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The concept of quadruple therapy as a "one-size-fit-all" approach is effective among all eligible patients with heart failure with reduced ejection fraction, with consistent and significant clinical benefits including reduced mortality across various subgroups. However, with exception of sodium-glucose cotransporter 2 inhibitors, the consistency of benefit with therapies does not extend to patients with heart failure with preserved ejection fraction. The clinical benefits of other promising medical therapies, such as angiotensin receptor–neprilysin inhibitors, mineralocorticoid receptor antagonists, and glucagon-like peptide-1 receptor agonists, have been demonstrated only in certain phenotypes of the highly heterogenous heart failure with preserved ejection fraction population. This variability can confuse frontline practicing cardiologists, potentially leading to the under-implementation of these medications. Therefore, we propose a simple approach: "targeted" combination therapy. This strategy aims to optimize evidence-based medications in heart failure with preserved ejection fraction by tailoring treatments to specific subgroups within the heart failure with preserved ejection fraction population where significant benefits are most evident. [ABSTRACT FROM AUTHOR]

Background: Glucagon-like peptide-1 receptor agonists are a viable option for the prevention of Alzheimer's disease (AD) but the mechanisms of this potential disease modifying action are unclear. We investigated the effects of once-weekly exenatide (EQW) on AD associated proteomic clusters. Methods: The Exenatide Study of Cardiovascular Event Lowering study compared the cardiovascular effects of EQW 2 mg with placebo in 13,752 people with type 2 diabetes mellitus. 4,979 proteins were measured (Somascan V0.4) on baseline and 1-year plasma samples of 3,973 participants. C-reactive protein (CRP), ficolin-2 (FCN2), plasminogen activator inhibitor 1 (PAI-1), soluble vascular cell adhesion protein 1 (sVCAM1) and 4 protein clusters were tested in multivariable mixed models. Results: EQW affected FCN2 (Cohen's d -0.019), PAI-1 (Cohen's d -0.033), sVCAM-1 (Cohen's d 0.035) and a cytokine-cytokine cluster (Cohen's d 0.037) significantly compared with placebo. These effects were sustained in individuals over the age of 65 but not in those under 65. Conclusions: EQW treatment was associated with significant change in inflammatory proteins associated with AD. Trial Registration: EXSCEL is registered on ClinicalTrials.gov: NCT01144338 on 10th of June 2010. [ABSTRACT FROM AUTHOR]

Aims: Clinical trials in heart failure with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF) commonly have detailed eligibility criteria. This may contribute to challenges with efficient enrolment and questions regarding the generalizability of trial findings. Methods and results: Patients with HFmrEF/HFpEF from a large US healthcare system were identified through a computable phenotype applied in linked imaging and electronic health record databases. We evaluated shared eligibility criteria from five recent/ongoing HFmrEF/HFpEF trials (PARAGON‐HF, EMPEROR‐Preserved, DELIVER, FINE‐ARTS, and SPIRRIT‐HFpEF) and compared clinical and echocardiographic features as well as outcomes between trial‐eligible and trial‐ineligible patients. Among 5552 patients with HFpEF/HFmrEF, 792 (14%) were eligible for trial consideration, having met all criteria assessed. Causes of ineligibility included lack of recent loop diuretics (37%), significant pulmonary disease (24%), reduced estimated glomerular filtration rate (17%), recent stroke/transient ischaemic attack (13%), or low natriuretic peptides (12%); 53% of ineligible patients had >1 reason for exclusion. Compared with eligible patients, ineligible patients were younger (age 71 vs. 75 years, P < 0.001) with higher rates of coronary artery disease (66% vs. 59%, P < 0.001) and peripheral vascular disease (40% vs. 33%, P < 0.001), but less mitral regurgitation, lower E/e′ ratio, and smaller left atrial sizes. Both eligible and ineligible patients demonstrated high rates of structural heart disease consistent with HFpEF [elevated left atrial size or left ventricular (LV) hypertrophy/increased LV mass], although this was slightly higher among eligible patients (95% vs. 92%, P = 0.001). The two cohorts demonstrated similar LV global longitudinal strain along with a similar prevalence of atrial fibrillation/flutter, hypertension, and obesity. Ineligible patients had similar all‐cause mortality (33% vs. 33% at 3 years) to those eligible but lower rates of heart failure hospitalization (20% vs. 28% at 3 years, P < 0.001). Conclusions: Among patients with HFmrEF/HFpEF from a large health system, approximately one in seven were eligible for major trials based on key criteria applied through a clinical computable phenotype. These findings highlight the large proportion of patients with HFmrEF/HFpEF ineligible for contemporary trials for whom the generalizability of trial findings may be questioned and further investigation would be beneficial. [ABSTRACT FROM AUTHOR]

Aims: The objective of this study was to examine associations between elevated depressive symptoms and increased risk of adverse clinical events patients with heart failure and reduced ejection fraction (HFrEF), as well as the potential contribution of health behaviours. Methods and results: One hundred forty‐two men and women with HFrEF were enrolled through heart failure (HF) clinics and followed over time. At baseline and 6 months, depressive symptoms were assessed by the Beck Depression Inventory‐II (BDI‐II) and HFrEF disease activity by B‐type natriuretic peptide (BNP). The Self‐Care of Heart Failure Index (SCHFI) was used to assess HF self‐care behaviours. Proportional hazards regression models assessed the contribution of depressive symptoms and HFrEF disease biomarkers on death or cardiovascular hospitalization. Over a median follow‐up period of 4 years, 42 patients (30%) died, and 84 (60%) had cardiovascular hospitalizations. A 10‐point higher baseline BDI‐II score was associated with a 35% greater risk of death or cardiovascular hospitalization. Higher baseline BDI‐II scores were associated with poorer HF self‐care maintenance behaviours (R = −0.30, P < 0.001) and fewer daily steps (R = −0.19, P = 0.04), suggesting that elevated depressive symptoms may diminish important health behaviours. Increases in plasma BNP over 6 months were associated with worse outcomes. Changes in BDI‐II and plasma BNP over 6 months were positively related (R = 0.25, P = 0.004). Conclusions: This study confirms that elevated depressive symptoms are associated with an increased likelihood of adverse clinical outcomes in patients with HFrEF. Poor health behaviours may contribute to the adverse association of elevated depressive symptoms with the increased hazard of adverse clinical outcomes. [ABSTRACT FROM AUTHOR]

Quadruple therapy is effective for patients with heart failure with reduced ejection fraction, providing significant clinical benefits, including reduced mortality. Clinicians are now in an era focused on how to initiate and titrate quadrable therapy in the early phase of the disease trajectory, including during heart failure hospitalization. However, patients with heart failure with reduced ejection fraction still face a significant "residual risk" of mortality and heart failure hospitalization. Despite the effective implementation of quadruple therapy, high mortality and rehospitalization rates persist in heart failure with reduced ejection fraction, and many patients cannot maximize therapy due to side effects such as hypotension and renal dysfunction. In this context, ivabradine, vericiguat, and omecamtiv mecarbil may have adjunct roles in addition to quadruple therapy (note that omecamtiv mecarbil is not currently approved for clinical use). However, the contemporary use of ivabradine and vericiguat is relatively low globally, likely due in part to the under-recognition of the role of these therapies as well as costs. This review offers clinicians a straightforward guide for bedside evaluation of potential candidates for these medications. Quadruple therapy, with strong evidence to reduce mortality, should always be prioritized for implementation. As second-line therapies, ivabradine could be considered for patients who cannot achieve optimal heart rate control (≥ 70 bpm at rest) despite maximally tolerated beta-blocker dosing. Vericiguat could be considered for high-risk patients who have recently experienced worsening heart failure events despite being on quadrable therapy, but they should not have N-terminal pro–B-type natriuretic peptide levels exceeding 8000 pg/mL. In the future, omecamtiv mecarbil may be considered for severe heart failure (New York Heart Association class III to IV, ejection fraction ≤ 30%, and heart failure hospitalization within 6 months) when current quadrable therapy is limited, although this is still hypothesis-generating and requires further investigation before its approval. [ABSTRACT FROM AUTHOR]

Current understanding of iron-deficient heart failure is based on blood tests that are thought to reflect systemic iron stores, but the available evidence suggests greater complexity. The entry and egress of circulating iron is controlled by erythroblasts, which (in severe iron deficiency) will sacrifice erythropoiesis to supply iron to other organs, e.g. the heart. Marked hypoferraemia (typically with anaemia) can drive the depletion of cardiomyocyte iron, impairing contractile performance and explaining why a transferrin saturation < ≈15%–16% predicts the ability of intravenous iron to reduce the risk of major heart failure events in long-term trials (Type 1 iron-deficient heart failure). However, heart failure may be accompanied by intracellular iron depletion within skeletal muscle and cardiomyocytes, which is disproportionate to the findings of systemic iron biomarkers. Inflammation- and deconditioning-mediated skeletal muscle dysfunction—a primary cause of dyspnoea and exercise intolerance in patients with heart failure—is accompanied by intracellular skeletal myocyte iron depletion, which can be exacerbated by even mild hypoferraemia, explaining why symptoms and functional capacity improve following intravenous iron, regardless of baseline haemoglobin or changes in haemoglobin (Type 2 iron-deficient heart failure). Additionally, patients with advanced heart failure show myocardial iron depletion due to both diminished entry into and enhanced egress of iron from the myocardium; the changes in iron proteins in the cardiomyocytes of these patients are opposite to those expected from systemic iron deficiency. Nevertheless, iron supplementation can prevent ventricular remodelling and cardiomyopathy produced by experimental injury in the absence of systemic iron deficiency (Type 3 iron-deficient heart failure). These observations, taken collectively, support the possibility of three different mechanistic pathways for the development of iron-deficient heart failure: one that is driven through systemic iron depletion and impaired erythropoiesis and two that are characterized by disproportionate depletion of intracellular iron in skeletal and cardiac muscle. These mechanisms are not mutually exclusive, and all pathways may be operative at the same time or may occur sequentially in the same patients. [ABSTRACT FROM AUTHOR]

Aim: The TRANSFORM‐HF trial demonstrated no significant outcome differences between torsemide and furosemide following hospitalization for heart failure (HF), but may have been impacted by non‐adherence to the randomized diuretic. The current study sought to determine the treatment effect of torsemide versus furosemide using an on‐treatment analysis inclusive of all randomized patients except those confirmed non‐adherent to study diuretic. Methods and results: TRANSFORM‐HF was an open‐label, pragmatic randomized trial of 2859 patients hospitalized for HF from June 2018 through March 2022. Patients were randomized to a loop diuretic strategy of torsemide versus furosemide with investigator‐selected dosage. This post‐hoc on‐treatment analysis included all patients alive with either known or unknown diuretic status, and excluded patients confirmed to be non‐adherent to study diuretic. This modified on‐treatment definition was applied separately at time of hospital discharge and 30‐day follow‐up. All‐cause mortality and hospitalization outcomes were assessed over 12 months. Overall, 2570 (89.9%) and 2374 (83.0%) patients were included in on‐treatment analyses at discharge and 30‐day follow‐up, respectively. There was no significant difference in all‐cause mortality between torsemide and furosemide in patients on‐treatment at discharge (17.5% vs. 17.8%; hazard ratio [HR] 1.01 [95% confidence interval [CI] 0.83–1.22], p = 0.96) and at 30‐day follow‐up (14.5% vs. 15.0%; HR 1.02 [95% CI 0.81–1.27], p = 0.90). All‐cause mortality or all‐cause hospitalization was similar between torsemide and furosemide in patients who were on‐treatment at discharge (58.3% vs. 61.3%; HR 0.92 [95% CI 0.82–1.03]) and 30‐day follow‐up (60.9% vs. 64.4%; HR 0.93 [95% CI 0.82–1.05]). In patients who were on‐treatment at 30‐day follow‐up, there were 677 total hospitalizations in the torsemide group and 686 total hospitalizations in the furosemide group (rate ratio 0.99 [95% CI 0.86–1.14], p = 0.87). Conclusions: In TRANSFORM‐HF, a post‐hoc on‐treatment analysis did not meaningfully differ from the original trial results. Among those deemed compliant with the assigned diuretic, there remained no significant difference in mortality or hospitalization after HF hospitalization with a strategy of torsemide versus furosemide. Clinical Trail Registration: ClinicalTrials.gov Identifier: NCT03296813. [ABSTRACT FROM AUTHOR]

Key Points: Question: What is the natural history and cardiovascular burden of the V142I variant of the transthyretin (TTR) gene among US Black carriers across mid to late life? Findings: Across 4 cohort studies, carriers (754/23 338) faced a substantially increased risk for heart failure (by age 63 years) and death (by age 72 years), similarly in men and women, which was estimated to contribute to approximately 1 million years of life lost among US Black individuals aged ≥50 years. Meaning: These data show the large, age-dependent burden of V142I, which may guide discussions regarding the initiation and results of genetic screening, provide clinicians with risk estimates to share with patients, and inform strategies for early targeted therapy. Importance: Individual cohort studies concur that the amyloidogenic V142I variant of the transthyretin (TTR) gene, present in 3% to 4% of US Black individuals, increases heart failure (HF) and mortality risk. Precisely defining carrier risk across relevant clinical outcomes and estimating population burden of disease are important given established and emerging targeted treatments. Objectives: To better define the natural history of disease in carriers across mid to late life, assess variant modifiers, and estimate cardiovascular burden to the US population. Design, Setting, and Participants: A total of 23 338 self-reported Black participants initially free from HF were included in 4 large observational studies across the US (mean [SD], 15.5 [8.2] years of follow-up). Data analysis was performed between May 2023 and February 2024. Exposure: V142I carrier status (n = 754, 3.2%). Main Outcomes and Measures: Hospitalizations for HF (including subtypes of reduced and preserved ejection fraction) and all-cause mortality. Outcomes were analyzed by generating 10-year hazard ratios for each age between 50 and 90 years. Using actuarial methods, mean survival by carrier status was estimated and applied to the 2022 US population using US Census data. Results: Among the 23 338 participants, the mean (SD) age at baseline was 62 (9) years and 76.7% were women. Ten-year carrier risk increased for HF hospitalization by age 63 years, predominantly driven by HF with reduced ejection fraction, and 10-year all-cause mortality risk increased by age 72 years. Only age (but not sex or other select variables) modified risk with the variant, with estimated reductions in longevity ranging from 1.9 years (95% CI, 0.6-3.1) at age 50 to 2.8 years (95% CI, 2.0-3.6) at age 81. Based on these data, 435 851 estimated US Black carriers between ages 50 and 95 years are projected to cumulatively lose 957 505 years of life (95% CI, 534 475-1 380 535) due to the variant. Conclusions and Relevance: Among self-reported Black individuals, male and female V142I carriers faced similar and substantial risk for HF hospitalization, predominantly with reduced ejection fraction, and death, with steep age-dependent penetrance. Delineating the individual contributions of, and complex interplay among, the V142I variant, ancestry, the social construct of race, and biological or social determinants of health to cardiovascular disease merits further investigation. This study used data on Black participants in 4 large observational studies to better define the natural history of disease in V142I variant carriers across mid to late life, assess variant modifiers, and estimate cardiovascular burden to the US population. [ABSTRACT FROM AUTHOR]

According to current guidelines, iron deficiency is defined by a serum ferritin level <100 ng/ml or a transferrin saturation (TSAT) <20% if the serum ferritin level is 100–299 μg/L. These criteria were developed to encourage the use of intravenous iron as an adjunct to erythropoiesis‐stimulating agents in the treatment of renal anaemia. However, in patients with heart failure, these criteria are not supported by any pathophysiological or clinical evidence that they identify an absolute or functional iron deficiency state. A low baseline TSAT—but not serum ferritin level—appears to be a reliable indicator of the effect of intravenous iron to reduce major heart failure events. In randomized controlled trials, intravenous iron decreased the risk of cardiovascular death or total heart failure hospitalization in patients with a TSAT <20% (risk ratio 0.67 [0.49–0.92]) but not in patients with a TSAT ≥20% (risk ratio 0.99 [0.74–1.30]), with the magnitude of the risk reduction being proportional to the severity of hypoferraemia. Patients who were enrolled in clinical trials solely because they had a serum ferritin level <100 μg/L showed no significant benefit on heart failure outcomes, and it is noteworthy that serum ferritin levels of 20–300 μg/L lie entirely within the range of normal values for healthy adults. Current guidelines reflect the eligibility criteria of clinical trials, which inadvertently adopted unvalidated criteria to define iron deficiency. Reliance on these guidelines would lead to the treatment of many patients who are not iron deficient (serum ferritin level <100 μg/L but normal TSAT) and ignores the possibility of iron deficiency in patients with a low TSAT but with serum ferritin level of >300 μg/L. Importantly, analyses of benefit based on trial eligibility‐driven guidelines substantially underestimate the magnitude of heart‐failure‐event risk reduction with intravenous iron in patients who are truly iron deficient. Based on all available data, we recommend a new mechanism‐based and trial‐tested approach that reflects the totality of evidence more faithfully than the historical process adopted by clinical investigators and by the guidelines. Until additional evidence is forthcoming, an iron deficiency state in patients with heart failure should be defined by a TSAT <20% (as long as the serum ferritin level is <400 μg/L), and furthermore, the use of a serum ferritin level <100 μg/L alone as a diagnostic criterion should be discarded. [ABSTRACT FROM AUTHOR]

The article discusses the use of intravenous iron therapy in patients with heart failure with preserved ejection fraction (HFpEF). Iron deficiency is common in HFpEF and is associated with worse exercise capacity and quality of life. The article presents the results of a randomized controlled trial that evaluated the effects of intravenous ferric carboxymaltose (FCM) on exercise capacity in HFpEF patients with iron deficiency. The study found that patients receiving FCM showed a significant improvement in exercise capacity compared to those receiving a placebo. However, there was no significant difference between the groups in patient global assessment or health-related quality of life. The article emphasizes the need for further investigation and larger-scale trials to confirm the benefits of intravenous iron therapy in HFpEF. [Extracted from the article]

Aim: Among patients discharged after hospitalization for heart failure (HF), a strategy of torsemide versus furosemide showed no difference in all‐cause mortality or hospitalization. Clinicians have traditionally favoured torsemide in the setting of kidney dysfunction due to better oral bioavailability and longer half‐life, but direct supportive evidence is lacking. Methods and results: The TRANSFORM‐HF trial randomized patients hospitalized for HF to a long‐term strategy of torsemide versus furosemide, and enrolled patients across the spectrum of renal function (without dialysis). In this post‐hoc analysis, baseline renal function during the index hospitalization was assessed as categories of estimated glomerular filtration rate (eGFR; <30, 30–<60, ≥60 ml/min/1.73 m2). The interaction between baseline renal function and treatment effect of torsemide versus furosemide was assessed with respect to mortality and hospitalization outcomes, and the change in Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ‐CSS). Of 2859 patients randomized, 336 (11.8%) had eGFR <30 ml/min/1.73 m2, 1138 (39.8%) had eGFR 30–<60 ml/min/1.73 m2, and 1385 (48.4%) had eGFR ≥60 ml/min/1.73 m2. Baseline eGFR did not modify treatment effects of torsemide versus furosemide on all adverse clinical outcomes including individual components or composites of all‐cause mortality and all‐cause (re)‐hospitalizations, both when assessing eGFR categorically or continuously (p‐value for interaction all >0.108). Similarly, no treatment effect modification by eGFR was found for the change in KCCQ‐CSS (p‐value for interaction all >0.052) when assessing eGFR categorically or continuously. Conclusion: Among patients discharged after hospitalization for HF, there was no significant difference in clinical and patient‐reported outcomes between torsemide and furosemide, irrespective of renal function. [ABSTRACT FROM AUTHOR]

Sodium and fluid restriction has traditionally been advocated in patients with heart failure (HF) due to their sodium and water avid state. However, most evidence regarding the altered sodium handling, fluid homeostasis and congestion‐related signs and symptoms in patients with HF originates from untreated patient cohorts and physiological investigations. Recent data challenge the beneficial role of dietary sodium and fluid restriction in HF. Consequently, the European Society of Cardiology HF guidelines have gradually downgraded these recommendations over time, now advising for the limitation of salt intake to no more than 5 g/day in patients with HF, while contemplating fluid restriction of 1.5–2 L/day only in selected patients. Therefore, the objective of this clinical consensus statement is to provide advice on fluid and sodium intake in patients with acute and chronic HF, based on contemporary evidence and expert opinion. [ABSTRACT FROM AUTHOR]

Aims: In VICTORIA, vericiguat compared with placebo reduced the risk of cardiovascular death (CVD) and heart failure hospitalization (HFH) in patients enrolled after a worsening heart failure (WHF) event. We examined clinical outcomes and efficacy of vericiguat as it relates to background use of loop diuretics in patients with WHF. Methods and results: We calculated the total daily loop diuretic dose equivalent to furosemide dosing at randomization and categorized these as: no loop diuretic, 1–39, 41–80, 40, and >80 mg total daily dose (TDD). The primary composite outcome of CVD/HFH and its components were evaluated based on TDD loop diuretic and expressed as adjusted hazard ratios with 95% confidence intervals. Post‐randomization rates of change in TDD were also examined. Of 4974 patients (98% of the trial) with diuretic dose information available at randomization, 540 (10.8%) were on no loop diuretic, 647 (13.0%) were on 1–39, 1633 (32.8%) were on 40, 1185 (23.8%) were on 41–80, and 969 (19.4%) were on >80 mg TDD. Patients with higher TDD had a higher rate of primary and secondary clinical outcomes. There were no significant interactions with TDD at randomization and efficacy of vericiguat versus placebo for any outcome (all pinteraction > 0.5). Post‐randomization diuretic dose changes for vericiguat and placebo showed similar rates of up‐titration (19.6 and 20.2/100 person‐years), down‐titration (16.8 and 18.1/100 person‐years), and stopping diuretics (22.9 and 24.2/100 person‐years). Conclusions: Loop diuretic TDD at randomization was independently associated with worse outcomes in this high‐risk population. The efficacy of vericiguat was consistent across the range of diuretic doses. [ABSTRACT FROM AUTHOR]

The article is a systematic review of randomized controlled trials comparing the effectiveness and safety of two diuretics, torsemide and furosemide, in heart failure patients. The review included 9 trials with a total of 3928 patients. The results showed no significant difference in mortality, hospitalization, cardiac mortality, and adverse events between the two diuretics. However, more research is needed to explore potential benefits of torsemide. [Extracted from the article]

Background and Aims Whereas a beneficial effect of intravenous ferric carboxymaltose (FCM) on symptoms and exercise capacity among patients with iron deficiency and heart failure (HF) has been consistently demonstrated, the effects of treatment on clinical events remain the subject of research. This meta-analysis aimed to characterize the effects of FCM therapy on hospitalizations and mortality. Methods Patient-level data from randomized, placebo-controlled FCM trials including adults with HF and iron deficiency with ≥52 weeks follow-up were analysed. The co-primary efficacy endpoints were (i) composite of total/recurrent cardiovascular hospitalizations and cardiovascular death and (ii) composite of total HF hospitalizations and cardiovascular death, through 52 weeks. Key secondary endpoints included individual composite endpoint components. Event rates were analysed using a negative binomial model. Treatment-emergent adverse events were also examined. Results Three FCM trials with a total of 4501 patients were included. Ferric carboxymaltose was associated with a significantly reduced risk of co-primary endpoint 1 (rate ratio 0.86; 95% confidence interval 0.75–0.98; P =.029; Cochran Q : 0.008), with a trend towards a reduction of co-primary endpoint 2 (rate ratio 0.87; 95% confidence interval 0.75–1.01; P =.076; Cochran Q : 0.024). Treatment effects appeared to result from reduced hospitalization rates, not improved survival. Treatment appeared to have a good safety profile and was well tolerated. Conclusions In iron-deficient patients with HF with reduced left ventricular ejection fraction, intravenous FCM was associated with significantly reduced risk of hospital admissions for HF and cardiovascular causes, with no apparent effect on mortality. [ABSTRACT FROM AUTHOR]

The HEART-FID trial, the largest randomized trial of intravenous iron replacement therapy in patients with heart failure (HF) and iron deficiency, showed a modest benefit in improving outcomes such as all-cause mortality, HF hospitalization risk, and 6-minute walk distance. This result contrasts with previous studies that showed greater improvement in functional capacity and health status with iron replacement therapy. Iron deficiency affects approximately 50% of HF patients and is associated with worse outcomes. While the trial did not achieve the pre-specified significance level, it provides important insights into the role of iron therapy in HF patients. [Extracted from the article]

Background: Heart failure (HF), chronic kidney disease (CKD), and type 2 diabetes mellitus (T2DM) are common and interrelated conditions, each with a significant burden of disease. HF and kidney disease progress through pathophysiologic pathways that culminate in end-stage disease, for which T2DM is a major risk factor. Intervention within these pathways can disrupt disease processes and improve patient outcomes. Sodium-glucose cotransporter-2 inhibitors (SGLT2is) have been investigated in patient populations with combinations of T2DM, CKD, and/or HF. However, until recently, the effect of these agents in patients with HF with preserved ejection fraction (HFpEF) was not well studied. Main body: The aim of this review is to summarize key information regarding the interaction between HFpEF, CKD, and T2DM and discuss the role of SGLT2 inhibition in the management of patients with comorbid HFpEF and CKD, with or without T2DM. Literature was retrieved using Boolean searches for English-language articles in PubMed and Google Scholar and included terms related to SGLT2is, HFpEF, T2DM, and CKD. The reference lists from retrieved articles were also considered. Conclusion: SGLT2is are efficacious and safe in treating HFpEF in patients with comorbid CKD with and without T2DM. The totality of evidence from clinical trials data suggests there are benefits in using SGLT2is across the spectrum of left ventricular ejection fractions, but there may be a potential for different renal effects in the different ejection fraction groups. Further analysis of these clinical trials has highlighted the need to obtain more accurate phenotypes for patients with HF and CKD to better determine which patients might respond to guideline-directed medical therapies, including SGLT2is. CI confidence interval, EF ejection fraction, eGFR estimated glomerular filtration rate, HF heart failure, HHF hospitalization for HF, HR hazard ratio, LVEF left ventricular ejection fraction, SGLT2i sodium-glucose cotransporter-2 inhibitor, UACR urine albumin-creatinine ratio. a Mean value, unless otherwise stated, b SGLT2i vs. placebo, c Data reanalyzed using more conventional endpoints (≥ 50% sustained decrease in eGFR, and including renal death) (UACR at baseline not stated in trial reports) [ABSTRACT FROM AUTHOR]

Aim: Expected 1‐year survival is essential to risk stratification of patients with heart failure (HF); however, little is known about the 1‐year prognosis of patients with HF and cancer. Thus, the objective was to investigate the 1‐year prognosis following new‐onset HF stratified by cancer status in patients with breast, gastrointestinal, or lung cancer. Methods and results: All Danish patients with new‐onset HF from 2000 to 2018 were included. Cancer status was categorized as history of cancer (no cancer‐related contact within 5 years of HF diagnosis), non‐active cancer (curative intended procedure administered) and active cancer. Standardized 1‐year all‐cause mortality was reported using G‐computation. Age‐stratified 1‐year all‐cause mortality was estimated using the Kaplan–Meier estimator. In total, 193 359 patients with HF were included, 7.3% had either a breast, gastrointestinal, or lung cancer diagnosis. Patients with cancer were older and more comorbid than patients without cancer. Standardized 1‐year all‐cause mortality (95% confidence intervals) was 24.6% (23.0–26.2%), 27.1% (25.5–28.6%), and 29.9% (25.9–34.0%) for history of breast, gastrointestinal and lung cancer, respectively, which was comparable to patients with non‐active cancers. For active breast, gastrointestinal and lung cancer, standardized 1‐year all‐cause mortality was 36.2% (33.8–38.6%), 49.0% (47.2–50.9%), and 61.6% (59.7–63.5%), respectively. One‐year all‐cause mortality increased incrementally with age, except for active lung cancer. Conclusion: Standardized 1‐year all‐cause mortality was comparable for patients with history of cancer and non‐active cancer regardless of cancer type, but varied comprehensively for active cancers. Prognostic impact of age was limited for active lung cancer. Thus, granular stratification of cancer is necessary for optimized management of new‐onset HF. [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]

Aims The PARAGLIDE-HF trial demonstrated reductions in natriuretic peptides with sacubitril/valsartan compared with valsartan in patients with heart failure (HF) with mildly reduced or preserved ejection fraction who had a recent worsening HF event, but was not adequately powered to examine clinical outcomes. PARAGON-HF included a subset of PARAGLIDE-HF-like patients who were recently hospitalized for HF. Participant-level data from PARAGLIDE-HF and PARAGON-HF were pooled to better estimate the efficacy and safety of sacubitril/valsartan in reducing cardiovascular and renal events in HF with mildly reduced or preserved ejection fraction. Methods and results Both PARAGLIDE-HF and PARAGON-HF were multicentre, double-blind, randomized, active-controlled trials of sacubitril/valsartan vs. valsartan in patients with HF with mildly reduced or preserved left ventricular ejection fraction (LVEF >40% in PARAGLIDE-HF and ≥45% in PARAGON-HF). In the pre-specified primary analysis, we pooled participants in PARAGLIDE-HF (all of whom were enrolled during or within 30 days of a worsening HF event) with a 'PARAGLIDE-like' subset of PARAGON-HF (those hospitalized for HF within 30 days). We also pooled the entire PARAGLIDE-HF and PARAGON-HF populations for a broader context. The primary endpoint for this analysis was the composite of total worsening HF events (including first and recurrent HF hospitalizations and urgent visits) and cardiovascular death. The secondary endpoint was the pre-specified renal composite endpoint for both studies (≥50% decline in estimated glomerular filtration rate from baseline, end-stage renal disease, or renal death). Compared with valsartan, sacubitril/valsartan significantly reduced total worsening HF events and cardiovascular death in both the primary pooled analysis of participants with recent worsening HF [ n = 1088; rate ratio (RR) 0.78; 95% confidence interval (CI) 0.61–0.99; P = 0.042] and in the pooled analysis of all participants (n = 5262; RR 0.86; 95% CI: 0.75–0.98; P = 0.027). In the pooled analysis of all participants, first nominal statistical significance was reached by Day 9 after randomization, and treatment benefits were larger in those with LVEF ≤60% (RR 0.78; 95% CI 0.66–0.91) compared with those with LVEF >60% (RR 1.09; 95% CI 0.86–1.40; P interaction = 0.021). Sacubitril/valsartan was also associated with lower rates of the renal composite endpoint in the primary pooled analysis [hazard ratio (HR) 0.67; 95% CI 0.43–1.05; P = 0.080] and the pooled analysis of all participants (HR 0.60; 95% CI 0.44–0.83; P = 0.002). Conclusion In pooled analyses of PARAGLIDE-HF and PARAGON-HF, sacubitril/valsartan reduced cardiovascular and renal events among patients with HF with mildly reduced or preserved ejection fraction. These data provide support for use of sacubitril/valsartan in patients with HF with mildly reduced or preserved ejection fraction, particularly among those with an LVEF below normal, regardless of care setting. [ABSTRACT FROM AUTHOR]

Women with heart failure report worse health-related quality of life on average, than men. This may result from actual differences in care or differing interpretations of and responses to survey questions. We investigated potential gender-based differential item functioning on the Kansas City Cardiomyopathy Questionnaire (KCCQ) Physical Limitations domain. Using data from the HF-ACTION trial, a multicenter, randomized controlled trial of exercise training in patients with chronic heart failure with reduced ejection fraction (661 women, 1670 men), we assessed gender-based differential item functioning using a Wald test based on item response theory and ordinal logistic regression. Both methods evaluated how men and women responded to each KCCQ item after adjusting for physical limitation status. No item exhibited statistically significant differential item functioning using the Wald method. Two items exhibited differential item functioning using the ordinal logistic regression method (KCCQ1e: Climbing a flight of stairs without stopping; KCCQ1f: Hurrying or jogging) (P < 0.01), but the magnitude of differential item functioning was negligible. To accurately measure patient-reported outcomes, it is important to evaluate potential biases that may influence the ability to compare patient subgroups. The magnitude of differential item functioning on a 5-item KCCQ Physical Limitation domain was negligible. [ABSTRACT FROM AUTHOR]

Conventional randomized controlled trials (RCTs) can be expensive, time intensive, and complex to conduct. Trial recruitment, participation, and data collection can burden participants and research personnel. In the past two decades, there have been rapid technological advances and an exponential growth in digitized healthcare data. Embedding RCTs, including cardiovascular outcome trials, into electronic health record systems or registries may streamline screening, consent, randomization, follow-up visits, and outcome adjudication. Moreover, wearable sensors (i.e. health and fitness trackers) provide an opportunity to collect data on cardiovascular health and risk factors in unprecedented detail and scale, while growing internet connectivity supports the collection of patient-reported outcomes. There is a pressing need to develop robust mechanisms that facilitate data capture from diverse databases and guidance to standardize data definitions. Importantly, the data collection infrastructure should be reusable to support multiple cardiovascular RCTs over time. Systems, processes, and policies will need to have sufficient flexibility to allow interoperability between different sources of data acquisition. Clinical research guidelines, ethics oversight, and regulatory requirements also need to evolve. This review highlights recent progress towards the use of routinely generated data to conduct RCTs and discusses potential solutions for ongoing barriers. There is a particular focus on methods to utilize routinely generated data for trials while complying with regional data protection laws. The discussion is supported with examples of cardiovascular outcome trials that have successfully leveraged the electronic health record, web-enabled devices or administrative databases to conduct randomized trials. [ABSTRACT FROM AUTHOR]

Aim: To examine sex differences in the characteristics and outcomes in participants with type 2 diabetes (T2D), with or without cardiovascular disease (CVD), randomized to once‐weekly exenatide (EQW) or placebo in the Exenatide Study of Cardiovascular Event Lowering (EXSCEL). Materials and Methods: Baseline characteristics were summarized and compared by sex. Cox proportional hazards regression models were used for clinical outcomes, including the primary composite outcome of cardiovascular (CV) death, non‐fatal myocardial infarction or non‐fatal stroke (MACE3). Models including sex‐by‐treatment interaction were used to evaluate differences in effects of EQW. Results: Overall, 5603 women and 9149 men were followed for a median of 3.2 years. Women were younger (mean 61.4 vs. 62.2 years, P <.001) and had a shorter duration of diabetes (mean 12.9 vs. 13.2 years, P =.039) and less coronary artery disease (35.2% vs. 61.0%, P <.001) than men, but also a less favourable metabolic risk profile and lower use of cardioprotective medications. MACE3 occurred in 9.1% of women and 13.5% of men, corresponding to 2.82 versus 4.40 events/100 participant‐years (adjusted hazard ratio 0.80, 95% CI: 0.70‐0.93, P =.003). There was no difference in MACE3 with EQW compared with placebo, or evidence of heterogeneity of treatment effect by sex. Conclusions: This analysis of a large population of individuals with T2D, with or without established CVD, identified between‐sex differences in clinical characteristics and care. Despite having worse management of CV risk factors, women had significantly lower rates of important CV events not attributable to the effects of study treatment. [ABSTRACT FROM AUTHOR]

Natriuretic peptides, brain (B‐type) natriuretic peptide (BNP) and N‐terminal prohormone of brain natriuretic peptide (NT‐proBNP) are globally and most often used for the diagnosis of heart failure (HF). In addition, they can have an important complementary role in the risk stratification of its prognosis. Since the development of angiotensin receptor–neprilysin inhibitors (ARNIs), the use of natriuretic peptides as therapeutic agents has grown in importance. The present document is the result of the Trilateral Cooperation Project among the Heart Failure Association of the European Society of Cardiology, the Heart Failure Society of America and the Japanese Heart Failure Society. It represents an expert consensus that aims to provide a comprehensive, up‐to‐date perspective on natriuretic peptides in the diagnosis and management of HF, with a focus on the following main issues: (1) history and basic research: discovery, production and cardiovascular protection; (2) diagnostic and prognostic biomarkers: acute HF, chronic HF, inclusion/endpoint in clinical trials, and natriuretic peptide‐guided therapy; (3) therapeutic use: nesiritide (BNP), carperitide (ANP) and ARNIs; and (4) gaps in knowledge and future directions. [ABSTRACT FROM AUTHOR]

Despite significant therapeutic advancements in heart failure with reduced ejection fraction (HFrEF), the residual risk of all-cause mortality and hospitalizations remains high among patients with HFrEF. Vericiguat is a novel oral soluble guanylate cyclase (sGC) stimulator which was approved by the US Food and Drug administration (FDA) in January 2021 for use in patients with symptomatic chronic HF and an ejection fraction less than 45% following a hospitalization for HF or the need for outpatient intravenous diuretics. We provide a concise review of the pharmacology, clinical efficacy, and tolerability of vericiguat in HFrEF. We also discuss the role of vericiguat in current clinical practice. Vericiguat reduces the risk of cardiovascular mortality or HF hospitalizations by an absolute event-rate reduction of 4.2 events per 100 patient-years with a number needed to treat of 24 patients, on a background of guideline-directed medical therapy. Almost 90% of the patients with HFrEF were adherent to the 10 mg dose of vericiguat in the VICTORIA trial with a favorable tolerability and safety profile. Considering the high residual risk that persists in HFrEF, vericiguat has a role to improve outcomes among patients with worsening HFrEF. [ABSTRACT FROM AUTHOR]

Aims: There is considerable variability in the effect of intravenous iron on hard cardiovascular (CV)‐related outcomes in patients with heart failure (HF) in randomized controlled trials (RCTs). We use a meta‐analytic approach to analyse data from existing RCTs to derive a more robust estimate of the effect size of intravenous iron infusion on CV‐related outcomes in patients with HF. Method and results: PubMed/Medline was searched using the following terms: ('intravenous' and 'iron' and 'heart failure') from inception till 6 November 2022 for RCTs comparing intravenous iron infusion with placebo or standard of care in patients with HF and iron deficiency. Outcomes were the composite of CV mortality and first hospitalization for HF; all‐cause mortality; CV mortality; first hospitalization for HF; and total hospitalizations for HF. Random effects risk ratio (RR) with 95% confidence intervals (CIs) were calculated. Ten RCTs with a total of 3438 patients were included. Intravenous iron resulted in a significant reduction in the composite of CV mortality and first hospitalization for HF [RR 0.0.85; 95% CI (0.77, 0.95)], first hospitalization for HF [RR 0.82; 95% CI (0.67, 0.99)], and total hospitalizations for HF [RR 0.74; 95% CI (0.60, 0.91)] but no statistically significant difference in all‐cause mortality [RR 0.95; 95% CI. (0.83, 1.09)] or CV mortality [OR 0.89; 95% CI (0.75, 1.05)]. Conclusions: Intravenous iron infusion in patients with HF reduces the composite risk of first hospitalization for HF and CV mortality as well as the risks of first and recurrent hospitalizations for HF, with no effect on all‐cause mortality or CV mortality alone. [ABSTRACT FROM AUTHOR]

Key Points: Question: Does torsemide reduce all-cause mortality compared with furosemide in patients with heart failure following hospitalization? Findings: In this randomized clinical trial of 2859 patients, 26.1% of patients randomized to torsemide and 26.2% randomized to furosemide died over a median follow-up of 17.4 months without a significant difference between groups. Meaning: Among patients discharged after hospitalization for heart failure, torsemide compared with furosemide did not result in a significant difference in all-cause mortality over 12 months; however, interpretation of these findings is limited by loss to follow-up and participant crossover and nonadherence. Importance: Although furosemide is the most commonly used loop diuretic in patients with heart failure, some studies suggest a potential benefit for torsemide. Objective: To determine whether torsemide results in decreased mortality compared with furosemide among patients hospitalized for heart failure. Design, Setting, and Participants: TRANSFORM-HF was an open-label, pragmatic randomized trial that recruited 2859 participants hospitalized with heart failure (regardless of ejection fraction) at 60 hospitals in the United States. Recruitment occurred from June 2018 through March 2022, with follow-up through 30 months for death and 12 months for hospitalizations. The final date for follow-up data collection was July 2022. Interventions: Loop diuretic strategy of torsemide (n = 1431) or furosemide (n = 1428) with investigator-selected dosage. Main Outcomes and Measures: The primary outcome was all-cause mortality in a time-to-event analysis. There were 5 secondary outcomes with all-cause mortality or all-cause hospitalization and total hospitalizations assessed over 12 months being highest in the hierarchy. The prespecified primary hypothesis was that torsemide would reduce all-cause mortality by 20% compared with furosemide. Results: TRANSFORM-HF randomized 2859 participants with a median age of 65 years (IQR, 56-75), 36.9% were women, and 33.9% were Black. Over a median follow-up of 17.4 months, a total of 113 patients (53 [3.7%] in the torsemide group and 60 [4.2%] in the furosemide group) withdrew consent from the trial prior to completion. Death occurred in 373 of 1431 patients (26.1%) in the torsemide group and 374 of 1428 patients (26.2%) in the furosemide group (hazard ratio, 1.02 [95% CI, 0.89-1.18]). Over 12 months following randomization, all-cause mortality or all-cause hospitalization occurred in 677 patients (47.3%) in the torsemide group and 704 patients (49.3%) in the furosemide group (hazard ratio, 0.92 [95% CI, 0.83-1.02]). There were 940 total hospitalizations among 536 participants in the torsemide group and 987 total hospitalizations among 577 participants in the furosemide group (rate ratio, 0.94 [95% CI, 0.84-1.07]). Results were similar across prespecified subgroups, including among patients with reduced, mildly reduced, or preserved ejection fraction. Conclusions and Relevance: Among patients discharged after hospitalization for heart failure, torsemide compared with furosemide did not result in a significant difference in all-cause mortality over 12 months. However, interpretation of these findings is limited by loss to follow-up and participant crossover and nonadherence. Trial Registration: ClinicalTrials.gov Identifier: NCT03296813 This clinical trial compares the efficacy of torsemide vs furosemide in decreasing the risk of death from any cause among patients hospitalized for heart failure (regardless of ejection fraction). [ABSTRACT FROM AUTHOR]

Heart failure (HF) is a complex, multifactorial and heterogeneous syndrome with substantial mortality and morbidity. Over the last few decades, numerous attempts have been made to develop targeted therapies that may attenuate the known pathophysiological pathways responsible for causing the progression of HF. However, therapies developed with this objective have sometimes failed to show benefit. The pathophysiological construct of HF with numerous aetiologies suggests that interventions with broad mechanisms of action which simultaneously target more than one pathway maybe more effective in improving the outcomes of patients with HF. Indeed, current therapeutics with clinical benefits in HF have targeted a wider range of intermediate phenotypes. Despite extensive scientific breakthroughs in HF research recently, questions persist regarding the ideal therapeutic targets which may help achieve maximum benefit. In this review, we evaluate the mechanism of action of current therapeutic strategies, the pathophysiological pathways they target and highlight remaining knowledge gaps regarding the mode of action of these interventions. [ABSTRACT FROM AUTHOR]

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous entity with complex pathophysiology and manifestations. Phenomapping is the process of applying statistical learning techniques to patient data to identify distinct subgroups based on patterns in the data. Phenomapping has emerged as a technique with potential to improve the understanding of different HFpEF phenotypes. Phenomapping efforts have been increasing in HFpEF over the past several years using a variety of data sources, clinical variables, and statistical techniques. This review summarizes methodologies and key takeaways from these studies, including consistent discriminating factors and conserved HFpEF phenotypes. We argue that phenomapping results to date have had limited implications for clinical care and clinical trials, given that the phenotypes, as currently described, are not reliably identified in each study population and may have significant overlap. We review the inherent limitations of aggregating and utilizing phenomapping results. Lastly, we discuss potential future directions, including using phenomapping to optimize the likelihood of clinical trial success or to drive discovery in mechanisms of the disease process of HFpEF. [ABSTRACT FROM AUTHOR]

Background: Older patients hospitalized with acute decompensated heart failure (ADHF) have marked functional impairments, which may contribute to their delayed and incomplete recovery and persistently poor outcomes. However, whether impairment severity differs by race and sex is unknown. Methods: REHAB‐HF trial participants (≥60 years) were assessed just before discharge home from ADHF hospitalization. Physical function [Short Physical Performance Battery; 6‐min walk distance (6MWD)], frailty (Fried criteria), cognition [Montreal Cognitive Assessment (MoCA)], quality‐of‐life [Kansas City Cardiomyopathy Questionnaire, Short‐Form‐12, EuroQol‐5D‐5L], and depression [Geriatric Depression Scale (GDS)] were examined by race and sex. Results: This prespecified subgroup cross‐sectional analysis included 337 older adults (52% female, 50% Black). Black participants were on average younger than White participants (70.3 ± 7.2 vs. 74.7 ± 8.3 years). After age, body mass index, ejection fraction, comorbidity, and education adjustment, and impairments were similarly common and severe across groups except: Black male and Black and White female participants had more severely impaired walking function compared with White male participants [6MWD (m) 187 ± 12, 168 ± 9170 ± 11 vs. 239 ± 9, p < 0.001]; gait speed (m/s) (0.61 ± 0.03, 0.56 ± 0.02, 0.55 ± 0.02 vs. 0.69 ± 0.02, p < 0.001); White female participants had the highest frailty prevalence (72% vs. 47%–51%, p = 0.007); and Black participants had lower MoCA scores compared with White participants (20.9 ± 4.5 vs. 22.8 ± 3.9, p < 0.001). Depressive symptoms were common overall (43% GDS ≥5), yet underrecognized clinically (18%), especially in Black male participants compared with White male participants (7% vs. 20%). Conclusion: Among older patients hospitalized for ADHF, frailty and functional impairments with high potential to jeopardize patient HF self‐management, safety, and independence were common and severe across all race and sex groups. Impairment severity was often worse in Black participant and female participant groups. Formal screening across frailty and functional domains may identify those who may require greater support and more tailored care to reduce the risk of adverse events and excess hospitalizations and death. [ABSTRACT FROM AUTHOR]

2022; 145: e895 - e1032. https://doi.org/10.1161/CIR.0000000000001063 9 McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). B This article refers to 'Effect of intravenous iron replacement on recurrent heart failure hospitalizations and cardiovascular mortality in patients with heart failure and iron deficiency: A Bayesian meta-analysis' by S.D. Anker I et al i ., published in this issue on pages 1080-1090. b Iron deficiency frequently complicates heart failure (HF) with reduced ejection fraction (HFrEF), with an estimated prevalence of 37-58%, and has been associated with increased mortality and hospitalization, worsened quality of life, and reduced functional capacity.[[1], [3]] Past studies of patients with HFrEF and iron deficiency have shown that intravenous (IV) iron repletion improves exercise capacity and quality of life, and as a result IV iron supplementation in this population has a IIa recommendation in both the ACC/AHA/HFSA and ESC guidelines for HF management.[[4], [6], [8]] The impact of iron repletion on rates of HF hospitalization and cardiovascular (CV) death remains unclear, though several studies (and one meta-analysis) have suggested that IV iron repletion may reduce a composite of HF hospitalization and CV death.[[4], [10]] To date, no randomized clinical trial has definitively shown that iron repletion reduces these clinical endpoints for patients with HFrEF and comorbid iron deficiency. [Extracted from the article]

Patients with heart failure with reduced ejection fraction (HFrEF) have a high residual risk of adverse outcomes, even when treated with optimal guideline‐directed medical therapy and in a clinically stable state. Soluble guanylate cyclase (sGC) stimulators have the potential to lower this risk by modifying the nitric oxide–sGC–cyclic guanosine monophosphate cascade – a pathophysiological pathway that has been targeted with limited success in HFrEF previously. Vericiguat, an sGC stimulator, was shown to improve outcomes in patients with HFrEF in the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial. However, this trial included patients with recently worsening disease. In this brief review, we discuss the rationale of evaluating sGC stimulators in lower‐risk HFrEF patients. First, all key HFrEF medications have been evaluated in both higher‐ and lower‐risk populations, and the treatment effect is not always consistent across the risk spectrum. Second, pre‐clinical studies and post‐hoc studies of the VICTORIA trial have suggested that sGC stimulators may have cardioprotective effects – these effects may be more apparent when the medication is initiated earlier in the disease process. Third, the effect of vericiguat on cardiovascular mortality remains uncertain and a trial with a longer follow‐up in a lower‐risk population may allow better assessment of its effect on cardiovascular mortality. Therefore, there is a pertinent need to investigate the effects of vericiguat in optimally treated, low‐risk HFrEF patients (i.e. those without recently worsening heart failure). [ABSTRACT FROM AUTHOR]

Aims: We aimed to investigate the impact of obstructive coronary artery disease (CAD) in patients with acute decompensated heart failure (ADHF), and examine potential differences in prognostic utility for heart failure with reduced (HFrEF) versus preserved ejection fraction (HFpEF). Methods and results: The Atherosclerosis Risk in Communities study conducted hospital surveillance of ADHF from 2005 to 2014. Obstructive CAD was defined as ≥50% or ≥75% stenosis, respectively, for the left main and other major epicardial arteries. Adjusted associations between obstructive CAD and 30‐, 60‐, and 90‐day mortality were analysed. A total of 934 (4146 weighted) patients admitted with ADHF (mean age 72 years, 46% women, 30% Black, 30% HFpEF) had available angiography (61% performed in hospital). Obstructive CAD was more prevalent with HFrEF than HFpEF, whether at the left main (15% vs. 11%), left anterior descending (LAD) (48% vs. 30%), left circumflex (37% vs. 32%), right coronary (42% vs. 32%), or multiple coronary arteries (45% vs. 33%). In‐hospital revascularization was performed in 25% and 22% of patients with HFrEF and HFpEF, respectively. Obstructive CAD was associated with higher adjusted mortality, particularly with left main or LAD involvement, and had a more pronounced association with 90‐day mortality in HFrEF (odds ratio [OR] 2.77; 95% confidence interval [CI] 1.53–5.02) than HFpEF (OR 0.94; 95% CI 0.36–2.41) (p‐interaction = 0.05). Conclusion: Patients hospitalized with ADHF and coexisting obstructive CAD have higher short‐term mortality, warranting the need for effective interventions and secondary prevention. [ABSTRACT FROM AUTHOR]