Marina Maggini

Cholinesterase Inhibitors in Mild Cognitive Impairment: A Systematic Review of Randomised Trials

Background Mild cognitive impairment (MCI) refers to a transitional zone between normal ageing and dementia. Despite the uncertainty regarding the definition of MCI as a clinical entity, clinical trials have been conducted in the attempt to study the role of cholinesterase inhibitors (ChEIs) currently approved for symptomatic treatment of mild to moderate Alzheimer disease (AD), in preventing progression from MCI to AD. The objective of this review is to assess the effects of ChEIs (donepezil, rivastigmine, and galantamine) in delaying the conversion from MCI to Alzheimer disease or dementia. Methods and Findings The terms “donepezil”, “rivastigmine”, “galantamine”, and “mild cognitive impairment” and their variants, synonyms, and acronyms were used as search terms in four electronic databases (MEDLINE, EMBASE, Cochrane, PsycINFO) and three registers: the Cochrane Collaboration Trial Register, Current Controlled Trials, and ClinicalTrials.gov. Published and unpublished studies were included if they were randomized clinical trials published (or described) in English and conducted among persons who had received a diagnosis of MCI and/or abnormal memory function documented by a neuropsychological assessment. A standardized data extraction form was used. The reporting quality was assessed using the Jadad scale. Three published and five unpublished trials met the inclusion criteria (three on donepezil, two on rivastigmine, and three on galantamine). Enrolment criteria differed among the trials, so the study populations were not homogeneous. The duration of the trials ranged from 24 wk to 3 y. No significant differences emerged in the probability of conversion from MCI to AD or dementia between the treated groups and the placebo groups. The rate of conversion ranged from 13% (over 2 y) to 25% (over 3 y) among treated patients, and from 18% (over 2 y) to 28% (over 3 y) among those in the placebo groups. Only for two studies was it possible to derive point estimates of the relative risk of conversion: 0.85 (95% confidence interval 0.64–1.12), and 0.84 (0.57–1.25). Statistically significant differences emerged for three secondary end points. However, when adjusting for multiple comparisons, only one difference remained significant (i.e., the rate of atrophy in the whole brain). Conclusions The use of ChEIs in MCI was not associated with any delay in the onset of AD or dementia. Moreover, the safety profile showed that the risks associated with ChEIs are not negligible. The uncertainty regarding MCI as a clinical entity raises the question as to the scientific validity of these trials.

Incidence of Coronary Heart Disease in Type 2 Diabetic Men and Women Impact of microvascular complications, treatment, and geographic location

OBJECTIVE—Cardiovascular disease (CVD) is the main cause of morbidity/mortality in diabetes. We set forth to determine incidence and identify predictors (including microvascular complications and treatment) of first coronary heart disease (CHD) event in CVD-free type 2 diabetic patients. RESEARCH DESIGN AND METHODS—A cohort of 6,032 women and 5,612 men, sampled from a nationwide network of hospital-based diabetes clinics, was followed up for 4 years. Baseline assessment included retinopathy, nephropathy, and foot ulcers. First CHD events (myocardial infarction, coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, and electrocardiogram-proven angina) were analyzed for 29,069 person-years. RESULTS—The age-standardized incidence rate (per 1,000 person-years) of first CHD event (n = 881) was 28.8 (95% CI 5.4–32.2) in men and 23.3 (20.2–26.4) in women. Major CHD (myocardial infarction, coronary artery bypass grafting, and percutaneous transluminal coronary angioplasty) was less frequent in women (5.8 [4.3–7.2]) than in men (13.1 [10.9–15.4]; a sex ratio of 0.5 [0.4–0.6]). Incidence rates of all outcomes were higher in patients with microvascular complications (for major CHD, age-adjusted rate ratios were 1.6 [1.2–2.21] in men and 1.5 [1.0–2.2] in women). By multivariate Cox analysis, age and diabetes duration were risk predictors common in both sexes. In men, glycemic control and treated hypertension were additional independent risk factors, but residing in the south was associated with a significant 29% risk reduction. In women, higher triglycerides/lower HDL cholesterol and microvascular complications were independent risk factors. CONCLUSIONS—In CVD-free patients with type 2 diabetes, risk of first CHD event depends on sex, geographic location, and presence of microvascular disease. Hyperglycemia and hypertension, particularly in men, and diabetic dyslipidemia, especially in women, are risk factors amenable to more aggressive treatment.

Gastroduodenal toxicity of different nonsteroidal antiinflammatory drugs.

Although the etiologic relation between nonsteroidal antiinflammatory drug (NSAID) use and gastrointestinal lesions is well documented, newly introduced NSAIDs deserve a fresh examination for their risk/benefit ratio. To estimate the association between consumption of ketorolac and the occurrence of gastroduodenal lesions, we conducted a case-control study. The study population comprised 600 outpatients with a confirmed endoscopic diagnosis of ulcer and erosion in 1991 and 1992 and 6,000 community controls matched by age and sex. We retrieved the prescription history through a computerized prescription monitoring system. We defined exposure to each study drug as “current” (month of endoscopy and preceding month), “recent” (second or third month preceding endoscopy), and “past” (fourth to sixth month preceding endoscopy). Current users of NSAIDs showed a 30% increase in the incidence of gastroduodenal lesions [odds ratio (OR) = 1.3; 95% confidence interval (CI) = 0.98–1.8] after adjustment for recent or past use of any NSAID, recent or past gastrotoxic therapy, recent or past use of gastroprotective drugs, and recent or past use of any other drug. Among NSAIDs, ketorolac was the only one showing a distinctly elevated risk of gastroduodenal lesions (OR = 4.2; 95% CI = 1.9–9.4). Current use of any NSAID was associated with almost a doubling of risk for ulcer alone (OR = 1.9; 95% CI = 1.3–3.0); no elevation in risk was found for erosions. The adjusted relative risk for ulcer associated with current use of ketorolac was 9.8 (95% CI = 3.4–28.1). Recent and past use of NSAIDs does not increase the risk of ulcer. The use of ketorolac appears to carry a greater gastrotoxicity than other NSAIDs.

Recurrence of Cardiovascular Events in Patients With Type 2 Diabetes : Epidemiology and risk factors

OBJECTIVE—The purpose of this study was to assess incidence of and risk factors for recurrent cardiovascular disease (CVD) in type 2 diabetes. RESEARCH DESIGN AND METHODS—We estimated the incidence of recurrent cardiovascular events in type 2 diabetic patients, aged 40–97 years, followed by a network of diabetes clinics. The analysis was conducted separately for 2,788 patients with CVD at enrollment (cohort A) and for 844 patients developing the first episode during the observation period (cohort B). RESULTS—During 4 years of follow-up, in cohort A the age-adjusted incidence of a recurrent event (per 1,000 person-years) was 72.7 (95% CI 58.3–87.1) in men and 32.5 (21.2–43.7) in women, whereas in cohort B it was 40.1 (17.4–62.9) in men and 22.4 (12.9–32.0) in women. After controls were included for potential predictors (familial CVD, obesity, smoking, diabetes duration, glycemic control, microvascular complications, geographic area, and antihypertensive and lipid-lowering treatment), male sex, older age, and insulin use were significant independent risk predictors (cohort A) and serum triglyceride levels ≥1.69 mmol/l emerged as the only metabolic (negative) prognostic factor (cohort B). In both cohorts, a prior CVD episode, especially myocardial infarction, was by far the strongest predictor of recurrent CVD. CONCLUSIONS—Approximately 6% of unselected diabetic patients in secondary prevention develop recurrent major CVD every year. Those with long-standing previous CVD show a higher incidence of recurrence. Male sex, age, high triglyceride levels, and insulin use are additional predictors of recurrence.

Lower extremity amputations in persons with and without diabetes in Italy: 2001-2010.

Objective To analyze hospitalization for lower extremity amputations (LEAs) and amputee rates in persons with and without diabetes in Italy. Research Design and Methods All patients with LEAs in the period 2001–2010 were identified analyzing the National Hospital Discharge Record database. For each year, amputee and hospitalization rates for LEAs were calculated either for persons with diabetes or without. Time trend for major and minor amputations were analysed. Results From 2001 to 2010 a mean annual number of 11,639 individuals underwent a lower extremity amputation: 58.6% had diabetes accounting for 60.7% of total hospitalizations. In 2010, the crude amputee rate for LEAs was 20.4 per 100,000 inhabitants: 247.2 for 100.000 persons with diabetes, and 8.6 for those without diabetes. Having diabetes was associated to an increased risk of amputation (Poisson estimated RR 10.9, 95%CI 9.4–12.8). Over the whole period, a progressive reduction of amputee rates was observed for major amputations either among persons with diabetes (−30.7%) or without diabetes (−12.5%), while the rates of minor amputations increased progressively (+22.4%) among people without diabetes and were nearly stable in people with diabetes (−4.6%). A greater number of minor amputations were performed among persons with than without diabetes: in 2010, the minor-to-major ratio among persons with diabetes (2.5) was more than twice than in those without diabetes (1.0). Conclusions The nationwide analyses confirm a progressive reduction of hospitalization and amputee rates for major LEAs, suggesting an earlier and more diffuse approach aimed at limb salvage.

Gangliosides and Guillain-Barré syndrome

Cases of Guillain-Barré syndrome (GBS) associated with parenteral use of gangliosides have been reported in several European countries. To evaluate the hypothesis of association between ganglioside exposure and occurrence of GBS, a case-control study was conducted. GBS cases discharged during 1989 from public and private hospitals in three Italian provinces were identified: 42 GBS cases and 420 controls matched on age and gender were enrolled. Data of onset of symptoms of GBS was taken from clinical records. Exposure status of subjects was ascertained through the regional computerized drug prescription monitoring system. The odds ratio of association between ganglioside use, in the 30 days prior to onset of symptoms, and GBS was 9.1 (95% confidence interval 2.8-29.4). Although there are formidable difficulties in distinguishing prodromal therapy of GBS from drug causation, the association with ganglioside therapy is strong and supportive of the hypothesis of a role of ganglioside preparations in the occurrence of GBS.

Ketorolac use in outpatients and gastrointestinal hospitalization: a comparison with other non-steroidal anti-inflammatory drugs in Italy

AbstractObjective: To compare the risk of hospitalization for gastroduodenal ulcer associated with the use of ketorolac and other non-steroidal anti-inflammatory drugs (NSAIDs). Methods: A cohort and a nested case-control study were carried out. All residents in the region of Umbria (Italy), aged 35–84 years, who had been given at least one NSAID prescription in 1993 and 1994 were identified. Exposure to drugs was ascertained through a drug prescription database. We estimated rate ratios of hospitalization for gastroduodenal ulcer with or without complications in the current, recent or past period according to exposure to different NSAIDs. Results: Rate ratio estimates, adjusted for age and sex, were 2.8 for any current NSAID and 1.4 for any recent NSAID. The highest rate ratios of lesions of any severity for current NSAID use were observed for piroxicam (RR: 4.6) and ketorolac (RR: 3.4). For gastrointestinal haemorrhage or perforation the highest rate ratios were those for ketorolac (RR: 5.9) and piroxicam (RR: 4.8). Rate ratio estimates did not change after adjustment for concomitant use of gastrotoxic drugs, use of gastroprotective agents not associated with NSAIDs and prior use of NSAIDs. Conclusion: Our study demonstrates the need to adhere to the restrictions relating to the indications and duration of use of ketorolac. At present piroxicam represents a greater public health concern since it is confirmed to be among the most gastrotoxic NSAIDs and is one of the most commonly prescribed NSAIDs in Italy.

Temporal trend in hospitalizations for acute diabetic complications: a nationwide study, Italy, 2001-2010.

Background We investigated temporal trends and geographic variations in both hospitalizations and in-hospital mortality rates for acute diabetic complications (ADC) in the Italian universal health care system. Methods and Findings A retrospective review of the medical records of patients with either primary or secondary discharge diagnosis of hyperglycaemic acute complications (ICD-9-CM codes 250.1, 250.2, 250.3) or hypoglycemic coma (ICD-9-CM code 251.0) was performed in period 2001–2010. Standardized rates by age and gender on 2001 Italian population and by diabetic population were calculated. We identified 7,601.883 diabetes-related hospital discharges. Out of them, 266,374 (3.5%) were due to ADC, either ketoacidosis/hyperosmolarity (94.4%) or hypoglycemic coma (5.6%). The rate of discharge for ADC decreased by 51.1% from 2001 to 2010 (14.4 vs. 7.1 discharge rate/1,000 diabetic people; 5.7% decrease per year, test for trend, p<0.001) with a similar trend for both hyperglycemic and hypoglycemic complications. Diabetic people in the younger age groups (≤19 and 20–44 years old) had a significantly greater rate of discharge for ADC than people aged 65 years and over (≤19 10-fold increase; 20–44: 2-fold increase). In-hospital mortality rate was 7.6%, with 211 preventable deaths in younger diabetic people (≤44 years old). There was a large variability among Italian Regions and the ratio between the highest and the lowest regional discharge rate reached 300% in 2010. Conclusions Decreasing temporal trend in hospitalizations for preventable ADC suggests improving outpatient care. In younger diabetic patients, however, both hospitalization rates and in-hospital mortality are still a matter of concern.

Epidemiological use of drug prescriptions as markers of disease frequency: An Italian experience

All Italian citizens are covered by the National Health Service (NHS) and medical records of individual drug prescriptions are routinely collected and processed. A procedure entitled EPIFAR has been developed which, on the basis of a computer routine, makes it possible to trace back the prescription history of each individual included in the NHS. The validity of information gathered through the EPIFAR procedure to provide estimates of tuberculosis (TB) prevalence has been evaluated. A comparison with routine surveillance data has been made. The EPIFAR procedure identified a total figure of TB patients seven times higher than that from official notifications. A sample survey was conducted among the prescribing physicians in order to quantify the proportion of TB cases among subjects receiving prescriptions of anti-TB drugs. According to general practitioner recall 66.4% of the patients were treated because of TB diagnosis, TB prophylaxis and TB relapse.

The Unconventional Di Bella Cancer Treatment. A Reflection on the Italian Experience

Supported by a specific act of the Italian Parliament.The committees and members of the Italian StudyGroup for the Di Bella Multitherapy Trials are asfollows. Research Coordinating Center: D. Greco,R. Raschetti, B. Caffari, F. Chiarotti, R. Da Cas, B.De Mei, G. Di Giovambattista, M. Maggini, F. Men-niti-Ippolito, S. Modigliani, P. Popoli, P. Ruggeri, S.Spila-Alegiani, C. Tomino, G. Traversa, P. Bruzzi, T.Gamucci. Steering Committee: G. Benagiano, D.Amadori, P. Bruzzi, E. Buiatti, E. Ciranni, F. Cog-netti, G. Colucci, P.F. Conte, G. Di Bella*, D. Greco,S. Iacobelli, F. Mandelli, E. Marubini, M. Massotti,S. Monfardini, F. Oleari, R. Raschetti, G. L. San-nazzari, L. Tomatis, U. Veronesi. (*Dr. G. Di Bella,the son of Dr. L. Di Bella, only participated in thefirst two meetings of the Steering Committee. Onmany occasions, he strongly disagreed with theperformance and results of the trials. No part ofthe current article has been discussed with orendorsed by Dr. G. Di Bella.) International ReviewBoard: P. Calabresi (Rhode Island), F. Cavalli (Bell-inzona, Switzerland), P. Kleihues (Lyon Cedex,France), J.G. Mc Vie (London, UK), H. Pinedo (Am-sterdam, The Netherlands), K. Sikora (Lyon Cedex,France), T. Tursz (Villejuif Cedex, France). Indepen-dent Endpoint Evaluation Committee: A. R. Bianco,R. Labianca, P. L. Rossi Ferrini, G. Simonetti, A.Sobrero. Investigators: Ancona—R. Cellerino, S.Antognoli, R. Berardi, R. Bracci, P. Lippe, F. Pulita;Aosta—F. Di Vito, D. Martinod, M. Musi; Avi-ano—A. Veronesi, R. Lazzarini; Bari—G. Colucci(Principal Investigator [PI]), V. Attolico, F. Giotta, M.Longo, E. Maiello; Bologna—S. Tura, F. Gherlin-zoni, M. Tani; Bolzano—H. Amor, P. Borona, F.Girardi, C. Graiff; Cagliari—G. Broccia, M. G. Co-rona, A. Desogus, V. Mascia, S. Pasqualucci; Ca-tania—G. Failla, M. R. Aiello, S. Cordio, P. Finoc-chiaro. Chieti—S. Iacobelli (PI), E. Melena, M. DeTursi, M. T. Scognamiglio, N. Tinari; Forli`—D.Amadori (PI), M. Maltoni, O. Nanni, F. Scardovi, P.Serra; Genoa—R. Rosso, F. Boccardo, A. Barp, T.Coli, M. Grimaldi; Milan—N. Cascinelli, L. Ascani,E. Bajetta, P. Bidoli, A. Cassata, D. De Candis, W.Giannessi, G. Procopio; Milan—S. Di Donato, A.Boiardi, D. Cerri, M. Eoli, A. Silvani; Milan—U.Veronesi (PI), M. Colleoni, N. Rotmensz; Na-ples—S. Monfardini (PI), G. Comella, A. De Mat-teis, A. Gravina, C. Gridelli, F. Perrone, M. R.Salzano, C. Sandomenico; Naples—C. Battista, G.Iodice, R. Fico, A. Nicchia; Padua—M. Lise, G. L.De Salvo, E. Di Lenardo, G. Iadicicco; Palermo—B.Agostara, I. Cafarelli; Perugia—M. Tonato, F.Radicchi, S. Sorbolini, O. Taschini; Pisa—P. F.Conte (PI), A. Carmignani, L. Del Mastro, A. Gen-nari, C. Orlandini; Potenza—L. Manzione, A. Di-nota, G. Lombardi; Reggio Calabria—G. Gasparini,M. G. Arena, M. Fanelli, F. Modafferi, A. Morabito;Rome—F. Mandelli (PI), P. Fazi, F. Mauro, M.Martelli, C. Ricci, M. Vignetti; Rome—F. Cognetti(PI), A. D’Alessio, S. De Marco, V. Ferraresi, T.Gamucci, D. Giannarelli, E. Magnani, P. Rellecati,E. M. Ruggeri, M. Zeuli; Turin—G. L. Sannazzari(PI), M. Borgognone, R. Chio`, A. Gasco, R. Ragona,M. Sacco, R. Soffietti, R. Verna, M. Tessa;Turin—A. Pileri; Trento—E. Galligioni, A. Lucenti,F. Moltrer, F. Paolazzi.The authors thank the Stabilimento ChimicoFarmaceutico Militare, Florence, Italy (Colonel G.Muzzi, Director), for the production of the melato-nin tablets and retinoid solution and the Group forthe supervision and control of custom-made drugsof the Istituto Superiore di Sanita`, Roma (E. Cir-anni, Director; R. Alimenti, S. Alimonti, G. Cavaz-zutti, L. Gagliardi, B. Gallinella, G. Incarnato, F. LaTorre, A. Mosca, G. Multari, L. Turchetto, L. Valvo).Address for reprints: Giuseppe Traversa, M.D., De-partment of Epidemiology and Biostatistics, IstitutoSuperiore di Sanita`, Viale Regina Elena 299, 00161Rome, Italy.Received April 26, 1999; revision received July 22,1999; accepted July 29, 1999.