Objective To compare the efficacy, safety, and cost effectiveness of direct acting oral anticoagulants (DOACs) for patients with atrial fibrillation.Design Systematic review, network meta-analysis, ...and cost effectiveness analysis. Data sources Medline, PreMedline, Embase, and The Cochrane Library.Eligibility criteria for selecting studies Published randomised trials evaluating the use of a DOAC, vitamin K antagonist, or antiplatelet drug for prevention of stroke in patients with atrial fibrillation.Results 23 randomised trials involving 94 656 patients were analysed: 13 compared a DOAC with warfarin dosed to achieve a target INR of 2.0-3.0. Apixaban 5 mg twice daily (odds ratio 0.79, 95% confidence interval 0.66 to 0.94), dabigatran 150 mg twice daily (0.65, 0.52 to 0.81), edoxaban 60 mg once daily (0.86, 0.74 to 1.01), and rivaroxaban 20 mg once daily (0.88, 0.74 to 1.03) reduced the risk of stroke or systemic embolism compared with warfarin. The risk of stroke or systemic embolism was higher with edoxaban 60 mg once daily (1.33, 1.02 to 1.75) and rivaroxaban 20 mg once daily (1.35, 1.03 to 1.78) than with dabigatran 150 mg twice daily. The risk of all-cause mortality was lower with all DOACs than with warfarin. Apixaban 5 mg twice daily (0.71, 0.61 to 0.81), dabigatran 110 mg twice daily (0.80, 0.69 to 0.93), edoxaban 30 mg once daily (0.46, 0.40 to 0.54), and edoxaban 60 mg once daily (0.78, 0.69 to 0.90) reduced the risk of major bleeding compared with warfarin. The risk of major bleeding was higher with dabigatran 150 mg twice daily than apixaban 5 mg twice daily (1.33, 1.09 to 1.62), rivaroxaban 20 mg twice daily than apixaban 5 mg twice daily (1.45, 1.19 to 1.78), and rivaroxaban 20 mg twice daily than edoxaban 60 mg once daily (1.31, 1.07 to 1.59). The risk of intracranial bleeding was substantially lower for most DOACs compared with warfarin, whereas the risk of gastrointestinal bleeding was higher with some DOACs than warfarin. Apixaban 5 mg twice daily was ranked the highest for most outcomes, and was cost effective compared with warfarin.Conclusions The network meta-analysis informs the choice of DOACs for prevention of stroke in patients with atrial fibrillation. Several DOACs are of net benefit compared with warfarin. A trial directly comparing DOACs would overcome the need for indirect comparisons to be made through network meta-analysis.Systematic review registration PROSPERO CRD 42013005324.
Apixaban is an oral, direct factor Xa inhibitor that inhibits both free and clot-bound factor Xa, and has been approved for clinical use in several thromboembolic disorders, including reduction of ...stroke risk in non-valvular atrial fibrillation, thromboprophylaxis following hip or knee replacement surgery, the treatment of deep vein thrombosis or pulmonary embolism, and prevention of recurrent deep vein thrombosis and pulmonary embolism. The absolute oral bioavailability of apixaban is ~ 50%. Food does not have a clinically meaningful impact on the bioavailability. Apixaban exposure increases dose proportionally for oral doses up to 10 mg. Apixaban is rapidly absorbed, with maximum concentration occurring 3–4 h after oral administration, and has a half-life of approximately 12 h. Elimination occurs via multiple pathways including metabolism, biliary excretion, and direct intestinal excretion, with approximately 27% of total apixaban clearance occurring via renal excretion. The pharmacokinetics of apixaban are consistent across a broad range of patients, and apixaban has limited clinically relevant interactions with most commonly prescribed medications, allowing for fixed dosages without the need for therapeutic drug monitoring. The pharmacodynamic effect of apixaban is closely correlated with apixaban plasma concentration. This review provides a summary of the pharmacokinetic, pharmacodynamic, biopharmaceutical, and drug–drug interaction profiles of apixaban. Additionally, the population-pharmacokinetic analyses of apixaban in both healthy subjects and in the target patient populations are discussed.
BackgroundDirect oral anticoagulants (DOACs) require different follow-up than vitamin K inhibitors. DOACs dose adjustment depends on indication, age, renal function and weight, which could made ...dosage errors easier.PurposeTo analyse the use of DOACs and their prescription profile in the indications funded by the national health system.Material and methodsThe retrospective observational study considered patients admitted in February 2017 with a prescription of some DOACs included in the Hospital Pharmacotherapeutic Guide (apixaban, dabigatran and rivaroxaban). Data sources: electronic medical records, primary care prescription and hospital electronic prescription. Data collected: age, sex, DOAC, previous anticoagulant and reason for change, dose, schedule, indication and creatinine level at admission and discharge.ResultsThirty-five patients were included, of whom 51.4% were female; median age was 82 (IQR 78.75–86.25) years. Sixteen (47.1%) patients had previously received acenocoumarol, owing to overdose or haemorrhage (five patients), stroke (four), poor control of INR (four) and patient preference (three). Thirty-six DOACs were prescribed: dabigatran in four (11.1%) patients, rivaroxaban in eight (22.2%) and apixaban in 24 (66.7%).Two (5.7%) patients were treated with rivaroxaban to prevent thromboembolism in knee replacement with 10 mg every 24 hours for 34 and 49 days, respectively (2 weeks is the optimal duration).In 33 (94.3%) patients, the indication was prevention of stroke and embolism in patients with non-valvular atrial fibrillation with some risk factor. Twenty-four patients were admitted with DOACs: four with dabigatran, one of them (25%) underdosed; six with rivaroxaban, two of them (33.3%) underdosed; 14 patients with apixaban, five (35.7%) underdosed; and three (21.4%) impossible to evaluate because the weight was unknown. During the admission 10 treatments were initiated, four suspended and three patients died. Three patients were discharged with dabigatran, one of them (33.3%) underdosed; three with rivaroxaban, two of them (66.7%) underdosed; and 23 with apixaban, nine of them (39.1%) underdosed; and three with weight undocumented.ConclusionDOACs require less follow-up than classic anticoagulants, however it is necessary that the dose adjustment is optimised, the control of treatment length and the promotion of the use of these drugs for their approval indications to ensure their safety and efficacy.References and/or acknowledgementsNo conflict of interest.
BackgroundThe direct oral thrombin inhibitor (dabigatran) and the inhibitors of the X activated factor (rivaroxaban, apixaban and edoxaban) represent the pharmacological class of non-vitamin K oral ...anticoagulants (NOACs). In clinical practice this class of drugs can be utilised in: nonvalvular atrial fibrillation with one or more risk factors, prevention of thromboembolic venous events in adult patients undergoing hip or knee elective surgery, treatment of deep venous thrombosis, pulmonary embolism (PE) and in the prevention of recurring DVT and PE in adults.PurposeThe main aim of this study is to describe the suspected adverse drug reactions (ADRs) that have been observed in cases of anticoagulant therapies based on NOACs in our hospital.Material and methodsAll reports produced between 1 January 2017 and 31 August 2018 have been processed from the pharmacovigilance national net (RNF) and analysed. Using pivot tables, information regarding demographic characteristics of the patients, the suspected active ingredient, seriousness, severity and the MedDRA terms of adverse drug reactions, have been extracted.ResultsIn the period under examination, 28 ADRs have been observed and added to the RNF: nine related to Dabigatran, eight relative to Apixaban, seven to Rivaroxaban and four to Edoxaban. The demographic distribution shows a slight prevalence of the female gender (71%) and higher incidence rates in patients between 70 and 80 years of age. Five are the ADR signalled as severe, two of which presented the haemorrhage MedDRA term. Twenty-three are the ADR signalled as not severe. The most common adverse reactions are itch, erythema and heartburn. Most ADRs have been reported by the Vigifarmaco web platform. The most common source appears to be the Physicians Clinic (23 ADRs), while the rest of the signalling (five ADRs) comes from general practitioners.ConclusionThe post-marketing phase is a sensitive aspect of the research on the safety profile of drugs. A greater involvement of all health professionals, in particular general practitioners, is a priority in order to implement the surveillance of patients treated with NOACs, in order to improve knowledge on the safety profile of drugs.References and/or acknowledgementsSafety profile of the direct oral anticoagulants.No conflict of interest.
Abstract
Introduction: Oral anticoagulant-associated intracerebral hemorrhages (OAC-ICHs) account for nearly 20% of all ICH and are associated with high mortality. The number of patients with an ...indication for oral anticoagulant therapy (OAT) is increasing with the aging population; therefore, despite the improved safety profile of non-vitamin K oral anticoagulants (NOACs), the number of patients with OAC-ICH will increase. OAT was simplified with the introduction of NOACs, which are easy to handle and show a favorable risk-benefit profile. The rate of ICH is lower than for vitamin K antagonists (VKA) and routine coagulation testing is not required. Nevertheless, OAC-ICH does occur and is still a devastating disease, thus representing the most feared complication in OAT, irrespective of treatment with VKA or NOAC.
Purpose: The aim of this article is to address the clinical problem of bleeding management in patients with ICH due to OAC and will consider anticoagulation with NOAC and VKA.
Recommendations: Restoring coagulation as soon as possible is the main goal and, therefore, knowledge of the actual coagulation status is essential. In VKA-associated ICH, the international normalized ratio (INR) should be lowered to below 1.3. However, laboratory measurement of anticoagulant activity in NOAC patients is more complex, rendering OAC-ICH treatment more complicated. The best assays are specialized and not widely available, whereas more accessible tests such as prothrombin time and activated partial thromboplastin time have important limitations. For VKA-ICH, prothrombin complex concentrate (PCC) should be administered to reverse the INR. For dabigatran-related ICH, 5 g idarucizumab should be administered. For factor Xa inhibitors, PCC is recommended in the absence of andexanet alfa as soon as an OAC-related ICH evolves. Resuming OAC after ICH should be considered, depending on risk factors and a risk-benefit evaluation.
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