Use of calcium antagonists and hemoglobin loss in hospitalized elderly patients: a cohort study. Gruppo Italiano di Farmacoepidemiologia nell'Anziano (GIFA) investigators.

OBJECTIVE: To assess the association between in-hospital use of calcium antagonists and incident reduction in hemoglobin levels, as well as the impact of individual baseline risk for gastrointestinal bleeding on such an association. METHODS: The association between calcium antagonists and hemoglobin decrease > 1.2 g/dL was examined in 6,721 patients enrolled in a collaborative pharmacoepidemiology study who did not take calcium antagonists before admission and with baseline hemoglobin > or =12 g/dL. Among these participants, 1,076 patients started taking calcium antagonists during their hospital stays. Demographic variables, comorbid conditions, medications, and objective tests that were associated with incident hemoglobin loss in separate age- and sex-adjusted logistic regression models were examined as potential confounders in a summary model. Higher risk for gastrointestinal bleeding was defined by diagnosis, treatment for peptic disease, or both. RESULTS: Hemoglobin decrease was detected in 24% of participants who started treatment with calcium antagonists and in 19% of other patients (P < .0001). In addition, use of calcium antagonists was independently associated with increased probability of hemoglobin loss (odds ratio [OR], 1.22; 95% confidence interval [CI], 1.03 to 1.45; P = .018) after adjusting for potential confounders. Treatment with calcium antagonists was associated with hemoglobin loss in patients with higher baseline risk for gastrointestinal bleeding (OR, 1.67; 95% CI, 1.26 to 2.22; P < .0001) but not among other participants (OR, 1.02; 95% CI, 0.82 to 1.25). CONCLUSION: Starting treatment with calcium antagonists is associated with a reduction in hemoglobin levels during a hospital stay. However, the increased risk of hemoglobin loss seems to be limited to patients with diagnosis or symptoms of peptic disease.

Association of serum creatinine and age with headache caused by nitrates. Gruppo Italiano di Farmacovigilanza nell'Anziano.

To assess whether serum creatinine and age are associated with headache induced by nitrates, 2742 hospitalized patients taking nitrates were studied during their hospital stay. Those patients with admission serum creatinine levels from 97 to 133 mumol/L and > 133 mumol/L were compared with patients with creatinine levels < 97 mumol/L. Gender, body mass index, comorbidity, cognitive status, new intake of nitrates, number of daily administrations, and daily dosage, as well as intake of angiotensin converting enzyme inhibitors, calcium antagonists, diuretics and nonsteroidal anti-inflammatory drugs were examined as possible confounders. Fifty-six patients had headaches that had a causal link with intake of nitrates. Compared with the lowest creatinine group, after adjustment for potential confounding variables, the odds ratios and 95% confidence interval (95% CI) for headache caused by nitrates associated with increasing serum creatinine levels were 0.6 (95% CI, 0.3 to 1.1) and 0.2 (95% CI, 0.0 to 1.2), respectively (p for trend = 0.013). Increasing age was inversely associated with headache (odds ratio for 10-year increase, 0.6 [95% CI, 0.5 to 0.7]). Serum creatinine and age were independently and inversely associated with headache caused by nitrates.

Hypotension and cognitive impairment: Selective association in patients with heart failure.

BACKGROUND: Arterial hypotension has been associated with increased risk of dementia in some large prospective studies; and cognitive impairment is common among elderly with left ventricular function. The authors assessed whether arterial hypotension might be associated with cognitive impairment among older subjects with heart failure. METHODS: This study involved all 13,635 patients (of whom 1,583 had heart failure) without cerebrovascular disease or AD, admitted to 81 Italian academic hospitals in 1995 and 1997. The association between blood pressure and cognitive impairment (as indicated by a Hodkinson Mental Test score < 7) according to the presence of heart failure was assessed by univariate analyses, including linear discriminant analysis. This association was also verified by multivariate analyses after stratifying for diagnosis of heart failure. RESULTS: Cognitive impairment was found in 26% of patients with heart failure and in 19% of remaining subjects (Fisher exact p < 0.0001). Blood pressure levels did not differ according to diagnosis of heart failure, but discriminant analysis indicated that systolic blood pressure levels below 130 mm Hg predicted cognitive impairment only among participants with heart failure. Among such participants, systolic blood pressure was associated with cognitive impairment in multiple logistic regression modeling (for 10 mm Hg intervals, OR = 0.78; 95% CI = 0.71 to 0.86). Again, this association was not found among participants without heart failure. CONCLUSIONS: Systolic hypotension is selectively associated with cognitive impairment in older patients with heart failure. As early treatment of cardiac low-output states can reverse cognitive dysfunction, the routine management of heart failure should include systematic assessment of cognitive performance.

A controlled trial of verapamil in patients after acute myocardial infarction: results of the calcium antagonist reinfarction Italian study (CRIS)

A multicenter, double-blind, randomized, placebo-controlled trial was conducted to assess the effects of verapamil on total mortality, cardiac mortality, reinfarction, and angina after an acute myocardial infarction. All patients, aged 30 to 75 years, consecutively admitted for acute myocardial infarction between 1985 and 1987 to the participating centers, and without contraindications to verapamil or history of severe heart failure were enrolled. Seven to 21 days (mean 13.8) after myocardial infarction, 531 patients were randomized to verapamil retard 360 mg/day, and 542 patients to placebo. At baseline, the 2 groups of patients had similar characteristics. Mean age was 55.5 years and 91% were men. During a mean follow-up of 23.5 months, 5.5% of the patients died. No differences between verapamil and placebo were observed in total mortality (n = 30 and 29, respectively) and cardiac death (n = 21 and 22, respectively). The verapamil group had nonsignificant lower reinfarction rates (n = 39 vs 49). The number of patients developing angina was significantly less in the verapamil group (n = 100 vs 132, RR = 0.8, 95% confidence interval 0.5 to 0.9). There were no differences in discontinuation of therapy caused by adverse reactions. This trial showed no effect of verapamil on mortality. The lower reinfarction rates found in the verapamil group are in agreement with the results of other studies.

Age and severe adverse drug reactions caused by nifedipine and verapamil. Gruppo Italiano di Farmacovigilanza nell' Anziano (GIFA).

The association of age with risk for severe adverse drug reactions (SADRs) was studied in 2371 and 862 hospitalized patients taking nifedipine and verapamil, respectively. Nifedipine caused hypotension (n = 22), tachycardia (n = 3), and acute renal failure (n = 1) (total SADR rate, 1.1%, 26/2371). Verapamil caused hypotension (n = 3), bradycardia (n = 9), and atrioventricular blocks (n = 2) (total SADR rate, 1.6%, 14/862). The mean age of patients with and without SADRs was for nifedipine 77.1 +/- 1.7 and 71.8 +/- 0.8 years, respectively (p < 0.05), and for verapamil 73.4 +/- 2.9 and 73.1 +/- 0.4 years, respectively. Sex, length of stay, comorbidity, polypharmacy, intake of slow-release preparations, daily dosage, and new intake of calcium antagonists were examined as potential confounders of the age-SADR association. After adjusting for potential confounders, age was significantly and independently associated with SADRs caused by nifedipine, but not with SADRs caused by verapamil (OR = 1.69, 95% CI = 1.05-2.72 and OR = 1.06, 95% CI = 0.63-1.68 for 10-year increase, respectively). Although nifedipine and verapamil did not have significantly different rates of SADRs, an age-related gradient was found only for nifedipine.

The impact of age on risk of adverse drug reactions to digoxin. For The Gruppo Italiano di Farmacovigilanza nell' Anziano.

To assess the association of age and other potential risk factors with digoxin toxicity, adverse drug reactions to digoxin (ADRDIG) were studied in all patients (n = 1338) on digoxin therapy consecutively admitted to 41 clinical wards throughout Italy during 4 months in 1988. At the time of admission, 28 patients (2.1%) had evidence of ADRDIG. In multivariate logistic regression analysis, significant associations with ADRDIG were found for age > or = 80 years compared to age 65-79 years (OR = 2.75, 95% CI = 1.17-6.45), daily digoxin dosage of > or = 0.25 mg (OR = 2.51, 95% CI = 1.16-5.47), serum creatinine > or = 120 mumol/L (OR = 3.75, 95% CI = 1.69-8.32), and for treatment with amiodarone, propafenone, quinidine or verapamil (OR = 2.60, 95% CI = 1.07-6.30). Those aged < 65 years had a similar risk of digoxin toxicity as those aged 65-79 years (OR = 1.07, 95% CI = 0.28-4.12). Adverse drug reactions to digoxin were found in 1 in 50 patients hospitalized on digoxin therapy. Patients aged 65-79 years were not at increased risk for digoxin toxicity compared to younger patients, while advanced age (> or = 80 years) was an independent risk factor for this outcome.

Reasons prompting digitalis therapy in the acute care hospital.

BACKGROUND: The choice of administering digitalis to older patients with congestive heart failure (CHF) cannot be made on the account of univocally defined criteria because of uncertainty about efficacy and concern about safety of digitalis in this population. The purpose of this study was to verify whether the clinical characteristics on admission to the acute care hospital determine the use of digitalis therapy in elderly patients. METHODS: A total of 1239 patients (mean age 77.8 +/- 7.1 years, range 65-100 years, males 49.8%) consecutively admitted to 69 General Medicine and Geriatrics wards over a 4-month period were grouped by combining two dichotomous factors (Carlson's score > 4: definite or possible diagnosis of CHF; Carlson's score < 5: unlikely diagnosis of CHF; in-hospital adoption of digitalis therapy: yes or no) as follows: Group A: Carlson's score > 4, digitalis (n = 413); Group B: Carlson's score > 4, no digitalis (n = 260); Group C: Carlson's score < 5, digitalis (n = 104); Group D: Carlson's score < 5, no digitalis (n = 462). Variables significantly distinguishing groups were entered into a discriminant analysis aimed at assessing the group specificity of individual clinical profiles. RESULTS: Use of digoxin at home, atrial fibrillation, older age, and comorbidity (mainly COPD and chronic renal failure) characterized most of the patients given digoxin with or without a definite diagnosis of CHF. Clinical profiles of groups A, B, and C largely overlapped. CONCLUSION: Age, historical use of digitalis, and comorbidity might lead to seemingly incongruous digitalis prescription. The choice of adopting digitalis therapy cannot be reliably predicted on the basis of clinical variables only. Presently unexplored physician-related factors, such as cultural background, likely outweigh clinical variables in prompting digitalis prescription.

Older age and in-hospital development of hypokalemia from loop diuretics: results from a multicenter survey. GIFA Investigators. Multicenter Italian Pharmacoepidemiologic Study Group.

BACKGROUND: Hypokalemia is a common finding among older patients taking diuretic medications. However, it is not known whether older age per se carries an increased risk of hypokalemia, particularly during a patient's treatment with loop diuretics. METHODS: The association between age and incident hypokalemia was examined in 18,872 patients with normal baseline serum potassium enrolled during three yearly multicenter surveys; 4,035 patients started receiving loop diuretics during their hospital stay. Demographic variables, comorbid conditions, medications, and objective tests that were associated with incident hypokalemia in separate age- and sex-adjusted logistic regression models were examined as potential confounders. RESULTS: Among patients with normal baseline serum potassium, the factors of age, presence of coronary disease or diabetes, comorbidity, the use of ACE inhibitors, loop diuretics, digitalis, corticosteroids, or insulin, and baseline serum potassium were associated with incident hypokalemia in initial models. After these variables were adjusted for, age (for each decade, odds ratio = 1.30; 95% confidence interval = 1.17-1.46; p < .0001) was associated with incident hypokalemia. The use of parenteral (2.30; 1.53-3.46; p < .0001) but not oral (1.16; 0.79-1.69; p = .44) loop diuretics was associated with hypokalemia. Eventually, age was associated with hypokalemia when the summary regression model was analyzed in patients taking loop diuretics (1.33; 1.03-1.71; p = .027), as well as in those taking intravenous loop diuretics only (1.84; 1.25-2.70; p = .002). CONCLUSIONS: Older age is independently associated with the in-hospital development of hypokalemia, particularly among patients taking loop diuretics. Monitoring of serum potassium levels is therefore advisable when older patients are treated with these agents.

Digitalis in the treatment of heart failure in the elderly. The GIFA study results.

Digitalis glycosides have played an important role in the treatment of patients with heart failure (HF) for more than two centuries. Despite the introduction of new therapeutic strategies in the treatment of HF, and controversies regarding the role of digitalis in HF in sinus rhythm and its effect on mortality, digoxin is one of the most commonly prescribed drugs in the community and in hospital settings, particularly in the elderly. The Italian Group of Pharmacosurveillance in the Elderly (GIFA) monitored 20,047 hospitalized patients in 1988, 1991 and 1993, and found that digoxin was the most frequently prescribed drug in the management of HF. Inappropriate prescriptions of digitalis, defined with standardized criteria, were uncommon, and the mean daily dosage was low. Compared to earlier studies the incidence rate of adverse drug reactions (ADRs) to digoxin, was also low. The reduction in ADRs incidence was probably due to a better understanding of digoxin pharmacokinetics and to a lower daily dosage in the elderly. Nevertheless, digoxin toxicity was significantly more frequent in patients aged >or= 80 years than in those aged < 65 and and 65-79 years. In a multidrug approach to the treatment of chronic HF, digoxin exerts clinical benefits also in patients with sinus rhythm, it is not costly, it is easy to administer, and toxic effects are not common.

Serum magnesium levels and cognitive impairment in hospitalized hypertensive patients.

We performed this cross-sectional case control study to investigate the association between low serum magnesium levels and cognitive impairment in hypertensive hospitalized patients. The study was carried out in general medical care units at 81 hospitals participating in the Gruppo Italiano di Farmacovigilanza nell'Anziano (GIFA) study throughout Italy, and a total of 1058 patients with diagnoses of hypertension at the discharge were studied. The occurrence of cognitive impairment at discharge was the primary outcome of our study. Cognitive impairment was ascertained using the Hodkinson Abbreviated Mental Test (HAMT). Sociodemographic variables, body mass index, laboratory parameters, comorbidity, use of antihypertensive drugs and number of drugs were considered as potential confounders. Twenty-nine percent of the selected hypertensive patients were classified as having cognitive impairment. In univariate analysis, older age, female sex, and low educational level showed a significant trend for association to cognitive impairment. Moreover the proportion of subjects with cognitive impairment decreased with increasing alcohol consumption, and the prevalence of ex smokers and smokers was significantly lower in patients with cognitive impairment. The lower tertiles for serum albumin and creatinine clearance were more frequent among patients with cognitive impairment, and the lower tertile for serum magnesium levels was significantly more frequent in these patients. Number of drugs was slightly lower in cognitively impaired patients, while number of diagnoses and length of hospital stay were higher in these subjects. In the multivariate logistic regression analysis cognitive impairment decreased with increasing education level (highest education: OR 0.11; 95 per cent CI 0.05-0.25). The lower tertile for serum albumin (< 3.5 g/dl) was significantly associated to cognitive impairment (OR 2.14; 95 per cent CI 1.31-3.49), as well as the lower tertiles for serum magnesium (0.74-0.86 mmol/L: OR 1.54; 95 per cent CI 1.06-2.22; < 0.74 mmol/L: OR 1.75; 95 per cent CI 1.13-2.72]. Our results demonstrate the existence of a significant association between magnesium imbalance and cognitive impairment. These data suggest that the assessment of magnesium status may be of some relevance in hypertensive subjects with cognitive disorders.

Age-related differences in isolated rat sinus node function.

In order to rule out age-related differences in the sinus node (SN) function, the effects of different substances were tested in SN isolated preparations from adult (4-5-month-old) and old (24-25-month-old) rats. No difference was seen in the in vivo heart rate between adult and old rats, whereas sinus node rate (SNR) was significantly lower in the old rather than in the adult preparations. The effects of acetylcholine (10(-9)-10(-5) M) were similar between the two groups of preparations. The response to adenosine (10(-9)-10(-4) M) was significantly higher in the adult than in the old preparations (p less than 0.05). No significant difference was noted in the response to isoproterenol (10(-10)-10(-6) M). High calcium (5.4-8.1 mM) caused an increase of the SNR that was significantly greater in the old than in the adult preparations (p less than 0.005). In conclusion, our results show an age-related decrease in the isolated SNR that does not seem to be mediated by different responses to neuromediators but is probably due to an alteration of the intrinsic activity of the SN cells.

Construct validity of the abbreviated mental test in older medical inpatients.

OBJECTIVES: To evaluate validity and internal structure of the Abbreviated Mental Test (AMT), and to assess the dependence of the internal structure upon the characteristics of the patients examined. DESIGN: Cross-sectional examination using data from the Italian Group of Pharmacoepidemiology in the Elderly (GIFA) database. SETTING: Twenty-four acute care wards of Geriatrics or General Medicine. PARTICIPANTS: Two thousand eight hundred and eight patients consecutively admitted over a 4-month period. MEASUREMENTS: Demographic characteristics, functional status, medical conditions and performance on AMT were collected at discharge. Sensitivity, specificity and predictive values of the AMT <7 versus a diagnosis of dementia made according to DSM-III-R criteria were computed. The internal structure of AMT was assessed by principal component analysis. The analysis was performed on the whole population and stratified for age (<65, 65-80 and >80 years), gender, education (<6 or >5 years) and presence of congestive heart failure (CHF). RESULTS: AMT achieved high sensitivity (81%), specificity (84%) and negative predictive value (99%), but a low positive predictive value of 25%. The principal component analysis isolated two components: the former component represents the orientation to time and space and explains 45% of AMT variance; the latter is linked to memory and attention and explains 13% of variance. Comparable results were obtained after stratification by age, gender or education. In patients with CHF, only 48.3% of the cumulative variance was explained; the factor accounting for most (34.6%) of the variance explained was mainly related to the three items assessing memory. CONCLUSION: AMT >6 rules out dementia very reliably, whereas AMT <7 requires a second level cognitive assessment to confirm dementia. AMT is bidimensional and maintains the same internal structure across classes defined by selected social and demographic characteristics, but not in CHF patients. It is likely that its internal structure depends on the type of patients. The use of a sum-score could conceal some part of the information provided by the AMT.

Trends of the characteristics and appropriateness of admissions to acute geriatric and medical wards in Italy from 1988 through 1993. Gruppo Italiano di Farmacovigilanza nell'Anziano--GIFA.

Recent modifications in the health care system in Italy reduced the number of inpatient care beds and limited the access to outpatient services while the proportion of older persons increased. To assess the burden of these changes on hospital care the characteristics of admissions to 35 acute geriatric wards and 31 internal medicine wards in Italy were studied between 1988 and 1993. All patients admitted during 4 months in 1988, 1 month in 1991 and 4 months in 1993 were enrolled in the study. The appropriateness of admission was assessed by means of the Appropriateness Evaluation Protocol criteria. The Charlson comorbidity index score was used to quantify comorbidity. Between 1988 and 1993, 18,790 patients were studied. The mean age increased from 67.9 +/- 0.2 to 71.7 +/- 0.2 years (p < 0.0001), the mean number of drugs taken during hospital stay increased from 5.2 +/- 0.0 to 5.5 +/- 0.0 drugs (p < 0.0001), the mean Charlson comorbidity index score increased from 1.33 +/- 0.02 to 1.50 +/- 0.03 (p < 0.0001) and the mean length of stay decreased from 17.6 +/- 0.2 to 16.1 +/- 0.2 days (p < 0.0001). The rate of appropriate admissions increased from 68.6% to 85.5% (p < 0.0001). Consistent results were found when the data were stratified according to gender and type of ward. It was concluded that in Italy, concurrently to an increased load of hospital care, inappropriate admissions diminished over time. These data show that the need for geriatric care is increasing.

Age-related incidence of reperfusion- and reoxygenation-induced ventricular tachyarrhythmias in the isolated rat heart.

Reperfusion- and reoxygenation-induced ventricular tachyarrhythmias were studied on 6-month-old (adult) and 24-month-old (senescent) Langendorff perfused rat hearts. The incidence of arrhythmias was significantly higher in the group of senescent hearts. Furthermore, the reperfusion- and reoxygenation-induced contracture was also more frequent in the group of senescent hearts. The interrelation between contracture and arrhythmias might represent an indirect evidence to suggest that alterations in cell calcium homeostasis have an important role in the origin of both phenomena and, possibly, in their increased incidence in the senescent heart.

Pharmacosurveillance in hospitalized patients in Italy. Study design of the 'Gruppo Italiano di Farmacovigilanza nell'Anziano' (GIFA).

The Italian Group of Pharmacoepidemiology in the Elderly (Gruppo Italiano di Farmacovigilanza nell'Anziano, GIFA) is a collaborative pharmacosurveillance study in hospitalized patients, sponsored by the Italian National Research Council (CNR) and the Italian Society of Gerontology and Geriatrics. It was founded in 1987 with the aim to constitute a multicentre research group to study quality of care and problems related to pharmacological therapy in the elderly. Until now the GIFA study has completed seven periodical surveys and enrolled a total of 28,411 hospitalized patients in 83 clinical centres. The database of the study contains approximately 174,000 in-hospital drug prescriptions, approximately 88,000 discharge diagnoses and a great deal of data on topical geriatric items such as cognitive performance, disability, comorbidity, adverse drug reactions and incontinence. This paper describes the general organization and the methods of the GIFA study and shows in detail the type of data collected.

Physical restraint and subcutaneous hematoma in an anticoagulated patient.

A large subcutaneous hematoma extending from the breastbone region to the left axillary region and left flank developed in a 86-year-old anticoagulated man because of repeated microtrauma from a physical restraint used to prevent his rising from a chair. Physicians, nurses, and physiotherapists should recognize that physical restraints causing pressure on the skin increase hemorrhagic risk in patients who take low molecular weight heparin. Accordingly, they should systematically check for hemorrhagic complications and attempt to limit the use of such devices.

The cardiomyopathic hamster as model of early myocardial aging.

Few experimental studies are available on aging, because of the lack of suitable experimental models to test specific pathophysiologic mechanisms. In the present study, the cardiomyopathic Syrian hamster is proposed as experimental model of the aging myocardium. In fact, the hamster myocardium develops an early alpha to beta myosin isoform shifting in ventricles that is independent of hemodynamic overload and repeats the phenomenon physiologically occurring in healthy hamsters during the entire lifespan. At the same time, in atria there is a progressive decline of ANF production that is independent of intracavitary pressure. Conversely, ANF production in ventricles is enhanced before the onset of hemodynamic overload, but parallel to the increase in the fibrotic proportion of the ventricular wall. These characteristics mimic the modifications occurring in otherwise healthy aged mammals and candidate the cardiomyopathic hamster as a model of early myocardial aging.

Verapamil disposition and cardiovascular effects in elderly patients after single intravenous and oral doses.

Pharmacokinetics and pharmacodynamics of verapamil were studied in 11 elderly subjects (age = 79.67 +/- 4.74 years) and in 11 middle-aged subjects (age = 45 +/- 11.37 years) following intravenous (IV), single oral, and long-term oral administration. Plasma verapamil concentrations were determined using high-pressure liquid chromatography (HPLC). Twenty-four hour dynamic Holter electrocardiographic (ECG) recordings were employed to study heart rate (HR) and P-R interval. No difference in plasma half-life, distribution volume, body clearance, and area under the curve (AUC) was observed between the two groups after IV and oral verapamil administration. Blood pressure (BP) and HR were significantly reduced after verapamil IV administration in the elderly group only (p less than 0.05, p less than 0.01, respectively). After single and long-term oral administration, variable HR and BP responses were observed in both groups. The P-R prolongation following both IV and single oral doses exhibited a delay with respect to the peak plasma concentration, inducing a definite hysteresis loop. The slope of P-R variations (using a linear pharmacodynamic model) was greater in the elderly both after IV and single oral verapamil administration, but statistical significance was obtained only after the single oral dose (p less than 0.05). In the elderly group, after long-term oral administration, there was a significant prolongation of the P-R interval (p less than 0.0001) with respect to the corresponding time point of the 24-hour predrug period. Such variations in pharmacodynamic parameters in the elderly did not, however, cause any clinical problem.(ABSTRACT TRUNCATED AT 250 WORDS)