Empagliflozin after Acute Myocardial Infarction.

BACKGROUND: Empagliflozin improves cardiovascular outcomes in patients with heart failure, patients with type 2 diabetes who are at high cardiovascular risk, and patients with chronic kidney disease. The safety and efficacy of empagliflozin in patients who have had acute myocardial infarction are unknown. METHODS: In this event-driven, double-blind, randomized, placebo-controlled trial, we assigned, in a 1:1 ratio, patients who had been hospitalized for acute myocardial infarction and were at risk for heart failure to receive empagliflozin at a dose of 10 mg daily or placebo in addition to standard care within 14 days after admission. The primary end point was a composite of hospitalization for heart failure or death from any cause as assessed in a time-to-first-event analysis. RESULTS: A total of 3260 patients were assigned to receive empagliflozin and 3262 to receive placebo. During a median follow-up of 17.9 months, a first hospitalization for heart failure or death from any cause occurred in 267 patients (8.2%) in the empagliflozin group and in 298 patients (9.1%) in the placebo group, with incidence rates of 5.9 and 6.6 events, respectively, per 100 patient-years (hazard ratio, 0.90; 95% confidence interval [CI], 0.76 to 1.06; P = 0.21). With respect to the individual components of the primary end point, a first hospitalization for heart failure occurred in 118 patients (3.6%) in the empagliflozin group and in 153 patients (4.7%) in the placebo group (hazard ratio, 0.77; 95% CI, 0.60 to 0.98), and death from any cause occurred in 169 (5.2%) and 178 (5.5%), respectively (hazard ratio, 0.96; 95% CI, 0.78 to 1.19). Adverse events were consistent with the known safety profile of empagliflozin and were similar in the two trial groups. CONCLUSIONS: Among patients at increased risk for heart failure after acute myocardial infarction, treatment with empagliflozin did not lead to a significantly lower risk of a first hospitalization for heart failure or death from any cause than placebo. (Funded by Boehringer Ingelheim and Eli Lilly; EMPACT-MI ClinicalTrials.gov number, NCT04509674.).

Left Ventricular Function, Congestion, and Effect of Empagliflozin on Heart Failure Risk After Myocardial Infarction.

BACKGROUND: Empagliflozin reduces the risk of heart failure (HF) hospitalizations but not all-cause mortality when started within 14 days of acute myocardial infarction (AMI). OBJECTIVES: This study sought to evaluate the association of left ventricular ejection fraction (LVEF), congestion, or both, with outcomes and the impact of empagliflozin in reducing HF risk post-AMI. METHODS: In the EMPACT-MI (Trial to Evaluate the Effect of Empagliflozin on Hospitalization for Heart Failure and Mortality in Patients with Acute Myocardial Infarction) trial, patients were randomized within 14 days of an AMI complicated by either newly reduced LVEF<45%, congestion, or both, to empagliflozin (10 mg daily) or placebo and were followed up for a median of 17.9 months. RESULTS: Among 6,522 patients, the mean baseline LVEF was 41 ± 9%; 2,648 patients (40.6%) presented with LVEF <45% alone, 1,483 (22.7%) presented with congestion alone, and 2,181 (33.4%) presented with both. Among patients in the placebo arm of the trial, multivariable adjusted risk for each 10-point reduction in LVEF included all-cause death or HF hospitalization (HR: 1.49; 95% CI: 1.31-1.69; P < 0.0001), first HF hospitalization (HR: 1.64; 95% CI: 1.37-1.96; P < 0.0001), and total HF hospitalizations (rate ratio [RR]: 1.89; 95% CI: 1.51-2.36; P < 0.0001). The presence of congestion was also associated with a significantly higher risk for each of these outcomes (HR: 1.52, 1.94, and RR: 2.03, respectively). Empagliflozin reduced the risk for first (HR: 0.77; 95% CI: 0.60-0.98) and total (RR: 0.67; 95% CI: 0.50-0.89) HF hospitalizations, irrespective of LVEF or congestion, or both. The safety profile of empagliflozin was consistent across baseline LVEF and irrespective of congestion status. CONCLUSIONS: In patients with AMI, the severity of left ventricular dysfunction and the presence of congestion was associated with worse outcomes. Empagliflozin reduced first and total HF hospitalizations across the range of LVEF with and without congestion. (Trial to Evaluate the Effect of Empagliflozin on Hospitalization for Heart Failure and Mortality in Patients with Acute Myocardial Infarction [EMPACT-MI]; NCT04509674).

Effect of Empagliflozin on Heart Failure Outcomes After Acute Myocardial Infarction: Insights From the EMPACT-MI Trial.

BACKGROUND: Empagliflozin reduces the risk of heart failure (HF) events in patients with type 2 diabetes at high cardiovascular risk, chronic kidney disease, or prevalent HF irrespective of ejection fraction. Whereas the EMPACT-MI trial (Effect of Empagliflozin on Hospitalization for Heart Failure and Mortality in Patients With Acute Myocardial Infarction) showed that empagliflozin does not reduce the risk of the composite of hospitalization for HF and all-cause death, the effect of empagliflozin on first and recurrent HF events after myocardial infarction is unknown. METHODS: EMPACT-MI was a double-blind, randomized, placebo-controlled, event-driven trial that randomized 6522 patients hospitalized for acute myocardial infarction at risk for HF on the basis of newly developed left ventricular ejection fraction of <45% or signs or symptoms of congestion to receive empagliflozin 10 mg daily or placebo within 14 days of admission. In prespecified secondary analyses, treatment groups were analyzed for HF outcomes. RESULTS: Over a median follow-up of 17.9 months, the risk for first HF hospitalization and total HF hospitalizations was significantly lower in the empagliflozin compared with the placebo group (118 [3.6%] versus 153 [4.7%] patients with events; hazard ratio, 0.77 [95% CI, 0.60, 0.98]; P=0.031, for first HF hospitalization; 148 versus 207 events; rate ratio, 0.67 [95% CI, 0.51, 0.89]; P=0.006, for total HF hospitalizations). Subgroup analysis showed consistency of empagliflozin benefit across clinically relevant patient subgroups for first and total HF hospitalizations. The need for new use of diuretics, renin-angiotensin modulators, or mineralocorticoid receptor antagonists after discharge was less in patients randomized to empagliflozin versus placebo (all P<0.05). CONCLUSIONS: Empagliflozin reduced the risk of HF in patients with left ventricular dysfunction or congestion after acute myocardial infarction. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04509674.

A Randomized, double-blind, dose ranging clinical trial of intravenous FDY-5301 in acute STEMI patients undergoing primary PCI.

BACKGROUND: Ischemia-reperfusion injury remains a major clinical problem in patients with ST-elevation myocardial infarction (STEMI), leading to myocardial damage despite early reperfusion by primary percutaneous coronary intervention (PPCI). There are no effective therapies to limit ischemia-reperfusion injury, which is caused by multiple pathways activated by rapid tissue reoxygenation and the generation of reactive oxygen species (ROS). FDY-5301 contains sodium iodide, a ubiquitous inorganic halide and elemental reducing agent that can act as a catalytic anti-peroxidant. We tested the feasibility, safety and potential utility of FDY-5301 as a treatment to limit ischemia-reperfusion injury, in patients with first-time STEMI undergoing emergency PPCI. METHODS: STEMI patients (n = 120, median 62 years) presenting within 12 h of chest pain onset were randomized at 20 PPCI centers, in a double blind Phase 2 clinical trial, to receive FDY-5301 (0.5, 1.0 or 2.0 mg/kg) or placebo prior to reperfusion, to evaluate the feasibility endpoints. Participants underwent continuous ECG monitoring for 14 days after PPCI to address pre-specified cardiac arrhythmia safety end points and cardiac magnetic resonance imaging (MRI) at 72 h and at 3 months to assess exploratory efficacy end points. RESULTS: Intravenous FDY-5301 was delivered before re-opening of the infarct-related artery in 97% participants and increased plasma iodide levels ~1000-fold within 2 min. There was no significant increase in the primary safety end point of incidence of cardiac arrhythmias of concern. MRI at 3 months revealed median final infarct sizes in placebo vs. 2.0 mg/kg FDY-5301-treated patients of 14.9% vs. 8.5%, and LV ejection fractions of 53.9% vs. 63.2%, respectively, although the study was not powered to detect statistical significance. In patients receiving FDY-5301, there was a significant reduction in the levels of MPO, MMP2 and NTproBNP after PPCI, but no reduction with placebo. CONCLUSIONS: Intravenous FDY-5301, delivered immediately prior to PPCI in acute STEMI, is feasible, safe, and shows potential efficacy. A larger trial is justified to test the effects of FDY-5301 on acute ischemia-reperfusion injury and clinical outcomes. CLINICAL TRIAL REGISTRATION: CT.govNCT03470441; EudraCT 2017-000047-41.

Controlled decongestion by Reprieve therapy in acute heart failure: results of the TARGET-1 and TARGET-2 studies.

AIMS: Safe and effective decongestion is the main goal of therapy in acute heart failure (AHF). In the non-randomized, prospective TARGET-1 and TARGET-2 studies (NCT03897842), we investigated whether adding the Reprieve System® (which continuously monitors urine output and delivers a matched volume of hydration fluid sufficient to maintain the set fluid balance rate) to standard diuretic-based regimen improves decongestion in AHF. METHODS AND RESULTS: The population consisted of 19 patients hospitalized with AHF (mean age 67 ± 10 years, 18 male, ejection fraction 34 ± 15%, median N-terminal pro-B-type natriuretic peptide 4492 pg/mL). Patients served as their own controls: each patient underwent 24 h of standard diuretic therapy followed by 24 h of diuretics with Reprieve therapy (with normal saline used for matched volume replacement). The primary efficacy endpoint of actual fluid loss not exceeding the target fluid loss at the end of therapy was met in all 19 (100%) patients. The mean diuresis during Reprieve therapy was 6284 ± 2679 mL (vs. 1966 ± 1057 mL 24 h before therapy) and 2053 ± 888 mL (24 h after therapy) (both P < 0.0001). At the end of therapy, patient global assessment improved from 7.7 ± 1.1 to 3.0 ± 1.3 points (P < 0.001), central venous pressure decreased from 15.5 ± 5.3 mmHg to 12.8 ± 4.8 mmHg (P < 0.05) and the median urine sodium loss was 9.7 [3-13] mmol/h. The Reprieve therapy was safe, systolic blood pressure remained stable, mean creatinine dropped from 1.45 ± 0.4 mg/dL to 1.26 ± 0.4 mg/dL (P < 0.001) and biomarkers of renal injury did not change during treatment. CONCLUSIONS: The Reprieve System in conjunction with diuretic therapy supports safe and controlled decongestion in AHF.

[Application of levosimendan in acute heart failure patients with symptoms of low cardiac output: case series report]. / Zastosowanie lewosimendanu u chorych z ostra niewydolnoscia serca z objawami malego rzutu minutowego serca: opis serii przypadków.

The report presents single centre experience in application of levosimendan in patients with acute heart failure with low cardiac output. All patients underwent haemodynamic measurement before and after administration of the drug. Levosimendan improved haemodynamics and was useful in this subpopulation of patients.

Liver function tests in patients with acute heart failure.

INTRODUCTION: Acute heart failure (AHF) is associated with multiorgan dysfunction, which may unfavorably affect prognosis. OBJECTIVES: We investigated the prevalence, clinical determinants, and prognostic consequences of abnormal liver function tests (LFTs) in population with AHF. PATIENTS AND METHODS: We conducted a retrospective analysis of patients with AHF, in whom the following LFTs were performed on admission: serum bilirubin, aspartate transaminase (AST), alanine transaminase (ALT), and albumin. Abnormal LFTs were defined as the elevation above the upper normal limit of bilirubin, AST, and ALT, or reduction below the lower normal limit of albumin. RESULTS: The study involved 189 patients (age, 68 ±11 years; men, 68%; de novo AHF, 25%). On admission, abnormal LFTs were observed in 46% of the patients for AST, 31% for ALT, 33% for bilirubin, and 44% for albumin. Only 29% of the patients had all LFTs within the normal ranges. The following variables were independently related to abnormal LFTs: high hemoglobin and N­terminal pro­B­type natriuretic peptide (NT­proBNP) levels for AST; high hemoglobin, bilirubin, and NT­proBNP levels for ALT; high hemoglobin, low sodium levels, and dilated right ventricle for bilirubin; and high NT­proBNP levels for albumin (all P <0.05). In 21 patients, hemodynamic monitoring was performed, which revealed that among LFTs only elevated bilirubin independently correlated with higher right atrial pressure (P <0.005). In a univariate Cox model, among LFTs, low albumin and markedly elevated AST and ALT (>3 times above the upper normal limit) were associated with increased mortality during 180­day follow­up. CONCLUSIONS: Abnormal LFTs are common in patients with AHF and may have prognostic relevance. Among them, only elevated bilirubin was correlated with impaired hemodynamic parameters.

Clinical characteristics and predictors of in-hospital mortality in 270 consecutive patients hospitalised due to acute heart failure in a single cardiology centre during one year.

BACKGROUND: Acute heart failure (HF) is an emerging problem in clinical practice, associated with high in-hospital mortality and a high short-term readmission rate. AIM: To describe the clinical characteristics and define predictors of in-hospital mortality in patients with acute HF. METHODS: We conducted a prospective registry of all consecutive patients hospitalised due to acute HF from October 2008 to November 2009 in a single cardiology centre. Clinical status and laboratory parameters were analysed on admission and after 48 h. RESULTS: We examined 270 patients (age 68 ± 13 years, 71% men, 27% with de novo acute HF, 55% with ischaemic aetiology, 56% with decompensated chronic HF, 80% with warm-wet haemodynamic profile). In-hospital mortality was 8.5% (n = 23). There were no differences between survivors vs non-survivors regarding age, gender, HF aetiology, prevalence of de novo acute HF, and baseline heart rate and body weight values and changes of these parameters during hospitalisation (p > 0.2 for all comparisons). Cardiogenic shock and isolated right-sided HF were more common in patients who died as compared to survivors (17% vs 1% and 22% vs 2%, respectively; p < 0.001), as were the cold-wet and cold-dry haemodynamic profiles (22% vs 2% and 17% vs 1%, respectively; p < 0.001). The most common factor precipitating decompensation in non-survivors was an acute coronary syndrome (17% vs 7%), while elevation of blood pressure and inadequate diuretic therapy were the most common causes of acute HF in survivors (26% vs 4% and 45% vs 22%, respectively; p < 0.05). Baseline mean blood pressure and serum Na(+) level were higher in survivors than in non-survivors (94 ± 20 vs 79 ± 19 mm Hg and 140 ± 4 vs 136 ± 5 mmol/L, respectively; p < 0.001) and both remained higher during follow-up. There were no differences in baseline haemoglobin and serum K(+) levels between these groups. Haemoglobin level decreased after 48 h of therapy only in patients who died (11.1 ± 2.4 vs 12.5 ± 2.1 g/dL; p < 0.01), whereas a reduction in serum K(+) level after 48 h was observed only in survivors (4.2 ± 0.6 vs 3.9 ± 0.5 mmol/L; p < 0.05), probably reflecting effective diuretic therapy. Baseline renal function was more impared in non-survivors (serum creatinine 1.7 [1, 2.5] vs 1.2 [1, 1.6] mg/dL, and blood urea nitrogen 40 [24, 65] vs 24 [19, 33] mg/dL; p < 0.05) and deteriorated further during hospitalisation (serum creatinine 2.0 [1.2, 2.5] vs 1.2 [0.9, 1.5] mg/dL, blood urea nitrogen 64 [45, 77] vs 27 [19, 36] mg/dL; p < 0.01). Baseline plasma N-terminal proB-type natriuretic peptide (NT-proBNP) level did not differentiate these two groups, but plasma NT-proBNP level measured after 48 h was lower in survivors compared to non- -survivors (3560 [1711, 6738] vs 11780 [5371, 18912] pg/mL; p < 0.01); data are shown as medians [lower, upper quartile]. CONCLUSIONS: In our registry, in-hospital mortality in patients admitted due to acute HF was slightly higher compared to other reports. Baseline values of some parameters (e.g. blood pressure, serum Na(+), renal function) as well as their changes during hospitalisation (e.g. serum K(+), renal function, plasma NT-proBNP) can help identify acute HF patients at a higher risk of in-hospital mortality.

Effect of darbepoetin alfa on exercise tolerance in anemic patients with symptomatic chronic heart failure: a randomized, double-blind, placebo-controlled trial.

OBJECTIVES: This study sought to investigate whether darbepoetin alfa, an erythropoiesis-stimulating protein (ESP), improves exercise capacity in patients with symptomatic chronic heart failure (CHF) and anemia. BACKGROUND: Anemia is common in patients with CHF. METHODS: In a multicenter, randomized, double-blind, placebo-controlled study, CHF patients with anemia (hemoglobin > or =9.0 to < or =12.0 g/dl) received subcutaneous placebo (n = 22) or darbepoetin alfa (n = 19) at a starting dose of 0.75 microg/kg every 2 weeks for 26 weeks. The primary end point was change in exercise tolerance from baseline to week 27 as measured by peak oxygen uptake (ml/min/kg body weight). Other end points included changes in absolute peak VO2 (ml/min), exercise duration, and health-related quality of life. RESULTS: Differences (95% confidence interval) in mean changes from baseline to week 27 between treatment groups were 1.5 g/dl (0.5 to 2.4) for hemoglobin concentration (p = 0.005), 0.5 ml/kg/min (-0.7 to 1.7) for peak VO2 (p = 0.40), 45 ml/min (-35 to 127) for absolute peak VO2 (p = 0.27), and 108 s (-11 to 228) for exercise duration (p = 0.075). Patients receiving darbepoetin alfa compared with placebo had an improvement in self-reported Patient's Global Assessment of Change (79% vs. 41%, p = 0.01) but no significant differences in the Kansas City Cardiomyopathy and Minnesota Living with Heart Failure Questionnaire scores. Darbepoetin alfa was well tolerated. CONCLUSIONS: In patients with symptomatic CHF and anemia, darbepoetin alfa increased and maintained hemoglobin concentrations and improved health-related quality of life. A trend toward increased exercise time but not peak VO2 was observed. (Impact of Darbepoetin Alfa on Exercise Tolerance and Left Ventricular Structure in Subjects With Symptomatic Congestive Heart Failure (CHF) and Anemia; http://clinicaltrials.gov/ct/show/NCT00117234?order = 1; NCT00117234).

[Clinical use of ventilation measurement during early phase of exercise in patients with chronic heart failure]. / Kliniczna przydatnosc oceny wentylacji we wczesnej fazie wysilku fizycznego u chorych z niewydolnoscia serca.

BACKGROUND: In patients with chronic heart failure (CHF) augmented exercise ventilation is related to functional severity and increased mortality. Nevertheless, the optimal approach to the assessment of ventilatory response to controlled exercise has not been established. AIM: The study was carried out to evaluate the clinical application of the measurement of ventilatory response to the early phase of exercise in the non-selected group of patients with CHF. MATERIAL AND METHODS: We investigated 180 consecutive patients with CHF (155 men, age: 59 +/- 11 years, left ventricle ejection fraction: 31 +/- 7%; NYHA class I/II/III/IV: 13/90/60/17). All patients underwent the cardiopulmonary exercise testing (CPX) with RER > 1.0 (mean peak oxygen consumption [peakVO2]: 15.5 +/- 4.8 ml/kg/min). Ventilatory response to exercise was assessed: 1) during the whole exercise--expressed as a correlation coefficient of linear regression describing the relationship between minute ventilation (VE) and carbon dioxide production (VCO2) during the whole exercise (VE-VCO2 100%); 2) during the early phase of exercise--expressed as VE-VCO2 derived from VE and VCO2 during first 180 seconds of exercise (VE-VCO2 180 s). RESULTS: Ventilatory responses to early and maximal exercise were significantly augmented in CHF patients (VE-VCO2 100% -36.1 +/- 9.8, VE-VCO2 180% -34.4 +/- 10.3; p < 0.0001 vs values in the reference group without CHF). Ventilatory responses to early and whole exercise were strongly interrelated (r = 0.88, p < 0.0001). Indices of exercise ventilation correlated with the severity of CHF expressed as NYHA class (for VE-VCO2 100% and VE-VCO2 180 s -r = 0.52 and r = 0.51) and peak VO2 (for VE-VCO2 100% and VE-VCO2 180 s, r = -0.49 and r = -0.47, respectively) (p < 0.0001 for all correlations). Among echocardiographic parameters only right ventricular systolic pressure correlated with indices of exercise ventilation (for VE-VCO2 100% -r = 0.45, p = 0.001; for VE-VCO2 180 s -r = 0.35, p = 0.01). The reproducibility of indices of exercise ventilation was assessed in 19 CHF patients (another CPX during 2-9 days), and variability coefficients reached 7.8% for VE-VCO2 100% and 8.5% for VE-VCO2 180 s. CONCLUSIONS: Indices of ventilatory response to both early and maximal exercise can significantly differentiate the CHF patients with regard to their exercise capacity, are highly reproducible, and may therefore constitute useful parameters carrying an important clinical message. The assessment of ventilatory response during the early stage of exercise seems to be of a particular significance in CHF patients who are unable to perform the maximal exercise effort, as diagnostic data obtained during first 180 seconds of exercise are in accordance to those derived from the standard maximal CPX.