This study is to demonstrate the safety and efficacy profile, in two different dose regimens of Edoxaban (DU-176b), (an investigational new drug being tested for the prevention of stroke/systemic embolic events (SEE)), in individuals with atrial fibrillation. Patients will be randomized to one of three treatment groups: High Dose Regimen, Low Dose Regimen, \& Warfarin. The expected duration of the study is 24 months.
CONTEXTE: antivitamines K ont été les antithrombotique oral standard utilisé depuis plus d'un demi-siècle pour la prévention et le traitement de la maladie thromboembolique. Leurs limitations comprennent la nourriture multiple et les interactions médicamenteuses et la nécessité d'ajustements de suivi et dose fréquents. Edoxaban est un inhibiteur sélectif du facteur Xa et direct qui peut fournir une anticoagulation efficace, sûr et plus pratique.
Conception de l'étude: ENGAGE AF-TIMI 48 est une phase 3, randomisée, en double aveugle et double placebo, multinational, la conception de non-infériorité mégaprocès comparant 2 stratégies d'exposition de edoxaban à la warfarine. Environ 20.500 sujets seront randomisés pour edoxaban une exposition élevée (60 mg par jour, ajusté pour la clairance du médicament), edoxaban faible exposition (30 mg par jour, ajusté pour la clairance du médicament), ou de la warfarine titré à un rapport international normalisé de 2,0 à 3,0. Les stratégies edoxaban prévoient des réductions de dose dynamiques chez les sujets ayant une exposition prévue accrue de drogues. Traitement en aveugle est maintenue grâce à l'utilisation de faux rapports internationaux normalisés chez les patients recevant edoxaban. Les critères d'admissibilité comprennent la documentation électrique de la fibrillation auriculaire ≤ 12 mois et un CHADS (2) score ≥ 2. La randomisation est stratifiée par CHADS (2) l'exposition au médicament score et attendu. L'objectif principal est de déterminer si edoxaban est non inférieur à la warfarine pour la prévention de l'AVC et de l'embolie systémique. Le point final primaire de sécurité est modifié Société internationale de thrombose et d'hémostase saignements majeurs. Le recrutement a commencé en Novembre 2008. La attendue suivi médian est de 24 mois.
CONCLUSIONS: ENGAGE AF-TIMI 48 est une comparaison de phase 3 du facteur Xa oral novateur inhibiteur edoxaban à la warfarine pour la prévention de la maladie thromboembolique chez les patients atteints de fibrillation auriculaire.
CONTEXTE: Edoxaban est un inhibiteur du facteur Xa oral direct avec des effets antithrombotiques éprouvées. L'efficacité à long terme et la sécurité des edoxaban par rapport à la warfarine chez les patients atteints de fibrillation auriculaire ne sont pas connus.
MÉTHODES: Nous avons mené une, randomisée en double aveugle et double placebo essai comparant deux schémas fois par jour de edoxaban avec la warfarine dans 21 105 patients atteints de risque modéré à élevé de fibrillation auriculaire (suivi médian de 2,8 ans). Le point final d'efficacité primaire était un AVC ou d'embolie systémique. Chaque traitement a été testé pour edoxaban non-infériorité à la warfarine au cours de la période de traitement. Le point final principal de sécurité était saignements majeurs.
Résultats: Le taux annualisé du point final primaire pendant le traitement était de 1,50% avec la warfarine (temps médian de l'intervalle thérapeutique, 68,4%), par rapport à 1,18% avec la dose élevée edoxaban (hazard ratio, 0,79; 97,5% intervalle de confiance [ IC], 0,63 à 0,99, P <0,001 pour la non infériorité) et 1,61% avec edoxaban à faible dose (hazard ratio, 1,07; IC à 97,5%, de 0,87 à 1,31, P = 0,005 pour la non infériorité). Dans l'analyse en intention de traiter, il y avait une tendance en faveur edoxaban haute dose par rapport à la warfarine (hazard ratio, 0,87; IC à 97,5%, de 0,73 à 1,04, p = 0,08) et une évolution défavorable avec edoxaban faible dose par rapport à la warfarine ( hazard ratio, 1,13; IC à 97,5%, de 0,96 à 1,34, p = 0,10). Le taux annualisé de saignements majeurs était de 3,43% avec la warfarine par rapport à 2,75% avec edoxaban haute dose (hazard ratio 0,80, IC 95%, 0,71 à 0,91, p <0,001) et de 1,61% avec edoxaban à faible dose (hazard ratio 0,47 IC à 95%, de 0,41 à 0,55, P <0,001). Les taux annualisés correspondant de décès de causes cardiovasculaires étaient 3.17% contre 2.74% (hazard ratio, 0,86; IC 95%, 0,77 à ,97, P = 0,01), et 2,71% (hazard ratio 0,85, IC 95%, 0,76 au 0,96 P = 0,008), et les taux correspondants du point de fin secondaire clé (un composite de la course, l'embolie systémique, ou décès d'origine cardiovasculaire) s'est établi à 4,43% contre 3,85% (hazard ratio 0,87, IC 95%, 0,78 à 0,96 P = 0,005), et 4,23% (hazard ratio 0,95, IC 95%, 0,86 à 1,05, p = 0,32).
CONCLUSIONS: Les deux régimes une fois par jour de edoxaban étaient non inférieur à la warfarine par rapport à la prévention de l'AVC ou d'embolie systémique et ont été associés à des taux significativement plus faibles de saignement et décès d'origine cardiovasculaire. (Financé par Daiichi Sankyo Pharma développement; ENGAGE AF-TIMI 48 nombre ClinicalTrials.gov, NCT00781391.).
<b>BACKGROUND: </b>The use of non-vitamin K antagonist oral anticoagulants (NOACs) instead of vitamin K antagonists (VKAs) in patients with atrial fibrillation (AF) and coexisting valvular heart disease (VHD) is of substantial interest.<b>OBJECTIVES: </b>This study explored outcomes in patients with AF with and without VHD in the ENGAGE AF-TIMI 48 (Effective Anticoagulation with factor Xa Next Generation in Atrial Fibrillation-Thrombolysis In Myocardial Infarction 48) trial, comparing edoxaban with warfarin.<b>METHODS: </b>Valvular heart disease was defined as history or baseline echocardiography evidence of at least moderate aortic/mitral regurgitation, aortic stenosis, or prior valve surgery (bioprosthesis replacement, valve repair, valvuloplasty). Patients with moderate to severe mitral stenosis or mechanical heart valves were excluded from the trial. Comparisons were made of rates of stroke/systemic embolic event (SSEE), major bleeding, additional efficacy and safety outcomes, as well as net clinical outcomes, in patients with or without VHD treated with edoxaban or warfarin, using adjusted Cox proportional hazards.<b>RESULTS: </b>After adjustment for multiple baseline characteristics, compared with no-VHD patients (n = 18,222), VHD patients (n = 2,824) had a similar rate of SSEE but higher rates of death (hazard ratio [HR]: 1.40; 95% confidence interval [CI]:1.26 to 1.56; p <0.001), major adverse cardiovascular events (HR: 1.29; 95% CI: 1.16 to 1.43; p <0.001), and major bleeding (HR: 1.21; 95% CI: 1.03 to 1.42; p = 0.02). Higher-dose edoxaban regimen had efficacy similar to warfarin in the presence of VHD (for SSEE, HR: 0.69; 95% CI: 0.44 to 1.07, in patients with VHD, and HR: 0.91; 95% CI: 0.77 to 1.07, in patients without VHD; p interaction [pint] = 0.26; and for less major bleeding, HR: 0.74; 95% CI: 0.53 to 1.02 in patients with VHD, and HR: 0.82; 95% CI: 0.71 to 0.94, in patients with no VHD; pint = 0.57).<b>CONCLUSIONS: </b>The presence of VHD increased the risk of death, major adverse cardiovascular events, and major bleeding but did not affect the relative efficacy or safety of higher-dose edoxaban versus warfarin in AF. (Global Study to Assess the Safety and Effectiveness of Edoxaban (DU-176b) vs. Standard Practice of Dosing With Warfarin in Patients With Atrial Fibrillation [ENGAGE AF-TIMI 48]; NCT00781391).
Background The ENGAGE AF-TIMI 48 trial (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) demonstrated noninferiority of once-daily 60 mg (30 mg dose-reduced) edoxaban compared with warfarin for prevention of stroke/systemic embolism in patients with atrial fibrillation. No previous analysis has explored the impact of treatment with edoxaban versus warfarin on rates of hospitalizations. Methods Detailed healthcare resource utilization data from ENGAGE AF-TIMI 48 for the 14 024 randomized patients who received at least one dose of study drug were used to compare the rates of bleeding- and cardiovascular-related hospitalizations for edoxaban versus warfarin. Hospitalization rates were calculated for each treatment group, and relative rates were estimated using Poisson regression. The influence of patient characteristics on the impact of edoxaban versus warfarin was evaluated through the inclusion of interaction terms. Results The overall rate of cardiovascular- or bleeding-related hospitalization was significantly lower for edoxaban than warfarin (relative rate [RR], 0.91 [95% CI, 0.85-0.97], P=0.003). Rates of hospitalizations for cardiovascular reasons (RR, 0.91 [95% CI, 0.85-0.97], P=0.004), stroke (RR, 0.80 [95% CI, 0.72-0.88], P<0.0001), and for each stroke subtype (ischemic: RR, 0.89 [95% CI, 0.81-0.99], P=0.03; hemorrhagic: RR, 0.60 [95% CI, 0.54-0.68], P<0.0001) were also lower for edoxaban. Notably, significantly greater reductions with edoxaban versus warfarin were seen for ischemic stroke-related hospitalizations in vitamin K antagonist naive patients and patients with CHADS2 scores 4 to 6, previous stroke or transient ischemic attack, age ≥75, and no previous coronary artery disease. For nonstroke bleeding-related hospitalizations, greater reductions with edoxaban were seen in vitamin K antagonist naive patients, patients with CHADS2 scores 4 to 6, and patients with moderate renal dysfunction. Conclusions Edoxaban 60 mg (30 mg dose-reduced) was associated with a significantly lower overall rate of cardiovascular- or bleeding-related hospitalization and significant reductions in the subcategories of cardiovascular-related, stroke-related, bleed-related, and nonstroke cardiovascular-related hospitalizations, when compared with warfarin. These results suggest the potential for cost offsets with edoxaban, with even greater reductions in higher-risk patients. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00781391.
<b>BACKGROUND: </b>In the ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis In Myocardial Infarction 48) trial, the lower dose edoxaban regimen (LDER) and the higher dose edoxaban regimen (HDER) were noninferior to well-managed warfarin for stroke prevention in atrial fibrillation.<b>OBJECTIVES: </b>The objective of the present analysis of the ENGAGE AF TIMI-48 trial was to comprehensively compare the net clinical outcome (NCO) of LDER (30 mg once daily, dose reduced to 15 mg in selective patients) versus HDER (60 mg once daily, dose reduced to 30 mg in selective patients).<b>METHODS: </b>This study performed a pre-specified analysis of the ENGAGE AF-TIMI 48 trial, comparing patients on LDER versus HDER.<b>RESULTS: </b>The pre-defined primary NCO (stroke/systemic embolism [SEE], major bleeding, death) was less frequent with LDER (7.26% vs. 8.01%; hazard ratio: 0.90; 95% confidence interval: 0.84 to 0.98; p = 0.014). The secondary (disabling stroke, life-threatening bleeding, or all-cause mortality) and tertiary pre-defined NCOs (stroke, SEE, life-threatening bleeding, or all-cause mortality) were similar between the 2 dosing regimens. Patients randomized to LDER versus HDER had a significantly higher risk of stroke/SEE (2.04% vs. 1.56%; hazard ratio: 1.31; 95% confidence interval: 1.12 to 1.52; p < 0.001). Conversely, major bleeding, intracranial hemorrhage, major gastrointestinal bleeding, and life-threatening bleeding occurred significantly less frequently with LDER compared with those of HDER. These findings were supported by multiple pharmacokinetic findings.<b>CONCLUSIONS: </b>In the ENGAGE AF-TIMI 48 trial, the primary NCO was reduced with LDER versus HDER, whereas the secondary and tertiary NCOs were similar between the 2 dosing regimens. These results may aid physicians in evidence-based individualization of edoxaban dosing. However, the approved HDER remains the standard therapy among the available edoxaban dosing regimens for stroke prevention in atrial fibrillation. (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis In Myocardial Infarction 48 [ENGAGE AF-TIMI 48]; NCT00781391).
This study is to demonstrate the safety and efficacy profile, in two different dose regimens of Edoxaban (DU-176b), (an investigational new drug being tested for the prevention of stroke/systemic embolic events (SEE)), in individuals with atrial fibrillation. Patients will be randomized to one of three treatment groups: High Dose Regimen, Low Dose Regimen, \& Warfarin. The expected duration of the study is 24 months.
Pays»Czech Republic,Argentina,Australia,Belgium,Brazil,Bulgaria,Canada,Chile,China,Colombia,Croatia,Denmark,Estonia,Finland,France,Germany,Greece,Guatemala,Hungary,India,Israel,Italy,Japan,Korea, Republic of,Mexico,Netherlands,New Zealand,Norway,Peru,Philippines,Poland,Portugal,Romania,Russian Federation,Serbia,Slovakia,South Africa,Spain,Sweden,Switzerland,Thailand,Turkey,Ukraine,United Kingdom,United States
