Long-term safety and efficacy of anacetrapib in patients with atherosclerotic vascular disease.

AIMS: REVEAL was the first randomized controlled trial to demonstrate that adding cholesteryl ester transfer protein inhibitor therapy to intensive statin therapy reduced the risk of major coronary events. We now report results from extended follow-up beyond the scheduled study treatment period. METHODS AND RESULTS: A total of 30 449 adults with prior atherosclerotic vascular disease were randomly allocated to anacetrapib 100 mg daily or matching placebo, in addition to open-label atorvastatin therapy. After stopping the randomly allocated treatment, 26 129 survivors entered a post-trial follow-up period, blind to their original treatment allocation. The primary outcome was first post-randomization major coronary event (i.e. coronary death, myocardial infarction, or coronary revascularization) during the in-trial and post-trial treatment periods, with analysis by intention-to-treat. Allocation to anacetrapib conferred a 9% [95% confidence interval (CI) 3-15%; P = 0.004] proportional reduction in the incidence of major coronary events during the study treatment period (median 4.1 years). During extended follow-up (median 2.2 years), there was a further 20% (95% CI 10-29%; P < 0.001) reduction. Overall, there was a 12% (95% CI 7-17%, P < 0.001) proportional reduction in major coronary events during the overall follow-up period (median 6.3 years), corresponding to a 1.8% (95% CI 1.0-2.6%) absolute reduction. There were no significant effects on non-vascular mortality, site-specific cancer, or other serious adverse events. Morbidity follow-up was obtained for 25 784 (99%) participants. CONCLUSION: The beneficial effects of anacetrapib on major coronary events increased with longer follow-up, and no adverse effects emerged on non-vascular mortality or morbidity. These findings illustrate the importance of sufficiently long treatment and follow-up duration in randomized trials of lipid-modifying agents to assess their full benefits and potential harms. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number (ISRCTN) 48678192; ClinicalTrials.gov No. NCT01252953; EudraCT No. 2010-023467-18.

Effect of canrenone on left ventricular mechanics in patients with mild systolic heart failure and metabolic syndrome: the AREA-in-CHF study.

BACKGROUND AND AIM: We analyzed the effect of the mineralocorticoid receptor antagonist canrenone on LV mechanics in patients with or without metabolic syndrome (MetS) and compensated (Class II NYHA) heart failure (HF) with reduced ejection fraction (EF≤45%) on optimal therapy (including ACE-i or ARB, and ß-blockers). METHODS AND RESULTS: From a randomized, double-blind placebo-controlled trial (AREA-in-CHF), patients with (73 on canrenone [Can] and 77 on placebo [Pla]), based on modified ATPIII definition (BMI≥30kg/m(2) instead of waist girth) or without MetS (146 by arm). In addition to traditional echocardiographic parameters, we also evaluated myocardial mechano-energetic efficiency (MME) based on a previously reported method. At baseline, Can and Pla did not differ in age, BMI, blood pressure (BP), metabolic profile, BNP, and PIIINP. Compared with MetS-Pla, and controlling for age, sex and diabetes, at the final control MetS-Can exhibited increased MME, preserved E/A ratio, and decreased atrial dimensions (0.04

Treatment of chronic heart failure with beta adrenergic blockade beyond controlled clinical trials: the BRING-UP experience.

BACKGROUND: Several large controlled trials have shown that beta blockers given to patients with heart failure (New York Heart Association functional class II-IV) reduce morbidity and mortality. Despite these impressive results, implementing the use of beta blockade in clinical practice appears slow and difficult. The BRING-UP study was designed to tackle this problem. OBJECTIVES: To accelerate the adoption of beta blockade in clinical practice; to provide an epidemiological estimate of the proportion of patients with heart failure suitable for this treatment in general cardiology care; and to assess effectiveness of these drugs outside the setting of clinical trials. METHODS: The design of the study and recommendations derived from available evidence on the use of beta blockers were discussed with cardiologists during regional meetings. All consecutive heart failure patients in a one month period, whether treated or not with beta blockers, were eligible for the study. In each patient, the decision to prescribe a beta blocker was a free choice for the participating physicians. All centres were provided with carvedilol, metoprolol, and bisoprolol at appropriate doses; the choice of the drug and dosage was left to the responsible clinician. All patients were followed for one year. RESULTS: 197 cardiological centres enrolled 3091 patients, 24.9% of whom were already on beta blocker treatment at baseline. beta Blockers were newly prescribed in 32.7% of cases, more often in younger and less severely ill patients. The mean daily dose of the drugs used at one year corresponded to about 70% of the maximum dose used in clinical trials. Starting treatment with beta blockers did not affect the prescription or dosage of other recommended drugs. The overall rate of beta blocker treatment increased over the year of the study from 24.9% to 49.7%. During the 12 month period, 351 deaths occurred (11.8%). In multivariate analysis, the use of beta blockers was independently associated with a better prognosis, with a relative risk of 0.60 and a lower incidence of hospital admissions for worsening heart failure. CONCLUSIONS: The implementation of beta blockers in clinical practice is feasible and could be accelerated. These drugs are associated with a lower mortality and reduced hospital admission rates, not only in clinical trials but also in the normal clinical setting.

Relation between early mitral regurgitation and left ventricular thrombus formation after acute myocardial infarction: results of the GISSI-3 echo substudy.

OBJECTIVE: To evaluate the prevalence and correlates of left ventricular thrombosis in patients with acute myocardial infarction, and whether the occurrence of early mitral regurgitation has a protective effect against the formation of left ventricular thrombus. DESIGN AND SETTING: Multicentre clinical trial carried out in 47 Italian coronary care units. PATIENTS AND METHODS: 757 patients from the GISSI-3 echo substudy population with their first acute myocardial infarct were studied by echocardiography at 24-48 hours from symptom onset (S1), at discharge (S2), at six weeks (S3), and at six months (S4). The diagnosis of left ventricular thrombosis was based on the detection of an echo dense mass with defined margins visible throughout the cardiac cycle in at least two orthogonal views. RESULTS: In 64 patients (8%), left ventricular thrombosis was detected in one or more examinations. Compared with the remaining 693 patients, subjects with left ventricular thrombosis were older (mean (SD) age: 64.6 (13.0) v 59.8 (11.7) years, p < 0.005), and had larger infarcts (extent of wall motion asynergy: 40.9 (11.5)% v 24.9 (14)%, p < 0.001), greater depression of left ventricular ejection fraction at S1 (43.3 (6.9)% v 48.1 (6.8)%, p < 0.001), and greater left ventricular volumes at S1 (end diastolic volume: 87 (22) v 78 (18) ml/m(2), p < 0.001; end systolic volume: 50 (17) v 41 (14) ml/m(2), p < 0.001). The prevalence of moderate to severe mitral regurgitation on colour Doppler at S1 was greater in patients who had left ventricular thrombosis at any time (10.2% v 4.2%, p < 0.05). On stepwise multiple logistic regression analysis the only independent variables related to the presence of left ventricular thrombosis were the extent of wall motion asynergy and anterior site of infarction. CONCLUSIONS: Left ventricular thrombosis is not reduced, and may even be increased, by early moderate to severe mitral regurgitation after acute myocardial infarction. The only independent determinant of left ventricular thrombosis is the extent of the akinetic-dyskinetic area detected on echocardiography between 24-48 hours from symptom onset.

Precipitating factors and decision-making processes of short-term worsening heart failure despite "optimal" treatment (from the IN-CHF Registry).

This study sought to prospectively assess which factors were related to short-term worsening heart failure (HF) leading to or not to hospital admission, in long-term outpatients followed by cardiologists. The subsequent decision-making process was also analyzed. The study population consisted of 2,701 outpatients enrolled in the registry of the Italian Network on Congestive Heart Failure (IN-CHF) and followed by 133 cardiology centers (19% of all existing Italian cardiology centers). Clinical and follow-up data were collected by local trained clinicians; 215 patients (8%) had short-term decompensation (on average 2 months after the index outpatient visit). Multivariate analysis showed that previous hospitalization, long duration of symptoms, ischemic etiology, atrial fibrillation, higher functional class (New York Heart Association classification III to IV), higher heart rate, and low systolic blood pressure were independently associated with HF destabilization. Poor compliance (21%) and infection (12%) were the most frequent precipitating factors, but a precipitating factor was not identified in 40% of the patients. Poor compliance was more common in women, but no other clinical characteristics emerged as being related with a specific precipitating factor. Fifty-seven percent of the patients with a short-term recurrence of worsening HF required hospital admission; infusion treatment with inotropes and/or vasodilators was necessary in 19% of them. Long-term therapy was changed in 48% of the patients. Thus, in ambulatory HF patients, short-term worsening HF can be predicted according to the clinical characteristics on an outpatient basis. Nearly 1/3 of precipitating factors can be prevented. Patient education and avoidance of inappropriate treatment may reduce the number of relapses.

Heterogeneity of left ventricular remodeling after acute myocardial infarction: results of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico-3 Echo Substudy.

BACKGROUND: Left ventricular (LV) remodeling after acute myocardial infarction has still to be clarified in the thrombolytic era. METHODS: To evaluate timing and the magnitude and pattern of postinfarct LV remodeling, a subset of 614 patients enrolled in the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico-3 Echo Substudy underwent serial 2-dimensional echocardiograms at 24 to 48 hours from symptom onset (S1), at hospital discharge (S2), at 6 weeks (S3), and at 6 months (S4) after acute myocardial infarction. RESULTS: During the study period the end-diastolic volume index (EDVi) increased (P <.001) and wall motion abnormalities (%WMA) decreased (P <.001), whereas ejection fraction (EF) remained unchanged. Nineteen percent of patients showed a > 20% increase in EDVi at S2 compared with S1 (severe early dilation), and 16% of patients showed a > 20% dilation at S4 compared with S2 (severe late dilation). Independent predictors of severe in-hospital LV dilation were relatively small EDVi (odds ratio [OR] 0.961, 95% confidence interval [CI] 0.947-0.974, P =.0001) and relatively large %WMA (OR 1.030, 95% CI 1.013-1.048, P =.0005). Similarly, smaller predischarge EDVi (OR 0.975, 95% CI 0. 963-0.987, P =.0001), greater %WMA (OR 1.026, 95% CI 1.008-1.045, P =.0042), and moderate to severe mitral regurgitation (OR 2.261, 95% CI 1.031-4.958, P = 0.0417) independently predicted severe late dilation. Importantly, 92% of the patients with severe early dilation did not have further dilation at S4, and 91% of patients with severe late dilation did not have in-hospital dilation. EF was unchanged over time in patients with early dilation, whereas it significantly decreased in those with late dilation. CONCLUSIONS: Although in-hospital LV enlargement is not predictive of subsequent dilation and dysfunction, late remodeling is associated with progressive deterioration of global ventricular function over time: patients with extensive %WMA and not significantly enlarged ventricular volume before discharge are at higher risk for progressive dilation and dysfunction.

[Cardiologists and limitations of statins reimbursement]. / I cardiologi e la limitazione della rimborsabilità delle statine.

BACKGROUND: In Italy of five approved HMG-CoA reductase inhibitors (atorvastatin, cerivastatin, fluvastatin, pravastatin, and simvastatin) only the last two are reimbursed by the National Health System for secondary prevention of coronary artery disease. METHODS: During the 1999 Annual Meeting of the National Association of Hospital Cardiologists (ANMCO) a questionnaire was included in the meeting material. The aim was two-fold: 1) to evaluate whether Italian cardiologists approve the National Health System policy to reimburse only pravastatin and simvastatin for secondary prevention, and 2) to assess which end-points are considered sufficient to grant the reimbursement of additional HMG-CoA reductase inhibitors. RESULTS: Two hundred and thirty-two completed questionnaires were collected and analyzed: 90.1% (95% confidence interval-CI between 85.1 and 93.6%) of cardiologists agree that only HMG-CoA reductase inhibitors with evidence-based mortality reduction should be reimbursed in Italy for secondary prevention; 75.0% (95% CI between 69.4 and 80.6%) follow the State guidelines in order to choose the approved HMG-CoA reductase inhibitors and 69.4% (95% CI between 63.5 and 75.3%) judge that at least the demonstration of coronary artery plaque reduction should be considered as an evidence-based decision to include new HMG-CoA reductase inhibitors for reimbursement. CONCLUSIONS: Most of Italian cardiologists who answered the questionnaire agreed with the limitation of reimbursement to only HMG-CoA reductase inhibitors with evidence-based demonstration of mortality reduction and asserted that the only reduction in blood cholesterol levels should not be considered proof of efficacy.

Epidemiologic study of use of resources in patients with unstable angina: the EARISA registry. On behalf on the EARISA Investigators (Epidemiologia dell'Assorbimento di Risorse nell'Ischemia, Scompenso e Angina).

AIM: The EARISA Registry was designed to describe diagnostic and therapeutic resources used in Italian cardiology centers for patients with the epidemiologically most relevant cardiac diseases. This article focuses on patients with unstable angina; characteristics associated with invasive procedures were specifically analyzed. METHODS AND RESULTS: Information was collected over a 2-week period on 1420 patients with unstable angina discharged from 308 cardiology centers. The mean length of stay was 9 +/- 6 days; 51% of patients were admitted to a coronary care unit (mean length of stay, 4 +/- 3 days). Noninvasive procedures included echocardiography (64%), Holter monitoring (25%), exercise stress testing (24%), and echocardiographic stress testing or nuclear imaging (7%). Invasive procedures were coronary angiography (39%) and percutaneous transluminal coronary angioplasty or coronary artery bypass grafting (13%). Unstable angina had a greater impact on invasive procedures than acute myocardial infarction. Variables independently associated with a higher rate of coronary angiographic procedures were younger age, higher technologic level of the hospital, and need for intravenous therapy. CONCLUSION: In Italy, approximately half the patients with unstable angina are admitted to hospitals without catheterization laboratories or cardiac surgery facilities. This fact supports the concept that treatments that can be administered in all types of hospitals are more likely to affect the outcome of patients with unstable angina. Overall, the rates of coronary angiography and revascularization procedures appeared low, and the setting where cardiologists practice, rather than patient characteristics, is the major determinant of the care given to patients with unstable angina.

Comparison of one-year outcome in women versus men with chronic congestive heart failure.

Using information from the Italian Network on Congestive Heart Failure, we examined whether clinical epidemiologic characteristics, drug prescription patterns, and outcome of patients with congestive heart failure differed according to sex and whether gender was an independent risk factor for mortality and hospital admissions.

Clinical correlates of elevated plasma natriuretic peptides and Big endothelin-1 in a population of ambulatory patients with heart failure. A substudy of the Italian Network on Congestive Heart Failure (IN-CHF) registry. IN-CHF Investigators.

BACKGROUND: Activation of neuroendocrine factors plays a major role in the pathophysiology and progression of heart failure. The aim of the present study was 1) to assess the clinical correlates of elevated plasma natriuretic peptides [atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP)] and Big endothelin-1 in a population of 180 ambulatory patients from the Italian registry of heart failure (Italian Network on Congestive Heart Failure, IN-CHF) in 22 clinical centers, 2) to assess the within-patient variability of plasma BNP concentration, and 3) to evaluate the analytical agreement for BNP determination between a core laboratory and local sites. METHODS: ANP and BNP were measured with specific immunoradiometric methods, Big endothelin-1 with an enzyme immunoassay. RESULTS: Elevated BNP was associated with severe mitral valve regurgitation (odds ratio 8.546, 95% confidence interval 1.879-38.510, p = 0.0052); high circulating concentrations of ANP and BNP were found in older patients, and in patients with higher NYHA functional class or reduced left ventricular ejection fraction. Elevated plasma concentration of Big endothelin-1 was a strong and independent predictor of atrial fibrillation (odds ratio 4.001, 95% confidence interval 1.531-10.454, p = 0.0047). Plasma concentration of BNP was reasonably stable at 3-month interval in patients with mild-to-moderate heart failure (mean between-visit difference -1.5+/-45 pg/ml, n = 96). There was a satisfactory analytical agreement between the central laboratory and sites, over a broad range of concentrations (2-1133 pg/ml, n = 283) with a slope for the best line fitted by linear regression of 1.09 (r2 = 0.96). CONCLUSIONS: BNP assay may become an appropriate tool for routine clinical practice in patients with congestive heart failure.

Comparison of electrocardiographic criteria for diagnosis of left ventricular hypertrophy in hypertension: the MAVI study.

BACKGROUND: Standard electrocardiography (ECG) is a specific, but poorly sensitive tool for diagnosis of left ventricular (LV) hypertrophy. In a large population of subjects with hypertension we tested some standard ECG criteria in their sensitivity and specificity for LV hypertrophy. LV mass at echocardiography was the reference standard. METHODS: In the setting of the MAVI (MAssa Ventricolare sinistra nel soggetto Iperteso) study, the ECG and echocardiographic tracings of 947 hypertensive subjects were read blindly in a central office. RESULTS: Prevalence of LV hypertrophy at ECG was 0.6, 3.0, 4.8, 7.1, 11.1, 11.9 and 18.4%, respectively, using the following criteria: Wilson, typical strain, Romhilt-Estes score > or = 5 points, Gubner-Ungerleider, Sokolow-Lyon, Cornell voltage (S(V3)+R(avL) > 2.8 mV in men or 2.0 mV in women) and Perugia score (positivity of at least one of the following: S(V3)+R(aVL) > 2.4 mV in men or > 2.0 mV in women, a typical strain pattern, or a Romhilt-Estes point score >or = 5). Prevalence of LV hypertrophy at echocardiography ranged from 27.2% (LV mass > 125 g/m2) to 49.9% (LV mass > 51.0 g/m2.7). Using the latter gold standard, sensitivity and specificity of the above ECG criteria were 0.8 and 99.6% (Wilson), 3.8 and 97.9% (strain), 5.9 and 96.4% (Romhilt-Estes), 9.7 and 95.6% (Gubner-Ungerleider), 11.2 and 91.1% (Sokolow-Lyon), 15.2 and 91.4% (Cornell), and 22.2 and 85.4% (Perugia score). CONCLUSIONS: Sensitivity of traditional ECG criteria for LV hypertrophy in subjects with hypertension is poor. However, the combination of three highly specific criteria (Romhilt-Estes, LV strain and Cornell) in a cumulative score produces a rise in sensitivity without excessive deterioration of specificity, with a prevalence of LV hypertrophy at ECG of 18.4%. Traditional interpretation of ECG is valuable and should be reconsidered in the clinical work-up of subjects with hypertension.

Electrocardiographic evolutionary changes and left ventricular remodeling after acute myocardial infarction: results of the GISSI-3 Echo substudy.

OBJECTIVES: The aim of this study was to describe the electrocardiographic (ECG) evolutionary changes after an acute myocardial infarction (AMI) and to evaluate their correlation with left ventricular function and remodeling. BACKGROUND: The QRS complex changes after AMI have been correlated with infarct size and left ventricular function. By contrast, the significance of T wave changes is controversial. METHODS: We studied 536 patients enrolled in the GISSI-3-Echo substudy who underwent ECG and echocardiographic studies at 24 to 48 h (S1), at hospital discharge (S2), at six weeks (S3) and six months (S4) after AMI. RESULTS: The number of Qwaves (nQ) and QRS quantitative score (QRSs) did not change over time. From S2 to S4, the number of negative T waves (nT NEG) decreased (p < 0.0001), wall motion abnormalities (%WMA) improved (p < 0.001), ventricular volumes increased (p < 0.0001) while ejection fraction remained stable. According to the T wave changes after hospital discharge, patients were divided into four groups: stable positive T waves (group 1, n = 35), patients who showed a decrease > or =1 in nT NEG (group 2, n = 361), patients with no change in nT NEG (group 3, n = 64) and those with an increase > or =1 in nT NEG (group 4, n = 76). The QRSs and nQ remained stable in all groups. Groups 3 and 4 showed less recovery in %WMA, more pronounced ventricular enlargement and progressive decline in ejection fraction than groups 1 and 2 (interaction time x groups p < 0.0001). CONCLUSIONS: The analysis of serial ECG can predict postinfarct left ventricular remodeling. Normalization of negative T waves during the follow-up appears more strictly related to recovery of regional dysfunction than QRS changes. Lack of resolution and late appearance of new negative T predict unfavorable remodeling with progressive deterioration of ventricular function.

Epidemiology of post-infarction risk stratification strategies in a country with a low volume of revascularization procedures. GISSI-Prognosis Investigators.

AIMS: The aims of the GISSI Prognosis Registry were to describe the diagnostic strategies initiated in acute myocardial infarction patients by a representative sample of Italian cardiological centres, and to determine which clinical or hospital characteristics were associated with the initiation of invasive diagnostic or therapeutic procedures. METHODS AND RESULTS: Baseline characteristics, major in-hospital events and the indication and results of invasive and non-invasive procedures were collected on 1489 acute myocardial infarction patients discharged alive from 65 Italian cardiological centres over a period of 3 months. Twenty-five percent of centres had on site catheterization laboratories while the rest did not. Statistical significance was analysed by chi-square tests for categorical variables. A two-sample Student t-test was used to compare continuous variables. The adjusted analysis was performed utilizing multiple logistic regression models. The most performed procedures were standard, non-invasive: 57.8% of the patients underwent an exercise stress test, 70.8% ambulatory ECG monitoring and 95.6% two-dimensional echocardiography. Nuclear or echocardiographic imaging tests were performed in 40% of acute myocardial infarction survivors. Overall, coronary angiography was planned in 549 patients (36.9%). Variables independently associated with the indication for coronary angiography were residual ischaemia, younger age, contraindication to exercise stress testing, level of patients' education, higher volume of non-invasive diagnostic tests, and male sex. Overall, during a 6-month follow-up period, coronary angiography, percutaneous transluminal coronary angioplasty and coronary artery bypass surgery were performed, respectively in 35%, 10% and 8% of the study population. CONCLUSIONS: The setting where cardiologists practise determines the patterns of care in acute myocardial infarction patients more than the characteristics of the patient. The absence of evidence-based guidelines on the more complex and expensive procedures favour empirical attitudes and practices. The confirmation in a prospective cohort of patients, which aims to represent the care of a whole country, suggests that more effort should be given to the implementation of controlled studies rather than periodical reformulation of guidelines not supported by hard data.

Reproducibility of wall motion score and its correlation with left ventricular ejection fraction in patients with acute myocardial infarction.

The inter- and intraobserver variability, as well as the relation to left ventricular (LV) function indexes, of LV wall motion score calculated using the 16- and 11-segment models of LV segmentation were assessed in 105 patients with acute myocardial infarction who were examined at 36 +/- 7 hours from onset of symptoms. In these patients, the use of the 16-segment model of LV segmentation portends to a significantly higher inter- and intraobserver reproducibility of segmental wall motion score than the use of the 11-segment model. In addition, wall motion score assessed with the more detailed 16-segment model of LV segmentation showed a significantly higher correlation with LV ejection fraction than the wall motion score assessed using the 11-segment model.

Comprehension of affect in context in children with pervasive developmental disorders.

Fifteen children with Pervasive Developmental Disorders (PDD) (mean age 12.7 years) were compared to mental age matched normal children on matching a context to its appropriate emotion. PDD children were slightly but significantly impaired on this task relative to a non-social task equated for difficulty. Both matching tasks were highly correlated with cognitive variables; the social matching task alone was correlated with social skill level, and neither task was correlated with ratings of social deviance. Results are discussed in terms of the demands of social cognitive tasks, the magnitude of social cognitive findings, control group selection and individual differences.