Search

Background: The existence, the components and the clinical relevance of treatment related cardiotoxicity in breast cancer patients are still the subject of controversial findings and recommendations. Two of the possible main determinants of uncertainty were taken as the focus of the present analysis of cardiovascular (CV) mortality and morbidity: the overtime changing risk profile of breast cancer protocols; the age-dependence of the role of background CV risk. Methods: Prospective comparative assessment of two cohorts of breast cancer women, cases, and their closely matched controls followed for three (36 330) and five years (23 906), covering the period Jan 1, 2007 to Dec 31, 2013. The pertinent NHS administrative databases were analyzed with Cox proportional hazards regression models to assess the differences in the incidence of fatal and not fatal CV events between pre-stratified cohorts of cases and controls representing three successive generations of breast cancer care and three age groups

Child health inequalities violate children’s rights to optimal wellbeing. Different issues worldwide affect children’s physical and mental health as well as their development, influencing their future as adults. Inequities are avoidable inequalities. Despite improvements in the past two decades, the ambitious goals of global agendas have, for the most part, remained as expectations with regard to childhood rights, social justice, and health equity in practice. The concept of social determinants of health has become part of the common language in certain settings, but this is still too little to improve health in practice on a global scale, particularly for underprivileged subgroups of the community, as children and adolescents often are. Pediatric health professionals and their organizations are also responsible for guaranteeing children’s and adolescents’ right to health and better wellbeing, helping to reduce health inequalities.

Background Economic crises have heterogeneous effects on population-level mortality between high- and low- or middle-income countries. Argentina – a middle income country- has suffered economic crises repeatedly over the past 30 years and is a model case study for the effects of economic crises on mortality. Methods Over 28 years (1990-2017), all death records in Argentina were analysed at the most disaggregated level possible (departments, that is, second-level administrative divisions). Age-and-sex-standardized all-cause mortality, premature death (

Based on a synthetic overview that embraces the evolution of the ‘health’ concept, and its related institutions, from the role of health as the main indicator of fundamental human rights—as envisaged in the Universal Declaration of Human Rights—to its qualification as the systems of disease control dependent on criteria of economic sustainability, the paper focuses on the implications and the impact of such evolution in two model scenarios which are centred on the COVID-19 pandemia. The article analyses COVID-19 both in the characteristics of its global dynamics and in its concrete management, as performed in a model medium income country, Argentina. In a world which has progressively assigned market values and goods an absolute strategic and political priority over the health needs and the rights to health of individual and peoples, the recognition of health as human right is confined to aspirational recommendations and rather hollowed out declarations of good will.

The prognostic impact of hyperuricemia on long-term clinical outcomes in patients with chronic heart failure (HF) has been investigated in observational registries and clinical trials, but the results have been often inconclusive. We examined the prognostic impact of elevated serum uric acid levels on long-term clinical outcomes in the GISSI-HF (Gruppo Italiano per lo Studio della Sopravvivenza nella Insufficienza Cardiaca-Heart Failure) trial.CLINICALTRIALS.NCT00336336.We assessed the rates of all-cause death, cardiovascular death, cardiovascular hospitalization and the composite of all-cause death or cardiovascular hospitalization over a median follow-up of 3.9 years among 6683 ambulatory patients with chronic HF.Patients in the 3rd serum uric acid tertile (7.2 mg/dl) had a nearly 1.8-fold increased risk of both all-cause death and cardiovascular death, and a nearly 1.5-fold increased risk of cardiovascular hospitalization and of the composite endpoint compared to those in the 1st uric acid tertile (5.7 mg/dl). Beyond serum uric acid ≥ 7 mg/dl the risk of outcomes increased sharply and linearly. The significant association between elevated serum uric acid levels and adverse outcomes persisted after adjustment for multiple established cardiovascular risk factors, HF etiology, left ventricular ejection fraction, medication use and other potential confounders, with an adjusted hazard ratio of 1.37 (95% CI 1.22-1.55) for all-cause death, 1.48 (1.29-1.69) for cardiovascular death, 1.19 (1.09-1.30) for cardiovascular hospitalization and 1.21 (1.11-1.31) for the composite endpoint, respectively.Elevated serum uric acid levels are independently associated with poor long-term survival and increased risk of cardiovascular hospitalization in patients with chronic HF.

Background Dysregulation of the vitamin D system promotes renal dysfunction and has direct detrimental effects on the heart. Progressive deterioration of renal function is common in patients with chronic heart failure (HF) and is invariably associated with unfavorable outcomes which can be improved by early identification and timely interventions. We examined the relation between two plasma markers of vitamin D metabolism and worsening of renal function (WRF) in a large cohort of patients with chronic HF. Methods Plasma levels of 1,25-dihydroxyvitamin D (1,25(OH) 2 D) and parathyroid hormone PTH (1–84) were measured in 1237 patients with clinical evidence of chronic and stable HF enrolled in the multicentre GISSI-HF trial and followed for 3.9years. We examined the relation of 1,25(OH) 2 D, PTH(1–84), and their ratio with WRF, defined as first increase in serum creatinine concentration ≥0.3mg/dL and ≥25% at two consecutive measurements at any time during the study. Results Lower 1,25(OH) 2 D/PTH(1–84) ratio was associated with a higher baseline serum concentration of creatinine, winter season, female sex and older age; 335 patients (29.6%) experienced an episode of WRF. After adjustment, a lower 1,25(OH) 2 D/PTH(1–84) ratio remained significantly associated with a higher risk of WRF (HR=0.75 [0.62–0.90], p=0.002) and correctly reclassified events. This ratio also independently predicted mortality and admission to hospital for cardiovascular reasons. Conclusions The plasma 1,25(OH) 2 D/PTH(1–84) ratio is a promising indicator of future risk of deterioration of renal function in patients with chronic HF and mild renal impairment, that may serve to optimize therapies and improve outcomes.

The Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico-Heart Failure (GISSI-HF) study reported benefits of n-3 fatty acid (FA) treatment on cardiovascular (CV) events, but the effects of treatment on a putative CV disease risk factor, the red blood cell (RBC) n-3 FA level (the omega-3 index), have not been examined in this context. We hypothesized that treatment with prescription omega-3 acid ethyl esters (O3AEE) would increase the omega-3 index to the proposed cardioprotective value of 8%. RBCs were collected from a subset of patients participating in the GISSI-HF study (n=461 out of 6975 randomized), at baseline and after 3 months of treatment with either an olive oil placebo or O3AEE (1 g/d). RBC FA levels were expressed as a percentage of total FA. Patients also reported their typical olive oil and fish intakes. RBC oleic acid levels were directly correlated with reported frequency of olive oil consumption, and the omega-3 index was correlated with reported fish intake (P for trends

BACKGROUND Acute kidney injury (AKI) occurs in many critically ill patients and is associated with high mortality. We examined whether proenkephalin could predict incident AKI and its improvement in septic patients. METHODS Plasma proenkephalin A 119–159 (penKid) was assayed in 956 patients with sepsis or septic shock enrolled in the multicenter Albumin Italian Outcome Sepsis (ALBIOS) trial to test its association with incident AKI, improvement of renal function, need for renal replacement therapy (RRT), and mortality. RESULTS Median [Q1–Q3] plasma penKid concentration on day 1 [84 (20–159) pmol/L[ was correlated with serum creatinine concentration (r = 0.74); it was higher in patients with chronic renal failure and rose progressively with the renal Sequential Organ Failure Assessment subscore. It predicted incident AKI within 48 h (adjusted odds ratio, 3.3; 95% CI, 2.1–5.1; P < 0.0001) or 1 week [adjusted hazard ratio, 2.1 (1.7–2.8); P < 0.0001] and future RRT during the intensive care unit stay [odds ratio, 4.0 (3.0–5.4)]. PenKid was also associated with improvements in renal function in patients with baseline serum creatinine >2 mg/dL, both within the next 48 h [adjusted odds ratio, 0.31 (0.18–0.54), P < 0.0001] and 1 week [0.23 (0.12–0.45)]. The time course of penKid concentrations predicted AKI and 90-day mortality. CONCLUSIONS Early measurement and the trajectory of penKid predict incident AKI, improvement of renal function, and the need for RRT in the acute phase after intensive care unit admission during sepsis or septic shock. PenKid measurement may be a valuable tool to test early therapies aimed at preventing the risk of AKI in sepsis.

Aims Uncertainties remain on the biological and prognostic significance and therapeutic implications of loss in body weight (W-LOSS) in chronic heart failure (HF) patients. We assessed whether W-LOSS added additional prognostic value to classical clinical risk factors in two separate and large cohorts of patients with chronic HF. The factors associated with W-LOSS were studied. Methods and results W-LOSS and estimated plasma volume changes were measured serially in the GISSI-HF (n = 6820) and Val-HeFT trials (n = 4892). In both studies, experiencing at least one episode of ≥5% W-LOSS during the first year of follow-up was considered a sign of wasting. In GISSI-HF, self-reported unintentional W-LOSS ≥2 kg between two consecutive clinical visits within 1 year was also considered a sign of wasting. W-LOSS occurred in 16.4% and 15.7% of the patients enrolled in GISSI-HF and Val-HeFT, respectively (unintentional ≥2 kg W-LOSS occurred in 18.9% in GISSI-HF). In multivariable analyses adjusting for a number of baseline covariates as well as for plasma volume changes, W-LOSS was found to be independently associated with mortality and adverse cardiovascular and non-cardiovascular outcomes, with a significant net reclassification improvement (cfNRI) and an increase in integrated discrimination improvement (IDI). W-LOSS was independently associated with several features representing the severity of HF, including baseline NT-proBNP and high sensitivity C-reactive protein (hsCRP) in Val-HeFT. Conclusions W-LOSS was a frequent finding in the GISSI-HF and Val-HeFT trials, associated with multiple patient features, and added additional prognostic information beyond clinical variables of HF severity, including estimated plasma volume changes.

Recent guidelines expand indications for statins. However, research on practical economic feasibility and cost-effectiveness in low-risk people is lacking. We aimed to describe the incidence of cardiovascular events (CVE), their total direct costs and the hypothetical effects of wide provision of statins on those rates and expenditures. We conducted a population-based cohort study using administrative data among low risk individuals. Estimators of effects of statins were taken from Cholesterol Treatment trialist metaanalysis and from Heart Protection Study trial. Two statin prices were used for analyses: National Italian Health System (€ 0.36) and the International Drug Price Indicator (€ 0.021). Overall, 920,067 persons at low risk were identified and 14,849 CVE were registered (incidence rate 27.3 per 10,000 person-years). Direct costs for hospitalizations for CVE were 143 M €. Universal provision of statins would result in a significant decrease in CVE rates, from 27.3 to 17.5 per 10,000 person-years (PY) (95 % confidence interval (CI): 15.8–19.4). Universal prescription of simvastatin 20 mg would cost 802 M €. Otherwise, provision of simvastatin at International Drug Price Indicator’s prices would be both clinically effective and cost saving in men older than age 44 (observed expenditures 120 M €, expected 97.4 M €) but not in women (observed expenditures 22.7 M €, expected 36.5 M €). Among a low-risk population, hypothetical universal provision of low-cost simvastatin to men over 44 years could be both clinically effective and a cost-saving strategy.

Background Postoperative atrial fibrillation (POAF) is a common complication after cardiac surgery and predicts increased morbidity and mortality. Identification of patients at high risk of POAF with the help of circulating biomarkers may enable early preventive treatment but data are limited, especially in contemporary surgical patients. Methods Plasma concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) were measured at enrolment, on the morning of cardiac surgery, at end surgery, and 2 days postsurgery in 562 patients undergoing cardiac surgery, randomized to perioperative supplementation with oral fish oil or placebo in the Omega-3 Fatty Acids for Prevention of Post-Operative Atrial Fibrillation trial (OPERA). The primary endpoint was incident POAF lasting ≥ 30 s, centrally adjudicated and confirmed electrocardiographically. Results Higher levels of NT-proBNP and hs-cTnT before surgery were associated with older age, renal or cardiac dysfunction and EuroSCORE. NT-proBNP peaked on postoperative day 2 (2172 [1238–3758] ng/L, median [Q1–Q3]), while hs-cTnT peaked at the end of surgery (373 [188–660] ng/L). Fish oil supplementation did not alter the time course of the cardiac biomarkers (P > 0·05). Concentrations of NT-proBNP or hs-cTnT, on the morning of surgery, or changes in their level between morning of surgery and postsurgery, were not significantly associated with POAF after adjustment for clinical and surgical characteristics. Conclusion Among patients undergoing cardiac surgery, NT-proBNP and hs-cTnT are related to clinical and surgical characteristics, have different perioperative time courses but are not independently associated with risk of POAF.

The use of Hydroxyurea (HU) as first line therapy in polycythemia vera (PV) has been criticized because no solid demonstration that this drug prevents thrombosis or prolongs survival has been so far produced. Here we present the outcomes of a large cohort of patients with PV included in the European Collaborative Low-dose Aspirin (ECLAP) study. We selected 1,042 patients who, during the follow-up, had received only phlebotomy (PHL) or HU to maintain the hematocrit level

Background To evaluate the association of wine intake with incident cardiovascular events (CVE) and total mortality after myocardial infarction (MI). Methods We used prospectively ascertained information among 11,248 Italian patients with recent MI enrolled in the GISSI-Prevenzione Trial. Usual wine consumption has been categorised as never/almost never, up to 0.5L/day, and >0.5L/day. Multiple imputation was used for missing values at baseline and during follow-up. We assessed adjudicated cumulative incidence of major CVE during 3.5years of follow-up and total mortality at long-term follow-up (7.3years), respectively. Multivariate Cox proportional hazards models were fitted to estimate hazard ratios (HR) first using data at baseline and then updated using time-varying covariates. Results During 37,021 person-years of follow-up, 1168 CVE occurred. Moderate wine intake at baseline was associated with significantly reduced risk of CVE (adjusted HR 0.87; 95% CI 0.76–0.99) as compared with non-drinkers. In time-updated analyses, results were virtually the same, though they were barely statistically not significant (adjusted HR 0.88; 95% CI 0.77–1.00). Wine intake was associated with lower risk of total mortality. In time-updated adjusted analyses, patients with wine consumption up to 0.5L/day (HR 0.83; 95% CI 0.74–0.92) and >0.5L/day (HR 0.77; 95% CI 0.63–0.94) had lower mortality compared with non-drinkers (P for trend=0.0003). Conclusions Among patients with established heart disease, moderate consumption of wine seems to be associated with lower incidence of CVE and total mortality as compared with non drinkers.

n-3 Polyunsaturated fatty acid (n-3PUFA) supplementation in the Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza Cardiaca (GISSI-HF) study reduced total mortality in patients with heart failure (HF), but the mechanism of action is still debated. The hypothesis of the present GISSI-HF substudy was that n-3PUFA may have beneficial effects on cardiac autonomic control.To evaluate the effect of 1 g/day of n-3PUFA vs placebo on heart rate variability variables, deceleration capacity, and turbulence slope.The GISSI-HF study enrolled patients with HF of any cause and severity. Twenty-four-hour (range 16-24 hours) Holter recordings were performed and analyzed in 388 patients at baseline, 3 months, and 12 months. Baseline characteristics were compared by using the χ(2) test, t test, or nonparametric Wilcoxon 2-sample test. Changes over time were tested by using the analysis of covariance adjusted by baseline values.At baseline, 36% of the patients were older than 70 years, 82% were men, 92% presented a left ventricular ejection fraction40%, and 80% were in New York Heart Association class II. An increase in mean RR interval, standard deviation of all normal-to-normal RR intervals, very low frequency power (all P.05), and turbulence slope (P = .05) was observed after 3 months in the n-3PUFA group compared to the placebo group, independently of the frequency of dietary fish consumption or beta-blocker treatment. These differences between study groups were no longer statistically significant at 12 months. A per-protocol analysis in patients compliant with study treatment showed similar results.n-3PUFA supplementation partially restored autonomic modulation in patients with chronic HF; this effect was maximal after 3 months of treatment.

Dysregulation of the vitamin D system promotes renal dysfunction and has direct detrimental effects on the heart. Progressive deterioration of renal function is common in patients with chronic heart failure (HF) and is invariably associated with unfavorable outcomes which can be improved by early identification and timely interventions. We examined the relation between two plasma markers of vitamin D metabolism and worsening of renal function (WRF) in a large cohort of patients with chronic HF.Plasma levels of 1,25-dihydroxyvitamin D (1,25(OH)Lower 1,25(OH)The plasma 1,25(OH)

Background: The impact of treatment with vasodilators on the survival of patients with pulmonary arterial hypertension (PAH) remains uncertain. Despite several clinical trials have been carried out in the last 15 years, their primary objective was not to assess mortality but the changes on surrogate end points. Methods and results: We reviewed the results of all clinical trials with vasodilators in PAH and the main results of different metaanalysis. Clinical trials and systematic reviews confirm that vasodilator therapies in patients with PAH who are non-vasoreactive produce a consistent, statistically significant but a marginal effect on exercise capacity assessed by the six-minute walk test. The weighted mean difference (95% CI) achieved with epoprostenol (EPO) or other prostacyclin analogues (PCA), endothelin receptor antagonists (ETRA) and phosphodiesterase-type-5 inhibitors (PDE5-I) was 35.4 m (17.3-53.5), 46.1 m (38.1-54.2) and 33.8 m (24.8-42.7), respectively. When considering the cumulative effects within each drug family, no class of drug produced a statistically significant reduction in all cause mortality. The relative risk rates (95% CI) conferred by EPO or PCA, ETRA and PDE5-I were 0.66 (0.36-1.21), 0.48 (0.19-1.23) and 0.65 (0.16-2.67), respectively. Interpretation: Further trials utilizing similar classes of drugs, and following similar trial designs are unlikely to yield different results or offer any more clinical benefits. Given that PAH is a fatal disease this raises concerns about whether they are ethical to conduct or not. Future trials will need to utilize clinical endpoints rather than the ones that are easy to administer and will need to include longer durations of study and other strategies to test the durability of effect.

Eur J Clin Invest 2011; 41 (12): 1330–1338 Abstract Background We hypothesized that, besides type 2 diabetes (T2D) and body mass index (BMI), circulating adiponectin concentration would be associated with variants of the ADIPOQ gene in patients with chronic heart failure (CHF). We also assessed the influence of these confounders on the prognostic value of adiponectin. Methods Plasma adiponectin was measured at entry and after 3 months in approximately 1200 patients with CHF enrolled in the GISSI-HF trial. Four common single-nucleotide polymorphisms (SNPs) spanning the ADIPOQ gene were studied: rs17300539 (−11391GA), rs266729 (−11377CG), rs2241766 (+45TG) and rs1501299 (+276GT). Associations with clinical characteristics and mortality were evaluated in patients with or without T2D. Results Adiponectin concentrations were negatively related to BMI, higher in women and older persons, but lower in patients with diabetes. T-allele carriers for rs1501299 and A-allele carriers for rs17300539 had significantly elevated adiponectin concentrations. Irrespective of diabetes, baseline plasma adiponectin was independently associated with mortality (adjusted HR [95%CI] per 1 SD increase in adiponectin concentration = 1·24[1·12–1·37], P

Background The prognostic value of plasma renin activity (PRA) in chronic heart failure (HF) has been assessed before the widespread use of angiotensin-converting enzyme inhibitors (ACEi) and beta-blockers, which exert opposite effects on renin secretion. We evaluated the association between PRA and outcome in patients with chronic HF treated with ACEi and beta-blockers. Methods and Results PRA was measured in 4,291 patients from the Valsartan Heart Failure Trial (Val-HeFT). The prognostic performance of PRA in patients who were or were not taking ACEi or beta-blockers was evaluated by multivariable Cox models. PRA was elevated in patients on ACEi (median 5.85 [interquartile range (IQR) 1.82–17.83] ng/mL/h) compared with those not on ACEi (1.57 [0.74–4.15] ng/mL/h), and lower in those on beta-blockers (3.89 [1.17–12.61] ng/mL/h) than in those not on beta-blockers (6.21 [1.97–19.24] ng/mL/h). Lower systolic blood pressure, higher plasma aldosterone, and ACEi were associated with high PRA. Higher PRA was a strong and independent predictor of mortality in the whole population and in patients who were or were not treated with ACEi or beta-blockers. Conclusions PRA is a powerful prognostic marker of death over a wide range of concentrations in patients with chronic HF. Prescription of ACEi and/or beta-blockers does not influence the relation between PRA and outcome.

Background: Prone position ventilation for acute hypoxemic respiratory failure (AHRF) improves oxygenation but not survival, except possibly when AHRF is severe. Objective: To determine effects of prone versus supine ventilation in AHRF and severe hypoxemia [partial pressure of arterial oxygen (PaO 2)/inspired fraction of oxygen (FiO2)

Introduction In recent years, the availability of effective oral pharmacological treatment for erectile dysfunction (ED) has revolutionized its management; however, it is still unclear how everyday clinical practice has changed in response to this evolving scenario. Aim The aim of this study is to describe general practitioners’ (GPs) beliefs and attitudes toward the management of ED. Methods Each GP was asked to recruit consecutive men aged ≥18 years and sexually active, with already known erectile problems or with newly diagnosed ED. Main Outcomes Measures A written questionnaire was used to investigate GPs’ sociodemographic characteristics and their beliefs toward the management of ED. Results Overall, 127 GPs (53.4%) returned the questionnaire and 124 enrolled patients for the study. Only 9.5% of the GPs reported routinely inquiring about ED of patients >40 years of age, whereas 45.7% did it only when the patient raised the problem. GPs’ gender and age were associated with their beliefs about ED treatment and referral to specialist care. Overall, 932 patients were enrolled, of whom 38% had newly diagnosed ED. The problem came to light for initiative of patient in 80% of cases, and 84.8% of men were prescribed a treatment. Patients who on their own initiative discussed of their condition had an almost 3-fold increased probability to be treated than those whose GP began the discussion about ED (odds ratio [OR] = 2.6, confidence interval [CI] 95% 1.5–4.5). Patients followed by female physicians were significantly more likely to be referred to a specialist than those followed by male physicians (OR = 3.3, CI 95% 1.4–5.0). Conclusions The management of ED has become an integral component of clinical practice in primary care. Nevertheless, barriers in addressing sexual issues still persist. Appropriate training is needed for a proactive approach to ED screening and management in men over 40s. De Berardis G, Pellegrini F, Franciosi M, Pamparana F, Morelli P, Tognoni G, and Nicolucci A on behalf of the EDEN study group. Management of erectile dysfunction in general practice. J Sex Med **;**:**–**.

Objectives This study sought to evaluate the association between changes over time of N-terminal pro-brain natriuretic peptide (NT-proBNP) expressed in different ways and outcome in patients with stable and chronic heart failure (HF). Background Although previous studies examined the prognostic value of repeated determinations of BNP in HF, there are only limited data on the clinical utility of serial measurements of the inactive peptide NT-proBNP in a large population of ambulatory patients with chronic HF with sufficient follow-up time. Methods The NT-proBNP was measured at randomization and after 4 months in 1,742 patients enrolled in the placebo arm of Val-HeFT (Valsartan Heart Failure Trial). Changes in NT-proBNP concentrations over 4 months were expressed as absolute change from baseline, percent relative changes, or categorical changes across a threshold value and related to subsequent mortality. Results A single determination of NT-proBNP (area under the curve at 4 months: 0.702, 95% confidence interval [CI]: 0.669 to 0.735) showed a higher prognostic discrimination than continuous changes of concentrations, expressed either as absolute (0.592, 95% CI: 0.549 to 0.634) or relative changes (0.602, 95% CI: 0.566 to 0.639). A Cox proportional hazards model showed that stratification of patients into 4 categories according to NT-proBNP levels at 2 time points 4 months apart with respect to a threshold concentration provided prognostic information in patients with chronic HF beyond that of a single determination. Conclusions Serial determinations of NT-proBNP concentration and classification into few categories of changes according to threshold levels may be a superior strategy for risk stratification of patients with chronic and stable HF.

Background and aim In the context of the QuED Study we assessed whether a quality of care summary score was able to predict the development of cardiovascular (CV) events in patients with type 2 diabetes. Methods and results The score was calculated using process and intermediate outcome indicators (HbA 1c , blood pressure, low-density lipoprotein cholesterol, microalbuminuria) and ranged from 0 to 40. Overall, 3235 patients were enrolled, of whom 492 developed a CV event after a median follow-up of 5 years. The incidence rate (per 1000 person-years) of CV events was 62.4 in patients with a score ≤10, 54.8 in those with a score between 15 and 20, and 39.8 in those with a score >20. In adjusted multilevel regression models, the risk to develop a CV event was 89% greater in patients with a score of ≤10 (rate ratio [RR] = 1.89; 95% confidence interval [CI] 1.43–2.50) and 43% higher in those with a score between 10 and 20 (RR = 1.43; 95% CI 1.14–1.79), as compared to those with a score >20. A difference between centers of 5 points in the mean quality score was associated with a difference of 16% in CV event risk (RR = 0.84; 95% CI 0.72–0.98). Conclusion Our study documented for the first time a close relationship between a score of quality of diabetes care and long-term outcomes.

Despite significant progress in the prevention and treatment of cardiovascular disease, sudden cardiac death (SCD) is a major public health problem. Statins showed consistent benefits on cardiovascular events, but scant data were available about their effects on SCD. This meta-analysis aimed to assess the effect of statins on SCD. Additional analyses were carried out to evaluate lipid reduction as a possible mediator of the effect. Randomized controlled trials from January 1966 to July 2006 were retrieved by searching the MEDLINE database. Inclusion criteria were outcome focusing on the incidence of SCD, statin treatment compared with placebo or no treatment, randomized design,or=100 patients enrolled, and follow-upor=6 months. Data were independently abstracted by 2 investigators using a standardized protocol. Ten randomized controlled trials enrolling a total of 22,275 patients were included in the meta-analysis. Risks of SCD were 3% in patients receiving statins and 3.8% in control patients. Statin treatment was associated with a significant 19% risk reduction for SCD (odds ratio 0.81, 95% confidence interval 0.71 to 0.93, p=0.003). In subgroup analysis, the benefit of statins was independent from the main characteristics of the studies and changes in patient lipid levels during the study. In conclusion, our results suggest that statins decrease the risk of SCD.

Chronic obstructive pulmonary disease (COPD) and heart failure are major causes of death and disability. Because little information is available about the population of patients with both syndromes, we assessed the characteristics and the independent contribution of COPD to outcomes in patients with stable chronic heart failure.The clinical, neurohormonal, and echocardiographic characteristics of the 5010 patients enrolled in the Valsartan Heart Failure Trial were compared in patients with or without COPD. The prognostic value of COPD was tested by multivariate Cox proportional hazard models.Patients with COPD were older, more symptomatic, and less likely to be receiving beta-blocker therapy, and had a higher mortality (27.4% vs. 18.4%, P.0001). Echocardiographic parameters were not different, and brain natriuretic peptide was only minimally increased. Norepinephrine, inflammatory markers, cardiac troponin T, and creatinine values were significantly higher. After adjustment, COPD no longer predicted all-cause mortality but remained predictive of noncardiovascular mortality (hazard ratio 2.50; 95% confidence interval: 1.58-3.96; P.0001) and hospitalizations, especially noncardiovascular (hazard ratio 1.71; 95% confidence interval; 1.43-2.06; P.0001).Patients with COPD are more symptomatic and have worse outcomes that are not explained by poorer left ventricular function. After adjustment for demographic, clinical, biohumoral, and treatment variables, COPD is a weak predictor of all-cause mortality but a strong predictor of noncardiovascular events. Awareness and optimized treatment of heart failure and COPD may reduce the clinical burden of these patients.

Although the negative prognostic implication of a clinical history of arterial hypertension in myocardial infarction (MI) survivors is well known, the predictive role of the blood pressure (BP) regimen after MI is not well defined. The aim of this study was to investigate the prognostic significance of different BP indices in post-MI.We evaluated the relationship between baseline systolic, diastolic, pulse and mean arterial pressure (MAP), measured by sphygmomanometry at discharge from hospital or within 3 months of an MI, and total and cardiovascular mortality in 11 116 patients enrolled in the GISSI-Prevenzione trial. Over 3.5 years of follow-up, 999 patients died, 657 of them from cardiovascular causes. Low mean and high pulse pressure were significantly associated with total and cardiovascular mortality after controlling for potential confounders in the multivariate analysis. As compared with patients with less extreme BP values, patients with MAP of 80 mmHg or less (n = 1241; 11.2%) had a 48% higher risk of cardiovascular death [95% confidenceinterval (CI) 1.16-1.87; P = 0.001] and those with pulse pressure greater than 60 mmHg (n = 958; 8.6%) had a 35% higher risk (95% CI 1.09-1.69; P = 0.007); only four subjects (0.04%) had both a high pulse pressure and a low MAP (relative risk of cardiovascular death 3.48; 95% CI 0.48-25.88; P = 0.218).Our results show for the first time an additional prognostic importance of two easily measurable components of BP, definitely high pulse pressure (60 mmHg) and low MAP (or = 80 mmHg), in a large sample of non-selected patients surviving MI who entered a modern programme of cardiovascular prevention.

Endothelin is elevated in heart failure and contributes to neurohormonal activation, hemodynamic deterioration, and cardiovascular remodeling. Here, we examined its prognostic value in a large population of patients with chronic heart failure.Big endothelin-1 (Big ET-1) and 4 other neurohormones were measured at study entry in 2359 patients enrolled in the Valsartan Heart Failure Trial (Val-HeFT) and their concentrations related to outcome over a median follow-up of 23 months. Baseline concentration of Big ET-1 (median 0.80 pmol/L) was proportional to severity of disease (New York Heart Association class, left ventricular structure and function). High circulating concentrations of brain natriuretic peptide (BNP), creatinine and bilirubin, advanced New York Heart Association class, elevated body mass index, and the presence of atrial fibrillation were independently associated to higher concentrations of Big ET-1. Big ET-1 (ranking second just behind BNP among neurohormonal factors) was an independent predictor of outcome defined as all-cause mortality (hazard ratio 1.49, 95% CI 1.20-1.84, P = .0003) or the combined endpoint of mortality and morbidity (hazard ratio 1.43, 95% CI 1.20-1.69, P.0001) and provided incremental prognostic value compared with BNP.In a large population of patients with symptomatic heart failure, the circulating concentration of Big ET-1, a precursor of the paracrine and bioactive peptide ET-1, was an independent marker of mortality and morbidity. In this setting, BNP remained the strongest neurohormonal prognostic factor.

Although results from basic science suggested a protective role of vitamin E treatment in the prevention of cardiovascular disease, recent evidence indicates increased cardiovascular mortality due to vitamin E treatment. Recently, the HOPE trial showed an increment of the incidence of congestive heart failure (CHF) in patients treated with vitamin E.We explored the effect of vitamin E on development of CHF in 8415 postinfarction patients without CHF at baseline, with an echocardiographic measure of left ventricular ejection fraction, who have been followed up for 3.5 years in the GISSI-Prevenzione trial. CHF during follow-up was defined as hospitalization or death for CHF. Cox regression models adjusted for relevant prognostic indicators were fitted.Main clinical characteristics were balanced in the 4202 and 4213 patients allocated vitamin E and control group, respectively. During follow-up, 220 patients (2.6%) developed CHF. Patients allocated vitamin E had a nonsignificant 20% (95% confidence intervals 0.92-1.56, P = 0.18) increased risk of developing CHF. Vitamin E treatment, however, was associated with a significant 50% increase (95% confidence intervals 1.03-2.20, P = 0.034) of CHF in patients with left ventricular dysfunction (ejection fraction50%).Our results confirm and extend previous evidence on the possible harmful effect of vitamin E on ventricular function in patients with cardiovascular disease. Available evidence should discourage the use of vitamin E in patients with left ventricular dysfunction.

The possibility of preventing atrial fibrillation recurrence with anti-arrhythmic agents is very limited, given the discouraging results obtained with current drugs in many patients. Data from experimental studies suggest that angiotensin II AT1-receptor blockers can influence atrial remodelling, a key factor in atrial fibrillation initiation and maintenance. Moreover, some preliminary clinical data show that angiotensin II AT1 -receptor blockers can prevent atrial fibrillation episodes. The GISSI-Atrial Fibrillation (AF) trial is a randomized, prospective, parallel group, placebo-controlled, multicentre study designed to test whether angiotensin II AT1-receptor blockers can reduce atrial fibrillation recurrence.The primary objective of the study is to demonstrate that, in patients with a history of recent atrial fibrillation who are treated with the best recommended therapies, the addition of the angiotensin II AT1-receptor blocker valsartan (titrated up to 320 mg) is superior to placebo in reducing atrial fibrillation recurrence. A substudy will analyse the effect of valsartan on left atrial dimensions and on neurohormones. The study population consists of patients with symptomatic atrial fibrillation (at least two electrocardiogram documented atrial fibrillation episodes in the previous 6 months or successful cardioversion in the last 2 weeks) with underlying cardiovascular diseases or comorbidities. With approximately 100 centres participating in Italy, a total of 1402 patients are randomized in a 1 : 1 ratio to receive valsartan or placebo. The enrolment period will last 12 months and the patients will be followed for 12 months from study entry.The GISSI-AF is the largest trial aimed at assessing the role of angiotensin receptor blockade in reducing the recurrence of atrial fibrillation and its possible mechanisms of action in terms of its effects on atrium remodelling and neurohormones.

The problem of missing values has increasingly being recognized in epidemiology. New methods allow for the analysis of missing data that can provide valid estimates of epidemiological quantities of interest. The GISSI-Prevenzione study was aimed to reliably assess the long-term relationship between the consumption of foods typical of the Mediterranean diet and the risk of mortality amongst 11,323 Italians with prior myocardial infarction. Food intake frequencies were recorded repeatedly over the 4.5 years of follow-up and missing values affected each food variable at increasing rates over the course of the study. Comparisons were made between the results obtained from the analysis of the complete data and those obtained after imputing the missing data with simple imputation methods and with various implementations of the multiple imputation (MI) method. MI appeared to best address the issue of missing data on the food intake frequencies, preserving the observed distributions and relationships between variables whilst producing plausible estimates of variability. Given its theoretical properties and flexibility to different types of data, MI is more likely to provide valid estimates, compared to complete data analysis and imputation by simple methods, and is thus worthy of wider consideration amongst epidemiological researchers.

OBJECTIVE—In the context of the QuED (Quality of Care and Outcomes in Type 2 Diabetes) project, we evaluated the longitudinal changes over 3 years in quality of life (QoL) in patients with type 2 diabetes according to the presence or the development of erectile dysfunction (ED). RESEARCH DESIGN AND METHODS—Patients were requested to fill in a questionnaire investigating the presence of ED and QoL (SF-36 Health Survey, depression symptoms [Center for Epidemiologic Studies–Depression], and quality of sexual life) every 6 months for 3 years. The analyses were based on multilevel models, adjusted for patient clinical and sociodemographic characteristics. RESULTS—The study involved 1,456 patients, of whom 34% reported frequent erectile problems at baseline; 192 developed ED during the follow-up. No changes in QoL measures were detected in patients without ED; in those with ED at baseline, a worsening in all SF-36 scales was observed, reaching statistical significance for physical functioning (P = 0.03). Among patients who developed ED during the study, a deterioration in all SF-36 dimensions and a worsening in depressive symptoms preceded the development of ED. The onset of ED was associated with a further marked worsening in physical functioning (P = 0.0008), general health perception (P = 0.02), and social functioning (P = 0.04) on SF-36 subscales, as well as in the summary physical and mental components scores (P = 0.04 and P = 0.07, respectively). The development of ED was also associated with a highly significant increase in depressive symptoms (P = 0.001) and a marked decrease in quality of sexual life (P < 0.0001). CONCLUSIONS—This longitudinal study documents for the first time the impact of ED onset on several aspects of QoL in patients with type 2 diabetes. The study also shows that QoL tended to further decrease during 3 years in patients with ED at baseline but not in those without this condition.

Background Sudden death (SD) has a major impact on mortality (M) in patients with left ventricular systolic dysfunction (SyD). In GISSI-Prevenzione, treatment with n-3 polyunsaturated fatty acids (PUFA) reduced M and SD in post-MI patients, but their effect in patients with SyD is unknown. Methods 11,323 patients with prior MI and NYHA class≤II were recruited. After excluding patients with no ejection fraction (EF) measurement (1684), and those with missing data (n=9), 9630 patients were available for analysis. Multivariate Cox regression adjusted models were fitted. Results Compared to patients with EF>50%, SyD patients had higher M (12.3% vs. 6.0%) and SD (3.4% vs. 1.4%) rates. PUFA reduced M similarly in patients with (RR 0.76 (0.60–0.96) P=0.02) and without SyD (RR 0.81 (0.59–1.10) P=0.17) (heterogeneity tests P=0.55). In contrast, the effect on SD was markedly asymmetrical: PUFA produced a marked reduction (RR 0.42 (0.26–0.67) P=0.0003) of risk in SyD patients whereas the effect was less evident (RR 0.89 (0.41–1.69) P=0.71) in patients with EF>50% (heterogeneity tests P=0.07). There was a significant increase in SD with worsening EF (P test for trend=0.02), the benefit on SD in patients with EF≤40% being 4-fold higher than in those with EF>50%. Conclusions Increasing SyD is associated with elevated risk of SD and with increasing benefit from PUFA. The effect of PUFA on SD reduction was greater in patients with SyD. Prospective trials testing the effect of PUFA in populations with SyD are required.

ObjectivesWe aimed to assess the prevalence and prognostic role of metabolic syndrome (METS) and diabetes in post-myocardial infarction (MI) patients.BackgroundDiabetes is a well known risk factor for patients with previous MI, but glycemic dysmetabolism develops over a protracted period of time. Scanty data are available on the role of METS in patients with previous MI.MethodsAdjusted Cox’s regression models, having diabetes, death, major cardiovascular events (CVE), and hospitalization for congestive heart failure (CHF) during follow-up as outcome events, were fitted on 11,323 patients with prior MI enrolled in the GISSI-Prevenzione Trial.ResultsAt baseline, 21% and 29% of patients had diabetes mellitus and METS, respectively. The METS patients had a significant (93%) increased risk of diabetes during follow-up. As compared with control subjects, the probability of death and CVE were higher in both METS (+29%, p = 0.002; +23%, p = 0.005) and diabetic patients (+68%, p −10%) weight reduction were associated with a significant (18% and 41%, respectively) decreased risk of diabetes. Weight gain was significantly associated with increased risk of diabetes. The risk conferred by METS and diabetes tended to be higher among women.ConclusionsIn patients with MI, METS and diabetes were highly prevalent and are associated with increased risk of death and CVE. Diabetes is also associated with increased risk of hospitalization for CHF. Weight reduction significantly decreased the risk of becoming diabetic in patients with METS.

Purpose The clinical course of polycythemia vera is often complicated by thrombosis as well as by the possible transition to myeloid metaplasia with myelofibrosis or acute myeloid leukemia. The aim of this study was to assess the rate of these complications in subjects receiving currently recommended treatments. Patients and Methods Overall, 1,638 patients from 12 countries were enrolled onto a large, prospective multicenter project aimed at describing the clinical history of polycythemia vera for the following outcomes: survival, the cumulative rate of cardiovascular death and thrombosis, the cumulative rate of leukemia, myelodysplasia, and myelofibrosis. The mean duration of the disease at entry and the duration of the follow-up were 4.9 and 2.7 years, respectively. Results The overall mortality rate of 3.7 deaths per 100 persons per year resulted from a moderate risk of cardiovascular death and a high risk of death from noncardiovascular causes (mainly hematologic transformations). Age older than 65 years and a positive history of thrombosis were the most important predictors of cardiovascular events. Antiplatelet therapy, but not cytoreductive treatment, was significantly associated with a lower risk of cardiovascular events. We found a consistent association between age and risk of leukemia, and between duration of the disease with risk of myelofibrosis. Conclusion The European Collaboration on Low-Dose Aspirin in Polycythemia Vera study documents that large international collaborative studies are feasible in this field, in which few epidemiologic data are available. The persistently high mortality rate from hematologic malignancies characterizes the unmet therapeutic need of polycythemic patients and suggests a priority for future studies in this disease.

The dramatic reduction of pediatric cancer mortality rates has been one of the greatest accomplishments of contemporary medicine. About 80% of children with cancer are now expected to be cured by current therapies. However, most of the world's children have no access to cancer treatment. The translation of effective pediatric cancer therapies to impoverished regions of the world presents an enormous challenge to the health care profession. Over the past 20 years, efforts have been under way to extend adequate cancer treatment to an increasing number of children in developing countries. These initiatives, collectively designated "twinning programs," consist essentially of a partnership between a pediatric cancer unit in a developing country and a group of health care providers in the developed world. Here we review the twinning programs that have been implemented in Central America, discuss their impact on the development of local resources and the outcome of childhood cancer, and propose a collaborative research initiative aimed at improving the international dissemination of progress in pediatric hematology-oncology.

In the context of an Italian nation-wide outcomes research program on type 2 diabetes, we investigated the contribution of both patient and setting-related factors to patient satisfaction with their relationship with their physicians. The level of patient satisfaction was measured using the American Board of Internal Medicine (ABIM) 14 patient satisfaction questionnaire. The main results were obtained using multilevel analysis, a statistical technique that takes into account the clustered nature of our data. Overall, 3563 patients were recruited by 101 diabetologists and 103 general practitioners (GPs). Information on patients' satisfaction was available for 2515 patients (71% of the whole sample). Patients' satisfaction was related to patient characteristics and attitudes, but not with physician's sex, age, speciality, and setting of care. In particular, patients who were less likely to delegate to physicians responsibility for diabetes management and those perceiving a lower degree of involvement in disease management showed lower levels of satisfaction. Lower satisfaction scores were also related to lower levels of school education, more severe clinical conditions, and lower psychological adaptation to diabetes. However, patients reporting higher levels of diabetes related worries and more frequent encounters with health care providers showed higher levels of satisfaction. In conclusion, patient satisfaction with physicians' humanness and communication skills is strongly related to personal characteristics, attitudes, expectations, and perceived health. In deciding the best decision-making approach to adopt in individual patients, it is of primary importance to measure how the patient perceives and engages in relationships.

Methods are now available to measure the magnitude of iron accumulation in the heart. Their validation currently relies on indirect evidence and not on chemical estimation in cardiac biopsies. All patients with symptomatic heart disease appear to have abnormal T2* values, but many patients without symptomatic heart disease also have evidence of increased myocardial iron. Although there is no proof to date that increased myocardial iron, as evidenced by abnormal magnetic resonance imaging, carries an adverse prognosis, it is likely that such new information will affect the chelating programme of patients. In these cases, there are a number of options available: (i) ongoing treatment with either desferrioxamine (DFO) or deferiprone may be intensified; (ii) the patient may be switched to the alternative chelator or (iii) combined chelation with both DFO and deferiprone may be started, which is more effective than using either chelator alone. For patients with symptomatic heart disease, continuous intravenous DFO with, or without deferiprone, remains the currently recommended treatment, in view of its documented ability to salvage these patients.

Although previous data suggested that only doses of 4 g/day or higher of n-3 polyunsaturated fatty acids (PUFA) have had a beneficial effect in the prevention of atherosclerosis and cardiovascular diseases, the GISSI-Prevenzione Study in a 3-year trial showed that 1 g/day reduced total and cardiovascular mortality in over 11,000 post-infarction patients. The aim of this study was to investigate the time course and the extent of incorporation of n-3 fatty acids in plasma and blood cells after 1 g/day of n-3 PUFA, the dose effective in the GISSI-Prevenzione in comparison with higher doses.Thirty-six healthy volunteers were given 1, 2 and 4 g/day of n-3 PUFA ethyl esters for 12 weeks, followed by a 4-week washout. Blood was collected at weeks 0, 1, 2, 4, 8, 12 and 16 and used for lipid profile analysis and measurement of fatty acid composition in plasma phospholipids, platelets and mononucleates.Total n-3 PUFA increased by 2.0-, 2.2- and 2.9-fold versus baseline after 12-week treatment with 1, 2 and 4 g respectively. A statistically significant raise of total n-3 PUFA was seen in platelets and mononucleates. Among individual n-3 PUFA, 22:5 n-3 was enriched early and dose dependently in plasma phospholipids, platelets and mononucleates; the raise of 22:6 n-3 was less marked especially in platelets and mononucleates.One gram per day of n-3 PUFA induces fast (within 1 week) and striking changes in blood composition of PUFA that may well explain their beneficial effects against cardiovascular diseases.