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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.

107 publications regarding Cardiovascular
  • 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)
  • 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 dablGatran etexilate in patients after heart valve replacemeNt (RE-ALIGN).
    Source:
    Am Heart J 163 (6), 931-937.e1 (2012)
  • 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)
  • 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)
  • Author:
    Hatala R; Urban L; Hlivak P; Smolkova K; Spitzerova H
    Title:
    Quality of oral anticoagulation therapy with warfarin in the outpatient clinical practice in Slovakia 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)
  • 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)
  • 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:
    Zhou W; Schwarting S; Illanes S; Liesz A; Middelhoff M; Zorn M; Bendszus M; Heiland S; van Ryn J; Veltkamp R
    Title:
    Hemostatic therapy in experimental intracerebral hemorrhage associated with the direct thrombin inhibitor dabigatran.
    Source:
    Stroke 42 (12), 3594-3599 (2011)
    Abstract:
    Background and Purpose: Dabigatran-etexilate (DE) recently has been approved for stroke prevention in atrial fibrillation. However, lack of effective antagonists represents a major concern in the event of intracerebral hemorrhage (ICH). The aims of the present study were to establish a murine model of ICH associated with dabigatran, and to test the efficacy of different hemostatic factors in preventing hematoma growth. Methods: In C57BL/6 mice receiving DE (4.5 or 9.0 mg/kg), in vivo and in vitro coagulation assays and dabigatran plasma levels were measured repeatedly. Thirty minutes after inducing ICH by striatal collagenase injection, mice received an intravenous injection of saline, prothrombin complex concentrate (PCC; 100 U/kg), murine fresh-frozen plasma (200 ?L), or recombinant human factor VIIa (8.0 mg/kg). ICH volume was quantified on brain cryosections 24 hours later. Results: DE substantially prolonged tail vein bleeding time and ecarin clotting time for 4 hours corresponding to dabigatran plasma levels. Intracerebral hematoma expansion was observed mainly during the first 3 hours on serial T2 * MRI. Anticoagulation with high doses of DE increased the hematoma volume significantly. PCC and, less consistently, fresh-frozen plasma prevented excess hematoma expansion caused by DE, whereas recombinant human factor VIIa was ineffective. Prevention of hematoma growth and reversal of tail vein bleeding time by PCC were dose-dependent. Conclusions: The study provides strong evidence that PCC and, less consistently, fresh-frozen plasma prevent excess intracerebral hematoma expansion in a murine ICH model associated with dabigatran. The efficacy and safety of this strategy must be further evaluated in clinical studies.
  • 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 Article in Press (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:
    Ovbiagele B; Bath PM; Cotton D; Vinisko R; Diener HC
    Title:
    Obesity and recurrent vascular risk after a recent ischemic stroke.
    Source:
    Stroke 42 (12), 3397-3402 (2011)
    Abstract:
    Background and Purpose: Although obesity is an established risk factor for the occurrence of a primary stroke, little is known about the impact of baseline obesity on recurrent vascular risk among patients with recently symptomatic cerebrovascular disease. We evaluated the association of obesity with future vascular risk in patients with a recent history of stroke. Methods: We analyzed the database of a multicenter trial involving 20 332 patients with recent ischemic stroke followed for 2.5 years. Subjects were divided into 3 groups according to recognized body mass index categories representing lean, overweight, and obese. Primary outcome was time to first recurrent stroke and secondary outcome time to stroke, myocardial infarction, or vascular death. The independent association of obesity with outcome was assessed by controlling for other known risk factors. Results: Of 20 246 eligible subjects, 4805 (24%) were obese. After adjusting for confounders, compared with the lean group, being overweight (hazard ratio, 0.95; 95% CI, 0.85-1.06) or obese (hazard ratio, 0.95; 95% CI, 0.83-1.08) was not associated with increased recurrent stroke risk, but being overweight (hazard ratio, 0.84; 95% CI, 0.77-0.92) or obese (hazard ratio, 0.86; 95% CI, 0.77-0.96) was associated with lower risk of a major vascular event. Conclusions: Obesity is not related to recurrent stroke risk, but obese patients with stroke are at lower overall vascular risk than their leaner counterparts, supporting the widely held notion of the existence of a cardiovascular "obesity paradox."
  • 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:
    Ovbiagele B; Diener H-Ch; Yusuf S; Martin RH; Cottn D; Vinisko R; Donnan GA; Bath PM
    Title:
    Level of systolic blood pressure within the normal range and risk of recurrent stroke.
    Source:
    JAMA 306 (19), 2137-2144 (2011)
  • Author:
    Gallagher AM; Setakis E; Plumb JM; Clemens A; van Staa T-P
    Title:
    Risk of stroke and mortality associated with suboptimal anticoagulation in atrial fibrillation patients.
    Source:
    Thromb Haemost 106 (5), 968-977 (2011)
    Abstract:
    Atrial fibrillation (AF) carries an increased risk of ischaemic stroke, and oral anticoagulation with warfarin can reduce this risk. The objective of this study was to evaluate the association between time in therapeutic International Normalised Ratio (INR) range when receiving warfarin and the risk of stroke and mortality. The study cohort included AF patients aged 40 years and older included in the UK General Practice Research Database. For patients treated with warfarin we computed the percentage of follow-up time spent within therapeutic range. Cox regression was used to assess the association between INR and outcomes while controlling for patient demographics, health status and concomitant medication. The study population included 27,458 warfarintreated (with at least 3 INR measurements) and 10,449 patients not treated with antithrombotic therapy. Overall the warfarin users spent 63% of their time within therapeutic range (TTR). This percentage did not vary substantially by age, sex and CHA2DS2-VASc score. Patients who spent at least 70% of time within therapeutic range had a 79% reduced risk of stroke compared to patients with =30% of time in range (adjusted relative rate of 0.21; 95% confidence interval 0.18-0.25). Mortality rates were also significantly lower with at least 70% of time spent within therapeutic range. In conclusion, good anticoagulation control was associated with a reduction in the risk of stroke.
  • Author:
    Mancia G; Schumacher H; Redon J; Verdecchia P; Schmieder R; Jennings G; Yusoff K; Ryden L; Liu GL; Teo K; Slight P; Yusuf S
    Title:
    Blood pressure targets recommended by guidelines and incidence of cardiovascular and renal events in the ongoing telmisartan alone and in combination with ramipril global endpoint trial (ONTARGET).
    Source:
    Circulation 124 (16), 1727-1736 (2011)
    Abstract:
    BACKGROUND-: Hypertension treatment guidelines recommend that blood pressure (BP) be lowered to <140/90 mm Hg, but that a reduction to <130/80 mm Hg be adopted in patients at high cardiovascular (CV) risk. We investigated the CV and renal benefits associated with these BP targets in the high-CV-risk population of the Ongoing Telmisartan Alone and in Combination With Ramipril Global End Point Trial (ONTARGET). METHODS AND RESULTS-: Patients were divided into 4 groups according to the proportion of in-treatment visits before the occurrence of an event (<25%->75%) in which BP was reduced to <140/90 or <130/80 mm Hg. After adjustment for demographic and clinical variables, a progressive increase in the proportion of visits in which BP was reduced to <140/90 or <130/80 mm Hg was associated with a progressive reduction in the risk of stroke, new onset of microalbuminuria or macroalbuminuria, and return to normoalbuminuria in albuminuric patients. An increased frequency of BP control to either target did not have any consistent effect on the adjusted risk of myocardial infarction and heart failure. The adjusted risk of CV events was reduced by increasing the frequency of BP control to <140/90 mm Hg, but not to <130/80 mm Hg. Similar findings were obtained for the achievement of the BP target in the visit preceding a CV event. CONCLUSION-: The more frequent achievement of the BP targets recommended by guidelines led to cerebrovascular and renal protection, but did not increase cardiac protection. Overall, CV protection was favorably affected by the less tight but not by the tighter BP target.
  • Author:
    Neldam St; Edwards C; Jones R
    Title:
    Switching patients with uncontrolled hypertension on amlodipine 10mg to single-pill combinations of telmisartan and amlodipine: Results of the TEAMSTA-10 study.
    Source:
    Curr Med Res Opin 27 (11), 2145-2153 (2011)
  • Author:
    Barzilay JI; Gao P; Ryden L; Schumacher H; Probstfield J; Commerford P; Dans A; Ferreira R; Keltai M
    Title:
    Effects of telmisartan on glucose levels in people at high for cardiovascular disease but free from diabetes the transcent study.
    Source:
    Diabetes Care 34 (9), 1902-1907 (2011)
  • Author:
    Lee S; Shafe ACE; Cowie MR
    Title:
    UK stroke incidence, mortality and cardiovascular risk management 1999-2008: time-trend analysis from the general practice research database.
    Source:
    BMJ open 1 (2), e000269 (2011)
  • Author:
    Berard E; Bongard V; Roche N; Perez T; Broquires D; Taraszkiewicz D; Fieves S; Denis F; Escamilla R; Ferries J
    Title:
    Undiagnosed airflow limitation in patients at cardiovascular risk.
    Source:
    Arch Cardiovasc Dis 104 (12), 619-626 (2011)
    Abstract:
    Background: Chronic obstructive pulmonary disease (COPD) and cardiovascular diseases (CVD) share risk factors and impair each other's prognosis. Aims: To assess the prevalence of airflow limitation (AL) compatible with COPD in a population at cardiovascular risk and to identify determinants of AL. Methods: All consecutive patients referred to the cardiovascular prevention unit of a university hospital in 2009 were studied in a cross-sectional analysis. Patients answered questionnaires on socioeconomic status, medical history and lifestyle, and underwent extensive physical examinations, biological measures and spirometry testing. AL was defined as FEV1/FVC < 0.70, without any history of asthma. Determinants of AL were assessed using logistic regression. Results: The sample comprised 493 participants (mean age 57.4 ± 11.1 years); 60% were men, 18% were current smokers, 42% were ex-smokers and 10% of patients had a history of CVD. Ten-year risk of coronary heart disease (CHD) according to the Framingham equation was intermediate (10-20%) for 25% of patients and high (> 20%) for 10%. Prevalence of AL was 5.9% (95% confidence interval [CI] 4.0-8.3%) in the whole population and 4.3% (2.6-6.6%) among subjects in primary cardiovascular prevention. AL was independently associated with CVD (adjusted odds ratio 4.18, 95% CI 1.72-10.15; P = 0.002) but not with Framingham CHD risk. More than 80% of patients screened with AL had not been diagnosed previously and more than one in two patients was asymptomatic. Conclusion: Patients with CVD are at increased risk of AL and thus should benefit from AL screening as they are frequently asymptomatic.
  • Author:
    Oldgren J; Alings M; Darius H; Diener H-C; Eikelboom J; Ezekowitz MD; Kamensky G; Reilly PA; Yang S; Yusuf S; Wallentin L; Connolly SJ
    Title:
    Risks for stroke, bleeding and death in patients with atrial fibrillation receiving dabigatran or warfarin in relation to the CHADS2 score: A subgroup analysis of the RE-LY trial.
    Source:
    Ann Intern Med 155 (10), 660-667 (2011)
    Abstract:
    Background: CHADS2 is a simple, validated risk score for predicting the risk for stroke in patients with atrial fibrillation not treated with anticoagulants. There are sparse data on the risk for thrombotic and bleeding complications according to the CHADS2 score in patients receiving anticoagulant therapy. Objective: To evaluate the prognostic importance of CHADS2 risk score in patients with atrial fibrillation receiving oral anticoagulants, including the vitamin K antagonist warfarin and the direct thrombin inhibitor dabigatran. Design: Subgroup analysis of a randomized, controlled trial. (ClinicalTrials. gov registration number: NCT00262600) Setting: Multinational study setting. Patients: 18 112 patients with atrial fibrillation who were receiving oral anticoagulants. Measurements: Baseline CHADS2 score, which assigns 1 point each for congestive heart failure, hypertension, age 75 years or older, and diabetes mellitus and 2 points for stroke. Results: Distribution of CHADS2 scores were as follows: 0 to 1-5775 patients; 2-6455 patients; and 3 to 6-5882 patients. Annual rates of the primary outcome of stroke or systemic embolism among all participants were 0.93% in patients with a CHADS2 score of 0 to 1, 1.22% in those with a score of 2, and 2.24% in those with a score of 3 to 6. Annual rates of other outcomes among all participants with CHADS2 scores of 0 to 1, 2, and 3 to 6, respectively, were the following: major bleeding, 2.26%, 3.11%, and 4.42%; intracranial bleeding, 0.31%, 0.40%, and 0.61%; and vascular mortality, 1.35%, 2.39%, and 3.68% (P &lt;0.001 for all comparisons). Rates of stroke or systemic embolism, major and intracranial bleeding, and vascular and total mortality each increased in the warfarin and dabigatran groups as CHADS2 score increased. The rates of stroke or systemic embolism with dabigatran, 150 mg twice daily, and of intracranial bleeding with dabigatran, 150 mg or 110 mg twice daily, were lower than those with warfarin; there was no significant heterogeneity in subgroups defined by CHADS2 scores. Limitation: These analyses were not prespecified and should be deemed exploratory. Conclusion: Higher CHADS2 scores were associated with increased risks for stroke or systemic embolism, bleeding, and death in patients with atrial fibrillation receiving oral anticoagulants. Primary Funding Source: Boehringer Ingelheim.
  • Author:
    Chaykovska L; von Websky K; Rahnenfuehrer J; Alter M; Heiden S; Fuchs H; Runge F; Klein T; Hocher B
    Title:
    Effects of DPP-4 inhibitors on the heart in a rat model of uremic cardiomyopathy.
    Source:
    Plos One 6 (11) art no. e27861 (2011)
    Abstract:
    Background: Uremic cardiomyopathy contributes substantially to mortality in chronic kidney disease (CKD) patients. Glucagon-like peptide-1 (GLP-1) may improve cardiac function, but is mainly degraded by dipeptidyl peptidase-4 (DPP-4). Methodology/Principal Findings: In a rat model of chronic renal failure, 5/6-nephrectomized [5/6N] rats were treated orally with DPP-4 inhibitors (linagliptin, sitagliptin, alogliptin) or placebo once daily for 4 days from 8 weeks after surgery, to identify the most appropriate treatment for cardiac dysfunction associated with CKD. Linagliptin showed no significant change in blood level AUC(0-?) in 5/6N rats, but sitagliptin and alogliptin had significantly higher AUC(0-?) values; 41% and 28% (p = 0.0001 and p = 0.0324), respectively. No correlation of markers of renal tubular and glomerular function with AUC was observed for linagliptin, which required no dose adjustment in uremic rats. Linagliptin 7 ?mol/kg caused a 2-fold increase in GLP-1 (AUC 201.0 ng/l*h) in 5/6N rats compared with sham-treated rats (AUC 108.6 ng/l*h) (p = 0.01). The mRNA levels of heart tissue fibrosis markers were all significantly increased in 5/6N vs control rats and reduced/normalized by linagliptin. Conclusions/Significance: DPP-4 inhibition increases plasma GLP-1 levels, particularly in uremia, and reduces expression of cardiac mRNA levels of matrix proteins and B-type natriuretic peptides (BNP). Linagliptin may offer a unique approach for treating uremic cardiomyopathy in CKD patients, with no need for dose-adjustment.
  • 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:
    Libonati JR; Sabri A; Xiao C; MacDonnell SM; Renn BF
    Title:
    Exercise training improves systolic function in hypertensive myocardium.
    Source:
    J Appl Physiol 111 (6), 1637-1643 (2011)
    Abstract:
    The general purpose of this study was to test the effect of exercise training on the left ventricular (LV) pressure-volume relationship (LV/PV) and apoptotic signaling markers in normotensive and hypertensive hearts. Four-month-old female normotensive Wistar-Kyoto rats (WKY; n = 37) and spontaneously hypertensive rats (SHR; n = 38) were assigned to a sedentary (WKY-SED, n = 21; SHR-SED, n = 19) or treadmilltrained (WKY-TRD, n = 16; SHR-TRD, n = 19) group (?60% V ? O2peak, 60 min/day, 5 days/wk, 12 wk). Ex vivo LV/PV were established in isovolumic Langendorff-perfused hearts, and LV levels of Akt, phosphorylated Akt (Akt Pi), Bad, phosphorylated Bad (BadPi) c-IAP, x-IAP, calcineurin, and caspases 3, 8, and 9 were measured. Heart-to-body weight ratio was increased in SHR vs. WKY (P &lt; 0.05), concomitant with increased calcineurin mRNA (P &lt; 0.05). There was a rightward shift in the LV/PV (P &lt; 0.05) and a reduction in systolic elastance (Es) in SHR vs. WKY. Exercise training corrected Es in SHR (P &lt; 0.05) but had no effect on the LV/PV in WKY. Caspase 3 was increased in SHR-SED relative to WKY-SED, while BadPi, c-IAP, and x-IAP were significantly lower in SHR relative to WKY (P &lt; 0.05). Exercise training increased BadPi in both WKY and SHR but did not alter caspase 9 activity in either group. While caspase 3 activity was increased with training in WKY (P &lt; 0.05), it was unchanged with training in SHR. We conclude that moderate levels of regular aerobic exercise attenuate systolic dysfunction early in the compensatory phase of hypertrophy, and that a differential phenotypical response to moderate-intensity exercise exists between WKY and SHR.
  • Author:
    Oldgren J; Siegbahn A; Wallentin L; Budaj A; Granger ChB; Khder Y; Roberts J; Tijssen JGP; van de Werf F
    Title:
    Dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, double-blind, phase II trial.
    Source:
    Eur Heart J 32 (22), 2781-2789 (2011)
    Abstract:
    Aim After an acute coronary syndrome, patients remain at risk of recurrent ischaemic events, despite contemporary treatment, including aspirin and clopidogrel. We evaluated the safety and indicators of efficacy of the novel oral direct thrombin inhibitor dabigatran. Methods and results In this double-blind, placebo-controlled, dose-escalation trial, 1861 patients (99.2% on dual antiplatelet treatment) in 161 centres were enrolled at mean 7.5 days (SD 3.8) after an ST-elevation (60%) or non-ST-elevation (40%) myocardial infarction and randomized to twice daily treatment with dabigatran 50 mg (n = 369), 75 mg (n = 368), 110 mg (n = 406), 150 mg (n = 347), or placebo (n = 371). Primary outcome was the composite of major or clinically relevant minor bleeding during the 6-month treatment period. There were 96 primary outcome events and, compared with placebo, a dose-dependent increase with dabigatran, hazard ratio (HR) 1.77 (95% confidence intervals 0.70, 4.50) for 50 mg; HR 2.17 (0.88, 5.31) for 75 mg; HR 3.92 (1.72, 8.95) for 110 mg; and HR 4.27 (1.86, 9.81) for 150 mg. Compared with placebo, D-dimer concentrations were reduced in all dabigatran dose groups by an average of 37 and 45% at weeks 1 and 4, respectively (P < 0.001). Fourteen (3.8%) patients died, had a myocardial infarction or stroke in the placebo group compared with 17 (4.6%) in 50 mg, 18 (4.9%) in 75 mg, 12 (3.0%) in 110 mg, and 12 (3.5%) in the 150 mg dabigatran groups. Conclusions Dabigatran, in addition to dual antiplatelet therapy, was associated with a dose-dependent increase in bleeding events and significantly reduced coagulation activity in patients with a recent myocardial infarction.
  • Author:
    Liesenfeld KH; Lehr T; Dansirikul C; Reilly PA; Connolly 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-valvular atrial fibrillation from the RE-LY trial.
    Source:
    J Thromb Haemost 9 (11), 2168-2175 (2011)
    Abstract:
    Background: Dabigatran etexilate (DE) is an orally absorbed prodrug of dabigatran, a thrombin inhibitor that exerts potent anticoagulant and antithrombotic activity. Objectives: To characterize the pharmacokinetics of dabigatran in patients with non-valvular atrial fibrillation (AF) from the Randomized Evaluation of Long-term Anticoagulant Therapy (RE-LY) trial and to quantify the effect of selected factors on pharmacokinetic (PK) model parameters. Patients and methods: A total of 27 706 dabigatran plasma concentrations from 9522 patients who received DE 110 or 150 mg twice daily were analyzed with non-linear mixed-effects modeling. Results: The pharmacokinetics of dabigatran were best described by a two-compartment disposition model with first-order absorption. The covariates creatinine clearance (CRCL), age, sex, heart failure and the ethnic subgroup 'South Asian' exhibited statistically significant effects on apparent clearance of dabigatran. Body weight and hemoglobin significantly influenced the apparent volume of distribution of the central compartment. Concomitant medication with proton-pump inhibitors, amiodarone and verapamil significantly affected the bioavailability. However, all of the statistically significant factors that were identified, except for renal function status, showed only small to moderate effects (< 26% change in exposure at steady state). On the basis of simulations from the final population PK model, a dose of 75 mg twice daily would result in similar exposure for severely renally impaired patients with CRCL of 15-30 mL min(-1) and patients with normal renal function receiving 150 mg twice daily. Conclusions: The analysis provides a thorough PK characterization of dabigatran in the AF patient population from RE-LY. None of the covariates investigated, with the exception of renal function, warrants dose adjustment.
  • Author:
    Barzilay JI; Gao P; Ryden L; Schumacher H; Probstfield J; Commerford P; Dans A; Ferreira R; Keltai M; Paolasso E; Yusuf S; Teo K
    Title:
    Effects of telmisartan on glucose levels in people at high risk for cardiovascular disease but free from diabetes the transcend study.
    Source:
    Diabetes Care 34 (9), 1902-1907 (2011)
    Abstract:
    OBJECTIVE-Several large clinical trials suggest that ACE inhibitors may reduce the incidence of diabetes. Less is known about the effects of angiotensin receptor blockers (ARBs) on reducing incident diabetes or leading to regression of impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) to normoglycemia. RESEARCH DESIGN AND METHODS-Participants were 3,488 adults at high risk for cardiovascular disease but free from diabetes (mean age 67 years; 61% male) in the Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease (TRANSCEND) study. The participants were randomized to the ARB telmisartan 80 mg (n = 1,726) or placebo (n = 1,762) in addition to usual care. RESULTS-During a median 56 months, 21.8% of participants treated with telmisartan and 22.4% of those on placebo developed diabetes (relative ratio 0.95 [95% CI 0.83-1.10]; P = 0.51). Participants originally diagnosed with IFG and/or IGT were equally likely to regress to normoglycemia (26.9 vs. 24.5%) or to progress to incident diabetes (20.1 vs. 21.1%; P = 0.59) on telmisartan or placebo. CONCLUSIONS-There was no evidence that addition of the ARB telmisartan to usual care prevents incident diabetes or leads to regression of IFG or IGT in people at high risk for cardiovascular disease but free from diabetes.
  • 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:
    Guthrie RM; Dahloef B; Jamerson KA; Olvera R; Seeber M; Schumacher H; Oigman W
    Title:
    Efficacy and tolerability of telmisartan plus amlodipine in added-risk hypertensive patients.
    Source:
    Curr Med Res Opin 27 (10), 1995-2008 (2011)
    Abstract:
    Objectives: Added-risk hypertensive patients with co-morbidities such as diabetes and metabolic syndrome often require two or more antihypertensives to achieve blood pressure (BP) targets. The aim of this sub-analysis was to determine the efficacy and safety of telmisartan 40 or 80mg plus amlodipine 5 or 10mg in patients with hypertension, stratified according to certain criteria such as type 2 diabetes mellitus and metabolic syndrome. Methods: Patients were treated for 8 weeks with telmisartan 2080mg plus amlodipine 2.510mg. This post-hoc analysis included patients treated with higher doses, and stratified according to a number of sub-populations (age, race, diabetes, obesity, metabolic syndrome, elevated baseline systolic BP (SBP), renal impairment). Results: Eight weeks' treatment with telmisartan plus amlodipine combinations provided consistent reductions in mean SBP/diastolic BP (DBP) across the different sub-populations, similar to the overall population. SBP/DBP reductions ranged from-13.5 to-34.7/-12.6 to-26.1mmHg and BP goal rates (<140/90mmHg) ranged from 29.8100% for the four key dose combinations of telmisartan plus amlodipine. For the highest dose combination of telmisartan 80mg plus amlodipine 10mg, SBP/DBP reduction ranged from-19.1 to-34.7/-16.4 to-22.8mmHg and goal attainment rate from 66.7% to 87.0%. Across the sub-populations, high SBP and DBP response rates were seen with combination treatment (83.397.7% and 75.095.7%, respectively, with telmisartan 80mg plus amlodipine 10mg). The combination was safe and well tolerated across all sub-populations and the incidence of peripheral oedema with telmisartan 4080mg plus amlodipine 10mg was generally lower than with A10 monotherapy. Conclusions: Despite small patient numbers in some sub-populations and the post-hoc nature of the analysis, this does show that the combination of telmisartan plus amlodipine provides an effective, safe and well-tolerated antihypertensive treatment for added-risk hypertensive patients. - Derwent Abstract - This study evaluated the efficacy and tolerability of telmisartan + amlodipine in 1461 added-risk hypertensive patients. 8 Wk treatment with telmisartan (20-80 mg) + amlodipine (2.5-10 mg) combinations provided consistent reductions in mean systolic B.P. (SBP)/diastolic B.P. (DBP) across the different sub-populations similar to the overall population. Across the sub-populations, high SBP and DBP response rates were seen with combination treatment. The combination was safe and well tolerated across all sub-populations and the incidence of peripheral edema with telmisartan + amlodipine was generally low. Thus, the combination of telmisartan + amlodipine provides an effective safe and well-tolerated antihypertensive treatment for added-risk hypertensive patients.
  • 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)
  • Author:
    Litzenburger T; Park J; Waterman A; Canada K; Kroe-Barrett R; Singh S; Hauel N; Sarko C; van Ryn J
    Title:
    An antibody selective to dabigatran safely neutralizes both dabigatran-induced anticoagulant and bleeding activity in in vitro and in vivo models.
    Source:
    J Thromb Haemost 9 (Supp.[2]), 110 (2011)
  • Author:
    Roskell NS; Wolowacz SE; Ziemiecki R; Gallagher AM; Feuring M; Fraessdorf M; Hass B
    Title:
    The impact of anticoagulant monitoring and control on recurrent venous thromboembolism and bleeding in routine clinical practice.
    Source:
    J Thromb Haemost 9 (Supp.[2]), 193 (2011)
  • Author:
    Rosencher J; Bongard V; Elbaz M; Puel J; Charpentier S; Tazarourte K; Soulot L; Savary D; Miljkovic D; Cottin Y; Lambert Y; Steg Ph G
    Title:
    A simple nomogram for early prediction of myocardial reperfusion after pre-hospital thrombolysis.
    Source:
    Eurointervention 7 (2), 248-255 (2011)
    Abstract:
    Aims: To discriminate early ST-segment elevation myocardial infarction (STEMI) presenters at a high probability of successful pre-hospital thrombolysis (PHT) using a simple nomogram based on independent predictors of complete ST resolution. Methods and results: OPTIMAL was an observational, prospective study undertaken at 79 medical centres in France in patients with STEMI undergoing pre-hospital thrombolysis (PHT) within six hours of symptom onset and coronary angiography within six hours of thrombolysis. The baseline and pre-coronary angiography ECGs of 800 patients were analysed. The main outcome measure was ST segment resolution >= 70%. ST resolution was associated with a significant reduction in mortality (1.8% vs. 4.3%; p=0.05). After multivariable logistic regression analysis, five independent predictors of successful myocardial reperfusion were identified: <= 1 h between pain onset and thrombolysis (odds ratio [OR] 1.76, 95% confidence interval [CI] 1.18-2.62); body mass index (BMI) <30 kg/m(2) (OR 1.74, CI 1.12-2.72); current/previous smoking (OR 1.71, CI 1.21-2.43); non-anterior infarct territory (OR 1.75, CI 1.27-2.41); and maximum amplitude of ST elevation <3 mm (OR 1.83, CI 1.32-2.54). The C-statistic of the model was 0.71 (95% CI 0.67-0.74). Using these five independent factors, a simple nomogram was developed to assess the probability of ST resolution after PHI. This nomogram allows discrimination of probabilities ranging from 13 to 72%. Conclusions: This simple nomogram can predict the probability of successful myocardial reperfusion after thrombolysis. This may be useful in the triage of STEMI presenters.
  • Author:
    Holmstrom M; Kivisto S; Antila M; Lauerma K; Helio T; Jurkko R; Kaartinen M; Reissell E; Kuusisto J; Karkkainen S; Peuhkurinen K; Koikkalainen J; Loltjonen J
    Title:
    Late gadolinium enhanced cardiovascular magnetic resonance of lamin A/C gene mutation related dilated cardiomyopathy.
    Source:
    J Cardiovasc Magn Reson 13 (2011)
    Abstract:
    Background: The purpose of this study was to identify early features of lamin A/C gene mutation related dilated cardiomyopathy (DCM) with cardiovascular magnetic resonance (CMR). We characterise myocardial and functional findings in carriers of lamin A/C mutation to facilitate the recognition of these patients using this method. We also investigated the connection between myocardial fibrosis and conduction abnormalities. Methods: Seventeen lamin A/C mutation carriers underwent CMR. Late gadolinium enhancement (LGE) and cine images were performed to evaluate myocardial fibrosis, regional wall motion, longitudinal myocardial function, global function and volumetry of both ventricles. The location, pattern and extent of enhancement in the left ventricle (LV) myocardium were visually estimated. Results: Patients had LV myocardial fibrosis in 88% of cases. Segmental wall motion abnormalities correlated strongly with the degree of enhancement. Myocardial enhancement was associated with conduction abnormalities. Sixty-nine percent of our asymptomatic or mildly symptomatic patients showed mild ventricular dilatation, systolic failure or both in global ventricular analysis. Decreased longitudinal systolic LV function was observed in 53% of patients. Conclusions: Cardiac conduction abnormalities, mildly dilated LV and depressed systolic dysfunction are common in DCM caused by a lamin A/C gene mutation. However, other cardiac diseases may produce similar symptoms. CMR is an accurate tool to determine the typical cardiac involvement in lamin A/C cardiomyopathy and may help to initiate early treatment in this malignant familiar form of DCM.
  • Author:
    Schmieder RE; Mann JFE; Schumacher H; Gao P; McQueen M; Koon T; Yusuf S; Mancia G; Weber MA
    Title:
    Changes in albuminuria predict mortality and morbidity in patients with vascular disease.
    Source:
    J Am Soc Nephrol 22 (7), 1353-1364 (2011)
    Abstract:
    The degree of albuminuria predicts cardiovascular and renal outcomes, but it is not known whether changes in albuminuria also predict similar outcomes. In two multicenter, multinational, prospective observational studies, a central laboratory measured albuminuria in 23,480 patients with vascular disease or high-risk diabetes. We quantified the association between a greater than or equal to twofold change in albuminuria in spot urine from baseline to 2 years and the incidence of cardiovascular and renal outcomes and all-cause mortality during the subsequent 32 months. A greater than or equal to twofold increase in albuminuria from baseline to 2 years, observed in 28%, associated with nearly 50% higher mortality (HR 1.48; 95% CI 1.32 to 1.66), and a greater than or equal to twofold decrease in albuminuria, observed in 21%, associated with 15% lower mortality (HR 0.85; 95% CI 0.74 to 0.98) compared with those with lesser changes in albuminuria, after adjustment for baseline albuminuria, BP, and other potential confounders. Increases in albuminuria also significantly associated with cardiovascular death, composite cardiovascular outcomes (cardiovascular death, myocardial infarction, stroke, and hospitalization for heart failure), and renal outcomes including dialysis or doubling of serum creatinine (adjusted HR 1.40; 95% CI 1.11 to 1.78). In conclusion, in patients with vascular disease, changes in albuminuria predict mortality and cardiovascular and renal outcomes, independent of baseline albuminuria. This suggests that monitoring albuminuria is a useful strategy to help predict cardiovascular risk.
  • Author:
    Suhre K; Roemisch-Margel W; de Angelis MH; Adamski J; Luippold G; Augustin R
    Title:
    Identification of a potential biomarker for FABP4 inhibition. The power of lipodomics in preclinical drug testing.
    Source:
    J Biomol Screen 16 (5), 467-475 (2011)
    Abstract:
    The fatty acid binding protein 4 (FABP4) belongs to the family of lipid chaperones that control intracellular fluxes and compartmentalization of their respective ligands (e.g., fatty acids). FABP4, which is almost exclusively expressed in adipocytes and macrophages, contributes to the development of insulin resistance and atherosclerosis in mice. Lack of FABP4 protects against the development of insulin resistance associated with genetic or diet-induced obesity in mice. Furthermore, total or macrophage-specific FABP4 deficiency is protective against atherosclerosis in apolipoprotein E-deficient mice. The FABP4 small-molecule inhibitor BMS309403 has demonstrated efficacy in mouse models for type 2 diabetes mellitus and atherosclerosis, resembling phenotypes of mice with FABP4 deficiency. However, despite the therapeutically attractive long-term effects of FABP4 inhibition, an acute biomarker for drug action is lacking. The authors applied mass spectrometry lipidomics analysis to in vitro and in vivo (plasma and adipose tissue) samples upon inhibitor treatment. They report the identification of a potential biomarker for acute in vivo FABP4 inhibition that is applicable for further investigations and can be implemented in simple and fast-flow injection mass spectrometry assays. In addition, this approach can be considered a proof-of-principle study that can be applied to other lipid-pathway targeting mechanisms.
  • Author:
    Ring A; Clemens A; Rathgen K; Stangier J; Feifel U; Reilly P; Friedman J
    Title:
    Dabigatran does not prolong the QTC interval with supratherapeutic exposure: A thorough QTC study.
    Source:
    60th Annual Sientific Session and Expo of the American College of Cardiology, New Orleans (United States), Apr 3-5, 2011J Am Coll Cardiol 57 (14) (Supp.[1]), E56 (2011)
  • Author:
    Uchiyama S; Ikeda Y; Urano Y; Horie Y; Yamaguchi T
    Title:
    The Japanese aggrenox (extended-release dipyridamole plus aspirin) stroke prevention versus aspirin programme (JASAP) study: A randomized, double-blind, controlled trial.
    Source:
    Cerebrovasc Dis 31 (6), 601-613 (2011)
    Abstract:
    Background: Despite improvements in treatment, stroke still carries a high death toll and disability in Asia. Extended-release dipyridamole (ER-DP) plus acetylsalicylic acid (ASA) has consistently been shown to be superior over conventional platelet inhibition by ASA. ER-DP plus ASA is well established in the secondary prevention of stroke in a lot of countries including the USA and Europe. DP has an established benefit in the treatment of heart disease in Japan; however, for the prevention of stroke, the fixed-dose combination of ER-DP plus ASA has only been investigated in a small number of patients in Japan. Methods: The aim of this double-blind, randomized clinical trial was to investigate the efficacy and safety of ER-DP plus ASA versus 81 mg ASA over 1 year. The primary end point of this study was the event rate of recurrent ischemic stroke (fatal or nonfatal) using the Kaplan-Meier method and Cox regression analysis. Results: Of the 1,294 enrolled patients, the primary end point was analyzed in 652 patients in the ER-DP plus ASA group and 639 in the ASA group. The incidence of ischemic stroke was 6.9% for ER-DP plus ASA and 5.0% for ASA with a hazard ratio of 1.47 (95% confidence interval 0.93-2.31) for the primary end point. The ASA treatment group was found to have a lower than expected yearly event rate, compared to other studies in Japanese stroke patients. Noninferiority of ER-DP plus ASA versus ASA could not be shown. The risks of major bleeding events and intracranial hemorrhage were found to be similar between the treatment arms. There were 4 deaths (0.6%) in the ER-DP plus ASA group and 10 (1.6%) in the ASA group. Conclusions: The results of the study are inconclusive. Noninferiority of ER-DP plus ASA versus ASA could not be established, a difference between treatments could not be shown for the primary end point. Possible reasons for this result include a small sample size, low event rates and too short a treatment duration. - DERWENT Abstract - This Japanese Aggrenox (Extended-Release (ER) Dipyridamole (DP) + Aspirin) Stroke Prevention versus Aspirin Programme (JASAP), a phase III, randomized, double-blind, parallel-group, active, controlled comparative study evaluated the efficacy and safety of extended-release dipyridamole + aspirin vs. aspirin over 1 yr in 1294 patients with stroke. The incidence of ischemic stroke was 6.9% for extended-release dipyridamole + aspirin-and 5.0% for aspirin-treated patients with a hazard ratio of 1.47 for the primary end point. The aspirin treatment group was lower than expected yearly event rate. The risks of major bleeding events and intracranial hemorrhage were found to be similar between the treatment arms. Noninferiority of extended-release dipyridamole + aspirin vs. aspirin could not be established, a difference between treatments could not be shown for the primary end point. Methods 1294 Patients (925 male, mean age 66.1 yr) with stroke were treated with extended-release dipyridamole (200 mg b.i.d.) + aspirin (25 mg b.i.d.; both p.o.) or aspirin (81 mg/day). Results Recurrent ischemic stroke occurred in 45/652 patients in the extended-release dipyridamole + aspirin group, and in 32/639 patients in the aspirin group. Non-inferiority of extended-release dipyridamole + aspirin vs. aspirin was not shown. The event rate of stroke was significantly higher for extended-release dipyridamole + aspirin vs. aspirin. There was no significant difference between treatment groups for the other secondary end points (cerebral hemorrhage, subarachnoid hemorrhage, transient ischemic attack, acute coronary syndromes, other vascular events, ischemic vascular composite end point, and stroke). Higher modified Rankin Scale values and established end organ damage at baseline had a deleterious effect on the primary outcome, whereas the concomitant therapy with statins had a beneficial effect. There were 4 and 10 deaths in the extended-release dipyridamole + aspirin group in the aspirin group. Adverse events were nasopharyngitis, metabolism and nutrition disorders, headache, eye disorders, vascular disorders, respiratory, thoracic and mediastinal disorders, GI disorders, diarrhea, skin and subcutaneous tissue disorders, musculoskeletal and connective tissue disorders, injury, poisoning and procedural complications, fall, and ischemic stroke.
  • Author:
    Eikelboom JW; Wallentin L; Connolly SJ; Ezekowitz M; Healey JS; Oldgren J; Yang S; Alings M; Kaatz S; Hohnloser SH; Diener HC; Franzosi MG; Huber K; Reilly P; Varrone J; Yusuf S
    Title:
    Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial.
    Source:
    Circulation 123 (21), 2363-NIL-72 (2011)
    Abstract:
    ABSTRACT: Background-Dabigatran 150 and 110 mg twice a day and warfarin are effective for stroke prevention in atrial fibrillation. The purpose of this study was to compare their risks of bleeding in the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) trial. Methods and Results-The RE-LY trial randomized 18 113 patients to receive dabigatran 110 or 150 mg twice a day or warfarin dose adjusted to an international normalized ratio of 2.0 to 3.0 for a median follow-up of 2.0 years. Compared with warfarin, dabigatran 110 mg twice a day was associated with a lower risk of major bleeding (2.87% versus 3.57%; P=0.002), whereas dabigatran 150 mg twice a day was associated with a similar risk of major bleeding (3.31% versus 3.57%; P=0.32). There was a significant treatment-by-age interaction, such that dabigatran 110 mg twice a day compared with warfarin was associated with a lower risk of major bleeding in patients aged <75 years (1.89% versus 3.04%; P<0.001) and a similar risk in those aged >= 75 years (4.43% versus 4.37%; P=0.89; P for interaction <0.001), whereas dabigatran 150 mg twice a day compared with warfarin was associated with a lower risk of major bleeding in those aged <75 years (2.12% versus 3.04%; P<0.001) and a trend toward higher risk of major bleeding in those aged >= 75 years (5.10% versus 4.37%; P=0.07; P for interaction <0.001). The interaction with age was evident for extracranial bleeding, but not for intracranial bleeding, with the risk of the latter being consistently reduced with dabigatran compared with warfarin irrespective of age. Conclusions-In patients with atrial fibrillation at risk for stroke, both doses of dabigatran compared with warfarin have lower risks of both intracranial and extracranial bleeding in patients aged <75 years. In those aged >= 75 years, intracranial bleeding risk is lower but extracranial bleeding risk is similar or higher with both doses of dabigatran compared with warfarin. - DERWENT Abstract - The Authors compared the risks of bleeding in the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) trial involving 18113 patients with atrial fibrillation at risk for stroke who received dabigatran 110 or 150 mg b.i.d. or warfarin dose adjusted to an international normalized ratio of 2.0 to 3.0 for a median follow-up of 2 yr. Both doses of dabigatran exhibited lower risks of both intracranial and extracranial bleeding in patients younger than 75 yr compared with warfarin. Intracranial bleeding risk was lower but extracranial bleeding risk was similar or higher with both doses of dabigatran compared with warfarin in those 75 yr or older. Methods 18113 Patients with atrial fibrillation at risk for stroke were randomized to receive dabigatran 110 mg b.i.d. (n=6015, mean age 71.4 yr, 3865 male), dabigatran 150 mg b.i.d. (n=6076, mean age 71.5 yr, 3840 male) or warfarin dose adjusted to an international normalized ratio of 2.0 to 3.0 (n=6022, mean age 71.6 yr, 3809 male) for a median follow-up of 2 yr. Results Compared with warfarin, dabigatran 110 mg b.i.d. was associated with a lower risk of major bleeding (2.87% vs. 3.57%), whereas dabigatran 150 mg b.i.d. was associated with a similar risk of major bleeding (3.31% vs. 3.57%). There was a treatment-by-age interaction, such that dabigatran 110 mg b.i.d. compared with warfarin was associated with a lower risk of major bleeding in patients younger than 75 yr (1.89% vs. 3.04%) and a similar risk in those 75 yr or older (4.43% vs. 4.37%), whereas dabigatran 150 mg b.i.d. was associated with a lower risk of major bleeding in those younger than 75 yr (2.12% vs. 3.04%) and a trend toward higher risk of major bleeding in those 75 yr or older (5.10% vs. 4.37%) compared with warfarin. The interaction with age was evident for extracranial bleeding, but not the intracranial bleeding, with the risk of the latter being consistently reduced with dabigatran compared with warfarin irrespective of age.
  • Author:
    Sorensen SV; Kansal AR; Connolly S; Peng S; Linnehan J; Bradley-Kennedy C; Plumb JM
    Title:
    Cost-effectiveness of dabigatran etexilate for the prevention of stroke and systemic embolism in atrial fibrillation: A Canadian payer perspective.
    Source:
    Thromb Haemost 105 (5) (SI), 908-919 (2011)
    Abstract:
    Oral dabigatran etexilate is indicated for the prevention of stroke and systemic embolism in patients with atrial fibrillation (AF) in whom anticoagulation is appropriate. Based on the RE-LY study we investigated the cost-effectiveness of Health Canada approved dabigatran etexilate dosing (150 mg bid for patients <80 years, 110 mg bid for patients ?80 years) versus warfarin and "real-world" prescribing (i.e. warfarin, aspirin, or no treatment in a cohort of warfarin-eligible patients) from a Canadian payer perspective. A Markov model simulated AF patients at moderate to high risk of stroke while tracking clinical events [primary and recurrent ischaemic strokes, systemic embolism, transient ischaemic attack, haemorrhage (intracranial, extracranial, and minor), acute myocardial infarction and death] and resulting functional disability. Acute event costs and resulting long-term follow-up costs incurred by disabled stroke survivors were based on a Canadian prospective study, published literature, and national statistics. Clinical events, summarized as events per 100 patient-years, quality-adjusted life years (QALYs), total costs, and incremental cost effectiveness ratios (ICER) were calculated. Over a lifetime, dabigatran etexilate treated patients experienced fewer intracranial haemorrhages (0.49 dabigatran etexilate vs. 1.13 warfarin vs. 1.05 "real-world" prescribing) and fewer ischaemic strokes (4.40 dabigatran etexilate vs. 4.66 warfarin vs. 5.16 "real-world" prescribing) per 100 patient-years. The ICER of dabigatran etexilate was $10,440/QALY versus warfarin and $3,962/QALY versus "real-world" prescribing. This study demonstrates that dabigatran etexilate is a highly cost-effective alternative to current care for the prevention of stroke and systemic embolism among Canadian AF patients. - DERWENT Abstract - The Authors examined the cost-effectiveness of Health Canada approved dabigatran etexilate (DB) dosing vs. warfarin and real-world prescribing from a Canadian payer perspective in patients with atrial fibrillation. Acute event costs and resulting long-term follow-up costs incurred by disabled stroke survivors were based on a Canadian prospective study, published literature, and national statistics. Over a lifetime, DB etexilate treated patients experienced fewer intracranial hemorrhages (ICH) and fewer ischemic strokes per 100 patient-yr. The incremental cost effectiveness ratios (ICER) of DB etexilate was 10440 dollars/QALY vs. warfarin and 3962 dollars/QALY vs. real-world prescribing. Results demonstrate that DB etexilate is a highly cost-effective alternative to current care for the prevention of stroke and systemic embolism among Canadian atrial fibrillation patients. Methods Patients with atrial fibrillation aged less than 80 yr received DB (150 mg b.i.d.) and patients aged 80 yr or more received DB (110 mg b.i.d). Results Compared to trial-like warfarin, patients treated sequentially over a lifetime with DB (150 mg b.i.d.) prior to age 80 and DB (110 mg b.i.d.) at ages 80 or more experienced fewer ICH (0.49 vs. 1.13) and ischemic stroke (4.40 vs. 4.66) events/100 patient-yr, but more extracranial hemorrhages and acute MI events/100 patient-yr. In the real-world prescribing scenario, patients receiving DB experienced fewer ischemic stroke, systemic embolism, transient ischemic attack, and ICH events/100 patient-yr, but more extracranial hemorrhage and acute MI events/100 patient-yr. Follow-up care costs incurred by disabled stroke survivors contributed approximately 60-70% to the total costs incurred/patient. At Canadian dollars (CAD) 3.20/day for either dose, the ICER of sequentially dosed DB vs. trial-like warfarin was CAD 10440. The ICER of DB (150 mg b.i.d.) vs. trial-like warfarin was CAD 9041/QALY, and it was CAD 29994 in the 110 mg b.i.d. group. Significant differences in the cost of INR monitoring while on warfarin also impacted the overall cost-effectiveness of DB. Varying the fraction of patients that achieved good INR control with warfarin from 40 to 80% caused a shift in ICER from CAD 1716/QALY to CAD 23263/QALY. The results of the PSA showed that the ICER of DB dosed sequentially were below an assumed conservative willingness to pay threshold of CAD 30000/QALY vs. trial-like warfarin in 82% of the simulations, and in 99% of the simulations vs. real-world prescribing.
  • Author:
    English J; Hetts St; Smith W; Eisert W
    Title:
    Aggrenox significantly reduces restenosis and plaque burden in cerebrovascular arterial stents.
    Source:
    International Stroke Conference, Los Angeles (United States), Feb 8-10, 2011Stroke 42 (3), E47 (2011)
    Abstract:
    he Authors hypothesized that Aggrenox, a combination of aspirin and sustained-release dipyridamole and an approved therapy for stroke prevention, in comparison to standard medical therapy (aspirin and clopidogrel) reduced restenosis in uncoated cerebrovascular arterial stents in 40 patients in a randomized, open label, blinded, end-point evaluation study. Aggrenox treatment reduced restenosis and percent change in plaque burden. No significant difference in adverse events was noted between the treatment arms. In conclusion, Aggrenox may provide additional benefit beyond stroke prevention and transient ischemic attack (TIA) in patients treated with cerebrovascular arterial stents. Methods 40 Patients treated with extracranial or intracranial cerebrovascular bare metal stents received standard medical therapy (aspirin and clopidogrel) or standard medical therapy+Aggrenox. Patients were randomized to control arm (n=19) or Aggrenox (n=21). Results Treatment with Aggrenox was associated with a reduction of restenosis (control group: 17.9%; Aggrenox group: -2.2%) and percent change in plaque burden (control group: 9.9%; Aggrenox group: -1.1%).
  • Author:
    Fulton RL; Lees KR; Senn S; Bluhmki E; Biegert G; Albers GK; Davis St; Donnan GK; Grotta JC; Hacke W; Kaste M; von Kummer R; Shuaib A; Toni D
    Title:
    Selection for delayed intravenous alteplase treatment based on prognostic score.
    Source:
    Stroke 42 (3), E112 (2011)
  • Author:
    Zalewski J; Bogaerts K; Desmet W; Sinnaeve P; Berger P; Grines C; Danays T; Armstrong P; Van de Werf F
    Title:
    Intraluminal thrombus in facilitated versus primary percutaneous coronary intervention an angiographic substudy of the ASSENT-4 PCI (Assessment of the safety and efficacy of a new treatment strategy with percutaneous coronary intervention) trial.
    Source:
    J Am Coll Cardiol 57 (19), 1867-1873 (2011)
    Abstract:
    Objectives: This study investigated the occurrence of intraluminal thrombus and its potential implications with facilitated percutaneous coronary interventions (fPCIs). Background: The effect of fPCI on the presence and consequences of intraluminal thrombus is unknown. Methods: Thrombolysis In Myocardial Infarction (TIMI) flow grade, frame count, and thrombus grade; distal embolization; and slow flow in the infarct-related artery were assessed in a blinded fashion on coronary angiograms in 1,342 patients from the ASSENT-4 PCI (Assessment of the Safety and Efficacy of a New Treatment Strategy With Percutaneous Coronary Intervention) trial. Residual TIMI thrombus grade <2 and/or distal embolization and/or slow flow, reflecting thrombus burden (TB), following PCI were correlated with ST-segment resolution, epicardial blood flow, and clinical outcome. The clinical composite endpoint was death, congestive heart failure, or shock. Results: In the fPCI group, more TIMI flow grade 2/3 in the infarct-related artery at the first angiogram (73.7% vs. 33.4%, p < 0.001) and a higher TB following PCI (19.7% vs. 13.4%, p = 0.002) were found in comparison with the primary PCI group. Post-PCI TIMI thrombus grade was significantly associated with ST-segment resolution (p < 0.001) and TIMI frame count (p < 0.0001) in both groups. In the fPCI group, the presence of post-PCI thrombus was associated with a significantly worse outcome at 90 days (clinical composite endpoint: 32.1% vs. 18.6%, p = 0.023). Multivariable logistic regression showed that facilitation with tenecteplase (p = 0.005) and TB (odds ratio: 2.43, 95% confidence interval: 1.30 to 4.51, p = 0.0052) were independent predictors of 90-day mortality. Conclusions: In ASSENT-4 PCI, despite more patency, residual TB was significantly higher in fPCI patients and was associated with less efficient tissue reperfusion and worse clinical outcomes. (A Trial Evaluating the Efficacy and Safety of Tenecteplase Together With Unfractionated Heparin Prior to Early Percutaneous Coronary Intervention [PCI] as Compared to Standard Primary PCI in Patients With Acute Myocardial Infarction [ASSENT-4 PCI]; NCT00168792). - DERWENT Abstract - This study (NCT00168792) examined the occurrence of intraluminal thrombus and its potential implications with facilitated percutaneous coronary intervention (fPCI) in 1342 patients from the ASSENT-4 PCI trial. The patients were assigned to either fPCI (group A, GA) or primary PCI (pPCI) (GB). Post-PCI Thrombolysis in MI (TIMI) thrombus grade (TTG) was associated with ST-segment resolution (STR) and TIMI frame count in both groups. In GA, the presence of post-PCI thrombus was associated with worse outcome at 90 days. Facilitation with tenecteplase and TB were identified as independent predictors of 90-day mortality in a multivariate analysis. In ASSENT-4 PCI, despite more patency, residual TB was higher in fPCI patients and was associated with less efficient tissue reperfusion and worse clinical outcomes. Methods The occurrence of intraluminal thrombus and its potential implications with fPCI were investigated in 1342 patients from the ASSENT-4 PCI trial. The patients were assigned to either fPCI (GA, n=656, mean age 60.8 yr, 497 male) or pPCI (GB, n=686, mean age 59.9 yr, 527 male). Results A clopidogrel loading dose after the procedure and glycoprotein IIb/IIIa inhibitors before and after PCI were more frequent in GB vs. GA. The clinical composite endpoint (death, CHF, or shock 90 days postrandomization) and reinfarction rates were higher in GA at 30 and 90 days, and by 90 days, there was also a tendency for excess death, CHF, and shock in GA. After fibrinolytic therapy, higher rates of TTG 0 to 3 were seen in GA, and more frequent TTG 5 was present in GB. During PCI, more patent vessels without thrombosis were found in GA, while more arteries with medium-size thrombus (TTG 2/3) were present in GB. After PCI, no significant differences in TTG were present. However, trends toward more distal embolization and large (TTG 2 or greater) residual thrombus were seen in GA. The calculated TB was greater in GA (19.7% vs. 13.%, GB). The relationship between post-PCI TTG and TIMI frame counts was significant in GA vs. GB but different between the groups. GA had higher STR at 60 min (38.6% vs. 28.6%), while STR at 180 min was similar in the 2 groups (71.4% vs. 71.2%). Compared to GB, in GA, post-PCI TTG 1 to 5 was associated with a higher risk of combined clinical endpoint and TTG 0 with a higher risk of reinfarction. Multivariable logistic regression showed that facilitation with tenecteplase and TB were independent predictors of 90-day mortality.
  • Author:
    Eriksson BI; Dahl OE; Huo MH; Kurth AA; Hantel S; Hermansson K; Schnee JM; Friedman RJ
    Title:
    Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (re-novate II) a randomised, double-blind, non-inferiority trial.
    Source:
    Thromb Haemost 105 (4), 721-7289 (2011)
    Abstract:
    This trial compared the efficacy and safety of oral dabigatran, a direct thrombin inhibitor, versus subcutaneous enoxaparin for extended thromboprophylaxis in patients undergoing total hip arthroplasty. A total of 2,055 patients were randomised to 28-35 days treatment with oral dabigatran, 220 mg once-daily, starting with a half-dose 1-4 hours after surgery, or subcutaneous enoxaparin 40 mg once-daily, starting the evening before surgery. The primary efficacy outcome was a composite of total venous thromboembolism [VTE] (venographic or symptomatic) and death from all-causes. The main secondary composite outcome was major VTE (proximal deep-vein thrombosis or non-fatal pulmonary embolism) plus VTE-related death. The main safety outcome was major bleeding. In total, 2,013 were treated, of whom 1,577 operated patients were included in the primary efficacy analysis. The primary efficacy outcome occurred in 7.7% of the dabigatran group versus 8.8% of the enoxaparin group, risk difference (RD) -1.1% (95%CI - 3.8 to 1.6%); p<0.0001 for the pre-specified non-inferiority margin. Major VTE plus VTE-related death occurred in 2.2% of the dabigatran group versus 4.2% of the enoxaparin group, RD -1.9% (-3.6% to -0.2%); p=0.03. Major bleeding occurred in 1.4% of the dabigatran group and 0.9% of the enoxaparin group (p=0.40). The incidence of adverse events, including liver enzyme elevations and cardiac events, during treatment was similar between the groups. Extended prophylaxis with oral dabigatran 220 mg once-daily was as effective as subcutaneous enoxaparin 40 mg once-daily in reducing the risk of VTE after total hip arthroplasty, and superior to enoxaparin for reducing the risk of major VTE. The risk of bleeding and safety profiles were similar.
  • Author:
    Hori M; Connolly SJ; Yusuf S; Ezekowitz MD; Reilly PA; Wallentin L
    Title:
    Efficacy and safety of dabigatran vs. warfarin in patients with atrial fibrillation - sub-analysis in Japanese population in RE-LY trial.
    Source:
    Circ J 75 (4), 800-805 (2011)
    Abstract:
    Background: RE-LY (Randomized Evaluation of Long-term Anticoagulation Therapy) is an international multi-center study (18,113 patients from 967 centers in 44 countries) that demonstrated the ability of dabigatran to reduce the occurrence of both stroke and hemorrhage in patients who had atrial fibrillation (AF) with high risks of stroke compared with patients who received warfarin. From Japan, 326 patients were randomized in RE-LY. Methods and Results: RE-LY was designed to compare 2 fixed doses (110 mg or 150 mg, twice daily) of dabigatran, each administered in a blinded manner, with open-label use of warfarin. There were no major differences in patient demographic information among the overall study population and Japanese patients. However. in Japanese patients, the proportion of prior stroke was higher but prior myocardial infarction was lower than in the overall. The yearly rate for the primary endpoints (stroke and systemic embolism) was 1.38, 0.67 and 2.65%/year for 110 mg and 150 mg dabigatran twice daily and warfarin, respectively. These results were similar to the overall results (1.54, 1.11 and 1.71%/year for each group, respectively). For any bleeding, the relative risk of dabigatran at 110 mg and 150 mg twice daily over warfarin was 0.79 and 1.06, respectively, which was similar to the findings overall (dabigatran 110 mg twice daily: 0.78; 150 mg twice daily: 0.91). Conclusions: In RE-LY, the efficacy and safety profiles of dabigatran for Japanese AF patients at high risk of stroke were essentially the same as for the study population overall. - DERWENT Abstract - The Authors reported on data from 326 Japanese patients involved in RE-LY, an international multicenter study of 18113 patients from 967 centers in 44 countries that demonstrated the ability of dabigatran to reduce the occurrence of both stroke and hemorrhage in patients who had atrial fibrillation (AF) with high risks of stroke compared with patients who received warfarin. In Japanese patients, the proportion of prior stroke was higher but prior MI was lower than in the overall. Yearly rates for stroke and systemic embolism (SEE) for 110 mg and 150 mg dabigatran b.i.d. (DE110 and DE150) and warfarin were similar to the overall. For any bleeding, the relative risks (RR) of DE110 and DE150 over warfarin were similar to the overall. Efficacy and safety profiles of dabigatran for Japanese AF patients at high risk of stroke are essentially the same as for the study population overall. The yearly rates far stroke/SEE were 1.38%/yr, 0.67%/yr, and 2.65%/yr in the DE110, DE150, and warfarin groups, respectively, and were comparable with the yearly rates for stroke/SEE in the overall study population (1.54%/yr, 1.11%/yr, and 1.71%/yr in the DE110, DE150, and warfarin groups, respectively). No SEE occurred in the dabigatran groups. The RR for stroke/SEE with DE110 and DE150 over warfarin in the Japanese patient population was 0.52 and 0.25, respectively. In the overall study population, both doses of dabigatran were noninferior to warfarin but DE150 was superior to warfarin for the primary efficacy end point (stroke/SEE). The RR for stroke/SEE using DE110 and DE150 was 0.90 and 0.65, respectively. In the Japanese patients, MI did not occur during the trial in any of the groups. Among the Japanese patients, there were 18 major bleeding events: 8 for the DE110 group, 5 for the DE150 group, and 5 for the warfarin group (yearly rate: DL110, 5.53%/yr; DE150, 3.33%/yr; warfarin, 3.31%/yr). These results were not heterogeneous compared with the overall study results. Regarding the GI major bleeding, the yearly rate for the DE110, DE150, and warfarin groups of Japanese patients was 2.11, 0.67, and 0.67, respectively. For minor bleeding, the yearly rate for the DE110, DE150, and warfarin groups of Japanese patients was 24.19%/yr, 33.26%/yr, and 33.14%/yr (13.16%/yr, 14.85%/yr, and 16.37%/yr in the overall population, respectively). For any bleeding, the RR of DE110 and DE150 over warfarin was 0.79 and 1.06, respectively, and these patterns were similar to those in the overall study population (DE110, 0.78; DE150, 0.91).
  • Author:
    Libonati JR; MacDonnel SM
    Title:
    Cardiac beta-adrenergic responsiveness with exercise.
    Source:
    Eur J Appl Physiol 111 (11), 2735-2741 (2011)
    Abstract:
    Left ventricular performance is enhanced with chronic exercise training. Alterations in cardiomyocyte ?-adrenergic responsiveness (BAR) may, in part, mediate this response. In this study, cardiac BAR and the expression of some key cardiac hypertrophic signaling molecules following 3 months of treadmill training were examined. Four-month old, female, Wistar Kyoto (WKY) rats were randomly assigned into either a sedentary (WKY-SED, n = 15) or an exercise-trained (WKY-TRD, n = 11) group. All rats were maintained on a 12-h light/dark cycle, and fed ad libitum. Exercise training consisted of motorized treadmill training at 25 m/min, 0% grade, 60 continuous minutes, 5 days/week for a period of 12 weeks. RT-PCR was used to establish basal cardiac calcineurin A, ANP, and AKT mRNA expression. In vitro cardiac BAR responsiveness was determined in Langendorff, isolated hearts. Following baseline, isoproterenol (ISO) was incrementally infused at concentrations ranging from 1 × 10-10 to 1 × 10-7 mol/L. There were no group differences for heart weight, heart to body weight ratio, calcineurin A, ANP, or AKT mRNA levels between WKY-SED and WKY-TRD. WKY-TRD showed enhanced cardiac BAR relative to WKY-SED (at ISO 1 × 10-7 mol/L; P &lt; 0.05). Moderate intensity treadmill exercise improved cardiac BAR responsiveness to a high concentration of isoproterenol. This adaptation was independent of training-induced alterations in cardiac hypertrophy or hypertrophic marker expression.
  • Author:
    Mueller S; Wilke T; Pfannkuche M; Messer I; Kurth A; Merk H; Steinfeldt F; Ganzer D; Perka C
    Title:
    Patient pathways in thrombosis prophylaxis after hip and knee replacement surgery - results of a survey.
    Source:
    Orthopaede 40 (7), 585-590 (2011)
    Abstract:
    A key element of patient care after hip and knee replacement is medication-based thrombosis prophylaxis. Due to decreasing lengths of acute hospital stays the question arises to what extent outpatients are taking responsibility thrombosis prophylaxis (patient pathway analysis). To analyze patient pathways a telephone survey of 668 patients was conducted. On average patients were interviewed 38 days following surgery with a focus on low molecular weight heparins. The analysis showed that nearly 90% of patients need to carry out thrombosis prophylaxis in an outpatient or home environment for at least 1 day and for 47.2% of patients a linking period between acute and rehabilitation stay is relevant. The obviously existing quantitative importance of outpatient thrombosis prophylaxis is also reflected by its duration and 45.7% of interviewed patients needed at least 5 days of outpatient prophylaxis. Outpatient thrombosis prophylaxis clearly makes high demands on the patients, in particular when combined with the task of administering complex forms of injections. Those involved in inpatient and outpatient provision of care should not assume that all patients carry out the necessary prophylaxis at the required level of reliability. On the contrary initial evidence shows that the non-adherence of patients during ambulatory thrombosis prophylaxis presents a genuine challenge to care providers.
  • Author:
    Charles RL; Burgoyne JR; Eaton Ph; Mayr M; Weldon StM; Hubner N; Dong H; Morisseau Ch; Hammock BD; Landar A
    Title:
    Redox regulation of soluble epoxide hydrolase by 15-Deoxy.-delta.-prostaglandin J2 controls coronary hypoxic vasodilation.
    Source:
    Circ Res 108 (3), 324-334 (2011)
    Abstract:
    Rationale: 15-Deoxy-.DELTA.-prostaglandin (15d-PG)J2 is an electrophilic oxidant that dilates the coronary vasculature. This lipid can adduct to redox active protein thiols to induce oxidative posttranslational modifications that modulate protein and tissue function. Objective: To investigate the role of oxidative protein modifications in 15d-PGJ 2-mediated coronary vasodilation and define the distal signaling pathways leading to enhanced perfusion. Methods and Results: Proteomic screening with biotinylated 15d-PGJ2 identified novel vascular targets to which it adducts, most notably soluble epoxide hydrolase (sEH). 15d-PGJ 2 inhibited sEH by specifically adducting to a highly conserved thiol (Cys521) adjacent to the catalytic center of the hydrolase. Indeed a Cys521Ser sEH "redox-dead" mutant was resistant to 15d-PGJ2-induced hydrolase inhibition. 15d-PGJ2 dilated coronary vessels and a role for hydrolase inhibition was supported by 2 structurally different sEH antagonists each independently inducing vasorelaxation. Furthermore, 15d-PGJ2 and sEH antagonists also increased coronary effluent epoxyeicosatrienoic acids consistent with their vasodilatory actions. Indeed 14,15-EET alone induced relaxation and 15d-PGJ2-mediated vasodilation was blocked by the EET receptor antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE). Additionally, the coronary vasculature of sEH-null mice was basally dilated compared to wild-type controls and failed to vasodilate in response to 15d-PGJ2. Coronary vasodilation to hypoxia in wild-types was accompanied by 15d-PGJ2 adduction to and inhibition of sEH. Consistent with the importance of hydrolase inhibition, sEH-null mice failed to vasodilate during hypoxia. CONCLUSION:: This represents a new paradigm for the regulation of sEH by an endogenous lipid, which is integral to the fundamental physiological response of coronary hypoxic vasodilation.
  • Author:
    Mercaldi CJ; Ciarametaro M; Hahn B; Chalissery G; Reynolds MW; Sander SD; Samsa GP; Matchar DB
    Title:
    Cost efficiency of anticoagulation with warfarin to prevent stroke in medicare beneficiaries with nonvalvular atrial fibrillation.
    Source:
    Stroke 42 (1), 112-118 (2011)
    Abstract:
    Background and Purpose-In controlled trials, anticoagulation with warfarin reduces stroke risk by nearly two thirds, but the benefit has been less pronounced in clinical practice. This report describes the extent of warfarin use, its effectiveness, and its impact on medical costs among Medicare patients with nonvalvular atrial fibrillation. Methods-Using claims from >2 million beneficiaries in the Centers for Medicare and Medicaid Services 5% Sample Standard Analytic Files, we identified patients with nonvalvular atrial fibrillation from 2004 to 2005. Warfarin use was inferred from 3 or more tests of the international normalized ratio within 1 year. Incidence of ischemic/hemorrhagic stroke and major bleeding was evaluated. Adjusted risk was calculated by Cox proportional-hazards regression. Medical costs (reimbursed amounts in 2006 US dollars) were estimated by multivariate linear regression. Results-Of patients with nonvalvular atrial fibrillation (N = 119 764, mean age = 79.3 years), 58.5% were categorized as warfarin users based on the study definition. During an average of 2.1 years' follow-up, the rate of ischemic stroke was 3.9 per 100 patient-years. After multivariate adjustment, ischemic stroke incidence was 27% lower in patients taking warfarin than in patients not taking warfarin (P<0.0001), with no increase in hemorrhagic stroke and a slightly elevated risk of a major bleed. Use of warfarin was independently associated with lower total medical costs, averaging $9836 per patient per year. Conclusions-These results indicate that 41.5% of Medicare patients with nonvalvular atrial fibrillation are not anticoagulated with warfarin. The incidence of stroke and overall medical costs were significantly lower in patients treated with warfarin. - DERWENT Abstract - This study evaluated the extent of warfarin use, its effectiveness, and its impact on medical costs among 119764 Medicare patients with nonvalvular atrial fibrillation. During an average of 2.1 yr follow-up, the rate of ischemic stroke was 3.9 per 100 patient-yr. After multivariate adjustment, ischemic stroke incidence was 27% lower in patients taking warfarin than in patients not taking warfarin, with no increase in hemorrhagic stroke and a slightly elevated risk of a major bleed. Use of warfarin was independently associated with lower total medical costs, averaging 9836 US dollars per patient per yr. Thus, 41.5% of Medicare patients with nonvalvular atrial fibrillation are not anticoagulated with warfarin.
  • Author:
    Nagarakanti R; Ezekowitz MD; Oldgren J; Yang S; Chernick M; Aikens TH; Flaker G; Brugada J; Kamensky G; Parekh A; Reilly PA; Yusuf S; Connolly SJ
    Title:
    Dabigatran versus warfarin in patients with atrial fibrillation: an analysis of patients undergoing cardioversion.
    Source:
    Circulation 123 (2), 131-136 (2011)
    Abstract:
    Background-: The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial compared dabigatran 110 mg BID (D110) and 150 mg BID (D150) with warfarin for stroke prevention in 18 113 patients with nonvalvular atrial fibrillation. Methods and results-: Cardioversion on randomized treatment was permitted. Precardioversion transesophageal echocardiography was encouraged, particularly in dabigatran-assigned patients. Data from before, during, and 30 days after cardioversion were analyzed. A total of 1983 cardioversions were performed in 1270 patients: 647, 672, and 664 in the D110, D150, and warfarin groups, respectively. For D110, D150, and warfarin, transesophageal echocardiography was performed before 25.5%, 24.1%, and 13.3% of cardioversions, of which 1.8%, 1.2%, and 1.1% were positive for left atrial thrombi. Continuous treatment with study drug for .gtoreq.3 weeks before cardioversion was lower in D110 (76.4%) and D150 (79.2%) compared with warfarin (85.5%; P<0.01 for both). Stroke and systemic embolism rates at 30 days were 0.8%, 0.3%, and 0.6% (D110 versus warfarin, P=0.71; D150 versus warfarin, P=0.40) and similar in patients with and without transesophageal echocardiography. Major bleeding rates were 1.7%, 0.6%, and 0.6% (D110 versus warfarin, P=0.06; D150 versus warfarin, P=0.99). Conclusions-: This study is the largest cardioversion experience to date and the first to evaluate a novel anticoagulant in this setting. The frequencies of stroke and major bleeding within 30 days of cardioversion on the 2 doses of dabigatran were low and comparable to those on warfarin with or without transesophageal echocardiography guidance. Dabigatran is a reasonable alternative to warfarin in patients requiring cardioversion.
  • Author:
    Rabe E; Stuecker M; Esperester A; Schaefer E; Ottillinger B
    Title:
    Efficacy and tolerability of a red-vine-leaf extract in patients: Suffering from chronic venous insufficiency - results of a double-blind placebo-controlled study.
    Source:
    Eur J Vasc Endovasc Surg 41 (4), 540-547 (2011)
    Abstract:
    Objectives: The aim of this study was to investigate the effect of a red-vine-leaf extract (AS195, Antistax<sup>®</sup>, Boehringer Ingelheim Pharma GmbH &amp; Co. KG, Ingelheim, Germany) on the volume of the leg and clinical symptoms in patients with chronic venous insufficiency (CVI). Design, materials and methods: A multicentre, randomised, double-blind and placebo-controlled study was carried out with 720 mg AS195 per day over 12 weeks in CVI patients (CEAP Grades 3-4a) and moderate-to-severe clinical symptoms. Efficacy endpoints were changes in limb volume determined by water displacement volumetry, clinical CVI symptoms assessed on a 10-cm visual analogue scale and global efficacy evaluations. Results: The full-analysis set included 248 patients (placebo: n = 122; AS195: n = 126). After 12 weeks, AS195 significantly reduced lower limb volume by a mean of 19.9 standard error (SE) 8.9 ml over placebo (95% confidence interval (CI): -37.5, -2.3; p = 0.0268; analysis of covariance, ANCOVA). The standardised effect size of 0.28 for volume reduction indicates a clinically relevant effect. On Day 84, the symptom of 'pain in the legs' assessed by visual analogue scale decreased in the AS195 group compared with the placebo group: mean difference -6.6 SD 3.3 mm (95% CI: -13.1,-0.1; p = 0.047). Other symptoms showed no significant change. The tolerability of AS195 was similar to that of placebo. Conclusions: AS195 treatment for 84 days resulted in an approximately 20 ml reduction of limb volume in the active treatment group compared with the placebo group. Patients reported subjective improvement following treatment with AS195 compared with placebo. However, patients' overall rating of efficacy did not correlate well with measured reductions in limb volume. Trial Registration: ClinicalTrials.gov NCT00855179.
  • Author:
    Anderson C; Teo K; Gao P; Arima H; Dans A; Unger T; Commerford P; Dyal L; Schumacher H; Pogue J; Paolasso E; Holwerda N; Chazova I; Binbrek A; Young J; Yusuf B
    Title:
    Renin-angiotensin system blockade and cognitive function in patients at high risk of cardiovascular disease: analysis of data from the ONTARGET and TRANSCEND studies.
    Source:
    Lancet Neurol 10 (1), 43-53 (2011)
    Abstract:
    Background: Cardiovascular risk factors are associated with dementia and cognitive decline. We investigated the effects of renin-angiotensin system blockade on cognitive function in patients aged 55 years and older with established atherosclerotic cardiovascular disease or diabetes with end-organ damage in two clinical trials. Methods: In the main study, ONTARGET, a double-blind, double-dummy, randomised controlled trial, the effects on cardiovascular outcomes of standard doses of an angiotensin-converting enzyme (ACE) inhibitor (ramipril), an angiotensin-receptor blocker (telmisartan), and a combination of the drugs were evaluated in 25 620 participants. In the parallel TRANSCEND trial, the effects of telmisartan were compared with those of placebo in 5926 participants intolerant to ACE inhibitors. Secondary outcomes included cognitive impairment (defined by investigator-reported diagnosis of dementia or significant cognitive dysfunction, or a score of ?23 on the Mini-Mental State Examination [MMSE]) and cognitive decline (a decrease of ?3 points on the MMSE from baseline during follow-up). Analyses were by intention to treat. We pooled data from these studies to identify baseline predictors of cognitive impairment and its frequency according to mean systolic blood pressure during follow-up. These studies were registered with ClinicalTrials.gov, number NCT00153101. Findings: During a median duration of 56 months (IQR 51-64) of follow-up in ONTARGET, cognitive impairment occurred in 652 (8%) of 7865 patients allocated ramipril, 584 (7%) of 7797 allocated telmisartan, and 618 (8%) of 7807 allocated combination treatment (combination vs ramipril, odds ratio [OR] 0·95, 95% CI 0·85-1·07, p=0·39; telmisartan vs ramipril, OR 0·90, 0·80-1·01, p=0·06). Corresponding figures for cognitive decline were 1314 (17%), 1279 (17%), and 1240 (17%) in each of the groups, respectively (telmisartan vs ramipril, OR 0·97, 0·89-1·06, p=0·53; combination vs ramipril, OR 0·95, 0·88-1·04, p=0·28). In TRANSCEND, cognitive impairment occurred in 239 (9%) of 2694 participants allocated telmisartan compared with 245 (9%) of 2689 allocated placebo (OR 0·97, 0·81-1·17, p=0·76). The corresponding figures for cognitive decline were 454 (17%) and 412 (16%; OR 1·10, 0·95-1·27, p=0·22). Interpretation: In patients with cardiovascular disease or diabetes, different approaches to blocking of the renin-angiotensin system had no clear effects on cognitive outcomes. Although patients with the lowest systolic blood pressure had the greatest preservation of cognitive function, meta-regression analyses did not show any benefits of blood-pressure lowering on cognition over several years of treatment. Funding: Boehringer-Ingelheim.
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