Park K; Goldring C
    Title:
    Safety pharmacology - Current and emerging concepts
    Source:
    Toxicol Appl Pharmacol Article in press (2013)
    Abstract:
    Safety pharmacology (SP) is an essential part of the drug development process that aims to identify and predict adverse effects prior to clinical trials. SP studies are described in the International Conference on Harmonisation (ICH) S7A and S7B guidelines. The core battery and supplemental SP studies evaluate effects of a new chemical entity (NCE) at both anticipated therapeutic and supra-therapeutic exposures on major organ systems, including cardiovascular, central nervous, respiratory, renal and gastrointestinal. This review outlines the current practices and emerging concepts in SP studies including frontloading, parallel assessment of core battery studies, use of non-standard species, biomarkers, and combining toxicology and SP assessments. Integration of the newer approaches to routine SP studies may significantly enhance the scope of SP by refining and providing mechanistic insight to potential adverse effects associated with test compounds. © 2013 Elsevier Inc. All rights reserved.
  • Author:
    van Ryn J; Schurerand J; Giemens A
    Title:
    Assessment of dabigatran activity using the activated clotting time assay with concomitant heparin in vitro: comparison of two different point of care tests
    Source:
    24th Congress of the international Society on Thrombosis & Hemostasis (ISTH), Amsterdam, Netherland, Jun 29-Jul 4, 2013
  • Author:
    Hayes C S; Shicora A; Ashley GossLJ; Van Ryn J; Gilmour S K
    Title:
    Synergistic anti-cancer effects with dabigatran etexilate and Gisplatin or cyclophosphamide
    Source:
    24 th Congress of the International Society on Thrombosis & Hemostasis (ISTH), Amsterdam, Netherlands, Jun 29- Jul 4, 2013
  • Author:
    Herzog E; Kasperei C F; Krege W; Pragst I; Ryn v J; Dickneite G
    Title:
    Non-clinical safety and efficacy of prothrombin complex concentrates (PCC) for the reversal of dabigatran mediated anticoagulation
    Source:
    24 th Congress of the International Society on Thrombosis & Hemostasis (ISTH), Amsterdam, Netherlands, Jun 29- Jul 4, 2013,
  • 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:
    Böhm M; Schumacher H; Laufs U; Sleight P; Schmieder R; Unger T; Teo K; Yusuf S
    Title:
    Effects of nonpersistence with medication on outcomes in high-risk patients with cardiovascular disease
    Source:
    Am Heart J 166 (2), 306-314 (2013)
    Abstract:
    Background The impact of nonpersistence on events and of events on persistence is unclear. We studied the effects of nonpersistence on outcomes and events on nonadherence in a randomized placebo controlled trial in 40 countries on 25,620 patients. Methods In the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET), persistent patients (n = 20,991) were compared with individuals who had permanently stopped study medications (n = 4,629). Results Older age, female gender, less physical activity, less education, and history of stroke/transient ischemic attack, depression, and diabetes were associated with nonpersistence. After adjustment, nonpersistence was associated with the composite end point of cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure (hazard ratio 1.24, 99% CI 1.09-1.40, P <.0001), cardiovascular death alone (1.87, 1.60-2.19, P <.0001), and heart failure hospitalization alone (1.32, 1.04-1.67, P =.0023). Cardiovascular events increased when medications were stopped, whereas noncardiovascular outcomes did not. Nonpersistence rapidly increased within the first year after nonfatal events such as myocardial infarction (hazard ratio 3.37, 99% CI 2.72-4.16, P <.0001), stroke (3.25, 2.59-4.07, P <.0001), and hospitalization for heart failure (3.67, 2.95-4.57, P <.0001). Persistence was poorer with more frequent and earlier events. Patients stopping medication after an event were at greater risk for subsequent events. Conclusions Improving medications persistence could interrupt this vicious circle and may improve outcomes. © 2013 Mosby, Inc.
  • Author:
    Offman E; Schobelock MJ; Brickl R; Vandermaelen CP; Ehrlich J; Eisert W
    Title:
    Pharmacokinetics and pharmacodynamics of the antiplatelet combination aspirin (Acetylsalicylic Acid) plus extended-release dipyridamole are not altered by coadministration with the potent CYP2C19 inhibitor omeprazole
    Source:
    Am J Cardiovasc Drugs 13 (2), 113-120 (2013)
    Abstract:
    Background: The fixed-dose combination of aspirin (acetylsalicylic acid) 25 mg plus extended-release dipyridamole 200 mg (ASA + ER-DP) is used for long-term secondary stroke prevention in patients who have experienced non-cardioembolic stroke or transient ischemic attack. Although the theoretical risk is low that the antiplatelet activity of ASA + ER-DP will be affected by concomitant use of a proton pump inhibitor (PPI), no formal drug-drug interaction studies have been conducted. Objective: This study aimed to determine whether the PPI omeprazole influences the pharmacokinetic (PK) and pharmacodynamic (PD) behavior of ASA + ER-DP. Study Design and Setting: This was a randomized, open-label, multiple-dose, crossover, drug-drug interaction study carried out in a clinical trial unit. Participants: Sixty healthy male and female volunteers aged 18-50 years were included in the study. Intervention: Participants were randomized to one of two treatment sequences (ABCD or CDAB), each comprising four 7-day treatments with a washout of .14 days between the second and third treatments. Treatment A = ASA + ER-DP 25 mg/200 mg (Aggrenox®) twice daily (BID) alone; B = ASA + ER-DP 25 mg/200 mg BID + omeprazole (Prilosec®) 80 mg once daily (QD) following ASA + ER-DP alone for 7 days; C = omeprazole 80 mg QD alone; D = omeprazole 80 mg QD + ASA + ER-DP 25 mg/200 mg BID following omeprazole alone for 7 days. Main Outcome Measures: The main outcome measures were systemic PK exposure to ER-DP and ASA inhibition of arachidonic acid-induced platelet aggregation. Results: Systemic exposure to ER-DP was similar with and without omeprazole, based on steady-state area under the concentration-time curve (AUC) from 0 to 12 h (AUC0-12,ss, ng.h/mL) and maximum plasma concentration (C max,ss, ng/mL). For the treatment comparison D versus A, the percent mean ratios were 96.38 (90 % confidence interval [CI] 90.96-102.13) for AUC 0-12,ss and 92.03 (86.95-97.40) for Cmax,ss. The ER-DP concentration versus time profiles were nearly superimposable. There was no effect on the PDs of the ASA component: the extent of ASA inhibition of arachidonic acid-induced platelet aggregation was almost identical with and without omeprazole, with a percent mean ratio for treatment D versus A = 99.02 (90 % CI 98.32-99.72) at 4 h after last dose. All treatments were well tolerated. Conclusion: The PK and PD behavior of ASA + ER-DP was not altered by concurrent administration of omeprazole. © 2013 Springer International Publishing Switzerland.
  • Author:
    Oelze M; Kröller-Schön S; Zinßius E; Stamm P; Hausding M; Mayoux E; Wenzel P; Schulz E; Münzel T; Daiber A
    Title:
    Effects of Empagliflozin on Oxidative Stress and Endothelial Dysfunction in STZ-Induced Type 1 Diabetic Rat
    Source:
    Poster
  • Author:
    Connolly SJ; Wallentin L; Ezekowitz MD; Eikelboom J; Oldgren J; Reilly PA; Brueckmann M; Pogue J; Alings M; Amerena JV; Avezum A; Baumgartner I; Budaj AJ; Chen J-H; Dans AL; Darius H; Di Pasquale G; Ferreira J; Flaker GC; Flather MD; Franzosi MG; Golitsyn SP; Halon DA; Heidbuchel H; Hohnloser SH; Huber K; Jansky P; Kamensky G; Keltai M; Kim SS; Lau C-P; Le Heuzey J-Y; Lewis BS; Liu L; Nanas J; Omar R; Pais P; Pedersen KE; Piegas LS; Raev D; Smith PJ; Talajic M; Tan RS; Tanomsup S; Toivonen L; Vinereanu D; Xavier D; Zhu J; Wang SQ; Duffy CO; Themeles E; Yusuf S
    Title:
    The long-term multicenter observational study of dabigatran treatment in patients with atrial fibrillation (RELY-ABLE) study
    Source:
    Circulation 128 (3), 237-243 (2013)
    Abstract:
    BACKGROUND - : During follow-up of between 1 and 3 years in the Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial, 2 doses of dabigatran etexilate were shown to be effective and safe for the prevention of stroke or systemic embolism in patients with atrial fibrillation. There is a need for longer-term follow-up of patients on dabigatran and for further data comparing the 2 dabigatran doses. METHODS AND RESULTS - : Patients randomly assigned to dabigatran in RE-LY were eligible for the Long-term Multicenter Extension of Dabigatran Treatment in Patients with Atrial Fibrillation (RELY-ABLE) trial if they had not permanently discontinued study medication at the time of their final RE-LY study visit. Enrolled patients continued to receive the double-blind dabigatran dose received in RE-LY, for up to 28 months of follow up after RE-LY (median follow-up, 2.3 years). There were 5851 patients enrolled, representing 48% of patients originally randomly assigned to receive dabigatran in RE-LY and 86% of RELY-ABLE-eligible patients. Rates of stroke or systemic embolism were 1.46% and 1.60%/y on dabigatran 150 and 110 mg twice daily, respectively (hazard ratio, 0.91; 95% confidence interval, 0.69-1.20). Rates of major hemorrhage were 3.74% and 2.99%/y on dabigatran 150 and 110 mg (hazard ratio, 1.26; 95% confidence interval, 1.04-1.53). Rates of death were 3.02% and 3.10%/y (hazard ratio, 0.97; 95% confidence interval, 0.80-1.19). Rates of hemorrhagic stroke were 0.13% and 0.14%/y. CONCLUSIONS - : During 2.3 years of continued treatment with dabigatran after RE-LY, there was a higher rate of major bleeding with dabigatran 150 mg twice daily in comparison with 110 mg, and similar rates of stroke and death. CLINICAL TRIAL REGISTRATION - : URL: http://www.clinicaltrials.gov. Unique identifier: NCT00808067. © 2013 American Heart Association, Inc.
  • Author:
    Hass B; Pooley J; Harrington AE; Clemens A; Feuring M
    Title:
    Treatment of venous thromboembolism - effects of different therapeutic strategies on bleeding and recurrence rates and considerations for future anticoagulant management
    Source:
    Thromb J 10 (1) art no 24 (2012)
    Abstract:
    Effective treatment of venous thromboembolism (VTE) strikes a balance between prevention of recurrence and bleeding complications. The current standard of care is heparin followed by a vitamin K antagonist such as warfarin. However, this option is not without its limitations, as the anticoagulant effect of warfarin is associated with high inter- and intra-patient variability and patients must be regularly monitored to ensure that anticoagulation is within the narrow target therapeutic range. Several novel oral anticoagulant agents are in the advanced stages of development for VTE treatment, some of which are given after an initial period of heparin treatment, in line with current practice, while others switch from high to low doses after the initial phase of treatment. In this review we assess the critical considerations for treating VTE in light of emerging clinical data for new oral agents and discuss the merits of novel treatment regimens for patients who have experienced an episode of deep vein thrombosis or pulmonary embolism. .COPYRGT. 2012 Hass et al.; licensee BioMed Central Ltd.
  • Author:
    Fryer RM; Muthukumarana A; Harrison PC; Nodop Mazurek S; Chen RR; Harrington KE; Dinallo RM; Horan JC; Patnaude L; Modis LK; Reinhart GA
    Title:
    The clinically-tested S1P receptor agonists, FTY720 and BAF312, demonstrate subtype-specific bradycardia (S1P.) and hypertension (S1P.) in rat
    Source:
    PloS ONE 7 (12) e52985 (2012)
    Abstract:
    Sphingosine-1-phospate (S1P) and S1P receptor agonists elicit mechanism-based effects on cardiovascular function in vivo. Indeed, FTY720 (non-selective S1P(X) receptor agonist) produces modest hypertension in patients (2-3 mmHg in 1-yr trial) as well as acute bradycardia independent of changes in blood pressure. However, the precise receptor subtypes responsible is controversial, likely dependent upon the cardiovascular response in question (e.g. bradycardia, hypertension), and perhaps even species-dependent since functional differences in rodent, rabbit, and human have been suggested. Thus, we characterized the S1P receptor subtype specificity for each compound in vitro and, in vivo, the cardiovascular effects of FTY720 and the more selective S1P.,. agonist, BAF312, were tested during acute i.v. infusion in anesthetized rats and after oral administration for 10 days in telemetry-instrumented conscious rats. Acute i.v. infusion of FTY720 (0.1, 0.3, 1.0 mg/kg/20 min) or BAF312 (0.5, 1.5, 5.0 mg/kg/20 min) elicited acute bradycardia in anesthetized rats demonstrating an S1P. mediated mechanism-of-action. However, while FTY720 (0.5, 1.5, 5.0 mg/kg/d) elicited dose-dependent hypertension after multiple days of oral administration in rat at clinically relevant plasma concentrations (24-hr mean blood pressure.=.8.4, 12.8, 16.2 mmHg above baseline vs. 3 mmHg in vehicle controls), BAF312 (0.3, 3.0, 30.0 mg/kg/d) had no significant effect on blood pressure at any dose tested suggesting that hypertension produced by FTY720 is mediated S1P. receptors. In summary, in vitro selectivity results in combination with studies performed in anesthetized and conscious rats administered two clinically tested S1P agonists, FTY720 or BAF312, suggest that S1P. receptors mediate bradycardia while hypertension is mediated by S1P. receptor activation.
  • Author:
    Hori M; Connolly S J; Zhu J; Liu L S; Lau C P; Pais P; Xavier D; Kim S S; Omar R
    Title:
    Efficacy and Safety of Dabigatran Versus Warfarin in Patients with Atrial Fibrillation: Analysis in Asian Population in RE-LY Trial.
    Source:
    Cerebrovasc Dis 34 (1), 9 (2012)
    Abstract:
    his study evaluated the efficacy and safety of dabigatran-etexilate (DE) vs. warfarin in 18,113 patients with atrial fibrillation. Efficacy of DE on stroke/systemic embolism (SE) was consistent between Asians and non-Asians, but the reductions in major bleeding were greater with DE compared to warfarin in Asians. The rates of hemorrhagic stroke in individuals receiving warfarin were much higher in Asians compared to non-Asians, thus, with a larger risk reduction with DE in Asians. (conference abstract: Annual Conference of the Asia Pacific Stroke Organization, APSO, Tokyo, Japan, 10/09/2012-12/09/2012) ABEX Methods Of 18,113 in the RE-LY, Asian patients (n=2,782 in 10 countries) were compared with non-Asian patients n=15,331 in 34 countries). Results Rates of stroke/SE in Asia were 3.06%/yr on warfarin, 2.50%/yr on DE 110 mg b.i.d. and 1.39%/yr on DE 150 mg b.i.d. The rates of major bleeding in Asia were lower on DE (both doses) than warfarin; 3.82%/yr on warfarin, 2.22%/yr on DE 110 mg b.i.d. and 2.17%/yr on DE 150 mg b.i.d. The rate of hemorrhagic stroke on warfarin treated patients was more than 2-fold higher in Asian than in non-Asian patients despite younger age in Asians. (C97)
  • Author:
    Fryer Ryan M; Muthukumarana Akalushi; Harrison Paul C; Mazurek Suzanne Nodop; Chen Rong Rhonda; Harrington Kyle E; Dinallo Roger M; Horan Joshua C; Patnaude Lori; Modis Louise K; Reinhart Glenn A
    Title:
    The Clinically-tested S1P Receptor Agonists, FTY720 and BAF312, Demonstrate Subtype-Specific Bradycardia (S1P(1)) and Hypertension(S1P(3)) in Rat
    Source:
    PloS One 7 (12) e52985 (2012)
    Abstract:
    Sphingosine-1-phospate (S1P) and S1P receptor agonists elicit mechanism-based effects on cardiovascular function in vivo. Indeed, FTY720 (non-selective S1P(X) receptor agonist) produces modest hypertension in patients (2-3 mmHg in 1-yr trial) as well as acute bradycardia independent of changes in blood pressure. However, the precise receptor subtypes responsible is controversial, likely dependent upon the cardiovascular response in question (e.g. bradycardia, hypertension), and perhaps even species-dependent since functional differences in rodent, rabbit, and human have been suggested. Thus, we characterized the S1P receptor subtype specificity for each compound in vitro and, in vivo, the cardiovascular effects of FTY720 and the more selective S1P.,. agonist, BAF312, were tested during acute i.v. infusion in anesthetized rats and after oral administration for 10 days in telemetry-instrumented conscious rats. Acute i.v. infusion of FTY720 (0.1, 0.3, 1.0 mg/kg/20 min) or BAF312 (0.5, 1.5, 5.0 mg/kg/20 min) elicited acute bradycardia in anesthetized rats demonstrating an S1P. mediated mechanism-of-action. However, while FTY720 (0.5, 1.5, 5.0 mg/kg/d) elicited dose-dependent hypertension after multiple days of oral administration in rat at clinically relevant plasma concentrations (24-hr mean blood pressure.=.8.4, 12.8, 16.2 mmHg above baseline vs. 3 mmHg in vehicle controls), BAF312 (0.3, 3.0, 30.0 mg/kg/d) had no significant effect on blood pressure at any dose tested suggesting that hypertension produced by FTY720 is mediated S1P. receptors. In summary, in vitro selectivity results in combination with studies performed in anesthetized and conscious rats administered two clinically tested S1P agonists, FTY720 or BAF312, suggest that S1P. receptors mediate bradycardia while hypertension is mediated by S1P. receptor activation.
  • Author:
    van Ryn Joanne; Goss Ashley; Hauel Norbert; Wienen Wolfgang; Priepke Henning; Nar Herbert; Clemens Andreas
    Title:
    The discovery of dabigatran etexilate.
    Source:
    Front Pharmacol 4, 12 (2013)
    Abstract:
    Thromboembolic disease is a major cause of mortality and morbidity in the developed world and is caused by an excessive stimulation of coagulation. Thrombin is a key serine protease in the coagulation cascade and numerous efforts have been made to develop safe and effective orally active direct thrombin inhibitors (DTIs). Current anticoagulant therapy includes the use of indirect thrombin inhibitors (e.g., heparins, low-molecular-weight-heparins) and vitamin K antagonists such as warfarin. However there are several caveats in the clinical use of these agents including narrow therapeutic window, parenteral delivery, and food- and drug-drug interactions. Dabigatran is a synthetic, reversible DTI with high affinity and specificity for its target binding both free and clot-bound thrombin, and offers a favorable pharmacokinetic profile. Large randomized clinical trials have demonstrated that dabigatran provides comparable or superior thromboprophylaxis in multiple thromboembolic disease indications compared to standard of care. This minireview will highlight the discovery and development of dabigatran, the first in a class of new oral anticoagulant agents to be licensed worldwide for the prevention of thromboembolism in the setting of orthopedic surgery and stroke prevent in atrial fibrillation
  • 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 letter 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".
    Source:
    Circulation 127 (2), e278-e279 (2013)
    Abstract:
    -
  • Author:
    Marfatia Ravi; White William B; Schumacher Helmut
    Title:
    Effects of telmisartan with hydrochlorothiazide versus valsartan with hydrochlorothiazide in patients with moderate-to-severe hypertension.
    Source:
    Int J Hypertens 2012 art no 976828 (2012)
    Abstract:
    Combination therapy is recommended for patients with blood pressure (BP) significantly above goal by recent consensus guidelines around the globe. The use of angiotensin II receptor blockers (ARBs) alone or in combination with a thiazide diuretic is a preferred treatment strategy due to both efficacy and safety considerations. However, there are few data known about the benefits of ARB-diuretic combination therapy in patients with moderate-to-severe hypertension. We performed a subanalysis from two large clinical trials that compared the antihypertensive effects of telmisartan 80.mg versus valsartan 160.mg, both combined with hydrochlorothiazide (HCTZ) 25.mg in a subpopulation of 725 patients with moderate-to-severe hypertension (systolic BP SBP . 160.mm.Hg). Treatment with telmisartan-HCTZ induced significantly greater reductions in BP (.31.1/.18.3.mm.Hg) than valsartan-HCTZ (.28.4/.16.3.mm.Hg; SBP .. = 0 . 0 2 6 5 , diastolic BP .. = 0 . 0 0 4 1 ). More patients receiving the telmisartan combination achieved a BP goal < 140/90.mm.Hg than those receiving valsartan-HCTZ. There were similar safety and tolerability data for the two active treatment groups. These findings support the use of longer-acting ARBs combined with higher doses of thiazide diuretic to improve BP control in patients with moderate-to-severe hypertension.
  • Author:
    Ring Arne; Rathgen Karin; Stangier Joachim; Reilly Paul; Clemens Andreas; Friedman Jeffrey
    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.
  • Author:
    Rosenstock J; Marx N; Kahn SE; Zinman B; Kastelein JJ; Lachin JM; Bluhmki E; Patel S; Johansen O-E; Woerle H-J
    Title:
    Cardiovascular outcome trials in type 2 diabetes and the sulphonylurea controversy: Rationale for the active-comparator CAROLINA trial
    Source:
    Diabetes Vasc Dis Res 10 (4), 289-301 (2013)
    Abstract:
    Sulphonylureas (SUs) are widely used glucose-lowering agents in type 2 diabetes mellitus (T2DM) with apparent declining efficacy over time. Concerns have been raised from observational retrospective studies on the cardiovascular (CV) safety of SUs but there are few long-term data on CV outcomes from randomized controlled trials (RCTs) involving the use of this class of agents. Most of the observational studies and registry data are conflicting and vary with study population and methodology used for analyses. To address the SU controversy, we reviewed the recently published literature (until end of the year 2011) to evaluate the impact of SUs on CV outcomes in modern, longer-term (.72 weeks) RCTs where they were compared in a head-to-head fashion versus an active comparator or were used as part of a treatment strategy. We identified 15 trials and found no report of an increase in the incidence of CV events with the use of SUs. However, the available data are limited, and, most importantly, there was no adequately powered formal head-to-head CV outcome trial designed to address CV safety. Since SUs are still being advocated as second-line therapy added-on to metformin, as one of several classes, and in certain circumstances first-line therapy in T2DM management, definitive data from a dedicated RCT addressing the CV safety question with SUs would be informative. Cardiovascular Outcome Study of Linagliptin versus Glimepiride in Patients with Type 2 Diabetes (CAROLINA) is such a trial, ongoing since November 2010, and is currently the largest head-to-head CV outcome trial that involves a comparison of a SU (glimepiride) with a dipeptidyl peptidase-4 (DPP-4) inhibitor (linagliptin) and will provide a unique perspective with respect to CV outcomes with these two commonly used agents. © The Author(s) 2013.
  • Author:
    Sorensen SV; Peng S; Monz BU; Bradley-Kennedy C; Kansal AR
    Title:
    A comparative analysis of models used to evaluate the cost-effectiveness of dabigatran versus warfarin for the prevention of stroke in atrial fibrillation
    Source:
    Pharmacoeconomics 31 (7), 589-604 (2013)
    Abstract:
    Background: A number of models exploring the cost-effectiveness of dabigatran versus warfarin for stroke prevention in atrial fibrillation have been published. These studies found dabigatran was generally cost-effective, considering well-accepted willingness-to-pay thresholds, but estimates of the incremental cost-effectiveness ratios (ICERs) varied, even in the same setting. The objective of this study was to compare the findings of the published economic models and identify key model features accounting for differences. Methods: All aspects of the economic evaluations were reviewed: model approach, inputs, and assumptions. A previously published model served as the reference model for comparisons of the selected studies in the US and UK settings. The reference model was adapted, wherever possible, using the inputs and key assumptions from each of the other published studies to determine if results could be reproduced in the reference model. Incremental total costs, incremental quality-adjusted life years (QALYs), and ICERs (cost per QALY) were compared between each study and the corresponding adapted reference model. The impact of each modified variable or assumption was tracked separately. Results: The selected studies were in the US setting (2), the Canadian setting (1), and the UK setting (2). All models used the Randomized Evaluation of Long-Term Anticoagulation study (RE-LY) as the main source for clinical inputs, and all used a Markov modelling approach, except one that used discrete event simulation. The reference model had been published in the Canadian and UK settings. In the UK setting, the reference model reported an ICER of UK£4,831, whereas the other UK-based analysis reported an ICER of UK£23,082. When the reference model was modified to use the same population characteristics, cost inputs, and utility inputs, it reproduced the results of the other model (ICER UK£25,518) reasonably well. Key reasons for the different results between the two models were the assumptions on the event utility decrement and costs associated with intracranial haemorrhage, as well as the costs of warfarin monitoring and disability following events. In the US setting, the reference model produced an ICER similar to the ICER from one of the US models (US 15,115/QALY versus US $12,386/QALY, respectively) when modelling assumptions and input values were transferred into the reference model. Key differences in results could be explained by the population characteristics (age and baseline stroke risk), utility assigned to events and specific treatments, adjustment of stroke and intracranial haemorrhage risk over time, and treatment discontinuation and switching. The reference model was able to replicate the QALY results, but not the cost results, reported by the other US cost-effectiveness analysis. The parameters driving the QALY results were utility values by disability levels as well as utilities assigned to specific treatments, and event and background mortality rates. Conclusions: Despite differences in model designs and structures, it was mostly possible to replicate the results published by different authors and identify variables responsible for differences between ICERs using a reference model approach. This enables a better interpretation of published findings by focusing attention on the assumptions underlying the key model features accounting for differences. © 2013 The Author(s). Reference:.
  • Author:
    Hori M; Connolly SJ; Zhu J; Liu LS; Lau C-P; Pais P; Xavier D; Kim SS; Omar R; Dans AL; Tan RS; Chen J-H; Tanomsup S; Watanabe M; Koyanagi M; Ezekowitz MD; Reilly PA; Wallentin L; Yusuf S
    Title:
    Dabigatran versus warfarin: Effects on ischemic and hemorrhagic strokes and bleeding in asians and non-Asians with atrial fibrillation
    Source:
    Stroke 44 (7), 1891-1896 (2013)
    Abstract:
    BACKGROUND AND PURPOSE - : Intracranial hemorrhage rates are higher in Asians than non-Asians, especially in patients receiving warfarin. This randomized evaluation of long-term anticoagulation therapy subgroup analysis assessed dabigatran etexilate (DE) and warfarin effects on stroke and bleeding rates in patients from Asian and non-Asian countries. METHODS - : There were 2782 patients (15%) from 10 Asian countries and 15 331 patients from 34 non-Asian countries. A Cox regression model, with terms for treatment, region, and their interaction was used. RESULTS - : Rates of stroke or systemic embolism in Asians were 3.06% per year on warfarin, 2.50% per year on DE 110 mg BID (DE 110), and 1.39% per year on DE 150 mg BID (DE 150); in non-Asians, the rates were 1.48%, 1.37%, and 1.06% per year with no significant treatment-by-region interactions. Hemorrhagic stroke on warfarin occurred more often in Asians than non-Asians (hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.3-4.7; P=0.007), with significant reductions for DE compared with warfarin in both Asian (DE 110 versus warfarin HR, 0.15; 95% CI, 0.03-0.66 and DE 150 versus warfarin HR, 0.22; 95% CI, 0.06-0.77) and non-Asian (DE 110 versus warfarin HR, 0.37; 95% CI, 0.19-0.72 and DE 150 versus warfarin HR, 0.28; 95% CI, 0.13-0.58) patients. Major bleeding rates in Asians were significantly lower on DE (both doses) than warfarin (warfarin 3.82% per year, DE 110 2.22% per year, and DE 150 2.17% per year). CONCLUSIONS - : Hemorrhagic stroke rates were higher on warfarin in Asians versus non-Asians, despite similar blood pressure, younger age, and lower international normalized ratio values. Hemorrhagic strokes were significantly reduced by DE in both Asians and non-Asians. DE benefits were consistent across Asian and non-Asian subgroups. CLINICAL TRIAL REGISTRATION - : URL: http://www.clinicaltrials.gov. Unique identifier: NCT00262600. © 2013 American Heart Association, Inc.
  • Author:
    Neldam S; Zhu D; Schumacher H
    Title:
    Efficacy of telmisartan plus amlodipine in nonresponders to CCB monotherapy
    Source:
    J Hypertens art no 627938 (2013)
    Abstract:
    Hypertensive patients unable to reach blood pressure (BP) targets with antihypertensive monotherapy may be switched to a combination of two medications with complementary modes of action for improved treatment response. This post hoc analysis pools data from 2812 patients, 1891 of whom were not at goal (diastolic BP [DBP] <90 mm Hg) with amlodipine 5 mg (A5) monotherapy who subsequently switched to telmisartan 40 or 80 mg (T80)/A5 single-pill combination (SPC) or amlodipine 10 mg (A10) monotherapy, and considers an additional 921 patients, 616 of whom were not at goal with A10 monotherapy who switched to telmisartan/amlodipine SPC. Patients switched to telmisartan/amlodipine SPC achieved significantly greater BP reductions compared with continued monotherapy (P<0.0001) with reductions of -15.2/-10.9 mm Hg seen with T80/A5 after 8 weeks in patients switched from A5. BP goal (<140/90 mm Hg), systolic BP goal (<140 mm Hg), and DBP goal (<90 mm Hg) were reached by significantly more patients with telmisartan/amlodipine than with monotherapy (P<0.0001 for all comparisons; 56.1%, 69.7%, and 66.9%, resp., in patients who switched from A5 to T80/A5). Early use of such combination therapy should be considered to quickly reach BP targets, particularly in patients with added risk. © 2013 Steen Neldam et al.
  • Author:
    Tse H-F; Wang Y-J; Ahmed Ai-Abdullah M; Pizarro-Borromeo AB; Chiang C-E; Krittayaphong R; Singh B; Vora A; Wang C-X; Zubaid M; Clemens A; Lim P; Hu D
    Title:
    An Asian stroke perspective Stroke prevention in atrial fibrillation
    Source:
    Heart Rhythm 19 (7), 1082-1088 (2013)
    Abstract:
    Despite relatively lower prevalence of atrial fibrillation (AF) in Asians (~1%) than in Caucasians (~2%), Asia has a much higher overall disease burden because of its proportionally larger aged population. For example, on the basis of reported age-adjusted prevalence rates and projected population figures in China, there will be an estimated 5.2 million men and 3.1 million women with AF older than 60 years by year 2050. Stroke is a disabling complication of AF that is of increasing cause for concern in Asians patients. Implementing consensus expert recommendations for managing stroke risk in patients with AF can considerably reduce stroke rates. However, caution is necessary when aligning management of Asian patients with AF to that of their Caucasian counterparts. Current international guidelines and risk stratification tools for AF management are based on findings in predominantly Caucasian populations and may therefore have limited relevance, in certain respects, to Asian patients. Oral anticoagulants play an important role in preventing AF-related stroke. The vitamin K antagonist warfarin is recommended for reducing the risk of stroke and thromboembolism in high-risk patients with nonvalvular AF; however, warfarin interacts with many drugs and food ingredients, which may pose significant challenges in administration and monitoring among Asian patients. Further research is needed to inform specific guidance on the implications of different stroke and bleeding profiles in Asians vs Caucasians. Moreover, there is scope to improve physician perceptions and patient knowledge, as well as considering alternative new oral anticoagulants, for example, direct thrombin inhibitors or factor Xa inhibitors. © 2013 Heart Rhythm Society.
  • Author:
    Worthmann H; Schwartz A; Heidenreich F; Sindern E; Lorenz R; Adams H-A; Flemming A; Luettje K; Walter U; Haertle B; Dengler R
    Title:
    Educational campaign on stroke in an urban population in Northern Germany: Influence on public stroke awareness and knowledge
    Source:
    Int J Stroke 8 (5), 286-292 (2013)
    Abstract:
    Background Public stroke awareness and knowledge may be supportive for stroke prevention and emergency care-seeking behavior after the acute event, which is highly important for early treatment onset. Aims: In an urban population in Northern Germany (Hannover), a six-month stroke educational campaign was conducted. We expected an increase in stroke knowledge and awareness thereafter. Methods: Computer-assisted telephone interviews were randomly conducted among 1004 representative participants before and 1010 immediately after the educational multimedia campaign. The computer-assisted telephone interviews focused on questions about stroke knowledge and interventions remembered. Results: Knowledge of stroke risk factors increased during the campaign for overweight, physical inactivity, old age, and stroke in family (P<0.05). The knowledge of stroke warning signs was low, although it significantly increased during the campaign (P<0.001) as paresis/weakness (46%) and speech problems (31%) were most frequently named. The majority of respondents indicated that the first action after suffering from stroke should be calling emergency care (74% before vs. 84% after campaign, P<0.001). Conclusions: Our data indicate that stroke knowledge and awareness, which could provide earlier presentation to the emergency unit for timely treatment onset, are still low in urban Northern Germany but may decisively be increased by educational campaigns. © 2012 World Stroke Organization.
  • Author:
    Brandes A; Overgaard M; Plauborg L; Dehlendorff C; Lyck F; Peulicke J; Poulsen SV; Husted S
    Title:
    Guideline adherence of antithrombotic treatment initiated by general practitioners in patients with nonvalvular atrial fibrillation: A danish survey
    Source:
    Clin Cardiol 37 (7), 427-432 (2013)
    Abstract:
    Background The aim of this prospective survey was to describe the demographics, stroke risk profile, and the guideline adherence of antithrombotic treatment in a Danish primary care population of patients with nonvalvular atrial fibrillation (AF). Hypothesis We hypothesized that a significant proportion of patients with nonvalvular AF do not receive guideline-adherent antithrombotic treatment in primary care. Methods We performed a cross-sectional survey of antithrombotic treatment using data of AF patients from general practices. Results Sixty-four general practitioners enrolled 1743 patients with a mean age of 74.8 ± 11.2 years. The mean CHADS2 and CHA 2DS2-VASc scores were 1.9 ± 1.3 and 3.5 ± 1.8, respectively. Of the patients, 12.4% and 4.04%, respectively, were at truly low risk, with a CHADS2 and CHA2DS2-VASc score 0 (P &lt; 0.001). A score of 1 was seen in 28.0% vs 9.0% (P &lt; 0.001) of the patients. Of all patients, 66.3% were treated with oral anticoagulants, 18.7% with antiplatelet drugs only, and 15% received no antithrombotic therapy. Based on the CHADS2 score, 75.7% of the patients were treated in adherence with the guidelines, 16% were undertreated, and 8.4% overtreated. The corresponding numbers for the CHA2DS2-VASc score were 75.4%, 22.7%, and 1.8%, respectively. The differences in guideline adherence applying the 2 scores were significant (P &lt; 0.001). Of patients receiving no antithrombotic therapy, 64.1% were treated in adherence to the guidelines according to the CHADS2 score. Applying the CHA2DS 2-VASc score, this proportion was only 53.4%. Antiplatelet drug treatment was in adherence to the guidelines (CHADS2 and CHA 2DS2-VASc score of 1) in only 31% and 12% of the patients, respectively. Conclusions Antithrombotic treatment of AF patients is in general well performed in primary care in Denmark. Further improvements may be achieved by thorough stroke risk stratification on the basis of current evidence-based guidelines. © 2013 Wiley Periodicals, Inc.
  • Author:
    Hesselbjerg LJ; Pedersen HS; Asmussen MB; Petersen KD
    Title:
    Is dabigatran considered a cost-effective alternative to warfarin treatment: A review of current economic evaluations worldwide
    Source:
    J Med Econ 16 (7), 845-858 (2013)
    Abstract:
    Objective: Dabigatran was the first of a new generation of anticoagulation drugs for the indication of non-valvular atrial fibrillation (AF) to be approved. Evidence show that dabigatran 150 mg twice daily significantly reduces the risk of stroke and systemic embolism (RR = 0.65; p < 0.001) and shows a comparable rate of major bleedings (RR = 0.93; p = 0.32), whereas dabigatran 110 mg twice daily was associated with a comparable rate of stroke and systemic embolism (RR = 0.90; p = 0.30) and a significantly lower rate of major bleedings compared to warfarin treatment (RR = 0.80; p = 0.003). The purpose is to review current economic evaluations of these alternatives for healthcare professionals to include these findings in their decision-making. Methods: A systematic literature search identified 43 economic evaluations, of which 10 were included and evaluated according to the Consensus Health Economic Criteria list (CHEC-list) and the Oxford model. Results: Six economic evaluations concluded that dabigatran was a cost-effective alternative to warfarin. One evaluation concluded the same except when quality in warfarin treatment was excellent, with a mean time in therapeutic range (TTR) > 73%. Three evaluations concluded that dabigatran was a cost-effective alternative to warfarin in patient sub-groups; TTR 64%, congestive heart failure, hypertension, age . 75, diabetes mellitus, prior stroke or transient ischemic attack (CHADS2 score) .3, or a CHADS2 score = 2 unless international normalized ratio (INR) control was excellent, and with high risk of stroke or in a low-quality warfarin treatment. Dabigatran 110 mg twice daily was in general dominated by dabigatran 150 mg twice daily. Limitations: The evaluations were not fully homogeneous, as some did not include loss of productivity, costs of dyspepsia, and annual costs of dabigatran patient management. Conclusions: In the majority of the economic evaluations, dabigatran is a cost-effective alternative to warfarin treatment. In some evaluations dabigatran is only cost-effective in sub-groups, such as patients with a low TTR-value in warfarin treatment and a CHADS2 score .2. © 2013 All rights reserved.
  • Author:
    Dukeck R; Sieger P; Karmwar P
    Title:
    Investigation and correlation of physical stability, dissolution behaviour and interaction parameter of amorphous solid dispersions of telmisartan: A drug development perspective Investigation and correlation of physical stability, dissolution behaviour and interaction parameter of amorphous solid dispersions of telmisartan
    Source:
    Eur J Pharm Sci 49 (4), 723-731 (2013)
    Abstract:
    The aim of this study was to investigate if amorphous solid dispersions of telmisartan, prepared in presence of different polymers, exhibit different structural and thermodynamic characteristics and whether these differences can be correlated to their physical stability (time to crystallisation) and dissolution behaviour. Amorphous samples were prepared by melt quenching. The resulting amorphous materials were characterised using X-ray diffraction, Raman spectroscopy and differential scanning calorimetry. All freshly prepared samples were completely X-ray amorphous (with a halo being the only feature in the diffractograms). The shape of the halos in the diffractograms varied suggesting structural variations in the near order of the molecules between the different amorphous solid dispersions (ASDs). Principal component analysis of the Raman spectra of the various ASD revealed that the samples clustered in the scores plot, again suggesting structural differences due to the presence of different drug-polymer interaction. The ranking of the samples with respect to physical stability and interaction parameter was: ASD of telmisartan:eudragit. > ASD of telmisartan:soluplus. > ASD of telmisartan:HPMC. > ASD of telmisartan:PVP. > amorphous telmisartan. The interaction parameter, calculated by using the Flory Huggins theory, showed a good correlation with the experimentally determined stability whereas a weak correlation was found with dissolution behaviour of different ASD. This study showed that correlation of physical stability and dissolution behaviour with calculated interaction parameter is possible for the same amorphous systems prepared by using different polymers. This could aid in selecting the most appropriate polymer for the development of optimised formulations containing amorphous drugs. It can be concluded that ASD prepared by using different polymers have different structural and thermal properties. These differences affect the physical stability and dissolution profiles of the amorphous solids. Thus, choosing the right polymer for preparing ASD is critical for producing materials with desired dissolution profiles and enhanced stability. © 2013 Elsevier B.V.
  • Author:
    Böhm M; Schumacher H; Laufs U; Sleight P; Schmieder R; Unger T; Teo K; Yusuf S
    Title:
    Effects of nonpersistence with medication on outcomes in high-risk patients with cardiovascular disease
    Source:
    Am Heart J Article in press (2013)
    Abstract:
    Background: The impact of nonpersistence on events and of events on persistence is unclear. We studied the effects of nonpersistence on outcomes and events on nonadherence in a randomized placebo controlled trial in 40 countries on 25,620 patients. Methods: In the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET), persistent patients (n = 20,991) were compared with individuals who had permanently stopped study medications (n = 4,629). Results: Older age, female gender, less physical activity, less education, and history of stroke/transient ischemic attack, depression, and diabetes were associated with nonpersistence. After adjustment, nonpersistence was associated with the composite end point of cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure (hazard ratio 1.24, 99% CI 1.09-1.40, P < .0001), cardiovascular death alone (1.87, 1.60-2.19, P < .0001), and heart failure hospitalization alone (1.32, 1.04-1.67, P = .0023). Cardiovascular events increased when medications were stopped, whereas noncardiovascular outcomes did not. Nonpersistence rapidly increased within the first year after nonfatal events such as myocardial infarction (hazard ratio 3.37, 99% CI 2.72-4.16, P < .0001), stroke (3.25, 2.59-4.07, P < .0001), and hospitalization for heart failure (3.67, 2.95-4.57, P < .0001). Persistence was poorer with more frequent and earlier events. Patients stopping medication after an event were at greater risk for subsequent events. Conclusions: Improving medications persistence could interrupt this vicious circle and may improve outcomes. © 2013 Mosby, Inc. All rights reserved.
  • Author:
    Hori Masatsugu; Connolly Stuart J; Zhu Jun; Liu Li Sheng; Lau Chu-Pak; Pais Prem; Xavier Denis; Kim Sung Soon; Omar Razali; Dans Antonio L; Tan Ru San; Chen Jyh-Hong; Tanomsup Supachai; Watanabe Mitsunori; Koyanagi Masahide; Ezekowitz Michael D; Reilly Paul A; Wallentin Lars; Yusuf Salim
    Title:
    Dabigatran Versus Warfarin: Effects on Ischemic and Hemorrhagic Strokes and Bleeding in Asians and Non-Asians With Atrial Fibrilla tion.
    Abstract:
    BACKGROUND AND PURPOSE: Intracranial hemorrhage rates are higher in Asians than non-Asians, especially in patients receiving warfarin. This randomized evaluation of long-term anticoagulation therapy subgroup analysis assessed dabigatran etexilate (DE) and warfarin effects on stroke and bleeding rates in patients from Asian and non-Asian countries. METHODS: There were 2782 patients (15%) from 10 Asian countries and 15 331 patients from 34 non-Asian countries. A Cox regression model, with terms for treatment, region, and their interaction was used. RESULTS: Rates of stroke or systemic embolism in Asians were 3.06% per year on warfarin, 2.50% per year on DE 110 mg BID (DE 110), and 1.39% per year on DE 150 mg BID (DE 150); in non-Asians, the rates were 1.48%, 1.37%, and 1.06% per year with no significant treatment-by-region interactions. Hemorrhagic stroke on warfarin occurred more often in Asians than non-Asians (hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.3-4.7; P=0.007), with significant reductions for DE compared with warfarin in both Asian (DE 110 versus warfarin HR, 0.15; 95% CI, 0.03-0.66 and DE 150 versus warfarin HR, 0.22; 95% CI, 0.06-0.77) and non-Asian (DE 110 versus warfarin HR, 0.37; 95% CI, 0.19-0.72 and DE 150 versus warfarin HR, 0.28; 95% CI, 0.13-0.58) patients. Major bleeding rates in Asians were significantly lower on DE (both doses) than warfarin (warfarin 3.82% per year, DE 110 2.22% per year, and DE 150 2.17% per year). CONCLUSIONS: Hemorrhagic stroke rates were higher on warfarin in Asians versus non-Asians, despite similar blood pressure, younger age, and lower international normalized ratio values. Hemorrhagic strokes were significantly reduced by DE in both Asians and non-Asians. DE benefits were consistent across Asian and non-Asian subgroups. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00262600.
  • Author:
    Kjeldsen S; Mancia G; Schmieder R; Mattheus M; Unger T
    Title:
    An update on telmisartan/hydrochlorothiazide combinations for the management of hypertensive patients with additional cardiovascular risk factors
    Source:
    Expert Rev Cardiovasc Ther 11 (6), 673-682 (2013)
    Abstract:
    International hypertension guidelines endorse the use of combination therapy to achieve blood pressure control in the majority of patients. Angiotensin AT1 receptor blockers, in combination with diuretics, are among the preferred combinations, with telmisartan plus hydrochlorothiazide (HCTZ) being an effective and well-tolerated combination. This article provides an up-to-date review of the existing data on telmisartan/HCTZ combination for the management of hypertension in patients with additional cardiovascular risk factors, including reports emerging from a number of recent clinical trials and secondary analyses of older trials. The accumulated evidence from clinical trials demonstrates that telmisartan/HCTZ combinations are effective and well tolerated in patients with mild-to-severe hypertension, including subgroups of patients with cardiovascular risk factors such as advanced age, obesity, chronic kidney disease, diabetes mellitus and treatment-resistant hypertension. © 2013 2013 Expert Reviews Ltd.
  • Author:
    Verheugt FWA; Clemmensen P; Mehran R; Agewall S; Pocock SJ; Goldstein S; Torp-Pedersen C; Simoons ML; Borer JS; Khder YM; Burton P; Deliargyris E; McMurray JJV; Berkowitz SD; Stough WG; Zannad F
    Title:
    Antithrombotic outcome trials in acute coronary syndromes: Seeking the optimal balance between safety and efficacy
    Source:
    Eur Heart J 34 (22), 1621-1629 (2013)
    Abstract:
    no abstract available
  • Author:
    Hocher B; Sharkovska Y; Mark M; Klein T; Pfab T
    Title:
    The novel DPP-4 inhibitors linagliptin and BI 14361 reduce infarct size after myocardial ischemia/reperfusion in rats
    Source:
    Int J Cardiol 167 (1), 87-93 (2013)
    Abstract:
    Background: Dipeptidylpeptidase-4 inhibition is reported to have beneficial effects on myocardial ischemia. Mechanisms might include a reduced degradation of stromal cell-derived factor-1 alpha with subsequent increased recruitment of circulating stem cells and/or incretin receptor-dependent pathways. This study evaluated the novel xanthine-based dipeptidylpeptidase-4 inhibitors linagliptin (BI 1356) and BI 14361 in cardiac ischemia. Methods: Male Wistar rats were pretreated with linagliptin or BI 14361 and subjected to ligation of the left anterior descending coronary artery for 30 min. Results: Dipeptidylpeptidase-4 inhibition significantly reduced the infarct size after 7 days (-27.7%, p < 0.05) and 8 weeks (-18.0%, p < 0.05). There was a significantly improved maximum rate of left ventricular pressure decline (dP/dt min) in linagliptin-treated animals 8 weeks after ischemia/reperfusion. Apart from that, treatment did not improve cardiac function as determined by echocardiography and cardiac catheterization. Immunohistological staining revealed an increased number of cells positive for stromal cell-derived factor-1 alpha, CXCR-4 and CD34 within and around the infarcted area of BI 14361-treated animals. Conclusions: Linagliptin and BI 14361 are able to reduce infarct size after myocardial ischemia. The immunohistological findings support the hypothesis that dipeptidylpeptidase-4 inhibition via reduced cleavage of stromal cell-derived factor-1 alpha might lead to an enhanced recruitment of CXCR-4 + circulating progenitor cells. © 2011 Elsevier Ireland Ltd.
  • Author:
    van Ryn J; Giessmann T; Gouya G; Wolzt M; Schurer J; Lobmeyer M T; Brueckmann M
    Title:
    Differential effects of dabigatran etexilate and ticagrelor on bleeding as assessed by washed blood and shed blood tests in healthy subjects
    Source:
    XXIV Congress of the International Society on Thrombosis & Hemostasis (ISTH), Amsterdam, June 29-July 4, 2013
  • Author:
    Goss A; van Ryn J; Schurer J; Clemens A
    Title:
    Assessment of cross-reactivity in three different fecal occult blood test systems with dabigatran and dabigatran etexilate: identification of useful test methods for gastrointestinal bleeding
    Source:
    XXIV Congress of the International Society on Thrombosis & Hemostasis (ISTH), Amsterdam, June 29-July 4, 2013
  • Author:
    van Ryn J; Schurer J; Clemens A
    Title:
    Assessment of dabigatran activity using the activated clotting time assay with concomitant heparin in vitro: comparison of two different point of care tests
    Source:
    XXIV Congress of the International Society on Thrombosis & Hemostasis (ISTH), Amsterdam, June 29-July 4, 2013
  • Author:
    Stangier J; Schmohl D; Gannser D; Moschetti V; Ley L
    Title:
    Measurement of Dabigatran Concentrations by Calibrated Thrombin Clotting Time in Dialysis Patients With End Stage Renal Disease in Comparison to LC-MS/MS
    Source:
    Int. Soc. Thromb. Hemostasis, ISTH, XXIV Congress
  • Author:
    van Ryn J; Kink-Eiband M; Fischer D; Schurer J; Clemens A
    Title:
    Increased Sensitivity to recombinant Tissue Plasminogen Activator (rtPA)-induced Lysis in vitro of Thrombi Produced in Human Platelet Rich Plasma containing Dabigatran
    Source:
    International Stroke Conference, Honolulu, 6-8 Feb 20123
  • Author:
    van Ryn J; Litzenburger T; Gan G; Coble K; Schurer J
    Title:
    In Vitro Characterization, Pharmacokinetics and Reversal of Supratherapeutic Doses of Dabigatran-Induced Bleeding in Rats by a Specific Antibody Fragment Antidote to Dabigatran
    Source:
    International Stroke Conference, Honolulu, Feb 6-8, 2013
  • Author:
    van Ryn J; Schurer J; Kink-Eiband M; Litzenburger T; Clemens A
    Title:
    Reversal of dabigatran clotting activity in the rat ex vivo by a specific and selective antibody fragment antidote: are there non-specific effects on warfarin, rivaroxaban and apixaban?
    Source:
    European Society of Cardiology (ESC), Amsterdam, August 31-September 4, 2013
  • Author:
    Renda G; Malatesta G; Lanuti P; Bucciarelli V; Candelori L; Moretti L; van Ryn J; Marchisio M; Miscia S; de Caterina R
    Title:
    Effects of the direct thrombin inhibitor dabigatran etexilate vs warfarin on platelet function in patients with atrial fibrillation
    Source:
    European Society of Cardiology (ESC), Amsterdam, August Aug 31-Sep 4, 2013
  • Author:
    Mader M; Hausding M; Schuhmacher S; Oelze M; Steven S; Daub S; Schulz E; Münzel T; Klein T; Daiber A
    Title:
    Comparison of Linagliptin and Liraglutide on Survival in Experimental Sepsis
    Source:
    EASD, September 2013, Barcelona
  • Author:
    Kadoglou NPE; Kapelouzou A; Moustardas P; Katsimpoulas M; Dimitriou C; Kostomitsopoulos N; Liapis CD
    Title:
    The effects of combined treatment with dabigatran etexilate and exercice training on the development and stability of athero-thrombotic lesions in ApoE knockout mice
    Source:
    2013 Scientific Sessions of the American Heart Association, Dallas, 16-20 Nov 2013
  • Author:
    Grotke O; van Ryn J; Zentai C; ten Cate H; Spronk H
    Title:
    Resuscitation with Different Infusion Solutions does not influence Binding of Dabigatran to its Specific Antidote in a Pig Model of Hemorrhagic Schock
    Source:
    2013 Scientific Sessions of the American Heart Association, Dallas, Nov 16-20, 2013
  • Author:
    van Ryn J; Schiele F; Litzenburger T; Schurer J; Nar H
    Title:
    In vitro characterization, pharmacokinetics and reversal of supratherpeutic doses of dabigatran-iduced bleeding in rats by a specific antibody fragment antidote to dabigatran
    Source:
    International Stroke Conference, Honolulu Feb 6-8, 2013
  • Author:
    Grottke O; van Ryn J; Spronk H; Rossaint R
    Title:
    Ex-vivo prothrombin complex concetrates are effective in reversing dabigatran-induced coagulopathy in pigs
    Source:
    2013 Scientific Sessions of the American Heart Association, Dallas, 16-20 Nov 2013
  • Author:
    Glund S; Stangier J; Schmohl M; De Smet M; Gansser D; Lang B; Moschetti V; Ramael S; Reilly P
    Title:
    A specific antidote for dabigatran: Immediate, complete and sustained reversal of dabigatran induced anticoagulation in healthy male voluteers
    Source:
    Am. Heart Association - Annual Meeting 2013
  • Author:
    Zubaid M; Saad H; Ridha M; Nair KKM; Rashed W; Alhamdan R; Alene F; Maghami M; Sadek A
    Title:
    Quality of anticoagulation with warfarin across Kuwait
    Source:
    Hell J Cardiol 54 (2), 102-106 (2013)
    Abstract:
    Introduction: Warfarin is widely used in patients with non-valvular atrial fibrillation (AF) because it is effective in reducing thromboembolic complications. However, it has a narrow safe therapeutic window. We aimed to examine the frequency of maintaining this therapeutic window in daily practice. Methods: We enrolled consecutive patients with non-valvular AF presenting to five busy general hospitals in Kuwait for regular international normalised ratio (INR) testing. Patients were required to be on warfarin for more than 3 months and to have had at least 5 INR measurements. We recorded up to 20 INR measurements per patient. Time in therapeutic range (TTR) was assessed by the Rosendaal method and the percentage of INR measurements in the therapeutic range was recorded. Results: A total of 369 patients with non-valvular AF underwent 4392 INR measurements. (mean age 62.89 ± 11 years, 56% women, 78% had hypertension and 58% had diabetes). Mean duration of warfarin use was 13 ± 9.1 months. Of all INR measurements, 47% were in the therapeutic range of 2-3 and TTR by Rosendaal method was 52.6%. Conclusions: The quality of anticoagulation with warfarin in non-selected daily practice in Kuwait is poor. This could have serious implications for patients' outcomes.
  • Author:
    Tse H-F; Wang Y- J; Ahmed Ai-Abdullah M; Pizarro-Borromeo AB; Chiang C-E; Krittayaphong R; Singh B; Vora A; Wang C-X; Zubaid M; Clemens A; Lim P; Hu D
    Title:
    Stroke prevention in atrial fibrillation-An Asian stroke perspective
    Source:
    Heart Rhythm Article in press (2013)
    Abstract:
    Despite relatively lower prevalence of atrial fibrillation (AF) in Asians (~1%) than in Caucasians (~2%), Asia has a much higher overall disease burden because of its proportionally larger aged population. For example, on the basis of reported age-adjusted prevalence rates and projected population figures in China, there will be an estimated 5.2 million men and 3.1 million women with AF older than 60 years by year 2050. Stroke is a disabling complication of AF that is of increasing cause for concern in Asians patients. Implementing consensus expert recommendations for managing stroke risk in patients with AF can considerably reduce stroke rates. However, caution is necessary when aligning management of Asian patients with AF to that of their Caucasian counterparts. Current international guidelines and risk stratification tools for AF management are based on findings in predominantly Caucasian populations and may therefore have limited relevance, in certain respects, to Asian patients. Oral anticoagulants play an important role in preventing AF-related stroke. The vitamin K antagonist warfarin is recommended for reducing the risk of stroke and thromboembolism in high-risk patients with nonvalvular AF; however, warfarin interacts with many drugs and food ingredients, which may pose significant challenges in administration and monitoring among Asian patients. Further research is needed to inform specific guidance on the implications of different stroke and bleeding profiles in Asians vs Caucasians. Moreover, there is scope to improve physician perceptions and patient knowledge, as well as considering alternative new oral anticoagulants, for example, direct thrombin inhibitors or factor Xa inhibitors. © 2013 Heart Rhythm Society.
  • Author:
    González-Juanatey JR; Martínez-Rubio A; González-Rojas N
    Title:
    On the cost-effectiveness of dabigatran. Response [Sobre el coste-efectividad de dabigatrán. Respuesta]
    Source:
    Rev Esp Cardiol 66 (6), 513 (2013)
    Abstract:
    no Abstract available
  • Author:
    González-Juanatey JR; Lobos JM; Reverter JC; Becerra V
    Title:
    Self-management of vitamin k antagonists is more cost-effective than dabigatran for stroke prevention in non-valvular atrial fibrillation in Spain. Response [El autocontrol de la terapia con cumarínicos es más eficiente que dabigatrán para prevenir ictus en fibrilación auricular no valvular en España. Respuesta]
    Source:
    Rev Esp Cardiol 66 (6), 511 (2013)
    Abstract:
    no abstract available
  • Author:
    Khadzhynov D; Wagner F; Formella S; Wiegert E; Moschetti V; Slowinski T; Neumayer H-H; Liesenfeld K-H; Lehr T; Härtter S; Friedman J; Peters H; Clemens A
    Title:
    Effective elimination of dabigatran by haemodialysis: A phase I single-centre study in patients with end-stage renal disease
    Source:
    Thromb Haemost 109 (4), 596-605 Cited 1 time (2013)
    Abstract:
    Dabigatran, a specific, reversible direct thrombin inhibitor, is used to prevent ischaemic and haemorrhagic strokes in patients with atrial fibrillation. As with every anticoagulant, there is a need to rapidly reverse its effects in emergency situations. In an open-label, singlecentre phase I study with two fixed multiple dosing periods, we investigated the pharmacokinetics, pharmacodynamics and safety of dabigatran before, during and after 4 hour haemodialysis sessions with either 200 or 400 ml/min targeted blood flow in seven end-stage renal disease patients without atrial fibrillation. Dabigatran was administered over three days in a regimen designed to achieve peak plasma concentrations comparable to those observed in atrial fibrillation patients receiving 150 mg b.i.d. and to attain adequate distribution of dabigatran in the central and peripheral compartments. Plasma concentration- time profiles were similar in both periods on Day 3 (Cmax: 176 and 159 ng/ml). Four hours of haemodialysis removed 48.8% and 59.3% of total dabigatran from the central compartment with 200 and 400 ml/minute targeted blood flow, respectively. The anticoagulant activity of dabigatran was linearly related to its plasma levels. There was a minor redistribution of dabigatran (<16%) after the end of the haemodialysis session. In conclusion, a 4 hour haemodialysis session can rapidly eliminate a substantial amount of dabigatran from the central compartment with a concomitant marked reduction in its anticoagulant activity. There was a clinically negligible redistribution of dabigatran after haemodialysis. These results demonstrate that haemodialysis can be a suitable approach to eliminate dabigatran in emergency situations. © Schattauer 2013.
  • Author:
    Bergh M; Marais C A; Miller-Jansön H; Salie F; Stander M P
    Title:
    Economic appraisal of dabigatran as first-line therapy for stroke prevention in atrial fibrillation
    Source:
    S Afr Med J 103 (4), 241-245 (2013)
    Abstract:
    Background. Dabigatran is an oral anticoagulant direct thrombin inhibitor recently registered in South Africa (SA) to reduce the risk of stroke and systemic embolism in patients with atrial fibrillation (AF). Owing to the price disparity between warfarin (the current gold standard for treatment of patients with AF) and dabigatran, we conducted an economic appraisal of the use of dabigatran compared with warfarin from a payer perspective in the South African private healthcare setting. Objectives. To estimate the cost-effectiveness (CE) and budget impact of dabigatran compared with warfarin for the prevention of stroke in AF patients. Methods. A previously published Markov model was populated with SA cost and mortality data to estimate the CE and budget impact analysis of dabigatran over a lifetime horizon. The model population consisted of a cohort of patients of whom those aged younger than 80 years used dabigatran 150 mg twice daily and those older than 80 years 110 mg twice daily. Modelled outcomes included total cost, quality-adjusted life years (QALYs) and incremental CE ratio (ICER), with the effectiveness measured by QALYs gained. Results. Dabigatran compared with warfarin as first-line treatment was estimated to have an ICER of R93 290 and an average incremental cost per beneficiary per month of R0.39 over a 5-year period. Conservative assumptions were made regarding the number of international normalised ratio monitoring tests for patients on warfarin, and the ICER is estimated to decrease by as much as 15.7% under less stringent assumptions. A robust sensitivity analysis was also performed. Conclusion. Dabigatran as first-line treatment compared with warfarin for the use of stroke prevention in patients with AF is deemed cost-effective when used in accordance with its registered indication in the SA private sector.
  • Author:
    Bays H; Gao P; Völker B; Mattheus M; Ruilope L M; Zhu D
    Title:
    Efficacy of single-pill combination of telmisartan 80 mg and hydrochlorothiazide 25 mg in patients with cardiovascular disease risk factors: A prospective subgroup analysis of a randomized, double-blind, and controlled trial
    Source:
    Int J Hypertens art.no.749830 (2013)
    Abstract:
    Objective. Report of prespecified and post hoc subgroup analyses of a randomized, controlled trial comparing telmisartan 80 mg/hydrochlorothiazide 25 mg (T80/H25) combination therapy with T80 monotherapy, according to the presence of cardiovascular disease (CVD) risk factors. Methods. Hypertensive patients were randomized (2: 1) to receive T80/H25 or T80 for 6 weeks, following a 1-week, low-dose, and run-in period. Systolic blood pressure (SBP) and diastolic BP reductions and BP goal achievement were evaluated in patients with CVD risk factors: presence of diabetes mellitus (DM), renal impairment, increased body mass index (BMI), and 10-year estimated risk for coronary heart disease (CHD). Results. In total, 888 patients received treatment. Overall, T80/H25 therapy significantly reduced SBP more than T80 monotherapy, irrespective of patient subgroup. In patients with DM, renal impairment, high BMI, and high CHD risk, BP goal achievement rates (<140/90 mm Hg) at Week 7, among those treated with T80/H25, were 52.8%, 52.8%, 50.6%, and 38.5%, respectively. More patients with DM reached a guideline-based BP goal (<130/80 mm Hg) at 7 weeks with T80/H25 than with T80 monotherapy (16.7% versus 8.8%). Rates of treatment-related adverse events were low and comparable across patient subgroups. Conclusions. Antihypertensive treatment with T80/H25 single-pill combination is effective and generally well tolerated, irrespective of the presence of CVD risk factors. © 2013 Harold Bays et al.
  • Author:
    Brandes A; Overgaard M; Plauborg L; Dehlendorff C; Lyck F; Peulicke J; Poulsen S V; Husted S
    Title:
    Guideline Adherence of Antithrombotic Treatment Initiated by General Practitioners in Patients With Nonvalvular Atrial Fibrillation: A Danish Survey
    Source:
    Clin Cardiol Article in Press (2013)
    Abstract:
    Background: The aim of this prospective survey was to describe the demographics, stroke risk profile, and the guideline adherence of antithrombotic treatment in a Danish primary care population of patients with nonvalvular atrial fibrillation (AF). Hypothesis: We hypothesized that a significant proportion of patients with nonvalvular AF do not receive guideline-adherent antithrombotic treatment in primary care. Methods: We performed a cross-sectional survey of antithrombotic treatment using data of AF patients from general practices. Results: Sixty-four general practitioners enrolled 1743 patients with a mean age of 74.8±11.2 years. The mean CHADS2 and CHA2DS2-VASc scores were 1.9±1.3 and 3.5±1.8, respectively. Of the patients, 12.4% and 4.04%, respectively, were at truly low risk, with a CHADS2 and CHA2DS2-VASc score 0 (P &lt; 0.001). A score of 1 was seen in 28.0% vs 9.0% (P &lt; 0.001) of the patients. Of all patients, 66.3% were treated with oral anticoagulants, 18.7% with antiplatelet drugs only, and 15% received no antithrombotic therapy. Based on the CHADS2 score, 75.7% of the patients were treated in adherence with the guidelines, 16% were undertreated, and 8.4% overtreated. The corresponding numbers for the CHA2DS2-VASc score were 75.4%, 22.7%, and 1.8%, respectively. The differences in guideline adherence applying the 2 scores were significant (P &lt; 0.001). Of patients receiving no antithrombotic therapy, 64.1% were treated in adherence to the guidelines according to the CHADS2 score. Applying the CHA2DS2-VASc score, this proportion was only 53.4%. Antiplatelet drug treatment was in adherence to the guidelines (CHADS2 and CHA2DS2-VASc score of 1) in only 31% and 12% of the patients, respectively. Conclusions: Antithrombotic treatment of AF patients is in general well performed in primary care in Denmark. Further improvements may be achieved by thorough stroke risk stratification on the basis of current evidence-based guidelines. © 2013 Wiley Periodicals, Inc.
  • Author:
    Summerfield N J; Boswood A; O'Grady M R; Gordon S G; Dukes-Mc-Ewan J; Oyama M A; Smith S; Patteson M; French A T; Culshaw G J; Braz-Ruivo L; Estrada A; O'Sullivan M L; Loureiro J; Willis R; Watson P
    Title:
    Efficacy of pimobendan in the prevention of congestive heart failure or sudden death in Doberman Pinschers with preclinical dilated cardiomyopathy (The PROTECT Study) [Wirksamkeit von Pimobendan bei der Prävention von kongestiver Herzinsuffizienz oder plötzlichem Herztod bei Dobermann Pinschern mit präklinischer dilatativer Kardiomyopathie (Die PROTECT-Studie)]
    Source:
    Kleintierpraxis 58 (4), 169-186 (2013)
    Abstract:
    The benefit of pimobendan in delaying the progression of preclinical dilated cardiomyopathy (DCM) in Dobermans is not reported. The hypothesis is that chronic oral administration of pimobendan to Dobermans with preclinical DCM will delay the onset of CHF or sudden death and improve survival. Seventy-six client-owned Dobermans recruited at 10 centers in the UK and North America. The trial was a randomized, blinded, placebo-controlled, parallel group multicenter study. Dogs were allocated in a 1:1 ratio to receive pimobendan (Vetmedin * capsules) or visually identical placebo. The composite primary endpoint was prospectively defined as either onset of CHF or sudden death. Time to death from all causes was a secondary endpoint. The proportion of dogs reaching the primary endpoint was not significantly different between groups (P = 0.1). The median time to the primary endpoint (onset of CHF or sudden death) was significantly longer in the pimobendan (718 days, IQR 441-1152 days) versus the placebo group (441 days, IQR 151-641 days) (log-rank P = 0.0088). The median survival time was significantly longer in the pimobendan (623 days, IQR 491-1531 days) versus the placebo group (466 days, IQR 236-710 days) (log-rank P = 0.034). The administration of pimobendan to Dobermans with preclinical DCM prolongs the time to the onset of clinical signs and extends survival. Treatment of dogs in the preclinical phase of this common cardiovascular disorder with pimobendan can lead to improved outcome.
  • 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:
    Monz B U; Connolly S J; Korhonen M; Noack H; Pooley J
    Title:
    Assessing the impact of dabigatran and warfarin on health-related quality of life: Results from an RE-LY sub-study
    Source:
    Int J Cardiol Article in press (2013)
    Abstract:
    Background: Anticoagulation is recommended in patients with atrial fibrillation (AF) to prevent strokes. Vitamin K antagonists, such as warfarin, are associated with numerous practical limitations - frequent anticoagulation monitoring, lifestyle and dietary restrictions - that complicate patient management and may impact health-related quality of life (HRQoL). This study derived HRQoL estimates for AF patients receiving warfarin or dabigatran etexilate (dabigatran), a new oral anticoagulant not requiring anticoagulation monitoring, during one year of stable treatment, i.e. in the absence of outcome events, such as strokes or major bleedings. Methods: Changes in HRQoL over time and between treatments were assessed using the EQ-5D (utility and Visual Analogue Scale (VAS) scores) at baseline, 3 and 12 months in a sub-group of 1435 patients participating in the RE-LY trial. RE-LY was a phase III study that compared the safety and efficacy of warfarin, dabigatran 150 mg bid and dabigatran 110 mg bid for stroke prevention in patients with AF. Results: Utilities ranged from 0.805 (dabigatran 150 mg bid) to 0.811 (dabigatran 110 mg bid) at baseline, and did not change over the one year observation period. No differences between the dabigatran groups and warfarin were statistically significant except for the dabigatran 150 mg bid group at 3 months. Similarly, none of the within-group or between-group differences in VAS scores were statistically significant. Conclusions: Over the course of one year, all anticoagulated patients without outcome events (e.g. strokes or major bleedings) had stable HRQoL. Scores between dabigatran and warfarin were comparable, which was unexpected given the known complexities of warfarin treatment. © 2013.
  • Author:
    Kourlaba G; Fragoulakis V; Theodoratou D; Maniadakis, N
    Title:
    Economic evaluation of telmisartan, valsartan and losartan in combination with hydrochlorothiazide for treatment of mild-to-moderate hypertension in Greece: A cost-utility analysis
    Source:
    J Pharm Health Serv Res 4 (2), 81-88 (2013)
    Abstract:
    Objectives: To evaluate the cost-utility of combined therapy of telmisartan with hydrochlorothiazide (HCTZ) compared to commonly used alternatives, losartan/HCTZ and valsartan/HCTZ, in patients with mild-to-moderate hypertension in Greece. Methods: A Markov model was constructed from the third-party-payer perspective. The cycle length of the model was one year. Risk equations derived from the HellenicSCORE and Framingham Heart Study were used to estimate transition probabilities between states. Treatment effectiveness and utility values were obtained from published clinical trials and studies. Costs assigned to each health state were obtained from real data and reflected the years 2012. Key findings: The model predicted that discounted quality-adjusted life-years (QALYs) were higher in the telmisartan/HCTZ group compared to losartan/HCTZ group by 0.09 and 0.03 in men and women, respectively. Moreover, telmisartan/HCTZ was found to be related to higher total lifetime costs per patient than losartan/HCTZ by €98 and €276 in men and women, respectively. Similarly, the comparison between telmisartan/HCTZ and valsartan/HCTZ revealed that the former is more effective (QALYs, gained 0.12 and 0.04, in men and women, respectively) and more costly by €536 and €780 in men and women, respectively. Based upon a willingness-to-pay threshold of €30000 per QALY gained, telmisartan/HCTZ was found to be cost-effective as the incremental cost-effectiveness ratios were estimated at €3002 and €4806 per QALY gained in men and €10856 and €25837 in women. Conclusion: The analysis revealed that telmisartan/HCTZ may be a cost effective alternative to generic losartan/HCTZ and valsartan/HTCZ for treatment of mild-to-moderate hypertension in the Greek setting. © 2013 Royal Pharmaceutical Society.
  • Author:
    Walsh, EP; Bar-Cohen, Y; Batra, A S; Dick II; Erickson C; Fish F; Hamilton R M; Kanter R J; Reed J H; Van Hare G F; Vetter V L; Webster G
    Title:
    Recommendations for advanced fellowship training in clinical pediatric and congenital electrophysiology: A report from the training and credentialing committee of the pediatric and congenital electrophysiology society
    Source:
    Heart Rhythm 10 (5), 775-781 (2013)
    Abstract:
    no abstract available
  • Author:
    Frank B; Grotta J C; Alexandrov A V; Bluhmki E; Lyden P; Meretoja A; Mishra N K; Shuaib A; Wahlgren N G; Weimar C; Lees K R
    Title:
    Thrombolysis in stroke despite contraindications or warnings?
    Source:
    Stroke 44 (3), 727-733 (2013)
    Abstract:
    Background and Purpose-Intravenous thrombolysis with alteplase is approved for acute ischemic stroke, but its use is limited by numerous contraindications and warnings arising from trial selection criteria or expert opinions. We examined outcomes from alteplase-treated versus untreated patients, registered in a trials archive, according to presence or absence of specified contraindications and warnings. Methods-We analyzed 90-day modified Rankin Scale across the whole distribution of scores using the Cochran-Mantel- Haenszel test, with adjustment for age and baseline National Institutes of Health Stroke Score, followed by proportional odds logistic regression analysis to estimate the odds ratios for preferred outcome. Results-We used data from 9613 ischemic stroke patients of whom 2755 were treated with thrombolysis. Adjusted odds ratios showed a broad trend of more favorable 3-month outcome associated with alteplase treatment versus no treatment in various subgroups of patients with contraindications and warnings; for example, 1.40 (95% confidence interval [CI], 1.14-1.70) in patients aged >80 (n=1805), 1.50 (95% CI, 1.03-2.18) in patients with combined history of prior stroke and diabetes mellitus (n=672), 1.42 (95% CI, 1.19-1.70) in patients on prior single antiplatelet agent (n=1626), 2.20 (95% CI, 1.12-4.32) in patients on oral anticoagulation, and International Normalized Ratio?1.7 (n=157), 1.50 (95% CI, 1.15-1.97) in patients with baseline glucose >180 (n=879), and 1.57 (95% CI, 1.12-2.18) in patients with pretreatment National Institutes of Health Stroke Score >22 (n=620). Conclusions-This comprehensive retrospective analysis of various contraindications and warnings provides reassurance about benefits and risks of intravenous alteplase treatment in common clinical situations. © 2013 American Heart Association, Inc.
  • Author:
    Gonzales-Juanatey J R; Martinez-Rubio A; Gonzalez-Rojas N
    Title:
    On the Cost-effectiveness of Dabigatran. Response [Sobre el coste-efectividad de dabigatrán. Respuesta]
    Source:
    Rev Esp Cardiol article in press (2013)
    Abstract:
    no abstract available
  • Author:
    Madrigano J; Mittleman M A; Baccarelli A; Goldberg R; Melly S; Von Klot S; Schwarzt J
    Title:
    Temperature, myocardial infarction, and mortality: Effect modification by individual-and area-level characteristics
    Source:
    Epidemiology 24 (3), 439-446 (2013)
    Abstract:
    BACKGROUND: Although several studies have examined associations between temperature and cardiovascular-disease-related mortality, fewer have investigated the association between temperature and the development of acute myocardial infarction (MI). Moreover, little is known about who is most susceptible to the effects of temperature. METHODS: We analyzed data from the Worcester Heart Attack Study, a community-wide investigation of acute MI in residents of the Worcester (MA) metropolitan area. We used a case-crossover approach to examine the association of apparent temperature with acute MI occurrence and with all-cause in-hospital and postdischarge mortality. We examined effect modification by sociodemographic characteristics, medical history, clinical complications, and physical environment. RESULTS: A decrease in an interquartile range in apparent temperature was associated with an increased risk of acute MI on the same day (hazard ratio = 1.15 [95% confidence interval = 1.01-1.31]). Extreme cold during the 2 days prior was associated with an increased risk of acute MI (1.36 [1.07-1.74]). Extreme heat during the 2 days prior was also associated with an increased risk of mortality (1.44 [1.06-1.96]). Persons living in areas with greater poverty were more susceptible to heat. CONCLUSIONS: Exposure to cold increased the risk of acute MI, and exposure to heat increased the risk of dying after an acute MI. Local area vulnerability should be accounted for as cities prepare to adapt to weather fluctuations as a result of climate change. Copyright © 2013 by Lippincott Williams &Wilkins.
  • Author:
    Kjeldsen S E; Schumacher H; Neldam S; Guthrie R M
    Title:
    Telmisartan/Hydrochlorothiazide Combination Therapy for the Treatment of Hypertension: A Pooled Analysis in Older and Younger Patients
    Source:
    J Clin Hypertens Article in Press (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:
    Rosenstock J; Marx N; Johansen O E; Wörle H J
    Title:
    Cardiovascular effects of diabetes drugs: Making the dark ages brighter with CAROLINA
    Source:
    Ann Intern Med 158 (6), 499 (2013)
    Abstract:
    no abstract available
  • Author:
    Taylor S J; Soleymanzadeh F; Muegge I; Akiba I; Taki N; Ueda S; Mainolfi E; Eldrup A B
    Title:
    Deconstruction of sulfonamide inhibitors of the urotensin receptor (UT) and design and synthesis of benzylamine and benzylsulfone antagonists
    Source:
    Bioorg Med Chem Lett 23 (7), 2177-2180 (2013)
    Abstract:
    Potent small molecule antagonists of the urotensin receptor are described. These inhibitors were derived via systematically deconstructing a literature inhibitor to understand the basic pharmacophore and key molecular features required to inhibit the protein receptor. The series of benzylamine and benzylsulfone antagonists herein reported display a combination of nanomolar molecular and cellular potency as well as acceptable in vitro permeability and metabolic stability. © 2013 Elsevier Ltd. All rights reserved.
  • Author:
    Mercaldi C J; Siu K; Sander S D; Walker D R; Wu Y; Li Q; Wu N
    Title:
    Long-term costs of ischemic stroke and major bleeding events among medicare patients with nonvalvular atrial fibrillation
    Source:
    Cardiol Res Pract 1 (1) art.no. 645469 (2012)
    Abstract:
    Purpose. Acute healthcare utilization of stroke and bleeding has been previously examined among patients with nonvalvular atrial fibrillation (NVAF). The long-term cost of such outcomes over several years is not well understood. Methods. Using 1999-2009 Medicare medical and enrollment data, we identified incident NVAF patients without history of stroke or bleeding. Patients were followed from the first occurrence of ischemic stroke, major bleeding, or intracranial hemorrhage (ICH) resulting in hospitalization. Those with events were matched with 1-5 NVAF patients without events. Total incremental costs of events were calculated as the difference between costs for patients with events and matched controls for up to 3 years. Results. Among the 25,465 patients who experienced events, 94.5% were successfully matched. In the first year after event, average incremental costs were $32,900 for ischemic stroke, $23,414 for major bleeding, and $47,640 for ICH. At 3 years after these events, costs remained elevated by $3,156-$5,400 per annum. Conclusion. While the costs of stroke and bleeding among patients with NVAF are most dramatic in the first year, utilization remained elevated at 3 years. Cost consequences extend beyond the initial year after these events and should be accounted for when assessing the cost-effectiveness of treatment regimens for stroke prevention. © 2012 Catherine J. Mercaldi et al.
  • Author:
    Esperester A; Schütt T; Ottillinger B
    Title:
    [Drugs in chronic venous insufficiency--the challenge of demonstrating clinical efficacy]. [Der Nachweis der klinischen Wirksamkeit von Odemprotektiva und seine Tücken.]
    Source:
    Med Monatsschr Pharm 36 (2), 44-51 (2013)
    Abstract:
    Approximately 90% of German adults show alterations of their lower limb veins; about every fifth suffers from symptoms of chronic venous insufficiency (CVI). With compression therapy showing low compliance, CVI oedemas and accompanying subjective symptoms are frequently treated with anti-oedematous drugs of herbal origin. A guideline outlines the requirements for clinical studies with CVI drugs. Water displacement plethysmometry (volumetry) is the gold standard for determining the reduction ofoedemas. Besides reducing oedemas, drugs should also demonstrate effects on accompanying symptoms influencing quality of life. Despite assistance provided by the guideline, clinical studies in CVI are complex and subject to multiple error sources in planning and execution. The corroboration of successful studies in further confirmatory studies is good practice and demanded by regulatory authorities. This practice reduces the risk of drugs being accepted as effective just based on the play of chance. As an example, placebo controlled studies with an extract from red vine leaves show that a careful definition of patients as well as meticulous study planning and execution can reproducibly verify significant and clinically relevant treatment effects. When evaluating clinical studies it is recommended to refer to the CONSORT statement. Publications missing certain minimum information make interpretation difficult and may result in a biased judgment of the effects of therapy.
  • Author:
    Ebner T; Schänzle G; Weber W; Sent U; Elliot J
    Title:
    In vitro glucuronidation of the angiotensin II receptor antagonist telmisartan in the cat: A comparison with other species
    Source:
    J Vet Pharmacol Ther 36 (2), 154-160 (2013)
    Abstract:
    Glucuronidation of telmisartan comprises nearly its entire metabolic clearance in several mammalian species including human. However, data were lacking for the cat, a species noted for its inability to glucuronidate some drugs. Therefore, the glucuronidation of telmisartan was investigated using feline liver microsomes and compared to liver microsomes of rats, dogs, and human, intestinal human microsomes and cell lines expressing human UDP-glucuronosyltransferases (UGT). Incubation of telmisartan with cat liver microsomes readily yielded telmisartan glucuronide, and pooled (N=3 for each gender) cat liver microsomes even showed the highest glucuronidation rate (cat&gt;dog&gt;&gt;human&gt;rat). Michaelis Menten kinetics were observed with Km of 7.5 and 10?m and Vmax of 3.9 and 3.3nmol/min/mg for male and female cats, respectively. Confirming the in vitro data, telmisartan glucuronide was detected as the major circulating metabolite in cat plasma. To elucidate which UGT enzymes are involved, telmisartan was incubated with cell lines expressing human UGTs. The highest glucuronidation activity was observed for UGT1A8, UGT1A7, and UGT1A9. In conclusion, telmisartan was effectively glucuronidated in cats. Defects of the UGT1A6 gene in cats do not affect the glucuronidation of telmisartan as it is not a substrate of human UGT1A6. © 2012 Blackwell Publishing Ltd.
  • Author:
    Doods H; Wu D
    Title:
    Sabiporide reduces ischemia-induced arrhythmias and myocardial infarction and attenuates ERK Phosphorylation and iNOS induction in rats
    Source:
    BioMed Res Int art.no.504320 (2013)
    Abstract:
    The aim of the present study was to investigate the effects of sabiporide, a potent and selective NHE1 inhibitor, on myocardial ischemia-induced arrhythmias and myocardial infarction and the possible pathways related to the cardioprotection afforded by sabiporide treatment. Anesthetized rats were subjected to myocardial ischemia via left main coronary artery occlusion for 30 minutes, followed by 2 hours of reperfusion. Administration of sabiporide (0.01-3.0 mg/kg) prior to coronary artery occlusion dose-dependently reduced ischemia-induced arrhythmias and infarct size with an ED50 value of 0.14 mg/kg. Administration of sabiporide (1.0 mg/kg) prior to reperfusion also reduced infarct size by 38.6%. The reduction in infarct size was accompanied by a decrease in circulating levels of creatine phosphokinase and troponin I. In addition, sabiporide (1.0 mg/kg) given prior to coronary artery occlusion or immediately before reperfusion significantly reduced phosphorylation of the extracellular signal-regulated kinase (ERK1/2) and the expression of the inducible nitric oxide synthase (iNOS) following myocardial ischemia- reperfusion. This study demonstrates that sabiporide is a potent and effective cardioprotective agent during myocardial ischemia and reperfusion, by reducing serious ventricular arrhythmias and myocardial infarct size. The cardioprotection afforded by sabiporide is attributed in part to inhibition of ERK1/2 phosphorylation and suppression of iNOS expression. © 2013 Henri Doods and Dongmei Wu.
  • Author:
    Bytzer P; Connolly S J; Yang S; Ezekowitz M; Fromella S; Reilly P A; Aisenberg J
    Title:
    Analysis of upper gastrointestinal adverse events among patients given dabigatran in the RE-LY trial
    Source:
    Gastroenterol Hepatol 11 (3), 246-252 e5 (2013)
    Abstract:
    Background & Aims: Dabigatran is an oral and direct inhibitor of thrombin. In a study of patients with atrial fibrillation (the RE-LY trial), twice as many subjects given dabigatran reported dyspepsia-like symptoms compared with those given warfarin (controls). We analyzed data from this trial to quantify upper gastrointestinal nonbleeding adverse events (NB-UGI AEs). Methods: We analyzed the AE database from the RE-LY trial (18,113 subjects) and assigned NB-UGI AEs to 4 groups: those associated with gastroesophageal reflux (GERD), upper abdominal pain and dyspepsia, dysmotility, or gastroduodenal injury. We analyzed frequency, timing, and severity, and clinical variables associated with NB-UGI AEs. Results: NB-UGI AEs occurred in 16.9% of subjects given dabigatran and in 9.4% of controls (relative risk [RR], 1.81; 95% confidence interval [CI], 1.66%-1.97%; P < .001). Rates of AEs were not associated with the dose of dabigatran. Among subjects with any UGI symptom who were given dabigatran (n = 2045), symptoms were rated as mild in 46.3%, moderate in 44.8%, and severe in 8.9%; these values were similar to those of controls. GERD-associated NB-UGI AEs were most frequent among the 4 groups (compared with controls, RR, 3.71; 95% CI, 2.98%-4.62%; P < .001). Four percent of subjects stopped taking dabigatran because of NB-UGI AEs (most within 3 months of starting therapy), compared with 1.7% of controls (RR, 2.34; 95% CI, 1.90%-2.88%; P < .001). NB-UGI AEs slightly increased risk of major GI bleeding among subjects given dabigatran and controls (6.8% vs 2.3%, P < .001). Conclusions: Among patients given dabigatran for atrial fibrillation, NB-UGI AEs are generally mild or moderate; 4% stopped taking the drug over a median of 21.7 months. The greatest increase was in GERD-type NB-UGI AEs. These observations should guide management and prevention strategies. © 2013 AGA Institute.
  • Author:
    Schulman S; Kearon C; Kakkar A K; Schellong S; Eriksson H; Baanstra D; Kvamme A M; Friedman J; Mismetti P; Goldhaber S Z
    Title:
    Extended Use of dabigatran, warfarin, or placebo in venous thromboembolism
    Source:
    N Engl J Med 368 (8), 709-718 (2013)
    Abstract:
    BACKGROUND: Dabigatran, which is administered in a fixed dose and does not require laboratory monitoring, may be suitable for extended treatment of venous thromboembolism. METHODS: In two double-blind, randomized trials, we compared dabigatran at a dose of 150 mg twice daily with warfarin (active-control study) or with placebo (placebo-control study) in patients with venous thromboembolism who had completed at least 3 initial months of therapy. RESULTS: In the active-control study, recurrent venous thromboembolism occurred in 26 of 1430 patients in the dabigatran group (1.8%) and 18 of 1426 patients in the warfarin group (1.3%) (hazard ratio with dabigatran, 1.44; 95% confidence interval [CI], 0.78 to 2.64; P=0.01 for noninferiority). Major bleeding occurred in 13 patients in the dabigatran group (0.9%) and 25 patients in the warfarin group (1.8%) (hazard ratio, 0.52; 95% CI, 0.27 to 1.02). Major or clinically relevant bleeding was less frequent with dabigatran (hazard ratio, 0.54; 95% CI, 0.41 to 0.71). Acute coronary syndromes occurred in 13 patients in the dabigatran group (0.9%) and 3 patients in the warfarin group (0.2%) (P=0.02). In the placebo-control study, recurrent venous thromboembolism occurred in 3 of 681 patients in the dabigatran group (0.4%) and 37 of 662 patients in the placebo group (5.6%) (hazard ratio, 0.08; 95% CI, 0.02 to 0.25; P<0.001). Major bleeding occurred in 2 patients in the dabigatran group (0.3%) and 0 patients in the placebo group. Major or clinically relevant bleeding occurred in 36 patients in the dabigatran group (5.3%) and 12 patients in the placebo group (1.8%) (hazard ratio, 2.92; 95% CI, 1.52 to 5.60). Acute coronary syndromes occurred in 1 patient each in the dabigatran and placebo groups. CONCLUSIONS: Dabigatran was effective in the extended treatment of venous thromboembolism and carried a lower risk of major or clinically relevant bleeding than warfarin but a higher risk than placebo. (Funded by Boehringer Ingelheim; RE-MEDY and RE-SONATE ClinicalTrials.gov numbers, NCT00329238 and NCT00558259, respectively.) Copyright © 2013 Massachusetts Medical Society.
  • Author:
    Gonzáles-Juanatey J R; Reverter J C; Bcerra V
    Title:
    Self-management of Vitamin K Antagonists Is More Cost-effective Than Dabigatran for Stroke Prevention in Non-valvular Atrial Fibrillation in Spain. Response [El autocontrol de la terapia con cumarínicos es más eficiente que dabigatrán para prevenir ictus en fibrilación auricular no valvular en España. Respuesta]
    Source:
    Rev Esp Cardiol Article in Press (2013)
    Abstract:
    no Abstract available
  • Author:
    Below A; Bickmann D; Breitkreutz J
    Title:
    Assessing the performance of two dry powder inhalers in preschool children using an idealized pediatric upper airway model
    Source:
    Int J Pharm 444 (1-2), 169-174 (2013)
    Abstract:
    High prevalence of pulmonary diseases in childhood requires inhalable medication even for young children. Little is known about the efficiency of aerosol therapy especially in preschool children. One factor which limits the lung dose is the upper airway geometry. Based on clinical data a recently developed idealized pediatric upper airway model (children 4-5 years) was used to investigate the performance of two dry powder inhalers (Easyhaler and Novolizer). In vitro investigations were first examined using steady flow rates and an inhalation volume of 1 L. Chosen flow rates were 28, 41 and 60 L/min (Easyhaler) and 45, 60 and 75 L/min (Novolizer). Afterwards inhalation profiles simulated by an electronic lung were included. The investigations showed high amounts of drug particles (up to 80%) which were deposited in the upper airway model. The pulmonary deposition in vitro using the Easyhaler was about 28% (28-60 L/min) and 22% (inhalation profile). Using the Novolizer in vitro pulmonary doses of 8-12% (45-75 L/min) and about 5% (inhalation profile) were observed. The idealized model shows good performance reproducibility of dry powder inhalers. We have shown that age-dependent models might be appropriate tools for formulation and device development in pediatric age groups. © 2013 Elsevier B.V. All rights reserved.
  • 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:
    Vranckx P; Verheugt F W A; De Maat M P; Ulmans V A W M; Regar E; Smits P; Ten Berg J M; Lindeboom W; Jones R L; Friedman J; Reilly P; Leebek F W G
    Title:
    A randomised study of dabigatran in elective percutaneous coronary intervention in stable coronary artery disease Patients
    Source:
    Eurointervention 8 (9), 1052-1060 (2013)
    Abstract:
    Aims: Patients receiving long-term anticoagulant treatment with dabigatran may need to undergo a percutaneous coronary intervention (PCI). We studied markers of coagulation activation during elective PCI in patients using dabigatran in order to investigate whether coagulation activation upon balloon inflation and stenting is suppressed by dabigatran without additional heparin treatment. Methods and results: This phase IIa, exploratory, multicentre, randomised, open-label study included 50 stable patients having an elective PCI. Patients on standard dual antiplatelet therapy (DAPT) were randomised (2:2:1) to either pre-procedural dabigatran 110 mg BID (n=19) or 150 mg BID (n=21), as compared to standard intraprocedural unfractionated heparin (UFH) (n=10). Following PCI, a significant increase in the levels of prothrombin fragment 1+2 (F1+2) in the combined dabigatran group was observed compared to the level just before the start of PCI (159.1 [1.4] pmol/l; geometric mean [gSD]). Levels at 0.5, 1.0, 1.5 and 2 hrs after the start of PCI ranged from 193.5 (1.4) to 270.6 pmol/l (1.7); (p-value for paired analysis=0.015, 0.022, 0.2342, 0.0379, respectively). Also, thrombin-antithrombin (TAT) complexes were increased significantly in the combined dabigatran group compared to pre-PCI levels (4.2 [2.2] ug/l). Levels ranged from 5.2 (2.5) to 8.5 (2.3) (p=0.0497, 0.0343, 0.005 and 0.1628, respectively). In contrast, in the control group of patients treated with UFH, no increase was observed in F1+2 and TAT complexes during PCI. Five out of 40 (12.5%) patients required bail-out anticoagulation in the dabigatran group, of whom four experienced a procedural myocardial infarction (MI), versus one out of 10 in the UFH group, who had a stent thrombosis without MI prior to the study-PCI. One minor access-site bleeding occurred in the dabigatran group. Conclusions: Dabigatran treatment (110 mg or 150 mg BID) may not provide sufficient anticoagulation during PCI. © Europa Digital & Publishing 2013. All rights reserved.
  • Author:
    Dans A L; Conolly S J; Wallentin L; Yang S; Nakamya J; Brueckmann M; Ezekowitz M; Oldgren J; Eikelboom J W; Reilly P A; Yusuf S
    Title:
    Concomitant use of antiplatelet therapy with dabigatran or warfarin in the randomized evaluation of long-term anticoagulation therapy (RE-LY) trial
    Source:
    Circulation 127 (5), 634-640 (2013)
    Abstract:
    BACKGROUND-: The Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial showed that dabigatran etexilate 150 mg BID was superior and dabigatran etexilate 110 mg BID was noninferior to warfarin in preventing stroke and systemic embolism in patients with atrial fibrillation. In this subgroup analysis, we assess the efficacy and safety of dabigatran in patients who did and did not receive concomitant antiplatelets. METHODS AND RESULTS-: All comparisons used a Cox proportional hazards model with adjustments made for risk factors for bleeding. A time-dependent analysis was performed when comparing patients with concomitant antiplatelets with those without. Of 18 113 patients, 6952 (38.4%) received concomitant aspirin or clopidogrel at some time during the study. Dabigatran etexilate 110 mg BID was noninferior to warfarin in reducing stroke and systemic embolism, whether patients received antiplatelets (hazard ratio [HR], 0.93; 95% confidence interval [95% CI], 0.70-1.25) or not (HR, 0.87; 95% CI, 0.66-1.15; interaction P=0.738). There were fewer major bleeds than warfarin in both subgroups (HR, 0.82; 95% CI, 0.67-1.00 for patients who used antiplatelets; HR, 0.79; 95% CI, 0.64-0.96 for patients who did not; interaction P=0.794). Dabigatran etexilate 150 mg BID reduced the primary outcome of stroke and systemic embolism in comparison with warfarin. This effect seemed attenuated among patients who used antiplatelets (HR, 0.80; 95% CI, 0.59-1.08) in comparison with those who did not (HR, 0.52; 95% CI, 0.38-0.72; P for interaction=0.058). Major bleeding was similar to warfarin regardless of antiplatelet use (HR, 0.93; 95% CI, 0.76-1.12 for patients who used antiplatelets; HR, 0.94; 95% CI, 0.78-1.15 for patients who did not; P for interaction=0.875). In the time-dependent analysis, concomitant use of a single antiplatelet seemed to increase the risk of major bleeding (HR, 1.60; 95% CI, 1.42-1.82). Dual antiplatelet seemed to increased this even more (HR, 2.31; 95% CI, 1.79-2.98). The absolute risks were lowest on dabigatran etexilate 110 mg BID in comparison with dabigatran etexilate 150 mg BID or warfarin. CONCLUSIONS-: Concomitant antiplatelet drugs appeared to increase the risk for major bleeding in RE-LY without affecting the advantages of dabigatran over warfarin. Choosing between dabigatran etexilate 110 mg BID and dabigatran etexilate 150 mg BID requires a careful assessment of characteristics that influence the balance between benefit and harm. CLINICAL TRIAL REGISTRATION-: URL: http://clinicaltrials.gov. Unique identifier: NCT00262600. © 2012 American Heart Association, Inc.
  • Author:
    Fryer R M
    Title:
    Mathematical Derivation of Therapeutic Index Based on hERG IC50 Taking Into Account Fraction Unbound in Plasma and Clinical Cmax
    Source:
    Drug Inf J 46 (5), 519-520 (2012)
    Abstract:
    no abstract available
  • Author:
    Wouters, H.; Thijs, V; Annemans, L.
    Title:
    Cost-effectiveness of dabigatran etexilate in the prevention of stroke and systemic embolism in patients with atrial fibrillation in Belgium
    Source:
    J. Med. Econ. 16 (3), 407-414 (2013)
    Abstract:
    Objective: To assess the cost-effectiveness of dabigatran etexilate ('dabigatran') vs vitamin K antagonists (VKAs) in the Belgian healthcare setting for the prevention of stroke and systemic embolism (SE) in patients with non-valvular atrial fibrillation (AF). Research design and methods: A Markov model was used to calculate the cost-effectiveness of dabigatran vs VKAs in Belgium, whereby warfarin was considered representative for the VKA class. Efficacy and safety data were taken from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial and a network meta-analysis. Local resource use and unit costs were included in the model. Effectiveness was expressed in Quality Adjusted Life-Years (QALYs). The model outcomes were total costs, total QALYs, incremental costs, incremental QALYs and the incremental cost-effectiveness ratio (ICER). The level of International Normalized Ratio (INR) control and the use of other antithrombotic therapies observed in Belgian clinical practice were reflected in two scenario analyses. Results: In the base case analysis, total costs per patient were €13,333 for dabigatran and €12,454 for warfarin. Total QALYs per patient were 9.51 for dabigatran and 9.19 for warfarin. The corresponding ICER was €2807/QALY. The ICER of dabigatran was €970/QALY vs warfarin with real-world INR control and €5296/QALY vs a mix of warfarin, aspirin, and no treatment. Results were shown to be robust in one-way and probabilistic sensitivity analyses. Limitations: The analysis does not include long-term costs for clinical events, as these data were not available for Belgium. As in any economic model based on data from a randomized clinical trial, several assumptions had to be made when extrapolating results to routine clinical practice in Belgium. Conclusion: This analysis suggests that dabigatran, a novel oral anticoagulant, is a cost-effective treatment for the prevention of stroke and SE in patients with non-valvular AF in the Belgian healthcare setting. © 2013 Informa UK Ltd All rights reserved.
  • Author:
    Scowcroft ACE; Lee S; Mant J
    Title:
    Thromboprophylaxis of elderly patients with AF in the UK: An analysis using the general practice research database (GPRD) 2000 - 2009.
    Source:
    Heart (Lond) 99 (2), 127-132 (2013)
  • Author:
    Fryer RM; Muthukumarana A; Harrison PC; Nodop Mazurek S; Chen RR; Harrington KE; Dinallo RM; Horan JC; Patnaude L; Modis LK; Reinhart GA
    Title:
    The clinically-tested S1P receptor agonist, FTY720 and BAF312, demonstrate subtype-specific bradycardia (S1P1) and hypertension (S1P3) in rat.
    Source:
    PLoS ONE 7 (12) art.no.e52985 (2012)
    Abstract:
    Sphingosine-1-phospate (S1P) and S1P receptor agonists elicit mechanism-based effects on cardiovascular function in vivo. Indeed, FTY720 (non-selective S1PX receptor agonist) produces modest hypertension in patients (2-3 mmHg in 1-yr trial) as well as acute bradycardia independent of changes in blood pressure. However, the precise receptor subtypes responsible is controversial, likely dependent upon the cardiovascular response in question (e.g. bradycardia, hypertension), and perhaps even species-dependent since functional differences in rodent, rabbit, and human have been suggested. Thus, we characterized the S1P receptor subtype specificity for each compound in vitro and, in vivo, the cardiovascular effects of FTY720 and the more selective S1P1,5 agonist, BAF312, were tested during acute i.v. infusion in anesthetized rats and after oral administration for 10 days in telemetry-instrumented conscious rats. Acute i.v. infusion of FTY720 (0.1, 0.3, 1.0 mg/kg/20 min) or BAF312 (0.5, 1.5, 5.0 mg/kg/20 min) elicited acute bradycardia in anesthetized rats demonstrating an S1P1 mediated mechanism-of-action. However, while FTY720 (0.5, 1.5, 5.0 mg/kg/d) elicited dose-dependent hypertension after multiple days of oral administration in rat at clinically relevant plasma concentrations (24-hr mean blood pressure = 8.4, 12.8, 16.2 mmHg above baseline vs. 3 mmHg in vehicle controls), BAF312 (0.3, 3.0, 30.0 mg/kg/d) had no significant effect on blood pressure at any dose tested suggesting that hypertension produced by FTY720 is mediated S1P3 receptors. In summary, in vitro selectivity results in combination with studies performed in anesthetized and conscious rats administered two clinically tested S1P agonists, FTY720 or BAF312, suggest that S1P1 receptors mediate bradycardia while hypertension is mediated by S1P3 receptor activation. © 2012 Fryer et al.
  • Author:
    Wu D; Lin X; Bernloehr C; Hildebrandt T; Doods H
    Title:
    Effects of a novel bradykinin B1 receptor Antagonist and Angiotensin II Receptor Blockade on Experimental Myocardial infarction in Rats
    Source:
    PLoS ONE 7 (12) art.no.e51151 (2012)
    Abstract:
    Background: The aim of the present study was to evaluate the cardiovascular effects of the novel bradykinin B1 receptor antagonist BI-113823 following myocardial infarction (MI) and to determine whether B1 receptor blockade alters the cardiovascular effects of an angiotensin II type 1 (AT1) receptor antagonist after MI in rats. Methodology/Principal Findings: Sprague Dawley rats were subjected to permanent occlusion of the left descending coronary artery. Cardiovascular function was determined at 7 days post MI. Treatment with either 131 receptor antagonist (BI-113823) or AT1 receptor antagonist (irbesartan) alone or in combination improved post-MI cardiac function as evidenced by attenuation of elevated left ventricular end diastolic pressure (LVEDP); greater first derivative of left ventricular pressure (± dp/dt max), left ventricle ejection fraction, fractional shorting, and better wall motion; as we as reductions in post-MI up-regulation of matrix metalloproteinases 2 (MMP-2) and collagen III. In addition, the cardiac upregulation of B1 receptor and AT1 receptor mRNA were markedly reduced in animals treated with BI 113823, although bradykinin B2 receptor and angiotensin 1 converting enzyme (ACE1) mRNA expression were not significantly affected by 131 receptor blockade. Conclusions/Significance: The present study demonstrates that treatment with the novel 131 receptor antagonist, BI 113823 improves post-MI cardiac function and does not influence the cardiovascular effects of AT1 receptor antagonist following MI. @ 2012 Wu et al.
  • Author:
    Ley L; Schumacher H
    Title:
    Telmisartan plus amlodipine single-pill combination for the management of hypertensive patients with a metabolic risk profile (added-risk patients)
  • Author:
    van Spall HGC; Wallentin L; Yusuf S; Eikelboom JW; Nieuwlaat R; Yang S; Kabali C; Reilly PA; Ezekowitz MD; Connoly SJ
    Title:
    Variation in warfarin dose adjustment practice is responsible for differences in the quality of anticoagulation control between centers and countries: An analysis of patients receiving warfarin in the randomized evaluation of long-term anticoagulation therapy (RE-LY) trial.
    Source:
    Circulation 126 (19), 2309-2316 (2012)
  • Author:
    Lizn L; Gimenez E; Gonzalez-rojas N; Angeles Fernandez M; Heineger AI; Paz S
    Title:
    Conjoint analysis in oral anticoagulant treatment. Replicia
  • Author:
    Boehm M; Cotton D; Foster L; Custodis F; Laufs U; Sacco R; Bath PMW; Yusuf S; Diener H-C
    Title:
    Impact of resting heart rat on mortality, disability and cognitive decline in patients after ischaemic stroke.
    Source:
    Eur Heart J 33 (22), 2804-2812 (2012)
  • Author:
    Smoyer-Tomic K; Siu K; Walker DR; Johnson BH; Smith DM; Sander S; Amin A
    Title:
    Anticoagulant use, the prevalence of bridging, and relation to length of stay among hospitalized patients with non-vascular atrial fibrillation.
    Source:
    Am J Cardiovasc Drugs 12 (6), 403-413 (2012)
    Abstract:
    Objective: The objectives of this study were to describe inpatient anticoagulation and bridging in patients with non-valvular atrial fibrillation (NVAF) and to identify whether differences exist in length of stay (LOS) among bridged versus non-bridged NVAF patients. Design: Administrative claims data were used to select patients years with a primary or secondary discharge diagnosis of NVAF and inpatient warfarin use from 1 July 2004 to 30 September 2009. Patients with valvular or transient causes of NVAF or pregnancy were excluded. Inpatient bridging was defined as receipt of an anticoagulant in addition to warfarin during the hospitalization. LOS was reported for nonbridged patients (warfarin only) and compared with three bridging regimens: low molecular weight heparin/pentasaccharide (LMWH/PS); unfractionated heparin (UFH); and two-agent bridging (LMWH/PS and UFH). Multivariate analyses were performed to evaluate the association between bridging and LOS, adjusting for demographic and clinical variables. Results: Of 6340 NVAF patients, 48% received inpatient warfarin (mean LOS 5.5 days); among them, 64% received bridging therapy (mean LOS 6.3 days) [LMWH/PS 45% (mean LOS 5.6 days), UFH 36% (mean LOS 6.0 days), two-agent bridging 18% (mean LOS 8.4 days)]. Following multivariate analysis, relative to patients who received inpatient warfarin only, LOS was significantly higher for patients withUFH(19.3%) and patients with two-agent bridging (45.1%). Patients with pre-period warfarin, cancer, or diabetes mellitus who received bridging agents had significantly longer LOSthan patients with those conditions who were not bridged. Conclusion: LOS was longer for bridged than non-bridged patients. Further studies are needed to identify predictors of bridging and to explain why bridged NVAF patients had longer LOS. Adis © 2012 Springer International Publishing AG. All rights reserved
  • Author:
    Burton TM; Lacey M; Liu F; Yu Y; Monsalvo ML; Lang K; Sander S
    Title:
    One-year follow-up healthcare costs of patient hospitalized for transient ischemic attack or ischemic stroke and discharged with aspirin plus extended-release dipyridamole or clopidogrel.
    Source:
    J Med Econ 15 (6), 1217-1225 (2012)
  • Author:
    Dahl OE; Kurth AA; Rosencher N; Noack H; Clemens A; Eriksson BI
    Title:
    Erratum to: Thromboprophylaxis in patients older than 75 years or with moderate renal impairment undergoing knee or hip relacement surgery. (International Orthopaedics (DOI: 10.1007/s00264-011-1393-5).
    Source:
    Int Orthop 36 (5), 1113 (2012)
  • Author:
    Zhu DL; Bays H; Gao P; Mattheus M; Voelker B; Ruilope LM
    Title:
    Efficacy and tolerability of initial therapy with single-pill combination telmisartan/hydrochlorothiazide 80/25 mg in patients with grade 2 or 3 hypertension: A multinational, randomized, double-blind, active-controlled trial.
    Source:
    Clin Ther 34 (7), 1613-1624 (2012)
    Abstract:
    Background: Patients with grade 2 or 3 hypertension may require high-dose combination therapy to achieve blood pressure (BP) targets in a timely manner. Objectives: This study compared the effectiveness and tolerability of a single-pill combination (SPC) of telmisartan/hydrochlorothiazide 80/25 mg (T80/H25) with T80 monotherapy. Methods: In a Phase IV, multinational, randomized, double-blind, double-dummy, active-controlled, parallel-group trial, 894 patients with mean seated trough cuff systolic BP [SBP] =160 mm Hg and diastolic BP [DBP] =100 mm Hg were randomly assigned in a 2:1 ratio to receive T40/H12.5 SPC or telmisartan 40 mg monotherapy for 1 week before the dose was uptitrated to T80/H25 SPC or T80, respectively, administered for 6 weeks. The primary efficacy measure was the change from baseline in mean seated cuff trough SBP. Adverse events (AEs) were recorded. Results: A total of 888 patients received treatment (294 and 594 patients in the T80/H25 and T80 groups, respectively) (mean age, 57.0 years; age =65 years, 25.7%; male, 53.8%; white, 68.0%); 61 patients prematurely discontinued. Mean baseline SBP/DBP values were 172.3/104.3 mm Hg (T80/H25) and 173.3/104.5 mm Hg (T80). After 7 weeks, SBP was changed by -37.0 and -28.5 mm Hg in the T80/H25 and T80 groups (P < 0.0001); DBP was changed by -18.6 and -15.4 mm Hg respectively (P < 0.0001). These differences were significant after 2 weeks at the higher dosage (P < 0.0001). BP target (SBP/DBP <140/<90 mm Hg) was achieved in 55.5% and 34.7% of patients in the T80/H25 and T80 groups (P < 0.0001). T80/H25 SPC and T80 had a similar frequency of overall AEs (16.0% vs 17.0%). The prevalences of treatment-related AEs with T80/H25 SPC and T80 were low (4.6% and 2.8%), as were the rates of AEs that led to discontinuation (1.0% and 2.8%). Conclusions: In these patients with grade 2 or 3 hypertension, initial therapy with T80/H25 was associated with a significantly greater reduction in mean seated cuff trough SBP compared with T80 alone, as well as with improved hypertension goal attainment rates. Both treatments appeared to be well tolerated. ClinicalTrials.gov identifier: NCT00926289
  • Author:
    Healey JS; Eikelboom J; Douketis J; Wallentin L; Oldgren J; Yang S; Themeles E; Heidbuchle H; Avezum A; Reilly P; Connolly SJ; Yusuf S; Ezekowitz M
    Title:
    Periprocedural bleeding and thromboembolic events with dabigatran compared with warfarin: Results from the randomized evaluation of long-term anticoagulation therapy (RE-LY) randomized trial.
    Source:
    Circulation 126 (3), 343-348 (2012)
    Abstract:
    Background-Dabigatran reduces ischemic stroke in comparison with warfarin; however, given the lack of antidote, there is concern that it might increase bleeding when surgery or invasive procedures are required. Methods and Results-The current analysis was undertaken to compare the periprocedural bleeding risk of patients in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial treated with dabigatran and warfarin. Bleeding rates were evaluated from 7 days before until 30 days after invasive procedures, considering only the first procedure for each patient. A total of 4591 patients underwent at least 1 invasive procedure: 24.7% of patients received dabigatran 110 mg, 25.4% received dabigatran 150 mg, and 25.9% received warfarin, P=0.34. Procedures included: pacemaker/defibrillator insertion (10.3%), dental procedures (10.0%), diagnostic procedures (10.0%), cataract removal (9.3%), colonoscopy (8.6%), and joint replacement (6.2%). Among patients assigned to either dabigatran dose, the last dose of study drug was given 49 (35-85) hours before the procedure on comparison with 114 (87-144) hours in patients receiving warfarin, P<0.001. There was no significant difference in the rates of periprocedural major bleeding between patients receiving dabigatran 110 mg (3.8%) or dabigatran 150 mg (5.1%) or warfarin (4.6%); dabigatran 110 mg versus warfarin: relative risk, 0.83; 95% CI, 0.59 to 1.17; P=0.28; dabigatran 150 mg versus warfarin: relative risk, 1.09; 95% CI, 0.80 to 1.49; P=0.58. Among patients having urgent surgery, major bleeding occurred in 17.8% with dabigatran 110 mg, 17.7% with dabigatran 150 mg, and 21.6% with warfarin: dabigatran 110 mg; relative risk, 0.82; 95% CI, 0.48 to 1.41; P=0.47; dabigatran 150 mg: relative risk, 0.82; 95% CI, 0.50 to 1.35; P=0.44. Conclusions- Dabigatran and warfarin were associated with similar rates of periprocedural bleeding, including patients having urgent surgery. Dabigatran facilitated a shorter interruption of oral anticoagulation. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00262600
  • Author:
    Gonzalez-Rojas N; Gimenez E; Angeles Fernandez M; Heineger AI; Martinez JL; Lopez JV; Lizan L
    Title:
    Preferences for oral anticoagulant treatment in the medium and long term prevention of stroke in non valvular atrial fibrillation.
    Source:
    Rev Neurol (Barc) 55 (1), 11-19 (2012)
    Abstract:
    Introduction. About 40% of patients who receive oral anticoagulation would not start treatment with vitamin K antagonists due to the regular control they require and their interference with the diet and other concomitant medications. Aim. To analyze the preferences of patients with non valvular atrial fibrillation for oral anticoagulants (OAs) for the stroke prevention. Patients and methods. Observational, multicentric study on preferences and maximum willingness to pay based on conjoint analysis: literature review, focus groups and semi-structured interviews with physicians and patients (n = 295) to define the attributes of OAs and their levels. Definition of scenarios that patients ordered according to their preferences. Clusters analysis to identify population groups by their preferences. Results. Eight scenarios were defined based on five attributes: efficacy, security, a fixed dose, need for coagulation controls and interactions with diet and medication. The most preferred attribute was the smaller number of embolisms in a year (importance: 30.15%) followed by the fixed dose of the OA (25.45%) and the smaller number of intracranial hemorrhage in a year (21.57%). Three clusters population were identified. The maximum amount patients' were willingness to pay for the OA was 66.76 ± 54.64 euros (mean) per month. Conclusions. Efficacy and a fixed dose are the attributes of OA most valued by non valvular atrial fibrillation patients. There are groups of patients who differ in their preferences. This differences should be taken into account when deciding instauration or change on the OA treatment to ameliorate the accomplishment and prevention in this patients
  • Author:
    Song X; Sander SD; Varker H; Amin A
    Title:
    Patterns and predictors of use of warfarin and other common long-term medications in patients with atrial fibrillation.
    Source:
    Am J Cardiovasc Drugs 12 (4), 245-253 (2012)
    Abstract:
    Background and Objective: No study has been published that compared persistence and discontinuation of warfarin with other long-term medications in patients with atrial fibrillation (AF). The objective of this studywas to evaluate persistence and discontinuation patterns inAFpatients taking warfarin and other common long-term medications and identify predictors of persistence and discontinuation in this population. Methods: Patients with warfarin prescription within 3 months after AF hospitalization discharge and 12-month data before and after the first prescription were evaluated using administrative claims data (1 January 2005 - 31 December 2007). For comparison, persistence patterns for other long-term medications for treatment of hypertension, hyperglycemia, heart disease, and dyslipidemia, including once- (od) and twice- (bid) daily medications, were evaluated. Non-persistence was defined as the presence of a =60-day gap in medication use. Permanent discontinuation was defined as no use of the medication for =90 days until the end of the follow-up period. Multivariate analysis was conducted to identify predictors of warfarin nonpersistence and discontinuation. Results: 28 384 patients with AF were identified; 16 036 (56.5%) had a warfarin prescription following AF hospitalization. 53.5% of warfarin users were persistent for at least 1 year, similar to other long-term medications commonly prescribed to the AF population (ranging between 45.2% and 61.3%). 42.6% of warfarin users permanently discontinued warfarin within 1 year, also consistent with the discontinuation rate of 32.9-52.0% of other long-term medications. Residence in the South and West regions of the US, history of cardiac dysrhythmias, and warfarin cost-sharing significantly decreased the likelihood of warfarin persistence and increased the likelihood of discontinuation, while older age, history of ischemic stroke, and warfarin use before hospitalization significantly increased warfarin persistence and decreased the likelihood of discontinuation. Adherence of od and bid medications was similar. Conclusion: Persistence and discontinuation with warfarin in patients with AF is consistent with other longterm medications. Identifying factors associated with non-persistence and discontinuation with long-term medications can help in developing targeted adherence programs.
  • Author:
    Eriksson BI; Smith JJ; Caprini J; Hantel S; Clemens A; Feuring M; Schnee J; Barsness GW
    Title:
    Evaluation of the acute coronary syndrome safety profile of dabigatran etexilate in patients undergoing major orthopedic surgery: Findings from four phase 3 trials.
    Source:
    Thromb Res 130 (3), 396-402 (2012)
    Abstract:
    Introduction: Several anticoagulants have been associated with a 'rebound effect' that potentially increases the risk of thrombosis and cardiovascular events following discontinuation. Four Phase 3 trials of dabigatran etexilate in major orthopedic surgery incorporated measures to assess the risk of acute coronary syndrome (ACS) events during and after treatment. Materials and methods: Patients in RE-MOBILIZE®, RE-MODEL™, RE-NOVATE®, and RENOVATE® II were randomized to dabigatran etexilate (150 mg or 220 mg once daily) or enoxaparin for 6-35 days, and followed for up to 90 days. ACS data were tabulated from investigator-reported serious adverse events using ACS-specific Medical Dictionary for Regulatory Authorities (MedDRA) lower-level terms. To ensure that all ACS events were identified in the initial three studies, RE-MOBILIZE®, RE-MODEL™, and RE-NOVATE®, a broader list of MedDRA terms was prespecified that would trigger treatment-blinded adjudication. Results: When pooling the four trials, patients receiving dabigatran etexilate 220 mg had the fewest treatment-emergent, investigator-reported ACS events (6 [0.16%] vs 14 [0.51%] for dabigatran 150 mg and 13 [0.35%] for enoxaparin). Corresponding post-treatment rates were 2 (0.06%), 1 (0.04%), and 4 (0.11%). Similarly, treatment-emergent centrally adjudicated definite or likely ACS events in the first three trials were fewer in patients on dabigatran 220 mg (16 [0.60%]) than dabigatran 150 mg (26 [0.95%]) and enoxaparin (20 [0.74%]). The corresponding numbers post treatment were 2, 2, and 7. None of these between-group differences were statistically significant. Conclusion: No increased ACS signal was detected with dabigatran etexilate compared with enoxaparin during or after treatment
  • Author:
    Friedman RJ; Kurth AA; Clemens A; Noack H; Eriksson BI; Caprini JA
    Title:
    Dabigatran etexilate and concomitant use of non-steroidal anti-inflammatory drugs or acetylsalicylic acid in patients undergoing total hip and total knee arthroplasty: No increased risk of bleeding
    Source:
    Thromb Haemost 108 (1), 183-190 (2012)
    Abstract:
    Patients undergoing total hip or knee arthroplasty should receive anticoagulant therapy because of the high risk of venous thromboembolism. However, many are already taking non-steroidal anti-inflammatory drugs (NSAIDs) or acetylsalicylic acid (ASA) that can have antihaemostatic effects. We assessed the bleeding risk in patients treated with thromboprophylactic dabigatran etexilate, with and without concomitant NSAID or ASA. A post-hoc analysis was undertaken of the pooled data from trials comparing dabigatran etexilate (220 mg and 150 mg once daily) and enoxaparin. Major bleeding event (MBE) rates were determined and odds ratios (ORs) generated for patients who received study treatment plus NSAID (half-life =12 hours) or ASA (=160 mg/day) versus study treatment alone. Relative risks were calculated for comparisons between treatments. Overall, 4,405/8,135 patients (54.1%) received concomitant NSAID and 386/8,135 (4.7%) received ASA.Ors for the comparison with/without concomitant NSAID were 1.05 (95% confidence interval [CI] 0.55-2.01) for 220 mg dabigatran etexilate; 1.19 (0.55-2.55) for 150 mg; and 1.32 (0.67-2.57) for enoxaparin. Ors for the comparison with/without ASA were 1.14 (0.26-5.03); 1.64 (0.36-7.49); and 2.57 (0.83-7.94), respectively. For both NSAIDs and ASA there was no significant difference in bleeding between patients with and without concomitant therapy in any treatment arm. Patients concomitantly taking NSAIDs or ASA have a similar risk of MBE to those taking dabigatran etexilate alone. No significant differences in MBE were detected between dabigatran etexilate and enoxaparin within comedication subgroups, suggesting that no increased major bleeding risk exists when dabigatran etexilate is administered with NSAID or ASA. © Schattauer 2012.
  • Author:
    Gallagher AM; De Viries F; Plumb JM; Hass B; Clemens A; Van Staa T-P
    Title:
    Quality of INR control and outcomes following venous thromboembolism.
    Source:
    Clin Appl Thromb Hemost 18 (4), 370-378 (2012)
    Abstract:
    Introduction: The objective of this study was to evaluate the pattern of anticoagulation after venous thromboembolism (VTE) in actual clinical practice. Material and Methods: This study used the General Practice Research Database. Individuals aged 18+ years with VTE were matched to 3 controls. Results: Of the 46 335 patients with VTE and 138 024 controls, 70.2% of cases and 86.6% of controls had no obvious risk factors. The mortality risk was increased substantially around the time of diagnosis (relative hazard rate [RR] around 21) but remained elevated for a further 4 years (RRs around 1.5-2.0). The mean percentage of time spent within the therapeutic range for international normalized ratio (INR) was 57.0%. The lowest rate of VTE recurrence occurred in patients with =70% time spent within therapeutic range (RR of 0.50, 95% CI 0.39-0.63 compared to <30%). Conclusions: Higher time spent within therapeutic INR range was associated with lower risks of VTE recurrence and death due to VTE. © The Author(s) 2012. |
  • Author:
    Haertter S; Sennewald R; Schepers C; Baumann S; Fritsch H; Friedman J
    Title:
    Pharmacokinetic and pharmacodynamic effects of commedication of clopidogrel and dabigatgran etexilate in healthy male volunteers.
    Source:
    Eur J Clin Pharmacol, 1-13 (2012)
    Abstract:
    Purpose: To evaluate the pharmacokinetic and pharmacodynamic effects of concomitant administration of single loading doses of clopidogrel or multiple doses of clopidogrel with multiple doses of dabigatran etexilate. Methods: This was an open-label trial in healthy male subjects. In part 1 (pilot, n = 8) and part 3 (n = 12), a single dose of clopidogrel (300 or 600 mg, respectively) was given concomitantly with dabigatran etexilate at steady state; part 2 was a randomized, multiple-dose, crossover study with the test treatment being clopidogrel at steady state [300 mg loading dose on day 1, then 75 mg once daily (qd)] with concomitant dabigatran. Results: Bioavailability was moderately increased when a loading dose of clopidogrel (300 mg in part 1 and 600 mg in part 3) was administered concomitantly with dabigatran etexilate 150 mg twice daily (bid). Test/reference ratios for AUC t,ss were 135% (90% CI 107-169%) and 132% (90% CI 112-156%), respectively. Steady-state dosing of clopidogrel 75 mg qd and dabigatran etexilate 150 mg bid (part 2) demonstrated minor effects on dabigatran pharmacokinetics (AUC t,ss ratio test/reference: 91.9%, 90% CI 78.7-107%) or its pharmacokinetic/pharmacodynamic relationships (activated partial thromboplastin time, ecarin clotting time, thrombin time). Similarly, clopidogrel bioavailability remained unchanged by chronic administration of dabigatran etexilate (part 3: ratio test/reference for AUC 0-24 was 103%; 90% CI 80.3-131%), as did its pharmacodynamic effects on the inhibition of platelet aggregation. Conclusions: When given concomitantly, dabigatran etexilate and clopidogrel at clinically relevant doses did not appear to have significant effects on the pharmacokinetic and pharmacodynamic profiles of either agent.
  • Author:
    Huber J D; Bentzien J; Boyer S J; Burke J; De Lombaert S; Eickmeier C; Guo X; Haist J V; Hickey E R; Kaplita P; Karmazyn M; kemper R; Kennedy C A; Kirrane T; Madwed J B; Mainolfi E; Nagaraja N; Soleymanzadeh F; Swinamer A; Eldrup A B
    Title:
    Identification of a potent sodium hydrogen exchanger isoform 1 (NHE1) inhibitor with a suitable profile for chronic dosing and demonstrated cardioprotective effects in a preclinical model of myocardial infarction in the rat
    Source:
    J Med Chem 55 (16), 7114-7140 (2012)
    Abstract:
    Sodium-hydrogen exchanger isoform 1 (NHE1) is a ubiquitously expressed transmembrane ion channel responsible for intracellular pH regulation. During myocardial ischemia, low pH activates NHE1 and causes increased intracellular calcium levels and aberrant cellular processes, leading to myocardial stunning, arrhythmias, and ultimately cell damage and death. The role of NHE1 in cardiac injury has prompted interest in the development of NHE1 inhibitors for the treatment of heart failure. This report outlines our efforts to identify a compound suitable for once daily, oral administration with low drug-drug interaction potential starting from NHE1 inhibitor sabiporide. Substitution of a piperidine for the piperazine of sabiporide followed by replacement of the pyrrole moiety and subsequent optimization to improve potency and eliminate off-target activities resulted in the identification of N-[4-(1-acetyl- piperidin-4-yl)-3-trifluoromethyl-benzoyl]-guanidine (60). Pharmacological evaluation of 60 revealed a remarkable ability to prevent ischemic damage in an ex vivo model of ischemia reperfusion injury in isolated rat hearts. © 2012 American Chemical Society.
  • Author:
    Gonzáles-Juanatey J R; Álvarez-Sabin J; Lobos J M; Martinez-Rubio A; Reverter J C; Oyagüez I; González-Rojas N; Becerra V
    Title:
    Cost-effectiveness of dabigatran for stroke prevention in non-valvular atrial fibrillation in Spain
    Source:
    Rev Esp Cardiol 65 (10), 901-910 (2012)
    Abstract:
    Introduction and objectives: Assessment of the cost-effectiveness of dabigatran for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation in Spain, from the perspective of the National Health System. Methods: Adaptation of a Markov chain model that simulates the natural history of the disease over the lifetime of a cohort of 10 000 patients with non-valvular atrial fibrillation. Model comparators were warfarin in a first scenario, and a real world prescribing pattern in a second scenario, in which 60% of the patients were treated with vitamin K antagonists, 30% with acetylsalicylic acid, and 10% received no treatment. Deterministic and probabilistic sensitivity analyses were performed. Results: Dabigatran reduced the occurrence of clinical events in both scenarios, providing gains in quantity and quality of life. The incremental cost-effectiveness ratio for dabigatran compared to warfarin was 17 581 euros/quality-adjusted life year gained and 14 118 euros/quality-adjusted life year gained when compared to the real world prescribing pattern. Efficiency in subgroups was demonstrated. When the social costs were incorporated into the analysis, dabigatran was found to be a dominant strategy (ie, more effective and less costly). The model proved to be robust. Conclusions: From the perspective of the Spanish National Health System, dabigatran is an efficient strategy for the prevention of stroke in patients with non-valvular atrial fibrillation compared to warfarin and to the real-world prescribing pattern; incremental cost-effectiveness ratios were below the 30 000 euros/quality-adjusted life year threshold in both scenarios. Dabigatran would also be a dominant strategy from the societal perspective, providing society with a more effective therapy at a lower cost compared to the other 2 alternatives. Full English text available from: www.revespcardiol.org. ©2012 Sociedad Espanola de Cardiolog?a. Publicado por Elsevier Espana, S.L. Todos los derechos reservados.
  • Author:
    van de Werf F; Brueckmann M; Connolly SJ; Friedman J; Granger CB; Haertter S; Harper R; Kappetein AP; Lehr T; Mack MJ; Noack H; Eickelboom JW
    Title:
    A comparison of dabigatran etexilate with warfarin in patients with mechanical heart valves: The Randomized, phase II study to Evaluate the sAfety and pharmacokinetics of oraL dabIGatran etexilate in patients after heart valve replacemeNt (RE-ALIGN)
    Source:
    Am Heart J 163 (6), 931-937.e1 (2012)
    Abstract:
    Background: Vitamin K antagonists are the only oral anticoagulants approved for long-term treatment of patients with a cardiac valve replacement. Objective: This study aims to test a new dosing regimen for dabigatran etexilate in patients with a mechanical bileaflet valve. Methods: Patients aged =18 years and =75 years, either undergoing implantation of a mechanical bileaflet valve (aortic or mitral or both) during the current hospital stay or having undergone implantation a mitral bileaflet valve >3 months before randomization, will be randomized between dabigatran etexilate or warfarin (in a ratio of 2:1) in an open-label design. Initial doses of dabigatran will be based on the estimated creatinine clearance, and the doses will be adjusted based on measuring trough dabigatran plasma levels to achieve levels =50 ng/mL at steady state. Doses will range between 150 mg twice a day and 300 mg twice a day. Warfarin management and target international normalized ratio will be according to current practice guidelines at the discretion of the treating physicians. The plan is to treat 270 patients with dabigatran etexilate for a total study population of approximately 405 patients. Clinical efficacy and safety outcomes will be analyzed in an exploratory manner. Conclusions: RE-ALIGN is the first study to test an alternative to warfarin in patients with mechanical heart valves. A definitive phase III study will be planned based on the results of this study. © 2012 Mosby, Inc.
  • Author:
    Kroeller-Schoen S; Knorr M; Hausding M; Oelze M; Schuff A; Schell R; Sudowe S; Scholz A; Daub S; Karbach S; Kossmann S; Gori T; Wenzel P; Schulz E; Grabbe S; Klein T; Muenzel T; Daiber A
    Title:
    Glucose-independent improvement of vascular dysfunction in experimental sepsis by dipeptidyl-peptidase 4 inhibition
    Source:
    Cardiovasc Res 96 (1), 140-149 (2012)
    Abstract:
    Aims Dipeptidyl peptidase-4 (DPP-4) inhibitors are a novel class of drugs for the treatment of hyperglycaemia. Preliminary evidence suggests that their antioxidant and anti-inflammatory effects may have beneficial effects on the cardiovascular complications of diabetes. In the present study, we investigate in an experimental sepsis model whether linagliptin exerts pleiotropic vascular effects independent of its glucose-lowering properties.Methods and resultsLinagliptin (83 mg/kg chow for 7days) was administered in a rat model of lipopolysaccharide (LPS) (10 mg/kg, single i.p. dose/24 h)-induced sepsis. Vascular relaxation, reactive oxygen species (ROS) formation, expression of NADPH oxidase subunits and proinflammatory markers, and white blood cell infiltration in the vasculature were determined. Oxidative burst and adhesion of isolated human neutrophils to endothelial cells were measured in the presence of different DPP-4 inhibitors, and their direct vasodilatory effects (isometric tension in isolated aortic rings) were compared. In vivo linagliptin treatment ameliorated LPS-induced endothelial dysfunction and was associated with reduced formation of vascular, cardiac, and blood ROS, aortic expression of inflammatory genes and NADPH oxidase subunits in addition to reduced aortic infiltration with inflammatory cells. Linagliptin was the most potent inhibitor of oxidative burst in isolated activated human neutrophils and it suppressed their adhesion to activated endothelial cells. Of the inhibitors tested, linagliptin and alogliptin had the most pronounced direct vasodilatory potency. ConclusionLinagliptin demonstrated pleiotropic vasodilatory, antioxidant, and anti-inflammatory properties independent of its glucose-lowering properties. These pleiotropic properties are generally not shared by other DPP-4 inhibitors and might translate into cardiovascular benefits in diabetic patients. © 2012 The Author.
  • Author:
    Hughes R O; Bartolozzi A; Takahashi H
    Title:
    Inflammatory Targets for the Treatment of Atherosclerosis
    Source:
    Annu Rep Med Chem 47, 223-235 (2012)
    Abstract:
    Atherosclerosis is a complex disease of the aterial wall and is the primary cause of coronary artery disease, peripheral vascular disease, and stroke and, thus, a leading cause of death worldwide. Despite many clinically useful treatment options for managing atherosclerosis in at risk patients, there remains a high residual risk for major adverse cardiovascular events. Recently, an improved appreciation of the role of inflammation play in the pathogenesis of atherosclerosis has revealed many druggable targets suitable for small molecule intervention. Here in, we present select evidence, both clinical and preclinical, for small molecule druggable anti-inflammatory targets. While the optimization and clinical programs against these targets may not have been initially directed toward their potential to treat atherosclerosis, the availability of high-quality chemical matter against a variety of targets should allow for clinical proof-of-concept studies to be conducted and hypotheses tested. © 2012 Elsevier Inc.
  • Author:
    Van de Werf F; Connolly SJ; Kappetein AP; Brueckmann M; Mack MJ; Granger CB; Eikelboom J
    Title:
    Letter by Van de Werf et al regarding article, "using dabigatran in patients with stroke: A practical guide for clinicians"
    Source:
    Stroke 43 (5), e46-e47 (2012)
    Abstract:
    no abstract available
  • Author:
    Eriksson B I; Dahl O E; Rosencher N; Clemens A; Hantel S; Kurth A A
    Title:
    Efficacy of delayed thromboprophylaxis with dabigatran: Pooled analysis
    Source:
    Thromb Res 130 (6), 871-876 (2012)
    Abstract:
    Introduction: Oral thromboprophylaxis with dabigatran etexilate should be initiated as a half dose 1 to 4 h after major orthopaedic surgery. However, a delay in dosing could occur for clinical or logistical reasons. A post hoc analysis was carried out to determine if patients with delayed dosing received adequate anticoagulation. Patients and methods: The RE-MODEL™ and RE-NOVATE® trials compared 220 mg and 150 mg dabigatran etexilate with 40 mg enoxaparin. Pooled data for major venous thromboembolism (VTE) and VTE-related mortality (efficacy outcome) and major bleeding events (MBE), MBE/clinically relevant bleeding events, and all bleeding events (safety outcomes) were analysed. Results in patients with dosing delayed more than 4 h postsurgery were compared with those of patients without a delay. Results: Onset of treatment was delayed in 724 (13.3%) of 5425 patients. Efficacy of 220 mg dabigatran etexilate was similar in patients without delayed dosing, patients with a delay and patients with a delay until the day after surgery. Rates of efficacy outcome were higher in patients on 150 mg dabigatran etexilate, but more than 80% of these patients were undertreated based on age or renal clearance status. Some differences in bleeding events were seen among patient groups by treatment arm. Conclusion: Dabigatran etexilate thromboprophylaxis should be initiated 1 to 4 h postsurgery. Results from our post-hoc analysis indicate that no loss of efficacy appears to occur if initiation of dabigatran etexilate 220 mg needs to be delayed. © 2012 Elsevier Ltd. All rights reserved.
  • Author:
    Nar H
    Title:
    The role of structural information in the discovery of direct thrombin and factor Xa inhibitors.
    Source:
    Trends Pharmacol Sci 33 (5), 279-288 (2012)
    Abstract:
    The quest for novel medications to treat thromboembolic disorders such as venous thrombosis, pulmonary embolism and stroke received a boost when the 3D structures of two major players in the blood coagulation cascade were determined in 1989 and 1993. Structure-guided design of inhibitors of thrombin (factor IIa, fIIa) and factor Xa (fXa) eventually led to the discovery of potent, selective, efficacious, orally active and safe compounds that proved successful in clinical studies. In 2008, the direct thrombin inhibitor dabigatran etexilate developed by Boehringer Ingelheim became the first novel antithrombotic molecular entity to enter the market in 50 years. Additional compounds targeting factor Xa were subsequently granted marketing authorization or are in late-stage clinical studies. In this review, I use selected case studies to describe the discovery of novel fIIa and fXa inhibitors, with a particular emphasis on the pre-eminent role that structural information played in this process. © 2012 Elsevier Ltd. All rights reserved.
  • Author:
    Hatala R; Urban L; Hlivák P; Smolková K; Spitzerová H
    Title:
    Quality of oral anticoagulation therapy with warfarin in the outpatient clinical practice in Slovakia in patients with nonvalvular atrial fibrillation.
    Abstract:
    Background: Correct management of oral anticoagulation therapy with warfarin is crucial for effective prevention of stroke and systemic thromboembolism in higher risk patients with nonvalvular atrial fibrillation. Warfarin therapy is effective and safe only under the condition that the achieved anticoagulation level is within the optimal therapeutic range with INR values 2-3. Warfarin is widely used drug for the prevention of thromboembolism of atrial fibrillation in clinical practice in Slovakia, however, there are no systematic data on the quality of anticoagulation management in these patients. Objective: The aim of this retrospective multicentre epidemiological survey was to evaluate the quality of anticoagulation in real life outpatient clinical practice among cardiologists and internists working in the Slovak Republic. Patients and methods: This survey has recruited patient with nonvalvular atrial fibrillation using warfarin continuously without interruption for at least two years. The quality of anticoagulation therapy management was assessed as the proportion of time when the patients was within optimal therapeutic range of INR 2-3 during the last 12 months of anticoagulation therapy (time in therapeutic range - TTR). The data were acquired retrospectively from charts of 540 patients (55% men). Mean age of men was 65.4 years (SD 9.1); the mean age of women was 70.5 years (SD 8.6). All patients were systematically followed in outpatient clinics of 108 internists and cardiologists. The regional distribution of patients corresponds to the demographic distribution of the Slovak population. Results: In the analyzed cohort of patients with nonvalvular atrial fibrillation the observed TTR has achieved 56%. The mean time interval between INR controls was 40.3 days (SD 0,7 days). We have identified significant differences in the quality of anticoagulation therapy among internists and cardiologists as well as among individual regions within Slovakia. Conclusions: The presented analysis of the quality of anticoagulation therapy with warfarin in real life outpatient clinical practice in the Slovak Republic in patients with nonvalvular atrial fibrillation demonstrated a suboptimal level of anticoagulation with INR outside the therapeutic range in 44% of time. These results are comparable with the data from several national registries from other countries and point out to a need for principal improvement of the prevention of thromboembolic complications in patients with nonvalvular atrial fibrillation
  • Author:
    Markert M; Trautmann T; Gross M; Ege A; Mayer K; Guth B
    Title:
    Evaluation of a method to correct the contractility index LVdP/dt max for changes in heart rate.
    Source:
    J Pharmacol Toxicol Methods Article in Press (2012)
  • Author:
    Kolte D; Bryant JW; Gibson GW; Wang J; Shariat-Madar Z
    Title:
    PF-04886847 (an inhibitor of plasma kallikrein) attenuates inflammatory mediators and activation of blood coagulation in rat model of lipopolysaccharide (LPS) - induced sepsis.
    Source:
    Cardiovasc Hematol Agents Med Chem 10 (2), 154-166 (2012)
    Abstract:
    The plasma kallikrein-mediated proteolysis regulates both thrombosis and inflammation. Previous study has shown that PF-04886847 is a potent and competitive inhibitor of kallikrein, suggesting that it might be useful for the treatment of kallikrein-kinin mediated inflammatory and thrombotic disorders. In the rat model of lipopolysaccharide (LPS) -induced sepsis used in this study, pretreatment of rats with PF-04886847 (1 mg/kg) prior to LPS (10 mg/kg) prevented endotoxin-induced increase in granulocyte count in the systemic circulation. PF-04886847 significantly reduced the elevated plasma 6-keto PGF 1alpha levels in LPS treated rats, suggesting t hat PF-04886847 could be useful in preventing hypotensive shock during sepsis. PF-04886847 did not inhibit LPS-induced increase in plasma TNF-? level. Pretreatment of rats with PF-04886847 prior to LPS did not attenuate endotoxin-induced decrease in platelet count and plasma fibrinogen levels as well as increase in plasma D-dimer levels. PF-04886847 did not protect the animals against LPS-mediated acute hepatic and renal injury and disseminated intravascular coagulation (DIC). Since prekallikrein (the zymogen form of plasma kallikrein) deficient patients have prolonged activated partial thromboplastin time (aPTT) without having any bleeding disorder, the anti-thrombotic property and mechanism of action of PF-04886847 was assessed. In a rabbit balloon injury model designed to mimic clinical conditions of acute thrombotic events, PF-04886847 reduced thrombus mass dose-dependently. PF-04886847 (1 mg/kg) prolonged both aPTT and prothrombin time (PT) in a dose-dependent manner. Although the findings of this study indicate that PF-04886847 possesses limited anti-thrombotic and anti-inflammatory effects, PF-04886847 may have therapeutic potential in other kallikrein-kinin mediated diseases. © 2012 Bentham Science Publishers
  • Author:
    Diederichs CP; Wellmann J; Bartels DB; Ellert U; Hoffmann W; Berger K
    Title:
    How to weight chronic diseases in multimorbidity indices? Development of a new method on the basis of individual data from five population-based studies
    Source:
    J Clin Epidemiol 65 (6), 679-685 (2012)
    Abstract:
    Objective: In multimorbidity indices, chronic conditions are often weighted according to their severity or their impact on different outcomes. These weights are mostly developed on the basis of only one study population by using very specific study participants, such as hospital patients. To overcome the limited validity of the indices, mean weights across five population-based studies were calculated according to the impact of diseases on self-reported health status. Study Design and Setting: Individual data was provided from the National Health Interview and Examination Survey (n = 1,010), Dortmund Health Study (n = 281), Memory and Morbidity in Augsburg Elderly Study (n = 385), Survey of Health, Aging and Retirement in Europe Study (n = 1,278), and Study of Health in Pomerania Study (n = 962). By using logistic regression analysis, odds ratios (ORs) were calculated for reporting a fair or poor health status resulting from one of 10 different chronic conditions compared with a reference group without the specific disease, controlling for age and sex. If the results were homogenous across studies (I 2 < 40%), significant pooled ORs were considered valid weights for a multimorbidity index. Results: Myocardial infarction has the highest impact on self-reported health status across studies with a pooled OR of 3.9, followed by chronic obstructive pulmonary disease (pooled OR: 3.1). A medium impact was observed for arthrosis, asthma, diabetes mellitus, and osteoporosis. Conclusion: This method provided valid weights for seven chronic conditions. © 2012 Elsevier Inc. All rights reserved.
  • Author:
    Wild P S; Zeller T; Beutel M; Blettner M; Dugi K A; Lackern K J; Pfeiffer N; Münzel T; Blankenberg S
    Title:
    The Gutenberg Health Study [Die Gutenberg Gesundheitsstudie]
    Source:
    Bundesgesundheitsblatt 55 (6-7), 824-830 (2012)
    Abstract:
    The Gutenberg Health Study is a population-based, prospective, single-center cohort study that started in 2007 at the University Medical Center Mainz. The project focuses on cardiovascular diseases, cancer, eye diseases, metabolic diseases, diseases of the immune system and mental diseases. The study aims at improving the individual risk prediction for diseases. Therefore, lifestyle, psychosocial factors, environment, laboratory parameters as well as the extent of the subclinical disease are investigated. A comprehensive biobank enables biomolecular examinations including a systems biological approach. During the baseline visit 15,000 individuals aged 35-74 years were invited to a 5 h examination program in the study center. This will be followed by a computer-assisted telephone interview with a standardized interview and assessment of endpoints after 2.5 years. After 5 years a detailed follow-up examination comparable to the visit at study inclusion will be performed in the study center. Further follow-up visits of the cohort are envisaged. © Springer-Verlag 2012.
  • Author:
    Pragst I; Zeitler S H; Doerr B; Kaspereit F J; Herzog E; Dickneite G; van Ryn J
    Title:
    Reversal of dabigatran anticoagulation by prothrombin complex concentrate (Beriplex P/N) in a rabbit model
    Source:
    Source:
    J Thromb Haemost 10 (9), 1841-1848 (2012)
    Abstract:
    Background: One limitation of the direct thrombin inhibitor dabigatran is the lack of specific antidotes that allow acute bleeding events to be managed or urgent interventional procedures performed. Prothrombin complex concentrates (PCCs) have served as a standard treatment for the reversal of coumarin anticoagulation. Objectives: This study was designed to determine in an animal model whether a PCC (Beriplex P/N) can effectively reverse the effects of dabigatran. An additional objective was to evaluate markers of dabigatran-associated bleeding diathesis. Methods: Anesthetized rabbits were treated with 0.4mgkg -1 dabigatran followed by PCC doses of 20, 35 or 50IUkg -1 or placebo. After a standardized kidney incision, volume of blood loss and time to hemostasis were determined. Results: From an initial mean of 29mL, blood loss progressively declined by 5.44mL with a 95% confidence interval (CI) of 2.21-8.67mL per 10IUkg -1 increment in PCC dose (P=0.002). At a PCC dose of 50IUkg -1 blood loss was fully normalized. Increasing PCC doses shortened the median time to hemostasis from 20.0 to 5.7min (P&lt;0.001). The rate of hemostasis was nearly trebled with each 10IUkg -1 increment in PCC dose (rate ratio, 2.89; CI, 1.64-5.09). Conclusions: In this animal study, PCC showed potential as an agent for reversing the effects of dabigatran. Further investigation is warranted. © 2012 International Society on Thrombosis and Haemostasis.
  • Author:
    Weber R; Weimar C; Blatchford J; Hermansson K; Wanke I; Möller-Harmann C; Gizewski E R; Forsting M; Demchuk AM; Sacco R L; Saver J L; Warach S; Diener H C; Diehl A
    Title:
    Telmisartan on top of antihypertensive treatment does not prevent progression of cerebral white matter lesions in the prevention regimen for effectively avoiding second strokes (PRoFESS) MRI substudy
    Source:
    Stroke 43 (43) (9), 2336-2342 (2012)
    Abstract:
    BACKGROUND AND PURPOSE-: High blood pressure is one of the main risk factors for cerebral white matter lesions (WMLs). There is limited evidence from one randomized trial that blood pressure-lowering is able to slow WML progression. We investigated whether telmisartan prevents WML progression in the imaging substudy of the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial. METHODS-: This predefined substudy comprised 771 patients (mean age, 65 years) with recent ischemic stroke of noncardioembolic origin who received telmisartan or placebo during a mean follow-up of 27.9 (SD, 7.6) months and had 2 evaluable MRI examinations after index stroke and at study closeout. All MRI scans were centrally adjudicated for progression of periventricular and subcortical WML by 2 neuroradiologists blinded to treatment allocation. RESULTS-: Mean blood pressure was 3.0/1.3 mm Hg lower with telmisartan compared with placebo at follow-up MRI. There was no statistically significant difference in progression of the mean periventricular WML score (least squares mean difference, 0.14; 95% CI, -0.12 to 0.39; P=0.29) and mean subcortical WML diameter (least squares mean difference, -0.35 mm; 95% CI, -1.00 to 0.31 mm; P=0.30) during follow-up between patients on telmisartan and placebo. CONCLUSIONS-: Treatment with telmisartan on top of existing antihypertensive medication did not result in significant blood pressure-lowering and did not prevent the progression of WML in patients with a recent ischemic stroke in this patient cohort. Our analysis is limited by the relatively short follow-up period. CLINICAL TRIAL REGISTRATION-: URL: http://clinicaltrials.gov. Unique Identifier: NCT00153062. © 2012 American Heart Association, Inc.
  • Author:
    Gonzàles J R; Alvarez-Sabin J; Martinez-Rubio A; Reverter J C; Oyagüez I; González-Rojas N; Becerra V
    Title:
    Cost-effectiveness of Dabigatran for Stroke Prevention in Non-valvular Atrial Fibrillation in Spain [Análisis coste-efectividad de dabigatrán para la prevención de ictus y embolia sistémica en fibrilación auricular no valvular en España]
    Source:
    Rev Esp Cardiol 65 (10), 901-910 (2012)
    Abstract:
    Introduction and objectives: Assessment of the cost-effectiveness of dabigatran for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation in Spain, from the perspective of the National Health System. Methods: Adaptation of a Markov chain model that simulates the natural history of the disease over the lifetime of a cohort of 10 000 patients with non-valvular atrial fibrillation. Model comparators were warfarin in a first scenario, and a real world prescribing pattern in a second scenario, in which 60% of the patients were treated with vitamin K antagonists, 30% with acetylsalicylic acid, and 10% received no treatment. Deterministic and probabilistic sensitivity analyses were performed. Results: Dabigatran reduced the occurrence of clinical events in both scenarios, providing gains in quantity and quality of life. The incremental cost-effectiveness ratio for dabigatran compared to warfarin was 17 581 euros/quality-adjusted life year gained and 14 118 euros/quality-adjusted life year gained when compared to the real world prescribing pattern. Efficiency in subgroups was demonstrated. When the social costs were incorporated into the analysis, dabigatran was found to be a dominant strategy (ie, more effective and less costly). The model proved to be robust. Conclusions: From the perspective of the Spanish National Health System, dabigatran is an efficient strategy for the prevention of stroke in patients with non-valvular atrial fibrillation compared to warfarin and to the real-world prescribing pattern; incremental cost-effectiveness ratios were below the 30 000 euros/quality-adjusted life year threshold in both scenarios. Dabigatran would also be a dominant strategy from the societal perspective, providing society with a more effective therapy at a lower cost compared to the other 2 alternatives. Full English text available from: www.revespcardiol.org. © 2012 Sociedad Española de Cardiología.
  • Author:
    Hart R G; Diener H-C; Yang S; Connolly S J; Wallentin L; Reilly P A; Ezekowitz M D; Yusuf S
    Title:
    Intracranial hemorrhage in atrial fibrillation patients during anticoagulation with warfarin or dabigatran: The RE-LY trial.
    Source:
    Stroke 43 (6), 1511-1517 (2012)
    Abstract:
    Background and Purpose-: Intracranial hemorrhage is the most devastating complication of anticoagulation. Outcomes associated with different sites of intracranial bleeding occurring with warfarin versus dabigatran have not been defined. Methods-: Analysis of 18 113 participants with atrial fibrillation in the Randomized Evaluation of Long-term anticoagulant therapY (RE-LY) trial assigned to adjusted-dose warfarin (target international normalized ratio, 2-3) or dabigatran (150 mg or 110 mg, both twice daily). Results-: During a mean of 2.0 years of follow-up, 154 intracranial hemorrhages occurred in 153 participants: 46% intracerebral (49% mortality), 45% subdural (24% mortality), and 8% subarachnoid (31% mortality). The rates of intracranial hemorrhage were 0.76%, 0.31%, and 0.23% per year among those assigned to warfarin, dabigatran 150 mg, and dabigatran 110 mg, respectively (P<0.001 for either dabigatran dose versus warfarin). Fewer fatal intracranial hemorrhages occurred among those assigned dabigatran 150 mg and 110 mg (n=13 and n=11, respectively) versus warfarin (n=32; P<0.01 for both). Fewer traumatic intracranial hemorrhages occurred among those assigned to dabigatran (11 patients with each dose) compared with warfarin (24 patients; P<0.05 for both dabigatran doses versus warfarin). Independent predictors of intracranial hemorrhage were assignment to warfarin (relative risk, 2.9; P<0.001), aspirin use (relative risk, 1.6; P=0.01), age (relative risk, 1.1 per year; P<0.001), and previous stroke/transient ischemic attack (relative risk, 1.8; P=0.001). Conclusions-: The clinical spectrum of intracranial hemorrhage was similar for patients given warfarin and dabigatran. Absolute rates at all sites and both fatal and traumatic intracranial hemorrhages were lower with dabigatran than with warfarin. Concomitant aspirin use was the most important modifiable independent risk factor for intracranial hemorrhage. © 2012 American Heart Association, Inc
  • Author:
    Clemens A; van Ryn J; Sennewald R; Yamamura N; Stangier J; Feuring M; Haertter S
    Title:
    Switching from enoxaparin to dabigatran etexilate: pharmacokinetics, pharmacodynamics and safety profile.
    Source:
    Eur J Clin Pharmacol, 1-10 Ariicle in Press (2012)
  • Author:
    Hohnloser SH; Oldgren J; Yang S; Wallentin L; Ezekowitz M; Reilly P; Eikelboom J; Brueckmann M; Yusuf S; Connolly SJ
    Title:
    Myocardial ischemic events in patients with atrial fibrillation treated with dabigatran or warfarin in the RE-LY (Randomized evaluation of long-term anticoagulation therapy) trial.
    Source:
    Circulation 125 (5), 669-676 (2012)
  • Author:
    Haertter S; Yamamura N; Stangier J; Reily PA; Clemens A
    Title:
    Pharmacokinetics and pharmacodynamics in Japanese and Caucasian subjects after oral administration of dabigatran etexilate.
    Source:
    Thromb Haemost 107 (2), 260-269 (2012)
  • Author:
    Gavagna G
    Title:
    Medicinal mishap: Dabigatran - a new safe drug to replace an old poison?
    Source:
    Aust Prescrib (35) (4), 109-110 (2012)
  • Author:
    Tolstrup A B; Enenkel B; Schlatter S; Schaub J; Bradl H; Puklowski A; Schulz P; Khetan A; Kaufmann H
    Title:
    Optimizing expression systems: The Bi-Hex Mammalian Expression Platform
    Source:
    BioPharm Int 25 (7), 26-27 (2012)
  • Author:
    Lee P; Yan P; Ewart P; Kohl P; Loew L M; Bollensdorff C
    Title:
    Simultaneous measurement and modulation of multiple physiological parameters in the isolated heart using optical techniques
    Source:
    Pfluegers Arch, 1-12 Article in Press (2012)
    Abstract:
    Whole-heart multi-parametric optical mapping has provided valuable insight into the interplay of electrophysiological parameters, and this technology will continue to thrive as dyes are improved and technical solutions for imaging become simpler and cheaper. Here, we show the advantage of using improved 2nd-generation voltage dyes, provide a simple solution to panoramic multi-parametric mapping, and illustrate the application of flash photolysis of caged compounds for studies in the whole heart. For proof of principle, we used the isolated rat whole-heart model. After characterising the blue and green isosbestic points of di-4-ANBDQBS and di-4-ANBDQPQ, respectively, two voltage and calcium mapping systems are described. With two newly custom-made multi-band optical filters, (1) di-4-ANBDQBS and fluo-4 and (2) di-4-ANBDQPQ and rhod-2 mapping are demonstrated. Furthermore, we demonstrate three-parameter mapping using di-4-ANBDQPQ, rhod-2 and NADH. Using off-the-shelf optics and the di-4-ANBDQPQ and rhod-2 combination, we demonstrate panoramic multi-parametric mapping, affording a 360° spatiotemporal record of activity. Finally, local optical perturbation of calcium dynamics in the whole heart is demonstrated using the caged compound, o-nitrophenyl ethylene glycol tetraacetic acid (NP-EGTA), with an ultraviolet light-emitting diode (LED). Calcium maps (heart loaded with di-4-ANBDQPQ and rhod-2) demonstrate successful NP-EGTA loading and local flash photolysis. All imaging systems were built using only a single camera. In conclusion, using novel 2nd-generation voltage dyes, we developed scalable techniques for multi-parametric optical mapping of the whole heart from one point of view and panoramically. In addition to these parameter imaging approaches, we show that it is possible to use caged compounds and ultraviolet LEDs to locally perturb electrophysiological parameters in the whole heart. © 2012 The Author(s).
  • Author:
    Mancia G; Schumacher H
    Title:
    Incidence of adverse events with telmisartan compared with ACE inhibitors. Evidence from a pooled analysis of clinical trials.
  • Author:
    Fryer RM; Muthukumarana A; Chen RR; Smith JD; Mazurek SN; Harrington KE; Dinallo RM; Burke J; DiCapua FM; Guo X; Kirrane TM; Snow RJ; Zhang Y; Soleymanzadeh F; Madwed JB; Kashem MA; Kugler SZ; O'Neill MM; Harrison PC; Reinhart GA; Boyer SJ
    Title:
    Mitigation of off-target adrenergic binding and effects on cardiovascular function in the discovery of novel ribosomal S6 kinase 2 inhibitors.
    Source:
    J Pharmacol Exp Ther 340 (3), 492-500 (2012)
    Abstract:
    We previously reported the discovery of a novel ribosomal S6 kinase 2 (RSK2) inhibitor, (R)-5-Methyl-1-oxo-2,3,4,5- tetrahydro-1H-[1,4]diazepino[1,2- a] indole-8-carboxylic acid [1-(3-dimethylamino-propyl)-1H-benzoimidazol-2-yl]- amide (BIX 02565), with high potency (IC 50 = 1.1 nM) targeted for the treatment of heart failure. In the present study, we report that despite nanomolar potency at the target, BIX 02565 elicits off-target binding at multiple adrenergic receptor subtypes that are important in the control of vascular tone and cardiac function. To elucidate in vivo the functional consequence of receptor binding, we characterized the cardiovascular (CV) profile of the compound in an anesthetized rat CV screen and telemetry-instrumented conscious rats. Infusion of BIX 02565 (1, 3, and 10 mg/kg) in the rat CV screen resulted in a precipitous decrease in both mean arterial pressure (MAP; to -65 ± 6 mm Hg below baseline) and heart rate (-93 ± 13 beats/min). In telemetry-instrumented rats, BIX 02565 (30, 100, and 300 mg/kg p.o. QD for 4 days) elicited concentration-dependent decreases in MAP after each dose (to -39 ± 4 mm Hg on day 4 at T max); analysis by Demming regression demonstrated strong correlation independent of route of administration and influence of anesthesia. Because of pronounced off-target effects of BIX 02565 on cardiovascular function, a high-throughput selectivity screen at adrenergic ? 1A and ? 2A was performed for 30 additional RSK2 inhibitors in a novel chemical series; a wide range of adrenergic binding was achieved (0-92% inhibition), allowing for differentiation within the series. Eleven lead compounds with differential binding were advanced to the rat CV screen for in vivo profiling. This led to the identification of potent RSK2 inhibitors (cellular IC 50 <0.14 nM) without relevant ? 1A and ? 1A inhibition and no adverse cardiovascular effects in vivo. Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
  • Author:
    Worthmann H; Dengler R; Schumacher H; Schwartz A; Eisert W G; Lichtinghagen R; Weissenborn K
    Title:
    Monocyte chemotactic protein-1 as a potential biomarker for early anti-thrombotic therapy after ischemic stroke
    Source:
    Int J Mol Sci 13 (7), 8670-8678 (2012)
    Abstract:
    Inflammation following ischemic brain injury is correlated with adverse outcome. Preclinical studies indicate that treatment with acetylsalicylic acid + extended-release dipyridamole (ASA + ER-DP) has anti-inflammatory and thereby neuroprotective effects by inhibition of monocyte chemotactic protein-1 (MCP-1) expression. We hypothesized that early treatment with ASA + ER-DP will reduce levels of MCP-1 also in patients with ischemic stroke. The EARLY trial randomized patients with ischemic stroke or TIA to either ASA + ER-DP treatment or ASA monotherapy within 24 h following the event. After 7 days, all patients were treated for up to 90 days with ASA + ER-DP. MCP-1 was determined from blood samples taken from 425 patients on admission and day 8. The change in MCP-1 from admission to day 8 did not differ between patients treated with ASA + ER-DP and ASA monotherapy (p > 0.05). Comparisons within MCP-1 baseline quartiles indicated that patients in the highest quartile (> 217-973 pg/mL) showed improved outcome at 90 days if treated with ASA + ER-DP in comparison to treatment with ASA alone (p = 0.004). Our data does not provide any evidence that treatment with ASA + ER-DP lowers MCP-1 in acute stroke patients. However, MCP-1 may be a useful biomarker for deciding on early stroke therapy, as patients with high MCP-1 at baseline appear to benefit from early treatment with ASA + ER-DP. © 2012 by the authors; licensee MDPI, Basel, Switzerland.
  • Author:
    Dansirikul C; Lehr T; Liesenfeld K-H; Haerter S; Staab A
    Title:
    A combined pharmacometric analysis of dabigatran etexilate in healthy volunteers and patients with atrial fibrillation or undergoing orthopaedic surgery.
    Source:
    Thromb Haemost 107 (4), 775-785 (2012)
  • Author:
    Song X; Sander SD; Johnson BH; Varker H; Amin AN
    Title:
    Impact of atrial fibrillation and oral anticoagulation on hospital costs and length of stay.
    Source:
    Am J Health Syst Pharm 69 (4), 329-338 (2012)
  • Author:
    Clemens A; Van Ryn J; Sennewald R; Yamamura N; Stangier J; Feuring M; Härtter S
    Title:
    Switching from enoxaparin to dabigatran etexilate: Pharmacokinetics, pharmacodynamics, and safety profile
    Source:
    Eur J Clin Pharmacol 68, 607-616 (2012)
    Abstract:
    Purpose: Dabigatran etexilate is an oral, reversible, direct thrombin inhibitor licensed for the prevention of venous thromboembolism and stroke prevention in patients with atrial fibrillation. The aim of this study was to investigate whether, and to what extent, a switch from enoxparin to dabigatran etexilate affects the pharmacokinetic (PK) and pharmacodynamic (PD) parameters and safety profile of dabigatran. Methods: Enoxaparin 40 mg was administered subcutaneously once daily for 3 days followed by a single dose of dabigatran etexilate 220 mg (test treatment) on day 4 in an open-label, two-way cross-over trial in healthy volunteers. Dabigatran plasma levels were measured using a validated high-performance liquid chromatography tandem mass spectrometry method. Anticoagulant activity was measured using a number of clotting tests, including prothrombinase-induced clotting time (PiCT), activated partial thromboplastin time (aPTT), ecarin clotting time (ECT), and diluted thrombin time (dTT). Results: PK, PD, and safety data were available for 23 subjects for each treatment. The adjusted geometric mean test/reference ratio of area under the concentration-time curve for total dabigatran was 84% (90% confidence interval 67.2-105.0%) and 86% (67.0-110.0%) for maximum plasma concentration. The PiCT test/reference ratio, which represents the activity of enoxaparin and dabigatran, was elevated by approximately 15% for peak maximum effect ratio to baseline and total area under the effect curve (AUEC 0-48) activity, suggesting that some anticoagulant activity of enoxaparin was still present. Enoxaparin pre-treatment increased the AUEC 0-48 of activated partial thromboplastin time by approximately 14%. All other dabigatran-related PD markers were unaffected. Tolerability was good, with only mild and reversible adverse events during the treatment. Conclusion: Prior administration of enoxaparin did not meaningfully affect the PK or PD properties of dabigatran, and the switch from enoxaparin to dabigatran etexilate was well tolerated among the study subjects. These data support the safety of switching patients from enoxaparin to dabigatran etexilate. © The Author(s) 2012.
  • Author:
    Eriksson B I; Dahl O E; Feuring M; Clemens A; Noack H; Hantel S; Friedman R J; Huo M
    Title:
    Dabigatran is effective with a favourable safety profile in normal and overweight patients undergoing major orthopaedic surgery: A pooled analysis
    Source:
    Thromb Res Article in Press (2012)
    Abstract:
    Introduction: Three pivotal phase 3 trials have demonstrated that oral dabigatran etexilate showed similar safety and efficacy to enoxaparin 40 mg once daily (qd) for venous thromboembolism (VTE) prevention in patients undergoing total knee or hip replacement. Obesity is an established independent risk factor for VTE. Methods: A post-hoc pooled analysis of the three trials was performed to evaluate the safety and efficacy of dabigatran 220 mg qd versus enoxaparin 40 mg qd in patients with a normal body mass index (BMI) of &gt; 20-25 kg/m 2, pre-obese patients (BMI &gt; 25-30 kg/m 2) and obese patients (BMI &gt; 30 kg/m 2). The primary efficacy endpoint was major VTE and VTE-related mortality; safety endpoints included major, clinically relevant, or any bleeding events. Results: The mean BMIs for patients in the dabigatran and enoxaparin arms from all three trials, separately, were between 27.5 and 29.9 kg/m 2. Of the participants, 1417 (24.9%) had a normal BMI, 2373 (41.7%) were pre-obese and 1826 (32.1%) obese. In patients with normal BMI, the rates of the primary efficacy endpoint were significantly lower in the dabigatran than in the enoxaparin group (2.1% versus 4.3%; OR 0.48; 95% CI 0.24-0.97, P = 0.037). No significant difference between dabigatran and enoxaparin in the primary efficacy endpoint was observed in the other subgroups. Bleeding rates were also similar between treatments for BMI subgroups. Conclusions: Dabigatran is an effective thromboprophylactic therapy for normal, pre-obese and obese patients, and outcomes in patients with a BMI &gt; 25 kg/m 2 do not differ from the overall population. © 2012.
  • Author:
    Liesenfeld K-H; Lehr T; Dansirikul C; Reily PA; Connoly SJ; Ezekowitz MD; Yusuf S; Wallentin L; Haertter S; Staab A
    Title:
    Population pharmacokinetic analysis of the oral thrombin inhibitor dabigatran etexilate in patients with non-vascular atrial fibrillation from the RE-LY trial: Reply to a rebuttal.
    Source:
    J Thromb Haemost 10 (3), 502-504 (2012)
  • Author:
    Segura J; de la Sierra A; Fernández S; Ruilope L M
    Title:
    Relevance of diabetes in high cardiovascular risk hypertensive patients [Influencia de la diabetes sobre la prevalencia de lesión de órganos diana y enfermedad cardiovascular en los pacientes hipertensos de alto riesgo]
    Source:
    Med Clin (Barc) Article in Press (2012)
    Abstract:
    Background and objective: The aim of this cross-sectional study was to compare the prevalence of target organ damage (TOD) and established cardiovascular disease (CVD) in a cohort of nondiabetic hypertensive patients with 3 or more cardiovascular risk factors (CVRF) against a group of hypertensives with type 2 diabetes. Patients and method: We included 4,725 hypertensive patients, 62% male, mean age 64 (SD 12) years, with type 2 diabetes mellitus, independently of the number of associated CVRF (N = 2,608), or non-diabetics, in which case we required the presence of 3 CVRF (N = 2,117). The prevalence of established CVD (clinical interview) and TOD (left ventricular hypertrophy by electrocardiogram, microalbuminuria and estimated glomerular filtration rate) were estimated. Results: Hypertensive patients with type 2 diabetes had an older age and more marked obesity. Furthermore, these patients showed a higher prevalence of micro- and macroalbuminuria, renal failure, left ventricular hypertrophy, atherosclerotic plaques in carotid arteries and CVD compared with nondiabetic hypertensive patients with 3 or more CVRF. Multivariate analysis showed that the risk of TOD or established CVD were associated independently with the presence of diabetes. Conclusion: Hypertensive patients with type 2 diabetes have a higher prevalence of LOD and CVD compared to nondiabetic hypertensive patients with 3 or more CVRF. Although both situations are included in the high cardiovascular risk stratum, it would be expected an increased incidence of cardiovascular complications in hypertensive diabetic patients. © 2012 Elsevier España, S.L. All rights reserved.
  • Author:
    Popow J; Schleiffer A; Martinez J
    Title:
    Diversity and roles of (t)RNA ligases
    Source:
    Cell Mol Life Sci 69 (16), 2657-2670 (2012)
    Abstract:
    Background and objective: The aim of this cross-sectional study was to compare the prevalence of target organ damage (TOD) and established cardiovascular disease (CVD) in a cohort of nondiabetic hypertensive patients with 3 or more cardiovascular risk factors (CVRF) against a group of hypertensives with type 2 diabetes. Patients and method: We included 4,725 hypertensive patients, 62% male, mean age 64 (SD 12) years, with type 2 diabetes mellitus, independently of the number of associated CVRF (N = 2,608), or non-diabetics, in which case we required the presence of 3 CVRF (N = 2,117). The prevalence of established CVD (clinical interview) and TOD (left ventricular hypertrophy by electrocardiogram, microalbuminuria and estimated glomerular filtration rate) were estimated. Results: Hypertensive patients with type 2 diabetes had an older age and more marked obesity. Furthermore, these patients showed a higher prevalence of micro- and macroalbuminuria, renal failure, left ventricular hypertrophy, atherosclerotic plaques in carotid arteries and CVD compared with nondiabetic hypertensive patients with 3 or more CVRF. Multivariate analysis showed that the risk of TOD or established CVD were associated independently with the presence of diabetes. Conclusion: Hypertensive patients with type 2 diabetes have a higher prevalence of LOD and CVD compared to nondiabetic hypertensive patients with 3 or more CVRF. Although both situations are included in the high cardiovascular risk stratum, it would be expected an increased incidence of cardiovascular complications in hypertensive diabetic patients. © 2012 Elsevier España, S.L. All rights reserved.
  • Author:
    Neldam S; Edwards C; Lang M; Jones R
    Title:
    Long-term tolerability and efficacy of single-pill combinations of telmisartan 40-80 mg plus amlodipine 5 or 10 mg in patients whose blood pressure was not initially controlled by amlodipine 5-10 mg: Open-label, long-term follow-ups of the TEAMSTA-5 and TEAMSTA-10 studies.
    Source:
    Curr Ther Res 73 (1-2), 65-84 (2012)
    Abstract:
    Background: Two 8-week, randomized, double-blind, controlled studies previously evaluated the efficacy and tolerability of single-pill combinations of telmisartan 40-80 mg/amlodipine 5-10 mg (T40-80/A5-10) in patients with hypertension not at diastolic blood pressure (DBP) goal (DBP <90 mm Hg) after 6 weeks of amlodipine 5 mg monotherapy (A5) (TEAMSTA-5) or amlodipine 10 mg monotherapy (A10) (TEAMSTA-10). The long-term (=6 months) tolerability and efficacy of single-pill combinations of T40-T80/A5-A10 have now been evaluated in 2 open-label studies in patients who had successfully completed either TEAMSTA-5 or TEAMSTA-10 (TEAMSTA-5 and TEAMSTA-10 Follow-Ups). Methods: In the TEAMSTA-5 Follow-Up, 976 patients whose blood pressure was not initially controlled by taking A5 received T40/A5 for 4 or 8 weeks, with consecutive uptitration to T80/A5 if DBP was =90 mm Hg. In TEAMSTA-10 Follow-Up, 838 patients not initially achieving blood pressure control using A10 received T40/A10 for 4 weeks before randomization to T40/A10 or T80/A10; after 4 weeks, patients randomized to T40/A10 with DBP =90 mm Hg were uptitrated to T80/A10. In both studies, add-on antihypertensive medication was allowed if DBP was not at goal. Results: Treatment compliance in both follow-up studies was =98.4%. Single-pill combinations of T40-T80/A5-A10 resulted in additional clinically relevant blood pressure reductions and 67% to 93% of patients achieved DBP goal (<90 mm Hg); only 1% to 19% of patients received additional medication for hypertension, of whom 29% to 76% achieved DBP goal. Long-term treatment with T40-T80/A5-A10 was well tolerated, with comparable adverse event profiles for all telmisartan/amlodipine combinations. The most common drug-related adverse events were peripheral edema (1.9%-3.9%) and dizziness (1.5% in the T80/A5 group only); these were consistent with the known tolerability profiles of telmisartan/amlodipine combinations. Overall treatment discontinuation rates due to adverse events were low (0.7%-1.5%). Conclusions: In patients not achieving DBP goal with either A5 or A10 monotherapy, the vast majority achieved DBP goal with single-pill combinations of T40-T80/A5-A10. Long-term treatment was well tolerated with high compliance, promoting treatment adherence regardless of telmisartan/amlodipine dose. . ClinicalTrials.gov identifiers: . NCT00614380 (TEAMSTA-5 Follow-up) and . NCT00624052 (TEAMSTA-10 Follow-up).
  • Author:
    Sharma AM; Bakris G; Neutel JM; Littlejohn TW; Kobe M; Ting N; Ley L
    Title:
    Single-pill combination of telmisartan/amlodipine versus amlodipine monotherapy in diabetic hypertensive patients. An 8-week randomized parallel-group, double-blind trial.
    Source:
    Clin Ther 34 (3), 537-551 (2012)
    Abstract:
    Background: Hypertensive patients with diabetes often require combination therapy to achieve a blood pressure (BP) goal, and evidence suggests that time to BP goal is crucial to decrease cardiovascular risk. Objective: The aim of the study was to investigate whether the single-pill combination of telmisartan and amlodipine was superior to amlodipine alone as initial antihypertensive therapy in patients with diabetes and hypertension. Methods: An 8-week, randomized, parallel-group, double-blind international trial comparing the once-daily single-pill combination of telmisartan 80 mg and amlodipine 10 mg (T/A; n = 352) with once-daily amlodipine 10 mg (A; n = 354) in patients with type 2 diabetes mellitus and stage 1 or 2 hypertension (systolic BP [SBP] >150 mm Hg). Results: Patient demographics were similar between treatment groups, with an mean (SD) age of 60.5 (10.1) years; 51.7% were male, the mean (SD) body mass index was 32.0 (6.1) and the mean (SD) duration of hypertension was 8.8 (7.9) years. After 8 weeks (primary end point) as well as after 1, 2, and 4 weeks (key secondary end points), significantly greater decreases in the in-clinic mean seated trough cuff SBP with T/A versus A were achieved (-29.0 mm Hg vs -22.9 mm Hg at 8 weeks; P < 0.0001). After 8 weeks, 71.4% versus 53.8% of patients achieved the BP goal (<140/90 mm Hg) with T/A versus A, with mean SBPs of 131.9 and 137.9 mm Hg, respectively. Similar results were observed in the obese (metabolic syndrome) subpopulation. The more stringent goal (<130/80 mm Hg) was achieved by 36.4% and 17.9% patients in the T/A and A groups, respectively. The most common adverse events were peripheral edema, headache, and dizziness. Conclusions: In this selected population of patients with diabetes and hypertension, T/A provided prompt and greater BP decreases compared with A monotherapy, with the majority of patients achieving the BP goal (<140/90 mm Hg).
  • Author:
    Kansal AR; Sorensen SV; Gani R; Robinson P; Pan F; Plum JM; Cowie JR
    Title:
    Cost-effectiveness of dabigatran etexilate for the prevention of stroke and systemic embolism in UK patients with atrial fibrillation.
    Source:
    Heart (Lond) 98 (7), 573-578 (2012)
  • Author:
    van Ryn J; Baruch L; Clemens A
    Title:
    Interpretation of point-of-care INR results in patients treated with dabigatran.
    Source:
    Am J Med 125 (4), 417-420 (2012)
  • Author:
    Neldam S; Schumacher H; Guthrie R
    Title:
    Telmisartan 80 mg/Hydrochlorothiazide 25 mg provides clinically relevant blood pressure reductions across baseline blood pressures.
    Source:
    Adv Ther 29 (4), 327-338 (2012)
    Abstract:
    Introduction: Most patients with hypertension require combination therapy to achieve optimal reduction of blood pressure (BP). The angiotensin II receptor blocker, telmisartan, provides 24-hour BP-lowering efficacy and is proven to prevent cardiovascular morbidity in high-risk patients. Methods: Pooled data from seven randomized controlled trials (3,654 patients with stage 1-2 hypertension) were analyzed to investigate the BP-lowering efficacy of telmisartan 40 or 80 mg (T40 or T80) in combination with hydrochlorothiazide 12.5 or 25 mg (H12.5 or H25) when compared with either placebo or telmisartan monotherapy, relative to patients' baseline BP. BP-lowering efficacy was also assessed in subpopulations. The primary endpoint was the change from baseline in seated trough clinic systolic BP (SBP) and diastolic BP (DBP). Results: In the overall population and across all baseline BP categories, T40/H12.5, T80/H12.5, and T80/H25 resulted in additional BP reductions to those provided by telmisartan monotherapy. In patients with baseline SBP ? 170 mmHg, T80/H25 effected a mean SBP change of -39.2 mmHg compared with changes of -25.5 mmHg and -8.3 mmHg observed with T80 and placebo treatment, respectively. Mean DBP changes were -20.4 mmHg T80/H25, -12.2 T80 and -5.9 placebo in patients with baseline DBP ? 105 mmHg. T80/H25 also resulted in larger BP reductions than telmisartan monotherapy in black patients with hypertension, irrespective of baseline BP. In patients with hypertension with type 2 diabetes and in patients with moderate or severe renal impairment, both T80/H12.5 and T80/H25 were more effective than monotherapy in reducing BP in all baseline BP categories. Conclusion: Combination treatment of telmisartan and hydrochlorothiazide results in large and clinically relevant BP reductions additional to those provided by monotherapy.
  • Author:
    Neutel JM; Mancia G; Black HR; Dahloef B; Defeo H; Ley L; Vinisko R; Donova T; Gotcheva N; Milanov S; Mincheva V; Pencheva G; Zlatareva N; Raev D; Stoimenov S; Petranov S; Homy I; Jerabek O; Karen I; Kuchar JC; Krumlov Lorenc Z; Nagel J; Petenka M; Zidkova E; Barucq F; Queguiner A; Robin F; Touzet P; Bismuth M; Bourgoin M; Giraldi C; Breton M; Combet R; Venturini G; Causse P; Henriot F; Khennouf A; Lecaignard D; Cayron P; Chalaux P; Chaleon A; Chalvignac A; Forestier BD; Deme JC; Fivel C; Depoisier M; Dimon B; Flosi M; MacAgno A; Ripoll M; Geronimi O; Michalak B; Geoffray B; Hannoush E; Jacquet J-P; Jappy L; Jordan E; Lacoin F; Lefort D; Lemarie B; Martocq G; Michellier P; Nabedian E; Percheron C-A; Perrin B; Pouget M; Roger J-J; Rouviere G; Sacareau D; Taminau D; Vuong M-H; Zimmermann D; Andras V; Livia T; Ferenc P; Gabriella N; Laszloe I; Ibolya P; Judit S; Karoly Z; Judit R; Benedek I; Cristea M; Tatu-Chitoiu GP; Dragulescu S; Gaita D; Georgescu CA; Minescu B; Manitiu I; Matei A; Salajan M; Tyurina T; Vishnevsky A; Baek S-H; Kang S-M; Kwon H-M; Park C-G; Kim M-H; Lee M-Y; Yang JY; Gonsorcik J; Hojenova S; Hranai M; Kolikova V; Ruffini L; Zareczky P; Gil-Extremera B; Munoz J; Olivan J; Pont F; Tovar J-L; Faynyk A; Goloborodko B; Shatilo V; Sirenko Y; Svyshchenko Y; Vykhovanyuk I; Yena L; Karpenko O; Kononenko L; Zehnder B; Portnoy EB; Punzi HA; Ricci DR; Samson MB; Slabic S; Struble R; Tidman RE; Wayne J; Webster DE; Winer N; Jagminas L; Kanna B; Khronusova Y; Lane´PJ; Lewinson L; Marple R; Mello CJ; Patel NR; Paltron A; Pool JL; Korzh O; Kraiz I; Bittar N; Cheung DG; Crump K; Diaz JL; Eddy PL; Eyzaguirre RD; Graf RJ; Hill JM; Jack DB
    Title:
    Single-pill combination of telmisartan/amlodipine in patients with serve hypertension: Results from the TEAMSTA serve HTN study.
    Source:
    J Clin Hypertens 14 (4), 206-215 (2012)
    Abstract:
    Despite the well documented benefits conferred by adequate control of hypertension, the majority of hypertensive patients display suboptimal control and few patients achieve blood pressure (BP) levels <14090mmHg. As a consequence, combination therapy will be required in the majority of patients to achieve target BP. Fixed-dose combinations of antihypertensives not only simplify treatment regimens, contributing to enhanced patient adherence, they provide superior BP-lowering efficacy and an improved tolerability profile. Fixed-dose combinations have become the strategy of choice in high-risk patients or those with stage 23 hypertension. The combination of a renin-angiotensin system inhibitor (RASI) with a calcium channel blocker (CCB) is a first-line combination that, in addition to its antihypertensive efficacy, reduces oedema, the main adverse effect of the dihydropyridine CCB and the main factor limiting their use. In morbiditymortality studies, this fixed-dose combination has also demonstrated superiority over a RASI combined with a diuretic. The single-pill combination of telmisartan and amlodipine has been shown to produce a dose-dependent BP-lowering effect significantly greater than that of either agent administered as monotherapy. These findings have been confirmed by ambulatory BP monitoring in patients with stage 1 and 2 hypertension, which demonstrated that single-pill telmisartanamlodipine provides substantial 24-hour BP-lowering efficacy. A higher proportion of patients achieved 24-hour BP goals of <13080mmHg on combination therapy. The superior efficacy of combination therapy has been demonstrated across a broad range of patients, including those with moderate-to-severe hypertension, diabetes mellitus and obesity. Moreover, combined use of telmisartan and amlodipine reduces the incidence of amlodipine-induced oedema, making it a preferred combination for the treatment of hypertension. © 2011 Adis Data Information BV. All rights reserved
  • Author:
    Hijazi Z; Oldgren J; Andersson U; Connolly SJ; Ezekowitz MD; Hohnloser SH; Reilly PA; Vinereanu D; Siegbahn A; Yusuf S; Wallentin L
    Title:
    Cardiac biomarkers are associated with an increased risk of stroke and death in patients with atrial fibrillation: A randomized evaluation of long-termn anticoagulation therapy (RE-LY) substudy.
    Source:
    Circulation 125 (13), 1605-1616 (2012)
  • Author:
    Fryer RM; Herrison PC; Muthukumarana A; Nodop Mazurek SG; Ng KJ; Chen RR; Harrington KE; Dinallo RM; Chi L; Reinhart GA
    Title:
    Strategic integration of in vivo cardiovascular models during lead optimization: Predictive value of 4 models independent of species, role of administration, and influence of anesthesia.
    Source:
    J Cardiovasc Pharmacol 59 (4), 369-376 (2012)
  • Author:
    Hallen J
    Title:
    Troponin for the estimation of infarct size: What have we learned?
    Source:
    Cardiology 121 (3), 204-212 (2012)
  • Author:
    Walter S; Kostopoulos P; Haass A; Keller I; Lesmeister M; Schlechtriemen T; Roth C; Papanagiotou P; Grunwald I; Schumacher H; Helwig S; Viera J; Koemer H; Alexandrou M; Yilmaz U; Ziegler K; Schmidt K; Dabew R; Kubulus D; Liu Y; Volk T; Kronfeld K; Ruckes C; Bertsch T; Reith W; Fassbender K
    Title:
    Diagnosis and treatment of patients with stroke in a mobile stroke unit versus in hospital: A randomised controlled trial.
    Source:
    Lancet Neurol 11 (5), 397-404 (2012)
  • Author:
    Huisman MV; Lip GYH; Diener H-C; Brueckemann M; van Ryn J; Clemens A
    Title:
    Dabigatran etexilate for stroke prevention in patients with atrial fibrillation: resolving uncertainties in routine practice.
    Source:
    Thromb Haemost 107 (5), 838-847 (2012)
  • Author:
    Haertter S; Yamamura M; Stangier J; Reilly PA; Clemens A
    Title:
    Pharmacokinetics and pharmacodynamics in Japanese and Caucasian subjects after oral administration of dabigatran etexilate.
    Source:
    Thromb Haemost 107 (2), 260-269 (2012)
    Abstract:
    Ethnic differences in drug disposition may potentially influence therapeutic response to dabigatran, a reversible direct thrombin inhibitor used for the prevention and/or treatment of various thromboembolic disorders. This analysis of data from 18 clinical studies in healthy volunteers and patients with non-valvular atrial fibrillation (AF) or undergoing knee or hip arthroplasty investigated whether there were any clinically relevant differences in the pharmacokinetics and pharmacodynamics of dabigatran, the active form of dabigatran etexilate, between Japanese and Caucasian subjects. In pooled data from 14 phase I trials, total exposure (i.e. area under the plasma concentrationtime curve [AUC]) after administration of dabigatran 150 mg once or twice-daily was on average 20% higher in Japanese than Caucasian subjects (median [10 th to 90 th percentile] 1,110 [644-1,824] vs. 924 [420-1,654] ng·h/ml) although the difference between the groups was not significant. Within-trial comparisons in subjects treated with dabigatran 150 mg twice-daily showed that AUC and maximum plasma con-centration differed by less than 10% between the two groups. In patients with AF, trough concentrations after administration of 150 mg twice-daily were similar in Japanese and Caucasian subjects (80.1 [34.5-193.8] vs. 71.0 [34.0-190] ng/ml). Various factors, including body weight and renal clearance, may explain these observed pharmacokinetic differences. The relationship between plasma concentration and coagulation markers was similar and indicative of no difference in the exposure-pharmacodynamic response between these two groups. In conclusion, the results of this analysis show that the pharmacokinetics and pharmacodynamics of dabigatran are similar in Japanese and Caucasian subjects and suggest that there is no need for dose adjustment of dabigatran in Japanese subjects.
  • Author:
    Hohnloser SH; Oldgren J; Yang S; Wallentin L; Ezekowitz M; Reilly P; Eikelboom J; Brueckmann M; Yusuf S; Connolly SJ
    Title:
    Myocardial ischemic events in patients with atrial fibrillation treated with dabigatran or warfarin in the RE-LY (Randomized evaluation of long-term anticoagulation therapy) trial.
    Source:
    Circulation 125 (5), 669-676 (2012)
    Abstract:
    Background-There is a modest risk of myocardial infarction (MI) and myocardial ischemic events in patients with atrial fibrillation. Methods and Results-Data from the RE-LY study (Randomized Evaluation of Long-Term Anticoagulation Therapy) were used to report rates of MI, unstable angina, cardiac arrest, and cardiac death and the prespecified net clinical benefit and treatment effects of dabigatran versus warfarin. MI occurred at annual rates of 0.82% and 0.81% with dabigatran 110 or 150 mg BID compared with 0.64% with warfarin (hazard ratio [HR] 1.29, 95% confidence interval [CI] 0.96-1.75, P=0.09 for dabigatran 110 mg; HR 1.27, 95% CI 0.94-1.71, P=0.12 for dabigatran 150 mg). Annual rates of a composite of MI, unstable angina, cardiac arrest, and cardiac death were 3.16% per year with dabigatran 110 mg, 3.33% per year with dabigatran 150 mg, and 3.41% per year with warfarin (HR versus warfarin 0.93, 95% CI 0.80-1.06, P=0.28 for dabigatran 110 mg and HR 0.98, 95% CI 0.85-1.12, P=0.77 for dabigatran 150 mg). Events prespecified as "net clinical benefit" (all strokes, systemic embolism, MI, pulmonary embolism, major bleeding, and all-cause death) occurred at a rate of 7.34% per year with dabigatran 110 mg, 7.11% per year with dabigatran 150 mg, and 7.91% per year with warfarin (HR 0.92, 95% CI 0.84-1.01, P=0.09 for dabigatran 110 mg and HR 0.90, 95% CI 0.82-0.99, P=0.02 for dabigatran 150 mg). The relative effects of dabigatran versus warfarin on myocardial ischemic events were consistent in patients with or without a baseline history of MI or coronary artery disease. Conclusions-There was a nonsignificant increase in MI with dabigatran compared with warfarin, but other myocardial ischemic events were not increased. Treatment effects of dabigatran were consistent in patients at higher and lower risk of myocardial ischemic events. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT 00262600.
  • Author:
    Eikelboom JW; Connoly SJ; Healey JS; Yang s; Yusuf S; Wallentin L; Oldgren J; Ezekowitz M; Alings M; Kaatz S; Hohnloser SH; Diener H-C; Franzosi MG; Huber K; Reilly P; Varrone J
    Title:
    Reply to letters regarding article. "risk of bleeding with 2 doses of daigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term therapy (RE-LY) trial.
    Source:
    Circulation 125 (3), e293-e294 (2012)
    Abstract:
    no Abstract
  • Author:
    Carrero-Gonzles L; Kaulisch T; Ruiz-Cabello J; Perez-Sanchez JM; Peces-Barba G; Stiller D; Rodriguez I
    Title:
    Apparent diffusion coefficient of hyperpolarized 3He with minimal influence of the residual gas in small animals.
    Source:
    NMR Biomed 25 (9), 1026-1032 (2012)
  • Author:
    Bangalore S; Ley L
    Title:
    Improving treatment adhernce to antihypertensive therapy. The role of single-pill combinations.
    Source:
    Expert Opin Pharmacother 13 (3), 345-355 (2012)
  • Author:
    Weber R; Weimar C; Wanke I; Moeller-Hartmann C; Gizewski ER; Blatchford J; Hermansson K; Denchuk AM; Forsting M; Sacco RL; Saver JL; Warach S; Diener HC; Diehl A
    Title:
    Risk of recurrent stroke in patients with silent brain infarction in the prevention regimen for effectively avoiding second strokes (PRoFESS) imaging substudy.
    Source:
    Stroke 43 (2), 350-355 (2012)
  • Author:
    Clemens A; Haertter S; Friedman J; Brueckmann M; Stangier J; van Ryn J; Lehr T
    Title:
    Twice daly dosing of dabigatran for stroke prevention in atrial fibrillation: A pharmacokinetic justification.
    Source:
    Curr Med Res Opin 28 (2), 195-201 (2012)
  • Author:
    Stangier J; Feuring M
    Title:
    Using the HEMOCLOT direct thrombin inhibitor assay to determine plasma concentrations of dabigatran.
    Source:
    Blood Coagul Fibrinolysis 23 (2), 138-143 (2012)
    Abstract:
    The objective of the present study was to assess the suitability of an accurate, sensitive, standardized, chronometric blood coagulation test to determine the anticoagulation activity of dabigatran and to quantify concentrations of dabigatran in plasma. Dabigatran was spiked at increasing concentrations in pooled citrated normal human plasma to measure diluted thrombin time with the HEMOCLOT THROMBIN INHIBITOR assay. Calibration curve linearity, inter-assay and intra-assay precision, and assay accuracy were investigated. Dabigatran stability in plasma and the feasibility of lyophilized dabigatran standards for assay calibration were assessed. Data are presented as back-calculated plasma concentrations of dabigatran using regression analysis. Dabigatran's calibration curve for thrombin clotting time was linear over the concentration range 0-4000nmol/l (0-1886ng/ml). The R was 0.99. Total assay imprecision for dabigatran was 4.7-12.0% coefficient of variation, with 1.2-3.1% for intra-run imprecision, 4.0-10.0% for inter-run precision and 0.3-8.3% for between-day imprecision. Assay accuracy was determined at three dabigatran concentrations; deviation from sample target concentrations ranged from -20.7% (100nmol/l; 47.15ng/ml) to 5.6% (1500nmol/l; 707.3ng/ml). Assay robustness was determined by analysing identical dabigatran samples in two independent laboratories. The mean bias of dabigatran coagulation times between laboratories was 6.6%. The HEMOCLOT Thrombin Inhibitors assay is suitable for determining the anticoagulant activity and calculating plasma concentrations of dabigatran using simple and widely available chronometric coagulation devices. The use of this rapid, established, standardized and calibrated assay should provide accurate and consistent results when assessing the anticoagulant activity of dabigatran.
  • Author:
    Dahl OE; Kurth AA; Rosencher N; Noack H; Clemens A; Eriksson BI
    Title:
    Thromboprophylaxis with dabigatran etexilate in patients over seventy-five years of age with moderate renal impairment undergoing or knee replacement.
    Source:
    Int Orthop 36 (4), 741-748 (2012)
    Abstract:
    Purpose: Prospective, double-blind studies in orthopaedic patients have been conducted using the direct thrombin inhibitor dabigatran etexilate (hereafter referred to as dabigatran), with two doses investigated and approved for adults (220 mg and 150 mg once daily) to prevent venous thromboembolism (VTE). The European Medicines Agency decided that in major joint orthopaedic surgery, the lower dose should be used in elderly patients (aged over 75 years) and those with reduced renal function (creatinine clearance between 30 and 50 ml/min). Our objective was to understand the efficacy and bleeding data for the lower dose in this subpopulation. Methods: We extracted and analysed data from the elderly or from moderately renally impaired patients (n 632 of = 5,539) from the orthopaedic clinical development programme of dabigatran. Results: Dabigatran 150 mg once daily was as effective as the standard European enoxaparin regimen, with numerically fewer major bleeding events. Rates of major VTE were 4.3% vs 6.4% of patients, respectively. Major bleeding events occurred in four (1.3%) vs 11 (3.3%), which shows a trend towards lower bleeding with dabigatran 150 mg [odds ratio (OR) 0.40; 95% confidence interval (CI) 0.13-1.25; p = 0.110]. Mean volume of blood loss was 395 vs 417 ml, and transfused units were 2.4 vs 2.5, respectively. Other safety parameters, including the incidence of wound infections and complications, were similar for 150 mg once daily dabigatran and enoxaparin. Conclusion: For patients at higher risk of bleeding, dabigatran 150 mg once daily is as effective as enoxaparin following major orthopaedic surgery and is associated with a favourable bleeding rate.
  • Author:
    Sinnaeve PR; Brueckmann M; Clemens A; Oldgren J; Eikelboom J; Healey JS
    Title:
    Stroke prevention in elderly patients atrial fibrillation: Challenges for anticoagulation.
    Source:
    J Intern Med 271 (1), 15-24 (2012)
    Abstract:
    Elderly patients with atrial fibrillation (AF), who constitute almost half of all AF patients, are at increased risk of stroke. Anticoagulant therapies, especially vitamin K antagonists (VKA), reduce the risk of stroke in all patients including the elderly but are frequently under-used in older patients. Failure to initiate VKA in elderly AF patients is related to a number of factors, including the limitations of current therapies and the increased risk for major haemorrhage associated with advanced age and anticoagulation therapy. Of particular concern is the risk of intracranial haemorrhages (ICH), which is associated with high rates of mortality and morbidity. Novel oral anticoagulant agents that are easier to use and might offer similar or better levels of stroke prevention with a similar or reduced risk of bleeding should increase the use of antithrombotic therapy in the management of elderly AF patients. Amongst these new agents, the recently approved direct thrombin inhibitor dabigatran provides effective stroke prevention with a significant reduction of ICH, and enables clinicians to tailor the dose according to age and haemorrhagic risk.
  • Author:
    Kirchhof P; Lip GYH; van Gelder IC; Bax J; Hylek E; Kaab S; Schotten U; Wegscheider K; Boriani G; Brandes A; Ezekowitz M; Diener H; Haegli L; Heidbuchel H; Lane D; Mont L; Willems S; Dorian P; Aunes-Jansson M; Blomsrom-Lundqvist C; Borentain M; Breitenstein S; Brueckmann M; Cater N; Clemens A; Dobrev D; Dudner S; Edvardsson NG; Friberg L; Goette A; Gulizia M; Hatala R; Honwood J; Szumowski L; Kappenberger L; Kautzner J; Leute A; Lobban T; Meyer R; Millerhagen J; Morgan J; Muenzel F; Nabauer M; Baertels C; Oeff M; Paar D; Polifka J; Ravens U; Rosin L; Stegink W; Steinbeck G; Vardas P; Vincent A; Walter M; Breithardt G; Camm AJ
    Title:
    Comprehensive risk reduction in patients with atrial fibrillation: Emerging diagnostic and therapeutic optionsa report from the 3rd aterial fibrillation competence NET work european heart rhytm association consensus conference.
    Source:
    Europace 14 (1), 8-27 (2012)
    Abstract:
    While management of atrial fibrillation (AF) patients is improved by guideline-conform application of anticoagulant therapy, rate control, rhythm control, and therapy of accompanying heart disease, the morbidity and mortality associated with AF remain unacceptably high. This paper describes the proceedings of the 3rd Atrial Fibrillation NETwork (AFNET)/European Heart Rhythm Association (EHRA) consensus conference that convened over 60 scientists and representatives from industry to jointly discuss emerging therapeutic and diagnostic improvements to achieve better management of AF patients. The paper covers four chapters: (i) risk factors and risk markers for AF; (ii) pathophysiological classification of AF; (iii) relevance of monitored AF duration for AF-related outcomes; and (iv) perspectives and needs for implementing better antithrombotic therapy. Relevant published literature for each section is covered, and suggestions for the improvement of management in each area are put forward. Combined, the propositions formulate a perspective to implement comprehensive management in AF.
  • Author:
    Redon J; Mancia G; Sleight P; Schumacher H; Gao P; Pogue J; Fagard R; Verdecchia P; Weber M; Boehm M; Williams B; Yusoff K; Teo K; Yusuf S
    Title:
    Safety and efficacy of low blood pressures among patients with diabetes. Subgroup analyses from the ontarget (ongoing telmisartan alone and in combination with ramipril global trial endpoint).
    Source:
    J Am Coll Cardiol 59 (1), 74-83 (2012)
    Abstract:
    We sought to determine whether the blood pressure (BP) levels at which cardiovascular (CV) protection is achieved differ between diabetic and nondiabetic patients from the ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial). Greater absolute benefits of BP reductions have been claimed for diabetic as compared with nondiabetic patients. A total of 25,584 patients (9,603 diabetic), older than 55 years, at high CV risk were randomized to ramipril, telmisartan, or both and observed for 4.6 years. We pooled the treatment arms to examine the relationships between BP and the primary composite outcome (CV death, nonfatal myocardial infarction or stroke, or hospitalized heart failure) and its components. The primary outcome occurred in 1,938 (20.2%) diabetic patients and in 2,276 (14.2%) nondiabetic patients. Compared with nondiabetic patients, diabetic patients had a significantly higher risk for the primary endpoint (hazard ratio [HR]: 1.48; 95% confidence interval [CI]: 1.38 to 1.57) and CV death (HR: 1.56; 95% CI: 1.42 to 1.71); myocardial infarction (HR: 1.30 (95% CI: 1.17 to 1.46); stroke (HR: 1.39; 95% CI: 1.23 to 1.56); and congestive heart failure hospitalization (HR: 2.06; 95% CI: 1.82 to 2.32). The CV risk was significantly higher in diabetic than in nondiabetic patients regardless of the systolic BP changes during treatment. In both diabetic and nondiabetic patients, progressively greater systolic BP reductions were accompanied by reduced risk for the primary outcome only if baseline systolic BP levels ranged from 143 to 155 mm Hg; except for stroke, there was no benefit in fatal or nonfatal CV outcomes by reducing systolic BP below 130 mm Hg. The relationship between BP and overall CV risk had a similar pattern in diabetic and nondiabetic patients over a wide range of baseline and in-treatment BP values although, for the same systolic BP, a higher risk is observed in diabetic patients. (Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial [ONTARGET]; NCT00153101)
  • Author:
    Leishman DJ; Beck TW; Dybdal N; Gallacher DJ; Guth BD; Holbrook M; Roche B; Wallis RM
    Title:
    Best practice in the conduct of key nonclinical cardiovascular assessments in drug development: Current recommendations from the Safety Pharmacology Society.
    Source:
    J Pharmacol Toxicol Methods 65 (3), 93-101 (2012)
    Abstract:
    A cardiovascular safety pharmacology assessment is routinely conducted prior to first administration of a new chemical entity or biopharmaceutical to man. These assessments are used to inform clinicians of potential effects in those initial clinical studies. They may also indicate more subtle effects having more relevance for longer term patient treatment studies such as a potential effect in a Thorough QT (TQT) study or a small persistent increase in blood pressure. Many pharmaceutical companies use the nonclinical studies for early decision making to avoid the clinical development of any compound likely to have a positive signal in a TQT study. These latter purposes generally require more sensitive assay systems and a confidence in their translation to man. At present it is often unclear whether any given study meets the standard required to convincingly detect these subtle effects. The Safety Pharmacology Society (SPS) brought together a group of over 50 experts to discuss best practices for dog and monkey cardiovascular assessments in safety pharmacology and toxicology studies in order to build overall confidence in the ability of a study to test a given hypothesis. It is clearly impossible to dictate a very specific standard practice for assays which are conducted globally in very different facilities using different equipment. However it was clear that a framework could be described to improve comparison and interpretation. Recommendations can be summarized on the basis of three key criteria: 1) know your study population quantitatively and qualitatively, 2) know how well your current study matches the historical data and 3) support your conclusions on the basis of the specific study's determined ability to detect change.
  • Author:
    Krause G; Patz M; Isaeva P; Wigger M; Baki I; Vondey V; Kerwien S; Kuckertz M; Brinker R; Claasen J; Frenzel LP; Wendtner C-M; Heider K-H; Hallek M
    Title:
    Action of novel CD37 antibodies on chronic lymphocytic leukemia cells.
    Source:
    Leukemia 26 (3), 546-549 (2012)