Trends in oral anticoagulant use in patients with atrial fibrillation in Belgium from 2013 to 2019: A nationwide cohort study.

AIM: Non-vitamin K antagonist oral anticoagulants (NOACs) are increasingly preferred over vitamin K antagonists (VKAs) in atrial fibrillation (AF) management. However, differences in oral anticoagulant (OAC) prescribing according to patient's age, sex and physician's specialty may be present. Therefore, incident and prevalent use of OACs, NOACs and VKAs, stratified by age, sex and prescriber, and factors associated with the choice of OAC were investigated. METHODS: Using two Belgian nationwide healthcare databases, AF patients ≥45 years old with ≥1 OAC prescription claim between 2013 and 2019 were identified. OAC use was investigated per half-year. Factors influencing NOAC vs. VKA initiation were identified by multivariable logistic regression. RESULTS: Among 448 661 included OAC-treated AF patients, 297 818 were newly treated. Incident OAC use ranged from 45-49 to 42-44 users/10 000 persons between 2013 and 2019, whereas prevalent OAC use increased from 337 to 435 users/10 000 persons. Incident and prevalent NOAC use exceeded VKA use since 2013 and 2015, respectively, and NOACs represented 92% of incident and 81% of prevalent OAC users in 2019. Apixaban was the most frequently used NOAC since 2016. NOACs were significantly more prescribed by cardiologists and to older patients, whereas VKAs were more initiated in patients with cardiovascular, renal and hepatic comorbidities. Prevalent OAC use increased less in women than men (25.3% vs. 33.0% between 2013 and 2019) and female subjects had 5% significantly lower odds of NOAC vs. VKA initiation than men. CONCLUSION: Since 2013, prevalent anticoagulant use increased almost one third in Belgium, while incident use was stable. Potential (N)OAC underuse in women requires further exploration.

Non-vitamin K Antagonist Oral Anticoagulants (NOACs) Versus Warfarin in Patients with Atrial Fibrillation Using P-gp and/or CYP450-Interacting Drugs: a Systematic Review and Meta-analysis.

PURPOSE: Non-vitamin K antagonist oral anticoagulants (NOACs) are excreted by P-glycoprotein (P-gp) and some are metabolized by CYP450 enzymes such as CYP3A4. Although fewer drug interactions are present with NOACs, it is unclear whether NOACs should also be preferred over vitamin K antagonists (VKAs) in patients with atrial fibrillation (AF) using pharmacokinetically interacting drugs. Therefore, the benefit-risk profile of NOACs versus VKAs was investigated in AF patients treated with P-gp and/or CYP450-interacting drugs. METHODS: Using PubMed and Embase, randomized controlled trials and observational studies on the effectiveness and safety of NOACs versus VKAs in AF patients using P-gp and/or CYP450-interacting drugs were included. A meta-analysis was performed, calculating relative risks (RR) and 95% confidence intervals (CI) with the Mantel-Haenszel method. RESULTS: Twelve studies were included, investigating 10,793 NOAC and 10,096 VKA users treated with P-gp/CYP3A4 inhibitors, whereas no studies on P-gp and/or CYP450-inducing drugs were identified. Compared to VKAs, NOACs were associated with a borderline non-significantly lower stroke or systemic embolism (stroke/SE) risk (RR 0.85, 95%CI (0.72-1.01)), significantly lower intracranial bleeding (RR 0.47, 95%CI (0.34-0.65)) and all-cause mortality risks (RR 0.87, 95%CI (0.79-0.95), but significantly higher gastrointestinal bleeding risk (RR 1.74, 95%CI (1.06-2.86)). Among AF patients using amiodarone, NOACs were associated with significantly lower stroke/SE (RR 0.71, 95%CI (0.54-0.93)) and intracranial bleeding risks (RR 0.51, 95%CI (0.29-0.88)), but significantly higher gastrointestinal bleeding risk (RR 2.15, 95%CI (1.24-3.72)) than VKAs. CONCLUSION: The benefit-risk profile of NOACs compared to VKAs was preserved in AF patients using P-gp/CYP3A4 inhibitors, including amiodarone.

Minimal Adherence Threshold to Non-Vitamin K Antagonist Oral Anticoagulants in Patients with Atrial Fibrillation to Reduce the Risk of Thromboembolism and Death: A Nationwide Cohort Study.

PURPOSE: Poor adherence to non-vitamin K antagonist oral anticoagulants (NOACs) may raise thromboembolic risks in patients with atrial fibrillation (AF). However, the minimal adherence to maintain the protective effect of NOACs is currently unknown. Therefore, we investigated thresholds of NOAC adherence in association with thromboembolic and mortality risks. METHODS: Patients with AF initiating NOACs between 2013 and 2019 were identified in Belgian nationwide data. Adherence was measured using the proportion of days covered (PDC) after one year of treatment. Inverse probability of treatment weighted Cox regression was used to investigate outcomes. RESULTS: 92,111 persons were included (250,750 person-years). Compared to NOAC users with a one-year PDC of 100%, significantly higher risks of stroke or systemic embolism were observed among NOAC users with PDCs of 85-89% (adjusted hazard ratio (aHR) 1.35, 95% confidence interval (CI) (1.19-1.54)), 80-84% (aHR 1.31, 95%CI (1.08-1.58)) and < 80% (aHR 1.64, 95%CI (1.34-2.01)), while no significant differences were observed among NOAC users with one-year PDCs of 95-99% (aHR 1.02, 95%CI (0.94-1.12)) or 90-94% (aHR 1.06, 95%CI (0.95-1.18)). Significantly higher risks of all-cause mortality were observed with decreasing levels of NOAC adherence, which were already higher among NOAC users with a one-year PDC of 90-94% versus 100% (aHR 1.09, 95%CI (1.01-1.17)). Findings were similar with once-daily and twice-daily dosed NOACs. CONCLUSION: Poor adherence to NOACs is associated with increased risks of thromboembolism and all-cause mortality. The minimal adherence threshold should be ≥ 90%, preferably even ≥ 95%.

Pharmacodynamic Drug-Drug Interactions and Bleeding Outcomes in Patients with Atrial Fibrillation Using Non-Vitamin K Antagonist Oral Anticoagulants: a Nationwide Cohort Study.

PURPOSE: Pharmacodynamic drug-drug interactions (PD DDIs) may influence the safety of non-vitamin K antagonist oral anticoagulants (NOACs), but the extent to which PD DDIs increase bleeding risks, remains unclear. Therefore, the impact of PD DDIs on bleeding outcomes in NOAC-treated patients with atrial fibrillation (AF) was investigated. METHODS: Using Belgian nationwide data, NOAC-treated AF patients were included between 2013-2019. Concomitant use of PD interacting drugs when initiating NOAC treatment was identified. RESULTS: Among 193,072 patients, PD DDIs were identified in 114,122 (59.1%) subjects. After multivariable adjustment, concomitant use of PD interacting drugs was associated with significantly higher risks of major or clinically-relevant non-major bleeding (adjusted hazard ratio (aHR) 1.19, 95% confidence interval (CI) (1.13-1.24)), gastrointestinal (aHR 1.12, 95%CI (1.03-1.22)), urogenital (aHR 1.21, 95%CI (1.09-1.35)) and other bleeding (aHR 1.28, 95%CI (1.20-1.36)), compared to NOAC-treated AF patients without PD interacting drug use. Increased bleeding risks were most pronounced with P2Y12 inhibitors (aHR 1.62, 95%CI (1.48-1.77)) and corticosteroids (aHR 1.53, 95%CI (1.42-1.66)), followed by selective serotonin or serotonin and norepinephrine reuptake inhibitors (SSRI/SNRI, aHR 1.26, 95%CI (1.17-1.35)), low-dose aspirin (aHR 1.14, 95%CI (1.08-1.20)) and non-steroidal anti-inflammatory drugs (NSAID, aHR 1.10, 95%CI (1.01-1.21)). Significantly higher intracranial bleeding risks in NOAC users were observed with SSRI/SNRIs (aHR 1.50, 95%CI (1.25-1.81)) and corticosteroids (aHR 1.49, 95%CI (1.21-1.84)). CONCLUSION: Concomitant use of PD interacting drugs, especially P2Y12 inhibitors and corticosteroids, was associated with higher major, gastrointestinal, urogenital, and other bleeding risks in NOAC-treated AF patients. Remarkably, higher intracranial bleeding risks were observed with SSRI/SNRIs and corticosteroids.

Comparing the risk of dementia in subjects with atrial fibrillation using non-vitamin K antagonist oral anticoagulants versus vitamin K antagonists: a Belgian nationwide cohort study.

BACKGROUND: Atrial fibrillation (AF) is associated with cognitive decline, with anticoagulated subjects potentially having a reduced risk compared with non-anticoagulated subjects. However, whether non-vitamin K antagonist oral anticoagulants (NOACs) may reduce the risk of dementia compared with vitamin K antagonists (VKAs) is unclear yet. Therefore, the risk of dementia was compared between AF subjects on NOACs versus VKAs. METHODS: AF subjects initiating anticoagulation between 2013 and 2019 were identified in Belgian nationwide data. Inverse probability of treatment weighted Cox regression was used to investigate cognitive outcomes. RESULTS: Among 237,012 AF subjects (310,850 person-years (PYs)), NOAC use was associated with a significantly lower risk of dementia (adjusted hazard ratio (aHR) 0.91, 95% confidence interval (CI) (0.85-0.98)) compared with VKAs. A trend towards a lower risk of vascular dementia (aHR 0.89, 95% CI (0.76-1.04)) and significantly lower risk of other/unspecified dementia (aHR 0.91, 95% CI (0.84-0.99)) were observed with NOACs compared with VKAs, whereas the risk of Alzheimer's disease was similar (aHR 0.99, 95% CI (0.88-1.11)). Apixaban (aHR 0.91, 95% CI (0.83-0.99)) and edoxaban (aHR 0.79, 95% CI (0.63-0.99)) were associated with significantly lower risks of dementia compared with VKAs, while risks were not significantly different with dabigatran (aHR 1.02, 95% CI (0.93-1.12)) and rivaroxaban (aHR 0.97, 95% CI (0.90-1.05)). Comparable risks of dementia were observed between individual NOACs, except for significantly lower risks of dementia (aHR 0.93, 95% CI (0.87-0.98)) and other/unspecified dementia (aHR 0.90 (0.84-0.97)) with apixaban compared with rivaroxaban. CONCLUSION: NOACs were associated with a significantly lower risk of dementia compared with VKAs, likely driven by apixaban and edoxaban use.

Determinants for under- and overdosing of direct oral anticoagulants and physicians' implementation of clinical pharmacists' recommendations.

AIMS: To analyse the appropriateness of direct oral anticoagulant (DOAC) dosing and determinants for under-and overdosing as well as acceptance and implementation rates of pharmacists' interventions. METHODS: Cross-sectional study in a tertiary hospital in hospitalized patients with atrial fibrillation on DOACs in 2019 (n = 1688). Primary outcome was the proportion of patients with inappropriate DOAC prescribing with identification of determinants for under-and overdosing. Secondary outcomes included acceptance and implementation rates of pharmacists' recommendations and determination of reasons for nonacceptance/nonimplementation. RESULTS: Inappropriate prescribing was observed in 16.9% of patients (n = 286) with underdosing (9.7%) being more prevalent than overdosing (6.9%). For all DOACs considered together, body weight<60 kg (odds ratio [OR] 0.46 [0.27-0.77]), edoxaban use (OR 0.42 [0.24-0.74]), undergoing surgery (OR 0.57 [0.37-0.87]) and being DOAC naïve (OR 0.45 [0.29-0.71]) were associated with significantly lower odds of underdosing. Bleeding history (OR 1.86 [1.24-2.80]) and narcotic use (OR 1.67 [1.13-2.46]) were associated with significantly higher odds for underdosing. Determinants with a significantly higher odds of overdosing were renal impairment (OR 11.29 [6.23-20.45]) and body weight<60 kg (OR 2.34 [1.42-3.85]), whereas dabigatran use (OR 0.24 [0.08-0.71]) and apixaban (OR 0.18 [0.10-0.32]) were associated with a significantly lower odds of overdosing compared to rivaroxaban. Physicians accepted the pharmacists' advice in 179 cases (79.2%) consisting of 92 (51.4%) recommendations for underdosing, 82 (45.8%) for overdosing and 5 (2.8%) for contraindications. CONCLUSION: Inappropriate DOAC prescribing remains common, although there is a slight improvement compared to our study of 2016. Clinical services led by pharmacists help physicians to reduce the number of inadequate prescriptions for high-risk medications such as DOACs.

Assessment of adherence, treatment satisfaction and knowledge of direct oral anticoagulants in atrial fibrillation patients.

AIMS: Direct oral anticoagulants (DOACs) are increasingly used for stroke prevention in atrial fibrillation. However, little is known about the association between medication adherence, patient satisfaction and treatment knowledge. The objective was to determine patients' DOAC adherence and their treatment satisfaction over time. Furthermore, we respectively investigated possible associations of treatment satisfaction and treatment knowledge in relation to adherence. METHODS: Longitudinal study conducted in atrial fibrillation patients hospitalized in 2019 in a tertiary university hospital. DOAC adherence, treatment satisfaction and knowledge were assessed with validated questionnaires. Mixed effects logistic regression was modelled to investigate the effect of both treatment satisfaction and knowledge on DOAC adherence over time. RESULTS: In total, 164 patients participated of whom 128 and 101 patients could be recontacted after a period of, respectively, 3 (first contact) and 6 months (second contact) to assess adherence and treatment satisfaction. Suboptimal adherence was observed in 40.6% of the patients after 3 months and in 42.6% after 6 months (P = .78). There was no significant difference (P = .29) in the total score for treatment satisfaction between the first (79.2%) and the second contact (80.6%). DOAC adherence was not affected by time (P = .71) nor by total knowledge score (P = .61) or treatment satisfaction score (P = .34). Nonetheless, a strong correlation between treatment satisfaction and knowledge was found (P = .004). CONCLUSION: DOAC adherence was suboptimal. Treatment satisfaction and knowledge were not associated with DOAC adherence over a 6-month period. Knowledge gaps were identified that could be remediated through patient education and follow-up.

Impact of P-glycoprotein and/or CYP3A4-interacting drugs on effectiveness and safety of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation: A meta-analysis.

AIMS: P-glycoprotein (P-gp) and CYP3A4-interacting drugs influence plasma levels of non-vitamin K antagonist oral anticoagulants (NOACs). However, the clinical relevance is questioned. Therefore, the impact of pharmacokinetically-interacting drugs on the effectiveness and safety of NOACs in patients with atrial fibrillation (AF) was investigated. METHODS: A meta-analysis was performed based on randomized controlled trials and observational studies retrieved from Pubmed and Embase that investigated the impact of concomitantly used P-gp/CYP3A4-interacting drugs on the risk-benefit profile of NOACs in AF patients. RESULTS: Fifteen studies were included, investigating 21 711 and 306 421 NOAC-treated AF patients with and without P-gp/CYP3A4 inhibitor use respectively, while only 1 study included P-gp/CYP3A4 inducers. In NOAC-treated AF patients, concomitant use of P-gp/CYP3A4 inhibitors was associated with significantly higher major bleeding (relative risk [RR] 1.10, 95% confidence interval [CI; 1.01-1.19]) and all-cause mortality risks (RR 1.14, 95%CI [1.05-1.23]) compared to not using P-gp/CYP3A4 inhibitors, while the risks of stroke/systemic embolism (RR 0.88, 95%CI [0.77-1.01]), intracranial bleeding (RR 0.89, 95%CI [0.68-1.15]) and gastrointestinal bleeding (RR 1.09, 95%CI [0.91-1.30]) were not significantly different. Concomitant use of amiodarone with NOACs was associated with lower thromboembolic (RR 0.75, 95%CI [0.61-0.92]), similar major bleeding (RR 0.92, 95%CI [0.80-1.07]) but higher mortality risks (RR 1.21, 95%CI [1.05-1.39]). Coadministration of verapamil or diltiazem was associated with higher major bleeding risks (RR 1.64, 95%CI [1.31-2.06]), but comparable thromboembolic (RR 1.10, 95%CI [0.75-1.61]) and mortality risks (RR 1.01, 95%CI [0.77-1.33]). CONCLUSION: Given the higher bleeding and mortality risks in NOAC-treated AF patients concomitantly using P-gp/CYP3A4 inhibitors, close monitoring is warranted.

Worldwide trends in oral anticoagulant use in patients with atrial fibrillation from 2010 to 2018: a systematic review and meta-analysis.

AIMS: Non-vitamin K antagonist oral anticoagulants (NOACs) are effective and safe alternatives compared with vitamin K antagonists (VKAs) for thromboembolic prevention in atrial fibrillation (AF), while antiplatelets are no longer recommended. However, to which extent NOAC introduction and guideline updates have increased OAC use in AF, is unclear. Therefore, worldwide trends in real-life prescribing of OACs, NOACs, VKAs, and antiplatelet monotherapy in AF patients were investigated. METHODS AND RESULTS: Using PubMed and Embase, observational nationwide cohort studies on annual prevalent and/or incident OAC use in non-selected AF patients since 2010 were included. A meta-analysis of single proportions was performed. Twenty-one studies were included assessing prevalent and incident use among 9 758 637 and 197 483 OAC-eligible AF patients, respectively. Worldwide prevalence and incidence of OAC users increased from 0.42 [95% confidence interval (CI) 0.22-0.65] and 0.43 (95% CI 0.37-0.49) in 2010 to 0.78 (95% CI 0.77-0.78) and 0.75 (95% CI 0.74-0.76) in 2018, respectively. Prevalent and incident NOAC users increased globally from 0 in 2010 to 0.45 (95% CI 0.45-0.46) and 0.68 (95% CI 0.67-0.69) in 2018, respectively, whereas prevalent and incident VKA use decreased from 0.42 (95% CI 0.22-0.65) and 0.42 (95% CI 0.36-0.49) in 2010 to 0.32 (95% CI 0.32-0.32) and 0.06 (95% CI 0.06-0.07) in 2018, respectively. Prevalent antiplatelet monotherapy use decreased from 0.37 (95% CI 0.32-0.42) in 2010 to 0.09 (95% CI 0.09-0.10) in 2018. CONCLUSION: The proportion of OAC users worldwide almost doubled following NOAC introduction. As one-quarter of OAC-eligible AF subjects were not anticoagulated and 9% were only treated with antiplatelets in 2018, there is still room for improvement.

Non-Vitamin K Antagonist Oral Anticoagulants (NOACs) Versus Warfarin in Patients with Atrial Fibrillation and (Morbid) Obesity or Low Body Weight: a Systematic Review and Meta-Analysis.

PURPOSE: Oral anticoagulants are crucial for preventing systemic thromboembolism in atrial fibrillation (AF), with guidelines preferring non-vitamin K antagonist oral anticoagulants (NOACs) over vitamin K antagonists (VKAs) in the general AF population. However, as NOACs are administered in fixed doses, concerns of unintentional underdosing in morbidly obese patients and unintentional overdosing in underweight patients have emerged. Therefore, a critical appraisal of the benefit-risk profile of NOACs in AF patients across the body weight spectrum is needed. METHODS AND RESULTS: After searching Medline, this systematic review discusses the impact of body weight on the risk-benefit profile of NOACs versus VKAs. The meta-analysis demonstrated that NOAC use in obese and class III obese AF patients (body mass index (BMI) ≥ 30 and ≥ 40 kg/m2, respectively) was associated with significantly lower stroke/systemic embolism (stroke/SE) risks (RR 0.82, 95%CI [0.71-0.96] and RR 0.75, 95%CI [0.64-0.87], respectively), similar to lower major bleeding risks (RR 0.83, 95%CI [0.69-1.00] and RR 0.74, 95%CI [0.57-0.95], respectively) and similar mortality risks (RR 0.92, 95%CI [0.73-1.15] and RR 1.17, 95%CI [0.83-1.64], respectively) compared to VKAs. In AF patients ≤ 60 kg, significantly lower stroke/SE (RR 0.63, 95%CI [0.56-0.71]) and major bleeding risks (RR 0.71, 95%CI [0.62-0.80]), but similar mortality risks (RR 0.68, 95%CI [0.42-1.10]), were observed for NOAC- versus VKA-treated patients. CONCLUSION: The benefit-risk profile of NOACs seems preserved in (morbidly) obese AF patients and patients with low body weight. However, more data are needed on underweight AF patients (BMI < 18.5 kg/m2) and on differences between NOACs in these patients.

Clinical Decision Support Systems for Drug Allergy Checking: Systematic Review.

BACKGROUND: Worldwide, the burden of allergies-in particular, drug allergies-is growing. In the process of prescribing, dispensing, or administering a drug, a medication error may occur and can have adverse consequences; for example, a drug may be given to a patient with a documented allergy to that particular drug. Computerized physician order entry (CPOE) systems with built-in clinical decision support systems (CDSS) have the potential to prevent such medication errors and adverse events. OBJECTIVE: The aim of this review is to provide a comprehensive overview regarding all aspects of CDSS for drug allergy, including documenting, coding, rule bases, alerts and alert fatigue, and outcome evaluation. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed as much as possible and searches were conducted in 5 databases using CPOE, CDSS, alerts, and allergic or allergy as keywords. Bias could not be evaluated according to PRISMA guidelines due to the heterogeneity of study types included in the review. RESULTS: Of the 3160 articles considered, 60 met the inclusion criteria. A further 9 articles were added based on expert opinion, resulting in a total of 69 articles. An interrater agreement of 90.9% with a reliability Κ=.787 (95% CI 0.686-0.888) was reached. Large heterogeneity across study objectives, study designs, study populations, and reported results was found. Several key findings were identified. Evidence of the usefulness of clinical decision support for drug allergies has been documented. Nevertheless, there are some important problems associated with their use. Accurate and structured documenting of information on drug allergies in electronic health records (EHRs) is difficult, as it is often not clear to healthcare providers how and where to document drug allergies. Besides the underreporting of drug allergies, outdated or inaccurate drug allergy information in EHRs poses an important problem. Research on the use of coding terminologies for documenting drug allergies is sparse. There is no generally accepted standard terminology for structured documentation of allergy information. The final key finding is the consistently reported low specificity of drug allergy alerts. Current systems have high alert override rates of up to 90%, leading to alert fatigue. Important challenges remain for increasing the specificity of drug allergy alerts. We found only one study specifically reporting outcomes related to CDSS for drug allergies. It showed that adverse drug events resulting from overridden drug allergy alerts do not occur frequently. CONCLUSIONS: Accurate and comprehensive recording of drug allergies is required for good use of CDSS for drug allergy screening. We found considerable variation in the way drug allergy are recorded in EHRs. It remains difficult to reduce drug allergy alert overload while maintaining patient safety as the highest priority. Future research should focus on improving alert specificity, thereby reducing override rates and alert fatigue. Also, the effect on patient outcomes and cost-effectiveness should be evaluated.

Determinants of medication use in a multi-ethnic population of pregnant women: a cross-sectional study.

OBJECTIVES: To investigate determinants of medication use among multi-ethnic pregnant women. METHODS: A total of 641 pregnant women participated in this cross-sectional study in a Brussels university hospital. A questionnaire was used to obtain data on socio-demographic characteristics and medication use. Chi-squared tests and binary logistic regression analyses were performed using SPSS 19. RESULTS: Medication use during pregnancy (37%) was positively associated with age older than 35 years, Western origin, being born in Belgium, high education and employment status. Highly educated Western women had a greater exposure to drugs with an unknown safety profile than Arab/Turkish and 'Other (non-Western) origins' women. In the latter two groups, low education and nulliparity were the most important determinants of lower drug use. Nulliparous Arab/Turkish women used significantly less medications (17%) during pregnancy than parous women with the same ethnic background (34%; p = 0.024). CONCLUSIONS: Medication use during pregnancy is considerable but differs according to ethnicity. Age, parity, educational level, occupational status and duration of stay in Belgium are important determinants that should be taken into account for risk assessment and preventive measures targeting pregnant women.

Impact of frailty on the effectiveness and safety of non-vitamin K antagonist oral anticoagulants (NOACs) in patients with atrial fibrillation: a nationwide cohort study.

AIMS: Data on non-vitamin K antagonist oral anticoagulants (NOACs) use in patients with atrial fibrillation (AF) and frailty are scarce. Therefore, the impact of frailty on AF-related outcomes and benefit-risk profiles of NOACs in patients with frailty were investigated. METHODS AND RESULTS: AF patients initiating anticoagulation between 2013 and 2019 were included using Belgian nationwide data. Frailty was assessed with the Claims-based Frailty Indicator. Among 254 478 anticoagulated AF patients, 71 638 (28.2%) had frailty. Frailty was associated with higher all-cause mortality risks [adjusted hazard ratio (aHR) 1.48, 95% confidence interval (CI) (1.43-1.54)], but not with thromboembolism or bleeding. Among subjects with frailty (78 080 person-years of follow-up), NOACs were associated with lower risks of stroke or systemic embolism (stroke/SE) [aHR 0.77, 95%CI (0.70-0.86)], all-cause mortality [aHR 0.88, 95%CI (0.84-0.92)], and intracranial bleeding [aHR 0.78, 95%CI (0.66-0.91)], a similar major bleeding risk [aHR 1.01, 95%CI (0.93-1.09)], and higher gastrointestinal bleeding risk [aHR 1.19, 95%CI (1.06-1.33)] compared with VKAs. Major bleeding risks were lower with apixaban [aHR 0.84, 95%CI (0.76-0.93)], similar with edoxaban [aHR 0.91, 95%CI (0.73-1.14)], and higher with dabigatran [aHR 1.16, 95%CI (1.03-1.30)] and rivaroxaban [aHR 1.11, 95%CI (1.02-1.21)] compared with VKAs. Apixaban was associated with lower major bleeding risks compared with dabigatran [aHR 0.72, 95%CI (0.65-0.80)], rivaroxaban [aHR 0.78, 95%CI (0.72-0.84)] and edoxaban [aHR 0.74, 95%CI (0.65-0.84)], but mortality risk was higher compared with dabigatran and edoxaban. CONCLUSION: Frailty was an independent risk factor of death. Non-vitamin K antagonist oral anticoagulants had better benefit-risk profiles than VKAs in patients with frailty, especially apixaban, followed by edoxaban.

The Impact of Polypharmacy on the Effectiveness and Safety of Non-vitamin K Antagonist Oral Anticoagulants in Patients with Atrial Fibrillation.

BACKGROUND: Polypharmacy may affect outcomes in patients with atrial fibrillation (AF) using non-vitamin K antagonist oral anticoagulants (NOACs) or vitamin K antagonists (VKAs) due to interactions or reduced adherence, but comparative data are lacking. Therefore, the impact of polypharmacy on AF-related outcomes and benefit-risk profiles of NOACs in patients with polypharmacy were investigated. METHODS: AF patients initiating anticoagulation between 2013 and 2019 were included using Belgian nationwide data. Inverse probability of treatment weighted Cox regression was used to investigate outcomes. RESULTS: Among 254,478 AF patients, 167,847 (66.0%) used ≥5 drugs. Polypharmacy was associated with higher stroke or systemic embolism (stroke/SE) (adjusted hazard ratio [aHR]: 1.08, 95% confidence interval [CI]: 1.02-1.15), all-cause mortality (aHR: 1.45, 95% CI: 1.40-1.50), and major bleeding risks (aHR: 1.29, 95% CI: 1.23-1.35). Among patients with polypharmacy, NOACs were associated with lower stroke/SE (aHR: 0.68, 95% CI: 0.63-0.73), all-cause mortality (aHR: 0.80, 95% CI: 0.77-0.84), major bleeding (aHR: 0.92, 95% CI: 0.87-0.97), and intracranial bleeding risks (aHR: 0.77, 95% CI: 0.69-0.85), but higher gastrointestinal bleeding risks (aHR: 1.10, 95% CI: 1.01-1.19) compared to VKAs. Major bleeding risks were lower with apixaban (aHR: 0.79, 95% CI: 0.74-0.85), but nonsignificantly different with other NOACs compared to VKAs. Lower major bleeding risks were observed with dabigatran (aHR: 0.91, 95% CI: 0.85-0.97) and apixaban (aHR: 0.77, 95% CI: 0.73-0.81) compared to rivaroxaban, and with apixaban compared to dabigatran (HR: 0.83, 95% CI: 0.77-0.90) and edoxaban (HR: 0.77, 95% CI: 0.70-0.85). CONCLUSION: Polypharmacy was associated with increased thromboembolic, bleeding, and mortality risks in AF patients. NOACs had better benefit-risk profiles than VKAs in patients with polypharmacy.

Development and partial validation of Be-CLIPSS: a classification system for hospital clinical pharmacy activities.

BACKGROUND: Documentation of drug related problems (DRPs) and pharmaceutical interventions (PIs) is essential for an objective evaluation of the pharmacist's contribution to pharmacotherapy. However, in Belgium, a nationally used classification system is not available, prohibiting structured and uniform documentation of DRPs and PIs. AIM: To develop and validate a national classification system for in-hospital clinical pharmacy activities, based on literature and field experience, specifically intended for routine registration. METHOD: Based on a literature review, a survey among Belgian hospital pharmacists and a stakeholder focus group, a first version of Be-CLIPSS (Belgian CLInical Pharmacy claSsification System) was developed. Inter-rater reliability of the DRPs and PIs was assessed. Additionally, its usability was reviewed. The system was further refined, followed by a second validation. RESULTS: Both the survey and focus group discussion revealed little use of validated DRP and PI classification systems in Belgium, although these were considered highly desirable if practical and minimally time-consuming. The final classification system encompassed seven clinical pharmacy activities, grouped into four activity classes. The inter-rater reliability for the second activity class was substantial for the DRPs (κ = 0.737) and almost perfect for the PIs (κ = 0.872). The interpretability (86.4%), user-friendliness (61.4%), user satisfaction (84.1%), interest for use in daily practice (68.2%) and difficulty in correctly classifying the DRP and PI (31.8%) were assessed. CONCLUSION: Be-CLIPSS, a newly developed and partially validated classification system for DRPs and PIs, was found to be user-friendly, with a good interpretability and user satisfaction, resulting in a high interest for use in daily practice.

A Retrospective Study Evaluating Guideline Adherence of Neonatal Parenteral Nutrition in a Belgian Neonatal Intensive Care Unit.

Introduction Clinical nutrition for preterm and critically ill neonates remains a challenge. Preterms are often hemodynamically and metabolically compromised, which limits infusion volumes of nutrients and hinders achieving recommended nutrient intakes. While guidelines provide recommended ranges for parenteral nutrition (PN) intakes, they generally recommend enteral nutrition as soon as possible. Thus, in clinical practice, gradually increasing EN intakes complicates assessments of PN guideline adherence. Via a pragmatic approach, we assessed adherence to PN recommendations for macronutrients and energy as stated in the 2018 guidelines of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN). Methods In this retrospective study, we assessed the nutrition of preterm and critically ill term neonates from the neonatal intensive care unit of the University Hospital Brussels. We analyzed intakes for the first week of life, in which critically ill neonates at our center usually receive the majority of nutrients via PN. The PN-based provision of macronutrients and energy was analyzed descriptively in relation to the ESPGHAN 2018 recommendations. Results Macronutrients and energy provision gradually increased until they reached recommended or targeted values. Compared to term neonates, energy and lipid provision for preterms increased faster, while amino acid provision exceeded the ESPGHAN 2018 recommendations. Conclusions This study adds clinical practice data to the severely understudied field of the ESPGHAN 2018 PN guideline compliance. Using a pragmatic assessment of our nutrition protocols, we found the need to reduce the amount of amino acids per kg body weight per day to meet guideline recommendations.

Rhinitis Control and Medication Use in a Real-World Sample of Patients With Persistent Rhinitis or Rhinosinusitis: A Community Pharmacy Study.

BACKGROUND: Little is known about rhinitis control in real-life, nor about the contribution of treatment-related and patient-related factors. OBJECTIVE: This study aimed to examine the level of rhinitis control and rhinitis medication utilization in patients with persistent rhinitis and to identify predictors of rhinitis control. METHODS: A cross-sectional observational study was conducted in patients with persistent rhinitis recruited in community pharmacies. Participants completed the Rhinitis Control Assessment Test, a questionnaire on patient/rhinitis characteristics, and rhinitis medication use. A visual analog scale for nasal symptoms was also completed. Pharmacy dispensing data were used to calculate adherence to intranasal glucocorticoids. Nasal spray technique was evaluated using a standardized checklist. Predictors of rhinitis control were explored using a linear regression model. RESULTS: A total of 1,514 patients, recruited in 215 pharmacies, participated in the study (mean age 48.7 y, 62% female). Almost 60% exhibited suboptimal rhinitis control (Rhinitis Control Assessment Test ≤ 21 of 30). A 50-mm cut-off on the visual analog scale yielded 78.1% sensitivity to identify suboptimal rhinitis control. Participants most frequently used intranasal glucocorticoids (55.6%) and intranasal decongestants (47.4%). Only 10.3% of current nasal spray users demonstrated perfect technique. More than half (54.8%) of glucocorticoid users were identified as underadherent. Female sex, self-reported nasal hyperreactivity, active asthma, and use of oral/intranasal decongestants or nasal saline were identified as predictors of worse rhinitis control. CONCLUSIONS: Suboptimal rhinitis control was common in this real-life sample of persistent rhinitis patients. Improving use of rhinitis medication may be key to increase disease control.

Medication Review: What's in a Name and What Is It about?

BACKGROUND: Medication review is a multifaceted service aimed at optimizing the use of medicines and enhancing the health outcomes of patients. Due to its complexity, it is crucial to clearly describe the service, its variants, and its components to avoid confusion and ensure a better understanding of medication review among healthcare providers. AIM: This study aims to bring clarity to the origins, definitions, abbreviations, and types of medication reviews, together with the primary criteria that delineate key features of this service. METHOD: A narrative review approach was employed to clarify the diverse terminology associated with "medication review" services. Relevant references were initially identified through searches on PubMed and Google Scholar, complementing the existing literature known to the authors. RESULTS: The study uncovers a complicated and sometimes convoluted history of "medication review" in different regions around the world. The initial optimization of medicine use had an economic purpose before evolving subsequently into a more patient-oriented approach. A selection of abbreviations, definitions, and types were outlined to enhance the understanding of the service. CONCLUSIONS: The study underscores the urgent need for comprehensive information and standardization regarding the content and quality of the services, collectively referred to as "medication review".

Retrospective analysis of gastrointestinal bleedings with direct oral anticoagulants reported to EudraVigilance.

Direct oral anticoagulants (DOACs) are increasingly used and are an important cornerstone in antithrombotic therapy. Adverse drug reactions (ADRs) such as bleedings have only partially been investigated during clinical trials. The primary goal was to analyse pharmacovigilance data based on spontaneous reports of gastrointestinal (GI) bleedings with DOACs reported to EudraVigilance. A second goal was to compare GI safety profiles between DOACs based on these signals. All DOAC related GI bleedings mentioned in individual case safety reports (ICSRs) from 2012 till 2017 in the European Economic Area were classified in four GI categories based on the reported site of occurrence of the haemorrhage. Age group and gender of the patient, seriousness and ADR outcome, and the reporter's qualification were assessed per category and per DOAC. Disproportionality analyses were performed to evaluate whether or not the reported ADRs were more prevalent with a given DOAC. ICSRs were bleeding-related in about half of the cases (n = 28,992/53,471). Of these bleedings, >25% was GI-related. Most patients experiencing GI bleedings were between 65 and 85 years old, with no obvious differences between men and women. Stomach, ulcer-related duodenal, and rectal bleedings were the most reported GI bleedings with a fatal outcome in 5.8%, 7.5%, and 9.8% of the cases for rivaroxaban, apixaban, and dabigatran, respectively. The disproportionality data suggest that dabigatran is more frequently involved in GI bleeding events than the other DOACs. DOACs were significantly associated with GI bleedings. Although the data should be interpreted with caution, it seems that dabigatran was associated more often than other DOACs with GI bleedings based on the analysis of spontaneous pharmacovigilance reports.

Long-term comparative effectiveness and safety of dabigatran, rivaroxaban, apixaban and edoxaban in patients with atrial fibrillation: A nationwide cohort study.

Background: Although non-vitamin K antagonist oral anticoagulants (NOACs) are recommended over vitamin K antagonists (VKAs) in atrial fibrillation (AF) management, direct long-term head-to-head comparisons are lacking. Therefore, their risk-benefit profiles were investigated compared to VKAs and between NOACs. Methods: AF patients initiating anticoagulation between 2013-2019 were identified in Belgian nationwide data. Inverse probability of treatment weighted Cox regression was used to investigate effectiveness and safety outcomes and were additionally stratified by NOAC dose. Results: Among 254,478 AF patients (328,796 person-years of follow-up), NOACs were associated with significantly lower risks of stroke or systemic embolism (stroke/SE) (hazard ratio (HR) 0.68, 95% confidence interval (CI) (0.64-0.72)), all-cause mortality (HR 0.76, 95%CI (0.74-0.79)), major or clinically relevant non-major bleeding (MB/CRNMB) (HR 0.94, 95%CI (0.91-0.98)) and intracranial hemorrhage (HR 0.73, 95%CI (0.66-0.79)), but non-significantly different risks of myocardial infarction, gastrointestinal and urogenital bleeding compared to VKAs. Despite similar stroke/SE risks, dabigatran and apixaban were associated with significantly lower MB/CRNMB risks compared to rivaroxaban (HR 0.86, 95%CI (0.83-0.90); HR 0.86, 95%CI (0.83-0.89), respectively) and edoxaban (HR 0.91, 95%CI (0.83-0.99); HR 0.86, 95%CI (0.81-0.91), respectively), and apixaban with significantly lower major bleeding risks compared to dabigatran (HR 0.86, 95%CI (0.80-0.92)) and edoxaban (HR 0.79, 95%CI (0.72-0.86)). However, higher mortality risks were observed in some risk groups including with apixaban in patients with diabetes or concomitantly using digoxin compared to dabigatran and edoxaban, respectively. Conclusion: NOACs had better long-term risk-benefit profiles than VKAs. While effectiveness was comparable, apixaban was overall associated with a more favorable safety profile followed by dabigatran.