Abstract The ODYSSEY OUTCOMES trial, comprising over 47 000 patient-years of placebo-controlled observation, demonstrated important reductions in the risk of recurrent ischaemic cardiovascular events with the monoclonal antibody to proprotein convertase subtilisin/kexin type 9 alirocumab, as well as lower all-cause death. These benefits were observed in the context of substantial and persistent lowering of low-density lipoprotein cholesterol with alirocumab compared with that achieved with placebo. The safety profile of alirocumab was indistinguishable from matching placebo except for a ∼1.7% absolute increase in local injection site reactions. Further, the safety of alirocumab compared with placebo was evident in vulnerable groups identified before randomization, such as the elderly and those with diabetes mellitus, previous ischaemic stroke, or chronic kidney disease. The frequency of adverse events and laboratory-based abnormalities was generally similar to that in placebo-treated patients. Thus, alirocumab appears to be a safe and effective lipid-modifying treatment over a duration of at least 5 years.

Abstract Aims Long-term, placebo-controlled cholesterol-lowering trials have demonstrated legacy effects (clinical benefits that persist or emerge after trial end). It is unknown whether legacy effects follow a short period of very low low-density lipoprotein cholesterol (LDL-C) levels achieved with statin plus proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor. Methods and results In 18 924 patients with recent acute coronary syndrome, the ODYSSEY OUTCOMES trial compared the PCSK9 inhibitor alirocumab with placebo, each added to high-intensity or maximum-tolerated statin therapy. Patients with two consecutive LDL-C levels <0.39 mmol/L (15 mg/dL) on alirocumab had blinded placebo substitution for the remainder of the trial with continued statin treatment. In post hoc analyses, major adverse cardiovascular events (MACE) in these patients were compared to MACE in propensity score–matched patients from the placebo group with similar baseline characteristics and study medication adherence. In the alirocumab group, 730 patients had blinded placebo substitution at a median of 8.3 months from randomization, after a median of 6.0 months with LDL-C <0.39 mmol/L. They were matched to 1460 placebo patients. Both groups had lower baseline LDL-C and lipoprotein(a) and better study medication adherence than those of the overall cohort. Over a median follow-up of 2.8 years, MACE occurred in 47 (6.4%) alirocumab patients with limited-duration, very low achieved LDL-C vs. 122 (8.4%) matched placebo patients (treatment hazard ratio 0.72; 95% confidence interval 0.51, 0.997; P = 0.047). Conclusion A short period of LDL-C levels <0.39 mmol/L achieved with statin and alirocumab, followed by statin monotherapy, was associated with a lower risk of MACE than statin monotherapy throughout the observation period. Clinical benefit persisted for several years. Trial registration ClinicalTrials.gov NCT01663402

Background: The prevalence of chronic heart failure (CHF) is up to 1-2% of the adult population in developed countries, rising to >10% after the age of 70. Heart failure with reduced ejection fraction (HFrEF) remains a prevalent clinical syndrome associated with significant morbidity and mortality. Objective: The aim of this study was to evaluate the clinical efficacy of sacubitril/valsartan in a group of ambulatory patients with heart failure with reduced ejection fraction (HFrEF) and its effect on the hemodynamic, metabolic, renal, and cardiac remodeling parameters. Methods: From January 2018 to May 2021, 106 patients with chronic heart failure with reduced ejection fraction (HFrEF) were prospectively enrolled. Patients treated with sacubitril/valsartan (ARNI) were compared with an arm of the same size (n = 53) and matched by age and gender who were taking a standard optimal medical therapy for HFrEF. Results: The 106 patients completing the study were characterized by age: 69.5 ± 8.0, 64% are male gender. The mean duration of follow-up in the 2 treatment arms was 12 months. In the ARNI arm, we evaluate the hemodynamic, metabolic, renal, and cardiac remodeling parameters upon the initial evaluation and at the end of the follow-up after 12 months treatment with sacubitril/valsartan. The LVEF values increased significantly (p < 0.001) in the ARNI arm compared to the OMT arm, 42.1 % vs. 30.1%. The LVMI decreased from a baseline value of 153.1 g/m2 to 147.8 g/m2 with significant improvement only in the arm treated with ARNI. The eGFR values increased significantly (p < 0.001) in the ARNI arm compared to the OMT arm 70.1 vs. 64.9 mL/min/1.73 m2. Initiation and titration of sacubitril-valsartan was associated with a reduction in NT-pro-BNP concentration, the values of NT-pro-BNP improved significantly only in the arm treated with ARNI 3107.1 vs. 5678.2. Mortality and re-hospitalization due to HF were lower in the arm treated with ARNI compared to the control (20.3 vs. 32.4 % and 25.3 vs. 46.6 %, respectively; p < 0.05). Conclusion: Sacubitril/valsartan is an important advancement in the treatment of HFrEF. Sacubitril/valsartan induce “hemodynamic recovery”. This study provides real-world data demonstrating incremental improvements in functional and echocardiographic outcomes in optimally treated patients with HFrEF switched to sacubitril/valsartan in ambulatory setting.

Objective: The aim of this study was to evaluate corelation of serum level of NGAL to severity of hypertension and diastolic disfunction in patients with ST- segment elevation myocardial infarction treated with fibrinolytic therapy. Design and method: We included 54 consecutive ST-segment elevation myocardial infarction patients treated with fibrinolytic therapy (alteplase). The median follow-up time was 6 days (interquartile range, 5 to 7 days). Blood samples were drawn immediately after admission prior to fibrinolytic administration. The endpoints were mean systolic and diastolic pressure (continuously monitored) and mean E/A ratio as a measure of diastolic function. Results: Patients with high NGAL (above 134,05 &mgr;g/l; 75th percentile) had significantly higher mean systolic and mean diastolic blood pressure compared to patients with low NGAL (under 134,05 &mgr;g/l; 75th percentile), p = 0,001 and p = 0,003; respectively. Patients with high NGAL (above 134,05 &mgr;g/l; 75th percentile) had significantly lower E/A ratio compared to patients with low NGAL (under 134,05 &mgr;g/l; 75th percentile), p = 0,004. Conclusions: High NGAL significantly corelates with severity of hypertension and diastolic dysfunction in patients with acute STEMI.

Objective: The aim of this study was to evaluate corelation of serum level of NGAL to severity of hypertension and diastolic disfunction in patients with ST- segment elevation myocardial infarction treated with fibrinolytic therapy. Design and method: We included 54 consecutive ST-segment elevation myocardial infarction patients treated with fibrinolytic therapy (alteplase). The median follow-up time was 6 days (interquartile range, 5 to 7 days). Blood samples were drawn immediately after admission prior to fibrinolytic administration. The endpoints were mean systolic and diastolic pressure (continuously monitored) and mean E/A ratio as a measure of diastolic function. Results: Patients with high NGAL (above 134,05 &mgr;g/l; 75th percentile) had significantly higher mean systolic and mean diastolic blood pressure compared to patients with low NGAL (under 134,05 &mgr;g/l; 75th percentile), p = 0,001 and p = 0,003; respectively. Patients with high NGAL (above 134,05 &mgr;g/l; 75th percentile) had significantly lower E/A ratio compared to patients with low NGAL (under 134,05 &mgr;g/l; 75th percentile), p = 0,004. Conclusions: High NGAL significantly corelates with severity of hypertension and diastolic dysfunction in patients with acute STEMI.

Introduction: Atrial fibrillation (AF) is the most common form of cardiac arrhythmia in clinical practice and its prevalence increases with age. Patients who develop AF also have cardiovascular risk factors, structural heart disease, and comorbidities, all of which can increase mortality. AF causes a significant economic burden with the increasing trend in AF prevalence and hospitalizations. Research Objectives: The objective of our study is to evaluate the impact of the most common known risk factors on the incidence of atrial fibrillation as an important precursor of cardiac and cerebrovascular morbidity and mortality among our patients in Bosnia and Herzegovina during median follow up period (September 2006 - September 2016). The other objective is to estimate the CHA2DS2-VASc score among our patients based on clinical parameters. Patients and methods: This study includes 2352 ambulant and hospitalized patients with atrial fibrillation. All patients underwent clinical evaluation which includes thorough assessment for potential risk factors and concomitant conditions in order to determine which of them represent the most common among examinees with atrial fibrillation. Results: The results show that male gender has slightly more incidence of AF. Obesity and overweight with BMI ≥ 27, cigarettes smoking and sedentary life style are almost present in patients with AF. Arterial hypertension, coronary artery disease, diabetes mellitus, chronic obstructive pulmonary disease, chronic renal dysfunction, structural and valvular heart disease and peripheral vascular disease are the most common comorbidities among our patients. The mean CHA2DS2-VASc score was 3.2±1.4 and the mean HAS-BLED score was 2.1±1.2. Conclusion: Atrial fibrillation is the most common sustained cardiac rhythm disorder. The study shows that obesity, alcohol consumption, smoking cigarettes and dyslipidemia can be considered as triggers and predisposing factors for appearance of AF. Arterial hypertension, coronary artery disease, chronic obstructive pulmonary disease, diabetes mellitus, Peripheral vascular disease and chronic kidney disease are playing important role in developing of AF.

Introduction: Atrial fibrillation represents the most common cardiac arrhythmia in clinical practice. By year 2030, 14–17 million AF patients are anticipated in the European Union. Atrial fibrillation remains one of the major causes of stroke, heart failure, sudden death all over the world. Research Objectives: The objective of our study is to determine the cardiac and cerebrovascular events (myocardial infarction, heart failure, stroke, sudden cardiac death) and their cumulative incidence during 11 years follow up period. Patients and methods: This study includes 2352 ambulant and hospitalized patients with atrial fibrillation (AF) who were enrolled during the follow up period. All patients underwent clinical evaluation in order to determine cardiac and cerebrovascular events (myocardial infarction, heart failure, stroke, sudden cardiac death) and their cumulative incidence. Results: The results of cumulative incidence for sudden cardiac death was 1.71%, for stroke 2.56%, for myocardial infarction 1.20% and for heart failure was 5.73%. In our study the age-adjusted incidence and prevalence of AF are slightly lower in women. The study shows that the risk of death is higher in females than in males with AF. Conclusion: Despite good progress in the management of patients with atrial fibrillation (AF), this arrhythmia remains one of the major causes of stroke, heart failure, sudden death. Effective treatment of patients with atrial fibrillation includes not only rate control, rhythm control, and prevention of stroke, but also management of cardiovascular risk factors and concomitant diseases.

Being a narrow therapeutic index drug, digoxin may cause harm if dosed without regular measurements of serum levels. Due to various limitations in its dosing, different challenges still exist in clinical practice. This study aimed to assess digoxin though concentrations after different regimens in adult and elderly patients, and to identify predictor variables for the ratio of given dose and digoxin trough level. This was prospective open-label study. Digoxin was administered per os as 0.125 or 0.25 mg during different continuous and interrupted dosage regimens. Study protocol allowed an additional therapy according to contemporary guidelines. Digoxin concentrations were determined using Abbott AxSYM Digoxin II assay in trough samples (1-3 per patient) after 3-4 weeks stable regimen. In total, 191 concentrations (104 patients) were analyzed. Digoxin weekly dose was in range 0.375-1.75 mg. On average, we observed slightly lower digoxin levels in HF patients. Results showed that in patients receiving digoxin with interrupted dosage regimen post- pause digoxin level was statistically significantly lower than pre-pause (p < 0.05). Based on multi- ple linear regression, the ratio of given dose and trough concentration was mainly predicted by clearance creatinine, and to lesser extent by patient's ideal body weight. Interrupted dosing schedule shows greater variability in drug levels comparing to continuous dosing, and it additionally causes difficulties in reaching and maintaining steady trough levels between doses. Hence, individualization of dosing regimen should be carefully guided based on target levels and not solely on clinical signs and symptoms.