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1.
The dawn of the four-drug era? SGLT2 inhibition in heart failure with reduced ejection fraction.
Genuardi, MV, Mather, PJ
Therapeutic advances in cardiovascular disease. 2021;:17539447211002678
Abstract
Sodium-glucose cotransporter type 2 (SGLT2) inhibitors are a relatively new class of antihyperglycemic drug with salutary effects on glucose control, body weight, and blood pressure. Emerging evidence now indicates that these drugs may have a beneficial effect on outcomes in heart failure with reduced ejection fraction (HFrEF). Post-approval cardiovascular outcomes data for three of these agents (canagliflozin, empagliflozin, and dapagliflozin) showed an unexpected improvement in cardiovascular endpoints, including heart failure hospitalization and mortality, among patients with type 2 diabetes mellitus (T2DM) and established cardiovascular disease or risk factors. These studies were followed by a placebo controlled trial of dapagliflozin in patients with HFrEF both with and without T2DM, showing a reduction in all-cause mortality comparable to current guideline-directed HFrEF medical therapies such as angiotensin-converting enzyme inhibitors and beta-blockers. In this review, we discuss the current landscape of evidence, safety and adverse effects, and proposed mechanisms of action for use of these agents for patients with HFrEF. The United States (US) and European guidelines are reviewed, as are the current US federally approved indications for each SGLT2 inhibitor. Use of these agents in clinical practice may be limited by an uncertain insurance environment, especially in patients without T2DM. Finally, we discuss practical considerations for the cardiovascular clinician, including within-class differences of the SGLT2 inhibitors currently available on the US market (217/300).
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2.
Effects of GLP-1 receptor agonists and SGLT-2 inhibitors on cardiac structure and function: a narrative review of clinical evidence.
Natali, A, Nesti, L, Tricò, D, Ferrannini, E
Cardiovascular diabetology. 2021;(1):196
Abstract
The impressive results of recent clinical trials with glucagon-like peptide-1 receptor agonists (GLP-1Ra) and sodium glucose transporter 2 inhibitors (SGLT-2i) in terms of cardiovascular protection prompted a huge interest in these agents for heart failure (HF) prevention and treatment. While both classes show positive effects on composite cardiovascular endpoints (i.e. 3P MACE), their actions on the cardiac function and structure, as well as on volume regulation, and their impact on HF-related events have not been systematically evaluated and compared. In this narrative review, we summarize and critically interpret the available evidence emerging from clinical studies. While chronic exposure to GLP-1Ra appears to be essentially neutral on both systolic and diastolic function, irrespective of left ventricular ejection fraction (LVEF), a beneficial impact of SGLT-2i is consistently detectable for both systolic and diastolic function parameters in subjects with diabetes with and without HF, with a gradient proportional to the severity of baseline dysfunction. SGLT-2i have a clinically significant impact in terms of HF hospitalization prevention in subjects at high and very high cardiovascular risk both with and without type 2 diabetes (T2D) or HF, while GLP-1Ra have been proven to be safe (and marginally beneficial) in subjects with T2D without HF. We suggest that the role of the kidney is crucial for the effect of SGLT-2i on the clinical outcomes not only because these drugs slow-down the time-dependent decline of kidney function and enhance the response to diuretics, but also because they attenuate the meal-related anti-natriuretic pressure (lowering postprandial hyperglycemia and hyperinsulinemia and preventing proximal sodium reabsorption), which would reduce the individual sensitivity to day-to-day variations in dietary sodium intake.
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3.
Iron therapy in iron-deficiency patients with heart failure with preserved ejection fraction: A protocol for meta-analysis.
Fukuta, H, Hagiwara, H, Kamiya, T
Medicine. 2021;(32):e26919
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Abstract
BACKGROUND Nearly half of patients with heart failure (HF) have preserved ejection fraction (EF) and the mortality and morbidity of patients with HF with preserved EF (HFpEF) are high. However, there is no established therapy to improve survival in these patients. HFpEF patients are often elderly and their primary chronic symptom is severe exercise intolerance. Thus, improvement of exercise capacity presents another important clinical outcome in HFpEF patients. Iron deficiency is common in HF patients, and the presence of iron deficiency, regardless of concomitant anemia, is associated with worse symptoms, impaired exercise capacity, and higher mortality and hospitalization in these patients. Several meta-analyses of randomized controlled trials reported that iron administration improved HF symptoms, exercise capacity, and clinical outcomes in iron-deficiency patients with HF with reduced EF. However, there is insufficient evidence as to the effect of iron administration in iron-deficiency HFpEF patients. METHODS AND RESULTS This meta-analysis will include randomized controlled trials on the effects of iron administration on HF symptoms, exercise capacity, and health-related quality of life in iron-deficiency HFpEF patients. Information of studies will be collected from PubMed, Web of Science, Cochrane Library, and ClinicalTrials.gov. The primary outcome will be exercise capacity (6-minute walking distance). The secondary outcomes will be HF symptoms, health-related quality of life, and mortality and hospitalization rates. CONCLUSION This meta-analysis will evaluate the effect of iron therapy in iron-deficiency HFpEF patients, providing evidence as to the iron administration in these patients. SYSTEMATIC REVIEW REGISTRATION PROSPERO CRD42020205297.
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4.
Practical management of worsening renal function in outpatients with heart failure and reduced ejection fraction: Statement from a panel of multidisciplinary experts and the Heart Failure Working Group of the French Society of Cardiology.
Mewton, N, Girerd, N, Boffa, JJ, Courivaud, C, Isnard, R, Juillard, L, Lamblin, N, Legrand, M, Logeart, D, Mariat, C, et al
Archives of cardiovascular diseases. 2020;(10):660-670
Abstract
Renal function is often affected in patients with chronic heart failure with reduced ejection fraction (HFrEF). The complex interplay between heart and renal dysfunction makes renal function and potassium monitoring mandatory. Renin-angiotensin-aldosterone system (RAAS) blockers are a life-saving treatment for patients with HFrEF, regardless of worsening renal function. Uptitration to the maximum-tolerated dose should be a constant goal. This simple fact is all too often forgotten (only 30% of patients with heart failure receive the target dosage of RAAS blockers), and the RAAS blocker effect on renal function is sometimes misunderstood. RAAS blockers are not nephrotoxic drugs as they only have a functional effect on renal function. In many routine clinical cases, RAAS blockers are withheld or stopped because of this misunderstanding, combined with suboptimal assessment of the clinical situation and underestimation of the life-saving effect of RAAS blockers despite worsening renal function. In this expert panel, which includes heart failure specialists, geriatricians and nephrologists, we propose therapeutic management algorithms for worsening renal function for physicians in charge of outpatients with chronic heart failure. Firstly, the essential variables to take into consideration before changing treatment are the presence of concomitant disorders that could alter renal function status (e.g. infection, diarrhoea, hyperthermia), congestion/dehydration status, blood pressure and intake of nephrotoxic drugs. Secondly, physicians are invited to adapt medication according to four clinical scenarios (patient with congestion, dehydration, hypotension or hyperkalaemia). Close biological monitoring after treatment modification is mandatory. We believe that this practical clinically minded management algorithm can help to optimize HFrEF treatment in routine clinical practice.
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The conundrum of patients with obesity, exercise intolerance, elevated ventricular filling pressures and a measured ejection fraction in the normal range.
Packer, M
European journal of heart failure. 2019;(2):156-162
Abstract
Patients with obesity, a reduced exercise capacity, increased cardiac filling pressures and a measured left ventricular ejection fraction in the normal range do not have a homogeneous disorder, but instead, exhibit one of three phenotypes. First, many obese people exhibit sodium retention, plasma volume expansion and cardiac enlargement, and some are likely to have heart failure that is related to hypervolaemia, even though cardiac index and circulating levels of natriuretic peptides are not meaningfully increased. Second, in some middle-aged men and women (particularly those with minimal co-morbidities), levels of natriuretic peptides increase markedly and can lower systemic vascular resistance, thus leading to high-output heart failure (HOHF) and glomerular hyperfiltration. Third, older obese people, particularly women with multiple co-morbidities, exhibit the syndrome of heart failure with a preserved ejection fraction (HFpEF). Despite degrees of plasma volume expansion similar to HOHF, these patients exhibit only modestly increased ventricular dimensions and circulating levels of natriuretic peptides (despite a high prevalence of atrial fibrillation), and glomerular function is characteristically impaired. A conceptual framework is proposed to distinguish among the three phenotypes seen in obese patients with exercise intolerance, increased ventricular filling pressures and a measured left ventricular ejection fraction in the normal range, since they may respond differently to therapeutic interventions. Efforts are needed to enhance the recognition of heart failure in obese people and to ensure that clinical trials that are designed to study patients with HFpEF actually enrol those who have the disease.
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6.
The effects of sodium-glucose cotransporter 2 inhibitors on left ventricular function: current evidence and future directions.
Lan, NSR, Fegan, PG, Yeap, BB, Dwivedi, G
ESC heart failure. 2019;(5):927-935
Abstract
Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a unique class of oral anti-hyperglycaemic medications that act to reduce glucose reabsorption in the renal proximal tubules, thereby enhancing urinary glucose excretion. Large randomized placebo-controlled trials in people with diabetes at high cardiovascular risk have demonstrated that SGLT2 inhibitors reduce heart failure hospitalization within months of commencing therapy. These findings are of considerable interest, as diabetes is associated with an increased risk of both heart failure with reduced ejection fraction and heart failure with preserved ejection fraction. In addition, left ventricular (LV) hypertrophy and impaired diastolic function is thought to be more prevalent in people with diabetes. Although many hypotheses have been proposed, the underlying mechanisms through which SGLT2 inhibitors reduce the risk of heart failure in people with diabetes are not fully understood. Given the rapid reduction in heart failure hospitalization, it is conceivable that the benefits of SGLT2 inhibitors are due to favourable haemodynamic and metabolic effects on LV function. Several clinical studies have been conducted to investigate the effect of SGLT2 inhibitors on LV structure and function and have found that LV mass index and diastolic function improve following SGLT2 inhibitor therapy in people with type 2 diabetes. If these findings are confirmed in future studies utilizing novel cardiac imaging modalities and large randomized controlled trials, then this will bring new hope for the prevention and management of heart failure with preserved ejection fraction, for which no current treatments have been shown to reduce mortality. At the present time, SGLT2 inhibitors are indicated for the treatment of type 2 diabetes; however, the results of ongoing trials in participants with heart failure but without diabetes are eagerly awaited. The purpose of this review is to summarize current knowledge regarding the effects of SGLT2 inhibitors on LV function, particularly the findings from clinical studies, proposed biological mechanisms, and future directions.
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7.
Cardiac contractility modulation: mechanisms of action in heart failure with reduced ejection fraction and beyond.
Tschöpe, C, Kherad, B, Klein, O, Lipp, A, Blaschke, F, Gutterman, D, Burkhoff, D, Hamdani, N, Spillmann, F, Van Linthout, S
European journal of heart failure. 2019;(1):14-22
Abstract
Heart failure (HF) is responsible for substantial morbidity and mortality and is increasing in prevalence. Although there has been remarkable progress in the treatment of HF with reduced ejection fraction (HFrEF), morbidity and mortality are still substantial. Cardiac contractility modulation (CCM) signals, consisting of biphasic high-voltage bipolar signals delivered to the right ventricular septum during the absolute refractory period, have been shown to improve symptoms, exercise tolerance and quality of life and reduce the rate of HF hospitalizations in patients with ejection fractions (EF) between 25% and 45%. CCM therapy is currently approved in the European Union, China, India, Australia and Brazil for use in symptomatic HFrEF patients with normal or slightly prolonged QRS duration. CCM is particularly beneficial in patients with baseline EF between 35% and 45%, which includes half the range of HF patients with mid-range EFs (HFmrEF). At the cellular level, CCM has been shown in HFrEF patients to improve calcium handling, to reverse the foetal myocyte gene programme associated with HF, and to facilitate reverse remodelling. This review highlights the preclinical and clinical literature related to CCM in HFrEF and HFmrEF and outlines the potential of CCM for HF with preserved EF, concluding that CCM may fill an important unmet need in the therapeutic approach to HF across the range of EFs.
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8.
Vitamin D and new-onset atrial fibrillation: A meta-analysis of randomized controlled trials.
Huang, WL, Yang, J, Yang, J, Wang, HB, Yang, CJ, Yang, Y
Hellenic journal of cardiology : HJC = Hellenike kardiologike epitheorese. 2018;(2):72-77
Abstract
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, which affects 1.5% to 2% of the general population. More than six million Europeans suffer from AF. To research vitamin D levels in the prevention of new-onset atrial fibrillation (AF), we conducted a systematic review of randomized controlled trials (RCTs). We focused on the vitamin D levels in the prevention of new-onset AF. The outcomes assessed were vitamin D levels, left ventricular ejection fraction (LVEF), and left atrium diameter. Six RCTs ultimately met the inclusion criteria in the meta-analysis. The outcomes of Vitamin D levels (MD = -4.27, 95% CI = -5.20 to-3.34, P = 0.30) in the new-onset AF showed no significant difference. The left atrium diameter (MD = 1.96, 95% CI = 1.48 to 2.60, P < 0.01) between new-onset AF and LVEF (MD = -0.92, 95% CI = -1.59 to -0.26, P < 0.01) showed significant difference. Our study shows that circulating vitamin D levels may not play a major role in the development of new-onset AF.
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9.
Effects of High-Intensity Interval Training on Aerobic Capacity in Cardiac Patients: A Systematic Review with Meta-Analysis.
Xie, B, Yan, X, Cai, X, Li, J
BioMed research international. 2017;:5420840
Abstract
Purpose. The aim of this study was to compare the effects of high-intensity interval training (INTERVAL) and moderate-intensity continuous training (CONTINUOUS) on aerobic capacity in cardiac patients. Methods. A meta-analysis identified by searching the PubMed, Cochrane Library, EMBASE, and Web of Science databases from inception through December 2016 compared the effects of INTERVAL and CONTINUOUS among cardiac patients. Results. Twenty-one studies involving 736 participants with cardiac diseases were included. Compared with CONTINUOUS, INTERVAL was associated with greater improvement in peak VO2 (mean difference 1.76 mL/kg/min, 95% confidence interval 1.06 to 2.46 mL/kg/min, p < 0.001) and VO2 at AT (mean difference 0.90 mL/kg/min, 95% confidence interval 0.0 to 1.72 mL/kg/min, p = 0.03). No significant difference between the INTERVAL and CONTINUOUS groups was observed in terms of peak heart rate, peak minute ventilation, VE/VCO2 slope and respiratory exchange ratio, body mass, systolic or diastolic blood pressure, triglyceride or low- or high-density lipoprotein cholesterol level, flow-mediated dilation, or left ventricular ejection fraction. Conclusions. This study showed that INTERVAL improves aerobic capacity more effectively than does CONTINUOUS in cardiac patients. Further studies with larger samples are needed to confirm our observations.
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10.
Proposal for a functional classification system of heart failure in patients with end-stage renal disease: proceedings of the acute dialysis quality initiative (ADQI) XI workgroup.
Chawla, LS, Herzog, CA, Costanzo, MR, Tumlin, J, Kellum, JA, McCullough, PA, Ronco, C, ,
Journal of the American College of Cardiology. 2014;(13):1246-1252
Abstract
Structural heart disease is highly prevalent in patients with chronic kidney disease requiring dialysis. More than 80% of patients with end-stage renal disease (ESRD) are reported to have cardiovascular disease. This observation has enormous clinical relevance because the leading causes of death for patients with ESRD are of cardiovascular disease etiology, including heart failure, myocardial infarction, and sudden cardiac death. The 2 systems most commonly used to classify the severity of heart failure are the New York Heart Association (NYHA) functional classification and the American Heart Association (AHA)/American College of Cardiology (ACC) staging system. With rare exceptions, patients with ESRD who do not receive renal replacement therapy (RRT) develop signs and symptoms of heart failure, including dyspnea and edema due to inability of the severely diseased kidneys to excrete sodium and water. Thus, by definition, nearly all patients with ESRD develop a symptomatology consistent with heart failure if fluid removal by RRT is delayed. Neither the AHA/ACC heart failure staging nor the NYHA functional classification system identifies the variable symptomatology that patients with ESRD experience depending upon whether evaluation occurs before or after fluid removal by RRT. Consequently, the incidence, severity, and outcomes of heart failure in patients with ESRD are poorly characterized. The 11th Acute Dialysis Quality Initiative has identified this issue as a critical unmet need for the proper evaluation and treatment of heart failure in patients with ESRD. We propose a classification schema based on patient-reported dyspnea assessed both pre- and post-ultrafiltration, in conjunction with echocardiography.