Eduardo Ramacciotti

Apixaban: an Oral Direct Factor-Xa Inhibitor

Apixaban is a highly selective, reversible, direct factor Xa inhibitor that inhibits both free factor Xa and prothrombinase activity, and clot-bound factor Xa activity. A predictable pharmacokinetic profile, multiple pathways of elimination, an improved bleeding profile relative to warfarin with a lack of other significant adverse events, and no need for routine anticoagulation monitoring make apixaban appealing. Apixaban is currently approved for venous thromboembolism (VTE) prophylaxis in total hip replacement and total knee replacement in Europe, Brazil, Australia, and New Zealand, and has been pre-approved in Indonesia and the Philippines. Completed phase 3 trials suggest that apixaban has promise as an alternative to aspirin and warfarin for prevention of stroke and systemic embolism in patients with atrial fibrillation. Results of a large phase 3 trial were the first to show a survival benefit for this new class of oral anticoagulants in patients with atrial fibrillation. In patients with acute coronary syndrome, apixaban added to dual antiplatelet therapy with aspirin and clopidogrel resulted in unacceptably high rates of major bleeding. In medically ill patients, an extended course of thromboprophylaxis with apixaban was not superior to a shorter course with enoxaparin, and was associated with significantly more major bleeding events than enoxaparin. Ongoing phase 3 trials will provide data regarding the efficacy and safety of apixaban for treatment of acute deep vein thrombosis and pulmonary embolism.

A Comprehensive Overview of Direct Oral Anticoagulants for the Management of Venous Thromboembolism

ABSTRACT Venous thromboembolism (VTE) is a prevalent, potentially fatal health problem. Although standard anticoagulant therapy is effective when compared with the newer direct oral anticoagulants (DOACs), it has disadvantages. Heparin and its derivatives must be administered parenterally, whereas use of oral vitamin K antagonists is complicated by unpredictable pharmacokinetics and pharmacodynamics, drug‐food and drug‐drug interactions and the requirement for frequent laboratory monitoring. Randomized phase 3 trials have demonstrated that patients receive similarly effective anticoagulation with the DOACs dabigatran, edoxaban, rivaroxaban and apixaban when compared with warfarin, with similar or reduced risk of bleeding. Extended therapy trials have consistently demonstrated superior effectiveness for DOAC treatment when compared with placebo in preventing VTE recurrence. This article presents a comprehensive review of the pharmacokinetics, pharmacodynamics and accumulated clinical trial evidence for each DOAC for short‐term, long‐term and extended VTE therapy, and it considers the potential implications these agents have for the clinical management of VTE.

Venous thromboembolism prophylaxis and clinical consequences in medically ill patients.

The objective of this study was to examine venous thromboembolism (VTE) prophylaxis use, risk reduction, and readmission in medically ill patients during hospitalization and after discharge. This 5-year retrospective study linked outpatient files from MarketScan Commercial and Medicare Supplemental databases. Patients were categorized into prophylaxis and non-prophylaxis groups based on guideline-recommended anticoagulant use from the index date to 180 days posthospital discharge and before the first VTE event date. Outcome variables were VTE events and rehospitalization. Risk adjustment was conducted within the prophylaxis group and between the prophylaxis and non-prophylaxis groups using propensity score matching. Among 4467 patients, 28.99% of the patients (n = 1295) were admitted with cancer, 18.03% (n = 805) with pneumonia, 14.06% (n = 628) with heart failure, 11.06% (n = 494) with stroke, 11.11% (n = 496) with sepsis, 8.08% (n = 361) with infectious diseases, 5.6% (n = 250) with severe respiratory disorders, 1.81% (n = 81) with inflammatory bowel disease, 1.05% (n = 47) with obesity, 0.20% (n = 9) with neurologic disorders, and 0.02% (n = 1) with acute rheumatic fever. Among those with 180-day continuous enrollment after the index date (n = 3511), 51.81% (n = 1819) received anticoagulant therapy only, 2.48% (n = 87) received mechanical compression treatment only (stocking or pneumatic compression), and 4.41% (n = 155) received both during hospitalization. Anticoagulant therapy rates ranged from 88.64% (obesity) to 32.39% (inflammatory bowel disease). Among anticoagulant therapy patients, 740 patients (40.68%) received low–molecular weight heparin only and 806 patients (44.31%) received unfractionated heparin. After risk adjustment, compared with patients without VTE prophylaxis, anticoagulant prophylaxis patients had lower VTE (3.62% vs. 4.27%, P < 0.04) and readmission rates (24.22% vs. 27.95%, P < 0.02) during the 6 months post-index hospital admission. In conclusion anticoagulant prophylaxis is underutilized and is associated with reduced VTE risk and a decrease in rehospitalizations for medically ill patients.

Apixaban pharmacodynamic activity in umbilical cord, paediatric, and adult plasma

The objective was to characterise apixaban pharmacodynamic (PD) activity in umbilical cord (UC), paediatric, and adult plasma. Plasma was obtained from blood samples from six UC donors, 70 paediatric (neonates [birth-≤1 month], infants [>1-≤6 months], toddlers [>6 months-≤2 years], young children [>2-≤6 years], children [>6-≤12 years], adolescents [>12-≤18 years]), and six adult (19-45 years) subjects. Plasma spiked with apixaban 0 (baseline), 30, or 110 ng/ml was analysed for anti-factor Xa activity, factor X levels, prothrombin time (PT), and modified PT (mPT). Apixaban had similar concentration-related effects on anti-factor Xa activity across groups (30 ng/ml: 0.223-0.295 IU/ml; 110 ng/ml: 1.212-1.474 IU/ml). Endogenous baseline factor X levels were 43 %-68 % lower in plasma from UC and subjects ≤6 months versus adults. Factor Xa inhibition (percentage change from baseline in apparent factor X levels) was similar for both apixaban concentrations across groups, except UC, neonate, and infant groups, which showed greater inhibition vs adults for apixaban 110 ng/ml. Baseline PT and mPT were similar across groups. Apixaban had no effect on PT at the concentrations tested. Apixaban 110 ng/ml prolonged mPT similarly across groups (44.4-53.2 s to 64.5-70.0 s); no prolongation was found with apixaban 30 ng/ml. Apixaban demonstrated consistent concentration-related effects on other PD endpoints in plasma samples from all age groups, except factor Xa inhibition.

Enoxaparin dosing after discharge from US hospitals in patients with total knee replacement.

Background: Prophylaxis for venous thromboembolism after total knee replacement (TKR) is standard of care. Two enoxaparin regimens are approved for thromboprophylaxis, one in the United States (30 mg twice daily [bid]) and another in the rest of the world (40 mg once daily [qd]). Data on frequency of utilization of these 2 regimens at discharge from US hospitals after TKR are not available. Methods: We conducted a retrospective/descriptive analysis of the PharMetrics claims database to estimate the frequency of utilization of enoxaparin 40 mg qd compared to 30 mg bid after discharge for TKR from US hospitals. Results: Of the 44 552 TKR patients identified, 7198 had an outpatient claim for enoxaparin within 14 days postoperatively. The 40 mg strength of enoxaparin was prescribed more commonly (~51%) than the 30 mg strength (~46%). Conclusions: Enoxaparin 40 mg qd is prescribed in approximately the same proportion of patients as the current Food and Drug Administration–approved regimen of 30 mg bid.

Warfarin Discontinuation in Patients With Unprovoked Venous Thromboembolism: A Large US Insurance Database Analysis.

This study examined warfarin therapy discontinuation and its risk factors among patients with unprovoked venous thromboembolism (VTE) in the US clinical practice setting. Adult patients with unprovoked VTE were identified from the MarketScan claims database from January 1, 2006 to December 31, 2012. The index date was defined as the date of first VTE diagnosis. Patients were required to have no VTE diagnosis in the 6 months before index date and continuous health plan enrollment for 6 months before and 12 months after the index date. Warfarin discontinuation rates and adjusted hazard ratios (HRs) were reported. Of 21,163 eligible patients, 15,463 were diagnosed with deep vein thrombosis (DVT) only (73.1%), 5027 with pulmonary embolism (PE) only (23.7%), and 673 with DVT and PE (3.2%). The average duration of warfarin therapy was 5.2 months (SD = 3.0). During 1-year follow-up, 21.4% patients discontinued therapy within 3 months, 42.8% within 6 months, and 70.1% within 12 months. PE versus DVT [HR = 0.77, 95% confidence interval (CI) = 0.74–0.80], comorbid atrial fibrillation (HR = 0.73, 95% CI = 0.66–0.81), thrombophilia (HR = 0.62, 95% CI = 0.54–0.71), and age >40 years (41–65 years: HR = 0.86, 95% CI = 0.81–0.91; >65 years: HR = 0.82, 95% CI = 0.77–0.87) were significantly associated with reduced risk of warfarin discontinuation. Alcohol abuse/dependence (HR = 1.36, 95% CI = 1.20–1.55), cancer history (HR = 1.13, 95% CI = 1.07–1.19), bleeding (HR = 1.07, 95% CI = 1.01–1.15), and catheter ablation (HR = 1.10, 95% CI = 1.00–1.20) in the 6 months before index date were significantly associated with increased risk for warfarin discontinuation. In conclusion, nearly 1 of 4 patients with unprovoked VTE discontinued warfarin within 3 months. Three of 4 patients discontinued therapy within 1 year. Younger age and multiple clinical factors are associated with warfarin therapy discontinuation.

Pharmacological Prophylaxis for Venous Thromboembolism Among Hospitalized Patients With Acute Medical Illness: An Electronic Medical Records Study

Patients hospitalized with acute medical illness have an elevated risk of venous thromboembolism (VTE). American College of Chest Physicians guidelines list various chronic illnesses, sepsis, advanced age, history of VTE, and immobility as risk factors and recommend prophylactic anticoagulation using fondaparinux, low–molecular weight heparin, or low-dose unfractionated heparin. The objectives of this study were to examine pharmacological prophylaxis against VTE among hospitalized medically ill patients and to assess demographic and clinical correlates related to VTE prophylaxis. A retrospective (1999–2010) electronic medical records study included patients aged 40 years and older hospitalized for at least 3 days, with significant medical illness or with a VTE hospitalization 30–365 days before admission. Each patients first qualifying hospitalization was analyzed. Exclusions were if VTE treatment was started within 1 day of admission, or if warfarin (and not heparin or enoxaparin) was used. Prophylaxis was defined if the first inpatient dose of subcutaneous heparin or enoxaparin was at prophylaxis levels (lower than treatment levels). Multivariable logistic regression was used to examine factors associated with VTE prophylaxis. Among 12,980 patients, 22.1% received prophylaxis (11.8% with enoxaparin, 10.3% with heparin). VTE prophylaxis was positively associated with year of hospitalization, subcutaneous heparin in the month before admission, aspirin, self-pay status, age, and sepsis. VTE prophylaxis was negatively associated with smoking, alcohol, warfarin in the past 30 days, and primary diagnoses of stroke, infectious disease, or inflammatory bowel disease. Pharmacological VTE prophylaxis has increased significantly over the past 12 years but is still largely underused in patients hospitalized with acute medical illness. Multiple demographic, behavioral, and clinical factors are associated with inpatient VTE prophylaxis.