| 1. |
- Aulin, Julia, et al.
(författare)
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Serial measurement of interleukin-6 and risk of mortality in anticoagulated patients with atrial fibrillation : Insights from ARISTOTLE and RE-LY trials.
- 2020
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Ingår i: Journal of Thrombosis and Haemostasis. - : Elsevier BV. - 1538-7933 .- 1538-7836. ; 18:9, s. 2287-2295
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The inflammatory biomarker interleukin-6 (IL-6) is associated with mortality in atrial fibrillation (AF).OBJECTIVE: To investigate if repeated IL-6 measurements improve the prognostication for stroke or systemic embolism, major bleeding, and mortality in anticoagulated patients with AF.METHODS: IL-6 levels by ELISA were measured at study entry and at 2 months in 4830 patients in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial with 1.8 years median follow-up. In the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial, IL-6 was measured at study entry, 3, 6, and 12 months in 2559 patients with 2.0 years median follow-up. Associations between a second IL-6 measurement and outcomes, adjusted for baseline IL-6, clinical variables, and other cardiovascular biomarkers, were analyzed by Cox regression.RESULTS: Median IL-6 levels were 2.0 ng/L (interquartile range [IQR] 1.30-3.20) and 2.10 ng/L (IQR 1.40-3.40) at the two time-points in ARISTOTLE, and, in RE-LY, 2.5 ng/L (IQR 1.6-4.3), 2.5 ng/L (IQR 1.6-4.2), 2.4 ng/L (IQR 1.6, 3.9), and 2.4 ng/L (IQR 1.5, 3.9), respectively. IL-6 was associated with mortality; hazard ratios per 50% higher IL-6 at 2 or 3 months, respectively, were 1.32 (95% confidence interval, 1.23-1.41; P < .0001) in ARISTOTLE, and 1.11 (1.01-1.22, P = .0290) in RE-LY; with improved C index from 0.74 to 0.76 in ARISTOTLE, but not in the smaller RE-LY cohort. There were no consistent associations with second IL-6 and stroke or systemic embolism, or major bleeding.CONCLUSIONS: Persistent systemic inflammatory activity, assessed by repeated IL-6 measurements, is associated with mortality independent of established clinical risk factors and other strong cardiovascular biomarkers in anticoagulated patients with AF.
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| 2. |
- Boehm, Michael, et al.
(författare)
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Changes in Renal Function in Patients With Atrial Fibrillation An Analysis From the RE-LY Trial
- 2015
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Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 65:23, s. 2481-2493
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND Vitamin K-dependent factors protect against vascular and renovascular calcification, and vitamin K antagonists may be associated with a decreased glomerular filtration rate (GFR). OBJECTIVES This study analyzed changes in GFR during long-term treatment with warfarin or dabigatran etexilate (DE) in patients enrolled in the RE-LY (Randomized Evaluation of Long Term Anticoagulation Therapy) trial. METHODS Of the 18,113 patients in the RE-LY study randomized to receive DE (110 mg or 150 mg twice daily) or warfarin, 16,490 patients with atrial fibrillation had creatinine values measured at baseline and at least 1 follow-up visit. Changes in GFR for up to 30 months were evaluated. RESULTS GFR declined in all treatment groups. After an average of 30 months, the mean +/- SE decline in GFR was significantly greater with warfarin (-3.68 +/- 0.24 ml/min) compared with DE 110 mg (-2.57 +/- 0.24 ml/min; p = 0.0009 vs. warfarin) and DE 150 mg (-2.46 +/- 0.23 ml/min; p = 0.0002 vs. warfarin). A decrease in GFR >25% was less likely with DE 110 mg (hazard ratio: 0.81 [95% confidence interval: 0.69 to 0.96]; p = 0.017) or DE 150 mg (hazard ratio: 0.79 [95% confidence interval: 0.68 to 0.93]; p = 0.0056) than with warfarin in the observation period >18 months. Patients with poor international normalized ratio control (i.e., time in therapeutic range <65%) exhibited a faster decline in GFR. A more pronounced decline in GFR was associated with previous warfarin use and with the presence of diabetes. CONCLUSIONS Patients with atrial fibrillation receiving oral anticoagulation exhibited a decline in renal function that was greater in those taking warfarin versus DE, and it was amplified by diabetes and previous vitamin K antagonist use.
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| 3. |
- Böhm, Michael, et al.
(författare)
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Cardiovascular outcomes, bleeding risk, and achieved blood pressure in patients on long-term anticoagulation with the thrombin antagonist dabigatran or warfarin : data from the RE-LY trial
- 2020
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Ingår i: European Heart Journal. - : Oxford University Press. - 0195-668X .- 1522-9645. ; 41:30, s. 2848-2859
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Tidskriftsartikel (refereegranskat)abstract
- Aims A J-shaped association of cardiovascular events to achieved systolic (SBP) and diastolic (DBP) blood pressure was shown in high-risk patients. This association on oral anticoagulation is unknown. This analysis from RELY assessed the risks of death, stroke or systemic emboli, and bleeding according to mean achieved SBP and DBP in atrial fibrillation on oral anticoagulation. Methods RE-LY patients were followed for 2 years and recruited between 22 December 2005 until 15 December 2007. and results 18.113 patients were randomized in 951 centres in 54 countries and 18,107 patients with complete blood pressure (BP) data were analysed with a median follow-up of 2.0 years and a complete follow-up in 99.9%. The association between achieved mean SBP and DBP on all-cause death, stroke and systemic embolic events (SSE), major, and any bleeding were explored. On treatment, SBP >140 mmHg and <120 mmHg was associated with all-cause death compared with SBP 120-130 mmHg (reference). For SSE, risk was unchanged at SBP <110 mmHg but increased at 140-160 mmHg (adjusted hazard ratio (HR) 1.81; 1.40-2.33) and SBP >160 mmHg (HR 3.35; 2.09-5.36). Major bleeding events were also increased at <110 mmHg and at 110 to <120 mmHg. Interestingly, there was no increased risk of major bleeding at SBP >130 mmHg. Similar patterns were observed for DBP with an increased risk at <70 mmHg (HR 1.55; 1.35-1.78) and >90 mmHg (HR 1.88; 1.43-2.46) for all-cause death compared to 70 to <80 mmHg (reference). Risk for any bleeding was increased at low DBP <70 mmHg (HR 1.46; 1.37-1.56) at DBP 80 to <90 mmHg (HR 1.13; 1.06-1.31) without increased risk at higher achieved DBP. Dabigatran 150 mg twice daily showed an advantage in all patients for all-cause death and SSE and there was an advantage for 110 mg dabigatran twice daily for major bleeding and any bleeding irrespective of SBP or DBP achieved. Similar results were obtained for baseline BP, time-updated BP, and BP as time-varying covariate. Conclusion Low achieved SBP associates with increased risk of death, SSE, and bleeding in patients with atrial fibrillation on oral anticoagulation. Major bleeding events did not occur at higher BP. Low BP might identify high-risk patients not only for death but also for high bleeding risks.
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| 4. |
- Böhm, Michael, et al.
(författare)
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Reply : Anticoagulant-Related Nephropathy
- 2015
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Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 66:23, s. 2682-
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Tidskriftsartikel (refereegranskat)
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| 5. |
- 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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| 6. |
- Hijazi, Ziad, et al.
(författare)
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Cardiac Biomarkers and Left Ventricular Hypertrophy in Relation to Outcomes in Patients With Atrial Fibrillation : Experiences From the RE-LY Trial
- 2019
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Ingår i: Journal of the American Heart Association. - 2047-9980. ; 8:2
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundCardiac 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 ResultsPlasma 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.ConclusionsCardiac 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.
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| 7. |
- Hijazi, Ziad, et al.
(författare)
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Cardiac Biomarkers Are Associated With an Increased Risk of Stroke and Death in Patients With Atrial Fibrillation : A Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) Substudy
- 2012
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Ingår i: Circulation. - 0009-7322 .- 1524-4539. ; 125:13, s. 1605-1616
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Tidskriftsartikel (refereegranskat)abstract
- Background—Cardiac biomarkers are strong predictors of adverse outcomes in several patient populations. We evaluated the prevalence of elevated troponin I and N-terminal pro-B-type natriuretic peptide (NT-proBNP) and their association to cardiovascular events in atrial fibrillation (AF) patients in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial.Methods and Results—Biomarkers at randomization were analyzed in 6189 patients. Outcomes were evaluated by Cox proportional hazards models adjusting for established cardiovascular risk factors and the CHADS2 and CHA2DS2-VASc risk scores. Patients were stratified based on troponin I concentrations: <0.010 μg/L, n=2663; 0.010 to 0.019 μg/L, n=2006; 0.020 to 0.039 μg/L, n=1023; ≥0.040 μg/L, n=497; and on NT-proBNP concentration quartiles: <387; 387 to 800; 801 to 1402; >1402 ng/L. Rates of stroke were independently related to levels of troponin I with 2.09%/year in the highest and 0.84%/year in the lowest troponin I group (hazard ratio [HR], 1.99 [95% CI, 1.17–3.39]; P=0.0040), and to NT-proBNP with 2.30%/year versus 0.92% in the highest versus lowest NT-proBNP quartile groups, (HR, 2.40 [95% CI, 1.41–4.07]; P=0.0014). Vascular mortality was also independently related to biomarker levels with 6.56%/year in the highest and 1.04%/year the lowest troponin I group (HR, 4.38 [95% CI, 3.05–6.29]; P<0.0001), and 5.00%/year in the highest and 0.61%/year in the lowest NT-proBNP quartile groups (HR, 6.73 [3.95–11.49]; P<0.0001). Biomarkers increased the C-statistic from 0.68 to 0.72, P<0.0001, for a composite of thromboembolic events.Conclusions—Elevations of troponin I and NT-proBNP are common in patients with AF and independently related to increased risks of stroke and mortality. Cardiac biomarkers seem useful for improving risk prediction in AF beyond currently used clinical variables.
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| 8. |
- Hijazi, Ziad, et al.
(författare)
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Efficacy and safety of dabigatran compared with warfarin in patients with atrial fibrillation in relation to renal function over time-A RE-LY trial analysis
- 2018
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Ingår i: American Heart Journal. - : MOSBY-ELSEVIER. - 0002-8703 .- 1097-6744. ; 198, s. 169-177
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Tidskriftsartikel (refereegranskat)abstract
- Background: Renal function may decline over time, and the efficacy and safety of dabigatran in atrial fibrillation (AF) in relation to renal function changes are unknown.& para;& para;Methods: The RE-LY trial randomized 18,113 patients with AF to 2 doses of dabigatran or warfarin for stroke prevention. Serial creatinine measurements were available in 16,988 patients. The relations between treatment, outcomes, and renal function (Cockcroft-Gault) were investigated using Cox-regression (1) with renal function as a time-dependent covariate and (2) according to worsening renal function (WRF) during follow-up, predefined as a decline in estimated glomerular filtration rate >20% from baseline.& para;& para;Results: During a median follow-up of 1.8 years, 4,106 (24.2%) participants were observed to have WRF, and 12,882 (75.8%) had stable renal function. The risks of all-cause mortality and major bleeding were higher in patients with WRF versus those with stable renal function (hazard ratio [95% CI]: 2.17 [1.81-2.59] and 1.43 [1.19-1.71]. respectively; both P < .0005). The efficacy and safety of dabigatran versus warfarin were similar irrespective of renal function changes over time (interaction P values >= .13 in both models). Dabigatran 110 mg showed a greater relative risk reduction of major bleeding in patients with normal renal function (estimated glomerular filtration rate >80 mL/min) during follow-up (interaction P= .026).& para;& para;Conclusions: In AF, WRF was associated with a higher risk of death and major bleeding. The efficacy and safety profile of dabigatran compared with warfarin was similar irrespective of renal function changes over time. Dabigatran 110 mg showed a greater relative risk reduction of major bleeding in patients with normal renal function during follow-up.
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| 9. |
- Hijazi, Ziad, et al.
(författare)
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Efficacy and Safety of Dabigatran Compared With Warfarin in Relation to Baseline Renal Function in Patients With Atrial Fibrillation A RE-LY (Randomized Evaluation of Long-term Anticoagulation Therapy) Trial Analysis
- 2014
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Ingår i: Circulation. - 0009-7322 .- 1524-4539. ; 129:9, s. 961-970
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Tidskriftsartikel (refereegranskat)abstract
- Background Renal impairment increases the risk of stroke and bleeding in patients with atrial fibrillation. In the Randomized Evaluation of Long-Term Anticoagulant Therapy (RELY) trial, dabigatran, with approximate to 80% renal elimination, displayed superiority over warfarin for prevention of stroke and systemic embolism in the 150-mg dose and significantly less major bleeding in the 110-mg dose in 18 113 patients with nonvalvular atrial fibrillation. This prespecified study investigated these outcomes in relation to renal function. Methods and Results Glomerular filtration rate was estimated with the Cockcroft-Gault, Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), and Modification of Diet in Renal Disease (MDRD) equations in all randomized patients with available creatinine at baseline (n=17 951), and cystatin C-based glomerular filtration rate was estimated in a subpopulation with measurements available (n=6190). A glomerular filtration rate 80, 50 to <80, and <50 mL/min was estimated in 32.6%, 47.6%, and 19.8% and in 21.6%, 59.6%, and 18.8% of patients based on Cockcroft-Gault and CKD-EPI, respectively. Rates of stroke or systemic embolism, major bleeding, and all-cause mortality increased as renal function decreased. The rates of stroke or systemic embolism were lower with dabigatran 150 mg and similar with 110 mg twice daily compared with warfarin, without significant heterogeneity in subgroups defined by renal function (interaction P>0.1 for all). For the outcome of major bleeding, there were significant interactions between treatment and renal function according to CKD-EPI and MDRD equations, respectively (P<0.05). The relative reduction in major bleeding with either dabigatran dose compared with warfarin was greater in patients with glomerular filtration rate 80 mL/min. Conclusions The efficacy of both dosages of dabigatran was consistent with the overall trial irrespective of renal function. However, with the CKD-EPI and MDRD equations, both dabigatran dosages displayed significantly lower rates of major bleeding in patients with glomerular filtration rate 80 mL/min. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00262600.
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| 10. |
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