Empagliflozin to elderly and obese patients with increased risk of developing heart failure: Study protocol for the Empire Prevent trial program.

INTRODUCTION: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have previously demonstrated cardioprotective properties in patients with type 2 diabetes, suggesting a preventive effect on heart failure (HF). The Empire Prevent trial program investigates the therapeutic potential for HF prevention by evaluating the cardiac, metabolic, and renal effects of the SGLT2 inhibitor empagliflozin in patients with increased risk of developing HF, but without diabetes or established HF. METHODS: The Empire Prevent trial program is an investigator-initiated, double-blind, randomized clinical trial program including elderly and obese patients (60-84 years, body mass index >28 kg/m2) with at least one manifestation of hypertension, cardiovascular or chronic kidney disease, but no history of diabetes or HF. The aims are to investigate the effects of empagliflozin on 1) physical capacity and left ventricular and atrial structural changes with peak oxygen consumption and left ventricular mass as primary endpoints (Empire Prevent Cardiac), and 2) cardiac-adipose tissue interaction and volume homeostasis with primary endpoints of changes in epicardial adipose tissue and estimated extracellular volume (Empire Prevent Metabolic). At present, 138 of 204 patients have been randomized in the Empire Prevent trial program. Patients are randomized 1:1 to 180 days treatment with empagliflozin 10 mg daily or placebo, while undergoing a comprehensive examination program at baseline and follow-up. DISCUSSION: The Empire Prevent trial program will mark the first step towards elucidating the potential of SGLT2 inhibition for HF prevention in an outpatient setting in elderly and obese patients with increased risk of developing HF, but with no history of diabetes or established HF. Furthermore, the Empire Prevent trial program will supplement the larger event-driven trials by providing mechanistic insights to the beneficial effects of SGLT2 inhibition. TRIAL REGISTRATION: Both parts of the trial program have been registered on September 13th 2021 (Clinical Trial Registration numbers: NCT05084235 and NCT05042973) before enrollment of the first patient. All patients will provide oral and written informed consent. The trial is approved by The Regional Committee on Health Research Ethics and the Danish Medicines Agency. Data will be disseminated through scientific meetings and peer-reviewed journals irrespective of outcome.

Does targeted positioning of the left ventricular pacing lead towards the latest local electrical activation in cardiac resynchronization therapy reduce the incidence of death or hospitalization for heart failure?

BACKGROUND: Cardiac resynchronization therapy (CRT) improves symptoms, health-related quality of life and long-term survival in patients with systolic heart failure (HF) and shortens QRS duration. However, up to one third of patients attain no measurable clinical benefit from CRT. An important determinant of clinical response is optimal choice in left ventricular (LV) pacing site. Observational data have shown that achieving an LV lead position at a site of late electrical activation is associated with better clinical and echocardiographic outcomes compared to standard placement, but mapping-guided LV lead placement towards the site of latest electrical activation has never been investigated in a randomized controlled trial (RCT). The purpose of this study was to evaluate the effect of targeted positioning of the LV lead towards the latest electrically activated area. We hypothesize that this strategy is superior to standard LV lead placement. METHODS: The DANISH-CRT trial is a national, double-blinded RCT (ClinicalTrials.gov NCT03280862). A total of 1,000 patients referred for a de novo CRT implantation or an upgrade to CRT from right ventricular pacing will be randomized 1:1 to receive conventional LV lead positioning preferably in a nonapical posterolateral branch of the coronary sinus (CS) (control group) or targeted positioning of the LV lead to the CS branch with the latest local electrical LV activation (intervention group). In the intervention group, late activation will be determined using electrical mapping of the CS. The primary endpoint is a composite of death and nonplanned HF hospitalization. Patients are followed for a minimum of 2 years and until 264 primary endpoints occurred. Analyses will be conducted according to the intention-to-treat principle. Enrollment for this trial began in March 2018, and per April 2023, a total of 823 patients have been included. Enrollment is expected to be complete by mid-2024. CONCLUSIONS: The DANISH-CRT trial will clarify whether mapping-guided positioning of the LV lead according to the latest local electrical activation in the CS is beneficial for patients in terms of reducing the composite endpoint of death or nonplanned hospitalization for heart failure. Results from this trial are expected to impact future guidelines on CRT. GOV IDENTIFIER: NCT03280862.

Prevalence of heart failure phenotypes and current use of therapies in primary care: results from a nationwide study.

AIMS: Heart failure (HF) is an increasing concern worldwide. A rising HF burden is expected due to the prospected future demographic changes with aging populations. Consequently, the long-term follow-up and treatment will be performed increasingly by primary care physicians in the future. Contemporary data on HF patients in primary care are needed to plan and ensure an effective and safe follow-up of future patients. METHODS AND RESULTS: The electronic patient journals of 148 primary care clinics in Denmark were searched in a standardized manner to identify patients with HF [code K77 of the International Classification of Primary Care, Second Edition]. Prespecified variables including demographic information, clinical variables, co-morbidities, prescribed medications, and setting of follow-up were recorded. In total, 1111 patients were included in the study. The mean timepoint for the HF diagnosis was August 2018. In 95% of cases, the diagnosis of HF was made in a specialized setting. The echocardiogram data used for phenotyping were available in 1042 (94%) of the 1111 patients. HF with reduced ejection fraction (HFrEF) was present in 43%, recovered HFrEF in 31%, and HF with mildly reduced (HFmrEF) or preserved ejection fraction (HFpEF) in 26%. In patients with HFrEF or recovered HFrEF, fundamental treatments were prescribed in 86% for angiotensin converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), or angiotensin receptor neprilysin inhibitor (ARNI), in 82% for beta-blocker, in 38% for mineralocorticoid receptor antagonist (MRA), and in 12% for sodium-glucose co-transporter-2 inhibitor (SGLT2i). Older patients were treated to a significantly lesser extent than young patients for all drug classes [odds ratio (OR) point estimates 0.50 to 0.69, all P-values < 0.05]. In patients with HFmrEF or HFpEF, an ACEI, ARB, or ARNI was prescribed in 67%, beta-blocker in 67%, MRA in 22%, and SGLT2i in 7.4% with significantly lower probability of treatment compared to patients with HFrEF or recovered HFrEF [OR point estimates 0.33 to 0.57, all P-values < 0.05]. The setting of follow-up was available in 96% of patients. Irrespective of HF phenotype, follow-up was performed solely in primary care in 64%. These patients were generally treated to a lesser extent with HF therapies compared with patients where follow-up included specialized care, yet differences were generally small. CONCLUSIONS: HFrEF is the most common phenotype of HF in primary care followed by recovered HFrEF and fundamental therapies are markedly underutilized. Initiatives to increase the use of recommended therapies are needed to improve the future care of patients with HF.

Influence of angiotensin receptor-neprilysin inhibition on the efficacy of Empagliflozin on cardiac structure and function in patients with chronic heart failure and a reduced ejection fraction: The Empire HF trial.

Study objective: The objective was to assess the effect of ongoing angiotensin receptor-neprilysin inhibitor(ARNI) on the effect of the sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin on left ventricular (LV) size and function in patients with heart failure and reduced ejection fraction(HFrEF). Design: Post hoc analysis of the Empire HF trial, an investigator-initiated, double-blind, randomized controlled trial. Participants: 190 patients with HFrEF with New York Heart association class I-III symptoms with an ejection fraction of 40 % or below. Patients were stratified according to ongoing ARNI treatment at baseline. Intervention: Empagliflozin 10 mg daily or placebo for 12 weeks. Echocardiography at baseline and follow-up. Main outcome measures: Left ventricular end-systolic volume index (LVESVI), end-diastolic volume index (LVEDVI), left atrial volume index (LAVI), left ventricular ejection fraction (LVEF). Results: A total of 58 patients (31 %) received ARNI at baseline. Compared to with placebo, empagliflozin reduced the LVESVI ([-6.2 (-14.1 to 1.6); p = 0.12] and [-3.3 (-8.2 to 1.6); p = 0.19], interaction P = 0.49), LVEDVI ([-11.2 (-21.2 to -1.2); p = 0.03] and [-2.9 (-8.7 to 2.9); p = 0.32], interaction P = 0.13), and LAVI ([-3.9 (-9.1 to 1.2); p = 0.14] and. [-1.8 (-4.4 to 0.7); p = 0.16], respectively, interaction P = 0.9) in patients treated with and without ARNI at baseline, respectively. No treatment-by-ARNI subgroup interaction were found. Unaffected by baseline ARNI treatment, empagliflozin did not improve LVEF. Conclusion: The effect of empagliflozin on cardiac structure and function compared to placebo was not affected by background treatment with ARNI.

Determinants of Antibody Response to a Third SARS-CoV-2 mRNA Vaccine Dose in Solid Organ Transplant Recipients: Results from the Prospective Cohort Study COVAC-Tx.

BACKGROUND: We studied factors related to humoral response in solid organ transplant (SOT) recipients following a three-dose regimen of an mRNA-based SARS-CoV-2 vaccine. METHOD: This was a prospective study of SOT recipients who received a third homologous dose of the BNT162b2 (Pfizer-BioNTech) vaccine. The anti-spike S1 IgG response was measured using the SARS-CoV-2 IgG II Quant assay (Abbott Laboratories) with a cut-off of 7.1 BAU/mL. Multiple logistic regression was used to determine the factors associated with humoral response. RESULTS: In total, 395 SOT recipients were included. Anti-spike IgG was detected in 195/395 (49.4%) patients after the second dose and 261/335 (77.9%) patients after the third dose. The overall mean increase in antibody concentration after the third dose was 831.0 BAU/mL (95% confidence interval (CI) 687.4-974.5) and 159 (47.5%) participants had at least a 10-fold increase in antibody concentration after the third dose. The increase in antibody concentration was significantly higher among patients with detectable antibodies after the second dose than those without. Cumulative time from transplantation and liver recipients was positively associated with an antibody response, whereas older age, administration of prednisolone, and proliferation inhibitors were associated with diminished antibody response. CONCLUSION: Although the third dose of the BNT162b2 vaccine improved humoral responses among SOT non-responders following the second dose, the overall response remained low, and 22.1% did not develop any response. Patients at risk of a diminished vaccine response require repeated booster doses and alternative treatment approaches.

Effect of Empagliflozin on Blood Volume Redistribution in Patients With Chronic Heart Failure and Reduced Ejection Fraction: An Analysis From the Empire HF Randomized Clinical Trial.

BACKGROUND: Stressed blood volume (SBV) is a major determinant of systemic and pulmonary venous pressures which, in turn, determine left and right ventricular fillings and regulates cardiac output via the Frank-Starling mechanism. It is not known whether inhibition of the SGLT2 (sodium-glucose cotransporter-2) favorably affects SBV. We investigated the effect of empagliflozin on estimated SBV in patients with heart failure and reduced ejection fraction compared with placebo. METHODS: This was a post hoc analysis of an investigator-initiated, double-blinded, placebo-controlled, randomized trial. Seventy patients were assigned to empagliflozin 10 mg or matching placebo once daily for 12 weeks. Patients underwent right heart catheterization at rest and during exercise at baseline and follow-up. The outcome was change in estimated SBV after 12 weeks of empagliflozin treatment over the full range of exercise, determined using a recently introduced analytical approach based on invasive hemodynamic assessment. RESULTS: Patients with heart failure and reduced ejection fraction, mean age, 57 years and mean ejection fraction 27%, with 47 patients (71%) receiving diuretics were randomized. The effect of empagliflozin on estimated SBV over the full range of exercise loads showed a statistically significant reduction compared with placebo (-198.4 mL [95% CI, -317.4 to -79.3] P=0.001), a 9% decrease. The decrease in estimated SBV by empagliflozin was significantly correlated with the decrease in PCWP (R=-0.33, P<0.0001). The effect of empagliflozin was consistent across subgroup analysis. CONCLUSIONS: Empagliflozin treatment significantly reduced SBV compared with placebo after 12 weeks of treatment in patients with stable chronic heart failure and reduced ejection fraction during sub maximal exercise. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03198585.

Diagnostic Accuracy of a Bespoke Multiorgan Ultrasound Approach in Suspected Pulmonary Embolism.

Purpose The aims of this study were to prospectively assess the diagnostic accuracy of a bespoke multiorgan point-of-care ultrasound approach for suspected pulmonary embolism and evaluate if this model allows reduced referral to further radiation diagnostics while maintaining safety standards. Materials and Methods Patients with suspected pulmonary embolism referred for CT pulmonary angiography or ventilation/perfusion scintigraphy were included as a convenience sample. All patients were subject to blinded ultrasound investigation with cardiac, lung, and deep venous ultrasound. The sensitivity and specificity of applied ultrasound signs and the hypothetical reduction in the need for further diagnostic workup were calculated. Results 75 patients were prospectively enrolled. The Wells score was below 2 in 48 patients, between 2 and 6 in 24 patients, and above 6 in 3 patients. The prevalence of pulmonary embolism was 28%. The most notable ultrasound signs were presence of a deep venous thrombus, at least two hypoechoic pleural-based lesions, the D-sign, the 60/60-sign, and a visible right ventricular thrombus which all had a specificity of 100%. Additionally, a multiorgan ultrasound investigation with no findings compatible with pulmonary embolism yielded a sensitivity of 95.2% (95%CI: 76.2-99.9). CT or scintigraphy could be safely avoided in 70% of cases (95%CI: 63.0-83.1%). Conclusion The findings of our study suggest that implementation of a multiorgan ultrasound assessment in patients with suspected pulmonary embolism may safely reduce the need for CT or scintigraphy by confirming or dismissing the suspicion.

[Rational dosing of diuretics in the treatment of chronic heart failure with acute deterioration].

For decades, diuretics have been the cornerstone in the treatment of patients with chronic heart failure with reduced ejection fraction (HFrEF) presenting with congestion. However, evidence guiding the use of diuretics is generally lacking. Adequate dosing and evaluation of diuretic effect are important for treatment success. Measuring the concentration of sodium in urine in addition to urinary output has been suggested as a good marker to guide the use of diuretics. This review summaries the current knowledge on the use of diuretics in patients with HFrEF presenting with congestion.

Hemodynamic Determinants of Activity Measured by Accelerometer in Patients With Stable Heart Failure.

OBJECTIVES: This study examined the link between accelerometer recordings and cardiac pathophysiology measured with right heart cauterization at rest and with exercise in patients with HFrEF. BACKGROUND: Patient-worn accelerometers are increasingly being used in patients with heart failure with reduced ejection fraction (HFrEF) to assess activity and serve as surrogate endpoints in heart failure trials. METHODS: Physical average daily activity (PADA) and total average daily activity according to accelerometer units were assessed in 63 patients (mean age 58 ± 10 years; mean ejection fraction 26% ± 4%). Patients underwent hemodynamic exercise testing and accelerometry. Patients were divided according to PADA in PADALow and PADAHigh activity level groups based on median counts per minute of physical activity. RESULTS: Patients in the PADALow group were older and more frequently treated with diuretics. At rest, the PADALow group was characterized by a lower cardiac index (2.2 ± 0.4 L/min/m2 vs 2.4 ± 0.4 L/min/m2; P = 0.01) and stroke volume (70 ± 19 mL vs 81 ± 17 mL; P = 0.02) but not pulmonary capillary wedge pressure (12 ± 5 mm Hg vs 11 ± 5 mm Hg; P = 0.3). The PADALow group reached a lower cardiac index (4.8 ± 1.7 L/min/m2 vs 6.6 ± 1.7 L/min/m2; P < 0.001) but not in pulmonary capillary wedge pressure (31 ± 12 mm Hg vs 27 ± 8 mm Hg; P = 0.2) at peak exercise. The attenuated increase was associated with an attenuated increase in stroke volume (94 ± 32 mL vs 121 ± 29 mL; P < 0.001) rather than a reduced increase in heart rate (42 ± 23 beats/min vs 52 ± 21 beats/min; P = 0.07). PADA and total average daily accelerometer units were associated with patient-reported functional impairment according to the Kansas City Cardiomyopathy Questionnaire but not with New York Heart Association functional class. CONCLUSIONS: Among stable ambulatory patients with HFrEF, lower daily activity is associated with poorer cardiac index reserve and reduced cardiac index during exercise. (Empagliflozin in Heart Failure Patients With Reduced Ejection Fraction; NCT03198585).

Immunogenicity of SARS-CoV-2 mRNA vaccine in solid organ transplant recipients.

BACKGROUND: It is currently not well described if a two-dose regimen of a Covid-19 vaccine is sufficient to elicit an immune response in solid organ transplant (SOT) recipients. RESULTS: A total of 80 SOT recipients completed a two-dose regimen with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger RNA vaccine. Only 35.0% (n = 28) were able to mount a positive IgG immune response 6 weeks after the second dose of vaccine. CONCLUSION: This emphasizes that SOT recipients need continued use of personal protective measures. Future studies need to closely examine the cellular immune response in patients with compromised antibody response to Covid-19 vaccination.

Associations of Empagliflozin With Left Ventricular Volumes, Mass, and Function in Patients With Heart Failure and Reduced Ejection Fraction: A Substudy of the Empire HF Randomized Clinical Trial.

Importance: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) improve outcomes in patients with heart failure and a reduced ejection fraction (HFrEF). The association with cardiac remodeling has not been investigated. Objective: To investigate the outcome of the SGLT2i empagliflozin, compared with placebo, on cardiac remodeling in patients with HFrEF. Design, Setting, and Participants: This exploratory post hoc analysis included participants with stable HFrEF and ejection fractions of 40% or less, who were randomly enrolled in an investigator-initiated, multicenter, double-blind, placebo-controlled randomized clinical trial in Denmark. Enrollment commenced on June 29, 2017, and continued through September 10, 2019, with the last participant follow-up on December 20, 2019. Interventions: Randomization (1:1) to empagliflozin (10 mg once daily) or matching placebo in addition to recommended heart failure therapy for 12 weeks. Main Outcomes and Measures: Efficacy measures were changes from baseline to week 12 in left ventricular end-systolic and end-diastolic volume indexes, left atrial volume index, and left ventricular ejection fraction adjusted for age, sex, type 2 diabetes, and atrial fibrillation. Secondary efficacy measures included changes in left ventricular mass index, global longitudinal strain, and relative wall thickness. Results: A total of 190 patients were randomized (95 each receiving empagliflozin and placebo), with a mean (SD) age of 64 (11) years; 162 were men (85.3%), 97 (51.1%) had ischemic HFrEF, 24 (12.6%) had type 2 diabetes, and the mean (SD) latest recorded left ventricular ejection fraction was 29% (8%). Of the 190, 186 completed the study. Empagliflozin significantly reduced left ventricular end-systolic volume index (-4.3 [95% CI, -8.5 to -0.1] mL/m2; P = .04), left ventricular end-diastolic volume index (-5.5 [95% CI, -10.6 to -0.4] mL/m2; P = .03), and left atrial volume index (-2.5 [95% CI, -4.8 to -0.1] mL/m2; P = .04) compared with placebo at 12 weeks' follow-up, with no change in left ventricular ejection fraction (1.2% [95% CI, -1.2% to 3.6%]; P = .32). These findings were consistent across subgroups. Of secondary efficacy measures, left ventricular mass index was significantly reduced by empagliflozin (-9.0 [95% CI, -17.2 to -0.8] g/m2; P = .03). Conclusions and Relevance: In this small, randomized, short-term study, empagliflozin was associated with modest reductions in left ventricular and left atrial volumes with no association with ejection fraction. Effects beyond 12 weeks of SGLT2i use require further study. Trial Registration: ClinicalTrials.gov Identifier: NCT03198585.

The DANish randomized, double-blind, placebo controlled trial in patients with chronic HEART failure (DANHEART): A 2 × 2 factorial trial of hydralazine-isosorbide dinitrate in patients with chronic heart failure (H-HeFT) and metformin in patients with chronic heart failure and diabetes or prediabetes (Met-HeFT).

OBJECTIVES: The DANHEART trial is a multicenter, randomized (1:1), parallel-group, double-blind, placebo-controlled study in chronic heart failure patients with reduced ejection fraction (HFrEF). This investigator driven study will include 1500 HFrEF patients and test in a 2 × 2 factorial design: 1) if hydralazine-isosorbide dinitrate reduces the incidence of death and hospitalization with worsening heart failure vs. placebo (H-HeFT) and 2) if metformin reduces the incidence of death, worsening heart failure, acute myocardial infarction, and stroke vs. placebo in patients with diabetes or prediabetes (Met-HeFT). METHODS: Symptomatic, optimally treated HFrEF patients with LVEF ≤40% are randomized to active vs. placebo treatment. Patients can be randomized in either both H-HeFT and Met-HeFT or to only one of these study arms. In this event-driven study, it is anticipated that 1300 patients should be included in H-HeFT and 1100 in Met-HeFT and followed for an average of 4 years. RESULTS: As of May 2020, 296 patients have been randomized at 20 centers in Denmark. CONCLUSION: The H-HeFT and Met-HeFT studies will yield new knowledge about the potential benefit and safety of 2 commonly prescribed drugs with limited randomized data in patients with HFrEF.

Effect of Empagliflozin on Hemodynamics in Patients With Heart Failure and Reduced Ejection Fraction.

BACKGROUND: Inhibition of the sodium-glucose cotransporter-2 (SGLT2i) improves outcomes in patients with heart failure (HF) and reduced ejection fraction (HFrEF), but the mechanism by which they improve outcomes remains unclear. OBJECTIVES: This study aimed to investigate the effects of sodium-glucose cotransporter-2 inhibitor empagliflozin on central hemodynamics in patients with HF and HFrEF. METHODS: This investigator-initiated, double-blinded, placebo-controlled, randomized trial enrolled 70 patients with HFrEF from March 6, 2018, to September 10, 2019. Patients were assigned to empagliflozin of 10 mg or matching placebo once daily on guideline-driven HF therapy for 12 weeks. The primary outcome was ratio of pulmonary capillary wedge pressure (PCWP) to cardiac index (CI) at peak exercise after 12 weeks. Patients underwent right-heart catheterization at rest and during exercise at baseline and 12-week follow-up. RESULTS: Patients with HFrEF, mean age of 57 years, mean left-ventricular ejection fraction, 26%, and 12 (17%) with type 2 diabetes mellitus were randomized. There was no significant treatment effect on peak PCWP/CI (-0.13 mm Hg/l/min/m2; 95% confidence interval: -1.60 to 1.34 mm Hg/l/min/m2; p = 0.86). Considering hemodynamics over the full range of exercise loads, PCWP was significantly reduced (-2.40 mm Hg; 95% confidence interval: -3.96 to -0.84 mm Hg; p = 0.003), but not CI (-0.09 l/min/m2; 95% confidence interval: -0.14 to 0.32 l/min/m2; p = 0.448) by empagliflozin. This was consistent among patients with and without type 2 diabetes. CONCLUSIONS: Among patients with stable HFrEF, empagliflozin for 12 weeks reduced PCWP compared with placebo. There was no significant improvement in neither CI nor PCWP/CI at rest or exercise.

Twelve weeks of treatment with empagliflozin in patients with heart failure and reduced ejection fraction: A double-blinded, randomized, and placebo-controlled trial.

AIMS: To investigate the effect of the sodium-glucose co-transporter-2 inhibitor empagliflozin on N-terminal pro-b-type natriuretic peptide (NT-proBNP) in patients with heart failure (HF) and reduced ejection fraction (HFrEF). METHODS AND RESULTS: Empire HF was an investigator-initiated, multi-center, double-blinded, placebo-controlled, randomized trial. Patients with mildly symptomatic HFrEF, mean (standard deviation (SD)) age 64 (11) years, 85% male, and mean left ventricular ejection fraction 29% (8), on recommended HF therapy were assigned to receive either empagliflozin 10 mg once daily or placebo for 12 weeks. The primary endpoint was the between-group difference in the change of NT-proBNP from baseline to 12 weeks. In total, 95 patients were assigned to empagliflozin and 95 to placebo. No significant difference in the change of NT-proBNP with empagliflozin versus placebo was observed [Empagliflozin: baseline, median (interquartile range (IQR)) 582 (304-1020) pg/mL, 12 weeks, 478 (281-961) pg/mL; Placebo: baseline, 605 (322-1070) pg/mL, 12 weeks, 520 (267-1075) pg/mL, adjusted ratio of change empagliflozin/placebo 0.98; 95% confidence interval (CI) 0.82-1.11, P = 0.7]. Further, no significant difference was observed in accelerometer-measured daily activity level [adjusted mean difference of change, empagliflozin versus placebo, -26.0 accelerometer counts; 95% CI -88.0 to 36.0, P = 0.4] or Kansas City Cardiomyopathy Questionnaire Overall Summary Score [adjusted mean difference of change, empagliflozin versus placebo 0.8; 95% CI -2.3 to 3.9, P = 0.6]. CONCLUSION: In low-risk patients with HFrEF with mild symptoms and on recommended HF therapy, empagliflozin did not change NT-proBNP after 12 weeks. Further, no change in daily activity level or health status was observed.

Empagliflozin in heart failure patients with reduced ejection fraction: a randomized clinical trial (Empire HF).

BACKGROUND: Data from recent cardiovascular outcome trials in patients with type 2 diabetes (T2D) suggest that sodium-glucose cotransporter 2 (SGLT2) inhibitors can prevent development of heart failure (HF) and prolong life in patients without HF. Ongoing event-driven trials are investigating whether the same effect is present in patients with well-defined HF. The mechanism behind the effect of SGLT2 inhibitors in patients with T2D and the potential effect in patients with overt HF is presently unknown. METHODS: This is a randomized, double-blinded, placebo-controlled, parallel group, clinical trial including HF patients with reduced left ventricular ejection fraction (HFrEF) with an ejection fraction ≤ 40% on optimal therapy recruited from specialized HF clinics in Denmark. The primary aim is to investigate the effect of the SGLT2 inhibitor empagliflozin on N-terminal pro-brain natriuretic peptide (NT-proBNP). Secondary endpoints include cardiac biomarkers, function and hemodynamics, metabolic and renal parameters, daily activity level, and quality of life. Patients are assigned 1:1 to 90 days treatment with empagliflozin 10 mg daily or placebo. Patients with T2D are required to be on recommended doses of anti-glycemic therapy with a hemoglobin A1c (HbA1c) of 6.5-10.0% (48-86 mmol/mol). To show a between-group difference in the change of NT-proBNP of 30%, a total of 189 patients will be included. DISCUSSION: The Empire HF trial will elucidate the effects and modes of action of empagliflozin in HFrEF patients with and without T2D and provide important mechanistic data which will complement ongoing event-driven trials. TRIAL REGISTRATION: Clinicaltrialsregister.eu, EudraCT Number 2017-001341-27 . Registered on 29 May 2017. ClinicalTrials.gov, NCT03198585 . Registered on 26 June 2017.

[Randomised double-blind tests and invasive cardiology].

Virtually all the new medical treatments nowadays are tested in randomised double-blind tests, before they are introduced as routine treatment. However, this is not always the case for the new surgical or catheter-based treatments. Although different in some aspects, it is practically possible for surgical and catheter-based treatments to follow the same scientific principles as medical treatments in order to test their efficacy. In this review, we argue that it is necessary to conduct randomised double-blind tests of these interventions prior to their introduction in clinical practice.

Long-Term Risk of Heart Failure in Breast Cancer Patients After Adjuvant Chemotherapy With or Without Trastuzumab.

OBJECTIVES: This study sought to evaluate the long-term risk of developing heart failure (HF) in patients receiving trastuzumab therapy. BACKGROUND: Trastuzumab has improved the prognosis in patients with HER2-positive breast cancer, but it can induce left ventricular dysfunction with reduced ejection fraction or HF during treatment. The long-term risk of HF is less well described. METHODS: In a nationwide Danish retrospective cohort study, 9,901 patients scheduled for adjuvant treatment for early-stage breast cancer were identified in the Danish Breast Cancer Cooperative Group database. Of these, 8,812 patients (25% HER2-positive; 51.7 ± 8.5 years of age) received chemotherapy including anthracycline; and if they were HER2 positive, trastuzumab was added. The primary endpoint was a diagnosis of HF assessed before and after 18 months in a landmark analysis to distinguish short- and long-term risks. RESULTS: Median follow-up was 5.4 years (interquartile range [IQR]: 4.1 to 6.8 years). In the trastuzumab group, 60 patients had HF by 9 years versus 51 in the group who were treated with chemotherapy alone, corresponding to incidence rates per 1,000 patient years of 5.3 (95% confidence interval [CI]: 4.1 to 6.8) versus 1.4 (95% CI: 1.1 to 1.8), respectively. The cumulative incidence of HF was higher in the trastuzumab group at both the short- and long-term (p < 0.01), yielding adjusted hazard ratios of 8.7 (95% CI: 4.6 to 16.5; p < 0.01) for early HF and 1.9 (95% CI: 1.2 to 3.3; p = 0.01) for late HF associated with trastuzumab treatment. CONCLUSIONS: Trastuzumab treatment is associated with a 2-fold increased risk of late HF compared with chemotherapy treatment alone.

A case report: haemodynamic instability due to true dynamic left ventricular outflow tract obstruction and systolic anterior motion following resuscitation: reversal of haemodynamics on supportive veno-arterial extracorporeal membrane oxygenation.

BACKGROUND: Obstruction of the left ventricular outflow tract (LVOT) as seen in hypertrophic cardiomyopathy is a dynamic condition with a wide range of clinical presentations and symptoms. CASE SUMMARY: We report the use of veno-arterial extracorporeal membrane oxygenation in a female patient who was resuscitated after out-of-hospital cardiac arrest. Soon after admission the patient developed critical haemodynamic compromise due to severe obstruction of the left ventricle outflow tract and systolic anterior motion (SAM) of the mitral valve. Veno-arterial extracorporeal membrane oxygenation restored haemodynamics and was weaned after 4 days without any haemodynamic compromise due to SAM. The patient was discharged from the intensive care unit at Day 13, and after 3 days at the coronary care unit, she was discharged to ambulatory follow-up with no sequelae. DISCUSSION: Veno-arterial extracorporeal membrane oxygenation restored haemodynamic stability in this patient with dynamic severe LVOT obstruction following cardiac arrest.

Is cardiovascular disease in patients with diabetes associated with serum levels of MMP-2, LOX, and the elastin degradation products ELM and ELM-2?

BACKGROUND: Diabetes mellitus type 2 (T2DM) is a significant risk factor for the development of cardiovascular diseases (CVDs). In a previous microarray study of internal mammary arteries from patients with and without T2DM, we observed several elastin-related genes with altered mRNA-expression in diabetic patients, namely matrix metalloproteinase 2 (MMP-2), lysyl oxidase (LOX) and elastin itself. In this study we investigate whether the serum concentrations of elastin-related proteins correlate to signs of CVD in patients with T2DM. METHODS: Blood samples from 302 type 2 diabetic patients were analysed for MMP-2, LOX, and the elastin degradation products ELM and ELM2. The results were investigated for correlations to signs of CVD in different vascular territories, as determined by myocardial perfusion scintigraphy, carotid artery thickness and ankle-brachial blood pressure index. RESULTS: T2DM patients with peripheral arterial disease (low ankle-brachial index) (PAD) display higher levels of MMP-2 and ELM compared to patients without PAD. However, none of the proteins or degradation products correlated with myocardial ischemia or a combined measure of CVD-signs, including myocardial ischemia, increased carotid thickness and decreased ankle-brachial blood pressure. CONCLUSIONS: Our results suggest that the diabetic environment affects the circulating amounts of MMP-2 and ELM in patients with PAD. However, the same connection could not be seen in diabetic patients with CVD broadly identified in three vascular territories. LOX and ELM-2 did not correlate to any type of CVD. Overall, serum levels of elastin-related molecules are only remotely related to CVD in type 2 diabetes.