Pharmacokinetic drug-drug interactions with direct anticoagulants in the management of cancer-associated thrombosis.

Drug-drug interactions (DDIs) are common in cancer management and complicate the choice of anticoagulation in cancer-associated thrombosis. Cancer confers an increased risk of thrombotic events. Also, more bleeding events are observed in those who receive anticoagulation compared to those without cancer. In the treatment of cancer-associated thrombosis, direct oral anticoagulants (DOACs) have been found to be at least as effective as low-molecular weight heparins, which became the standard of care after several trials demonstrated superiority over vitamin K antagonists. Non-inferiority compared to low-molecular weight heparins has been shown for rivaroxaban, edoxaban and apixaban with a signal of fewer recurrent thrombotic events, albeit with an increase in bleeding events. Yet, potentially major pharmacokinetic drug-drug interactions have been identified as a reason to withhold DOACs and to rather choose an alternative. Practical guidance on what constitutes a major pharmacokinetic interaction and/or how to deal with these interactions in clinical practice is limited. Hence, here we have provided a framework to allow clinicians to better deal with pharmacokinetic drug-drug interactions between DOACs and cancer therapies in the management of cancer-associated thrombosis. In this review we have discussed the current literature, how the pharmacokinetic profile links to the label information on DDI, and have provided a practical proposal, applied to a clinical case.

The impact of a pharmacist intervention on post-discharge hypnotic drug discontinuation in geriatric inpatients: a before-after study.

BACKGROUND: Chronic use of hypnotic agents is prevalent in older adults, who as a result are at increased risk for certain adverse events, such as day-time drowsiness and falls. Multiple strategies to discontinue hypnotics have been tested in geriatric patients, but evidence remains scarce. Hence, we aimed to investigate a multicomponent intervention to reduce hypnotic drug use in geriatric inpatients. METHODS: A before-after study was performed on the acute geriatric wards of a teaching hospital. The before group (= control group) received usual care, while intervention patients (= intervention group) were exposed to a pharmacist-led deprescribing intervention, comprising education of health care personnel, access to standardized discontinuation regimens, patient education and support of transitional care. The primary outcome was hypnotic drug discontinuation at one month after discharge. Secondary outcomes among others were sleep quality and hypnotic use at one and two weeks after enrolment and at discharge. Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI) upon inclusion, two weeks after enrolment and one month after discharge. Determinants for the primary outcome were identified using regression analysis. RESULTS: A total of 173 patients were enrolled, with 70.5% of patients taking benzodiazepines. Average age was 85 years (interquartile range 81-88.5) and 28.3% were male. A higher discontinuation rate at one month after discharge was observed in favour of the intervention (37.7% vs. 21.9%, p = 0.02281). No difference in sleep quality was found between both groups (p = 0.719). The average sleep quality was 8.74 (95% confidence interval (CI): 7.98-9.49) and 8.57 (95% CI: 7.75-9.39) in the control and intervention groups respectively. Determinants for discontinuation at one month were: the intervention (odds ratio (OR) 2.36, 95% CI: 1.14-4.99), fall on admission (OR 2.05; 95% CI: 0.95-4.43), use of a z-drug (OR 0.54, 95% CI: 0.23-1.22), PSQI score on admission (OR 1.08, 95% CI: 0.97-1.19) and discontinuation prior to discharge (OR 4.71, 95% CI: 2.26-10.17). CONCLUSIONS: A pharmacist-led intervention in geriatric inpatients was associated with a reduction of hypnotic drug use one month after discharge, without any loss in sleep quality. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05521971 (retrospectively registered on 29th of August 2022).

Community pharmacists' perceptions on multidisciplinary heart failure care: an exploratory qualitative study.

BACKGROUND: Heart failure (HF) is an important health problem and guidelines recommend multidisciplinary management. The pharmacist is an important member of the multidisciplinary heart failure team, both in the hospital and community setting. This study aims to explore the perceptions of community pharmacists on their role in HF care. METHODS: We conducted a qualitative study based on face-to-face semi-structured interviews with 13 Belgian community pharmacists between September 2020 and December 2020. We used the Qualitative Analysis Guide of Leuven (QUAGOL) method as guidance for data analysis until data saturation was reached. We structured interview content into a thematic matrix. RESULTS: We identified two major themes: heart failure management and multidisciplinary management. Pharmacists feel responsible for the pharmacological and non-pharmacological management of heart failure, citing easy access and pharmacological expertise as important assets. Diagnostic uncertainty, lack of knowledge and time, disease complexity and difficulties in communication with patients and informal care providers are barriers to optimal management. General practitioners are the most important partners in multidisciplinary community heart failure management, although pharmacists perceive a lack of appreciation and cooperation and deplore communication difficulties. They feel intrinsically motivated to provide extended pharmaceutical care in HF but cite the lack of financial viability and information sharing structures as important barriers. CONCLUSION: The importance of pharmacist involvement in multidisciplinary heart failure teams is undisputed by Belgian pharmacists, who cite easy access and pharmacological expertise as important assets. They point out several barriers impeding evidence-based pharmacist care for outpatients with heart failure: diagnostic uncertainty and disease complexity, lack of multidisciplinary information technology and insufficient resources. We recommend that future policy should focus on improved medical data exchanges between primary and secondary care electronic health records as well as the reinforcement of interprofessional relationships between locally affiliated pharmacists and general practitioners.

Improving appropriate use of anticoagulants in hospitalised patients: A pharmacist-led Check of Medication Appropriateness intervention.

AIMS: Inappropriate anticoagulant use increases the risk of bleeding and thrombotic events. We implemented clinical decision rules to promote judicious medication use, as part of the 'Check of Medication Appropriateness' (CMA). The CMA is a pharmacist-led review service, targeting potentially inappropriate prescriptions (PIPs). In this analysis, we aimed to evaluate the impact of the CMA on anticoagulant prescribing. METHODS: The number of anticoagulant-related PIPs was evaluated before and after implementation of the intervention in a quasi-experimental interrupted time series analysis. The pre-implementation cohort received usual care. The anticoagulant-focused CMA, comprising 13 clinical rules pertaining to anticoagulation therapies, was implemented in the post-implementation cohort. Segmented regression analysis was used to assess the impact of the intervention on the number of residual PIPs. A residual PIP was defined as a PIP which persisted up to 48 hours after the CMA intervention. Total number of recommendations and acceptance rate were documented for the 2-year post-implementation period. RESULTS: Pre-implementation, we observed 501 PIPs in 466 inpatients on 36 days, with a median proportion of 78.5% (range: 46.2%-100%) residual PIPs per day. Post-implementation, 538 PIPs were detected in 485 patients over the same number of days. The CMA intervention reduced the median proportion to 18.2% (range: 0-100%) per day. The effect coincided with an immediate relative reduction of 70% (95%CI 0.19-0.46) in anticoagulant-related residual PIPs. Post-implementation, 2778 recommendations were provided and 75.1% were accepted. CONCLUSION: Our CMA approach significantly reduced anticoagulant-related PIPs. Implementing a pharmacist-led intervention, based on clinical rules, may support safer prescribing of anticoagulants.

Pharmacokinetics of 2 oral paracetamol formulations in hospitalized octogenarians.

AIMS: It is currently unclear how paracetamol should be dosed in order to increase its efficacy while warranting safety in very old adults. The objective was to evaluate the pharmacokinetics of 2 oral paracetamol formulations and its metabolites in hospitalized octogenarians. METHODS: Geriatric inpatients aged 80 years and older received a 1000-mg paracetamol tablet or granulate at 08.00, 14.00 and 20.00. After at least 4 consecutive gifts, plasma samples were collected around the 08.00 dose (trough, +0.5, +1, +2, +4, +5 and +6 h). Plasma concentrations of paracetamol and its metabolites were determined and individual pharmacokinetic parameters were derived. The Edmonton Frail Scale was used to assess frailty. An analgesic plasma target was defined as an average plasma concentration (Cavg ) of 10 mg/L. RESULTS: The mean (±standard deviation) age was 86.78 (±4.20) years. The majority (n = 26/36, 72%) received the tablet, 10 (28%) the granulate. Thirty patients (85%) were classified with moderate to severe frailty. Seven (21%) patients had a Cavg above 10 mg/L. The median [interquartile range] time to reach the peak concentration was 50.5 [31.50-92.50] and 42.50 [33.75-106.75] min for the tablet and granulate, respectively. The coefficient of variation was 95% for time to reach the peak concentration and 30% for Cavg of paracetamol. A correlation of Cavg of paracetamol was observed with female sex and total serum bilirubin. CONCLUSION: Large interindividual differences were found for pharmacokinetic parameters of oral paracetamol in frail inpatients after multiple dosing. Female sex and higher total serum bilirubin concentrations were associated with paracetamol exposure. No significant differences were observed between the tablet and granulate.

The value and limitations of new oral anticoagulant plasma level assessments.

The class of new oral anticoagulants (NOACs) has been developed to provide reliable oral anticoagulation without the need for therapeutic drug monitoring. Based on phase I and II trials and pharmacokinetic and pharmacodynamic modeling, fixed drug doses have been selected for large phase III clinical trials for each currently available NOAC. In these trials, the use of the fixed dose without plasma level assessments was shown to be at least as effective and at least as safe as vitamin K antagonists with continuous therapeutic drug monitoring. Real world evidence reaffirms that the use of a fixed NOAC dose without plasma level assessment is safe and effective in a large variety of patients. Nevertheless, measurement of NOAC plasma levels can add information that may be useful in some clinical scenarios. This review discusses the possible use cases, the limitations, and the practical implementation of measuring NOAC plasma concentrations.

End-users feedback and perceptions associated with the implementation of a clinical-rule based Check of Medication Appropriateness service.

BACKGROUND: To support appropriate prescribing hospital-wide, the 'Check of Medication Appropriateness' (CMA) service was implemented at the University Hospitals Leuven. The CMA concerns a clinical rule based and pharmacist-led medication review service. The aim of this study was to explore both physicians' and pharmacists' feedback on the optimised CMA service to further improve the service. METHODS: An anonymous e-questionnaire was sent to all physicians active in the University Hospitals Leuven (n = 1631) and to all clinical pharmacists performing the CMA service (n = 16). Feedback was collected using multiple choice questions. During a 5-month period, physicians were also contacted in case of non-acceptance of recommendations to investigate barriers affecting implementation. Thematic analysis was performed and additional acceptance after telephone contact within 24 h was registered. RESULTS: A total of 119 physicians (7.3%) and 16 pharmacists (100%) completed the e-questionnaire. The overall service was assessed as clinically relevant to highly relevant by 77.7% of physicians. The main reasons for non-acceptance of recommendations were related to workload, work environment and time constraints. About two thirds (66.3%) of initially not-accepted recommendations were accepted after phone contact. A nearly full consensus was reached among pharmacists (15/16) on the centralised CMA being complementary to current clinical pharmacy activities. Two major barriers were reported by pharmacists: (1) too limited time allocation and (2) a large number of irrelevant alerts. CONCLUSIONS: The CMA was perceived as clinically relevant by the majority of end-users. Acceptance rate of pharmaceutical recommendations was further increased by calling the physician. Increasing the specificity of clinical rules in the future is imperative.

Overall performance of a drug-drug interaction clinical decision support system: quantitative evaluation and end-user survey.

BACKGROUND: Clinical decision support systems are implemented in many hospitals to prevent medication errors and associated harm. They are however associated with a high burden of false positive alerts and alert fatigue. The aim of this study was to evaluate a drug-drug interaction (DDI) clinical decision support system in terms of its performance, uptake and user satisfaction and to identify barriers and opportunities for improvement. METHODS: A quantitative evaluation and end-user survey were performed in a large teaching hospital. First, very severe DDI alerts generated between 2019 and 2021 were evaluated retrospectively. Data collection comprised alert burden, override rates, the number of alert overrides reviewed by pharmacists and the resulting pharmacist recommendations as well as their acceptance rate. Second, an e-survey was carried out among prescribers to assess satisfaction, usefulness and relevance of DDI alerts as well as reasons for overriding. RESULTS: A total of 38,409 very severe DDI alerts were generated, of which 88.2% were overridden by the prescriber. In 3.2% of reviewed overrides, a recommendation by the pharmacist was provided, of which 79.2% was accepted. False positive alerts were caused by a too broad screening interval and lack of incorporation of patient-specific characteristics, such as QTc values. Co-prescribing of a non-vitamin K oral anticoagulant and a low molecular weight heparin accounted for 49.8% of alerts, of which 92.2% were overridden. In 88 (1.1%) of these overridden alerts, concurrent therapy was still present. Despite the high override rate, the e-survey revealed that the DDI clinical decision support system was found useful by prescribers. CONCLUSIONS: Identified barriers were the lack of DDI-specific screening intervals and inclusion of patient-specific characteristics, both leading to a high number of false positive alerts and risk for alert fatigue. Despite these barriers, the added value of the DDI clinical decision support system was recognized by prescribers. Hence, integration of DDI-specific screening intervals and patient-specific characteristics is warranted to improve the performance of the DDI software.

[Case of hepatotoxicity of atorvastatin: the search for a possible etiology]. / Casus over hepatotoxiciteit door atorvastatine: de zoektocht naar mogelijke etiologie.

We describe a case of a geriatric patient with repeated hepatotoxicity after (re)start of atorvastatin. We also noticed an increased effect, a fast decline of LDL-cholesterol, after intake of atorvastatin. The intake of rosuvastatin or low dose lovastatin was not associated with hepatotoxicity. Multiple hypotheses were investigated and applied on the case. Genetic testing of statin transporters and CYP-enzymes and medication interactions could not explain the hepatotoxicity.

Venous Thromboembolism in Patients Discharged after COVID-19 Hospitalization.

BACKGROUND: Venous thromboembolism (VTE) is a frequent complication of COVID-19, so that the importance of adequate in-hospital thromboprophylaxis in patients hospitalized with COVID-19 is well established. However, the incidence of VTE after discharge and whether postdischarge thromboprophylaxis is beneficial and safe are unclear. In this prospective observational single-center study, we report the incidence of VTE 6 weeks after hospitalization and the use of postdischarge thromboprophylaxis. METHODS: Patients hospitalized with confirmed COVID-19 were invited to a multidisciplinary follow-up clinic 6 weeks after discharge. D-dimer and C-reactive protein were measured, and all patients were screened for deep vein thrombosis with venous duplex-ultrasound. Additionally, selected high-risk patients received computed tomography pulmonary angiogram or ventilation-perfusion (V/Q) scan to screen for incidental pulmonary embolism. RESULTS: Of 485 consecutive patients hospitalized from March through June 2020, 146 patients were analyzed, of which 39% had been admitted to the intensive care unit (ICU). Postdischarge thromboprophylaxis was prescribed in 28% of patients, but was used more frequently after ICU stay (61%) and in patients with higher maximal D-dimer and C-reactive protein levels during hospitalization. Six weeks after discharge, elevated D-dimer values were present in 32% of ward and 42% of ICU patients. Only one asymptomatic deep vein thrombosis (0.7%) and one symptomatic pulmonary embolism (0.7%) were diagnosed with systematic screening. No bleedings were reported. CONCLUSION: In patients who had been hospitalized with COVID-19, systematic screening for VTE 6 weeks after discharge revealed a low incidence of VTE. A strategy of selectively providing postdischarge thromboprophylaxis in high-risk patients seems safe and potentially effective.

Polypharmacy and excessive polypharmacy in community-dwelling middle aged and aged adults between 2011 and 2015.

AIMS: We aimed to assess the prevalence, components and evolution of polypharmacy and to evaluate risk factors associated with polypharmacy. METHODS: A retrospective dynamic cohort study was performed, using a primary healthcare database comprising Flemish community-dwelling adults aged ≥40 years between 2011 and 2015. Polypharmacy and excessive polypharmacy were defined as the use of 5-9 or minimum 10 different medications during 1 year, respectively. Temporal changes were analysed using an autoregressive error model. Risk factors for polypharmacy were evaluated using logistic regression. RESULTS: In total, 68 426 patients were included in the analysis. The prevalence of polypharmacy was 29.5% and 16.1% for excessive polypharmacy in 2015. The age-standardised prevalence rate of patients using minimum five medications increased with 1.3% per year (95% confidence interval (CI): 0.1968-2.4279). The mean number of unplanned hospital admissions was 0.07 (standard deviation (SD) 0.33) for polypharmacy patients and 0.19 (SD 0.53) for excessive polypharmacy patients. Four risk factors were found to be significantly correlated with polypharmacy: age (odds ratio (OR) 1.015; 95% CI: 1.013-1.017), female gender (OR 1.161; 95% CI: 1.108-1.216), number of chronic diseases (OR 1.126; 95% CI: 1.114-1.139) and number of general practitioner contacts (OR 1.283; 95% CI: 1.274-1.292). CONCLUSION: The prevalence of polypharmacy increased between 2011 and 2015. Polypharmacy and excessive polypharmacy patients appeared to differ based on our observations of characteristics, drug therapy and outcomes. Age, female gender, number of chronic diseases and number of general practitioner contacts were associated with polypharmacy.

Efficacy and safety of non-benzodiazepine and non-Z-drug hypnotic medication for insomnia in older people: a systematic literature review.

PURPOSE: Insomnia is highly prevalent in older persons and significantly impacts quality of life, functional abilities, and health status. It is frequently treated with benzodiazepines or Z-drugs. Due to adverse events, an increased use of alternative sedative medications has been observed in older adults. We aimed to study the efficacy and safety of alternative sedative medications for treating insomnia in older people, excluding benzodiazepines and Z-drugs. METHODS: We conducted a systematic search of MEDLINE (PubMed), EMBASE, and the Cochrane Central register of Controlled Trials databases. We included randomized controlled trials and prospective and retrospective quasi-experimental studies, conducted in patients older than 65 years, without psychiatric or neurological comorbidities. RESULTS: The systematic search yielded 9483 articles, of which 24 were included in this review, describing nine different sleep medications in total. No clear beneficial impact on sleep could be demonstrated in studies investigating the impact of melatonin (n = 10), paroxetine (n = 1), diphenhydramine (n = 1), tiagabine (n = 2), and valerian (n = 1). Ramelteon slightly improved sleep latency (n = 4), while doxepin was found to provide a sustained sleep improvement with a safety profile that was comparable to placebo (n = 3). Suvorexant showed an improved sleep maintenance with only mild side effects (n = 1). One study detected increased adverse effects of trazodone after 3 months but did not evaluate the effect on sleep. CONCLUSIONS: The overall level of evidence was limited, making it difficult to draw robust conclusions. Preliminary evidence points towards suvorexant, doxepin, and possibly ramelteon as effective and safe pharmacological alternatives for treating insomnia in older adults.

Medication review versus usual care to improve drug therapies in older inpatients not admitted to geriatric wards: a quasi-experimental study (RASP-IGCT).

BACKGROUND: Interdisciplinary geriatric consultation teams (IGCT) are regularly requested to provide comprehensive geriatric assessments in older inpatients. Our primary aim was to evaluate whether medication reviews increased the number of IGCT-provided drug-related recommendations. Secondary aims were to reduce the number of potentially inappropriate medications (PIMs), and to identify the acceptance rate of and determinants for the number of recommendations. METHODS: A before-after study was performed in older inpatients not admitted to acute geriatric wards. The before cohort received usual care (UC); the after cohort was subjected to the intervention (I), consisting of a systematic medication review, based on but not limited to the RASP (Rationalization of Home Medication by an Adjusted STOPP in Older Patients) list. The primary outcome measure was the number of IGCT-provided drug-related recommendations. Age, sex, Charlson Comorbidity Index, creatinine clearance and serum creatinine were ascertained upon enrolment. Following variables were determined on admission and at discharge: number of drugs and number as well as type of RASP-identified PIMs. Acceptance by ward-based physicians was also determined. Poisson regression was performed to identify determinants for the primary outcome measure. RESULTS: Fifty-nine participants were enrolled (nUC = 29; nI = 30). The intervention increased the number of drug-related recommendations from a median of 0 (IQR: 0-1) to 8 (IQR: 6.75-10) (p < 0.001). The median number of accepted recommendations differed significantly as well (UC vs. I: 0.0 (0.0-0.5) vs. 3.0 (0.0-5.3); p < 0.001). In the intervention cohort, patients were discharged with fewer drugs compared to admission (UC vs. I: 108.5%, IQR: 100.0-135.8% vs. 92%, IQR: 80.5-103.5%; p = 0.002). More RASP PIMs were discontinued in the intervention cohort, with a mean difference of 1.49 RASP PIMs (95% confidence interval (CI): 0.70, 2.23; p < 0.001). Regression analysis identified two determinants: allocation to the intervention cohort with an incidence rate ratio (IRR) of 14.1 (95% CI: 8.30, 23.8) and the number of preadmission drugs with an IRR of 1.06 (95% CI: 1.03, 1.09). CONCLUSIONS: A structured medication review as part of usual IGCT care may contribute to an increased detection of drug-related problems and help to further reduce polypharmacy in older inpatients, not admitted to acute geriatric care wards. TRIAL REGISTRATION: NCT02165618 , retrospectively registered June 17, 2014.

Predictors for unintentional medication reconciliation discrepancies in preadmission medication: a systematic review.

PURPOSE: Discrepancies in preadmission medication (PAM) are common and potentially harmful. Medication reconciliation is able to reduce the discrepancy rate, yet implementation is challenging. In order for reconciliation efforts to be more cost-effective, patients at high risk for reconciliation errors should be identified. The purpose of this systematic review is to identify predictors for unintentional discrepancies in PAM. METHODS: Medline and Embase were searched systematically until June 2017. Only studies concerning adult subjects were retained. Quantitative studies were included if predictors for unintentional discrepancies in the PAM had been determined on hospital admission. Variables were divided into patient-, medication-, and setting-related predictors based on a thematic analysis. Studies on identification of predictors for discrepancies and potentially harmful discrepancies were handled separately. RESULTS: Thirty-five studies were eligible, of which 5 studies focused on potentially harmful discrepancies. The following 16 significant variables were identified using multivariable prediction models: number of preadmission drugs, patient's age, availability of a drug list, patients' understanding of medication, usage of different outpatient pharmacies, number of high-risk drugs, discipline for which the patient is admitted, admitting physician's experience, number and type of consulted sources, patient's gender, type of care before admission, number of outpatient visits during the past year, class of medication, number of reimbursements, use of an electronic prescription system, and type of admission (elective vs emergency). The number of preadmission drugs was identified as a predictor in 20 studies. Potentially harmful discrepancies were ascertained in 5 studies with age found to have a predictive value in all 5 studies. CONCLUSION: Multiple suitable predictors for PAM-related discrepancies were identified of which higher age and polypharmacy were reported most frequently.

Prevalence and trends in polypharmacy and excessive polypharmacy: a retrospective national database analysis (2012-2021).

BACKGROUND: Polypharmacy is a growing concern, impacting patient safety and healthcare costs. Monitoring its prevalence and temporal trends is essential for effective healthcare management. AIM: This study aimed to determine prevalence and trends of polypharmacy and excessive polypharmacy in Belgium. METHOD: Utilizing a federal claims database, medication data were analyzed from 2012 to 2021. Polypharmacy (≥ 5 medications) and excessive polypharmacy (≥ 10 medications) were evaluated, with prevalence calculated per 1000 inhabitants, and reported per year, age group and region. Linear regression estimated the impact of age and year on polypharmacy prevalence. RESULTS: In 2021, polypharmacy and excessive polypharmacy were reported in 135/1000 and 31/1000 Belgians respectively. Prevalence of both increased steadily from 2012 to 2021, with excessive polypharmacy rising more prominently. Among adults aged ≥ 65 years, prevalence rates were higher, with polypharmacy at 434/1000 and excessive polypharmacy at 106/1000. Regional variations were observed, with prevalence highest in the Walloons region. Patient age and year (2012-2021) were associated with both polypharmacy and excessive polypharmacy (p < 0.001). CONCLUSION: We observed increases in polypharmacy and excessive polypharmacy over a decade in Belgium, particularly among older adults. Efforts to monitor, manage, and optimize medication use are imperative to ensure safe and effective healthcare delivery.