| 121. |
- Paré, Guillaume, et al.
(författare)
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Genetic Determinants of Dabigatran Plasma Levels and Their Relation to Bleeding
- 2013
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Ingår i: Circulation. - 0009-7322 .- 1524-4539. ; 127:13, s. 1404-
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundFixed-dose unmonitored treatment with dabigatran etexilate is effective and has a favorable safety profile in prevention of stroke in atrial fibrillation patients compared to warfarin. We hypothesized that genetic variants could contribute to inter-individual variability in blood concentrations of the active metabolite of dabigatran etexilate, and influence the safety and efficacy of dabigatran.Methods and ResultsWe successfully conducted a genome-wide association study in 2,944 RE-LY participants. The CES1 SNP rs2244613 was associated with trough concentrations, and the ABCB1 SNP rs4148738 and CES1 SNP rs8192935 were associated with peak concentrations at genome-wide significance (P<9 x 10-8) with a gene-dose effect. Each minor allele of the CES1 SNP rs2244613 was associated with lower trough concentrations (15% decrease per allele, 95%CI 10-19%; P=1.2 x 10-8) and a lower risk of any bleeding (OR=0.67, 95%CI 0.55-0.82; P=7 x 10-5) in dabigatran-treated participants, with a consistent but non-significant lower risk of major bleeding (OR=0.66, 95%CI 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 (HR=0.59, 95%CI 0.46-0.76; P=5.2 x 10-5) in contrast to no difference in noncarriers (HR=0.96, 95%CI 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.ConclusionsGenome-wide association analysis identified that carriage of CES1 rs2244613 minor allele occurred in 32.8% of patients in RELY and was associated with lower exposure to active dabigatran metabolite. The presence of the polymorphism was associated with a lower risk of bleeding.
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| 122. |
- Peden, John F., et al.
(författare)
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A genome-wide association study in Europeans and South Asians identifies five new loci for coronary artery disease
- 2011
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 43:4, s. 339-344
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies have identified 11 common variants convincingly associated with coronary artery disease (CAD)(1-7), a modest number considering the apparent heritability of CAD(8). All of these variants have been discovered in European populations. We report a meta-analysis of four large genome-wide association studies of CAD, with similar to 575,000 genotyped SNPs in a discovery dataset comprising 15,420 individuals with CAD (cases) (8,424 Europeans and 6,996 South Asians) and 15,062 controls. There was little evidence for ancestry-specific associations, supporting the use of combined analyses. Replication in an independent sample of 21,408 cases and 19,185 controls identified five loci newly associated with CAD (P < 5 x 10(-8) in the combined discovery and replication analysis): LIPA on 10q23, PDGFD on 11q22, ADAMTS7-MORF4L1 on 15q25, a gene rich locus on 7q22 and KIAA1462 on 10p11. The CAD-associated SNP in the PDGFD locus showed tissue-specific cis expression quantitative trait locus effects. These findings implicate new pathways for CAD susceptibility.
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| 123. |
- Peters, Ron J. G., et al.
(författare)
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The role of fondaparinux as an adjunct to thrombolytic therapy in acute myocardial infarction : a subgroup analysis of the OASIS-6 trial
- 2008
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 29:3, s. 324-331
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: No antithrombotic therapy has been shown to reduce mortality when used with thrombolytics in acute myocardial infarction (AMI). In the OASIS-6 trial, fondaparinux significantly reduced mortality and reinfarction without increasing bleeding in 12 092 patients with acute ST elevation MI. METHODS AND RESULTS: We report the results of a subgroup analysis in the 5436 patients (45%) receiving thrombolytics. According to local practice, 4415 patients did not have an indication for unfractionated heparin (stratum 1) and 1021 did (stratum 2). Fondaparinux reduced the primary study outcome of death or MI at 30 days [Hazard ratio (HR) 0.79, 95% confidence interval (CI) 0.68-0.92] with consistent reductions in both mortality (HR and CI) and reinfarction (HR and CI). There was a non-significantly lower rate of stroke (HR 0.77, CI 0.48-1.25). The risk of severe bleeding was significantly reduced (HR 0.62, CI 0.40-0.94), and thus the balance of benefit and risk (death, MI and severe haemorrhage) was clearly reduced by fondaparinux (HR 0.77, 95% CI 0.67-0.90). Results were consistent in the two strata, by the different types of thrombolytics and across various time intervals from symptom onset to treatment. CONCLUSION: In STEMI patients treated with thrombolytic agents (predominantly streptokinase), fondaparinux significantly reduced the risk of death, re-MI and severe bleeds.
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| 124. |
- Platz, Elke, et al.
(författare)
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Prevalence and prognostic importance of precipitating factors leading to heart failure hospitalization: Recurrent hospitalizations and mortality
- 2018
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Ingår i: European Journal of Heart Failure. - : Wiley. - 1388-9842 .- 1879-0844. ; 20:2, s. 295-303
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Tidskriftsartikel (refereegranskat)abstract
- © 2017 The Authors European Journal of Heart Failure. Aims: Hospitalizations for heart failure (HF) are common and are associated with significant morbidity, mortality and cost. However, precipitating factors leading to HF hospitalization and their importance with respect to subsequent outcomes are not well understood. Methods and results: The symptoms and signs present at admission and investigator-identified factors thought to have contributed to the first adjudicated HF hospitalization in the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) programme were prospectively collected and stratified by ejection fraction (EF). Potential precipitants were collected using a specifically designed case report form and categorized according to the presence of cardiovascular (CV), non-CV and unknown factors. Associations between these factors and subsequent rehospitalization and mortality rates were examined. Of 1668 patients who experienced HF hospitalization, 1152 had reduced EF (≤40%) (HFrEF) and 516 had preserved EF (HFpEF). Overall, 54% had CV, 32% had non-CV and 14% had unknown factors thought to have precipitated HF, with similar proportions in the HFrEF and HFpEF groups. The most common precipitants were arrhythmia (15%), other non-CV factors (11%) and respiratory infection (10%). Subsequent CV readmission rates were highest in those whose initial HF hospitalization was precipitated by CV factors. However, mortality rates were similar among patients with any of the three categories of precipitating factors. Results were similar in HFrEF and HFpEF. Conclusions: Among chronic HF patients hospitalized for decompensation, the investigator-reported precipitating factor was not associated with the subsequent mortality rate, but was associated with type of readmission: readmissions for CV reasons were more likely when the index precipitant was CV.
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| 125. |
- Pol, Tymon, et al.
(författare)
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Using multimarker screening to identify biomarkers associated with cardiovascular death in patients with atrial fibrillation.
- 2021
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Ingår i: Cardiovascular Research. - : Oxford University Press. - 0008-6363 .- 1755-3245. ; 118:9, s. 2112-2123
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Atrial fibrillation (AF) is associated with higher mortality. Biomarkers may improve the understanding of key pathophysiologic processes in AF that lead to death. Using a new multiplex analytic technique, we explored the association between 268 biomarkers and cardiovascular (CV) death in anticoagulated patients with AF.METHODS AND RESULTS: A case-cohort design with 1.8 -1.9 years follow-up. The identification cohort included 517 cases and 4057 randomly selected patients from ARISTOTLE. The validation cohort included 277 cases and 1042 randomly selected controls from RE-LY. Plasma collected at randomization was analyzed with conventional immunoassays and the OLINK proximity extension assay-panels; CVDII, CVDIII, and Inflammation. Association between biomarkers and CV-death was evaluated using Random Survival Forest, Boruta and adjusted Cox-regression analyses.The biomarkers most strongly and consistently associated with CV-death were (hazard ratio for inter-quartile comparison [95% CI]): N-terminal pro-B-type natriuretic peptide (NT-proBNP; 1.63 [1.37-1.93]), cardiac troponin T (cTnT-hs; 1.60[1.35-1.88]), interleukin-6 (IL-6; 1.29[1.13-1.47]), growth differentiation factor-15 (GDF-15; 1.30[1.10-1.53]) fibroblast growth factor 23 (FGF-23; 1.21[1.10-1.33]), urokinase receptor (uPAR; 1.38[1.16-1.64]), trefoil factor 3 (TFF3; 1.27[1.10-1.46]), tumor necrosis factor receptor 1 (TNFR1; 1.21[1.01-1.45]), TNF-related apoptosis-inducing ligand receptor 2 (TRAILR2; 1.18[1.04-1.34]) and cathepsin L1 (CTSL1; 1.22[1.07-1.39]).CONCLUSION: In this comprehensive screening of 268 biomarkers in anticoagulated patients with AF the underlying mechanisms most strongly associated with CV-death were cardiorenal dysfunction (NT-proBNP, cTnT-hs, CTSL1, TFF3), oxidative stress (GDF-15), inflammation (IL-6, GDF-15), calcium balance, vascular and renal dysfunction (FGF-23), fibrinolysis (suPAR) and apoptosis (TNFR1, TRAILR2). These findings provide novel insights into pathophysiologic aspects associated with CV-death in AF.TRANSLATIONAL PERSPECTIVE: In patients with AF there is an unmet need for better understanding of the pathophysiological processes involved with CV-death. Using a targeted proteomic approach, 10 biomarkers were identified as having a strong association with CV-death. The identified biomarkers reflect several biological pathways involved with CV-death in AF. The present study provides valuable insights into important processes involved with CV-death in patients with AF and may facilitate the identification of important risk factors for death, thus allowing for earlier intervention and possibly even for targeted therapy to reduce AF-related mortality.CLINICALTRIALS.GOV IDENTIFIER: NCT00412984 and NCT00262600.
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| 126. |
- Reddin, Catriona, et al.
(författare)
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Association of Psychosocial Stress With Risk of Acute Stroke.
- 2022
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Ingår i: JAMA network open. - : American Medical Association (AMA). - 2574-3805. ; 5:12
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Tidskriftsartikel (refereegranskat)abstract
- Psychosocial stress is considered a modifiable risk factor for stroke. Given the prevalence of chronic and acute exposure to stress, it represents a potentially attractive target for population-health interventions.To determine the association of psychosocial stress with the risk of acute stroke and explore factors that might modify the association of stress with risk of acute stroke in a large international population.INTERSTROKE is an international retrospective case-control study of risk factors for first acute stroke in 32 countries in Asia, North and South America, Europe, Australia, the Middle East, and Africa. A total of 13 462 patients with stroke and 13 488 matched controls were recruited between January 11, 2007, and August 8, 2015. The present analyses were performed from June 1 to 30, 2021, and included 13 350 cases and 13 462 controls with available data on psychosocial stress.Psychosocial stress and occurrence of stressful life events within the preceding year were measured using a standardized questionnaire of self-reported stress at home and work.The association of stress with acute stroke and its subtypes was examined using multivariable conditional logistic regression and factors that might modify the association, particularly self-reported locus of control.Among 26 812 participants included in the analysis, the mean (SD) age of cases was 62.2 (13.6) years; that of controls, 61.3 (13.3) years; 7960 cases (59.6%) and 8017 controls (59.6%) were men. Several periods of stress and permanent stress were reported for 2745 cases (20.5%) and 1933 controls (14.4%), with marked regional variation in prevalence, with the lowest in China (201 of 3981 [5.0%] among controls and 364 of 3980 [9.1%] among cases) and highest in South East Asia (233 of 855 [26.1%] among controls and 241 of 782 [30.8%] among cases). Increased stress at home (odds ratio [OR], 1.95 [95% CI, 1.77-2.15]) and at work (OR, 2.70 [95% CI, 2.25-3.23]) and recent stressful life events (OR, 1.31 [95% CI, 1.19-1.43]) were associated with an increased risk of acute stroke on multivariable analyses (vs no self-reported stress). Higher locus of control at home was associated with a reduced odds of all stroke (OR, 0.73 [95% CI, 0.68-0.79]), and higher locus of control both at work and at home were associated with a lower odds of acute stroke and significantly diminished the association with stress at work (OR, 2.20 [95% CI, 1.88-2.58]; P = .008 for interaction) and home (OR, 1.69 [95% CI, 1.44-1.98]; P < .001 for interaction) for acute stroke.Psychosocial stress is a common risk factor for acute stroke. The findings of this case-control study suggest that higher locus of control is associated with lower risk of stroke and may be an important effect modifier of the risk associated with psychosocial stress.
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| 127. |
- Reilly, Paul A., et al.
(författare)
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The Effect of Dabigatran Plasma Concentrations and Patient Characteristics on the Frequency of Ischemic Stroke and Major Bleeding in Atrial Fibrillation Patients The RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy)
- 2014
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Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 63:4, s. 321-328
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Tidskriftsartikel (refereegranskat)abstract
- Objectives The goal of this study was to analyze the impact of dabigatran plasma concentrations, patient demographics, and aspirin (ASA) use on frequencies of ischemic strokes/systemic emboli and major bleeds in atrial fibrillation patients. Background The efficacy and safety of dabigatran etexilate were demonstrated in the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial, but a therapeutic concentration range has not been defined. Methods In a pre-specified analysis of RE-LY, plasma concentrations of dabigatran were determined in patients treated with dabigatran etexilate 110 mg twice daily (bid) or 150 mg bid and correlated with the clinical outcomes of ischemic stroke/systemic embolism and major bleeding using univariate and multivariate logistic regression and Cox regression models. Patient demographics and ASA use were assessed descriptively and as covariates. Results Plasma concentrations were obtained from 9,183 patients, with 112 ischemic strokes/systemic emboli (1.3%) and 323 major bleeds (3.8%) recorded. Dabigatran levels were dependent on renal function, age, weight, and female sex, but not ethnicity, geographic region, ASA use, or clopidogrel use. A multiple logistic regression model (c-statistic 0.657, 95% confidence interval [CI]: 0.61 to 0.71) showed that the risk of ischemic events was inversely related to trough dabigatran concentrations (p = 0.045), with age and previous stroke (both p < 0.0001) as significant covariates. Multiple logistic regression (c-statistic 0.715, 95% CI: 0.69 to 0.74) showed major bleeding risk increased with dabigatran exposure (p < 0.0001), age (p < 0.0001), ASA use (p < 0.0003), and diabetes (p = 0.018) as significant covariates. Conclusions Ischemic stroke and bleeding outcomes were correlated with dabigatran plasma concentrations. Age was the most important covariate. Individual benefit-risk might be improved by tailoring dabigatran dose after considering selected patient characteristics. (Randomized Evaluation of Long Term Anticoagulant Therapy [RE-LY] With Dabigatran Etexilate; NCT00262600) (C) 2014 by the American College of Cardiology Foundation
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| 128. |
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| 129. |
- Ross, Stephanie, et al.
(författare)
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Association of cyclooxygenase-2 genetic variant with cardiovascular disease
- 2014
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 35:33, s. 2242-2248
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Tidskriftsartikel (refereegranskat)abstract
- Aim Agenetic variant (rs20417) of the PTGS2 gene, encoding for COX-2, has been associated with decreased COX-2 activity and a decreased risk of cardiovascular disease (CVD). However, this genetic association and the role of COX-2 in CVD remain controversial. Methods and results The association of rs20417 with CVD was prospectively explored in 49 232 subjects (ACTIVE-A, CURE, epiDREAM/DREAM, ONTARGET, RE-LY, and WGHS) and the effect of potentially modifiable risk factors on the genetic association was further explored in 9363 INTERHEART participants. The effect of rs20417 on urinary thromboxane and prostacyclin metabolite concentrations was measured in 117 healthy individuals. Carriage of the rs20417 minor allele was associated with a decreased risk of major CVD outcomes (OR = 0.78, 95% CI: 0.70-0.87; P = 1.2 x 10(-5)). The genetic effect was significantly stronger in aspirin users (OR: 0.74, 95% CI: 0.64-0.84; P = 1.20 x 10(-5)) than non-users (OR: 0.87, 95% CI: 0.72-1.06; P = 0.16) (interaction P-value: 0.0041). Among patients with previous coronary artery disease (CAD), rs20417 carriers had a stronger protective effect on risk of major adverse events when compared with individuals without previous CAD (interaction P-value: 0.015). Carriers had significantly lower urinary levels of thromboxane (P = 0.01) and prostacyclin (P = 0.01) metabolites when compared with non-carriers. Conclusion The rs20417 polymorphism is associated with a reduced risk of major cardiovascular events and lower levels of thromboxane and prostacyclin. Our results suggest that a genetic decrease in COX-2 activity may be beneficial with respect to CVD risk, especially, in higher risk patients on aspirin.
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| 130. |
- Salam, Abdul, et al.
(författare)
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Effects of blood pressure lowering on cardiovascular events, in the context of regression to the mean : a systematic review of randomized trials
- 2019
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Ingår i: Journal of Hypertension. - : Lippincott Williams & Wilkins. - 0263-6352 .- 1473-5598. ; 37:1, s. 16-23
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Forskningsöversikt (refereegranskat)abstract
- Objective: To assess the clinical relevance of regression to the mean for clinical trials and clinical practice. Methods: MEDLINE was searched until February 2018 for randomized trials of BP lowering with over 1000 patient-years follow-up per group. We estimated baseline mean BP, follow-up mean (usual) BP amongst patients grouped by 10 mmHg strata of baseline BP, and assessed effects of BP lowering on coronary heart disease (CHD) and stroke according to these BP levels. Results: Eighty-six trials (349 488 participants), with mean follow-up of 3.7 years, were included. Most mean BP change was because of regression to the mean rather than treatment. At high baseline BP levels, even after rigorous hypertension diagnosis, downwards regression to the mean caused much of the fall in BP. At low baseline BP levels, upwards regression to the mean increased BP levels, even in treatment groups. Overall, a BP reduction of 6/3 mmHg lowered CHD by 14% (95% CI 11-17%) and stroke by 18% (15-22%), and these treatment effects occurred at follow-up BP levels much closer to the mean than baseline BP levels. In particular, more evidence was available in the SBP 130-139 mmHg range than any other range. Benefits were apparent in numerous high-risk patient groups with baseline mean SBP less than 140 mmHg. Conclusion: Clinical practice should focus less on pretreatment BP levels, which rarely predict future untreated BP levels or rule out capacity to benefit from BP lowering in high cardiovascular risk patients. Instead, focus should be on prompt, empirical treatment to maintain lower BP for those with high BP and/or high risk.
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