Oral Apixaban for the Treatment of Acute Venous Thromboembolism

Agnelli, Giancarlo; Büller, Harry R.; Cohen, Alexander T.; Curto, Madelyn; Gallus, Alexander; Johnson, Margot; Masiukiewicz, Urszula; Pak, Raphael; Thompson, John R.; Raskob, Gary E.; Weitz, Jeffrey I.

doi:10.1056/nejmoa1302507

Cited by 1,995 publications

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“…Patients were largely excluded from randomized controlled trials of NOACs if baseline liver function was abnormal 9, 10, 11, 12, 24, 25, 26, 27. ROCKET AF (Rivaroxaban Once‐daily oral direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) and EINSTEIN (Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Acute Symptomatic Deep‐Vein Thrombosis or Pulmonary Embolism) trials excluded patients with ALT levels >3 times the upper limit of normal 9, 25.…”

Section: Discussionmentioning

confidence: 99%

“…RE‐LY (Randomized Evaluation of Long Term Anticoagulant Therapy) and RE‐COVER (Efficacy and Safety of Dabigatran Compared to Warfarin for 6 Month Treatment of Acute Symptomatic Venous Thromboembolism) trials excluded patients with AST or ALT levels more than twice the upper limit of normal 12, 27. ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation), AMPLIFY (Apixaban for the Initial Management of Pulmonary Embolism and Deep‐Vein Thrombosis as First‐Line Therapy), ENGAGE AF (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation), and Hokusai‐VTE (Comparative Investigation of Low Molecular Weight Heparin/Edoxaban Tosylate Versus Low Molecular Weight Heparin/Warfarin in the Treatment of Symptomatic Deep‐Vein Blood Clots and/or Lung Blood Clots) trials excluded patients with AST or ALT levels greater than twice the upper limit of normal or total bilirubin levels >1.5‐fold the upper limit of normal,10, 11, 24, 26 which was used as the criteria for ILF in the present study. Because major trials of NOAC excluded patients with ILF, data comparing NOAC and warfarin therapies in patients with ILF are restricted to small cohort studies 16, 17, 18.…”

Section: Discussionmentioning

confidence: 99%

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Efficacy and Safety of Non–Vitamin K Antagonist Oral Anticoagulants in Atrial Fibrillation Patients With Impaired Liver Function: A Retrospective Cohort Study

Wang

Kuo

et al. 2018

JAHA

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BackgroundPatients with impaired liver function (ILF) were excluded from clinical trials that investigated non–vitamin K antagonist oral anticoagulants (NOACs) for stroke prevention in patients with atrial fibrillation. The aim of this study was to evaluate the efficacy and safety of NOACs in atrial fibrillation patients with ILF.Methods and ResultsA cohort study based on electronic medical records was conducted from 2009 to 2016 at a multicenter healthcare provider in Taiwan and included 6451 anticoagulated atrial fibrillation patients (aged 76.7±7.0 years, 52.5% male). Patients were classified into 2 subgroups: patients with normal liver function (n=5818) and patients with ILF (n=633, 9.8%). Cox regression analysis was performed to investigate the risks of thromboembolism, bleeding, and death associated with use of NOACs and warfarin in patients with normal liver function and ILF, respectively. In patients with normal liver function, compared with warfarin therapy (n=2928), NOAC therapy (n=4048) was associated with significantly lower risks of stroke or systemic embolism (adjusted hazard ratio: 0.75; 95% confidence interval, 0.65–0.88; P<0.001) and death (adjusted hazard ratio: 0.69; 95% confidence interval, 0.60–0.80; P<0.001) with no difference in major bleeding or gastrointestinal bleeding. In patients with ILF, compared with warfarin therapy (n=394), NOAC therapy (n=342) was associated with significantly lower risk of death (adjusted hazard ratio: 0.64; 95% confidence interval, 0.49–0.83; P<0.001), but no difference in stroke or systemic embolism, major bleeding, or gastrointestinal bleeding.ConclusionsIn atrial fibrillation patients with ILF, NOAC therapy and warfarin therapy were associated with similar risks of stroke or systemic embolism, major bleeding, and gastrointestinal bleeding.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Efficacy and Safety of Non–Vitamin K Antagonist Oral Anticoagulants in Atrial Fibrillation Patients With Impaired Liver Function: A Retrospective Cohort Study

Wang

Kuo

et al. 2018

JAHA

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“…Atrial fibrillation has become a cardiovascular epidemic, and is associated with significant morbidity and mortality, with considerable implications for population disease burden and medical costs 2, 3, 4. Oral anticoagulants, which include vitamin K antagonists (VKA) and direct oral anticoagulants (DOACs), are used to prevent thromboembolism including stroke and systemic embolism in this patient population 5, 6, 7, 8, 9, 10, 11, 12. Patients on oral anticoagulants frequently undergo invasive procedures that require temporary interruption of anticoagulation.…”

Section: Introductionmentioning

confidence: 99%

Perioperative interruption of direct oral anticoagulants in patients with atrial fibrillation: A systematic review and meta‐analysis

Shaw

Woodfine

Douketis

et al. 2018

Research and Practice in Thrombosis and Haemostasis

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Essentials Little evidence exists to guide procedural interruption of direct oral anticoagulants (DOACs).Conducted a meta‐analysis of the interruption of DOACs in patients with atrial fibrillation (AF).The 30‐day risk for thromboembolic and major bleeding events were 0.4% and 1.8%, respectively.Perioperative interruption of DOACs in patients with AF appears to be safe and effective. BackgroundPatients with atrial fibrillation (AF) frequently undergo invasive procedures that require temporary interruption of anticoagulation. There is little evidence to guide the perioperative interruption of direct oral anticoagulants (DOACs).MethodsA systematic literature search including studies that evaluated the perioperative interruption of DOACs for non‐emergent invasive procedures in patients with AF was performed. The primary outcomes of interest were the 30‐day risk of thromboembolic events and major bleeding. Secondary outcomes of interest included the 30‐day risk of minor bleeding and overall mortality. The systematic review protocol and search strategy were registered online (PROSPERO January 27th 2017:CRD42017056124).ResultsA total of 8 publications encompassing 14 446 patients and 17 107 periprocedural interruptions were included in our study. Our analysis revealed a pooled postoperative 30‐day thromboembolic complication risk of 0.41% (95% CI 0.29‐ 0.54), and a pooled 30‐day postoperative major bleeding risk of 1.81% (95% CI 0.84‐3.13). Pooled 30‐day postoperative risks of minor bleeding and overall mortality were 3.08% (95% CI 1.02‐6.20) and 0.67% (95% CI 0.29‐1.23), respectively. Meta‐analysis of the included comparative studies did not reveal any significant differences in these postoperative outcomes following the perioperative interruption of DOACs or vitamin K antagonists.ConclusionsThe perioperative interruption of DOACs in patients with AF was associated with 0.4% thromboembolic and 1.8% major bleeding events at 30 days post surgery. These findings seem reassuring, but require validation in large prospective management studies where pre‐operative DOAC levels are measured and compared with clinical outcomes in this patient population.

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“…Apixaban is a novel, orally active, selective, direct, reversible inhibitor of the coagulation factor Xa and is approved in a number of countries for multiple indications, including thromboprophylaxis after knee or hip replacement surgery, treatment of deep vein thrombosis (DVT) and PE, prevention of recurrent DVT and PE, and reduction of the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (NVAF) 1, 2, 3, 4, 5, 6, 7…”

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confidence: 99%

Population Pharmacokinetics of Apixaban in Subjects With Nonvalvular Atrial Fibrillation

Cirincione

Kowalski²,

Nielsen³

et al. 2018

CPT Pharmacom & Syst Pharma

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This analysis describes the population pharmacokinetics (PPK) of apixaban in nonvalvular atrial fibrillation (NVAF) subjects, and quantifies the impact of intrinsic and extrinsic factors on exposure. The PPK model was developed using data from phase I–III studies. Apixaban exposure was characterized by a two‐compartment PPK model with first‐order absorption and elimination. Predictive covariates on apparent clearance included age, sex, Asian race, renal function, and concomitant strong/moderate cytochrome P450 (CYP)3A4/P‐glycoprotein (P‐gp) inhibitors. Individual covariate effects generally resulted in < 25% change in apixaban exposure vs. the reference NVAF subject (non‐Asian, male, aged 65 years, weighing 70 kg without concomitant CYP3A4/P‐gp inhibitors), except for severe renal impairment, which resulted in 55% higher exposure than the reference subject. The dose‐reduction algorithm resulted in a ~27% lower median exposure, with a large overlap between the 2.5‐mg and 5‐mg groups. The impact of Asian race on apixaban exposure was < 15% and not considered clinically significant.

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Oral Apixaban for the Treatment of Acute Venous Thromboembolism

Abstract: A fixed-dose regimen of apixaban alone was noninferior to conventional therapy for the treatment of acute venous thromboembolism and was associated with significantly less bleeding (Funded by Pfizer and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00643201).

Cited by 1,995 publications

References 14 publications

Efficacy and Safety of Non–Vitamin K Antagonist Oral Anticoagulants in Atrial Fibrillation Patients With Impaired Liver Function: A Retrospective Cohort Study

Efficacy and Safety of Non–Vitamin K Antagonist Oral Anticoagulants in Atrial Fibrillation Patients With Impaired Liver Function: A Retrospective Cohort Study

Perioperative interruption of direct oral anticoagulants in patients with atrial fibrillation: A systematic review and meta‐analysis

Population Pharmacokinetics of Apixaban in Subjects With Nonvalvular Atrial Fibrillation

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