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

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

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

Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 107 randomized trials and 19,805 patients, on behalf of MACH-NC Group

Background and purposeThe Meta-Analysis of Chemotherapy in squamous cell Head and Neck Cancer (MACH-NC) demonstrated that concomitant chemotherapy (CT) improved overall survival (OS) in patients without distant metastasis. We report the updated results.Materials and methodsPublished or unpublished randomized trials including patients with non-metastatic carcinoma randomized between 1965 and 2016 and comparing curative loco-regional treatment (LRT) to LRT + CT or adding another timing of CT to LRT + CT (main question), or comparing induction CT + radiotherapy to radiotherapy + concomitant (or alternating) CT (secondary question) were eligible. Individual patient data were collected and combined using a fixed-effect model. OS was the main endpoint.ResultsFor the main question, 101 trials (18951 patients, median follow-up of 6.5 years) were analyzed. For both questions, there were 16 new (2767 patients) and 11 updated trials. Around 90% of the patients had stage III or IV disease. Interaction between treatment effect on OS and the timing of CT was significant (p < 0.0001), the benefit being limited to concomitant CT (HR: 0.83, 95%CI [0.79; 0.86]; 5(10)-year absolute benefit of 6.5% (3.6%)). Efficacy decreased as patients age increased (p_trend = 0.03). OS was not increased by the addition of induction (HR = 0.96 [0.90; 1.01]) or adjuvant CT (1.02 [0.92; 1.13]). Efficacy of induction CT decreased with poorer performance status (p_trend = 0.03). For the secondary question, eight trials (1214 patients) confirmed the superiority of concomitant CT on OS (HR = 0.84 [0.74; 0.95], p = 0.005).ConclusionThe update of MACH-NC confirms the benefit and superiority of the addition of concomitant CT for non-metastatic head and neck cancer