Lipid-lowering approaches to manage statin-intolerant patients.

Statins have improved the potential to prevent cardiovascular disease events and to prolong the lives of patients. Statins, among the most widely used drugs worldwide, reduce the levels of low-density lipoprotein cholesterol (LDL-C) by an average of 30-50%. However, non-adherence to statin therapy, due to statin intolerance, might be as high as 60% after 24 months of treatment and is associated with a 70% increase in the risk of cardiovascular disease events. Statin intolerance can be classified as a complete inability to tolerate any dose of a statin or a partial intolerance with the inability to tolerate the dose necessary to achieve the patient-specific therapeutic objective. Reasons for discontinuation are many, with statin-associated muscle symptoms being cited as the most frequent reason for stopping therapy and the incidence of muscle symptoms increasing with treatment intensity. Considering the causal effect of LDL-C in the atherosclerotic process, clinicians should consider that regardless of the lipid-lowering drugs patients are willing to take, any reduction in LDL-C they achieve will afford them some benefit in reducing cardiovascular risk. Besides statins, the current therapeutic armamentarium offers different strategies to reach LDL-C targets in statin-intolerant patients (i.e. a fixed combination between a lower dose of statin plus ezetimibe, bempedoic acid, or proprotein convertase subtilisin/kexin type 9 inhibition).

Accuracy of Physicians in Differentiating Type 1 and Type 2 Myocardial Infarction Based on Clinical Information.

BACKGROUND: Physicians commonly judge whether a myocardial infarction (MI) is type 1 (thrombotic) vs type 2 (supply/demand mismatch) based on clinical information. Little is known about the accuracy of physicians' clinical judgement in this regard. We aimed to determine the accuracy of physicians' judgement in the classification of type 1 vs type 2 MI in perioperative and nonoperative settings. METHODS: We performed an online survey using cases from the Optical Coherence Tomographic Imaging of Thrombus (OPTIMUS) Study, which investigated the prevalence of a culprit lesion thrombus based on intracoronary optical coherence tomography (OCT) in patients experiencing MI. Four MI cases, 2 perioperative and 2 nonoperative, were selected randomly, stratified by etiology. Physicians were provided with the patient's medical history, laboratory parameters, and electrocardiograms. Physicians did not have access to intracoronary OCT results. The primary outcome was the accuracy of physicians' judgement of MI etiology, measured as raw agreement between physicians and intracoronary OCT findings. Fleiss' kappa and Gwet's AC1 were calculated to correct for chance. RESULTS: The response rate was 57% (308 of 536). Respondents were 62% male; median age was 45 years (standard deviation ± 11); 45% had been in practice for > 15 years. Respondents' overall accuracy for MI etiology was 60% (95% confidence interval [CI] 57%-63%), including 63% (95% CI 60%-68%) for nonoperative cases, and 56% (95% CI 52%-60%) for perioperative cases. Overall chance-corrected agreement was poor (kappa = 0.05), consistent across specialties and clinical scenarios. CONCLUSIONS: Physician accuracy in determining MI etiology based on clinical information is poor. Physicians should consider results from other testing, such as invasive coronary angiography, when determining MI etiology.

CONTEXTE: Les médecins déterminent généralement s'ils sont en présence d'un infarctus du myocarde (IM) de type 1 (thrombotique) ou de type 2 (demande accrue ou apport réduit en oxygène) sur la base des renseignements cliniques. On en sait cependant très peu au sujet de la justesse du jugement clinique des médecins à cet égard. Nous avons donc cherché à déterminer si les médecins réussissent à distinguer correctement les IM de type 1 et de type 2 dans les contextes périopératoire et non opératoire. MÉTHODOLOGIE: Nous avons mené une enquête en ligne en utilisant les cas de l'étude OPTIMUS ( Op tical Coherence T omographic Im aging of Thromb us ), qui avait évalué la prévalence des lésions causant un thrombus au moyen de la tomographie par cohérence optique (TCO) endocoronaire chez les patients subissant un IM. Nous avons choisi au hasard quatre cas d'IM stratifiés en fonction de leur cause : deux cas en contexte périopératoire et deux cas en contexte non opératoire. Les médecins avaient accès aux antécédents médicaux, aux résultats des analyses de laboratoire et aux électrocardiogrammes des patients, mais pas aux résultats de la TCO endocoronaire. Le principal paramètre d'évaluation était la justesse du jugement du médecin concernant la cause de l'IM, mesurée en fonction de la concordance approximative entre le jugement du médecin et les observations à la TCO endocoronaire. Les coefficients de concordance kappa de Fleiss et AC1 de Gwet ont servi à corriger pour le hasard. RÉSULTATS: Le taux de réponse était de 57 % (308 sur 536). Des participants, 62 % étaient des hommes et 45 % exerçaient depuis plus de 15 ans; l'âge médian était de 45 ans (écart-type : ± 11). La justesse globale avec laquelle les répondants ont déterminé la cause des IM était de 60 % (intervalle de confiance [IC] à 95 % : 57-63 %) : 63 % (IC à 95 % : 60-68 %) dans le cas des IM en contexte non opératoire et 56 % (IC à 95 % : 52-60 %) dans le cas des IM en contexte périopératoire. La concordance globale corrigée pour le hasard était faible (kappa = 0,05) et demeurait constante, sans égard au domaine de spécialité ou au scénario clinique. CONCLUSIONS: La justesse du jugement des médecins évaluant la cause d'un IM en fonction des renseignements cliniques est faible. Les médecins devraient envisager de recourir à des tests additionnels, y compris la coronarographie invasive, avant de déterminer la cause d'un IM.

Favourable effects of heart rate reduction with intravenous administration of ivabradine in patients with advanced heart failure.

BACKGROUND: Heart rate (HR) reduction may be useful in treatment of patients with heart failure (HF). There are no data on the haemodynamic effects of ivabradine (a selective I(f) current inhibitor) in advanced HF patients. AIMS: To assess the haemodynamic effects of ivabradine in patients with advanced HF and markedly depressed left ventricular (LV) function. METHODS AND RESULTS: Ten NYHA class III patients (50+/-12 years, LV ejection fraction 21+/-7%) underwent 24-h haemodynamic monitoring. Ivabradine 0.1 mg/kg was infused over 90', followed by 0.05-0.075 mg/kg in the subsequent 90'. Baseline HR was 93+/-8 bpm, cardiac index (CI) 2.2+/-0.6 l/min*m2; LV stroke volume 44+/-11 ml and systolic work 39+/-13 g. Ivabradine significantly reduced HR, by a maximum of 27% (to 68+/-9 bpm) at 4 h, without decreasing CI. Ivabradine increased stroke volume and LV systolic work by a maximum of 51% (to 66+/-17 ml) and 53% (to 58+/-20 g) at 4 h. No serious adverse events occurred. CONCLUSION: In patients with advanced HF and markedly depressed LV function, the acute administration of ivabradine is well tolerated, effectively reduces HR, markedly increases stroke volume and preserves cardiac output. Ivabradine appears a promising approach for the treatment of patients with moderate and advanced heart failure.

Paclitaxel coated balloons for coronary artery interventions: a comprehensive review of preclinical and clinical data.

After the "mechanical era" in interventional cardiology (represented by balloon angioplasty and bare metal stent implantation), arrived the "local dispensing" era, began with the intracoronary delivery of antithrombotic or antirestenotic drugs. However, even drug eluting stents have some pitfalls and cannot be used in all clinical subsets. In this article we will review the significant data on the paclitaxel-coated balloons for the treatment of coronary artery disease. Particularly, we will review the rationale of this new treatment strategy, the preclinical data and will focus on available clinical studies in humans. After the initial boost of the paclitaxel coated balloons with the Paccocath technology in in-stent restenotic lesions, the experimentation of newer devices in native coronary arteries raised some concerns on their efficacy and safety. We will comment on this topic trying to understand the reasons of this failure, and will discuss on possible future developments and applications for these devices for the treatment of coronary artery disease.

Drug-eluting stents perform better than bare metal stents in small coronary vessels: a meta-analysis of randomised and observational clinical studies with mid-term follow up.

BACKGROUND: We tested drug-eluting stent (DES) and bare metal stent (BMS) performance in small coronary vessels by means of meta-analysis of all available clinical studies. METHODS: The analysis included randomised controlled trials (RCT), subgroups of RCT and observational studies with a follow-up of at least six months comparing the use of DES and BMS during percutaneous interventions involving small coronary arteries (diameter<3mm). The primary endpoint was target vessel failure (TVF); the others were pooled and isolated major adverse cardiovascular events (MACE), stent thrombosis (ST), binary restenosis and late lumen loss at the longest available follow-up. The effect of treatment was evaluated in terms of odds ratios (OR) and 95% confidence intervals (95% CI) for binary variables, and mean difference (MD)± standard deviation (SD) for continuous variables. Fixed- or random-effect models were used depending on the statistical heterogeneity of studies. The analyses of major endpoints were stratified by study type, length of follow-up, and type of DES. RESULTS: We pooled 12 studies involving 3182 patients. Trial heterogeneity was a minor issue. TVF (OR: 0.35; CI: 0.24-0.51), MACE (OR: 0.36; CI: 0.29-0.45), binary restenosis (OR: 0.15; CI: 0.12-0.20) and late lumen loss (MD: -0.46; SD: -0.55 to -0.38) all significantly improved with DES treatment; ST (OR: 0.63; CI: 0.34-1.17) was not statistically different between studies. CONCLUSIONS: DES are superior to BMS in terms of their efficacy in managing small coronary arteries (diameter<3mm), and at least equivalent in terms of safety. The use of DES should be considered the treatment of choice in this setting.

High-dose erythropoietin in patients with acute myocardial infarction: a pilot, randomised, placebo-controlled study.

BACKGROUND: Mortality and morbidity after acute myocardial infarction (AMI) remain high even when myocardial reperfusion is successful. Erythropoietin (EPO) protects against experimental MI. METHODS: The aim of this single-centre study was to investigate the effects of short-term high-dose erythropoietin on peripheral blood cells (PBCs) and infarct size in 30 patients with a first uncomplicated AMI undergoing percutaneous coronary intervention (PCI) who were randomly assigned to treatment with EPO (33 × 10(3)IU before PCI, and 24 and 48 h after admission), or placebo. We considered short-term CD34+ cell mobilisation, quantitative PBC gene expression in the apoptotic, angiogenic and inflammatory pathways, and enzymatically estimated infarct size. Echocardiographic and cardiac magnetic resonance studies were performed in the acute phase and six months later. RESULTS: CD34+ cell mobilisation 72 h after admission was greater in the EPO-treated patient group (93 cells/µl [36-217] vs 22 cells/µl [6-51]; p = 0.002), who also showed higher expression of the anti-apoptotic AKT and NFkB, the pro-angiogenic VEGFR-2, and the EPO-R genes, and lower expression of the pro-apoptotic CASP3 and TP53 and pro-inflammatory IL12a genes. Moreover, they showed smaller infarct size (30% reduction in CK-MB release; p = 0.025), and a favourable pattern of left ventricular remodelling. CONCLUSIONS: Short-term high-dose EPO administration in patients with AMI treated by PCI and standard anti-platelet therapy increases the levels of circulating CD34+ cells, shifts PBC gene expression towards anti-apoptotic, pro-angiogenic and anti-inflammatory pathways, and decreases infarct size. The clinical relevance of these results needs to be confirmed in specifically tailored trials.

Baroreflex sensitivity predicts long-term cardiovascular mortality after myocardial infarction even in patients with preserved left ventricular function.

OBJECTIVES: This study sought to assess the long-term predictive power of depressed baroreflex sensitivity (BRS) among post-myocardial infarction (MI) patients with preserved left ventricular function. BACKGROUND: Risk stratification after MI is primarily performed by identifying patients with depressed left ventricular ejection fraction (LVEF) because of their greater mortality. Autonomic markers can help refining risk stratification. Depressed BRS (<3 ms/mm Hg) correlated with cardiovascular mortality in 1,284 post-MI patients during a 21-month follow-up in the multicenter ATRAMI (Autonomic Tone and Reflexes After Myocardial Infarction) study, but had no significant predictive power in patients with LVEF >35% or above age 65 years. METHODS: Two hundred forty-four consecutive post-MI patients (age 59 +/- 10 years) with LVEF >35% (average 54 +/- 8%) were enrolled. They underwent a complete assessment, including BRS 4 weeks after MI. RESULTS: During a 5-year mean follow-up, 14 (5.7%) patients died of cardiovascular causes. Multivariate analysis identified BRS (p = 0.0001), but not LVEF and age, as predictive of cardiovascular mortality. The relative risk (95% confidence interval [CI]) for depressed BRS was 11.4 (95% CI 3.3 to 39.0) for the overall population, 19.6 (95% CI 4.1 to 94.8) for patients

Increased circulating hematopoietic and endothelial progenitor cells in the early phase of acute myocardial infarction.

Endothelial progenitor cell (EPC) mobilization has been reported following tissue damage, whereas no data are available regarding the mobilization of hematopoietic progenitor cells (HPCs). We performed the phenotypic and functional analysis of circulating CD34+ progenitor cells in patients with acute myocardial infarction (AMI), assessed from admission up to 60 days, in patients with stable angina pectoris (SA), and in healthy controls (CTRLs). In patients with AMI at admission (T0), the number of circulating CD34+ cells was higher (P < .001) than in CTRLs and became comparable with CTRLs within 60 days. Both the number of CD34+ cells coexpressing CD33, CD38, or CD117 and the number of HPCs was higher (P < .02 for all) in patients with AMI at T0 than in CTRLs, as was the number of hematopoietic colonies (P < .03). Patients with AMI (T0) had a significantly increased number of CD34+ vascular endothelial growth factor receptor 2-positive (VEGFR-2+) cells (P < .002) with respect to CTRLs, including CD34(+) CD133(+)VEGFR-2+ and CD34+ CD117(+)VEGFR-2+ EPCs. The number of endothelial colonies was higher in patients with AMI (T0) than in CTRLs (P < .05). No significant difference was documented between patients with SA and CTRLs. Spontaneous mobilization of both HPCs and EPCs occurs within a few hours from the onset of AMI and is detectable until 2 months.