Apixaban Concentrations with Lower than Recommended Dosing in Older Adults with Atrial Fibrillation

OBJECTIVES: Lower than recommended doses of direct-acting oral anticoagulants are often prescribed to older adults with nonvalvular atrial fibrillation (NVAF). Our goal was to determine the consequences of lower than recommended dosing on plasma apixaban concentrations during the clinical care of older adults with NVAF. DESIGN: Convenience sample of patients receiving anticoagulation during 2017. SETTING: Academic medical center. PARTICIPANTS: Stable adults older than 65 years with NVAF receiving apixaban on a chronic basis. MEASUREMENTS: Patient age, weight, creatinine, co-medications, and apixaban concentrations. RESULTS: A total of 110 older adults with NVAF (mean age = 80.4 y; range = 66-100 y with 45% women) were studied. Overall, 48 patients received recommended dosing of 5 mg twice/day, and 42 received lower than recommended dosing. One patient in each category had concentrations below the expected 5% to 95% range at time of peak concentrations. Differences in proportion of apixaban concentrations within or outside expected ranges were not significant between patients receiving lower than recommended doses and those dosed as recommended at 5 mg twice/day (P =.35). However, in patients dosed as recommended with 5 mg twice/day, four had concentrations above the 5% to 95% range for peak levels expected at 3 to 4 hours after dosing; in two, this occurred around the midpoint of the dosing interval. Twenty patients received 2.5 mg twice/day as recommended. One-third had apixaban concentrations higher than expected peak concentrations compared with the clinical trials, and more than two-thirds had levels above the reported median for peak concentrations. CONCLUSIONS: Apixaban concentrations in older adults with NVAF seen clinically were higher than expected based on clinical trial data. The findings raise questions about the optimal dosing of apixaban in older adults with NVAF encountered outside of clinical trials and suggest a role for the monitoring of apixaban concentrations during care of patients that differ from those in randomized trials or when considering dosing outside of published guidelines. J Am Geriatr Soc 67:1902–1906, 2019

Drug interactions and pharmacogenetic factors contribute to variation in apixaban concentration in atrial fibrillation patients in routine care

Factor Xa-inhibitor apixaban is an oral anticoagulant prescribed in atrial fibrillation (AF) for stroke prevention. Its pharmacokinetic profile is known to be affected by cytochrome P450 (CYP)3A metabolism, while it is also a substrate of the efflux transporters ATP-binding cassette (ABC)B1 (P-glycoprotein) and ABCG2 (breast cancer resistance protein, BCRP). In this study, we assessed the impact of interacting medication and pharmacogenetic variation to better explain apixaban concentration differences among 358 Caucasian AF patients. Genotyping (ABCG2, ABCB1, CYP3A4*22, CYP3A5*3) was performed by TaqMan assays, and apixaban quantified by mass spectrometry. The typical patient was on average 77.2 years old, 85.5 kg, and had a serum creatinine of 103.1 µmol/L. Concomitant amiodarone, an antiarrhythmic agent and moderate CYP3A/ABCB1 inhibitor, the impaired-function variant ABCG2 c.421C \u3e A, and sex predicted higher apixaban concentrations when controlling for age, weight and serum creatinine (multivariate regression; R2 = 0.34). Our findings suggest that amiodarone and ABCG2 genotype contribute to interpatient apixaban variability beyond known clinical factors

Effect of Drain Duration and Output on Perioperative Outcomes and Readmissions after Lumbar Spine Surgery

Study design: Single-center retrospective cohort. Purpose: To compare surgical outcomes of patients based on lumbar drain variables relating to output and duration. Overview of literature: The use of drains following lumbar spine surgery, specifically with respect to hospital readmission, postoperative hematoma, postoperative anemia, and surgical site infections, has been controversial. Methods: Patients aged ≥18 years who underwent lumbar fusion with a postoperative drain between 2017 and 2020 were included and grouped based on hospital readmission status, last 8-hour drain output (\u3c40 mL cutoff), or drain duration (2 days cutoff). Total output of all drains, total output of the primary drain, drain duration in days, drain output per day, last 8-hour output, penultimate 8-hour output, and last 8-hour delta (last 8-hour output subtracted by penultimate 8-hour output) were collected. Continuous and categorical data were compared between groups. Multivariate logistic regression analysis and receiver operating characteristic (ROC) analysis were performed to determine whether drain variables can predict hospital readmission, postoperative blood transfusions, and postoperative anemia. Alpha was 0.05. Results: Our cohort consisted of 1,166 patients with 111 (9.5%) hospital readmissions. Results of regression analysis did not identify any of the drain variables as independent predictors of hospital readmission, postoperative blood transfusion, or postoperative anemia. ROC analysis demonstrated the drain variables to be poor predictors of hospital readmission, with the highest area under curve of 0.524 (drain duration), corresponding to a sensitivity of 61.3% and specificity of 49.9%. Conclusions: Drain output or duration did not affect readmission rates following lumbar spine surgery

What is the role of the placebo effect for pain relief in neurorehabilitation? Clinical implications from the Italian consensus conference on pain in neurorehabilitation

Background: It is increasingly acknowledged that the outcomes of medical treatments are influenced by the context of the clinical encounter through the mechanisms of the placebo effect. The phenomenon of placebo analgesia might be exploited to maximize the efficacy of neurorehabilitation treatments. Since its intensity varies across neurological disorders, the Italian Consensus Conference on Pain in Neurorehabilitation (ICCP) summarized the studies on this field to provide guidance on its use. Methods: A review of the existing reviews and meta-analyses was performed to assess the magnitude of the placebo effect in disorders that may undergo neurorehabilitation treatment. The search was performed on Pubmed using placebo, pain, and the names of neurological disorders as keywords. Methodological quality was assessed using a pre-existing checklist. Data about the magnitude of the placebo effect were extracted from the included reviews and were commented in a narrative form. Results: 11 articles were included in this review. Placebo treatments showed weak effects in central neuropathic pain (pain reduction from 0.44 to 0.66 on a 0-10 scale) and moderate effects in postherpetic neuralgia (1.16), in diabetic peripheral neuropathy (1.45), and in pain associated to HIV (1.82). Moderate effects were also found on pain due to fibromyalgia and migraine; only weak short-term effects were found in complex regional pain syndrome. Confounding variables might have influenced these results. Clinical implications: These estimates should be interpreted with caution, but underscore that the placebo effect can be exploited in neurorehabilitation programs. It is not necessary to conceal its use from the patient. Knowledge of placebo mechanisms can be used to shape the doctor-patient relationship, to reduce the use of analgesic drugs and to train the patient to become an active agent of the therapy

What is the role of the placebo effect for pain relief in neurorehabilitation? Clinical implications from the Italian Consensus Conference on Pain in Neurorehabilitation

Background: It is increasingly acknowledged that the outcomes of medical treatments are influenced by the context of the clinical encounter through the mechanisms of the placebo effect. The phenomenon of placebo analgesia might be exploited to maximize the efficacy of neurorehabilitation treatments. Since its intensity varies across neurological disorders, the Italian Consensus Conference on Pain in Neurorehabilitation (ICCP) summarized the studies on this field to provide guidance on its use. Methods: A review of the existing reviews and meta-analyses was performed to assess the magnitude of the placebo effect in disorders that may undergo neurorehabilitation treatment. The search was performed on Pubmed using placebo, pain, and the names of neurological disorders as keywords. Methodological quality was assessed using a pre-existing checklist. Data about the magnitude of the placebo effect were extracted from the included reviews and were commented in a narrative form. Results: 11 articles were included in this review. Placebo treatments showed weak effects in central neuropathic pain (pain reduction from 0.44 to 0.66 on a 0-10 scale) and moderate effects in postherpetic neuralgia (1.16), in diabetic peripheral neuropathy (1.45), and in pain associated to HIV (1.82). Moderate effects were also found on pain due to fibromyalgia and migraine; only weak short-term effects were found in complex regional pain syndrome. Confounding variables might have influenced these results. Clinical implications: These estimates should be interpreted with caution, but underscore that the placebo effect can be exploited in neurorehabilitation programs. It is not necessary to conceal its use from the patient. Knowledge of placebo mechanisms can be used to shape the doctor-patient relationship, to reduce the use of analgesic drugs and to train the patient to become an active agent of the therapy

Peer support and online cognitive behavioural therapy for substance use concerns: protocol for a randomised controlled trial.

INTRODUCTION: Hazardous alcohol and drug use is associated with substantial morbidity, mortality and societal cost worldwide. Yet, only a minority of those struggling with substance use concerns receive specialised services. Numerous barriers to care exist, highlighting the need for scalable and engaging treatment alternatives. Online interventions have exhibited promise in the reduction of substance use, although studies to date highlight the key importance of patient engagement to optimise clinical outcomes. Peer support may provide a way to engage patients using online interventions. The goal of this study is to evaluate the efficacy and cost-effectiveness of Breaking Free Online (BFO), an online cognitive-behavioural intervention for substance use, delivered with and without peer support. METHODS AND ANALYSIS: A total of 225 outpatients receiving standard care will be randomised to receive clinical monitoring with group peer support, with BFO alone, or with BFO with individual peer support, in an 8-week trial with a 6-month follow-up. The primary outcome is substance use frequency; secondary outcomes include substance use problems, depression, anxiety, quality of life, treatment engagement and cost-effectiveness. Mixed effects models will be used to test hypotheses, and thematic analysis of qualitative data will be undertaken. ETHICS AND DISSEMINATION: The protocol has received approval by the Centre for Addiction and Mental Health Research Ethics Board. Results will help to optimise the effectiveness of structured online substance use interventions provided as an adjunct to standard care in hospital-based treatment programmes. Findings will be disseminated through presentations and publications to scholarly and knowledge user audiences. TRIAL REGISTRATION NUMBER: NCT0512773

GeriMedRisk, a telemedicine geriatric pharmacology consultation service to address adverse drug events in long-term care: a stepped-wedge cluster randomized feasibility trial protocol (ISRCTN17219647)

Abstract Background Multimorbidity, polypharmacy, and older age predispose seniors to adverse drug events (ADE). Seniors with an ADE experience greater morbidity, mortality, and health care utilization compared to their younger counterparts. To mitigate and manage ADEs among this vulnerable population, we designed a geriatric pharmacology consultation service connecting clinicians with specialist physicians and pharmacists and will investigate the feasibility and acceptability of this complex intervention in the long-term care setting, prior to conducting a larger efficacy trial. Methods/Design We will conduct a cluster randomized feasibility trial and qualitative analysis of GeriMedRisk among four long-term care homes in the Waterloo-Wellington region from May 1 to December 31, 2017. The primary outcome is the feasibility and acceptability of GeriMedRisk and the stepped-wedge cluster randomized controlled trial design. We hypothesize that GeriMedRisk is a feasible intervention and its potential to decrease falls and drug-related hospital visits can be evaluated with a stepped-wedge cluster randomized controlled trial design. Discussion This mixed methods study will inform a larger efficacy trial of GeriMedRisk’s ability to decrease adverse drug events among seniors in the long-term care setting. Ethics and dissemination The Hamilton Integrated Research Ethics Board granted the approval for this study protocol 2812. We plan to disseminate the results of this study in peer-reviewed journals and also to our partners and stakeholders. Trial registration ISRCTN clinical trials registry, ISRCTN17219647 (March 27, 2017

The association between insulin resistance and depression in the Korean general population

Background: Previous studies showed that the insulin resistance (IR) could be related to depression. However, this association is still equivocal in the general population. Herein, we aimed to investigate the association between IR and depressive symptoms in a large sample in South Korea. Methods: A cross-sectional study was carried out for 165,443 Korean men and women who received a health checkup including various clinical parameters and the Center for Epidemiologic Studies Depression scales (CES-D). Subjects were stratified into subgroups by CES-D score, sex, age, and presence of diabetes. The odd ratios (ORs) for homeostasis model assessment of insulin resistance (HOMA-IR) were compared between groups using multivariable logistic regression analyses. Results: After adjusting covariates (e.g. smoking, family income, marriage state, unemployment status, average alcohol use, BMI, physical activity, systolic blood pressure, diabetes), increased IR was weakly associated with greater depressive symptoms (adjusted OR=1.01 [95% CI 1.0001-1.03]). Subgroup analysis revealed this association was statistically significant in females (adjusted OR-1.03, [95% CI 1.001-1.06]), non-diabetic group (adjusted OR-1.04, [95% CI 1.02-1.06]), and young participants under the age of thirty (adjusted OR-1.17, [95% CI 1.07-1.27]). But we couldn't find significant association in diabetic and middle to elderly participants. Conclusions: This study demonstrates that there is a relationship between IR and depressive symptoms in the Korean general population. Results from this epidemiological study revealed that young adults and non-diabetic individuals with increased IR may be related with depressive symptoms.FAPESP, BrazilLundbeck, CanadaLundbeckJanssenOrthoShirePurdueAstraZenecaPfizerOtsukaAllerganStanley Medical Research Institute (SMRI)Elli-LillyJohnson JohnsonMoksha8SunovionMitsubishiTakedaForestBristol-Myers SquibbUniv Hlth Network, Mood Disorders Psychopharmacol Unit, Toronto, ON, CanadaUniv Toronto, Dept Psychiat, Toronto, ON M5S 1A1, CanadaSungkyunkwan Univ, Sch Med, Samsung Seoul Hosp, Dept Psychiat, Seoul, South KoreaSungkyunkwan Univ, Sch Med, Kangbuk Samsung Hosp, Total Healthcare Ctr, Seoul, South KoreaKyung Hee Univ, Sch Med, Dept Prevent Med, Seoul, South KoreaNatl Canc Ctr, Natl Canc Control Inst, Canc Registrat & Stat Branch, Goyang, South KoreaUniv Fed Sao Paulo UNIFESP, Dept Psychiat, Interdisciplinary Lab Clin Neurosci LING, Sao Paulo, SP, BrazilUniv Western Ontario, Schulich Sch Med & Dent, Dept Med, London, ON N6A 3K7, CanadaUniv Toronto, Inst Med Sci, Toronto, ON, CanadaUniv Toronto, Dept Pharmacol, Toronto, ON M5S 1A1, CanadaUniv Fed Sao Paulo UNIFESP, Dept Psychiat, Interdisciplinary Lab Clin Neurosci LING, Sao Paulo, SP, BrazilWeb of Scienc