Apixaban versus Warfarin in Patients with Atrial Fibrillation

Granger, Christopher B.; Alexander, John H.; McMurray, John J.V.; Lópes, Renato D.; Hylek, Elaine M.; Hanna, Michael; Al‐Khalidi, Hussein R.; Ansell, Jack; Atar, Dan; Avezum, Álvaro; Bahit, M. Cecilia; Dı́az, Rafael; Easton, J. Donald; Ezekowitz, Justin A.; Flaker, Greg; García, David; Geraldes, Margarida; Gersh, Bernard J.; Golitsyn, S. P.; Goto, Shinya; Hermosillo, Antonio G.; Hohnloser, Stefan H.; Horowitz, John D.; Mohan, Puneet; Jánský, Petr; Lewis, Basil S.; López‐Sendón, José; Пайс, Прем; Parkhomenko, Alexander; Verheugt, Freek W.A.; Zhu, Jun; Wallentin, Lars

doi:10.1056/nejmoa1107039

Cited by 7,513 publications

(5,973 citation statements)

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“…The distribution of the predicted total daily exposure (area under the curve at steady‐state (AUC ss )) stratified by dose for subjects enrolled in the ARISTOTLE study4 is shown in Figure 2 . The median exposure predicted by the PPK model is lower for the dose‐modification group than the reference group assigned to the 5‐mg b.i.d.…”

Section: Resultsmentioning

confidence: 99%

“…4, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 This analysis utilized a two‐stage approach so the majority of PK model development could be performed with data from the phase I and phase II studies (stage 1). Once data from the phase III study became available, the stage 1 models were re‐estimated (updated stage 1) and then redefined with additional covariate testing (stage 2).…”

Section: Methodsmentioning

confidence: 99%

“…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%

“…Two NVAF phase III trials evaluating apixaban have demonstrated a significantly improved benefit–risk profile compared to the standard of care 3, 4. The selected apixaban dose of 5 mg b.i.d.…”

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confidence: 99%

“…was based primarily on the results and analysis of the phase II dose‐ranging study in venous thromboembolism prevention 16, 17. Additionally, the phase III studies3, 4 implemented a dose‐modification strategy (which was not evaluated in phase II) based on advanced age, low body weight, and reduced renal function to minimize the potential for higher exposures in a population that may be at an inherently higher bleeding risk than the typical subject 18, 19. Although results of the clinical pharmacology studies indicated that these factors individually have limited effect on apixaban exposure, a combination of more than one intrinsic factor may increase apixaban exposure to a greater extent than a given factor alone 20, 21, 22.…”

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confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Population Pharmacokinetics of Apixaban in Subjects With Nonvalvular Atrial Fibrillation

Cirincione

Kowalski²,

Nielsen³

et al. 2018

CPT Pharmacom & Syst Pharma

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How to Use a Noninferiority Trial

Mulla¹,

Scott²,

Jackevicius³

et al. 2012

JAMA

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You are an internist seeing a 51-yearold woman with severe osteoarthritis and limited mobility who presents with progressive dyspnea over a 3-day period. She is subjectively in distress, with a pulse rate of 105, a respiratory rate of 28 breaths per minute, and an arterial oxygen saturation of 85% while breathing room air. Aside from her arthritis, the physical examination is unremarkable, and the lower extremity examination shows no sign of deep venous thrombosis. A computed tomographic (CT) pulmonary angiogram reveals unequivocal clot in 2 lobar arteries.Recently, you have been treating patients with deep venous thrombosis without hospital admission using lowmolecular-weight heparin (LMWH) administrationintheoutpatientsetting.You are less comfortable with this approach in the more dangerous setting of pulmonaryembolism.Yourecallreceiving,from the updating service to which you subscribe, a recent trial that addressed this issue. Before discussing the issue of inpatientvsoutpatienttreatmentwithyourpatient, you quickly retire to your office to review the article. 1 In doing so, you find that the trial tested for noninferiority and you wonder, as you begin to read the methods and results, if there are special issues you should consider when using this article to guide your clinical care.

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