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Background: Sodium-glucose cotransporter-2 inhibitors have emerged as a key pharmacotherapy in heart failure (HF) with both reduced and preserved ejection fraction. The benefit of other HF therapies may be modified by sex, but whether sex modifies the treatment effect and safety profile of sodium-glucose cotransporter-2 inhibitors remains unclear. Our analyses aim to assess the effect of sex on the efficacy and safety of dapagliflozin. Methods: In a prespecified patient-level pooled analysis of DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure), clinical outcomes were compared by sex (including the composite of cardiovascular death or worsening HF events, cardiovascular death, all-cause death, total events [first and recurrent HF hospitalization and cardiovascular death], and Kansas City Cardiomyopathy Questionnaire scores) across the spectrum of left ventricular ejection fraction. Results: Of a total of 11 007 randomized patients, 3856 (35%) were women. Women with HF were older and had higher body mass index but were less likely to have a history of diabetes and myocardial infarction or stroke and more likely to have hypertension and atrial fibrillation compared with men. At baseline, women had higher ejection fraction but worse Kansas City Cardiomyopathy Questionnaire scores than men did. After adjustment for baseline differences, women were less likely than men to experience cardiovascular death (adjusted hazard ratio, 0.69 [95% CI, 0.60-0.79]), all-cause death (adjusted hazard ratio, 0.69 [95% CI, 0.62-0.78]), HF hospitalizations (adjusted hazard ratio, 0.82 [95% CI, 0.72-0.94]), and total events (adjusted rate ratio, 0.77 [95% CI, 0.71-0.84]). Dapagliflozin reduced the primary end point in both men and women similarly (Pinteraction=0.77) with no sex-related differences in secondary outcomes (all Pinte

Despite worsening heart failure (HF) being extremely common, expensive, and associated with substantial risk of death, there remain no dedicated clinical practice guidelines for the specific management of these patients. The lack of a management guideline is despite a rapidly evolving evidence-base, as a number of recent clinical trials have demonstrated multiple therapies to be safe and efficacious in this high-risk population. Herein, we propose a framework for treating worsening HF with reduced ejection fraction with the sense of urgency it deserves. This includes treating congestion; managing precipitants; and establishing a foundation of rapid-sequence, simultaneous, and/or in-hospital initiation of quadruple medical therapy for HF with reduced ejection fraction, with the top priority being at least low doses of all 4 medications. Moreover, to maximally reduce residual clinical risk, we further propose consideration of upfront simultaneous use of vericiguat (ie, quintuple medical therapy) and administration of intravenous iron for those who are iron deficient.

Despite worsening heart failure (HF) being extremely common, expensive, and associated with substantial risk of death, there remain no dedicated clinical practice guidelines for the specific management of these patients. The lack of a management guideline is despite a rapidly evolving evidence-base, as a number of recent clinical trials have demonstrated multiple therapies to be safe and efficacious in this high-risk population. Herein, we propose a framework for treating worsening HF with reduced ejection fraction with the sense of urgency it deserves. This includes treating congestion; managing precipitants; and establishing a foundation of rapid-sequence, simultaneous, and/or in-hospital initiation of quadruple medical therapy for HF with reduced ejection fraction, with the top priority being at least low doses of all 4 medications. Moreover, to maximally reduce residual clinical risk, we further propose consideration of upfront simultaneous use of vericiguat (ie, quintuple medical therapy) and administration of intravenous iron for those who are iron deficient.

Heart failure (HF) is a progressive disease characterized by variable durations of symptomatic stability often punctuated by episodes of worsening despite continued therapy. These periods of clinical worsening are increasingly recognized as a distinct phase in the history of HF, termed worsening HF (WHF). The definition of WHF continues to evolve from a historical focus solely on hospitalization to now include nonhospitalization events (eg, need for intravenous diuretic therapy in the emergency or outpatient setting). Most HF clinical trials to date have had HF hospitalization and death as primary endpoints, and only recently, some studies have included other WHF events regardless of location of care. This article reviews the evolution of the WHF definition, highlights the importance of considering the onset of WHF as an event that marks a new phase of HF, summarizes the latest clinical trials investigating novel therapies, and outlines unmet needs regarding identification and treatment of WHF.

Despite worsening heart failure (HF) being extremely common, expensive, and associated with substantial risk of death, there remain no dedicated clinical practice guidelines for the specific management of these patients. The lack of a management guideline is despite a rapidly evolving evidence-base, as a number of recent clinical trials have demonstrated multiple therapies to be safe and efficacious in this high-risk population. Herein, we propose a framework for treating worsening HF with reduced ejection fraction with the sense of urgency it deserves. This includes treating congestion; managing precipitants; and establishing a foundation of rapid-sequence, simultaneous, and/or in-hospital initiation of quadruple medical therapy for HF with reduced ejection fraction, with the top priority being at least low doses of all 4 medications. Moreover, to maximally reduce residual clinical risk, we further propose consideration of upfront simultaneous use of vericiguat (ie, quintuple medical therapy) and administration of intravenous iron for those who are iron deficient.

With modern treatments for heart failure with reduced ejection fraction (EF), indicative of impaired cardiac systolic function, patients may exhibit an increase in EF. Limited data are available regarding the clinical management of this growing population, categorized as heart failure with improved EF (HFimpEF), which has a high event rate and has been excluded from virtually all prior heart failure outcomes trials. In a prespecified analysis of the DELIVER trial ( NCT03619213 ), of a total of 6,263 participants with symptomatic heart failure and a left ventricular EF $>$40%, 1,151 (18%) had HFimpEF, defined as patients whose EF improved from $<$/=40% to $>$40%. Participants were randomized to 10 mg dapagliflozin or placebo daily and the primary outcome of the trial was a composite of cardiovascular death or worsening heart failure (heart failure hospitalization or an urgent heart failure visit). Participants with HFimpEF had similar event rates to those with an EF consistently $>$40%. In participants with HFimpEF, dapagliflozin reduced the primary composite outcome (hazard ratio (HR) = 0.74, 95% confidence interval (CI) = 0.56-0.97), first worsening heart failure events (HR = 0.78, 95% CI = 0.61-1.14), cardiovascular death (HR = 0.62, 95% CI = 0.41-0.96) and total worsening heart failure events (rate ratio = 0.68, 95% CI = 0.50-0.94) to a similar extent as for individuals with an EF consistently $>$40%. These data suggest that patients with HFimpEF who are symptomatic may benefit from the addition of a sodium/glucose cotransporter 2 inhibitor to previously instituted guideline-directed medical therapy to further reduce morbidity and mortality.

Pericardiocentesis is undertaken in patients with cancer for diagnostic and therapeutic purposes. However, there are limited data on the frequency, characteristics and mortality of patients with different cancers undergoing pericardiocentesis.All hospitalisations of adult cancer patients (≥18 years) in the US National Inpatient Sample between January 2004 and December 2017 were included. The cohort was stratified by discharge code of pericardiocentesis and cancer, using the International Classification of Diseases. The prevalence of pericardiocentesis, patient characteristics, cancer types and in-hospital all-cause mortality were analysed between cancer patients undergoing pericardiocentesis versus not.A total of 19,773,597 weighted cancer discharges were analysed, out of which 18,847 (0.1%) underwent pericardiocentesis. The most common cancer types amongst the patients receiving pericardiocentesis were lung (51.3%), haematological (15.9%), breast (5.4%), mediastinum/heart (3.2%), gastroesophageal (2.2%) and female genital cancer (1.8%), whilst 'other' cancer types were present in 20.2% patients. Patients undergoing pericardiocentesis had significantly higher mortality (15.6% vs. 4.2%, p < 0.001) compared to their counterparts. The presence of metastatic disease (aOR 2.67 95% CI 1.79-3.97), weight loss (aOR 1.48 95% CI 1.33-1.65) and coagulopathy (aOR 3.22 95% CI 1.63-6.37) were each independently associated with higher mortality in patients who underwent pericardiocentesis.Pericardiocentesis is an infrequent procedure in cancer patients and is most commonly performed in patients with lung, haematological and breast cancer. Cancer patients undergoing pericardiocentesis have increased mortality, irrespective of the underlying cancer type.

What was once considered a topic best avoided, managing heart failure with reduced ejection fraction (HFrEF) has become the focus of many drug and device therapies. While the four pillars of guideline-directed medical therapies have successfully reduced heart failure hospitalizations, and some have even impacted cardiovascular mortality in randomized controlled trials (RCTs), patient-reported outcomes have emerged as important endpoints that merit greater emphasis in future studies. The prospect of an oral inotrope seems more probable now as targets for drug therapies have moved from neurohormonal modulation to intracellular mechanisms and direct cardiac myosin stimulation. While we have come a long way in safely providing durable mechanical circulatory support to patients with advanced HFrEF, several percutaneous device therapies have emerged, and many are under investigation. Biomarkers have shown promise in not only improving our ability to diagnose incident heart failure but also our potential to implicate specific pathophysiological pathways. The once forgotten concept of discordance between pressure and volume, the forgotten splanchnic venous and lymphatic compartments, have all emerged as promising targets for diagnosing and treating heart failure in the not-so-distant future. The increase in heart failure-related cardiogenic shock (CS) has revived interest in defining optimal perfusion targets and designing RCTs in CS. Rapid developments in remote monitoring, telemedicine, and artificial intelligence promise to change the face of heart failure care. In this state-of-the-art review, we reminisce about the past, highlight the present, and predict what might be the future of HFrEF therapies.

What was once considered a topic best avoided, managing heart failure with reduced ejection fraction (HFrEF) has become the focus of many drug and device therapies. While the four pillars of guideline-directed medical therapies have successfully reduced heart failure hospitalizations, and some have even impacted cardiovascular mortality in randomized controlled trials (RCTs), patient-reported outcomes have emerged as important endpoints that merit greater emphasis in future studies. The prospect of an oral inotrope seems more probable now as targets for drug therapies have moved from neurohormonal modulation to intracellular mechanisms and direct cardiac myosin stimulation. While we have come a long way in safely providing durable mechanical circulatory support to patients with advanced HFrEF, several percutaneous device therapies have emerged, and many are under investigation. Biomarkers have shown promise in not only improving our ability to diagnose incident heart failure but also our potential to implicate specific pathophysiological pathways. The once forgotten concept of discordance between pressure and volume, the forgotten splanchnic venous and lymphatic compartments, have all emerged as promising targets for diagnosing and treating heart failure in the not-so-distant future. The increase in heart failure-related cardiogenic shock (CS) has revived interest in defining optimal perfusion targets and designing RCTs in CS. Rapid developments in remote monitoring, telemedicine, and artificial intelligence promise to change the face of heart failure care. In this state-of-the-art review, we reminisce about the past, highlight the present, and predict what might be the future of HFrEF therapies.

With modern treatments for heart failure with reduced ejection fraction (EF), indicative of impaired cardiac systolic function, patients may exhibit an increase in EF. Limited data are available regarding the clinical management of this growing population, categorized as heart failure with improved EF (HFimpEF), which has a high event rate and has been excluded from virtually all prior heart failure outcomes trials. In a prespecified analysis of the DELIVER trial (NCT03619213), of a total of 6,263 participants with symptomatic heart failure and a left ventricular EF >40%, 1,151 (18%) had HFimpEF, defined as patients whose EF improved from ≤40% to >40%. Participants were randomized to 10 mg dapagliflozin or placebo daily and the primary outcome of the trial was a composite of cardiovascular death or worsening heart failure (heart failure hospitalization or an urgent heart failure visit). Participants with HFimpEF had similar event rates to those with an EF consistently >40%. In participants with HFimpEF, dapagliflozin reduced the primary composite outcome (hazard ratio (HR) = 0.74, 95% confidence interval (CI) = 0.56–0.97), first worsening heart failure events (HR = 0.78, 95% CI = 0.61–1.14), cardiovascular death (HR = 0.62, 95% CI = 0.41–0.96) and total worsening heart failure events (rate ratio = 0.68, 95% CI = 0.50–0.94) to a similar extent as for individuals with an EF consistently >40%. These data suggest that patients with HFimpEF who are symptomatic may benefit from the addition of a sodium/glucose cotransporter 2 inhibitor to previously instituted guideline-directed medical therapy to further reduce morbidity and mortality.

The sodium-glucose cotransporter 2 inhibitor empagliflozin reduces the risk of cardiovascular death or heart failure hospitalization in patients with chronic heart failure, but whether empagliflozin also improves clinical outcomes when initiated in patients who are hospitalized for acute heart failure is unknown. In this double-blind trial (EMPULSE; NCT04157751), 530 patients with a primary diagnosis of acute de novo or decompensated chronic heart failure regardless of left ventricular ejection fraction were randomly assigned to receive empagliflozin 10 mg once daily or placebo. Patients were randomized in-hospital when clinically stable (median time from hospital admission to randomization, 3 days) and were treated for up to 90 days. The primary outcome of the trial was clinical benefit, defined as a hierarchical composite of death from any cause, number of heart failure events and time to first heart failure event, or a 5 point or greater difference in change from baseline in the Kansas City Cardiomyopathy Questionnaire Total Symptom Score at 90 days, as assessed using a win ratio. More patients treated with empagliflozin had clinical benefit compared with placebo (stratified win ratio, 1.36; 95% confidence interval, 1.09-1.68; P =0.0054), meeting the primary endpoint. Clinical benefit was observed for both acute de novo and decompensated chronic heart failure and was observed regardless of ejection fraction or the presence or absence of diabetes. Empagliflozin was well tolerated; serious adverse events were reported in 32.3% and 43.6% of the empagliflozin- and placebo-treated patients, respectively. These findings indicate that initiation of empagliflozin in patients hospitalized for acute heart failure is well tolerated and results in significant clinical benefit in the 90 days after starting treatment.

The sodium-glucose cotransporter 2 inhibitor empagliflozin reduces the risk of cardiovascular death or heart failure hospitalization in patients with chronic heart failure, but whether empagliflozin also improves clinical outcomes when initiated in patients who are hospitalized for acute heart failure is unknown. In this double-blind trial (EMPULSE; NCT04157751), 530 patients with a primary diagnosis of acute de novo or decompensated chronic heart failure regardless of left ventricular ejection fraction were randomly assigned to receive empagliflozin 10 mg once daily or placebo. Patients were randomized in-hospital when clinically stable (median time from hospital admission to randomization, 3 days) and were treated for up to 90 days. The primary outcome of the trial was clinical benefit, defined as a hierarchical composite of death from any cause, number of heart failure events and time to first heart failure event, or a 5 point or greater difference in change from baseline in the Kansas City Cardiomyopathy Questionnaire Total Symptom Score at 90 days, as assessed using a win ratio. More patients treated with empagliflozin had clinical benefit compared with placebo (stratified win ratio, 1.36; 95% confidence interval, 1.09-1.68; P =0.0054), meeting the primary endpoint. Clinical benefit was observed for both acute de novo and decompensated chronic heart failure and was observed regardless of ejection fraction or the presence or absence of diabetes. Empagliflozin was well tolerated; serious adverse events were reported in 32.3% and 43.6% of the empagliflozin- and placebo-treated patients, respectively. These findings indicate that initiation of empagliflozin in patients hospitalized for acute heart failure is well tolerated and results in significant clinical benefit in the 90 days after starting treatment.

Myocardial infarction (MI) and heart failure are the two major health care burdens around the world. Resveratrol, a plant polyphenol, is well-documented for its benefits in the setting of MI. However, it is also important to understand the comparative and combinatorial efficacy of resveratrol alongside the established therapies to translate the pre-clinical findings to the clinical setting. In the first study, left anterior descending coronary artery ligated (MI-induced) and sham-operated male Sprague Dawley rats were treated with vehicle, resveratrol, angiotensin-converting enzyme inhibitor perindopril, or a combination of both for 8 weeks. Echocardiography was performed to assess the cardiac structure and function. MI rats treated with resveratrol, perindopril and a combination of both had significantly reduced left ventricular (LV) dilatation and improved LV ejection fraction (LVEF). Resveratrol, perindopril and a combination of both significantly decreased cardiac oxidative stress, inflammation and fibrosis and improved the activity of antioxidant enzymes in MI rats. In the second study, MI-induced and sham-operated rats received vehicle, angiotensin receptor blocker/neprilysin inhibitor sacubitril/valsartan, angiotensin receptor blocker valsartan, resveratrol or sacubitril/valsartan + resveratrol for 8 weeks. Echocardiography was performed at the endpoint. Treatment with resveratrol, sacubitril/valsartan, valsartan and sacubitril/valsartan + resveratrol significantly prevented LV dilatation and improved LVEF in MI rats. Resveratrol, sacubitril/valsartan, valsartan and sacubitril/valsartan + resveratrol also significantly reduced oxidative stress, inflammation and brain natriuretic peptide in MI rats. In the final study, adult rat cardiomyocytes were pre-treated with resveratrol or left untreated and exposed to norepinephrine (NE). NE-exposure resulted in significant cardiomyocyte contractile dysfunction, reduced cell viability and an increase in oxidative stres

Myocardial infarction (MI) and heart failure are the two major health care burdens around the world. Resveratrol, a plant polyphenol, is well-documented for its benefits in the setting of MI. However, it is also important to understand the comparative and combinatorial efficacy of resveratrol alongside the established therapies to translate the pre-clinical findings to the clinical setting. In the first study, left anterior descending coronary artery ligated (MI-induced) and sham-operated male Sprague Dawley rats were treated with vehicle, resveratrol, angiotensin-converting enzyme inhibitor perindopril, or a combination of both for 8 weeks. Echocardiography was performed to assess the cardiac structure and function. MI rats treated with resveratrol, perindopril and a combination of both had significantly reduced left ventricular (LV) dilatation and improved LV ejection fraction (LVEF). Resveratrol, perindopril and a combination of both significantly decreased cardiac oxidative stress, inflammation and fibrosis and improved the activity of antioxidant enzymes in MI rats. In the second study, MI-induced and sham-operated rats received vehicle, angiotensin receptor blocker/neprilysin inhibitor sacubitril/valsartan, angiotensin receptor blocker valsartan, resveratrol or sacubitril/valsartan + resveratrol for 8 weeks. Echocardiography was performed at the endpoint. Treatment with resveratrol, sacubitril/valsartan, valsartan and sacubitril/valsartan + resveratrol significantly prevented LV dilatation and improved LVEF in MI rats. Resveratrol, sacubitril/valsartan, valsartan and sacubitril/valsartan + resveratrol also significantly reduced oxidative stress, inflammation and brain natriuretic peptide in MI rats. In the final study, adult rat cardiomyocytes were pre-treated with resveratrol or left untreated and exposed to norepinephrine (NE). NE-exposure resulted in significant cardiomyocyte contractile dysfunction, reduced cell viability and an increase in oxidative stres