Appropriateness of antithrombotics in geriatric inpatients with atrial fibrillation: a retrospective, cross-sectional study.

BACKGROUND: Atrial fibrillation occurs in nearly half of geriatric inpatients and is a major cause of morbidity and mortality. Suboptimal anticoagulation use is an important concern in this population. This study aimed to evaluate the appropriateness of antithrombotic therapies in this patient cohort. METHODS: A retrospective analysis was conducted on the geriatric wards of a teaching hospital in Belgium, on a background of clinical pharmacy services. The first 90 atrial fibrillation patients from 2020 to 2022 were included if they received an oral anticoagulant. We assessed utilisation and appropriateness of antithrombotics at discharge, examined reasons for guideline deviations, and explored factors associated with underdosing. Temporal associations for appropriateness and type of anticoagulant (vitamin K antagonist (VKA) vs direct oral anticoagulant (DOAC)) were assessed. RESULTS: The mean age of patients was 86.5 (±5.3) years and the median CHA2DS2-VASc score was 5 (interquartile range (IQR) 4-6). At discharge, 256 (94.8%) patients used a DOAC; nine (3.3%) used a VKA; one (0.4%) a DOAC-antiplatelet combination, and in four patients (1.5%) all antithrombotics were discontinued. The majority (64.4%) of patients received reduced DOAC doses with apixaban prescribed in 40.7%. In 39 (14.4%) patients, antithrombotic use was considered inappropriate, mostly without a rationale (23/39). Year 2022 (odds ratio (OR) 0.104; 95% confidence interval (CI), 0.012-0.878) was the sole determinant for underdosing. No significant differences were found with respect to appropriateness (p=0.533) or anticoagulant class (p=0.479) over time. CONCLUSION: Most geriatric inpatients received a justified reduced DOAC dose. A significant proportion was managed inappropriately with underdosing (= unjustified reduced dose) being most common. Frequently no rationale was provided for deviating from trial-tested doses.

Agreement Between a Colorimetric Assay and Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry for Quantifying Paracetamol Plasma Concentrations.

Special populations, like geriatric patients, experience altered paracetamol pharmacokinetics (PK), complicating pain management. More PK research is essential to optimize paracetamol (acetaminophen) dosing. Yet, the reference method ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) is not readily available. Therefore, we aimed to evaluate the agreement between UPLC-MS/MS and the more accessible colorimetric Roche acetaminophen (ACETA) assay in quantifying paracetamol plasma concentrations, to facilitate PK studies and therapeutic drug monitoring for pain management. Patient data and plasma samples were obtained from a prospective study including geriatric patients admitted to the geriatric wards. ACETA and UPLC-MS/MS assays were performed in two separate laboratories. Bland-Altman plot and Passing-Bablok regression were used to assess agreement. Accuracy was evaluated using the McNemar test for a threshold value of 10 mg/L. Population PK modeling was employed to bridge PK data obtained from both methods (NONMEM 7.5). A total of 242 plasma sample pairs were available from 40 geriatric patients (age range, 80-95 years). Paracetamol plasma concentrations from ACETA (median 9.8 [interquartile range 6.1-14.4] mg/L) and UPLC-MS/MS (9.5 [6.2-14.8] mg/L) did not differ significantly (P > 0.05). No significant proportional nor additive bias was observed between both assay methods. The classification accuracy (at threshold 10 mg/L) was 85% (P = 0.414). The conversion factor between ACETA and UPLC-MS/MS was estimated at 1.06 (relative standard error 5%), yet with a 13.4% (relative standard error 23%) interindividual variability. ACETA assay showed no systematic bias in comparison with the UPLC-MS/MS assay in determining paracetamol exposure in geriatric blood samples despite the imprecision.

Therapy and guideline adherence at a multidisciplinary hypertension clinic: A prospective, observational study.

BACKGROUND: Hypertension is highly prevalent and remains one of the most frequent and preventable causes of cardiovascular morbidity and mortality. Yet, suboptimal blood pressure control is common. Hypertension clinics might play an important role in improving target attainment, by targeting drug therapy adherence, improving guideline compliance and by involving pharmacists. OBJECTIVES: We aimed to characterize patient drug therapy adherence, prescriber guideline compliance and pharmacist interventions at the hypertension clinic. METHODS: A prospective observational study was performed at the hypertension clinic of a large, academic hospital. Adult Dutch-speaking patients were eligible for inclusion. Following data were collected: patient demographics, medication use, patient adherence to prescribed antihypertensive drug therapies according to the BAASIS tool and prescriber compliance to the 2018 European Society of Cardiology (ESC) hypertension guidelines. RESULTS: A cohort of 108 patients was included with 51.9% male and aged 65 (IQR: 52-75) years. In total, 104 patients took at least 1 antihypertensive drug and 46 patients (44.2%) were classified as non-adherent with regard to their antihypertensive treatment; 82 patients (78.8%) had suboptimal blood pressure control. Compliance with the ESC guidelines was 66.3% prior to the consultation at the clinic and significantly increased to 77.9% thereafter (p = 0.0015). The clinical pharmacist performed a medication review for 27 patients with a total of 44 recommendations and an acceptance rate of 59.1%. CONCLUSION: A visit to the multidisciplinary hypertension clinic improved prescriber guideline compliance and the use of single pill combinations. Involvement of a clinical pharmacist could be beneficial to further improve patient drug therapy adherence and guideline compliance.

Predictors for unplanned hospital admissions in community dwelling adults: A dynamic cohort study.

BACKGROUND: Polypharmacy and inappropriate medication use are associated with unplanned hospital admissions. Targeted interventions might reduce the hospitalization risk. Yet, it remains unclear which patient profiles derive the largest benefit from such interventions. OBJECTIVE: The aim of this study was to determine independent risk factors, among which polypharmacy, for unplanned hospital admissions in a cohort of community dwelling adults. METHODS: A retrospective study was performed using a large general practice registry and an insurance database in Flanders, Belgium. Community dwelling adults aged 40 years or older with data for 2013-2015 were included. The index date was the last general practitioner contact in 2014. Determinants were collected during the preceding year. Unplanned hospital admissions were determined during the year after the index date. Univariable logistic regression models were fitted on each risk factor for an unplanned hospital admission as the primary outcome. Two multivariable models were derived. RESULTS: In total, 40411 patients were included and 2126 (5.26%) experienced an unplanned hospital admission. Mean age was 58.3 (±12.3) years. The two models identified the following determinants for an unplanned hospital admission: excessive polypharmacy, older age, male sex, number of comorbidities, atrial fibrillation, chronic obstructive pulmonary disease or stroke, low hemoglobin, use of hypnotics, antipsychotics, antidepressants or antiepileptics and prior hospital and general practitioner visits. Prior hospital visits was the largest determinant. CONCLUSIONS: In our study we identified and confirmed the presence of known determinants for unplanned hospital admissions in community dwelling adults, most of which align with a geriatric phenotype. Our findings can inform the allocation of interventions aiming to reduce unplanned hospital admissions.

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).

Guideline-Directed Medical Therapies for Heart Failure with a Reduced Ejection Fraction in Older Adults: A Narrative Review on Efficacy, Safety and Timeliness.

Heart failure is a prevalent syndrome among older adults, with a major impact on morbidity and mortality. Higher age is correlated with underuse of guideline-directed medical therapies which, in turn, has been linked to worse clinical outcomes. Importantly, most evidence so far has been collected in adults who were younger, less multi-morbid and polymedicated compared with those who are commonly treated in daily clinical practice. Hence, we aimed to assess and describe the evidence base for pharmacotherapy in older adults with heart failure with a reduced ejection. First, a narrative review was undertaken using Medline, from inception to January 2023. Four foundational therapies were selected based on the latest European Society of Cardiology clinical practice guideline: angiotensin-converting enzyme inhibitors/angiotensin receptor neprilysin inhibitors, beta blockers, mineralocorticoid receptor antagonists and sodium-glucose cotransporter-2 inhibitors. Post hoc analyses from landmark heart failure drug trials were searched and included if they contained data on the impact of age on efficacy, safety and/or timeliness of therapies in the management of heart failure with a reduced ejection fraction. Second, a proposal was developed to support and promote the use of evidence-based heart failure pharmacotherapy in complex, older adults. In total, 11 articles were selected: 4 meta-analyses, 6 post hoc analyses and 1 review paper. No attenuation of efficacy for any of the foundational agents was found in older adults. Regarding safety, dedicated analyses showed that beta blockers, mineraloid receptor antagonists, sacubitril-valsartan, dapagliflozin and empagliflozin retained their overall benefit-risk profile regardless of age. Time to benefit was short and occurred generally within 1 month. Consensus was achieved on a five-step proposal to manage complex medication regimens in older adults suffering from heart failure. In conclusion, older adults suffering from heart failure with a reduced ejection fraction should not be denied treatment based on their age.

Should vericiguat be initiated in geriatric inpatients with heart failure with reduced ejection fraction and a worsening heart failure event prior to discharge?

Heart failure (HF) occurs predominantly in older adults. HF patients have an increased risk for an acute exacerbation, which commonly requires hospitalisation. Such a worsening HF (WHF) event has an impact on prognosis. Vericiguat is a novel agent which has been shown to reduce the HF hospitalisation risk in patients with a recent WHF event. It is not fully clear how to position this novel agent in geriatric HF inpatients.

Age is just a number: the concept of time to benefit in older adults.

A female nursing home resident aged >70 years was admitted to the geriatric ward with de novo dysphagia 6 days after being discharged from the stroke unit. Metformin and ezetimibe had been added to her treatment regimen which already consisted of clopidogrel, atorvastatin, denosumab, calcium and vitamin D. At the geriatric ward a multidisciplinary team involving clinical pharmacists reviewed all treatments and appraised the time to benefit, ascertaining whether there was sufficient time left to experience therapeutic benefits. As a result, metformin, ezetimibe, denosumab, calcium and vitamin D were discontinued. This case report illustrates that both mortality risk assessment and evaluation of the time to benefit should be part of any medication review in frail older adults. Conversely, with limited available data pertaining to the concept of time to benefit, we advocate a broader awareness among pharmacists and a systematic assessment in future clinical trials.

[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.

Estimating the Time to Benefit for Therapies in Heart Failure with Reduced Ejection Fraction: A Case Study of Sacubitril-Valsartan Using Reconstructed Data from a Randomized Controlled Trial.

BACKGROUND: Foundational therapies in heart failure improve clinical outcomes in heart failure with a reduced ejection fraction (HFrEF). Underuse of these life-prolonging heart failure therapies, such as sacubitril-valsartan, is common in older adults and has been associated with worse clinical outcomes. Characterizing the early benefits seen with these therapies might help increase their uptake in older adults. OBJECTIVE: We applied several methods to estimate the time to benefit of an HFrEF therapy, using sacubitril-valsartan as a case study. METHODS: PARADIGM-HF was a randomized controlled study on sacubitril-valsartan versus enalapril in stable, ambulatory HFrEF patients (n = 8399). The primary endpoint, a composite of death from cardiovascular causes or a first hospitalization for heart failure, was significantly reduced (sacubitril-valsartan (21.8%) versus enalapril (26.5%), hazard ratio (HR) 0.80 (95% confidence interval [CI] 0.73-0.87). We extracted and tabulated the Kaplan-Meier (KM) curves of the primary endpoint. An individual patient dataset was then reconstructed. The following methods were applied to explore the time to benefit of sacubitril-valsartan versus enalapril: visual estimation of the point of divergence of the KM curves, statistical process control (SPC), unadjusted landmark analyses using Cox proportional hazards analysis with 30-day increments until significance was persistently achieved, and comparing the survival probabilities of the extracted life tables. RESULTS: Six raters visually estimated the time to benefit at a median of 60 days (interquartile range 38-10 days). Using SPC we found an early benefit from 28 days on, using the longest predefined control period of 28 days. An absolute risk reduction of 1 and 2% was found after 59 and 250 days, respectively. The reconstructed dataset provided a similar HR of 0.8004 (95% CI 0.7331-0.8739). Landmark analyses persistently showed statistical significance from 390 days and later. Survival probabilities differed from 35 days onward. CONCLUSION: Using multiple approaches, the earliest benefit of sacubitril-valsartan compared to enalapril in stable HFrEF was found at about 1 month after initiation.

Consensus validation of a screening tool for cardiovascular pharmacotherapy in geriatric patients: the RASP_CARDIO list (Rationalization of Home Medication by an Adjusted STOPP list in Older Patients).

PURPOSE: Cardiovascular agents commonly used in geriatric patients, are linked to potentially avoidable harm and might hence be a suitable substrate for medication review practices. Therefore, we sought to update and validate the content of the cardiovascular segment of the previously published Rationalization of Home Medication by an Adjusted STOPP list in Older Patients (RASP) List. METHODS: A three-step study was conducted by the pharmacy department in collaboration with the geriatric medicine and cardiology department at the University Hospitals Leuven, Belgium. First, the cardiovascular segment of the RASP list version 2014 was updated taking into account published research, other screening tools and the input of end-users. Secondly, this draft was reviewed during three panel discussions with five expert cardiologists and three clinical pharmacists, all of whom had relevant expertise in geriatric pharmacotherapy. Thirdly, the content was validated using a modified Delphi Technique by a panel of European hospital pharmacists, cardiologists, geriatricians and an internal medicine physician. RESULTS: After the first and second step, the RASP_CARDIO list comprised 94 statements. Consensus (≥ 80% agreement) of all statements and one new statement about gliflozins in heart failure was achieved by a panel of seventeen experts across four European countries after two validation rounds. The final construct comprised a list of 95 statements related to potentially inappropriate prescribing of cardiovascular agents. CONCLUSION: The RASP_CARDIO list is an updated and validated explicit screening tool to optimize cardiovascular pharmacotherapy in geriatric patients.

The effect of a trAnSitional Pharmacist Intervention in geRiatric inpatients on hospital visits after dischargE (ASPIRE): Protocol for a randomized controlled trial.

BACKGROUND: Unplanned rehospitalizations occur frequently in older patients. Drug-related problems constitute a major and largely preventable cause with inappropriate prescribing being a substantial culprit. Solutions are needed to reduce this risk by targeting pharmacotherapy both during and after hospital stay. Therefore, we aim to perform a randomized controlled trial in geriatric inpatients to investigate the impact of a multifaceted clinical pharmacy intervention on health-related outcomes. METHODS/DESIGN: The study concerns a monocenter, non-blinded, randomized controlled trial that will take place at the acute geriatric wards of a large academic hospital. Patients being in a palliative stage with active therapy withdrawal or patients discharged to another ward within the same hospital or another hospital are excluded. In total, 828 patients will be randomized (1:1) to the usual care or intervention group. The multifaceted clinical pharmacy intervention comprises medication reconciliation at admission and discharge, medication review, patient/caregiver education, intensified communication with primary care providers and post-discharge follow-up, which also includes a telepharmacology service. The primary endpoint is defined as the time to an all-cause, unplanned hospital revisit within six months after discharge. Other health-related outcomes such as drug-related readmissions, quality of life and number of potentially inappropriate medications will be analyzed as secondary endpoints. Patient inclusion started in February 2021. DISCUSSION: This study will provide useful insights regarding the impact of clinical pharmacy interventions on geriatric wards with the goal to optimize health-related outcomes such as hospital revisits. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04617340.

Drug-related hospital admissions in older adults: comparison of the Naranjo algorithm and an adjusted version of the Kramer algorithm.

PURPOSE: Drug-related admissions (DRAs) are an important cause of preventable harm in older adults. Multiple algorithms exist to assess causality of adverse drug reactions, including the Naranjo algorithm and an adjusted version of the Kramer algorithm. The performance of these tools in assessing DRA causality has not been robustly shown. This study aimed to evaluate the ability of the adjusted Kramer algorithm to adjudicate DRA causality in geriatric inpatients. METHODS: DRAs were assessed in a convenience sample of patients admitted to the acute geriatric wards of an academic hospital. DRAs were identified by expert consensus and causality was evaluated using the Naranjo and the adjusted Kramer algorithms. Positive agreement with expert consensus was calculated for both algorithms. A multivariable logistic regression analysis was performed to explore determinants for a DRA. RESULTS: A total of 218 geriatric inpatients was included of whom 65 (29.8%) experienced a DRA. Positive agreement was 72.3% (95% confidence interval (CI), 59.6-82.3%) and 100% (95% CI, 93.0-100%) for the Naranjo and the adjusted Kramer algorithm, respectively. Diuretics were the main culprits and most DRAs were attributed to a fall (n = 18; 27.7%). A fall-related principal diagnosis was independently associated with a DRA (odds ratio 20.11; 95% CI, 5.60-72.24). CONCLUSION: The adjusted Kramer algorithm demonstrated a higher positive agreement with expert consensus in assessing DRA causality in geriatric inpatients compared to the Naranjo algorithm. Our results further support implementation of the adjusted Kramer algorithm as part of a standardized DRA assessment in older adults.

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.

SGLT2 Inhibitors in Older Adults with Heart Failure with Preserved Ejection Fraction.

Heart failure is an important medical condition that is prevalent in older adults. Multiple therapies have been identified that improve clinical outcome in heart failure with a reduced ejection fraction. Conversely, this has not been the case in heart failure with preserved ejection fraction (HFpEF). Until now, empagliflozin is the first therapy that has convincingly been shown to improve clinical outcome in HFpEF. Importantly, some key points should be considered to better understand the impact of empagliflozin on the patient trajectory, particularly in older adults with HFpEF. In this current opinion article, we have therefore provided more information on how to translate the findings of the EMPEROR-Preserved trial to the setting of older adults, with a focus on the impact of empagliflozin on hospitalizations, both heart failure-related and all-cause. To better understand the importance of EMPEROR-Preserved findings, we compared these findings with previous relevant HFpEF and heart failure with reduced ejection fraction (HFrEF) trials and provided information on ongoing trials in the HFpEF setting.

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.