W arfarin, a vitamin K antagonist, is a commonly used anticoagulant in patients with atrial fibrillation (AF). Metaanalyses of randomized trials have shown that it reduces the risk of embolic stroke by 40% to 80% and of mortality by ≈30% but also doubles the risk of intracranial hemorrhage and increases the risk of extracranial bleeding by up to 66%. [1][2][3] It can be difficult to maintain patients in the therapeutic range (international normalized ratio of 2-3). A meta-analysis found that warfarintreated patients were in the therapeutic range 61% of the time. 4 In this study, an international normalized ratio <2 was associated with a 5-fold increase in stroke risk, and an international normalized ratio >3 was associated with a 3-fold increase in bleeding risk. Clinical Perspective on p 164Dabigatran is a competitive direct thrombin inhibitor approved in the United States to reduce the risk of stroke and systemic embolization in patients with nonvalvular AF. 5 In the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial, patients with AF were randomized to dabigatran doses of 110 or 150 mg twice daily or adjusted-dose warfarin. 6 At the dose subsequently approved in the United States (150 mg twice daily), dabigatran reduced the risk of stroke and intracranial hemorrhage and increased the risk of major gastrointestinal hemorrhage compared with warfarin. 6 Although dabigatranBackground-The comparative safety of dabigatran versus warfarin for treatment of nonvalvular atrial fibrillation in general practice settings has not been established. Methods and Results-We formed new-user cohorts of propensity score-matched elderly patients enrolled in Medicare who initiated dabigatran or warfarin for treatment of nonvalvular atrial fibrillation between October 2010 and December 2012. Among 134 414 patients with 37 587 person-years of follow-up, there were 2715 primary outcome events. The hazard ratios (95% confidence intervals) comparing dabigatran with warfarin (reference) were as follows: ischemic stroke, 0.80 (0.67-0.96); intracranial hemorrhage, 0.34 (0.26-0.46); major gastrointestinal bleeding, 1.28 (1.14-1.44); acute myocardial infarction, 0.92 (0.78-1.08) ; and death, 0.86 (0.77-0.96). In the subgroup treated with dabigatran 75 mg twice daily, there was no difference in risk compared with warfarin for any outcome except intracranial hemorrhage, in which case dabigatran risk was reduced. Most patients treated with dabigatran 75 mg twice daily appeared not to have severe renal impairment, the intended population for this dose. In the dabigatran 150-mg twice daily subgroup, the magnitude of effect for each outcome was greater than in the combined-dose analysis. Conclusions-In general practice settings, dabigatran was associated with reduced risk of ischemic stroke, intracranial hemorrhage, and death and increased risk of major gastrointestinal hemorrhage compared with warfarin in elderly patients with nonvalvular atrial fibrillation. These associations were most pronounced in patients treated...
IMPORTANCEDabigatran and rivaroxaban are non-vitamin K oral anticoagulants approved for stroke prevention in patients with nonvalvular atrial fibrillation (AF). There are no randomized head-to-head comparisons of these drugs for stroke, bleeding, or mortality outcomes. OBJECTIVE To compare risks of thromboembolic stroke, intracranial hemorrhage (ICH), major extracranial bleeding including major gastrointestinal bleeding, and mortality in patients with nonvalvular AF who initiated dabigatran or rivaroxaban treatment for stroke prevention. DESIGN, SETTING, AND PARTICIPANTSRetrospective new-user cohort study of 118 891 patients with nonvalvular AF who were 65 years or older, enrolled in fee-for-service Medicare, and who initiated treatment with dabigatran or rivaroxaban from November 4, 2011, through June 30, 2014. Differences in baseline characteristics were adjusted using stabilized inverse probability of treatment weights based on propensity scores. The data analysis was performed from May 7, 2015, through June 30, 2016.EXPOSURES Dabigatran, 150 mg, twice daily; rivaroxaban, 20 mg, once daily.MAIN OUTCOMES AND MEASURES Adjusted hazard ratios (HRs) for the primary outcomes of thromboembolic stroke, ICH, major extracranial bleeding including major gastrointestinal bleeding, and mortality, with dabigatran as reference. Adjusted incidence rate differences (AIRDs) were also estimated.RESULTS A total of 52 240 dabigatran-treated and 66 651 rivaroxaban-treated patients (47% female) contributed 15 524 and 20 199 person-years of on-treatment follow-up, respectively, during which 2537 primary outcome events occurred. Rivaroxaban use was associated with a statistically nonsignificant reduction in thromboembolic stroke (HR, 0.81; 95% CI, 0.65-1.01; P = .07; AIRD = 1.8 fewer cases/1000 person-years), statistically significant increases in ICH (HR, 1.65; 95% CI, 1.20-2.26; P = .002; AIRD = 2.3 excess cases/1000 person-years) and major extracranial bleeding (HR, 1.48; 95% CI, 1.32-1.67; P < .001; AIRD = 13.0 excess cases/1000 person-years), including major gastrointestinal bleeding (HR, 1.40; 95% CI, 1.23-1.59; P < .001; AIRD = 9.4 excess cases/1000 person-years), and with a statistically nonsignificant increase in mortality (HR, 1.15; 95% CI, 1.00-1.32; P = .051; AIRD = 3.1 excess cases/1000 person-years). In patients 75 years or older or with CHADS 2 score greater than 2, rivaroxaban use was associated with significantly increased mortality compared with dabigatran use. The excess rate of ICH with rivaroxaban use exceeded its reduced rate of thromboembolic stroke. CONCLUSIONS AND RELEVANCETreatment with rivaroxaban 20 mg once daily was associated with statistically significant increases in ICH and major extracranial bleeding, including major gastrointestinal bleeding, compared with dabigatran 150 mg twice daily.
Among patients in the US Medicare nondialysis population with first exposure to IV iron, the risk of anaphylaxis was highest for iron dextran and lowest for iron sucrose.
This study aimed to identify the frequency and distribution of developing B cell populations in the kidney of the rainbow trout, using four molecular B cell markers that are highly conserved between species, including two transcription factors, Pax5 and EBF1, recombination activating gene RAG1, and the immunoglobulin heavy chain mu. Three distinct B cell stages were defined: early developing B cells (CLP, pro-B, and early pre-B cells), late developing B cell (late pre-B, immature B, and mature B cells), and IgM-secreting cells. Developmental stage-specific, combinatorial expression of Pax5, EBF1, RAG1 and immunoglobulin mu was determined in trout anterior kidney cells by flow cytometry. Trout staining patterns were compared to a well-defined primary immune tissue, mouse bone marrow, and using mouse surface markers B220 and CD43. A remarkable level of similarity was uncovered between the primary immune tissues of both species. Subsequent analysis of the entire trout kidney, divided into five contiguous segments K1-K5, revealed a complex pattern of early developing, late developing, and IgM-secreting B cells. Patterns in anterior kidney segment K1 were most similar to those of mouse bone marrow, while the most posterior part of the kidney, K5, had many IgM-secreting cells, but lacked early developing B cells. A potential second B lymphopoiesis site was uncovered in segment K4 of the kidney. The B cell patterns, or "B cell signatures" described here provide information on the relative abundance of distinct developing B cell populations in the trout kidney, and can be used in future studies on B cell development in other vertebrate species.
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