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1.
Circulation ; 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31747786

RESUMO

Background: The use of nonsteroidal anti-inflammatory drugs (NSAIDs) with oral anticoagulants has been associated with an increased risk of bleeding. We investigated the risk of bleeding and major cardiovascular outcomes in patients with atrial fibrillation (AF) taking NSAIDs and apixaban or warfarin. Methods: The ARISTOTLE trial (n=18,201) compared apixaban with warfarin in patients with AF at increased risk of stroke. Patients in ARISTOTLE without severe renal (creatine clearance ≤30 mL/min) or liver disease were included in this analysis (n=17,423). NSAID use at baseline, NSAID use during the trial (incident NSAID use) and never users were described. The primary outcome was major bleeding. Secondary outcomes included clinically relevant non-major (CRNM) bleeding, gastrointestinal bleeding, heart failure hospitalization, stroke or systemic embolism, and all-cause mortality. NSAID use during the trial and the interaction between randomized treatment and was analyzed using time dependent Cox proportional hazards models. Results: Those with baseline NSAID use (n=832 [4.8%]), incident NSAID use (n=2185 [13.2%]), and never users were similar in median age [25th, 75th] (70 [64, 77] vs. 70 [63, 75] vs. 70 [62, 76]). Those with NSAID use at baseline and incident NSAID use were more likely to have a history of bleeding (24.5% vs. 21.0% vs 15.6%) than never users. During a median follow-up [25th, 75th] of 1.8 [1.4, 2.3]) years and when excluding those taking NSAID at baseline, we found that incident NSAID use was associated with an increased risk of major bleeding (hazard ratio [HR] 1.61, 95% CI 1.11-2.33) and clinically relevant non-major bleeding (HR 1.70, 95% CI 1.16-2.48), but not gastrointestinal bleeding. No significant interaction was observed between NSAID use and randomized treatment for any outcome. Conclusions: A substantial number of patients in the ARISTOTLE trial took NSAIDs. Incident NSAID use was associated with major and CRNM bleeding, but not gastrointestinal bleeding. The safety and efficacy of apixaban versus warfarin appeared not significantly to be altered by NSAID use. This study warrants more investigation of the effect of NSAIDs on the outcomes of patients treated with apixaban. Clinical Trial Registration: URL: https://clinicaltrials.gov Unique Identifier: NCT00412984.

2.
Eur J Prev Cardiol ; : 2047487319886959, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31698965

RESUMO

BACKGROUND: A novel approach to determine the effect of a treatment is to calculate the delay of event, which estimates the gain of event-free time. The aim of this study was to estimate gains in event-free time for stroke or systemic embolism, death, bleeding events, and the composite of these events, in patients with atrial fibrillation randomized to either warfarin or apixaban in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation trial (ARISTOTLE). DESIGN: The ARISTOTLE study was a randomized double-blind trial comparing apixaban with warfarin. METHODS: Laplace regression was used to estimate the delay in time to the outcomes between the apixaban and the warfarin group in 6, 12, 18 and 22 months of follow-up. RESULTS: The gain in event-free time for apixaban versus warfarin was 181 (95% confidence interval 76 to 287) days for stroke or systemic embolism and 55 (-4 to 114) days for death after 22 months of follow-up. The corresponding gains in event-free times for major and intracranial bleeding were 206 (130 to 281) and 392 (249 to 535) days, respectively. The overall gain for the composite of all these events was a gain of 116 (60 to 171) days. CONCLUSIONS: In patients with atrial fibrillation, 22 months of treatment with apixaban, as compared with warfarin, provided gains of approximately 6 months in event-free time for stroke or systemic embolism, 7 months for major bleeding and 13 months for intracranial bleeding.

3.
J Am Coll Cardiol ; 74(14): 1760-1768, 2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31582135

RESUMO

BACKGROUND: Dabigatran and idarucizumab, its reversal agent, are renally cleared. OBJECTIVES: The purpose of this study was to determine the extent of reversal and outcomes according to baseline renal function in dabigatran-treated nondialysis patients receiving idarucizumab. METHODS: In 503 patients in RE-VERSE AD (Reversal of Effects of Idarucizumab in Patients on Active Dabigatran), the extent of dabigatran reversal and clinical outcomes were compared according to baseline renal function (creatinine clearance: normal ≥80, mild 50 to <80, moderate 30 to <50, and severe <30 ml/min). RESULTS: Compared with patients with normal renal function, those with impaired renal function were older, were more often women, and had lower body mass indexes, more comorbidities, higher CHADS2 scores, and higher dabigatran plasma levels despite more frequent use of lower-dose dabigatran regimens. Regardless of renal function, median reversal measured by dilute thrombin time was 100% within 4 h of idarucizumab administration, and over 98% of patients achieved this with corresponding undetectable levels of unbound dabigatran. By 12 or 24 h, 56% of patients with severe, 29.1% with moderate, and 9.2% with mild renal impairment had dabigatran levels >20 ng/ml compared with 8.3% of patients with normal renal function at baseline. Time to cessation of bleeding and the proportion with normal hemostasis with procedures were similar regardless of renal function, but patients with severe renal impairment had higher 30- and 90-day mortality rates. CONCLUSIONS: Idarucizumab completely reverses dabigatran in >98% of patients regardless of renal function. Although re-elevation of dabigatran levels within 12 to 24 h is more common with renal impairment, the time to bleeding cessation and the extent of hemostasis during procedures are similar. (Reversal of Dabigatran Anticoagulant Effect With Idarucizumab; NCT02104947).

4.
JAMA Cardiol ; 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31268487

RESUMO

Importance: Bleeding and thrombotic events (eg, stroke and systemic embolism) are common in patients with atrial fibrillation (AF) taking warfarin sodium despite a well-established therapeutic range. Objective: To evaluate whether history of therapeutic warfarin control in patients with AF is independently associated with subsequent bleeding or thrombotic events. Design, Setting, and Participants: In this multicenter cohort study of 176 primary care, cardiology, and electrophysiology clinics in the United States, data were obtained during 51 830 visits among 10 137 patients with AF in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) Registry; 5545 patients treated with warfarin were included in the bleeding analysis, and 5635 patients were included in the thrombotic event analysis. Patient follow-up was performed from June 29, 2010, to November 30, 2014. Data analysis was performed from August 4, 2016, to February 15, 2019. Exposures: Multiple measures of warfarin control within the preceding 6 months were analyzed: time in therapeutic range of 2.0 to 3.0, most recent international normalized ratio (INR), percentage of time that a patient had interpolated INR values less than 2.0 or greater than 3.0, INR variance, INR range, and percentage of INR values in therapeutic range. Main Outcomes and Measures: Association of INR measures, alone or in combination, with clinical factors and risk for thrombotic events and bleeding during the subsequent 6 months was assessed post hoc using logistic regression models. Results: A total of 5545 patients (mean [SD] age, 74.5 [9.8] years; 3184 [57.4%] male) with AF were included in the major bleeding analysis and 5635 patients (mean [SD] age, 74.5 [9.8] years; 3236 [57.4%] male) in the thrombotic event analysis. During a median follow-up of 1.5 years (interquartile range, 1.0-2.5 years), there were 339 major bleeds (6.1%) and 51 strokes (0.9%). Multiple metrics of warfarin control were individually associated with subsequent bleeding. After adjustment for clinical bleeding risk, 3 measures-time in therapeutic range (per 1-SD increase ≤55: adjusted odds ratio [aOR], 1.16; 95% CI, 1.02-1.32), variation in INR values (aOR, 1.32; 95% CI, 1.19-1.47), and maximum INR (aOR, 1.20; 95% CI, 1.10-1.31)-remained associated with bleeding risk. Adding INR variance to a clinical risk model slightly increased the C statistic from 0.68 to 0.69 and had a net reclassification improvement index of 0.028 (95% CI, -0.029 to 0.067). No INR measures were associated with subsequent stroke risk. Conclusions and Relevance: Three metrics of prior warfarin control were associated with bleeding risk but only marginally more so than traditional clinical factors. This study did not identify any measures of INR control that were significantly associated with stroke risk.

5.
J Am Coll Cardiol ; 73(25): 3309-3311, 2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31248552
6.
J Thromb Thrombolysis ; 48(1): 27-34, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30972712

RESUMO

We explored associations between INR measures and clinical outcomes in patients with AF using warfarin, and whether INR history predicted future INR measurements. We included patients in ARISTOTLE who were randomized to and received warfarin. Among patients who had events, we included those with ≥ 3 INR values in the 180 days prior to the event, with the most recent ≤ 60 days prior to the event, who were on warfarin at the time of event (n = 545). Non-event patients were included in the control group if they had ≥ 180 days of warfarin exposure with ≥ 3 INR measurements (n = 7259). The median (25th, 75th) number of INR values per patient was 29 (21, 38) over a median follow-up of 1.8 years. A total of 87% had at least one INR value < 1.5; 49% had at least one value > 4.0. The last INRs before events (median 14 [24, 7] days) were < 3.0 for at least 75% of patients with major bleeding and > 2.0 for half of patients with ischemic stroke. Historic time in therapeutic range (TTR) was weakly associated with future TTR (R2 = 0.212). Historic TTR ≥ 80% had limited predictive ability to discriminate future TTR ≥ 80% (C index 0.61). In patients with AF receiving warfarin, most bleeding events may not have been preventable despite careful INR control. Our findings suggest that INRs collected through routine management are not sufficiently predictive to provide reassurance about future time in therapeutic range or to prevent subsequent outcomes, and might be over-interpreted in clinical practice.

7.
J Am Heart Assoc ; 8(9): e011205, 2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-31023126

RESUMO

Background Patient satisfaction with therapy is an important metric of care quality and has been associated with greater medication persistence. We evaluated the association of patient satisfaction with warfarin therapy to other metrics of anticoagulation care quality and clinical outcomes among patients with atrial fibrillation ( AF ). Methods and Results Using data from the ORBIT - AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation) registry, patients were identified with AF who were taking warfarin and had completed an Anti-Clot Treatment Scale ( ACTS ) questionnaire, a validated metric of patient-reported burden and benefit of oral anticoagulation. Multivariate regressions were used to determine association of ACTS burden and benefit scores with time in therapeutic international normalized ratio range ( TTR ; both ≥75% and ≥60%), warfarin discontinuation, and clinical outcomes (death, stroke, major bleed, and all-cause hospitalization). Among 1514 patients with AF on warfarin therapy (75±10 years; 42% women; CHA 2 DS 2- VAS c 3.9±1.7), those most burdened with warfarin therapy were younger and more likely to be women, have paroxysmal AF , and to be treated with antiarrhythmic drugs. After adjustment for covariates, ACTS burden scores were independent of TTR ( TTR ≥75%: odds ratio, 1.01 [95% CI , 0.99-1.03]; TTR ≥60%: odds ratio, 1.01 [95% CI , 0.98-1.05]), warfarin discontinuation (odds ratio, 0.99; 95% CI , 0.97-1.01), or clinical outcomes. ACTS benefit scores were also not associated with TTR , warfarin discontinuation, or clinical outcomes. Conclusions In a large registry of patients with AF taking warfarin, ACTS scores provided independent information beyond other traditional metrics of oral anticoagulation care quality and identified patient groups at high risk for dissatisfaction with warfarin therapy.

8.
Am Heart J ; 211: 77-89, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30901602

RESUMO

BACKGROUND: The incidence of cognitive impairment and frailty increase with age and may impact both therapy and outcomes in atrial fibrillation (AF). METHODS: We examined the prevalence of clinically recognized cognitive impairment and frailty (as defined by the American Geriatric Society Criteria) in the Outcomes Registry for Better Informed Care in AF (ORBIT AF) and associated adjusted outcomes via multivariable Cox regression. The interaction between cognitive impairment and frailty and oral anticoagulation (OAC) in determining outcomes was examined. RESULTS: Among 9749 patients with AF [median (IQR) age 75 (67-82) y, 57% male], cognitive impairment and frailty was identified in 293 (3.0%) and 575 (5.9%) patients respectively. Frail patients (68 vs 77%, P < .001) and those with cognitive impairment (70 vs 77%, P = .006) were both less likely to receive an OAC. Both cognitive impairment [HR (95% CI) 1.34 (1.05-1.72), P = .0198] and frailty [HR 1.29 (1.08-1.55), P = .0060] were associated with increased risk of death. Cognitive impairment and frailty were not associated with stroke/transient ischemic attack (TIA) or major bleeding. In multivariable analysis, there was no interaction between OAC use and cognitive impairment or frailty in their associations with mortality, major bleeding and a composite end point of stroke, non-central nervous system systemic embolism, TIA, myocardial infarction or cardiovascular death. CONCLUSION: Those with cognitive impairment or frailty in AF had higher predicted risk for stroke and higher observed mortality, yet were less likely to be treated with OAC. Despite this, the benefits of OAC were similar in patients with and without cognitive impairment or frailty.

10.
J Thromb Thrombolysis ; 47(3): 345-352, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30790160

RESUMO

Warfarin is dependent on multiple hepatic enzymes for metabolism while apixaban is a substrate for P-glycoprotein (P-gp) transport and hepatic CYP3A4 metabolism. The aim of this analysis was to assess the impact of interacting medication use on the treatment effects of apixaban versus warfarin. Outcomes were compared between apixaban and warfarin using Cox proportional hazards modeling according to the use of interacting medications at randomization in ARISTOTLE (n = 18,201). Interacting medications for apixaban were identified as combined P-gp and 3A4 inhibitors or inducers while interacting medications for warfarin were defined as those highly probable for warfarin potentiation or inhibition. At randomization, 5547 (30.5%) patients were on an interacting medication, including 2722 on apixaban and 2825 on warfarin. Patients using an interacting medication were more likely to be female, taking aspirin, and have a history of prior bleeding and were less likely to have a prior stroke or transient ischemic attack. No significant differences were observed on the treatment effect of apixaban compared with warfarin in patients on and off interacting medications for outcomes including the primary efficacy outcome of stroke or systemic embolism (P for interaction = 0.79) or the primary safety outcome of major bleeding (P for interaction = 0.75). Use of interacting medications with anticoagulants occurs often in patients with atrial fibrillation. Despite the potential for altered exposure, interacting medication use was not associated with a significant change in the efficacy or safety of apixaban compared with warfarin in the ARISTOTLE trial.Trial registration ClinicalTrials.gov, NCT00412984.


Assuntos
Fibrilação Atrial/tratamento farmacológico , Interações de Medicamentos , Pirazóis/administração & dosagem , Piridonas/administração & dosagem , Varfarina/administração & dosagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/administração & dosagem , Embolia/induzido quimicamente , Inibidores do Fator Xa/administração & dosagem , Inibidores do Fator Xa/efeitos adversos , Feminino , Hemorragia/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Pirazóis/efeitos adversos , Piridonas/efeitos adversos , Acidente Vascular Cerebral/induzido quimicamente , Resultado do Tratamento , Varfarina/efeitos adversos , Adulto Jovem
11.
Int J Cardiol ; 286: 198-207, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-30777407

RESUMO

Thrombotic and bleeding risks, as well as the incidence and presentation of cardiovascular events and related outcomes, appear to differ between genders, partly in relation to variability in age, comorbidities and body size. Women experience frequent fluctuations of pro-thrombotic activity during their lifetime, related to menstrual cycles, the use of oral contraceptives, pregnancy, menopause, and hormone replacement therapy, all with potential impact on the clinical manifestations of atherosclerotic disease. On the other hand, compared with men, women feature an increased risk of bleeding during hospitalization in the setting of acute coronary syndromes or percutaneous coronary interventions. At the same time, benefits of antithrombotic therapy may differ in women compared with men in several clinical settings and according to the type of antithrombotic agent used for primary and secondary cardiovascular prevention, for the prevention of thromboembolism in patients with atrial fibrillation, and for the prevention and treatment of venous thromboembolism. Data from observational and interventional studies do not exclude gender-specific differences in either the thrombotic and hemorrhagic burden, and the effects of antithrombotic drugs on clinical outcomes might also differ between men and women. Pathophysiological mechanisms causing these disparities are not entirely clear. Multiple factors in platelet function and coagulation mechanisms in different vascular beds, partly related to the hormonal status, might contribute to such gender differences.

13.
Int J Cardiol ; 274: 152-157, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30144994

RESUMO

BACKGROUND: Renal function has been associated with an increased stroke risk in patients with atrial fibrillation (AF). However, whether renal function incrementally adds to risk prediction in both anticoagulated and non-anticoagulated patients with AF is unclear. METHODS: We used data from the Outcomes Registry for Better Informed Treatment of AF (ORBIT-AF)-a national, prospective, outpatient AF registry in patients aged >18 years (2010-2011). The association between baseline renal function and risk of stroke/systemic embolism (SSE) was evaluated in proportional hazards models adjusting for stroke risk score components. We compared discrimination of 2-year outcomes using C-indices and evaluated calibration by comparing event rates in ORBIT-AF to published rates from an external clinical trial population (ROCKET AF) and an observational cohort (ATRIA). RESULTS: Among 9743 patients included in the analysis, the median age was 75 years (interquartile range [IQR] 67-82), 89.5% were white, 43% were female, and 76% were taking oral anticoagulation (OAC). Over a median follow-up of 2.3 years, 214 SSE events occurred (1.00 per 100 patient-years). Continuous creatinine clearance (CrCl) was not associated with SSE risk after adjusting for other clinical factors (components of CHADS2 or CHA2DS2-VASc). Discrimination for predicting stroke (C-index; 95% CI) was similar for R2CHADS2 (0.65; 0.61-0.69), CHADS2 (0.65; 0.61-0.69), and CHA2DS2-VASc (0.66; 0.62-0.70). CONCLUSIONS AND RELEVANCE: In a community patient population with AF, renal dysfunction was not independently associated with embolic risk beyond other established risk factors in either OAC-treated or untreated patients. Additional study is needed to identify clinical factors that incrementally add to stroke risk prediction.


Assuntos
Fibrilação Atrial/complicações , Isquemia Encefálica/etiologia , Rim/fisiopatologia , Sistema de Registros , Medição de Risco/métodos , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/fisiopatologia , Isquemia Encefálica/epidemiologia , Isquemia Encefálica/prevenção & controle , Creatinina/sangue , Feminino , Seguimentos , Humanos , Incidência , Testes de Função Renal , Masculino , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Fatores de Risco , Estados Unidos/epidemiologia
14.
Am Heart J ; 208: 123-131, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30579505

RESUMO

BACKGROUND: Patients with atrial fibrillation (AF) often have multi-morbidity, defined as ≥3 comorbid conditions. Multi-morbidity is associated with polypharmacy, adverse events, and frailty potentially altering response to anticoagulation. We sought to describe the prevalence of multi-morbidity among older patients with AF and determine the association between multi-morbidity, clinical outcomes, and the efficacy and safety of apixaban compared with warfarin. METHODS: In this post-hoc subgroup analysis of the ARISTOTLE trial, we studied enrolled patients age ≥ 55 years (n = 16,800). Patients were categorized by the number of comorbid conditions at baseline: no multi-morbidity (0-2 comorbid conditions), moderate multi-morbidity (3-5 comorbid conditions), and high multi-morbidity (≥6 comorbid conditions). Association between multi-morbidity and clinical outcomes were analyzed by treatment with a median follow-up of 1.8 (1.3-2.3) years. RESULTS: Multi-morbidity was present in 64% (n = 10,713) of patients; 51% (n = 8491) had moderate multi-morbidity, 13% (n = 2222) had high multi-morbidity, and 36% (n = 6087) had no multi-morbidity. Compared with the no multi-morbidity group, the high multi-morbidity group was older (74 vs 69 years), took twice as many medications (10 vs 5), and had higher CHA2DS2-VASc scores (4.9 vs 2.7) (all P < .001). Adjusted rates per 100 patient-years for stroke/systemic embolism, death, and major bleeding increased with multi-morbidity (Reference no multi-morbidity; moderate multi-morbidity 1.42 [1.24-1.64] and high multi-morbidity 1.92 [1.59-2.31]), with no interaction in relation to efficacy or safety of apixaban. CONCLUSIONS: Multi-morbidity is prevalent among the population with AF; efficacy and safety of apixaban is preserved in this subgroup supporting extension of trial results to the most complex AF patients.


Assuntos
Anticoagulantes/uso terapêutico , Fibrilação Atrial/epidemiologia , Embolia/epidemiologia , Inibidores do Fator Xa/uso terapêutico , Hemorragia/epidemiologia , Multimorbidade , Pirazóis/uso terapêutico , Piridonas/uso terapêutico , Acidente Vascular Cerebral/epidemiologia , Varfarina/uso terapêutico , Fibrilação Atrial/complicações , Método Duplo-Cego , Embolia/etiologia , Embolia/prevenção & controle , Feminino , Hemorragia/induzido quimicamente , Hemorragia/prevenção & controle , Humanos , Masculino , Pessoa de Meia-Idade , Polimedicação , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/prevenção & controle
15.
Thromb Haemost ; 118(12): 2018-2019, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30453349
16.
J Am Heart Assoc ; 7(16): e008764, 2018 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-30369317

RESUMO

Background Current American College of Cardiology/American Heart Association guidelines suggest that for patients with atrial fibrillation who are at low risk for stroke (CHA2DS2VASc=1) (or women with CHA2DS2VASc=2) a variety of treatment strategies may be considered. However, in clinical practice, patterns of treatment in these "low-risk" patients are not well described. The objective of this analysis is to define thromboembolic event rates and to describe treatment patterns in patients with low-risk CHA2DS2VASc scores. Methods and Results We compared characteristics, treatment strategies, and outcomes among patients with a CHA2DS2VASc=0, CHA2DS2VASc=1, females with a CHA2DS2VASc=2, and CHA2DS2VASc ≥2 in ORBIT-AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation) I & II. Compared with CHA2DS2VASc ≥2 patients (84.2%), those with a CHA2DS2VASc=0 (60.3%), 1 (69.9%), and females with a CHA2DS2VASc score=2 (72.4%) were significantly less often treated with oral anticoagulation ( P<0.0001). Stroke rates were low overall and ranged from 0 per 100 patient-years in those with CHA2DS2VASc=0, 0.8 (95% confidence interval [CI] [0.5-1.2]) in those with CHA2DS2VASc=1, 0.8 (95% CI [0.4-1.6]) in females with a CHA2DS2VASc score=2, and 1.7 (95% CI [1.6-1.9]) in CHA2DS2VASc ≥2. All-cause mortality (per 100 patient-years) was highest in females with a CHA2DS2VASc score=2 (1.4) (95% CI [0.8-2.3]), compared with patients with a CHA2DS2VASc=0 (0.2) (95% CI [0.1-1.0]), and CHA2DS2VASc=1 (1.0) (95% CI [0.7-1.4]), but lower than patients with a CHA2DS2VASc ≥2 (5.7) (95% CI [5.4-6.0]). Conclusion The majority of CHA2DS2VASc=0-1 patients are treated with oral anticoagulation. In addition, the absolute risks of death and stroke/transient ischemic attack were low among both male and females CHA2DS2VASc=0-1 as well as among females with a CHA2DS2VASc score=2. Clinical Trial Registration URL: http://www.clinicaltrials.gov . Unique identifier: NCT01701817.

17.
J Am Heart Assoc ; 7(18): e008928, 2018 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-30371218

RESUMO

Background Chronic kidney disease ( CKD ) is a common comorbidity in patients with atrial fibrillation. The presence of CKD complicates drug selection for stroke prevention and rhythm control. Methods and Results Patients enrolled in ORBIT AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation) with baseline renal function and follow-up data were included (N=9019). CKD was defined as an estimated creatinine clearance <60 mL /min. Patient characteristics were compared by CKD status, and Cox proportional hazards modeling was used to examine the association between oral anticoagulant ( OAC ) use and outcomes and antiarrhythmic drug use and outcomes stratified by CKD stages. At enrollment, 3490 (39%) patients had an estimated creatinine clearance <60 mL /min. Patients with CKD were older and had higher CHA 2 DS 2 VAS c and Anticoagulant and Risk Factors in Atrial Fibrillation (ATRIA) scores. A rhythm control strategy was selected less frequently in patients with CKD , while OAC use was lower among Stage IV and V CKD patients. After adjustment, no significant interaction was noted for OAC and CKD on all-cause mortality ( P=0.5442) or cardiovascular death ( P=0.1233), although a trend for increased major bleeding ( P=0.0608) and stroke, systemic embolism or transient ischemic attack ( P=0.0671) was observed. No interaction was noted for antiarrhythmic drug use and CKD status on all-cause mortality ( P=0.9706), or stroke, systemic embolism or transient ischemic attack ( P=0.4218). Conclusions Patients with atrial fibrillation and CKD are less likely to be treated with rhythm control. Patients with advanced CKD are less likely to receive OAC . Finally, outcomes with OAC in patients with advanced CKD may be materially different with higher rates of both bleeding and stroke.

18.
Circulation ; 138(15): 1534-1536, 2018 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-30354524
19.
Heart ; 2018 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-30209126

RESUMO

OBJECTIVES: Compare the effect of apixaban and warfarin on coagulation and primary haemostasis biomarkers in atrial fibrillation (AF). METHODS: The biomarker substudy from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation trial included 4850 patients with AF randomised to treatment with apixaban or warfarin. Sixty per cent of patients used vitamin K antagonist (VKA) within 7 days before randomisation. Prothrombin fragment 1+2 (F1+2), D-dimer, soluble CD40 ligand (sCD40L) and von Willebrand factor (vWF) antigen were analysed at randomisation and after 2 months of study treatment. RESULTS: In patients not on VKA treatment at randomisation, F1+2 and D-dimer levels were decreased by 25% and 23%, respectively, with apixaban, and by 59% and 38%, respectively, with warfarin (p<0.0001 for treatment differences for both). In patients on VKA at randomisation, F1+2 and D-dimer levels increased by 41% and 10%, respectively, with apixaban and decreased by 37% and 11%, respectively, with warfarin (p<0.0001 for treatment differences for both). sCD40L levels were slightly increased at 2 months, regardless of VKA or randomised treatment. Apixaban and warfarin also both reduced vWF antigen regardless of VKA treatment. The efficacy (stroke) and safety (bleeding) of apixaban compared with warfarin was similar irrespectively of biomarker levels at 2 months. CONCLUSIONS: Treatment with apixaban compared with warfarin for stroke prevention in patients with AF was associated with less reduction in thrombin generation and fibrin turnover. This effect of apixaban could contribute to the clinical results where apixaban was superior to warfarin both in stroke prevention and in reducing bleeding risk. TRIAL REGISTRATION NUMBER: NCT00412984.

20.
J Am Coll Cardiol ; 72(7): 721-733, 2018 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-30092948

RESUMO

BACKGROUND: There is little mechanistic information on factors predisposing atrial fibrillation (AF) patients to thromboembolism or bleeding, but generation of nitric oxide (NO) might theoretically contribute to both. OBJECTIVES: The authors tested the hypothesis that plasma levels of the methylated arginine derivatives asymmetric and symmetric dimethylarginine (ADMA/SDMA), which inhibit NO generation, might be associated with outcomes in AF. METHODS: Plasma samples were obtained from 5,004 patients with AF at randomization to warfarin or apixaban in the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial. ADMA and SDMA concentrations were measured by high-performance liquid chromatography. Relationships to clinical characteristics were evaluated by multivariable analyses. Associations with major outcomes, during a median of 1.9 years follow-up, were evaluated by adjusted Cox proportional hazards models. RESULTS: Both ADMA and SDMA plasma concentrations at study entry increased significantly with patients' age, female sex, renal impairment, permanent AF, or congestive heart failure. ADMA and SDMA increased (p < 0.001) with both increased CHA2DS2-VASc and HAS-BLED scores, but decreased in the presence of diabetes. On multivariable analysis adjusting for established risk factors and treatment, tertile groups of ADMA concentrations were significantly associated with stroke/systemic embolism (p = 0.034), and death (p < 0.0001), whereas tertile groups of SDMA were associated with major bleeding and death (p < 0.001 for both). Incorporating ADMA and SDMA into CHA2DS2-VASc or HAS-BLED predictive models improved C-indices for those outcomes. Neither ADMA nor SDMA predicted differential responses to warfarin or apixaban. CONCLUSIONS: In anticoagulated patients with AF, elevated ADMA levels are weakly associated with thromboembolic events, elevated SDMA levels with bleeding events and both are strongly associated with increased mortality. These findings suggest that disturbances of NO function modulate both thrombotic and hemorrhagic risk in anticoagulated patients with AF. (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation [ARISTOTLE]; NCT00412984).

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