| 1. |
- Boehm, Michael, et al.
(author)
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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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In: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 65:23, s. 2481-2493
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Journal article (peer-reviewed)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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| 2. |
- Böhm, Michael, et al.
(author)
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Reply : Anticoagulant-Related Nephropathy
- 2015
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In: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 66:23, s. 2682-
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Journal article (peer-reviewed)
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| 3. |
- Alexander, John H, et al.
(author)
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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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In: JAMA cardiology. - : American Medical Association (AMA). - 2380-6583 .- 2380-6591. ; 1:6, s. 673-681
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Journal article (peer-reviewed)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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| 4. |
- Aulin, Julia, et al.
(author)
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Interleukin-6 and C-reactive protein and risk for death and cardiovascular events in patients with atrial fibrillation
- 2015
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In: American Heart Journal. - : Elsevier BV. - 0002-8703 .- 1097-6744. ; 170:6, s. 1151-1160
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Journal article (peer-reviewed)abstract
- Background Inflammation has been associated with cardiovascular disease and the burden of atrial fibrillation (AF). In this study we evaluate inflammatory biomarkers and future cardiovascular events in AF patients in the RE-LY study. Methods Interleukin-6 (IL-6), C-reactive protein (CRP) (n = 6,187), and fibrinogen (n = 4,893) were analyzed at randomization; outcomes were evaluated by Cox models and C-statistics. Results Adjusted for clinical risk factors IL-6 was independently associated with stroke or systemic embolism (P =.0041), major bleedings (P =.0001), vascular death (P<.0001), and a composite thromboembolic outcome (ischemic stroke, systemic embolism, myocardial infarction, pulmonary embolism and vascular death) (P<.0001). CRP was independently related to myocardial infarction (P =.0047), vascular death (P =.0004), and the composite thromboembolic outcome (P =.0001). When further adjusted for cardiac (troponin andN-terminal fragment B-type natriuretic peptide [NT-proBNP]) and renal (cystatin-C) biomarkers on top of clinical risk factors IL-6 remained significantly related to vascular death (P<.0001), major bleeding (P<.0170) and the composite thromboembolic outcome (P<.0001), and CRP to myocardial infarction (.0104). Fibrinogen was not associated with any outcome. C-index for stroke or systemic embolism increased from 0.615 to 0.642 (P =.0017) when adding IL-6 to the clinically used CHA(2)DS(2)-VASc risk score with net reclassification improvement of 28%. Conclusion In patients with AF, IL-6 is related to higher risk of stroke and major bleeding, and both markers are related to higher risk of vascular death and the composite of thromboembolic events independent of clinical risk factors. Adjustment for cardiovascular biomarkers attenuated the prognostic value, although IL-6 remained related to mortality, the composite of thromboembolic events, and major bleeding, and CRP to myocardial infarction.
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| 5. |
- Bekwelem, Wobo, et al.
(author)
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Extracranial Systemic Embolic Events in Patients With Nonvalvular Atrial Fibrillation Incidence, Risk Factors, and Outcomes
- 2015
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In: Circulation. - 0009-7322 .- 1524-4539. ; 132:9, s. 796-803
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Journal article (peer-reviewed)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. |
- Brambatti, Michela, et al.
(author)
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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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In: International Journal of Cardiology. - : Elsevier BV. - 0167-5273 .- 1874-1754. ; 196, s. 127-131
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Journal article (peer-reviewed)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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| 7. |
- Das, D., et al.
(author)
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Ivabradine in Heart Failure: The Representativeness of SHIFT (Systolic Heart Failure Treatment With the IF Inhibitor Ivabradine Trial) in a Broad Population of Patients With Chronic Heart Failure
- 2017
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In: Circulation Heart Failure. - : LIPPINCOTT WILLIAMS & WILKINS. - 1941-3289 .- 1941-3297. ; 10:9
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Journal article (peer-reviewed)abstract
- BACKGROUND: The sinus node inhibitor ivabradine was approved for patients with heart failure (HF) after the ivabradine and outcomes in chronic HF (SHIFT [Systolic Heart Failure Treatment With the IF Inhibitor Ivabradine Trial]) trial. Our objective was to characterize the proportion of patients with HF eligible for ivabradine and the representativeness of the SHIFT trial enrollees compared with those in the Swedish Heart Failure Registry. METHODS AND RESULTS: We examined 26 404 patients with clinical HF from the Swedish Heart Failure Registry and divided them into SHIFT type (left ventricular ejection fraction <40%, New York Heart Association class II-IV, sinus rhythm, and heart rate >/=70 beats per minute) and non-SHIFT type. Baseline characteristics and medication use were compared and change in eligibility over time was reported at 6 months and 1 year in a subset of patients. Overall, 14.2% (n=3741) of patients were SHIFT type. These patients were more likely to be younger, men, have diabetes mellitus, ischemic heart disease, lower left ventricular ejection fraction, and more recent onset HF (<6 months; all, P<0.001). Although 88.9% of SHIFT type and 88.5% of non-SHIFT type (P=0.421) were receiving selected beta-blockers, only 58.8% and 67.3% (P<0.001) were on >50% of target dose. From those patients who had repeated visits within 6 months (n=5420) and 1 year (n=6840), respectively, 10.2% (n=555) and 10.6% (n=724) of SHIFT-type patients became ineligible, 77.3% (n=4188) and 77.3% (n=5287) remained ineligible, and 4.6% (n=252) and 4.9% (n=335) of non-SHIFT-type patients became eligible for initiation of ivabradine. CONCLUSIONS: From the Swedish Heart Failure Registry, 14.2% of patients with HF were eligible for ivabradine. These patients more commonly were not receiving target beta-blocker dose. Over time, a minority of patients became ineligible and an even smaller minority became eligible.
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| 8. |
- Douketis, James D., et al.
(author)
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Urgent surgery or procedures in patients taking dabigatran or warfarin : Analysis of perioperative outcomes from the RE-LY trial
- 2016
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In: Thrombosis Research. - : Elsevier BV. - 0049-3848 .- 1879-2472. ; 139, s. 77-81
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Research review (peer-reviewed)abstract
- Background: There is concern about the management of anticoagulated patients with atrial fibrillation (AF) who require an urgent surgery/procedure, especially in those who are receiving a direct oral anticoagulant such as dabigatran. Methods: We accessed the database from RE-LY, a randomized trial comparing dabigatran (110 mg and 150 mg twice daily) with warfarin for stroke prevention in AF, to assess patients who had an urgent and elective surgery/procedure. We compared the risk for thromboembolism, major bleeding and mortality according to treatment allocation (dabigatran 110 mg or 150 mg, or warfarin) or surgery/procedure type (urgent or elective). Outcomes were assessed from day-7 to day 30 after a surgery/procedure. Results: 353 patients (2.0% of study population) had an urgent surgery/procedure and 4168 patients (23.1% of study population) had an elective surgery/procedure. In patients on dabigatran 110 mg, dabigatran 150 mg and warfarin who had an urgent surgery/procedure: rates of thromboembolism were 16.1%, 7.4%, and 10.5%; rates of major bleeding were 17.0%, 17.6%, and 22.9%; rates of mortality were 6.3%, 1.5%, and 2.9%, respectively (P > 0.50 for all comparisons). Rates of these outcomes were multi-fold higher in patients having an urgent rather than an elective surgery/procedure (P < 0.5 for all comparisons). Conclusion: In anticoagulated patients with atrial fibrillation who require an urgent surgery/procedure, the risks for thromboembolism, major bleeding and mortality did not differ depending on treatment with dabigatran or warfarin, but rates of these outcomes were multi-fold higher than in patients having an elective surgery/procedure.
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| 9. |
- Eriksson, Niclas, et al.
(author)
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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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In: Pharmacogenomics (London). - : Future Medicine Ltd. - 1462-2416 .- 1744-8042. ; 17:13, s. 1425-1439
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Journal article (peer-reviewed)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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| 10. |
- Essebag, Vidal, et al.
(author)
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Short-term dabigatran interruption before cardiac rhythm device implantation : multi-centre experience from the RE-LY trial
- 2017
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In: Europace. - : OXFORD UNIV PRESS. - 1099-5129 .- 1532-2092. ; 19:10, s. 1630-1636
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Journal article (peer-reviewed)abstract
- Aims: Cardiac implantable electronic device (CIED) surgery is commonly performed in patients with atrial fibrillation (AF). The current analysis was undertaken to compare peri-operative anticoagulation management, bleeding, and thrombotic events in AF patients treated with dabigatran vs. warfarin.Methods and results: This study included 611 patients treated with dabigatran vs. warfarin who underwent CIED surgery during the RE-LY trial. Among 201 warfarin-treated patients, warfarin was interrupted a median of 144 (inter-quartile range, IQR: 120-216) h, and 37 (18.4%) patients underwent heparin bridging. In dabigatran-treated patients (216 on 110 mg bid and 194 on 150 mg bid), the duration of dabigatran interruption was a median of 96 (IQR: 61-158) h. Pocket hematomas occurred in 9 (2.20%) patients on dabigatran and 8 (3.98%) patients on warfarin (P = 0.218). The occurrence of pocket hematomas was lower with dabigatran compared with warfarin with heparin bridging (RD: -8.62%, 95% CI: -24.15 to - 0.51%, P = 0.034) but not when compared with warfarin with no bridging (P = 0.880). Ischemic stroke occurred in 2 (0.3%) patients; one in the warfarin group (without bridging) and one in the dabigatran 150 mg bid group (P = 0.735).Conclusion: In patients treated with dabigatran undergoing CIED surgery, interruption of dabigatran is associated with similar or lower incidence of pocket hematoma, when compared with warfarin interruption without or with heparin bridging, respectively. Whether uninterrupted dabigatran can reduce pocket hematoma or ischemic stroke remains to be evaluated.
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| 11. |
- Ezekowitz, Justin A., et al.
(author)
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Clinical outcomes of patients with diabetes and atrial fibrillation treated with apixaban : results from the ARISTOTLE trial
- 2015
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In: European Heart Journal - Cardiovascular Pharmacotherapy. - : OXFORD UNIV PRESS. - 2055-6837 .- 2055-6845. ; 1:2, s. 86-94
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Journal article (peer-reviewed)abstract
- Aims We compared clinical outcomes in patients with AF with and without diabetes in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation trial. Methods and results The main efficacy endpoints were SSE and mortality; safety endpoints were major and major/clinically relevant non-major bleeding. A total of 4547/18 201 (24.9%) patients had diabetes who were younger (69 vs. 70 years), more had coronary artery disease (39 vs. 31%), and higher mean CHADS(2) (2.9 vs. 1.9) and HAS-BLEDscores (1.9 vs. 1.7) (all P, 0.0001) than patients without diabetes. Patients with diabetes receiving apixaban had lower rates of SSE [hazard ratio (HR) 0.75, 95% confidence interval (CI) 0.53-1.05), all-cause mortality (HR 0.83, 95% CI 0.67-1.02), cardiovascular mortality (HR 0.89, 95% CI 0.66-1.20), intra-cranial haemorrhage (HR 0.49, 95% CI 0.25-0.95), and a similar rate of myocardial infarction (HR 1.02, 95% CI 0.62-1.67) compared with warfarin. For major bleeding, a quantitative interaction was seen (P-interaction = 0.003) with a greater reduction in major bleeding in patients without diabetes even after multivariable adjustment. Other measures of bleeding showed a consistent reduction with apixaban compared with warfarin without a significant interaction based on diabetes status. Conclusion Apixaban has similar benefits on reducing stroke, decreasing mortality, and causing less intra-cranial bleeding than warfarin in patients with and without diabetes.
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| 12. |
- Ezekowitz, Michael D., et al.
(author)
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Apixaban compared to heparin/vitamin K antagonist in patients with atrial fibrillation scheduled for cardioversion : the EMANATE trial
- 2018
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In: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 39:32, s. 2959-2971
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Journal article (peer-reviewed)abstract
- Aim The primary objective was to compare apixaban to heparin/ vitamin K antagonist (VKA) in patients with atrial fibrillation (AF) and <= 48 h anticoagulation prior to randomization undergoing cardioversion. Methods One thousand five hundred patients were randomized. The apixaban dose of 5mg b.i.d. was reduced to 2.5 mg b.i.d. in patients with two of the following: age >= 80 years, weight <= 60 kg, or serum creatinine >= 133 mu mol/L. To expedite cardioversion, at the discretion of the investigator, imaging and/or a loading dose of 10 mg (down-titrated to 5 mg) was allowed. The endpoints for efficacy were stroke, systemic embolism (SE), and death. The endpoints for safety were major bleeding and clinically relevant non-major (CRNM) bleeding. Results There were 1038 active and 300 spontaneous cardioversions; 162 patients were not cardioverted. Imaging was performed in 855 patients, and 342 received a loading dose of apixaban. Comparing apixaban to heparin/VKA in the full analysis set, there were 0/753 vs. 6/747 strokes [relative risk (RR) 0; 95% confidence interval (95% CI) 0-0.64; nominal P = 0.015], no SE, and 2 vs. 1 deaths (RR 1.98; 95% CI 0.19-54.00; nominal P > 0.999). In the safety population, there were 3/735 vs. 6/721 major (RR 0.49; 95% CI 0.10-2.07; nominal P = 0.338) and 11 vs. 13 CRNM bleeding events (RR 0.83; 95% CI 0.34-1.89; nominal P = 0.685). On imaging, 60/61 with thrombi continued randomized treatment; all (61) were without outcome events. Conclusions Rates of strokes, systemic emboli, deaths, and bleeds were low for both apixaban and heparin/VKA treated AF patients undergoing cardioversion.
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| 13. |
- Ezekowitz, Michael D., et al.
(author)
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Apixaban compared with parenteral heparin and/or vitamin K antagonist in patients with nonvalvular atrial fibrillation undergoing cardioversion : Rationale and design of the EMANATE trial
- 2016
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In: American Heart Journal. - : Elsevier BV. - 0002-8703 .- 1097-6744. ; 179, s. 59-68
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Journal article (peer-reviewed)abstract
- Background: Stroke prevention in anticoagulation-nafve patients with atrial fibrillation undergoing cardioversion has not been systematically studied.Objective: To determine outcomes in anticoagulation-naive patients (defined as those receiving an anticoagulant for <48 hours during the index episode of atrial fibrillation) scheduled for cardioversion.Methods: This is a randomized, prospective, open-label, real-world study comparing apixaban to heparin plus warfarin. Early image-guided cardioversion is encouraged. For apixaban, the usual dose is 5 mg BID with a dose reduction to 2.5 mg BID if 2 of the following are present: age >80 years, weight <60 kg, or serum creatinine >1.5 mg/dL. If cardioversion is immediate, a single starting dose of 10 mg (or 5 mg if the dose is down-titrated) of apixaban is administered. Cardioversion may be attempted up to 90 days after randomization. Patients are followed up for 30 days after cardioversion or 90 days postrandomization if cardioversion is not performed within that timeframe. Outcomes are stroke, systemic embolization, major bleeds, clinically relevant nonmajor bleeding, and death, all adjudication-blinded.Statistics: The warfarin-naive cohort from the ARISTOTLE study was considered the closest data set to the patients being recruited into this study. The predicted incidence of stroke, systemic embolism, and major bleeding within 30 days after randomization was approximately 0.75%. To adequately power for a noninferiority trial, approximately 48,000 participants would be needed, a number in excess of feasibility. The figure of 1,500 patients was considered clinically meaningful and achievable.
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| 14. |
- Ezekowitz, Michael D., et al.
(author)
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Comparison of Dabigatran and Warfarin in Patients With Atrial Fibrillation and Valvular Heart Disease The RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulant Therapy)
- 2016
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In: Circulation. - 0009-7322 .- 1524-4539. ; 134:8, s. 589-598
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Journal article (peer-reviewed)abstract
- BACKGROUND: The RE-LY trial (Randomized Evaluation of Long-Term Anticoagulant Therapy) compared dabigatran 150 and 110 mg twice daily with warfarin in 18 113 patients with atrial fibrillation. Those with prosthetic heart valves, significant mitral stenosis, and valvular heart disease (VHD) requiring intervention were excluded. Others with VHD were included. METHODS: This is a post hoc analysis of the RE-LY trial. RESULTS: There were 3950 patients with any VHD: 3101 had mitral regurgitation, 1179 with tricuspid regurgitation, 817 had aortic regurgitation, 471 with aortic stenosis, and 193 with mild mitral stenosis. At baseline, patients with any VHD had more heart failure, coronary disease, renal impairment, and persistent atrial fibrillation. Patients with any VHD had higher rates of major bleeds (hazard ratio [HR], 1.32; 95% confidence interval [CI], 1.16-1.5) but similar stroke or systemic embolism event rates (HR, 1.09; 95% CI, 0.88-1.33). For patients receiving dabigatran 110 mg, major bleed rates were lower than for patients taking warfarin (HR, 0.73; 95% CI, 0.56-0.95 with VHD; HR, 0.84; 95% CI, 0.71-0.99 without VHD), and major bleed rates for dabigatran 150 mg were similar to those for warfarin in patients with VHD (HR, 0.82; 95% CI, 0.64-1.06) or without VHD (HR, 0.98; 95% CI, 0.83-1.15). For dabigatran 150 mg, stroke/systemic embolic event rates were lower compared with warfarin in those with VHD (HR, 0.59; 95% CI, 0.37-0.93) and those without VHD (HR, 0.67; 95% CI, 0.52-0.86), and stroke/systemic embolic event rates were similar for warfarin and dabigatran 110 mg regardless of the presence of VHD (HR, 0.97; 95% CI, 0.65-1.45; and HR, 0.88; 95% CI, 0.70-1.10). Intracranial bleeds and death rates for dabigatran 150 and 110 mg were lower compared with warfarin independently of the presence of VHD. CONCLUSIONS: The presence of any VHD did not influence the comparison of dabigatran with warfarin.
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| 15. |
- Ezekowitz, Michael D., et al.
(author)
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Long-term evaluation of dabigatran 150 vs. 110 mg twice a day in patients with non-valvular atrial fibrillation
- 2016
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In: Europace. - : Oxford University Press (OUP). - 1099-5129 .- 1532-2092. ; 18:7, s. 973-978
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Journal article (peer-reviewed)abstract
- Aims The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial allowed patients who completed the trial receiving their assigned dabigatran 150 mg (D150) or 110 mg (D110) twice a day to continue into the Long-term Multicenter Extension of Dabigatran Treatment in Patients with Atrial Fibrillation (RELY-ABLE) trial. This permitted assessment of outcomes over a median of 4.6 and a maximum of 6.7 years, respectively. Methods and results The analysed population included only those patients who completed RE-LY on dabigatran and continued into RELYABLE without interruption of assigned dabigatran. Cumulative risk was expressed as Kaplan-Meier plots. Outcomes were compared using Cox proportional hazard modelling. Stroke or systemic embolization rates were 1.25 and 1.54% per year (D150 and D110, respectively); hazard ratio (HR) 0.81 [95% confidence interval (CI): 0.68-0.96] (P = 0.02). Ischaemic stroke was 1.03 (D150) and 1.29%/year (D110); HR 0.79 (95% CI: 0.66-0.95) (P = 0.01). Haemorrhagic stroke rates were 0.11 (D150) and 0.13%/year (D110); HR 0.91 (95% CI: 0.51-1.62) (P = 0.75). Rates of major haemorrhage were 3.34 (D150) and 2.76%/year (D110); HR 1.22 (95% CI: 1.08-1.37) (P = 0.0008). Intracranial haemorrhage rates were 0.32 (D150) and 0.23%/year (D110); HR 1.37 (95% CI: 0.93-2.01) (P = 0.11). Mortality was 3.43 (D150) and 3.55%/year (D110); HR 0.97 (95% CI: 0.87-1.08) (P = 0.54). Conclusion Annualized rates of all outcomes were constant with better efficacy of D150, less major bleeding with D110, and low intracerebral haemorrhage rates for both doses. There were no additional safety concerns. This is the longest continuous randomized experience of a novel anticoagulant.
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| 16. |
- Flack, Kathryn F., et al.
(author)
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Major Gastrointestinal Bleeding Often Is Caused by Occult Malignancy in Patients Receiving Warfarin or Dabigatran to Prevent Stroke and Systemic Embolism From Atrial Fibrillation
- 2017
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In: Clinical Gastroenterology and Hepatology. - : ELSEVIER SCIENCE INC. - 1542-3565 .- 1542-7714. ; 15:5, s. 682-690
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Journal article (peer-reviewed)abstract
- BACKGROUND & AIMS: Gastrointestinal (GI) bleeding in patients receiving anticoagulation agents can be caused by occult malignancies. We investigated the proportions and features of major GI bleeding (MGIB) events related to occult GI cancers in patients receiving anticoagulation therapy.METHODS: We analyzed data from the Randomized Evaluation of Long Term Anticoagulant Therapy study (conducted between December 2005 and March 2009 in 951 clinical centers in 44 countries worldwide), which compared the abilities of dabigatran vs warfarin to prevent stroke and systemic embolism in 18,113 patients with atrial fibrillation. Two blinded gastroenterologists independently reviewed source documents of MGIB events (n = 595) that occurred during the study period. We collected data on MGIB events caused by previously unidentified GI malignancies, and compared characteristics of MGIB events in patients who received dabigatran vs warfarin (primary end point), and in patients with bleeding from cancer, vs patients bleeding from a nonmalignant or unidentified source.RESULTS: Of 546 unique MGIB events, 44 (8.1%) were found to be from GI cancers (34 of 398 MGIB events in dabigatran users and 10 of 148 MGIB events in warfarin users; P = .60). Colorectal cancer accounted for 35 of 44 of all cancers identified. There were more colorectal cancer-associated MGIB events in the dabigatran group (30 of 34) than in the warfarin group (5 of 10) (P = .02), but more gastric cancer-associated MGIB events in the warfarin group (5 of 10) than in the dabigatran group (1 of 34) (P = .001). There were no differences in the short-term outcomes of cancer-related MGIB events in the dabigatran vs the warfarin group, but 75% of all cancer-related MGIB events required at least 1 blood transfusion and the mean hospital stay was 10.1 days. Compared with MGIB events from a nonmalignant or unidentified source, MGIB from cancer occurred sooner (343.0 vs 223.1 d; P = .003), but the bleeding was more likely to be chronic (for > 7 d) (27.3% vs 63.6%; P < .001).CONCLUSIONS: In evaluating data from a study of the effects of anticoagulation therapy, we found approximately 1 of every 12 MGIB events to be related to an occult cancer. Approximately two thirds of cancer-related MGIB presents with chronic bleeding, and morbidity, and resource utilization is high.
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| 17. |
- Hijazi, Ziad, et al.
(author)
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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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In: European Heart Journal. - : OXFORD UNIV PRESS. - 0195-668X .- 1522-9645. ; 39:6, s. 477-485
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Journal article (peer-reviewed)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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| 18. |
- Hijazi, Ziad, et al.
(author)
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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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In: Journal of the American Heart Association. - 2047-9980. ; 8:2
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Journal article (peer-reviewed)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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| 19. |
- Hijazi, Ziad, et al.
(author)
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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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In: American Heart Journal. - : MOSBY-ELSEVIER. - 0002-8703 .- 1097-6744. ; 198, s. 169-177
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Journal article (peer-reviewed)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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| 20. |
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| 21. |
- Hijazi, Ziad, et al.
(author)
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Growth-differentiation factor 15 and risk of major bleeding in atrial fibrillation : Insights from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial
- 2017
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In: American Heart Journal. - : Elsevier BV. - 0002-8703 .- 1097-6744. ; 190, s. 94-103
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Journal article (peer-reviewed)abstract
- OBJECTIVE: To evaluate and validate the prognostic value of growth-differentiation factor 15 (GDF-15) beyond clinical characteristics and other biomarkers concerning bleeding and stroke outcomes in patients with atrial fibrillation in the RE-LY trial.METHODS: GDF-15 was measured in samples collected at randomization in 8,474 patients with a median follow-up time of 1.9 years. Patients were stratified based on predefined GDF-15 cutoffs: group 1, <1,200 ng/L (the 90th percentile in healthy individuals); group 2, 1,200-1,800; and group 3, >1,800 ng/L (high-risk individuals). Efficacy and safety outcomes were compared across groups of GDF-15 in Cox models adjusted for baseline characteristics, cardiac (N-terminal pro-b-type natriuretic peptide, high-sensitive troponin T), inflammatory (interleukin 6, C-reactive protein) and coagulation (D-dimer) biomarkers, and randomized treatment.RESULTS: GDF-15 concentrations were <1,200 ng/L in 2,647 (31.2%), between 1,200 and 1,800 ng/L in 2,704 (31.9%), and >1,800 ng/L in 3,123 (36.9%) participants, respectively. Annual rates of stroke, major bleeding, and mortality increased with higher GDF-15 levels. The prognostic value of GDF-15 was independent of clinical characteristics for these outcomes. In models also adjusted for biomarkers, GDF-15 remained significantly associated with major bleeding (hazard ratio [95% CI] group 3 vs group 1 1.76 [1.28-2.42], P < .0005) and all-cause mortality (hazard ratio 1.72 [1.30-2.29], P < .0005). GDF-15 improved the c index of both the HAS-BLED (0.62-0.69) and ORBIT (0.68-0.71) bleeding risk scores.CONCLUSIONS: In patients with atrial fibrillation, GDF-15 is an independent risk indicator for major bleeding and all-cause mortality, but not for stroke. Therefore, GDF-15 seems useful as a specific marker of bleeding in patients with AF on oral anticoagulant treatment.
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| 22. |
- Hijazi, Ziad, et al.
(author)
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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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In: The Lancet. - 0140-6736 .- 1474-547X. ; 387:10035, s. 2302-2311
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Journal article (peer-reviewed)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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| 23. |
- Hohnloser, Stefan H., et al.
(author)
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Efficacy and Safety of Apixaban Versus Warfarin in Patients With Atrial Fibrillation and Extremes in Body Weight : Insights From the ARISTOTLE Trial
- 2019
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In: Circulation. - : LIPPINCOTT WILLIAMS & WILKINS. - 0009-7322 .- 1524-4539. ; 139:20, s. 2292-2300
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Journal article (peer-reviewed)abstract
- BACKGROUND: Guidelines caution against the use of non-vitamin K antagonist oral anticoagulants in patients with extremely high (> 120 kg) or low (= 60 kg) body weight because of a lack of data in these populations.METHODS: In a post hoc analysis of ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation; n= 18 201), a randomized trial comparing apixaban with warfarin for the prevention of stroke in patients with atrial fibrillation, we estimated the randomized treatment effect (apixaban versus warfarin) stratified by body weight (= 60, > 60-120, > 120 kg) using a Cox regression model and tested the interaction between body weight and randomized treatment. The primary efficacy and safety outcomes were stroke or systemic embolism and major bleeding.RESULTS: Of the 18 139 patients with available weight and outcomes data, 1985 (10.9%) were in the low-weight group (= 60 kg), 15 172 (83.6%) were in the midrange weight group (> 60-120 kg), and 982 (5.4%) were in the high-weight group (> 120 kg). The treatment effect of apixaban versus warfarin for the efficacy outcomes of stroke/systemic embolism, all-cause death, or myocardial infarction was consistent across the weight spectrum (interaction P value> 0.05). For major bleeding, apixaban had a better safety profile than warfarin in all weight categories and even showed a greater relative risk reduction in patients in the low (= 60 kg; HR, 0.55; 95% CI, 0.36-0.82) and midrange (> 60-120 kg) weight groups (HR, 0.71; 95% CI, 0.61-0.83; interaction P value= 0.016).CONCLUSIONS: Our findings provide evidence that apixaban is efficacious and safe across the spectrum of weight, including in low-(= 60 kg) and highweight patients (> 120 kg). The superiority on efficacy and safety outcomes of apixaban compared with warfarin persists across weight groups, with even greater reductions in major bleeding in patients with atrial fibrillation with low to normal weight as compared with high weight. The superiority of apixaban over warfarin in regard to efficacy and safety for stroke prevention seems to be similar in patients with atrial fibrillation across the spectrum of weight, including in low-and very high-weight patients. Thus, apixaban appears to be appropriate for patients with atrial fibrillation irrespective of body weight.
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| 24. |
- Joseph, Philip, et al.
(author)
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Dabigatran etexilate and reduction in serum apolipoprotein B
- 2016
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In: Heart. - : BMJ. - 1355-6037 .- 1468-201X. ; 102:1, s. 57-62
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Journal article (peer-reviewed)abstract
- Objective Carboxylesterases, which convert dabigatran etexilate to its active form, dabigatran, have also been shown to influence lipoprotein metabolism, although any pleotropic effects of the drug based on this possible mechanism has not been evaluated. We examined the effects of dabigatran etexilate on serum lipoprotein markers in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study. Methods 2513 participants from the RE-LY randomised control trial with baseline and 3-month apolipoprotein B (ApoB) and apolipoprotein A1 (ApoA1) measurements were included. We prospectively compared the effects of dabigatran 110mg twice daily, dabigatran 150mg twice daily and warfarin on changes in ApoB and ApoA1 concentrations using a mixed model analysis. Results From baseline to 3months, a significant reduction in ApoB concentration was observed with low-dose dabigatran (-0.057 (95% CI -0.069 to -0.044) g/L, p<0.001) and high-dose dabigatran (-0.065 (95% CI -0.078 to -0.053) g/L, p<0.001) but not warfarin (-0.006g/L (95% CI -0.018 to 0.007) g/L, p=0.40). Compared with warfarin, ApoB reduction was significantly greater with both doses of dabigatran (p<0.001 for both groups). Reductions in ApoA1 concentrations did not statistically differ with either dose of dabigatran when compared with warfarin. Conclusions Dabigatran is associated with a significant (approximate to 7%) reduction in ApoB concentration, suggesting a novel effect of this drug on lipoprotein metabolism. Further studies are needed to determine the mechanism of this observed effect, and its impact on clinical outcomes.
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| 25. |
- Kent, Anthony P., et al.
(author)
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Concomitant Oral Anticoagulant and Nonsteroidal Anti-Inflammatory Drug Therapy in Patients With Atrial Fibrillation
- 2018
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In: Journal of the American College of Cardiology. - : ELSEVIER SCIENCE INC. - 0735-1097 .- 1558-3597. ; 72:3, s. 255-267
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Journal article (peer-reviewed)abstract
- BACKGROUND Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used medications that can potentially increase the risk of bleeding and thrombosis. OBJECTIVES This study quantified the effect of NSAIDs in the RE-LY (Randomized Evaluation of Long Term Anticoagulant Therapy) trial. METHODS This was a post hoc analysis of NSAIDs in the RE-LY study, which compared dabigatran etexilate (DE) 150 and 110 mg twice daily (b.i.d.) with warfarin in patients with atrial fibrillation. Treatment-independent, multivariate-adjusted Cox regression analysis assessed clinical outcomes by comparing NSAID use with no NSAID use. Interaction analysis was obtained from treatment-dependent Cox regression modeling. Time-varying covariate analysis for NSAID use was applied to the Cox model. RESULTS Among 18,113 patients in the RE-LY study, 2,279 patients used NSAIDs at least once during the trial. Major bleeding was significantly elevated with NSAID use (hazard ratio [HR]: 1.68; 95% confidence interval [CI]: 1.40 to 2.02; p < 0.0001). NSAID use did not significantly alter the risk of major bleeding for DE 150 or 110 mg b.i.d. relative to warfarin (pinteraction = 0.63 and 0.93, respectively). Gastrointestinal major bleeding was significantly elevated with NSAID use (HR: 1.81; 95% CI: 1.35 to 2.43; p < 0.0001). The rate of stroke or systemic embolism (stroke/SE) with NSAID use was significantly elevated (HR: 1.50; 95% CI: 1.12 to 2.01; p = 0.007). The use of NSAIDs did not significantly alter the relative efficacy on stroke/SE for DE 150 or 110 mg b.i.d. relative to warfarin (p(interaction) = 0.59 and 0.54, respectively). Myocardial infarction rates were similar with NSAID use compared with no NSAID use (HR: 1.22; 95% CI: 0.77 to 1.93; p = 0.40). Patients were more frequently hospitalized if they used an NSAID (HR: 1.64; 95% CI: 1.51 to 1.77; p < 0.0001). CONCLUSIONS The use of NSAIDs was associated with increased risk of major bleeding, stroke/SE, and hospitalization. The safety and efficacy of DE 150 and 110 mg b.i.d. relative to warfarin were not altered. (Randomized Evaluation of Long Term Anticoagulant Therapy [RE-LY]; NCT00262600)
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| 26. |
- Kolb, Jennifer M., et al.
(author)
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Locations and Mucosal Lesions Responsible for Major Gastrointestinal Bleeding in Patients on Warfarin or Dabigatran
- 2018
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In: Digestive Diseases and Sciences. - : SPRINGER. - 0163-2116 .- 1573-2568. ; 63:7, s. 1878-1889
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Journal article (peer-reviewed)abstract
- Different oral anticoagulants may be associated with gastrointestinal bleeding (GIB) from different locations or mucosal lesions. We aimed to test this hypothesis. Two blinded gastroenterologists independently analyzed source documents from the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial of dabigatran 150 mg BID (D150), dabigatran 110 mg BID (D110) versus warfarin in non-valvular atrial fibrillation (NVAF). Major GIB events (total n = 546) and life-threatening GIB events (n = 258) were more common with D150 versus warfarin (RR 1.57 [1.28-1.92] and RR 1.62 [1.20-2.18], respectively) and similar for D110 compared to warfarin (RR 1.11 [0.89-1.38] and RR 1.16 [0.84-1.61], respectively). Fatal bleeding was similarly rare across treatment groups. Lower GI major bleeding and life-threatening bleeding were more common with D150 compared to warfarin (RR 2.23 [1.47, 3.38] and RR 2.64 [1.36, 5.13], respectively) and with D110 compared to warfarin (RR 1.78 [1.16, 2.75] and RR 2.00 [1.00, 4.00], respectively). MGIB from colonic angiodysplasia was increased with dabigatran versus warfarin (P < 0.01 for both dose comparisons). Subacute and chronic MGIB events were more common with D150 than with warfarin (RR 1.72 [1.06, 2.78] and RR 1.66 [1.12, 2.45], respectively), as were hematochezia or melena (RR 1.67 [1.18, 2.36] and RR 1.72 [1.20, 2.47], respectively). In a chronic NVAF population, D150 but not D110 is associated with increased major and life-threatening GI bleeding in comparison with warfarin. At both dabigatran doses, increased bleeding from the colorectum, in particular from angiodysplasia, is seen.
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| 27. |
- Lauw, Mandy N., et al.
(author)
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Effects of dabigatran according to age in atrial fibrillation
- 2017
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In: Heart. - : BMJ PUBLISHING GROUP. - 1355-6037 .- 1468-201X. ; 103:13, s. 1015-1023
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Journal article (peer-reviewed)abstract
- Objective: The prevalence of atrial fibrillation (AF) and the risk of stroke and bleeding vary according to age. To estimate effects of dabigatran, compared with warfarin, on stroke, bleeding and mortality in patients with AF in the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) trial according to age, we analysed treatment effects using age as a continuous variable and using age categories.Methods: RE-LY included 10 855 (59.9%) patients aged <75 years, 4231 patients (23.4%) aged 75-79 years, 2305 (12.7%) aged 80-84 years and 722 (4.0%) aged >= 85 years at baseline.Results: Benefits of dabigatran versus warfarin regarding stroke (HR range 0.63 (95% CI 0.46 to 0.86) to 0.70 (0.31 to 1.57) for dabigatran 150 mg twice daily), HR range 0.52 (0.21 to 1.29) to 1.08 (0.73 to 1.60) for dabigatran 110 mg twice daily) and intracranial bleeding were maintained across all age groups (interaction p values all not significant). There was a highly significant interaction (p value interaction <0.001) between age and treatment for extracranial major bleeding, with lower rates with both doses of dabigatran compared with warfarin in younger patients (HR 0.78 (0.62 to 0.97) for 150 mg twice daily, HR 0.72 (0.57 to 0.90) for 110 mg twice daily) but similar (HR 1.50 (1.03 to 2.18) for 110 mg twice daily) or higher rates (HR 1.68 (1.18 to 2.41) for 150 mg twice daily) in older patients (>= 80 years).Conclusion: Effects of dabigatran compared with warfarin on stroke prevention and intracranial bleeding are consistent across all age groups. Effects of dabigatran on extracranial major bleeding are age dependent, supporting selection of dabigatran 110 mg twice daily for elderly patients (age >= 80 years).
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| 28. |
- Nagarakanti, Rangadham, et al.
(author)
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Comparison of Characteristics and Outcomes of Dabigatran Versus Warfarin in Hypertensive Patients With Atrial Fibrillation (from the RE-LY Trial)
- 2015
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In: American Journal of Cardiology. - : Elsevier BV. - 0002-9149 .- 1879-1913. ; 116:8, s. 1204-1209
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Journal article (peer-reviewed)abstract
- Hypertension is frequent in patients with atrial fibrillation (AF) and is an independent risk factor for stroke. The Randomized Evaluation of Long Term Anticoagulant TherapY (RE-LY) trial found dabigatran 110 mg (D110) and 150 mg twice daily (D150) noninferior or superior to warfarin for stroke reduction in patients with AF, with either a reduction (D110) or similar rates (D150) of major bleeding. Baseline characteristics and outcomes were compared in patients with and without hypertension. The quality of blood pressure control was also assessed. In RE-LY, 14,283 patients (78.9%) had hypertension. The mean blood pressure at baseline was 132.6 +/- 17.6/77.7 +/- 10.6 and 124.8 +/- 16.7/74.6 +/- 10.0 mm Hg for patients with and without hypertension, respectively. More patients with hypertension were diabetic (25.6% vs 14.8%, p <0.001), women (38.6% vs 28.3%, p <0.001), and had greater CHADS(2) (2.3 vs 1.4, p <0.001) and CHA(2)DS(2)-VASc scores (3.8 vs 2.8, p <0.001). Mean blood pressure in all treatment arms in hypertensive patients was similar (130 +/- 18/76 +/- 11 mm Hg) during the trial. The efficacy and safety of D110 and D150 compared to warfarin were similar (p = nonsignificant) in hypertensive (stroke/systemic embolism rate of 1.47%, 1.20%, and 1.81% and major bleed rate of 2.89%, 3.70%, and 3.69% in the D110, D150, and W, respectively) and normotensive patients (stroke/systemic embolism rate of 1.79%, 0.78%, and 1.36% and major bleed rate of 2.84%, 2.37%, and 3.03% per year in the D110, D150, and W, respectively). Hypertensive patients had more major bleeds (3.39% vs. 2.76%; p = 0.007). Intracranial bleeds were similar (0.47% vs 0.31%; p = 0.12). In conclusion, patients with hypertension in RE-LY were more likely female, diabetic, with a greater CHADS(2) and CHA(2)DS(2)-VASc scores. Blood pressure control in RE-LY was excellent. The benefits of dabigatran over warfarin, including a substantial reduction of intracranial hemorrhage, were similar in both hypertensive and non-hypertensive patients.
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| 29. |
- Oldgren, Jonas, et al.
(author)
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External Validation Of The Biomarker-Based ABC-Stroke Risk Score For Atrial Fibrillation
- 2016
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In: Journal of the American College of Cardiology. - Uppsala Univ, Dept Med Sci, Cardiol, Uppsala, Sweden. Uppsala Univ, Uppsala Clin Res Ctr, Uppsala, Sweden.. - 0735-1097 .- 1558-3597. ; 67:13, s. 879-879
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Journal article (other academic/artistic)
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| 30. |
- Oldgren, Jonas, et al.
(author)
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Performance and Validation of a Novel Biomarker-Based Stroke Risk Score for Atrial Fibrillation
- 2016
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In: Circulation. - 0009-7322 .- 1524-4539. ; 134:22, s. 1697-1707
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Journal article (peer-reviewed)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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| 31. |
- Sandhu, Roopinder K., et al.
(author)
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Obesity paradox on outcome in atrial fibrillation maintained even considering the prognostic influence of biomarkers : insights from the ARISTOTLE trial
- 2018
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In: Open heart. - : BMJ. - 2053-3624. ; 5:2
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Journal article (peer-reviewed)abstract
- ObjectiveWe investigated the association between obesity and biomarkers indicating cardiac or renal dysfunction or inflammation and their interaction with obesity and outcomes.MethodsA total of 14 753 patients in the Apixaban for Reduction In STroke and Other ThromboemboLic Events in Atrial Fibrillation (ARISTOTLE) trial provided plasma samples at randomisation to apixaban or warfarin. Median follow-up was 1.9 years. Body Mass Index (BMI) was measured at baseline and categorised as normal, 18.5-25 kg/m(2); overweight, >25 to <30 kg/m(2); and obese, >= 30 kg/m(2). We analysed the biomarkers high-sensitivity C reactive protein (hs-CRP), interleukin 6 (IL-6), growth differentiation factor-15 (GDF-15), troponin T and N-terminal B-type natriuretic peptide (NT-pro-BNP). Outcomes included stroke/systemic embolism (SE), myocardial infarction (MI), composite (stroke/SE, MI, or all-cause mortality), all-cause and cardiac mortality, and major bleeding.ResultsCompared with normal BMI, obese patients had significantly higher levels of hs-CRP and IL-6 and lower levels of GDF-15, troponin T and NT-pro-BNP. In multivariable analyses, higher compared with normal BMI was associated with a lower risk of all-cause mortality (overweight: HR 0.73 (95% CI 0.63 to 0.86); obese: 0.67 (0.56 to 0.80), p<0.0001), cardiac death (overweight: HR 0.74 (95% CI 0.60 to 0.93); obese: 0.71 (0.56 to 0.92), p=0.01) and composite endpoint (overweight: 0.80 (0.70 to 0.92); obese: 0.72 (0.62 to 0.84), p<0.0001).ConclusionsRegardless of biomarkers indicating inflammation or cardiac or renal dysfunction, obesity was independently associated with an improved survival in anticoagulated patients with AF.
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| 32. |
- Sandhu, Roopinder K., et al.
(author)
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The 'obesity paradox' in atrial fibrillation : observations from the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial
- 2016
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In: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 37:38, s. 2869-2878
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Journal article (peer-reviewed)abstract
- AIMS: The prognostic implication of adiposity on clinical outcomes in atrial fibrillation (AF) patients treated with oral anticoagulation is unclear.METHODS AND RESULTS: A total of 17 913 patients in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation trial had body mass index (BMI) measured at baseline. For the primary analysis, BMI was categorized as normal (18.5 to <25 kg/m(2)), overweight (25 to <30 kg/m(2)), and obese (≥30 kg/m(2)). Waist circumference (WC) was defined as high if >102 cm for men and >88 cm in women. Outcomes were stroke or systemic embolism, a composite endpoint (stroke, systemic embolism, myocardial infarction, or all-cause mortality), all-cause mortality, and major bleeding. Cox models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) across categories of BMI and WC adjusting for established risk factors and treatment allocation. At baseline, 4052 (22.6%) patients had a normal BMI, 6702 (37.4%) were overweight, and 7159 (40.0%) were obese. In multivariable analyses, higher BMI was associated with a lower risk of all-cause mortality [overweight: HR 0.67 (95% CI 0.59-0.78); obese: HR 0.63 (95% CI 0.54-0.74), P < 0.0001] and the composite endpoint [overweight: HR 0.74 (95% CI 0.65-0.84); obese: HR 0.68 (95% CI 0.60-0.78), P < 0.0001] compared with normal BMI. In women, high WC was associated with a 31% lower risk of all-cause mortality (P = 0.001), 27% lower risk of the composite endpoint (P = 0.001), and 28% lower risk of stroke or systemic embolism (P = 0.048) but not in men. There was no significant association between adiposity and major bleeding.CONCLUSION: In patients with AF treated with oral anticoagulants, higher BMI and WC are associated with a more favourable prognosis.
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| 33. |
- Sharma, Abhinav, et al.
(author)
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Use of Biomarkers to Predict Specific Causes of Death in Patients With Atrial Fibrillation : Insights From the ARISTOTLE Trial
- 2018
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In: Circulation. - : LIPPINCOTT WILLIAMS & WILKINS. - 0009-7322 .- 1524-4539. ; 138:16, s. 1666-1676
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Journal article (peer-reviewed)abstract
- Background: Atrial fibrillation is associated with an increased risk of death. High-sensitivity troponin T, growth differentiation factor-15, NT-proBNP (N-terminal pro-B-type natriuretic peptide), and interleukin-6 levels are predictive of cardiovascular events and total cardiovascular death in anticoagulated patients with atrial fibrillation. The prognostic utility of these biomarkers for cause-specific death is unknown. Methods: The ARISTOTLE trial (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation) randomized 18201 patients with atrial fibrillation to apixaban or warfarin. Biomarkers were measured at randomization in 14798 patients (1.9 years median follow-up). Cox models were used to identify clinical variables and biomarkers independently associated with each specific cause of death. Results: In total, 1272 patients died: 652 (51%) cardiovascular, 32 (3%) bleeding, and 588 (46%) noncardiovascular/nonbleeding deaths. Among cardiovascular deaths, 255 (39%) were sudden cardiac deaths, 168 (26%) heart failure deaths, and 106 (16%) stroke/systemic embolism deaths. Biomarkers were the strongest predictors of cause-specific death: a doubling of troponin T was most strongly associated with sudden death (hazard ratio [HR], 1.48; P<0.001), NT-proBNP with heart failure death (HR, 1.62; P<0.001), and growth differentiation factor-15 with bleeding death (HR, 1.72; P=0.028). Prior stroke/systemic embolism (HR, 2.58; P>0.001) followed by troponin T (HR, 1.45; P<0.0029) were the most predictive for stroke/ systemic embolism death. Adding all biomarkers to clinical variables improved discrimination for each cause-specific death. Conclusions: Biomarkers were some of the strongest predictors of cause-specific death and may improve the ability to discriminate among patients' risks for different causes of death. These data suggest a potential role of biomarkers for the identification of patients at risk for different causes of death in patients anticoagulated for atrial fibrillation. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00412984.
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| 34. |
- Siegbahn, Agneta, et al.
(author)
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D-dimer and factor VIIa in atrial fibrillation : prognostic values for cardiovascular events and effects of anticoagulation therapy. A RE-LY substudy
- 2016
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In: Thrombosis and Haemostasis. - 0340-6245 .- 2567-689X. ; 115:5, s. 921-930
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Journal article (peer-reviewed)abstract
- Coagulation markers may improve monitoring the risk of stroke and bleeding in patients with atrial fibrillation (AF) during anticoagulant treatment. We examined baseline levels of D-dimer and their association with stroke, cardiovascular death and major bleeding in 6,202 AF patients randomised to dabigatran or warfarin in the RE-LY trial. The effects of treatment on serial levels of D-dimer and coagulation factor (F) VIIa in 2,567 patients were also analysed. Baseline D-dimer levels were related to the rate of stroke/systemic embolism (SEE) with 0.64 % in the lowest quartile (Q1, as reference) (D-dimer < 298 µg/l), 1.38 % Q2 (D-dimer 298-473 µg/l), 1.71 % Q3 (D-dimer 474-822 µg/l) and 2.00 % in Q4 (D-dimer > 822 µg/l) (p=0.0007). Similar associations were shown for cardiovascular death and major bleeding. Addition of baseline D-dimer to established clinical risk factors improved prediction of stroke/SEE, cardiovascular death and major bleeding (C-index increased from 0.66 to 0.68, 0.71 to 0.73 and 0.66 to 0.67, respectively). Dabigatran provided a greater reduction of D-dimer levels than warfarin regardless of baseline anticoagulant treatment. On-treatment levels of FVIIa were markedly reduced by warfarin (median 12.1-13.8 mU/ml) but significantly higher with dabigatran (median 39.4-49.0 mU/ml) at all-time points. Dabigatran is associated with greater reduction in D-dimer without the pronounced reduction of FVIIa seen with warfarin. These different effects on the coagulation system might explain the better efficacy and less intracranial bleeding observed with dabigatran compared with warfarin.
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| 35. |
- Verdecchia, Paolo, et al.
(author)
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Dabigatran vs. warfarin in relation to the presence of left ventricular hypertrophy in patients with atrial fibrillation-the Randomized Evaluation of Long-term anticoagulation therapY (RE-LY) study
- 2018
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In: Europace. - : OXFORD UNIV PRESS. - 1099-5129 .- 1532-2092. ; 20:2, s. 253-262
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Journal article (peer-reviewed)abstract
- Aim: We tested the hypothesis that left ventricular hypertrophy (LVH) interferes with the antithrombotic effects of dabigatran and warfarin in patients with atrial fibrillation (AF).Methods and results: This is a post-hoc analysis of the Randomized Evaluation of Long-term anticoagulation therapY (RE-LY) Study. We defined LVH by electrocardiography (ECG) and included patients with AF on the ECG tracing at entry. Hazard ratios (HR) for each dabigatran dose vs. warfarin were calculated in relation to LVH. LVH was present in 2353 (22.7%) out of 10 372 patients. In patients without LVH, the rates of primary outcome were 1.59%/ year with warfarin, 1.60% with dabigatran 110 mg (HR vs. warfarin 1.01, 95% confidence interval (CI) 0.75-1.36) and 1.08% with dabigatran 150 mg (HR vs. warfarin 0.68, 95% CI 0.49-0.95). In patients with LVH, the rates of primary outcome were 3.21%/ year with warfarin, 1.69% with dabigatran 110 mg (HR vs. warfarin 0.52, 95% CI 0.32-0.84) and 1.55% with 150 mg (HR vs. warfarin 0.48, 95% CI 0.29-0.78). The interaction between LVH status and dabigatran 110 mg vs. warfarin was significant for the primary outcome (P = 0.021) and stroke (P = 0.016). LVH was associated with a higher event rate with warfarin, not with dabigatran. In the warfarin group, the time in therapeutic range was significantly lower in the presence than in the absence of LVH.Conclusions: LVH was associated with a lower antithrombotic efficacy of warfarin, but not of dabigatran, in patients with AF. Consequently, the relative benefit of the lower dose of dabigatran compared to warfarin was enhanced in patients with LVH. The higher dose of dabigatran was superior to warfarin regardless of LVH status.
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