Genetic determinants of dabigatran plasma levels and their relation to bleeding.


BACKGROUND:Fixed-dose unmonitored treatment with dabigatran etexilate is effective and has a favorable safety profile in the prevention of stroke in atrial fibrillation patients compared with warfarin. We hypothesized that genetic variants could contribute to interindividual variability in blood concentrations of the active metabolite of dabigatran etexilate and influence the safety and efficacy of dabigatran. METHODS AND RESULTS:We successfully conducted a genome-wide association study in 2944 Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) participants. The CES1 single-nucleotide polymorphism rs2244613 was associated with trough concentrations, and the ABCB1 single-nucleotide polymorphism rs4148738 and the CES1 single-nucleotide polymorphism rs8192935 were associated with peak concentrations at genome-wide significance (P<9×10(-8)) with a gene-dose effect. Each minor allele of the CES1 single-nucleotide polymorphism rs2244613 was associated with lower trough concentrations (15% decrease per allele; 95% confidence interval, 10-19; P=1.2×10(-8)) and a lower risk of any bleeding (odds ratio, 0.67; 95% confidence interval, 0.55-0.82; P=7×10(-5)) in dabigatran-treated participants, with a consistent but nonsignificant lower risk of major bleeding (odds ratio, 0.66; 95% confidence interval, 0.43-1.01). The interaction between treatment (warfarin versus all dabigatran) and carrier status was statistically significant (P=0.002), with carriers having less bleeding with dabigatran than warfarin (hazard ratio, 0.59; 95% confidence interval, 0.46-0.76; P=5.2×10(-)5) in contrast to no difference in noncarriers (hazard ratio, 0.96; 95% confidence interval, 0.81-1.14; P=0.65). There was no association with ischemic events, and neither rs4148738 nor rs8192935 was associated with bleeding or ischemic events. CONCLUSIONS:Genome-wide association analysis identified that carriage of the CES1 rs2244613 minor allele occurred in 32.8% of patients in RE-LY and was associated with lower exposure to active dabigatran metabolite. The presence of the polymorphism was associated with a lower risk of bleeding. CLINICAL TRIAL REGISTRATION:URL: Unique identifier: NCT00262600.






Paré G,Eriksson N,Lehr T,Connolly S,Eikelboom J,Ezekowitz MD,Axelsson T,Haertter S,Oldgren J,Reilly P,Siegbahn A,Syvanen AC,Wadelius C,Wadelius M,Zimdahl-Gelling H,Yusuf S,Wallentin L




Has Abstract


2013-04-02 00:00:00














  • Human C-reactive protein does not promote atherosclerosis in transgenic rabbits.

    abstract:BACKGROUND:Although there is a statistically significant association between modestly raised baseline plasma C-reactive protein (CRP) values and future cardiovascular events, the debate is still unsettled in regard to whether CRP plays a causal role in the pathogenesis of atherosclerosis. METHODS AND RESULTS:We genera...


    pub_type: 杂志文章


    authors: Koike T,Kitajima S,Yu Y,Nishijima K,Zhang J,Ozaki Y,Morimoto M,Watanabe T,Bhakdi S,Asada Y,Chen YE,Fan J

    更新日期:2009-11-24 00:00:00

  • Peripartum cardiomyopathy as a part of familial dilated cardiomyopathy.

    abstract:BACKGROUND:Anecdotal cases of familial clustering of peripartum cardiomyopathy (PPCM) and familial occurrences of PPCM and idiopathic dilated cardiomyopathy (DCM) together have been observed, suggesting that genetic factors play a role in the pathogenesis of PPCM. We hypothesized that some cases of PPCM are part of the...


    pub_type: 杂志文章


    authors: van Spaendonck-Zwarts KY,van Tintelen JP,van Veldhuisen DJ,van der Werf R,Jongbloed JD,Paulus WJ,Dooijes D,van den Berg MP

    更新日期:2010-05-25 00:00:00

  • Randomized trial of acupuncture to lower blood pressure.

    abstract:BACKGROUND:Arterial hypertension is a prime cause of morbidity and mortality in the general population. Pharmacological treatment has limitations resulting from drug side effects, costs, and patient compliance. Thus, we investigated whether traditional Chinese medicine acupuncture is able to lower blood pressure. METH...


    pub_type: 杂志文章,随机对照试验


    authors: Flachskampf FA,Gallasch J,Gefeller O,Gan J,Mao J,Pfahlberg AB,Wortmann A,Klinghammer L,Pflederer W,Daniel WG

    更新日期:2007-06-19 00:00:00

  • Cardiac mortality is higher around Christmas and New Year's than at any other time: the holidays as a risk factor for death.

    abstract:BACKGROUND:Research published in Circulation has shown that cardiac mortality is highest during December and January. We investigated whether some of this spike could be ascribed to the Christmas/New Year's holidays rather than to climatic factors. METHODS AND RESULTS:We fitted a locally weighted polynomial regression...


    pub_type: 杂志文章,评审


    authors: Phillips DP,Jarvinen JR,Abramson IS,Phillips RR

    更新日期:2004-12-21 00:00:00

  • Coagulant activities of platelets in coronary artery disease.

    abstract::Platelets have been implicated in the pathogenesis of coronary artery disease, and a number of studies have examined platelet function and coagulation parameters in such patients. We have examined platelet coagulant activities, volumes, and aggregate ratios in 23 patients with chest pain, seven of whom had normal coro...


    pub_type: 杂志文章


    authors: Rao AK,Mintz PD,Lavine SJ,Bove AA,McDonough MT,Spann JF,Walsh PN

    更新日期:1984-01-01 00:00:00

  • Direct evidence for cytokine involvement in neointimal hyperplasia.

    abstract:BACKGROUND:Tumor necrosis factor-alpha (TNF-alpha) and interleukin 1 (IL-1) are proximal inflammatory cytokines that stimulate expression of adhesion molecules and induce synthesis of other proinflammatory cytokines. In addition, TNF-alpha and IL-1 influence vascular smooth muscle cell migration and proliferation in vi...


    pub_type: 杂志文章


    authors: Rectenwald JE,Moldawer LL,Huber TS,Seeger JM,Ozaki CK

    更新日期:2000-10-03 00:00:00

  • ERG-APLNR axis controls pulmonary venule endothelial proliferation in pulmonary veno-occlusive disease.

    abstract:BACKGROUND:Pulmonary veno-occlusive disease is caused by excessive cell proliferation and fibrosis, which obliterate the lumen of pulmonary venules, leading to pulmonary hypertension, right ventricular failure, and death. This condition has no effective treatment and a 5-year survival of <5%. Understanding the mechanis...


    pub_type: 杂志文章


    authors: Lathen C,Zhang Y,Chow J,Singh M,Lin G,Nigam V,Ashraf YA,Yuan JX,Robbins IM,Thistlethwaite PA

    更新日期:2014-09-30 00:00:00

  • Premortem assessment of myocardial area at risk with the use of intracoronary technetium macroaggregated albumin and gated nuclear imaging.

    abstract::The purpose of this study was to develop a clinically applicable system for quantifying premortem myocardial area at risk. Coronary artery occlusion was performed in 18 closed-chest dogs (11 left anterior descending and seven circumflex). 99mTc (15 mCi)-labeled macroaggregated albumin was then injected through an angi...


    pub_type: 杂志文章


    authors: Feiring AJ,Bruch P,Husayni TS,Kirchner PT,Marcus ML

    更新日期:1986-03-01 00:00:00

  • Parvovirus B19 infection mimicking acute myocardial infarction.

    abstract:BACKGROUND:Enteroviruses (EVs) and adenoviruses (ADVs) have been considered common causes of myocarditis and dilated cardiomyopathy. In the present study, we report on the association of parvovirus B19 (PVB19) genomes in the clinical setting of acute myocarditis. METHODS AND RESULTS:This study included 24 consecutive ...


    pub_type: 杂志文章


    authors: Kühl U,Pauschinger M,Bock T,Klingel K,Schwimmbeck CP,Seeberg B,Krautwurm L,Poller W,Schultheiss HP,Kandolf R

    更新日期:2003-08-26 00:00:00

  • L-4F, an apolipoprotein A-1 mimetic, restores nitric oxide and superoxide anion balance in low-density lipoprotein-treated endothelial cells.

    abstract:BACKGROUND:Low-density lipoprotein (LDL) impairs endothelial cell function by uncoupling endothelial nitric oxide synthase (eNOS) activity, which allows superoxide anion (O2*-)) to be generated rather than nitric oxide (*NO). Recent reports indicate that apolipoprotein (apo) A-1 mimetics inhibit the development of athe...


    pub_type: 杂志文章


    authors: Ou Z,Ou J,Ackerman AW,Oldham KT,Pritchard KA Jr

    更新日期:2003-03-25 00:00:00

  • Medical Therapy for Systemic Right Ventricles: A Systematic Review (Part 1) for the 2018 AHA/ACC Guideline for the Management of Adults With Congenital Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on

    abstract::Patients with systemic morphological right ventricles (RVs), including congenitally corrected transposition of the great arteries and dextro-transposition of the great arteries with a Mustard or Senning atrial baffle repair, have a high likelihood of developing systemic ventricular dysfunction. Unfortunately, there ar...


    pub_type: 杂志文章,meta分析


    authors: Zaragoza-Macias E,Zaidi AN,Dendukuri N,Marelli A

    更新日期:2019-04-02 00:00:00

  • Ticlopidine and clopidogrel.

    abstract::The thienopyridines ticlopidine and clopidogrel are inhibitors of platelet function in vivo. Their mode of action has not been defined, but it appears that they require conversion to as yet unidentified metabolites that are noncompetitive antagonists of the platelet ADP receptor. Inhibition of platelet aggregation wit...


    pub_type: 杂志文章,评审


    authors: Quinn MJ,Fitzgerald DJ

    更新日期:1999-10-12 00:00:00

  • Quantitative measurements of cardiac phosphorus metabolites in coronary artery disease by 31P magnetic resonance spectroscopy.

    abstract:BACKGROUND:31P metabolite measurements in the human heart by magnetic resonance spectroscopy (MRS) have been reported previously. By use of a method in which metabolite content was quantified with reference to a standard located outside the chest, it has become possible to measure the content of phosphocreatine (PCr) a...


    pub_type: 杂志文章


    authors: Yabe T,Mitsunami K,Inubushi T,Kinoshita M

    更新日期:1995-07-01 00:00:00

  • Evidence for a reversible oxygen radical-mediated component of reperfusion injury: reduction by recombinant human superoxide dismutase administered at the time of reflow.

    abstract::It has been suggested that the beneficial effects of reperfusing ischemic myocardium might be in part reversed by the occurrence of "reperfusion injury." One possible mechanism could be the generation of oxygen free radicals. Superoxide dismutase enzymatically scavenges superoxide radicals by dismutation to hydrogen p...


    pub_type: 杂志文章


    authors: Ambrosio G,Weisfeldt ML,Jacobus WE,Flaherty JT

    更新日期:1987-01-01 00:00:00

  • Surgical treatment of aneurysms of the ascending aorta.

    abstract::From January 1970 to April 1975, 132 patients underwent surgical repair of aneurysms of the ascending aorta at this institution, 24 of whom had acute dissections. In almost all cases the ascending aorta was replaced with a Dacron tube graft. Aortic valve replacement was performed in 100 patients and 23 patients underw...


    pub_type: 杂志文章


    authors: Kidd JN,Ruel GJ Jr,Cooley DA,Sandiford FM,Kyger ER 3rd,Wukasch DC

    更新日期:1976-12-01 00:00:00

  • Higher Visit-to-Visit Low-Density Lipoprotein Cholesterol Variability Is Associated With Lower Cognitive Performance, Lower Cerebral Blood Flow, and Greater White Matter Hyperintensity Load in Older Subjects.

    abstract:BACKGROUND:Recently, it was shown that intraindividual variation in low-density lipoprotein cholesterol (LDL-C) predicts both cerebrovascular and cardiovascular events. We aimed to examine whether this extends to cognitive function and examined possible pathways using a magnetic resonance imaging substudy. METHODS:We ...


    pub_type: 杂志文章,多中心研究,随机对照试验


    authors: Smit RA,Trompet S,Sabayan B,le Cessie S,van der Grond J,van Buchem MA,de Craen AJ,Jukema JW

    更新日期:2016-07-19 00:00:00

  • Spontaneous occurrence of symptomatic paroxysmal atrial fibrillation and paroxysmal supraventricular tachycardia in untreated patients.

    abstract:BACKGROUND:Ambulatory outpatients (n = 150) with a history of paroxysmal supraventricular arrhythmia were studied to establish the characteristics of the first recurrence of symptomatic tachycardia (time to first recurrence, heart rate during tachycardia, and observed rhythm that was regular versus irregular) when no a...


    pub_type: 杂志文章


    authors: Clair WK,Wilkinson WE,McCarthy EA,Page RL,Pritchett EL

    更新日期:1993-04-01 00:00:00

  • S100B expression modulates left ventricular remodeling after myocardial infarction in mice.

    abstract:BACKGROUND:S100B, a 20-kDa, Ca2+-binding dimer, is a putative intrinsic negative regulator of myocardial hypertrophy expressed after myocardial infarction. S100B-overexpressing transgenic (TG) and S100B-knockout (KO) mice have been generated to assess the consequences of S100B expression and altered hypertrophy after i...


    pub_type: 杂志文章


    authors: Tsoporis JN,Marks A,Haddad A,Dawood F,Liu PP,Parker TG

    更新日期:2005-02-08 00:00:00

  • Genetic Obesity and the Risk of Atrial Fibrillation: Causal Estimates from Mendelian Randomization.

    abstract:BACKGROUND:Observational studies have identified an association between body mass index (BMI) and incident atrial fibrillation (AF). Inferring causality from observational studies, however, is subject to residual confounding, reverse causation, and bias. The primary objective of this study was to evaluate the causal as...


    pub_type: 杂志文章,meta分析


    authors: Chatterjee NA,Giulianini F,Geelhoed B,Lunetta KL,Misialek JR,Niemeijer MN,Rienstra M,Rose LM,Smith AV,Arking DE,Ellinor PT,Heeringa J,Lin H,Lubitz SA,Soliman EZ,Verweij N,Alonso A,Benjamin EJ,Gudnason V,Stricker BHC

    更新日期:2017-02-21 00:00:00

  • Multitargeted effects of statin-enhanced thrombolytic therapy for stroke with recombinant human tissue-type plasminogen activator in the rat.

    abstract:BACKGROUND:Microvascular dysfunction posttreatment of stroke with recombinant human tissue-type plasminogen activator (rht-PA) constrains the therapeutic window to 3 hours. Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) promote vascular thrombolysis and reduce the inflammation response. We therefo...


    pub_type: 杂志文章


    authors: Zhang L,Zhang ZG,Ding GL,Jiang Q,Liu X,Meng H,Hozeska A,Zhang C,Li L,Morris D,Zhang RL,Lu M,Chopp M

    更新日期:2005-11-29 00:00:00

  • Comparison between 201Tl and 99mTc sestamibi uptake during adenosine-induced vasodilation as a function of coronary stenosis severity.

    abstract:BACKGROUND:Myocardial uptake of either 201Tl or 99mTc-sestamibi (sestamibi) is known to plateau at high coronary flow rates. However, few direct comparisons have been made between these tracers to determine what effect differences in the uptake plateau for the two tracers may have on the detection of coronary stenoses ...


    pub_type: 杂志文章


    authors: Glover DK,Ruiz M,Edwards NC,Cunningham M,Simanis JP,Smith WH,Watson DD,Beller GA

    更新日期:1995-02-01 00:00:00

  • Magnetic resonance imaging assessment of the severity of mitral regurgitation. Comparison with invasive techniques.

    abstract:BACKGROUND:In the patient with mitral regurgitation who is being considered for valvular surgery, cardiac catheterization is usually performed to quantify the severity of regurgitation and to determine its influence on left ventricular volumes and systolic function. Magnetic resonance imaging (MRI) potentially provides...


    pub_type: 杂志文章


    authors: Hundley WG,Li HF,Willard JE,Landau C,Lange RA,Meshack BM,Hillis LD,Peshock RM

    更新日期:1995-09-01 00:00:00

  • Abnormal blood pathways in left ventricular cavity in acute myocardial infarction. Experimental observations with special reference to regional wall motion abnormality and hemostasis.

    abstract::To elucidate the mechanism of regional hemostasis in the left ventricular (LV) cavity during myocardial infarction, the blood pathway in LV cavity was examined with contrast echocardiography injected from the left atrium before and after coronary ligation in nine canines. Before coronary ligation, contrast echoes spre...


    pub_type: 杂志文章


    authors: Beppu S,Izumi S,Miyatake K,Nagata S,Park YD,Sakakibara H,Nimura Y

    更新日期:1988-07-01 00:00:00

  • Mutant caveolin-3 induces persistent late sodium current and is associated with long-QT syndrome.

    abstract:BACKGROUND:Congenital long-QT syndrome (LQTS) is a primary arrhythmogenic syndrome stemming from perturbed cardiac repolarization. LQTS, which affects approximately 1 in 3000 persons, is 1 of the most common causes of autopsy-negative sudden death in the young. Since the sentinel discovery of cardiac channel gene mutat...


    pub_type: 杂志文章


    authors: Vatta M,Ackerman MJ,Ye B,Makielski JC,Ughanze EE,Taylor EW,Tester DJ,Balijepalli RC,Foell JD,Li Z,Kamp TJ,Towbin JA

    更新日期:2006-11-14 00:00:00

  • Stabilization of atherosclerotic plaques by blockade of macrophage migration inhibitory factor after vascular injury in apolipoprotein E-deficient mice.

    abstract:BACKGROUND:Macrophage migration inhibitory factor (MIF), a cytokine that controls cell-mediated inflammatory responses, is upregulated in atherogenesis; however, its functional contribution to lesion development has not been evaluated. METHODS AND RESULTS:We studied the role of MIF on neointima lesion formation after ...


    pub_type: 杂志文章


    authors: Schober A,Bernhagen J,Thiele M,Zeiffer U,Knarren S,Roller M,Bucala R,Weber C

    更新日期:2004-01-27 00:00:00

  • Short-term synchronized retroperfusion before reperfusion reduces infarct size after prolonged ischemia in dogs.

    abstract:BACKGROUND:Previous studies have demonstrated that synchronized coronary venous retroperfusion (SRP) can restore blood flow to the ischemic myocardium, resulting in infarct size reduction and improvement of the left ventricular function. Despite the nutritive blood flow achieved by SRP being relatively limited, SRP has...


    pub_type: 杂志文章


    authors: Wakida Y,Nordlander R,Kobayashi S,Kar S,Haendchen R,Corday E

    更新日期:1993-11-01 00:00:00

  • Phenotypic Consequences of a Genetic Predisposition to Enhanced Nitric Oxide Signaling.

    abstract:BACKGROUND:Nitric oxide signaling plays a key role in the regulation of vascular tone and platelet activation. Here, we seek to understand the impact of a genetic predisposition to enhanced nitric oxide signaling on risk for cardiovascular diseases, thus informing the potential utility of pharmacological stimulation of...


    pub_type: 杂志文章


    authors: Emdin CA,Khera AV,Klarin D,Natarajan P,Zekavat SM,Nomura A,Haas M,Aragam K,Ardissino D,Wilson JG,Schunkert H,McPherson R,Watkins H,Elosua R,Bown MJ,Samani NJ,Baber U,Erdmann J,Gormley P,Palotie A,Stitziel NO,Gup

    更新日期:2018-01-16 00:00:00

  • Homozygosity for factor V Leiden leads to enhanced thrombosis and atherosclerosis in mice.

    abstract:BACKGROUND:Activated protein C resistance due to factor V Leiden (FVL) is a common genetic risk factor for venous thrombosis in humans. Although the impact of FVL on the development of venous thrombosis is well established, its effect on arterial thrombosis and atherosclerosis is controversial. METHODS AND RESULTS:To ...


    pub_type: 杂志文章


    authors: Eitzman DT,Westrick RJ,Shen Y,Bodary PF,Gu S,Manning SL,Dobies SL,Ginsburg D

    更新日期:2005-04-12 00:00:00

  • Inhibition of phosphodiesterase 2 augments cGMP and cAMP signaling to ameliorate pulmonary hypertension.

    abstract:BACKGROUND:Pulmonary hypertension (PH) is a life-threatening disorder characterized by increased pulmonary artery pressure, remodeling of the pulmonary vasculature, and right ventricular failure. Loss of endothelium-derived nitric oxide (NO) and prostacyclin contributes to PH pathogenesis, and current therapies are tar...


    pub_type: 杂志文章


    authors: Bubb KJ,Trinder SL,Baliga RS,Patel J,Clapp LH,MacAllister RJ,Hobbs AJ

    更新日期:2014-08-05 00:00:00

  • Association between 2 angiographic subtypes of renal artery fibromuscular dysplasia and clinical characteristics.

    abstract:BACKGROUND:Initially based on histology, the diagnosis of renal artery fibromuscular dysplasia (FMD) is now based mostly on angiographic appearance because arterial tissue samples are rarely available. This retrospective cross-sectional study aimed to assess the clinical relevance of a binary angiographic classificatio...


    pub_type: 杂志文章


    authors: Savard S,Steichen O,Azarine A,Azizi M,Jeunemaitre X,Plouin PF

    更新日期:2012-12-18 00:00:00