The golden hour in shock management: do a lot, do it quickly.

Cardiogenic shock can be defined as a state of inadequate organ perfusion linked primarily to cardiac pump dysfunction. The two predominant causes of this condition are acute myocardial infarction and acutely decompensated heart failure (ADHF). In recent years, a significant increase in cases of cardiogenic shock from ADHF has been described. Recent evidence has defined that the factors with the greatest impact on the prognosis in this context are the early clinical assessment, the definition of the aetiology, the timely application of pharmacological therapies, or individualized mechanical supports for the circulation. Haemodynamic monitoring can help in the phenotyping of cardiogenic shock and therefore guide therapeutic choices, especially if implemented with the aid of advanced monitoring tools such as the Swan-Ganz catheter. Finally, the presence of a dedicated shock team in the 'hub' centres is fundamental, which facilitates the choice of the best therapeutic strategy on a case-by-case basis.

Acute heart failure: differential diagnosis and treatment.

Acute heart failure is a heterogeneous clinical syndrome and is the first cause of unplanned hospitalization in people >65 years. Patients with heart failure may have different clinical presentations according to clinical history, pre-existing heart disease, and pattern of intravascular congestion. A comprehensive assessment of clinical, echocardiographic, and laboratory data should aid in clinical decision-making and treatment. In some cases, a more accurate evaluation of patient haemodynamics via a pulmonary artery catheter may be necessary to undertake and guide escalation and de-escalation of therapy, especially when clinical, echo, and laboratory data are inconclusive or in the presence of right ventricular dysfunction. Similarly, a pulmonary artery catheter may be useful in patients with cardiogenic shock undergoing mechanical circulatory support. With the subsequent de-escalation of therapy and haemodynamic stabilization, the implementation of guideline-directed medical therapy should be pursued to reduce the risk of subsequent heart failure hospitalization and death, paying particular attention to the recognition and treatment of residual congestion.

ANMCO/SIC Consensus Document: cardiology networks for outpatient heart failure care.

Changing demographics and an increasing burden of multiple chronic comorbidities in Western countries dictate refocusing of heart failure (HF) services from acute in-hospital care to better support the long inter-critical out-of- hospital phases of HF. In Italy, as well as in other countries, needs of the HF population are not adequately addressed by current HF outpatient services, as documented by differences in age, gender, comorbidities and recommended therapies between patients discharged for acute hospitalized HF and those followed-up at HF clinics. The Italian Working Group on Heart Failure has drafted a guidance document for the organisation of a national HF care network. Aims of the document are to describe tasks and requirements of the different health system points of contact for HF patients, and to define how diagnosis, management and care processes should be documented and shared among health-care professionals. The document classifies HF outpatient clinics in three groups: (i) community HF clinics, devoted to management of stable patients in strict liaison with primary care, periodic re-evaluation of emerging clinical needs and prompt treatment of impending destabilizations, (ii) hospital HF clinics, that target both new onset and chronic HF patients for diagnostic assessment, treatment planning and early post-discharge follow-up. They act as main referral for general internal medicine units and community clinics, and (iii) advanced HF clinics, directed at patients with severe disease or persistent clinical instability, candidates to advanced treatment options such as heart transplant or mechanical circulatory support. Those different types of HF clinics are integrated in a dedicated network for management of HF patients on a regional basis, according to geographic features. By sharing predefined protocols and communication systems, these HF networks integrate multi-professional providers to ensure continuity of care and patient empowerment. In conclusion, This guidance document details roles and interactions of cardiology specialists, so as to best exploit the added value of their input in the care of HF patients and is intended to promote a more efficient and effective organization of HF services.

Evolution of Cardiogenic Shock Management and Development of a Multidisciplinary Team-Based Approach: Ten Years Experience of a Single Center.

Background: The management of cardiogenic shock (CS) after ACS has evolved over time, and the development of a multidisciplinary team-based approach has been shown to improve outcomes, although mortality remains high. Methods: All consecutive patients with ACS-CS admitted at our CICU from March 2012 to July 2021 were included in this single-center retrospective study. In 2019, we established a "shock team" consisting of a cardiac intensivist, an interventional cardiologist, an anesthetist, and a cardiac surgeon. The primary outcome was in-hospital mortality. Results: We included 167 patients [males 67%; age 71 (61-80) years] with ischemic CS. The proportion of SCAI shock stages from A to E were 3.6%, 6.6%, 69.4%, 9.6%, and 10.8%, respectively, with a mean baseline serum lactate of 5.2 (3.1-8.8) mmol/L. Sixty-six percent of patients had severe LV dysfunction, and 76.1% needed ≥ 1 inotropic drug. Mechanical cardiac support (MCS) was pursued in 91.1% [65% IABP, 23% Impella CP, 4% VA-ECMO]. From March 2012 to July 2021, we observed a significative temporal trend in mortality reduction from 57% to 29% (OR = 0.90, p = 0.0015). Over time, CS management has changed, with a significant increase in Impella catheter use (p = 0.0005) and a greater use of dobutamine and levosimendan (p = 0.015 and p = 0.0001) as inotropic support. In-hospital mortality varied across SCAI shock stages, and the SCAI E profile was associated with a poor prognosis regardless of patient age (OR 28.50, p = 0.039). Conclusions: The temporal trend mortality reduction in CS patients is multifactorial, and it could be explained by the multidisciplinary care developed over the years.

Safety and Efficacy of Dapagliflozin in Patients with Heart Failure with Reduced Ejection Fraction: Multicentre Retrospective Study on Echocardiographic Parameters and Biomarkers of Heart Congestion.

Objectives: Dapagliflozin has shown efficacy in clinical trials in patients with heart failure and reduced ejection fraction (HFrEF). However, real-world data on its use and outcomes in routine clinical practice are limited. We aimed to evaluate the utilisation and safety profile of dapagliflozin in a real-world population of HFrEF patients within the Marche region. Methods: Nine cardiology departments within the Marche region retrospectively included HFrEF patients who were initiated on dapagliflozin therapy in an outpatient setting. Data on medical history, comorbidities, echocardiographic parameters, and laboratory tests were collected at baseline and after 6 months. Telephone follow-up interviews were conducted at 1 and 3 months to assess adverse events. We defined the composite endpoint score as meeting at least 50% of four objective measures of improvement among: weight loss, NYHA decrease, ≥50% Natriuretic peptides (NP) decrease, and guideline/directed medical therapy (GDMT) up titration. Results: We included 95 HFrEF patients aged 66 ± 12 years, 82% were men, 48% had ischemic heart disease, and 20% had diabetes. At six months, glomerular filtration rate declined (p = 0.03) and natriuretic peptides levels decreased, on average, by 23% (p < 0.001). Echocardiographic measurements revealed a decrease in pulmonary artery pressure (p < 0.001) and E/e' (p < 0.001). In terms of drug therapy, furosemide dosage decreased (p = 0.001), and the percentage of the target dose achieved for angiotensin receptor-neprilysin inhibitors increased (p = 0.003). By multivariable Cox regression, after adjustment for age, sex, the presence of diabetes/prediabetes, and HF duration, higher baseline Hb concentrations (HR 1.347, 95% CI 1.038-1.746, p = 0.025), and eGFR levels (HR 1.016, 95% CI 1.000-1.033, p = 0.46). Conclusions: In a real-life HFrEF population, dapagliflozin therapy is safe and well-tolerated, improves echocardiographic parameters and biomarkers of congestion, and can also facilitate the titration of drugs with a prognostic impact.

Epidemiology of cardiomyopathies: essential context knowledge for a tailored clinical work-up.

Cardiomyopathies (CMPs) are primary disorders of myocardial structure and function in the absence of coronary artery disease, hypertension, valvular disease, and congenital heart disease. Knowledge of the incidence and prevalence of CMPs may help clinicians to compare their observations in clinical practice with expected cases per person-year and to avoid under-reporting in clinical context. Currently, available estimates of prevalence and incidence of CMPs are based on clinical data, collected with a wide variability in population-source, and before the genetic testing evolved as a standard diagnostic tool. This review focuses on the epidemiology of CMPs in subjects aged between 18 and 55 years. A structured up-to-date diagnostic flow-chart for CMPs diagnosis and assessment is proposed to avoid misdiagnosis of CMPs in the young population and in subjects with unexplained cardiac disorders.

Pre- and in-hospital anticoagulation therapy in coronavirus disease 2019 patients: a propensity-matched analysis of in-hospital outcomes.

AIMS: To estimate if chronic anticoagulant (CAC) treatment is associated with morbidity and mortality outcomes of patients hospitalized for SARS-CoV-2 infection. METHODS: In this European multicentric cohort study, we included 1186 patients of whom 144 were on CAC (12.1%) with positive coronavirus disease 2019 testing between 1 February and 30 July 2020. The average treatment effect (ATE) analysis with a propensity score-matching (PSM) algorithm was used to estimate the impact of CAC on the primary outcomes defined as in-hospital death, major and minor bleeding events, cardiovascular complications (CCI), and acute kidney injury (AKI). We also investigated if different dosages of in-hospital heparin were associated with in-hospital survival. RESULTS: In unadjusted populations, primary outcomes were significantly higher among CAC patients compared with non-CAC patients: all-cause death (35% vs. 18% P < 0.001), major and minor bleeding (14% vs. 8% P = 0.026; 25% vs. 17% P = 0.014), CCI (27% vs. 14% P < 0.001), and AKI (42% vs. 19% P < 0.001). In ATE analysis with PSM, there was no significant association between CAC and primary outcomes except for an increased incidence of AKI (ATE +10.2%, 95% confidence interval 0.3-20.1%, P = 0.044). Conversely, in-hospital heparin, regardless of dose, was associated with a significantly higher survival compared with no anticoagulation. CONCLUSIONS: The use of CAC was not associated with the primary outcomes except for the increase in AKI. However, in the adjusted survival analysis, any dose of in-hospital anticoagulation was associated with significantly higher survival compared with no anticoagulation.

Would You Prescribe Mobile Health Apps for Heart Failure Self-care? An Integrated Review of Commercially Available Mobile Technology for Heart Failure Patients.

Treatment of chronic diseases, such as heart failure, requires complex protocols based on early diagnosis; self-monitoring of symptoms, vital signs and physical activity; regular medication intake; and education of patients and caregivers about relevant aspects of the disease. Smartphones and mobile health applications could be very helpful in improving the efficacy of such protocols, but several barriers make it difficult to fully exploit their technological potential and produce clear clinical evidence of their effectiveness. App suppliers do not help users distinguish between useless/dangerous apps and valid solutions. The latter are few and often characterised by rapid obsolescence, lack of interactivity and lack of authoritative information. Systematic reviews can help physicians and researchers find and assess the 'best candidate solutions' in a repeatable manner and pave the way for well-grounded and fruitful discussion on their clinical effectiveness. To this purpose, the authors assess 10 apps for heart failure self-care using the Intercontinental Marketing Statistics score and other criteria, discuss the clinical effectiveness of existing solutions and identify barriers to their use in practice and drivers for change.

[ANMCO/FADOI/SIAARTI/SIC/SIMG/SIMI/SIMEU consensus document: The clinical care pathway of acute heart failure patients from symptom onset to discharge from the emergency department]. / Documento di consenso ANMCO/FADOI/SIAARTI/SIC/SIMG/SIMI/SIMEU: Il percorso clinico-diagnostico e terapeutico del paziente con scompenso cardiaco acuto dal domicilio alla dimissione dal Pronto Soccorso/ Dipartimento di Emergenza-Accettazione.

Acute heart failure (AHF) represents a relevant burden for emergency departments worldwide. AHF patients have markedly worse long-term outcomes than patients with other acute cardiac diseases (e.g. acute coronary syndromes); mortality or readmissions rates at 3 months approximate 33%, whereas 1-year mortality from index discharge ranges from 25% to 50%.The multiplicity of healthcare professionals acting across the care pathway of AHF patients represents a critical factor, which generates the need for integrating the different expertise and competence of general practitioners, emergency physicians, cardiologists, internists, and intensive care physicians to focus on care goals able to improve clinical outcomes.This consensus document results from the cooperation of the scientific societies representing the different healthcare professionals involved in the care of AHF patients and describes shared strategies and pathways aimed at ensuring both high quality care and better outcomes. The document describes the patient journey from symptom onset to the clinical suspicion of AHF and home management or referral to emergency care and transportation to the hospital, through the clinical diagnostic pathway in the emergency department, acute treatment, risk stratification and discharge from the emergency department to ordinary wards or home. The document analyzes the potential role of a cardiology fast-track and Observation Units and the transition to outpatient care by general practitioners and specialist heart failure clinics.The increasing care burden and complex problems generated by AHF are unlikely to be solved without an integrated multidisciplinary approach. Efficient networking among emergency departments, intensive care units, ordinary wards and primary care settings is crucial to achieve better outcomes. Thanks to the joint effort of qualified scientific societies, this document aims to achieve this goal through an integrated, shared and applicable pathway that will contribute to a homogeneous care management of AHF patients across the country.

A human fatty acid amide hydrolase (FAAH) functional gene variant is associated with lower blood pressure in young males.

BACKGROUND: Fatty acid amide hydrolase (FAAH) inhibitors, preventing endocannabinoid (EC) degradation, reduce blood pressure (BP) and heart rate in young male (YM) hypertensive rodents. The functional human FAAH 129T gene variant results in reduced protein level and enzymatic activity but its relationship with BP is unknown. This study investigates the relationship among FAAH P129T alleles and cardiovascular features in YMs at baseline and after 9-year follow-up, and in older male obese hypertensive (OH) patients, in whom the EC system (ECS) is overactive. METHODS: Genotype analysis was performed in 215 Caucasian male students (24 (0.2) years old) and in 185 older OH patients (50 (0.2) years old). YMs were also followed up for 9 years. Clinical and anthropometric variables, BP, cardiac and carotid artery echographic measurements were evaluated. RESULTS: YMs with the FAAH 129T allele had lower systolic (P = 0.042) and mean BP (P = 0.022), and a trend toward lower diastolic BP (P = 0.06). Such significant association was maintained at follow-up. In contrast, the same allele was not associated with BP in older OH. No association was found with other cardiac and vascular variables. CONCLUSION: An FAAH defective gene variant results in lower BP in YMs, similar to the findings in young rodents. This effect is lost in older OH patients. Because cannabinoid CB1 receptor blockade is associated with BP reduction in OH patients, EC effects and the use of ECS-interfering drugs is likely to be age and clinical-condition dependent.

Standardization of Impella®-assisted patient management.

The presence of high-risk features on candidates to percutaneous revascularization is increasingly leading to Impella®-assisted procedures (IAPs). While IAPs are safe and effective procedures, they still require managing a degree of complexity. Clinicians often rely on their ability to recall every step of operative procedures. However, during stressful situations, levels of cognitive function are compromised leading to planning and execution failures and decreased safety. Many high-risk activities such as aviation, aerospace industry, and nuclear plants have been using protocols, standardized procedures and checklists for many years. The purpose of the present article is to make a proposal for the standardization of ordinary medical activities required outside the Cath Lab for the management of patients before and after IAPs.

[Primary cardiac lymphoma in an immunocompetent young adult: outcome with chemotherapy]. / Linfoma primitivo cardiaco in un giovane adulto immunocompetente: outcome positivo a medio termine con trattamento chemioterapico.

Primitive cardiac lymphoma (PCL) is a rare disease accounting for only 1-2% of primary cardiac tumors. Diffuse large B cell lymphoma is the most common type and shows a rapid progression with poor prognosis. The clinical presentation of PCL is nonspecific, and echocardiographic study is essential to the initial work-up. Magnetic resonance imaging and computed tomography scan are the methods of choice for the assessment of tumor extension. The definitive diagnosis is histopathology examination. Chemotherapy and radiotherapy represent the best treatment and should be started promptly after PCL diagnosis. We here report a case of PCL in a 59-year-old man complicated by pulmonary microembolism, atrial fibrillation and signs of right outflow tract obstruction.

Safety and efficacy of non-continuous echocardiography-guided pericardiocentesis: a single-center study of 478 patients.

BACKGROUND: There are limited contemporary data on the safety and efficacy of echocardiography-guided pericardiocentesis in Italy. The aim of the study was to evaluate safety and efficacy of pericardiocentesis, performed with non-continuous echocardiography monitoring. All the procedures performed at Department of Cardiovascular Disease, Ospedali Riuniti Ancona, from January 2001 to June 2013, were retrospectively analyzed to determine risks connected to the procedure and its success rate. Epidemiological data, procedure indications and etiology of the effusions were also recorded. METHODS: In the study period, 478 pericardiocentesis were performed for cardiac tamponade (N.=161), to remove large amount of fluid (N.=215) or for diagnostic purposes (N.=102). Echocardiographic evaluation, performed just before the procedure, was used to define the site of entry, to measure the distance from the skin to the fluid, and to establish how to direct the needle. RESULTS: We observed an extremely low rate of complications (<1%), without any death. The procedure was fully successful in 98% of cases and achieved only partial fluid removal in the remained 10 patients. The etiology of the effusion was malignancy or post cardiothoracic surgery in almost 60% of cases. Over the years there was an increase of pericardiocentesis performed after a cardiothoracic surgery (P=0.002); There was a significant reduction of the average amount of drained fluid in the years 2010-2013 vs. the period 2001-2009. CONCLUSIONS: Echocardiography-guided pericardiocentesis is an effective and safe procedure, with a low rate of complications.

[Cardiogenic shock: from early diagnosis to multiparameter monitoring]. / Shock cardiogeno: dalla diagnosi precoce al monitoraggio multiparametrico.

Cardiogenic shock (CS) is a life-threatening condition that occurs in response to reduced cardiac output, in the presence of adequate intravascular volume, and results in tissue hypoxia. CS can occur as a result of several etiologies but the most common is acute myocardial infarction. Despite the introduction of emergency revascularization for CS complicating acute myocardial infarction, mortality still remains exceptionally high, particularly in patients with refractory CS. The diagnosis of CS is sometimes challenging and it is based on clinical, hemodynamic, and biochemical signs. A multidisciplinary technical platform as well as specialized and experienced medical teams are crucial to treat this group of patients.We briefly summarize the main aspects of diagnosis, etiology and pathophysiology with a particular focus on macro- and microhemodynamic parameters that are essential for the diagnosis and treatment of this patient population.

[Cardiogenic shock: from pharmacological treatment to mechanical circulatory support]. / Shock cardiogeno: dal trattamento farmacologico all'assistenza meccanica al circolo.

Cardiogenic shock (CS) is a state of critical end-organ hypoperfusion due to reduced cardiac output, despite adequate filling status. The development of multiorgan dysfunction is believed to be the major contributor to the high early mortality. Little evidence exists as to which vasopressor or inotrope should best be used for early treatment; however, customized pharmacological therapy, tailored on hemodynamic monitoring, is essential to achieve normal peripheral perfusion. Moreover, an increasing number of mechanical circulatory support devices are available for hemodynamic support in patients with CS but, at present, data derived from randomized clinical trials on the effectiveness, safety, differential indications for mechanical support devices, and optimal implant timing are limited.The aim of this review is to offer an overview of the pharmacological and device options, providing a practical approach to the treatment of patients with CS.

[Cardiogenic shock is a rare disease: the dedicated network]. / Lo shock cardiogeno è una malattia rara che necessita di una rete dedicata.

Cardiogenic shock (CS) is a rare disease that needs a rapid and multiparameter diagnosis and a timely, aggressive and multidisciplinary goal-oriented treatment. Recently published epidemiological studies and registries underline how SC represents an infrequent clinical entity still burdened by high mortality rates, substantially unchanged over the years. Currently, only few patients with CS are treated with circulatory assistance in dedicated centers. Some consensus documents and expert recommendations emphasize the importance of early diagnosis of CS, immediate pharmacological support, and treatment of precipitating causes, and stress the need for hospitalization in high-volume intensive care centers. The aim of this review is to show the instructions for the creation of a SC network, emphasizing the necessary elements, in agreement with available resources and existing health regulations for giving the same care opportunities to all the patients.

[Noninvasive ventilation and sedation: evidence and practical tools for its utilization]. / Ventilazione non invasiva e sedazione: evidenze a supporto e consigli pratici.

Noninvasive ventilation (NIV) has gained increased acceptance inside the critical area, since it has been shown to be effective in reducing or avoiding the need for oro-tracheal intubation. NIV efficacy is dependent on the selection of the appropriate patients and on their compliance to therapy. Actually, full collaboration is not easily reached especially in agitated patients.Sedation during NIV is useful to reduce the rate of treatment failure, but robust data to guide the development of best practice are limited and sometimes local customs appear to exert a strong influence on patterns of care. Different sedative drugs are ready for use but none of currently available agents fulfill the criteria for the ideal drug. Knowledge of the pharmacological and hemodynamic characteristics of every single sedative agent is crucial to choose the right drug for every clinical scenario. Close monitoring is mandatory to avoid adverse effects. The aim of this article is to review the currently available literature, to recognize the contraindications for sedation use and to provide practical guidance.

Heart rate modulation in stable coronary artery disease without clinical heart failure: What we have already learned from SIGNIFY?

An elevated heart rate is a marker of cardiovascular risk in patients with stable coronary artery disease. Ivabradine selectively inhibits the "f" current in the sinus node and reduces heart rate without any modifications of blood pressure, myocardial contractility and arteriolar resistance. However the addition of ivabradine to standard therapy to reduce heart rate did not improve outcomes in the recent SIGNIFY trial. Moreover, a significant interaction between the effect of ivabradine among subgroups with and without angina was detected, with a worse outcome in patients in CCS class >II at baseline. The explanation for this surprising finding despite a significant reduction in angina and myocardial revascularization procedures is uncertain. A J-curve for heart rate was not demonstrated. We speculate a significant interference on adverse events (mainly atrial fibrillation and consequently acute coronary syndromes) and on the outcome of unfavorable interactions between ivabradine and diltiazem, verapamil and strong inhibitors of CYP3A4 (4.6% of the total population). Indeed, when these patients are excluded from subgroup analysis, the harmful effect of Ivabradine among patients with severe angina disappears. In conclusion, heart rate is a marker of risk but is not a risk factor and/or a target of therapy in patients with stable coronary artery disease and preserved ventricular systolic function. Standard doses of ivabradine are indicated for treatment of angina as an alternative or in addition to beta-blockers, but should not be administered in association with CYP3A4 inhibitors or heart rate-lowering calcium-channel blockers.

[ANMCO/SIC Consensus document: The heart failure network: organization of outpatient care]. / Documento di consenso ANMCO/SIC. La rete cardiologica per la cura del malato con scompenso cardiaco: organizzazione dell'assistenza ambulatoriale.

Changing demographics and an increasing burden of multiple chronic comorbidities in western countries dictate refocusing of heart failure (HF) services from acute in-hospital care to better support the long inter-critical out-of-hospital phases of HF. The needs of the HF population are not adequately addressed by current HF outpatient services, as documented by differences in age, gender, comorbidities and recommended therapies between patients discharged for hospitalized HF and those followed up at HF clinics.The Working Group on Heart Failure of the Italian Association of Hospital Cardiologists (ANMCO) has drafted a consensus document for the organization of a national HF care network. The aims of this document are to describe tasks and requirements of the different health system points of contact for HF patients, and to define how diagnosis, management and care processes should be documented and shared among healthcare professionals. In this document, HF clinics are classified into three groups: 1) community HF clinics, devoted to the management of stable patients in strict liaison with primary care, regular re-evaluation of emerging clinical needs and prompt treatment of impending destabilizations, 2) hospital HF clinics, that target both new-onset and chronic HF patients for diagnostic assessment, treatment planning and early post-discharge follow-up. They act as main referral for medicine units and community clinics; 3) advanced HF clinics, directed at patients with severe disease or persistent clinical instability, candidates to advanced treatment options such as heart transplant or mechanical circulatory support. These different types of HF clinics are integrated in a dedicated network for the management of HF patients on a regional basis, according to geographic features. By sharing predefined protocols and communication systems, these HF networks integrate multiprofessional providers to ensure continuity of care. This consensus document is expected to promote a more efficient organization of HF care, in particular for elderly patients and in transition phases from acute to chronic HF, by networking outpatient cardiology offer and primary care.

[Heart rate modulation in stable ischemic heart disease: what we have learned from the SIGNIFY study?]. / La modulazione della frequenza cardiaca nella cardiopatia ischemica stabile: cosa abbiamo imparato dallo studio SIGNIFY?

Elevated heart rate is a marker of cardiovascular risk in patients with stable coronary artery disease. The addition of ivabradine to standard therapy to reduce heart rate did not improve outcomes in the recent SIGNIFY trial. Moreover, a significant interaction between the effect of ivabradine among subgroups with and without angina with a worse outcome in patients in CCS class >II at baseline was detected. The explanation for this surprising finding despite a significant reduction in angina and myocardial revascularization procedures is uncertain. A J-curve for heart rate was not demonstrated. We speculate a significant interference on adverse events (mainly atrial fibrillation and consequently acute coronary syndromes) and on the outcome of unfavorable interactions between ivabradine and diltiazem, verapamil and strong inhibitors of CYP3A4 (4.6% of the total population). Excluding this subgroup, there are no significant changes in outcomes between the two treatment groups (ivabradine and placebo). In conclusion, heart rate is a marker of risk but is not a risk factor and/or a target of therapy in patients with stable coronary artery disease and preserved ventricular systolic function. Standard doses of ivabradine are indicated for treatment of angina as an alternative or in addition to beta-blockers, but should not be administered in association with CYP3A4 inhibitors or heart rate-lowering calcium antagonists.