| 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. |
- Benz, Alexander P., et al.
(författare)
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Stroke risk prediction in patients with atrial fibrillation with and without rheumatic heart disease
- 2021
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Ingår i: Cardiovascular Research. - : Oxford University Press. - 0008-6363 .- 1755-3245. ; 118:1, s. 295-304
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Tidskriftsartikel (refereegranskat)abstract
- Aims Patients with atrial fibrillation (AF) and rheumatic heart disease (RHD), especially mitral stenosis, are assumed to be at high risk of stroke, irrespective of other factors. We aimed to re-evaluate stroke risk factors in a contemporary cohort of AF patients. Methods and results We analysed data of 15 400 AF patients presenting to an emergency department and who were enrolled in the global RE-LY AF registry, representing 47 countries from all inhabited continents. Follow-up occurred at 1 year after enrolment. A total of 1788 (11.6%) patients had RHD. These patients were younger (51.4 +/- 15.7 vs. 67.8 +/- 13.6 years), more likely to be female (66.2% vs. 44.7%) and had a lower mean CHA(2)DS(2)-VASc score (2.1 +/- 1.7 vs. 3.7 +/- 2.2) as compared to patients without RHD (all P<0.001). Significant mitral stenosis (average mean transmitral gradient 11.5 +/- 6.5 mmHg) was the predominant valve lesion in those with RHD (59.6%). Patients with RHD had a higher baseline rate of anticoagulation use (60.4% vs. 45.2%, P<0.001). Unadjusted stroke rates at 1 year were 2.8% and 4.1% for patients with and without RHD, respectively. The performance of the CHA(2)DS(2)-VASc score was modest in both groups [stroke at 1 year, c-statistics 0.69, 95% confidence interval (CI) 0.60-0.78 and 0.63, 95% CI 0.61-0.66, respectively]. In the overall cohort, advanced age, female sex, prior stroke, tobacco use, and non-use of anticoagulation were predictors for stroke (all P<0.05). Mitral stenosis was not associated with stroke risk (adjusted odds ratio 1.07, 95% CI 0.67-1.72, P=0.764). Conclusion The performance of the CHA(2)DS(2)-VASc score was modest in AF patients both with and without RHD. In this cohort, moderate-to-severe mitral stenosis was not an independent risk factor for stroke.
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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. |
- Hijazi, Ziad, et al.
(författare)
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Screening of Multiple Biomarkers Associated With Ischemic Stroke in Atrial Fibrillation
- 2020
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Ingår i: Journal of the American Heart Association. - 2047-9980 .- 2047-9980. ; 9:24
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundTo explore the pathophysiological features of ischemic stroke in patients with atrial fibrillation (AF), we evaluated the association between 268 plasma proteins and subsequent ischemic stroke in 2 large AF cohorts receiving oral anticoagulation.Methods and ResultsA case‐cohort sample of patients with AF from the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial, including 282 cases with ischemic stroke or systemic embolism and a random sample of 4124 without these events, during 1.9 years of follow‐up was used for identification. Validation was provided by a similar case‐cohort sample of patients with AF from the RE‐LY (Randomized Evaluation of Long‐Term Anticoagulation Therapy) trial, including 149 cases with ischemic stroke/systemic embolism and a random sample of 1062 without these events. In plasma obtained before randomization, 268 unique biomarkers were measured with OLINK proximity extension assay panels (CVD II, CVD III, and Inflammation) and conventional immunoassays. The association between biomarkers and outcomes was evaluated by random survival forest and adjusted Cox regression. According to random survival forest or Cox regression analyses, the biomarkers most strongly and consistently associated with ischemic stroke/systemic embolism were matrix metalloproteinase‐9, NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide), osteopontin, sortilin, soluble suppression of tumorigenesis 2, and trefoil factor‐3. The corresponding hazard ratios (95% CIs) for an interquartile difference were as follows: 1.18 (1.00–1.38), 1.55 (1.28–1.88), 1.28 (1.07–1.53), 1.19 (1.02–1.39), 1.23 (1.05–1.45), and 1.19 (0.97–1.45), respectively.ConclusionsIn patients with AF, of 268 unique biomarkers, the 6 biomarkers most strongly associated with subsequent ischemic stroke/systemic embolism represent fibrosis/remodeling (matrix metalloproteinase‐9 and soluble suppression of tumorigenesis 2), cardiac dysfunction (NT‐proBNP), vascular calcification (osteopontin), metabolism (sortilin), and mucosal integrity/ischemia (trefoil factor‐3).RegistrationURL: https://www.clinicaltrials.gov. Unique Identifiers: NCT00412984 and NCT00262600.
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| 5. |
- Kloosterman, Marielle, et al.
(författare)
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Characteristics and outcomes of atrial fibrillation in patients without traditional risk factors : an RE-LY AF registry analysis
- 2020
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Ingår i: Europace. - : Oxford University Press (OUP). - 1099-5129 .- 1532-2092. ; 22:6, s. 870-877
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Data on patient characteristics, prevalence, and outcomes of atrial fibrillation (AF) patients without traditional risk factors, often labelled 'lone AF', are sparse. Methods and results: The RE-LY AF registry included 15 400 individuals who presented to emergency departments with AF in 47 countries. This analysis focused on patients without traditional risk factors, including age >= 60years, hypertension, coronary artery disease, heart failure, left ventricular hypertrophy, congenital heart disease, pulmonary disease, valve heart disease, hyperthyroidism, and prior cardiac surgery. Patients without traditional risk factors were compared with age- and region-matched controls with traditional risk factors (1:3 fashion). In 796 (5%) patients, no traditional risk factors were present. However, 98% (779/796) had less-established or borderline risk factors, including borderline hypertension (130-140/80-90mmHg; 47%), chronic kidney disease (eGFR<60mL/min; 57%), obesity (body mass index>30; 19%), diabetes (5%), excessive alcohol intake (>14 units/week; 4%), and smoking (25%). Compared with patients with traditional risk factors (n=2388), patients without traditional risk factors were more often men (74% vs. 59%, P<0.001) had paroxysmal AF (55% vs. 37%, P<0.001) and less AF persistence after 1 year (21% vs. 49%, P<0.001). Furthermore, 1-year stroke occurrence rate (0.6% vs. 2.0%, P=0.013) and heart failure hospitalizations (0.9% vs. 12.5%, P<0.001) were lower. However, risk of AF-related re-hospitalization was similar (18% vs. 21%, P=0.09). Conclusion: Almost all patients without traditionally defined AF risk factors have less-established or borderline risk factors. These patients have a favourable 1-year prognosis, but risk of AF-related re-hospitalization remains high. Greater emphasis should be placed on recognition and management of less-established or borderline risk factors.
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| 6. |
- McAlister, Finlay A., et al.
(författare)
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Hypertension prevalence but not control varies across the spectrum of risk in patients with atrial fibrillation : A RE-LY atrial fibrillation registry sub-study
- 2020
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Ingår i: PLOS ONE. - : PUBLIC LIBRARY SCIENCE. - 1932-6203. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Although hypertension is the most common risk factor for atrial fibrillation (AF), whether blood pressure (BP) control varies across the spectrum of stroke risk in patients with AF or by adequacy of their thromboprophylaxis management is unclear. Methods We examined data from the RE-LY AF registry conducted at 164 emergency departments (EDs) in 47 countries between December 2007 and October 2011. Results Of the 15,400 patients in the registry, we analyzed the 9929 (mean age 67.5 years, 51.9% men) with a prior history of AF and complete BP data. While 6508 (66.5%) AF patients had hypertension, the prevalence varied widely depending on comorbidity profiles: from 45.4% in those without other cardiovascular risk factors to 82.5% in those with AF and diabetes. Although 93.9% of AF patients with hypertension were on at least one antihypertensive agent, fewer than half had BP levels <= 140/90 with no difference across risk profiles: 45.9% of those with NVAF and CHADS(2) scores of 1 and 45.6% of those with NVAF and CHADS(2) scores of 2 or more (46.9% and 45.3% for CHA(2)DS(2)-VASc scores of 1 versus 2 or more). BP control rates were not significantly better in those NVAF patients receiving guideline concordant thromboprophylaxis management (47.2%, aOR 1.03, 95%CI 0.89-1.20) than in those not receiving guideline-concordant antithrombotic therapy (45.3%). Conclusions Hypertension was common in patients with AF but BP control rates were sub-optimal and varied little across the spectrum of stroke risk or by adequacy of thromboprophylaxis. This highlights the need for an increased focus on total atherosclerotic risk rather than just thromboprophylaxis management in AF patients.
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| 7. |
- Millenaar, Dominic, et al.
(författare)
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Cardiovascular Outcomes According to Polypharmacy and Drug Adherence in Patients with Atrial Fibrillation on Long-Term Anticoagulation (from the RE-LY Trial)
- 2021
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Ingår i: American Journal of Cardiology. - : EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC. - 0002-9149 .- 1879-1913. ; 149, s. 27-35
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Tidskriftsartikel (refereegranskat)abstract
- Prevalence of atrial fibrillation (AF) increases with age, along with comorbidities and, thus, polypharmacy. Non-adherence is associated with polypharmacy. This study aimed to identify patients at risk for cardiovascular events according to their pharmacological treatment intensity and adherence. Patients (n = 18,113) with a mean age of 71.5 +/- 8.7 years, at high cardiovascular risk were followed between December 2005 until December 2007 for a median time of 2 years. The association between polypharmacy and adherence and their impact on cardiovascular and bleeding events were explored. Adherence was defined as a study drug intake of >= 80%. Patients with more co-medications had a higher body mass index, higher prevalence of hypertension, coronary heart disease, heart failure, and diabetes mellitus (all p < 0.0001) compared to <= 4 or 5-8 co-medications, but no differences in history of stroke (p = 0.68) or transient ischemic attack (p = 0.065). Across all treatments, the adjusted hazard ratios (HRs) increased in patients with more co-medications (>= 9 vs <= 4) for all-cause death (HR 1.30; 1.06-1.59), major bleeding (HR 1.65; 1.33-2.05), and all bleeding events (HR 1.44; 1.31-1.59). Yearly event rates were higher in non-adherent than adherent patients for stroke and systemic embolism (SSE) (3.14 vs 1.00), all-cause death (7.76 vs 2.66), major bleeding (6.21 vs 2.65), and all bleeding (28.71 vs 19.05; all p < 0.0001). After an event the patients were more likely to become non-adherent (adherence after SSE 30.3%, after major bleeding 33.4%, after all bleeding 66.7%; all p < 0.0001). The treatment effects were consistent to the overall group in the different polypharmacy groups. In conclusion, polypharmacy and non-adherence are risk indicators for increased adverse cardiovascular and bleeding events. Dabigatran is safe to use across the full spectrum of AF patients, independent of the number of co-medications and adherence. Patients with co-medications and comorbidities require special attention and encouragement to adhere to oral anticoagulation. (C) 2021 Elsevier Inc. All rights reserved.
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| 8. |
- 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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| 9. |
- Siegbahn, Agneta, 1947-, et al.
(författare)
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Multiplex protein screening of biomarkers associated with major bleeding in patients with atrial fibrillation treated with oral anticoagulation.
- 2021
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Ingår i: Journal of Thrombosis and Haemostasis. - : John Wiley & Sons. - 1538-7933 .- 1538-7836. ; 19:11, s. 2726-2737
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Oral anticoagulants (OAC) in patients with atrial fibrillation (AF) prevent thromboembolic events, but are associated with significant risk of bleeding.OBJECTIVES: To explore associations between a wide range of biomarkers and bleeding risk in patients with AF on OAC.METHOD: Biomarkers were analyzed in a random sample of 4200 patients, 204 cases with major bleedings, from ARISTOTLE. The replication cohort included 344 cases with major bleeding and 1024 random controls from RE-LY. Plasma samples obtained at randomization were analyzed by the Olink Proximity Extension Assay cardiovascular and inflammation panels and conventional immunoassays. The associations between biomarker levels and major bleeding over 1 to 3 years of follow-up were evaluated by random survival forest/Boruta analyses and Cox regression analyses to assess linear associations and hazard ratios for identified biomarkers.RESULTS: Out of 268 proteins, nine biomarkers were independently associated with bleeding in both cohorts. In the replication cohort the linear hazard ratios (95% confidence intervals) per interquartile range were for these biomarkers: TNF-R1 1.748 (1.456, 2.098), GDF-15 1.653 (1.377, 1.985), EphB4 1.575 (1.320, 1.880), suPAR 1.548 (1.294, 1.851), OPN 1.476 (1.240, 1.757), OPG 1.397 (1.156, 1.688), TNF-R2 1.360 (1.144,1.616), cTnT-hs 1.232 (1.067, 1.423), and TRAIL-R2 1.202 (1.069, 1.351).CONCLUSIONS: In patients with AF on OAC, GDF-15, cTnT-hs, and seven novel biomarkers were independently associated with major bleedings and reflect pathophysiologic processes of inflammation, apoptosis, oxidative stress, vascular calcification, coagulation, and fibrinolysis. Investigations of the utility of these markers to refine risk stratification and guide the management of patients at high risk of bleeding are warranted.
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| 10. |
- Wallentin, Lars, 1943-, et al.
(författare)
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Angiotensin-converting enzyme 2 (ACE2) levels in relation to risk factors for COVID-19 in two large cohorts of patients with atrial fibrillation.
- 2020
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Ingår i: European Heart Journal. - : Oxford Academic. - 0195-668X .- 1522-9645. ; 41:41, s. 4037-4046
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: The global COVID-19 pandemic is caused by the SARS-CoV-2 virus entering human cells using angiotensin-converting enzyme 2 (ACE2) as a cell surface receptor. ACE2 is shed to the circulation, and a higher plasma level of soluble ACE2 (sACE2) might reflect a higher cellular expression of ACE2. The present study explored the associations between sACE2 and clinical factors, cardiovascular biomarkers, and genetic variability.METHODS AND RESULTS: Plasma and DNA samples were obtained from two international cohorts of elderly patients with atrial fibrillation (n = 3999 and n = 1088). The sACE2 protein level was measured by the Olink Proteomics® Multiplex CVD II96 × 96 panel. Levels of the biomarkers high-sensitive cardiac troponin T (hs-cTnT), N-terminal probrain natriuretic peptide (NT-proBNP), growth differentiation factor 15 (GDF-15), C-reactive protein, interleukin-6, D-dimer, and cystatin-C were determined by immunoassays. Genome-wide association studies were performed by Illumina chips. Higher levels of sACE2 were statistically significantly associated with male sex, cardiovascular disease, diabetes, and older age. The sACE2 level was most strongly associated with the levels of GDF-15, NT-proBNP, and hs-cTnT. When adjusting for these biomarkers, only male sex remained associated with sACE2. We found no statistically significant genetic regulation of the sACE2 level.CONCLUSIONS: Male sex and clinical or biomarker indicators of biological ageing, cardiovascular disease, and diabetes are associated with higher sACE2 levels. The levels of GDF-15 and NT-proBNP, which are associated both with the sACE2 level and a higher risk for mortality and cardiovascular disease, might contribute to better identification of risk for severe COVID-19 infection.
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