How enoxaparin underdosing and sex contribute to achieving therapeutic anti-Xa levels.

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.

Clinical outcomes of MR-guided adrenal stereotactic ablative radiotherapy with preferential sparing of organs at risk.

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 < 0.90 in 52 % of all plans. Recurrences were independent of the prescription doses. Conclusion: MRgRT for adrenal metastases is well tolerated with high local control rates despite prioritizing OAR sparing over PTV coverage. Studies using deformable dose accumulation may lead to a better understanding of dose-response relationship with adaptive SABR.

Closed System Transfer Devices (CSTDs): Understanding Potential Over- and Under- Dosing of Liquid Vial Drug Products and How to Generally Mitigate.

Closed system transfer devices (CSTDs) are a major challenge for drug manufacturers to assess and assure drug compatibility and acceptable dosing accuracy for a range of clinical administration strategies. In this article, we systematically investigate parameters affecting the loss of product during transfer by CSTDs from vials to infusion bags. We show that liquid volume loss increases with vial size, vial neck diameter, and solution viscosity - while dependent on stopper design. We further compared CSTDs' performance with a traditional syringe transfer and learned that loss is larger for CSTDs than for syringe transfer. Based on experimental data, a statistical model was developed to predict drug loss upon transfer by CSTDs. The model predicted that, for single dose vials with USP<1151> conforming overfill, a complete extraction and transfer of the full dose can be assured for a broad range of CSTDs, product viscosities, and vial types (2R, 6R, 10R, 20R) if a flush (of syringe, syringe adaptor, bag spike) is performed. The model also predicted that complete transfer cannot be achieved for fill volumes ≤ 2.0 mL. For multi-dose vials and pooling of several vials, respectively, the effective dose transfer (i.e., ≥ 95%) for all CSTDs tested was predicted to be achieved if a minimum of 5.0 mL is transferred.

[Survey on the use of antibiotics among Swiss equine veterinarians]. / Umfrage zum Antibiotikagebrauch bei Schweizer Tierärzten mit Pferdeanteil.

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.

INTRODUCTION: L'objectif de cette étude était d'évaluer l'utilisation actuelle des antibiotiques par les vétérinaires équins suisses et de comparer les résultats avec une étude similaire de 2013 avant l'introduction de l'outil web AntibioticScout. L'enquête a été envoyée aux vétérinaires équins selon la base de données des membres de la Société des Vétérinaires Suisses (SVS). Les données démographiques des répondants et leur utilisation d'antibiotiques ont été collectées. En outre, six scénarios de cas différents ont été présentés avec des questions quant à l'utilisation potentielle d'antibiotiques, la substance active/préparation et le schéma posologique. La posologie fournie a été comparée à celle approuvée par Swissmedic dans les informations destinées aux professionnels de la santé et aux recommandations de l'AntibioticScout. Une analyse de régression logistique inverse a été réalisée pour évaluer l'association entre les différents aspects de l'utilisation des antibiotiques et les données démographiques. Le taux de réponse était de 94/739 (13 %), 22 des 94 (23 %) avaient également participé à l'étude de 2013. 47/94 (50 %) des répondants ont obtenu leurs informations à partir de AntibioticScout. Les répondants ont indiqué avoir utilisé un antibiotique dans 16 %-88 % selon le cas de figure. Ni les céphalosporines de 3ème ou 4ème génération ni les fluoroquinolones n'ont été utilisées dans les scénarios de cas. La dihydrostreptomycine a été indiquée comme un antibiotique possible dans un scénario de cas par 14/94 (15 %) des répondants. Les répondants qui avaient déjà participé à l>enquête de 2013 ont utilisé la dihydrostreptomycine significativement plus fréquemment (7/22, 32 % vs. 7/72, 10 % ; p = 0,047). 29/81 (36 %) avaient sous-dosé par rapport aux informations de prescription et 38/81 (47 %) par rapport à AntibioticScout ; ni l'un ni l'autre n'était associé aux données démographiques. L'utilisation de produits antimicrobiens non homologués pour les équidés était directement liée au nombre de vétérinaires dans le cabinet (p = 0,007) et au pourcentage de chevaux (p = 0,02). Aucune association entre les données démographiques et l'utilisation périopératoire d'antibiotiques >24h (17/44, 39 %) n'a été détectée. Les habitudes de prescription d'antibiotiques des vétérinaires équins suisses se sont améliorées au cours des 10 dernières années. L'utilisation d'antibiotiques a diminué par rapport à l'étude de Schwechler et al. en 2013 de 0 à 16 % selon le scénario du cas. L'utilisation des céphalosporines de 3ème et 4ème génération a été réduite de 4 % et les fluoroquinolones de 7 %. Le sous-dosage selon les recommandations scientifiques a été réduit de 32 %. Il est d'autre part nécessaire d>obtenir des informations supplémentaires concernant l>indication de l>utilisation d>antimicrobiens et l>utilisation adéquate des antibiotiques périopératoires.

Drug monitoring detects under- and overdosing in patients receiving 5-fluorouracil-containing chemotherapy-results of a prospective, multicenter German observational study.

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.

Prevalence and predictors of inappropriate dosing of direct oral anticoagulants.

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 CHA2 DS2 -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.

Prevalence and risk of inappropriate dosing of direct oral anticoagulants in two Swiss atrial fibrillation registries.

BACKGROUND: 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. METHODS AND RESULTS: 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 CHA2DS2-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. CONCLUSION: 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.

Off-label underdosing of four individual NOACs in patients with nonvalvular atrial fibrillation: A systematic review and meta-analysis of observational studies.

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.

Off-label-dosing of non-vitamin K-dependent oral antagonists in AF patients before and after stroke: results of the prospective multicenter Berlin Atrial Fibrillation Registry.

AIMS: We aimed to analyze prevalence and predictors of NOAC off-label under-dosing in AF patients before and after the index stroke. METHODS: The post hoc analysis included 1080 patients of the investigator-initiated, multicenter prospective Berlin Atrial Fibrillation Registry, designed to analyze medical stroke prevention in AF patients after acute ischemic stroke. RESULTS: At stroke onset, an off-label daily dose was prescribed in 61 (25.5%) of 239 NOAC patients with known AF and CHA2DS2-VASc score ≥ 1, of which 52 (21.8%) patients were under-dosed. Under-dosing was associated with age ≥ 80 years in patients on rivaroxaban [OR 2.90, 95% CI 1.05-7.9, P = 0.04; n = 29] or apixaban [OR 3.24, 95% CI 1.04-10.1, P = 0.04; n = 22]. At hospital discharge after the index stroke, NOAC off-label dose on admission was continued in 30 (49.2%) of 61 patients. Overall, 79 (13.7%) of 708 patients prescribed a NOAC at hospital discharge received an off-label dose, of whom 75 (10.6%) patients were under-dosed. Rivaroxaban under-dosing at discharge was associated with age ≥ 80 years [OR 3.49, 95% CI 1.24-9.84, P = 0.02; n = 19]; apixaban under-dosing with body weight ≤ 60 kg [OR 0.06, 95% CI 0.01-0.47, P < 0.01; n = 56], CHA2DS2-VASc score [OR per point 1.47, 95% CI 1.08-2.00, P = 0.01], and HAS-BLED score [OR per point 1.91, 95% CI 1.28-2.84, P < 0.01]. CONCLUSION: At stroke onset, off-label dosing was present in one out of four, and under-dosing in one out of five NOAC patients. Under-dosing of rivaroxaban or apixaban was related to old age. In-hospital treatment after stroke reduced off-label NOAC dosing, but one out of ten NOAC patients was under-dosed at discharge. CLINICAL TRIAL REGISTRATION: NCT02306824.

Differences in Preferences Between Clinicians and Patients for the Use and Dosing of Direct Oral Anticoagulants for Atrial Fibrillation.

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<0.001). Conclusions There are considerable knowledge gaps regarding DOAC dosing in clinicians treating patients with atrial fibrillation, as well as significant differences in treatment dosing preferences between clinicians and patients.

Off-label use of reduced dose direct oral factor Xa inhibitors in subjects with atrial fibrillation: a review of clinical evidence.

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.

Label Adherence of Direct Oral Anticoagulants Dosing and Clinical Outcomes in Patients With Atrial Fibrillation.

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<0.001) and had higher CHA2DS2-VASc scores (4.6±1.7 and 5.3±1.7 versus 4.5±1.8, respectively; P<0.001). NOAC overdosing was associated with increased risk for stroke or systemic embolism (5.76 versus 4.03 events/100 patient-years, P<0.001), major bleeding (4.77 versus 2.94 events/100 patient-years, P<0.001), and all-cause mortality (5.43 versus 3.05 events/100 patient-years, P<0.001) compared with label-adherent use. Conclusions In real-world practice, a significant proportion (almost 2 in 5) of AF patients received NOAC doses inconsistent with drug labeling. NOAC overdosing is associated with worse clinical outcomes in Asian AF patients.

Outcomes associated with under-dosing of rivaroxaban for management of non-valvular atrial fibrillation in real-world Japanese clinical settings.

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.

Is lower-dose sugammadex a cost-saving strategy for reversal of deep neuromuscular block? Facts and fiction.

BACKGROUND: Sugammadex, a γ-cyclodextrin derivative, belongs to a new class of selective relaxant binding agents. Sugammadex was approved 10-years ago by the European medicines agency and today is used in clinical anesthesia and emergency medicine globally. In this review, indications for neuromuscular block, the challenge of neuromuscular monitoring and the practice of under-dosing of sugammadex as a potential cost-saving strategy are discussed. MAIN BODY: Reversal of neuromuscular block is important to accelerate the spontaneous recovery of neuromuscular function. Sugammadex is able to reverse a rocuronium- or vecuronium-induced neuromuscular block rapidly and efficiently from every depth of neuromuscular block. However, since sugammadex was introduced in clinical anesthesia, several studies have reported administration of a lower-than-recommended dose of sugammadex. The decision to under-dose sugammadex is often motivated by cost reduction concerns, as the price of sugammadex is much higher than that of neostigmine outside the United States. However, under-dosing of sugammadex leads to an increased risk of recurrence of neuromuscular block after an initial successful (but transient) reversal. Similarly, when not using objective neuromuscular monitoring, under-dosing of sugammadex may result in residual neuromuscular block in the postoperative care unit, with its attendant negative pulmonary outcomes. Therefore, an appropriate dose of sugammadex, based on objective determination of the depth of neuromuscular block, should be administered to avoid residual or recurrent neuromuscular block and attendant postoperative complications. Whether the reduction in perioperative recovery time of the patient can be translated into additional procedural cases performed, faster operative turnover times, or improved organizational resource utilization, has yet to be determined in actual clinical practice that includes verification of neuromuscular recovery prior to tracheal extubation. CONCLUSIONS: The current review addresses the indications for neuromuscular block, the challenge of neuromuscular monitoring, the practice of under-dosing of sugammadex as a potential cost-saving strategy in reversal of deep neuromuscular block, the economics of sugammadex administration and the potential healthcare cost-saving strategies.

Non-flushing of IV administration sets: an under-recognised under-dosing risk.

BACKGROUND: intravenous (IV) drugs are administered widely and under-dosing can result in therapy failure. The aim of this study was to quantify frequency, volume and dose of drug discarded within administration sets in the clinical setting. METHODS: residual volume for 24 different administration sets was measured under controlled conditions in a laboratory. Clinical assessment of current practice regarding post-infusion flushing occurred in 6 departments of one teaching hospital in the UK over 7 days. Details of drug last infused, (concentration, diluent and volume) and type and brand of administration set were collected. RESULTS: 74% of administration sets were not flushed. Non-flushing exceeded 90% and 61% for gravity and pump infusions respectively (p<0.001) in all areas excluding oncology. Oncology was the only area where flushing was standard practice for all infusions (p<0.001). Mean residual volume of the administration sets was 13.1 ml and 16.7 ml for gravity and pump sets respectively. Antibiotics were commonly infused and up to 21% of antibiotic dose was frequently discarded. CONCLUSIONS: the findings suggest disposal of substantial volumes of drugs occurs frequently in general hospital areas. Without clear national and local policies this unrecognised under-dosing will continue.

The Dose of Direct Oral Anticoagulants and Stroke Severity in Patients with Acute Ischemic Stroke and Nonvalvular Atrial Fibrillation.

BACKGROUND: The severity and the functional outcome of patients with stroke occurring during off-label underdosing of direct-acting oral anticoagulants (DOACs) remain uncertain. METHODS: We studied 53 consecutive patients with acute ischemic stroke and nonvalvular atrial fibrillation who were treated with DOACs before the onset of stroke. Thirty patients were treated for primary prevention of stroke and 23 patients were treated for secondary prevention. DOAC treatments were categorized into 3 groups based on the following doses: (1) standard-dose group (n = 17), (2) low-dose group (n = 23), and (3) off-label underdose group (n = 13). RESULTS: Age was significantly older in the low-dose group than in the standard-dose group (P = .026). The standard-dose group and the low-dose group showed higher CHA2DS2-VASc scores (median, 4) compared with the off-label underdose group (median, 3). More than half of the patients had a National Institutes of Health Stroke Scale score of less than 8, and many patients had a good outcome (modified Rankin Scale score ≤1). There were no differences in stroke severity and outcome among the 3 groups. The ratio of being discharged home was the highest in the standard-dose group. CONCLUSIONS: This study shows that patients who have off-label underdosing of DOACs do not develop more severe stroke and a poorer outcome than those with the recommended dose. Careful attention to recommended doses is required for the full benefits from DOACs.

Effects of antirheumatic drug underutilization on rheumatoid arthritis disease activity.

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.

Failure of dihydroartemisinin plus piperaquine treatment of falciparum malaria by under-dosing in an overweight patient.

BACKGROUND: Artemisinin-based combination therapy (ACT) introduced in the mid-1990s has been recommended since 2005 by the World Health Organization as first-line treatment against Plasmodium falciparum in all endemic countries. In 2010, the combination dihydroartemisinin-piperaquine (DP) was recommended for the treatment of uncomplicated P. falciparum malaria. DP is one of the first-line treatments used by the French army since 2013. CASE PRESENTATION: A case of P. falciparum clinical failure with DP at day 20 was described in a 104 kg French soldier deployed in Djibouti. He was admitted to hospital for supervision of oral treatment with DP [40 mg dihydroartemisinin (DHA) plus 320 mg piperaquine tetraphosphate (PPQ)]. This corresponded to a cumulative dose of 4.6 mg/kg DHA and 37 mg/kg PPQ in the present patient, which is far below the WHO recommended ranges. No mutation was found in the propeller domain of the Kelch 13 (k13) gene, which is associated with artemisinin resistance in Southeast Asia. Pfmdr1 N86, 184F, S1034 and N1042 polymorphisms and haplotype 72-76 CVIET for the pfcrt gene were found in the present case. There was no evidence of resistance to DP. CONCLUSION: This case confirms the risk of therapeutic failure with dihydroartemisinin-piperaquine by under-dosing in patients weighing more than 100 kg. This therapeutic failure with DP by under-dosing highlighted the importance of appropriate dosing guidelines and the need of research data (efficacy, pharmacokinetics and pharmacodynamics) in over-weight patient group.

Augmented renal clearance is a common finding with worse clinical outcome in critically ill patients receiving antimicrobial therapy.

INTRODUCTION: We describe incidence and patient factors associated with augmented renal clearance (ARC) in adult intensive care unit (ICU) patients. MATERIALS AND METHODS: A prospective observational study in a mixed cohort of surgical and medical ICU patients receiving antimicrobial therapy at the Ghent University Hospital, Belgium. Kidney function was assessed by the 24-hour creatinine clearance (Ccr); ARC defined as at least one Ccr of >130 mL/min per 1.73 m2. Multivariate logistic regression analysis: to assess variables associated with ARC occurrence. Therapeutic failure (TF): an impaired clinical response and need for alternate antimicrobial therapy. RESULTS: Of the 128 patients and 599 studied treatment days, ARC was present in 51.6% of the patients. Twelve percent permanently expressed ARC. ARC patients had a median Ccr of 144 mL/min per 1.73 m2 (IQR 98-196). Median serum creatinine concentration on the first day of ARC was 0.54 mg/dL (IQR 0.48-0.69). Patients with ARC were significantly younger (P<.001). Age and male gender were independently associated with ARC whereas the APACHE II score was not. ARC patients had more TF (18 (27.3%) vs. 8 (12.9%); P=.04). CONCLUSION: ARC was documented in approximately 52% of a mixed ICU patient population receiving antibiotic treatment with worse clinical outcome. Young age and male gender were independently associated with ARC presence.