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Introduction: Anti-Xa serves as a clinical surrogate for assessing the efficacy and bleeding risk in patients treated with enoxaparin for thromboembolic events. Evidence from the literature and empirical observations suggest that patients are underdosed in clinical practice to avoid bleeding complications. This study aimed to investigate such underdosing of enoxaparin and its potential impact on achieving therapeutic anti-Xa levels. Methods: This multicentric, retrospective, observational study included patients with acute ischemic stroke due to atrial fibrillation. All patients received enoxaparin in the therapeutic setting with subsequent anti-Xa measurements. The one-sample, one-tailed Wilcoxon signed-rank test was used to identify a significant difference between the doses administered and the recommended daily dose. Logistic regression model analysis was performed to identify additional predictors affecting achievement of the therapeutic anti-Xa target range. Stepwise forward-backward selection with Akaike's information criterion as metric was applied to refine the logistic regression model. Results: A total of 145 patients from the university hospitals of St. Pölten and Tulln in Lower Austria were included. The median daily enoxaparin dose administered was 1.23 mg/kg, resulting in an overall target range achievement rate of 66%. As compared to recommended therapeutic doses, significant underdosing of enoxaparin was evident in both participating centers (p < 0.001). The calculated threshold dose to achieve the therapeutic target range with a 90% probability was 1.5 mg/kg enoxaparin daily. Female sex was found to be a strong independent predictor of achieving a therapeutic target range (OR 9.44; 95% CI 3.40-30.05, p < 0.001). Conclusion: Despite the underdosing observed in both centers, therapeutic anti-Xa levels were achieved with lower than recommended doses of enoxaparin, and women required even lower doses than men. These findings warrant further confirmation by prospective studies. [ABSTRACT FROM AUTHOR]

IntroductionAnti-Xa serves as a clinical surrogate for assessing the efficacy and bleeding risk in patients treated with enoxaparin for thromboembolic events. Evidence from the literature and empirical observations suggest that patients are underdosed in clinical practice to avoid bleeding complications. This study aimed to investigate such underdosing of enoxaparin and its potential impact on achieving therapeutic anti-Xa levels.MethodsThis multicentric, retrospective, observational study included patients with acute ischemic stroke due to atrial fibrillation. All patients received enoxaparin in the therapeutic setting with subsequent anti-Xa measurements. The one-sample, one-tailed Wilcoxon signed-rank test was used to identify a significant difference between the doses administered and the recommended daily dose. Logistic regression model analysis was performed to identify additional predictors affecting achievement of the therapeutic anti-Xa target range. Stepwise forward-backward selection with Akaike’s information criterion as metric was applied to refine the logistic regression model.ResultsA total of 145 patients from the university hospitals of St. Pölten and Tulln in Lower Austria were included. The median daily enoxaparin dose administered was 1.23 mg/kg, resulting in an overall target range achievement rate of 66%. As compared to recommended therapeutic doses, significant underdosing of enoxaparin was evident in both participating centers (p < 0.001). The calculated threshold dose to achieve the therapeutic target range with a 90% probability was 1.5 mg/kg enoxaparin daily. Female sex was found to be a strong independent predictor of achieving a therapeutic target range (OR 9.44; 95% CI 3.40–30.05, p < 0.001).ConclusionDespite the underdosing observed in both centers, therapeutic anti-Xa levels were achieved with lower than recommended doses of enoxaparin, and women required even lower doses than men. These findings warrant further confirmation by prospective studies.

Background: Information on inappropriate dosing of direct oral anticoagulants (DOACs) is scarce in the Australian context. Aim: To describe the prevalence and potential predictors of inappropriate dosing of DOACs. Methods: Patients who received DOACs during admission under a general medical unit over a 2‐year period (from January 2017 to December 2018) were retrospectively studied. Appropriateness of the dosing regimen was verified against the recommendations of the Therapeutic Goods Administration of Australia. Data were obtained from medical records and analysed in univariate and multivariate logistic regression models. The variables associated with under‐ and overdosing were also determined. Results: A total of 203 (mean age 71.6 ± 14.5 years, females 52%) patients were studied. Inappropriate dosing occurred in 44 (22%) patients: underdosing 27 (13%) and overdosing 17 (8%). Age ≥75 years (P < 0.01), lower estimated creatinine clearance (CrCl) (P < 0.01), prescription of DOAC prior to index admission (P < 0.01) and higher Charlson Comorbidity Index (P < 0.01), HAS‐BLED (P < 0.01) and CHA2DS2‐VASc (P < 0.01) scores had a significant univariate association with inappropriate dosing. However, in the multivariate logistic regression only lower CrCl (odds ratio (OR) 1.04, 95% confidence interval (CI): 1.01–1.07, P < 0.01) and prescription of DOAC prior to index admission (OR 2.62, 95% CI: 1.01–6.75, P = 0.047) remained significantly associated with inappropriate dosing. Impaired renal function also had a significant association with underdosing (OR 1.04, 95% CI: 1.01–1.07, P = 0.01) and borderline significance with overdosing (OR 1.03, 95% CI: 1.00–1.07, P = 0.06). Conclusion: Inappropriate dosing of DOACs, especially underdosing, is common in clinical practice. Clinicians should exercise due diligence when prescribing DOACs to patients with renal impairment and in outpatient settings. [ABSTRACT FROM AUTHOR]

Background and purpose: The optimal stereotactic ablative radiotherapy (SABR) doses for adrenal tumors are unknown. Some trials have specified that organ at risk (OAR) dose constraints should take priority over target coverage. We performed a retrospective review of the outcomes of MR-guided adrenal SABR (MRgRT) delivered with OAR sparing. Materials and methods: Patients who underwent adrenal MRgRT between 2016 and 2023 were identified from our Ethics-approved institutional database. Dose ranged between 8 and 24 Gy per fraction, delivered in 1–5 fractions. A 3 mm margin was added to the breath-hold gross tumor volume (GTV) to derive a PTV. Plan were delivered to an ‘optimized’ PTV that was generated by excluding any overlap with OARs. Results: Adrenal SABR was performed in 107 patients (114 metastases). The commonest scheme used 5 fractions of 10 Gy (53.5 %); 82 % of plans delivered a BED10 ≧ 80 Gy. Systemic therapy was administered within 3 months preceding or following SABR in 53.5 % of patients. Grade 3 acute toxicity (CTCAE v5.0) occurred in 0.9 % of patients, and 4.4 % reported late toxicity, consisting of adrenal insufficiency and a vertebral collapse. Median follow-up was 13.8 months (range, 0.0–73.4 months). Local progression occurred in 7.4 % of evaluable patients. PTV underdosage was frequent, with a coverage compromise index (D99/prescription dose) of

Background: Underdoses of direct oral anticoagulants (DOAC) are sometimes prescribed due to bleeding risk concerns in patients with atrial fibrillation (AF). We investigated the prevalence of DOAC underdosing and its impact on clinical outcomes in AF patients undergoing percutaneous coronary intervention (PCI)., Methods and Results: This multicenter observational cohort study enrolled patients with AF on DOAC undergoing PCI between January 2015 and March 2021 at 15 institutions across Japan. Clinical outcomes within 1 year, including major adverse cardiovascular events (MACE), all-cause mortality, ischemic stroke, and major bleeding events, were evaluated. Of 623 patients enrolled, 167 (26.8%) received underdoses, 224 (36.0%) received appropriate low doses, 210 (33.7%) received appropriate standard doses, and 22 (3.5%) received overdoses. Clinical outcomes were compared between patients with underdoses (n=167) and appropriate doses (n=434). Although the incidence of MACE, all-cause mortality, and major bleeding events did not differ significantly between the 2 groups (log-rank P=0.850, P=0.163, and P=0.711, respectively), ischemic stroke occurred more frequently in the underdose than appropriate-dose group (log-rank P=0.011). After propensity score matching, the same result was observed for the frequency of ischemic stroke (log-rank P=0.026)., Conclusions: Compared with appropriate doses of DOAC, DOAC underdosing was associated with a higher incidence of ischemic stroke, despite no significant difference in MACE, all-cause mortality, and major bleeding events in AF patients undergoing PCI.

Background: Although several meta‐analyses have examined the effects of off‐label underdosing of nonvitamin K antagonist oral anticoagulants (NOACs) compared with their recommended doses in patients with atrial fibrillation (AF), they combined different kinds of NOACs in their primary analyses. Herein, we first conducted a meta‐analysis to separately assess the effects of off‐label underdosing versus on‐label dosing of four individual NOACs on adverse outcomes in the AF population. Methods: The PubMed and Embase database were systemically searched until November 2021 to identify the relevant studies. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were pooled by utilizing a random‐effects model. Results: A total of nine studies with 144,797 patients taking NOACs were included in the meta‐analysis. In the pooled analysis, off‐label underdosing of rivaroxaban was related to an increased risk of stroke or systemic embolism (HR = 1.31, 95% CI 1.05–1.63; p =.02), whereas off‐label underdosing of apixaban was associated with a higher risk of all‐cause death (HR = 1.21, 95% CI 1.05–1.40; p =.01). When comparing off‐label underdosing versus on‐label dosing of dabigatran or edoxaban, no differences were found in the primary and secondary clinical outcomes. Conclusion: Off‐label underdosing of rivaroxaban may increase the risk of stroke or systematic embolism, whereas off‐label underdosing of apixaban may heighten the incidence of all‐cause death. [ABSTRACT FROM AUTHOR]

Background Direct oral anticoagulants (DOACs) are effective in reducing the stroke risk for patients with nonvalvular atrial fibrillation if prescribed at the labeled dose, yet underdosing is frequent. Little is known about clinician knowledge and patient or clinician preferences for DOAC dosing. Methods and Results From April 2019 to March 2020, 240 clinicians and 343 patients with atrial fibrillation completed an assessment of anticoagulation knowledge/preferences. Clinician knowledge of DOAC dosing was tested with 4 hypothetical patient scenarios. Patients and clinicians were asked to grade the importance of 25 factors in anticoagulation decision making. Among clinicians, the median age was 55 years, and 23% were primary care clinicians. In scenarios of a patient indicated for full‐dose DOAC, 41.2% of clinicians underdosed apixaban and 17.6% underdosed rivaroxaban. In scenarios of a patient indicated for reduced‐dose DOAC, 64.6% and 71.7% of clinicians chose to use reduced‐dose apixaban and rivaroxaban, respectively. Only 35.0% of clinicians correctly answered all 4 scenarios with the label‐indicated dose; this knowledge gap was similar between clinicians who did and did not underdose. Among patients with atrial fibrillation, the median age was 65 years, and 89% were currently anticoagulated. Patients and clinicians ranked stroke prevention and avoiding severe bleeding as very important to anticoagulation decision making. Patients were more likely than clinicians to rank the ability to reduce anticoagulation dose if needed as very important (70.5% versus 43.6%; P

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. We assessed the frequency of label adherence of NOAC dosing among AF patients and the associations between off‐label NOAC dosing and clinical outcomes. Methods and Results We evaluated 53 649 AF patients treated with an NOAC using Korean National Health Insurance Service database during the period from 2013 to 2016. NOAC doses were classified as either underdosed or overdosed, consistent with Korea 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. Overall, 16 757 NOAC‐treated patients (31.2%) were underdosed, 4492 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 (aged 71±8 and 75±7 years versus 70±9 years, respectively; P

The approved dose of oral anticoagulant rivaroxaban for patients with non-valvular atrial fibrillation (NVAF) in Japan is 15 mg once daily (od) in patients whose creatinine clearance is ≥ 50 mL/min, but recent real-world studies have demonstrated that these patients often received less than the recommended dose due to bleeding concerns. The effect of under-dosing on safety and effectiveness outcomes remains unclear. We used 1-year follow-up data from the XAPASS, a real-world Japanese prospective, single-arm, observational study. Of the 11,308 patients, 6521 patients who completed a 1-year follow-up and had a creatinine clearance ≥ 50 mL/min were included in this sub-analysis. Primary endpoints were any bleeding and a composite of stroke/non-central nervous system systemic embolism (non-CNS SE)/myocardial infarction (MI). Among the 6521 patients, 4185 (64.2%; mean CHADS2 score: 1.8) received the 15 mg od (recommended dose), whereas 2336 (35.8%; mean CHADS2 score: 2.3) received 10 mg od (under-dose). After adjusting for patient characteristics by propensity scoring and inverse probability of treatment weighting, incidence rates of major bleeding were comparable between under-dosed patients and patients who received the recommended dose (1.34 vs. 1.63 events/100 patient-years, p = 0.197), although the incidence rates of stroke/non-CNS SE/MI were higher in under-dosed patients than in those who received the recommended dose (2.15 vs. 1.48 events/100 patient-years, p = 0.009). In Japanese clinical practice, some NVAF patients receive rivaroxaban doses inconsistent with the recommendation. Considering the total clinical benefit, the recommended dose may be preferable in terms of balance of safety and effectiveness. Clinicaltrials.gov NCT01582737. [ABSTRACT FROM AUTHOR]

This work aims to evaluate the tranquilization, the hematological and the physiological parameters of domestic cats undergoing pharmacupuncture with acepromazine maleate. Seven animals received 5% of the dose of the drug indicated for this species in acupoint Yintang (GI) and seven (GII) received the same dose intramuscularly. The reassurance was assessed using a scale adapted from Dobbins et al. (2002). The GI group demonstrated that 71.43% of the animals presented drowsiness and projection of the third eyelid and 28.47% were less active. In GII group, 14.28% of cats were less active and 85.72% demonstrated were unchanged. About the hematologicals changing, the two groups demonstrated a slight increase of leukocytes, in GI decreased hematocrit and erythrocytes. According to physiological parameters, GI presented decrease rectal temperature and increase in respiratory rate. There were no significant changes on the heart rate and systolic blood pressure in any cat. In GII, occurred a decrease in diastolic blood pressure. The pharmacupunture showed effectiveness in cats tranquilization, besides clinical safety

Background: Following the recommended guidelines is crucial for achieving patient remission in rheumatoid arthritis. The aim of this study was to assess the effect of proper drug utilization of antirheumatic drugs on disease activity and drug safety in Jordan. Methods: In a retrospective cross-sectional study, patient's demographics, clinical variables, drug regimens and side effects were recorded and the 28-joint disease activity scores were calculated. Patients were stratified into high, moderate, low disease activity or remission group. Results: Around 80% of patients were using methotrexate which was under-dosed in 82% of them. Only 25% were using biologic drugs. Surprisingly, only 10% of patients had low disease activity and only 4% were in a remission state. Anaemia (32.3%) and mild renal impairment (27.6%) were the most common side effects. Conclusions: The low frequency of well-controlled disease activity is interpreted by high occurrence of methotrexate underdosing and biologic agent underprescription. Implementing the role of a clinical pharmacist could have a real impact on tight control of such disease issues in Jordan. [ABSTRACT FROM AUTHOR]

Direct oral anticoagulants (DOACs) have a favourable risk-benefit profile compared to vitamin K-antagonists (VKAs) in atrial fibrillation (AF). Dosing is based on age, weight and renal function, without need of routine monitoring. In two prospective, multicentre AF cohorts (Swiss-AF, BEAT-AF) patients were stratified as receiving VKAs or adequately-, under- or overdosed DOACs, according to label. Primary outcome was a composite of major adverse clinical events (MACE), defined as cardiovascular death, myocardial infarction (MI), ischaemic stroke and systemic embolism. Secondary outcomes included major bleeding. Adjustment for confounding was performed. Median follow-up was 4 years. Of 3236 patients, 1875 (58%) were on VKAs and 1361 (42%) were on DOACs, of which 1137 (83%) were adequately-, 134 (10%) over- and 90 (7%) under-dosed. Compared to adequately dosed individuals, overdosed patients were more likely to be older and female. Underdosing correlated with concomitant aspirin therapy and coronary artery disease. Both groups had higher CHA 2 DS 2 -VASc scores. Patients on overdosed DOACs had higher incidence of MACE (HR 1.75; CI 1.10–2.79; adjusted-HR: 1.22) and major bleeding (HR 1.99; CI 1.14–3.48; adjusted-HR: 1.51). Underdosing was not associated with a higher incidence of MACE (HR 0.94; CI 0.46–1.92; adjusted-HR 0.61) or major bleeding (HR 1.07; CI 0.46–2.46; adjusted-HR 0.82). After adjustment, all CIs crossed 1.0. Inappropriate DOAC-dosing was more prevalent in multimorbid patients, but did not correlate with higher risks of adverse events after adjusting for confounders. DOAC prescription should follow label. [ABSTRACT FROM AUTHOR]

Introduction: Body surface area (BSA)-based dosing of 5-fluorouracil (5-FU) results in marked inter-individual variability in drug levels, whereas determination of plasma 5-FU concentration and area under the curve (AUC) is a more precise dosing method but has not been integrated into clinical routine. We conducted a multicenter, prospective study to study 5-FU AUC distributions and assess clinical factors predicting therapeutic dosing in patients receiving BSA-dosed 5-FU., Methods: Between June 2017 and January 2018, a total of 434 patients receiving continuous, infusional BSA-dosed 5-FU from 37 sites in Germany were included. Plasma 5-FU concentration and AUC were measured in venous blood samples at steady state. The primary objective was to determine 5-FU AUC distributions in relation to the target range, which is defined as 20-30 mg × h/l. The second objective was to explore clinical parameters that correlate with achievement of 5-FU AUC target range., Results: The primary tumor was mainly located in the gastrointestinal tract (96.3%), with colorectal cancer being the most common (71.2%) tumor entity. 5-FU was administered as monotherapy (8.1%) or as part of FOLFOX (33.2%), FOLFIRI (26.3%), or other regimens (12.4%). Treatment setting was adjuvant (31.3%) or metastatic (64.5%). The median AUC was 16 mg × h/l. Only 20.3% of patients received 5-FU treatment within the target range, whereas the majority of patients (60.6%) were underdosed and 19.1% of patients were overdosed. In the univariate logistic regression, treatment setting was the only clinical parameter that significantly correlated with achievement of the target range. Patients treated in the metastatic setting had a 2.1 (95% confidence interval 1.186-3.776, P = 0.011) higher odds to reach the target range compared with patients treated in the adjuvant setting., Conclusions: The majority of patients received suboptimal doses of 5-FU using BSA dosing. Therapeutic drug monitoring of 5-FU is an option for optimized individualized cancer therapy and should be integrated into the clinical practice., Competing Interests: Disclosure RDH has received honoraries for lectures and/or ad hoc advisory boards from Amgen, Astra-Zeneca, Bayer, Bristol Myers Squibb, Daiichi, Leo Pharma GmbH, Lilly, medac, Merck KGaA, Merck Sharp & Dohme, Nordic, Pierre-Fabre, Roche, Saladax, Sanofi, and Servier. MK has served on advisory boards for Novartis, BeiGene, Janssen, and Alexion. All other authors have declared no conflicts of interest. Data sharing The data that support the findings of this study are available from the corresponding author upon reasonable request., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: The aim of this study was to evaluate the current use of antibiotics by Swiss equine veterinarians and to compare the results with a similar study from 2013 before the introduction of the web tool Antibiotic Scout. The survey was sent to equine veterinarians according to the member database of the Swiss Veterinary Association (GST, SVS). The demographic data of the respondents and their antibiotics usage were collected. In addition, six different case scenarios were presented with questions to their potential antibiotic usage, active substance/preparation and the dosing scheme. The dosage provided was compared with the dosage information approved by Swissmedic in the information for healthcare professionals and the recommendations of the antibiotic scout. A backward logistic regression analysis was performed to assess the association between different aspects of antibiotic use and demographic data. The response rate was 94/739 (13 %), 22 of the 94 (23 %) had also participated in the 2013 study. 47/94 (50 %) of the respondents obtained their information from the antibiotic scout. The respondents indicated that they used an antibiotic in 16 %-88 % depending on the case scenario. Neither 3rd nor 4th generation cephalosporins or fluoroquinolones were used in the case scenarios. Dihydrostreptomycin was indicated as a possible antibiotic in a case scenario by 14/94 (15 %) of the respondents. Respondents who had already taken part in the 2013 survey used dihydrostreptomycin significantly more frequently (7/22, 32 % vs. 7/72, 10 %; p = 0,047). 29/81 (36 %) had underdosed compared to the prescribing information and 38/81 (47 %) compared to the antibiotic scout; neither was associated with demographic data. The use of non-equine-licensed antimicrobial products was directly related to the number of veterinarians in the practice (p = 0,007) and to the percentage of horses (p = 0,02). No association between demographics and peri-operative antibiotic use >24h (17/44, 39 %) was detected. The antibiotic prescribing habits of Swiss equine veterinarians have improved over the last 10 years. The antibiotic use decreased compared to the study of Schwechler et al. in 2013 by 0-16 % depending on the case scenario. The use of 3rd and 4th generation cephalosporins was reduced by 4 % and fluoroquinolones by 7 %. Underdosing according to scientific recommendations was reduced by 32 %. Furthermore, there is a need for additional information regarding the indication for antimicrobial use and the adequate use of perioperative antibiotics.

Purpose: Age-related physiological changes affect body systems, altering pharmacokinetics, which may potentiate or alter the effects of drugs. The aim of this study was to assess the influence of age on the steady-state pharmacokinetics and pharmacokinetic/pharmacodynamic parameters of ampicillin/sulbactam in the population of elderly patients (age ≥65 years) with community-acquired pneumonia (CAP). Patients and methods: The pharmacokinetics and pharmacokinetic/pharmacodynamic parameters of ampicillin/sulbactam were determined at steady state in a total of 13 elderly patients with CAP following the administration of multiple intravenous doses of 2 g ampicillin + 1 g sulbactam (Unacid, Pfizer), each over 15 min thrice a day. Results: A reduced C, AUC and total clearance, a prolonged half-life, and an increased steady-state volume of distribution were observed for ampicillin. The mean estimated free C of 1.8 mg/L for ampicillin was higher than that predicted to be effective against Streptococcus pneumoniae. Based on an MIC of 1 mg/L for Streptococcus pneumoniae, the calculated T > MIC and T > 4 × MIC for ampicillin was 75-100 % (median 100 %) and 12.5-100 % (median 50 %), respectively. A T > 4 × MIC of at least 50 % was achieved in 7 of 13 elderly patients with CAP. Conclusions: Age and, probably, pneumonia did affect the pharmacokinetics of ampicillin and sulbactam. Despite the reduced C, adequate free C/MIC ratios due to impaired renal function were observed in elderly patients with CAP. In elderly patients without renal impairment and/or in severe infection with less susceptible pathogens, more frequent dosing of ampicillin 2 g/sulbactam 1 g can be necessary to avoid the risk of underdosing in CAP. [ABSTRACT FROM AUTHOR]

Summary: Molecular targeted therapies with tyrosine kinase inhibitors (TKIs) have been a recent breakthrough in cancer treatment. These small molecules are mainly used at a fixed dose ignoring the possible need for dose individualization. Fixed dosing may indeed result in suboptimal treatment or excessive toxicity considering the high inter-individual variability in the pharmacokinetics (PK) of these therapies. The PK, toxicity and efficacy of ten commonly used molecular targeted anti-cancer therapies were reviewed in order to optimize their prescription. A wide interpatient variability in the pharmacokinetics of these small molecules is demonstrated. Moreover associations between certain toxicities and the treatment efficacy have also been demonstrated for some agents, such as erlotinib and skin rash, that may be used as a surrogate marker. Other biomarkers intended to substitute for a clinical endpoint have been described for some TKIs and may be useful for dose individualization. Promising alternatives to fixed dosing were explored such as therapeutic drug monitoring, genotype and phenotype adjusted dosing, and toxicity-adjusted dosing. Prospective studies are needed to validate these methods so that dosing algorithms may be developed in the near future in order to personalize therapeutics to the individual needs of each cancer patient. [ABSTRACT FROM AUTHOR]

In real-world clinical practice, underdosing, i.e. off-label use of reduced doses (RDs), of oral factor Xa inhibitors (oFXaIs) is quite common in stroke prevention in non-valvular atrial fibrillation, possibly reflecting the hope to increase safety without reducing efficacy in selected patients. To assess whether this strategy is associated with some clinical benefit, we used a physician-centred approach to evaluate whether current evidence supports the hypothesis that a substantial proportion of underdosing may be voluntary rather than casual, whether and to what extent oFXaIs' dose rather than patients' characteristics are associated with bleeding events, and which are the safety and efficacy clinical implications of oFXaIs' underdosing. Our review found consistent evidence that underdosing is often an intentional strategy; however, available studies do not demonstrate a sizeable net clinical benefit of using off-label RD oFXaIs., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)