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Aims Epidemiological studies reported two contrasting trends: on one hand, a significant improvement in the use of evidence-based treatments of patients discharged with a myocardial infarction (MI). On the other hand, the increasing number of elderly and co-morbid patients who are usually less treated. The aim of this study is to examine whether improvements in the treatment of MI are homogeneously distributed throughout all subgroups of patients. Methods and results Based on record linkage of administrative registers, 21 423 patients discharged with MI in three different periods (2003, 2005, and 2007), were identified and followed up for major clinical events up to 1 year. Using as a reference temporal category those patients discharged in 2003 (odds ratios, 95% confidence intervals) and as a demographic category male patients aged ≤75 years (1.00), the study identified: in-hospital mortality significantly decreased in all periods and in all groups of patients; out-of-hospital mortality decreased only in younger patients and not in older patients; prescription of evidence-based treatments increased in all periods for all patients; however, the magnitude of improvement was mostly concentrated in younger patients. Conclusion Although there was a mean improvement in the treatment and outcome of patients discharged from an MI, most of these benefits were strongly concentrated in younger, healthier patients. Old and co-morbid populations-although representing a substantial proportion of the burden of disease-received significant less attention and barely improved their survival.

Aims Plasma levels of individual neurohormones (NH) have been proposed as reliable indicators for risk stratification of patients with heart failure (HF). Mainly because of small sample size, the predictive value of different NH has never been compared, while taking into account demographic, clinical and echocardiographic markers of risk in HF. Methods and results Plasma brain natriuretic peptide (BNP), norepinephrine (NE), renin activity (PRA), aldosterone (aldo) and endothelin were measured in 4300 patients before randomization in Val-HeFT. Univariate and multivariate Cox proportional hazard analyses were performed to investigate the relationship between NH and two primary study outcomes, mortality and combined mortality and morbidity (M/M). Higher baseline values for all NH were related to mortality and M/M, with univariate hazard ratios ranging from 1.13 \[95% CI 0.99–1.30\] (aldo) to 2.47 \[2.13–2.87\] (BNP) for mortality, and from 1.24 \[1.11–1.39\] (aldo) to 2.56 \[2.28–2.89\] (BNP) for M/M. In multivariate analyses, BNP had the strongest association with outcome, followed by NE and PRA. Patients with more activation of renin-angiotensin-aldosterone system tended to show greater benefit from valsartan; but the trend was not statistically significant. Conclusion All the NHs evaluated in 4300 patients with stable moderate to severe HF were found to be significant markers of outcome, despite therapy with ACEi, BB and randomization to an angiotensin receptor blocker or placebo. Several of these markers have been implicated as contributors to progression of HF, but BNP, which is thought to be protective, was the most powerful indicator for poor outcome.

Aims Many clinical trials conducted in the 1970s and early 1980s have shown that the long-term use of beta-blockers after an acute myocardial infarction significantly reduces mortality and reinfarction rates. This study assessed the impact of these findings in clinical practice. Methods We retrospectively analysed the beta-blocker prescriptions for 36 817 patients with acute myocardial infarction included in three large randomized clinical trials (Gruppo Italiano di Studio sulla Sopravvivenza nell'Infarto Miocardico—GISSI, 1, 2 and 3), conducted by a highly representative sample (about 75%) of Italian coronary care units in 1984–85, 1988–89 and 1991–93. Results The prescription of beta-blockers at discharge increased gradually from 8·5% in 1984–85 to 25·0% in 1988–89 and to 31·4% in 1991–93. A similar trend was apparent for beta-blocker prescriptions 6 months after acute myocardial infarction. The strongest predictors of beta-blocker prescription are the presence of post-infarctual angina and a history of arterial hypertension. Besides the classical contraindications, advanced age, transitory cardiac failure or arrhythmias in the acute phase of acute myocardial infarction are important predictors of nonprescription. Conclusion The use of beta-blockers after acute myocardial infarction in Italy has increased more than three-fold in the last decade, but they are still prescribed to too few patients, especially those at higher risk, for whom the expected benefit is greater.

BACKGROUND: Clinical and epidemiological studies support the hypothesis that ischaemic cardiovascular diseases are consistently associated with psychological, social and behavioural factors. Nevertheless, the joint effect of clinical characteristics and psychological variables in determining the prognosis of acute myocardial infarction survivors has been seldom investigated. METHODS AND RESULTS: In the framework of the GISSI-2 trial, the impact of psychological factors on 6-month mortality and their interaction with clinical features was included as an ad hoc research project. Overall, 2449 patients were evaluated, 63 of whom died during the study period. All patients undertook a self-administered questionnaire (Cognitive Behavioural Assessment Hospital Form), investigating 16 psychological dimensions relative to three areas (state variables, vital exhaustion, trait variables). The impact of psychological variables on prognosis and their interaction with clinical variables were investigated by using a tree-growing technique (RECursive Partitioning and AMalgamation-RECPAM) applied to survival analysis. This statistical method allowed the identification of three separate classes, characterized by different prognoses: Class I (presence of vital exhaustion), Class II (concomitance of no vital exhaustion, depression and low levels of anxiety) and Class III (all other patients). After adjusting for the clinical variables, Class I was associated with an intermediate prognosis (hazard ratio [HR] = 2.2; 95% confidence intervals [CI], 1.2-4.0) and Class II to the worst (HR = 3.2; 95% CI = 1.6-6.2), as compared to Class III. High levels of neuroticism and extroversion were associated with a better prognosis. When clinical and psychological variables were simultaneously investigated by RECPAM, Type A behaviour was shown to be an important risk predictor among patients with better clinical conditions, i.e. those eligible for exercise test (HR = 2.6, 95% CI = 1.2-5.5). Finally, a striking difference in the impact of the most predictive clinical variables (exercise test ineligibility, late and early ventricular failure) was found among patients with and without vital exhaustion. CONCLUSIONS: This study shows that acute myocardial infarction survivors are heterogeneous with respect to 6-month mortality according to their psychological profile. More important, the impact of these variables appears comparable to that of very well known clinical risk predictors. The availability of a large study population, together with the use of innovative statistical techniques, allowed us to identify subgroups of patients for whom the joint action of clinical and psychological characteristics has been clearly documented. This suggests the need for incorporating psychological evaluation in the care of acute myocardial infarction patients.

The pharmacological treatment, mainly based on diuretics, of isolated systolic hypertension (ISH) has recently been shown to reduce the risk of stroke and coronary heart disease in the elderly. The purpose of this study was to compare the antithypertensive effect and tolerability of different drug regimens in elderly subjects with ISH (systolic blood pressure—SBP —≥160 mmHg and diastolic blood pressure — DBP —

Aims Both reduced glomerular filtration and increased urinary albumin excretion independently determine outcome in patients with chronic heart failure (HF). However, tubulo-interstitial injury might indicate renal damage, even in the presence of normal glomerular filtration. We studied the relationship between tubular damage, glomerular filtration, urinary albumin excretion, and outcome in HF patients. Methods and results In 2130 patients participating in the GISSI-HF trial, we measured urinary albumin-to-creatinine ratio (UACR), estimated glomerular filtration rate (eGFR), and three urinary markers of tubular damage: N -acetyl-beta-d-glucosaminidase (NAG), kidney injury molecule 1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL). We assessed the relationship between the individual tubular damage markers and the combined endpoint of all-cause mortality and HF hospitalizations. Mean age was 67 ± 11 years, and 21% were female. Urinary NAG 13.7 (7.8–22) U/gCr, KIM-1 1939 (671–3871) ng/gCr, and NGAL 36 (14–94) µg/gCr were markedly elevated above normal levels. All individual tubular markers were independently associated with the combined endpoint: NAG: adjusted hazard ratio (HR) 1.22; 95% confidence interval (CI), 1.10–1.36; P < 0.001, KIM-1 HR 1.13; 95% CI, 1.02–1.24; P = 0.018 and NGAL HR 1.10; 95% CI, 1.00–1.20; P = 0.042; all per log standard deviation increase). Even in patients with a normal eGFR, increased tubular markers were related to a poorer outcome. The combination of impaired eGFR, increased UACR, and high NAG was associated with a HR of 3.00; 95% CI, 2.29–3.95; P < 0.001, compared with those without these abnormalities. Conclusion Tubular damage is related to a poor clinical outcome in HF patients even when eGFR is normal. ClinicalTrials.gov Identifier: [NCT00336336][1] (for the main study). [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00336336&atom=%2Fehj%2F32%2F21%2F2705.atom

The prevalence of orthostatic hypotension (OH) in an elderly outpatient population was assessed according to the most common criteria given in the literature. Short-term OH variability and relationships between OH and its known risk factors were also analysed. A sample of 3858 elderly outpatients aged 65 years or more was randomly recruited by 444 Italian general practitioners. The patients' blood pressure (BP) and heart rate were recorded in both lying and standing positions at two visits 7 days apart. Three definitions were used for the identification of OH: (1) a decrease in systolic BP greater than 20 mmHg (SOH); (2) a decrease in both systolic (greater than 20 mmHg) and diastolic (greater than 10 mmHg) BP (SDOH); (3) any decrease in systolic BP associated with symptoms (SyOH). Prevalence figures for SOH were 13.8% at the first and 12.6% at the second visit, and respectively 5.3 and 4.8% for SDOH, 14.1 and 11.8% for SyOH. All the criteria were met by less than 2% of subjects at each visit. The diagnosis of OH was confirmed at both visits in 36.3% of cases for SOH, in 25.7% for SDOH, and in 43.9% for SyOH. Each different OH definition identifies a population subgroup characterized by different sets of risk-factors. The presence and prevalence of OH is difficult to define because different people may be identified by the currently accepted criteria or by the same criterion over a short time.

Recently, major scientific societies in Europe and USA have issued guidelines on diabetes and cardiovascular (CV) disease. The conclusions of the two panels of experts regarding the use of aspirin for the primary prevention of CV disease in individuals with diabetes are totally divergent. The US statement recommends the use of aspirin for primary prevention in all individuals aged > 40 or with additional risk factors. In contrast, in the European guidelines there is no mention of aspirin for the primary prevention of myocardial infarction or CV death, while it is recommended for the prevention of stroke. Both recommendations seem mainly based on extrapolations from data on other high-risk groups, rather than on a comprehensive review of pertinent data. Actually, a body of evidence suggests that the efficacy of aspirin in patients with diabetes is substantially lower than in individuals without diabetes. Nevertheless, existing knowledge is mainly derived from dated trials, including small numbers of patients, and hardly representing current strategies for the management of CV risk factors. The high level of uncertainty regarding the balance between benefits and risks of aspirin therapy have important implications for clinical practice, auditing activities, and the design and conduct of randomized clinical trials.

Controversy exists with regard to the influence of APOE polymorphisms on coronary heart disease development and on the efficacy of statin treatment. we investigated the relationship between apoe, mortality and the response to treatment in Mediterranean myocardial infarction (mi) survivors.We analysed 3304 Italian patients with MI randomized to pravastatin or no treatment in the GISSI-Prevenzione study, with a mean follow-up time of 23.0 +/- 6.7 months (median 24.3 months). Mortality curves were calculated using Kaplan-Meier method, and differences in survival were tested using the log-rank test. There were 109 deaths during follow-up. Patients treated with pravastatin showed a significant decrease in mortality compared with non-treated patients (HR 0.67, 95% confidence interval 0.45-0.97, P = 0.038). Among the 3304 patients, 554 (16.8%) were epsilon4 carriers and 2750 (83.2%) were non-epsilon4 carriers. No significant difference in terms of mortality was observed between the epsilon4 and the non-epsilon4 carriers (3.61% vs. 3.24%, P = 0.67). However, although in non-epsilon4 carriers no significant difference in mortality was observed between patients treated with pravastatin and non-treated (2.81% vs. 3.67%, P = 0.21), among the epsilon4 carriers a significant reduction in mortality was observed in patients treated compared with non-treated (1.85% vs. 5.28%, P = 0.023).We found that epsilon4 allele is a determinant of pravastatin response in terms of survival. Though in the entire population investigated,we found a beneficial effect of pravastatin in terms of survival, only the epsilon4 carriers seemed to have gained a significant benefit from this treatment. We suggest that the effect of statins is of particular interest in this fraction of the population. Genetic markers can help in identifying patients that benefit more from statin treatment.

Aims To assess the use of antithrombotic treatment (ATT) after hospitalization with atrial fibrillation (AF) and the attributable effectiveness of ATT during follow-up. Methods and results On the basis of record linkage of administrative registers, 1812 patients discharged with AF were identified and followed-up for major clinical events up to 1 year. Mean age was 79 years. After hospitalization, 56% of the patients received ATT: 29% anticoagulants, 22% antiplatelets (APs), and 5% both agents. Among patients without comorbidities, 63.0% were exposed to ATT. Several factors significantly influence the use of antithrombotic agents, including increasing age [odds ratio (OR) 0.93 (95% confidence interval (CI), 0.92–0.95)], chronic obstructive pulmonary disease [0.77 (0.59–1.00)], malignancy [0.57 (0.39–0.82)], and previous use of ATT [4.56 (3.67–5.67)]. A significantly lower mortality was observed in patients exposed to ATT [hazard ratio (HR) 0.36 (95% CI, 0.28–0.47)], both to anticoagulants [0.23 (0.15–0.35)] and to APs [0.66 (0.50–0.86)]. ATT was associated with the reduction of thrombo-embolic events [0.52 (0.25–1.07)]. Major bleeding did not contribute to increased morbidity. Subgroups analysis, propensity score (PS), and sensitivity analysis confirmed these results. Conclusion Our data demonstrated that ATT was underused, also in patients without comorbidities. Exposure to ATT is associated with improved survival among elderly high-risk community patients hospitalized with AF.

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.

Left ventricular dilatation and a low ejection fraction after acute myocardial infarction are independent indicators of a poor prognosis. ACE inhibitors have been shown to decrease left ventricular dilatation after myocardial infarction. In the GISSI-3 trial, patients were randomly assigned, within 24 h of onset of myocardial infarction symptoms, to 6 weeks of treatment with lisinopril, nitroglycerin, both or neither, in an open, 2 x 2 factorial design. The study showed that early treatment in relatively unselected patients with lisinopril decreases mortality at 6 weeks and severe left ventricular dysfunction. We assessed (1) the prognostic value of pre-discharge 2-D echocardiographic variables, and (2) the effects of lisinopril on the progression of left ventricular dilatation.2-D echocardiograms were available pre-discharge in 8619 GISSI-3 trial patients discharged alive. In 6405 of these patients, a 2-D echocardiographic study was also available at 6 weeks, and at 6 months. Pre-discharge end-diastolic and end-systolic volumes, and ejection fraction predicted 6-month mortality and non-fatal clinical congestive heart failure (P0.01). The increase in left ventricular volumes over time was significantly reduced by 6 weeks' lisinopril treatment in patients with wall motion asynergy pre-discharge ofor = 27%. Patients with wall motion asynergy27% showed no dilatation and lisinopril did not affect volumes at 6 months. Patients randomized to lisinopril also had smaller volumes after withdrawal of treatment at 6 weeks. Lisinopril did not affect left ventricular ejection fraction.2-D echocardiography independently contributes to pre-discharge risk stratification in terms of 6-month mortality and clinical heart failure after myocardial infarction, and early, short-term treatment with lisinopril in unselected myocardial infarction patients attenuates left ventricular dilatation; an effect evident in patients with larger infarcts. These results probably only partly explain the effect of lisinopril on total mortality concentrated in the first week after infarction.