Systematically missing confounders in individual participant data meta-analysis of observational cohort studies.

One difficulty in performing meta-analyses of observational cohort studies is that the availability of confounders may vary between cohorts, so that some cohorts provide fully adjusted analyses while others only provide partially adjusted analyses. Commonly, analyses of the association between an exposure and disease either are restricted to cohorts with full confounder information, or use all cohorts but do not fully adjust for confounding. We propose using a bivariate random-effects meta-analysis model to use information from all available cohorts while still adjusting for all the potential confounders. Our method uses both the fully adjusted and the partially adjusted estimated effects in the cohorts with full confounder information, together with an estimate of their within-cohort correlation. The method is applied to estimate the association between fibrinogen level and coronary heart disease incidence using data from 154,012 participants in 31 cohorts

[Preadolescents' nutritional habits: a survey in the secondary schools in Brianza]. / Le abitudini alimentari dei preadolescenti: indagine nelle scuole medie della Brianza.

AIM: This study was aimed at assessing eating habits among preadolescents living in Brianza, with a special focus on snacking' and breakfast' habits. METHODS: The research was carried out in 12 post-primary schools in Brianza and included 802 students attending 43 different classes (49.3% males and 50.7% females; mean age:12.6 years). The research tool was an ad hoc questionnaire administered to the preadolescents attending school on the day of the research. Data were analyzed using program Epi Info 6. RESULTS: Many students (78.3%) had breakfast in the morning of the questionnaire's administration. Among those perceiving themselves as overweight, not having breakfast is more common than among others. This information is the opposite of what preadolescents say when inquired about their habit to have ''a good breakfast'': only 36.8% of the responders declare that it happens on a daily basis. As to snacking, 18.7% of the students declare to be used to having multiple snacking during the day; during school recess on the day of the survey, 39.9% of respondents declared that they had eaten various industrial snacks, while 27.4% had cakes or fresh bread, 1.2% both of them and 0.6% fruit. On a daily basis, 59.5% report to eat various and different fruits and 62.9% report the same when inquired about vegetables. CONCLUSION: Considering the importance of a correct nutrition during developmental age and the importance of the phase of adolescence in establishing permanent nutritional habits that will last life-long, it is thus an educational priority to help preadolescents to choose the best foods for their health and well being.

[Pre-adolescents and sport: results of a health survey in some secondary schools of Brianza]. / I preadolescenti e lo sport: risultati di un'indagine in alcune scuole medie dell'area brianzola.

This study is aimed at assessing time dedicated to, motivation and involvement in physical activity on behalf of pre-adolescents. 802 students (49.3% boys and 50.7% girls; mean age: 12.6) attending 43 classes of 11 Brianza's post-elementary schools. A questionnaire was prepared and administered to the involved sample. Classes took part in this study through randomized selection and data were analyzed using program Epi Info 6. Most of the respondents (60.1%) stay involved in sport because "it makes me feel good" and 32.4% because sport is "enjoyable and entertaining". Pre-adolescents chose the sport in which they become engaged on the basis of personal inclination (40%), in order to share experiences and their free time with friends (15.4%); 13.7% declare to prefer sport to be practiced in team. (13.7%). The most practiced sport are: football (51.3% boys, 4.5% girls), volley (3.9%-36.4%), dance (0.8%-25.2%) e swimming (9.4%-14%). 80.8% in the sample practice physical activity in settings outside schools and, among these, 51.7% dedicate three or more hours weekly to extra-school activities. There are significant differences (p < 0.05) between males' and females' engagement in physical activity (mean value: 4.1 hours; males: 4.6 h, females: 3.5 h). Among pre-teens, 18% declare to be physically inactive at all; 15.7% do not take part in sport activities because afraid to be bullied or shamed by peers. Research show that males are significantly more involved in physical activity than females.

Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality: an individual participant meta-analysis.

CONTEXT: Plasma fibrinogen levels may be associated with the risk of coronary heart disease (CHD) and stroke. OBJECTIVE: To assess the relationships of fibrinogen levels with risk of major vascular and with risk of nonvascular outcomes based on individual participant data. DATA SOURCES: Relevant studies were identified by computer-assisted searches, hand searches of reference lists, and personal communication with relevant investigators. STUDY SELECTION: All identified prospective studies were included with information available on baseline fibrinogen levels and details of subsequent major vascular morbidity and/or cause-specific mortality during at least 1 year of follow-up. Studies were excluded if they recruited participants on the basis of having had a previous history of cardiovascular disease; participants with known preexisting CHD or stroke were excluded. DATA EXTRACTION: Individual records were provided on each of 154,211 participants in 31 prospective studies. During 1.38 million person-years of follow-up, there were 6944 first nonfatal myocardial infarctions or stroke events and 13,210 deaths. Cause-specific mortality was generally available. Analyses involved proportional hazards modeling with adjustment for confounding by known cardiovascular risk factors and for regression dilution bias. DATA SYNTHESIS: Within each age group considered (40-59, 60-69, and > or =70 years), there was an approximately log-linear association with usual fibrinogen level for the risk of any CHD, any stroke, other vascular (eg, non-CHD, nonstroke) mortality, and nonvascular mortality. There was no evidence of a threshold within the range of usual fibrinogen level studied at any age. The age- and sex- adjusted hazard ratio per 1-g/L increase in usual fibrinogen level for CHD was 2.42 (95% confidence interval [CI], 2.24-2.60); stroke, 2.06 (95% CI, 1.83-2.33); other vascular mortality, 2.76 (95% CI, 2.28-3.35); and nonvascular mortality, 2.03 (95% CI, 1.90-2.18). The hazard ratios for CHD and stroke were reduced to about 1.8 after further adjustment for measured values of several established vascular risk factors. In a subset of 7011 participants with available C-reactive protein values, the findings for CHD were essentially unchanged following additional adjustment for C-reactive protein. The associations of fibrinogen level with CHD or stroke did not differ substantially according to sex, smoking, blood pressure, blood lipid levels, or several features of study design. CONCLUSIONS: In this large individual participant meta-analysis, moderately strong associations were found between usual plasma fibrinogen level and the risks of CHD, stroke, other vascular mortality, and nonvascular mortality in a wide range of circumstances in healthy middle-aged adults. Assessment of any causal relevance of elevated fibrinogen levels to disease requires additional research.

Antiarrhythmic mechanisms of n-3 PUFA and the results of the GISSI-Prevenzione trial.

The purpose of this paper is twofold: on the one hand, to confirm the positive results on n-3 PUFA from the overall results Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GlSSI)-Prevenzione trial; on the other, to summarize and describe how the results of an important trial can help generate hypotheses either on mechanisms of action or on differential results in particular subgroups of patients, as well as test the pathophysiological hypotheses that have accompanied in the years the story of the hypothesized mechanisms of action of a drug. GISSI-Prevenzione was conceived as a pragmatic population trial on patients with recent myocardial infarction and it was conducted in the framework of the Italian public health system. In GISSI-Prevenzione, 11,323 patients were enrolled in a clinical trial aimed at testing the effectiveness of n-3 polyunsaturated fatty acids (PUFA) and vitamin E. Patients were invited to follow Mediterranean dietary habits, and were treated with up-to-date preventive pharmacological interventions. Long-term n-3 PUFA at 1 g daily, but not vitamin E at 300 mg daily, was beneficial for death and for combined death, non-fatal myocardial infarction, and stroke. All the benefit, however, was attributable to the decrease in risk for overall (-20%), cardiovascular (-30%), and sudden death (-45%). At variance from the orientation of a scientific scenario largely dominated by the "cholesterol-heart hypothesis", GISSI-Prevenzione results indicate n-3 PUFA (virtually devoid of any cholesterol-lowering effect) as a relevant pharmacological treatment for secondary prevention after myocardial infarction.

Mediterranean diet and all-causes mortality after myocardial infarction: results from the GISSI-Prevenzione trial.

OBJECTIVE: To ascertain whether simple dietary advice to increase the consumption of Mediterranean foods, given in a clinical setting, leads to reduced mortality after a myocardial infarction. DESIGN: Data were used from the GISSI-Prevenzione clinical trial, analysed as a cohort study with adjustment for treatment allocation. SETTING: A total of 172 centres in Italy. SUBJECTS: A total of 11323 men and women with myocardial infarction. All subjects received advice to increase their consumption of fish, fruit, raw and cooked vegetables and olive oil. MEASUREMENTS: The intakes of the five foods were assessed at baseline, 6, 18 and 42 months. Associations of food intakes, a combined dietary score, and the risk of death over 6.5 y were estimated adjusting for several non-dietary variables, using pooled logistic regression. RESULTS: Subjects generally improved their diet according to the advice given. All foods were associated with a significant reduction in risk of death. Compared with people in the worst dietary score quarter, the odds ratio for those in the best score quarter was 0.51 (95% CI 0.44-0.59). A good diet had a protective effect in sub-groups defined by age, sex, smoking, randomized treatment and concomitant drug therapy. CONCLUSIONS: Myocardial infarction patients can respond positively to simple dietary advice, and this can be expected to lead to a substantial reduction in the risk of early death. Regardless of any drug treatment prescribed, clinicians should routinely advise patients with myocardial infarction to increase their frequency of consumption of Mediterranean foods.

Assessment of absolute risk of death after myocardial infarction by use of multiple-risk-factor assessment equations: GISSI-Prevenzione mortality risk chart.

AIMS: To present and discuss a comprehensive and ready to use prediction model of risk of death after myocardial infarction based on the very recently concluded follow-up of the large GISSI-Prevenzione cohort and on the integrated evaluation of different categories of risk factors: those that are non-modifiable, and those related to lifestyles, co-morbidity, background, and other conventional clinical complications produced by the index myocardial infarction. METHODS: The 11-324 men and women recruited in the study within 3 months from their index myocardial infarction have been followed-up to 4 years. The following risk factors have been used in a Cox proportional hazards model: non-modifiable risk factors: age and sex; complications after myocardial infarction: indicators of left ventricular dysfunction (signs or symptoms of acute left ventricular failure during hospitalization, ejection fraction, NYHA class and extent of ventricular asynergy at echocardiography), indicators of electrical instability (number of premature ventricular beats per hour, sustained or repetitive arrhythmias during 24-h Holter monitoring), indicators of residual ischaemia (spontaneous angina pectoris after myocardial infarction, Canadian Angina Classification class, and exercise testing results); cardiovascular risk factors: smoking habits, history of diabetes mellitus and arterial hypertension, systolic and diastolic blood pressure, blood total and HDL cholesterol, triglycerides, fibrinogen, leukocytes count, intermittent claudication, and heart rate. Multiple regression modelling was assessed by receiver operating characteristic (ROC) analysis. Generalizability of the models was assessed through cross validation and bootstrapping techniques. POPULATION AND RESULTS: During the 4 years of follow-up, a total of 1071 patients died. Age and left ventricular dysfunction were the most relevant predictors of death. Because of pharmacological treatments, total blood cholesterol, triglycerides, and blood pressure values were not significantly associated with prognosis. Sex-specific prediction equations were formulated to predict risk of death according to age, simple indicators of left ventricular dysfunction, electrical instability, and residual ischaemia along with the following cardiovascular risk factors: smoking habits, history of diabetes mellitus and arterial hypertension, blood HDL cholesterol, fibrinogen, leukocyte count, intermittent claudication, and heart rate. The predictive models produced on the basis of information available in the routine conditions of clinical care after myocardial infarction provide ready to use and highly discriminant criteria to guide secondary prevention strategies. CONCLUSIONS AND IMPLICATIONS: Besides documenting what should be the preferred and practicable focus of clinical attention for today's patients, the experience of GISSI-Prevenzione suggests that periodically and prospectively collected databases on naturalistic' cohorts could be an important option for updating and verifying the impact of guidelines, which should incorporate the different components of the complex profile of cardiovascular risk. The GISSI Prevenzione risk function is a simple tool to predict risk of death and to improve clinical management of subjects with recent myocardial infarction. The use of predictive risk algorithms can favour the shift from medical logic, based on the treatment of single risk factors, to one centred on the patient as a whole as well as the tailoring of medical interventions according to patients' overall risk.

Alterations of cardiac structure in patients with isolated office, ambulatory, or home hypertension: Data from the general population (Pressione Arteriose Monitorate E Loro Associazioni [PAMELA] Study).

BACKGROUND: The prevalence and clinical significance of isolated office (or white coat) hypertension is controversial, and population data are limited. We studied the prevalence of this condition and its association with echocardiographic left ventricular mass in the general population of the PAMELA (Pressione Arteriose Monitorate E Loro Associazioni) Study. METHODS AND RESULTS: The study involved a large, randomized sample (n=3200) representative of the Monza (Milan) population, 25 to 74 years of age. Participants in the study (64% of the sample) underwent measurements of office, home, 24-hour ambulatory blood pressure, and echocardiography. Isolated office hypertension was defined as systolic or diastolic values >/=140 mm Hg or >/=90 mm Hg, respectively. Home and ambulatory normotension were defined according to criteria previously established from the PAMELA Study, for example, <132/83 mm Hg (systolic/diastolic) for home and 125/79 mm Hg for 24-hour average blood pressure. Treated hypertensive subjects were excluded from analysis that was made on a total of 1637 subjects. Depending on normotension being established on systolic or diastolic blood pressure measured at home or over 24 hours, the prevalence of isolated office hypertension ranged from 9% to 12%. In these subjects, left ventricular mass index was greater (P<0.01) than in subjects with normotension both in and outside the office. This was the case also for prevalence of left ventricular hypertrophy. Left ventricular mass index and hypertrophy were similarly greater in subjects found to have normal office but elevated home or ambulatory blood pressure ( approximately 10% of the population). CONCLUSIONS: Isolated office hypertension has a noticeable prevalence in the population and is accompanied by structural cardiac alterations, suggesting that it is not an entirely harmless phenomenon. This is the case also for the opposite condition, that is, normal office but elevated home or ambulatory blood pressure, which implies that limiting blood pressure measurements to office values may not suffice in identification of subjects at risk.

Echocardiography-guided pericardiocentesis with probe-mounted needle: report of 53 cases.

Fifty-three pericardiocentesis procedures were performed on 48 patients from 1993 to 2000 at our coronary care unit. Percutaneous puncture (anterior thoracic in 43 cases, subxiphoid in 10 cases) was performed at the site closest to the exploring probe, where the largest amount of fluid was detected. A needle carrier supported by a bracket with two fixed angulations was mounted on the probe. The needle was advanced through the tissues and inside the pericardial space under continuous visualization. The procedure was successful in 52 of 53 cases. In 1 case of diagnostic pericardiocentesis, the pericardial space was impossible to reach because of the minimal amount of pericardial fluid. In 1 case of acute tamponade after transcatheter ablation of the atrioventricular node, the pericardial puncture caused a pleural-pericardial shunt with consequent drainage of pericardial fluid into the pleural space and symptom resolution. In 1 case, a transient atrioventricular type III block occurred. Emergency surgical drainage was not required in any of the cases. No puncture of cardiac walls ever occurred in this series of patients. No major complications occurred; the incidence of minor sequelae was lower than the incidence reported by other studies on pericardiocentesis without continuous visualization. Our technique appears to be safe and easy to perform even in the presence of minimal amounts of pericardial fluid.

Cost-effectiveness analysis of n-3 polyunsaturated fatty acids (PUFA) after myocardial infarction: results from Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto (GISSI)-Prevenzione Trial.

OBJECTIVE: To estimate the cost effectiveness of treatment with n-3 polyunsaturated fatty acids (PUFA) for secondary prevention after myocardial infarction (MI). DESIGN AND SETTING: The cost-effectiveness analysis of n-3 PUFA treatment after MI was based on morbidity and mortality data and the use of resources obtained prospectively during the 3.5 year follow-up period of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto (GISSI)-Prevenzione study. The cost-effectiveness analysis took into account the incremental number of life-years gained and the incremental costs for hospital admissions, diagnostic tests and drugs, applying a 5% discount rate. The value for money of n-3 PUFA treatment was assessed using the cost-effectiveness ratio and the number needed to treat (NNT) approach. PERSPECTIVE: Third-party payer. MAIN OUTCOME MEASURES AND RESULTS: The incremental cost-effectiveness ratio for n-3 PUFA in the basecase scenario was 24,603 euro (EUR, 1999 values) per life-year gained (95% confidence interval: 22,646 to 26,930). Sensitivity analysis included the analysis of extremes, producing estimates varying from EUR15,721 to EUR52,524 per life-year gained. 172 patients would need to be treated per year with n-3 PUFA, at an annual cost of EUR68,000, in order to save 1 patient. This is comparable with the NNT value, and associated annual cost for simvastatin, but less costly than that for pravastatin. CONCLUSIONS: The cost effectiveness of long term treatment with n-3 PUFA is comparable with other drugs recently introduced in the routine care of secondary prevention after MI. Since the clinical benefit provided by n-3 PUFA is additive, this therapy should be added to the established routine practice, with additive costs.

[Heart arrest]. / L'arresto cardiaco.

Cardiac arrest is one of the leading causes of mortality in industrialized countries and is mainly due to ischemic heart disease. According to ISTAT estimates, approximately 45,000 sudden deaths occur annually in Italy whereas according to the World Health Organization, its incidence is 1 per 1000 persons. The most common cause of cardiac arrest is ventricular fibrillation due to an acute ischemic episode. During acute ischemia the onset of a ventricular tachyarrhythmia is sudden, unpredictable and often irreversible and lethal. Each minute that passes, the probability that the patient survives decreases by 10%. For this reason, the first 10 min are considered to be priceless for an efficacious first aid. The possibility of survival depends on the presence of witnesses, on the heart rhythm and on the resolution of the arrhythmia. In the majority of cases, the latter is possible by means of electrical defibrillation followed by the reestablishment of systolic function. An increase in equipment alone does not suffice for efficacious handling of cardiac arrest occurring outside the hospital premises. Above all, an adequate intervention strategy is required. Ambulance personnel must be well trained and capable of intervening rapidly, possibly within the first 5 min. The key to success lies in the diffusion and proper use of defibrillators. The availability of new generation instruments, the external automatic defibrillators, encourages their widespread use. On the territory, these emergencies are the responsibility of the 118 organization based, according to the characteristics specific to each country, on the regulated coordination between the operative command, the crews and the first-aid means. Strategies for the handling of these emergencies within hospitals have been proposed by the Conference of Bethesda and tend to guarantee an efficacious resuscitation with a maximum latency of 2 min between cardiac arrest and the first electric shock. The diffusion of external automatic defibrillators is a preventive measure. Such equipment has permitted early defibrillation by non-medical first-aid personnel. These instruments contain software capable of recognizing an arrhythmia which may be defibrillated and of instructing the operator whether and when to press the defibrillation button. The latest instruments deliver the shock by means of a biphasic wave necessitating a lesser amount of energy which can be provided by lighter condensers. Thus such equipment weighs just a couple of kilograms. As suggested by ILCOR, for reasons of priority, such instruments should not only be available within hospitals and in ambulances but also on the territory, in particular in more crowded places. The availability of external automatic defibrillators in such places should reduce the time latency before intervention and thus increase survival. The ILCOR guidelines have suggested the constitution of an itinerary team well equipped for defibrillation and composed of trained personnel of State Institutions such as the Municipal Police, Traffic Police and the Fire Brigades. With regard to the majority of arrhythmias amenable to defibrillation which occur at home or in less crowded places, other strategies, such as primary prevention and training programs for categories at increased risk, must be employed. Antiarrhythmic drugs have long been considered the best solution for the prevention and treatment of ventricular tachyarrhythmias. However, the approach to these pathologies has drastically changed during the last few years owing to accumulating evidence in favor of defibrillators which may be implanted for the primary and secondary prevention of malignant ventricular arrhythmias. For patients with previous cardiac arrest, randomized studies have proven the advantages of such an approach compared to medical therapy. On the basis of the above, the guidelines for the use of antiarrhythmic implants have been modified. In most western countries, the laws regarding this aspect of medicine have recently been renewed. In the United States, where there is the "Law of the Good Samaritan", in order to protect and acquit persons who give first-aid, many states have adopted new laws which promote the use of external automatic defibrillators. Following recent dispositions by the President of the United States that defibrillators should be present in all Federal properties and on civil aircraft, a new Federal Law is about to pass. Italy lacks legislation regarding the use of defibrillators: in order to rectify this position, which is still anchored to existing dispositions of the civil and penal codes including those regarding the omission of first-aid, a bill entitled "The definition and modalities of the use of the external cardiac defibrillator" has recently been presented.

The consequences of under-use of coronary revascularization; results of a cohort study in Northern Italy.

AIM: To assess whether under-use of coronary artery bypass graft (CABG) or percutaneous transluminal coronary angioplasty (PTCA) affects patient outcome. PATIENTS AND METHODS: A prospective observational study was performed following up a cohort of patients, candidates for a revascularization procedure (either CABG or PTCA) after an index angiogram. A total of 1258 patients, candidates -- according to explicit criteria -- for either CABG or PTCA entered the study enrolled by 16 hospitals located in a Northern Italian region (Lombardia). Information on demographic and clinical characteristics, type of care received (i.e. CABG or PTCA performed Yes/No) and vital status was obtained from revascularization laboratories, patients' hospital medical records and local census offices of the town of patients' residence. The main outcome measure was total unadjusted and adjusted mortality at a minimum follow-up of 9 months after the index cardiac angiogram. RESULTS: Patients who received CABG or PTCA (n=863) had lower mortality than those who did not (n=350) (4.8% vs 10.6%, P=0.001). This held true after adjustment for relevant risk factors between the two groups such as extent of coronary artery disease, clinical symptoms, and cardiac surgical risk index (adjusted odds ratio=0.48; 95% confidence intervals=0.30--0.77) and after performing a survival analysis (adjusted hazard ratio=0.31; 95% confidence intervals=0.19--0.50). CONCLUSIONS: Failure to perform a revascularization procedure when it was indicated led, in this study, to a significantly increased mortality showing that under-use of effective procedures may represent a significant quality of care problem even in areas where health care systems are well developed. Although the study was not specifically designed to identify determinants of under-use (i.e. reduced capacity leading to waiting lists, physicians' competence or patients' refusal to undergo a recommended procedure) our data suggest that limited capacity could have been the most important reason. Our findings also provide further evidence of the validity of the RAND method to assess the impact of under-use of coronary revascularization procedures.

Efficacy of n-3 polyunsaturated fatty acids after myocardial infarction: results of GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico.

Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardio (GISSI)-Prevenzione was conceived as a population, pragmatic trial on patients with recent myocardial infarctions conducted in the framework of the Italian public health system. In GISSI-Prevenzione, patients were invited to follow Mediterranean dietary habits, and were treated with up-to-date preventive pharmacological interventions. Long-term n-3 PUFA (1 g daily) but not vitamin E (300 mg daily) was beneficial for death and for combined death, nonfatal myocardial infarction, and stroke. All the benefit, however, was attributable to the decrease in risk for overall, cardiovascular, cardiac, coronary, and sudden death. At variance with the orientation of a scientific scenario largely dominated by the "cholesterol-heart hypothesis," GISSI-Prevenzione results indicate n-3 PUFA (virtually devoid of any cholesterol-lowering effect) as a relevant pharmacological treatment for secondary prevention after myocardial infarction. As to the relevance and comparability of GISSI-Prevenzione results, up to 5.7 lives could be saved every 1000 patients with previous myocardial infarction treated with n-3 PUFA (1 g daily) per year. Such a result is comparable to that observed in the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) trial, where 5.2 lives could be saved per 1000 hypercholesterolemic, coronary heart disease patients treated with pravastatin for 1 yr. The choice of a relatively low-dose regimen (1-g capsule daily) more acceptable for long-term treatment in a population of patients following Mediterranean dietary habits, and the pattern of effects seen in GISSI-Prevenzione (namely, reduction of overall mortality with no decrease in the rate of nonfatal myocardial infarction) all strongly suggest that n-3 PUFA treatment should be considered a recommended new component of secondary prevention. The importance of this combined/additive effect is further suggested by the analyses of the interplay between diet and n-3 PUFA: There is an interesting direct correlation between size of the effect and "correctness" of background diets. It can be anticipated that a conceptual barrier must be overcome: A "dietary drug" should be added to "dietary advice," which remains fundamental to allow this statement to become true in clinical practice.

Antioxidant vitamins and prevention of cardiovascular disease: epidemiological and clinical trial data.

Naturally occurring antioxidants such as vitamin E, beta-carotene, and vitamin C can inhibit the oxidative modification of low density lipoproteins. This action could positively influence the atherosclerotic process and, as a consequence, the progression of coronary heart disease. A wealth of experimental studies provide a sound biological rationale for the mechanisms of action of antioxidants, whereas epidemiologic studies strongly sustain the "antioxidant hypothesis." To date, however, clinical trials with beta-carotene supplements have been disappointing, and their use as a preventive intervention for cancer and coronary heart disease should be discouraged. Only scanty data from clinical trials are available for vitamin C. As to vitamin E, discrepant results have been obtained by the Alpha-Tocopherol, Beta Carotene Cancer Prevention Study with a low-dose vitamin E supplementation (50 mg/d) and the Cambridge Heart Antioxidant Study (400-800 mg/d). The results of the GISSI-Prevenzione (300 mg/d) and HOPE (400 mg/d) trials suggest the absence of relevant clinical effects of vitamin E on the risk of cardiovascular events. Currently ongoing are several large-scale clinical trials that will help in clarifying the role of vitamin E in association with other antioxidants in the prevention of atherosclerotic coronary disease.

[Is a previous neurosurgical intervention a contraindication to fibrinolytic therapy? Description of two cases and review of the literature]. / Un precedente intervento di neurochirurgia è una controindicazione al trattamento fibrinolitico? Descrizione di due casi e revisione della letteratura.

The presence of a cerebral pathology or of previous hemorrhagic cerebrovascular accidents is considered a contraindication to fibrinolytic therapy during acute myocardial infarction due to the elevated risk of intracranial hemorrhage. Lytic therapy reduces early mortality by 25-50% in patients with anterior myocardial infarction, and logistic considerations make primary angioplasty unfeasible in most clinical centers. Present guidelines exclude most patients who are at risk of a hemorrhagic stroke from fibrinolytic therapy, depriving some of them of a cure which has been demonstrated to be effective. Here we describe 2 cases of patients who had previously been treated for cerebral aneurysms and who were later treated with fibrinolytics during the course of an acute myocardial infarction. Based on the observation of these 2 cases and on the data available in the literature, we identified some patients with cerebral aneurysms or cerebral artero-venous malformations, whose pathology, once adequately corrected, cannot be considered an absolute contraindication to lytic therapy in the presence of a large myocardial infarction, when an emergency coronary angioplasty cannot be performed.