Prasugrel versus Clopidogrel for Acute Coronary Syndromes without Revascularization

peer reviewedBACKGROUND: The effect of intensified platelet inhibition for patients with unstable angina or myocardial infarction without ST-segment elevation who do not undergo revascularization has not been delineated. METHODS: In this double-blind, randomized trial, in a primary analysis involving 7243 patients under the age of 75 years receiving aspirin, we evaluated up to 30 months of treatment with prasugrel (10 mg daily) versus clopidogrel (75 mg daily). In a secondary analysis involving 2083 patients 75 years of age or older, we evaluated 5 mg of prasugrel versus 75 mg of clopidogrel. RESULTS: At a median follow-up of 17 months, the primary end point of death from cardiovascular causes, myocardial infarction, or stroke among patients under the age of 75 years occurred in 13.9% of the prasugrel group and 16.0% of the clopidogrel group (hazard ratio in the prasugre

Lipoprotein‐Associated Phospholipase A2 Activity Is a Marker of Risk But Not a Useful Target for Treatment in Patients With Stable Coronary Heart Disease

Background: We evaluated lipoprotein‐associated phospholipase A2 (Lp‐PLA2) activity in patients with stable coronary heart disease before and during treatment with darapladib, a selective Lp‐PLA2 inhibitor, in relation to outcomes and the effects of darapladib in the STABILITY trial. Methods and Results: Plasma Lp‐PLA2 activity was determined at baseline (n=14 500); at 1 month (n=13 709); serially (n=100) at 3, 6, and 18 months; and at the end of treatment. Adjusted Cox regression models evaluated associations between Lp‐PLA2 activity levels and outcomes. At baseline, the median Lp‐PLA2 level was 172.4 μmol/min per liter (interquartile range 143.1–204.2 μmol/min per liter). Comparing the highest and lowest Lp‐PLA2 quartile groups, the hazard ratios were 1.50 (95% CI 1.23–1.82) for the primary composite end point (cardiovascular death, myocardial infarction, or stroke), 1.95 (95% CI 1.29–2.93) for hospitalization for heart failure, 1.42 (1.07–1.89) for cardiovascular death, and 1.37 (1.03–1.81) for myocardial infarction after adjustment for baseline characteristics, standard laboratory variables, and other prognostic biomarkers. Treatment with darapladib led to a ≈65% persistent reduction in median Lp‐PLA2 activity. There were no associations between on‐treatment Lp‐PLA2 activity or changes of Lp‐PLA2 activity and outcomes, and there were no significant interactions between baseline and on‐treatment Lp‐PLA2 activity or changes in Lp‐PLA2 activity levels and the effects of darapladib on outcomes. Conclusions: Although high Lp‐PLA2 activity was associated with increased risk of cardiovascular events, pharmacological lowering of Lp‐PLA2 activity by ≈65% did not significantly reduce cardiovascular events in patients with stable coronary heart disease, regardless of the baseline level or the magnitude of change of Lp‐PLA2 activity

Effects of serelaxin in patients with acute heart failure

Background: Serelaxin is a recombinant form of human relaxin-2, a vasodilator hormone that contributes to cardiovascular and renal adaptations during pregnancy. Previous studies have suggested that treatment with serelaxin may result in relief of symptoms and in better outcomes in patients with acute heart failure. Methods: In this multicenter, double-blind, placebo-controlled, event-driven trial, we enrolled patients who were hospitalized for acute heart failure and had dyspnea, vascular congestion on chest radiography, increased plasma concentrations of natriuretic peptides, mild-to-moderate renal insufficiency, and a systolic blood pressure of at least 125 mm Hg, and we randomly assigned them within 16 hours after presentation to receive either a 48-hour intravenous infusion of serelaxin (30 μg per kilogram of body weight per day) or placebo, in addition to standard care. The two primary end points were death from cardiovascular causes at 180 days and worsening heart failure at 5 days. Results: A total of 6545 patients were included in the intention-to-treat analysis. At day 180, death from cardiovascular causes had occurred in 285 of the 3274 patients (8.7%) in the serelaxin group and in 290 of the 3271 patients (8.9%) in the placebo group (hazard ratio, 0.98; 95% confidence interval [CI], 0.83 to 1.15; P=0.77). At day 5, worsening heart failure had occurred in 227 patients (6.9%) in the serelaxin group and in 252 (7.7%) in the placebo group (hazard ratio, 0.89; 95% CI, 0.75 to 1.07; P=0.19). There were no significant differences between the groups in the incidence of death from any cause at 180 days, the incidence of death from cardiovascular causes or rehospitalization for heart failure or renal failure at 180 days, or the length of the index hospital stay. The incidence of adverse events was similar in the two groups. Conclusions: In this trial involving patients who were hospitalized for acute heart failure, an infusion of serelaxin did not result in a lower incidence of death from cardiovascular causes at 180 days or worsening heart failure at 5 days than placebo. (Funded by Novartis Pharma; RELAX-AHF-2 ClinicalTrials.gov number, NCT01870778. opens in new tab.

Effect of Systemic Hypertension With Versus Without Left Ventricular Hypertrophy on the Progression of Atrial Fibrillation (from the Euro Heart Survey).

Hypertension is a risk factor for both progression of atrial fibrillation (AF) and development of AF-related complications, that is major adverse cardiac and cerebrovascular events (MACCE). It is unknown whether left ventricular hypertrophy (LVH) as a consequence of hypertension is also a risk factor for both these end points. We aimed to assess this in low-risk AF patients, also assessing gender-related differences. We included 799 patients from the Euro Heart Survey with nonvalvular AF and a baseline echocardiogram. Patients with and without hypertension were included. End points after 1 year were occurrence of AF progression, that is paroxysmal AF becoming persistent and/or permanent AF, and MACCE. Echocardiographic LVH was present in 33% of 379 hypertensive patients. AF progression after 1 year occurred in 10.2% of 373 patients with rhythm follow-up. In hypertensive patients with LVH, AF progression occurred more frequently as compared with hypertensive patients without LVH (23.3% vs 8.8%, p = 0.011). In hypertensive AF patients, LVH was the most important multivariably adjusted determinant of AF progression on multivariable logistic regression (odds ratio 4.84, 95% confidence interval 1.70 to 13.78, p = 0.003). This effect was only seen in male patients (27.5% vs 5.8%, p = 0.002), while in female hypertensive patients, no differences were found in AF progression rates regarding the presence or absence of LVH (15.2% vs 15.0%, p = 0.999). No differences were seen in MACCE for hypertensive patients with and without LVH. In conclusion, in men with hypertension, LVH is associated with AF progression. This association seems to be absent in hypertensive women

Dalla progettazione all’utilizzo di un sistema informativo geologico al servizio del rilevamento geologico: la banca dati della Regione Lombardia e la cartografia geologica derivata

In questa Tesi è descritto il processo di creazione di un Sistema Informativo Geologico e degli strumenti informatici per la gestione dell’informazione su base geografica, o più semplicemente GIS (Geographic Information System), al servizio delle attività di rilevamento geologico, finalizzato alla raccolta dei dati ed alla loro rappresentazione cartografica nell'ambito di un Sistema Informativo Territoriale (SIT). Un SIT è definibile come l'insieme di uomini, strumenti e procedure che, nell’ambito di una organizzazione, permettono l’acquisizione e la distribuzione dei dati relativi alla conoscenza dei fenomeni e degli attori presenti su territorio; tutto questo è facilitato in gran parte dalle capacità e funzionalità dei GIS. Il Sistema Informativo Territoriale orientato alla Geologia (SIG – Sistema Informativo Geologico) della Regione Lombardia è costituito da un gruppo di lavoro composto da geologi, informatici e geologi-informatici dell’Ente regionale e della società Lombardia Servizi (Gruppo Lombardia Informatica). Ho fatto parte del team di consulenza tecnico-scientifica incaricato da Lombardia Servizi per la realizzazione del SIG regionale. I compiti del gruppo di lavoro sono: - definizione di ruoli e metodi per la costituzione del SIG; - definizione delle logiche per la creazione di strumenti finalizzati all’archiviazione del dato geologico in una banca dati geologica e loro manutenzione; Il progetto è inserito nel più ampio processo di aggiornamento della Cartografia Geologica nazionale (progetto CARG). Il SIG ha come principali obiettivi: - la pianificazione ed esecuzione del rilevamento geologico di dettaglio (scala 1:10.000) del territorio lombardo; - la costruzione di un database della geologia di superficie (ma anche del sottosuolo per le aree di pianura) interrogabile e aggiornabile ; - il supporto ai processi di analisi finalizzati alla descrizione della geologia superficiale e ricostruzione degli eventi che hanno creato il paesaggio attuale; - la rappresentazione cartografica dell’ambiente geologico a partire dal database creato. - la distribuzione dell’informazione geologica archiviata in vari formati (cartaceo e digitale); Sono qui descritte ed analizzate criticamente la filosofia di costruzione delle procedure e le soluzioni tecniche e metodologiche adottate per realizzare gli obiettivi prefissi. L’APAT (Agenzia per la Protezione dell'Ambiente e per i servizi Tecnici nazionali) ha ereditato dal Servizio Geologico il compito di rilevare, aggiornare e pubblicare la Carta Geologica d'Italia (progetto nazionale CARG) quale organo cartografico dello Stato in base alla legge 68/60. Nel 1976 era stato completato il rilevamento della Carta geologica d'Italia alla scala 1:100.000 costituita da 278 fogli a copertura del territorio nazionale; per il suo aggiornamento sono stati definiti strumenti normativi idonei a garantire l'omogeneità dei contenuti e della rappresentazione cartografica; la definizione delle norme discende dall'applicazione di linee guida, frutto dell'attività di Commissioni e Gruppi di lavoro, pubblicate nei Quaderni della serie III (ed. APAT). L’Ente Regione Lombardia, per rispondere all’impegno istituzionale di aggiornamento della Carta Geologica, all’interno del più ampio e strutturato Sistema Informativo Territoriale regionale, ha dunque creato il Sistema Informativo Geologico (SIG) regionale. Il rapido evolversi delle ricerche nel campo delle Scienze della Terra e l'importanza che riveste la cartografia geologica nella gestione del territorio, hanno spinto la Regione Lombardia a progettare un rilevamento geologico di dettaglio per dotarsi di una banca dati geologica dalla quale derivare la propria cartografia geologica (alla scala 1:10.000). Sono stati quindi definiti standard specifici rispondenti a questa esigenza di maggior dettaglio (rispetto a quanto indicato dal progetto nazionale CARG) ed è stato pianificato e in gran parte realizzato un rilevamento ex-novo finalizzato alla pubblicazione del dato alla scala del rilevamento e per la sua generalizzazione alle scale 1:25.000 e 50.000. Alla fine del processo saranno stati realizzati 14 fogli del territorio lombardo relativamente alle aree alpine e di passaggio alla pianura (Bergamo, Bormio, Breno, Clusone, Lecco, Iseo, Malonno, Ponte di Legno, Sondrio, Vimercate, Milano, Bagolino, Seregno, Voghera). In tale progetto sono anche coinvolti le Università di Milano, di Pavia e di Bolona, il Politecnico di Milano e il CNR - Centro di Studio per la Geodinamica Alpina e Quaternaria di Milano. L’attività di rilevamento geologico è di competenza dei funzionari regionali della Struttura Sistema Informativo Territoriale della Direzione Generale Territorio e Urbanistica che, coadiuvati da geologi rilevatori, realizzano tutte le fasi del lavoro, dalla raccolta del dato fino alla sua pubblicazione. L’ambiente informatico GIS sviluppato, denominato CARGeo (Cartografia Geologica), permette di inserire i dati raccolti da geologi rilevatori in un database appositamente predisposto, mediante interfacce grafiche semplificate e procedure standard di archiviazione e controllo di correttezza formale. La banca dati è costruita in modo da facilitare l’archiviazione della maggior parte dei dati che normalmente il geologo registra nella carta e nei taccuini di terreno e, allo stesso tempo, guidarlo nella raccolta organica dell’informazione geologica. Nella strutturazione del database è stata privilegiata la possibilità di inserire attributi direttamente associabili agli elementi geometrici anziché attraverso schede associate a punti di osservazione. Il geologo rilevatore interviene per correggere errori di digitalizzazione o di attribuzione con un processo ciclico, fino ad ottenere una banca dati corretta secondo gli standard predefiniti. Gli strumenti di creazione della banca dati permettono anche di: - disegnare gli schemi accessori (sezioni geologiche, schemi stratigrafici e strutturali etc.); - eseguire lo “sfoltimento” e posizionamento delle annotazioni sulla mappa (sigle di unità litologiche e parametri di inclinazione delle giaciture) secondo criteri di leggibilità della carta - creare le legende; - creare banche dati a scala inferiore (1:25.000 e 50.000); - stampare e pubblicare carte geologiche complete di schemi e legende. Il sistema contiene gli strumenti necessari alla migrazione della banca dati dalla struttura proprietaria CARG-Regione Lombardia a quella CARG-APAT secondo la struttura definita nei Quaderni della serie III Il Sistema nel corso del biennio 2006-2007 ha raggiunto la fase di consegna dei dati (derivazione e generalizzazione della banca dati CARG-APAT 1.50.000 da quella 1:10.000 CARG-Regione Lombardia) dei primi fogli completati (ISEO, MALONNO, LECCO e SONDRIO) con ritardo rispetto alla programmazione. Sono state analizzate le cause che hanno portato a questo rallentamento del flusso di lavoro, quindi apportate le necessarie modifiche al Sistema. Sono qui descritti i problemi e le soluzioni trovate per migliorare l'efficienza del sistema. Attualmente il Sistema Informativo Geologico è in una fase di ristrutturazione, che vede la migrazione verso un’architettura informatica basata sulla piattaforma ARCGis® 9.x. Attraverso il Sistema Informativo Geologico viene tentata una sintesi fra le logiche metodologiche dei due ambiti tecnico-scientifici coinvolti (Geologia e Informatica), in un ambiente dove ricercatori e tecnici lavorano sperimentando l’interazione tra le conoscenze e le metodologie conoscitive tipiche delle Scienze Geologiche e le tecnologie e processi logici delle Scienze Informatiche. Con questa Tesi è documentato tutto il percorso di costruzione della banca dati geologica attraverso e all’interno del sistema realizzato assieme gruppo di lavoro composto da geologi e tecnici informatici, cui ho partecipato, riassumendo gli oltre 9 anni di lavoro dall’ideazione del progetto CARGeo, anche in funzione del suo miglioramento

Progression From Paroxysmal to Persistent Atrial Fibrillation. Clinical Correlates and Prognosis

Objectives: We investigated clinical correlates of atrial fibrillation (AF) progression and evaluated the prognosis of patients demonstrating AF progression in a large population. Background: Progression of paroxysmal AF to more sustained forms is frequently seen. However, not all patients will progress to persistent AF. Methods: We included 1,219 patients with paroxysmal AF who participated in the Euro Heart Survey on AF and had a known rhythm status at follow-up. Patients who experienced AF progression after 1 year of follow-up were identified. Results: Progression of AF occurred in 178 (15%) patients. Multivariate analysis showed that heart failure, age, previous transient ischemic attack or stroke, chronic obstructive pulmonary disease, and hypertension were the only independent predictors of AF progression. Using the regression coefficient as a benchmark, we calculated the HATCH score. Nearly 50% of the patients with a HATCH score >5 progressed to persistent AF compared with only 6% of the patients with a HATCH score of 0. During follow-up, patients with AF progression were more often admitted to the hospital and had more major adverse cardiovascular events. Conclusions: A substantial number of patients progress to sustained AF within 1 year. The clinical outcome of these patients regarding hospital admissions and major adverse cardiovascular events was worse compared with patients demonstrating no AF progression. Factors known to cause atrial structural remodeling (age and underlying heart disease) were independent predictors of AF progression. The HATCH score may help to identify patients who are likely to progress to sustained forms of AF in the near future. \ua9 2010 American College of Cardiology Foundation

Cardiac myosin activation with omecamtiv mecarbil in systolic heart failure

Background: The selective cardiac myosin activator omecamtiv mecarbil has been shown to improve cardiac function in patients with heart failure with a reduced ejection fraction. Its effect on cardiovascular outcomes is unknown. Methods: We randomly assigned 8256 patients (inpatients and outpatients) with symptomatic chronic heart failure and an ejection fraction of 35% or less to receive omecamtiv mecarbil (using pharmacokinetic-guided doses of 25 mg, 37.5 mg, or 50 mg twice daily) or placebo, in addition to standard heart-failure therapy. The primary outcome was a composite of a first heart-failure event (hospitalization or urgent visit for heart failure) or death from cardiovascular causes. Results: During a median of 21.8 months, a primary-outcome event occurred in 1523 of 4120 patients (37.0%) in the omecamtiv mecarbil group and in 1607 of 4112 patients (39.1%) in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI], 0.86 to 0.99; P=0.03). A total of 808 patients (19.6%) and 798 patients (19.4%), respectively, died from cardiovascular causes (hazard ratio, 1.01; 95% CI, 0.92 to 1.11). There was no significant difference between groups in the change from baseline on the Kansas City Cardiomyopathy Questionnaire total symptom score. At week 24, the change from baseline for the median N-terminal pro–B-type natriuretic peptide level was 10% lower in the omecamtiv mecarbil group than in the placebo group; the median cardiac troponin I level was 4 ng per liter higher. The frequency of cardiac ischemic and ventricular arrhythmia events was similar in the two groups. Conclusions: Among patients with heart failure and a reduced ejection, those who received omecamtiv mecarbil had a lower incidence of a composite of a heart-failure event or death from cardiovascular causes than those who received placebo. (Funded by Amgen and others; GALACTIC-HF ClinicalTrials.gov number, NCT02929329. opens in new tab; EudraCT number, 2016-002299-28. opens in new tab.

Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Background: Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods: For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings: Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8-13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05-6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50-75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation: Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation