Carmelinda Ruggiero

The Persistent Exclusion of Older Patients From Ongoing Clinical Trials Regarding Heart Failure

BACKGROUND Much clinical research of relevance to elderly patients examines individuals who are younger than those who have the disease in question. A good example is heart failure. Therefore, we investigated the extent of exclusion of older individuals in ongoing clinical trials regarding heart failure. METHODS In the context of the Increasing the PaRticipation of the ElDerly in Clinical Trials (PREDICT) study, data from ongoing clinical trials regarding heart failure were extracted from the World Health Organization Clinical Trials Registry Platform on December 1, 2008. Main outcome measures were the proportion of trials excluding patients by an arbitrary upper age limit or by other exclusion criteria that might indirectly cause limited recruitment of older individuals. We classified exclusion criteria into 2 categories: justified or poorly justified. RESULTS Among 251 trials investigating treatments for heart failure, 64 (25.5%) excluded patients by an arbitrary upper age limit. Such exclusion was significantly more common in trials conducted in the European Union than in the United States (31/96 [32.3%] vs 17/105 [16.2%]; P = .007) and in drug trials sponsored by public institutions vs those by private entities (21/59 [35.6%] vs 5/36 [13.9%]; P = .02). Overall, 109 trials (43.4%) on heart failure had 1 or more poorly justified exclusion criteria that could limit the inclusion of older individuals. A similar proportion of clinical trials with poorly justified exclusion criteria was found in pharmacologic and nonpharmacologic trials. CONCLUSION Despite the recommendations of national and international regulatory agencies, exclusion of older individuals from ongoing trials regarding heart failure continues to be widespread.

Unexplained anaemia in older persons is characterised by low erythropoietin and low levels of pro-inflammatory markers.

Epidemiological studies report that a third of the cases of anaemia in older persons is unexplained. We compared erythropoietin (EPO), inflammatory markers and major comorbidities between older subjects with normal haemoglobin levels and those with different aetiologic forms of anaemia, including unexplained anaemia. Participants were a representative sample of 964 persons aged ≥65 years, with no evidence of bleeding, complete blood tests, and a complete blood count within 6 h of phlebotomy. Anaemia was defined as haemoglobin <130 g/l in men and 120 g/l in women, and classified as a result of chronic kidney disease, iron deficiency, chronic disease and B12/folate deficiency anaemia, or unexplained anaemia based on standard criteria. Of the 124 anaemic participants, 42 (36·8%) had unexplained anaemia. Participants with anaemia of chronic diseases had significantly higher interleukin‐6 (IL‐6) and C‐reactive protein (CRP) levels, while those with unexplained anaemia had significantly lower CRP than non‐anaemic controls. Iron deficiency anaemia was characterised by significantly higher EPO levels compared with other types of anaemia and normal haemoglobin, B12 and/or folate deficiency. Unexplained anaemia was characterised by unexpectedly low EPO and low lymphocyte count. Unexplained anaemia is associated with reduced kidney EPO response, low levels of pro‐inflammatory markers and low lymphocyte counts.

Role of Anti-Oxidants in Atherosclerosis: Epidemiological and Clinical Update

Low density lipoprotein (LDL) oxidative modification in the vascular wall seems to be a key factor in atherosclerosis development. Oxidised LDLs might recruit monocytes and favour their transformation into foam cells through a receptor-mediated intake (scavenger pathway). Moreover oxidised LDLs show cytotoxic potential which is probably responsible for endothelial cell damage and macrophage degeneration in the atherosclerotic human plaque. Following the oxidation hypothesis of atherosclerosis the role of natural antioxidants, i.e. Vitamin C, Vitamin E and carotenoids, has been investigated in a large number of epidemiological, clinical and experimental studies. Animal studies indicate that dietary antioxidants may reduce atherosclerosis progression, and observational data in humans suggest that antioxidant vitamin ingestion is associated with reduced cardiovascular disease, but the results of randomised controlled trials are mainly disappointing. It has been suggested that natural antioxidants may be effective only in selected subgroups of patients with high levels of oxidative stress or depletion of natural antioxidant defence systems. The favourable effects shown by some studies relating antioxidant dietary intake and cardiovascular disease, may have been exerted by other chemicals present in foods. Flavonoids are the ideal candidates, since they are plentiful in foods containing antioxidant vitamins (i.e. fruits and vegetables) and are potent antioxidants. Tea and wine, rich in flavonoids, seem to have beneficial effects on multiple mechanisms involved in atherosclerosis. Future studies should probably select patients in a context of high-oxidative stress / low-antioxidant defence, to verify if antioxidants may really prove useful as therapeutic anti-atherosclerotic agents.

Potentially inappropriate drug prescriptions and risk of hospitalization among older, Italian, nursing home residents: the ULISSE project

AbstractBackground Potentially inappropriate medications in older patients increase the risk of adverse drug events, which are an important cause of hospital admission and death among hospitalized patients. Little information is available about the prevalence of potentially inappropriate drug prescriptions (PIDPs) and the related health adverse outcomes among nursing home (NH) residents. Objective To estimate the prevalence of PIDPs and the association with adverse outcomes in NH residents. Methods A total of 1716 long-term residents aged ≥65 years participating in the ULISSE (Un Link Informatico sui Servizi Sanitari Esistenti per l’anziano [A Computerized Network on Health Care Services for Older People]) project were evaluated using a standardized comprehensive geriatric assessment instrument, i.e. the inter Resident Assessment Instrument Minimum Data Set. A thorough evaluation of residents’ drug use, medical diagnoses and healthcare resource utilization was performed. A PIDP was defined according to the most recent update of the Beers criteria. Results Almost one out of two persons (48%) had at least one PIDP and almost one out of five had two or more PIDPs (18%). Residents with a higher number of PIDPs had a higher likelihood of being hospitalized. Compared with residents without PIDPs, those with two or more PIDPs at baseline had a higher probability of being hospitalized (hazard ratio 1.73; 95% CI 1.14, 2.60) during the following 12 months. Risk of PIDP was positively associated with the total number of drugs and diseases, but negatively with age. PIDPs defined according to specific conditions (n = 780; 55%) were slightly more frequent than PIDPs based on single medications irrespective of specific indication (n=639; 45%). Conclusions PIDP is a significant problem among Italian NH residents. There is an urgent need for intervention trials to test strategies to reduce inappropriate drug use and its associated adverse health outcomes.

Dietary antioxidants as potential pharmacological agents for ischemic stroke.

Acute ischemic stroke is a leading cause of death and severe disability in industrialised countries and also in many developing countries. An excessive amount of free radicals is generated during cerebral ischemia, which significantly contributes to brain damage. Therefore, an increasing interest has been devoted to the potential benefits of antioxidant compounds in ischemic stroke patients. In this review, we examined the most relevant observational studies concerning the relationship between dietary antioxidants and ischemic stroke as well as clinical trials investigating the effects of single or multiple antioxidant supplementation in the prevention or treatment of acute ischemic stroke. Furthermore, we reviewed the most promising antioxidant compounds, i.e. dehydroascorbic acid, alpha-tocotrienol, gamma-tocopherol, flavonoids, resveratrol and gingko biloba, tested in animal models of acute ischemic stroke. Finally, we carefully evaluated the reasons for the discrepancy between experimental and clinical studies, and provided recommendations to improve the translation of the results obtained in animal models to patients with acute ischemic stroke.

Ω-3 Polyunsaturated Fatty Acids and Immune-Mediated Diseases: Inflammatory Bowel Disease and Rheumatoid Arthritis

Inflammation is part of the normal host response to infection and injury. However, inappropriate inflammation contributes to several diseases, including inflammatory bowel disease (IBD) and rheumatoid arthritis (RA). Both conditions are characterized by the excessive production of inflammatory cytokines, arachidonic acid (AA)-derived eicosanoids, and other inflammatory agents (e.g., reactive oxygen species, adhesion molecules). By virtue of their anti-inflammatory action, omega-3 polyunsaturated fatty acids (PUFA) may be beneficial in inflammatory diseases. A large body of evidence supports a protective effect of omega-3 PUFA in experimental animal and ex-vivo models of Crohns disease (CD), Ulcerative colitis (UC) and Rheumatoid arthritis (RA). Although fish oil supplementation in patients with IBD results in omega-3 PUFA incorporation into gut mucosal tissue and modification of inflammatory mediator profiles, the evidence of clinical benefits of omega-3 PUFA is weak. On the other hand, more convincing data support the efficacy of omega-3 PUFA in reducing pain, number of tender joints, duration of morning stiffness, use of non-steroidal anti-inflammatory drugs and improving physical performance in RA patients. In both IBD and RA further clinical trials with large sample size are needed to clarify the efficacy of omega-3 PUFA as a treatment.

Plasma Polyunsaturated Fatty Acids and the Decline of Renal Function

BACKGROUND Recent studies suggest an association between polyunsaturated fatty acids (PUFAs) and the development of chronic kidney disease. The aim of this study was to examine the relationship between PUFAs and renal function in older adults. METHODS We performed a cross-sectional and prospective analysis of 931 adults, > or = 65 years old, enrolled in the InCHIANTI study, a population-based cohort in Tuscany, Italy. Plasma PUFAs were measured at enrollment, and creatinine clearance was estimated by the Cockcroft-Gault equation at baseline and after 3-year follow-up. RESULTS At enrollment, participants with higher creatinine clearance had higher concentrations of HDL cholesterol, total plasma PUFAs, plasma n-3 fatty acid (FA), and plasma n-6 FA and lower triglycerides. From enrollment to the 3-year follow-up visit, creatinine clearance declined by 7.8 (12.2) mL/min (P <0.0001). Baseline total plasma PUFAs, n-3 FA, n-6 FA, and linoleic, linolenic, and arachidonic acids were strong independent predictors of less steep decline in creatinine clearance from baseline to follow-up (P <0.0001, after adjusting for baseline creatinine clearance). After adjusting for baseline creatinine, baseline total plasma PUFAs, n-3 FA, and linoleic, linolenic, and arachidonic acids were negatively associated with creatinine at 3-year follow-up. Participants with higher plasma PUFAs at enrollment had a lower risk of developing renal insufficiency, defined by a creatinine clearance <60 mL/min, during 3-year follow-up. CONCLUSION High PUFA concentrations, both n-3 FA and n-6 FA, may attenuate the age-associated decline in renal function among older community-dwelling women and men.

Predictors of hospitalization in Italian nursing home residents: the U.L.I.S.S.E. project.

OBJECTIVE To examine resident and facility characteristics associated with hospitalization in a cohort of Italian older nursing home residents. DESIGN A longitudinal observational study. SETTING The nursing homes participating in the U.L.I.S.S.E. study, a project evaluating the quality of care for older persons in Italy. SETTING PARTICIPANTS: Nursing home residents in 31 Italian nursing homes. MEASUREMENT Each resident underwent a comprehensive geriatric assessment at baseline, and after 6 months and 1 year by means of the RAI MDS 2.0. Facility characteristics were collected using an ad hoc designed questionnaire. Hospitalizations were self-reported by facilities. RESULTS A total of 170 (11.6%) of 1466 nursing home residents were admitted to the hospital at least once during the study period. Female gender and higher physician, nurse, and nursing assistant hours per resident were predictive of a lower probability to be admitted to the hospital, whereas a diagnosis of arrhythmia, a previous urinary tract infection, and polypharmacy were associated with a higher probability of being hospitalized. CONCLUSION These findings suggest that a reduction of hospitalization of nursing home residents could be achieved by providing an adequate amount of care and optimizing the management of chronic diseases and polypharmacy. This hypothesis should be tested in future clinical trials.

Development of CRIteria to Assess Appropriate Medication Use among Elderly Complex Patients (CRIME) Project: Rationale and Methodology

Pharmacological treatment of complex older adults with comorbidities, multiple impairments in function, cognition, social status and geriatric syndromes represents a challenge for prescribing physicians and often results in a high rate of iatrogenic illnesses. Clinical guidelines are commonly used to indicate appropriate prescription, but they are often based on the results of clinical trials that are conducted on young subjects with a low level of complexity. Therefore, the recommendations of clinical guidelines may be difficult to apply to older complex adults. In this paper we present the rationale and methodology of the Development of CRIteria to assess appropriate Medication use among Elderly complex patients (CRIME) project, a study aimed at producing recommendations to evaluate the appropriateness of pharmacological prescription in older complex patients, translating the recommendations of clinical guidelines to this type of patient. A literature search will be performed to integrate and revise the recommendations of disease-specific guidelines on the pharmacological treatment of patients with common chronic conditions. New recommendations will be provided and approved in a consensus meeting of international experts. Both data from randomized controlled trials and observational studies will be used to meet this aim. Recommendations provided by the CRIME project are not meant to replace existing clinical guidelines, but they may be used to help physicians in the prescribing process. Once completed these recommendations should be validated in interventional studies.

Uric Acid and Dementia in Community-Dwelling Older Persons

Background: The biological action of uric acid (UA) in humans is controversial. UA is considered an antioxidant compound, but preclinical evidence suggests a proinflammatory action. Epidemiological studies found that hyperuricemia is associated with conditions leading to dementia. Our aim is to investigate the relationship between UA levels and dementia in older persons. Methods: Cross-sectional study performed in 1,016 community-dwelling older persons participating in the InCHIANTI study. Participants underwent determination of circulating UA levels and neuropsychological evaluation. A multivariate logistic regression model was used to estimate the probability of participants belonging to the highest and middle UA tertile to be affected by dementia compared to those in the lowest tertile. Results: Demented persons had higher UA levels (p = 0.001) and the prevalence of persons affected by dementia increased across UA tertiles (p < 0.0001). Independent of several confounders, persons belonging to the highest UA tertile had a threefold (OR = 3.32; 95% CI: 1.06–10.42) higher probability to suffer from a dementia syndrome while those in the middle UA tertile tended to have a higher probability of being demented compared to those in the lowest tertile. Conclusion: In a population-based sample, high circulating UA levels are associated with an increased likelihood to be affected by a dementia syndrome.