| 1. |
- Eriksson, Niclas, et al.
(författare)
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Genetic determinants of warfarin maintenance dose and time in therapeutic treatment range : a RE-LY genomics substudy
- 2016
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Ingår i: Pharmacogenomics (London). - : Future Medicine Ltd. - 1462-2416 .- 1744-8042. ; 17:13, s. 1425-1439
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Tidskriftsartikel (refereegranskat)abstract
- Aims: We investigated associations between genetic variation in candidate genes and on a genome-wide scale with warfarin maintenance dose, time in therapeutic range (TTR), and risk of major bleeding. Materials & methods: In total, 982 warfarin-treated patients from the RE-LY trial were studied. Results: After adjusting for SNPs in VKORC1 and CYP2C9, SNPs in DDHD1 (rs17126068) and NEDD4 (rs2288344) were associated with dose. Adding these SNPs and CYP4F2 (rs2108622) to a base model increased R-2 by 2.9%. An SNP in ASPH (rs4379440) was associated with TTR (-6.8% per minor allele). VKORC1 was associated with time less than INR 2.0. VKORC1 and CYP2C9 were associated with time more than INR 3.0, but not with major bleeding. Conclusions: We identified two novel genes associated with warfarin maintenance dose and one gene associated with TTR. These genes need to be replicated in an independent cohort.
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| 2. |
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| 3. |
- 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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| 4. |
- Bassand, Jean-Pierre, et al.
(författare)
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Relationship between baseline haemoglobin and major bleeding complications in acute coronary syndromes
- 2010
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 31:1, s. 50-58
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: In patients with acute coronary syndromes (ACS), the negative impact of baseline haemoglobin levels on ischaemic events, particularly death, is well established, but the association with bleeding risk is less well studied. The aim of this study was to assess the impact of baseline haemoglobin levels on major bleeding complications. METHODS AND RESULTS: Pooled analysis of OASIS 5 and 6 data involving 32 170 patients with ACS with and without ST-segment elevation was performed. The association between baseline haemoglobin and major bleeding or ischaemic events was examined using multiple regression model. MAIN OUTCOME MEASURES: were 30-day rates of major bleeding, death, and death/myocardial infarction (MI) analysed according to baseline haemoglobin levels. Baseline haemoglobin level independently predicted the risk of overall, procedure-related, and non-procedure-related major bleedings at 30 days [odds ratio (OR) 0.94, 95% CI 0.90-0.98; OR 0.94, 95% CI 0.90-0.99; and OR 0.89, 95% CI 0.83-0.95, respectively, per 1 g/dL haemoglobin increment above 10 g/dL]. In addition, a curvilinear relationship between baseline haemoglobin levels and death at 30 days was observed with a 6% decrease in the risk for every 1 g/dL haemoglobin increment above 10 g/dL up to 15.9 g/dL (OR 0.94, 95% CI 0.90-0.98) and a 19% increase above this value (OR 1.19, 95% CI, 0.98-1.43). A similar relationship for the composite outcome of death/MI was observed. CONCLUSION: A low baseline haemoglobin level is an independent predictor of the risk of major bleeding in ACS as well as of the risk of death and death and MI. Among other predictors of bleeding risk, baseline haemoglobin should be taken into account in patients presenting with ACS. Clinical trial registration: ClinicalTrials.gov number, NCT00139815. http://clinicaltrials.gov/ct2/show/NCT00139815?term=NCT00139815&rank=1.
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| 5. |
- Bekwelem, Wobo, et al.
(författare)
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Extracranial Systemic Embolic Events in Patients With Nonvalvular Atrial Fibrillation Incidence, Risk Factors, and Outcomes
- 2015
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Ingår i: Circulation. - 0009-7322 .- 1524-4539. ; 132:9, s. 796-803
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Tidskriftsartikel (refereegranskat)abstract
- Background Nonvalvular atrial fibrillation is a major cause of thromboembolic events. In comparison with atrial fibrillation-related stroke, extracranial systemic embolic events (SEEs) remain poorly defined. Methods and Results All suspected SEEs reported among 37973 participants of 4 large contemporary randomized clinical trials of anticoagulation in atrial fibrillation were independently readjudicated for clinical and objective evidence of sudden loss of perfusion of a limb or organ. Over 91746 patient-years of follow-up, 221 SEEs occurred in 219 subjects. The SEE incidence was 0.24 of 100 and stroke incidence was 1.92 of 100 patient-years. In comparison with patients with stroke, those with SEE were more often female (56% versus 47%; P=0.01) and had comparable mean age (73.18.5 versus 73.5 +/- 8.8 years; P=0.57) and mean CHADS(2) scores (2.4 +/- 1.3 versus 2.5 +/- 1.2; P=0.33). SEEs more frequently involved the lower extremity (58%) than visceral-mesenteric (31%) or upper extremity (10%). SEE-related care involved clinic assessment alone in 5%, 30% were hospitalized without procedures, 60% underwent endovascular or surgical intervention, and 5% underwent amputation. Within 30 days, 54% of patients recovered fully, 20% survived with deficits, and 25% died. Thirty-day mortality was greater after visceral-mesenteric than lower- or upper-extremity SEE (55%, 17%, and 9%, respectively, P0.0001). The relative risk of death throughout follow-up was 4.33 (95% confidence interval, 3.29-5.70) after SEE versus 6.79 (95% confidence interval, 6.22-7.41) after stroke in comparison with patients without either event. Conclusions SEE constituted 11.5% of clinically recognized thromboembolic events in patients with atrial fibrillation and was associated with high morbidity and mortality. SEE mortality was comparable to that of ischemic stroke and varied by anatomic site.
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| 6. |
- 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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| 7. |
- 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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| 8. |
- Brambatti, Michela, et al.
(författare)
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Comparison of dabigatran versus warfarin in diabetic patients with atrial fibrillation : Results from the RE-LY trial
- 2015
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Ingår i: International Journal of Cardiology. - : Elsevier BV. - 0167-5273 .- 1874-1754. ; 196, s. 127-131
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Diabetes mellitus (DM) is frequent among patients with atrial fibrillation (AF). The RE-LY trial permits evaluation of patient characteristics, outcomes and the effectiveness of dabigatran etexilate among diabetic individuals. Methods: Patient characteristics and outcomes were compared between diabetic and non-diabetic patients and the relative efficacy of each dose of dabigatran (150 mg bid and 110 mg bid) versus warfarin was evaluated. Results: Of 18,113 patients in RE-LY, 4221 patients (23.3%) had DM. Patients with DM were younger (70.9 vs. 71.7 years), more likely to have hypertension (86.6% vs. 76.5%), coronary artery disease (37.4% vs. 24.9%) and peripheral vascular disease (5.6% vs. 3.2%); (all p < 0.01). Time in therapeutic range for warfarin-treated patients was 65% for diabetic versus 68% for non-diabetic patients (p < 0.001). Regardless of assigned treatment, stroke or systemic embolism was more common among patients with DM (1.9% per year vs. 1.3% per year, p < 0.001). DM was also associated with an increased risk of death (5.1% per year vs. 3.5% per year, p < 0.001) and major bleeding (4.2% per year vs. 3.0% per year, p < 0.001). The absolute reduction in stroke or systemic embolism with dabigatran compared to warfarin was greater among patients with DM than those without DM (dabigatran 110 mg: 0.59% per year vs. 0.05% per year; dabigatran 150 mg: 0.89% per year vs. 0.51% per year). Conclusions: Compared to non-DM patients, AF patients with DM derive a greater absolute risk reduction in embolic events when treated with dabigatran. ClinicalTrials.gov Identifier: NCT00262600.
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| 9. |
- Budaj, Andrzej, et al.
(författare)
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Improving clinical outcomes by reducing bleeding in patients with non-ST-elevation acute coronary syndromes
- 2009
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 30:6, s. 655-61
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Bleeding in patients with coronary artery disease has been linked with adverse outcomes. We examined the incidence and outcomes after bleeding in 20 078 patients with acute coronary syndromes (ACS) enrolled in the OASIS-5 trial who were treated with fondaparinux or the low-molecular weight heparin, enoxaparin. METHODS AND RESULTS: Nine hundred and ninety (4.9%) patients developed major bleeding and 423 (2.1%) developed minor bleeding. Fondaparinux compared with enoxaparin reduced fatal bleeding [0.07 vs. 0.22%, relative risk (RR) 0.30, 95% CI: 0.13-0.71], non-fatal major bleeding (2.2 vs. 4.2%, RR 0.52, 95% CI: 0.44-0.61), minor bleeding (1.1 vs. 3.2%, RR 0.34, 95% CI: 0.27-0.42), and need for transfusion (1.8 vs. 3.1%, RR 0.56, 95% CI: 0.47-0.61) during the first 9 days. One of every six deaths during the first 30 days occurred in patients who experienced bleeding. Cox proportional hazards model revealed that major bleeding was associated with about a four-fold increased hazard of death, myocardial infarction, or stroke during the first 30 days and about a three-fold increased hazard during 180 days of follow up. CONCLUSION: Bleeding in patients with ACS is a powerful determinant of fatal and non-fatal outcomes. Reducing the risk of bleeding using a safer anticoagulant strategy during the first 9 days is associated with substantial reductions in morbidity and mortality.
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| 10. |
- 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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