Pharmacokinetics and pharmacodynamics of drug‒drug interactions in hospitalized older adults treated with direct oral anticoagulants.

PURPOSE: Polypharmacy is a frequent situation in older adults that increases the risk of drug-drug interactions (DDIs), both pharmacokinetic (PK) and pharmacodynamic (PD). Direct oral anticoagulants (DOACs) are frequently prescribed in older adults, mainly because of the high prevalence of atrial fibrillation (AF). DOACs are subject to cytochrome P450 3A4 (CYP3A4)- and/or P-glycoprotein (P-gp)-mediated PK DDIs and PD DDIs when co-administered with drugs that interfere with platelet function. The aim of our study was to assess the prevalence of DDIs involving DOACs in older adults and the associated risk factors at admission and discharge. METHODS: This was a cross-sectional study conducted in an acute geriatric unit between January 1, 2018 and December 31, 2022, including patients over 75 years of age treated with DOACs at admission and/or discharge, for whom a comprehensive collection of co-medications was performed. RESULTS: From 909 hospitalizations collected, the prevalence of PK DDIs involving DOACs was 16.9% at admission and 20.7% at discharge, and the prevalence of PD DDIs was 20.7% at admission and 20.2% at discharge. Factors associated with DDIs were bleeding history [adjusted odds ratio (ORa) 1.74, 95% confidence interval (CI) 1.13-2.68], number of drugs > 6 (ORa 2.54, 95% CI 1.88-3.46) and reduced dose of DOACs (ORa 0.39, 95% CI 0.28-0.54) at admission and age > 87 years (ORa 0.74, 95% CI 0.55-0.99), number of drugs > 6 (ORa 2.01, 95% CI 1.48-2.72) and reduced dose of DOACs (ORa 0.41, 95% CI 0.30-0.57) at discharge. CONCLUSION: This study provides an indication of the prevalence of DDIs as well as the profile of DDIs and patients treated with DOACs.

Assessment of DOAC in GEriatrics (Adage Study): Rivaroxaban/Apixaban Concentrations and Thrombin Generation Profiles in NVAF Very Elderly Patients.

BACKGROUND: Although a growing number of very elderly patients with atrial fibrillation (AF), multiple conditions, and polypharmacy receive direct oral anticoagulants (DOACs), few studies specifically investigated both apixaban/rivaroxaban pharmacokinetics and pharmacodynamics in such patients. AIMS: To investigate: (1) DOAC concentration-time profiles; (2) thrombin generation (TG); and (3) clinical outcomes 6 months after inclusion in very elderly AF in-patients receiving rivaroxaban or apixaban. METHODS: Adage-NCT02464488 was an academic prospective exploratory multicenter study, enrolling AF in-patients aged ≥80 years, receiving DOAC for at least 4 days. Each patient had one to five blood samples at different time points over 20 days. DOAC concentrations were determined using chromogenic assays. TG was investigated using ST-Genesia (STG-ThromboScreen, STG-DrugScreen). RESULTS: We included 215 patients (women 71.1%, mean age: 87 ± 4 years), 104 rivaroxaban and 111 apixaban, and 79.5% receiving reduced-dose regimen. We observed important inter-individual variabilities (coefficient of variation) whatever the regimen, at C max [49-46%] and C min [75-61%] in 15 mg rivaroxaban and 2.5 mg apixaban patients, respectively. The dose regimen was associated with C max and C min plasma concentrations in apixaban (p = 0.0058 and p = 0.0222, respectively), but not in rivaroxaban samples (multivariate analysis). Moreover, substantial variability of thrombin peak height (STG-ThromboScreen) was noticed at a given plasma concentration for both xabans, suggesting an impact of the underlying coagulation status on TG in elderly in-patients. After 6-month follow-up, major bleeding/thromboembolic event/death rates were 6.7%/1.0%/17.3% in rivaroxaban and 5.4%/3.6%/18.9% in apixaban patients, respectively. CONCLUSION: Our study provides original data in very elderly patients receiving DOAC in a real-life setting, showing great inter-individual variability in plasma concentrations and TG parameters. Further research is needed to understand the potential clinical impact of these findings.

Bidirectional endoscopy in the assessment of iron deficiency in the elderly.

Iron deficiency is a common pathology in elderly patients. It is most often due to lesions in the digestive tract, which raises the issue of benefit/risk balance and yield from investigation. Current UK guidelines recommend that bidirectional endoscopy (oesophago-gastro-duodenoscopy and colonoscopy) is performed synchronously, with no upper age limit. In studies conducted in people over 75 years of age, the diagnostic yield varies between 63 and 68%, which is similar to that in younger people, with approximately 40% revealing upper lesions and 40% lower lesions. Approximately 10% of elderly patients show upper and lower digestive lesions at the same time. Complications as a result of oesophago-gastro-duodenoscopy are rare and mainly related to anaesthesia. The main complication of colonoscopy is perforation and there is a slightly higher risk of perforation in older patients. This risk is less significant for computed tomographic colonography. Contraindications of endoscopies are very rare. When endoscopy is negative, this raises the question of whether further investigations should be pursued.

Clinical characteristics of sleep apnea in middle-old and oldest-old inpatients: symptoms and comorbidities.

BACKGROUND: Obstructive sleep apnea (OSA) is prevalent in older adults but still underdiagnosed for many reasons, such as underreported symptoms, non-specific ones because of the comorbidities and polypharmacy, or the social belief of sleep problems as normal with aging. OBJECTIVES: To identify salient symptoms and comorbidities associated with OSA, diagnosed by nocturnal respiratory polygraphy in geriatric inpatients. METHOD: We conducted a retrospective, cross-sectional study in a sample of 102 geriatric inpatients from a French Geriatric University Hospital. We reviewed medical records to collect demographic, medical information including comorbidities, the geriatric cumulative illness rating scale (CIRS-G), subjective sleep-related symptoms and data of overnight level three portable sleep polygraphy recording. RESULTS: Among classic OSA symptoms, only excessive daytime sleepiness (p = 0.02) and nocturnal choking (p = 0.03) were more prevalent in older inpatients with OSA (n = 64) than in those without (n = 38). The prevalence of comorbidities and mean CIRS-G scores were not different between groups except for the lower prevalence of chronic obstructive pulmonary disease and the higher level of creatinine clearance in OSA patients. Multivariate analysis showed OSA was associated with excessive daytime sleepiness (OR = 2.83, p = 0.02) in symptoms-related model and with composite CIRS-G score (OR 1.26, p = 0.04) in comorbidities-related model. CONCLUSIONS: Only excessive daytime sleepiness and comorbidity severity (composite CIRS-G score) were associated with the objective diagnosis of OSA, while other usual clinical OSA symptoms and comorbidities in geriatric inpatients were not. These findings emphasize the importance of excessive daytime sleepiness symptom, when reported in comorbid older patients, strongly suggesting OSA and requiring adequate nocturnal exploration.

[Place of bidirectional endoscopy in the assessment of iron deficiency in the elderly]. / Place des explorations digestives couplées dans le bilan d'une carence martiale chez le sujet âgé.

Iron deficiency is a common pathology in elderly patients. It is most often due to digestive lesions, so we wonder the benefit-risk balance and yield of digestive explorations. The English recommendations recommend that bidirectional endoscopy (esophagogastroduodenoscopy (EGD) and colonoscopy) is performed at the same time, without any upper age limit. In studies conducted in people over 75 years of age, the yield of diagnostic varies between 63 and 68%, which is similar to that of younger people. There is about 40% of the upper lesion and 40% of the lower lesion. The simultaneous discovery of upper and lower digestive lesions represents about 10% of elderly patients. Complications of EGD are rare and mainly related to anaesthesia. The main complication of colonoscopy is perforation and there is a small over-risk of perforation in older patients. This risk is less important when we use computed tomographic colonography. Contraindications of endoscopies are very rare. In case of negative endoscopies, we will wonder if we need further explorations or not.

[Intravenous iron supplementation in the elderly patient]. / Supplémentation ferrique par voie intraveineuse chez le patient âgé.

Iron deficiency, absolute or functional, is a common pathology in elderly patients and the way of iron replacement therapy is a recurrent issue. It seems to be necessary to treat by intravenous iron instead of oral therapy because of defective iron absorption or side effects. Depending on the molecule chosen, the modes of administration, whether dilution, dose or rhythm, vary. The major risk of intravenous iron replacement is anaphylaxis, which is very rare, this is why it has to be an hospital administration.

[Von Willebrand disease in the elderly]. / Maladie de Willebrand du sujet âgé.

Von Willebrand disease in the elderly. Von Willebrand disease (VWD) is a rare inherited haemorrhagic disorder, the prevalence of symptomatic individuals is around 1/10 000. Von Willebrand factor level increases with advanced age, explaining a lower frequency and a lower severity of cutaneous haemorrhagic symptoms with aging. The management of comorbidities in VWD patients is multidisciplinary, on a case by case basis, taking into account scientific society guidelines and haemostasis expert recommendations. The haemorrhagic risk should be systematically evaluated before an invasive procedure or the start of treatment with anticoagulant or antiplatelet drugs, or before the use of some cancer chemotherapy.

Maladie de Willebrand du sujet âgé. La maladie de Willebrand est une maladie hémorragique rare héréditaire (prévalence des formes symptomatiques : 1/10 000). Le facteur Willebrand augmente physiologiquement avec l'âge, d'où une diminution de la fréquence et de la sévérité de la symptomatologie hémorragique. La prise en charge des comorbidités des patients âgés doit rester multidisciplinaire et se faire au cas par cas, en adaptant les recommandations des sociétés savantes et des spécialistes de l'hémostase. Le risque hémorragique est à évaluer avant toute procédure invasive ou tout traitement pouvant majorer ce risque (anticoagulants, antiagrégants plaquettaires, certaines chimiothérapies anticancéreuses).

[Oral administration of medicines in elderly patients and adaptation of galenic forms]. / Prise orale de médicaments chez les patients âgés et adaptations galéniques.

Physiological ageing and pathologies can have an influence on the pharmacology of numerous medicines, leading to serious iatrogenic accidents, polypharmacy and incorrect use of a medicine in elderly people. An observational study carried out in a short-stay geriatric unit focused on the issues surrounding the difficulties the elderly may encounter when taking medicines and the prevalence of the manipulation of galenic forms.

[Iron deficiency in elderly patients: use of biomarkers]. / Anémie par carence ferrique du sujet âgé : utilisation pratique des biomarqueurs.

Iron deficiency, due to blood loss or malabsorption, is commonly observed in geriatric practice. In elderly people, association of inflammatory diseases to iron loss makes diagnosis of absolute iron deficiency sometimes difficult. In case of inflammation, the interpretation of usual biomarkers of iron deficiency (serum ferritin, transferrin saturation, serum iron) may be difficult. The recent discovery of the role of hepcidine in the iron homeostasis, in physiological and pathological situation, contributes to better understanding of the iron regulation. The aim of this short paper is to underline some specificities of elderly iron physiology, to explain hepcidine's role in physiological and pathological situations and to propose a diagnostic approach for a better interpretation of usual biomarkers, in order to differentiate absolute iron deficiency and functional iron deficiency.

Anemia in the elderly: usefulness of an easy and comprehensive laboratory screen.

Anemia, the most common hematological disorder in the elderly, increases the risk of mortality and morbidity and adversely affects quality of life. However, few studies focused specifically on anemia in the elderly, especially regarding the underlying causes. The main objective of this prospective study was to evaluate the causes of anemia in non-institutionalized elderly patients. We included 190 consecutive patients ≥70 years, admitted to a geriatric short-stay unit over a 1-year period. When the hemoglobin level was <120 g/L, the following serum assays were performed routinely: iron, ferritin, transferrin saturation, folate, vitamin B12, C-reactive protein, TSH, albumin, and haptoglobin. When these tests were normal, bone marrow aspiration was performed to look for myelodysplastic syndrome. Hemoglobin was <120 g/L in 83 (43.7%) of 190 included patients. Patients with anemia had a mean hemoglobin level of 105 ± 11 g/L. The most common potential causes of anemia were inflammation, severe renal impairment, severe malnutrition, and iron deficiency; each of these causes was found in at least one-third of patients with anemia. Myelodysplastic syndrome was found in all anemic patients with a normal serum screen (12/83, 14.5%). Anemia was multifactorial in most patients: the mean number of potential causes per patient was 1.85 ± 1, and 65.4% of the patients had two to four concomitant causes. The serum screen used in our study is easy to perform in ambulatory patients and identifies potential causes of anemia for which safe and effective treatments are available. Second-line bone marrow aspiration adds to the diagnostic yield.

[Hodgkin lymphoma in the elderly]. / Le lymphome de Hodgkin chez le sujet âgé

We report a case of Hodgkin's lymphoma in a patient aged 75, presenting with acute cardiopulmonary insufficiency, hospitalized in a geriatrics ward. The deterioration of his general condition and the discovery of several lymph nodes led us to perform an aspiration of a lymph node and a bone marrow biopsy. Reed-Sternberg cells, pathognomonic of Hodgkin's disease were identified on the smears and biopsy sections. Due to the poor condition of the patient, it was decided not to treat with chemotherapy. The diagnostic approach and treatment strategy of Hodgkin's disease are summarized in this paper, especially the particular features of the disease in the elderly.

Human NK cells display major phenotypic and functional changes over the life span.

Aging is generally associated with an increased predisposition to infectious diseases and cancers, related in part to the development of immune senescence, a process that affects all cell compartments of the immune system. Although many studies have investigated the effects of age on natural killer (NK) cells, their conclusions remain controversial because the diverse health status of study subjects resulted in discordant findings. To clarify this situation, we conducted the first extensive phenotypic and functional analysis of NK cells from healthy subjects, comparing NK cells derived from newborn (cord blood), middle-aged (18-60 years), old (60-80 years), and very old (80-100 years) subjects. We found that NK cells in cord blood displayed specific features associated with immaturity, including poor expression of KIR and LIR-1/ILT-2 and high expression of both NKG2A and IFN-gamma. NK cells from older subjects, on the other hand, preserved their major phenotypic and functional characteristics, but with their mature features accentuated. These include a profound decline of the CD56(bright) subset, a specific increase in LIR-1/ILT-2, and a perfect recovering of NK-cell function following IL2-activation in very old subjects. We conclude that the preservation of NK cell features until very advanced age may contribute to longevity and successful aging.