New treatment opportunities for older patients with acute myeloid leukemia and the increasing importance of frailty assessment - An oncogeriatric perspective.

With the introduction of targeted chemotherapy drugs, a new age of treatment for acute myeloid leukemia (AML) has begun. The promotion of the azacitidine+venetoclax combination regimen to first line of treatment in patients deemed ineligible for intensive chemotherapy marks the first of many novel combination regimens becoming part of national treatment guidelines. We review recent phase II and III clinical trials and conclude that these novel regimens offer significant increases in response rates, remission rates, and overall survival. The incidence of adverse events, the accrued time toxicity, and the healthcare costs, however, are increasing as well. Compared with clinical trials, older patients in the real world frequently present with an inferior baseline health status, which is associated with an increased risk of experiencing side effects. The key to reaping the maximum benefit of the new agents and their combination regimens therefore lies in sufficient attention being given to a patients' preexisting comorbidities, potential frailty, and quality of life. A systematic collaboration between hemato-oncologists and geriatricians can be a potent first step towards addressing the increased treatment intensity patients with AML experience under the novel regimens. In this narrative review article we provide an overview of recent and ongoing clinical trials, highlight encountered adverse events, discuss frailty assessment options, and outline an oncogeriatic care path for older patients with AML.

Acute kidney injury associated with nephrotoxic drugs in critically ill patients: a multicenter cohort study using electronic health record data.

Background: Nephrotoxic drugs frequently cause acute kidney injury (AKI) in adult intensive care unit (ICU) patients. However, there is a lack of large pharmaco-epidemiological studies investigating the associations between drugs and AKI. Importantly, AKI risk factors may also be indications or contraindications for drugs and thereby confound the associations. Here, we aimed to estimate the associations between commonly administered (potentially) nephrotoxic drug groups and AKI in adult ICU patients whilst adjusting for confounding. Methods: In this multicenter retrospective observational study, we included adult ICU admissions to 13 Dutch ICUs. We measured exposure to 44 predefined (potentially) nephrotoxic drug groups. The outcome was AKI during ICU admission. The association between each drug group and AKI was estimated using etiological cause-specific Cox proportional hazard models and adjusted for confounding. To facilitate an (independent) informed assessment of residual confounding, we manually identified drug group-specific confounders using a large drug knowledge database and existing literature. Results: We included 92 616 ICU admissions, of which 13 492 developed AKI (15%). We found 14 drug groups to be associated with a higher hazard of AKI after adjustment for confounding. These groups included established (e.g. aminoglycosides), less well established (e.g. opioids) and controversial (e.g. sympathomimetics with α- and ß-effect) drugs. Conclusions: The results confirm existing insights and provide new ones regarding drug associated AKI in adult ICU patients. These insights warrant caution and extra monitoring when prescribing nephrotoxic drugs in the ICU and indicate which drug groups require further investigation.

[After bariatric surgery effects of medication are not always predictable]. / Farmacotherapie na bariatrische chirurgie: niet altijd voorspelbaar.

Bariatric surgery is widely used as an effective treatment for obesity. Changes in the anatomy of the digestive tract as a result of these operations may lead to changes in drug availability. This is illustrated by three cases in which problems arose with calcium metabolism, thyroid hormone substitution or weight. Effects on medication after bariatric surgery are not always predictable and there are no uniform guidelines how to handle. We advocate therefore a proactive attitude of physicians by monitoring direct effects (such as blood pressure, glucose, or mood) or determining drug concentrations, to prevent treatment failure or toxicity.

Low-dose ketamine or opioids combined with propofol for procedural sedation in the emergency department: a systematic review.

Procedural sedation is routinely performed for procedures in the emergency department (ED). Propofol is a commonly used sedative, frequently combined with an opioid or low-dose ketamine as an analgesic. However, there is still controversy on the optimal combination of agents in current guidelines. The objective of this systematic review is to identify and present studies comparing low-dose ketamine to opioids when combined with propofol for procedural sedation in the ED and to describe the dosing regimen, observed efficacy, and side effects. For this systematic review, following the Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines, EMBASE and PubMed databases were searched. Studies comparing propofol with opioids versus propofol with low-dose (es)ketamine in patients undergoing procedural sedation for procedures in the ED were included. Analyses were descriptive because of the high heterogeneity among included studies. The outcomes were dosing regimen, efficacy of analgesia, efficacy of sedation depth, efficacy of recovery and (adverse) events. We included four out of 2309 studies found in the literature search. Overall, the studies had a low risk of bias, but the Grading of Recommendations Assessment, Development, and Evaluation evidence profile was downgraded due to the imprecision and inconsistency of the studies. All studies compared low-dose ketamine with fentanyl. Dosing ranged from 0.3 to 1.0 mg/kg (ketamine), 1.0-1.5 µg/kg (fentanyl) and 0.4-1.0 mg/kg (propofol). The efficacy of analgesia was measured by two studies, one favoring the fentanyl group, and one favoring the ketamine group. The efficacy of sedation depth was measured by one study, with the fentanyl group having a deeper sedation score. Two studies showed shorter recovery time with low-dose ketamine. One study showed a higher incidence of cardio-respiratory clinical events and interventions in the fentanyl group. Two studies showed significant differences of overall sedation events in the fentanyl group. One study did not find any significant differences of the incidence of sedation events. This systematic review did not provide sufficient evidence that the combination of low-dose ketamine and propofol is associated with a shorter recovery time and fewer sedation events compared to the combination of opioids and propofol.

Adherence to protocols for the use of reversal agents in patients treated with direct oral anticoagulants.

OBJECTIVES: This study aimed to evaluate the adherence to protocols for the use of reversal agents in direct oral anticoagulant (DOAC) users in Dutch hospitals. METHODS: A retrospective cohort study was conducted in seven hospitals in the Netherlands. Treatment protocols for bleeding and (urgent) procedures in patients on DOAC were collected from each hospital. All patient data on the use of reversal agents were retrospectively collected from September 2021 to April 2022 and compared to the protocols. The degree of per-protocol adherence (compliance score) was categorized into four levels as follows: poor (<45%), moderate (45-79%), high (80-89%), and full (> 90%) adherence rates. RESULTS: A total of 290 patients were included in our study. In patients with bleeding under DOAC, the protocol adherence for prothrombin complex concentrate (PCC) was "moderate" (61%). In the remaining cases (39%), non-adherence was mainly caused by underdosing (68%), overdosing (12%), and a lack of indication (14%). Furthermore, idarucizumab was administered for bleeding with "full" adherence (96%). For andexanet alfa, adherence to the hospital bleeding protocol was "moderate" (67%), with a lack of indication being the only reason for non-adherence. In case of reversal for an urgent procedure, the protocol adherence for PCC was "low" (45%), with underdosing, a lack of indication, and missing lab data being the main reasons for non-adherence. Missing lab data on dabigatran plasma concentration before reversal was the main reason for "low" adherence (26%) in idarucizumab. The adherence for andexanet alfa was also "low" (0%). CONCLUSION: In case of reversal for bleeding under DOAC, overall adherence to the protocol was "moderate"; however, in patients needing an urgent procedure, it was "low." The major reasons for non-adherence were underdosing, off-label use, and a lack of specific lab testing. The results of this study can assist in improving the implementation of hospital protocols.

Clinical response to benralizumab can be predicted by combining clinical outcomes at 3†months with baseline characteristics.

Background: Benralizumab is highly effective in many, but not all, patients with severe asthma. Baseline characteristics alone are insufficient to predict an individual's probability of long-term benralizumab response. The objectives of the present study were to: 1) study whether parameters at 3 months, in addition to baseline characteristics, contribute to the prediction of benralizumab response at 1 year; and 2) develop an easy-to-use prediction tool to assess an individual's probability of long-term response. Methods: We assessed the effect of benralizumab treatment in 192 patients from the Dutch severe asthma registry (RAPSODI). To investigate predictors of long-term benralizumab response (≥50% reduction in maintenance oral corticosteroid (OCS) dose or annual exacerbation frequency) we used logistic regression, including baseline characteristics and 3-month Asthma Control Questionnaire (ACQ-6) score and maintenance OCS dose. Results: Benralizumab treatment significantly improved several clinical outcomes, and 144 (75%) patients were classified as long-term responders. Response prediction improved significantly when 3-month outcomes were added to a predictive model with baseline characteristics only (area under the receiver-operating characteristic (AUROC) 0.85 versus 0.72, p=0.001). Based on this model, a prediction tool using sex, prior biologic use, baseline blood eosinophils, forced expiratory volume in 1 s, and at 3 months OCS dose and ACQ-6 was developed which classified patients into three categories with increasing probability of long-term response (95% CI): 25% (3-65%), 67% (57-77%) and 97% (91-99%), respectively. Conclusion: In addition to baseline characteristics, treatment outcomes at 3 months contribute to the prediction of benralizumab response at 1 year in patients with severe eosinophilic asthma. Prediction tools as proposed in this study may help physicians optimise the use of costly biologics.

Effectiveness of a vitamin D regimen in deficient multiple myeloma patients and its effect on peripheral neuropathy.

PURPOSE: Peripheral neuropathy (PN) is common in multiple myeloma (MM) patients. More insight has been gained concerning the role of vitamin D in preventing PN. However, studies evaluating the effects of vitamin D3 supplementation on PN are lacking. The aims of this study are to (1) evaluate the effectiveness of a vitamin D3 regimen on achieving adequate vitamin D levels in deficient MM patients and to (2) exploratively evaluate the effect of vitamin D3 supplementation on PN. METHODS: Thirty-nine MM patients with inadequate (< 75 nmol/L [= 30 ng/mL]) 25-hydroxyvitamin D (25(OH)D) levels were included in this multicenter, prospective, single-arm study, of whom 35 patients completed the study. They received oral vitamin D3 for 6 months according to a dose escalation regimen that consisted of one or two loading doses of 200,000 international units (IU), and maintenance doses of 800, 1600, or 3200 IU/day depending on the 25(OH)D level. A validated questionnaire was used to measure PN. RESULTS: Median 25(OH)D increased from 38 (IQR 32-52) nmol/L at baseline to 77 (IQR 72-87) nmol/L after 6 months (P < 0.001). Adequate 25(OH)D levels were achieved by 66% of the subjects, and 34% were within the range of 50-75 nmol/L. Furthermore, in 37% of the participants, PN severity decreased (P = 0.007). CONCLUSION: The use of substantially higher vitamin D3 doses than recommended in current guidelines resulted in a significant increase in vitamin D levels in MM patients. Furthermore, evaluation of PN showed a significant decrease in PN grading. However, this exploratory evaluation needs further confirmatory research.

Treatment patterns in older patients with myelodysplastic syndromes: A population-based analysis reflecting the real world.

INTRODUCTION: Treatment for myelodysplastic syndromes (MDS) is complex, options are limited, and insight into consecutive treatments is lacking. We performed this study to assess the outcomes in a real-world cohort of patients with MDS. MATERIALS AND METHODS: An observational population-based study was performed using the HemoBase registry. Treatment patterns and overall survival (OS) were analyzed with Kaplan-Meier analyses. RESULTS: In 144 of 280 (51.4%) patients with MDS >50 years, first-line treatment was initiated. The median age was 75.1 years (range: 52.6-92.0); the majority were male (72.2%). Hypomethylating agents (HMA), intensive chemotherapy, lenalidomide, and erythropoiesis-stimulating agents (ESA) were given as first-line treatment to 31.1% (n = 45), 12.5% (n = 18), 2.8% (n = 4), and 53.5% (n = 77) of the population, respectively. The median treatment duration was 5.8 months (95% Confidence Interval [CI]: 1.1-10.4) for HMA, 1.7 months (95%CI: 0.9-2.6) for intensive chemotherapy, 10.8 months (95%CI: 4.7-17.0) for lenalidomide, and 14.8 months (95%CI: 11.4-18.1) for ESA. Consecutive treatments were given to 27.2% of patients. The main reasons for first-line treatment discontinuation were treatment failure (45.8%), toxicity (6.9%), or death (20.1%). Median OS after termination of the initial, second, and third treatment was 5.8 months (95%CI: 3.2-8.5), 9.3 months (95%CI: 0.0-19.6), and 1.0 months (95%CI: 0.0-5.1), respectively. DISCUSSION: This study shows the treatment outcomes in a real-world population of older patients with MDS. Treatment duration and median OS after treatment discontinuation were relatively limited. There is still an urgent need for new treatment options, strategies to further optimize duration of existing treatments, and communication of realistic treatment goals and expectations, especially for older, higher-risk patients with MDS with a poor prognosis.

Protocols for perioperative management of direct oral anticoagulants in hospitals: opportunities for improvement.

OBJECTIVES: To investigate and describe the protocolized perioperative management in patient using Direct oral anticoagulants (DOACs) in Dutch hospitals. METHODS: Between August and December 2020, a nationwide survey in 70 hospitals in the Netherlands was conducted. We asked hospital pharmacists to submit their protocols for perioperative management of DOAC (apixaban, dabigatran, edoxaban and rivaroxaban) users. The protocols were assessed for a number of parameters divided into categories: interruption and restart timetables DOACs for elective procedures, criteria for the start of an urgent procedure without antidotes, criteria for the use of antidotes and advised antidotes for urgent procedures. RESULTS: A total of 49 hospitals (70%) sent a protocol for perioperative management of DOACs. Two pairs of protocols were identical because hospitals cooperated closely, leaving 47 individual protocols for analysis. Thirty-five of these protocols contained a policy for both elective and urgent procedure; five protocols contained only a policy for elective and seven only for urgent procedures. In protocols for elective procedure, we found great variation in interruption and restart timetables intended for patients with renal impairment (Estimated Glomerular Filtration Ratio < 80 ml/min). In case of urgent procedures, there is variation in choice of antidote, criteria for administration of an antidote and antidote dosing. CONCLUSION: This study provides an overview of the current state of the perioperative protocols in the Netherlands in patients treated with direct oral anticoagulants. Protocols are often not complete and show important and unwanted variation. We have found that national guidelines do not provide unambiguous advice on all points (urgent procedures) and are therefore often elaborated at a local level. The results of this research can help in improving and harmonizing the perioperative protocols on a national level.

Protocolized management of bleeding in hospitals in The Netherlands in patients treated with direct oral anticoagulants.

OBJECTIVE: To investigate and describe the protocolized treatment of DOAC-related bleeds in all Dutch hospitals. METHODS: From August to December 2020 a nationwide survey among all 70 hospitals in the Netherlands was conducted on their protocols for management of bleeding in patients treated with direct oral anticoagulants (DOACs, i.e. apixaban, edoxaban, rivaroxaban and dabigatran). The protocols were assessed the following characteristics: bleeding definitions (mild, moderate and severe bleed), diagnostic parameters (hemoglobin [Hb], loss of blood, surgical procedure needed, etc), first and second choice of treatment, effectiveness criteria and the level of evidence/references upon which protocols were based. RESULTS: All 70 hospitals responded (100%). We received 69 protocols in total, 6 of which were identical because hospitals worked together. In 35 (50%) of the protocols a definition of minor, moderate or severe bleeds was described. Diagnostic parameters for bleeds were present in 2%, 41% and 47% of protocols for a mild, moderate and severe bleed. While the first choice treatment for severe bleeding under dabigatran was idarucizumab in 96% of protocols, considerably more therapeutic options (mostly different prothrombin complex concentrate (PCC) doses) are described for Xa inhibitors. When considering criteria for effectiveness more than 90% of protocols did not have a clear description. CONCLUSION: This study provides an overview of the current state of protocols for management of DOAC-related bleeding in The Netherlands. Protocols vary in the content of information provided and often do not include information, especially for diagnostic criteria and criteria for establishing the effectiveness of the intervention. The results of this study can assist in improving and harmonizing the protocols.

Increased prescription rate of anti-infective agents after diagnosis of myelodysplastic syndromes.

The a priori risk for infections in patients with myelodysplastic syndromes (MDS) is unknown. This study examines prescription rates of anti-infective agents in MDS patients before and after diagnosis, in both in- and outpatient settings, to provide information on infection management in clinical practice. We performed a population-based study using the HemoBase registry, containing data of all MDS patients diagnosed since 2005 in Friesland, the Netherlands. Community and hospital pharmacies provided prescription data from 1995 to 2020. Data were obtained for 203 of 292 patients (70%). Patients received significantly more anti-infective agents, predominantly antibacterials (70%), after diagnosis compared to before: 148.7 defined daily dose/1000 days (DID) (95% CI: 146.9-150.5) and 55.1 DID (95% CI: 54.5-55.8, p < 0.01), respectively, corresponding to median 23.5 and 7.6 treatment days/year. Higher-risk (449.9 DID) and lower-risk patients (129.1 DID) both received significantly more anti-infective agents after diagnosis; comorbidities, neutropenia, and age did not show significant differences relative to prescription rates. Before diagnosis, 10% of patients had infection-related hospital admissions versus 38% after diagnosis. In conclusion, MDS patients received significantly more anti-infective agents compared to before diagnosis. This is the first study that has quantified the prescription rate of anti-infective agents within and beyond the clinical setting in MDS.

Clinical view versus guideline adherence in ferritin monitoring and initiating iron chelation therapy in patients with myelodysplastic syndromes.

OBJECTIVES: In patients with myelodysplastic syndromes (MDS) with >20 transfusions and ferritin levels >1000 µg/L, international guidelines recommend iron chelation therapy (ICT). The study's objective was to determine guideline adherence and the intensity of ferritin monitoring in clinical practice. METHODS: We performed an observational population-based study using the HemoBase Registry, which contains data of all MDS patients diagnosed since 2005 in Friesland, the Netherlands. Clinical information on transfusions, ferritin measurements, ICT, and clinical performance as defined by age ≤ 80 years, Charlson Comorbidity Index <2 and lower-risk MDS was collected from health records. RESULTS: Two hundred and thirty seven of 292 patients (81.1%) received ≥1 transfusion, and 121 (41.4%) received >20 transfusions. In 57 of these 121 patients (47.1%), ferritin measurements were performed at least once. Clinical performance was significantly associated with monitoring ferritin around the 20th transfusion (RR: 2.49, p = .016). Clinical performance was also associated with initiating ICT (RR: 5.99, p < .001). ICT was offered to 22.3% (n = 25) of eligible patients. CONCLUSIONS: In this population-based study, ferritin levels were measured in <50% of MDS patients who received >20 transfusions, and clinical performance was significantly associated with measuring ferritin. Our study suggests that in heavily transfused MDS patients, ferritin monitoring is primarily based on patients' clinical performance rather than guideline recommendations.

Pharmacology, particle deposition and drug administration techniques of intranasal corticosteroids for treating allergic rhinitis.

This review presents an overview of the available literature regarding intranasal corticosteroids (INCs) for the treatment of allergic rhinitis (AR). Various treatment options exist for AR including INCs, antihistamines and leucotriene antagonists. INCs are considered to be the most effective therapy for moderate-to-severe AR, as they are effective against nasal and ocular symptoms and improve quality of life. Their safety has been widely observed. INCs are effective and safe for short-term use. Local adverse events are observed but generally well-tolerated. The occurrence of (serious) systemic adverse events is unlikely but cannot be ruled out. There is a lack of long-term safety data. INC may cause serious eye complications. The risk of INCs on the hypothalamic-pituitary-adrenal axis, on bone mineral density reduction or osteoporosis and on growth in children, should be considered during treatment. Pharmacological characteristics of INCs (e.g. the mode of action and pharmacokinetics) are well known and described. We sought to gain insight into whether specific properties affect the efficacy and safety of INCs, including nasal particle deposition, which the administration technique affects. However, advances are lacking regarding the improved understanding of the effect of particle deposition on efficacy and safety and the effect of the administration technique. This review emphasizes the gaps in knowledge regarding this subject. Advances in research and health care are necessary to improve care for patients with AR.

Thromboembolic Events While Taking Direct Oral Anticoagulants: An Analysis of Post-market WHO Database Reports from 2012 to 2020.

BACKGROUND AND OBJECTIVE: Several cases of venous thromboembolism in patients treated with direct oral anticoagulants (DOACs) have been reported in the literature, but a quantative analysis of postmarketing reports is lacking. The objective of this study was to determine the post-marketing odds ratio (OR) and reporting odds ratio (ROR) of venous thromboembolism in patients receiving DOACs compared among each other and to vitamin K antagonists (VKAs). METHODS: The OR and ROR were used to determine the ratio of reports for deep vein thrombosis and pulmonary embolism between 1 January, 2012 and 15 November, 2020 using the World Health Organization VigiLyze database. This was performed using all venous thromboembolism events in which a DOAC or a VKA was the suspected medication. The OR and ROR including 95% confidence intervals were calculated for each DOAC drug in comparison to all VKAs as a group. RESULTS: The OR of deep vein thrombosis was highest for rivaroxaban compared with dabigatran and apixaban [2.63 (2.41-2.89); 1.84 (1.72-1.97)]. The OR of deep vein thrombosis was lowest for edoxaban compared with dabigatran, apixaban and rivaroxaban [0.44 (0.32-0.61); 0.31 (0.22-0.42); 0.17 (0.12-0.23)]. The OR of pulmonary embolism was also highest for rivaroxaban compared with dabigatran and apixaban [2.59 (2.37-2.83); 1.79 (1.68-1.92)]. The OR of pulmonary embolism was also lowest for edoxaban compared with dabigatran, apixaban and rivaroxaban [0.77 (0.60-0.97); 0.59 (0.41-0.67); 0.30 (0.23-0.37)]. Comparing RORs of various DOACs with VKAs, rivaroxaban had the highest RORs for deep vein thrombosis/pulmonary embolism, in comparison to apixaban, dabigatran and edoxaban. CONCLUSIONS: Our findings may indicate a higher association between rivaroxaban therapy and venous thromboembolism as compared with apixaban, dabigatran and edoxaban. These findings are uncertain owing to the reliability of a post-marketing registration system that is negatively influenced by a high level of under-reporting. However, based on pharmacodynamics, we cannot exclude the possibility that there is a real effect that may be driven by non-adherence.

Adverse Drug Reactions of Intranasal Corticosteroids in the Netherlands: An Analysis from the Netherlands Pharmacovigilance Center.

BACKGROUND: Intranasal corticosteroids are one of the cornerstone treatment options for allergic rhinitis and chronic sinusitis complaints. Safety information in the summary of product characteristics may not be representative for observations in daily clinical practice. The Netherlands Pharmacovigilance Center (Lareb) collects post-marketing safety information, using spontaneous reporting systems. OBJECTIVE: Our objective was to analyse reports of adverse drug reactions associated with intranasal corticosteroids reported in the Dutch spontaneous reporting database of the Netherlands Pharmacovigilance Center Lareb to obtain insight into real-world safety data. METHODS: We retrospectively examined all adverse drug reactions of intranasal corticosteroids reported to the Netherlands Pharmacovigilance Center Lareb, entered into the database from 1991 until 1 July, 2020. RESULTS: In total, 2263 adverse drug reactions after intranasal corticosteroid use were reported in 1258 individuals. Headache (n = 143), epistaxis (n = 124) and anosmia (n = 57) were reported most frequently. Nasal septum perforation (reporting odds ratio 463.2; 95% confidence interval: 186.7-1149.7) had the highest reporting odds ratio, followed by nasal mucosal disorder (reporting odds ratio 104.5; 95% confidence interval 36.3-301.3) and hyposmia (reporting odds ratio 90.8; 95% confidence interval 45.1-182.7). Moreover, 101 (4.5%) reports were classified as serious by Lareb, including reports of Cushing's syndrome, adrenal cortical hypofunction and growth retardation. CONCLUSIONS: Many side effects are consistent with the safety information in the summary of product characteristics of intranasal corticosteroids. Several serious (systemic) side effects are reported and it is important to realise that intranasal corticosteroids may contribute to the development. Healthcare providers and patients should be aware of the potential (individual) adverse drug reactions of intranasal corticosteroids. This information could help in discussing treatment options.

Impact of minor bleeds on confidence in anticoagulation therapy, adherence to treatment and quality of life in patients using a non-vitamin K antagonist oral anticoagulant for atrial fibrillation.

OBJECTIVE: In a previous study on the reasons for discontinuation of novel oral anticoagulation therapy (NOAC) in patients with atrial fibrillation, we showed that minor bleeding was the second most important reason for NOAC discontinuation. This finding suggest that the impact of minor bleeds on the patient's perspective on NOACs cannot be ignored, especially those minor bleeds for which the patient searched medical care. We therefore performed a study in which we explored the impact of minor bleed (clinically relevant non-major bleeds) on patient confidence in therapy, adherence to treatment and quality of life in AF patients using NOAC's. METHODS: Details on NOAC therapy, level of confidence, adherence and quality of life were assessed using a semi-structured telephone interview. Questions related to annoyance, concern and trust were scored on a scale of 1-10, with score 10 representing the highest level of impact or trust. For the adherence to treatment before and after a minor bleed the Medication Adherence Rating Scale (MARS-5) questionnaire was used. The total MARS-5 score ranges from 5 to 25; score 5 is indicative of poor adherence and 25 suggest perfect adherence. Furthermore, the impact (restrictions) of a bleed on physical activities and daily life was assessed using a VAS score ranging from 1 to 10; score 10 representing the highest level of restriction. RESULTS: A total of 142 patients were included. During NOAC treatment, minor bleeds were reported by 87 patients (61%) of whom 16 (11%) suffered from a CRNMB. All patients that suffered from a CRNMB contacted their treating physician and 13 received treatment. The most frequently reported CRNMBs were epistaxis (n = 6), a bleed after injury (n = 3), rectal bleed (n = 2) and an eye bleed (n = 2). With regard to the impact of a CRNMB, the median level of annoyance was 8 (min-max 2-10)) and the level of concern 4 (min-max 1-10). The MARS-5 score for adherence to treatment was only marginally influenced. Also the level of trust remained high after the CRNMB. Out of 12 patients, only 2 patients reported a reduction of 1 and 8 points, respectively. Ten patients scored no change and one patient scored a 1 point increase in the level of trust. The mean reduction in trust was 0.7 (95%CI -0.8 to 2.2). With regard to the reported restrictions on physical activities, 8 out of 12 patients reported no (score 1) or only marginal impact (score 2), 2 patients reported a moderate impact (score 5 and 6) and 2 patients reported a high impact score 7 (mean score 2.9 (95%CI 1.3-4.5). For the daily life impact question, 5 out of 9 patients reported no or only marginal impact, 3 patients reported a moderate impact (scores 4 and 5) and 1 patient reported maximal impact (score 10) (mean score 3.2 (95%CI 0.9-5.5)). CONCLUSION: In our study the level of trust, annoyance and concern were not significantly impacted by the CRNMB, nor the adherence to treatment and impact on daily life and physical activities. However, on an individual basis, there were patients that reported a high impact. We hope that future data on impact of this type of minor bleeds will help us identify and guide suboptimaly adherent NOAC patients in shared decision manner.

Management of infection prophylaxis in Dutch patients with myelodysplastic syndromes, a web-based case vignette questionnaire: The MINDSET study.

OBJECTIVES: Infections are a major cause of morbidity and mortality in patients with myelodysplastic syndromes (MDS). The objective of the MINDSET study was to evaluate haematologists' management of infection prevention in MDS patients using a case vignette study and to assess the availability of guidelines. METHODS: We conducted a web-based, nationwide survey amongst haematologists in the Netherlands between September and December 2021. The survey included a set of case vignettes. In addition, the availability of protocols was evaluated. RESULTS: Sixty responses were obtained (23.6%). These responses were well distributed across hospital types as well as level of experience. No protocols regarding infection prophylaxis specifically for MDS patients were received. In the case vignette of a 75-year-old MDS patient, respondents would primarily prescribe infection prophylaxis in case of recurrent infections (96.7%) and neutropenia (75.0% for absolute neutrophil count [ANC] < 0.2 × 109 /L and 53.3% for ANC < 0.5 × 109 /L), especially in combination with hypomethylating agents (80.0%), lenalidomide (66.7%) or chemotherapy (51.7%). Respondents would predominantly choose antibacterial agents (85.0%), followed by antifungal agents (71.7%). CONCLUSIONS: This study showed diverse reasons and considerations of haematologists regarding whether to prescribe infection prophylaxis in MDS patients. Given the seriousness of infections in MDS patients, patient-tailored recommendations might be valuable in clinical decision-making.

Cumulative corticosteroid-sparing effect of anti-interleukin-5/5Ra in eosinophilic asthma.

BACKGROUND: Anti-interleukin (IL)-5/IL-5 receptor α (IL-5Ra) therapy has been shown to reduce maintenance oral corticosteroid (OCS) dose in severe eosinophilic asthma. However, the effect on cumulative OCS exposure is currently unknown. Neither is it known how prior OCS exposure affects response to anti-IL-5/5Ra treatment. We aimed primarily to compare the cumulative OCS exposure over a 2-year period before and after anti-IL-5/5Ra initiation, and secondarily to investigate whether duration and cumulative OCS exposure prior to anti-IL-5/5Ra influence the ability to discontinue OCS within 2 years of anti-IL-5/5Ra therapy. METHODS: This real-world nationwide observational registry-based study evaluated all dispensed OCS from 389 adults with severe eosinophilic asthma included in the Dutch Severe Asthma Registry (RAPSODI) 2 years before and 2 years after initiating anti-IL-5/5Ra. The Wilcoxon signed-rank test and multivariable regression analyses were used. RESULTS: Median (interquartile range) cumulative OCS exposure in the 2 years before and after anti-IL-5/5Ra initiation decreased from 2.715 (1.150-5.539) to 1.050 (0.300-3.640) g (p<0.001). 52% of patients were able to discontinue OCS within 2 years after anti-IL-5/5Ra therapy, which was independently predicted by lower and shorter prior OCS exposure. CONCLUSIONS: This real-world study showed that anti-IL-5/5Ra therapy leads to a significant reduction in cumulative OCS exposure over a 2-year period. Patients with lower and shorter OCS exposure were more likely to completely eliminate OCS. Since cumulative exposure increased progressively prior to anti-IL-5/5Ra initiation, our data suggest that early intervention leads to a better long-term prognosis in patients with severe eosinophilic asthma.

Patient-reported outcome measures after 8 weeks of mepolizumab treatment and long-term outcomes in patients with severe asthma: an observational study.

Background The novel anti-IL-5 drug mepolizumab improves asthma outcomes in the majority but not all patients with severe eosinophilic asthma. Currently it is difficult to predict an individuals' chance of being a responder. Early changes in patient-reported outcome measures may contribute to the prediction of long-term outcomes. Aim To compare early changes in patient-reported outcome measures after 8 weeks and long-term response to mepolizumab treatment. Method 22 severe eosinophilic asthma patients starting mepolizumab therapy in a severe asthma centre in the Netherlands were evaluated on baseline, 8 weeks and 52 weeks, collecting questionnaire scores and asthma-related parameters. Well-controlled asthma was defined as an asthma control questionnaire score ≤ 0.75. Long-term treatment response was defined as continuing mepolizumab therapy at 52 weeks. Results Nine patients (41%) had well-controlled asthma at 8 weeks and all were mepolizumab responders at 52 weeks (positive predictive value = 100%, 95%CI 66-100), versus only 5 responders out of 13 patients with not well-controlled asthma at 8 weeks (negative predictive value = 62%, 95%CI 32-86). Conclusion The results in this study suggest that patients receiving mepolizumab therapy with an ACQ-score ≤ 0.75 at 8 weeks are unlikely to need extensive monitoring, for they are very likely to be long-term responders.

Long-term Effect of Bariatric Surgery on the Use of Levothyroxine and Thyroid Levels.

BACKGROUND: The aim of this study was to evaluate the effect of bariatric surgery on the defined daily dose of levothyroxine (DDD LT4), thyroid-stimulating hormone (TSH), and free thyroxine (fT4) in female patients with hypothyroidism until 48 months after surgery. METHODS: A retrospective observational study of hypothyroid patients who underwent bariatric surgery. Changes in DDD LT4, TSH, and fT4 over a 48 month period after surgery were analyzed. RESULTS: Thirty-seven patients were included: 27 Roux-en-Y gastric bypass (RYGB), 6 sleeve gastrectomy (SG), 3 adjustable gastric band, and 1 one anastomosis gastric bypass. The median DDD LT4 decreased from 125 µg at baseline to 100 µg 12 months after surgery. From 24 to 48 months after surgery, the median DDD LT4 was stable at 125 µg. Most dose adjustments occurred during the first 24 months after surgery. In the time period of 24-48 months after surgery, the dose remained stable in 73.1% of the RYGB patients and in 60.0% of the SG patients. After 48 months in the RYGB group, no significant change in TSH and fT4 levels was observed. CONCLUSIONS: Bariatric surgery led to frequent dose adjustments during the first 2 years after surgery. However, 24-48 months after surgery in the majority of patients, the dosage remained stable. No significant change in TSH and fT4 was observed 48 months after RYGB. In the first 2 years after surgery, clinicians should frequently monitor TSH and fT4 for individual dose adjustment of levothyroxine. Thereafter, the frequency of monitoring may be decreased.