| 1. |
- Hijazi, Ziad, et al.
(författare)
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A biomarker-based risk score to predict death in patients with atrial fibrillation : the ABC (age, biomarkers, clinical history) death risk score
- 2018
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Ingår i: European Heart Journal. - : OXFORD UNIV PRESS. - 0195-668X .- 1522-9645. ; 39:6, s. 477-485
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Tidskriftsartikel (refereegranskat)abstract
- Aims: In atrial fibrillation (AF), mortality remains high despite effective anticoagulation. A model predicting the risk of death in these patients is currently not available. We developed and validated a risk score for death in anticoagulated patients with AF including both clinical information and biomarkers.Methods and results: The new risk score was developed and internally validated in 14 611 patients with AF randomized to apixaban vs. warfarin for a median of 1.9 years. External validation was performed in 8548 patients with AF randomized to dabigatran vs. warfarin for 2.0 years. Biomarker samples were obtained at study entry. Variables significantly contributing to the prediction of all-cause mortality were assessed by Cox-regression. Each variable obtained a weight proportional to the model coefficients. There were 1047 all-cause deaths in the derivation and 594 in the validation cohort. The most important predictors of death were N-terminal pro B-type natriuretic peptide, troponin-T, growth differentiation factor-15, age, and heart failure, and these were included in the ABC (Age, Biomarkers, Clinical history)-death risk score. The score was well-calibrated and yielded higher c-indices than a model based on all clinical variables in both the derivation (0.74 vs. 0.68) and validation cohorts (0.74 vs. 0.67). The reduction in mortality with apixaban was most pronounced in patients with a high ABC-death score.Conclusion: A new biomarker-based score for predicting risk of death in anticoagulated AF patients was developed, internally and externally validated, and well-calibrated in two large cohorts. The ABC-death risk score performed well and may contribute to overall risk assessment in AF.
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| 2. |
- Hijazi, Ziad, et al.
(författare)
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Comparison of Cardiac Troponins I and T Measured with High-Sensitivity Methods for Evaluation of Prognosis in Atrial Fibrillation : An ARISTOTLE Substudy
- 2015
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Ingår i: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 61:2, s. 368-378
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:Although cardiac troponin is associated with outcomes in atrial fibrillation (AF), the complementary prognostic information provided by cardiac troponin I (cTnI) and cTnT is unknown. This study investigated the distribution, determinants, and prognostic value of cTnI and cTnT concentrations in patients with AF.METHODS:At the time of randomization, we analyzed cTnI and cTnT concentrations of 14 806 AF patients in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial using high-sensitivity assays. Correlations (Spearman), determinants (multiple analysis of variance), and outcomes (adjusted Cox models and c-statistics) were investigated.RESULTS:Concentrations of cTnI and cTnT were correlated (r = 0.70) and measurable in most participants [cTnI 98.5% (median 5.4 ng/L, ≥99th percentile in 9.2%) and cTnT 93.5% (median 10.9 ng/L, ≥99th percentile in 34.4%)]. Renal impairment was the most important factor affecting the concentrations of both troponins. cTnI increase was more associated with heart failure, vascular disease, and persistent/permanent AF, and cTnT with age, male sex, and diabetes. Over a median 1.9 years of follow-up, patients with both troponins above the median had significantly higher risk for stroke/systemic embolism [hazard ratio (HR) 1.72 (95% CI 1.31-2.27)], cardiac death [3.14 (2.35-4.20)], and myocardial infarction [2.99 (1.78-5.03)] than those with both troponins below median (all P < 0.005). Intermediate risks were observed when only 1 troponin was above the median. When combined with clinical information, each marker provided similar prognostication and had comparable c-statistics.CONCLUSIONS:cTnI and cTnT concentrations are moderately correlated and measurable in plasma of most AF patients. The risk of stroke and cardiovascular events is highest when both troponins are above median concentrations. Each troponin provides comparable prognostic information when combined with clinical risk factors.
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| 3. |
- Hijazi, Ziad, et al.
(författare)
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The ABC (age, biomarkers, clinical history) stroke risk score : a biomarker-based risk score for predicting stroke in atrial fibrillation
- 2016
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 37:20, s. 1582-1590
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Atrial fibrillation (AF) is associated with an increased risk of stroke, which is currently estimated by clinical characteristics. The cardiac biomarkers N-terminal fragment B-type natriuretic peptide (NT-proBNP) and cardiac troponin high-sensitivity (cTn-hs) are independently associated with risk of stroke in AF. Our objective was to develop and validate a new biomarker-based risk score to improve prognostication of stroke in patients with AF.Methods: and results A new risk score was developed and internally validated in 14 701 patients with AF and biomarkers levels determined at baseline, median follow-up of 1.9 years. Biomarkers and clinical variables significantly contributing to predicting stroke or systemic embolism were assessed by Cox-regression and each variable obtained a weight proportional to the model coefficients. External validation was performed in 1400 patients with AF, median follow-up of 3.4 years. The most important predictors were prior stroke/transient ischaemic attack, NT-proBNP, cTn-hs, and age, which were included in the ABC (Age, Biomarkers, Clinical history) stroke risk score. The ABC-stroke score was well calibrated and yielded higher c-indices than the widely used CHA2DS2-VASc score in both the derivation cohort (0.68 vs. 0.62, P < 0.001) and the external validation cohort (0.66 vs. 0.58, P < 0.001). Moreover, the ABC-stroke score consistently provided higher c-indices in several important subgroups.Conclusion: A novel biomarker-based risk score for predicting stroke in AF was successfully developed and internally validated in a large cohort of patients with AF and further externally validated in an independent AF cohort. The ABC-stroke score performed better than the presently used clinically based risk score and may provide improved decision support in AF.
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| 4. |
- Hijazi, Ziad, et al.
(författare)
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The novel biomarker-based ABC (age, biomarkers, clinical history)-bleeding risk score for patients with atrial fibrillation : a derivation and validation study
- 2016
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Ingår i: The Lancet. - 0140-6736 .- 1474-547X. ; 387:10035, s. 2302-2311
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Tidskriftsartikel (refereegranskat)abstract
- Background: The benefit of oral anticoagulation in atrial fibrillation is based on a balance between reduction in ischaemic stroke and increase in major bleeding. We aimed to develop and validate a new biomarker-based risk score to improve the prognostication of major bleeding in patients with atrial fibrillation.Methods: We developed and internally validated a new biomarker-based risk score for major bleeding in 14 537 patients with atrial fibrillation randomised to apixaban versus warfarin in the ARISTOTLE trial and externally validated it in 8468 patients with atrial fibrillation randomised to dabigatran versus warfarin in the RE-LY trial. Plasma samples for determination of candidate biomarker concentrations were obtained at randomisation. Major bleeding events were centrally adjudicated. The predictive values of biomarkers and clinical variables were assessed with Cox regression models. The most important variables were included in the score with weights proportional to the model coefficients. The ARISTOTLE and RE-LY trials are registered with ClinicalTrials.gov, numbers NCT00412984 and NCT00262600, respectively.Findings: The most important predictors for major bleeding were the concentrations of the biomarkers growth differentiation factor-15 (GDF-15), high-sensitivity cardiac troponin T (cTnT-hs) and haemoglobin, age, and previous bleeding. The ABC-bleeding score (age, biomarkers [GDF-15, cTnT-hs, and haemoglobin], and clinical history [previous bleeding]) score yielded a higher c-index than the conventional HAS-BLED and the newer ORBIT scores for major bleeding in both the derivation cohort (0.68 [95% CI 0.66-0.70] vs 0.61 [0.59-0.63] vs 0.65 [0.62-0.67], respectively; ABC-bleeding vs HAS-BLED p< 0.0001 and ABC-bleeding vs ORBIT p= 0.0008). ABC-bleeding score also yielded a higher c-index score in the the external validation cohort (0.71 [95% CI 0.68-0.73] vs 0.62 [0.59-0.64] for HAS-BLED vs 0.68 [0.65-0.70] for ORBIT; ABC-bleeding vs HAS-BLED p< 0.0001 and ABC-bleeding vs ORBIT p= 0.0016). A modified ABC-bleeding score using alternative biomarkers (haematocrit, cTnI-hs, cystatin C, or creatinine clearance) also outperformed the HAS-BLED and ORBIT scores.Interpretation: The ABC-bleeding score, using age, history of bleeding, and three biomarkers (haemoglobin, cTn-hs, and GDF-15 or cystatin C/CKD-EPI) was internally and externally validated and calibrated in large cohorts of patients with atrial fibrillation receiving anticoagulation therapy. The ABC-bleeding score performed better than HAS-BLED and ORBIT scores and should be useful as decision support on anticoagulation treatment in patients with atrial fibrillation.
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| 5. |
- Oldgren, Jonas, et al.
(författare)
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Performance and Validation of a Novel Biomarker-Based Stroke Risk Score for Atrial Fibrillation
- 2016
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Ingår i: Circulation. - 0009-7322 .- 1524-4539. ; 134:22, s. 1697-1707
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: -Atrial fibrillation (AF) is associated with increased but variable risk of stroke. Our aim was to validate the recently developed biomarker-based ABC-stroke risk score and compare its performance with the CHA2DS2VASc and ATRIA risk scores.METHODS: -ABC-stroke score includes Age, Biomarkers (NT-proBNP and high-sensitivity [hs] troponin [cTn]), and Clinical history (prior stroke). This validation was based on 8,356 patients, 16,137 person-years of follow-up, and 219 adjudicated stroke or systemic embolic (SE) events in anticoagulated patients with AF in the RE-LY study. Levels of NT-proBNP, hs-cTnT, and hs-cTnI were determined in plasma samples obtained at study entry.RESULTS: -The ABC-stroke score was well calibrated with 0.76 stroke/SE events per 100 person-years in the predefined low (<1%/year) risk group, 1.48 in the medium (1-2%/year) risk group, and 2.60 in the high (>2%/year) risk group for the ABC-stroke score with hs-cTnT. Hazard ratios for stroke/SE were 1.95 for medium versus low risk, and 3.44 for high versus low risk groups. ABC-stroke score achieved C indices of 0.65 with both hs-cTnT and hs-cTnI, as compared with 0.60 for CHA2DS2VASc (p=0.004 for hs-cTnT and p=0.022 hs-cTnI) and 0.61 for ATRIA scores (p=0.005 hs-cTnT and p=0.034 for hs-cTnI).CONCLUSIONS: -The biomarker-based ABC-stroke score was well calibrated and consistently performed better than both the CHA2DS2VASc and ATRIA stroke scores. The ABC score should be considered an improved decision support tool in the care of patients with AF.
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| 6. |
- Alexander, John H, et al.
(författare)
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Apixaban 5 mg Twice Daily and Clinical Outcomes in Patients With Atrial Fibrillation and Advanced Age, Low Body Weight, or High Creatinine : A Secondary Analysis of a Randomized Clinical Trial
- 2016
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Ingår i: JAMA cardiology. - : American Medical Association (AMA). - 2380-6583 .- 2380-6591. ; 1:6, s. 673-681
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE: In the Apixaban for Reduction of Stroke and Other Thromboembolic Complications in Atrial Fibrillation (ARISTOTLE) trial, the standard dose of apixaban was 5 mg twice daily; patients with at least 2 dose-reduction criteria-80 years or older, weight 60 kg or less, and creatinine level 1.5 mg/dL or higher-received a reduced dose of apixaban of 2.5 mg twice daily. Little is known about patients with 1 dose-reduction criterion who received the 5 mg twice daily dose of apixaban.OBJECTIVE: To determine the frequency of 1 dose-reduction criterion and whether the effects of the 5 mg twice daily dose of apixaban on stroke or systemic embolism and bleeding varied among patients with 1 or no dose-reduction criteria.DESIGN, SETTING, AND PARTICIPANTS: Among 18 201 patients in the ARISTOTLE trial, 17 322 were included in this analysis. Annualized event rates of stroke or systemic embolism and major bleeding and hazard ratios (HRs) and 95% CIs were evaluated. Interactions between the effects of apixaban vs warfarin and the presence of 1 or no dose-reduction criteria were assessed. The first patient was enrolled in the ARISTOTLE trial on December 19, 2006, and follow-up was completed on January 30, 2011. Data were analyzed from January 2015 to May 30, 2016.MAIN OUTCOMES AND MEASURES: Analysis of major bleeding included events during study drug treatment. Analysis of stroke or systemic embolism was based on intention to treat.RESULTS: Of the patients with 1 or no dose-reduction criteria assigned to receive the 5 mg twice daily dose of apixaban or warfarin, 3966 had 1 dose-reduction criterion; these patients had higher rates of stroke or systemic embolism (HR, 1.47; 95% CI, 1.20-1.81) and major bleeding (HR, 1.89; 95% CI, 1.62-2.20) compared with those with no dose-reduction criteria (n = 13 356). The benefit of the 5 mg twice daily dose of apixaban (n = 8665) compared with warfarin (n = 8657) on stroke or systemic embolism in patients with 1 dose-reduction criterion (HR, 0.94; 95% CI, 0.66-1.32) and no dose-reduction criterion (HR, 0.77; 95% CI, 0.62-0.97) were similar (P for interaction = .36). Similarly, the benefit of 5 mg twice daily dose of apixaban compared with warfarin on major bleeding in patients with 1 dose-reduction criterion (HR, 0.68; 95% CI, 0.53-0.87) and no dose-reduction criterion (HR, 0.72; 95% CI, 0.60-0.86) were similar (P for interaction = .71). Similar patterns were seen for each dose-reduction criterion and across the spectrum of age, body weight, creatinine level, and creatinine clearance.CONCLUSIONS AND RELEVANCE: Patients with atrial fibrillation and isolated advanced age, low body weight, or renal dysfunction have a higher risk of stroke or systemic embolism and major bleeding but show consistent benefits with the 5 mg twice daily dose of apixaban vs warfarin compared with patients without these characteristics. The 5 mg twice daily dose of apixaban is safe, efficacious, and appropriate for patients with only 1 dose-reduction criterion.TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00412984.
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| 7. |
- Alexander, Karen P, et al.
(författare)
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Outcomes of apixaban versus warfarin in patients with atrial fibrillation and multi-morbidity : Insights from the ARISTOTLE trial
- 2019
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Ingår i: American Heart Journal. - : Elsevier BV. - 0002-8703 .- 1097-6744. ; 208, s. 123-131
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Patients with atrial fibrillation (AF) often have multi-morbidity, defined as ≥3 comorbid conditions. Multi-morbidity is associated with polypharmacy, adverse events, and frailty potentially altering response to anticoagulation. We sought to describe the prevalence of multi-morbidity among older patients with AF and determine the association between multi-morbidity, clinical outcomes, and the efficacy and safety of apixaban compared with warfarin.METHODS: In this post-hoc subgroup analysis of the ARISTOTLE trial, we studied enrolled patients age ≥ 55 years (n = 16,800). Patients were categorized by the number of comorbid conditions at baseline: no multi-morbidity (0-2 comorbid conditions), moderate multi-morbidity (3-5 comorbid conditions), and high multi-morbidity (≥6 comorbid conditions). Association between multi-morbidity and clinical outcomes were analyzed by treatment with a median follow-up of 1.8 (1.3-2.3) years.RESULTS: Multi-morbidity was present in 64% (n = 10,713) of patients; 51% (n = 8491) had moderate multi-morbidity, 13% (n = 2222) had high multi-morbidity, and 36% (n = 6087) had no multi-morbidity. Compared with the no multi-morbidity group, the high multi-morbidity group was older (74 vs 69 years), took twice as many medications (10 vs 5), and had higher CHA2DS2-VASc scores (4.9 vs 2.7) (all P < .001). Adjusted rates per 100 patient-years for stroke/systemic embolism, death, and major bleeding increased with multi-morbidity (Reference no multi-morbidity; moderate multi-morbidity 1.42 [1.24-1.64] and high multi-morbidity 1.92 [1.59-2.31]), with no interaction in relation to efficacy or safety of apixaban.CONCLUSIONS: Multi-morbidity is prevalent among the population with AF; efficacy and safety of apixaban is preserved in this subgroup supporting extension of trial results to the most complex AF patients.
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| 8. |
- Guimaraes, Patricia O., et al.
(författare)
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International normalized ratio control and subsequent clinical outcomes in patients with atrial fibrillation using warfarin
- 2019
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Ingår i: Journal of Thrombosis and Thrombolysis. - : Springer Science and Business Media LLC. - 0929-5305 .- 1573-742X. ; 48:1, s. 27-34
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Tidskriftsartikel (refereegranskat)abstract
- We explored associations between INR measures and clinical outcomes in patients with AF using warfarin, and whether INR history predicted future INR measurements. We included patients in ARISTOTLE who were randomized to and received warfarin. Among patients who had events, we included those with ≥ 3 INR values in the 180 days prior to the event, with the most recent ≤ 60 days prior to the event, who were on warfarin at the time of event (n = 545). Non-event patients were included in the control group if they had ≥ 180 days of warfarin exposure with ≥ 3 INR measurements (n = 7259). The median (25th, 75th) number of INR values per patient was 29 (21, 38) over a median follow-up of 1.8 years. A total of 87% had at least one INR value < 1.5; 49% had at least one value > 4.0. The last INRs before events (median 14 [24, 7] days) were < 3.0 for at least 75% of patients with major bleeding and > 2.0 for half of patients with ischemic stroke. Historic time in therapeutic range (TTR) was weakly associated with future TTR (R2 = 0.212). Historic TTR ≥ 80% had limited predictive ability to discriminate future TTR ≥ 80% (C index 0.61). In patients with AF receiving warfarin, most bleeding events may not have been preventable despite careful INR control. Our findings suggest that INRs collected through routine management are not sufficiently predictive to provide reassurance about future time in therapeutic range or to prevent subsequent outcomes, and might be over-interpreted in clinical practice.
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| 9. |
- Hijazi, Ziad, et al.
(författare)
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Biomarkers of inflammation and risk of cardiovascular events in anticoagulated patients with atrial fibrillation
- 2016
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Ingår i: Heart. - : BMJ. - 1355-6037 .- 1468-201X. ; 102:7, s. 508-517
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Atrial fibrillation (AF) is a risk factor for stroke and mortality and the prothrombotic state has been linked to inflammation. In this study we evaluated the relationship between inflammatory biomarkers at baseline and future risk of cardiovascular events in the Apixaban for Reduction In Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial.Methods: The ARISTOTLE trial randomised 18 201 patients with AF to apixaban or warfarin. Interleukin 6 (IL-6) and C reactive protein (CRP) were analysed in plasma obtained at randomisation from 14 954 participants, and median follow-up was 1.9 years. Association between quartile groups of IL-6 and CRP and outcomes were analysed by Cox regression adjusted for clinical risk factors and other cardiovascular biomarkers (NT-proBNP, troponin, GDF-15, cystatin C).Results: The IL-6 median level was 2.3 ng/L (IQR 1.5-3.9), median CRP level was 2.2 mg/L (1.0-4.8). IL-6 and CRP were significantly associated with all-cause mortality independent of clinical risk factors and other biomarkers (HR (95% CI) 1.93 (1.57 to 2.37) and 1.49 (1.24 to 1.79), respectively, Q4 vs Q1). IL-6 was associated with myocardial infarction, cardiovascular mortality, and major bleeding beyond clinical risk factors but not in the presence of cardiovascular biomarkers (NT-proBNP, troponin, GDF-15, cystatin C). Neither inflammatory biomarker was associated with stroke/systemic embolism. Risk prediction for stroke, death and major bleeding was not improved by IL-6 or CRP when added to clinical risk factors and the other cardiovascular biomarkers (NT-proBNP, troponin, GDF-15, cystatin C).Conclusions: In patients with AF on anticoagulation, after accounting for clinical risk factors and other biomarkers, biomarkers of inflammation were significantly associated with an increased risk of mortality. However, there were no associations with the risk of stroke or major bleeding.
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| 10. |
- Hijazi, Ziad, et al.
(författare)
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Efficacy and Safety of Apixaban Compared With Warfarin in Patients With Atrial Fibrillation in Relation to Renal Function Over Time : Insights From the ARISTOTLE Randomized Clinical Trial
- 2016
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Ingår i: JAMA cardiology. - : American Medical Association (AMA). - 2380-6583 .- 2380-6591. ; 1:4, s. 451-460
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE:Renal impairment confers an increased risk of stroke, bleeding, and death in patients with atrial fibrillation. Little is known about the efficacy and safety of apixaban in relation to renal function changes over time.OBJECTIVES:To evaluate changes of renal function over time and their interactions with outcomes during a median of 1.8 years of follow-up in patients with atrial fibrillation randomized to apixaban vs warfarin treatment.DESIGN, SETTING, AND PARTICIPANTS:The prospective, randomized, double-blind Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) clinical trial randomized 18 201 patients with atrial fibrillation to apixaban or warfarin. Serial creatinine measurements were available in 16 869 patients. Worsening of renal function was defined as an annual decrease in estimated glomerular filtration more than 20%. The relations between treatment, outcomes, and renal function were investigated using Cox regression models, with renal function as a time-dependent covariate.MAIN OUTCOMES AND MEASURES:Stroke or systemic embolism (primary outcome), major bleeding (safety outcome), and mortality were examined in relation to renal function over time estimated with both the Cockcroft-Gault and Chronic Kidney Disease Epidemiology Collaboration equations.RESULTS:Among 16 869 patients, the median age was 70 years and 65.2% of patients were men. Worsening in estimated glomerular filtration more than 20% was observed in 2294 patients (13.6%) and was associated with older age and more cardiovascular comorbidities. The risks of stroke or systemic embolism, major bleeding, and mortality were higher in patients with worsening renal function (HR, 1.53; 95% CI, 1.17-2.01 for stroke or systemic embolism; HR, 1.56; 95% CI, 1.27-1.93 for major bleeding; and HR, 2.31; 95% CI, 1.98-2.68 for mortality). The beneficial effects of apixaban vs warfarin on rates of stroke or systemic embolism and major bleeding were consistent in patients with normal or poor renal function over time and also in those with worsening renal function.CONCLUSIONS AND RELEVANCE:In patients with atrial fibrillation, declining renal function was more common in elderly patients and those with cardiovascular comorbidities. Worsening renal function was associated with a higher risk of subsequent cardiovascular events and bleeding. The superior efficacy and safety of apixaban as compared with warfarin were similar in patients with normal, poor, and worsening renal function.TRIAL REGISTRATION:clinicaltrials.gov Identifier: NCT00412984.
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