Ivan Milinković

Organization of heart failure management in European Society of Cardiology member countries: Survey of the Heart Failure Association of the European Society of Cardiology in collaboration with the Heart Failure National Societies/Working Groups

The aim of this document was to obtain a real‐life contemporary analysis of the demographics and heart failure (HF) statistics, as well as the organization and major activities of the Heart Failure National Societies (HFNS) in European Society of Cardiology (ESC) member countries.

Type 2 diabetes mellitus and heart failure: a position statement from the Heart Failure Association of the European Society of Cardiology

The coexistence of type 2 diabetes mellitus (T2DM) and heart failure (HF), either with reduced (HFrEF) or preserved ejection fraction (HFpEF), is frequent (30–40% of patients) and associated with a higher risk of HF hospitalization, all‐cause and cardiovascular (CV) mortality. The most important causes of HF in T2DM are coronary artery disease, arterial hypertension and a direct detrimental effect of T2DM on the myocardium. T2DM is often unrecognized in HF patients, and vice versa, which emphasizes the importance of an active search for both disorders in the clinical practice. There are no specific limitations to HF treatment in T2DM. Subanalyses of trials addressing HF treatment in the general population have shown that all HF therapies are similarly effective regardless of T2DM. Concerning T2DM treatment in HF patients, most guidelines currently recommend metformin as the first‐line choice. Sulphonylureas and insulin have been the traditional second‐ and third‐line therapies although their safety in HF is equivocal. Neither glucagon‐like preptide‐1 (GLP‐1) receptor agonists, nor dipeptidyl peptidase‐4 (DPP4) inhibitors reduce the risk for HF hospitalization. Indeed, a DPP4 inhibitor, saxagliptin, has been associated with a higher risk of HF hospitalization. Thiazolidinediones (pioglitazone and rosiglitazone) are contraindicated in patients with (or at risk of) HF. In recent trials, sodium–glucose co‐transporter‐2 (SGLT2) inhibitors, empagliflozin and canagliflozin, have both shown a significant reduction in HF hospitalization in patients with established CV disease or at risk of CV disease. Several ongoing trials should provide an insight into the effectiveness of SGLT2 inhibitors in patients with HFrEF and HFpEF in the absence of T2DM.

Diabetic cardiomyopathy: ongoing controversies in 2012

Diabetic cardiomyopathy is a controversial clinical entity that in its initial state is usually characterized by left ventricular diastolic dysfunction in patients with diabetes mellitus that cannot be explained by coronary artery disease, hypertension, or any other known cardiac disease. It was reported in up to 52–60% of well-controlled type-II diabetic subjects, but more recent studies, using standardized tissue Doppler criteria and more strict patient selection, revealed a much lower prevalence. The pathological substrate is myocardial damage, left ventricular hypertrophy, interstitial fibrosis, structural and functional changes of the small coronary vessels, metabolic disturbance, and autonomic cardiac neuropathy. Hyperglycemia causes myocardial necrosis and fibrosis, as well as the increase of myocardial free radicals and oxidants, which decrease nitric oxide levels, worsen the endothelial function, and induce myocardial inflammation. Insulin resistance with hyperinsulinemia and decreased insulin sensitivity may also contribute to the left ventricular hypertrophy. Clinical manifestations of diabetic cardiomyopathy may include dyspnea, arrhythmias, atypical chest pain, and dizziness. Currently, there is no specific treatment of diabetic cardiomyopathy that targets its pathophysiological substrate, but various therapeutic options are discussed that include improving diabetic control with both diet and drugs (metformin and thiazolidinediones), the use of ACE inhibitors, beta blockers, and calcium channel blockers. Daily physical activity and a reduction in body mass index may improve glucose homeostasis by reducing the glucose/insulin ratio and the increase of both insulin sensitivity and glucose oxidation by the skeletal and cardiac muscles.ZusammenfassungDie diabetische Kardiomyopathie stellt eine umstrittene klinische Entität dar, deren Anfangsstadium meist durch eine linksventrikuläre diastolische Dysfunktion bei Patienten mit Diabetes mellitus charakterisiert ist. Diese Funktionsstörung lässt sich nicht durch eine koronare Herzkrankheit (KHK), Bluthochdruck oder eine andere kardiale Ursache erklären. Ihr Vorkommen wurde bei 52–60% der Patienten mit einem gut eingestellten Typ-2-Diabetes angegeben, aber aktuellere Studien, in denen standardisierte Gewebedopplerkriterien verwendet wurden und eine strengere Patientenauswahl erfolgte, ergaben eine deutlich niedrigere Prävalenz. Das pathologische Substrat besteht aus degenerativen Veränderungen, einer linksventrikulären Hypertrophie und interstitiellen Fibrose, strukturellen und funktionellen Veränderungen kleiner Koronargefäße, metabolischen Veränderungen und einer autonomen kardialen Neuropathie. Die Hyperglykämie kann Myozytenuntergang, interstitielle Fibrose, die vermehrte Bildung von freien Radikalen und Oxidanzien verursachen, die die Stickoxid(NO)-Spiegel erniedrigen, die Endothelfunktion verschlechtern und eine Entzündung im Myokard begünstigen. Insulinresistenz mit Hyperinsulinämie und verminderter Insulinansprechbarkeit dürften zur Ausbildung einer Hypertrophie beitragen. – Das klinische Erscheinungsbild der diabetischen Kardiomyopathie umfasst Dyspnoe, Arrhythmien, atypische Herzschmerzen und Schwindelgefühl. Gegenwärtig gibt es keine Behandlung, die spezifisch das pathophysiologische Substrat einer diabetischen Kardiomyopathie anzugreifen vermag. Zu den gegenwärtig diskutierten therapeutischen Optionen gehören die diätetische und medikamentöse Optimierung des Diabetes durch Metformin und Thiazolidin sowie der Einsatz von ACE-Hemmern, Betablockern und Kalziumantagonisten. Tägliche körperliche Aktivität und, falls erforderlich, eine Gewichtsreduktion dürften die Glukosehomöostase durch Senkung der Glukose-Insulin-Ratio und die Erhöhung der Glukoseoxidation in Skelett- und Herzmuskel sowie der Insulinsensitivität verbessern.

Mineralocorticoid receptor antagonists, a class beyond spironolactone — Focus on the special pharmacologic properties of eplerenone

The renin-angiotensin-aldosterone system can be blocked at specific levels by using different classes of pharmacologic agents, including angiotensin-converting-enzyme inhibitors, angiotensin II receptor blockers and mineralocorticoid receptor antagonists. Broad use of the latter, such as spironolactone, has been limited by significant incidence of gynecomastia and other sex-related adverse effects. These problems can be overcome with use of eplerenone, a selective mineralocorticoid receptor antagonist. Eplerenone has been specifically developed to bind selectively to the mineralocorticoid receptors in order to minimize binding to the progesterone and androgen receptors. In the last decade, multiple scientific evidences have been accumulated showing the efficacy and safety of the drug in multiple clinical conditions, including heart failure and arterial hypertension. Eplerenone is generally well tolerated, with the most frequent adverse event being hyperkalemia, with sexual adverse events (i.e. gynecomastia) being more uncommon, due to the selectivity of eplerenone. This review focuses on the pharmacodynamic and pharmacokinetic properties of eplerenone, thus providing the scientific basis to fully understand drug-to-drug interactions, in particular, and its efficacy and tolerability, in general. Noteworthy, the activity of eplerenone in special conditions and different patient populations is summarized.

Adverse cardiovascular outcomes in atrial fibrillation: Validation of the new 2MACE risk score

BACKGROUND In addition to thromboembolism, atrial fibrillation (AF) may also predispose to major adverse cardiovascular events (MACE) attributable to coronary artery disease (CAD), including myocardial infarction (MI). The 2MACE score (2 points - Metabolic syndrome and Age≥75years, 1 point - MI/revascularization, Congestive heart failure/ejection-fraction <40%, and thrombo-Embolism) was recently proposed to help identify AF patients at risk of MACE. We assessed the predictive validity of the 2MACE score for MACE occurrence in AF patients free of CAD at baseline. METHODS Non-valvular AF patients (n=794) without CAD (mean-age, 62.5±12.1years, metabolic syndrome, 34.0%; heart failure/ejection-fraction <40%, 25.7%; thromboembolism, 9.7%) were prospectively followed for 5years, or until MACE (composite of non-fatal/fatal MI, revascularization and cardiovascular death). At inclusion, CAD was excluded by medical history, exercise-stress testing and/or coronary angiography. Also, the 2MACE score was determined. RESULTS At follow-up, 112 patients experienced MACE (2.8%/year). The 2MACE score demonstrated adequate discrimination (C-statistic, 0.699; 95% confidence interval [CI], 0.648-0.750; P<0.001) and calibration (Hosmer-Lemeshow P=0.79) for MACE. The score was significantly associated with MACE, with the adjusted Hazard Ratio (aHR) of 1.56 (95%CI, 1.35-1.73; P<0.001). As for individual outcomes, the score predicted MI (n=46; aHR, 1.49; 95%CI 1.23-1.80), revascularization (n=32; aHR, 1.41; 95%CI, 1.11-1.80) and cardiovascular death (n=34; aHR, 1.43; 95%CI, 1.14-1.81), all P<0.001. CONCLUSIONS The 2MACE score successfully predicts future MACE, including incident MI, coronary revascularization and cardiovascular death in AF patients free of CAD at baseline. It may have a role in risk-stratification and primary prevention of MACE in AF patients.

The role of glycemia in acute heart failure patients

Abstract Acute heart failure (AHF) is one of the most important cardiovascular syndromes associated with high cardiovascular morbidity, and is the major cause of admission in emergency departments worldwide. The clinical complexity of AHF has significantly increased, mostly due to the comorbidities: diabetes, arterial hypertension, dyslipidemia, obesity, peripheral vascular disease, renal insufficiency and anemia. Numerous clinical trials have demonstrated a frequent association of AHF and diabetes. Since AHF is a very heterogeneous condition, it is important to identify clinical and laboratory parameters useful for risk stratification of these populations. Hyperglycemia may be one of the most convenient, since it is widely measured, easily interpreted, and inexpensive. Acute coronary syndrome (ACS), arrhythmias and poor compliance to chronic medications are considered to be the most frequent precipitating factors of AHF in diabetics. Several studies identified diabetes as the most prominent independent predictor of morbidity and mortality in both acute and chronic heart failure (HF) patients. The following parameters were identified as the independent predictors of in-hospital mortality in patients with AHF and diabetes: older age, systolic blood pressure <100 mmHg, ACS, non-compliance, history of hypertension, left ventricular ejection fraction (LVEF) <50%, serum creatinine >1.5 mg/dL, marked elevation of natriuretic peptides, hyponatremia, treatment at admission without ACE inhibitors/ARBs/β-blockers, and no percutaneous coronary intervention (PCI) as a treatment modality. The most frequent cause of AHF is ACS, both with ST segment elevation (STEMI) or without (NSTEMI). Hyperglycemia is very common in these patients and although frequently unrecognized and untreated, has a large in-hospital and mortality significance.

Heart failure with improved ejection fraction: Is a newcomer in the family important?:

In the 2013 American College of Cardiology/American Heart Association guidelines, an emerging heart failure (HF) phenotype was introduced, named heart failure with preserved ejection fraction (HFpEF) improved. It is defined as improvement in left ventricular ejection fraction (LVEF) to> 40% in patients with previous heart failure with reduced ejection fraction (HFrEF). Later, similar entities with different names were described: heart failure with improved ejection fraction (HFIEF), heart failure with recovered ejection fraction (HFrecEF), and better HFEF. Although not consistent in cut-off LVEF values/degree of improvement, these groups of patients are clearly distinct from those with persistent HFrEF or HFpEF. In the current issue of the European Journal of Preventive Cardiology, Jorgensen and colleagues discuss the new HF entity, HFIEF. They should be acknowledged both for getting into the focus this important clinical topic and for using meta-analysis to get meaningful insights regarding a large number of the patients. They carried out a systematic review and meta-analysis on 24 observational studies in a group of 2663 patients with HFIEF (defined as 5% LVEF improvement) compared with 8355 patients with persistently reduced ejection fraction (HFpREF). LVEF was assessed at baseline and reassessed after 19 19 months, with follow-up of 39 12 months. The primary endpoints were all-cause mortality and appropriate implantable cardioverter defibrillator (ICD) discharge. Among HFIEF patients, LVEF improved by an average 16.3%. Meta-analysis covered studies with heterogeneous aetiology of HF, various therapeutic approaches and different baseline LVEF cut-off values. The results revealed a significantly lower risk of all-cause mortality in 25% of patients with HFIEF and a significantly lower risk of appropriate Implantable cardioverter defibrillator (ICD) activations, in comparison to HFpREF patients. The largest therapeutic benefit was demonstrated in patients who had cardiac resynchronization therapy-defibrillator (CRT-D) implantation. The variables associated with higher probability of HFIEF included: female sex, higher systolic blood pressure, absence of diabetes, nonischaemic origin for HF and lower left ventricular end-diastolic diameter LVEDD). Every meta-analysis has inherent methodological drawbacks, which may obscure the validity of the results and this study is not the exception to this rule. The meta-analysis of Jorgensen and colleagues was based on observational studies with some limitations such as: selection bias, different and unreported baseline variables, length of follow-up period and various definitions of LVEF improvement. The studies used in this meta-analysis came from a period with a long time span and, therefore, optimal HF medical therapy used was different or unreported. A major limitation was also a lead time bias, since HFIEF patients had to survive long enough for a second LVEF assessment. Furthermore, events occurring between the first and second LVEF measurements were not analysed, since patients later to be classified as HFpREF were more likely to die before reaching the second LVEF measurement. To make matters more complex, the precise time frame needed for ventricular remodelling to occur (spontaneously or under treatment) is unknown. The results obtained represent the patients who had both baseline and final data analysed (‘completers’), and it will be impossible to predict the effect of data from patients without full assessment (‘non-completers’) on the overall results. Furthermore, the methods for measurement of LVEF evolved significantly, from less precise to sophisticated methods, which may have altered the results. Finally, differentiation between long-term functional or structural improvement of LVEF, would need a ‘withdrawal’ study (LVEF reassessed after withdrawal of drug or device), which is obviously ethically challenging.

In the search for an ideal registry: Does the cloud have a silver lining?:

In recent decades, as a result of improvement in prevention and treatment, the incidence of acute myocardial infarction (AMI) decreased by about one-third, while the incidence of heart failure (HF) did not follow that trend. Guidelines provide clear therapeutic recommendations for both management of AMI and treatment of subsequent HF. Lifestyle changes and evidence-based medications, such as antiplatelets, statins, beta-blockers and angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) improve survival. In addition, if HF occurs, mineralocorticoid receptor antagonists (MRAs) and the implantable cardioverter-defibrillator (ICD) are indicated. Therefore, the assessment of left ventricular ejection fraction (LVEF) after AMI is obligatory, since patients with HF require more intense treatment and careful follow-up strategy. The study of Gasior et al., in the current issue of European Journal of Preventive Cardiology analysed combined data from the Polish registry of Acute Coronary Syndromes (PL-ACS) and national Acute Myocardial Infarction in Poland (AMI-PL), consisting of a total of 28,080 patients discharged after AMI (2009–2013), with LVEF 40%. The temporal trend in increase of patients age, number of co-morbidities, with fewer STEMI and cardiogenic shocks was demonstrated. Also, more percutaneous coronary interventions (PCIs) and fewer coronary artery by-pass graft (CABG) procedures were performed during index hospitalization. At discharge, a significant decrease in patients with low LVEF was revealed, while the percentage of guideline-recommended treatment (GRT) was high and stable. During follow-up, a temporal trend revealed higher frequency of PCIs, decrease in scheduled CABGs, and more ICDs and cardiac resynchronization therapy device (CRT) implantations. Most of the patients were treated by general practitioners, with the number of visits decreasing over time. At the 12-month follow-up, fewer recurrent AMIs were observed, but HF rehospitalizations and all-cause mortality did not decrease. After adjustment for sex and age, all-cause mortality and composite outcomes (death, myocardial infarction (MI), stroke or HF rehospitalization) revealed a significant decreasing trend. This publication presents a comprehensive analysis of temporal trends of a large number of patients treated for AMI at the national level. However, in this type of analysis, several limitations can be recognised such as inferior level of evidence, coding inconsistencies, hidden confoundings and difficulties in verifying information. Also, the study provides only association, but not causation, and suffers from the biases of misclassification, intention-to-treat and adherence-over-time. In addition, information about LVEF before AMI, essential if the correct assessment of the contractility after AMI is required, is lacking. It should be noted that AMI-PL is a national registry, while PL-ACS is an observational database that does not cover all of the hospitals in Poland. Since the study represents a single-country analysis, the results are not applicable for other countries, racial and ethnic groups. Furthermore, even in the same country, if an individual patient has treatment in several hospitals, the quality of diagnosis and management may be different, influencing the outcome. It is difficult to compare results of publication by Gasior et al. with other publications covering a similar topic, since the periods of follow-up are in a different time-frame, ranging from mid-1990s to 2015. Therefore, the demographics, co-morbidities, availability of drugs, procedures and devices differ significantly. Also, the use of guideline-based physician education has risen, starting in the first decade of the 21st century which has improved cardiovascular patient survival. Two peaks in increase of evidence-based treatment

A step forward in resolving an old issue: treatment of heart failure with preserved ejection fraction and renal dysfunction?

Heart failure with preserved ejection fraction (HFpEF) presently accounts for nearly 50% of all heart failure (HF) patients, and its prevalence is increasing. In comparison to heart failure with reduced ejection fraction (HFrEF), patients with HFpEF have a similar or higher risk of cardiovascular or all-cause mortality and non-cardiovascular hospitalization, which correlates with a considerable burden of comorbidities. Chronic kidney disease (CKD), defined as an estimated glomerular filtration rate (eGFR) of less than 60mL/min/1.73 m, affects up to 60% of HFpEF patients. Several studies have suggested that the presence of CKD outlines a distinct HFpEF phenotype characterised by a high risk of adverse outcomes. The excessive activity of the renin–angiotensin– aldosterone system (RAAS) plays a key role in the pathogenesis of both HF and renal dysfunction. Although evidence suggests that RAAS inhibition could prevent adverse events in CKD, treatment with RAAS inhibitors had a neutral effect on survival outcome in randomised clinical trials (RCTs) of unselected HFpEF patients. However, there is a possibility that RAAS inhibition could be beneficial for HFpEF patients with CKD, by targeting mechanisms that underlie the development of both HF and renal dysfunction. Currently, there is a paucity of data on the efficacy of RAAS inhibitors for the prevention of adverse outcomes in patients with HFpEF and CKD. This important matter was explored in a study presented in this issue of the European Journal of Preventive Cardiology by Tsujimoto and Kajio. This was an observational, retrospective analysis of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial data, including patients with HFpEF and mild-to-moderate CKD (i.e. eGFR <60mL/min/1.73 m or urine albumin-to-creatinine ratio 30mg/g). Patients with a eGFR of 30mL/min/ 1.73 m or less were excluded. The analysis included 239 patients receiving RAAS inhibitors (i.e. angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor type1 blockers (ARBs) or both in 68.6%, 28.9% and 2.5% of patients, respectively) and 1227 patients who did not receive RAAS inhibitors. The two groups were compared with respect to the primary composite outcome of all-cause death, non-fatal myocardial infarction or stroke, or hospitalisation for HF. All-cause mortality, adverse cardiovascular events (i.e. cardiovascular mortality, non-fatal myocardial infarction/stroke) and hospitalisation for HF were analysed separately as secondary outcomes. The association between RAAS inhibitors and study outcomes was first analysed using multivariable regression models. Due to a significant imbalance in baseline characteristics, the authors have defined a propensity score (based on potential confounders for receiving RAAS inhibitors) that was used to match 231 pairs of patients with and without RAAS inhibitors. Survival analysis was then repeated in the propensity score-matched patients, as a sensitivity analysis. The main result was that RAAS inhibition significantly reduced the risk of the composite outcome of all-cause mortality, adverse cardiovascular events and HF hospitalisation by 25% (adjusted hazard ratio (HR) 0.75, 95% confidence interval (CI) 0.69–0.94; P1⁄4 0.01). This observation was confirmed in the propensity score-matched analysis (HR 0.67, 95% CI 0.50–0.90; P1⁄4 0.008). Improvement in primary outcome was comparable between ACE inhibitors and ARBs (adjusted HR 0.76, 95% CI 0.59–0.97; and adjusted HR 0.73, 95% CI 0.56–0.96, respectively), and there was no interaction with diabetes. The survival benefit was primarily driven by a reduction in all-cause and cardiovascular mortality by nearly 40%, while there was no significant reduction in rates of HF hospitalisation. On that basis, the authors have concluded that RAAS inhibitors can

Long-term mortality is increased in patients with undetected prediabetes and type-2 diabetes hospitalized for worsening heart failure and reduced ejection fraction

Background We assessed the prevalence of newly diagnosed prediabetes and type-2 diabetes mellitus (T2DM), and their impact on long-term mortality in patients hospitalized for worsening heart failure with reduced ejection fraction (HFrEF). Methods We included patients hospitalized with HFrEF and New York Heart Association (NYHA) functional class II–III. Baseline two-hour oral glucose tolerance test was used to classify patients as normoglycaemic or having newly diagnosed prediabetes or T2DM. Outcomes included post-discharge all-cause and cardiovascular mortality during the median follow-up of 2.1 years. Results At baseline, out of 150 patients (mean-age 57 ± 12 years; 88% male), prediabetes was diagnosed in 65 (43%) patients, and T2DM in 29 (19%) patients. These patients were older and more often with NYHA class III symptoms, but distribution of comorbidities was similar to normoglycaemic patients. Taking normoglycaemic patients as a reference, adjusted risk of all-cause mortality was significantly increased both in patients with prediabetes (hazard ratio, 2.6; 95% confidence interval (CI), 1.1–6.3; p = 0.040) and in patients with T2DM (hazard ratio, 5.3; 95% CI, 1.7–15.3; p = 0.023). Likewise, both prediabetes (hazard ratio, 2.9; 95% CI, 1.1–7.9; p = 0.041) and T2DM (hazard ratio, 9.7; 95% CI 2.9–36.7; p = 0.018) independently increased the risk of cardiovascular mortality compared with normoglycaemic individuals. There was no interaction between either prediabetes or T2DM and heart failure aetiology or gender on study outcomes (all interaction p-values > 0.05). Conclusions Newly diagnosed prediabetes and T2DM are highly prevalent in patients hospitalized for worsening HFrEF and NYHA functional class II–III. Importantly, they impose independently increased long-term risk of higher all-cause and cardiovascular mortality.