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.

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.

Association of conflicting information from healthcare providers and poor shared decision making with suboptimal adherence in direct oral anticoagulant treatment: A cross-sectional study in patients with atrial fibrillation.

OBJECTIVE: To assess direct oral anticoagulant (DOAC) adherence and to determine possible determinants for suboptimal adherence in Dutch patients with atrial fibrillation (AF). METHODS: Cross-sectional study of DOAC users who completed a self-reported questionnaire. Adherence was measured with Morisky8-item Medication Adherence Scale (MMAS-8). Logistic regression analysis was conducted to investigate determinants affecting adherence. RESULTS: 398 DOAC users completed the questionnaire (mean age 70.6 ± 9.2years). Approximately one in four patients had suboptimal adherence (MMAS-8 < 8). Multivariable analysis showed that patients who felt to have received conflicting information about the treatment, patients with higher educational level and patients who were not sufficiently involved in the treatment choice had a higher odds of suboptimal adherence. CONCLUSION: DOAC adherence was suboptimal. Conflicting information received from different healthcare providers (HCPs), lack of shared decision making and the patients' educational level were determinants negatively affecting DOAC adherence. PRACTICE IMPLICATIONS: Efforts towards identifying suboptimally adherent DOAC patients are needed since they are at higher risk to develop thromboembolic events. Adherence counselling should be systematically and repeatedly encouraged and shared decision making should become more mainstream. Moreover, reinforced education of both patients and HCPs combined with interprofessional collaboration are potential solutions to prevent knowledge gaps and communication of conflicting information.

Community pharmacy-based study of adherence to non-vitamin K antagonist oral anticoagulants.

OBJECTIVE: This study aimed to assess implementation adherence (how well the patient's actual intake matches the prescribed dosing regimen) to non-vitamin K antagonist oral anticoagulants (NOACs) and to explore experiences with and beliefs about NOACs in a real-world sample of long-term NOAC users. METHODS: A cross-sectional observational study was conducted in home-dwelling adults who started taking a NOAC at least 1 year prior to inclusion. Pharmacy dispensing data were used to calculate the Medication Possession Ratio (MPR). Patients were recruited in 158 community pharmacies in Flanders, Belgium. They completed a questionnaire collecting basic characteristics and exploring self-reported adherence to NOACs (using the Medication Adherence Report Scale, MARS) and experiences with and beliefs about NOACs (using the Beliefs about Medicines Questionnaire, BMQ). RESULTS: A total of 766 patients (mean age 76.2±8.8 years, median CHA2DS2-VASc score 4 (IQR=3-4)) were included. The majority (93.5%) used NOAC for stroke prevention in atrial fibrillation. The median MPR was 95.2% (IQR=87.8-99.7) which corresponds with half of the study population not taking their NOAC on at least 17 cumulative days per year. Almost 21% of participants reported non-adherence on the MARS (score <25), with unintentional non-adherence (forgetfulness) most frequently reported (15.4%). Although two-thirds of NOAC users indicated to experience adverse drug reactions, the BMQ demonstrated a positive attitude towards NOAC therapy, where necessity beliefs outweigh the concerns. CONCLUSIONS: Our data indicate that long-term NOAC users have high implementation adherence and a positive attitude towards NOAC therapy. However, taking into account patients' thromboembolic risk and NOACs' short half-lives, further optimisation of NOAC use seems warranted in this population.

Appropriateness of DOAC Prescribing Before and During Hospital Admission and Analysis of Determinants for Inappropriate Prescribing.

Background and Objectives: Appropriate dosing of direct oral anticoagulants (DOACs) is required to avoid under- and overdosing that may precipitate strokes or thromboembolic events and bleedings, respectively. Our objective was to analyze the appropriateness of DOAC dosing according to the summaries of product characteristics (SmPC). Furthermore, determinants for inappropriate prescribing were investigated. Methodology: Retrospective cohort study of hospitalized patients aged ≥60 years with at least one DOAC intake during hospital stay. Descriptive analyses were used to summarize the characteristics of the study population. Chi-square test was used to evaluate differences between DOACs. Binary logistic regression analysis was performed to assess determinants for inappropriate prescribing. Results: For the 772 included patients, inappropriate dosing occurred in 25.0% of hospitalizations with 23.4, 21.9, and 29.7% for dabigatran, rivaroxaban, and apixaban, respectively (p = 0.084). Underdosing was most prevalent for apixaban (24.5%) compared to dabigatran (14.0%) and rivaroxaban (12.8%), p < 0.001. In 67.1% (apixaban), 26.7% (dabigatran), and 51.2% (rivaroxaban) of underdosed DOAC cases according to the SmPC, the dose would be considered appropriate according to the European Heart Rhytm Association (EHRA) guidelines. Overdosing was observed in 4.5% (apixaban), 4.7% (dabigatran), and 7.7% (rivaroxaban) of patients. For all DOACs, our analysis showed an age ≥80 years (p = 0.036), use of apixaban (p = 0.026), DOAC use before hospitalization (p = 0.001), intermediate renal function (p = 0.014), and use of narcotic analgesics (p = 0.019) to be associated with a higher rate of inappropriate prescribing. Undergoing surgery was associated with a lower odds of inappropriate prescribing (p = 0.012). For rivaroxaban, use of medication for hypothyroidism (p = 0.027) and the reduced dose (p < 0.001) were determinants for inappropriate prescribing. Treatment of venous thromboembolism was associated with less errors (p = 0.002). For apixaban, severe renal insufficiency (p < 0.001) and initiation in hospital (p = 0.016) were associated with less and the reduced dose (p < 0.001) with more inappropriate prescribing. No determinants were found in the dabigatran subgroup. Conclusions: Inappropriate DOAC prescribing is frequent with underdosing being the most common drug related problem when using the SmPC as reference. More appropriate prescriptions were found when taking the EHRA guidelines into account. Analysis of determinants of inappropriate prescribing yielded insights in the risk factors associated with inappropriate DOAC prescriptions.