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Wuttke, M., Li, Y., Li, M., Sieber, K. B., Feitosa, M. F., Gorski, M., . . . Pattaro, C. (2019). A catalog of genetic loci associated with kidney function from analyses of a million individuals. Nature Genetics, 51(6), 957-972
Open this publication in new window or tab >>A catalog of genetic loci associated with kidney function from analyses of a million individuals
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2019 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 51, no 6, p. 957-972Article in journal (Refereed) Published
Abstract [en]

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these,147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2019
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-387933 (URN)10.1038/s41588-019-0407-x (DOI)000469996900008 ()31152163 (PubMedID)
Funder
AstraZenecaNovo NordiskNIH (National Institute of Health)
Note

Group Authors: Lifelines COHort Study

Available from: 2019-06-26 Created: 2019-06-26 Last updated: 2019-06-26Bibliographically approved
Patel, R. S., Schmidt, A. F., Tragante, V., McCubrey, R. O., Holmes, M. V., Howe, L. J., . . . Asselbergs, F. W. (2019). Association of Chromosome 9p21 With Subsequent Coronary Heart Disease Events: A GENIUS-CHD Study of Individual Participant Data. Circulation: Genomic and Precision Medicine, 12(4), Article ID e002471.
Open this publication in new window or tab >>Association of Chromosome 9p21 With Subsequent Coronary Heart Disease Events: A GENIUS-CHD Study of Individual Participant Data
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2019 (English)In: Circulation: Genomic and Precision Medicine, ISSN 2574-8300, Vol. 12, no 4, article id e002471Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Genetic variation at chromosome 9p21 is a recognized risk factor for coronary heart disease (CHD). However, its effect on disease progression and subsequent events is unclear, raising questions about its value for stratification of residual risk.

METHODS: A variant at chromosome 9p21 (rs1333049) was tested for association with subsequent events during follow-up in 103 357 Europeans with established CHD at baseline from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) Consortium (73.1% male, mean age 62.9 years). The primary outcome, subsequent CHD death or myocardial infarction (CHD death/myocardial infarction), occurred in 13 040 of the 93 115 participants with available outcome data. Effect estimates were compared with case/control risk obtained from the CARDIoGRAMplusC4D consortium (Coronary Artery Disease Genome-wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) including 47 222 CHD cases and 122 264 controls free of CHD.

RESULTS: Meta-analyses revealed no significant association between chromosome 9p21 and the primary outcome of CHD death/myocardial infarction among those with established CHD at baseline (GENIUSCHD odds ratio, 1.02; 95% CI, 0.99-1.05). This contrasted with a strong association in CARDIoGRAMPlusC4D odds ratio 1.20; 95% CI, 1.18-1.22; P for interaction < 0.001 compared with the GENIUS-CHD estimate. Similarly, no clear associations were identified for additional subsequent outcomes, including all-cause death, although we found a modest positive association between chromosome 9p21 and subsequent revascularization (odds ratio, 1.07; 95% CI, 1.04-1.09).

CONCLUSIONS: In contrast to studies comparing individuals with CHD to disease-free controls, we found no clear association between genetic variation at chromosome 9p21 and risk of subsequent acute CHD events when all individuals had CHD at baseline. However, the association with subsequent revascularization may support the postulated mechanism of chromosome 9p21 for promoting atheroma development.

Keywords
chromosome, genetic, variation, myocardial infarction, risk factor, secondary prevention
National Category
Cardiac and Cardiovascular Systems Medical Genetics
Identifiers
urn:nbn:se:uu:diva-383874 (URN)10.1161/CIRCGEN.119.002471 (DOI)000466741600005 ()30897348 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, 201668EU, European Research Council, 294609EU, Horizon 2020, 01KL1802NIH (National Institute of Health)EU, Horizon 2020, 692145Wellcome trustEU, FP7, Seventh Framework Programme, 223004Forte, Swedish Research Council for Health, Working Life and Welfare
Available from: 2019-06-14 Created: 2019-06-14 Last updated: 2019-06-14Bibliographically approved
Hijazi, Z., Verdecchia, P., Oldgren, J., Andersson, U., Reboldi, G., Di Pasquale, G., . . . Wallentin, L. (2019). Cardiac Biomarkers and Left Ventricular Hypertrophy in Relation to Outcomes in Patients With Atrial Fibrillation: Experiences From the RE-LY Trial. Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, 8(2), Article ID e010107.
Open this publication in new window or tab >>Cardiac Biomarkers and Left Ventricular Hypertrophy in Relation to Outcomes in Patients With Atrial Fibrillation: Experiences From the RE-LY Trial
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2019 (English)In: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, ISSN 2047-9980, E-ISSN 2047-9980, Vol. 8, no 2, article id e010107Article in journal (Refereed) Published
Abstract [en]

Background

Cardiac biomarkers and left ventricular hypertrophy (LVH) are related to the risk of stroke and death in patients with atrial fibrillation. We investigated the interrelationship between LVH and cardiac biomarkers and their independent associations with outcomes.

Methods and Results

Plasma samples were obtained at baseline in 5275 patients with atrial fibrillation in the RE‐LY (Randomized Evaluation of Long‐Term Anticoagulation Therapy) trial. NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide), cardiac troponin I and T, and growth differentiation factor‐15 were determined using high‐sensitivity (hs) assays. LVH was defined by ECG. Cox models were adjusted for baseline characteristics, LVH, and biomarkers. LVH was present in 1257 patients. During a median follow‐up of 2.0 years, 165 patients developed a stroke and 370 died. LVH was significantly (P<0.0001) associated with higher levels of all biomarkers in linear regression analyses adjusting for baseline characteristics. Geometric mean ratios (95% CIs) were as follows: NT‐proBNP, 1.32 (1.25–1.38); hs cardiac troponin I, 1.67 (1.57–1.78); hs troponin T, 1.38 (1.32–1.44); and growth differentiation factor‐15, 1.09 (1.05–1.12). For stroke, the hazard ratios (95% CIs) per 50% increase were as follows: NT‐proBNP, 1.09 (1.00–1.19); hs cardiac troponin I, 1.09 (1.03–1.15); hs troponin T, 1.14 (1.06–1.24); and growth differentiation factor‐15, 1.22 (1.08–1.38) (all P<0.05). For death, hazard ratios (95% CIs) were as follows: NT‐proBNP, 1.24 (1.17–1.31); hs cardiac troponin I, 1.13 (1.10–1.17); hs troponin T, 1.28 (1.23–1.34); and growth differentiation factor‐15, 1.31 (1.22–1.42) (all P<0.0001). LVH was not significantly associated with stroke or death after adjustment for biomarkers.

Conclusions

Cardiac biomarkers are significantly associated with LVH. The prognostic value of biomarkers for stroke and death is not affected by LVH. The prognostic information of LVH is attenuated in the presence of cardiac biomarkers.

Keywords
atrial fibrillation, biomarker, left ventricular hypertrophy, risk prediction
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-379402 (URN)10.1161/JAHA.118.010107 (DOI)000460105800004 ()30651032 (PubMedID)
Available from: 2019-03-15 Created: 2019-03-15 Last updated: 2019-03-15Bibliographically approved
Christersson, C., Wallentin, L., Andersson, U., Alexander, J. H., Alings, M., De Caterina, R., . . . Siegbahn, A. (2019). Effect of apixaban compared with warfarin on coagulation markers in atrial fibrillation.. Heart, 105(3), 235-242
Open this publication in new window or tab >>Effect of apixaban compared with warfarin on coagulation markers in atrial fibrillation.
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2019 (English)In: Heart, ISSN 1355-6037, E-ISSN 1468-201X, Vol. 105, no 3, p. 235-242Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES: Compare the effect of apixaban and warfarin on coagulation and primary haemostasis biomarkers in atrial fibrillation (AF).

METHODS: The biomarker substudy from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation trial included 4850 patients with AF randomised to treatment with apixaban or warfarin. Sixty per cent of patients used vitamin K antagonist (VKA) within 7 days before randomisation. Prothrombin fragment 1+2 (F1+2), D-dimer, soluble CD40 ligand (sCD40L) and von Willebrand factor (vWF) antigen were analysed at randomisation and after 2 months of study treatment.

RESULTS: In patients not on VKA treatment at randomisation, F1+2 and D-dimer levels were decreased by 25% and 23%, respectively, with apixaban, and by 59% and 38%, respectively, with warfarin (p<0.0001 for treatment differences for both). In patients on VKA at randomisation, F1+2 and D-dimer levels increased by 41% and 10%, respectively, with apixaban and decreased by 37% and 11%, respectively, with warfarin (p<0.0001 for treatment differences for both). sCD40L levels were slightly increased at 2 months, regardless of VKA or randomised treatment. Apixaban and warfarin also both reduced vWF antigen regardless of VKA treatment. The efficacy (stroke) and safety (bleeding) of apixaban compared with warfarin was similar irrespectively of biomarker levels at 2 months.

CONCLUSIONS: Treatment with apixaban compared with warfarin for stroke prevention in patients with AF was associated with less reduction in thrombin generation and fibrin turnover. This effect of apixaban could contribute to the clinical results where apixaban was superior to warfarin both in stroke prevention and in reducing bleeding risk.

TRIAL REGISTRATION NUMBER: NCT00412984.

Keywords
atrial fibrillation
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-374491 (URN)10.1136/heartjnl-2018-313351 (DOI)000459806200013 ()30209126 (PubMedID)
Available from: 2019-01-21 Created: 2019-01-21 Last updated: 2019-03-21Bibliographically approved
Hohnloser, S. H., Fudim, M., Alexander, J. H., Wojdyla, D. M., Ezekowitz, J. A., Hanna, M., . . . Lopes, R. D. (2019). Efficacy and Safety of Apixaban Versus Warfarin in Patients With Atrial Fibrillation and Extremes in Body Weight: Insights From the ARISTOTLE Trial. Circulation, 139(20), 2292-2300
Open this publication in new window or tab >>Efficacy and Safety of Apixaban Versus Warfarin in Patients With Atrial Fibrillation and Extremes in Body Weight: Insights From the ARISTOTLE Trial
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2019 (English)In: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 139, no 20, p. 2292-2300Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Guidelines caution against the use of non-vitamin K antagonist oral anticoagulants in patients with extremely high (> 120 kg) or low (= 60 kg) body weight because of a lack of data in these populations.

METHODS: In a post hoc analysis of ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation; n= 18 201), a randomized trial comparing apixaban with warfarin for the prevention of stroke in patients with atrial fibrillation, we estimated the randomized treatment effect (apixaban versus warfarin) stratified by body weight (= 60, > 60-120, > 120 kg) using a Cox regression model and tested the interaction between body weight and randomized treatment. The primary efficacy and safety outcomes were stroke or systemic embolism and major bleeding.

RESULTS: Of the 18 139 patients with available weight and outcomes data, 1985 (10.9%) were in the low-weight group (= 60 kg), 15 172 (83.6%) were in the midrange weight group (> 60-120 kg), and 982 (5.4%) were in the high-weight group (> 120 kg). The treatment effect of apixaban versus warfarin for the efficacy outcomes of stroke/systemic embolism, all-cause death, or myocardial infarction was consistent across the weight spectrum (interaction P value> 0.05). For major bleeding, apixaban had a better safety profile than warfarin in all weight categories and even showed a greater relative risk reduction in patients in the low (= 60 kg; HR, 0.55; 95% CI, 0.36-0.82) and midrange (> 60-120 kg) weight groups (HR, 0.71; 95% CI, 0.61-0.83; interaction P value= 0.016).

CONCLUSIONS: Our findings provide evidence that apixaban is efficacious and safe across the spectrum of weight, including in low-(= 60 kg) and highweight patients (> 120 kg). The superiority on efficacy and safety outcomes of apixaban compared with warfarin persists across weight groups, with even greater reductions in major bleeding in patients with atrial fibrillation with low to normal weight as compared with high weight. The superiority of apixaban over warfarin in regard to efficacy and safety for stroke prevention seems to be similar in patients with atrial fibrillation across the spectrum of weight, including in low-and very high-weight patients. Thus, apixaban appears to be appropriate for patients with atrial fibrillation irrespective of body weight.

Place, publisher, year, edition, pages
LIPPINCOTT WILLIAMS & WILKINS, 2019
Keywords
atrial fibrillation, bleeding, non-vitamin K antagonist oral anticoagulants, stroke, warfarin
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-386162 (URN)10.1161/CIRCULATIONAHA.118.037955 (DOI)000468397500007 ()30773022 (PubMedID)
Available from: 2019-06-20 Created: 2019-06-20 Last updated: 2019-06-20Bibliographically approved
Guimaraes, P. O., Pokorney, S. D., Lopes, R. D., Wojdyla, D. M., Gersh, B. J., Giczewska, A., . . . Granger, C. B. (2019). Efficacy and safety of apixaban vs warfarin in patients with atrial fibrillation and prior bioprosthetic valve replacement or valve repair: Insights from the ARISTOTLE trial. Clinical Cardiology, 42(5), 568-571
Open this publication in new window or tab >>Efficacy and safety of apixaban vs warfarin in patients with atrial fibrillation and prior bioprosthetic valve replacement or valve repair: Insights from the ARISTOTLE trial
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2019 (English)In: Clinical Cardiology, ISSN 0160-9289, E-ISSN 1932-8737, Vol. 42, no 5, p. 568-571Article in journal (Refereed) Published
Abstract [en]

Background

The optimal anticoagulation strategy for patients with atrial fibrillation (AF) and bioprosthetic valve (BPV) replacement or native valve repair remains uncertain.

Hypothesis

We evaluated the safety and efficacy of apixaban vs warfarin in patients with AF and a history of BPV replacement or native valve repair.

Methods

Using data from Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) (n = 18 201), a randomized trial comparing apixaban with warfarin in patients with AF, we analyzed the subgroup of patients (n = 251) with prior valve surgery. We contacted sites by telephone to obtain additional data about prior valve surgery. Full data were available for 156 patients. The primary efficacy endpoint was stroke/systemic embolism. The primary safety endpoint was major bleeding. Treatment groups were compared using a Cox regression model.

Results

In ARISTOTLE, 104 (0.6%) patients had a history of BPV replacement (n = 73 [aortic], n = 26 [mitral], n = 5 [mitral and aortic]) and 52 (0.3%) had a history of valve repair (n = 50 [mitral], n = 2 [aortic]). Among patients with BPVs, 55 were randomized to apixaban and 49 to warfarin. Among those with a history of native valve repair, 32 were randomized to apixaban and 20 to warfarin. Overall clinical event rates were low, with no significant differences between apixaban and warfarin for any outcomes.

Conclusions

In patients with AF and a history of BPV replacement or repair, the safety and efficacy of apixaban compared with warfarin was consistent with results from ARISTOTLE. These data suggest that apixaban may be reasonable for patients with BPVs or prior valve repair, though future larger randomized trials are needed.

ClinicalTrials.gov

NCT00412984.

Keywords
apixaban, atrial fibrillation, bioprosthetic valves, valve repair
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-387295 (URN)10.1002/clc.23178 (DOI)000468080800011 ()30907005 (PubMedID)
Available from: 2019-06-24 Created: 2019-06-24 Last updated: 2019-06-24Bibliographically approved
Nunez, D. J., Alexander, M., Yerges-Armstrong, L., Singh, G., Byttebier, G., Fabbrini, E., . . . Ferrannini, E. (2019). Factors influencing longitudinal changes of circulating liver enzyme concentrations in subjects randomized to placebo in four clinical trials. American Journal of Physiology - Gastrointestinal and Liver Physiology, 316(3), G372-G386
Open this publication in new window or tab >>Factors influencing longitudinal changes of circulating liver enzyme concentrations in subjects randomized to placebo in four clinical trials
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2019 (English)In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 316, no 3, p. G372-G386Article in journal (Refereed) Published
Abstract [en]

Liver enzyme concentrations are measured as safety endpoints in clinical trials to detect drug-related hepatotoxicity, but little is known about the epidemiology of these biomarkers in subjects without hepatic dysfunction who are enrolled in drug trials. We studied alanine and aspartate aminotransferase (ALT, AST) in subjects randomized to placebo who completed assessments over 36 months in a cardiovascular outcome trial (the 'STABILITY' trial; n=4264; mean age: 64.2 yr) or over 12 months in 3 trials that enrolled only subjects with type 2 diabetes (T2D) (the 'DIA' trials; n=308; mean age: 62.4 yr) to investigate time-dependent relationships and the factors that might affect ALT and AST, including body mass index (BMI), T2D and renal function. Multivariate linear mixed models examined time-dependent relationships between liver enzyme concentrations as response variables, and BMI, baseline T2D status, hemoglobin A1c levels and renal function, as explanatory variables. At baseline, ALT was higher in individuals who were males, < 65 years old, obese and who had GFR > 60 mL/min/1.73m2. ALT was not significantly associated with T2D at baseline, although it was positively associated with HbA1c. GFR had a greater impact on ALT than T2D. ALT concentrations decreased over time in subjects who lost weight, but remained stable in individuals with increasing BMI. Weight change did not alter AST concentrations. We provide new insights on the influence of time, GFR and HbA1c on ALT and AST concentrations and confirm the effect of gender, age, T2D, BMI and BMI change in subjects receiving placebo in clinical trials.

Keywords
Alanine aminotransferase, aspartate aminotransferase, clinical trials, hepatotoxicity, metabolic covariates
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-375083 (URN)10.1152/ajpgi.00051.2018 (DOI)000465075000003 ()30495974 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme
Available from: 2019-01-25 Created: 2019-01-25 Last updated: 2019-05-27Bibliographically approved
Fanaroff, A. C., Clare, R., Pieper, K. S., Mahaffey, K. W., Melloni, C., Green, J. B., . . . Lopes, R. D. (2019). Frequency, Regional Variation, and Predictors of Undetermined Cause of Death in Cardiometabolic Clinical Trials: A Pooled Analysis of 9259 Deaths in 9 Trials. Circulation, 139(7), 863-873
Open this publication in new window or tab >>Frequency, Regional Variation, and Predictors of Undetermined Cause of Death in Cardiometabolic Clinical Trials: A Pooled Analysis of 9259 Deaths in 9 Trials
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2019 (English)In: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 139, no 7, p. 863-873Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Modern cardiometabolic clinical trials often include cardiovascular death as a component of a composite primary outcome, requiring central adjudication by a clinical events committee to classify cause of death. However, sometimes the cause of death cannot be determined from available data. The US Food and Drug Administration has indicated that this circumstance should occur only rarely, but its prevalence has not been formally assessed. METHODS: Data from 9 global clinical trials (2009-2017) with long-term follow-up and blinded, centrally adjudicated cause of death were used to calculate the proportion of deaths attributed to cardiovascular, noncardiovascular, or undetermined causes by therapeutic area (diabetes mellitus/pre-diabetes mellitus, stable atherosclerosis, atrial fibrillation, and acute coronary syndrome), region of patient enrollment, and year of trial manuscript publication. Patient-and trial-level variables associated with undetermined cause of death were identified using a logistic model. RESULTS: Across 127 049 enrolled participants from 9 trials, there were 9259 centrally adjudicated deaths: 5012 (54.1%) attributable to cardiovascular causes, 2800 (30.2%) attributable to noncardiovascular causes, and 1447 (15.6%) attributable to undetermined causes. There was variability in the proportion of deaths ascribed to undetermined causes by trial therapeutic area, region of enrollment, and year of trial manuscript publication. On multivariable analysis, acute coronary syndrome or atrial fibrillation trial (versus atherosclerotic vascular disease or diabetes mellitus/pre-diabetes mellitus), longer time from enrollment to death, more recent trial manuscript publication year, enrollment in North America (versus Western Europe), female sex, and older age were associated with greater likelihood of death of undetermined cause. CONCLUSIONS: In 9 cardiometabolic clinical trials with long-term followup, approximately 16% of deaths had undetermined causes. This provides a baseline for quality assessment of clinical trials and informs operational efforts to potentially reduce the frequency of undetermined deaths in future clinical research.

Keywords
clinical trial, cause of death, death, follow-up studies, quality control
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-378677 (URN)10.1161/CIRCULATIONAHA.118.037202 (DOI)000458410000008 ()30586739 (PubMedID)
Available from: 2019-03-12 Created: 2019-03-12 Last updated: 2019-03-12Bibliographically approved
Washam, J. B., Hohnloser, S. H., Lopes, R. D., Wojdyla, D. M., Vinereanu, D., Alexander, J. H., . . . Granger, C. B. (2019). Interacting medication use and the treatment effects of apixaban versus warfarin: results from the ARISTOTLE Trial. Journal of Thrombosis and Thrombolysis, 47(3), 345-352
Open this publication in new window or tab >>Interacting medication use and the treatment effects of apixaban versus warfarin: results from the ARISTOTLE Trial
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2019 (English)In: Journal of Thrombosis and Thrombolysis, ISSN 0929-5305, E-ISSN 1573-742X, Vol. 47, no 3, p. 345-352Article in journal (Refereed) Published
Abstract [en]

Warfarin is dependent on multiple hepatic enzymes for metabolism while apixaban is a substrate for P-glycoprotein (P-gp) transport and hepatic CYP3A4 metabolism. The aim of this analysis was to assess the impact of interacting medication use on the treatment effects of apixaban versus warfarin. Outcomes were compared between apixaban and warfarin using Cox proportional hazards modeling according to the use of interacting medications at randomization in ARISTOTLE (n=18,201). Interacting medications for apixaban were identified as combined P-gp and 3A4 inhibitors or inducers while interacting medications for warfarin were defined as those highly probable for warfarin potentiation or inhibition. At randomization, 5547 (30.5%) patients were on an interacting medication, including 2722 on apixaban and 2825 on warfarin. Patients using an interacting medication were more likely to be female, taking aspirin, and have a history of prior bleeding and were less likely to have a prior stroke or transient ischemic attack. No significant differences were observed on the treatment effect of apixaban compared with warfarin in patients on and off interacting medications for outcomes including the primary efficacy outcome of stroke or systemic embolism (P for interaction=0.79) or the primary safety outcome of major bleeding (P for interaction=0.75). Use of interacting medications with anticoagulants occurs often in patients with atrial fibrillation. Despite the potential for altered exposure, interacting medication use was not associated with a significant change in the efficacy or safety of apixaban compared with warfarin in the ARISTOTLE trial.Trial registration ClinicalTrials.gov, NCT00412984

Place, publisher, year, edition, pages
SPRINGER, 2019
Keywords
Atrial fibrillation, Interacting medications, Warfarin, Apixaban
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-382509 (URN)10.1007/s11239-019-01823-y (DOI)000463674900002 ()30790160 (PubMedID)
Available from: 2019-04-30 Created: 2019-04-30 Last updated: 2019-04-30Bibliographically approved
Justice, A. E., Giedraitis, V., Gustafsson, S., Ingelsson, E., Lind, L., Wallentin, L. & Lindgren, C. M. (2019). Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution. Nature Genetics, 51(3), 452-469
Open this publication in new window or tab >>Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution
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2019 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 51, no 3, p. 452-469Article in journal (Refereed) Published
Abstract [en]

Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.

National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-379344 (URN)10.1038/s41588-018-0334-2 (DOI)000459947200014 ()30778226 (PubMedID)
Funder
NIH (National Institute of Health), 1K99HL130580NIH (National Institute of Health), R01-DK089256NIH (National Institute of Health), 2R01HD057194NIH (National Institute of Health), U01HG007416NIH (National Institute of Health), R01DK101855NIH (National Institute of Health), T32 HL007055NIH (National Institute of Health), KL2TR001109
Note

For complete list of authors see http://dx.doi.org/10.1038/s41588-018-0334-2

Available from: 2019-03-15 Created: 2019-03-15 Last updated: 2019-03-15Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0003-0378-6531

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