Different glomerular filtration rate estimating formula for prescribing DOACs in oldest patients: appropriate dosage and bleeding risk. Post hoc analysis of a prospective cohort.

BACKGROUND: Direct oral anticoagulants (DOACs) pharmacokinetics depends on estimated glomerular filtration rate (eGFR), whose estimation is crucial for optimal risk/benefit balance. AIMS: To assess the concordance among different eGFR formulas and the potential impact on DOACs prescription appropriateness and bleeding risk in oldest hospitalized patients. METHODS: Post hoc analysis of a single-centre prospective cohort study. eGFR was calculated by creatinine-based (MDRD, CKD-EPICr, BIS1) and creatinine-cystatin-C-based (CKD-EPIComb and BIS2) formulas. Patients were stratified according to eGFR [severely depressed (SD) 15-29; moderately depressed (MD) 30-49; preserved/mildly depressed (PMD): ≥ 50 ml/min/1.73 m2]. Concordance between the different equations was assessed by Cohen's kappa coefficient. RESULTS: Among AF patients, 841 (59.2% women, mean age 85.9 ± 6.5 years) received DOACs. By CKD-EPICr equation, 135 patients were allocated in the SD, 255 in the MD and 451 in the PMD group. The concordance was excellent only between BIS 2 and CKD-EPIComb and MDRD and CKD-EPICr, while was worse (from good to poor) between the other formulas. Indeed, by adding cystatin-C almost over 1/3 of the patients were reallocated to a worse eGFR class. Bleeding prevalence increased by 2-3% in patients with discordant eGFR between formulas, reallocated to a worse chronic kidney disease (CKD) stage, although without reaching statistical significance. CKD-EPIComb resulted the best predictor of bleeding events (AUROC 0.71, p = 0.03). DISCUSSION: This study highlights the variability in CKD staging according to different eGFR formulas, potentially determining inappropriate DOACs dosing. Although the cystatin-C derived CKDEPIComb equation is the most accurate for stratifying patients, BIS1 may represent a reliable alternative.

Long-term effectiveness and safety of anticoagulation therapy in oldest old, frail people with atrial fibrillation.

BACKGROUND: Atrial Fibrillation (AF) represents a major cause of mortality and morbidity in older people; however, oldest-old frail patients are usually excluded from clinical trials. Aim of the study is to evaluate the impact of oral anticoagulation (OAC) therapy on long-term overall survival and clinically relevant bleedings in a large cohort of hospitalised frail, oldest-old patients with AF. PATIENTS AND METHODS: Prospective, observational, cohort study, evaluating patients consecutively hospitalized for acute illnesses in our Geriatrics Unit (January 2013-July 2017). Participants were divided in two groups, AF and sinus rhythm (SR). Besides recording demographic characteristics and clinical history, comprehensive geriatric assessment (CGA) was obtained. RESULTS: AF patients [1808/5093 (35.5%), 58.5% women] were older, with higher burden of comorbidity than those with SR. At discharge, HAS-BLED [OR 0.77 (95%CI 0.67-0.90), cognitive impairment [OR 0.92 (95%CI 0.90-0.95)], malnutrition [OR 0.74 (95%CI 0.57-0.97)] and CHA2DS2VASc [OR 1.33 (95%CI 1.20-1.47)] emerged as significant independent predictors of anticoagulant prescription. AF patients showed significantly reduced overall survival (OS) than those with SR (11.4 vs 19.4 months, p<.001). However, anticoagulated AF patients (75.2%) had three-times longer OS than those not anticoagulated (15.0 vs 5.6 months, p<.001), comparable to SR patients after adjustment for potential confounders [HR 1.04 (95%CI 0.99-1.10)]. ED readmittance risk for clinically relevant bleeding did not differ between AF patients receiving or not anticoagulation [HR 1.04 (95%CI 0.76-1.14)] CONCLUSION: anticoagulation therapy was associated with significant increase of long-term OS without increased risk of clinically relevant bleeding. CGA resulted an useful tool in OAC therapy decision-making.

Clinical differences among the elderly admitted to the emergency department for accidental or unexplained falls and syncope.

It is difficult to distinguish unexplained falls (UFs) from accidental falls (AFs) or syncope in older people. This study was designed to compare patients referred to the emergency department (ED) for AFs, UFs or syncope. Data from a longitudinal study on adverse drug events diagnosed at the ED (ANCESTRAL-ED) in older people were analyzed in order to select cases of AF, syncope, or UF. A total of 724 patients (median age: 81.0 [65-105] years, 66.3% female) were consecutively admitted to the ED (403 AF, 210 syncope, and 111 UF). The number of psychotropic drugs was the only significant difference in patients with AF versus those with UF (odds ratio [OR] 1.44; 95% confidence interval 1.17-1.77). When comparing AF with syncope, female gender, musculoskeletal diseases, dementia, and systolic blood pressure >110 mmHg emerged as significantly associated with AF (OR 0.40 [0.27-0.58], 0.40 [0.24-0.68], 0.35 [0.14-0.82], and 0.31 [0.20-0.49], respectively), while valvulopathy and the number of antihypertensive drugs were significantly related to syncope (OR 2.51 [1.07-5.90] and 1.24 [1.07-1.44], respectively). Upon comparison of UF and syncope, the number of central nervous system drugs, female gender, musculoskeletal diseases, and SBP >110 mmHg were associated with UF (OR 0.65 [0.50-0.84], 0.52 [0.30-0.89], 0.40 [0.20-0.77], and 0.26 [0.13-0.55]), respectively. These results indicate specific differences, in terms of demographics, medical/pharmacological history, and vital signs, among older patients admitted to the ED for AF and syncope. UF was associated with higher use of psychotropic drugs than AF. Our findings could be helpful in supporting a proper diagnostic process when evaluating older patients after a fall.

Cognitive Function and the Ageing Process: The Peculiar Role of Mild Thyroid Failure.

BACKGROUND: Over the last decades an increasing body of evidence suggested a possible relationship between thyroid hormone (TH) and the ageing process, and several efforts have been made to determine the actual role of TH dynamic during human life. It is still unclear whether the serum level shift of Thyroid Stimulating Hormone toward higher value, observed during ageing, is a normal adaptive response associated with senescence or an actual mild thyroid dysfunction. A growing body of evidence supports the hypothesis of a reset of the hypothalamus-pituitary-thyroid axis in order to contrast the catabolic status of the ageing process. On the other hand, several meta-analyses showed a direct link between subclinical hypothyroidism (sHT) and cardiovascular events (both ischemic heart disease and stroke), although mainly in individuals younger than 65 years. Similarly, a recent meta-analysis documented consistent data on a positive relationship between sHT and cognitive impairment, but only in individuals younger than 75 years. CONCLUSION: The available data suggest a complex relationship between mild thyroid failure and the ageing process as well as the development and progression of several cardiovascular and neurological diseases. In this paper, we reviewed the scientific English literature on sHT and the ageing process focusing on experimental evidences related to cognitive impairment and dementia. Moreover, we focused on new patents of treatments potentially able to improve the care of sHT patients, especially in the elderly, where treatment drawbacks may have negative impact on the long term outcome.

Tumour necrosis factor-alpha participates on the endothelin-1/nitric oxide imbalance in small arteries from obese patients: role of perivascular adipose tissue.

AIMS: We assessed the impact of vascular and perivascular tumour necrosis factor-alpha (TNF-α) on the endothelin (ET)-1/nitric oxide (NO) system and the molecular pathways involved in small arteries from visceral fat of obese patients (Obese) and Controls. METHODS AND RESULTS: Isolated small arteries from 16 Obese and 14 Controls were evaluated on a pressurized micromyograph. Endogenous ET-1 activity was assessed by the ETA blocker BQ-123. TNF-α and NO were tested by anti-TNF-α infliximab (IFX) and N(ω)-nitro-l-arginine methylester (L-NAME). Gene and protein expression of TNF-α, ET-1, ETA, and ETB receptors were determined by RT-PCR and IHC on arterial wall and in isolated adipocytes. Obese showed a blunted L-NAME-induced vasoconstriction, which was potentiated by IFX, and an increased relaxation to BQ-123, unaffected by L-NAME but attenuated by IFX. Perivascular adipose tissue (PVAT) removal reversed these effects. Obese showed intravascular superoxide excess, which was decreased by apocynin (NAD(P)H oxidase inhibitor), L-NAME, and BQ-123 incubations, and abolished by IFX. An increased vascular expression of ET-1, ETA, and ETB receptors, and higher vascular/perivascular TNF-α and TNF-α receptor expression were also detected. The arterial expression and phosphorylation of c-Jun N-terminal kinase (JNK) were higher in Obese vs. Controls, and downregulated by IFX. CONCLUSIONS: In small arteries of Obese, PVAT-derived TNF-α excess, and an increased vascular expression of ET-1 and ETA receptor, contribute to the ET-1/NO system imbalance, by impairing tonic NO release. Reactive oxygen species excess, via NAD(P)H oxidase activation, induces the endothelial nitric oxide synthase uncoupling, which in turn generates superoxide and impairs NO production. The up-regulated JNK pathway represents a crucial molecular signalling involved in this process.

Impact of inflammation on vascular disease in hypertension.

Low grade inflammation exerts a crucial pathogenic role in hypertension and cardiovascular disease. A large body of evidence indicates that innate and adaptive immune systems, and in particular T cells, are involved. A balance between T-effector lymphocytes and Treg lymphocytes represents a crucial regulatory mechanism that, when altered, favours blood pressure elevation and organ damage development. Of note, Treg lymphocytes exert important anti-inflammatory properties, whose activities guarantees vascular homeostasis and protects the vessel wall from the development of atherosclerosis. In humans, most of evidence ascertaining essential hypertension as a condition of chronic low-grade inflammatory status revealed a strict and independent association between CRP, TNF-α, IL-6 or adhesion molecules and vascular changes in essential hypertensive patients. Evidence of involvement of the immune system in vasculature from patients with hypertension or cardiovascular disease starts to appear in literature. Further investigation on immunity, including the role of T-lymphocytes, will help develop of new therapeutic targets that may improve outcomes in hypertension and cardiovascular disease and discover novel approaches in the treatment of hypertension and vascular disease.