Non-vitamin K Antagonist Oral Anticoagulants Dosing Research Articles

Persistence with Anticoagulation for Atrial Fibrillation: Report from the GLORIA-AF Phase III 1-Year Follow-up.

Background: We aimed to assess the extent to which drug persistence is better with non-vitamin K antagonist oral anticoagulants (NOACs) than vitamin K antagonists (VKAs) in atrial fibrillation (AF) patients and to estimate the difference in therapy persistence depending on NOAC dosing regimen (once daily (QD) vs. twice daily (BID)). Methods: Consecutive patients were followed for 1 year in phase III of the GLORIA-AF registry. Drug persistence was defined as the use of OAC without any discontinuation in >30 days or switching to alternative therapy. Results: Among 21,109 eligible patients in phase III, 17,266 patients who were prescribed OAC at baseline and those who took ≥1 OAC dose were included. The 1-year proportion of patients receiving NOAC and VKA who persisted on treatment was 80% and 75%, respectively. The 1-year persistence with NOACs BID and NOACs QD was 81% and 80%, respectively. Female gender, hypertension, older age, alcohol use, permanent, asymptomatic, and minimally symptomatic AF were associated with better OAC persistence. Region, medication usage predisposing to bleeding, being a current smoker, treatment reimbursement, and proton pump inhibitors were associated with lower OAC persistence. Conclusions: Drug persistence was higher with NOACs (1-year persistence was 80%) than with VKAs (75%). There was little difference in 1-year persistence between NOAC dosing regimens.

An Update on the Reversal of Non-Vitamin K Antagonist Oral Anticoagulants.

Non-vitamin K antagonist oral anticoagulants (NOACs) include thrombin inhibitor dabigatran and coagulation factor Xa inhibitors rivaroxaban, apixaban, edoxaban, and betrixaban. NOACs have several benefits over warfarin, including faster time to the achieve effect, rapid onset of action, fewer documented food and drug interactions, lack of need for routine INR monitoring, and improved patient satisfaction. Local hemostatic measures, supportive care, and withholding the next NOAC dose are usually sufficient to achieve hemostasis among patients presenting with minor bleeding. The administration of reversal agents should be considered in patients on NOAC's with major bleeding manifestations (life-threatening bleeding, or major uncontrolled bleeding), or those who require rapid anticoagulant reversal for an emergent surgical procedure. The Food and Drug Administration (FDA) has approved two reversal agents for NOACs: idarucizumab for dabigatran and andexanet alfa for apixaban and rivaroxaban. The American College of Cardiology (ACC), American Heart Association (AHA), and Heart Rhythm Society (HRS) have released an updated guideline for the management of patients with atrial fibrillation that provides indications for the use of these reversal agents. In addition, the final results of the ANNEXA-4 study that evaluated the efficacy and safety of andexanet alfa were recently published. Several agents are in different phases of clinical trials, and among them, ciraparantag has shown promising results. However, their higher cost and limited availability remains a concern. Here, we provide a brief review of the available reversal agents for NOACs (nonspecific and specific), recent updates on reversal strategies, lab parameters (including point-of-care tests), NOAC resumption, and agents in development.

P4758Label adherence of non-vitamin K antagonist oral anticoagulants and clinical outcomes in patients with atrial fibrillation: A nationwide study

Abstract Background Dose adjustment of non-vitamin K antagonist oral anticoagulants (NOACs) is indicated in some patients with atrial fibrillation (AF), based on selected patient factors or concomitant medications. Purpose We assessed the frequency of label adherence of NOAC dosing among AF patients and the associations between off-label NOAC dosing and clinical outcomes in real-world clinical practice. Methods We evaluated 53,649 AF patients treated with a NOAC using Korean National Health Insurance Service database during the period from January 2013 to December 2016. NOAC doses were classified as either underdosed or overdosed, consistent with U.S. Food and Drug Administration labeling. Cox proportional hazards regression was performed to investigate the effectiveness and safety outcomes including stroke or systemic embolism, major bleeding, and all-cause mortality. Results Overall, 16,757 NOAC-treated patients (31.2%) were underdosed, 4,492 were overdosed (8.4%), and 32,400 (60.4%) were dosed appropriately according to drug labeling. Compared with patients with label adherence, those who were underdosed or overdosed were older (71±8 and 75±7 years of age vs. 70±9 years of age, respectively; p<0.001), more likely female (39% and 53% vs. 38%, respectively; p<0.001), and had higher CHA2DS2-VASc scores (4.6±1.7 and 5.3±1.7 vs. 4.5±1.8, respectively; p<0.001). NOAC overdosing was associated with increased risk for stroke or systemic embolism (5.76 vs. 4.03 events/100 patient-years, p<0.001), major bleeding (4.77 vs. 2.94 events/100 patient-years, p<0.001), and all-cause mortality (5.43 vs. 3.05 events/100 patient-years, p<0.001) compared with label-adherent use. Figure 1 Conclusion In routine clinical practice, a significant proportion (almost 2 in 5) of AF patients received NOAC doses inconsistent with drug labeling. NOAC overdosing is associated with increased risk for stroke or systemic embolism, major bleeding, and all-cause mortality in Asian patient with AF.

P4759Factors associated with inappropriate under-dosing of non-vitamin k antagonist oral anticoagulants (NOACs) by labelling criterion in patients with non-valvular atrial fibrillation in the UK

Abstract Background Current labelling for NOACs considers dose adjustments based on renal function and for some also patients' age, weight, comorbidities, and concomitant treatments. There is limited data on factors associated with inappropriately underdosing of NOACs according to the label in routine care. Purpose To assess factors associated with inappropriate underdosing among patients initiating treatment with NOACs for NVAF in the United Kingdom (UK) general practice by applying respective EU labelling criterion. Methods This retrospective cohort study utilized data from The Health Improvement Network and Clinical Practice Research Datalink in the UK. New users of NOACs aged ≥18 years with ≥1-year enrolment in the databases from Jan 2011 - Dec 2016 were included. Three mutually exclusive cohorts of new users of apixaban, dabigatran and rivaroxaban with NVAF were identified with the date of prescription being the index date. Patients with any recent record (within 3 months) of other indications (DVT, PE or hip/knee surgery) were excluded. Appropriate and inappropriate underdosing were defined based on the criterion in the EU label of individual NOACs. Results There were 30,467 new users of NOACs with NVAF during the study period. Of these, 23,444 new users of NOACs received an appropriate dose based on label recommendations. They were 4,953 new users who were inappropriately under-dosed (29.4% in apixaban, 8.7% in dabigatran and 9.1% in rivaroxaban. Older age (70+) was a strong predictor of inappropriate underdosing among apixaban (odds ratio (OR) 7.3; 95% CI: 5.6–9.6) and rivaroxaban (OR 2.8; 95% CI: 2.1–5.4) but not for dabigatran users (OR 0.4; 95% CI: 0.3–0.6). Female apixaban and rivaroxaban users were at greater risk of inappropriate underdosing. For all three NOACs, inappropriate underdosing was less frequent in recent years. Inappropriate underdosing was more frequent among new users with antecedents of intracranial bleed. Inappropriate underdosing was more frequent in apixaban users with a history of ischaemic stroke and rivaroxaban users with history of Ischaemic heart disease. There was no inappropriate underdosing among all new users of NOACs with eGFR under 30. 25.5% of apixaban users and less than 0.5% of rivaroxaban new users with eGFR between 30 and 50 were inappropriately under-dosed. Frailty was a predictor of inappropriate underdosing among apixaban and rivaroxaban new users and the risk increased with greater level of frailty. CHA2DS2VASc score of ≥4 in apixaban users and increasing HAS-BLED scores in apixaban and dabigatran users were significantly associated with inappropriate underdosing but not in rivaroxaban. Conclusions Apixaban had the highest proportion of patients who were inappropriately under-dosed compared to other NOACs. Different factors associated with inappropriate dosing from this study would inform about the factors that are taken into consideration before prescribing different doses of NOACs. Acknowledgement/Funding The study is funded by Bayer AG

453Use of Non-vitamin K antagonist Oral Anticoagulants in a real-world setting: a community pharmacy-based study

Abstract Background The emergence of non-vitamin K antagonist oral anticoagulants (NOAC) has caused a paradigm shift in anticoagulation therapy, with NOAC being increasingly used compared to vitamin K antagonists. Despite the numerous RCTs with NOAC, further follow-up on how this high risk new drug class is used in real-world clinical practice is warranted. Purpose This study aimed to describe NOAC use in a primary care sample of long-term NOAC users, and investigated (i) adherence, (ii) patients' perceptions, (iii) drug interactions and (iv) appropriateness of dosing. Methods A cross-sectional observational study was conducted in 158 community pharmacies. Participants were home-dwelling adults treated with a NOAC for at least one year. They completed a questionnaire collecting data on socio-demographics, clinical characteristics, current medication use, self-reported adherence to NOAC (via Medication Adherence Report Scale, MARS), and beliefs and perceptions about NOAC (via Beliefs about Medicines Questionnaire, BMQ). Adherence to NOAC (self-reported (MARS) and calculated using pharmacy dispensing data (Medication Possession Ratio (MPR)); patients' beliefs and perceptions about NOAC (BMQ); and prevalence of drug interactions and inappropriate dosing (using the recommendations in the summary of product characteristics (SmPC) and the 2018 European Heart Rhythm Association (EHRA) Practical Guide) were assessed. Results Participants (n=766) had a mean age of 76.2±8.8 years, several co-morbidities (median of 5 (IQR 4–6)) and high thromboembolic risk (median CHA2DS2-VASc score of 4 (IQR 3–4)). The majority (93.5%) used NOAC for non-valvular atrial fibrillation, while the other 6.5% used it for the prevention of recurrent deep vein thrombosis or pulmonary embolism. Forty point five percent of the study sample used rivaroxaban, 36.2% apixaban, 21.1% dabigatran and 2.2% edoxaban. About 85% was adherent according to MPR (MPR ≥80%) and self-reported adherence was also high (mean MARS score 24.6±1.0). Two-thirds reported at least one adverse event of the NOAC, with easy bruising/bleeding being most prevalent (40.2% of patients). BMQ showed that 91.3% of patients favoured the “necessity” over the “concerns” of NOAC use. Thirty-one percent of patients had ≥1 drug interaction(s) with NOAC; amiodarone (10.4% of patients), antiplatelet agents (9.7%) and NSAIDs (9.0%) were the most common interacting drugs. NOAC dosing was inappropriate in 15.9% of patients according to SmPC and in 23.1% according to EHRA. Intriguingly, underdosing was more common using the SmPC as reference, while overdosing was more common using the EHRA guideline. Conclusions This real-world analysis of NOAC use revealed high adherence and necessity beliefs, drug interactions in 30% of patients, and suboptimal dosing in about one fifth of patients. These findings can inform the design of targeted community pharmacist interventions to improve quality of NOAC use.

Appropriateness of initial dose of non-vitamin K antagonist oral anticoagulants in patients with non-valvular atrial fibrillation in the UK

ObjectiveTo evaluate the appropriateness of the initial prescribed daily dose of non-vitamin K antagonist oral anticoagulants (NOACs) according to label in patients with non-valvular atrial fibrillation (NVAF) in the UK.DesignPopulation-based...

Non-Vitamin K Antagonist Oral Anticoagulants Versus Warfarin in Asians With Atrial Fibrillation: Meta-Analysis of Randomized Trials and Real-World Studies.

Background and Purpose- Several randomized trials and real-world studies have reported the efficacy and safety of non-vitamin K antagonist oral anticoagulants (NOACs) in Asian patients with atrial fibrillation; and therefore, this meta-analysis was aimed to compare the effects of NOACs with warfarin for atrial fibrillation stroke prevention in Asians. Methods- The PubMed and Embase databases were searched from January 2009 to February 2019 for studies on comparisons of NOACs versus warfarin in Asians. Risk ratios (RRs) with 95% CIs were pooled using a random-effects model. Results- Five NOAC trials and 21 observational cohorts were included. For the NOAC trials, compared with warfarin, NOACs was associated with reduced risks of stroke or systemic embolism (RR, 0.73; 95% CI, 0.59-0.90), all-cause death (RR, 0.83; 95% CI, 0.73-0.95), major bleeding (RR, 0.59; 95% CI, 0.48-0.72), and intracranial bleeding (RR, 0.36; 95% CI, 0.26-0.49). For the real-world data, compared with warfarin, NOACs was associated with decreased rates of stroke or systemic embolism (RR, 0.75; 95% CI, 0.68-0.82), ischemic stroke (RR, 0.70; 95% CI, 0.59-0.83), myocardial infarction (RR, 0.74; 95% CI, 0.58-0.93), all-cause death (RR, 0.67; 95% CI, 0.59-0.77), major bleeding (RR, 0.63; 95% CI, 0.55-0.73), intracranial bleeding (RR, 0.50; 95% CI, 0.43-0.59), and gastrointestinal bleeding (RR, 0.65; 95% CI, 0.51-0.84). The results did not change in the subgroup analyses based on the type and dose of NOACs. Conclusions- Based on published NOAC trials and real-world studies, the use of NOACs is noninferior to warfarin in Asians with atrial fibrillation irrespective of the NOAC type and dose.

Novel Oral Anticoagulants for Primary Stroke Prevention in Hypertrophic Cardiomyopathy Patients With Atrial Fibrillation.

Background and Purpose- Hypertrophic cardiomyopathy patients with atrial fibrillation are at increased risk of stroke, and anticoagulation is strongly recommended. However, limited data are available regarding the safety and effectiveness of non-vitamin K antagonist oral anticoagulants (NOACs) for primary prevention of stroke. Methods- Using the Korean Health Insurance Review and Assessment Service database, we identified 2397 patients with hypertrophic cardiomyopathy and nonvalvular atrial fibrillation on oral anticoagulation from 2013 to 2016 without history of ischemic stroke, intracranial hemorrhage (ICH), or gastrointestinal bleeding (992 on warfarin and 1405 on NOACs). Inverse probability of treatment weighting with propensity scores was used to balance covariates between treatment groups. Risk for ischemic stroke, ICH, gastrointestinal bleeding, death, and their composite outcome associated with NOAC use was assessed with warfarin use as the reference. Results- During a mean follow-up of 1.6 years, the incidence rates of ischemic stroke, ICH, gastrointestinal bleeding, death, and composite outcome were all significantly lower in the NOAC than in the warfarin group (stroke, 2.8 versus 5.0; ICH, 0.5 versus 1.3; gastrointestinal bleeding, 2.3 versus 3.0; death, 3.0 versus 5.1; composite, 7.5 versus 12.5 events per 100 person-years). NOACs were associated with significantly lower risks of ischemic stroke (hazard ratio [HR], 0.47; 95% CI, 0.32-0.68), ICH (HR, 0.31; 95% CI, 0.14-0.69), gastrointestinal bleeding (HR, 0.62; 95% CI, 0.40-0.96), death (HR, 0.45; 95% CI, 0.31-0.65), and the composite outcome (HR, 0.48; 95% CI, 0.38-0.61) than warfarin. The same trend was observed regardless of the NOAC dose and across various high-risk subgroups. In analysis of individual NOACs, all NOACs were associated with lower risks of ischemic stroke and composite outcome. Conclusions- NOACs showed superior effectiveness and safety versus warfarin in the primary prevention of stroke versus warfarin in real-world Asian hypertrophic cardiomyopathy with atrial fibrillation.

Causes and Risk Factors of Cerebral Ischemic Events in Patients With Atrial Fibrillation Treated With Non–Vitamin K Antagonist Oral Anticoagulants for Stroke Prevention

Background and Purpose- Despite treatment with oral anticoagulants, patients with nonvalvular atrial fibrillation (AF) may experience ischemic cerebrovascular events. The aims of this case-control study in patients with AF were to identify the pathogenesis of and the risk factors for cerebrovascular ischemic events occurring during non-vitamin K antagonist oral anticoagulants (NOACs) therapy for stroke prevention. Methods- Cases were consecutive patients with AF who had acute cerebrovascular ischemic events during NOAC treatment. Controls were consecutive patients with AF who did not have cerebrovascular events during NOACs treatment. Results- Overall, 713 cases (641 ischemic strokes and 72 transient ischemic attacks; median age, 80.0 years; interquartile range, 12; median National Institutes of Health Stroke Scale on admission, 6.0; interquartile range, 10) and 700 controls (median age, 72.0 years; interquartile range, 8) were included in the study. Recurrent stroke was classified as cardioembolic in 455 cases (63.9%) according to the A-S-C-O-D (A, atherosclerosis; S, small vessel disease; C, cardiac pathology; O, other causes; D, dissection) classification. On multivariable analysis, off-label low dose of NOACs (odds ratio [OR], 3.18; 95% CI, 1.95-5.85), atrial enlargement (OR, 6.64; 95% CI, 4.63-9.52), hyperlipidemia (OR, 2.40; 95% CI, 1.83-3.16), and CHA2DS2-VASc score (OR, 1.72 for each point increase; 95% CI, 1.58-1.88) were associated with ischemic events. Among the CHA2DS2-VASc components, age was older and presence of diabetes mellitus, congestive heart failure, and history of stroke or transient ischemic attack more common in patients who had acute cerebrovascular ischemic events. Paroxysmal AF was inversely associated with ischemic events (OR, 0.45; 95% CI, 0.33-0.61). Conclusions- In patients with AF treated with NOACs who had a cerebrovascular event, mostly but not exclusively of cardioembolic pathogenesis, off-label low dose, atrial enlargement, hyperlipidemia, and high CHA2DS2-VASc score were associated with increased risk of cerebrovascular events.

TCTAP A-094 Clinical Outcomes of Patients Received Lower Dose of Non-vitamin K Antagonist Oral Anticoagulants as a Medical Management for Acute Pulmonary Embolism

Recently, non-vitamin K antagonist oral anticoagulants (NOACs) was gradually being used as an attractive treatment option in patients with acute pulmonary embolism (PE) as an initial and maintenance therapy. The guidelines recommended a standard dose of NOAC as medical management for acute PE.

Recurrent ischemic stroke in atrial fibrillation with non-vitamin K antagonist oral anticoagulation

The etiology or rate of recurrent ischemic stroke according to dosing methods including drug adherence in patients taking non-vitamin K antagonist oral anticoagulants (NOACs) remain uncertain. We investigated the association between dosing methods including drug adherence achieved with NOACs and the presence of major vessel occlusion (MVO) in patients with ischemic stroke with non-valvular atrial fibrillation (NVAF). From July 2013 through December 2016, 120 patients with recurrent ischemic stroke with NVAF on NOACs were retrospectively analyzed. Patients taking non-standard doses of NOACs were divided into the missed dose group that discontinued NOACs for ≥48 h prior to arrival, and the under-dose group that used lower doses of NOACs. A logistic regression analysis was performed to determine the association between MVO and dosing methods including drug adherence. There were 60 (50.0%), 39 (32.5%), and 21 (17.5%) patients, respectively, in the standard dose, under-dose, and missed dose groups. Twelve patients (20.0%) in the standard dose group, 15 (38.5%) in the under-dose group, and 13 (61.9%) in the missed dose group had MVO. MVO was significantly higher in the missed dose group than in the standard dose and under-dose groups (P = 0.002). In patients with ischemic stroke with NVAF, who are on NOACs, anticoagulation caused by missed or lowered doses of NOACs was significantly associated with MVO in patients with recurrent cardioembolic stroke.

2018 Korean Heart Rhythm Society Guidelines for Non-Vitamin K Antagonist Oral Anticoagulants

Non-vitamin K antagonist oral anticoagulants (NOACs) are an alternative to vitamin K antagonists (VKAs) and have emerged as the treatment of choice in Korea. However, several questions remain regarding the optimal use of these agents in specific clinical situations. In this paper we discuss 1) patients with atrial fibrillation (AF) and coronary artery disease, 2) avoiding confusion with NOAC dosing across indications, 3) cardioversion in a patient treated with a NOAC, 4) AF patients who present with acute stroke while on NOACs, 5) NOACs in special situations, 6) anticoagulation in AF patients with a malignancy, and 7) optimizing VKA dose adjustments. (Korean J Med 2019;94:57-82)

Label Adherence for Non-Vitamin K Antagonist Oral Anticoagulants in a Prospective Cohort of Asian Patients with Atrial Fibrillation.

PurposeLabel adherence for non-vitamin K antagonist oral anticoagulants (NOACs) has not been well evaluated in Asian patients with non-valvular atrial fibrillation (AF). The present study aimed to assess label adherence for NOACs in a Korean AF population and to determine risk factors of off-label prescriptions of NOACs.Materials and MethodsIn this COmparison study of Drugs for symptom control and complication prEvention of AF (CODE-AF) registry, patients with AF who were prescribed NOACs between June 2016 and May 2017 were included. Four NOAC doses were categorized as on- or off-label use according to Korea Food and Drug Regulations.ResultsWe evaluated 3080 AF patients treated with NOACs (dabigatran 27.2%, rivaroxaban 23.9%, apixaban 36.9%, and edoxaban 12.0%). The mean age was 70.5±9.2 years; 56.0% were men; and the mean CHA2DS2-VASc score was 3.3±1.4. Only one-third of the patients (32.7%) was prescribed a standard dose of NOAC. More than one-third of the study population (n=1122, 36.4%) was prescribed an off-label reduced dose of NOAC. Compared to those with an on-label standard dosing, patients with an off-label reduced dose of NOAC were older (≥75 years), women, and had a lower body weight (≤60 kg), renal dysfunction (creatinine clearance ≤50 mL/min), previous stroke, previous bleeding, hypertension, concomitant dronedarone use, and anti-platelet use.ConclusionIn real-world practice, more than one-third of patients with NOAC prescriptions received an off-label reduced dose, which could result in an increased risk of stroke. Considering the high risk of stroke in these patients, on-label use of NOAC is recommended.

Outcomes After Use of Standard- and Low-Dose Non-Vitamin K Oral Anticoagulants in Asian Patients With Atrial Fibrillation.

Background and Purpose- Limited data are available describing the relative effectiveness, safety, and optimal dosing of non-vitamin K antagonist oral anticoagulants (NOACs) for treatment of nonvalvular atrial fibrillation in East Asian patients. We tried to compare effectiveness and safety outcomes of standard- and low-dose NOACs and warfarin in this population. Methods- Using nationwide administrative claims-based datasets from the Korean National Health Insurance Service Database (July 1, 2015, to December 31, 2016), this study comprised 56 504 anticoagulation-naive nonvalvular atrial fibrillation patients with high thromboembolic risk (CHA2DS2-VASc score, ≥2) treated with oral anticoagulants. Main study outcomes included thromboembolic events (ischemic stroke or systemic embolism), major bleeding, and mortality. Results- Among the study patients, 10 409 (18.4%) received warfarin and 46 095 (81.6%) were treated with NOACs: dabigatran (n=12 593; 22.3%), rivaroxaban (n=21 000; 37.2%), and apixaban (n=12 502; 22.1%). Low-dose NOAC (75.1% dabigatran, 59.7% rivaroxaban, and 62.7% apixaban) was more frequently used than standard-dose NOAC. During median follow-up of 15.0 months, each NOAC was associated with significantly lower risk of thromboembolic events (hazard ratio [HR], 0.76; 95% CI, 0.75-0.81 for dabigatran; HR, 0.74; 95% CI, 0.65-0.83 for rivaroxaban; and HR, 0.68; 95% CI, 0.59-0.78 for apixaban). Regarding safety outcomes, dabigatran (HR, 0.81; CI, 0.69-0.95) and apixaban (HR, 0.67; CI, 0.56-0.79) were associated with lower risk of major bleeding but not with rivaroxaban (HR, 0.96; CI, 0.84-1.11). Among adults <75 years of age without chronic kidney disease, use of low-dose apixaban did not demonstrate clinical benefit over warfarin with respect to thromboembolic events (HR, 0.99; CI, 0.76-1.28) and mortality (HR, 0.85; CI, 0.62-1.16). Conclusions- In this cohort of East Asian patients with nonvalvular atrial fibrillation, NOACs were associated with better effectiveness and safety outcomes versus warfarin. Lower NOAC doses were more often used, but an unjustified underdosing of apixaban seems to result in lower clinical benefit.

PCV135 - NON-VITAMIN K ANTAGONIST ORAL ANTICOAGULANTS PRESCRIPTION MONITORING: HOW TO OPTIMIZE VIGILANCE IN STROKE PREVENTION

Non-vitamin K antagonist oral anticoagulants (NOACs) are prescribed to patients with atrial fibrillation (AF) to reduce the risk of stroke. Prescribing the correct NOAC dose warrants careful consideration with the prevailing dose criteria that differ per NOAC. Electronic systems are useful to intercept prescriptions that are incorrect based on simple ‘primary’ criteria, for example the dosing frequency and drug-drug interactions with concomitant medication. However, these systems do not take into account patient characteristics such as age, renal function or weight which are crucial elements to determine the dose of NOACs. Our goal was to retrospectively determine the appropriateness of all electronic in-hospital prescriptions. Atrial Fibrillation patients with a primary NOAC prescription between January 2012 – December 2016, inpatient and outpatient, were identified from our electronic hospital information system (Martini Hospital, Groningen, The Netherlands). Appropriateness was determined, as compared to the product labelling approved by the European Medicines Agency, to address common pitfalls in prescribing NOACs and to identify targets for population-based prescription monitoring. The study included 3231 AF patients that initiated a NOAC, of which 10.7% had an inappropriate dose and the appropriateness of the prescription could not be determined in 14.1%. The most frequent reason for unknown appropriateness was an unknown renal function (13.9% of all patients). Apixaban, dabigatran and rivaroxaban were underdosed in 14.2% of the reduced dose prescriptions and overdosed in 4.5% of the full dose prescriptions. This study provides real-world evidence that underdosing of NOACs occurs more often than overdosing. Crucial patient-specific information to determine the correct dose is often lacking. Periodic population-based monitoring of anticoagulant prescriptions can help to achieve vigilance in stroke prevention with NOACs along the years.

Non-Vitamin K Antagonist Oral Anticoagulants in Patients With Atrial Fibrillation and Thrombocytopenia.

Thrombocytopenia was one of the exclusion criteria in randomized trials in which non-vitamin K antagonist oral anticoagulants (NOACs) were tested. The safety of NOACs in patients with atrial fibrillation (AF) and thrombocytopenia remains unclear. We studied 62 patients with AF aged from 53 to 85 (mean 70.5) years with platelet count from 50 to 100 × 109/L who were treated with rivaroxaban 15 mg once daily (33.9%), dabigatran 110 mg twice daily (bid) (54.8%), or apixaban 2.5 mg bid (11.3%). Age- and sex-matched AF patients with normal platelet count and similar CHA2DS2-VASc scores who were treated with the recommended doses of NOACs served as a reference group. Patients were followed for a mean of 55 months (range, 23-64 months). In the thrombocytopenia group bleeding risk was higher (mean HAS-BLED score 2.0, vs. 1.0, P < 0.0001). During follow-up in thrombocytopenic and normocytopenic patients, we observed similar rates of major bleeding (1.8%/year vs. 2.7%/year, P = 0.49), clinically relevant nonmajor bleeding (CRNMB) (1.5%/year vs. 1.1%/year, P = 0.74), ischemic stroke and transient ischemic attacks (1.8%/year vs. 1.5%/year, P = 0.8), and death (1.06%/year vs. 1.11%/year, P = 0.96). The risk of bleeding and stroke was unaffected by the type of the NOAC used in both groups. Major bleedings and clinically relevant nonmajor bleeding in thrombocytopenic patients on NOACs were predicted only by age (hazard ratio 1.1, 95% confidence interval 1.0-1.3, P = 0.04). Our findings indicate that in AF patients with mild thrombocytopenia, anticoagulation with NOAC at reduced doses seems to be safe and effective.

Variations in clinical management of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation according to different equations for estimating renal function : Post hoc analysis of a prospective cohort.

Prescription of non-vitamin K antagonist oral anticoagulants (NOACs) requires an assessment of renal function (RF) and the Cockcroft-Gault (CG) equation is traditionally recommended. The objective of the study was to evaluate the potential changes in NOACs management using different equations for estimating RF. In a post hoc analysis of a prospective cohort of patients with atrial fibrillation, we considered different equations: (1) CG for creatinine clearance (CrCl), (2) modification of diet in renal disease (MDRD), (3) CKD-EPI, (4) Berlin Initiative Study 1 (BIS-1) and (5) full age spectrum (FAS), for glomerular filtration rate (GFR). RF was classified according to CrCl in three categories: severely depressed (SD-RF) < 30ml/min; moderately depressed (MD-RF) 30-49ml/min; preserved/mildly depressed (P-RF) ≥ 50ml/min. Concordances in the assignments were analyzed. A population of 402 patients (61.2% males, age 72 ± 11) was categorized according to CrCl: 12 patients (2.9%) as SD-RF, 81 (20.1%) as MD-RF, 309 (76.8%) as P-RF. A potential change in NOACs management could occur using GFR equations rather than CrCl in 16.9% of patients using MDRD formula, in 11.7% using BIS-1, in 14.7% using CKD-EPI and in 12.9% using the FAS equation. Important changes in RF estimates were more frequent in patients aged ≥ 75, but also BMI had a meaningful impact. Use of equations estimating GFR instead of the Cockcroft-Gault equation may result in changes in NOACs management in 12-17% of patients. In the elderly ≥ 75, more pronounced changes in RF classification are detectable according to different equations and NOACs dosing should be further investigated.

Impact of BMI on clinical outcomes of NOAC therapy in daily care - Results of the prospective Dresden NOAC Registry (NCT01588119)

Direct acting non-Vitamin K antagonist oral anticoagulants (NOAC) are characterized by a fixed dosing regimen. Despite the potential for relative underdosing due to large distribution volumes, dose adjustments for patients with high body mass index (BMI) are not recommended. Since efficacy and safety data in obese patients are scarce, we evaluated the impact of BMI on clinical outcomes in daily care patients treated with NOAC for stroke prevention in atrial fibrillation or venous thromboembolism.Using prospectively collected data from a non-interventional registry, cardiovascular (CV), major bleeding events (MB) and all-cause mortality were evaluated according to BMI classes. All outcome events were centrally adjudicated using standard scientific definitions.Between November 1st 2011 and December 31st 2016, 3432 patients were enrolled into the registry (61.3% rivaroxaban; 20% apixaban; 10.1% dabigatran, 8.6% edoxaban; mean follow-up 998.1 ± 542.9 days; median 1004 days). With increasing BMI (range 13.7–57.2 kg/m2), the proportion of patients receiving standard (vs. reduced) NOAC dose increased from 64.7% (underweight) to 78.9% (obesity). Although obese patients had more cardiovascular risk factors compared to normal weight patients, on-treatment rates of clinical outcomes (CV, MB, all-cause-mortality) were lowest in overweight and obese patients.In a large set of real-life NOAC recipients we found no indication that high BMI is associated with inferior NOAC effectiveness or safety, which is in line with recent epidemiological data of a “BMI paradox” that indicates a somewhat protective effect of higher BMI regarding unfavourable outcomes also in patients receiving fixed dose NOAC anticoagulation without dose adjustment for higher BMI.

Evaluation of indications for reduced-dose non-vitamin K antagonist oral anticoagulants in hospitalised patients with atrial fibrillation.

Prevention of thromboembolic complications is a priority in patients with atrial fibrillation (AF). The use of non-vitamin K antagonist oral anticoagulants (NOACs) is more common and some patients have indications for a reduced dose. We sought to evaluate the frequency of NOACs being prescribed to AF patients and to compare the groups of AF patients receiving standard and reduced doses. The study included 1327 patients diagnosed with AF and hospitalised at an institution of the highest referral level in cardiology in the years 2015-2016. Final analysis encompassed 713 patients with nonvalvular AF, who were prescribed NOACs upon discharge. In the group of patients receiving NOACs, standard doses were used in 383 (53.7%) patients, while 330 (46.3%) patients received reduced doses. Among patients treated with reduced doses, dabigatran was prescribed to 186 (56.4%) patients, rivaroxaban to 124 (37.5%) patients, and apixaban to 20 (6.1%) patients. Absence of indications for dose reduction was identified in 54 out of 330 (16.4%) patients receiving reduced-dose NOACs, including six out of 20 patients receiving reduced-dose apixaban (30%), 21 out of 186 patients receiving reduced-dose dabigatran (11.3%), and 24 out of 124 pa-tients receiving reduced-dose rivaroxaban (19.3%). Among patients treated with reduced dose of dabigatran (n = 186), one indication for dose reduction was observed in 75 patients, and at least two indications were observed in 90 patients. One indication was observed in 71 patients, and at least two indications were observed in 30 patients treated with a reduced dose of rivaroxaban (n = 124). Standard doses of NOACs were prescribed to most hospitalised AF patients. Apixaban was prescribed more frequently in the reduced-dose regimen, while the frequencies of standard and reduced doses prescribed were similar for dabigatran and rivaroxaban. Absence of indications for dose reduction as defined in relevant guidelines and Summaries of Product Characteristics was identified in 15.5% of patients receiving reduced doses of NOACs. More than one indication for dose reduction was identified in most patients receiving reduced-dose dabigatran, while one indication was identified in most patients receiving reduced-dose rivaroxaban.

Telemonitoring-based feedback improves adherence to non-vitamin K antagonist oral anticoagulants intake in patients with atrial fibrillation.

To evaluate the effect of telemonitoring on adherence to non-vitamin K antagonist oral anticoagulants (NOACs) in atrial fibrillation (AF) patients. A randomized, single-blind, crossover, controlled trial in 48 AF patients on once or twice daily (OD or BID) NOAC. The Medication Event Monitoring System tracked NOAC intake during three phases of 3months each: daily telemonitoring, telemonitoring with immediate telephone feedback in case of intake errors, and an observation phase without daily transmissions. Unprotected days were defined as ≥ 3 or ≥ 1 consecutively missed doses for a BID or OD NOAC, respectively, or excess dose intake. Cost-effectiveness was calculated based on anticipated stroke reduction derived from patients' risk profile and measured intake. Persistence over the entire study was 98%. Telemonitoring-only already led to very high taking and regimen adherence (97.4% respectively 93.8%). Nevertheless, direct feedback further improved both to 99.0% and 96.8%, respectively (P < 0.001 respectively P = 0.002). Observation without daily monitoring resulted in a significant waning of taking adherence (94.3%; P = 0.049). Taking adherence was significantly higher for OD compared to BID NOAC, although unprotected days were similar. Feedback intervention had an incremental cost of €344289 to prevent one stroke, but this could be as low as €15488 in high-risk patients with low adherence and optimized technology. Telemonitoring resulted in high NOAC adherence due to the notion of being watched, as evidenced by the rapid decline during the observation period. Feedback further optimized adherence. Telemonitoring with or without feedback may be a cost-effective approach in high-risk patients deemed poorly adherent.