-
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).
-
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.
-
3.
A Novel Approach to Medical Management of Heart Failure With Reduced Ejection Fraction.
Miller, RJH, Howlett, JG, Fine, NM
The Canadian journal of cardiology. 2021;(4):632-643
Abstract
The advent of newly available medical therapies for heart failure with reduced ejection fraction (HFrEF) has resulted in many potential therapeutic combinations, increasing treatment complexity. Publication of expert consensus guidelines and initiatives aimed to improve implementation of treatment has emphasized sequential stepwise initiation and titration of medical therapy, which is labour intensive. Data taken from heart failure registries show suboptimal use of medications, prolonged titration times, and consequently little change in dose intensity, all of which indicate therapeutic inertia. Recently published evidence indicates that 4 medication classes-renin-angiotensin-neprilysin inhibitors, β-blockers, mineralocorticoid antagonists, and sodium-glucose cotransporter inhibitors-which we refer to as Foundational Therapy, confer rapid and robust reduction in both morbidity and mortality in most patients with HFrEF and that they work in additive fashion. Additional morbidity and mortality may be observed following addition of several personalized therapies in specific subgroups of patients. In this review, we discuss mechanisms of action of these therapies and propose a framework for their implementation, based on several principles. These include the critical importance of rapid initiation of all 4 Foundational Therapies followed by their titration to target doses, emphasis on multiple simultaneous drug changes with each patient encounter, attention to patient-specific factors in choice of medication class, leveraging inpatient care, use of the entire health care team, and alternative (ie, virtual visits) modes of care. We have incorporated these principles into a Cluster Scheme designed to facilitate timely and optimal medical treatment for patients with HFrEF.
-
4.
Meta-Analysis Assessing the Cardiovascular Efficacy of Sodium-Glucose Co-Transporter-2 Inhibitors According to Baseline Treatment of Interest.
Patoulias, D, Papadopoulos, C, Katsimardou, A, Doumas, M
The American journal of cardiology. 2021;:134-136
-
5.
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
-
-
Free full text
-
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.
-
6.
Risk of heart failure progression in patients with reduced ejection fraction: mechanisms and therapeutic options.
Gronda, E, Vanoli, E, Sacchi, S, Grassi, G, Ambrosio, G, Napoli, C
Heart failure reviews. 2020;(2):295-303
Abstract
Transition from stage C to stage D of heart failure (HF) represents an irreversible process toward end-stage disease. Crucial interventions to be adopted in the attempt to interfere with this process are represented by the identification of patients at high risk to develop HF progression and by an effective and prompt management. Markers of worse prognosis and disease progression are well established and include recurrence of HF decompensation, intolerance to the neurohormonal standard pharmacological treatment, and resistance to loop diuretics. In addition, both NT-proBNP and sympathetic nervous system (SNS) overdrive are strong predictors of adverse clinical outcome and allow to identify high-risk HF patients even in the presence of mild symptoms. To counteract the deleterious effects of the SNS activation, new strategies such as a new drug combining angiotensin receptor and neprilysin inhibition and baroreceptor stimulation therapy (BAT) have been investigated. Inability to properly counteract the SNS overdrive leads to acute HF decompensation by different mechanisms. The leading ones are represented by the progressive sodium and water retention with fluid overload and by the blood volume redistribution between splanchnic and non-splanchnic regions. The correct understanding of these mechanisms, together with the availability of new therapeutic options such as peritoneal ultrafiltration, represent the rationale but not infrequently overlooked therapeutic options to improve congestion management in HF patients.
-
7.
Sarcopenic Obesity in Heart Failure With Preserved Ejection Fraction.
Kirkman, DL, Bohmke, N, Billingsley, HE, Carbone, S
Frontiers in endocrinology. 2020;:558271
Abstract
Heart failure with preserved ejection fraction (HFpEF) is a public health epidemic that is projected to double over the next two decades. Despite the high prevalence of HFpEF, there are currently no FDA approved therapies for health-related outcomes in this clinical syndrome making it one the greatest unmet needs in cardiovascular medicine. Aging and obesity are hallmarks of HFpEF and therefore there is a high incidence of sarcopenic obesity (SO) associated with this syndrome. The presence of SO in HFpEF patients is noteworthy as it is associated with co-morbidities, worsened cardiovascular health, hospitalizations, quality of life, and mortality. Furthermore, SO plays a central role in exercise intolerance, the most commonly reported clinical symptom of this condition. The aim of this review is to provide insights into the current knowledge pertaining to the contributing pathophysiological mechanisms and clinical outcomes associated with HFpEF-related SO. Current and prospective therapies to address SO in HFpEF, including lifestyle and pharmaceutical approaches, are discussed. The urgent need for future research aimed at better understanding the multifaceted physiological contributions to SO in HFpEF and implementing interventional strategies to specifically target SO is highlighted.
-
8.
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.
-
9.
Angiotensin receptor/neprilysin inhibitor-a breakthrough in chronic heart failure therapy: summary of subanalysis on PARADIGM-HF trial findings.
Książczyk, M, Lelonek, M
Heart failure reviews. 2020;(3):393-402
-
-
Free full text
-
Abstract
It is over 4 years since the Prospective Comparison of angiotensin receptor/neprilysin inhibitor (ARNI) with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial was published in New England Journal of Medicine. The PARADIGM-HF trial was the one that contributed to the official approval to use ARNI simultaneously with cardiac resynchronisation therapy (CRT) or implantable cardioverter-defibrillator (ICD) in patients who receive optimal medical treatment and still presented NYHA II-IV class symptoms according to the 2016 European Society of Cardiology Guidelines for the diagnosis and treatment of acute and chronic heart failure. The aim of this article is to summarise current knowledge on the activity of ARNI in a selected group of patients with heart failure with reduced ejection fraction (HFrEF) based on a recent PARADIGM-HF subanalysis in the field of renal function in patients with and without chronic kidney disease, glycaemia control in patients with diabetes, ventricular arrhythmias and sudden cardiac death and health-related quality of life. This article includes also recently announced findings on the TRANSITION study which revealed that HFrEF therapy with ARNI might be safely initiated after an acute decompensated heart failure episode, including patients with heart failure de novo and ACEI/ARB naïve, both hospitalised or shortly after discharge, in contrary to the PARADIGM-HF trial, where patients had to be administered a stable dose of an ACEI/ARB equivalent to enalapril 10 mg a day for at least 4 weeks before the screening.
-
10.
Meta-Analysis of Antithrombotic Strategies in Patients With Heart Failure With Reduced Ejection Fraction and Sinus Rhythm.
Ueyama, H, Takagi, H, Briasoulis, A, Harrington, M, Steinberg, D, Kuno, T
The American journal of cardiology. 2020;:92-98
Abstract
Heart failure with reduced ejection fraction (HFrEF) is associated with an increased risk of thrombotic events. We compared the safety and efficacy of different antithrombotic strategies for HFrEF and sinus rhythm. PubMed and Embase were searched through January 2020 for studies comparing oral anticoagulants versus antiplatelet agents or placebo in HFrEF and sinus rhythm to include in this network meta-analysis. We identified 5 randomized controlled trials with a total of 9,390 patients randomized to low dose rivaroxaban, vitamin K antagonist (VKA), antiplatelets, or placebo. Low dose rivaroxaban and VKA did not show a significant decrease in stroke compared with placebo but were associated with an increased risk of major bleeding (risk ratio [RR] 6.86, 95% confidence interval [CI] 1.16 to 40.7; RR 8.62, 95% CI 1.52 to 48.9, respectively). When compared with antiplatelets, low dose rivaroxaban and VKA were associated with a significantly decreased risk of stroke (RR 0.67, 95% CI 0.47 to 0.96; RR 0.50, 95% CI 0.33 to 0.76, respectively), but with a significantly increased risk of major bleeding (RR 1.65, 95% CI 1.16 to 2.33; RR 2.07, 95% CI 1.51 to 2.84, respectively). There was no significant difference in these outcomes between low dose rivaroxaban versus VKA and antiplatelets versus placebo. There were no significant differences in all-cause mortality, myocardial infarction, or rehospitalization for heart failure among each treatment. In conclusion, in patient with HFrEF and sinus rhythm, use of oral anticoagulation with or without antiplatelet agents increases the risk of bleeding without substantial effects on the risk of ischemic stroke.