Neurocognitive effects associated with proprotein convertase subtilisin-kexin type 9 inhibitor use: a narrative review

Neurocognitive adverse events have been observed with the widespread use of 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors or “statins,” which reduce low-density lipoprotein cholesterol (LDL-C) levels and subsequently cardiovascular risk. The United States Food and Drug Association directed manufacturers of proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors to monitor for neurocognitive adverse events due to their potent effects on LDL-C reduction, which is a proposed mechanism for neuronal cell dysfunction. Other proposed mechanisms for PCSK9 inhibitor-associated neurocognitive adverse events include N-methyl-d-aspartate receptor modulation, dysregulation of lipid and glucose metabolism, and patient-specific risk factors for cognitive impairment. The purpose of this narrative review article is to describe the proposed mechanisms, incidence of neurocognitive adverse events from phase II and III trials for PCSK9 inhibitors, neurocognitive assessments utilized in clinical trials, and clinical implications. Given the increasing prevalence of PCSK9 inhibitor use and the neurocognitive adverse events observed with prior lipid-lowering therapies, clinicians should be aware of the risks associated with PCSK9 inhibitors, especially when therapy is indicated for patients at high risk for cardiovascular events. Overall, the incidence of PCSK9 inhibitor-associated neurocognitive appears to be uncommon. However, additional prospective studies evaluating cognitive impairment may be beneficial to determine the long-term safety of these agents.

Characteristics of voluntary reporting of adverse drug events related to antipsychotics in Australia: 14-year analysis

Background: Retrospective analyses of large databases of treated patients can provide useful links to the presence of drug misuse or rare and infrequent adverse effects, such as agranulocytosis, diabetic ketoacidosis or neuroleptic malignant syndrome. The aim of this study is to describe the adverse effects to antipsychotics reported in the Australian Database of Adverse Event Notifications (DAEN). Methods: Data were collected from the DAEN – a spontaneous reporting database. The database, which covered the period from January 2004 to December 2017, was obtained from the Therapeutic Goods Administration (TGA) website ( www.TGA.gov ). The drugs selected for this investigation are the following: aripiprazole, clozapine, olanzapine, paliperidone, risperidone, ziprasidone, quetiapine, haloperidol and pimozide. All data were analysed descriptively. Comparison of reporting and management of adverse events between adults (older than 20 years) and children (5–19 years) was undertaken using chi squared test, where p < 0.05 is significant. Results: A total of 7122 adverse events associated with the antipsychotics aripiprazole, clozapine, haloperidol, olanzapine, paliperidone, pimozide, quetiapine and risperidone were reported to the TGA between January 2004 and December 2017. On average, there were 2.6 adverse events reported for each case. The most common adverse event reported for antipsychotics was neuroleptic malignant syndrome. There were no significant differences in the number of co-medications, formulations, indications, therapeutic dose, hospital admission and overdose among the antipsychotics between paediatric and adult populations. However, there were significant differences between causality, death and the management of adverse events between adult and paediatric populations (5–19 years) ( p < 0.05, chi squared test). Conclusion: The antipsychotic drug associated with the highest adverse events in adults was clozapine, followed by olanzapine. The most common adverse event in adults, and reported with a number of antipsychotic drugs, was neuroleptic malignant syndrome. In children, the highest numbers of adverse events reported in the database were associated with risperidone, clozapine and olanzapine. Plain language summary Adverse events reported of antipsychotics Background: Retrospective analyses of large databases of treated patients can provide useful clues to the presence of drug misuse or rare and infrequent adverse effects associated with antipsychotics. The drugs selected for this investigation are the following: aripiprazole, clozapine, olanzapine, paliperidone, risperidone, ziprasidone, quetiapine, haloperidol and pimozide. Methods: All data were analysed descriptively and investigated for any associations between the variables collected. Comparison of reporting and management of adverse events between adults (older than 20 years) and children (5–19 years) was undertaken using chi squared test, where p < 0.05 is significant. Results: The antipsychotic drug associated with the highest adverse events was clozapine, followed by olanzapine. In children, the highest numbers of adverse events reported in the database were associated with risperidone, clozapine and olanzapine. The most common adverse event in adults, and reported with a number of antipsychotic drugs, was neuroleptic malignant syndrome. Conclusion: There were significant differences between causality, death and the management of adverse events between adult and paediatric populations (5–19 years).Keywords: Antipsychotics, adverse effects, adverse events, safety

Routine use of immunosuppressants is associated with mortality in hospitalised patients with COVID-19

Background: Whilst there is literature on the impact of SARS viruses in the severely immunosuppressed, less is known about the link between routine immunosuppressant use and outcome in COVID-19. Consequently, guidelines on their use vary depending on specific patient populations. Methods: The study population was drawn from the COPE Study (COVID-19 in Older People), a multicentre observational cohort study, across the UK and Italy. Data were collected between 27 February and 28 April 2020 by trained data-collectors and included all unselected consecutive admissions with COVID-19. Load (name/number of medications) and dosage of immunosuppressant were collected along with other covariate data. Primary outcome was time-to-mortality from the date of admission (or) date of diagnosis, if diagnosis was five or more days after admission. Secondary outcomes were Day-14 mortality and time-to-discharge. Data were analysed with mixed-effects, Cox proportional hazards and logistic regression models using non-users of immunosuppressants as the reference group. Results: In total 1184 patients were eligible for inclusion. The median (IQR) age was 74 (62–83), 676 (57%) were male, and 299 (25.3%) died in hospital (total person follow-up 15,540 days). Most patients exhibited at least one comorbidity, and 113 (~10%) were on immunosuppressants. Any immunosuppressant use was associated with increased mortality: aHR 1.87, 95% CI: 1.30, 2.69 (time to mortality) and aOR 1.71, 95% CI: 1.01–2.88 (14-day mortality). There also appeared to be a dose–response relationship. Conclusion: Despite possible indication bias, until further evidence emerges we recommend adhering to public health measures, a low threshold to seek medical advice and close monitoring of symptoms in those who take immunosuppressants routinely regardless of their indication. However, it should be noted that the inability to control for the underlying condition requiring immunosuppressants is a major limitation, and hence caution should be exercised in interpretation of the results. Plain Language Summary Regular Use of Immune Suppressing Drugs is Associated with Increased Risk of Death in Hospitalised Patients with COVID-19 Background: We do not have much information on how the COVID-19 virus affects patients who use immunosuppressants, drugs which inhibit or reduce the activity of the immune system. There are various conflicting views on whether immune-suppressing drugs are beneficial or detrimental in patients with the disease. Methods: This study collected data from 10 hospitals in the UK and one in Italy between February and April 2020 in order to identify any association between the regular use of immunosuppressant medicines and survival in patients who were admitted to hospital with COVID-19. Results: 1184 patients were included in the study, and 10% of them were using immunosuppressants. Any immunosuppressant use was associated with increased risk of death, and the risk appeared to increase if the dose of the medicine was higher. Conclusion: We therefore recommend that patients who take immunosuppressant medicines routinely should carefully adhere to social distancing measures, and seek medical attention early during the COVID-19 pandemic.

The use of a clinical decision support tool to assess the risk of QT drug–drug interactions in community pharmacies

Introduction: The handling of drug–drug interactions regarding QTc-prolongation (QT-DDIs) is not well defined. A clinical decision support (CDS) tool will support risk management of QT-DDIs. Therefore, we studied the effect of a CDS tool on the proportion of QT-DDIs for which an intervention was considered by pharmacists. Methods: An intervention study was performed using a pre- and post-design in 20 community pharmacies in The Netherlands. All QT-DDIs that occurred during a before- and after-period of three months were included. The impact of the use of a CDS tool to support the handling of QT-DDIs was studied. For each QT-DDI, handling of the QT-DDI and patient characteristics were extracted from the pharmacy information system. Primary outcome was the proportion of QT-DDIs with an intervention. Secondary outcomes were the type of interventions and the time associated with handling QT-DDIs. Logistic regression analysis was used to analyse the primary outcome. Results: Two hundred and forty-four QT-DDIs pre-CDS tool and 157 QT-DDIs post-CDS tool were included. Pharmacists intervened in 43.0% and 35.7% of the QT-DDIs pre- and post-CDS tool respectively (odds ratio 0.74; 95% confidence interval 0.49–1.11). Substitution of interacting agents was the most frequent intervention. Pharmacists spent 20.8 ± 3.5 min (mean ± SD) on handling QT-DDIs pre-CDS tool, which was reduced to 14.9 ± 2.4 min (mean ± SD) post-CDS tool. Of these, 4.5 ± 0.7 min (mean ± SD) were spent on the CDS tool. Conclusion: The CDS tool might be a first step to developing a tool to manage QT-DDIs via a structured approach. Improvement of the tool is needed in order to increase its diagnostic value and reduce redundant QT-DDI alerts. Plain Language Summary The use of a tool to support the handling of QTc-prolonging drug interactions in community pharmacies Introduction: Several drugs have the ability to cause heart rhythm disturbances as a rare side effect. This rhythm disturbance is called QTc-interval prolongation. It may result in cardiac arrest. For health care professionals, such as physicians and pharmacists, it is difficult to decide whether or not it is safe to proceed treating a patient with combinations of two or more of these QT-prolonging drugs. Recently, a tool was developed that supports the risk management of these QT drug–drug interactions (QT-DDIs). Methods: In this study, we studied the effect of this tool on the proportion of QT-DDIs for which an intervention was considered by pharmacists. An intervention study was performed using a pre- and post-design in 20 community pharmacies in The Netherlands. All QT-DDIs that occurred during a before- and after-period of 3 months were included. Results: Two hundred and forty-four QT-DDIs pre-implementation of the tool and 157 QT-DDIs post-implementation of the tool were included. Pharmacists intervened in 43.0% of the QT-DDIs before the tool was implemented and in 35.7% after implementation of the tool. Substitution of one of the interacting agents was the most frequent intervention. Pharmacists spent less time on handling QT-DDIs when the tool was used. Conclusion: The clinical decision support tool might be a first step to developing a tool to manage QT-DDIs via a structured approach.

Inappropriate medications and physical function: a systematic review

Background and aims: Inappropriate medication prescription is highly prevalent in older adults and is associated with adverse health outcomes. The aim of this study was to examine the associations between potentially inappropriate medications (PIMS) and potential prescribing omissions with physical function in older adults situated in diverse environments. Methods: A systematic search was completed using the following databases: MEDLINE, CINAHL, PsycINFO, EMBASE and COCHRANE. Results were extracted from the included studies. Results: In total, 55 studies reported on 2,767,594 participants with a mean age of 77.1 years (63.5% women). Study designs comprised 26 retrospective cohort studies, 21 prospective cohort studies and 8 cross-sectional studies. Inappropriate medications in community and hospital settings were significantly associated with higher risk of falls (21 out of 30 studies), higher risk of fractures (7 out of 9 studies), impaired activities of daily living (ADL; 8 out of 10 studies) and impaired instrumental ADL (IADL) score (4 out of 6 studies). Five out of seven studies also showed that PIMs were associated with poorer physical performance comprising the Timed Up and Go test, walking speed, grip strength, time to functional recovery, functional independence and scale of functioning. Many medication classes were implicated as PIMs in falls, fractures and impairment in physical performance including antipsychotic, sedative, anti-anxiety, anticholinergic, antidiabetic, opioid and antihypertensive medications. For patients not receiving musculoskeletal medications, such as calcium, vitamin D and bisphosphonates, older adults were found to be at risk of a hospital admission for a fall or fracture. Conclusion: Inappropriate medication prescriptions are associated with impaired physical function across longitudinal and cross-sectional studies in older adults situated in diverse settings. It is important to support older people to reduce their use of inappropriate medications and prevent prescribing omissions. Plain language summary Inappropriate medications and physical function Background and aims: The use of inappropriate medications is very common in older adults and is associated with harmful health problems. The aim was to examine associations between potentially inappropriate medications and potential prescribing omissions with physical function in older adults situated in diverse environments. Methods: Library databases were examined for possible studies to include and a systematic search was completed. Relevant information was obtained from the included studies. Results: In total, 55 studies reported on 2,767,594 participants who were an average age of 77.1 years and about 6 out of 10 were women. A variety of different study designs were used. Inappropriate medication prescriptions in community and hospital settings were significantly associated with higher risk of falls (21 out of 30 studies), higher risk of fractures (7 out of 9 studies), problems with activities of daily living (ADL), such as eating, bathing, dressing, grooming, walking and toileting (8 out of 10 studies) and problems with instrumental ADL such as managing medications, house cleaning and shopping (4 out of 6 studies). Five out of seven studies also showed that inappropriate medications were associated with poorer physical performance involving the Timed Up and Go test, walking speed, grip strength, time to functional recovery, functional independence and scale of functioning. Many types of medication classes were shown to be associated with a risk of falls, fractures and problems with physical performance. Omitted medications were also associated with falls and fractures. Conclusion: Inappropriate medication prescriptions are associated with problems relating to physical function. It is important to support older people to reduce their use of inappropriate medications and prevent prescribing omissions.

Anticholinergic burden in older adult inpatients: patterns from admission to discharge and associations with hospital outcomes

Background: Anticholinergic medications are associated with adverse outcomes in older adults and should be prescribed cautiously. We describe the Anticholinergic Risk Scale (ARS) scores of older inpatients and associations with outcomes. Methods: We included all emergency, first admissions of adults ⩾65 years old admitted to one hospital over 4 years. Demographics, discharge specialty, dementia/history of cognitive concern, illness acuity and medications were retrieved from electronic records. ARS scores were calculated as the sum of anticholinergic potential for each medication (0 = limited/none; 1 = moderate; 2 = strong and 3 = very strong). We categorised patients based on admission ARS score [ARS = 0 (reference); ARS = 1; ARS = 2; ARS ⩾ 3] and change in ARS score from admission to discharge [admission and discharge ARS = 0 (reference); same; decreased; increased]. We described anticholinergic prescribing patterns by discharge specialty and explored multivariable associations between ARS score categories and mortality using logistic regression [odds ratios (ORs), 95% confidence intervals (CIs)]. Results: From 33,360 patients, 10,183 (31%) were prescribed an anticholinergic medication on admission. Mean admission ARS scores were: Cardiology and Stroke = 0.56; General Medicine = 0.78; Geriatric Medicine = 0.83; Other medicine = 0.81; Trauma and Orthopaedics = 0.66; Other Surgery = 0.65. Mean ARS did not increase from admission to discharge in any specialty but reductions varied significantly, from 4.6% (Other Surgery) to 27.7% (Geriatric Medicine) ( p < 0.001). The odds of both 30-day inpatient and 30-day post-discharge mortality increased with admission ARS = 1 (OR = 1.21, 95% CI 1.01–1.44 and OR = 1.44, 1.18–1.74) but not with ARS = 2 or ARS ⩾ 3. The odds of 30-day post-discharge mortality were higher in all ARS change categories, relative to no anticholinergic exposure (same: OR = 1.45, 1.21–1.74, decreased: OR = 1.27, 1.01–1.57, increased: OR = 2.48, 1.98–3.08). Conclusion: The inconsistent dose–response associations with mortality may be due to confounding and measurement error which may be addressed by a prospective trial. Definitive evidence for this prevalent modifiable risk factor is required to support clinician behaviour-change, thus reducing variation in anticholinergic deprescribing by inpatient speciality. Plain language summary We describe how commonly medicines which block the chemical acetylcholine are prescribed to older adults admitted to hospital as an emergency and explore links between these medicines and death during or soon after hospital admission Backgroud: Medicines which block the chemical acetylcholine are commonly prescribed to treat symptoms such as itch and difficulty sleeping or to treat medical conditions such as depression. However, some studies in older adults have found potential links between these medicines and confusion and falls. Therefore, doctors are recommended to prescribe these drugs cautiously in adults aged 65 years and over. Methods: In our paper we use data collected as part of routine medical care at one university hospital to describe how often these medicines are prescribed in a large sample of older adults admitted to hospital as an emergency. We look at the medicines patients are prescribed on admission to the hospital and also when they are later discharged. Results: We find that these medicines are frequently prescribed. We also find that, in general, patients are prescribed fewer of these potentially harmful medicines on hospital discharge compared with hospital admission. This suggests that clinicians are aware of advice to prescribe acetylcholine blocking medicines cautiously and they are more often stopped in hospital than started. However, we find a lot of variation in practice depending on which hospital specialty was caring for the patient during their inpatient stay. We also find potential links with these medicines and death during the admission or soon after hospital discharge, but these potential links are not always consistent. Conclusion: Further study is needed to fully understand links between medicines that block acetylcholine and late life health. This will be important to reduce variation in prescribing practices.

Impact of deprescribing dual-purpose medications on patient-related outcomes for older adults near end-of-life: a systematic review and meta-analysis

Introduction: The decision to deprescribe medications used for both disease prevention and symptom control (dual-purpose medications or DPMs) is often challenging for clinicians. We aim to establish the impact of deprescribing DPMs on patient-related outcomes for older adults near end-of-life (EOL). Methods: This systematic review was conducted according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guideline. Literature was searched on PubMed, EMBASE, CINAHL, PsycINFO and Google Scholar until December 2019 for studies on deprescribing intervention with a control group (with or without randomisation); targeting ⩾65-year olds, at EOL, with at least one life-limiting illness and at least one potentially inappropriate DPM. We were interested in any patient-related outcomes. Studies with similar outcome assessment criteria were subjected to meta-analysis and narrative synthesis otherwise. The risk of bias was assessed using Cochrane Risk of Bias and ROBINS-I tools for randomised controlled trials (RCTs) and quasi-experimental non-randomised controlled studies, respectively. Results: Five studies covering 689 participants with mean age 81.6–85.7 years, the majority (74.6–100%) with dementia were included. The risk of bias was moderate to low. The deprescribing of DPMs lowered the risk of mortality (risk ratio (RR) = 0.59, 95% confidence interval (CI) = 0.44–0.79) and referral to acute care facilities (RR = 0.40, 95% CI = 0.22–0.73), but did not have a significant impact on the risk of falls, non-vertebral fracture, emergency presentation, unplanned hospital admission, or general practitioner visits. No significant difference was observed in the quality of life, physical and cognitive functions between the intervention and control groups. Conclusion: There is some evidence that deprescribing of DPMs for older adults near the EOL can lower the risk of mortality and referral to acute care facilities, but there are insufficient good-quality studies powered to confirm a benefit in terms of quality of life, physical or cognitive function, health service utilisation and adverse events. Plain Language Summary What is the health impact of withdrawal or dose reduction of medication used for disease prevention and symptom control in older adults near end-of-life? Introduction: Older adults (aged ⩾ 65 years) with advanced diseases such as cancer, dementia, and organ failure tend to have a limited life expectancy. With the progression of these diseases towards the end-of-life, the intensity for day-to-day supportive care becomes increasingly necessary. The use of medications for symptom management is a critical part of such care, but the use of medications for long-term disease prevention can become irrelevant due to the already shortened life expectancy and may become harmful due to alterations in physiology and pharmacology associated with age and frailty. This necessitates the withdrawal or dose reduction of inappropriate medications, the process called deprescribing. The decision to deprescribe medications used for both disease prevention and symptom control (DPMs) in this population is often challenging for clinicians. In this context, whether deprescribing of DPMs can improve patient-related health outcomes is unknown. Methods: Evidence from the literature was reviewed and analysed, and the quality of studies was assessed. Five studies were identified, which had 689 participants with an average age above 80 years and mostly suffering from dementia. Results: The analysis of these studies showed deprescribing of DPMs lowered the risk of death and referral to acute care facilities at 12 months but had no significant impact on falls, non-vertebral fractures, emergency presentations, unplanned hospital admission, general practitioner visits, quality of life, physical and mental functions. Conclusion: In conclusion, there were insufficient numbers of high-quality studies powered to confirm whether deprescribing of DPMs reduces adverse events, health service use, or improves the quality of life or functioning in older adults near the end of life.

Prediction of potential drug interactions between repurposed COVID-19 and antitubercular drugs: an integrational approach of drug information software and computational techniques data

Introduction: Tuberculosis is a major respiratory disease globally with a higher prevalence in Asian and African countries than rest of the world. With a larger population of tuberculosis patients anticipated to be co-infected with COVID-19 infection, an ongoing pandemic, identifying, preventing and managing drug–drug interactions is inevitable for maximizing patient benefits for the current repurposed COVID-19 and antitubercular drugs. Methods: We assessed the potential drug–drug interactions between repurposed COVID-19 drugs and antitubercular drugs using the drug interaction checker of IBM Micromedex®. Extensive computational studies were performed at a molecular level to validate and understand the drug–drug interactions found from the Micromedex drug interaction checker database at a molecular level. The integrated knowledge derived from Micromedex and computational data was collated and curated for predicting potential drug–drug interactions between repurposed COVID-19 and antitubercular drugs. Results: A total of 91 potential drug–drug interactions along with their severity and level of documentation were identified from Micromedex between repurposed COVID-19 drugs and antitubercular drugs. We identified 47 pharmacodynamic, 42 pharmacokinetic and 2 unknown DDIs. The majority of our molecular modelling results were in line with drug–drug interaction data obtained from the drug information software. QT prolongation was identified as the most common type of pharmacodynamic drug–drug interaction, whereas drug–drug interactions associated with cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) inhibition and induction were identified as the frequent pharmacokinetic drug–drug interactions. The results suggest antitubercular drugs, particularly rifampin and second-line agents, warrant high alert and monitoring while prescribing with the repurposed COVID-19 drugs. Conclusion: Predicting these potential drug–drug interactions, particularly related to CYP3A4, P-gp and the human Ether-à-go-go-Related Gene proteins, could be used in clinical settings for screening and management of drug–drug interactions for delivering safer chemotherapeutic tuberculosis and COVID-19 care. The current study provides an initial propulsion for further well-designed pharmacokinetic-pharmacodynamic-based drug–drug interaction studies. Plain Language Summary Introduction: Tuberculosis is a major respiratory disease globally with a higher prevalence in Asian and African countries than rest of the world. With a larger population of tuberculosis patients predicted to be infected with COVID-19 during this period, there is a higher risk for the occurrence of medication interactions between the medicines used for COVID-19 and tuberculosis. Hence, identifying and managing these interactions is vital to ensure the safety of patients undergoing COVID-19 and tuberculosis treatment simultaneously. Methods: We studied the major medication interactions that could likely happen between the various medicines that are currently given for COVID-19 and tuberculosis treatment using the medication interaction checker of a drug information software (Micromedex®). In addition, thorough molecular modelling was done to confirm and understand the interactions found from the medication interaction checker database using specific docking software. Molecular docking is a method that predicts the preferred orientation of one medicine molecule to a second molecule, when bound to each other to form a stable complex. Knowledge of the preferred orientation may be used to determine the strength of association or binding affinity between two medicines using scoring functions to determine the extent of the interactions between medicines. The combined knowledge from Micromedex and molecular modelling data was used to properly predict the potential medicine interactions between currently used COVID-19 and antitubercular medicines. Results: We found a total of 91 medication interactions from Micromedex. Majority of our molecular modelling findings matched with the interaction information obtained from the drug information software. QT prolongation, an abnormal heartbeat, was identified as one of the most common interactions. Our findings suggest that antitubercular medicines, mainly rifampin and second-line agents, suggest high alert and scrutiny while prescribing with the repurposed COVID-19 medicines. Conclusion: Our current study highlights the need for further well-designed studies confirming the current information for recommending safe prescribing in patients with both infections.