Mauro Tettamanti

Prevalence, incidence and types of mild anemia in the elderly: the “Health and Anemia” population-based study

Background Hemoglobin concentrations slightly below the lower limit of normal are a common laboratory finding in the elderly, but scant evidence is available on the actual occurrence of mild anemia despite its potential effect on health. The objectives of this study were to estimate the prevalence and incidence of mild grade anemia and to assess the frequency of anemia types in the elderly. Design and Methods This was a prospective, population-based study in all residents 65 years or older in Biella, Italy. Results Blood test results were available for analysis from 8,744 elderly. Hemoglobin concentration decreased and mild anemia increased steadily with increasing age. Mild anemia (defined as a hemoglobin concentration of 10.0–11.9 g/dL in women and 10.0–12.9 g/dL in men) affected 11.8% of the elderly included in the analysis, while the estimated prevalence in the entire population was 11.1%. Before hemoglobin determination, most mildly anemic individuals perceived themselves as non-anemic. Chronic disease anemia, thalassemia trait, and renal insufficiency were the most frequent types of mild anemia. The underlying cause of mild anemia remained unexplained in 26.4% of the cases, almost one third of which might be accounted for by myelodysplastic syndromes. In a random sample of non-anemic elderly at baseline (n=529), after about 2 years, the annual incidence rate of mild anemia was 22.5 per 1000 person-years and increased with increasing age. Conclusions The prevalence and incidence of mild anemia increase with age and mild anemia affects more than one out of ten elderly individuals. Unexplained anemia is common and may be due to myelodysplastic syndromes in some cases.

Association of Mild Anemia with Cognitive, Functional, Mood and Quality of Life Outcomes in the Elderly: The “Health and Anemia” Study

Background In the elderly persons, hemoglobin concentrations slightly below the lower limit of normal are common, but scant evidence is available on their relationship with significant health indicators. The objective of the present study was to cross-sectionally investigate the association of mild grade anemia with cognitive, functional, mood, and quality of life (QoL) variables in community-dwelling elderly persons. Methods Among the 4,068 eligible individuals aged 65–84 years, all persons with mild anemia (n = 170) and a randomly selected sample of non-anemic controls (n = 547) were included in the study. Anemia was defined according to World Health Organization (WHO) criteria and mild grade anemia was defined as a hemoglobin concentration between 10.0 and 11.9 g/dL in women and between 10.0 and 12.9 g/dL in men. Cognition and functional status were assessed using measures of selective attention, episodic memory, cognitive flexibility and instrumental and basic activities of daily living. Mood and QoL were evaluated by means of the Geriatric Depression Scale-10, the Short-Form health survey (SF-12), and the Functional Assessment of Cancer Therapy-Anemia. Results In univariate analyses, mild anemic elderly persons had significantly worse results on almost all cognitive, functional, mood, and QoL measures. In multivariable logistic regressions, after adjustment for a large number of demographic and clinical confounders, mild anemia remained significantly associated with measures of selective attention and disease-specific QoL (all fully adjusted p<.046). When the lower limit of normal hemoglobin concentration according to WHO criteria was raised to define anemia (+0.2 g/dL), differences between mild anemic and non anemic elderly persons tended to increase on almost every variable. Conclusions Cross-sectionally, mild grade anemia was independently associated with worse selective attention performance and disease-specific QoL ratings.

Association of mild anemia with hospitalization and mortality in the elderly: the Health and Anemia population-based study

Mild anemia is a frequent laboratory finding in the elderly usually disregarded in clinical practice. This study shows that mild anemia is associated with increased risk of hospitalization and all-cause mortality in the elderly. See perspective article on page 1. Background Mild anemia is a frequent laboratory finding in the elderly usually disregarded in everyday practice as an innocent bystander. The aim of the present population-based study was to prospectively investigate the association of mild grade anemia with hospitalization and mortality. Design and Methods A prospective population-based study of all 65 to 84 year old residents in Biella, Italy was performed between 2003 and 2007. Data from a total of 7,536 elderly with blood tests were available to estimate mortality; full health information available to evaluate health-related outcomes was available for 4,501 of these elderly subjects. Mild grade anemia was defined as a hemoglobin concentration between 10.0 and 11.9 g/dL in women and between 10.0 and 12.9 g/dL in men. Results The risk of hospitalization in the 3 years following recruitment was higher among the mildly anemic elderly subjects than among subjects who were not anemic (adjusted hazard ratio: 1.32; 95% confidence interval: 1.09–1.60). Mortality risk in the following 3.5 years was also higher among the mildly anemic elderly (adjusted hazard ratio: 1.86; 95% confidence interval: 1.34–2.53). Similar results were found when slightly elevating the lower limit of normal hemoglobin concentration to 12.2 g/dL in women and to 13.2 g/dL in men. The risk of mortality was significantly increased in mild anemia of chronic disease but not in that due to β-thalassemia minor. Conclusions After controlling for many potential confounders, mild grade anemia was found to be prospectively associated with clinically relevant outcomes such as increased risk of hospitalization and all-cause mortality. Whether raising hemoglobin concentrations can reduce the risks associated with mild anemia should be tested in controlled clinical trials.

Inflammatory markers in Alzheimer's disease and multi-infarct dementia

Inflammation has been involved in the pathogenesis of dementia. The study evaluates the presence and the source of pro- and anti- inflammatory cytokines in the blood of patients with Alzheimers disease (AD), multi-infarct dementia (MID) or in non-demented elderly people (controls). Tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, IL-10, IL-1 receptor antagonist (IL-1Ra) and soluble TNF receptor I (sTNF-RI) plasma concentrations and release from blood cells stimulated with lipopolysaccharide (LPS, 1 microg/ml) were determined. The results show that TNF-alpha released from blood cells is significantly decreased (27%) in all demented patients compared to controls. Circulating TNF-alpha is increased (400%) only in MID patients. In these patients plasma levels of sTNF-RI are increased (53%) and IL-10 from stimulated blood cells decreased (47%) compared to non-demented subjects. The results show that: (1) peripheral production of TNF-alpha is blunted in demented (both AD and MID) patients compared to non-demented age-matched subjects; (2) AD patients have a selective disregulation of the peripheral TNF-alpha system; (3) different cytokines are up- or down- regulated in MID patients showing that in this condition the pro- and anti-inflammatory peripheral cytokine system is more widely affected.

Doxycycline in Creutzfeldt-Jakob disease: a phase 2, randomised, double-blind, placebo-controlled trial.

BACKGROUND Creutzfeldt-Jakob disease (CJD) is a fatal, untreatable prion encephalopathy. Previous studies showed that doxycycline is effective in in-vitro and in-vivo models of disease, and patients with CJD who received compassionate treatment with doxycycline showed increased survival time compared with historical series. We therefore did a randomised, double-blind study of doxycycline versus placebo in CJD. METHODS We recruited patients older than 18 years old who had a diagnosis of definite or probable sporadic CJD or genetic forms of the disease via Italian reference centres and the French national referral system. Patients were randomly assigned (ratio 1:1) to receive oral doxycycline (100 mg daily) or placebo under double-blind conditions from the day of randomisation to death. Centralised randomisation was done independently of enrolment or evaluation of patients using a minimisation method in Italy and a simple randomisation in France. Participants, caregivers, and clinicians were masked to group assignment. The primary efficacy variable was the survival time from randomisation. Interim analyses were planned to detect a significant effect of treatment as early as possible. This trial is registered with EudraCT, 2006-001858-27 for the Italian study and 2007-005553-34 for the French study. FINDINGS From April 12, 2007, to Aug 19, 2010, in Italy, and from Jan 30, 2009, to Jan 10, 2012, in France, 121 patients with CJD were enrolled in the study, 62 of whom were randomly assigned to the treatment group and 59 to the placebo group. The first interim analysis showed absence of superiority of doxycycline compared with placebo, and the trial was stopped for futility. Efficacy analyses did not show significant differences between patients treated with doxycycline and placebo with regard to survival times (HR 1.1, 95% CI 0.8-1.7, p=0.50). Serious adverse events were judged not to be related to treatment, whereas a relation was deemed probable or possible for five non-serious adverse events that occurred in each treatment group. INTERPRETATION Doxycycline at a dose of 100 mg per day was well tolerated but did not significantly affect the course of CJD, at variance with the results of previous observational studies. Our experience could be useful in the design of large multinational controlled trials of potential anti-prion molecules in this rare disease. FUNDING Agenzia Italiana Farmaco, Italian Ministry of Health, AIEnP, and French Ministry of Health.

Potentially severe drug interactions in elderly outpatients: results of an observational study of an administrative prescription database

Purpose:  To estimate the prevalence of potentially severe drug–drug interactions (DDIs) and their relationship with age, sex and number of prescribed drugs.

The effect of a structured intervention on caregivers of patients with dementia and problem behaviors: a randomized controlled pilot study.

The objective was to assess the effect of a structured intervention on caregiver stress and the institutionalization rate of patients with dementia and problem behaviors. Caregivers contacting the Federazione Alzheimer Italia (AI) to receive help, advice, or information in relation to problem behaviors of outpatients were enrolled. Eligible caregiver-patient dyads were randomized to receive either a structured intervention or the counseling AI usually provides (control group). After basal assessment, families were reassessed at 6 and 12 months. Problem behavior (particularly agitation) was the only variable significantly correlated (P = 0.006) with the baseline caregivers’ stress score. Thirty-nine families completed the 12-month follow-up; the mean problem behavior score was significantly lower in the intervention than the control group (p < 0.03); the time needed for care of the patient increased by 0.5 ± 9.7 hours/day in the control group and decreased by 0.3 ± 4.1 in the intervention group (p = 0.4, Wilcoxon test). The main determinant of institutionalization seemed to be the level of caregiver stress (p = 0.03). In patients of the intervention group, there was a significant reduction in the frequency of delusions. This pilot study suggests that caregiver stress is relieved by a structured intervention. The number of families lost to follow-up, the relatively short duration of the study, and the ceiling effect due to the severity of the clinical characteristics of patients probably all partly dilute the observed findings.

Prevalence and appropriateness of drug prescriptions for peptic ulcer and gastro-esophageal reflux disease in a cohort of hospitalized elderly.

BACKGROUND Proton pump inhibitors (PPI) are among the most commonly prescribed medicines and their overuse is widespread in both primary and secondary care. Inappropriate prescription is of particular concern among elderly patients, who have often multiple comorbidities and need many drugs. METHODS We evaluate the appropriateness of drugs for peptic ulcer or gastro-esophageal reflux disease (GERD) in a sample of elderly patients (65 years old or older) at admission and discharge in 38 internal medicine wards between January 2008 and December 2008, according to the presence of specific conditions or gastro-toxic drug combinations. RESULTS Among 1155 patients eligible for the analysis, 466 (40.3%) were treated with drugs for GERD or peptic ulcer were at hospital admission and 647 (56.0%) at discharge; 62.4% of patients receiving a drug for peptic ulcer or GERD at admission and 63.2% at discharge were inappropriately treated. Among these, the number of other drugs prescribed was associated with greater use of drugs for peptic ulcer or GERD, even after adjustment for age, sex and number of diagnoses at admission (OR 95% CI=1.26 (1.18-1.34), p=.0001) or discharge (OR 95% CI=1.11 (1.05-1.18), p=0.0003). CONCLUSIONS Prevalence of inappropriate prescription of drugs for peptic ulcer or GERD remained almost the same at admission and discharge. Inappropriate use of these drugs is related to the concomitant use of other drugs. Careful assessment of clinical conditions and stricter adherence to evidence-based guidelines are essential for a rational and cost-effective use of drugs for peptic ulcer or GERD.

Homocysteine and B vitamins in mild cognitive impairment and dementia.

Abstract Elderly subjects with mild cognitive impairment have a high risk for conversion to Alzheimers disease or are already in a preclinical dementia stage. By cross-sectionally comparing subjects in prodromal and early phases of dementia with non-demented controls, we tested the hypothesis whether low serum vitamin B12 and folate and high plasma total homocysteine concentrations precede or are a consequence of dementia onset. From a large population of 623 consecutive subjects seen at the Memory Clinic (Ospedale Beata Vergine, Mendrisio, Switzerland), 433 subjects could be included in the analyses: 79 elderly controls, 218 Clinical Dementia Rating 0.5 subjects, and 136 demented patients (111 with Alzheimers disease and 25 with vascular dementia). As in an earlier report on a smaller sample of the same population (n=228), the lowest folate tertile was strongly associated with mild cognitive impairment (adjusted OR=3.1) and Alzheimers disease (adjusted OR=4.0). Hyperhomocysteinemia showed a significant association not only with Alzheimers disease (adjusted OR=3.1) but, at variance with the previous report, also with mild cognitive impairment (adjusted OR=2.6). Present reanalysis results suggest that subclinical folate deficiency and hyperhomocysteinemia might predate dementia onset, findings to be confirmed by longitudinal studies.

Association between clusters of diseases and polypharmacy in hospitalized elderly patients: Results from the REPOSI study

BACKGROUND Although the association between multimorbidity and polypharmacy has been clearly documented, no study has analyzed whether or not specific combinations of diseases influence the prescription of polypharmacy in older persons. We assessed which clusters of diseases are associated with polypharmacy in acute-care elderly in-patients. METHODS This cross-sectional study was held in 38 Italian internal medicine and geriatric wards participating in the Registro Politerapie SIMI (REPOSI) study during 2008. The study sample included 1155 in-patients aged 65 years or older. Clusters of diseases, defined as two or more co-occurring specific chronic diseases, were identified using the odds ratio (OR) for the associations between pairs of diseases followed by cluster analysis. Polypharmacy was defined as the prescription of five or more different medications at hospital discharge. Logistic regression models were run to analyze the association between clusters of diseases and polypharmacy. RESULTS Among clusters of diseases, the highest mean number of drugs (>8) was found in patients affected by heart failure (HF) plus chronic obstructive pulmonary disease (COPD), HF plus chronic renal failure (CRF), COPD plus coronary heart disease (CHD), diabetes mellitus plus CRF, and diabetes mellitus plus CHD plus cerebrovascular disease (CVD). The strongest association between clusters of diseases and polypharmacy was found for diabetes mellitus plus CHD plus CVD, diabetes plus CHD, and HF plus atrial fibrillation (AF). CONCLUSIONS The observed knowledge of the relationship among co-occurring diseases and polypharmacy should help to identify and monitor older in-patients at risk of polypharmacy.