Search

The article discusses the concept of disease modification in pulmonary arterial hypertension (PAH) and proposes a framework for its definition and evaluation in clinical trials. It defines disease modification as therapy-induced changes in clinical manifestations, disease trajectory, and outcomes due to an effect on the underlying pathophysiology. It proposes a randomized-withdrawal trial design to evaluate disease-modifying therapies effectively.

Aim: The EMPULSE (EMPagliflozin in patients hospitalised with acUte heart faiLure who have been StabilizEd) trial showed that, compared to placebo, the sodium–glucose cotransporter 2 inhibitor empagliflozin (10 mg/day) improved clinical outcomes of patients hospitalized for acute heart failure (HF). We investigated whether efficacy and safety of empagliflozin were consistent across the spectrum of left ventricular ejection fraction (LVEF). Methods and results: A total of 530 patients hospitalized for acute de novo or decompensated HF were included irrespective of LVEF. For the present analysis, patients were classified as HF with reduced (HFrEF, LVEF ≤40%), mildly reduced (HFmrEF, LVEF 41–49%) or preserved (HFpEF, LVEF ≥50%) ejection fraction at baseline. The primary endpoint was a hierarchical outcome of death, worsening HF events (HFE) and quality of life over 90 days, assessed by the win ratio. Secondary endpoints included individual components of the primary endpoint and safety. Out of 523 patients with baseline data, 354 (67.7%) had HFrEF, 54 (10.3%) had HFmrEF and 115 (22.0%) had HFpEF. The clinical benefit (hierarchical composite of all‐cause death, HFE and Kansas City Cardiomyopathy Questionnaire total symptom score) of empagliflozin at 90 days compared to placebo was consistent across LVEF categories (≤40%: win ratio 1.35 [95% confidence interval 1.04, 1.75]; 41–49%: win ratio 1.25 [0.66, 2.37)] and ≥50%: win ratio 1.40 [0.87, 2.23], pinteraction = 0.96) with a favourable safety profile. Results were consistent across individual components of the hierarchical primary endpoint. Conclusion: The clinical benefit of empagliflozin proved consistent across LVEF categories in the EMPULSE trial. These results support early in‐hospital initiation of empagliflozin regardless of LVEF. [ABSTRACT FROM AUTHOR]

Aims: In patients hospitalized for acute heart failure (AHF) empagliflozin produced greater clinical benefit than placebo. Many patients with AHF are treated with mineralocorticoid receptor antagonists (MRAs). The interplay between empagliflozin and MRAs in AHF is yet to be explored. This study aimed to evaluate the efficacy and safety of empagliflozin versus placebo according to MRA use at baseline in the EMPULSE trial (NCT04157751). Methods and results: In this analysis all comparisons were performed between empagliflozin and placebo, stratified by baseline MRA use. The primary outcome included all‐cause death, heart failure events, and a ≥5 point difference in Kansas City Cardiomyopathy Questionnaire (KCCQ) total symptom score at 90 days, assessed using the win ratio (WR). First heart failure hospitalization or cardiovascular death was a secondary outcome. From the 530 patients randomized, 276 (52%) were receiving MRAs at baseline. MRA users were younger, had lower ejection fraction, better renal function, and higher KCCQ scores. The primary outcome showed benefit of empagliflozin irrespective of baseline MRA use (WR 1.46, 95% confidence interval [CI] 1.08–1.97 and WR 1.27, 95% CI 0.93–1.73 in MRA users and non‐users, respectively; interaction p = 0.52). The effect of empagliflozin on first heart failure hospitalization or cardiovascular death was not modified by MRA use (hazard ratio [HR] 0.58, 95% CI 0.30–1.11 and HR 0.85, 95% CI 0.47–1.52 in MRA users and non‐users, respectively; interaction p = 0.39). Investigator‐reported and severe hyperkalaemia events were infrequent (<6%) irrespective of MRA use. Conclusions: In patients admitted for AHF, initiation of empagliflozin produced clinical benefit and was well tolerated irrespective of background MRA use. These findings support the early use of empagliflozin on top of MRA therapy in patients admitted for AHF. [ABSTRACT FROM AUTHOR]

Wearable devices stand to revolutionize the way healthcare is delivered. From consumer devices that provide general health information and screen for medical conditions to medical-grade devices that allow collection of larger datasets that include multiple modalities, wearables have a myriad of potential uses, especially in cardiovascular disorders. In this review, we summarize the underlying technologies employed in these devices and discuss the regulatory and economic aspects of such devices as well as the future implications of their use. [ABSTRACT FROM AUTHOR]

Aims: The EMPULSE trial evaluated the clinical benefit of empagliflozin versus placebo using the stratified win ratio approach in 530 patients with acute heart failure (HF) after initial stabilization. We aim to elucidate how this method works and what it means, thereby giving guidance for use of the win ratio in future trials. Methods and results: The primary trial outcome is a hierarchical composite of death, number of HF events, time to first HF event, or a ≥5‐point difference in Kansas City Cardiomyopathy Questionnaire (KCCQ) total symptom score change at 90 days. In an overall (unstratified) analysis we show how comparison of all 265 x 265 patients pairs contribute to 'wins' for empagliflozin and placebo at all four levels of the hierarchy, leading to an unstratified win ratio of 1.38 (95% confidence interval [CI] 1.11–1.71; p = 0.0036). How such a win ratio should (and should not) be interpreted is then described. The more complex primary analysis using a stratified win ratio is then presented in detail leading to a very similar overall result. Win ratios for de novo acute HF and decompensated chronic HF patients were 1.29 and 1.39, respectively, their weighted combination yielding an overall stratified win ratio of 1.36 (95% CI 1.09–1.68) (p = 0.0054). Alternative ways of including HF events and KCCQ scores in the clinical hierarchy are presented, leading to recommendations for their use in future trials. Specifically, inclusion of both number of HF events and time‐to‐first HF event appears an unnecessary complication. Also, the use of a 5‐point margin for KCCQ score paired comparisons is not statistically necessary. Conclusions: The EMPULSE trial findings illustrate how deaths, clinical events and patient‐reported outcomes can be integrated into a win ratio analysis strategy that yields clinically meaningful findings of patient benefit. This has implications for future trial designs that recognize the clinical priorities of patient evaluation and the need for efficient progress towards approval of new treatments. [ABSTRACT FROM AUTHOR]

Heart failure (HF) is a complex syndrome that affects mortality/morbidity and acts at different levels in the patient's life, resulting in a drastic impairment in multiple aspects of daily activities (e.g. physical, mental/emotional, and social) and leading to a reduction in quality of life. The definition of disease status and symptom severity has been traditionally based on the physician assessment, while the patient's experience of disease has been long overlooked. The active participation of patients in their own care is necessary to better understand the perception of disease and the multiple aspects of life affected, and to improve adherence to treatments. Patient‐reported outcomes (PROs) aim to switch traditional care to a more patient‐centred approach. Although PROs demonstrated precision in the evaluation of disease status and have a good association with prognosis in several randomized controlled trials, their implementation into clinical practice is limited. This review discusses the modalities of use of PROs in HF, summarizes the most largely adopted PROs in HF care, and provides an overview on the application of PROs in trials and the potential for their transition to clinical practice. By discussing the advantages and the disadvantages of their use, the reasons limiting their application in daily clinical routine, and the strategies that may promote their implementation, this review aims to foster the systematic integration of the patient's standpoint in HF care. [ABSTRACT FROM AUTHOR]

Aims Effective and safe decongestion remains a major goal for optimal management of patients with acute heart failure (AHF). The effects of the sodium–glucose cotransporter 2 inhibitor empagliflozin on decongestion-related endpoints in the EMPULSE trial (NCT0415775) were evaluated. Methods and results A total of 530 patients hospitalized for AHF were randomized 1:1 to either empagliflozin 10 mg once daily or placebo for 90 days. The outcomes investigated were: weight loss (WL), WL adjusted for mean daily loop diuretic dose (WL-adjusted), area under the curve of change from baseline in N-terminal pro-B-type natriuretic peptide levels, hemoconcentration, and clinical congestion score after 15, 30, and 90 days of treatment. Compared with placebo, patients treated with empagliflozin demonstrated significantly greater reductions in all studied markers of decongestion at all time-points, adjusted mean differences (95% confidence interval) at Days 15, 30, and 90 were: for WL −1.97 (−2.86, −1.08), −1.74 (−2.73, −0.74); −1.53 (−2.75, −0.31) kg; for WL-adjusted: −2.31 (−3.77, −0.85), −2.79 (−5.03, −0.54), −3.18 (−6.08, −0.28) kg/40 mg furosemide i.v. or equivalent; respectively (all P < 0.05). Greater WL at Day 15 (i.e. above the median WL in the entire population) was associated with significantly higher probability for clinical benefit at Day 90 (hierarchical composite of all-cause death, heart failure events, and a 5-point or greater difference in Kansas City Cardiomyopathy Questionnaire total symptom score change from baseline to 90 days) with the win ratio of 1.75 (95% confidence interval 1.37, 2.23; P < 0.0001). Conclusion Initiation of empagliflozin in patients hospitalized for AHF resulted in an early, effective and sustained decongestion which was associated with clinical benefit at Day 90. [ABSTRACT FROM AUTHOR]

Aim: The sodium–glucose cotransporter 2 (SGLT2) inhibitor empagliflozin improved clinical outcomes in patients hospitalized for acute heart failure. In patients with chronic heart failure, SGLT2 inhibitors cause an early decline in estimated glomerular filtration rate (eGFR) followed by a slower eGFR decline over time than placebo. However, the effects of SGLT2 inhibitors on renal function during a hospital admission for acute heart failure remain largely unknown. Methods and results: Between 1 and 5 days after a hospitalization for acute heart failure, 530 patients with an eGFR >20 ml/min/1.73 m2 were randomized to 10 mg of empagliflozin or placebo and treated for 90 days. Renal function and electrolytes were measured at baseline, and after 15, 30 and 90 days. We evaluated the effect of empagliflozin on eGFR over time and the impact of baseline eGFR on the primary hierarchical outcome of death, worsening heart failure events and quality of life. Mean baseline eGFR was 52.4 ml/min/1.73 m2 in the empagliflozin group and 55.7 ml/min/1.73 m2 in the placebo group. Empagliflozin caused an initial decline in eGFR (−2 ml/min/1.73 m2 at day 15 compared to placebo). At day 90, eGFR was similar between empagliflozin and placebo. Investigator‐reported acute renal failure occurred in 7.7% of empagliflozin versus 12.1% of placebo patients. The overall clinical benefit (hierarchical composite of all‐cause death, heart failure events and quality of life) of empagliflozin was unaffected by baseline eGFR. Conclusion: In patients hospitalized for acute heart failure, empagliflozin caused an early modest decline in renal function which was no longer evident after 90 days. Acute renal events were similar in both groups. The clinical benefit of empagliflozin was consistent regardless of baseline renal function. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension (PH) associated with interstitial lung disease (ILD) is an attractive target for clinical trials of PH medications. There are many factors that need to be considered to prime such studies for success. The patient phenotype most likely to respond to the intervention requires weighing the extent of the parenchymal lung disease against the severity of the hemodynamic impairment. The inclusion criteria should not be too restrictive, thus enabling recruitment. The trial should be of sufficient duration to meet the chosen endpoint which should reflect how the patient feels, functions, or survives. This paper summarizes prior studies in PH-ILD and provides a framework of the type of studies to be considered. Inclusion criteria, clinical trial endpoints, and pharmacovigilance in the context of PH-ILD trials are also addressed. Through lessons learnt from prior studies, suggestions and guidance for future clinical trials in PH-ILD are also provided. [ABSTRACT FROM AUTHOR]

Background: The use of veno-arterial extracorporeal membrane oxygenation (VA ECMO) for cardiogenic shock in pregnant and postpartum patients remains limited by concerns of bleeding, hemolysis, and fetal risks. This case series examines the underlying characteristics and management strategies for this high-risk population. Methods: All pregnant and post-partum patients who underwent VA ECMO in the cardiovascular intensive care unit between January 1, 2016 and November 1, 2019, were included in this retrospective study. Management of maternal and fetal O2 delivery, left ventricular (LV) unloading, anticoagulation, and ECMO circuit characteristics were evaluated. Results: Five patients required veno-arterial ECMO for restoration of systemic perfusion. Three patients developed peripartum cardiomyopathy, one septic cardiomyopathy, and one acute right ventricular (RV) failure. The median age was 30.6 years, with median gestational age in pregnant patients of 31 weeks. Maternal and fetal survival to discharge was 80%. Bleeding was the primary complication, with two patients requiring blood transfusions; one requiring interventional radiology (IR) embolization and the other requiring surgical intervention to control bleeding. One patient was successfully delivered on VA ECMO. No fetal complications were directly attributed to VA ECMO. Conclusions: VA ECMO can be employed successfully in obstetric patients with cardiogenic shock with appropriate patient selection. Further research is needed to determine if VA ECMO provides a survival advantage over traditional management strategies in this vulnerable population. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension (PH) has been linked to worse outcomes in chronic lung diseases. The presence of PH in the setting of underlying Interstitial Lung Disease (ILD) is strongly associated with decreased exercise and functional capacity, an increased risk of hospitalizations and death. Examining the scope of this issue and its impact on patients is the first step in trying to define a roadmap to facilitate and encourage future research in this area. The aim of our working group is to strengthen the communities understanding of PH due to lung diseases and to improve the care and quality of life of affected patients. This introductory statement provides a broad overview and lays the foundation for further in‐depth papers on specific topics pertaining to PH‐ILD. [ABSTRACT FROM AUTHOR]

Background: Loop diuretics are commonly used for patients with heart failure (HF) but it remains unknown if one loop diuretic is clinically superior. Hypothesis: Biomarkers and proteomics provide insight to how different loop diuretics may differentially affect outcomes. Methods: Blood and urine were collected from outpatients with HF who were taking torsemide or furosemide for >30 days. Differences were assessed in cardiac, renal, and inflammatory biomarkers and soluble protein panels using the Olink Cardiovascular III and inflammation panels. Results: Of 78 subjects, 55 (71%) were treated with furosemide and 23 (29%) with torsemide, and 25 provided a urine sample (15 treated with furosemide, 10 with torsemide). Patients taking torsemide were older (68 vs 64 years) with a lower mean eGFR (46 vs 54 ml/min/1.73 m2), a higher proportion were women (39% vs 24%) and Black (43% vs 27%). In plasma, levels of hs‐cTnT, NT‐proBNP, and hsCRP were not significantly different between groups. In urine, there were significant differences in urinary albumin, β‐2M, and NGAL, with higher levels in the torsemide‐treated patients. Of 184 proteins testing in Olink panels, in plasma, 156 (85%) were higher in patients taking torsemide but none were significantly different after correcting for false discovery. Conclusions: We show differences in urinary biomarkers but few differences in plasma biomarkers among HF patients on different loop diuretics. Olink technology can detect differences in plasma protein levels from multiple biologic domains. These findings raise the importance of defining differences in mechanisms of action of each diuretic in an appropriately powered study. [ABSTRACT FROM AUTHOR]

This case describes a 57-year-old man with unrecognized cardiac sarcoidosis who presented with progressive heart failure leading to cardiogenic shock. He required extracorporeal membrane oxygenation (ECMO) as a bridge to orthotopic heart transplantation. The case highlights the potential acute and severe electrical and hemodynamic manifestations of cardiac sarcoidosis. [ABSTRACT FROM AUTHOR]

Aims: Treatment with sodium–glucose co‐transporter 2 (SGLT2) inhibitors improves outcomes in patients with chronic heart failure (HF) with reduced ejection fraction. There is limited experience with the in‐hospital initiation of SGLT2 inhibitors in patients with acute HF (AHF) with or without diabetes. EMPULSE is designed to assess the clinical benefit and safety of the SGLT2 inhibitor empagliflozin compared with placebo in patients hospitalized with AHF. Methods: EMPULSE is a randomized, double‐blind, parallel‐group, placebo‐controlled multinational trial comparing the in‐hospital initiation of empagliflozin (10 mg once daily) with placebo. Approximately 500 patients admitted for AHF with dyspnoea, signs of fluid overload, and elevated natriuretic peptides will be randomized 1:1 stratified to HF status (de‐novo and decompensated chronic HF) to either empagliflozin or placebo at approximately 165 sites across North America, Europe and Asia. Patients will be enrolled regardless of ejection fraction and diabetes status and will be randomized during hospitalization and after stabilization (between 24 h and 5 days after admission), with treatment continued up to 90 days after initiation. The primary outcome is clinical benefit at 90 days, consisting of a composite of all‐cause death, HF events, and ≥5 point change from baseline in Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ‐TSS), assessed using a 'win‐ratio' approach. Secondary outcomes include assessments of safety, change in KCCQ‐TSS from baseline to 90 days and change in natriuretic peptides from baseline to 30 days. Conclusion: The EMPULSE trial will evaluate the clinical benefit and safety of empagliflozin in patients hospitalized for AHF. [ABSTRACT FROM AUTHOR]

The Heart Failure Academic Research Consortium is a partnership between the Heart Failure Collaboratory (HFC) and Academic Research Consortium (ARC), comprised of leading heart failure (HF) academic research investigators, patients, United States (US) Food and Drug Administration representatives, and industry members from the US and Europe. A series of meetings were convened to establish definitions and key concepts for the evaluation of HF therapies including optimal medical and device background therapy, clinical trial design elements and statistical concepts, and study endpoints. This manuscript summarizes the expert panel discussions as consensus recommendations focused on populations and endpoint definitions; it is not exhaustive or restrictive, but designed to stimulate HF clinical trial innovation. [ABSTRACT FROM AUTHOR]

Current pharmacological therapies for heart failure with reduced ejection fraction are largely either repurposed anti-hypertensives that blunt overactivation of the neurohormonal system or diuretics that decrease congestion. However, they do not address the symptoms of heart failure that result from reductions in cardiac output and reserve. Over the last few decades, numerous attempts have been made to develop and test positive cardiac inotropes that improve cardiac haemodynamics. However, definitive clinical trials have failed to show a survival benefit. As a result, no positive inotrope is currently approved for long-term use in heart failure. The focus of this state-of-the-art review is to revisit prior clinical trials and to understand the causes for their findings. Using the learnings from those experiences, we propose a framework for future trials of such agents that maximizes their potential for success. This includes enriching the trials with patients who are most likely to derive benefit, using biomarkers and imaging in trial design and execution, evaluating efficacy based on a wider range of intermediate phenotypes, and collecting detailed data on functional status and quality of life. With a rapidly growing population of patients with advanced heart failure, the epidemiologic insignificance of heart transplantation as a therapeutic intervention, and both the cost and morbidity associated with ventricular assist devices, there is an enormous potential for positive inotropic therapies to impact the outcomes that matter most to patients. [ABSTRACT FROM AUTHOR]

The article focuses on the U.S. Preventive Services Task Force (USPSTF) 2009 recommendations on the use of aspirin for primary prevention of cardiovascular diseaseS (CVD) which aimed to provide evidence-based management strategies. Topics discussed include National Health and Nutrition Examination Survey (NHANES) data from 2011 to 2012, contraindications to aspirin therapy, including history of gastrointestinal bleeding, and randomized controlled trials (RCTs) and meta-analyses.

Purpose of Review: Pulmonary hypertension (PH) frequently complicates heart failure and portends a worse prognosis. This review will summarize and discuss recent updates in the classification and management of patients with PH due to left heart disease. Recent Findings: Careful hemodynamic assessment is critical to the classification of patients with PH and heart failure. Two hemodynamic subgroups of PH in heart failure patients have been described: isolated post-capillary pulmonary hypertension and combined post- and precapillary pulmonary hypertension. The cornerstone in management of PH due to left heart disease is the treatment of the underlying left heart pathology; however, ongoing trials have been designed to test pulmonary vasodilators in this cohort. Summary: PH-specific therapies have not demonstrated a benefit in patients with pulmonary hypertension due to left heart disease. Understanding the distinct pathobiology of each hemodynamic subgroup may lead to the development of useful biomarkers and effective targeted therapies. [ABSTRACT FROM AUTHOR]